Novel Naphthyridones Targeting Pannexin 1 for Colitis Management.

Pannexin 1 (PANX1) forms cell-surface channels capable of releasing signaling metabolites for diverse patho-physiological processes. While inhibiting dysregulated PANX1 has been proposed as a therapeutic strategy for many pathological conditions, including inflammatory bowel disease (IBD), low efficacy, or poor specificity of classical PANX1 inhibitors introduces uncertainty for their applications in basic and translational research. Here, hit-to-lead optimization is performed and a naphthyridone, compound 12, is identified as a new PANX1 inhibitor with an IC of 0.

Automated Uniform Spheroid Generation Platform for High Throughput Drug Screening Process.

Three-dimensional (3D) spheroid models are crucial for cancer research, offering more accurate insights into tumour biology and drug responses than traditional 2D cell cultures. However, inconsistent and low-throughput spheroid production has hindered their application in drug screening. Here, we present an automated high-throughput platform for a spheroid selection, fabrication, and sorting system (SFSS) to produce uniform gelatine-encapsulated spheroids (GESs) with high efficiency.

Combined alkali-photocatalytic stimulation enables click microbial domestication for boosted ammonia nitrogen removal.

Microbe-driven ammonia nitrogen removal plays a crucial role in the nitrogen cycle and wastewater treatment. However, the rational methods and mechanisms for boosting nitrogen conversion through microbial domestication are still limited. Herein, a combined alkali-photocatalytic stimulation strategy was developed to activate the Halomonas shizuishanensis DWK9 for efficient ammonia nitrogen removal.

Health care transition models in spina bifida care: evidence-based lessons in support of neurosurgical practice.

Objective: The purpose of this study was to conduct a literature review on transition programs from pediatric to adult care and the role of neurosurgery as individuals with spina bifida (SB) transition, and to provide a framework for neurosurgical providers to assist in the transition to adult-centered care.

Methods: A comprehensive literature review was conducted according to the PRISMA statement, with a search in Medline and Embase to identify US clinical programs reporting on their experiences establishing a transition program for adolescents and young adults with SB. Data were collected for authors, year, transition clinic location, model of care for transition clinic, ages served, and specialty clinical team.

Inhalation of Curcumae Rhizoma volatile oil attenuates depression-like behaviours via activating the Nrf2 pathway to alleviate oxidative stress and improve mitochondrial dysfunction.

Objectives: Curcumae Rhizoma (CR) is a traditional Chinese medicine used frequently in clinics, which contains volatile components that exhibit various active effects. This study explores the effect of Curcumae Rhizoma volatile oil (CRVO) on depressive mice and its possible mechanism of action.

Methods: Chemical composition of CRVO was analysed by GC-MS.

UBA2 SUMOylates NQO1 and promotes the proliferation of hepatocellular carcinoma by modulating the MAPK pathway.

In our previous study, we found that small ubiquitin-related modifier (SUMO)-activating enzyme ubiquitin-associated-2 domain (UBA2) was upregulated in hepatocellular carcinoma (HCC) patients who were insensitive to chemoembolization. In this study, we aimed to investigate the role of UBA2 in HCC progression. Three cohorts were used to evaluate the efficacy of UBA2 as a prognostic factor for HCC.

Tandem LIM domain-containing proteins, LIMK1 and LMO1, directly bind to force-bearing keratin intermediate filaments.

The cytoskeleton of the cell is constantly exposed to physical forces that regulate cellular functions. Selected members of the LIM (Lin-11, Isl-1, and Mec-3) domain-containing protein family accumulate along force-bearing actin fibers, with evidence supporting that the LIM domain is solely responsible for this force-induced interaction. However, LIM domain's force-induced interactions are not limited to actin.

Multi-dimensional cell-free DNA-based liquid biopsy for sensitive early detection of gastric cancer.

Background: Gastric cancer is the fifth most common cancer type. Most patients are diagnosed at advanced stages with poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing associated mortality.

Nano-sensitizer with self-amplified drug release and hypoxia normalization properties potentiates efficient chemoradiotherapy of pancreatic cancer.

The hypoxic nature of pancreatic cancer, one of the most lethal malignancies worldwide, significantly impedes the effectiveness of chemoradiotherapy. Although the development of oxygen carriers and hypoxic sensitizers has shown promise in overcoming tumor hypoxia. The heterogeneity of hypoxia-primarily caused by limited oxygen penetration-has posed challenges.

Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial.

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates.

Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo.

Design, Setting, And Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up.

Interleukin-1 beta signals through the ERK signalling pathway to modulate human placental trophoblast migration and invasion in the first trimester of pregnancy.

Introduction: Interleukin-1 beta (IL-1β) can promote cell migration, invasion and metastasis in various cancer cells. The mechanism of its role in human trophoblast has not been fully investigated. Therefore, we aimed to investigate the expression level of IL-1β in first trimester decidua and placenta and its potential role in regulation of extravillous trophoblast cell (EVT) invasion and migration.

Fabrication of Rhenium Disulfide/Mesoporous Silica Core-Shell Nanoparticles for a pH-Responsive Drug Release and Combined Chemo-Photothermal Therapy.

A stimuli-responsive drug delivery nanocarrier with a core-shell structure combining photothermal therapy and chemotherapy for killing cancer cells was constructed in this study. The multifunctional nanocarrier ReS@mSiO-RhB entails an ReS hierarchical nanosphere coated with a fluorescent mesoporous silica shell. The three-dimensional hierarchical ReS nanostructure is capable of effectively absorbing near-infrared (NIR) light and converting it into heat.

Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling.

Background: Heterogeneity in the severity of cerebral cavernous malformations (CCMs) disease, including brain bleedings and thrombosis that cause neurological disabilities in patients, suggests that environmental, genetic, or biological factors act as disease modifiers. Still, the underlying mechanisms are not entirely understood. Here, we report that mild hypoxia accelerates CCM disease by promoting angiogenesis, neuroinflammation, and vascular thrombosis in the brains of CCM mouse models.

3D Printing of Glass Micro-Optics with Subwavelength Features on Optical Fiber Tips.

Integration of functional materials and structures on the tips of optical fibers has enabled various applications in micro-optics, such as sensing, imaging, and optical trapping. Direct laser writing is a 3D printing technology that holds promise for fabricating advanced micro-optical structures on fiber tips. To date, material selection has been limited to organic polymer-based photoresists because existing methods for 3D direct laser writing of inorganic materials involve high-temperature processing that is not compatible with optical fibers.

T-cell count and T-cell telomere length in patients with severe COVID-19.

Lymphocyte telomere length (TL) is highly variable and shortens with age. Short telomeres may impede TL-dependent T-cell clonal expansion with viral infection. As SARS-CoV-2 infection can induce prolonged and severe T-cell lymphopenia, infected adults, and particularly older adults with short telomeres, may display severe T-cell lymphopenia.

Transcriptional profile of human thymus reveals IGFBP5 is correlated with age-related thymic involution.

Thymus is the main immune organ which is responsible for the production of self-tolerant and functional T cells, but it shrinks rapidly with age after birth. Although studies have researched thymus development and involution in mouse, the critical regulators that arise with age in human thymus remain unclear. We collected public human single-cell transcriptomic sequencing (scRNA-seq) datasets containing 350,678 cells from 36 samples, integrated them as a cell atlas of human thymus.

A robot-rodent interaction arena with adjustable spatial complexity for ethologically relevant behavioral studies.

Outside of the laboratory, animals behave in spaces where they can transition between open areas and coverage as they interact with others. Replicating these conditions in the laboratory can be difficult to control and record. This has led to a dominance of relatively simple, static behavioral paradigms that reduce the ethological relevance of behaviors and may alter the engagement of cognitive processes such as planning and decision-making.

Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes.

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes.

A Systems Approach to Biomechanics, Mechanobiology, and Biotransport.

The human body represents a collection of interacting systems that range in scale from nanometers to meters. Investigations from a systems perspective focus on how the parts work together to enact changes across spatial scales, and further our understanding of how systems function and fail. Here, we highlight systems approaches presented at the 2022 Summer Biomechanics, Bio-engineering, and Biotransport Conference in the areas of solid mechanics; fluid mechanics; tissue and cellular engineering; biotransport; and design, dynamics, and rehabilitation; and biomechanics education.

Membrane transporters in drug development and as determinants of precision medicine.

The effect of membrane transporters on drug disposition, efficacy and safety is now well recognized. Since the initial publication from the International Transporter Consortium, significant progress has been made in understanding the roles and functions of transporters, as well as in the development of tools and models to assess and predict transporter-mediated activity, toxicity and drug-drug interactions (DDIs). Notable advances include an increased understanding of the effects of intrinsic and extrinsic factors on transporter activity, the application of physiologically based pharmacokinetic modelling in predicting transporter-mediated drug disposition, the identification of endogenous biomarkers to assess transporter-mediated DDIs and the determination of the cryogenic electron microscopy structures of SLC and ABC transporters.

Effects of Nutraceuticals on Cisplatin-Induced Cytotoxicity in HEI-OC1 Cells.

Cisplatin is a chemotherapeutic drug for the treatment of several solid tumors, whose use is limited by its nephrotoxicity, neurotoxicity, ototoxicity, and development of resistance. The toxicity is caused by DNA cross-linking, increase in reactive oxygen species and/or depletion of cell antioxidant defenses. The aim of the work was to study the effect of antioxidant compounds (Lisosan G, Taurisolo) or hydrogen sulfide (HS)-releasing compounds (erucin) in the auditory HEI-OC1 cell line treated with cisplatin.

A nonneural miRNA cluster mediates hearing via repression of two neural targets.

We show here that are absolutely essential for development and function of Johnston's organ (JO), the primary proprioceptive and auditory organ in Their deletion results in highly aberrant cell fate determination, including loss of scolopale cells and ectopic neurons, and mutants are electrophysiologically deaf. In vivo activity sensors and mosaic analyses indicate that these seed-related miRNAs function autonomously to suppress neural fate in nonneuronal cells. Finally, genetic interactions pinpoint two neural targets ( and ) that underlie miRNA mutant JO phenotypes.

Histatin-5 interacts with cellular copper to promote antifungal activity against Candida albicans.

Histatin-5 (Hist-5) is an antimicrobial peptide found in human saliva that functions to defend the oral cavity from microbial infections, such as those caused by the fungal pathogen Candida albicans (C. albicans). Hist-5 can bind Cu in multiple oxidation states, Cu2+ and Cu+in vitro, and supplemental Cu2+ has been shown to improve the fungicidal activity of the peptide against C.

Preclinical Development of PNT6555, a Boronic Acid-Based, Fibroblast Activation Protein-α (FAP)-Targeted Radiotheranostic for Imaging and Treatment of FAP-Positive Tumors.

The overexpression of fibroblast activation protein-α (FAP) in solid cancers relative to levels in normal tissues has led to its recognition as a target for delivering agents directly to tumors. Radiolabeled quinoline-based FAP ligands have established clinical feasibility for tumor imaging, but their therapeutic potential is limited due to suboptimal tumor retention, which has prompted the search for alternative pharmacophores. One such pharmacophore is the boronic acid derivative -(pyridine-4-carbonyl)-d-Ala-boroPro, a potent and selective FAP inhibitor (FAPI).