Discovery of Potential Candidate Genes for Coat Colour in Wuzhishan Pigs by Integrating SNPs and mRNA Expression Analysis.

Despite identifying genes regulating the coat colour in Western pig breeds, the genetic basis of the coat colour in Chinese indigenous pigs is still not understood due to the diversity of indigenous breeds and their genetic differences from exotic pigs. In this study, 215 Wuzhishan pigs with three coat colour patterns (white, black, and black-back/white-belly) were used to conduct a genome-wide association analysis. We found that genes responsible for the coat colour in the Wuzhishan breed are located on chromosome 8.

Effects of Hypomethylating Agents on Gene Modulation in the Leukemic Microenvironment and Disease Trajectory in a Mouse Model of AML.

Hypomethylating agents (HMAs), such as decitabine and 5-azacytidine (AZA), are valuable treatment options for patients with acute myeloid leukemia that are ineligible for intensive chemotherapy. Despite providing significant extensions in survival when used alone or in combination, eventual relapse and resistance to HMAs are observed. The mechanisms leading to these outcomes are still not well defined and may, in part, be due to a focus on leukemic populations with limited information on the effects of HMAs on non-leukemic cells in the blood and other tissue compartments.

Myosin VI drives arrestin-independent internalization and signaling of GPCRs.

G protein-coupled receptor (GPCR) endocytosis is canonically associated with β-arrestins. Here, we delineate a β-arrestin-independent endocytic pathway driven by the cytoskeletal motor, myosin VI. Myosin VI engages GIPC, an adaptor protein that binds a PDZ sequence motif present at the C-terminus of several GPCRs.

Tumor-Colonizing Expressing Both Collagenase and Hyaluronidase Enhances Therapeutic Efficacy of Gemcitabine in Pancreatic Cancer Models.

Desmoplasia is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC) that contributes significantly to treatment resistance. Approaches to enhance drug delivery into fibrotic PDAC tumors continue to be an important unmet need. In this study, we have engineered a tumor-colonizing -based agent that expresses both collagenase and hyaluronidase as a strategy to reduce desmoplasia and enhance the intratumoral perfusion of anticancer agents.

BaNDyT: Bayesian Network modeling of molecular Dynamics Trajectories.

Bayesian network modeling (BN modeling, or BNM) is an interpretable machine learning method for constructing probabilistic graphical models from the data. In recent years, it has been extensively applied to diverse types of biomedical datasets. Concurrently, our ability to perform long-timescale molecular dynamics (MD) simulations on proteins and other materials has increased exponentially.

RAD52 and ERCC6L/PICH have a compensatory relationship for genome stability in mitosis.

Mammalian RAD52 is a DNA repair factor with strand annealing and recombination mediator activities that appear important in both interphase and mitotic cells. Nonetheless, RAD52 is dispensable for cell viability. To query RAD52 synthetic lethal relationships, we performed genome-wide CRISPR knock-out screens and identified hundreds of candidate synthetic lethal interactions.

Distinct RORγt-dependent Th17 immune responses are required for autoimmune pathogenesis and protection against bacterial infection.

T helper (Th)17 cells mediate both protective anti-bacterial immune responses and autoimmune pathogenesis, but the distinct pathways regulating these Th17 responses remain unclear. Retinoid-related orphan receptor γ t (RORγt) is a master transcription factor that governs Th17 cell generation and effector functions. We found that a K256R mutation in RORγt impairs Th17-mediated experimental autoimmune encephalomyelitis (EAE) without affecting the clearance of Citrobacter rodentium.

Engineered odorant receptors illuminate the basis of odour discrimination.

How the olfactory system detects and distinguishes odorants with diverse physicochemical properties and molecular configurations remains poorly understood. Vertebrate animals perceive odours through G protein-coupled odorant receptors (ORs). In humans, around 400 ORs enable the sense of smell.

IL-17RA/CTSK axis mediates H. pylori-induced castration-resistant prostate cancer growth.

In this investigation, we explored the molecular dynamics guiding the progression of castration-resistant prostate cancer (CRPC) influenced by Helicobacter pylori (H. pylori)-mediated M2 polarization of macrophages through the IL-17RA/CTSK/EMT axis. An 830-patient clinical trial categorized subjects into hormone-sensitive prostate cancer (HSPC) and CRPC groups.

Systems profiling reveals recurrently dysregulated cytokine signaling responses in ER+ breast cancer patients' blood.

Cytokines operate in concert to maintain immune homeostasis and coordinate immune responses. In cases of ER breast cancer, peripheral immune cells exhibit altered responses to several cytokines, and these alterations are correlated strongly with patient outcomes. To develop a systems-level understanding of this dysregulation, we measured a panel of cytokine responses and receptor abundances in the peripheral blood of healthy controls and ER breast cancer patients across immune cell types.

Distinct functions of PAXX and MRI during chromosomal end joining.

A key step of Canonical Nonhomologous End Joining (C-NHEJ) is synapsis of DNA double strand break (DSB) ends for ligation. The DNA-PKcs dimer mediates synapsis in a long-range complex with DSB ends remaining apart, whereas the XLF homodimer can mediate synapsis in both long-range and short-range complexes. Recent structural studies found the PAXX homodimer may also facilitate synapsis in long-range complexes with DNA-PKcs via its interactions with Ku70.

Molecular recognition of an odorant by the murine trace amine-associated receptor TAAR7f.

There are two main families of G protein-coupled receptors that detect odours in humans, the odorant receptors (ORs) and the trace amine-associated receptors (TAARs). Their amino acid sequences are distinct, with the TAARs being most similar to the aminergic receptors such as those activated by adrenaline, serotonin, dopamine and histamine. To elucidate the structural determinants of ligand recognition by TAARs, we have determined the cryo-EM structure of a murine receptor, mTAAR7f, coupled to the heterotrimeric G protein G and bound to the odorant N,N-dimethylcyclohexylamine (DMCHA) to an overall resolution of 2.

small molecule screening to inform novel candidates for use in fluconazole combination therapy against .

Unlabelled: Identifying improved treatments for severe and refractory coccidioidomycosis (Valley fever) is needed. This endemic fungal disease is common in North and South America, and cases have increased substantially over the last 30 years. The current standard of care, oral daily fluconazole, often fails to completely eradicate infection; however, the high cost of identifying new compounds effective in treating Valley fever is a barrier to improving treatment.

Functions of PMS2 and MLH1 important for regulation of divergent repeat-mediated deletions.

Repeat-mediated deletions (RMDs) are a type of deletion rearrangement that utilizes two repetitive elements to bridge a DNA double-strand break (DSB) that leads to loss of the intervening sequence and one of the repeats. Sequence divergence between repeats causes RMD suppression and indeed this divergence must be resolved in the RMD products. The mismatch repair factor, MLH1, was shown to be critical for both RMD suppression and a polarity of sequence divergence resolution in RMDs.

Comparison of EV characterization by commercial high-sensitivity flow cytometers and a custom single-molecule flow cytometer.

High-sensitivity flow cytometers have been developed for multi-parameter characterization of single extracellular vesicles (EVs), but performance varies among instruments and calibration methods. Here we compare the characterization of identical (split) EV samples derived from human colorectal cancer (DiFi) cells by three high-sensitivity flow cytometers, two commercial instruments, CytoFLEX/CellStream, and a custom single-molecule flow cytometer (SMFC). DiFi EVs were stained with the membrane dye di-8-ANEPPS and with PE-conjugated anti-EGFR or anti-tetraspanin (CD9/CD63/CD81) antibodies for estimation of EV size and surface protein copy numbers.

A neurodevelopmental disorder mutation locks G proteins in the transitory pre-activated state.

Many neurotransmitter receptors activate G proteins through exchange of GDP for GTP. The intermediate nucleotide-free state has eluded characterization, due largely to its inherent instability. Here we characterize a G protein variant associated with a rare neurological disorder in humans.

Update: the role of epigenetics in the metabolic memory of diabetic complications.

Diabetes, a chronic disease characterized by hyperglycemia, is associated with significantly accelerated complications, including diabetic kidney disease (DKD), which increases morbidity and mortality. Hyperglycemia and other diabetes-related environmental factors such as overnutrition, sedentary lifestyles, and hyperlipidemia can induce epigenetic changes. Working alone or with genetic factors, these epigenetic changes that occur without alterations in the underlying DNA sequence, can alter the expression of pathophysiological genes and impair functions of associated target cells/organs, leading to diabetic complications like DKD.

Cellular lipids regulate the conformational ensembles of the disordered intracellular loop 3 in β2-adrenergic receptor.

The intracellular loops of G protein-coupled receptors (GPCRs) have been shown to play a key role in G protein coupling and selectivity. We recently showed that the intrinsically disordered third intracellular loop (ICL3) of β2-adrenergic receptor is dynamic and equilibrates between open and closed conformations to regulate the G protein coupling. In this study, using the extensive molecular dynamics simulations in multi-lipid bilayer models, we show that the lipid phosphatidylinositol 4,5-bisphosphate (PIP2) stabilizes the active state of β2-adrenergic receptor by keeping ICL3 in an open conformation.

Changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer's disease.

While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer's disease (LOAD), the Apolipoprotein E locus E4 haplotype is still the biggest driver of risk, with odds ratios for neuropathologically confirmed E44 carriers exceeding 30 (95% confidence interval 16.59-58.75).

Multivalent interactions of the disordered regions of XLF and XRCC4 foster robust cellular NHEJ and drive the formation of ligation-boosting condensates in vitro.

In mammalian cells, DNA double-strand breaks are predominantly repaired by non-homologous end joining (NHEJ). During repair, the Ku70-Ku80 heterodimer (Ku), X-ray repair cross complementing 4 (XRCC4) in complex with DNA ligase 4 (X4L4) and XRCC4-like factor (XLF) form a flexible scaffold that holds the broken DNA ends together. Insights into the architectural organization of the NHEJ scaffold and its regulation by the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) were recently obtained by single-particle cryo-electron microscopy analysis.

Targeting Patient-Derived Orthotopic Gastric Cancers with a Fluorescent Humanized Anti-CEA Antibody.

Background: Gastric cancer poses a major diagnostic and therapeutic challenge as surgical resection provides the only opportunity for a cure. Specific labeling of gastric cancer could distinguish resectable and nonresectable disease and facilitate an R0 resection, which could improve survival.

Methods: Two patient-derived gastric cancer lines, KG8 and KG10, were established from surgical specimens of two patients who underwent gastrectomy for gastric adenocarcinoma.

Function of Steroid Receptor Coactivators in T Cells and Cancers: Implications for Cancer Immunotherapy.

Steroid receptor coactivator (SRC) family members (SRC1, SRC2 and SRC3) are transcriptional co-regulators. SRCs orchestrate gene transcription by inducing transactivation of nuclear receptors and other transcription factors. Overexpression of SRCs is widely implicated in a range of cancers, especially hormone-related cancers.