Structure and function of the human mitochondrial MRS2 channel.

The human mitochondrial RNA splicing 2 protein (MRS2) has been implicated in Mg transport across mitochondrial inner membranes, thus having an important role in Mg homeostasis critical for mitochondrial integrity and function. However, the molecular mechanisms underlying its fundamental channel properties such as ion selectivity and regulation remain unclear. Here we present a structural and functional investigation of MRS2.

Evaluation of flood metrics across the Mississippi-Atchafalaya River Basin and their relation to flood damages.

Societal risks from flooding are evident at a range of spatial scales and climate change will exacerbate these risks in the future. Assessing flood risks across broad geographical regions is a challenge, and often done using streamflow time-series records or hydrologic models. In this study, we used a national-scale hydrological model to identify, assess, and map 16 different streamflow metrics that could be used to describe flood risks across 34,987 HUC12 subwatersheds within the Mississippi-Atchafalaya River Basin (MARB).

Storing and managing water for the environment is more efficient than mimicking natural flows.

Dams and reservoirs are often needed to provide environmental water and maintain suitable water temperatures for downstream ecosystems. Here, we evaluate if water allocated to the environment, with storage to manage it, might allow environmental water to more reliably meet ecosystem objectives than a proportion of natural flow. We use a priority-based water balance operations model and a reservoir temperature model to evaluate 1) pass-through of a portion of reservoir inflow versus 2) allocating a portion of storage capacity and inflow for downstream flow and stream temperature objectives.

Structural basis for hyperpolarization-dependent opening of human HCN1 channel.

Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear.

Glycemic Control and Obesity Among People With Type 2 Diabetes in Europe and Australia: A Retrospective Cohort Analysis.

Introduction: In people with type 2 diabetes (PwT2D) who also have obesity, efforts targeting weight loss, including lifestyle, medication and surgical interventions, are recommended. The objective of this study was to explore the relationship between glycemic control and obesity among PwT2D in Europe and Australia using recent real-world data and applying consistent methodology across countries.

Methods: Retrospective study utilizing IQVIA electronic medical records (EMR) databases grouped into panels based on specialty of contributing physicians.

The Decline of Small Practice in Colorectal Surgery: Practice Consolidation From 2015-2022.

Introduction: Physicians have gravitated toward larger group practice arrangements in recent years. However, consolidation trends in colorectal surgery have yet to be well described. Our objective was to assess current trends in practice consolidation within colorectal surgery and evaluate underlying demographic trends including age, gender, and geography.

Preventive treatment patterns in the adult migraine population: an observational UK study over 7 years.

Background: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are recommended by the United Kingdom National Institute of Health and Care Excellence for the prevention of migraine as treatment beyond third line. We report migraine prevalence and preventive treatment patterns in the adult United Kingdom primary care population over a 7.5-year period, focusing on patients ceasing ≥ 3 oral preventive medication classes.

Structure and function of the human mitochondrial MRS2 channel.

The human Mitochondrial RNA Splicing 2 protein (MRS2) has been implicated in Mg transport across mitochondrial inner membranes, thus playing an important role in Mg homeostasis critical for mitochondrial integrity and function. However, the molecular mechanisms underlying its fundamental channel properties such as ion selectivity and regulation remain unclear. Here, we present structural and functional investigation of MRS2.

Structural Basis for Hyperpolarization-dependent Opening of the Human HCN1 Channel.

Hyperpolarization and cyclic-nucleotide (HCN) activated ion channels play a critical role in generating self-propagating action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN channels activate upon membrane hyperpolarization, but the structural mechanisms underlying this gating behavior remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 in Closed, Intermediate, and Open states.

Characteristics of patients initiating treatment with baricitinib and outcomes at follow-up: analysis of BSRBR-RA Registry data.

Objectives: To describe selected baseline characteristics, continuation with baricitinib and disease activity over time in patients initiating treatment with baricitinib in a UK real-world rheumatology setting.

Methods: Baseline and follow-up data were analysed from baricitinib-treated patients newly recruited to the British Society for Rheumatology Biologics Registry-RA (BSRBR-RA) baricitinib cohort between 1 January 2018 and 31 March 2020. The primary objective was to evaluate continuation of baricitinib treatment in patients with at least one follow-up.

Structural basis for mechanotransduction in a potassium-dependent mechanosensitive ion channel.

Mechanosensitive channels of small conductance, found in many living organisms, open under elevated membrane tension and thus play crucial roles in biological response to mechanical stress. Amongst these channels, MscK is unique in that its activation also requires external potassium ions. To better understand this dual gating mechanism by force and ligand, we elucidate distinct structures of MscK along the gating cycle using cryo-electron microscopy.

A review of adverse events in animals and children after secondary exposure to transdermal hormone-containing medicinal products.

Background: Hormonal replacement therapy is widely used to treat conditions in humans, the most well-known indication being the relief of menopausal symptoms in women. Many of the hormone-containing products (HCP) are applied to the skin. This transdermal delivery poses a risk to animals and humans through secondary exposure, especially when product information is not strictly followed.

Nanopore tweezers measurements of RecQ conformational changes reveal the energy landscape of helicase motion.

Helicases are essential for nearly all nucleic acid processes across the tree of life, yet detailed understanding of how they couple ATP hydrolysis to translocation and unwinding remains incomplete because their small (∼300 picometer), fast (∼1 ms) steps are difficult to resolve. Here, we use Nanopore Tweezers to observe single Escherichia coli RecQ helicases as they translocate on and unwind DNA at ultrahigh spatiotemporal resolution. Nanopore Tweezers simultaneously resolve individual steps of RecQ along the DNA and conformational changes of the helicase associated with stepping.

Barriers and Facilitators to the Initiation of Injectable Therapies for Type 2 Diabetes Mellitus: A Mixed Methods Study.

Introduction: Initiation of injectable therapies in type 2 diabetes (T2D) is often delayed, however the reasons why are not fully understood.

Methods: A mixed methods study performed in sequential phases. Phase 1: focus groups with people with T2D (injectable naïve [n = 12] and experienced [n = 5]) and healthcare professionals (HCPs; nurses [n = 5] and general practitioners (GPs) [n = 7]) to understand their perceptions of factors affecting initiation of injectables.

Sequence-dependent mechanochemical coupling of helicase translocation and unwinding at single-nucleotide resolution.

We used single-molecule picometer-resolution nanopore tweezers (SPRNT) to resolve the millisecond single-nucleotide steps of superfamily 1 helicase PcrA as it translocates on, or unwinds, several kilobase-long DNA molecules. We recorded more than two million enzyme steps under various assisting and opposing forces in diverse adenosine tri- and diphosphate conditions to comprehensively explore the mechanochemistry of PcrA motion. Forces applied in SPRNT mimic forces and physical barriers PcrA experiences , such as when the helicase encounters bound proteins or duplex DNA.

Investigation of the distance to slaughterhouses and weather parameters in the occurrence of porcine reproductive and respiratory syndrome outbreaks in U.S. swine breeding herds.

Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically important diseases affecting the swine industry. The main objective of this study was to assess whether sow farm distance to slaughterhouses and meteorological variables were associated with PRRS outbreaks. This case-control study paired 104 sow farms with or without a reported PRRS outbreak (N = 208) during the same period.

Early and ongoing stable glycaemic control is associated with a reduction in major adverse cardiovascular events in people with type 2 diabetes: A primary care cohort study.

Aim: To determine whether achieving early glycaemic control, and any subsequent glycaemic variability, was associated with any change in the risk of major adverse cardiovascular events (MACE).

Materials And Methods: A retrospective cohort analysis from the Oxford-Royal College of General Practitioners Research and Surveillance Centre database-a large, English primary care network-was conducted. We followed newly diagnosed patients with type 2 diabetes, on or after 1 January 2005, aged 25 years or older at diagnosis, with HbA1c measurements at both diagnosis and after 1 year, plus five or more measurements of HbA1c thereafter.

Suboptimal Uptake, Retention, and Adherence of Daily Oral Prexposure Prophylaxis Among People With Opioid Use Disorder Receiving Hepatitis C Virus Treatment.

Background: Daily oral preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) prevents human immunodeficiency (HIV) among people who inject drugs (PWID). Despite rising HIV incidence and injection drug use (IDU), PrEP use remains low and there is limited research about uptake, adherence, and retention among PWID.

Methods: The ANCHOR investigation evaluated a community-based care model collocating hepatitis C virus (HCV) treatment, medication for opioid use disorder (OUD), and PrEP in individuals in Washington, DC, and Baltimore, Maryland.

Cardiovascular risk profiles: A cross-sectional study evaluating the generalizability of the glucagon-like peptide-1 receptor agonist cardiovascular outcome trials REWIND, LEADER and SUSTAIN-6 to the real-world type 2 diabetes population in the United Kingdom.

Aims: To determine the proportion of UK patients with type 2 diabetes (T2D) who meet the cardiovascular (CV) or combined CV/core eligibility criteria used for the CV outcome trials (CVOTs) of UK-marketed glucagon-like peptide-1 receptor agonists (GLP-1RAs) showing CV benefit (dulaglutide in REWIND, liraglutide in LEADER and injectable semaglutide in SUSTAIN-6).

Materials And Methods: Adults with T2D on/before June 2018 were identified from the UK Clinical Practice Research Datalink GOLD primary care database and linked to Hospital Episode Statistics data (Protocol 19_262). Patient CV and clinical data were evaluated against the CVOT eligibility criteria.

A survey of veterinary professionals in Sweden: Adverse event reporting and access to product safety information.

Background: Pharmacovigilance based on spontaneously reported suspected adverse events (AEs) from veterinary professionals is a powerful tool for detecting potential risks of using medicinal products. However, it is heavily dependent on the voluntary participation of veterinary professionals. Estimates suggest that over 90% of suspected AEs remain unreported.

Assessment of transportation system disruption and accessibility to critical amenities during flooding: Iowa case study.

Natural disasters, such as flooding, can cause severe social, environmental, and economic damage to a community. Transportation infrastructure plays an essential role in flood response and recovery efforts. However, flooding may disturb road functionality and generate direct and indirect adverse impacts, including the loss of access to essential services.