Thursday, July 16, 2009

Hot off the presses! Aug 01 Nat Rev Genet

The Aug 01 issue of the Nat Rev Genet is now up on Pubget (About Nat Rev Genet): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

Hot off the presses! Jul 18 Lancet

The Jul 18 issue of the Lancet is now up on Pubget (About Lancet): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

  • Embryonic stem cells, Francis Collins, and the NIH
    - Lancet 374(9685):175 (2009)
  • Phase 0 trials: a platform for drug development?
    - Lancet 374(9685):176 (2009)
  • Counteracting myths about immigration and health
    - Lancet 374(9685):176 (2009)
  • Facial transplantation: lessons so far
    - Lancet 374(9685):177-178 (2009)
  • Treatment of rheumatoid arthritis: we are getting there
    - Lancet 374(9685):178-180 (2009)
  • Interferon gamma for idiopathic pulmonary fibrosis
    - Lancet 374(9685):180-182 (2009)
  • Male circumcision and HIV risks and benefits for women
    - Lancet 374(9685):182-184 (2009)
  • PEPFAR's biggest success is also its largest liability
    - Lancet 374(9685):184-185 (2009)
  • Antiretroviral roll-out: the problem of second-line therapy
    - Lancet 374(9685):185-186 (2009)
  • Guatemala's malnutrition crisis
    - Lancet 374(9685):187-189 (2009)
  • Uganda to reintroduce female condoms
    - Lancet 374(9685):190 (2009)
  • AIDS treatment in Brazil: success beyond measure?
    - Lancet 374(9685):191-192 (2009)
  • Exploring epidemics
    - Lancet 374(9685):192 (2009)
  • Robin Gorna takes the helm at the International AIDS Society
    - Lancet 374(9685):193 (2009)
  • The patient's view: John Donne and Katharine Anne Porter
    - Lancet 374(9685):194-195 (2009)
  • Edward Bromfield
    - Lancet 374(9685):196 (2009)
  • Effect on survival of whole-body CT during trauma resuscitation
    - Lancet 374(9685):197 (2009)
  • Effect on survival of whole-body CT during trauma resuscitation
    - Lancet 374(9685):197 (2009)
  • Effect on survival of whole-body CT during trauma resuscitation
    - Lancet 374(9685):197-198 (2009)
  • Effect on survival of whole-body CT during trauma resuscitation
    - Lancet 374(9685):198 (2009)
  • Effect on survival of whole-body CT during trauma resuscitation – Authors' reply
    - Lancet 374(9685):198-199 (2009)
  • Haemodialysis access via tissue-engineered vascular graft
    - Lancet 374(9685):199-200 (2009)
  • Haemodialysis access via tissue-engineered vascular graft
    - Lancet 374(9685):200 (2009)
  • Haemodialysis access via tissue-engineered vascular graft
    - Lancet 374(9685):200 (2009)
  • Haemodialysis access via tissue-engineered vascular graft
    - Lancet 374(9685):200-201 (2009)
  • Haemodialysis access via tissue-engineered vascular graft – Authors' reply
    - Lancet 374(9685):201 (2009)
  • The Gates Foundation: looking at the bigger picture
    - Lancet 374(9685):201-202 (2009)
  • Who should defend us from collective defamation?
    - Lancet 374(9685):202 (2009)
  • Department of Error
    - Lancet 374(9685):202 (2009)
  • Near-total human face transplantation for a severely disfigured patient in the USA
    - Lancet 374(9685):203-209 (2009)
    Background Multiple reconstructive procedures are common for the reconstruction of complex facial deformities of skin, soft tissues, bony structures, and functional subunits, such as the nose, lips, and eyelids. However, the results have been unsatisfactory. An innovative approach entailing a single surgical procedure of face allograft transplantation is a viable alternative and gives improved results. Methods On Dec 9, 2008, a 45-year-old woman with a history of severe midface trauma underwent near-total face transplantation in which 80% of her face was replaced with a tailored composite tissue allograft. We addressed issues of immunosuppressive therapy, psychological and ethical outcomes, and re-integration of the patient into society. Findings After the operation, the patient did well physically and psychologically, and tolerated immunosuppression without any major complication. Routine biopsy on day 47 after transplantation showed rejection of graft mucosa; however, a single bolus of corticosteroids reversed rejection. During the first 3 weeks after transplantation, the patient accepted her new face; 6 months after surgery, the functional outcome has been excellent. In contrast to her status before transplantation, the patient can now breathe through her nose, smell, taste, speak intelligibly, eat solid foods, and drink from a cup. Interpretation We show the feasibility of reconstruction of severely disfigured patients in a single surgical procedure using composite face allotransplantation. Therefore, this should be taken in consideration as an early option for severely disfigured patients. Funding None.
  • Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor α inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial
    - Lancet 374(9685):210-221 (2009)
    Background Tumour necrosis factor α (TNFα) inhibitors are frequently used to treat rheumatoid arthritis, but whether use of a different TNFα inhibitor can improve patient response is unknown. We assess the efficacy and safety of the TNFα inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNFα inhibitors. Methods 461 patients with active rheumatoid arthritis from 82 sites in 10 countries were randomly allocated by interactive voice response system, stratified by study site and methotrexate use, to receive subcutaneous injections of placebo (n=155), 50 mg golimumab (n=153), or 100 mg golimumab (n=153) every 4 weeks between Feb 21, 2006, and Sept 26, 2007. Allocation was double-blind. Eligible patients had been treated with at least one dose of a TNFα inhibitor previously. Patients continued stable doses of methotrexate, sulfasalazine, hydroxychloroquine, oral corticosteroids, and non-steroidal anti-inflammatory drugs. The primary endpoint was achievement at week 14 of 20% or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis (ACR20). At week 16, patients who had less than 20% improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab, or from 50 mg to 100 mg golimum! ab. Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given. This study is registered with ClinicalTrials.gov, number NCT00299546. Findings Patients had discontinued previous TNFα inhibitors because of lack of effectiveness (269 [58%] patients) or reasons unrelated to effectiveness (246 [53%] patients), such as intolerance and accessibility issues. Patients had active disease, which was indicated by a median of 14·0 (IQR 9·0–22·0) swollen and 26·0 (16·0–41·0) tender joints for the whole group. 28 (18%) patients on placebo, 54 (35%) patients on 50 mg golimumab (odds ratio 2·5 [95% CI 1·5–4·2], p=0·0006), and 58 (38%) patients on 100 mg golimumab (2·8 [1·6–4·7], p=0·0001) achieved ACR20 at week 14. Two patients were never treated, and 57 patients did not complete the study because of adverse events, unsatisfactory treatment effect, loss to follow-up, death, or other reasons. 155 patients on placebo, 153 on 50 mg golimumab, and 153 on 100 mg golimumab were assessed for drug efficacy. For weeks 1–16, serious adverse events were recorded in 11 (7%) patients on placebo, 8 (5%) on 50 mg golimum! ab, and 4 (3%) on 100 mg golimumab. For weeks 1–24, after some patients were given rescue therapy, serious adverse events were recorded in 15 (10%) patients on placebo, 14 (5%) on 50 mg golimumab, and 8 (4%) on 100 mg golimumab. Interpretation Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNFα inhibitors. Funding Centocor Research and Development and Schering-Plough Research Institute.
  • Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial
    - Lancet 374(9685):222-228 (2009)
    Background Idiopathic pulmonary fibrosis is a fatal disease for which no effective treatment exists. We assessed whether treatment with interferon gamma-1b improved survival compared with placebo in patients with idiopathic pulmonary fibrosis and mild-to-moderate impairment of pulmonary function. Methods 826 patients with idiopathic pulmonary fibrosis were enrolled from 81 centres in seven European countries, the USA, and Canada. Patients were randomly assigned (double-blind) in a 2:1 ratio to receive 200 μg interferon gamma-1b (n=551) or equivalent placebo (n=275) subcutaneously, three times per week. Eligible patients were aged 40–79 years, had been diagnosed in the past 48 months, had a forced vital capacity of 55–90% of the predicted value, and a haemoglobin-corrected carbon monoxide diffusing capacity of 35–90% of the predicted value. The primary endpoint was overall survival time from randomisation measured at the second interim analysis, when the proportion of deaths had reached 75% of those expected by the study conclusion. This study is registered with ClinicalTrials.gov, number NCT00075998. Findings At the second interim analysis, the hazard ratio for mortality in patients on interferon gamma-1b showed absence of minimum benefit compared with placebo (1·15, 95% CI 0·77–1·71, p=0·497), and indicated that the study should be stopped. After a median duration of 64 weeks (IQR 41–84) on treatment, 80 (15%) patients on interferon gamma-1b and 35 (13%) on placebo had died. Almost all patients reported at least one adverse event, and more patients on interferon gamma-1b group had constitutional signs and symptoms (influenza-like illness, fatigue, fever, and chills) than did those on placebo. Occurrence of serious adverse events (eg, pneumonia, respiratory failure) was similar for both treatment groups. Treatment adherence was good and few patients discontinued treatment prematurely in either group. Interpretation We cannot recommend treatment with interferon gamma-1b since the drug did not improve survival for patients with idiopathic pulmonary fibrosis, which refutes previous findings from subgroup analyses of survival in studies of patients with mild-to-moderate physiological impairment of pulmonary function. Funding InterMune.
  • Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: a randomised controlled trial
    - Lancet 374(9685):229-237 (2009)
    Background Observational studies have reported an association between male circumcision and reduced risk of HIV infection in female partners. We assessed whether circumcision in HIV-infected men would reduce transmission of the virus to female sexual partners. Methods 922 uncircumcised, HIV-infected, asymptomatic men aged 15–49 years with CD4-cell counts 350 cells per μL or more were enrolled in this unblinded, randomised controlled trial in Rakai District, Uganda. Men were randomly assigned by computer-generated randomisation sequence to receive immediate circumcision (intervention; n=474) or circumcision delayed for 24 months (control; n=448). HIV-uninfected female partners of the randomised men were concurrently enrolled (intervention, n=93; control, n=70) and followed up at 6, 12, and 24 months, to assess HIV acquisition by male treatment assignment (primary outcome). A modified intention-to-treat (ITT) analysis, which included all concurrently enrolled couples in which the female partner had at least one follow-up visit over 24 months, assessed female HIV acquisition by use of survival analysis and Cox proportional hazards modelling. This trial is registered with ClinicalTrials.gov, number NCT00124878. Findings The trial was stopped early because of futility. 92 couples in the intervention group and 67 couples in the control group were included in the modified ITT analysis. 17 (18%) women in the intervention group and eight (12%) women in the control group acquired HIV during follow-up (p=0·36). Cumulative probabilities of female HIV infection at 24 months were 21·7% (95% CI 12·7–33·4) in the intervention group and 13·4% (6·7–25·8) in the control group (adjusted hazard ratio 1·49, 95% CI 0·62–3·57; p=0·368). Interpretation Circumcision of HIV-infected men did not reduce HIV transmission to female partners over 24 months; longer-term effects could not be assessed. Condom use after male circumcision is essential for HIV prevention. Funding Bill & Melinda Gates Foundation with additional laboratory and training support from the National Institutes of Health and the Fogarty International Center.
  • Nail-gun narcolepsy
    - Lancet 374(9685):238 (2009)
  • Bladder cancer
    - Lancet 374(9685):239-249 (2009)
    Bladder cancer is a heterogeneous disease, with 70% of patients presenting with superficial tumours, which tend to recur but are generally not life threatening, and 30% presenting as muscle-invasive disease associated with a high risk of death from distant metastases. The main presenting symptom of all bladder cancers is painless haematuria, and the diagnosis is established by urinary cytology and transurethral tumour resection. Intravesical treatment is used for carcinoma in situ and other high grade non-muscle-invasive tumours. The standard of care for muscle-invasive disease is radical cystoprostatectomy, and several types of urinary diversions are offered to patients, with quality of life as an important consideration. Bladder preservation with transurethral tumour resection, rad iation, and chemotherapy can in some cases be equally curative. Several chemotherapeutic agents have proven to be useful as neoadjuvant or adjuvant treatment and in patients with metastati! c disease. We discuss bladder preserving approaches, combination chemotherapy including new agents, targeted therapies, and advances in molecular biology.
  • Non-invasive ventilation in acute respiratory failure
    - Lancet 374(9685):250-259 (2009)
    Non-invasive mechanical ventilation has been increasingly used to avoid or serve as an alternative to intubation. Compared with medical therapy, and in some instances with invasive mechanical ventilation, it improves survival and reduces complications in selected patients with acute respiratory failure. The main indications are exacerbation of chronic obstructive pulmonary disease, cardiogenic pulmonary oedema, pulmonary infiltrates in immunocompromised patients, and weaning of previously intubated stable patients with chronic obstructive pulmonary disease. Furthermore, this technique can be used in postoperative patients or those with neurological diseases, to palliate symptoms in terminally ill patients, or to help with bronchoscopy; however further studies are needed in these situations before it can be regarded as first-line treatment. Non-invasive ventilation implemented as an alternative to intubation should be provided in an intensive care or high-dependency uni! t. When used to prevent intubation in otherwise stable patients it can be safely administered in an adequately staffed and monitored ward.
  • AIDS: lessons learnt and myths dispelled
    - Lancet 374(9685):260-263 (2009)
  • Eradication of insulin resistance
    - Lancet 374(9685):264 (2009)

Hot off the presses! Jul 17 Immunity

The Jul 17 issue of the Immunity is now up on Pubget (About Immunity): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

  • Does Def6 Deficiency Cause Autoimmunity?
    - Immunity 31(1):1-2 (2009)
  • Response to Letter from Altman and Bécart
    - Immunity 31(1):2-3 (2009)
  • A Nonself RNA Pattern: Tri-p to Panhandle
    - Immunity 31(1):4-5 (2009)
    In this issue of Immunity, Schlee et al. (2009) defines key RNA structures recognized by a cellular viral sensor, RIG-I. This and another recent report by Schmidt et al. (2009) provide new insights into the mechanism of antiviral innate immunity.
  • IL-33 Raises Alarm
    - Immunity 31(1):5-7 (2009)
    The interleukin-1 (IL-1)-like cytokine IL-33 is widely assumed to undergo proteolytic maturation by caspase-1. In this issue of Immunity, Lüthi et al. (2009) show that IL-33 is not a caspase-1 substrate. IL-33 is inactivated by caspase-3 and -7 to prevent an inappropriate immune response during apoptosis, but not in necrosis.
  • Integr-ating IL-1α in Antiviral Host Defenses
    - Immunity 31(1):7-9 (2009)
    Adenoviral vectors used in gene therapy induce inflammation, although the underlying mechanisms are currently unknown. In this issue of Immunity, Di Paolo et al. (2009) implicate interleukin-1α (IL-1α) in virus-induced inflammation and identify the β3 integrin as the key receptor regulating IL-1α activity.
  • How to be Naive
    - Immunity 31(1):9-11 (2009)
    The transcription factor KLF2 directs expression of receptors involved in trafficking of naive T cells. In this issue of Immunity, Weinreich et al. (2009) demonstrate that KLF2 additionally represses IL-4 production, which otherwise induces CXCR3 expression.
  • Helping the Helpers!
    - Immunity 31(1):12-14 (2009)
    T follicular helper (Tfh) cells are crucial for generating humoral immune responses. In this issue of Immunity, Schmitt et al. (2009) reveal the differentiation of human Tfh cells is dependent on dendritic cell-derived interleukin-12.
  • Interleukin-22-Producing Natural Killer Cells and Lymphoid Tissue Inducer-like Cells in Mucosal Immunity
    - Immunity 31(1):15-23 (2009)
    Blood, lymphoid tissues, and placenta contain diverse subpopulations of natural killer (NK) cells that possess distinct immune functions. Recent studies have shown that human and mouse gut-associated lymphoid tissues harbor a unique NK cell subset that specializes in production of interleukin (IL)-22. This cytokine plays a role in host defense of mucosal barriers, although dysregulated secretion may cause autoimmune disease. In parallel, human fetal lymphoid tissue inducer (LTi) cells and mouse adult LTi-like cells in secondary lymphoid tissues were found to release IL-22, as well as IL-17, a proinflammatory cytokine that mediates host defense against extracellular pathogens. Here, we compare these recently identified immune cells, reviewing what is known about their anatomical location, differentiation requirements, function, and potential involvement in host defense and autoimmunity. Finally, we discuss the challenges faced in furthering our understanding of the deve! lopmental relationships and role of NK and LTi-like cells in mucosal immune responses.
  • Recognition of 5′ Triphosphate by RIG-I Helicase Requires Short Blunt Double-Stranded RNA as Contained in Panhandle of Negative-Strand Virus
    - Immunity 31(1):25-34 (2009)
    Antiviral immunity is triggered by immunorecognition of viral nucleic acids. The cytosolic helicase RIG-I is a key sensor of viral infections and is activated by RNA containing a triphosphate at the 5′ end. The exact structure of RNA activating RIG-I remains controversial. Here, we established a chemical approach for 5′ triphosphate oligoribonucleotide synthesis and found that synthetic single-stranded 5′ triphosphate oligoribonucleotides were unable to bind and activate RIG-I. Conversely, the addition of the synthetic complementary strand resulted in optimal binding and activation of RIG-I. Short double-strand conformation with base pairing of the nucleoside carrying the 5′ triphosphate was required. RIG-I activation was impaired by a 3′ overhang at the 5′ triphosphate end. These results define the structure of RNA for full RIG-I activation and explain how RIG-I detects negative-strand RNA viruses that lack long double-stranded RNA but do contain blunt sho! rt double-stranded 5′ triphosphate RNA in the panhandle region of their single-stranded genome.
  • Structure of Natural Killer Cell Receptor KLRG1 Bound to E-Cadherin Reveals Basis for MHC-Independent Missing Self Recognition
    - Immunity 31(1):35-46 (2009)
    The cytolytic activity of natural killer (NK) cells is regulated by inhibitory receptors that detect the absence of self molecules on target cells. Structural studies of missing self recognition have focused on NK receptors that bind MHC. However, NK cells also possess inhibitory receptors specific for non-MHC ligands, notably cadherins, which are downregulated in metastatic tumors. We determined the structure of killer cell lectin-like receptor G1 (KLRG1) in complex with E-cadherin. KLRG1 mediates missing self recognition by binding to a highly conserved site on classical cadherins, enabling it to monitor expression of several cadherins (E-, N-, and R-) on target cells. This site overlaps the site responsible for cell-cell adhesion but is distinct from the integrin αEβ7 binding site. We propose that E-cadherin may coengage KLRG1 and αEβ7 and that KLRG1 overcomes its exceptionally weak affinity for cadherins through multipoint attachment to target cells, resulting ! in inhibitory signaling.
  • Differential Recognition of CD1d-α-Galactosyl Ceramide by the Vβ8.2 and Vβ7 Semi-invariant NKT T Cell Receptors
    - Immunity 31(1):47-59 (2009)
    The semi-invariant natural killer T cell receptor (NKT TCR) recognizes CD1d-lipid antigens. Although the TCRα chain is typically invariant, the β chain expression is more diverse, where three Vβ chains are commonly expressed in mice. We report the structures of Vα14-Vβ8.2 and Vα14-Vβ7 NKT TCRs in complex with CD1d-α-galactosylceramide (α-GalCer) and the 2.5 Å structure of the human NKT TCR-CD1d-α-GalCer complex. Both Vβ8.2 and Vβ7 NKT TCRs and the human NKT TCR ligated CD1d-α-GalCer in a similar manner, highlighting the evolutionarily conserved interaction. However, differences within the Vβ domains of the Vβ8.2 and Vβ7 NKT TCR-CD1d complexes resulted in altered TCRβ-CD1d-mediated contacts and modulated recognition mediated by the invariant α chain. Mutagenesis studies revealed the differing contributions of Vβ8.2 and Vβ7 residues within the CDR2β loop in mediating contacts with CD1d. Collectively we provide a structural basis for the differential! NKT TCR Vβ usage in NKT cells.
  • T Cell Receptor CDR2β and CDR3β Loops Collaborate Functionally to Shape the iNKT Cell Repertoire
    - Immunity 31(1):60-71 (2009)
    Mouse type I natural killer T cell receptors (iNKT TCRs) use a single Vα14-Jα18 sequence and Vβs that are almost always Vβ8.2, Vβ7, or Vβ2, although the basis of this differential usage is unclear. We showed that the Vβ bias occurred as a consequence of the CDR2β loops determining the affinity of the iNKT TCR for CD1d-glycolipids, thus controlling positive selection. Within a conserved iNKT-TCR-CD1d docking framework, these inherent Vβ-CD1d affinities are further modulated by the hypervariable CDR3β loop, thereby defining a functional interplay between the two iNKT TCR CDRβ loops. These Vβ biases revealed a broadly hierarchical response in which Vβ8.2 > Vβ7 > Vβ2 in the recognition of diverse CD1d ligands. This restriction of the iNKT TCR repertoire during thymic selection paradoxically ensures that each peripheral iNKT cell recognizes a similar spectrum of antigens.
  • Deltex1 Is a Target of the Transcription Factor NFAT that Promotes T Cell Anergy
    - Immunity 31(1):72-83 (2009)
    The molecular process underlying T cell anergy is incompletely understood. Deltex1 (DTX1) is a Notch target with unknown physiological function. Here we show that Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 β (Gadd45β) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1 therefore repr! esents a component downstream of calcium-NFAT signaling that regulates T cell anergy.
  • Suppression of Interleukin-33 Bioactivity through Proteolysis by Apoptotic Caspases
    - Immunity 31(1):84-98 (2009)
    Interleukin-33 (IL-33) is a member of the IL-1 family and is involved in polarization of T cells toward a T helper 2 (Th2) cell phenotype. IL-33 is thought to be activated via caspase-1-dependent proteolysis, similar to the proinflammatory cytokines IL-1β and IL-18, but this remains unproven. Here we showed that IL-33 was processed by caspases activated during apoptosis (caspase-3 and -7) but was not a physiological substrate for caspases associated with inflammation (caspase-1, -4, and -5). Furthermore, caspase-dependent processing of IL-33 was not required for ST2 receptor binding or ST2-dependent activation of the NF-κB transcription factor. Indeed, caspase-dependent proteolysis of IL-33 dramatically attenuated IL-33 bioactivity in vitro and in vivo. These data suggest that IL-33 does not require proteolysis for activation, but rather, that IL-33 bioactivity is diminished through caspase-dependent proteolysis within apoptotic cells. Thus, caspase-mediated proteoly! sis acts as a switch to dampen the proinflammatory properties of IL-33.
  • Integrin-Dependent Organization and Bidirectional Vesicular Traffic at Cytotoxic Immune Synapses
    - Immunity 31(1):99-109 (2009)
    Cytotoxic lymphocytes kill target cells by releasing the content of secretory lysosomes at the immune synapse. To understand the dynamics and control of cytotoxic immune synapses, we imaged human primary, live natural killer cells on lipid bilayers carrying ligands of activation receptors. Formation of an organized synapse was dependent on the presence of the β2 integrin ligand ICAM-1. Ligands of coactivation receptors 2B4 and NKG2D segregated into central and peripheral regions, respectively. Lysosomal protein LAMP-1 that was exocytosed during degranulation accumulated in a large and spatially stable cluster, which overlapped with a site of membrane internalization. Lysosomal compartments reached the plasma membrane at focal points adjacent to centrally accumulated LAMP-1. Imaging of fixed cells revealed that perforin-containing granules were juxtaposed to an intracellular compartment where exocytosed LAMP-1 was retrieved. Thus, cytotoxic immune synapses include a ce! ntral region of bidirectional vesicular traffic, which is controlled by integrin signaling.
  • Virus Binding to a Plasma Membrane Receptor Triggers Interleukin-1α-Mediated Proinflammatory Macrophage Response In Vivo
    - Immunity 31(1):110-121 (2009)
    The recognition of viral components by host pattern-recognition receptors triggers the induction of the antiviral innate immune response. Toll-like receptor 9 (TLR9) and NLRP3 inflammasome were shown to be the principal specific sensors of viral double-stranded DNA. Here we present evidence that macrophages in vivo activated an innate immune response to a double-stranded DNA virus, adenovirus (Ad), independently of TLR9 or NLRP3 inflammasome. In response to Ad, macrophage-derived IL-1α triggered IL-1RI-dependent production of a defined set of proinflammatory cytokines and chemokines. The IL-1α-mediated response required a selective interaction of virus arginine-glycine-aspartic acid (RGD) motifs with macrophage β3 integrins. Thus, these data identify IL-1α-IL-1RI as a key pathway allowing for the activation of proinflammatory responses to the virus, independently of its genomic nucleic acid recognition.
  • KLF2 Transcription-Factor Deficiency in T Cells Results in Unrestrained Cytokine Production and Upregulation of Bystander Chemokine Receptors
    - Immunity 31(1):122-130 (2009)
    The transcription factor KLF2 regulates T cell trafficking by promoting expression of the lipid-binding receptor S1P1 and the selectin CD62L. Recently, it was proposed that KLF2 also represses the expression of chemokine receptors. We confirmed the upregulation of the chemokine receptor CXCR3 on KLF2-deficient T cells. However, we showed that this was a cell-nonautonomous effect, as revealed by CXCR3 upregulation on wild-type bystander cells in mixed bone-marrow chimeras with KLF2-deficient cells. Furthermore, KLF2-deficient T cells overproduced IL-4, leading to the upregulation of CXCR3 through an IL-4-receptor- and eomesodermin-dependent pathway. Consistent with the increased IL-4 production, we found high concentrations of serum IgE in mice with T cell-specific KLF2 deficiency. Our findings support a model where KLF2 regulates T cell trafficking by direct regulation of S1P1 and CD62L and restrains spontaneous cytokine production in naive T cells.
  • Opposing Effects of TGF-β and IL-15 Cytokines Control the Number of Short-Lived Effector CD8+ T Cells
    - Immunity 31(1):131-144 (2009)
    An effective immune response against infectious agents involves massive expansion of CD8+ T cells. Once the infection is cleared, the majority of these effector cells die through unknown mechanisms. How is expansion controlled to maximize pathogen clearance and minimize immunopathology? We found, after Listeria infection, plasma transforming growth factor β (TGF-β) titers increased concomitant with the expansion of effector CD8+ T cells. Blocking TGF-β signaling did not affect effector function of CD8+ T cells. However, TGF-β controlled effector cell number by lowering Bcl-2 amounts and selectively promoting the apoptosis of short-lived effector cells. TGF-β-mediated apoptosis of this effector subpopulation occurred during clonal expansion and contraction, whereas interleukin-15 (IL-15) promoted their survival only during contraction. We demonstrate that the number of effector CD8+ T cells is tightly controlled by multiple extrinsic signals throughout effector dif! ferentiation; this plasticity should be exploited during vaccine design and immunotherapy against tumors and autoimmune diseases.
  • Cell-Intrinsic Transforming Growth Factor-β Signaling Mediates Virus-Specific CD8+ T Cell Deletion and Viral Persistence In Vivo
    - Immunity 31(1):145-157 (2009)
    Although deficient CD8+ T cell responses have long been associated with chronic viral infections, the underlying mechanisms are still unclear. Here we report that sustained transforming growth factor-β (TGF-β) expression and phosphorylation of its signaling mediator, Smad-2, were distinctive features of virus-specific CD8+ T cells during chronic versus acute viral infections in vivo. The result was TGF-β-dependent apoptosis of virus-specific CD8+ T cells that related to upregulation of the proapoptotic protein Bim during chronic infection. Moreover, selective attenuation of TGF-β signaling in T cells increased the numbers and multiple functions of antiviral CD8+ T cells and enabled rapid eradication of the persistence-prone virus and memory generation. Finally, we found that cell-intrinsic TGF-β signaling was responsible for virus-specific-CD8+ T cell apoptosis and decreased numbers but was not necessary for their functional exhaustion. Our findings reveal persist! ing TGF-β-Smad signaling as a hallmark and key regulator of CD8+ T cell responses during chronic viral infections in vivo.
  • Human Dendritic Cells Induce the Differentiation of Interleukin-21-Producing T Follicular Helper-like Cells through Interleukin-12
    - Immunity 31(1):158-169 (2009)
    T follicular helper (Tfh) cells help development of antibody responses via interleukin-21 (IL-21). Here we show that activated human dendritic cells (DCs) induced naive CD4+ T cells to become IL-21-producing Tfh-like cells through IL-12. CD4+ T cells primed with IL-12 induced B cells to produce immunoglobulins in a fashion dependent on IL-21 and inducible costimulator (ICOS), thus sharing fundamental characteristics with Tfh cells. The induction of Tfh-like cells by activated DCs was inhibited by neutralizing IL-12. IL-12 induced two different IL-21-producers: IL-21+IFN-γ+T-bet+ Th1 cells and IL-21+IFN-γ−T-bet− non-Th1 cells, in a manner dependent on signal transducer and activator of transcription 4 (STAT4). IL-12 also regulated IL-21 secretion by memory CD4+ T cells. Thus, IL-12 produced by activated DCs regulates antibody responses via developing IL-21-producing Tfh-like cells and inducing IL-21 secretion from memory CD4+ T cells. These data suggest that the d! evelopmental pathway of Tfh cells differs between mice and humans, which have considerable implications for vaccine development.
  • Cyclic Adenosine Monophosphate Suppresses the Transcription of Proinflammatory Cytokines via the Phosphorylated c-Fos Protein
    - Immunity 31(1):170 (2009)

Wednesday, July 15, 2009

Hot off the presses! Aug 01 Nat Rev Microbiol

The Aug 01 issue of the Nat Rev Microbiol is now up on Pubget (About Nat Rev Microbiol): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

Hot off the presses! Jul 16 Nature

The Jul 16 issue of the Nature is now up on Pubget (About Nature): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

  • Net gains
    - Nature 460(7253):307 (2009)
    The Moon landing was not the only world-changing event in the summer of '69.
  • Nowhere to hide
    - Nature 460(7253):307 (2009)
    The G8 has laid down a marker by promising to restrict the rise of global temperatures.
  • Animal behaviour: Smothered by a swarm
    - Nature 460(7253):308 (2009)
  • Palaeoclimatology: Tropical ice
    - Nature 460(7253):308 (2009)
  • Nanotechnology: Penned in protein
    - Nature 460(7253):308 (2009)
  • Chemical biology: A glowing report
    - Nature 460(7253):308 (2009)
  • Evolution: Nice guys finish last
    - Nature 460(7253):308 (2009)
  • Organic chemistry: Cockroach cruncher
    - Nature 460(7253):309 (2009)
  • Immunology: Themis in the thymus
    - Nature 460(7253):309 (2009)
  • Developmental biology: The turtle fold
    - Nature 460(7253):309 (2009)
  • Neurology: New neurons show the way
    - Nature 460(7253):309 (2009)
  • Journal club
    - Nature 460(7253):309 (2009)
  • NIH nominee draws scrutiny
    - Nature 460(7253):310-311 (2009)
    As Francis Collins prepares to take the helm of the US National Institutes of Health (NIH), opinions are divided about how the geneticist will steer the agency through its extraordinary funding boom. Following President Barack Obama's long-anticipated nomination of Collins on 8 July, Harold Varmus, NIH director from 1993 to 1999, and now president and chief executive of the Memorial Sloan-Kettering Cancer Center in New York, described him as "a terrific scientist, inspirational leader, superb manager, and adept politician.
  • Malaria drug-makers ignore WHO ban
    - Nature 460(7253):310-311 (2009)
    Health agency calls for clampdown on artemisinin monotherapy. There is a growing risk that malaria parasites will develop resistance to artemisinin because almost half of both its manufacturers and malaria-affected countries are failing to comply with World Health Organization (WHO) demands to sell it only in combination with other drugs. Artemisinin and its derivatives are the leading treatments for the disease, being the only antimalarials that have not yet seen widespread resistance in malaria parasites. The full scale of the problem is revealed in a soon-to-be-published WHO briefing seen by Nature, "Stop the marketing of oral artemisinin monotherapies", which calls for governments to empower national drug-regulatory authorities to clamp down on offending companies. Treatments that use only artemisinin need to be taken for seven days to kill all parasites, but patients often stop treatment after a few days when they begin to feel much better. This leaves the remaining parasites in contact with low levels of the drug — a recipe for resistance. The WHO recommended in January 2006 that artemisinin should always be given in combination with other drugs for at least three days, because a cocktail reduces the chances of resistance. The need to move away from monotherapies has become all the more urgent with recent reports of resistance arising in Cambodia. Although artemisinin-based combination therapies (ACTs) have become the treatment of choice for malaria, with a three-day programme curing more than 95% of patients, monotherapies are cheaper to produce and sell. ADVERTISEMENT Of the 69 manufacturers of artemisinin monotherapies that the WHO has identified, 21 have withdrawn monotherapies, and 14 say they intend to comply with the WHO's recommendations. But the remaining 34 have not yet disclosed their intentions. Many have not even replied to multiple WHO e-mail and fax requests for information, says Andrea Bosman, an official at the WHO's Global Malaria Programme (see http://tinyurl.com/m4gqmn). Regulatory authorities in just 39 of the 76 countries using malaria drugs have so far complied or said they intend to comply with the WHO's recommendations (see http://tinyurl.com/m94wqk). National regulatory authorities could help by banning monotherapies, says Bosman, but many are weak, understaffed and lack expertise. "It's terrible," says Bosman, adding that every country where malaria is endemic is affected by the problem. "Who says there is no profit to be made in malaria? When you see the number of companies operating in Africa, and the diversity of products, you'd just be amazed." Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
  • Flu furore hits Argentina
    - Nature 460(7253):311 (2009)
    Refusal to declare national emergency restricts pandemic measures. Argentines have been travelling abroad to buy flu drugs.E. Marcarian/Reuters Argentina's government has for more than two weeks ignored recommendations from a committee of influenza experts to declare a national health emergency. Such a declaration would prompt greater federal resources to combat the spread of the pandemic H1N1 2009 virus. The committee, specifically set up to advise the Ministry of Health on swine flu, issued its call just days before Argentina's national election on 28 June, which it feared could accelerate the spread of the virus. Following the committee's call for action, the health minister, Graciela Ocaña, asked for the election to be postponed, but her request was rejected. Ocaña subsequently resigned and left office on 29 June. Mirta Roses, director of the Pan American Health Organization — the Latin American and Caribbean arm of the World Health Organization (WHO) — has also criticized the decision to go ahead with the elections. "The delay was recommended because the agglomeration of people in places with little ventilation favours the transmission of the disease," says Jorge San Juan, coordinator of the expert committee and head of the intensive-care unit at Muñiz Hospital in Buenos Aires. The government now faces two lawsuits brought by individual lawyers who claim that its decision not to delay the elections recklessly endangered its citizens, who are legally required to vote. Epidemiologist Emilio Santabaya, former head of the Malbrán Institute in Buenos Aires — the country's main flu monitoring centre — adds that Argentina knew an epidemic was coming and did nothing, and that flu monitoring in the country is not adequate to track the spread of the virus. The situation contrasts with that of neighbouring country Chile, which has many more flu surveillance centres, according to Jorge Jimenez, who has worked both as Chile's health minister and as chairman of the WHO's executive committee. On 7 July, Chilean President Michelle Bachelet, who trained as an epidemiologist, signed a decree that gives health authorities in the country the power to cancel events that could spread swine flu. Meanwhile, a group of doctors, hospital workers and scientists called Médicos Sin Banderas (Doctors without Flags) has also accused the national government of deliberately hiding the full extent of the swine-flu outbreak. ADVERTISEMENT Ariel Umpierrez, a health economist who heads the group, says that its members have been sharing information about flu cases from their places of work across the country. Those data show that the government has lowered the official number of cases by excluding infected people who visit private clinics, he argues. Argentina's Ministry of Health has not responded to Nature's queries on the matter. Although scientists inside the country say they are being ignored, those outside are worried by reports of panicked Argentines travelling to Chile and Uruguay to buy flu drugs. The drugs, which are being taken without medical advice, are probably being used in a way that promotes the development of resistance, says Eric Toner, a senior associate at the University of Pittsburgh's Center for Biosecurity in Pennsylvania. Because Uruguay is heavily dependent on trade with Argentina, it is highly unlikely to prevent Argentines from entering the country — but the governments of Brazil and Bolivia are considering closing their borders to prevent the spread of infection. Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
  • Medical isotope shortage reaches crisis level
    - Nature 460(7253):312-313 (2009)
    The worldwide shortage of medical isotopes is about to get much worse this week, as the High Flux Reactor in Petten, the Netherlands, closes for a month-long maintenance inspection. It joins the National Research Universal reactor in Chalk River, Ontario, Canada, which has been closed since 15 May because of a heavy-water leak and is unlikely to restart before late 2009, according to Atomic Energy of Canada Limited, the government-sponsored body that runs the facility.
  • G8 climate target questioned
    - Nature 460(7253):313 (2009)
    The path to a meaningful deal at the Copenhagen climate summit in December seems more treacherous in the wake of last week's meeting of the G8 nations. Leaders gathered in the quake-struck Italian town of L'Aquila promised to try to prevent global temperatures from rising more than 2 °C above pre-industrial temperatures.
  • Shooting for the Moon
    - Nature 460(7253):314-315 (2009)
    The Apollo programme inspired thousands of people to pursue careers in science. Today, they still support human spacefaring — but baulk at the price. Richard Monastersky reports on the results of a Nature poll. In the heady days after the Apollo 11 lunar landing on 20 July 1969, countless children travelled to the Moon by cupping their hands over their mouths and announcing: "Houston, Tranquility Base, here. The Eagle has landed." With giant strides, they bounded across the landscape just like their heroes, Neil Armstrong and Buzz Aldrin. They practised lift-off by counting backwards to zero and blasting themselves skywards. And many of them landed, decades later, in scientific careers. Humans have not walked on the Moon since the Apollo 17 mission of 1972.NASA In fact, the Moon landings deserve credit for motivating a large fraction of today's scientists, according to a survey of almost 800 researchers who have published in Nature in the past three years1. Half of the researchers who responded to an online poll last month said that the Apollo missions had inspired them to pursue science — and not just in astronomy or planetary science (see 'Survey respondents'). "I became completely space crazy," said one life scientist. "I was certain I'd be an astronaut. My interest shifted to biology, but I still believe Apollo 11 was a major influence on me." The survey, intended to capture broad impressions rather than to precisely measure attitudes, also reveals surprisingly widespread support among scientists for human space exploration. Nearly 80% of scientists polled said that there are scientific research justifications for continuing human spaceflight. More than 80% felt that the life sciences, physical sciences, engineering and human physiology all benefited to some degree from human spaceflight, and almost 90% said that it still inspires younger generations to study science (see 'Survey results'). Their impressions are not without justification. The US National Research Council concluded in 2003 that work in microgravity has had a major effect on several areas of physical sciences, including research into fluids, combustion and crystal growth2. The Neurolab experiments, which flew on NASA's space shuttle Columbia in 1998, are regarded as the high point of life-sciences research in space and resulted in 100 publications, according to Joan Vernikos, former director of life sciences at NASA. Up, up and away In principle, the scientists who participated in the poll seemed to support manned space programmes, with 62% of Americans and 83% of Europeans rating their own country's expenditures on human spaceflight as "about right" or "not enough". The stronger support in Europe perhaps reflects a vast difference in spending on either side of the Atlantic. Including money provided by the stimulus package, NASA will pour US$9.7 billion into activities related to human spaceflight in the current fiscal year, roughly half of the agency's $18.7-billion budget. The European Space Agency (ESA) allocates only €481 million ($670 million), about 13% of its €3.6-billion ($5.0 billion) budget. But support for sending people to space flagged when participants were asked to prioritize spending. Nearly 80% would welcome a shift in spending from human spaceflight to unmanned space missions, whereas 70% would prefer some of that cash to be spent on other areas of scientific research. David Southwood, director of science and robotic missions for ESA, says that the affection for shifting money rests on a false premise, because money taken from human spaceflight would not go to unmanned projects. Indeed, written responses from several of those who completed the survey revealed the opposite sentiment: some supported human spaceflight thinking it would increase spending generally on space research. Southwood says that the positive attitudes seen in the Nature poll reflect the broad impact of human spaceflight, beyond simply yielding data for science. "It gives humans a vicarious means of breaking the surly bonds of gravity," he says, borrowing a phrase from the pilot–poet John Gillespie Magee. During the lead-up to the Apollo missions, scientists had similar outlooks to those seen in the current survey. A study conducted by the American Association for the Advancement of Science in 1964 found that scientists generally supported the goal of landing humans on the Moon, but they objected to the tight timetable and the extreme costs3. At the time, the NASA budget consumed 4.3% of the total US budget; it now accounts for just 0.5%. Scientists in the public eye have generally been more sceptical about human spaceflight than those in Nature's poll, says John Logsdon, an aerospace historian at the Smithsonian Institution in Washington DC. "There have been very few scientists publicly giving this kind of support for human spaceflight," he says. ADVERTISEMENT With some scientists, the support for spaceflight was quite personal (see 'Moondreams'). About 5% have applied to be an astronaut and 14% said they would pay between $10,000 and $50,000 for a brief sub-orbital trip into space. It remains to be seen whether NASA's space programme will continue to earn their enthusiasm. Next month, a panel convened by US President Barack Obama will issue its assessment of America's plans to return to the Moon by 2020 (ref. 4), and its approval of the programme is far from certain. Yet more than 36 years after man last ventured beyond the confines of low-Earth orbit during the Apollo 17 mission, Nature's survey would suggest that many will support the next grand voyage to the Moon and beyond. * References * http://www.nature.com/nature/newspdf/apollo_results.pdf * Assessment of Directions in Microgravity and Physical Sciences Research at NASA (National Academies Press, 2003). * Abelson, P. H. Science 145, 539 (1964). * Hand, E. Nature 459, 1038-1039 (2009). Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
  • Arms pact could boost US-Russian science
    - Nature 460(7253):316 (2009)
    Nuclear scientists in Russia and the United States say that the sputtering relationship between their weapons laboratories could be rekindled by an agreement to cut the nations' nuclear-weapons arsenals. US President Barack Obama and Russian President Dmitry Medvedev announced on 6 July that they intended to reduce their stockpile of warheads.
  • Europe attacks tactics that delay generic drugs
    - Nature 460(7253):317 (2009)
  • Obama names next head of US Geological Survey
    - Nature 460(7253):317 (2009)
  • El Niño arrives in the Pacific Ocean
    - Nature 460(7253):317 (2009)
    US climate scientists last week announced the arrival of El Niño, a cyclical rise in sea-surface temperatures in the central and eastern Pacific Ocean. The event is known to influence fisheries and global weather patterns. El Niños, which are associated with a weakening in the easterly trade wind, occur every two to five years and typically last for about a year. The current one is expected to continue developing over the next several months and to last through the winter, according to the National Oceanic and Atmospheric Administration in Washington DC. Previous El Niños have seen more rainfall over the central tropical Pacific, drought in Indonesia and powerful winter storms in California as well as flooding and mudslides in Central and South America. The phenomenon has also been linked to less hurricane activity in the Atlantic Ocean and additional winter precipitation in the arid southwestern United States. Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
  • German molecular biologist to head EMBO
    - Nature 460(7253):317 (2009)
  • US renewable energy gets cash boost
    - Nature 460(7253):317 (2009)
  • Mars Science Laboratory devours budgets
    - Nature 460(7253):317 (2009)
    NASA/JPL-CALTECH A further budget overrun for NASA's Mars Science Laboratory rover (pictured), due to launch in 2011, could for the first time delay other missions in the agency's cash-strapped planetary-science division. In a report due to be handed to Congress by the end of July, NASA will announce that the mission needs between $15 million and $115 million more than its estimated price tag — which, at $2.28 billion, is already 40% above an official $1.63-billion estimate made in 2006. The agency has so far raided technology-development funds within the Mars programme, but if additional costs rise too much, it may have to delay two planned Moon missions. "The time for some tough decisions is here," said NASA science chief Ed Weiler, breaking the news to planetary scientists at an advisory-committee meeting on 9 July at NASA headquarters in Washington DC. Weiler also confirmed, as expected, that NASA would work in partnership with the European Space Agency on all future major Mars missions. Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
  • Correction
    - Nature 460(7253):317 (2009)
    The News Feature 'One gene, twenty years' (Nature 460, 164–169; 2009) incorrectly stated Robert Beall's current title. He is, in fact, president and chief executive of the Cystic Fibrosis Foundation. Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
  • Cell biology: Ahead of the curve
    - Nature 460(7253):318-320 (2009)
    To view the innards of a cell is to view architecture reminiscent of Antoni Gaudi: the gentle arc of the cell membrane, the contortions of internal tubing, the tight bubbles of vesicles. But for biologists, this architecture is an intellectual puzzle as well as a beautiful structure.
  • Earth science: A lakeful of trouble
    - Nature 460(7253):321-323 (2009)
    Africa's Lake Kivu contains vast quantities of gas, which makes it both dangerous and valuable. Anjali Nayar asks whether it is possible to tap the gas without causing a disaster. Download a PDF of this story In late 2001, Mount Nyiragongo in the Democratic Republic of the Congo (DRC) was growing restless. Plumes of smoke issued from the central crater, alarming volcanologists in the nearby city of Goma. Then, on 17 January 2002, lava fountained from a fracture on Nyiragongo's southern flank. The molten rock snaked down the sides of the volcano and razed the centre of Goma, engulfing houses and setting off a string of explosions at fuel stations and power plants. That evening, the lava streamed into nearby Lake Kivu, generating a plume of water vapour that clouded the area for days1. More than 100 people were killed and nearly 300,000 people fled their homes. The only obvious refuge for the displaced people was along the shores of the lake. But Kivu poses its own threats. Beneath its placid surface, the lake contains 300 cubic kilometres of carbon dioxide and 60 cubic kilometres of methane. A disruption to the lake — such as a bigger, closer eruption — could cause a gas burst, with potentially deadly consequences for the roughly 2 million people who live along Kivu's shores. The risks are hard to quantify, however. Although scientists have studied the lake for decades, basic details about Kivu and its gases are still relatively scarce, and there is now debate about how hazardous the situation is. The issue is complicated by the lake's economic potential. The valuable methane dissolved in the water has started a feeding frenzy among energy companies working with the DRC and Rwanda, the other nation bordering the lake. In deals worth hundreds of millions of dollars, companies have started to siphon off the methane, in some cases working with the very scientists who have been assessing the lake's hazards. Proponents say that those degassing efforts will reduce the risk of gas eruption, but some researchers are worried that schemes to extract methane could make the situation more dangerous if they upset the lake's equilibrium. "It could be one of the great remediation projects of all time." George Kling "It could be one of the great remediation projects of all time: mitigating a lethal natural hazard and at the same time bringing power to people who desperately need it," says George Kling, a biogeochemist from the University of Michigan in Ann Arbor. "If it is done right." An expanding problem Lake Kivu lies in the Great Rift Valley, where tectonic forces are slowly ripping Africa apart. That movement brings up molten rock, which releases carbon dioxide that seeps into the bottom of Lake Kivu. Bacteria convert some of the carbon dioxide into methane, and other bacteria produce methane by breaking down organic matter in the deep waters (see graphic). Kivu is permanently stratified, with layers of dense salt-rich water below fresh water at the surface. Deeper than about 50–80 metres, the lake is anoxic and the concentrations of dissolved carbon dioxide and methane increase with depth2. The differences in density prevent the layers of water from vertically mixing, and so trap the gases at the bottom of the lake. Residents around the lake have known about the dissolved gases for many decades, but it wasn't generally thought to be a hazard. Then, in 1984, carbon dioxide erupted from Lake Monoun in Cameroon, killing 37 people. Two years later, another Cameroonian lake, Lake Nyos, spat up 0.3–1 cubic kilometres of carbon dioxide, asphyxiating more than 1,700 people. Kling was part of a team that visited Lake Nyos in the weeks following the eruption. "The animals were all dead, thousands of cattle just lying about," he says. Kling had been to Nyos the year before, but had only sampled surface waters. "We knew nothing about the gas bomb in the bottom of the lake," he says. It turned out that the deep waters of Lake Nyos were nearly saturated with carbon dioxide and, like in Lake Kivu, the gases were kept in solution by the pressure of the overlying water. Kling postulates that a landslide disturbed the lake's stratification, forcing gas-rich waters to move upwards3. That started a chain reaction. The reduction in pressure caused carbon dioxide to come out of solution and form bubbles, much like what happens when a bottle of champagne is uncorked. The rising bubbles dragged up the surrounding water, which also degassed, leading to a violent gas burst — a limnic eruption. Carbon dioxide is denser than air so, when it emerged, it hugged the ground, smothering everything as it spread up to 26 kilometres from the lake. The scale of the disaster compelled scientists to assess the risk at Kivu, the other lake known for its dissolved gases. Click to see a larger version. Latent threat There are no historic records of limnic eruptions in Lake Kivu. But gaps in layers of plankton fossils at the bottom of the lake suggest that such paroxysms have struck several times in the past 5,000 years4. If Kivu were to undergo a limnic eruption soon, it would dwarf the Nyos disaster. Kivu is more than 3,000 times larger and contains more than 350 times as much gas as was released by Lake Nyos. Kivu's shores are also densely populated. "Kivu is basically the nasty big brother of Nyos," says Kling. But there is no scientific consensus on the current risks of that kind of a disaster. "I'm not afraid of swimming in Lake Kivu." Martin Schmid Gas concentrations measured in 1974 and a limited study conducted in 2004 (ref. 5) show that there has been a 15–20% increase in methane and a 10% increase in carbon dioxide levels in the lake in the past 30 years, says Martin Schmid, a researcher at the Swiss Federal Institute of Aquatic Science and Technology in Kastanienbaum. If this trend continues, the lake will be saturated within the century and, like Lake Nyos, it could erupt with even the slightest disturbance. At the moment, however, the closest Kivu comes to gas overload is at a depth of 330 metres, where the water is 55% saturated — 10% with carbon dioxide and 45% with methane — says Schmid, so an eruption is less likely. (Methane contributes most of the gas pressure and the risk of eruption because it is less soluble than carbon dioxide.) According to modelling work, only an intense eruption in the gas-rich depths would be powerful enough to overturn the lake6. The 2002 eruption barely affected its stabili! ty because the magma did not reach those depths7. "The probability is low," says Schmid. "At least I am not afraid of swimming in Lake Kivu." But Dario Tedesco, a volcanologist from the Second University of Naples in Caserta, Italy, who is writing the DRC's Mount Nyiragongo eruption contingency plan for the United Nations, says an eruption at the bottom of Lake Kivu is a possibility. Tedesco has studied bathymetric surveys of the lake and found cone-like structures that are probably volcanic in origin, he says. That evidence matches some other signs. During the 2002 Nyiragongo eruption, new fractures opened on the south side of the volcano, just a few kilometres from the lake. The lava from the fractures was also compositionally different from the volcano's crater lake1, suggesting that there are separate reservoirs of magma in the region, some of which could extend under the lake. "Nyiragongo is going to erupt again," says Tedesco. "The only real question is where." Tedesco's research at Kivu highlights its complexity. The lake contains at least five basins, with different characteristics and different probabilities of turnover2. The Kabuno basin, in the lake's northwest corner, has high gas concentrations only 12 metres below the surface. An eruption in Kabuno could release at least three times more gas than Lake Nyos did. Researchers agree that it is important to relieve gas pressure at Lake Kivu to avoid a natural disaster — and the economic incentives are pushing that work forwards. The 60 cubic kilometres of methane equals roughly ten times the combined annual commercial energy needs of both the DRC and Rwanda. Tapping that reserve is particularly attractive to energy-starved Rwanda, and Lake Kivu has become the centrepiece of the country's plans to expand electricity production. Extracting methane from Kivu is not a new idea. A brewery in Rwanda burned the lake's methane to heat its boilers for 40 years before it shifted to electricity. But commercial interest in using methane to generate electricity only burgeoned in recent years, in part because of growing political stability in Rwanda. Around 60 companies, most of them from foreign countries, have approached the government for access to the lake since 2005, says Albert Butare, Rwanda's minister responsible for energy, water and sanitation. Rwanda has already handed out methane concessions totalling hundreds of megawatts to five consortia, including a US$325 million, 100-megawatt deal with ContourGlobal, an energy company based in New York. And in June, Rwanda and the DRC announced a new joint plan to develop an additional 200 megawatts from the lake. The growing interest in Kivu has kept scientists busy discussing best practices for methane removal. Most of the proposed models use a floating platform to suspend a vertical pipe down into the gas-rich layers. A small pump initially pulls up some of the bottom water to lower pressures, until it becomes saturated with gas and starts forming bubbles. After this priming, the bubbling drives water up the pipe without additional pumping. The extraction works like a controlled limnic eruption. The methane, being less soluble than the carbon dioxide, comes out of solution first. It is then piped onshore where it is burned to generate electricity. The problem is what to do with the carbon-dioxide-laden water. From the standpoint of safety, it would be ideal to extract the carbon dioxide and reinsert the degassed water into the deep parts of the lake, where it wouldn't disturb the equilibrium, says Kling. But removing the carbon dioxide makes the water lighter, hence less stable at depth. "We don't want to generate any sinking or rising of water masses that will cause mixing," he says. Only water from the very bottom of the lake would still be dense enough to be reinserted in the deepest layers once it was degassed, but that would be prohibitively expensive. So Kling suggests keeping the carbon dioxide in the water. "Every solution is a compromise," he says. Close call: lava from Mount Nyiragongo didn't go deep enough into lake Kivu in January 2002 to set off a limnic eruption, but next time it could.G. MULALA/REUTERS Conflict of interests? Klaus Tietze, a geophysicist and the director of Physik-Design-Technology, a consulting company based in Celle, Germany, argues that with carbon dioxide concentrations in the lake increasing at a rate of more than 3% a decade, "leaving the carbon dioxide in the lake is a very bad solution". He is pushing for removing both methane and carbon dioxide as quickly as possible and reinserting the water above the main gas accumulations in the lake, so that it doesn't dilute the methane resource. "This is pure business. This has nothing to do with the hazard of the situation." Dario Tedesco Schmid discounts that plan, however, because the nutrients in the degassed deep water would overload the lake's upper layers. With so much disagreement among scientists, the best way forwards for developers is unclear, especially because the extraction technology has been problematic. So far only one 4-megawatt platform, called KP, is sporadically generating electricity for Rwanda's national grid. Another, a 3.6-megawatt project funded by the Rwandan Investment Group, sank last year a week before it was scheduled to begin production. Some have attributed the loss to sabotage but others have blamed bad engineering. Complicating the situation is the potential for conflicts of interest; some of the scientists who studied the lake and identified its hazard are now involved in the methane extraction projects. For example, Michel Halbwachs, a recently retired physicist from University of Savoie in France, has spent two decades studying Nyos and Kivu and now spearheads the Rwandan Investment Group's project. He says that the engineering of the sunken platform was sound and the company is now rebuilding it. Halbwachs says that his previous work on the lake is not a conflict of interest, but rather makes him uniquely knowledgeable about how to extract gases safely. Tietze agrees that only the few scientists who "know the whole lake" through decades of experience are qualified to run the methane projects. He is also trying to get into the extraction game and is now looking for investors. But other scientists worry that the safety of the lake could be compromised if the researchers who are assessing the gas hazard are also working on commercial methane extraction. The best interests of the lake's two million inhabitants could get lost along the way, says Tedesco, who calls the plans for tapping methane "pure business". "This has nothing to do with the hazard of the situation," he adds. "It's a little bit like someone has dropped free money on the street and everyone's running around trying to gather it up," says Kling. He is part of an international team that is working with the World Bank and the involved nations to create rules for methane extraction in the lake. The team wants every project to be monitored through a local institute, which then reports to an international group of experts. "There has to be a separation between who is doing the work and who is checking the work," he says. In mid-June, the team came out with its first draft of legislation, which will now have to get parliamentary backing both in Rwanda and in the DRC. Although, in theory, removing the methane should make the lake safer, it remains unclear whether the hazard will be reduced. The plans for degassing are preliminary, and no one knows how they will affect the lake's stability. ADVERTISEMENT The chances of avoiding a disaster depend on many factors, some well beyond the control of the scientists or even the governments in that region. Armed militias in the DRC recently took over four of the area's seven seismic monitoring stations, hampering the ability of volcanologists to predict when Nyiragongo will erupt. And in the past few months, renewed fighting in rural areas has displaced hundreds of thousands of people. Goma's population has almost tripled since the 2002 Nyiragongo eruption, to an estimated 1.2 million people. There are shanties crammed into every usable piece of land, many constructed from lava blocks from the volcano's last eruption. So as scientists and developers fight over Lake Kivu's methane resource, the displaced people remain pinned between a volcano, the militias and an explosive lake. Anjali Nayar is an International Development Research Centre fellow at Nature. * References * Tedesco, D. et al. J. Geophys. Res. 112, B09202 (2007). * Tassi, F. et al. Geochem. Geophys. Geosyst. 10, Q02005 (2009). * Kling, G. W. et al. Science 236, 169-175 (1987). * Haberyan, K. A. & Hecky, R. E. Palaeogeogr. Palaeoclimatol. Palaeoecol. 61, 169-197 (1987). * Schmid, M. , Halbwachs, M. , Wehrli, B. & Wüest, A. Geochem. Geophys. Geosyst. 6, Q07009 (2005). * Schmid, M. et al. Acta Vulcanologica 14/15, 115-122 (2003). * Lorke, A. , Tietze, K. , Halbwachs, M. & Wuest, A. Limnol. Oceanogr. 49, 778-783 (2004). Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
  • Sharing different mouse strains is not always so simple
    - Nature 460(7253):324 (2009)
    I was disappointed by the view expressed in your Editorial 'The sharing principle' (Nature 459, 752; 2009) that the mouse community does not share its strains. This is untrue.
  • Invasion biology is a discipline that's too young to die
    - Nature 460(7253):324 (2009)
    Mark Davis suggests in his book Invasion Biology that the discipline should be reabsorbed into general community ecology, as Emma Marris reports in her Review 'The end of the invasion?' (Nature 459, 327–328; 2009).
  • For cancer, seek and destroy or live and let live?
    - Nature 460(7253):324 (2009)
    In his Essay 'A change of strategy in the war on cancer' (Nature 459, 508–509; 2009), Robert Gatenby proposes that controlling a tumour's growth may be more efficient in the long term than trying to eradicate it. However, it could be some time before we can establish whether such a switch in treatment strategy is clinically beneficial.
  • Why we need space travel
    - Nature 460(7253):325 (2009)
    Giovanni Bignami reflects on the people who persuaded him that we must send humans beyond Earth's orbit to inspire public and political support for science.
  • The slow slide towards a new battlefield?
    - Nature 460(7253):326-327 (2009)
    The cold war saw governments develop international policies to regulate outer space for military and civil uses. Loopholes in those policies must now be closed, writes Roald Sagdeev.
  • The return path to the Moon
    - Nature 460(7253):327-328 (2009)
    In The Seventh Landing, Michael Carroll adeptly lays out NASA's strategy for returning to the Moon, establishing a permanent outpost there, and, if all goes well, pushing on to Mars. It is a complex and ambitious undertaking, requiring a new fleet of launch vehicles, an updated crew module, a more versatile lunar lander, sophisticated all-terrain vehicles, souped-up spacesuits, lunar habitats and enough acronyms to make your head explode.
  • Apollo books
    - Nature 460(7253):328 (2009)
    The anniversary of the first footstep on the Moon is being celebrated in an array of new books. Drawing on NASA's archive of oral histories, and declassified Central Intelligence Agency material on the space race, historian Craig Nelson tells in Rocket Men (Viking) the full story of the Apollo programme from the crews' training to the first moonwalkers' return as media stars.
  • In Retrospect: Calvino's Cosmicomics
    - Nature 460(7253):329 (2009)
    The soaring imagination of the Italian author abounds in a new compilation of his cosmic fables. Mostly written in the age of the space race, they are heavily informed by science, finds Alan Lightman.
  • Ageing: A midlife longevity drug?
    - Nature 460(7253):331-332 (2009)
    The small molecule rapamycin, already approved for clinical use for various human disorders, has been found to significantly increase lifespan in mice. Is this a step towards an anti-ageing drug for people?
  • Atmospheric physics: Cosmic rays, clouds and climate
    - Nature 460(7253):332-333 (2009)
    Galactic cosmic rays could influence Earth's cloudiness by creating aerosol particles that prompt cloud formation. That possible effect looks to be smaller than thought, but the story won't end there.
  • Galaxy formation: Anatomy of elliptical galaxies
    - Nature 460(7253):333-334 (2009)
    The family of elliptical galaxies is remarkable for the structural regularity of its members. Inspecting irregularities in this regularity could help in understanding how these galaxies form.
  • Ecology: Towards a theory of biodiversity
    - Nature 460(7253):334-335 (2009)
    Models of ecological communities that incorporate mutation and spatial dispersal can yield results that go some way to explaining observations. A further step is to add sexual reproduction to the mix.
  • Climate change: Beyond the CO2 connection
    - Nature 460(7253):335-336 (2009)
    At times in the past, mobile ocean fronts in the subtropics have exercised an influence on the magnitude of climate change by decoupling temperature from levels of carbon dioxide in the atmosphere.
  • Photonics: Light control at will
    - Nature 460(7253):337 (2009)
    Microchips that make use of light instead of electrons could outperform their electronic counterparts if light flow can be controlled at will. Photonic crystals are instrumental in achieving such a manoeuvre.
  • Obituary: Jean Dausset (1916–2009)
    - Nature 460(7253):338 (2009)
    'Father' of the human leukocyte antigen system.
  • Primate archaeology
    - Nature 460(7253):339-344 (2009)
    All modern humans use tools to overcome limitations of our anatomy and to make difficult tasks easier. However, if tool use is such an advantage, we may ask why it is not evolved to the same degree in other species. To answer this question, we need to bring a long-term perspective to the material record of other members of our own order, the Primates.
  • The Schistosoma japonicum genome reveals features of host–parasite interplay
    - Nature 460(7253):345-351 (2009)
    Schistosoma japonicum is a parasitic flatworm that causes human schistosomiasis, which is a significant cause of morbidity in China and the Philippines. Here we present a draft genomic sequence for the worm. The genome provides a global insight into the molecular architecture and host interaction of this complex metazoan pathogen, revealing that it can exploit host nutrients, neuroendocrine hormones and signalling pathways for growth, development and maturation. Having a complex nervous system and a well-developed sensory system, S. japonicum can accept stimulation of the corresponding ligands as a physiological response to different environments, such as fresh water or the tissues of its intermediate and mammalian hosts. Numerous proteases, including cercarial elastase, are implicated in mammalian skin penetration and haemoglobin degradation. The genomic information will serve as a valuable platform to facilitate development of new interventions for schistosomiasis co! ntrol.
  • The genome of the blood fluke Schistosoma mansoni
    - Nature 460(7253):352-358 (2009)
    Schistosoma mansoni is responsible for the neglected tropical disease schistosomiasis that affects 210 million people in 76 countries. Here we present analysis of the 363 megabase nuclear genome of the blood fluke. It encodes at least 11,809 genes, with an unusual intron size distribution, and new families of micro-exon genes that undergo frequent alternative splicing. As the first sequenced flatworm, and a representative of the Lophotrochozoa, it offers insights into early events in the evolution of the animals, including the development of a body pattern with bilateral symmetry, and the development of tissues into organs. Our analysis has been informed by the need to find new drug targets. The deficits in lipid metabolism that make schistosomes dependent on the host are revealed, and the identification of membrane receptors, ion channels and more than 300 proteases provide new insights into the biology of the life cycle and new targets. Bioinformatics approaches have! identified metabolic chokepoints, and a chemogenomic screen has pinpointed schistosome proteins for which existing drugs may be active. The information generated provides an invaluable resource for the research community to develop much needed new control tools for the treatment and eradication of this important and neglected disease.
  • The active form of DNA polymerase V is UmuD'2C–RecA–ATP
    - Nature 460(7253):359-363 (2009)
    DNA-damage-induced SOS mutations arise when Escherichia coli DNA polymerase (pol) V, activated by a RecA nucleoprotein filament (RecA*), catalyses translesion DNA synthesis. Here we address two longstanding enigmatic aspects of SOS mutagenesis, the molecular composition of mutagenically active pol V and the role of RecA*. We show that RecA* transfers a single RecA–ATP stoichiometrically from its DNA 3'-end to free pol V (UmuD'2C) to form an active mutasome (pol V Mut) with the composition UmuD'2C–RecA–ATP. Pol V Mut catalyses TLS in the absence of RecA* and deactivates rapidly upon dissociation from DNA. Deactivation occurs more slowly in the absence of DNA synthesis, while retaining RecA–ATP in the complex. Reactivation of pol V Mut is triggered by replacement of RecA–ATP from RecA*. Thus, the principal role of RecA* in SOS mutagenesis is to transfer RecA–ATP to pol V, and thus generate active mutasomal complex for translesion synthesis.
  • Contamination of the asteroid belt by primordial trans-Neptunian objects
    - Nature 460(7253):364-366 (2009)
    The main asteroid belt, which inhabits a relatively narrow annulus 2.1–3.3 au from the Sun, contains a surprising diversity of objects ranging from primitive ice–rock mixtures to igneous rocks. The standard model used to explain this assumes that most asteroids formed in situ from a primordial disk that experienced radical chemical changes within this zone1. Here we show that the violent dynamical evolution of the giant-planet orbits required by the so-called Nice model2, 3, 4 leads to the insertion of primitive trans-Neptunian objects into the outer belt. This result implies that the observed diversity of the asteroid belt is not a direct reflection of the intrinsic compositional variation of the proto-planetary disk. The dark captured bodies, composed of organic-rich materials, would have been more susceptible to collisional evolution than typical main-belt asteroids. Their weak nature makes them a prodigious source of micrometeorites—sufficient to explain why ! most are primitive in composition and are isotopically different from most macroscopic meteorites5, 6.
  • Manipulation of photons at the surface of three-dimensional photonic crystals
    - Nature 460(7253):367-370 (2009)
    In three-dimensional (3D) photonic crystals1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, refractive-index variations with a periodicity comparable to the wavelength of the light passing through the crystal give rise to so-called photonic bandgaps, which are analogous to electronic bandgaps for electrons moving in the periodic electrostatic potential of a material's crystal structure. Such 3D photonic bandgap crystals are envisioned to become fundamental building blocks for the control and manipulation of photons in optical circuits. So far, such schemes have been pursued by embedding artificial defects3, 4, 5, 8, 9, 10, 11, 12 and light emitters4, 5, 6, 7, 8, 9 inside the crystals, making use of 3D bandgap directional effects. Here we show experimentally that photons can be controlled and manipulated even at the 'surface' of 3D photonic crystals, where 3D periodicity is terminated, establishing a new and versatile route for photon manipulation. By making use of an evanescent-! mode coupling technique, we demonstrate that 3D photonic crystals possess two-dimensional surface states, and we map their band structure. We show that photons can be confined and propagate through these two-dimensional surface states, and we realize their localization at arbitrary surface points by designing artificial surface-defect structures through the formation of a surface-mode gap. Surprisingly, the quality factors of the surface-defect mode are the largest reported for 3D photonic crystal nanocavities (Q up to 9,000). In addition to providing a new approach for photon manipulation by photonic crystals, our findings are relevant for the generation and control of plasmon-polaritons in metals and the related surface photon physics. The absorption-free nature of the 3D photonic crystal surface may enable new sensing applications and provide routes for the realization of efficient light–matter interactions.
  • Photoconductance and inverse photoconductance in films of functionalized metal nanoparticles
    - Nature 460(7253):371-375 (2009)
    In traditional photoconductors1, 2, 3, the impinging light generates mobile charge carriers in the valence and/or conduction bands, causing the material's conductivity to increase4. Such positive photoconductance is observed in both bulk and nanostructured5, 6 photoconductors. Here we describe a class of nanoparticle-based materials whose conductivity can either increase or decrease on irradiation with visible light of wavelengths close to the particles' surface plasmon resonance. The remarkable feature of these plasmonic materials is that the sign of the conductivity change and the nature of the electron transport between the nanoparticles depend on the molecules comprising the self-assembled monolayers (SAMs)7, 8 stabilizing the nanoparticles. For SAMs made of electrically neutral (polar and non-polar) molecules, conductivity increases on irradiation. If, however, the SAMs contain electrically charged (either negatively or positively) groups, conductivity decreases. ! The optical and electrical characteristics of these previously undescribed inverse photoconductors can be engineered flexibly by adjusting the material properties of the nanoparticles and of the coating SAMs. In particular, in films comprising mixtures of different nanoparticles or nanoparticles coated with mixed SAMs, the overall photoconductance is a weighted average of the changes induced by the individual components. These and other observations can be rationalized in terms of light-induced creation of mobile charge carriers whose transport through the charged SAMs is inhibited by carrier trapping in transient polaron-like states9, 10. The nanoparticle-based photoconductors we describe could have uses in chemical sensors and/or in conjunction with flexible substrates.
  • Evidence for middle Eocene Arctic sea ice from diatoms and ice-rafted debris
    - Nature 460(7253):376-379 (2009)
    Oceanic sediments from long cores drilled on the Lomonosov ridge, in the central Arctic1, contain ice-rafted debris (IRD) back to the middle Eocene epoch, prompting recent suggestions that ice appeared in the Arctic about 46 million years (Myr) ago2, 3. However, because IRD can be transported by icebergs (derived from land-based ice) and also by sea ice4, IRD records2, 3 are restricted to providing a history of general ice-rafting only. It is critical to differentiate sea ice from glacial (land-based) ice as climate feedback mechanisms vary and global impacts differ between these systems: sea ice directly affects ocean–atmosphere exchanges5, whereas land-based ice affects sea level and consequently ocean acidity6. An earlier report3 assumed that sea ice was prevalent in the middle Eocene Arctic on the basis of IRD, and although somewhat preliminary supportive evidence exists2, these data are neither comprehensive nor quantified. Here we show the presence of middle Eo! cene Arctic sea ice from an extraordinary abundance of a group of sea-ice-dependent fossil diatoms (Synedropsis spp.). Analysis of quartz grain textural characteristics further supports sea ice as the dominant transporter of IRD at this time. Together with new information on cosmopolitan diatoms and existing IRD records2, our data strongly suggest a two-phase establishment of sea ice: initial episodic formation in marginal shelf areas 47.5 Myr ago, followed 0.5 Myr later by the onset of seasonally paced sea-ice formation in offshore areas of the central Arctic. Our data establish a 2-Myr record of sea ice, documenting the transition from a warm, ice-free3 environment to one dominated by winter sea ice at the start of the middle Eocene climatic cooling phase7.
  • Migration of the subtropical front as a modulator of glacial climate
    - Nature 460(7253):380-383 (2009)
    Ice cores extracted from the Antarctic ice sheet suggest that glacial conditions, and the relationship between isotopically derived temperatures and atmospheric have been constant over the last 800,000 years of the Late Pleistocene epoch1. But independent lines of evidence, such as the extent of Northern Hemisphere ice sheets2, sea level3 and other temperature records4, point towards a fluctuating severity of glacial periods, particularly during the more extreme glacial stadials centred around 340,000 and 420,000 years ago (marine isotope stages 10 and 12). Previously unidentified mechanisms therefore appear to have mediated the relationship between insolation, CO2 and climate. Here we test whether northward migration of the subtropical front (STF) off the southeastern coast of South Africa acts as a gatekeeper for the Agulhas current5, 6, which controls the transport of heat and salt from the Indo-Pacific Ocean to the Atlantic Ocean. Using a new 800,000-year record o! f sea surface temperature and ocean productivity from ocean sediment core MD962077, we demonstrate that during cold stadials (particularly marine isotope stages 10 and 12), productivity peaked and sea surface temperature was up to 6 °C cooler than modern temperatures. This suggests that during these cooler stadials, the STF moved northward by up to 7° latitude, nearly shutting off the Agulhas current. Our results, combined with faunal assemblages from the south Atlantic7, 8 show that variable northwards migration of the Southern Hemisphere STF can modulate the severity of each glacial period by altering the strength of the Agulhas current carrying heat and salt to the Atlantic meridional overturning circulation. We show hence that the degree of northwards migration of the STF can partially decouple global climate from atmospheric partial pressure of carbon dioxide, , and help to resolve the long-standing puzzle of differing glacial amplitudes within a consistent range of ! atmospheric .
  • Global patterns of speciation and diversity
    - Nature 460(7253):384-387 (2009)
    In recent years, strikingly consistent patterns of biodiversity have been identified over space, time, organism type and geographical region1, 2. A neutral theory (assuming no environmental selection or organismal interactions) has been shown to predict many patterns of ecological biodiversity2, 3. This theory is based on a mechanism by which new species arise similarly to point mutations in a population without sexual reproduction. Here we report the simulation of populations with sexual reproduction, mutation and dispersal. We found simulated time dependence of speciation rates, species–area relationships and species abundance distributions consistent with the behaviours found in nature1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13. From our results, we predict steady speciation rates, more species in one-dimensional environments than two-dimensional environments, three scaling regimes of species–area relationships and lognormal distributions of species abundance with! an excess of rare species and a tail that may be approximated by Fisher's logarithmic series. These are consistent with dependences reported for, among others, global birds4 and flowering plants5, marine invertebrate fossils6, ray-finned fishes7, British birds8, 9 and moths10, North American songbirds11, mammal fossils from Kansas12 and Panamanian shrubs13. Quantitative comparisons of specific cases are remarkably successful. Our biodiversity results provide additional evidence that species diversity arises without specific physical barriers6, 11, 14. This is similar to heavy traffic flows, where traffic jams can form even without accidents or barriers15.
  • Evolution of a malaria resistance gene in wild primates
    - Nature 460(7253):388-391 (2009)
    The ecology, behaviour and genetics of our closest living relatives, the nonhuman primates, should help us to understand the evolution of our own lineage. Although a large amount of data has been amassed on primate ecology and behaviour, much less is known about the functional and evolutionary genetic aspects of primate biology, especially in wild primates. As a result, even in well-studied populations in which nongenetic factors that influence adaptively important characteristics have been identified, we have almost no understanding of the underlying genetic basis for such traits. Here, we report on the functional consequences of genetic variation at the malaria-related FY (DARC) gene in a well-studied population of yellow baboons (Papio cynocephalus) living in Amboseli National Park in Kenya. FY codes for a chemokine receptor normally expressed on the erythrocyte surface that is the known entry point for the malarial parasite Plasmodium vivax 1, 2, 3. We identified v! ariation in the cis-regulatory region of the baboon FY gene that was associated with phenotypic variation in susceptibility to Hepatocystis, a malaria-like pathogen that is common in baboons4, 5. Genetic variation in this region also influenced gene expression in vivo in wild individuals, a result we confirmed using in vitro reporter gene assays. The patterns of genetic variation in and around this locus were also suggestive of non-neutral evolution, raising the possibility that the evolution of the FY cis-regulatory region in baboons has exhibited both mechanistic and selective parallels with the homologous region in humans6, 7, 8. Together, our results represent the first reported association and functional characterization linking genetic variation and a complex trait in a natural population of nonhuman primates.
  • Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
    - Nature 460(7253):392-395 (2009)
    Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies1, 2, 3, 4, 5; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival poi! nt. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
  • A conserved ubiquitination pathway determines longevity in response to diet restriction
    - Nature 460(7253):396-399 (2009)
    Dietary restriction extends longevity in diverse species, suggesting that there is a conserved mechanism for nutrient regulation and prosurvival responses1. Here we show a role for the HECT (homologous to E6AP carboxy terminus) E3 ubiquitin ligase WWP-1 as a positive regulator of lifespan in Caenorhabditis elegans in response to dietary restriction. We find that overexpression of wwp-1 in worms extends lifespan by up to 20% under conditions of ad libitum feeding. This extension is dependent on the FOXA transcription factor pha-4, and independent of the FOXO transcription factor daf-16. Reduction of wwp-1 completely suppresses the extended longevity of diet-restricted animals. However, the loss of wwp-1 does not affect the long lifespan of animals with compromised mitochondrial function or reduced insulin/IGF-1 signalling. Overexpression of a mutant form of WWP-1 lacking catalytic activity suppresses the increased lifespan of diet-restricted animals, indicating that WWP! -1 ubiquitin ligase activity is essential for longevity. Furthermore, we find that the E2 ubiquitin conjugating enzyme, UBC-18, is essential and specific for diet-restriction-induced longevity. UBC-18 interacts with WWP-1 and is required for the ubiquitin ligase activity of WWP-1 and the extended longevity of worms overexpressing wwp-1. Taken together, our results indicate that WWP-1 and UBC-18 function to ubiquitinate substrates that regulate diet-restriction-induced longevity.
  • A reevaluation of X-irradiation-induced phocomelia and proximodistal limb patterning
    - Nature 460(7253):400-404 (2009)
    Phocomelia is a devastating, rare congenital limb malformation in which the long bones are shorter than normal, with the upper portion of the limb being most severely affected. In extreme cases, the hands or fingers are attached directly to the shoulder and the most proximal elements (those closest to the shoulder) are entirely missing. This disorder, previously known in both autosomal recessive and sporadic forms, showed a marked increase in incidence in the early 1960s due to the tragic toxicological effects of the drug thalidomide, which had been prescribed as a mild sedative1, 2. This human birth defect is mimicked in developing chick limb buds exposed to X-irradiation3, 4, 5. Both X-irradiation5 and thalidomide-induced phocomelia5, 6 have been interpreted as patterning defects in the context of the progress zone model, which states that a cell's proximodistal identity is determined by the length of time spent in a distal limb region termed the 'progress zone'7. In! deed, studies of X-irradiation-induced phocomelia have served as one of the two major experimental lines of evidence supporting the validity of the progress zone model. Here, using a combination of molecular analysis and lineage tracing in chick, we show that X-irradiation-induced phocomelia is fundamentally not a patterning defect, but rather results from a time-dependent loss of skeletal progenitors. Because skeletal condensation proceeds from the shoulder to fingers (in a proximal to distal direction), the proximal elements are differentially affected in limb buds exposed to radiation at early stages. This conclusion changes the framework for considering the effect of thalidomide and other forms of phocomelia, suggesting the possibility that the aetiology lies not in a defect in the patterning process, but rather in progenitor cell survival and differentiation. Moreover, molecular evidence that proximodistal patterning is unaffected after X-irradiation does not support t! he predictions of the progress zone model.
  • The AP-1 transcription factor Batf controls TH17 differentiation
    - Nature 460(7253):405-409 (2009)
    Activator protein 1 (AP-1, also known as JUN) transcription factors are dimers of JUN, FOS, MAF and activating transcription factor (ATF) family proteins characterized by basic region and leucine zipper domains1. Many AP-1 proteins contain defined transcriptional activation domains, but BATF and the closely related BATF3 (refs 2, 3) contain only a basic region and leucine zipper, and are considered to be inhibitors of AP-1 activity3, 4, 5, 6, 7, 8. Here we show that Batf is required for the differentiation of IL17-producing T helper (TH17) cells9. TH17 cells comprise a CD4+ T-cell subset that coordinates inflammatory responses in host defence but is pathogenic in autoimmunity10, 11, 12, 13. Batf-/- mice have normal TH1 and TH2 differentiation, but show a defect in TH17 differentiation, and are resistant to experimental autoimmune encephalomyelitis. Batf-/- T cells fail to induce known factors required for TH17 differentiation, such as RORt11 (encoded by Rorc) and the c! ytokine IL21 (refs 14–17). Neither the addition of IL21 nor the overexpression of RORt fully restores IL17 production in Batf-/- T cells. The Il17 promoter is BATF-responsive, and after TH17 differentiation, BATF binds conserved intergenic elements in the Il17a–Il17f locus and to the Il17, Il21 and Il22 (ref. 18) promoters. These results demonstrate that the AP-1 protein BATF has a critical role in TH17 differentiation.
  • Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus
    - Nature 460(7253):410-413 (2009)
    Cohesin-mediated sister chromatid cohesion is essential for chromosome segregation and post-replicative DNA repair1, 2. In addition, evidence from model organisms3, 4, 5, 6 and from human genetics7 suggests that cohesin is involved in the control of gene expression8, 9. This non-canonical role has recently been rationalized by the findings that mammalian cohesin complexes are recruited to a subset of DNase I hypersensitive sites and to conserved noncoding sequences by the DNA-binding protein CTCF10, 11, 12, 13. CTCF functions at insulators (which control interactions between enhancers and promoters) and at boundary elements (which demarcate regions of distinct chromatin structure)14, and cohesin contributes to its enhancer-blocking activity10, 11. The underlying mechanisms remain unknown, and the full spectrum of cohesin functions remains to be determined. Here we show that cohesin forms the topological and mechanistic basis for cell-type-specific long-range chromosoma! l interactions in cis at the developmentally regulated cytokine locus IFNG. Hence, the ability of cohesin to constrain chromosome topology is used not only for the purpose of sister chromatid cohesion1, 2, but also to dynamically define the spatial conformation of specific loci. This new aspect of cohesin function is probably important for normal development3, 4, 5, 6 and disease7.
  • Systems biology: Untangling the protein web
    - Nature 460(7253):415-418 (2009)
    Researchers have identified thousands of macromolecular interactions within cells. But, as Nathan Blow finds out, joining them up in networks and figuring out how they work still poses a big challenge.
  • Systems biology: Playing by the rules
    - Nature 460(7253):417 (2009)
    M. TYERS Graphical representation of the current budding-yeast interaction network. When researchers at Plectix BioSystems in Somerville, Massachusetts, began to use their new Cellucidate software to model the epidermal growth factor receptor pathway, they calculated that there were 1033 potential states — including all protein complexes and phosphorylation states — for the system. "This is the kind of complexity that scientists have to grapple with when it comes to cell-signalling networks," says Gordon Webster, vice-president of biology at Plectix. Although not all these potential states necessarily occur in that pathway, when it comes to creating more manageable models for understanding cell signalling researchers face a difficult question: what interaction data do they use in their models? Although many commercial and public databases still rely heavily on the small-scale protein–protein-interaction studies that appear in peer-reviewed literature, the emergence of high-throughput experimental approaches that generate very large interaction data sets is creating the need for a new set of rules. "In practice, what comes out of these high-throughput studies is not a yes/no thing — 'these interact, and these don't' — but in fact they generate a list of interactions and associated probabilities," says Jack Greenblatt from the University of Toronto in Canada. To generate such probabilities for his mass-spectrometry studies, Greenblatt applied a 'gold standard' for protein interactions — a set of protein complexes or interactions in which there is a strong amount of confidence according to the literature — as well as a set of proteins not known to interact with one another as a negative standard. He then tackled the question of whether or not data sets generated by mass spectrometry stacked up against protein-interaction reports seen in peer-reviewed literature. "What we did in the end was to use the same gold standard to look at the molecular-biology literature," says Greenblatt. After adjusting the cut-off point so that the average confidence score from a high-throughput study matched the confidence score of interactions reported in the literature, he says the interaction data from such studies are no better or worse than what is in the literature. Marc Vidal, a geneticist at the Dana–Farber Cancer Institute in Boston, Massachusetts, wants to see a similar approach taken with yeast two-hybrid and other binary screens. "Let's roll up our sleeves and decide on a positive and negative gold standard," he says. "But let's also use orthogonal assays to give confidence scores to the interactions." In January, Vidal and his colleagues published a series of papers6–9 suggesting the use of new binary interaction assays to build confidence in basic networks produced using yeast two-hybrid data sets. "You say 'OK, this is basic network' and then push that into a framework where all interactions are going to be tested by two or three orthogonal assays. And not only that, but do that under conditions where you have a positive and negative gold standard," says Vidal, adding that the high-scoring interactions can then serve as hypotheses for researchers to test. Whether or not these efforts and standards will lead researchers to rely more on large-scale data sets and mine them more deeply will only be known in time. For some, even with confidence measures, large-scale data sets lack information often found in smaller studies. "This is one of the paradoxes that we find when people talk about systems biology. With technology it is very easy to generate spreadsheets of interaction data, but that alone does not represent any knowledge," says Webster. But for Greenblatt and others, large-scale data sets represent a starting point for further research efforts. "To me, high-throughput studies are just like the conventional literature," he says, "providing a gold mine for people to dig into." N.B.
  • Systems biology: Table of suppliers
    - Nature 460(7253):419-420 (2009)
    Table 1
  • Makeover
    - Nature 460(7253):428 (2009)
    Off on the wrong track.

Hot off the presses! Jul 16 Neuron

The Jul 16 issue of the Neuron is now up on Pubget (About Neuron): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

  • Baby Got Brain: Fgf10 Sets Rostral Cortical Size
    - Neuron 63(1):1-3 (2009)
    Brain growth occurs throughout embryogenesis and early postnatal life, but its foundation is laid in the primitive neuroepithelium. In this issue of Neuron, Sahara and O'Leary identify Fgf10 as a key regulator of the neuroepithelial to radial glial transition and subsequently of size of the rostral forebrain.
  • According to GOSPEL: Filling in the GAP(DH) of NO-Mediated Neurotoxicity
    - Neuron 63(1):3-6 (2009)
    In addition to its role in glycolysis, GAPDH has been implicated as a mediator of neurotoxicity triggered by nitrosative stress. In this issue of Neuron, Sen et al. identify a novel, negative regulator of this GAPDH neurotoxic pathway termed GOSPEL, which, like GAPDH itself, is regulated by S-nitrosylation.
  • It's Lonely at the Top: Winning Climbing Fibers Ascend Dendrites Solo
    - Neuron 63(1):6-8 (2009)
    In mammals, climbing fiber axons compete for sole innervation at each Purkinje cell. At the same time, synapses disappear from Purkinje somata and appear in great numbers on the dendrites. In this issue of Neuron, Hashimoto et al. show that, by the time climbing fibers ascend the dendrites, the winner and losers are already decided.
  • Deal Breaker: Semaphorin and Specificity in the Spinal Stretch Reflex Circuit
    - Neuron 63(1):8-11 (2009)
    Stretch reflex circuits are a prime example of wiring specificity in the vertebrate spinal cord. Homonymous sensory afferents and motoneurons typically form monosynaptic connections, while neurons innervating antagonistic or unrelated muscles do not. Pecho-Vrieseling et al. now show that the semaphorin Sema3E and its receptor Plexin-D1 prevent monosynaptic connectivity in the cutaneous maximus muscle stretch reflex circuit.
  • Shotgun Proteomics in Neuroscience
    - Neuron 63(1):12-26 (2009)
    Mass spectrometry-based proteomics is increasingly used to address basic and clinical questions in biomedical research through studies of differential protein expression, protein-protein interactions, and posttranslational modifications. The complex structural and functional organization of the human brain warrants the application of high-throughput, systematic approaches to understand the functional alterations under normal physiological conditions and the perturbations of neurological diseases. This primer focuses on shotgun-proteomics-based tandem mass spectrometry for the identification of proteins in a complex mixture. It describes the basic concepts of protein differential expression analysis and posttranslational modification analysis and discusses several strategies to improve the coverage of the proteome.
  • Remote Control of Neuronal Activity in Transgenic Mice Expressing Evolved G Protein-Coupled Receptors
    - Neuron 63(1):27-39 (2009)
    Examining the behavioral consequences of selective CNS neuronal activation is a powerful tool for elucidating mammalian brain function in health and disease. Newly developed genetic, pharmacological, and optical tools allow activation of neurons with exquisite spatiotemporal resolution; however, the inaccessibility to light of widely distributed neuronal populations and the invasiveness required for activation by light or infused ligands limit the utility of these methods. To overcome these barriers, we created transgenic mice expressing an evolved G protein-coupled receptor (hM3Dq) selectively activated by the pharmacologically inert, orally bioavailable drug clozapine-N-oxide (CNO). Here, we expressed hM3Dq in forebrain principal neurons. Local field potential and single-neuron recordings revealed that peripheral administration of CNO activated hippocampal neurons selectively in hM3Dq-expressing mice. Behavioral correlates of neuronal activation included increased lo! comotion, stereotypy, and limbic seizures. These results demonstrate a powerful chemical-genetic tool for remotely controlling the activity of discrete populations of neurons in vivo.
  • In Vivo Cocaine Experience Generates Silent Synapses
    - Neuron 63(1):40-47 (2009)
    Studies over the past decade have enunciated silent synapses as prominent cellular substrates for synaptic plasticity in the developing brain. However, little is known about whether silent synapses can be generated postdevelopmentally. Here, we demonstrate that highly salient in vivo experience, such as exposure to cocaine, generates silent synapses in the nucleus accumbens (NAc) shell, a key brain region mediating addiction-related learning and memory. Furthermore, this cocaine-induced generation of silent synapses is mediated by membrane insertions of new, NR2B-containing N-methyl-D-aspartic acid receptors (NMDARs). These results provide evidence that silent synapses can be generated de novo by in vivo experience and thus may act as highly efficient neural substrates for the subsequent experience-dependent synaptic plasticity underlying extremely long-lasting memory.
  • Fgf10 Regulates Transition Period of Cortical Stem Cell Differentiation to Radial Glia Controlling Generation of Neurons and Basal Progenitors
    - Neuron 63(1):48-62 (2009)
    Radial glia (RG), the progenitors of cortical neurons and basal progenitors (BPs), differentiate from neuroepithelial cells (NCs) with stem cell properties. We show that the morphogen Fgf10 is transiently expressed by NCs coincident with the transition period of NC differentiation into RG. Targeted deletion of Fgf10 delays RG differentiation, whereas overexpression has opposing effects. Delayed RG differentiation in Fgf10 mutants occurs selectively in rostral cortex, paralleled by an extended period of symmetric NC divisions increasing progenitor number, coupled with delayed and initially diminished production of neurons and BPs. RG eventually differentiate in excess number and overproduce neurons and BPs rostrally resulting in tangential expansion of frontal areas and increased laminar thickness. Thus, transient Fgf10 expression regulates timely differentiation of RG, and through this function, determines both length of the early progenitor expansion phase and onset o! f neurogenesis and ultimately the number of progenitors and neurons fated to specific cortical areas.
  • Myosin II Motors and F-Actin Dynamics Drive the Coordinated Movement of the Centrosome and Soma during CNS Glial-Guided Neuronal Migration
    - Neuron 63(1):63-80 (2009)
    Lamination of cortical regions of the vertebrate brain depends on glial-guided neuronal migration. The conserved polarity protein Par6α localizes to the centrosome and coordinates forward movement of the centrosome and soma in migrating neurons. The cytoskeletal components that produce this unique form of cell polarity and their relationship to polarity signaling cascades are unknown. We show that F-actin and Myosin II motors are enriched in the neuronal leading process and that Myosin II activity is necessary for leading process actin dynamics. Inhibition of Myosin II decreased the speed of centrosome and somal movement, whereas Myosin II activation increased coordinated movement. Ectopic expression or silencing of Par6α inhibited Myosin II motors by decreasing Myosin light-chain phosphorylation. These findings suggest leading-process Myosin II may function to "pull" the centrosome and soma forward during glial-guided migration by a mechanism involving the conse! rved polarity protein Par6α.
  • GOSPEL: A Neuroprotective Protein that Binds to GAPDH upon S-Nitrosylation
    - Neuron 63(1):81-91 (2009)
    We recently reported a cell death cascade whereby cellular stressors activate nitric oxide formation leading to S-nitrosylation of GAPDH that binds to Siah and translocates to the nucleus. The nuclear GAPDH/Siah complex augments p300/CBP-associated acetylation of nuclear proteins, including p53, which mediate cell death. We report a 52 kDa cytosolic protein, GOSPEL, which physiologically binds GAPDH, in competition with Siah, retaining GAPDH in the cytosol and preventing its nuclear translocation. GOSPEL is neuroprotective, as its overexpression prevents NMDA-glutamate excitotoxicity while its depletion enhances death in primary neuron cultures. S-nitrosylation of GOSPEL at cysteine 47 enhances GAPDH-GOSPEL binding and the neuroprotective actions of GOSPEL. In intact mice, virally delivered GOSPEL selectively diminishes NMDA neurotoxicity. Thus, GOSPEL may physiologically regulate the viability of neurons and other cells.
  • Endocytic Trafficking and Recycling Maintain a Pool of Mobile Surface AMPA Receptors Required for Synaptic Potentiation
    - Neuron 63(1):92-105 (2009)
    At excitatory glutamatergic synapses, postsynaptic endocytic zones (EZs), which are adjacent to the postsynaptic density (PSD), mediate clathrin-dependent endocytosis of surface AMPA receptors (AMPAR) as a first step to receptor recycling or degradation. However, it remains unknown whether receptor recycling influences AMPAR lateral diffusion and whether EZs are important for the expression of synaptic potentiation. Here, we demonstrate that the presence of both EZs and AMPAR recycling maintain a large pool of mobile AMPARs at synapses. In addition, we find that synaptic potentiation is accompanied by an accumulation and immobilization of AMPARs at synapses resulting from both their exocytosis and stabilization at the PSD. Displacement of EZs from the postsynaptic region impairs the expression of synaptic potentiation by blocking AMPAR recycling. Thus, receptor recycling is crucial for maintaining a mobile population of surface AMPARs that can be delivered to synapses ! for increases in synaptic strength.
  • Translocation of a "Winner" Climbing Fiber to the Purkinje Cell Dendrite and Subsequent Elimination of "Losers" from the Soma in Developing Cerebellum
    - Neuron 63(1):106-118 (2009)
    Functional neural circuits are formed by eliminating early-formed redundant synapses and strengthening necessary connections during development. In newborn mouse cerebellum, each Purkinje cell (PC) is innervated by multiple climbing fibers (CFs) with similar strengths. Subsequently, a single CF is selectively strengthened by postnatal day 7 (P7). We find that this competition among multiple CFs occurs on the soma before CFs form synapses along dendrites. Notably, in most PCs, the single CF that has been functionally strengthened (the "winner" CF) undergoes translocation to dendrites while keeping its synapses on the soma. Synapses of the weaker CFs (the "loser" CFs) remain around the soma and form "pericellular nests" with synapses of the winner CFs. Then most perisomatic synapses are eliminated nonselectively by P15. Thus, our results suggest that the selective translocation of the winner CF to dendrites in each PC determines the single CF that survives su! bsequent synapse elimination and persistently innervates the PC.
  • Midbrain Dopamine Neurons Signal Preference for Advance Information about Upcoming Rewards
    - Neuron 63(1):119-126 (2009)
    The desire to know what the future holds is a powerful motivator in everyday life, but it is unknown how this desire is created by neurons in the brain. Here we show that when macaque monkeys are offered a water reward of variable magnitude, they seek advance information about its size. Furthermore, the same midbrain dopamine neurons that signal the expected amount of water also signal the expectation of information, in a manner that is correlated with the strength of the animal's preference. Our data show that single dopamine neurons process both primitive and cognitive rewards, and suggest that current theories of reward-seeking must be revised to include information-seeking.
  • Training Improves Multitasking Performance by Increasing the Speed of Information Processing in Human Prefrontal Cortex
    - Neuron 63(1):127-138 (2009)
    Our ability to multitask is severely limited: task performance deteriorates when we attempt to undertake two or more tasks simultaneously. Remarkably, extensive training can greatly reduce such multitasking costs. While it is not known how training alters the brain to solve the multitasking problem, it likely involves the prefrontal cortex given this brain region's purported role in limiting multitasking performance. Here, we show that the reduction of multitasking interference with training is not achieved by diverting the flow of information processing away from the prefrontal cortex or by segregating prefrontal cells into independent task-specific neuronal ensembles, but rather by increasing the speed of information processing in this brain region, thereby allowing multiple tasks to be processed in rapid succession. These results not only reveal how training leads to efficient multitasking, they also provide a mechanistic account of multitasking limitations, namely ! the poor speed of information processing in human prefrontal cortex.
  • Reading the Book of Memory: Sparse Sampling versus Dense Mapping of Connectomes
    - Neuron 63(1):139 (2009)

Monday, July 13, 2009

Hot off the presses! Jun 26 Mol Cell

The Jun 26 issue of the Mol Cell is now up on Pubget (About Mol Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

  • The Molecular Dating Game: An Antibody Heavy Chain Hangs Loose with a Chaperone while Waiting for Its Life Partner
    - Mol Cell 34(6):635-636 (2009)
    In a recent issue of Molecular Cell, Feige et al. (2009) utilize the murine immunoglobulin system to shed light on a long-standing puzzle: how do cells coordinate folding of different polypeptides that ultimately form a complex?
  • The Guardian Recruits Cops: The p53-p21 Axis Delegates Prosurvival Duties to the Keap1-Nrf2 Stress Pathway
    - Mol Cell 34(6):637-639 (2009)
    In this issue of Molecular Cell, Zhang and colleagues (Chen et al., 2009) report their identification of p21 as a positive regulator of Nrf2, which extends p53 prosurvival functions through recruitment of a master stress-response regulator.
  • A Histone Code for Regulating V(D)J Recombination
    - Mol Cell 34(6):639-640 (2009)
    In a recent issue of Molecular Cell, Shimazaki et al. (2009) show that an interaction between RAG2 and a methylated histone might play a critical regulatory role in V(D)J recombination by enhancing DNA binding and enzymatic activity of the V(D)J recombinase.
  • The Juxtamembrane Region of the EGF Receptor Functions as an Activation Domain
    - Mol Cell 34(6):641-651 (2009)
    In several growth factor receptors, the intracellular juxtamembrane (JM) region participates in autoinhibitory interactions that must be disrupted for tyrosine kinase activation. Using alanine scanning mutagenesis and crystallographic approaches, we define a domain within the JM region of the epidermal growth factor receptor (EGFR) that instead plays an activating—rather than autoinhibitory—role. Mutations in the C-terminal 19 residues of the EGFR JM region abolish EGFR activation. In a crystal structure of an asymmetric dimer of the tyrosine kinase domain, the JM region of an acceptor monomer makes extensive contacts with the C lobe of a donor monomer, thus stabilizing the dimer. We describe how an uncharacterized lung cancer mutation in this JM activation domain (V665M) constitutively activates EGFR by augmenting its capacity to act as an acceptor in the asymmetric dimer. This JM mutant promotes cellular transformation by EGFR in vitro and is tumorigenic in a xen! ograft assay.
  • KSR2 Is a Calcineurin Substrate that Promotes ERK Cascade Activation in Response to Calcium Signals
    - Mol Cell 34(6):652-662 (2009)
    Protein scaffolds have emerged as important regulators of MAPK cascades, facilitating kinase activation and providing crucial spatio/temporal control to their signaling outputs. Using a proteomics approach to compare the binding partners of the two mammalian KSR scaffolds, we find that both KSR1 and KSR2 interact with the kinase components of the ERK cascade and have a common function in promoting RTK-mediated ERK signaling. Strikingly, we find that the protein phosphatase calcineurin selectively interacts with KSR2 and that KSR2 uniquely contributes to Ca2+-mediated ERK signaling. Calcineurin dephosphorylates KSR2 on specific sites in response to Ca2+ signals, thus regulating KSR2 localization and activity. Moreover, we find that depletion of endogenous KSR2 impairs Ca2+-mediated ERK activation and ERK-dependent signaling responses in INS1 pancreatic β-cells and NG108 neuroblastoma cells. These findings identify KSR2 as a Ca2+-regulated ERK scaffold and reveal a new ! mechanism whereby Ca2+ impacts Ras to ERK pathway signaling.
  • Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response
    - Mol Cell 34(6):663-673 (2009)
    In response to oxidative stress, Nrf2 and p21Cip1/WAF1 are both upregulated to protect cells from oxidative damage. Nrf2 is constantly ubiquitinated by a Keap1 dimer that interacts with a weak-binding 29DLG motif and a strong-binding 79ETGE motif in Nrf2, resulting in degradation of Nrf2. Modification of the redox-sensitive cysteine residues on Keap1 disrupts the Keap1-29DLG binding, leading to diminished Nrf2 ubiquitination and activation of the antioxidant response. However, the underlying mechanism by which p21 protects cells from oxidative damage remains unclear. Here we present molecular and genetic evidence suggesting that the antioxidant function of p21 is mediated through activation of Nrf2 by stabilizing the Nrf2 protein. The 154KRR motif in p21 directly interacts with the 29DLG and 79ETGE motifs in Nrf2 and thus competes with Keap1 for Nrf2 binding, compromising ubiquitination of Nrf2. Furthermore, the physiological significance of our findings was demonstrat! ed in vivo using p21-deficient mice.
  • Allosteric Activation of E2-RING Finger-Mediated Ubiquitylation by a Structurally Defined Specific E2-Binding Region of gp78
    - Mol Cell 34(6):674-685 (2009)
    The activity of RING finger ubiquitin ligases (E3) is dependent on their ability to facilitate transfer of ubiquitin from ubiquitin-conjugating enzymes (E2) to substrates. The G2BR domain within the E3 gp78 binds selectively and with high affinity to the E2 Ube2g2. Through structural and functional analyses, we determine that this occurs on a region of Ube2g2 distinct from binding sites for ubiquitin-activating enzyme (E1) and RING fingers. Binding to the G2BR results in conformational changes in Ube2g2 that affect ubiquitin loading. The Ube2g2:G2BR interaction also causes an 50-fold increase in affinity between the E2 and RING finger. This results in markedly increased ubiquitylation by Ube2g2 and the gp78 RING finger. The significance of this G2BR effect is underscored by enhanced ubiquitylation observed when Ube2g2 is paired with other RING finger E3s. These findings uncover a mechanism whereby allosteric effects on an E2 enhance E2-RING finger interactions and, con! sequently, ubiquitylation.
  • Glutamine-Specific N-Terminal Amidase, a Component of the N-End Rule Pathway
    - Mol Cell 34(6):686-695 (2009)
    Deamidation of N-terminal Gln by NtQ-amidase, an N-terminal amidohydrolase, is a part of the N-end rule pathway of protein degradation. We detected the activity of NtQ-amidase, termed Ntaq1, in mouse tissues, purified Ntaq1 from bovine brains, identified its gene, and began analyzing this enzyme. Ntaq1 is highly conserved among animals, plants, and some fungi, but its sequence is dissimilar to sequences of other amidases. An earlier mutant in the Drosophila Cg8253 gene that we show here to encode NtQ-amidase has defective long-term memory. Other studies identified protein ligands of the uncharacterized human C8orf32 protein that we show here to be the Ntaq1 NtQ-amidase. Remarkably, "high-throughput" studies have recently solved the crystal structure of C8orf32 (Ntaq1). Our site-directed mutagenesis of Ntaq1 and its crystal structure indicate that the active site and catalytic mechanism of NtQ-amidase are similar to those of transglutaminases.
  • Cellular MicroRNA and P Bodies Modulate Host-HIV-1 Interactions
    - Mol Cell 34(6):696-709 (2009)
    MicroRNAs (miRNAs), 22 nt noncoding RNAs, assemble into RNA-induced silencing complexes (RISCs) and localize to cytoplasmic substructures called P bodies. Dictated by base-pair complementarity between miRNA and a target mRNA, miRNAs specifically repress posttranscriptional expression of several mRNAs. Here we report that HIV-1 mRNA interacts with RISC proteins and that disrupting P body structures enhances viral production and infectivity. In HIV-1-infected human T lymphocytes, we identified a highly abundant miRNA, miR-29a, which specifically targets the HIV-1 3′UTR region. Inhibiting miR-29a enhanced HIV-1 viral production and infectivity, whereas expressing a miR-29 mimic suppressed viral replication. We also found that specific miR-29a-HIV-1 mRNA interactions enhance viral mRNA association with RISC and P body proteins. Thus we provide an example of a single host miRNA regulating HIV-1 production and infectivity. These studies highlight the significance of miRNAs! and P bodies in modulating host cell interactions with HIV-1 and possibly other viruses.
  • Structural Basis of Transcription: Mismatch-Specific Fidelity Mechanisms and Paused RNA Polymerase II with Frayed RNA
    - Mol Cell 34(6):710-721 (2009)
    We show that RNA polymerase (Pol) II prevents erroneous transcription in vitro with different strategies that depend on the type of DNARNA base mismatch. Certain mismatches are efficiently formed but impair RNA extension. Other mismatches allow for RNA extension but are inefficiently formed and efficiently proofread by RNA cleavage. X-ray analysis reveals that a TU mismatch impairs RNA extension by forming a wobble base pair at the Pol II active center that dissociates the catalytic metal ion and misaligns the RNA 3′ end. The mismatch can also stabilize a paused state of Pol II with a frayed RNA 3′ nucleotide. The frayed nucleotide binds in the Pol II pore either parallel or perpendicular to the DNA-RNA hybrid axis (fraying sites I and II, respectively) and overlaps the nucleoside triphosphate (NTP) site, explaining how it halts transcription during proofreading, before backtracking and RNA cleavage.
  • Highly Transcribed RNA Polymerase II Genes Are Impediments to Replication Fork Progression in Saccharomyces cerevisiae
    - Mol Cell 34(6):722-734 (2009)
    Replication forks face multiple obstacles that slow their progression. By two-dimensional gel analysis, yeast forks pause at stable DNA protein complexes, and this pausing is greatly increased in the absence of the Rrm3 helicase. We used a genome-wide approach to identify 96 sites of very high DNA polymerase binding in wild-type cells. Most of these binding sites were not previously identified pause sites. Rather, the most highly represented genomic category among high DNA polymerase binding sites was the open reading frames (ORFs) of highly transcribed RNA polymerase II genes. Twice as many pause sites were identified in rrm3 compared with wild-type cells, as pausing in this strain occurred at both highly transcribed RNA polymerase II genes and the previously identified protein DNA complexes. ORFs of highly transcribed RNA polymerase II genes are a class of natural pause sites that are not exacerbated in rrm3 cells.
  • Crystal Structure of the Rad9-Rad1-Hus1 DNA Damage Checkpoint Complex—Implications for Clamp Loading and Regulation
    - Mol Cell 34(6):735-745 (2009)
    Rad9, Rad1, and Hus1 form a heterotrimeric complex (9-1-1) that is loaded onto DNA at sites of DNA damage. DNA-loaded 9-1-1 activates signaling through the Chk1 arm of the DNA damage checkpoint response via recruitment and stimulation of ATR. Additionally, 9-1-1 may play a direct role in facilitating DNA damage repair via interaction with a number of DNA repair enzymes. We have now determined the crystal structure of the human 9-1-1 complex, revealing a toroidal structure with a similar architecture to the homotrimeric PCNA DNA-binding clamp. The structure explains the formation of a unique heterotrimeric arrangement and reveals significant differences among the three subunits in the sites implicated in binding to the clamp loader and to ligand proteins. Biochemical analysis reveals a single repair enzyme-binding site on 9-1-1 that can be blocked competitively by the PCNA-binding cell-cycle regulator p21cip1/waf1.
  • Mechanical Constraints on Hin Subunit Rotation Imposed by the Fis/Enhancer System and DNA Supercoiling during Site-Specific Recombination
    - Mol Cell 34(6):746-759 (2009)
    Hin, a member of the serine family of site-specific recombinases, regulates gene expression by inverting a DNA segment. DNA inversion requires assembly of an invertasome complex in which a recombinational enhancer DNA segment bound by the Fis protein associates with the Hin synaptic complex at the base of a supercoiled DNA branch. Each of the four Hin subunits becomes covalently joined to the cleaved DNA ends, and DNA exchange occurs by translocation of a Hin subunit pair within the tetramer. We show here that, although the Hin tetramer forms a bidirectional molecular swivel, the Fis/enhancer system determines both the direction and number of subunit rotations. The chirality of supercoiling directs rotational direction, and the short DNA loop stabilized by Fis-Hin contacts limit rotational processivity, thereby ensuring that the DNA strands religate in the recombinant configuration. We identify multiple rotational conformers that are formed under different supercoiling! and solution conditions.
  • The Ordered Transcription of RNA Domains Is Not Essential for Ribosome Biogenesis in Escherichia coli
    - Mol Cell 34(6):760-766 (2009)
    Ribosome biogenesis is coupled to the transcription of ribosomal (r)RNAs, which enables an ordered and hierarchical assembly of the ribosome starting with the 5′-terminal domain. We constructed four circular permutants (CPs) of Escherichia coli rRNAs in which the original termini of 16S or 23S rRNAs were genetically connected, and new termini were created elsewhere within the same rRNAs (in helix 33 of 16S rRNA, or in helices 45, 63, and 78 of 23S rRNA). Unexpectedly, all CPs tested were able to rescue E. coli strain Δ7 prrn, which lacks all chromosomal rRNA operons. This result demonstrates that hierarchical assembly from the 5′-terminal domain of both 16S and 23S rRNAs is not essential for ribosomal formation in the cell. However, severe growth defects of all CPs were found in the absence of the DEAD box RNA helicase deaD, indicating that DeaD assists in the efficient assembly of each subunit in the cell.
  • Shifts in Replication Timing Actively Affect Histone Acetylation during Nucleosome Reassembly
    - Mol Cell 34(6):767-774 (2009)
    The entire genome is replicated in a programmed manner, with specific regions undergoing DNA synthesis at different times in S phase. Active genes generally replicate in early S phase, while repressed genes replicate late, and for some loci this process is developmentally regulated. Using a nuclear microinjection system, we demonstrate that DNA sequences originally packaged into nucleosomes containing deacetylated histones during late S become reassembled with acetylated histones after undergoing replication in early S. Conversely, a change from early to late replication timing is accompanied by repackaging into nucleosomes containing deacetylated histones. This is carried out by differential cell-cycle-controlled acetylation and deacetylation of histones H3 and H4. These studies provide strong evidence that switches in replication timing may play a role in the regulation of nucleosome structure during development.