297 research outputs found
The miswired brain: making connections from neurodevelopment to psychopathology
Developmental neurobiologists have made great progress in elucidating the molecular mechanisms underlying nervous system development. There has been less focus, however, on the consequences when these processes go wrong. As the evidence increases that mutations in neurodevelopmental genes are associated with major psychiatric disorders, defining these consequences assumes paramount importance in elucidating pathogenic mechanisms
Bottom mixed layer oxygen dynamics in the Celtic Sea
The seasonally stratified continental shelf seas are highly productive, economically important environments which are under considerable pressure from human activity. Global dissolved oxygen concentrations have shown rapid reductions in response to anthropogenic forcing since at least the middle of the twentieth century. Oxygen consumption is at the same time linked to the cycling of atmospheric carbon, with oxygen being a proxy for carbon remineralisation and the release of CO2. In the seasonally stratified seas the bottom mixed layer (BML) is partially isolated from the atmosphere and is thus controlled by interplay between oxygen consumption processes, vertical and horizontal advection. Oxygen consumption rates can be both spatially and temporally dynamic, but these dynamics are often missed with incubation based techniques. Here we adopt a Bayesian approach to determining total BML oxygen consumption rates from a high resolution oxygen time-series. This incorporates both our knowledge and our uncertainty of the various processes which control the oxygen inventory. Total BML rates integrate both processes in the water column and at the sediment interface. These observations span the stratified period of the Celtic Sea and across both sandy and muddy sediment types. We show how horizontal advection, tidal forcing and vertical mixing together control the bottom mixed layer oxygen concentrations at various times over the stratified period. Our muddy-sand site shows cyclic spring-neap mediated changes in oxygen consumption driven by the frequent resuspension or ventilation of the seabed. We see evidence for prolonged periods of increased vertical mixing which provide the ventilation necessary to support the high rates of consumption observed
Discovery of Quinazolines That Activate SOS1-Mediated Nucleotide Exchange on RAS.
Proteins in the RAS family are important regulators of cellular signaling and, when mutated, can drive cancer pathogenesis. Despite considerable effort over the last 30 years, RAS proteins have proven to be recalcitrant therapeutic targets. One approach for modulating RAS signaling is to target proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report hit-to-lead studies on quinazoline-containing compounds that bind to SOS1 and activate nucleotide exchange on RAS. Using structure-based design, we refined the substituents attached to the quinazoline nucleus and built in additional interactions not present in the initial HTS hit. Optimized compounds activate nucleotide exchange at single-digit micromolar concentrations in vitro. In HeLa cells, these quinazolines increase the levels of RAS-GTP and cause signaling changes in the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway
Accelerating the Gillespie Ï-Leaping Method Using Graphics Processing Units
The Gillespie Ï-Leaping Method is an approximate algorithm that is faster than the exact Direct Method (DM) due to the progression of the simulation with larger time steps. However, the procedure to compute the time leap Ï is quite expensive. In this paper, we explore the acceleration of the Ï-Leaping Method using Graphics Processing Unit (GPUs) for ultra-large networks ( reaction channels). We have developed data structures and algorithms that take advantage of the unique hardware architecture and available libraries. Our results show that we obtain a performance gain of over 60x when compared with the best conventional implementations
Extremely metal-poor stars from the cosmic dawn in the bulge of the Milky Way
This document is the Accepted Manuscript version of the following article: L. M. Howes, et al, âExtremely metal-poor stars from the cosmic dawn in the bulge of the Milky Wayâ, Nature, Vol. 527, November 2015. This manuscript version is made available under the Nature Researchâs Conditions of Use, http://www.nature.com/authors/policies/license.html#Self_archiving_policy. The final, published version is available online at DOI: http://www.nature.com/doifinder/10.1038/nature15747. © 2015 Macmillan Publishers Limited. All rights reservedThe first stars are predicted to have formed within 200 million years after the Big Bang, initiating the cosmic dawn. A true first star has not yet been discovered, although stars with tiny amounts of elements heavier than helium ('metals') have been found in the outer regions ('halo') of the Milky Way. The first stars and their immediate successors should, however, preferentially be found today in the central regions ('bulges') of galaxies, because they formed in the largest over-densities that grew gravitationally with time. The Milky Way bulge underwent a rapid chemical enrichment during the first 1-2 billion years, leading to a dearth of early, metal-poor stars. Here we report observations of extremely metal-poor stars in the Milky Way bulge, including one star with an iron abundance about 10,000 times lower than the solar value without noticeable carbon enhancement. We confirm that the most metal-poor bulge stars are on tight orbits around the Galactic Centre, rather than being halo stars passing through the bulge, as expected for stars formed at redshifts greater than 15. Their chemical compositions are in general similar to typical halo stars of the same metallicity although intriguing differences exist, including lower abundances of carbon.Peer reviewedFinal Accepted Versio
G6PD testing in support of treatment and elimination of malaria: recommendations for evaluation of G6PD tests
Malaria elimination will be possible only with serious attempts to address asymptomatic infection and chronic infection by both Plasmodium falciparum and Plasmodium vivax. Currently available drugs that can completely clear a human of P. vivax (known as âradical cureâ), and that can reduce transmission of malaria parasites, are those in the 8-aminoquinoline drug family, such as primaquine. Unfortunately, people with glucose-6-phosphate dehydrogenase (G6PD) deficiency risk having severe adverse reactions if exposed to these drugs at certain doses. G6PD deficiency is the most common human enzyme defect, affecting approximately 400 million people worldwide. Scaling up radical cure regimens will require testing for G6PD deficiency, at two levels: 1) the individual level to ensure safe case management, and 2) the population level to understand the risk in the local population to guide Plasmodium vivax treatment policy. Several technical and operational knowledge gaps must be addressed to expand access to G6PD deficiency testing and to ensure that a patientâs G6PD status is known before deciding to administer an 8-aminoquinoline-based drug.
In this report from a stakeholder meeting held in Thailand on October 4 and 5, 2012, G6PD testing in support of radical cure is discussed in detail. The focus is on challenges to the development and evaluation of G6PD diagnostic tests, and on challenges related to the operational aspects of implementing G6PD testing in support of radical cure. The report also describes recommendations for evaluation of diagnostic tests for G6PD deficiency in support of radical cure
Evidence for electron Landau damping in space plasma turbulence
How turbulent energy is dissipated in weakly collisional space and astrophysical plasmas is a major open question. Here, we present the application of a field-particle correlation technique to directly measure the transfer of energy between the turbulent electromagnetic field and electrons in the Earth's magnetosheath, the region of solar wind downstream of the Earth's bow shock. The measurement of the secular energy transfer from the parallel electric field as a function of electron velocity shows a signature consistent with Landau damping. This signature is coherent over time, close to the predicted resonant velocity, similar to that seen in kinetic Alfven turbulence simulations, and disappears under phase randomisation. This suggests that electron Landau damping could play a significant role in turbulent plasma heating, and that the technique is a valuable tool for determining the particle energisation processes operating in space and astrophysical plasmas.STFC Ernest Rutherford Fellowship [ST/N003748/2]; NASA HSR grant [NNX16AM23G]; NSF CAREER Award [AGS-1054061]; NASA HGI grant [80NSSC18K0643]; NASA MMS GI grant [80NSSC18K1371]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Familial association of pancreatic cancer with other malignancies in Swedish families
BACKGROUND: The aim of this study was to characterise the familial association of pancreatic cancer with other malignancies. METHODS: Relative risks (RRs) of pancreatic cancer according to family history of cancer were calculated using the updated Swedish Family-Cancer Database, which includes over 11.5 million individuals. Estimates were based on Poisson regression. RRs of tumours for individuals with a parental history of pancreatic cancer were also estimated. RESULTS: The risk of pancreatic cancer was elevated in individuals with a parental history of cancers of the liver (RR 1.41; 95% CI 1.10-1.81), kidney (RR 1.37; 95% CI 1.06-1.76), lung (RR 1.50; 95% CI 1.27-1.79) and larynx (RR 1.98; 95% CI 1.19-3.28). Associations were also found between parental history of pancreatic cancer and cancers of the small intestine, colon, breast, lung, testis and cervix in offspring. There was an increased risk of pancreatic cancer associated with early-onset breast cancer in siblings. CONCLUSION: Pancreatic cancer aggregates in families with several types of cancer. Smoking may contribute to the familial aggregation of pancreatic and lung tumours, and the familial clustering of pancreatic and breast cancer could be partially explained by inherited mutations in the BRCA2 gene. British Journal of Cancer (2009) 101, 1792-1797. doi: 10.1038/sj.bjc.6605363 www.bjcancer.com Published online 13 October 2009 (C) 2009 Cancer Research U
Knockout and transgenic mice of Trp53: what have we learned about p53 in breast cancer?
The human p53 tumor suppressor gene TP53 is mutated at a high frequency in sporadic breast cancer, and Li-Fraumeni syndrome patients who carry germline mutations in one TP53 allele have a high incidence of breast cancer. In the 10 years since the first knockout of the mouse p53 tumor suppressor gene (designated Trp53) was published, much has been learned about the contribution of p53 to biology and tumor suppression in the breast through the use of p53 transgenic and knockout mice. The original mice deficient in p53 showed no mammary gland phenotype. However, studies using BALB/c-Trp53-deficient mice have demonstrated a delayed involution phenotype and a mammary tumor phenotype. Together with other studies of mutant p53 transgenes and p53 bitransgenics, a greater understanding has been gained of the role of p53 in involution, of the regulation of p53 activity by hormones, of the effect of mouse strain and modifier genes on tumor phenotype, and of the cooperation between p53 and other oncogenic pathways, chemical carcinogens and hormonal stimulation in mammary tumorigenesis. Both p53 transgenic and knockout mice are important in vivo tools for understanding breast cancer, and are yet to be exploited for developing therapeutic strategies in breast cancer
Prefrontal dopamine and the dynamic control of human long-term memory
Dopaminergic projections to the prefrontal cortex support higher-order cognitive functions, and are critically involved in many psychiatric disorders that involve memory deficits, including schizophrenia. The role of prefrontal dopamine in long-term memory, however, is still unclear. We used an imaging genetics approach to examine the hypothesis that dopamine availability in the prefrontal cortex selectively affects the ability to suppress interfering memories. Human participants were scanned via functional magnetic resonance imaging while practicing retrieval of previously studied target information in the face of interference from previously studied non-target information. This retrieval practice (RP) rendered the non-target information less retrievable on a later final testâa phenomenon known as retrieval-induced forgetting (RIF). In total, 54 participants were genotyped for the catechol-O-methyltransferase (COMT) Val108/158Met polymorphism. The COMT Val108/158Met genotype showed a selective and linear gene-dose effect on RIF, with the Met allele, which leads to higher prefrontal dopamine availability, being associated with greater RIF. Mirroring the behavioral pattern, the functional magnetic resonance imaging data revealed that Met allele carriers, compared with Val allele carriers, showed a greater response reduction in inhibitory control areas of the right inferior frontal cortex during RP, suggesting that they more efficiently reduced interference. These data support the hypothesis that the cortical dopaminergic system is centrally involved in the dynamic control of human long-term memory, supporting efficient remembering via the adaptive suppression of interfering memories
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