Molt-dependent transcriptomic analysis of cement proteins in the barnacle Amphibalanus amphitrite

Abstract Background A complete understanding of barnacle adhesion remains elusive as the process occurs within and beneath the confines of a rigid calcified shell. Barnacle cement is mainly proteinaceous and several individual proteins have been identified in the hardened cement at the barnacle-substrate interface. Little is known about the molt- and tissue-specific expression of cement protein genes but could offer valuable insight into the complex multi-step processes of barnacle growth and adhesion. Methods The main body and sub-mantle tissue of the barnacle Amphibalanus amphitrite (basionym Balanus amphitrite) were collected in pre- and post-molt stages. RNA-seq technology was used to analyze the transcriptome for differential gene expression at these two stages and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) was used to analyze the protein content of barnacle secretions. Results We report on the transcriptomic analysis of barnacle cement gland tissue in pre- and post-molt growth stages and proteomic investigation of barnacle secretions. While no significant difference was found in the expression of cement proteins genes at pre- and post-molting stages, expression levels were highly elevated in the sub-mantle tissue (where the cement glands are located) compared to the main barnacle body. We report the discovery of a novel 114kD cement protein, which is identified in material secreted onto various surfaces by adult barnacles and with the encoding gene highly expressed in the sub-mantle tissue. Further differential gene expression analysis of the sub-mantle tissue samples reveals a limited number of genes highly expressed in pre-molt samples with a range of functions including cuticular development, biominerialization, and proteolytic activity. Conclusions The expression of cement protein genes appears to remain constant through the molt cycle and is largely confined to the sub-mantle tissue. Our results reveal a novel and potentially prominent protein to the mix of cement-related components in A. amphitrite. Despite the lack of a complete genome, sample collection allowed for extended transcriptomic analysis of pre- and post-molt barnacle samples and identified a number of highly-expressed genes. Our results highlight the complexities of this sessile marine organism as it grows via molt cycles and increases the area over which it exhibits robust adhesion to its substrate.http://deepblue.lib.umich.edu/bitstream/2027.42/115487/1/12864_2015_Article_2076.pd

Mate Value and Self-Esteem: Evidence from Eight Cultural Groups

This paper explores self-perceived mate value (SPMV), and its association with self-esteem, in eight cultures. 1066 participants, from 8 cultural groups in 7 countries, rated themselves on 24 SPMVs and completed a measure of self-esteem. Consistent with evolutionary theory, women were more likely to emphasise their caring and passionate romantic nature. In line with previous cross-cultural research, characteristics indicating passion and romance and social attractiveness were stressed more by respondents from individualistic cultures, and those higher on self-expression (rather than survival) values; characteristics indicative of maturity and confidence were more likely to be mentioned by those from Traditional, rather than Secular, cultures. Contrary to gender role theory, societal equality had only limited interactions with sex and SPMV, with honesty of greater significance for male self-esteem in societies with unequal gender roles. These results point to the importance of cultural and environmental factors in influencing self-perceived mate qualities, and are discussed in relation to broader debates about the impact of gender role equality on sex differences in personality and mating strategies

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas.

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P \u3c .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy

Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy. (C) 2017 by American Society of Clinical Oncolog

Pattern of Relapse and Treatment Response in WNT- Activated Medulloblastoma

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses

In-Datacenter Performance Analysis of a Tensor Processing Unit

Many architects believe that major improvements in cost-energy-performance must now come from domain-specific hardware. This paper evaluates a custom ASIC---called a Tensor Processing Unit (TPU)---deployed in datacenters since 2015 that accelerates the inference phase of neural networks (NN). The heart of the TPU is a 65,536 8-bit MAC matrix multiply unit that offers a peak throughput of 92 TeraOps/second (TOPS) and a large (28 MiB) software-managed on-chip memory. The TPU's deterministic execution model is a better match to the 99th-percentile response-time requirement of our NN applications than are the time-varying optimizations of CPUs and GPUs (caches, out-of-order execution, multithreading, multiprocessing, prefetching, ...) that help average throughput more than guaranteed latency. The lack of such features helps explain why, despite having myriad MACs and a big memory, the TPU is relatively small and low power. We compare the TPU to a server-class Intel Haswell CPU and an Nvidia K80 GPU, which are contemporaries deployed in the same datacenters. Our workload, written in the high-level TensorFlow framework, uses production NN applications (MLPs, CNNs, and LSTMs) that represent 95% of our datacenters' NN inference demand. Despite low utilization for some applications, the TPU is on average about 15X - 30X faster than its contemporary GPU or CPU, with TOPS/Watt about 30X - 80X higher. Moreover, using the GPU's GDDR5 memory in the TPU would triple achieved TOPS and raise TOPS/Watt to nearly 70X the GPU and 200X the CPU.Comment: 17 pages, 11 figures, 8 tables. To appear at the 44th International Symposium on Computer Architecture (ISCA), Toronto, Canada, June 24-28, 201

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Evaluating an addiction medicine unit in Sudbury, Ontario Canada: a mixed-methods study protocol

Abstract Background In response to the escalating global prevalence of substance use and the specific challenges faced in Northern Ontario, Canada, an Addiction Medicine Unit (AMU) was established at Health Sciences North (HSN) in Sudbury. This protocol outlines the approach for a comprehensive evaluation of the AMU, with the aim of assessing its impact on patient outcomes, healthcare utilization, and staff perspectives. Methods We conducted a parallel mixed-method study that encompassed the analysis of single-center-level administrative health data and primary data collection, including a longitudinal observational study (target n = 1,200), pre- and post-admission quantitative interviews (target n = 100), and qualitative interviews (target n = 25 patients and n = 15 staff). We implemented a participatory approach to this evaluation, collaborating with individuals who possess lived or living expertise in drug use, frontline staff, and decision-makers across the hospital. Data analysis methods encompass a range of statistical techniques, including logistic regression models, Cox proportional hazards models, Kaplan-Meier curves, Generalized Estimating Equations (GEE), and thematic qualitative analysis, ensuring a robust evaluation of patient outcomes and healthcare utilization. Discussion This protocol serves as the foundation for a comprehensive assessment designed to provide insights into the AMU’s effectiveness in addressing substance use-related challenges, reducing healthcare disparities, and improving patient outcomes. All study procedures have been meticulously designed to align with the ethical principles outlined in the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. The findings will be disseminated progressively through committees and working groups established for this research, and subsequently published in peer-reviewed journals. Anticipated outcomes include informing evidence-based healthcare decision-making and driving improvements in addiction treatment practices within healthcare settings