The solar particle event of July 16–19, 1966 and its possible association with a flare on the invisible solar hemisphere

An energetic solar proton and electron event was observed by particle detectors aboard Explorer 33 (AIMP-1) and OGO-3 during the period July 16–19, 1966. Optical and radio observations of the sun suggest that these particles were produced by a flare which may have occurred on July 16 near the central meridian of the invisible hemisphere. The active region to which the flare is assigned is known to have produced the energetic particle events of July 7 and 28 , 1966. The propagation of the particles in the July 16–19 event over the ∼180° extent of solar longitude from the flare to the earth is discussed, and it is concluded that there must exist a means of rapidly distributing energetic particles over a large area of the sun. Several possible mechanisms are suggested.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43748/1/11207_2004_Article_BF00150955.pd

PI 3 Kinase Related Kinases-Independent Proteolysis of BRCA1 Regulates Rad51 Recruitment during Genotoxic Stress in Human Cells

The function of BRCA1 in response to ionizing radiation, which directly generates DNA double strand breaks, has been extensively characterized. However previous investigations have produced conflicting data on mutagens that initially induce other classes of DNA adducts. Because of the fundamental and clinical importance of understanding BRCA1 function, we sought to rigorously evaluate the role of this tumor suppressor in response to diverse forms of genotoxic stress.We investigated BRCA1 stability and localization in various human cells treated with model mutagens that trigger different DNA damage signaling pathways. We established that, unlike ionizing radiation, either UVC or methylmethanesulfonate (MMS) (generating bulky DNA adducts or alkylated bases respectively) induces a transient downregulation of BRCA1 protein which is neither prevented nor enhanced by inhibition of PIKKs. Moreover, we found that the proteasome mediates early degradation of BRCA1, BARD1, BACH1, and Rad52 implying that critical components of the homologous recombination machinery need to be functionally abrogated as part of the early response to UV or MMS. Significantly, we found that inhibition of BRCA1/BARD1 downregulation is accompanied by the unscheduled recruitment of both proteins to chromatin along with Rad51. Consistently, treatment of cells with MMS engendered complete disassembly of Rad51 from pre-formed ionizing radiation-induced foci. Following the initial phase of BRCA1/BARD1 downregulation, we found that the recovery of these proteins in foci coincides with the formation of RPA and Rad51 foci. This indicates that homologous recombination is reactivated at later stage of the cellular response to MMS, most likely to repair DSBs generated by replication blocks.Taken together our results demonstrate that (i) the stabilities of BRCA1/BARD1 complexes are regulated in a mutagen-specific manner, and (ii) indicate the existence of mechanisms that may be required to prevent the simultaneous recruitment of conflicting signaling pathways to sites of DNA damage

New ABA-Hypersensitive Arabidopsis Mutants Are Affected in Loci Mediating Responses to Water Deficit and Dickeya dadantii Infection

On water deficit, abscisic acid (ABA) induces stomata closure to reduce water loss by transpiration. To identify Arabidopsis thaliana mutants which transpire less on drought, infrared thermal imaging of leaf temperature has been used to screen for suppressors of an ABA-deficient mutant (aba3-1) cold-leaf phenotype. Three novel mutants, called hot ABA-deficiency suppressor (has), have been identified with hot-leaf phenotypes in the absence of the aba3 mutation. The defective genes imparted no apparent modification to ABA production on water deficit, were inherited recessively and enhanced ABA responses indicating that the proteins encoded are negative regulators of ABA signalling. All three mutants showed ABA-hypersensitive stomata closure and inhibition of root elongation with little modification of growth and development in non-stressed conditions. The has2 mutant also exhibited increased germination inhibition by ABA, while ABA-inducible gene expression was not modified on dehydration, indicating the mutated gene affects early ABA-signalling responses that do not modify transcript levels. In contrast, weak ABA-hypersensitivity relative to mutant developmental phenotypes suggests that HAS3 regulates drought responses by both ABA-dependent and independent pathways. has1 mutant phenotypes were only apparent on stress or ABA treatments, and included reduced water loss on rapid dehydration. The HAS1 locus thus has the required characteristics for a targeted approach to improving resistance to water deficit. In contrast to has2, has1 exhibited only minor changes in susceptibility to Dickeya dadantii despite similar ABA-hypersensitivity, indicating that crosstalk between ABA responses to this pathogen and drought stress can occur through more than one point in the signalling pathway

AI-based dimensional neuroimaging system for characterizing heterogeneity in brain structure and function in major depressive disorder:COORDINATE-MDD consortium design and rationale

BACKGROUND: Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status and heterogeneous symptom states. METHODS: We describe a consortium to quantify neuroanatomical and neurofunctional heterogeneity via the dimensions of novel multivariate coordinate system (COORDINATE-MDD). Utilizing imaging harmonization and machine learning methods in a large cohort of medication-free, deeply phenotyped MDD participants, patterns of brain alteration are defined in replicable and neurobiologically-based dimensions and offer the potential to predict treatment response at the individual level. International datasets are being shared from multi-ethnic community populations, first episode and recurrent MDD, which are medication-free, in a current depressive episode with prospective longitudinal treatment outcomes and in remission. Neuroimaging data consist of de-identified, individual, structural MRI and resting-state functional MRI with additional positron emission tomography (PET) data at specific sites. State-of-the-art analytic methods include automated image processing for extraction of anatomical and functional imaging variables, statistical harmonization of imaging variables to account for site and scanner variations, and semi-supervised machine learning methods that identify dominant patterns associated with MDD from neural structure and function in healthy participants. RESULTS: We are applying an iterative process by defining the neural dimensions that characterise deeply phenotyped samples and then testing the dimensions in novel samples to assess specificity and reliability. Crucially, we aim to use machine learning methods to identify novel predictors of treatment response based on prospective longitudinal treatment outcome data, and we can externally validate the dimensions in fully independent sites. CONCLUSION: We describe the consortium, imaging protocols and analytics using preliminary results. Our findings thus far demonstrate how datasets across many sites can be harmonized and constructively pooled to enable execution of this large-scale project

P53 in human melanoma fails to regulate target genes associated with apoptosis and the cell cycle and may contribute to proliferation

<p>Abstract</p> <p>Background</p> <p>Metastatic melanoma represents a major clinical problem. Its incidence continues to rise in western countries and there are currently no curative treatments. While mutation of the <it>P53 </it>tumour suppressor gene is a common feature of many types of cancer, mutational inactivation of <it>P53 </it>in melanoma is uncommon; however, its function often appears abnormal.</p> <p>Methods</p> <p>In this study whole genome bead arrays were used to examine the transcript expression of P53 target genes in extracts from 82 melanoma metastases and 6 melanoma cell lines, to provide a global assessment of aberrant P53 function. The expression of these genes was also examined in extracts derived from diploid human melanocytes and fibroblasts.</p> <p>Results</p> <p>The results indicated that P53 target transcripts involved in apoptosis were under-expressed in melanoma metastases and melanoma cell lines, while those involved in the cell cycle were over-expressed in melanoma cell lines. There was little difference in the transcript expression of P53 target genes between cell lines with null/mutant <it>P53 </it>compared to those with wild-type <it>P53</it>, suggesting that altered expression in melanoma was not related to <it>P53 </it>status. Similarly, down-regulation of P53 by short-hairpin RNA (shRNA) had limited effect on P53 target gene expression in melanoma cells, whereas there were a large number of P53 target genes whose mRNA expression was significantly altered by P53 inhibition in melanocytes. Analysis of whole genome gene expression profiles indicated that the ability of P53 to regulate genes involved in the cell cycle was significantly reduced in melanoma cells. Moreover, inhibition of P53 in melanocytes induced changes in gene expression profiles that were characteristic of melanoma cells and resulted in increased proliferation. Conversely, knockdown of P53 in melanoma cells resulted in decreased proliferation.</p> <p>Conclusions</p> <p>These results indicate that P53 target genes involved in apoptosis and cell cycle regulation are aberrantly expressed in melanoma and that this aberrant functional activity of P53 may contribute to the proliferation of melanoma.</p

The Effectiveness of Pharmacological and Non-Pharmacological Interventions for Improving Glycaemic Control in Adults with Severe Mental Illness: A Systematic Review and Meta-Analysis

People with severe mental illness (SMI) have reduced life expectancy compared with the general population, which can be explained partly by their increased risk of diabetes. We conducted a meta-analysis to determine the clinical effectiveness of pharmacological and non-pharmacological interventions for improving glycaemic control in people with SMI (PROSPERO registration: CRD42015015558). A systematic literature search was performed on 30/10/2015 to identify randomised controlled trials (RCTs) in adults with SMI, with or without a diagnosis of diabetes that measured fasting blood glucose or glycated haemoglobin (HbA1c). Screening and data extraction were carried out independently by two reviewers. We used random effects meta-analysis to estimate effectiveness, and subgroup analysis and univariate meta-regression to explore heterogeneity. The Cochrane Collaboration’s tool was used to assess risk of bias. We found 54 eligible RCTs in 4,392 adults (40 pharmacological, 13 behavioural, one mixed intervention). Data for meta-analysis were available from 48 RCTs (n = 4052). Both pharmacological (mean difference (MD), -0.11mmol/L; 95% confidence interval (CI), [-0.19, -0.02], p = 0.02, n = 2536) and behavioural interventions (MD, -0.28mmol//L; 95% CI, [-0.43, -0.12], p<0.001, n = 956) were effective in lowering fasting glucose, but not HbA1c (pharmacological MD, -0.03%; 95% CI, [-0.12, 0.06], p = 0.52, n = 1515; behavioural MD, 0.18%; 95% CI, [-0.07, 0.42], p = 0.16, n = 140) compared with usual care or placebo. In subgroup analysis of pharmacological interventions, metformin and antipsychotic switching strategies improved HbA1c. Behavioural interventions of longer duration and those including repeated physical activity had greater effects on fasting glucose than those without these characteristics. Baseline levels of fasting glucose explained some of the heterogeneity in behavioural interventions but not in pharmacological interventions. Although the strength of the evidence is limited by inadequate trial design and reporting and significant heterogeneity, there is some evidence that behavioural interventions, antipsychotic switching, and metformin can lead to clinically important improvements in glycaemic measurements in adults with SMI

Ageing, adipose tissue, fatty acids and inflammation

A common feature of ageing is the alteration in tissue distribution and composition, with a shift in fat away from lower body and subcutaneous depots to visceral and ectopic sites. Redistribution of adipose tissue towards an ectopic site can have dramatic effects on metabolic function. In skeletal muscle, increased ectopic adiposity is linked to insulin resistance through lipid mediators such as ceramide or DAG, inhibiting the insulin receptor signalling pathway. Additionally, the risk of developing cardiovascular disease is increased with elevated visceral adipose distribution. In ageing, adipose tissue becomes dysfunctional, with the pathway of differentiation of preadipocytes to mature adipocytes becoming impaired; this results in dysfunctional adipocytes less able to store fat and subsequent fat redistribution to ectopic sites. Low grade systemic inflammation is commonly observed in ageing, and may drive the adipose tissue dysfunction, as proinflammatory cytokines are capable of inhibiting adipocyte differentiation. Beyond increased ectopic adiposity, the effect of impaired adipose tissue function is an elevation in systemic free fatty acids (FFA), a common feature of many metabolic disorders. Saturated fatty acids can be regarded as the most detrimental of FFA, being capable of inducing insulin resistance and inflammation through lipid mediators such as ceramide, which can increase risk of developing atherosclerosis. Elevated FFA, in particular saturated fatty acids, maybe a driving factor for both the increased insulin resistance, cardiovascular disease risk and inflammation in older adults

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Caenorhabditis briggsae Recombinant Inbred Line Genotypes Reveal Inter-Strain Incompatibility and the Evolution of Recombination

The nematode Caenorhabditis briggsae is an emerging model organism that allows evolutionary comparisons with C. elegans and exploration of its own unique biological attributes. To produce a high-resolution C. briggsae recombination map, recombinant inbred lines were generated from reciprocal crosses between two strains and genotyped at over 1,000 loci. A second set of recombinant inbred lines involving a third strain was also genotyped at lower resolution. The resulting recombination maps exhibit discrete domains of high and low recombination, as in C. elegans, indicating these are a general feature of Caenorhabditis species. The proportion of a chromosome's physical size occupied by the central, low-recombination domain is highly correlated between species. However, the C. briggsae intra-species comparison reveals striking variation in the distribution of recombination between domains. Hybrid lines made with the more divergent pair of strains also exhibit pervasive marker transmission ratio distortion, evidence of selection acting on hybrid genotypes. The strongest effect, on chromosome III, is explained by a developmental delay phenotype exhibited by some hybrid F2 animals. In addition, on chromosomes IV and V, cross direction-specific biases towards one parental genotype suggest the existence of cytonuclear epistatic interactions. These interactions are discussed in relation to surprising mitochondrial genome polymorphism in C. briggsae, evidence that the two strains diverged in allopatry, the potential for local adaptation, and the evolution of Dobzhansky-Muller incompatibilities. The genetic and genomic resources resulting from this work will support future efforts to understand inter-strain divergence as well as facilitate studies of gene function, natural variation, and the evolution of recombination in Caenorhabditis nematodes