Resource Use in the Randomized Master Protocol for Immune Modulators for Treating COVID-19 (ACTIV-1 IM): A Secondary Data Analysis.

Background: Coronavirus disease 2019 (COVID-19) pneumonia requires considerable healthcare resources.

Research Objective: Examine if a single dose of infliximab or abatacept, in addition to remdesivir and steroids, decreased resource utilization among participants hospitalized with COVID-19 pneumonia.

Study Design And Methods: Accelerating COVID-19 Therapeutic Interventions and Vaccines Immunomodulator (ACTIV-1 IM) master protocol was a randomized, placebo-controlled trial examining the potential benefit in time to recovery and mortality of immunomodulators infliximab, abatacept, and cenicriviroc.

Enhanced differentiation between 3-hydroxyglutaric and 2-hydroxyglutaric acids facilitates diagnostic testing for glutaric aciduria type 1.

Glutaric aciduria type 1 (GA1) is an inherited neurometabolic disorder, in which deficiency of glutaryl-CoA dehydrogenase leads to accumulation of glutaric acid (GA) and 3-hydroxyglutaric acid (3-HG). Some low excretors may exhibit only slight elevation of urinary 3-HG, with normal urinary GA, yet are at significant risk of severe clinical disease. Accurate quantitation of urinary 3-HG is crucial in diagnostic workup for GA1, but in this context, current gas chromatography-mass spectrometry (GC-MS) methods have inherent analytical challenges.

Win Ratio Analyses Using a Modified Hierarchical Composite Outcome: Insights From PARAGLIDE-HF.

Background: The win ratio (WR) is an emerging alternative for reporting composite outcomes, prioritizing clinically significant events such as mortality while incorporating surrogate measures. However, its benefits should be weighed against limitations, particularly the influence of lower hierarchical outcomes. This secondary analysis of the PARAGLIDE-HF trial performed a WR sensitivity analysis using a modified hierarchical composite outcome to assess the utility of WR sensitivity analysis and the efficacy of sacubitril/valsartan versus valsartan.

In vivo dissection of the mouse tyrosine catabolic pathway with CRISPR-Cas9 identifies modifier genes affecting hereditary tyrosinemia type 1.

Hereditary tyrosinemia type 1 is an autosomal recessive disorder caused by mutations (pathogenic variants) in fumarylacetoacetate hydrolase, an enzyme involved in tyrosine degradation. Its loss results in the accumulation of toxic metabolites that mainly affect the liver and kidneys and can lead to severe liver disease and liver cancer. Tyrosinemia type 1 has a global prevalence of approximately 1 in 100,000 births but can reach up to 1 in 1,500 births in some regions of Québec, Canada.

Type I Hsp40s/DnaJs aggregates exhibit features reminiscent of amyloidogenic structures.

A rise in temperature triggers a structural change in the human Type I 40 kDa heat shock protein (Hsp40/DnaJ), known as DNAJA1. This change leads to a less compact structure, characterized by an increased presence of solvent-exposed hydrophobic patches and β-sheet-rich regions. This transformation is validated by circular dichroism, thioflavin T binding, and Bis-ANS assays.

Improved Risk-Stratification Scheme for Mismatch-Repair Proficient Stage II Colorectal Cancers Using the Digital Pathology Biomarker QuantCRC.

Purpose: There is a need to improve current risk stratification of stage II colorectal cancer to better inform risk of recurrence and guide adjuvant chemotherapy. We sought to examine whether integration of QuantCRC, a digital pathology biomarker utilizing hematoxylin and eosin-stained slides, provides improved risk stratification over current American Society of Clinical Oncology (ASCO) guidelines.

Experimental Design: ASCO and QuantCRC-integrated schemes were applied to a cohort of 398 mismatch-repair proficient (MMRP) stage II colorectal cancers from three large academic medical centers.

J-domain proteins: From molecular mechanisms to diseases.

J-domain proteins (JDPs) are the largest family of chaperones in most organisms, but much of how they function within the network of other chaperones and protein quality control machineries is still an enigma. Here, we report on the latest findings related to JDP functions presented at a dedicated JDP workshop in Gdansk, Poland. The report does not include all (details) of what was shared and discussed at the meeting, because some of these original data have not yet been accepted for publication elsewhere or represented still preliminary observations at the time.

Three-Dimensional Cell Culture of Epididymal Basal Cells and Organoids: A Novel Tool for Toxicology.

Spermatozoa are formed in the testis but must transit through the epididymis to acquire motility and the ability to fertilize. The epididymis is a single convoluted tubule comprising several anatomically and physiologically distinct regions. The pseudostratified epithelium consists of multiple cell types, including principal cells, clear cells, narrow cells, and apical cells, that line the lumen of the epididymis.

Tumor Budding Assessment in Colorectal Carcinoma: Normalization Revisited.

Tumor budding (TB) is a powerful prognostic factor in colorectal cancer (CRC). An internationally standardized method for its assessment (International Tumor Budding Consensus Conference [ITBCC] method) has been adopted by most CRC pathology protocols. This method requires that TB counts are reported by field area (0.

Novel functions of the ER-located Hsp40s DNAJB12 and DNAJB14 on proteins at the outer mitochondrial membrane under stress mediated by CCCP.

The endoplasmic reticulum (ER) membrane provides infrastructure for intracellular signaling, protein degradation, and communication among the ER lumen, cytosol, and nucleus via transmembrane and membrane-associated proteins. Failure to maintain homeostasis at the ER leads to deleterious conditions in humans, such as protein misfolding-related diseases and neurodegeneration. The ER transmembrane heat shock protein 40 (Hsp40) proteins, including DNAJB12 (JB12) and DNAJB14 (JB14), have been studied for their importance in multiple aspects of cellular events, including degradation of misfolded membrane proteins, proteasome-mediated control of proapoptotic Bcl-2 members, and assembly of multimeric ion channels.

Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1.

Dried blood spot succinylacetone (SA) is often used as a biomarker for newborn screening (NBS) for tyrosinemia type 1 (TT1). However, false-positive SA results are often observed. Elevated SA may also be due to maleylacetoacetate isomerase deficiency (MAAI-D), which appears to be clinically insignificant.

Electronic health record characterization and outcomes of heart failure with preserved ejection fraction.

Background: Electronic health record (EHR)-based identification of heart failure with preserved ejection fraction (HFpEF) in the clinical setting may facilitate screening for clinical trials by improving the understanding of its epidemiology and outcomes; yet, previous data have yielded variable results. We sought to characterize groups identified with HFpEF by different EHR screening strategies and their associated long-term outcomes across a large and diverse population.

Methods: We retrospectively analyzed 116,499 consecutive patients from an academic referral center who underwent echocardiography, and 9,263 patients who underwent echocardiography within 6 months of right heart catheterization (RHC), between 2008 and 2018.

Vegetation browning: global drivers, impacts, and feedbacks.

As global climate conditions continue to change, disturbance regimes and environmental drivers will continue to shift, impacting global vegetation dynamics. Following a period of vegetation greening, there has been a progressive increase in remotely sensed vegetation browning globally. Given the many societal benefits that forests provide, it is critical that we understand vegetation dynamic alterations.

DNAJB12 and Hsp70 Mediate Triage of Misfolded Membrane Proteins for Proteasomal versus Lysosomal Degradation.

The endoplasmic reticulum (ER) fills the cell with a continuous network of sealed membrane tubules and sheets. The ER is subdivided into microdomains mediating one-third of total protein biosynthesis, oxidative protein folding, secretion, protein quality control, calcium signaling, marcoautophagy/autophagy, stress sensing, and apoptosis. Defects in ER-calcium homeostasis underlie several diseases.

Drought-induced increase in tree mortality and corresponding decrease in the carbon sink capacity of Canada's boreal forests from 1970 to 2020.

Canada's boreal forests, which occupy approximately 30% of boreal forests worldwide, play an important role in the global carbon budget. However, there is little quantitative information available regarding the spatiotemporal changes in the drought-induced tree mortality of Canada's boreal forests overall and their associated impacts on biomass carbon dynamics. Here, we develop spatiotemporally explicit estimates of drought-induced tree mortality and corresponding biomass carbon sink capacity changes in Canada's boreal forests from 1970 to 2020.

Temporal derivative computation in the dorsal raphe network revealed by an experimentally driven augmented integrate-and-fire modeling framework.

By means of an expansive innervation, the serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) are positioned to enact coordinated modulation of circuits distributed across the entire brain in order to adaptively regulate behavior. Yet the network computations that emerge from the excitability and connectivity features of the DRN are still poorly understood. To gain insight into these computations, we began by carrying out a detailed electrophysiological characterization of genetically identified mouse 5-HT and somatostatin (SOM) neurons.

The multiple facets of acetyl-CoA metabolism: Energetics, biosynthesis, regulation, acylation and inborn errors.

Acetyl-coenzyme A (Ac-CoA) is a core metabolite with essential roles throughout cell physiology. These functions can be classified into energetics, biosynthesis, regulation and acetylation of large and small molecules. Ac-CoA is essential for oxidative metabolism of glucose, fatty acids, most amino acids, ethanol, and of free acetate generated by endogenous metabolism or by gut bacteria.