A Hybrid Sequencing Approach Completes the Genome Sequence of Thermoanaerobacter ethanolicus JW 200

Thermoanaerobacter ethanolicus JW 200 has been identified as a potential sustainable biofuel producer due to its ability to readily ferment carbohydrates to ethanol. A hybrid sequencing approach, combining Oxford Nanopore and Illumina DNA sequence reads, was applied to produce a single contiguous genome sequence of 2,911,280 bp

Androgen Regulated Genes in Human Prostate Xenografts in Mice: Relation to BPH and Prostate Cancer

Benign prostatic hyperplasia (BPH) and prostate carcinoma (CaP) are linked to aging and the presence of androgens, suggesting that androgen regulated genes play a major role in these common diseases. Androgen regulation of prostate growth and development depends on the presence of intact epithelial-stromal interactions. Further, the prostatic stroma is implicated in BPH. This suggests that epithelial cell lines are inadequate to identify androgen regulated genes that could contribute to BPH and CaP and which could serve as potential clinical biomarkers. In this study, we used a human prostate xenograft model to define a profile of genes regulated in vivo by androgens, with an emphasis on identifying candidate biomarkers. Benign transition zone (TZ) human prostate tissue from radical prostatectomies was grafted to the sub-renal capsule site of intact or castrated male immunodeficient mice, followed by the removal or addition of androgens, respectively. Microarray analysis of RNA from these tissues was used to identify genes that were; 1) highly expressed in prostate, 2) had significant expression changes in response to androgens, and, 3) encode extracellular proteins. A total of 95 genes meeting these criteria were selected for analysis and validation of expression in patient prostate tissues using quantitative real-time PCR. Expression levels of these genes were measured in pooled RNAs from human prostate tissues with varying severity of BPH pathologic changes and CaP of varying Gleason score. A number of androgen regulated genes were identified. Additionally, a subset of these genes were over-expressed in RNA from clinical BPH tissues, and the levels of many were found to correlate with disease status. Our results demonstrate the feasibility, and some of the problems, of using a mouse xenograft model to characterize the androgen regulated expression profiles of intact human prostate tissues

Clinical Trial of Oral Nelfinavir before and during Radiation Therapy for Advanced Rectal Cancer

Purpose Nelfinavir, a PI3-kinase pathway inhibitor, is a radiosensitizer which increases tumor blood flow in preclinical models. We conducted an early-phase study to demonstrate the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to develop biomarkers of tumor perfusion and radiosensitization for this combinatorial approach. Patients and Methods Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1250 mg bd) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Perfusion CT (p-CT) and DCE-MRI scans were performed pre-treatment, after 7 days of nelfinavir and prior to last fraction of RT. Biopsies taken pre-treatment and 7 days after the last fraction of RT were analysed for tumor cell density (TCD). Results There were 3 drug-related grade 3 adverse events: diarrhea, rash, lymphopenia. On DCE-MRI, there was a mean 42% increase in median Ktrans, and a corresponding median 30% increase in mean blood flow on p-CT during RT in combination with nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT (P=0.01). Overall, 5/9 evaluable patients exhibited good tumor regression on MRI assessed by Tumor Regression Grade (mrTRG). Conclusions This is the first study to evaluate nelfinavir in combination with RT without concurrent chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT alone merits clinical evaluation, including measurement of tumor blood flow

The osteoarthritis prevention study (TOPS) - A randomized controlled trial of diet and exercise to prevent Knee Osteoarthritis:Design and rationale

Background: Osteoarthritis (OA), the leading cause of disability among adults, has no cure and is associated with significant comorbidities. The premise of this randomized clinical trial is that, in a population at risk, a 48-month program of dietary weight loss and exercise will result in less incident structural knee OA compared to control. Methods/design: The Osteoarthritis Prevention Study (TOPS) is a Phase III, assessor-blinded, 48-month, parallel 2 arm, multicenter randomized clinical trial designed to reduce the incidence of structural knee OA. The study objective is to assess the effects of a dietary weight loss, exercise, and weight-loss maintenance program in preventing the development of structural knee OA in females at risk for the disease. TOPS will recruit 1230 ambulatory, community dwelling females with obesity (Body Mass Index (BMI) ​≥ ​30 ​kg/m2) and aged ≥50 years with no radiographic (Kellgren-Lawrence grade ≤1) and no magnetic resonance imaging (MRI) evidence of OA in the eligible knee, with no or infrequent knee pain. Incident structural knee OA (defined as tibiofemoral and/or patellofemoral OA on MRI) assessed at 48-months from intervention initiation using the MRI Osteoarthritis Knee Score (MOAKS) is the primary outcome. Secondary outcomes include knee pain, 6-min walk distance, health-related quality of life, knee joint loading during gait, inflammatory biomarkers, and self-efficacy. Cost effectiveness and budgetary impact analyses will determine the value and affordability of this intervention. Discussion: This study will assess the efficacy and cost effectiveness of a dietary weight loss, exercise, and weight-loss maintenance program designed to reduce incident knee OA.Trial registration: ClinicalTrials.gov Identifier: NCT05946044.</p

Correlations between arm motor behavior and brain function following bilateral arm training after stroke:A systematic review

Background Bilateral training (BT) of the upper limb (UL) might enhance recovery of arm function after stroke. To better understand the therapeutic potential of BT, this study aimed to determine the correlation between arm motor behavior and brain structure/function as a result of bilateral arm training poststroke. Methods A systematic review of quantitative studies of BT evaluating both UL motor behavior and neuroplasticity was conducted. Eleven electronic databases were searched. Two reviewers independently selected studies, extracted data and assessed methodological quality, using the Effective Public Health Practice Project (EPHPP) tool. Results Eight studies comprising 164 participants met the inclusion criteria. Only two studies rated “strong” on the EPHPP tool. Considerable heterogeneity of participants, BT modes, comparator interventions and measures contraindicated pooled outcome analysis. Modes of BT included: in-phase and anti-phase; functional movements involving objects; and movements only. Movements were mechanically coupled, free, auditory-cued, or self-paced. The Fugl-Meyer Assessment (UL section) was used in six of eight studies, however, different subsections were used by different studies. Neural correlates were measured using fMRI and TMS in three and five studies, respectively, using a wide variety of variables. Associations between changes in UL function and neural plasticity were inconsistent and only two studies reported a statistical correlation following BT. Conclusions No clear pattern of association between UL motor and neural response to BT was apparent from this review, indicating that the neural correlates of motor behavior response to BT after stroke remain unknown. To understand the full therapeutic potential of BT and its different modes, further investigation is required

Informing prevention of stillbirth and preterm birth in Malawi:development of a minimum dataset for health facilities participating in the DIPLOMATIC collaboration

OBJECTIVE: The global research group, DIPLOMATIC (Using eviDence, Implementation science, and a clinical trial PLatform to Optimise MATernal and newborn health in low Income Countries), aims to reduce stillbirths and preterm births and optimise outcomes for babies born preterm. Minimum datasets for routine data collection in healthcare facilities participating in DIPLOMATIC (initially in Malawi) were designed to assist understanding of baseline maternal and neonatal care processes and outcomes, and facilitate evaluation of improvement interventions and pragmatic clinical trials. DESIGN: Published and grey literature was reviewed alongside extensive in-country consultation to define relevant clinical best practice guidance, and the existing local data and reporting infrastructure, to identify requirements for the minimum datasets. Data elements were subjected to iterative rounds of consultation with topic experts in Malawi and Scotland, the relevant Malawian professional bodies and the Ministry of Health in Malawi to ensure relevance, validity and feasibility. SETTING: Antenatal, maternity and specialist neonatal care in Malawi. RESULTS: The resulting three minimum datasets cover the maternal and neonatal healthcare journey for antenatal, maternity and specialist neonatal care, with provision for effective linkage of records for mother/baby pairs. They can facilitate consistent, precise recording of relevant outcomes (stillbirths, preterm births, neonatal deaths), risk factors and key care processes. CONCLUSIONS: Poor quality routine data on care processes and outcomes constrain healthcare system improvement. The datasets developed for implementation in DIPLOMATIC partner facilities reflect, and hence support delivery of, internationally agreed best practice for maternal and newborn care in low-income settings. Informed by extensive consultation, they are designed to integrate with existing local data infrastructure and reporting as well as meeting research data needs. This work provides a transferable example of strengthening data infrastructure to underpin a learning healthcare system approach in low-income settings.DIPLOMATIC is funded by the UK National Institute for Health Research

Schengen-pathway controls spatially separated and chemically distinct lignin deposition in the endodermis

Lignin is a complex polymer precisely deposited in the cell wall of specialised plant cells, where it provides essential cellular functions. Plants coordinate timing, location, abundance and composition of lignin deposition in response to endogenous and exogenous cues. In roots, a fine band of lignin, the Casparian strip encircles endodermal cells. This forms an extracellular barrier to solutes and water and plays a critical role in maintaining nutrient homeostasis. A signalling pathway senses the integrity of this diffusion barrier and can induce over-lignification to compensate for barrier defects. Here, we report that activation of this endodermal sensing mechanism triggers a transcriptional reprogramming strongly inducing the phenylpropanoid pathway and immune signaling. This leads to deposition of compensatory lignin that is chemically distinct from Casparian strip lignin. We also report that a complete loss of endodermal lignification drastically impacts mineral nutrients homeostasis and plant growth

The European Reference Genome Atlas: piloting a decentralised approach to equitable biodiversity genomics.

ABSTRACT: A global genome database of all of Earth’s species diversity could be a treasure trove of scientific discoveries. However, regardless of the major advances in genome sequencing technologies, only a tiny fraction of species have genomic information available. To contribute to a more complete planetary genomic database, scientists and institutions across the world have united under the Earth BioGenome Project (EBP), which plans to sequence and assemble high-quality reference genomes for all ∼1.5 million recognized eukaryotic species through a stepwise phased approach. As the initiative transitions into Phase II, where 150,000 species are to be sequenced in just four years, worldwide participation in the project will be fundamental to success. As the European node of the EBP, the European Reference Genome Atlas (ERGA) seeks to implement a new decentralised, accessible, equitable and inclusive model for producing high-quality reference genomes, which will inform EBP as it scales. To embark on this mission, ERGA launched a Pilot Project to establish a network across Europe to develop and test the first infrastructure of its kind for the coordinated and distributed reference genome production on 98 European eukaryotic species from sample providers across 33 European countries. Here we outline the process and challenges faced during the development of a pilot infrastructure for the production of reference genome resources, and explore the effectiveness of this approach in terms of high-quality reference genome production, considering also equity and inclusion. The outcomes and lessons learned during this pilot provide a solid foundation for ERGA while offering key learnings to other transnational and national genomic resource projects.info:eu-repo/semantics/publishedVersio

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements