Distinct inflammatory profiles in mustard lung: A study of sulfur mustard-exposed patients with serious pulmonary complications.

Mustard Lung (ML) refers to respiratory complications caused by sulfur mustard (SM) exposure, a chemical warfare agent. This study explores the inflammatory profile of SM-exposed veterans with serious ML, aiming to distinguish it from other respiratory diseases. The aim is also to comprehend the role of inflammatory markers in disease severity.

Social network dynamics of tobacco smoking and alcohol use among persons involved with the criminal legal system (PCLS): A modeling study.

Background: Tobacco smoking and alcohol use contribute to a synergy of epidemics (a "syndemic") that disproportionately affects persons involved with the criminal legal system (PCLS) and their social networks. An improved understanding of the complex interrelationships among the factors of the incarceration-tobacco-alcohol syndemic is essential to develop effective reform policies and interventions. However, collecting empirical data on these interrelationships is often hampered due to logistical and ethical challenges.

Overcoming Challenges in Small-Molecule Drug Bioavailability: A Review of Key Factors and Approaches.

The bioavailability of small-molecule drugs remains a critical challenge in pharmaceutical development, significantly impacting therapeutic efficacy and commercial viability. This review synthesizes recent advances in understanding and overcoming bioavailability limitations, focusing on key physicochemical and biological factors influencing drug absorption and distribution. We examine cutting-edge strategies for enhancing bioavailability, including innovative formulation approaches, rational structural modifications, and the application of artificial intelligence in drug design.

Role of Myeloid Cell-Specific Adenylyl Cyclase Type 7 in Lipopolysaccharide- and Alcohol-Induced Immune Responses.

Clinical and experimental evidence indicates that alcohol use causes various abnormalities in the immune system and compromises immune functions. However, the mechanistic understanding of ethanol's effects on the immune system remains limited. Cyclic AMP (cAMP) regulates multiple processes, including immune responses.

A Graphene-Based Bioactive Product with a Non-Immunological Impact on Mononuclear Cell Populations from Healthy Volunteers.

We previously described GMC, a graphene-based nanomaterial obtained from carbon nanofibers (CNFs), to be biologically compatible and functional for therapeutic purposes. GMC can reduce triglycerides' content in vitro and in vivo and has other potential bio-functional effects on systemic cells and the potential utility to be used in living systems. Here, immunoreactivity was evaluated by adding GMC in suspension at the biologically functional concentrations, ranging from 10 to 60 µg/mL, for one or several days, to cultured lymphocytes (T, B, NK), either in basal or under stimulating conditions, and monocytes that were derived under culture conditions to pro-inflammatory (GM-MØ) or anti-inflammatory (M-MØ) macrophages.

Cytokine signalling in formation of neutrophil extracellular traps: Implications for health and diseases.

Neutrophils, as essential component of the innate immune response, form a crucial part in the defence mechanisms through the release of extracellular traps (NETs). These web-like structures, composed of chromatin and antimicrobial proteins, are essential for the entrapment and inactivation of pathogens. However, either constitutive formation or inefficient clearance of NETs leads to adverse effects such as fibrosis, thrombosis, delayed wound healing and tissue damage in multiple diseases associated with sterile inflammation.

The distinctive mechanical and structural signatures of residual force enhancement in myofibers.

In muscle, titin proteins connect myofilaments together and are thought to be critical for contraction, especially during residual force enhancement (RFE) when steady-state force is elevated after an active stretch. We investigated titin's function during contraction using small-angle X-ray diffraction to track structural changes before and after 50% titin cleavage and in the RFE-deficient, titin mutant. We report that the RFE state is structurally distinct from pure isometric contractions, with increased thick filament strain and decreased lattice spacing, most likely caused by elevated titin-based forces.

Pathobiont-driven antibody sialylation through IL-10 undermines vaccination.

The pathobiont Staphylococcus aureus (Sa) induces nonprotective antibody imprints that underlie ineffective staphylococcal vaccination. However, the mechanism by which Sa modifies antibody activity is not clear. Herein, we demonstrate that IL-10 is the decisive factor that abrogates antibody protection in mice.

Mavacamten facilitates myosin head ON-to-OFF transitions and shortens thin filament length in relaxed skeletal muscle.

The first-in-its-class cardiac drug mavacamten reduces the proportion of so-called ON-state myosin heads in relaxed sarcomeres, altering contraction performance. However, mavacamten is not completely specific to cardiac myosin and can also affect skeletal muscle myosin, an important consideration since mavacamten is administered orally and so will also be present in skeletal tissue. Here, we studied the effect of mavacamten on skeletal muscle structure using small-angle X-ray diffraction.

Widespread gene-environment interactions shape the immune response to SARS-CoV-2 infection in hospitalized COVID-19 patients.

Genome-wide association studies performed in patients with coronavirus disease 2019 (COVID-19) have uncovered various loci significantly associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity. However, the underlying -regulatory genetic factors that contribute to heterogeneity in the response to SARS-CoV-2 infection and their impact on clinical phenotypes remain enigmatic. Here, we used single-cell RNA-sequencing to quantify genetic contributions to -regulatory variation in 361,119 peripheral blood mononuclear cells across 63 COVID-19 patients during acute infection, 39 samples collected in the convalescent phase, and 106 healthy controls.

Isolation and manipulation of meiotic spindles from mouse oocytes reveals migration regulated by pulling force during asymmetric division.

Spindles are essential for accurate chromosome segregation in all eukaryotic cells. This study presents a novel approach for isolating fresh mammalian spindles from mouse oocytes, establishing it as a valuable model system for a wide range of possible studies. Our method enables the investigation of the physical properties and migration force of meiotic spindles in oocytes.

Superresolution Imaging Reveals the Spatial Organization of CD81 Microdomains in Regulating Membrane Signaling on Jurkat T Cell Microvilli.

Tetraspanin proteins are closely associated with high-curvature membrane structures and play key roles in organizing membrane domains and regulating membrane signaling in immune cells. However, their specific roles in regulating T cell membrane signaling, particularly within the microvilli often characteristic of these cells, remain poorly understood. Here, we used Jurkat T cells as a model system and investigated CD81 as a member of the tetraspanin family.

TRPM7 activity drives human CD4 T-cell activation and differentiation in a magnesium dependent manner.

T lymphocyte activation is a crucial process in the regulation of innate and adaptive immune responses. The ion channel-kinase TRPM7 has previously been implicated in cellular Mg homeostasis, proliferation, and immune cell modulation. Here, we show that pharmacological and genetic silencing of TRPM7 leads to diminished human CD4 T-cell activation and proliferation following TCR mediated stimulation.

On the Analysis of Protein Genetic Architecture: Response to "Protein sequence landscapes are not so simple".

We recently reanalyzed 20 combinatorial mutagenesis datasets using a novel reference-free analysis (RFA) method and showed that high-order epistasis contributes negligibly to protein sequence-function relationships in every case. Dupic, Phillips, and Desai (DPD) commented on a preprint of our work. In our published paper, we addressed all the major issues they raised, but we respond directly to them here.

IFNγ-dependent metabolic reprogramming restrains an immature, pro-metastatic lymphatic state in melanoma.

Lymphatic vessels play a crucial role in activating anti-tumor immune surveillance but also contribute to metastasis and systemic tumor progression. Whether distinct lymphatic phenotypes exist that govern the switch between immunity and metastasis remains unclear. Here we reveal that cytotoxic immunity normalizes lymphatic function and uncouples immune and metastatic potential.

Study design and the sampling of deleterious rare variants in biobank-scale datasets.

One key component of study design in population genetics is the "geographic breadth" of a sample (i.e., how broad a region across which individuals are sampled).

Harnessing the FBXW7 somatic mutant R465C for targeted protein degradation.

Targeted protein degradation (TPD) is a pharmacological strategy that eliminates specific proteins from cells by harnessing cellular proteolytic degradation machinery. In proteasome-dependent TPD, expanding the repertoire of E3 ligases compatible with this approach could enhance the applicability of this strategy across various biological contexts. In this study, we discovered that a somatic mutant of FBXW7, R465C, can be exploited by heterobifunctional compounds for targeted protein degradation.

CrgA Forms a Dimeric Structure with Its Transmembrane Domain Sandwiched between Cytoplasmic and Periplasmic β-Sheets, Enabling Multiple Interactions with Other Divisome Proteins.

CrgA is a key transmembrane (TM) protein in the cell division process of (), the pathogen responsible for tuberculosis. While many of the divisome proteins have been identified, their structures and interactions remain largely unknown. Previous studies of CrgA using oriented-sample solid-state NMR have defined the tilt and rotation of the TM helices, but the cytoplasmic and periplasmic domains and even the oligomeric state were uncharacterized.

Effects of silica nanoparticle addition and PDMS coating on membrane performance and stability in the extraction of aromatic amines.

This study investigates novel strategies to improve membrane performance and stability in the extraction of aromatic amines for chiral amine production. The effects of silica nanoparticle addition and polydimethylsiloxane (PDMS) coating were explored, with a focus on the selective extraction of α-methylbenzylamine (MBA) and 1-methyl-3-phenylpropylamine (MPPA) from isopropyl amine (IPA). This work introduces a comparative analysis between open and tight membrane extraction (ME) systems, with and without the ionic liquid (IL) [P][N(Tf)].

Temperature-dependent fold-switching mechanism of the circadian clock protein KaiB.

The oscillator of the cyanobacterial circadian clock relies on the ability of the KaiB protein to switch reversibly between a stable ground-state fold (gsKaiB) and an unstable fold-switched fold (fsKaiB). Rare fold-switching events by KaiB provide a critical delay in the negative feedback loop of this posttranslational oscillator. In this study, we experimentally and computationally investigate the temperature dependence of fold switching and its mechanism.

The ternary complex of Mn, synthetic decapeptide DP1 (DEHGTAVMLK), and orthophosphate is a superb antioxidant.

Mn coordinated by orthophosphate (Pi), metabolites, or peptides acts as a superoxide dismutase (SOD), and these Mn antioxidant complexes are universally accumulated in extremely radiation-resistant cell types across the tree of life. This behavior prompted design of decapeptide DP1 (DEHGTAVMLK) as a Mn ligand, and development of a highly potent Mn-antioxidant (MDP) containing [Pi] = 25 mM, and [DP1] = 3 mM, the ratio found in the radioresistant bacterium , with [Mn] = 1 mM. MDP is an exceptional antioxidant, both in vitro and in vivo, and has reinvigorated the development of radiation-inactivated whole-cell vaccines.

Ion Channels in the Immune Response of Asthma.

Asthma is a common respiratory disorder characterized by chronic inflammation of the lower airways, contributing to significant morbidity, mortality, and a substantial global economic burden. It is now understood as a heterogeneous condition, with ongoing research shedding light on its complex immunological underpinnings. Ion channels, which are specialized transmembrane proteins that facilitate ion movement based on electrochemical gradients, play a crucial role in the pathophysiology of asthma.

Finding the last bits of positional information.

In a developing embryo, information about the position of cells is encoded in the concentrations of morphogen molecules. In the fruit fly, the local concentrations of just a handful of proteins encoded by the gap genes are sufficient to specify position with a precision comparable to the spacing between cells along the anterior-posterior axis. This matches the precision of downstream events such as the striped patterns of expression in the pair-rule genes, but is not quite sufficient to define unique identities for individual cells.

Arginine vasopressin (AVP) treatment increases the expression of inhibitory immune checkpoint molecules in monocyte-derived dendritic cells.

Arginine vasopressin (AVP) has disparate impacts on immune responses by divergent receptors on cells including DCs. This study was conducted with the aim of investigating the impact of AVP on the maturation and expression of the inhibitory immune checkpoint molecules in tolerogenic monocyte-derived DCs. CD14 marker was used to separate monocytes from peripheral blood mononuclear cells (PBMCs) by MACS method.