The Prototypical Oligopeptide Transporter YdgR From E. coli Exhibits a Strict Preference for β-Ala-Lys(AMCA).

Fluorescent probes are widely used in cellular imaging and disease diagnosis. Acting as substitute carriers, fluorescent probes can also be used to help transport drugs within cells. In this study, commonly used fluorophores, TAMRA (5-carboxytetramethylrhodamine), PBA (1-pyrenebutyric acid), NBD (nitrobenzoxadiazole), OG (Oregon Green), and CF (5-carboxyfluorescein) were conjugated with the dipeptide β-Ala-Lys, the peptide moiety of the well-established peptide transporter substrate β-Ala-Lys(AMCA) (AMCA: 7-amino-4-methyl-coumarin-3-acetic acid) by modifying it with respect to side-chain length and functional end groups.

The Effect of Assisted Reproductive Technologies on Human Sex Ratios.

Background: Modern assisted reproductive technology (ART), including pre-implantation genetic testing for aneuploidy (PGT-A), has opened new avenues in understanding early embryonic events and has simultaneously raised questions about the impact of ART itself on sex ratios.

Aims: The primary aim was to investigate whether patient demographic characteristics, ovarian stimulation protocols or laboratory characteristics in ART influence sex ratios. The secondary aim was to relate the blastocyst sex ratio (BSR) to the corresponding secondary sex ratio (SSR) in our patient cohort.

POLE mutations in endometrial carcinoma: Clinical and genomic landscape from a large prospective single-center cohort.

Background: To date, 11 DNA polymerase epsilon (POLE) pathogenic variants have been declared "hotspot" mutations. Patients with endometrial cancer (EC) characterized by POLE hotspot mutations (POLEmut) have exceptional survival outcomes. Whereas international guidelines encourage deescalation of adjuvant treatment in early-stage POLEmut EC, data regarding safety in POLEmut patients with unfavorable characteristics are still under investigation.

Bioactive Functionalized Chitosan Thermo-Responsive Hydrogels as Promising Platforms for Therapeutic, Regenerative Oral, and Maxillofacial Applications.

Due to their superior physicochemical features, chitosan thermosensitive hydrogels are multipurpose platforms that are frequently used in the biomedical industry. Many investigations have been conducted recently to modify their pore dimensions, expansion, biodegradability, stimulus-reaction characteristics, and other characteristics in order to better tailor them to the complex craniofacial tissues. They have been the focus of various studies that have attempted to load biological cargos for therapeutic and regenerative uses in the oro-facial tissues.

Conformational dynamics in specialized CH zinc finger domains enable zinc-responsive gene repression in S. pombe.

Loz1 is a zinc-responsive transcription factor in fission yeast that maintains cellular zinc homeostasis by repressing the expression of genes required for zinc uptake in high zinc conditions. Previous deletion analysis of Loz1 found a region containing two tandem CH zinc-fingers and an upstream "accessory domain" rich in histidine, lysine, and arginine residues to be sufficient for zinc-dependent DNA binding and gene repression. Here we report unexpected biophysical properties of this pair of seemingly classical CH zinc fingers.

Regulation of Rhizobial Nodulation Genes by Flavonoid-Independent NodD Supports Nitrogen-Fixing Symbioses With Legumes.

Rhizobia and legumes form a symbiotic relationship resulting in the formation of root structures known as nodules, where bacteria fix nitrogen. Legumes release flavonoids that are detected by the rhizobial nodulation (Nod) protein NodD, initiating the transcriptional activation of nod genes and subsequent synthesis of Nod Factors (NFs). NFs then induce various legume responses essential for this symbiosis.

Insights into the flexibility of the domain-linking loop in actinobacterial coproheme decarboxylase through structures and molecular dynamics simulations.

Prokaryotic heme biosynthesis in Gram-positive bacteria follows the coproporphyrin-dependent heme biosynthesis pathway. The last step in this pathway is catalyzed by the enzyme coproheme decarboxylase, which oxidatively transforms two propionate groups into vinyl groups yielding heme b. The catalytic reaction cycle of coproheme decarboxylases exhibits four different states: the apo-form, the substrate (coproheme)-bound form, a transient three-propionate intermediate form (monovinyl, monopropionate deuteroheme; MMD), and the product (heme b)-bound form.

Early Severe Cortical Involvement and Novel FUCA1 Mutations in a Pediatric Fucosidosis Case.

Background: Biallelic pathogenic variants in the FUCA1 gene are associated with fucosidosis. This report describes a 4-year-old boy presenting with psychomotor regression, spasticity, and dystonic postures.

Methods And Results: Trio-based whole exome sequencing revealed two previously unreported loss-of-function variants in the FUCA1 gene.

Knockout of Pro-Apoptotic BAX and BAK1 Genes in HEK293T Cells Enhances Adeno-Associated Virus (AAV) Production: AAV2 and AAV9.

Increasing demand for adeno-associated virus (AAV) used in gene therapy highlights the need to enhance AAV production. When intracellular AAV2 and extracellular AAV9 were produced in HEK293T cells using the triple transfection method, apoptosis occurred during the AAV production. To mitigate apoptosis induced by AAV production, the pro-apoptotic BAX/BAK1 genes were knocked out in HEK293T cells.

Cardiac Involvement and TBCK-Related Neurodevelopmental Disorder: Is It a New Feature of This Condition?

TBCK (TBC1 Domain-Containing Kinase) encodes a protein playing a role in actin organization and cell growth/proliferation via the mTOR signaling pathway. Deleterious biallelic TBCK variants cause Hypotonia, infantile, with psychomotor retardation and characteristic facies 3. We report on three affected sibs, also displaying cardiac malformations.

The up-regulation of RIPK3 mediated by ac4C modification promotes oxidative stress-induced granulosa cell senescence by inhibiting the Nrf2/HO-1 pathway.

Abnormality of granulosa cells (GCs) is the critical cause of follicular atresia in premature ovarian failure (POF). RIPK3 is highly expressed in GCs derived from atretic follicles. We focus on uncovering how RIPK3 contributes to ovarian GC senescence.

A novel method for expressing and purifying large quantities of functional and stable human voltage-gated proton channel (hH1).

Purifying membrane proteins has been the limiting step for studying their structure and function. The challenges of the process include the low expression levels in heterologous systems and the requirement for their biochemical stabilization in solution. The human voltage-gated proton channel (hH1) is a good example of that: the published protocols to express and purify hH1 produce low protein quantities at high costs, which is an issue for systematically characterizing its structure and function.

Adjusting for Ascertainment Bias in Meta-Analysis of Penetrance for Cancer Risk.

Multi-gene panel testing allows efficient detection of pathogenic variants in cancer susceptibility genes including moderate-risk genes such as ATM and PALB2. A growing number of studies examine the risk of breast cancer (BC) conferred by pathogenic variants of these genes. A meta-analysis combining the reported risk estimates can provide an overall estimate of age-specific risk of developing BC, that is, penetrance for a gene.

CaML: Chemistry-informed machine learning explains mutual changes between protein conformations and calcium ions in calcium-binding proteins using structural and topological features.

Proteins' flexibility is a feature in communicating changes in cell signaling instigated by binding with secondary messengers, such as calcium ions, associated with the coordination of muscle contraction, neurotransmitter release, and gene expression. When binding with the disordered parts of a protein, calcium ions must balance their charge states with the shape of calcium-binding proteins and their versatile pool of partners depending on the circumstances they transmit. Accurately determining the ionic charges of those ions is essential for understanding their role in such processes.

Engineered protein G variants for multifunctional antibody-based assemblies.

We have developed a portfolio of antibody-based modules that can be prefabricated as standalone units and snapped together in plug-and-play fashion to create uniquely powerful multifunctional assemblies. The basic building blocks are derived from multiple pairs of native and modified Fab scaffolds and protein G (PG) variants engineered by phage display to introduce high pair-wise specificity. The variety of possible Fab-PG pairings provides a highly orthogonal system that can be exploited to perform challenging cell biology operations in a straightforward manner.

Gene-Air Pollution Interaction and Diversity of Genetic Sampling: The Southern California Children's Health Study.

Gene-environment interactions have been observed for childhood asthma, however few have been assessed in ethnically diverse populations. Thus, we examined how polygenic risk score (PRS) modifies the association between ambient air pollution exposure (nitrogen dioxide [NO], ozone, particulate matter < 2.5 and < 10 μm) and childhood asthma incidence in a diverse cohort.

Noninvasive in vivo imaging of macrophages: understanding tumor microenvironments and delivery of therapeutics.

Macrophages are pivotal in the body's defense and response to inflammation. They are present in significant numbers and are widely implicated in various diseases, including cancer. While molecular and histological techniques have advanced our understanding of macrophage biology, their precise function within the cancerous microenvironments remains underexplored.

The role of myocardial energy metabolism perturbations in diabetic cardiomyopathy: from the perspective of novel protein post-translational modifications.

Diabetic cardiomyopathy (DbCM), a significant chronic complication of diabetes, manifests as myocardial hypertrophy, fibrosis, and other pathological alterations that substantially impact cardiac function and elevate the risk of cardiovascular diseases and patient mortality. Myocardial energy metabolism disturbances in DbCM, encompassing glucose, fatty acid, ketone body and lactate metabolism, are crucial factors that contribute to the progression of DbCM. In recent years, novel protein post-translational modifications (PTMs) such as lactylation, β-hydroxybutyrylation, and succinylation have been demonstrated to be intimately associated with the myocardial energy metabolism process, and in conjunction with acetylation, they participate in the regulation of protein activity and gene expression activity in cardiomyocytes.

Advances in Prenatal Cell-Free DNA Screening for Dominant Monogenic Conditions: A Review of Current Progress and Future Directions in Clinical Implementation.

Prenatal cell-free DNA (cfDNA) screening has advanced significantly, extending beyond detecting aneuploidies to sub-chromosomal copy number variations. However, its application for screening dominant single-gene conditions, often caused by de novo variants, remains underutilized in the general obstetric population. This study reviews recent data and experience on prenatal cfDNA screening for dominant monogenic conditions using multiple-gene panels, highlighting its potential to enhance early detection and management of genetic disorders.

Circulating Tumor DNA as a Marker of Recurrence Risk in Stage III Colorectal Cancer: The α-CORRECT Study.

Background And Objectives: Identification of colorectal cancer (CRC) patients at high risk of recurrence could be of substantial clinical use. We evaluated the association of ctDNA status, using a tumor-informed assay, with recurrence-free survival (RFS).

Methods: Stage III CRC patients were enrolled between 2016 and 2020.

Revealing Molecular Diagnosis With Whole Exome Sequencing in Patients With Inherited Retinal Disorders.

Inherited retinal diseases (IRDs) constitute a heterogeneous group of clinically and genetically diverse conditions, standing as a primary cause of visual impairment among individuals aged 15-45, with an estimated incidence of 1:2000. Our study aimed to comprehensively evaluate the genetic variants underlying IRDs in the Turkish population. This study included 50 unrelated Turkish IRD patients and their families.

Single-cell transcriptomics identify a novel macrophage population associated with bone invasion in pituitary neuroendocrine tumors.

Background: Bone-invasive Pituitary Neuroendocrine Tumors (BI PitNETs) epitomize an aggressive subtype of pituitary tumors characterized by bone invasion, culminating in extensive skull base bone destruction and fragmentation. This infiltration poses a significant surgical risk due to potential damage to vital nerves and arteries. However, the mechanisms underlying bone invasion caused by PitNETs remain elusive, and effective interventions for PitNET-induced bone invasion are lacking in clinical practice.

Cryo-EM SPR structures of Salmonella typhimurium ArnC; the key enzyme in lipid-A modification conferring polymyxin resistance.

Polymyxins are last-resort antimicrobial peptides administered clinically against multi-drug resistant bacteria, specifically in the case of Gram-negative species. However, an increasing number of these pathogens employ a defense strategy that involves a relay of enzymes encoded by the pmrE (ugd) loci and the arnBCDTEF operon. The pathway modifies the lipid-A component of the outer membrane (OM) lipopolysaccharide (LPS) by adding a 4-amino-4-deoxy-l-arabinose (L-Ara4N) headgroup, which renders polymyxins ineffective.

First evidence of the effectiveness of a field application of RNAi technology in reducing infestation of the mite Varroa destructor in the western honey bee (Apis mellifera).

Background: The mite Varroa destructor is the most serious pest of the western honey bee (Apis mellifera) and a major factor in the global decline of colonies. Traditional control methods, such as chemical pesticides, although quick and temporarily effective, leave residues in hive products, harming bees and operators' health, while promoting pathogen resistance and spread. As a sustainable alternative, RNA interference (RNAi) technology has shown great potential for honey bee pest control in laboratory assays, but evidence of effectiveness in the field has been lacking.

miR-208a-3p discriminates osteoporosis, predicts fracture, and regulates osteoclast activation through targeting STC1.

Background: Osteoporosis (OP) frequently occurs in post-menopausal women, increasing the risk of fracture. Early screening OP could improve the prevention of fractures.This study focused on the significance of miR-208a-3p in diagnosing OP and development regulation, aiming to explore a novel biomarker and therapeutic target for OP.