Hot off the presses! Jun 01 Nat Med

The Jun 01 issue of the Nat Med is now up on Pubget (About Nat Med): 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:

• Be prepared
  - Nat Med 15(6):585 (2009)
  Pushing 'shovel-ready' technologies through the pipeline has the potential to substantially bolster defenses against the emerging flu strain and future pandemics.
• Computational tools evolve to reveal patterns in flu data
  - Nat Med 15(6):587 (2009)
  When a new and suspicious strain of influenza emerges, authorities meticulously plan their public health response on the basis of how dangerous scientists think the strain is or could become. With the emergence of swine flu, or 'H1N1 influenza', this spring, scientists turned to a diverse range of computer-based tools to help predict the virus's virulence.
• Bone seems susceptible to range of drugs
  - Nat Med 15(6):588 (2009)
  Although it is often portrayed as inert and stonelike, bone is continuously reinventing itself. In fact, bone goes through cycles of construction and destruction, often in tandem and in sync with the rhythms of our lives.
• UK budget puts faith in biomedical sector
  - Nat Med 15(6):589 (2009)
  The UK budget for 2009, made public in April, revealed the full extent of the nation's worsening finances. But, amongst all the doom and gloom surrounding its release, there were a few bright spots for the life science sector.
• NIH draft seen as 'working compromise'
  - Nat Med 15(6):589 (2009)
  Draft guidelines on stem cell funding issued by the US National Institutes of Health (NIH) in mid-April might block federal funding for experiments that rely on certain commonly used stem cell lines."I think our main concern is that some perfectly valid lines don't get ruled out on a technicality," says Geoff Lomax, a lead member of the Interstate Alliance on Stem Cell Research (IASCR), an organization established in 2007 to promote stem cell research collaboration.
• Mind the skills gap
  - Nat Med 15(6):589 (2009)
  The Biotechnology and Biological Sciences Research Council (BBSRC), the UK funding agency for life science research, has launched a consultation to identify skills and expertise that are in danger of being lost from the nation's bioscience research community.The consultation will involve the UK's bioscience societies and industrial associations, who will be asked to highlight vulnerable areas of expertise.
• News in brief
  - Nat Med 15(6):590-591 (2009)
  Apr 16Pharmaceutical companies GlaxoSmithKline and Pfizer announced they would work together to develop and market HIV treatments by creating a new specialist company. This new company will market 11 HIV drugs that together make up 19% of the HIV drug market and will have six other medicines in development.
• Straight talk with ... Otto Yang and Patrick Miller
  - Nat Med 15(6):592-593 (2009)
  Even with a recent influx of research money into biomedical research, competition for grants is unlikely to ease off any time soon. For example, researchers submitted about 20,000 applications for the $1 million 'challenge grants' offered by the US National Institutes of Health (NIH). The agency originally announced it would fund just 200 of these grants, meaning only a tiny fraction applicants will succeed in obtaining them. Otto Yang and Patrick Miller have experienced firsthand the challenges of writing and reviewing research grants. Yang, an immunologist at the University of California–Los Angeles School of Medicine, has served on multiple NIH grant review panels. In 2005, he authored the Guide to Effective Grant Writing: How to Write an Effective NIH Grant Application. Miller, who currently runs a Chicago-area company that provides grant writing workshops and resources, published the book Grant Writing: Strategies for Developing Winning Government Proposals. Yang and Miller (pictured above left to right) shared some of their grant writing tips with Kirsten Dorans.
• A cultured response to HIV
  - Nat Med 15(6):594-597 (2009)
  In recent years, research has continued to demonstrate that HIV wreaks terrible havoc in the gut. A few scientists believe that probiotic yogurt might help to counter some of the virus's devastating effects on the intestine. Melinda Wenner reports on a pilot project that is helping a Tanzanian community make its own probiotic yogurt for HIV-infected locals and empowering women in the process.
• Publication of fake journals raises ethical questions
  - Nat Med 15(6):598 (2009)
  One of the world's largest publishers of medical literature, Elsevier, has come under fire for having distributed marketing periodicals that many people say deceptively resembled peer-reviewed journals.Since the 1980s, doctors have commonly received publications designed to promote pharmaceutical products through a mix of studies, opinion pieces and simple advertisements.
• Malaria drug delivery program launches amid skepticism
  - Nat Med 15(6):598 (2009)
  An innovative financial scheme launched in April aims to reduce the cost people in poor countries pay for effective malaria treatment. The program's key feature, heavily subsidizing the private market, is the brainchild of a Nobel laureate in economics.
• Worried about your memory?
  - Nat Med 15(6):599 (2009)
  
• Mesenchymal stem cells: another anti-inflammatory treatment for sepsis?
  - Nat Med 15(6):601-602 (2009)
  I read with great interest the paper by Nemeth et al.1 and the related News and Views article by Tyndall and Pistoia2 in the January issue. In this elegant study, the authors showed that injection of bone marrow stromal cells (BMSCs) could rescue mice from death after cecal ligation and puncture (CLP) as a result of the potent immunomodulatory and anti-inflammatory properties of these cells.
• Reply to 'Mesenchymal stem cells: another anti-inflammatory treatment for sepsis?'
  - Nat Med 15(6):602 (2009)
  A typical bench-to-bedside path in medicine is to first discover specific targets using basic science and then develop therapeutic agents that are tested clinically. In the field of bone marrow stromal cells (BMSCs; also referred to as mesenchymal stem cells or MSCs), this course was reversed—running from bedside to bench.
• Reassessing the human mammary stem cell concept by modeling limiting dilution transplantation assays
  - Nat Med 15(6):602-604 (2009)
  In a recent study in Nature Medicine, Eirew et al.1 described a new protocol that can be used to accurately determine the frequency of human mammary stem cells (termed mammary repopulating units, MRUs) by limiting dilution transplantation assays (LDTAs). The authors presented five LDTAs showing the regeneration of colony-forming cells (CFCs) in xenografted gels seeded with varying numbers of input mammary cells.
• Reply to 'Reassessing the human mammary stem cell concept by modeling limiting dilution transplantation assays'
  - Nat Med 15(6):604-605 (2009)
  In their letter to the Editor1, Bonnefoix and Callanan draw attention to the statistical analysis that accompanies a series of five limiting dilution experiments presented in our recent paper2. They argue that the size of the data set for each individual experiment in our study is too small to allow reliable use of the chi-squared test for the validity of a single-hit Poisson model (SHPM)1.
• In the shadow of the thrombus
  - Nat Med 15(6):607-608 (2009)
  Platelets accumulate on the downstream face of a developing blood clot after local changes in blood flow. These findings offer new insights into how platelets pile up at sites of vascular injury (pages 665–673).
• Tension in the vasculature
  - Nat Med 15(6):608-610 (2009)
  Blood vessels arise from progenitor cells, grow and branch by sprouting from preexisting vessels and remodel by splitting longitudinally. A new study proposes an additional mechanism. It seems that vascularization can proceed through the mechanical translocation and expansion of existing vessels, which loop into vascularising tissue (pages 657–664).
• Stomaching calcium for bone health
  - Nat Med 15(6):610-612 (2009)
  Calcium deficiency in the elderly is associated with low gastric acid secretion and bone loss. A new study linking defects in gastric acid secretion with bone destruction and impaired mineralization bolsters the view that calcium supplements can prevent these bone defects—but do they all work (pages 674–681)?
• IFN-alpha wakes up sleeping hematopoietic stem cells
  - Nat Med 15(6):612-613 (2009)
  The cytokine interferon-alpha stimulates the turnover and proliferation of hematopoietic cells in vivo (pages 696–700). The findings hint at a new strategy to treat hematopoietic cancers.
• Compound clamps down on prostate cancer
  - Nat Med 15(6):615 (2009)
  Most individuals with metastatic prostate cancer develop resistance to standard treatments, which antagonize the action of growth-promoting androgens. The origins of such 'castration-resistant' tumors have been traced in part to increases in expression of the androgen receptor and to shortcomings in receptor-blocking drugs, which can even act as agonists.
• Expansion and contraction: treating diabetes with bariatric surgery
  - Nat Med 15(6):616-617 (2009)
  Bariatric surgery is not only one of the most immediate and effective ways to slim down: recent clinical data show that certain procedures are also particularly good at quelling type 2 diabetes. In "Bedside to Bench," Allison Goldfine, Steven Shoelson and Vincent Aguirre outline how researchers can better understand these new clinical findings at the mechanistic level. In the accompanying "Bench to Bedside," Jorge Plutzky takes a look how proper regulation of the storage of fatty acids helps maintain their effectiveness as signaling molecules and reins in their potential pathological effects. Such research is leading to new ways of thinking about how to combat type 2 diabetes.
• Expansion and contraction: the mighty, mighty fatty acid
  - Nat Med 15(6):618-619 (2009)
  Long before recorded history, fatty acids must have been hard for any organism bent on survival to ignore. Fatty acid combustion yields more energy than almost any other resource—9 kcal per g, more than double the yield from glucose.
• Research Highlights
  - Nat Med 15(6):620-621 (2009)
  
• Netting neutrophils in autoimmune small-vessel vasculitis
  - Nat Med 15(6):623-625 (2009)
  Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.
• Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis
  - Nat Med 15(6):626-632 (2009)
  We describe here the paradoxical development of spontaneous experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a myelin oligodendrocyte glycoprotein (MOG)-specific T cell antigen receptor (TCR) in the absence of MOG. We report that in Mog-deficient mice (Mog-/-), the autoimmune response by transgenic T cells is redirected to a neuronal cytoskeletal self antigen, neurofilament-M (NF-M). Although components of radically different protein classes, the cross-reacting major histocompatibility complex I-Ab–restricted epitope sequences of MOG35–55 and NF-M18–30 share essential TCR contact positions. This pattern of cross-reaction is not specific to the transgenic TCR but is also commonly seen in MOG35–55–I-Ab–reactive T cells. We propose that in the C57BL/6 mouse, MOG and NF-M response components add up to overcome the general resistance of this strain to experimental induction of autoimmunity. Similar cumulative responses against more t! han one autoantigen may have a role in spontaneously developing human autoimmune diseases.
• Prostaglandin E2–EP4 signaling promotes immune inflammation through TH1 cell differentiation and TH17 cell expansion
  Yao C Sakata D Esaki Y Li Y Matsuoka T Kuroiwa K Sugimoto Y Narumiya S - Nat Med 15(6):633-640 (2009)
  Two distinct helper T (TH) subsets, TH1 and TH17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these TH subsets in human diseases, suggest the need for pharmacological measures to manipulate these TH subsets. Here we show that prostaglandin E2 (PGE2) acting on its receptor EP4 on T cells and dendritic cells not only facilitates TH1 cell differentiation but also amplifies interleukin-23–mediated TH17 cell expansion in vitro. Administration of an EP4-selective antagonist in vivo decreases accumulation of both TH1 and TH17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, PGE2-EP4 signaling promotes immune inflammation through TH1 differentiation and TH17 expans! ion, and EP4 antagonism may be therapeutically useful for various immune diseases.
• Toll-like receptor 2 ligands on the staphylococcal cell wall downregulate superantigen-induced T cell activation and prevent toxic shock syndrome
  - Nat Med 15(6):641-648 (2009)
  Staphylococcal superantigens are pyrogenic exotoxins that cause massive T cell activation leading to toxic shock syndrome and death. Despite the strong adaptive immune response induced by these toxins, infections by superantigen-producing staphylococci are very common clinical events. We hypothesized that this may be partly a result of staphylococcal strains having developed strategies that downregulate the T cell response to these toxins. Here we show that the human interleukin-2 response to staphylococcal superantigens is inhibited by the simultaneous presence of bacteria. Such a downregulatory effect is the result of peptidoglycan-embedded molecules binding to Toll-like receptor 2 and inducing interleukin-10 production and apoptosis of antigen-presenting cells. We corroborated these findings in vivo by showing substantial prevention of mortality after simultaneous administration of staphylococcal enterotoxin B with either heat-killed staphylococci or Staphylococcus ! aureus peptidoglycan in mouse models of superantigen-induced toxic shock syndrome.
• Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II–induced aortic aneurysms
  - Nat Med 15(6):649-656 (2009)
  Inflammation and oxidative stress are pathogenic mediators of many diseases, but molecules that could be therapeutic targets remain elusive. Inflammation and matrix degradation in the vasculature are crucial for abdominal aortic aneurysm (AAA) formation. Cyclophilin A (CypA, encoded by Ppia) is highly expressed in vascular smooth muscle cells (VSMCs), is secreted in response to reactive oxygen species (ROS) and promotes inflammation. Using the angiotensin II (AngII)-induced AAA model in Apoe-/- mice, we show that Apoe-/-Ppia-/- mice are completely protected from AngII–induced AAA formation, in contrast to Apoe-/-Ppia+/+ mice. Apoe-/-Ppia-/- mice show decreased inflammatory cytokine expression, elastic lamina degradation and aortic expansion. These features were not altered by reconstitution of bone marrow cells from Ppia+/+ mice. Mechanistic studies showed that VSMC-derived intracellular and extracellular CypA are required for ROS generation and matrix metalloprotein! ase-2 activation. These data define a previously undescribed role for CypA in AAA formation and suggest CypA as a new target for treating cardiovascular disease.
• Biomechanical regulation of blood vessel growth during tissue vascularization
  - Nat Med 15(6):657-664 (2009)
  Formation of new vessels in granulation tissue during wound healing has been assumed to occur solely through sprouting angiogenesis. In contrast, we show here that neovascularization can be accomplished by nonangiogenic expansion of preexisting vessels. Using neovascularization models based on the chick chorioallantoic membrane and the healing mouse cornea, we found that tissue tension generated by activated fibroblasts or myofibroblasts during wound contraction mediated and directed translocation of the vasculature. These mechanical forces pulled vessels from the preexisting vascular bed as vascular loops with functional circulation that expanded as an integral part of the growing granulation tissue through vessel enlargement and elongation. Blockade of vascular endothelial growth factor receptor-2 confirmed that biomechanical forces were sufficient to mediate the initial vascular growth independently of endothelial sprouting or proliferation. The neovascular network ! was further remodeled by splitting, sprouting and regression of individual vessels. This model explains the rapid appearance of large functional vessels in granulation tissue during wound healing.
• A shear gradient–dependent platelet aggregation mechanism drives thrombus formation
  - Nat Med 15(6):665-673 (2009)
  Platelet aggregation at sites of vascular injury is essential for hemostasis and arterial thrombosis. It has long been assumed that platelet aggregation and thrombus growth are initiated by soluble agonists generated at sites of vascular injury. By using high-resolution intravital imaging techniques and hydrodynamic analyses, we show that platelet aggregation is primarily driven by changes in blood flow parameters (rheology), with soluble agonists having a secondary role, stabilizing formed aggregates. We find that in response to vascular injury, thrombi initially develop through the progressive stabilization of discoid platelet aggregates. Analysis of blood flow dynamics revealed that discoid platelets preferentially adhere in low-shear zones at the downstream face of forming thrombi, with stabilization of aggregates dependent on the dynamic restructuring of membrane tethers. These findings provide insight into the prothrombotic effects of disturbed blood flow paramet! ers and suggest a fundamental reinterpretation of the mechanisms driving platelet aggregation and thrombus growth.
• Impaired gastric acidification negatively affects calcium homeostasis and bone mass
  - Nat Med 15(6):674-681 (2009)
  Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. Here we show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells, have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia. These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice. Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclas! ts and parietal cells, show hypocalcemia and osteopetrorickets. Although neither Src- nor Cckbr-deficient mice have this latter phenotype, the combined deficiency of both genes results in osteopetrorickets. Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification (pages 610–612).
• Inhibition of osteoblastic bone formation by nuclear factor-kappaB
  - Nat Med 15(6):682-689 (2009)
  An imbalance in bone formation relative to bone resorption results in the net bone loss that occurs in osteoporosis and inflammatory bone diseases. Although it is well known how bone resorption is stimulated, the molecular mechanisms that mediate impaired bone formation are poorly understood. Here we show that the time- and stage-specific inhibition of endogenous inhibitor of kappaB kinase (IKK)–nuclear factor-kappaB (NF-kappaB) in differentiated osteoblasts substantially increases trabecular bone mass and bone mineral density without affecting osteoclast activities in young mice. Moreover, inhibition of IKK–NF-kappaB in differentiated osteoblasts maintains bone formation, thereby preventing osteoporotic bone loss induced by ovariectomy in adult mice. Inhibition of IKK–NF-kappaB enhances the expression of Fos-related antigen-1 (Fra-1), an essential transcription factor involved in bone matrix formation in vitro and in vivo. Taken together, our results suggest tha! t targeting IKK–NF-kappaB may help to promote bone formation in the treatment of osteoporosis and other bone diseases.
• Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model
  - Nat Med 15(6):690-695 (2009)
  Distal myopathy with rimmed vacuoles (DMRV)–hereditary inclusion body myopathy (hIBM) is an adult-onset, moderately progressive autosomal recessive myopathy; eventually, affected individuals become wheelchair bound1. It is characterized clinically by skeletal muscle atrophy and weakness, and pathologically by rimmed vacuoles, which are actually accumulations of autophagic vacuoles2, 3, 4, scattered angular fibers and intracellular accumulation of amyloid and other proteins5. To date, no therapy is available for this debilitating myopathy, primarily because the disease pathomechanism has been enigmatic. It is known that the disease gene underlying DMRV-hIBM is GNE, encoding glucosamine (UDP-N-acetyl)-2-epimerase and N-acetylmannosamine kinase6, 7, 8—two essential enzymes in sialic acid biosynthesis9. It is still unclear, however, whether decreased sialic acid production causes muscle degeneration, as GNE has been proposed to have roles other than for sialic acid bio! synthesis10, 11, 12. By showing that muscle atrophy and weakness are completely prevented in a mouse model of DMRV-hIBM after treatment with sialic acid metabolites orally, we provide evidence that hyposialylation is indeed one of the key factors in the pathomechanism of DMRV-hIBM. These results support the notion that DMRV-hIBM can potentially be treated simply by giving sialic acids, a strategy that could be applied in clinical trials in the near future.
• Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon–dependent exhaustion
  - Nat Med 15(6):696-700 (2009)
  Type I interferons (IFNs), a family of cytokines, orchestrate numerous biological and cellular processes1, 2, 3. Although it is well known that type I IFNs are essential for establishing the host antiviral state4, their role in hematopoietic homeostasis has not been studied. Here we show that type I IFNs induce proliferation and exhaustion in hematopoietic stem cells (HSCs) and that interferon regulatory factor-2 (IRF2), a transcriptional suppressor of type I IFN signaling5, 6, preserves the self-renewal and multilineage differentiation capacity of HSCs. HSCs were substantially less abundant in the bone marrow of Irf2-/- as compared to Irf2+/- mice. Irf2-/- HSCs showed enhanced cell cycling status and failed to produce hematopoietic cells in competitive repopulation assays, and the reconstituting capacity of Irf2-/- HSCs was restored by disabling type I IFN signaling in these cells. In wild-type mice, injection of poly(I:C), an inducer of type I IFN signaling, or IFN-a! lpha induced HSC proliferation, and chronic type I IFN signaling further reduced the number of quiescent HSCs. Notably, combined poly(I:C) and 5-fluorouracil (5-FU) treatment allowed exogenous HSC engraftment and hematopoietic reconstitution in WT mice. Our findings provide insight into the molecular basis for the maintenance of HSC quiescence and may lead to improvements in bone marrow transplantation and type I IFN–based therapies for viral infection and cancer.
• Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche
  - Nat Med 15(6):701-706 (2009)
  The in vitro analysis of intestinal epithelium has been hampered by a lack of suitable culture systems. Here we describe robust long-term methodology for small and large intestinal culture, incorporating an air-liquid interface and underlying stromal elements. These cultures showed prolonged intestinal epithelial expansion as sphere-like organoids with proliferation and multilineage differentiation. The Wnt growth factor family positively regulates proliferation of the intestinal epithelium in vivo. Accordingly, culture growth was inhibited by the Wnt antagonist Dickkopf-1 (Dkk1) and markedly stimulated by a fusion protein between the Wnt agonist R-spondin-1 and immunoglobulin Fc (RSpo1-Fc). Furthermore, treatment with the gamma-secretase inhibitor dibenzazepine and neurogenin-3 overexpression induced goblet cell and enteroendocrine cell differentiation, respectively, consistent with endogenous Notch signaling and lineage plasticity. Epithelial cells derived from both ! leucine-rich repeat-containing G protein–coupled receptor-5–positive (Lgr5+) and B lymphoma moloney murine leukemia virus insertion region homolog-1–positive (Bmi1+) lineages, representing putative intestinal stem cell (ISC) populations, were present in vitro and were expanded by treatment with RSpo1-Fc; this increased number of Lgr5+ cells upon RSpo1-Fc treatment was subsequently confirmed in vivo. Our results indicate successful long-term intestinal culture within a microenvironment accurately recapitulating the Wnt- and Notch-dependent ISC niche.