Evaluating the roles of ion channels in cellular force sensing.

Mechanosensitive ion channels are found across all classes of life, suggesting that cellular force sensing is an ancient sense. In mammals, mechanosensitive ion channels are expressed in many cells and tissues, and disrupting their function can impact an array of physiological processes. The identification and characterisation of mammalian mechanosensitive ion channels has been driven by in vitro patch-clamp electrophysiology studies.

The evolutionarily conserved PhLP3 is essential for sperm development in Drosophila melanogaster.

Phosducin-like proteins (PhLP) are thioredoxin domain-containing proteins that are highly conserved across unicellular and multicellular organisms. PhLP family proteins are hypothesized to function as co-chaperones in the folding of cytoskeletal proteins. Here, we present the initial molecular, biochemical, and functional characterization of CG4511 as Drosophila melanogaster PhLP3.

Draft genome sequences of an and isolated from the urine of a male experiencing a catheter-associated urinary tract infection.

Catheter-associated urinary tract infections (CAUTIs) can be caused by a variety of microbes. Here, we describe the draft genome assemblies of two species and -purified from the catheterized urine sample of a male diagnosed with a CAUTI.

High-fidelity 3D live-cell nanoscopy through data-driven enhanced super-resolution radial fluctuation.

Live-cell super-resolution microscopy enables the imaging of biological structure dynamics below the diffraction limit. Here we present enhanced super-resolution radial fluctuations (eSRRF), substantially improving image fidelity and resolution compared to the original SRRF method. eSRRF incorporates automated parameter optimization based on the data itself, giving insight into the trade-off between resolution and fidelity.

Imaging structurally dynamic ribosomes with cryogenic electron microscopy.

Throughout the history of electron microscopy, ribosomes have served as an ideal subject for imaging and technological development, which in turn has driven our understanding of ribosomal biology. Here, we provide a historical perspective at the intersection of electron microscopy technology development and ribosome biology and reflect on how this technique has shed light on each stage of the life cycle of this dynamic macromolecular machine. With an emphasis on prokaryotic systems, we specifically describe how pairing cryo-EM with clever experimental design, time-resolved techniques, and next-generation heterogeneous structural analysis has afforded insights into the modular nature of assembly, the roles of the many transient biogenesis and translation co-factors, and the subtle variations in structure and function between strains and species.

Pore formation driven by particle impact in laser powder-blown directed energy deposition.

Process defects currently limit the use of metal additive manufacturing (AM) components in industries due to shorter fatigue life, potential for catastrophic failure, and lower strength. Conditions under which these defects form, and their mechanisms, are starting to be analyzed to improve reliability and structural integrity of these highly customized parts. We use in situ, high-speed X-ray imaging in conjunction with a high throughput laser, powder-blown directed energy deposition setup to observe powder particle impact behavior within the melt pool.

T Cell Membrane Heterogeneity Aids Antigen Recognition and T Cell Activation.

T cells are critical for co-ordinating the immune response. T cells are activated when their surface T cell receptors (TCRs) engage cognate antigens in the form of peptide-major histocompatibility complexes (pMHC) presented on the surface of antigen presenting cells (APCs). Large changes in the contact interface between T cells and APCs occur over the course of tens of minutes from the initial contact to the formation of a large-scale junction between the two cells.

Development of a National Aboriginal and Torres Strait Islander Cancer Framework: A Shared Process to Guide Effective Policy and Practice.

Indigenous Australians experience a substantially higher cancer mortality rate than non-Indigenous Australians. While cancer outcomes are improving for non-Indigenous Australians, they are worsening for Indigenous Australians. Reducing this disparity requires evidence-based and culturally-appropriate guidance.

Assessing the healthcare resource use associated with inappropriate prescribing of inhaled corticosteroids for people with chronic obstructive pulmonary disease (COPD) in GOLD groups A or B: an observational study using the Clinical Practice Research Datalink (CPRD).

Background: Recent recommendations from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) position inhaled corticosteroids (ICS) for use in chronic obstructive pulmonary disease (COPD) patients experiencing exacerbations (≥ 2 or ≥ 1 requiring hospitalisation); i.e. GOLD groups C and D.

Estimating the cost-effectiveness of daclatasvir + sofosbuvir versus sofosbuvir + ribavirin for patients with genotype 3 hepatitis C virus.

Background: As treatments for chronic hepatitis C are moving away from interferon-containing regimens, the most appropriate allocation of resources to higher cost, interferon-free, direct-acting antiviral (DAA) regimens needs to be assessed. Hepatitis C virus (HCV) genotype 3 is associated with faster disease progression and has fewer treatment options, historically, than other HCV genotypes. This analysis aims to estimate the comparative cost-effectiveness of two recently licenced interferon-free regimens for the treatment of HCV genotype 3.

Assessing the Budget Impact and Economic Outcomes of the Introduction of Daclatasvir + Asunaprevir and Sofosbuvir/Ledipasvir for the Treatment of Chronic Hepatitis C Virus Infection in Japan.

Background: The advent of highly efficacious, well-tolerated, all-oral direct-acting antiviral regimens has revolutionized the standard of care for patients chronically infected with hepatitis C virus. As efficacy and safety rates converge, prescribers and payers need to consider value for money.

Objectives: To evaluate the health economic value of daclatasvir + asunaprevir versus sofosbuvir/ledipasvir via a cost-effectiveness analysis, and determine the optimal treatment considering both costs and health outcomes in Japan.

Cobalamin riboswitches exhibit a broad range of ability to discriminate between methylcobalamin and adenosylcobalamin.

Riboswitches are a widely distributed class of regulatory RNAs in bacteria that modulate gene expression via small-molecule-induced conformational changes. Generally, these RNA elements are grouped into classes based upon conserved primary and secondary structure and their cognate effector molecule. Although this approach has been very successful in identifying new riboswitch families and defining their distributions, small sequence differences between structurally related RNAs can alter their ligand selectivity and regulatory behavior.

Estimating the Cost-Effectiveness of One-Time Screening and Treatment for Hepatitis C in Korea.

Background And Aims: This study aims to investigate the cost-effectiveness of a one-time hepatitis C virus (HCV) screening and treatment program in South Korea where hepatitis B virus (HBV) prevails, in people aged 40-70, compared to current practice (no screening).

Methods: A published Markov model was used in conjunction with a screening and treatment decision tree to model patient cohorts, aged 40-49, 50-59 and 60-69 years, distributed across chronic hepatitis C (CHC) and compensated cirrhosis (CC) health states (82.5% and 17.

A clinician's guide to the cost and health benefits of hepatitis C cure assessed from the individual patient perspective.

Background And Aims: The hepatitis C virus (HCV) remains a considerable public health challenge. Novel direct-acting antiviral (DAA) regimens offer high cure rates and the promise of reduced HCV incidence and prevalence following the up-scaling of treatment. This has focused attention towards affordability.

Hepatitis C disease transmission and treatment uptake: impact on the cost-effectiveness of new direct-acting antiviral therapies.

Background: Hepatitis C virus (HCV) treatment can reduce the incidence of future infections through removing opportunities for onward transmission. This benefit is not captured in conventional cost-effectiveness evaluations of treatment and is particularly relevant in patient groups with a high risk of transmission, such as those people who inject drugs (PWID), where the treatment rates have been historically low. This study aimed to quantify how reduced HCV transmission changes the cost-effectiveness of new direct-acting antiviral (DAA) regimens as a function of treatment uptake rates.

Value of Sustained Virologic Response in Patients with Hepatitis C as a Function of Time to Progression of End-Stage Liver Disease.

Background: Targeted intervention in patients with hepatitis C virus (HCV) closest to end-stage liver disease (ESLD) progression may offer an approach to treatment prioritisation whilst delivering benefits for patients and the healthcare system. In contrast to previous HCV economic analyses, this study aimed to estimate the health economic value of sustained virologic response (SVR) stratified by the patient's propensity to progress to ESLD.

Methods: An HCV natural history model was adapted to estimate the value of avoiding ESLD complications following SVR, assessed as cost offsets and quality-adjusted life year (QALY) gains, as a function of time to ESLD at treatment initiation.

The cost-effectiveness of daclatasvir-based regimens for the treatment of hepatitis C virus genotypes 1 and 4 in the UK.

Objective: This study aimed to determine the cost-effectiveness of daclatasvir in combination with other medicinal products for the treatment of patients with hepatitis C virus genotypes 1 and 4 and advanced liver disease in the UK.

Methods: A published and validated Markov model designed to simulate the natural history of chronic hepatitis C was used to compare daclatasvir with relevant treatment options for patients with hepatitis C virus genotypes 1 and 4 and a METAVIR score of F3-F4. Patients were defined according to their treatment status; that is, naive, experienced or interferon ineligible/intolerant.

Estimating the cost-effectiveness of daclatasvir plus asunaprevir in difficult to treat Japanese patients chronically infected with hepatitis C genotype 1b.

Aim: Standard of care for chronic hepatitis C in Japan is currently a pegylated interferon (IFN)-α + ribavirin (PR)-based regimen, notably associated with efficacy and tolerability issues. The advent of novel direct-acting antivirals (DAA) has provided more efficacious and better tolerated treatments. This study investigated the cost-effectiveness of the daclatasvir + asunaprevir (DCV + ASV) DAA regimen in patients infected with hepatitis C virus (HCV) genotype 1b who had previously not responded to or were ineligible for IFN-containing regimens.

Estimating the clinical and economic benefit associated with incremental improvements in sustained virologic response in chronic hepatitis C.

Introduction: Hepatitis C virus (HCV) infection is one of the principle causes of chronic liver disease. Successful treatment significantly decreases the risk of hepatic morbidity and mortality. Current standard of care achieves sustained virologic response (SVR) rates of 40-80%; however, the HCV therapy landscape is rapidly evolving.

Estimating the Long-Term Clinical and Economic Outcomes of Daclatasvir Plus Asunaprevir in Difficult-to-Treat Japanese Patients Chronically Infected with Hepatitis C Genotype 1b.

Objectives: Japan has one of the highest endemic rates of hepatitis C virus (HCV) infection. Treatments in Japan are currently limited to interferon-alfa-based regimens, which are associated with tolerability and efficacy issues. A novel regimen combining two oral HCV therapies, daclatasvir and asunaprevir (DCV + ASV), has shown favorable results in Japanese patients with chronic genotype 1b HCV infection.