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Proteasome dysfunction is implicated in the pathogenesis of neurodegenerative diseases and age-related proteinopathies. Using a C. elegans model, we demonstrate that 20S proteasome hyperactivation, facilitated by 20S gate-opening, accelerates the targeting of intrinsically disordered proteins. This leads to increased protein synthesis, extensive rewiring of the proteome and transcriptome, enhanced oxidative stress defense, accelerated lipid metabolism, and peroxisome proliferation. It also promotes ER-associated degradation (ERAD) of aggregation-prone proteins, such as alpha-1 antitrypsin (ATZ) and various lipoproteins...

The rational design of the antibiotic treatment of bacterial infections employs these drugs to reach concentrations that exceed the minimum needed to prevent the replication of the target bacteria. However, within a treated patient, spatial and physiological heterogeneity promotes antibiotic gradients such that the concentration of antibiotics at specific sites is below the minimum needed to inhibit bacterial growth. Here, we investigate the effects of sub-inhibitory antibiotic concentrations on three parameters central to bacterial infection and the success of antibiotic treatment, using in vitro experiments with Staphylococcus aureus and mathematical-computer simulation models...

Mosquito-borne viruses cause more than 400 million annual infections and place over half of the world's population at risk. Despite this importance, the mechanisms by which arboviruses infect the mosquito host and disseminate to tissues required for transmission are not well understood. Here, we provide evidence that mosquito immune cells, known as hemocytes, play an integral role in the dissemination of dengue virus (DENV) and Zika virus (ZIKV) in the mosquito Aedes aegypti . We establish that phagocytic hemocytes are a focal point for virus infection and demonstrate that these immune cell populations facilitate virus dissemination to the ovaries and salivary glands...

East African cichlid fishes have diversified in an explosive fashion, but the (epi)genetic basis of the phenotypic diversity of these fishes remains largely unknown. Although transposable elements (TEs) have been associated with phenotypic variation in cichlids, little is known about their transcriptional activity and epigenetic silencing. Here, we describe dynamic patterns of TE expression in African cichlid gonads and during early development. Orthology inference revealed an expansion of piwil1 genes in Lake Malawi cichlids, likely driven by PiggyBac TEs...

UNLABELLED: Both alcohol use disorder (AUD) and Alzheimer's Disease and Related Dementias (ADRD) appear to include disruption in the balance of excitation and inhibition in the cortex, but their potential interactions are unclear. We examined the effect of moderate voluntary binge alcohol consumption on the aged, pre-disease neuronal environment by measuring intrinsic excitability and spontaneous neurotransmission on prefrontal cortical pyramidal (excitatory, glutamatergic) and non-pyramidal (inhibitory, GABAergic) neurons following a prolonged period of abstinence from alcohol in mice...

BACKGROUND: Despite the widespread use of ultra-massive transfusion (UMT) as an intervention for trauma patients in hemorrhagic shock, no standard definition exists. We performed a systematic review to determine a consensus definition for UMT. METHODS: A search was performed from 1979-2022. The authors screened studies defining UMT and associated outcomes as defined by our prespecified PICO questions. The PRISMA guidelines were used. RESULTS: 1662 articles met criteria for eligibility assessment, 17 for full-text review and eight for data extraction...

The thesis of Weak Unrestricted Composition says that every pair of objects has a fusion. This thesis has been argued by Contessa (Analysis 72(3):455-457, 2012) and Smith (Erkenntnis 84(1):41-55, 2019) to be compatible with the world being junky and hence to evade an argument against the necessity of Strong Unrestricted Composition proposed by Bohn (Analysis 69(1):27-31, 2009a, Philos Q 59(235):193-201, 2009b). However, neither Weak Unrestricted Composition alone nor the different variants of it that have been proposed in the literature can provide us with a satisfying answer to the special composition question, or so we will argue...

OBJECTIVE: Provide benchmarks for the rates of complications by type of surgery performed. STUDY DESIGN: Prospective multicenter database. BACKGROUND: We have previously examined overall construct survival and complication rates for ASD surgery. However, the relationship between type of surgery and construct survival warrants more detailed assessment. METHODS: Eight surgical scenarios were defined based on the levels treated, previous fusion status (primary [P] vs...

BACKGROUND: Long covid (post covid-19 condition) is a complex condition with diverse manifestations, uncertain prognosis and wide variation in current approaches to management. There have been calls for formal quality standards to reduce a so-called "postcode lottery" of care. The original aim of this study-to examine the nature of quality in long covid care and reduce unwarranted variation in services-evolved to focus on examining the reasons why standardizing care was so challenging in this condition...

OBJECTIVE: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are novel high-cost treatments for the prevention of migraine. This study presents data on utilisation, expenditure and treatment patterns with CGRP mAbs available under a managed access protocol in Ireland, to a cohort of treatment refractory patients (failed three or more previous treatments) with chronic migraine. METHODS: Data was extracted from the Primary Care Reimbursement Service (PCRS) High Tech claims database and special drug request online system, and analysed using Microsoft Excel and SAS...

We approach the questions, what part of evolutionary change results from selection, and what is the adaptive information flow into a population undergoing selection, as a problem of quantifying the divergence of typical trajectories realized under selection from the expected dynamics of their counterparts under a null stochastic-process model representing the absence of selection. This approach starts with a formulation of adaptation in terms of information and from that identifies selection from the genetic parameters that generate information flow; it is the reverse of a historical approach that defines selection in terms of fitness, and then identifies adaptive characters as those amplified in relative frequency by fitness...

Cerebral amyloid angiopathy (CAA) is associated with the accumulation of fibrillar Aβ peptides upon and within the cerebral vasculature, which leads to loss of vascular integrity and contributes to disease progression in Alzheimer's disease (AD). We investigate the structure of human-derived Aβ40 fibrils obtained from patients diagnosed with sporadic or familial Dutch-type (E22Q) CAA. Using cryo-EM, two primary structures are identified containing elements that have not been observed in in vitro Aβ40 fibril structures...

Here, we report on the process of a highly impactful and successful creative, collaborative, and multi-partner public engagement project, Radiation Reveal. It brought together ten young adults aged 17-25-year-olds with experience of radiotherapy with researchers at Cancer Research UK RadNet City of London across three 2-hour online workshops. Our aims were to 1) initiate discussions between young adults and radiation researchers, and 2) identify what people wish they had known about radiotherapy before or during treatment...

INTRODUCTION: Post-operative pelvic & acetabular fixation patients are conventionally imaged using 3-view radiographs (AP, inlet and outlet). The efficacy of such radiographs is inconsistent due to technical difficulties capturing an adequate view, often necessitating repeat radiographs and therefore increasing radiation exposure. Radiographs can be difficult to interpret, limiting the assessment of fracture reduction and fixation, especially with respect to metalwork positioning around articular surfaces...

BACKGROUND AND OBJECTIVE: The European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Urological Pathology (ISUP)-International Society of Geriatric Oncology (SIOG) guidelines provide recommendations for the management of clinically localised prostate cancer (PCa). This paper aims to present a summary of the 2024 version of the EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on the screening, diagnosis, and treatment of clinically localised PCa...

BACKGROUND: We present the largest study of the frequency and nature of visual complications in a cohort of 350 patients consecutively diagnosed with giant cell arteritis (GCA). METHODS: All individuals were assessed using structured forms and diagnosed using imaging or biopsy. A binary logistic regression model was used to analyse data for predicting visual loss. RESULTS: Visual symptoms occurred in 101 (28.9%) patients, with visual loss in one or both eyes in 48 (13...

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Marine sponges, including the crumb of bread sponge, Hymeniacidon sinapium, display allorejection responses to contact with conspecifics in both experimental and natural settings. These responses have been used to infer immunocompetence in a variety of marine invertebrates. However, larvae and juveniles released from several marine sponge species fuse and form chimeras. Some of these chimeras persist, whereas others eventually break down, revealing a period of allogeneic non-responsiveness that varies depending on the species...

Current diagnostic systems for Alzheimer's disease (AD) rely upon clinical signs and symptoms, despite the fact that the multiplicity of clinical symptoms renders various neuropsychological assessments inadequate to reflect the underlying pathophysiological mechanisms. Since putative neuroimaging biomarkers play a crucial role in understanding the etiology of AD, we sought to stratify the diverse relationships between AD biomarkers and cognitive decline in the aging population and uncover risk factors contributing to the diversities in AD...

Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose...