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• Materials science: Shape shifts heat toleranceJ. Am. Chem. Soc. doi:10.1021/ja104691j (2010)Poorly soluble drugs and other chemicals can be dissolved in liquid by packaging them inside micelles ? soluble molecular assemblies that often assume hollow spherical or floral shapes. Heat can rattle these structures apart,
• Triggering of New Madrid seismicity by late-Pleistocene erosion
These authors argue that the concentration of magnitude-7 or larger earthquakes in the New Madrid seismic zone since the end of the last ice age results from the recent, climate-controlled, erosional history of the northern Mississippi embayment. They show that the upward flexure of the lithosphere caused a reduction of normal stresses in the upper crust sufficient to unclamp pre-existing faults close to failure equilibrium.
Nature Journals
• A novel pathway regulates memory and plasticity via SIRT1 and miR-134The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies. Its mammalian homologue, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 has a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor (BDNF), thereby impairing synaptic plasticity. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signalling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of central nervous system disorders.
• Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacia...
X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability. Causal mutations have been found in approximately 90 X-linked genes; however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD (plant homeo domain) finger protein 8) is a JmjC domain-containing protein and its mutations have been found in patients with XLMR and craniofacial deformities. Here we provide multiple lines of evidence establishing PHF8 as the first mono-methyl histone H4 lysine 20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcription start sites (TSS) of ?7,000 RefSeq genes and in gene bodies and intergenic regions (non-TSS). PHF8 depletion resulted in upregulation of H4K20me1 and H3K9me1 at the TSS and H3K9me2 in the non-TSS sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish brain and jaw development, thus providing a potentially relevant biological context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signalling and developmental pathways. Our findings indicate that an imbalance of histone methylation dynamics has a critical role in XLMR.
• A new DAF-16 isoform regulates longevity
The insulin/IGF-1 signalling (IIS) pathway has diverse roles from metabolism to longevity. In Caenorhabditis elegans, the single forkhead box O (FOXO) homologue, DAF-16, functions as the major target of the IIS pathway. One of two isoforms, DAF-16a, is known to regulate longevity, stress response and dauer diapause. However, it remains unclear how DAF-16 achieves its specificity in regulating these various biological processes. Here we identify a new isoform, DAF-16d/f, as an important isoform regulating longevity. We show that DAF-16 isoforms functionally cooperate to modulate IIS-mediated processes through differential tissue enrichment, preferential modulation by upstream kinases, and regulating distinct and overlapping target genes. Promoter-swapping experiments show both the promoter and the coding region of DAF-16 are important for its function. Importantly, in mammals, four FOXO genes have overlapping and different functions, and in C. elegans, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism.
• Live attenuated influenza virus vaccines by computer-aided rational design
Live attenuated viruses make more effective vaccines than newer protein subunit or recombinant DNA vaccines, but the traditional passaging methods used to generate them often fail to produce a suitable mutant. Mueller et al. improve the production of live attenuated influenza virus by extensive manipulation of codon-pair bias across the genome, which minimizes the risk of reversion to a virulent form.
• Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppre...
Autophagy is involved in tumour suppression. Cytoplasmic FoxO1 is acetylated in response to stress and binds the autophagy regulator Atg7 to promote autophagy, cell death and tumour suppression, independently of its transcriptional activity.
• Interplay between Cdh1 and JNK activity during the cell cycle
The stress-activated kinase, JNK, is regulated by the anaphase promoting complex (APC) ubiquitin ligase. Conversely, JNK also negatively controls the APC by directly phosphorylating the Cdh1 component of the APC and decreasing its affinity for the APC core subunits.
• Preempting and preventing drug-induced liver injury
A new study reports that susceptibility to drug-induced liver injury by the cyclooxygenase 2 (COX-2) inhibitor lumiracoxib is associated with a human lymphocyte antigen (HLA) class II haplotype. This finding suggests that those at risk of hepatotoxicity can be identified by HLA genotyping, raising the possibility that lumiracoxib can be resurrected as a useful drug.
• Genome-wide association study of follicular lymphoma identifies a risk locus ...
Christine Skibola and colleagues identify variants at 6p21.32 associated with risk of follicular lymphoma, providing further support that variation in the MHC region influences risk of this disease. They also replicate previously reported risk variants for chronic lymphocytic leukemia.
• Genome-wide association study identifies a susceptibility locus at 21q21 for ...
Connie Bezzina and colleagues report a genome-wide association study for ventricular fibrillation in individuals with acute myocardial infarction, a leading cause of total and cardiovascular mortality.
• Genome-wide association study identifies a sequence variant within the DAB2IP...
Solveig Gretarsdottir, Kari Stefansson and colleagues report a genome-wide association study for abdominal aortic aneurysm. They identified a variant located within the DAB2IP gene on 9q33 associated with risk of developing abdominal aortic aneurysm.
• Erratum: A genome-wide association study of cleft lip with and without cleft ...
• Timing is everything
Beginning in the 1970s, some hospitalized patients with schizophrenia began receiving drug injections that lasted for weeks in place of their daily antipsychotic pills. These extended doses helped them stick to their prescribed course of medicine but also carried the risk of causing irreversible neurological damage. Roxanne Khamsi reports on how newer versions of such long-acting injectables might radically change the treatment of ailments ranging from alcoholism to diabetes.
• Smoking and emphysema: the stress connection
The stress response protein Rtp801 mediates damage to the lung in response to smoke. This finding might lead to new ways to treat chronic obstructive pulmonary disease and emphysema (pages 767?773).
• Far from the Heart: Counteracting coagulation
Basic research on the mechanisms of blood coagulation and the inflammatory response during tissue damage has revealed new potential targets for antithrombotic drugs. In 'Bench to Bedside', Charles T. Esmon examines three such studies, which offer the possibility of developing badly needed drugs that could block thrombosis without increasing the risk of hemorrhage. Esmon also raises the possibility that the new research could help explain why distal injury may contribute to protection of organs such as the heart, a process called 'remote conditioning'. In 'Bedside to Bench', Christian Weber takes a closer look at a clinical trial of remote ischemic conditioning, involving intermittent periods of occlusion and reperfusion on the arm. He examines evidence that cross-talk between cytokine and opioid receptors may underlie the effectiveness of this technique in protecting the heart from damage.
• Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette...
Rubin Tuder and his colleagues show that cigarette smoke induces expression of Rtp801 (also known as Redd1), a hypoxia-inducible protein that inhibits mTOR activity and enhances oxidative stress?mediated cell death. They also show that mice deficient in Rtp801 are protected from cigarette smoke?induced lung injury, thus suggesting the protein as a target to prevent emphysema.
• An autoimmune-mediated strategy for prophylactic breast cancer vaccination
Immunologically targeting ?-lactalbumin, a breast-specific protein highly expressed in breast carcinomas but absent from nonlactating mammary cells, provides protection against breast cancer in mice. This strategy may protect women against breast cancer in their post?child-bearing years, when lactation is readily avoidable and risk for developing breast cancer is high.
• Acute D2 receptor blockade induces rapid, reversible remodeling in human cort...
Dopamine D2 receptor antagonists increase the risk of extrapyramidal symptoms (EPS) within minutes. This study reports significant reductions in the striatal volume of healthy human subjects within hours of D2R antagonist treatment; the volume changes predict structural-functional decoupling in motor circuits and acute EPS with high precision.
• Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosi...
The authors combine optogenetics, two-photon microscopy and glutamate uncaging to study D2-type dopamine receptor modulation of glutamatergic transmission in mouse striatopallidal neurons. They find that dopamine regulates spine calcium via multiple pathways.
Nature Reviews
• Better prospects for BRCA?Better prospects for BRCA?Women with inherited mutations in BRCA1 or BRCA2 are at a significantly increased risk of developing breast or ovarian cancer. However, cancers with these mutations seem to have an Achilles heel ? an increased sensitivity to inhibitors of the
• Angiogenesis: Reducing risk
Having an extra copy of an anti-angiogenic gene and several endothelial cell-specific genes on chromosome 21, which is present in triplicate in individuals with Down's syndrome, is sufficient to slow tumour growth by preventing angiogenesis.
• Ageing: Predicting long life
Many of us hope for a long and healthy life, but it is widely accepted that achieving this depends on a complex combination of environment and genetics. A genome-wide association study of centenarians has now confirmed the importance of genetic variation in predisposition to exceptional
• The X chromosome in immune functions: when a chromosome makes the difference
In response to various immune challenges, females show better survival than males; the X chromosome has an important role in this immunological advantage. X chromosome-linked diseases are usually restricted to males, who have only one copy of the X chromosome; however, females are more prone
• The changing face of rheumatoid arthritis: sustained remission for all?
Earlier diagnosis and treatment, plus biological therapies, have transformed the outlook for many patients with rheumatoid arthritis. In the future, new biomarkers for diagnosis, prognosis and therapeutic response will further improve outcomes. Additionally, preclinical diagnosis and tolerogenic therapies could provide sustained remission for some individuals,
• From the editors
To survive exposure to stress, such as high temperatures and infection, eukaryotes depend on the heat shock response. This is mediated by heat shock factors (HSFs) ? transcription factors that induce the expression of a family of molecular chaperones known as heat shock proteins (HSPs),
• Heat shock factors: integrators of cell stress, development and lifespan
Heat shock factors (HSFs) are essential for all organisms to survive exposures to acute stress. They are best known as inducible transcriptional regulators of genes encoding molecular chaperones and other stress proteins. Four members of the HSF family are also important for normal development and
• Progeria syndromes and ageing: what is the connection?
One of the many debated topics in ageing research is whether progeroid syndromes are really accelerated forms of human ageing. The answer requires a better understanding of the normal ageing process and the molecular pathology underlying these rare diseases. Exciting recent findings regarding a severe