A conifer metabolite corrects episodic ataxia type 1 by voltage sensor-mediated ligand activation of Kv1.1.

Loss-of-function sequence variants in , which encodes the voltage-gated potassium channel Kv1.1, cause Episodic Ataxia Type 1 (EA1) and epilepsy. Due to a paucity of drugs that directly rescue mutant Kv1.

Genesis and regulation of C-terminal cyclic imides from protein damage.

C-Terminal cyclic imides are posttranslational modifications that can arise from spontaneous intramolecular cleavage of asparagine or glutamine residues resulting in a form of irreversible protein damage. These protein damage events are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN), indicating that these aging-related modifications may require cellular quality control mechanisms to prevent deleterious effects. However, the factors that determine protein or peptide susceptibility to C-terminal cyclic imide formation or their effect on protein stability have not been explored in detail.

Integrin-activating protein Invasin sustains long-term expansion of primary epithelial cells as 2D organoid sheets.

Matrigel/BME, a basement membrane-like preparation, supports long-term growth of epithelial 3D organoids from adult stem cells [T. Sato , , 262-265 (2009); T. Sato , , 1762-1772 (2011)].

Mechanism-guided engineering of a minimal biological particle for genome editing.

The widespread application of genome editing to treat and cure disease requires the delivery of genome editors into the nucleus of target cells. Enveloped delivery vehicles (EDVs) are engineered virally derived particles capable of packaging and delivering CRISPR-Cas9 ribonucleoproteins (RNPs). However, the presence of lentiviral genome encapsulation and replication proteins in EDVs has obscured the underlying delivery mechanism and precluded particle optimization.

Quantitative LC-MS/MS Analysis of Endogenous Isomeric Metabolites Biliverdin IX Alpha, Beta, and Delta in Cell Culture Supernatant, Cell Pellet, and Lung Tissue.

() utilizes heme as an iron source from the host during infection. Biliverdin beta and delta (BVIXβ and BVIXδ) are generated by HemO, specific to , while biliverdin alpha is generated from the bacterial BphO system and by mammalian heme oxygenases. Here, we have developed and characterized a quantitative LC-MS/MS assay for the separation of three endogenous isomers, BVIXα, BVIXβ, and BVIXδ.

FRESH extrusion 3D printing of type-1 collagen hydrogels photocrosslinked using ruthenium.

The extrusion bioprinting of collagen material has many applications relevant to tissue engineering and regenerative medicine. Freeform Reversible Embedding of Suspended Hydrogels (FRESH) technology is capable of 3D printing collagen material with the specifications and details needed for precise tissue guidance, a crucial requirement for effective tissue repair. While FRESH has shown repeated success and reliability for extrusion printing, the mechanical properties of completed collagen prints can be improved further by post-print crosslinking methodologies.

National assessment on the frequency of pain medication prescribed for intrauterine device insertion procedures within the Veterans Affairs Health Care System.

Background: The intrauterine device (IUD) is a highly effective form of long-acting reversible contraception, widely recognized for its convenience and efficacy. Despite its benefits, many patients report moderate to severe pain during and after their IUD insertion procedure. Furthermore, reports suggest significant variability in pain control medications, including no adequate pain medication.

A national survey of career development according to gender and subspecialties among cardiologists in Japan.

Background: Training opportunities, work satisfaction, and the factors that influence them according to gender and subspecialties are understudied among Japanese cardiologists.

Methods: We investigated the career development of Japanese cardiologists with an e-mail questionnaire. Feelings of inequality in training opportunities, work dissatisfaction, and reasons were assessed by examining the cardiologists' gender and invasiveness of subspecialties.

Glaucoma Screening and Referral Risk Factors in a High-Risk Population: Follow-up Study of the Manhattan Vision Screening Study (NYC-SIGHT).

Prcis: Community-based eye health screenings that incorporated fundus photography and optometric exams in a high-risk NYC population effectively identified a higher than average number of participants that required an in-office glaucoma evaluation.

Purpose: To report glaucoma screening rates and risk factors associated with referral for in-office glaucoma evaluation in the Manhattan Vision Screening and Follow-up Study (NYC-SIGHT).

Methods: In this 5-year, cluster-randomized clinical trial, eligible individuals aged 40 and older were recruited from affordable housing developments and senior centers.

Synthesis and Biological Evaluation of a New Biphenyl-Based Organogold(III) Complex with In Vitro and In Vivo Anticancer Activity.

Despite recent advances in cancer treatment, there is still a need for novel compounds with antineoplastic activity. Among 11 biphenyl-based organogold(III) -heterocyclic carbene (NHC) (BGC) complexes of general formula [(C^C)Au(NHC-pyr)X], where (C^C) = 4,4'-ditertbutylbiphenyl, X = Cl or phenylacetylide, and (NHC-pyr) is a pyridyl-substituted NHC ligand, the complex bearing a 4-CF-pyridyl substituent and a chloride ligand showed promising antineoplastic activity on the triple negative breast cancer cell line. was able to induce cell apoptosis but had no effect on the cell cycle.

Machine Learning-Driven Prediction, Preparation, and Evaluation of Functional Nanomedicines Via Drug-Drug Self-Assembly.

Small molecules as nanomedicine carriers offer advantages in drug loading and preparation. Selecting effective small molecules for stable nanomedicines is challenging. This study used artificial intelligence (AI) to screen drug combinations for self-assembling nanomedicines, employing physiochemical parameters to predict formation via machine learning.

Discovery of Novel Small-Molecule Inhibitors Disrupting the MTDH-SND1 Protein-Protein Interaction.

MTDH-SND1 protein-protein interaction (PPI) plays an important role in the initiation and development of tumors, and it is a target for the treatment of breast cancer. In this study, we identified and synthesized a series of novel small-molecule inhibitors of MTDH-SND1 PPI. The representative compound showed potent activity against MTDH-SND1 PPI with an IC of 487 ± 99 nM and tight binding to the SND1-purified protein with a value of 279 ± 17 nM.

Disseminated organ and tissue infection secondary to carbapenem-resistant Klebsiella pneumoniae bloodstream infection for acute lymphoblastic leukemia treated with ceftazidime-avibactam: Two case reports.

Rationale: Carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections are a severe complication resulting from granulocyte deficiency following chemotherapy for hematologic malignancies and have a high mortality rate. However, reports of disseminated organ infections secondary to bloodstream infections are rare.

Patient Concerns And Diagnoses: We report 2 cases of patients with acute lymphoblastic leukemia who both developed CRKP bloodstream infections during the granulocyte deficiency stage following chemotherapy, with 1 case of secondary bacterial liver abscess and 1 case of secondary septic arthritis.

The application value of dynamic electroencephalography combined with brainstem auditory evoked potential in evaluating the degree of vascular stenosis and prognosis in patients with ischemic stroke: A retrospective analysis.

The aim was to explore the application value of dynamic electroencephalography (EEG) combined with brainstem auditory evoked potential (BAEP) in evaluating the degree of vascular stenosis and prognosis in patients with ischemic stroke (IS). This was a retrospective study using clinical data of patients with IS admitted to the First Affiliated Hospital of Chongqing Medical and Pharmaceutical College from March 2020 to March 2022. The degree of vascular stenosis and prognosis of patients were analyzed.

Bushen-Huoxue-Mingmu-Formula attenuates pressurization-induced retinal ganglion cell damage by reducing mitochondrial autophagy through the inhibition of the Pink1/Parkin pathway.

Background: Bushen-Huoxue-Mingmu-Formula (MMF) has achieved definite clinical efficacy. However, its mechanism is still unclear.

Objective: Investigating the molecular mechanism of MMF to protect retinal ganglion cells (RGCs).

Study on mechanism of Spatholobi Caulis in the treatment of the hand-foot skin reaction induced by targeted drug therapy based on network pharmacology and molecular docking: An observational study.

Based on network pharmacology and molecular docking methods, this study explored its active compounds and confirmed its potential mechanism of action against Hand-foot skin reaction induced by tumor-targeted drugs. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and UniProt Database were used to obtain the active ingredients and target proteins of Spatholobi Caulis. All hand-foot skin reaction (HFSR)-related targets were obtained with the help of the Human Gene Database, Online Mendelian Inheritance in Humans (OMIM), DisGeNET and DrugBank databases.

Evaluation of Larger Side-Group Functionalities and the Side/End-Group Interplay in Ritonavir-Like Inhibitors of CYP3A4.

A new series of 13 ritonavir-like inhibitors of human drug-metabolizing CYP3A4 was rationally designed to study the R side-group and R end-group interplay when the R side-group is represented by phenyl. Spectral, functional, and structural characterization showed no improvement in the binding affinity and inhibitory potency of R/R-phenyl inhibitors upon elongation and/or fluorination of R-Boc (tert-butyloxycarbonyl) or its replacement with benzenesulfonyl. When R is pyridine, the impact of R-phenyl-to-indole/naphthalene substitution was multidirectional and highly dependent on side-group stereo configuration.

A claudin5-binding peptide enhances the permeability of the blood-brain barrier in vitro.

The blood-brain barrier (BBB) maintains brain homeostasis but also prevents most drugs from entering the brain. No paracellular diffusion of solutes is allowed because of tight junctions that are made impermeable by the expression of claudin5 (CLDN5) by brain endothelial cells. The possibility of regulating the BBB permeability in a transient and reversible fashion is in strong demand for the pharmacological treatment of brain diseases.

Sequential Targeting Chondroitin Sulfate-Bilirubin Nanomedicine Attenuates Osteoarthritis via Reprogramming Lipid Metabolism in M1 Macrophages.

The infiltration and excessive polarization of M1 macrophages contribute to the induction and persistence of low-grade inflammation in joint-related degenerative diseases such as osteoarthritis (OA). The lipid metabolism dysregulation promotes M1 macrophage polarization by coordinating the compensatory pathways of the inflammatory and oxidative stress responses. Here, a self-assembling, licofelone-loaded nanoparticle (termed LCF-CSBN), comprising chondroitin sulfate and bilirubin joined by an ethylenediamine linker, is developed to selectively reprogram lipid metabolism in macrophage activation.

Aging-induced Alternation in the Gut Microbiota Impairs Host Antibacterial Defense.

Older individuals experience increased susceptibility and mortality to bacterial infections, but the underlying etiology remains unclear. Herein, it is shown that aging-associated reduction of commensal Parabacteroides goldsteinii (P. goldsteinii) in both aged mice and humans critically contributes to worse outcomes of bacterial infection.

Enzymatic Cascades for Stereoselective and Regioselective Amide Bond Assembly.

Amide bond formation is fundamental in nature and is widely used in the synthesis of pharmaceuticals and other valuable products. Current methods for amide synthesis are often step and atom inefficient, requiring the use of protecting groups, deleterious reagents and organic solvents that create significant waste. The development of cleaner and more efficient catalytic methods for amide synthesis remains an urgent unmet need.

Protocol for applying Tumor Treating Fields in mouse models of cancer using the inovivo system.

Tumor Treating Fields (TTFields) are electric fields clinically approved for cancer treatment, delivered via arrays attached to the patient's skin. Here, we present a protocol for applying TTFields to torso orthotopic and subcutaneous mouse tumor models using the inovivo system. We guide users on proper system component connections, study protocol design, mouse fur depilation, array application, and treatment condition adjustment and monitoring.

TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.

The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation.

Enhanced Costimulation Blockade With αCD154, αCD2, and αCD28 to Promote Heart Allograft Tolerance in Nonhuman Primates.

Background: Long-term renal allograft acceptance has been achieved in macaques using a transient mixed hematopoetic chimerism protocol, but similar regimens have proven unsuccessful in heart allograft recipients unless a kidney transplant was performed simultaneously. Here, we test whether a modified protocol based on targeting CD154, CD2, and CD28 is sufficient to prolong heart allograft acceptance or promote the expansion of regulatory T cells.

Methods: Eight macaques underwent heterotopic allo-heart transplantation from major histocompatibility complex-mismatched donors.