EZH2 directly methylates PARP1 and regulates its activity in cancer.

DNA repair dysregulation is a key driver of cancer development. Understanding the molecular mechanisms underlying DNA repair dysregulation in cancer cells is crucial for cancer development and therapies. Here, we report that enhancer of zeste homolog 2 (EZH2) directly methylates poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1), an essential enzyme involved in DNA repair, and regulates its activity.

A sodium channel mutant removes fast inactivation with the inactivation particle bound.

Fast inactivation is a key feature of voltage-gated sodium channels and is pivotal for countless physiological functions. Despite the prevalence of the canonical ball-and-chain model, more recent structural results suggest that fast inactivation requires multiple conformational changes beyond the binding of the inactivation particle, the IFM motif. Combining ionic current, gating current, and fluorescent measurements, here we showed that a double mutant at the bottom of the pore domain (CW) removes fast inactivation by interrupting the communication of the IFM motif and the pore.

MGA-related syndrome: A proposed novel disorder.

MGA (OMIM: 616061) encodes a dual-specificity transcription factor that regulates the expression of Max-network and T-box family target genes, important in embryogenesis. Previous studies have linked MGA to various phenotypes, including neurodevelopmental disorders, congenital heart disease, and early-onset Parkinson's disease. Here, we describe the clinical phenotype of individuals with de novo, heterozygous predicted loss-of-function variants in MGA, suggesting a unique disorder involving both neurodevelopmental and congenital anomalies.

Toward Polymeric Room Temperature Acid Generators.

Although a variety of acid-generating molecules have been developed, the formation of toxic byproducts and the need for light-activation or temperatures that may be incompatible with physiological conditions leave room for the optimization of biocompatible acid-generators. Herein, we report 4-hydroxybenzyl chloride derivatives that generate hydrochloric acid via hydrolysis at the benzylic position at room temperature in the absence of light. Utilizing the acetal protected 4-hydroxybenzyl chloride scaffold, we access a myriad of compounds that generate acid at different rates.

Improving Diagnosis and Management of Opioid-Induced Constipation (OIC) in Clinical Practice: An Italian Expert Opinion.

Opioid-induced constipation (OIC) is a very common and troublesome gastrointestinal side effect following the use of opioids. Despite existing international guidelines, OIC is largely underdiagnosed and undertreated. ECHO OIC is a European project designed to improve the diagnosis and management of OIC at the primary care level.

The Development of a Human Respiratory Mucosa-on-a-Chip Using Human Turbinate-Derived Mesenchymal Stem Cells.

: This study aimed to investigate the influence of a respiratory mucosa-on-a-chip on the respiratory epithelial differentiation potential of human nasal inferior turbinate-derived stem cells (hNTSCs). : After isolating hNTSCs from five patients, we divided the samples from the patients into the study group with a mucosa-on-a-chip and the control group with conventional differentiation (using conventional differentiation methods). The respiratory epithelial differentiation potential of hNTSCs was analyzed by histology and gene expression.

Hydrogen Gas Inhalation Alleviates Airway Inflammation and Oxidative Stress on Ovalbumin-Induced Asthmatic BALB/c Mouse Model.

Airway inflammatory diseases, such as asthma, are a global public health concern owing to their chronic inflammatory effects on the respiratory mucosa. Molecular hydrogen (H) has recently been recognized for its antioxidant and anti-inflammatory properties. In this study, we examined the therapeutic potential of H in airway inflammation using an ovalbumin (OVA)-induced BALB/c mouse model of allergic asthma.

Mechano-dependent sorbitol accumulation supports biomolecular condensate.

Condensed droplets of protein regulate many cellular functions, yet the physiological conditions regulating their formation remain largely unexplored. Increasing our understanding of these mechanisms is paramount, as failure to control condensate formation and dynamics can lead to many diseases. Here, we provide evidence that matrix stiffening promotes biomolecular condensation in vivo.

Aerosolized Harmful Algal Bloom Toxin Microcystin-LR Induces Type 1/Type 17 Inflammation of Murine Airways.

Harmful algal blooms are increasing globally and pose serious health concerns releasing cyanotoxins. Microcystin-LR (MC-LR), one of the most frequently produced cyanotoxins, has recently been detected in aerosols generated by the normal motions of affected bodies of water. MC-LR aerosol exposure has been linked to a pro-inflammatory influence on the airways of mice; however, little is understood about the underlying mechanism or the potential consequences.

Modulatory L-Alliin Effect on Acute Inflammatory Cytokines in Diet-Induced Obesity Mice.

The inflammatory response has evolved as a protective mechanism against pathogens and tissue damage. However, chronic inflammation can occur, potentially leading to severe disease. Low-grade chronic inflammation is associated with obesity, and the Th1 cytokine profile plays an important role in this proinflammatory environment.

Retargeting target-directed microRNA-decay sites to highly expressed viral or cellular miRNAs.

MicroRNAs (miRNAs) are pervasive regulators of gene expression, necessitating the development of tools to inhibit individual miRNAs for functional studies or therapeutic targeting. Specialized base-pairing configurations between a miRNA and an RNA target site can trigger the degradation of the targeting miRNA through target-directed miRNA decay (TDMD). Previous work has identified several natural sites that induce TDMD of specific miRNAs.

The Secretion of Inflammatory Cytokines Triggered by TLR2 Through Calcium-Dependent and Calcium-Independent Pathways in Keratinocytes.

Keratinocytes can be activated by , leading to the production of proinflammatory cytokines via toll-like receptors (TLRs) 2 and 4. Although several studies have investigated keratinocytes, the mechanism of calcium-mediated activation remains unclear. Herein, we investigated whether calcium influx via TLR2 and TLR4 stimulation was involved in cytokine secretion by keratinocytes in HaCaT cells.

Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis.

Over 60% of women with endometriosis experience abdominopelvic pain and broader pain manifestations, including chronic back pain, fibromyalgia, chronic fatigue, vulvodynia, and migraine. Although the imbalance of proinflammatory mediators, including the complement component C5a, is associated with endometriosis-related pain, the mechanisms causing widespread pain and the C5a role remain unclear. Female mice and women with endometriosis exhibit increased plasma C5a levels and pain.

NF-κB c-Rel is a critical regulator of TLR7-induced inflammation in psoriasis.

Background: Nuclear factor kappa B (NF-κB) c-Rel is a psoriasis susceptibility locus, however mechanisms underlying c-Rel transactivation during disease are poorly understood. Inflammation in psoriasis can be triggered following Toll-like Receptor 7 (TLR7) signalling in dendritic cells (DCs), and c-Rel is a critical regulator of DC function. Here, we studied the mechanism of TLR7-induced c-Rel-mediated inflammation in DCs.

Electrochemical cofactor recycling of bacterial microcompartments.

Bacterial microcompartments (BMCs) are prokaryotic organelles that consist of a protein shell which sequesters metabolic reactions in its interior. While most of the substrates and products are relatively small and can permeate the shell, many of the encapsulated enzymes require cofactors that must be regenerated inside. We have analyzed the occurrence of an enzyme previously assigned as a cobalamin (vitamin B) reductase and, curiously, found it in many unrelated BMC types that do not employ B cofactors.

Circular Engineered Sortase for Interrogating Histone H3 in Chromatin.

Reversible modification of the histone H3 N-terminal tail is critical in regulating the chromatin structure, gene expression, and cell states, while its dysregulation contributes to disease pathogenesis. Understanding the crosstalk between H3 tail modifications in nucleosomes constitutes a central challenge in epigenetics. Here, we describe an engineered sortase transpeptidase, cW11, that displays highly favorable properties for introducing scarless H3 tails onto nucleosomes.

The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction.

The partner and localizer of BRCA2 (PALB2) is a scaffold protein linking BRCA1 with BRCA2 and RAD51 during homologous recombination (HR). PALB2 interaction with DNA strongly enhances HR in cells, while the PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange . We determined that PALB2-DBD is intrinsically disordered beyond a single N-terminal α-helix.

Exploring Contraceptive Experiences of Abortion-Fund Clients in the Rocky Mountain Region of the United States from a Reproductive Justice Lens.

Objective: This study focuses on the contraceptive experiences of abortion fund applicants to draw attention to various elements that restrict the realization of reproductive justice in the Rocky Mountain Region of the United States.

Methods: This study uses qualitative data from 830 applications to an abortion fund submitted between 2013 and 2022.

Results: Our findings highlight a range of experiences, from contraceptive failure and side effects, to diminished access and reproductive coercion.

Molecular Changes in Aqueous Humor Associated with Inflammation Following Cataract Surgery in Patients with Fuchs' Endothelial Corneal Dystrophy.

Introduction: To evaluate the anterior chamber (AC) inflammation in the early postoperative period after cataract surgery and before Descemet membrane endothelial keratoplasty (DMEK) by quantifying oxidative stress and inflammatory mediators in aqueous humor of patients with Fuchs' endothelial corneal dystrophy (FECD).

Methods: In this prospective single-center study, 15 patients with FECD underwent cataract surgery and DMEK in a two-stage procedure. Aqueous humor was collected from the AC at the beginning of cataract surgery and 3 months later at the beginning of DMEK.

HDAC1 fine-tunes Th17 polarization in vivo to restrain tissue damage in fungal infections.

Histone deacetylases (HDACs) contribute to shaping many aspects of T cell lineage functions in anti-infective surveillance; however, their role in fungus-specific immune responses remains poorly understood. Using a T cell-specific deletion of HDAC1, we uncover its critical role in limiting polarization toward Th17 by restricting expression of the cytokine receptors gp130 and transforming growth factor β receptor 2 (TGF-βRII) in a fungus-specific manner, thus limiting Stat3 and Smad2/3 signaling. Controlled release of interleukin-17A (IL-17A) and granulocyte-macrophage colony-stimulating factor (GM-CSF) is vital to minimize apoptotic processes in renal tubular epithelial cells in vitro and in vivo.

Pro-inflammatory biomarkers and long term neurological outcomes in hypothermia plus melatonin treated asphyxiated newborns. A preliminary approach.

Objective: To evaluate serum neuronal and inflammatory biomarkers in asphyxiated newborns treated with hypothermia alone or hypothermia plus melatonin, and whether biomarkers correlate with neurodevelopmental outcomes.

Design: A pilot multicentre, randomized, controlled, double blind clinical trial. 25 newborns were recruited.