Functionally diversified BiP orthologs control body growth, reproduction, stress resistance, aging, and ER-Phagy in .

Cellular systems that govern protein folding rely on a delicate balance of functional redundancy and diversification to maintain protein homeostasis (proteostasis). Here, we use to demonstrate how both overlapping and divergent activities of two homologous endoplasmic reticulum (ER)-resident HSP70 family chaperones, HSP-3 and HSP-4, orchestrate ER proteostasis and contribute to organismal physiology. We identify tissue-, age-, and stress-specific protein expression patterns and find both redundant and distinct functions for HSP-3 and HSP-4 in ER stress resistance, reproduction, and body size regulation.

QUANT: a long-term multi-city commercial air sensor dataset for performance evaluation.

The QUANT study represents the most extensive open-access evaluation of commercial air quality sensor systems to date. This comprehensive study assessed 49 systems from 14 manufacturers across three urban sites in the UK over a three-year period. The resulting open-access dataset captures high time-resolution measurements of a variety of gasses (NO, NO, O, CO, CO), particulate matter (PM, PM, PM), and key meteorological parameters (humidity, temperature, atmospheric pressure).

Advancing Inclusive Mentoring: An Effective Mentor Training Program Across Comprehensive and R2 Public Universities.

Positive and inclusive mentoring of undergraduate research students, particularly of students from historically underrepresented groups is critical. The Advancing Inclusive Mentoring (AIM) program was developed to share inclusive mentoring practices with mentors at undergraduate-focused campuses and was assessed across five minority-serving universities. Self-ratings of mentorship skill as very- and exceptionally developed increased by 58% after AIM completion, and 93% of participants indicated they were likely to change their mentoring following AIM.

Small molecule FICD inhibitors suppress endogenous and pathologic FICD-mediated protein AMPylation.

The AMP transferase, FICD, is an emerging drug target finetuning stress signaling in the endoplasmic reticulum (ER). FICD is a bi-functional enzyme, catalyzing both AMP addition (AMPylation) and removal (deAMPylation) from the ER resident chaperone BiP/GRP78. Despite increasing evidence linking excessive BiP/GRP78 AMPylation to human diseases, small molecules to inhibit pathogenic FICD variants are lacking.

GRAIL1 Stabilizes Misfolded Mutant p53 through a Ubiquitin Ligase-Independent, Chaperone Regulatory Function.

Frequent (>70%) TP53 mutations often promote its protein stabilization, driving esophageal adenocarcinoma (EAC) development linked to poor survival and therapy resistance. We previously reported that during Barrett's esophagus progression to EAC, an isoform switch occurs in the E3 ubiquitin ligase RNF128 (aka GRAIL-gene related to anergy in lymphocytes), enriching isoform 1 (hereby GRAIL1) and stabilizing the mutant p53 protein. Consequently, GRAIL1 knockdown degrades mutant p53.

FICD deficiency protects mice from hypertrophy-induced heart failure via BiP-mediated activation of the UPR and ER-phagy.

Cardiomyocytes require the HSP70 chaperone BiP to maintain proteostasis in the endoplasmic reticulum (ER) following cardiac stress. The adenylyl transferase (AMPylase) FICD is increasingly recognized to regulate BiP activity through the post-translational addition of an adenosine monophosphate moiety to BiP surface residues. However, the physiological impact of FICD-mediated BiP regulation in the context of cardiovascular health is unknown.

Prognostic value of left atrial strain in aortic stenosis: A systematic review.

Purpose: Aortic stenosis (AS) is a common valvular heart disease with high morbidity and mortality. Recently, the association between peak atrial longitudinal strain (PALS) and AS clinical outcomes has been identified. This systematic review evaluates the prognostic value of PALS for adverse events in AS.

Direct Oral Anticoagulants in Patients With Cardiac Amyloidosis: A Systematic Review and Meta-Analysis.

Background And Objectives: Atrial fibrillation is common in patients with cardiac amyloidosis. However, the optimal anticoagulation strategy to prevent thromboembolic events in patients with cardiac amyloidosis and atrial fibrillation is unknown. This systematic review and meta-analysis compares direct oral anticoagulants (DOACs) vs.

Cardiac resynchronization therapy for pacing induced cardiomyopathy: Role of baseline right ventricular pacing burden.

Background: Cardiac resynchronization therapy (CRT) is indicated for patients with heart failure with reduced left ventricular ejection fraction (LVEF) and chronic right ventricular (RV) pacing burden ≥40% (pacing-induced cardiomyopathy, PICM). It is uncertain whether baseline RV pacing burden impacts response to CRT.

Methods: We conducted a retrospective study of all CRT upgrades for PICM at our hospital from January 2017 to December 2018.

Gerontology, Art, and Activism: Can the Intersection of Art, Social Research, and Community Power Lead to Lasting Change?

This paper seeks to address the question of what gerontologists and humanities scholars can learn from how their respective fields engage with critical issues of age-based intersectional disadvantage, inequality, colonialism, and exclusion. The paper considers the Uncertain Futures Project, a participatory arts-led social research study based in Manchester, United Kingdom. The project explores the inequalities of women over 50 regarding issues of work using an intersectional lens.

Low Contrast and Low kV CTA Before Transcatheter Aortic Valve Replacement: A Systematic Review.

Background: Minimizing contrast dose and radiation exposure while maintaining image quality during computed tomography angiography (CTA) for transcatheter aortic valve replacement (TAVR) is desirable, but not well established. This systematic review compares image quality for low contrast and low kV CTA versus conventional CTA in patients with aortic stenosis undergoing TAVR planning.

Methods: We performed a systematic literature review to identify clinical studies comparing imaging strategies for patients with aortic stenosis undergoing TAVR planning.

The CellPhe toolkit for cell phenotyping using time-lapse imaging and pattern recognition.

With phenotypic heterogeneity in whole cell populations widely recognised, the demand for quantitative and temporal analysis approaches to characterise single cell morphology and dynamics has increased. We present CellPhe, a pattern recognition toolkit for the unbiased characterisation of cellular phenotypes within time-lapse videos. CellPhe imports tracking information from multiple segmentation and tracking algorithms to provide automated cell phenotyping from different imaging modalities, including fluorescence.

Molecular subclusters of follicular lymphoma: a report from the United Kingdom's Haematological Malignancy Research Network.

Follicular lymphoma (FL) is morphologically and clinically diverse, with mutations in epigenetic regulators alongside t(14;18) identified as disease-initiating events. Identification of additional mutational entities confirms this cancer's heterogeneity, but whether mutational data can be resolved into mechanistically distinct subsets remains an open question. Targeted sequencing was applied to an unselected population-based FL cohort (n = 548) with full clinical follow-up (n = 538), which included 96 diffuse large B-cell lymphoma (DLBCL) transformations.

Direct oral anticoagulants in patients with atrial fibrillation and bioprosthetic valve replacement: A meta-analysis.

Objectives: This systematic review and meta-analysis compares direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) in patients with atrial fibrillation and bioprosthetic valve replacement or repair (BVR).

Background: The optimal anticoagulation therapy for patients with atrial fibrillation and a history of bioprosthetic valve replacement or repair (BVR) is not well understood.

Methods: We performed a systematic literature review to identify clinical studies that compared anticoagulation therapies for patients with atrial fibrillation and BVR.

Between a rock and a cold place: Neanderthal biocultural cold adaptations.

A large body of work focuses on the unique aspects of Neanderthal anatomy, inferred physiology, and behavior to test the assumption that Neanderthals were hyper-adapted to living in cold environments. This research has expanded over the years to include previously unexplored and potentially adaptive features such as brown adipose tissue and fire-usage. Here we review the current state of knowledge of Neanderthal cold adaptations along morphological, physiological, and behavioral lines.

Evidence of dental agenesis in late pleistocene Homo.

Objective: Differential diagnosis and tabulation of cases of dental agenesis in Middle and Upper Paleolithic Western Eurasian humans to synthesize this data and to test previous hypotheses about when recent human patterns of third molar agenesis were established.

Materials: 139 Late Pleistocene human remains and 149 individuals from three Epi-Paleolithic/ Holocene non-agricultural comparative collections.

Methods: All remains were visually and radiographically recorded by the author.

Impact of Renal Dysfunction on Outcomes after Left Ventricular Assist Device: A Systematic Review.

Background And Objectives: Renal dysfunction is a common comorbidity in patients with advanced heart failure who may benefit from left ventricular assist device (LVAD) therapy. The effect of preoperative renal dysfunction on clinical outcomes after LVAD implantation remains uncertain. We conducted a systematic review and meta-analysis to compare outcomes post-LVAD in patients with and without renal dysfunction.

The self-fulfilling prophecy of pulmonary fibrosis: a selective inspection of pathological signalling loops.

Pulmonary fibrosis is a devastating, progressive disease and carries a prognosis worse than most cancers. Despite ongoing research, the mechanisms that underlie disease pathogenesis remain only partially understood. However, the self-perpetuating nature of pulmonary fibrosis has led several researchers to propose the existence of pathological signalling loops.

Cathepsin K is a potent disaggregase of α-synuclein fibrils.

The intracellular accumulation of α-synuclein (α-syn) amyloid fibrils is a hallmark of Parkinson's disease. Because lysosomes are responsible for degrading aggregated species, enhancing lysosomal function could alleviate the overburden of α-syn. Previously, we showed that cysteine cathepsins (Cts) is the main class of lysosomal proteases that degrade α-syn, and in particular, CtsL was found to be capable of digesting α-syn fibrils.

Clinical Impact of Preexisting Right Bundle Branch Block after Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis.

Introduction: Transcatheter aortic valve replacement (TAVR) is now the treatment of choice for patients with severe aortic stenosis regardless of their surgical risk. Right bundle branch block (RBBB) can be a predictor for development of significant atrioventricular (AV) block after TAVR, requiring permanent pacemaker implantation (PPI). However, data related to the risk of PPI requirement with preexisting RBBB is scarce.

Oral pathological conditions of an Early Epipaleolithic human from Southwest Asia: Ohalo II H2 as a probable case of intentional dental ablation.

Objective: To describe the oral pathological conditions of Ohalo II H2, an Early Epipaleolithic human from southwest Asia.

Materials: The dentognathic skeleton of Ohalo II H2 and relevant comparative data from similar chronological and/or geographic contexts.

Methods: Gross and x-ray observations of oral pathological conditions and occlusal wear were made following published protocols.