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• Cell biology: The not-so-odd coupleActively dividing cells do so at a risk ? with each division, chromosome ends tend to shorten. Pairing proteins that promote cell division with a chromosome-end repair factor is a smart way to solve this problem.
• Cyclic AMP intoxication of macrophages by a Mycobacterium tuberculosis adenyl...
With 8.9 million new cases and 1.7 million deaths per year, tuberculosis is a leading global killer that has not been effectively controlled. The causative agent, Mycobacterium tuberculosis, proliferates within host macrophages where it modifies both its intracellular and local tissue environment, resulting in caseous granulomas with incomplete bacterial sterilization. Although infection by various mycobacterial species produces a cyclic AMP burst within macrophages that influences cell signalling, the underlying mechanism for the cAMP burst remains unclear. Here we show that among the 17 adenylate cyclase genes present in M. tuberculosis, at least one (Rv0386) is required for virulence. Furthermore, we demonstrate that the Rv0386 adenylate cyclase facilitates delivery of bacterial-derived cAMP into the macrophage cytoplasm. Loss of Rv0386 and the intramacrophage cAMP it delivers results in reductions in TNF-? production via the protein kinase A and cAMP response-element-binding protein pathway, decreased immunopathology in animal tissues, and diminished bacterial survival. Direct intoxication of host cells by bacterial-derived cAMP may enable M. tuberculosis to modify both its intracellular and tissue environments to facilitate its long-term survival.
Nature Journals
• Common polygenic variation contributes to risk of schizophrenia and bipolar d...Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%. We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
• Common variants conferring risk of schizophrenia
Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ?genomic disorders?, have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
• A conserved ubiquitination pathway determines longevity in response to diet r...
Dietary restriction extends longevity in diverse species, suggesting that there is a conserved mechanism for nutrient regulation and prosurvival responses. 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 pat...
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 sedative. This human birth defect is mimicked in developing chick limb buds exposed to X-irradiation. Both X-irradiation and thalidomide-induced phocomelia 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?. Indeed, 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 the predictions of the progress zone model.
• The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis
In fasted mammals, circulating pancreatic glucagon stimulates hepatic gluconeogenesis in part through the CREB regulated transcription coactivator 2 (CRTC2, also referred to as TORC2). Hepatic glucose production is increased in obesity, reflecting chronic increases in endoplasmic reticulum (ER) stress that promote insulin resistance. Whether ER stress also modulates the gluconeogenic program directly, however, is unclear. Here we show that CRTC2 functions as a dual sensor for ER stress and fasting signals. Acute increases in ER stress triggered the dephosphorylation and nuclear entry of CRTC2, which in turn promoted the expression of ER quality control genes through an association with activating transcription factor 6 alpha (ATF6?, also known as ATF6)?an integral branch of the unfolded protein response. In addition to mediating CRTC2 recruitment to ER stress inducible promoters, ATF6? also reduced hepatic glucose output by disrupting the CREB?CRTC2 interaction and thereby inhibiting CRTC2 occupancy over gluconeogenic genes. Conversely, hepatic glucose output was upregulated when hepatic ATF6? protein amounts were reduced, either by RNA interference (RNAi)-mediated knockdown or as a result of persistent stress in obesity. Because ATF6? overexpression in the livers of obese mice reversed CRTC2 effects on the gluconeogenic program and lowered hepatic glucose output, our results demonstrate how cross-talk between ER stress and fasting pathways at the level of a transcriptional coactivator contributes to glucose homeostasis.
• Macrophage elastase kills bacteria within murine macrophages
Macrophages are aptly positioned to function as the primary line of defence against invading pathogens in many organs, including the lung and peritoneum. Their ability to phagocytose and clear microorganisms has been well documented. Macrophages possess several substances with which they can kill bacteria, including reactive oxygen species, nitric oxide, and antimicrobial proteins. We proposed that macrophage-derived proteinases may contribute to the antimicrobial properties of macrophages. Macrophage elastase (also known as matrix metalloproteinase?12 or MMP12) is an enzyme predominantly expressed in mature tissue macrophages and is implicated in several disease processes, including emphysema. Physiological functions for MMP12 have not been described. Here we show that Mmp12-/- mice exhibit impaired bacterial clearance and increased mortality when challenged with both Gram-negative and Gram-positive bacteria at macrophage-rich portals of entry, such as the peritoneum and lung. Intracellular stores of MMP12 are mobilized to macrophage phagolysosomes after the ingestion of bacterial pathogens. Once inside phagolysosomes, MMP12 adheres to bacterial cell walls where it disrupts cellular membranes resulting in bacterial death. The antimicrobial properties of MMP12 do not reside within its catalytic domain, but rather within the carboxy-terminal domain. This domain contains a unique four amino acid sequence on an exposed ? loop of the protein that is required for the observed antimicrobial activity. The present study represents, to our knowledge, the first report of direct antimicrobial activity by a matrix metallopeptidase, and describes a new antimicrobial peptide that is sequentially and structurally unique in nature.
• CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT ...
Toll-like receptors (TLRs) are the best characterized pattern recognition receptors. Individual TLRs recruit diverse combinations of adaptor proteins, triggering signal transduction pathways and leading to the activation of various transcription factors, including nuclear factor ?B, activation protein 1 and interferon regulatory factors. Interleukin-2 is one of the molecules produced by mouse dendritic cells after stimulation by different pattern recognition receptor agonists. By analogy with the events after T-cell receptor engagement leading to interleukin-2 production, it is therefore plausible that the stimulation of TLRs on dendritic cells may lead to activation of the Ca2+/calcineurin and NFAT (nuclear factor of activated T cells) pathway. Here we show that mouse dendritic cell stimulation with lipopolysaccharide (LPS) induces Src-family kinase and phospholipase C?2 activation, influx of extracellular Ca2+ and calcineurin-dependent nuclear NFAT translocation. The initiation of this pathway is independent of TLR4 engagement, and dependent exclusively on CD14. We also show that LPS-induced NFAT activation via CD14 is necessary to cause the apoptotic death of terminally differentiated dendritic cells, an event that is essential for maintaining self-tolerance and preventing autoimmunity. Consequently, blocking this pathway in vivo causes prolonged dendritic cell survival and an increase in T-cell priming capability. Our findings reveal novel aspects of molecular signalling triggered by LPS in dendritic cells, and identify a new role for CD14: the regulation of the dendritic cell life cycle through NFAT activation. Given the involvement of CD14 in disease, including sepsis and chronic heart failure, the discovery of signal transduction pathways activated exclusively via CD14 is an important step towards the development of potential treatments involving interference with CD14 functions.
• T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 ...
Inflammation is a protective attempt by the host to remove injurious stimuli and initiate the tissue healing process. The inflammatory response must be actively terminated, however, because failure to do so can result in ?bystander? damage to tissues and diseases such as arthritis or type-2 diabetes. Yet the mechanisms controlling excessive inflammatory responses are still poorly understood. Here we show that mouse effector and memory CD4+ T cells abolish macrophage inflammasome-mediated caspase-1 activation and subsequent interleukin 1? release in a cognate manner. Inflammasome inhibition is observed for all tested NLRP1 (commonly called NALP1) and NLRP3 (NALP3 or cryopyrin) activators, whereas NLRC4 (IPAF) inflammasome function and release of other inflammatory mediators such as CXCL2, interleukin 6 and tumour necrosis factor are not affected. Suppression of the NLRP3 inflammasome requires cell-to-cell contact and can be mimicked by macrophage stimulation with selected ligands of the tumour necrosis factor family, such as CD40L (also known as CD40LG). In a NLRP3-dependent peritonitis model, effector CD4+ T cells are responsible for decreasing neutrophil recruitment in an antigen-dependent manner. Our findings reveal an unexpected mechanism of inflammasome inhibition, whereby effector and memory T cells suppress potentially damaging inflammation, yet leave the primary inflammatory response, crucial for the onset of immunity, intact.
• Uniparental expression of PolIV-dependent siRNAs in developing endosperm of A...
Most eukaryotes produce small RNA (sRNA) mediators of gene silencing that bind to Argonaute proteins and guide them, by base pairing, to an RNA target. MicroRNAs (miRNAs) that normally target messenger RNAs for degradation or translational arrest are the best-understood class of sRNAs. However, in Arabidopsis thaliana flowers, miRNAs account for only 5% of the sRNA mass and less than 0.1% of the sequence complexity. The remaining sRNAs form a complex population of more than 100,000 different small interfering RNAs (siRNAs) transcribed from thousands of loci. The biogenesis of most of the siRNAs in Arabidopsis are dependent on RNA polymerase IV (PolIV), a homologue of DNA-dependent RNA polymerase II. A subset of these PolIV-dependent (p4)-siRNAs are involved in stress responses, and others are associated with epigenetic modifications to DNA or chromatin; however, the biological role is not known for most of them. Here we show that the predominant phase of p4-siRNA accumulation is initiated in the maternal gametophyte and continues during seed development. Expression of p4-siRNAs in developing endosperm is specifically from maternal chromosomes. Our results provide the first evidence for a link between genomic imprinting and RNA silencing in plants.
• Increasing organismal healthspan by enhancing mitochondrial protein quality c...
Overexpression of the mitochondrial matrix-localized protease PaLON in Podospora anserina reduces levels of carbonylated and carboxymethylated proteins, resulting in a higher resistance to oxidative stress and an extended life span.
• BRIT1/MCPH1 links chromatin remodelling to DNA damage response
Chromatin decondensation is required for repair factors to access damaged DNA. BRIT1/MCPH1, a damage response protein mutated in microcephaly, recruits the chromatin remodelling complex SWI/SNF to sites of DNA damage after phosphorylation by ATM/ATR. This mechanism is critical for efficient DNA repair and survival.
• HLA-B*5701 genotype is a major determinant of drug-induced liver injury due t...
Ann Daly and colleagues report results of a genome-wide association study to identify common variants associated with drug-induced liver injury due to flucloxacillin. They show that carriers of the HLA-B*5701 allele in the MHC region are at 80-fold increased risk of developing this severe adverse drug reaction.
• REL, encoding a member of the NF-?B family of transcription factors, is a new...
Peter Gregersen and colleagues report that common variants at the REL locus are associated with risk of rheumatoid arthritis. REL encodes a member of the NF-?B family of transcription factors, which play key roles in coordinating immune and inflammatory responses.
• Genome-wide association study identifies new multiple sclerosis susceptibilit...
Justin Rubio and colleagues report results of a genome-wide association study of multiple sclerosis using cases from Australia and New Zealand. Their findings confirm several published risk loci for MS and identify two new risk loci on chromosomes 12 and 20.
• ASMase: the tailor of cytotoxic T cell granule exocytosis
Deficiency in acid sphingomyelinase causes lysosomal storage of sphingomyelin, mediates resistance to stress-induced apoptosis and alters susceptibility to certain infections. New work links acid sphingomyelinase to the granule exocytosis of cytotoxic T cells.
• Macrophage colony-stimulating factor induces the proliferation and survival o...
Macrophage colony-stimulating factor (M-CSF) induces the proliferation of mononuclear phagocytes, and DAP12 is needed for their function. Colonna and colleagues show that DAP12 is also needed for M-CSF-induced stabilization of ?-catenin.
• Immunological synapse formation inhibits, via NF-?B and FOXO1, the apoptosis ...
Immunological synapses (IS) involving surface receptors form between dendritic cells (DC) and T cells. Rodriguez-Fernandez and colleagues show that IS-induced signals activate Akt and NF-?B and suppress Foxo1 to promote DC survival.
• Interleukin 17 acts in synergy with B cell?activating factor to influence B c...
How interleukin 17 influences B cell biology is unclear. Bonnefoy-Bérard and colleagues find that interleukin 17 alone or in combination with B cell?activating factor controls the survival, proliferation of human B cells and their differentiation into immunoglobulin-secreting cells.
• Stomaching calcium for bone health
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)?
• Cyclophilin A enhances vascular oxidative stress and the development of angio...
The pathogenesis of aortic aneurysms involves inflammatory cell recruitment and increased levels of reactive oxygen species and matrix metalloproteases. Kimio Satoh et al. now mechanistically link the protein cyclophilin A?expressed in vascular smooth muscle cells?to these known mediators of aortic aneurysm formation and provide evidence in both mice and humans for the importance of cyclophilin A in aortic aneurysm formation.
Nature Reviews
• Genetic prognostic and predictive markers in colorectal cancerDespite many studies of the likely survival outcome of individual patients with colorectal cancer, our knowledge of this subject remains poor. Until recently, we had virtually no understanding of individual responses to therapy, but the discovery of the KRAS mutation as a marker of probable
• Senescence: Playing games with epigenetics
The CDKN2A locus encodes the tumour suppressors INK4A and ARF, which induce senescence through independent pathways. CDKN2A expression is repressed by histone H3 lysine 27 trimethylation (H3K27me3), which is mediated by polycomb group proteins. This repression is reversed in response to cellular stress,
• Angiogenesis: How Down's syndrome protects
Sandra Ryeom, George Daley and colleagues have identified a genetic explanation for the reduced risk of developing solid tumours that is evident in individuals with Down's syndrome. Having an extra copy of Down's syndrome candidate region 1 (DSCR1), a gene on chromosome 21
• Towards the identification of biomarkers of transplantation tolerance
Although transplantation has been a standard medical practice for decades, the marked morbidity from the use of immunosuppressive drugs and poor long-term graft survival remain important limitations in the field. Achieving tolerance to transplanted organs should solve both problems, but has been an elusive goal.
• Cracking the BAFF code
The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have
• New insights into the regulation of T cells by ?c family cytokines
Common cytokine receptor ?-chain (?c) family cytokines have crucial roles in the development, proliferation, survival and differentiation of multiple cell lineages of both the innate and adaptive immune systems. In this Review, we focus on our current understanding of the distinct and overlapping
• From the editors
Cytokines are the hormones of the immune system, necessary for the growth, survival and development of distinct cell subsets. Cells compete for these survival factors, and those that lose out risk death by apoptosis.The prototypical growth factor for T cells is interleukin-2 (IL-2), which