Incorporating Universal Design into Tsunami Modeling Results for Cascadia Subduction Zone Faults to Create an Inundation Map and Universally Designed Evacuation Map for Port Angeles, WA

Current tsunami hazard inundation and evacuation maps in the Puget Sound are based primarily on Cascadia and Seattle fault tsunamis. The standard evaluation process for tsunami impacts focuses on elevation and hypothetical fault rupture of known and predicted earthquakes. However, there are several known tsunami deposits in the Puget Sound that are not from Cascadia or Seattle fault tsunamis, potentially from other faults within the region, that could affect tsunami mitigation. Work to understand newly discovered crustal deformation and faults in Puget Sound is ongoing, therefore evacuation and inundation maps need to be updated to include these new faults and integrate universal design more broadly. Methods involved using GeoClaw software to map tsunamis from the Cascadia Subduction Zone (CSZ), Leech River fault (LRF), and Utsalady Point fault (UPF). Modeled tsunamis determined the overall inundation of Port Angeles, Washington through a wide range of earthquake inputs of magnitude, proximity, and recurrence. The output simulations were evaluated with key components of universal design to create a new tsunami hazard map. Comparison between the universal design-based map to current the tsunami hazard map allowed for an evaluation of the current evacuation map. This evaluation can improve the assessment of bridges and other evacuation mechanisms. This research can contribute to future tsunami hazard map revisions saving lives, can help with emergency management planning, and spur reevaluating evacuation plans within the tsunami impact area

UK Biobank: Opportunities for cardiovascular research

Cardiovascular disease and its associated risk factors, such as hypertension and high cholesterol, are major contributors towards global morbidity and mortality. Epidemiological studies provide the scientific evidence base to develop effective preventive strategies and treatments for cardiovascular disease. However, previous cohorts have been restricted by small sample sizes and/or a lack of diverse outcomes, thereby limiting the identification of small, but clinically relevant, associations as well as the opportunity to explore complex interactions between risk factors. To address this, UK Biobank was established as a population-based prospective study with data and samples of unparalleled breadth and depth from 500,000 UK adults, recruited between 2006 and 2010. Incident health outcomes are captured through linkage to electronic medical records over the long term. The biological samples collected have enabled biochemical measurements and genome-wide genotyping to be performed for the full cohort. Enhanced measures are being performed on large subsets, including the largest multimodal imaging study (100,000 participants), physical activity monitoring (100,000 participants) and a series of web-based questionnaires (over 100,000 participants). As a result, UK Biobank offers an invaluable opportunity to conduct novel epidemiological research focused on cardiovascular disease and its associated environmental and genetic risk factors as well as how these factors interact with non-cardiovascular outcomes. As an open-access resource, UK Biobank provides researchers from around the world with an opportunity to generate findings that will positively impact the prevention, treatment and diagnosis of cardiovascular disease in the foreseeable future

Parvalbumin basket cell myelination accumulates axonal mitochondria to internodes

Parvalbumin-expressing (PV+) basket cells are fast-spiking inhibitory interneurons that exert critical control over local circuit activity and oscillations. PV+ axons are often myelinated, but the electrical and metabolic roles of interneuron myelination remain poorly understood. Here, we developed viral constructs allowing cell type-specific investigation of mitochondria with genetically encoded fluorescent probes. Single-cell reconstructions revealed that mitochondria selectively cluster to myelinated segments of PV+ basket cells, confirmed by analyses of a high-resolution electron microscopy dataset. In contrast to the increased mitochondrial densities in excitatory axons cuprizone-induced demyelination abolished mitochondrial clustering in PV+ axons. Furthermore, with genetic deletion of myelin basic protein the mitochondrial clustering was still observed at internodes wrapped by noncompacted myelin, indicating that compaction is dispensable. Finally, two-photon imaging of action potential-evoked calcium (Ca2+) responses showed that interneuron myelination attenuates both the cytosolic and mitochondrial Ca2+ transients. These findings suggest that oligodendrocyte ensheathment of PV+ axons assembles mitochondria to branch selectively fine-tune metabolic demands

An AMPKa2-specific phospho-switch controls lysosomal targeting for activation

AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) are metabolic kinases that co-ordinate nutrient supply with cell growth. AMPK negatively regulates mTORC1, and mTORC1 reciprocally phosphorylates S345/7 in both AMPK α-isoforms. We report that genetic or torin1-induced loss of α2-S345 phosphorylation relieves suppression of AMPK signaling; however, the regulatory effect does not translate to α1-S347 in HEK293T or MEF cells. Dephosphorylation of α2-S345, but not α1-S347, transiently targets AMPK to lysosomes, a cellular site for activation by LKB1. By mass spectrometry, we find that α2-S345 is basally phosphorylated at 2.5-fold higher stoichiometry than α1-S347 in HEK293T cells and, unlike α1, phosphorylation is partially retained after prolonged mTORC1 inhibition. Loss of α2-S345 phosphorylation in endogenous AMPK fails to sustain growth of MEFs under amino acid starvation conditions. These findings uncover an α2-specific mechanism by which AMPK can be activated at lysosomes in the absence of changes in cellular energy

Collaborative care for the detection and management of depression among adults with hypertension in South Africa: study protocol for the PRIME-SA randomised controlled trial

Background: The high co-morbidity of mental disorders, particularly depression, with non-communicable diseases (NCDs) such as cardiovascular disease (CVD), is concerning given the rising burden of NCDs globally, and the role depression plays in confounding prevention and treatment of NCDs. The objective of this randomised control trial (RCT) is to determine the real-world effectiveness of strengthened depression identification and management on depression outcomes in hypertensive patients attending primary health care (PHC) facilities in South Africa (SA). Methods/design: The study design is a pragmatic, two-arm, parallel-cluster RCT, the unit of randomisation being the clinics, with outcomes being measured for individual participants. The 20 largest eligible clinics from one district in the North West Province are enrolled in the trial. Equal numbers of hypertensive patients (n = 50) identified as having depression using the Patient Health Questionnaire (PHQ-9) are enrolled from each clinic, making up a total of 1000 participants with 500 in each arm. The nurse clinicians in the control facilities receive the standard training in Primary Care 101 (PC101), a clinical decision support tool for integrated chronic care that includes guidelines for hypertension and depression care. Referral pathways available include referrals to PHC physicians, clinical or counselling psychologists and outpatient psychiatric and psychological services. In the intervention clinics, this training is supplemented with strengthened training in the depression components of PC101 as well as training in clinical communication skills for nurse-led chronic care. Referral pathways are strengthened through the introduction of a facility-based behavioural health counsellor, trained to provide structured manualised counselling for depression and adherence counselling for all chronic conditions. The primary outcome is defined as at least 50% reduction in PHQ-9 score measured at 6 months. Discussion: This trial should provide evidence of the real world effectiveness of strengtheneddepression identification and collaborative management on health outcomes of hypertensive patients withcomorbid depression attending PHC facilities in South Africa

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities.

Personalized cancer treatments using combinations of drugs with a synergistic effect is attractive but proves to be highly challenging. Here we present an approach to uncover the efficacy of drug combinations based on the analysis of mono-drug effects. For this we used dose-response data from pharmacogenomic encyclopedias and represent these as a drug atlas. The drug atlas represents the relations between drug effects and allows to identify independent processes for which the tumor might be particularly vulnerable when attacked by two drugs. Our approach enables the prediction of combination-therapy which can be linked to tumor-driving mutations. By using this strategy, we can uncover potential effective drug combinations on a pan-cancer scale. Predicted synergies are provided and have been validated in glioblastoma, breast cancer, melanoma and leukemia mouse-models, resulting in therapeutic synergy in 75% of the tested models. This indicates that we can accurately predict effective drug combinations with translational value

Genome-Wide Profiling of Histone H3 Lysine 4 and Lysine 27 Trimethylation Reveals an Epigenetic Signature in Prostate Carcinogenesis

BACKGROUND: Increasing evidence implicates the critical roles of epigenetic regulation in cancer. Very recent reports indicate that global gene silencing in cancer is associated with specific epigenetic modifications. However, the relationship between epigenetic switches and more dynamic patterns of gene activation and repression has remained largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Genome-wide profiling of the trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3) was performed using chromatin immunoprecipitation coupled with whole genome promoter microarray (ChIP-chip) techniques. Comparison of the ChIP-chip data and microarray gene expression data revealed that loss and/or gain of H3K4me3 and/or H3K27me3 were strongly associated with differential gene expression, including microRNA expression, between prostate cancer and primary cells. The most common switches were gain or loss of H3K27me3 coupled with low effect on gene expression. The least prevalent switches were between H3K4me3 and H3K27me3 coupled with much higher fractions of activated and silenced genes. Promoter patterns of H3K4me3 and H3K27me3 corresponded strongly with coordinated expression changes of regulatory gene modules, such as HOX and microRNA genes, and structural gene modules, such as desmosome and gap junction genes. A number of epigenetically switched oncogenes and tumor suppressor genes were found overexpressed and underexpressed accordingly in prostate cancer cells. CONCLUSIONS/SIGNIFICANCE: This work offers a dynamic picture of epigenetic switches in carcinogenesis and contributes to an overall understanding of coordinated regulation of gene expression in cancer. Our data indicate an H3K4me3/H3K27me3 epigenetic signature of prostate carcinogenesis

Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium

Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan). The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (< 2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer. Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2-8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52). These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation

Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct