Method to Predict Crowding Effects by Postprocessing Molecular Dynamics Trajectories: Application to the Flap Dynamics of HIV-1 Protease.

The internal dynamics of proteins inside of cells may be affected by the crowded intracellular environments. Here, we test a novel approach to simulations of crowding, in which simulations in the absence of crowders are postprocessed to predict crowding effects, against the direct approach of simulations in the presence of crowders. The effects of crowding on the flap dynamics of HIV-1 protease predicted by the postprocessing approach are found to agree well with those calculated by the direct approach. The postprocessing approach presents distinct advantages over the direct approach in terms of accuracy and speed and is expected to have broad impact on atomistic simulations of macromolecular crowding

Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples

Biometric Fish Classification of Temperate Species Using Convolutional Neural Network with Squeeze-and-Excitation

submittedVersio

Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed

Assessing connectivity between an overlying aquifer and a coal seam gas resource using methane isotopes, dissolved organic carbon and tritium

Coal seam gas (CSG) production can have an impact on groundwater quality and quantity in adjacent or overlying aquifers. To assess this impact we need to determine the background groundwater chemistry and to map geological pathways of hydraulic connectivity between aquifers. In south-east Queensland (Qld), Australia, a globally important CSG exploration and production province, we mapped hydraulic connectivity between the Walloon Coal Measures (WCM, the target formation for gas production) and the overlying Condamine River Alluvial Aquifer (CRAA), using groundwater methane (CH4) concentration and isotopic composition (δ13C-CH4), groundwater tritium (3H) and dissolved organic carbon (DOC) concentration. A continuous mobile CH4 survey adjacent to CSG developments was used to determine the source signature of CH4 derived from the WCM. Trends in groundwater δ13C-CH4 versus CH4 concentration, in association with DOC concentration and 3H analysis, identify locations where CH4 in the groundwater of the CRAA most likely originates from the WCM. The methodology is widely applicable in unconventional gas development regions worldwide for providing an early indicator of geological pathways of hydraulic connectivity

Serum Müllerian inhibiting substance levels are lower in premenopausal women with breast precancer and cancer

<p>Abstract</p> <p>Background</p> <p>In preclinical studies, müllerian inhibiting substance (MIS) has a protective affect against breast cancer. Our objective was to determine whether serum MIS concentrations were associated with cancerous or precancerous lesions. Blood from 30 premenopausal women was collected and serum extracted prior to their undergoing breast biopsy to assess a suspicious lesion found on imaging or physical examination. Based on biopsy results, the serum specimens were grouped as cancer (invasive or ductal carcinoma <it>in situ</it>), precancer (atypical hyperplasia or lobular carcinoma <it>in situ</it>), or benign.</p> <p>Findings</p> <p>Serum from women with cancer and precancer (p = .0009) had lower MIS levels than serum from women with benign disease.</p> <p>Conclusion</p> <p>Our findings provide preliminary evidence for MIS being associated with current breast cancer risk, which should be validated in a larger population.</p

Socioeconomic disparities in breast cancer survival: relation to stage at diagnosis, treatment and race

<p>Abstract</p> <p>Background</p> <p>Previous studies have documented lower breast cancer survival among women with lower socioeconomic status (SES) in the United States. In this study, I examined the extent to which socioeconomic disparity in breast cancer survival was explained by stage at diagnosis, treatment, race and rural/urban residence using the Surveillance, Epidemiology, and End Results (SEER) data.</p> <p>Methods</p> <p>Women diagnosed with breast cancer during 1998-2002 in the 13 SEER cancer registry areas were followed-up to the end of 2005. The association between an area-based measure of SES and cause-specific five-year survival was estimated using Cox regression models. Six models were used to assess the extent to which SES differences in survival were explained by clinical and demographical factors. The base model estimated the hazard ratio (HR) by SES only and then additional adjustments were made sequentially for: 1) age and year of diagnosis; 2) stage at diagnosis; 3) first course treatment; 4) race; and 5) rural/urban residence.</p> <p>Results</p> <p>An inverse association was found between SES and risk of dying from breast cancer (p < 0.0001). As area-level SES falls, HR rises (1.00 → 1.05 → 1.23 → 1.31) with the two lowest SES groups having statistically higher HRs. This SES differential completely disappeared after full adjustment for clinical and demographical factors (p = 0.20).</p> <p>Conclusion</p> <p>Stage at diagnosis, first course treatment and race explained most of the socioeconomic disparity in breast cancer survival. Targeted interventions to increase breast cancer screening and treatment coverage in patients with lower SES could reduce much of socioeconomic disparity.</p

Hybrid PET/CT and PET/MRI imaging of vulnerable coronary plaque and myocardial scar tissue in acute myocardial infarction

BACKGROUND: Following an acute coronary syndrome, combined CT and PET with 18F-NaF can identify coronary atherosclerotic plaques that have ruptured or eroded. However, the processes behind 18F-NaF uptake in vulnerable plaques remain unclear. METHODS AND RESULTS: Ten patients with STEMI were scanned after 18F-NaF injection, for 75 minutes in a Siemens PET/MR scanner using delayed enhancement (LGE). They were then scanned in a Siemens PET/CT scanner for 10 minutes. Tissue-to-background ratio (TBR) was compared between the culprit lesion in the IRA and remote non-culprit lesions in an effort to independently validate prior studies. Additionally, we performed a proof-of-principle study comparing TBR in scar tissue and remote myocardium using LGE images and PET/MR or PET/CT data. From the 33 coronary lesions detected on PET/CT, TBRs for culprit lesions were higher than for non-culprit lesions (TBR = 2.11 ± 0.45 vs 1.46 ± 0.48; P < 0.001). Interestingly, the TBR measured on the PET/CT was higher for infarcted myocardium than for remote myocardium (TBR = 0.81 ± 0.10 vs 0.71 ± 0.05; P = 0.003). These results were confirmed using the PET/MR data (TBR = 0.81 ± 0.10 for scar, TBR = 0.71 ± 0.06 for healthy myocardium, P = 0.03). CONCLUSIONS: We confirmed the potential of 18F-NaF PET/CT imaging to detect vulnerable coronary lesions. Moreover, we demonstrated proof-of-principle that 18F-NaF concurrently detects myocardial scar tissue

Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer's disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine tumour necrosis factor (TNF)-\u3b1 and lipopolysaccaride (LPS). TNF-\u3b1 time-dependently increased Saa1 (but not Saa3) mRNA expression in purified microglia, enriched astrocytes, and OPCs (as did LPS for microglia and astrocytes). Astrocytes depleted of microglia were markedly less responsive to TNF-\u3b1 and LPS, even after re-addition of microglia. Microglia and enriched astrocytes showed complementary Saa1 expression profiles following TNF-\u3b1 or LPS challenge, being higher in microglia with TNF-\u3b1 and higher in astrocytes with LPS. Recombinant human apo-SAA stimulated production of both inflammatory mediators and its own mRNA in microglia and enriched, but not microglia-depleted astrocytes. Co-ultramicronized palmitoylethanolamide/luteolin, an established anti-inflammatory/neuroprotective agent, reduced Saa1 expression in OPCs subjected to TNF-\u3b1 treatment. These last data, together with past findings suggest that co-ultramicronized palmitoylethanolamide/luteolin may be a novel approach in the treatment of inflammatory demyelinating disorders like MS

The use of quality information by general practitioners: does it alter choices? A randomized clustered study

Background: Following the introduction of elements of managed competition in the Netherlands in 2006, General Practitioners (GPs) and patients were given the role to select treatment hospital using public quality information. In this study we investigate to what extent hospital preferences of GP's are affected by performance indicators on medical effectiveness and patient experiences. We selected three conditions: breast cancer, cataract surgery, and hip and knee replacement. Methods. After an inquiry 26 out of 226 GPs in the region signed up to participate in our study. After a 2:1 randomization, we analyzed the referral patterns in the region using three groups of GPs: GPs (n=17) who used the report cards and received personal clarification, GPs that signed up for the study but were assigned to the control group (n=9), and the GPs outside the study (n=200).We conducted a difference in differences analysis where the choice for a particular hospital was the dependent variable and time (2009 or 2010), the sum score of the CQI, the sum score of the PI's and dummy variables for the individual hospitals were used as independent variables. Results: The analysis of the conditions together and cataract surgery and hip and knee replacement separately, showed no significant relationships between the scores on the report cards and the referral patterns of the GPs. For breast cancer our analysis revealed that GPs in the intervention group refer 1.0% (p=0.01) more to hospitals that score one percent point better on the indicators for medical effectiveness. Conclusion: Our study provides empirical evidence that GP referral patterns were unaffected by the available quality information, except for the outcome indicators for breast cancer care that were presented. This finding was surprising since our study was designed to identify changes in hospital preference (1) amongst the most motivated GP's, (2) that received personal clarification of the performance indicators, and (3) selected indicators/conditions from a large set of indicators that they believed were most important. This finding may differ when quality information is based on outcome indicators with a clinically relevant difference, as shown by our indicators for breast cancer treatment. We believe that the current set of (largely process) hospital quality indicators do not serve the GP's information needs and consequently quality plays little role in the selection of hospitals for treatment. © 2013 Ikkersheim and Koolman; licensee BioMed Central Ltd