Programmable epigenome editing by transient delivery of CRISPR epigenome editor ribonucleoproteins.

Programmable epigenome editors modify gene expression in mammalian cells by altering the local chromatin environment at target loci without inducing DNA breaks. However, the large size of CRISPR-based epigenome editors poses a challenge to their broad use in biomedical research and as future therapies. Here, we present Robust ENveloped Delivery of Epigenome-editor Ribonucleoproteins (RENDER) for transiently delivering programmable epigenetic repressors (CRISPRi, DNMT3A-3L-dCas9, CRISPRoff) and activator (TET1-dCas9) as ribonucleoprotein complexes into human cells to modulate gene expression.

Synergistic Multi-Pronged Interactions Mediate the Effective Inhibition of Alpha-Synuclein Aggregation by the Chaperone HtrA1.

Unlabelled: The misfolding, aggregation, and the seeded spread of alpha synuclein (α-Syn) aggregates are linked to the pathogenesis of various neurodegenerative diseases, including Parkinson's disease (PD). Understanding the mechanisms by which chaperone proteins prevent the production and seeding of α-Syn aggregates is crucial for developing effective therapeutic leads for tackling neurodegenerative diseases. We show that a catalytically inactive variant of the chaperone HtrA1 (HtrA1*) effectively inhibits both α-Syn monomer aggregation and templated fibril seeding, and demonstrate that this inhibition is mediated by synergistic interactions between its PDZ and Protease domains and α-Syn.

The case for microbial intervention at weaning.

Weaning, the transition from a milk-based diet to solid food, coincides with the most significant shift in gut microbiome composition in the lifetime of most mammals. Notably, this period also marks a "window of opportunity" where key components of the immune system develop, and host-microbe interactions shape long-term immune homeostasis thereby influencing the risk of autoimmune and inflammatory diseases. This review provides a comprehensive analysis of the changes in nutrition, microbiota, and host physiology that occur during weaning.

An Updated Evaluation of Atrazine-Cancer Incidence Associations among Pesticide Applicators in the Agricultural Health Study Cohort.

Background: Atrazine is a common agricultural herbicide in the United States. Few epidemiologic studies have evaluated cancer risks. Previous analyses within the Agricultural Health Study (AHS) have found some evidence of associations with cancer at some sites.

Evaluation of a Team-Based Flight Risk Assessment Tool in Air Medical Transport.

Objective: Fatigue is common in emergency medical services (EMS) and is exacerbated in air medical transport. There is no gold standard for recognizing high-risk factors contributing to fatigue. Current survey instruments designed to assess fatigue in EMS have limited evidence supporting their reliability and validity.

Resident Physicians' Knowledge of Emergency Medical Services: A Comparison Between Emergency Medicine and Non-Emergency Medicine Resident Physicians.

Background and objective Emergency medical services (EMS) are often assumed to only involve bringing patients to physicians for treatment in the emergency department. However, EMS staff are also responsible for responding to physicians in the primary care setting when medical emergencies arise. While emergency medicine (EM) residents are exposed to EMS as part of their curriculum, little is known about the knowledge of other resident physicians who may interact with EMS.

Prediction and design of protease enzyme specificity using a structure-aware graph convolutional network.

Site-specific proteolysis by the enzymatic cleavage of small linear sequence motifs is a key posttranslational modification involved in physiology and disease. The ability to robustly and rapidly predict protease-substrate specificity would also enable targeted proteolytic cleavage by designed proteases. Current methods for predicting protease specificity are limited to sequence pattern recognition in experimentally derived cleavage data obtained for libraries of potential substrates and generated separately for each protease variant.

The Diesel Exhaust in Miners Study (DEMS) II: Temporal Factors Related to Diesel Exhaust Exposure and Lung Cancer Mortality in the Nested Case-Control Study.

Background: The Diesel Exhaust in Miners Study (DEMS) was an important contributor to the International Agency for Research on Cancer reclassification of diesel exhaust as a Group I carcinogen and subsequent risk assessment. We extended the DEMS cohort follow-up by 18 y and the nested case-control study to include all newly identified lung cancer deaths and matched controls (DEMS II), nearly doubling the number of lung cancer deaths.

Objective: Our purpose was to characterize the exposure-response relationship with a focus on the effects of timing of exposure and exposure cessation.

A close-in giant planet escapes engulfment by its star.

When main-sequence stars expand into red giants, they are expected to engulf close-in planets. Until now, the absence of planets with short orbital periods around post-expansion, core-helium-burning red giants has been interpreted as evidence that short-period planets around Sun-like stars do not survive the giant expansion phase of their host stars. Here we present the discovery that the giant planet 8 Ursae Minoris b orbits a core-helium-burning red giant.

Modeling of ACE2 and antibodies bound to SARS-CoV-2 provides insights into infectivity and immune evasion.

Given the COVID-19 pandemic, there is interest in understanding ligand-receptor features and targeted antibody-binding attributes against emerging SARS-CoV-2 variants. Here, we developed a large-scale structure-based pipeline for analysis of protein-protein interactions regulating SARS-CoV-2 immune evasion. First, we generated computed structural models of the Spike protein of 3 SARS-CoV-2 variants (B.

IgA deficiency destabilizes homeostasis toward intestinal microbes and increases systemic immune dysregulation.

The ability of most patients with selective immunoglobulin A (IgA) deficiency (SIgAD) to remain apparently healthy has been a persistent clinical conundrum. Compensatory mechanisms, including IgM, have been proposed, yet it remains unclear how secretory IgA and IgM work together in the mucosal system and, on a larger scale, whether the systemic and mucosal anti-commensal responses are redundant or have unique features. To address this gap in knowledge, we developed an integrated host-commensal approach combining microbial flow cytometry and metagenomic sequencing (mFLOW-Seq) to comprehensively define which microbes induce mucosal and systemic antibodies.

Computational design of nanomolar-binding antibodies specific to multiple SARS-CoV-2 variants by engineering a specificity switch of antibody 80R using RosettaAntibodyDesign (RAbD) results in potential generalizable therapeutic antibodies for novel SARS-CoV-2 virus.

The human infectious disease COVID-19 caused by the SARS-CoV-2 virus has become a major threat to global public health. Developing a vaccine is the preferred prophylactic response to epidemics and pandemics. However, for individuals who have contracted the disease, the rapid design of antibodies that can target the SARS-CoV-2 virus fulfils a critical need.

Arresting microbiome development limits immune system maturation and resistance to infection in mice.

Disruptions to the intestinal microbiome during weaning lead to negative effects on host immune function. However, the critical host-microbe interactions during weaning that are required for immune system development remain poorly understood. We find that restricting microbiome maturation during weaning stunts immune system development and increases susceptibility to enteric infection.

Prediction and Design of Protease Enzyme Specificity Using a Structure-Aware Graph Convolutional Network.

Site-specific proteolysis by the enzymatic cleavage of small linear sequence motifs is a key post-translational modification involved in physiology and disease. The ability to robustly and rapidly predict protease substrate specificity would also enable targeted proteolytic cleavage - editing - of a target protein by designed proteases. Current methods for predicting protease specificity are limited to sequence pattern recognition in experimentally-derived cleavage data obtained for libraries of potential substrates and generated separately for each protease variant.

A comprehensive survey of coronaviral main protease active site diversity in 3D: Identifying and analyzing drug discovery targets in search of broad specificity inhibitors for the next coronavirus pandemic.

Although the rapid development of therapeutic responses to combat SARS-CoV-2 represents a great human achievement, it also demonstrates untapped potential for advanced pandemic preparedness. Cross-species efficacy against multiple human coronaviruses by the main protease (MPro) inhibitor nirmatrelvir raises the question of its breadth of inhibition and our preparedness against future coronaviral threats. Herein, we describe sequence and structural analyses of 346 unique MPro enzymes from all coronaviruses represented in the NCBI Virus database.

The Ability of Paramedics to Accurately Locate Correct Anatomical Sites for Intraosseous Needle Insertion.

Introduction Intraosseous (IO) access is an alternative to peripheral intravenous access, in which a needle is inserted through the cortical bone into the medullary space using either a manual driver or an electric drill. Although studies report high success rates of IO access, failures are often attributed to incorrect site placement due to failure to adhere to anatomical landmarks. This study was designed to evaluate the ability of paramedics to locate the correct anatomic location for IO needle insertion.

Ground Versus Air: Which Mode of Emergency Medical Service Transportation Is More Likely to Crash?

Objective: We analyzed helicopter emergency medical services (HEMS) and ground emergency medical services (GEMS) crash data in the United States during 1983 to 2020 to compare incidences of total, fatal, and injury crashes.

Methods: HEMS and GEMS total, fatal, and injury crashes during 1983 to 2020 and 1988 to 2020, respectively, were analyzed in this retrospective study. Data were obtained from the National Transportation Safety Board and the National Highway Traffic Safety Administration.

Paramedic Understanding of Tension Pneumothorax and Needle Thoracostomy (NT) Site Selection.

Introduction Tension pneumothorax is an immediate threat to life. Treatment in the prehospital setting is usually achieved by needle thoracostomy (NT). Prehospital personnel are taught to perform NT, frequently in the second intercostal space (ICS) at the mid-clavicular line (MCL).

Genetic and Structural Analysis of SARS-CoV-2 Spike Protein for Universal Epitope Selection.

Evaluation of immunogenic epitopes for universal vaccine development in the face of ongoing SARS-CoV-2 evolution remains a challenge. Herein, we investigate the genetic and structural conservation of an immunogenically relevant epitope (C662-C671) of spike (S) protein across SARS-CoV-2 variants to determine its potential utility as a broad-spectrum vaccine candidate against coronavirus diseases. Comparative sequence analysis, structural assessment, and molecular dynamics simulations of C662-C671 epitope were performed.

An Incomplete Medical Record: Transfer of Care From Emergency Medical Services to the Emergency Department.

Background: Transition of care from Emergency Medical Services (EMS) to the Emergency Department (ED) represents an intersection at high risk for error. Minimal research has quantitatively examined data transfer at this point. In Pennsylvania, this handoff consists of a transfer-of-care form (TOC) provided by EMS to ED in addition to a verbal report.