Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer.

Cyclin-dependent kinases (CDKs) 4 and 6 (CDK4/6) are important regulators of the cell cycle. Selective CDK4/6 small-molecule inhibitors have shown clinical activity in hormonal receptor-positive (HR) metastatic breast cancer, but their effectiveness remains limited in other cancer types. CDK4/6 degradation and improved selectivity across CDK paralogs are approaches that could expand the effectiveness of CDK4/6 targeting.

Plasma proteomic evidence for increased β-amyloid pathology after SARS-CoV-2 infection.

Previous studies have suggested that systemic viral infections may increase risks of dementia. Whether this holds true for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infections is unknown. Determining this is important for anticipating the potential future incidence of dementia.

Toward a biological definition of neuronal and glial synucleinopathies.

Cerebral accumulation of alpha-synuclein (αSyn) aggregates is the hallmark event in a group of neurodegenerative diseases-collectively called synucleinopathies-which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Currently, these are diagnosed by their clinical symptoms and definitively confirmed postmortem by the presence of αSyn deposits in the brain. Here, we summarize the drawbacks of the current clinical definition of synucleinopathies and outline the rationale for moving toward an earlier, biology-anchored definition of these disorders, with or without the presence of clinical symptoms.

Risk-directed management of chronic kidney disease.

The timely and rational institution of therapy is a key step towards reducing the global burden of chronic kidney disease (CKD). CKD is a heterogeneous entity with varied aetiologies and diverse trajectories, which include risk of kidney failure but also cardiovascular events and death. Developments in the past decade include substantial progress in CKD risk prediction, driven in part by the accumulation of electronic health records data.

A machine learning decision support tool optimizes WGS utilization in a neonatal intensive care unit.

The Mendelian Phenotype Search Engine (MPSE), a clinical decision support tool using Natural Language Processing and Machine Learning, helped neonatologists expedite decisions to whole genome sequencing (WGS) to diagnose patients in the neonatal intensive care unit. After the MPSE was introduced, utilization of WGS increased, time to ordering WGS decreased, and WGS diagnostic yield increased.

Targeting ABCD1-ACOX1-MET/IGF1R axis suppresses multiple myeloma.

Multiple myeloma (MM) remains an incurable hematological malignancy that necessitates the identification of novel therapeutic strategies. Here, we report that intracellular levels of very long chain fatty acids (VLCFAs) control the cytotoxicity of MM chemotherapeutic agents. Inhibition of VLCFA biosynthesis reduced cell death in MM cells caused by the proteasome inhibitor, bortezomib.

Improved constructs for bait RNA display in a bacterial three-hybrid assay.

We have previously developed a transcription-based bacterial three-hybrid (B3H) assay as a genetic approach to probe RNA-protein interactions inside of E. coli cells. This system offers a straightforward path to identify and assess the consequences of mutations in RBPs with molecular phenotypes of interest.

Muscarinic acetylcholine receptor 3 localized to primary endothelial cilia regulates blood pressure and cognition.

We previously demonstrated that the inability of primary endothelial cilia to sense fluid shear stress can lead to nitric oxide (NO) deficiency and cause hypertension (HTN). Decreased biosynthesis of NO contributes to cerebral amyloid angiopathy in Alzheimer's disease (AD) patients through increased deposition of amyloid beta (Aβ). However, the molecular mechanisms underlying the pathogenesis of HTN and AD are incompletely understood.

An optimized ensemble grey wolf-based pipeline for monkeypox diagnosis.

As the world recovered from the coronavirus, the emergence of the monkeypox virus signaled a potential new pandemic, highlighting the need for faster and more efficient diagnostic methods. This study introduces a hybrid architecture for automatic monkeypox diagnosis by leveraging a modified grey wolf optimization model for effective feature selection and weighting. Additionally, the system uses an ensemble of classifiers, incorporating confusion based voting scheme to combine salient data features.

Neonatal intermittent hypoxemia events are associated with later systemic hypertension.

Background: Approximately 5% of very premature infants delivered at less than 30 weeks' gestation have systemic hypertension. In adult human and animal models, intermittent hypoxemia events are associated with systemic hypertension. In neonates, intermittent hypoxemia events are associated with adverse outcomes, but it is unknown if they are a risk factor for hypertension.

Digital twin driven electrode optimization for wearable bladder monitoring via bioimpedance.

Monitoring fluid intake and output for congestive heart failure (CHF) patients is an essential tool to prevent fluid overload, a principal cause of hospital admissions. Addressing this, bladder volume measurement systems utilizing bioimpedance and electrical impedance tomography have been proposed, with limited exploration of continuous monitoring within a wearable design. Advancing this format, we developed a conductivity digital twin from radiological data, where we performed exhaustive simulations to optimize electrode sensitivity on an individual basis.

Essential oils modulate virulence phenotypes in a multidrug-resistant pyomelanogenic Pseudomonas aeruginosa clinical isolate.

Pyomelanogenic P. aeruginosa, frequently isolated from patients with urinary tract infections and cystic fibrosis, possesses the ability to withstand oxidative stress, contributing to virulence and resulting in persistent infections. Whole genome sequence analysis of U804, a pyomelanogenic, multidrug-resistant, clinical isolate, demonstrates the mechanism underlying pyomelanin overproduction.

Advancing ex vivo functional whole-organ prostate gland model for regeneration and drug screening.

Model organisms are vital for biomedical research and drug testing but face high costs, complexity, and ethical issues. While newer techniques like organoids and assembloids have shown improvements, they still remain inadequate in addressing all research needs. In this study, we present a new method for maintaining the prostate gland of the earthworm, Eudrilus eugeniae ex vivo and examine its potential for regeneration and drug screening.

Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth.

Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identify lysine methyltransferase (KMT)9 as a regulator of PDC activity. KMT9 is localized in mitochondria of PCa cells, but not in mitochondria of other tumor cell types.

Proteomic insights into dual-species biofilm formation of E. coli and E. faecalis on urinary catheters.

Infections associated with urinary catheters are often caused by biofilms composed of various bacterial species that form on the catheters' surfaces. In this study, we investigated the intricate interplay between Escherichia coli and Enterococcus faecalis during biofilm formation on urinary catheter segments using a dual-species culture model. We analyzed biofilm formation and global proteomic profiles to understand how these bacteria interact and adapt within a shared environment.

Deep mutational scanning of the Trypanosoma brucei developmental regulator RBP6 reveals an essential disordered region influenced by positive residues.

To regain infectivity, Trypanosoma brucei, the pathogen causing Human and Animal African trypanosomiasis, undergoes a complex developmental program within the tsetse fly known as metacyclogenesis. RNA-binding protein 6 (RBP6) is a potent orchestrator of this process, however, an understanding of its functionally important domains and their mutational constraints is lacking. Here, we perform deep mutational scanning of the entire RBP6 primary structure.

Chronic kidney disease.

Chronic kidney disease (CKD) is defined by persistent abnormalities of kidney function or structure that have consequences for the health. A progressive decline of excretory kidney function has effects on body homeostasis. CKD is tightly associated with accelerated cardiovascular disease and severe infections, and with premature death.

Understanding metastasis mixed-treatment responses through genomic analyses.

Early-stage and metastatic breast cancers (MBC) can exhibit genomic heterogeneity, even within the same individual. Response to therapy in metastatic breast cancer patients with multiple metastases can also be heterogeneous, with different degrees of responsiveness to the same drug(s) across metastatic sites, termed "mixed response," within the same patient. Whether this treatment response variability is influenced by factors such as intrinsic tumor characteristics of metastatic lesions and/or the microenvironment is unknown.

Prevalence of hypertensive disorders of pregnancy and chronic hypertension increased throughout the COVID-19 pandemic in South Carolina (2015-2021).

Hypertensive disorders of pregnancy (HDP) and chronic hypertension (CHTN) are related to maternal and infant morbidity and mortality. We aimed to assess HDP and CHTN prevalence changes before (January 2015-February 2020) and during the COVID-19 pandemic (March 2020-December 2021) in South Carolina (SC). SC live births (2015-2021) were included (194,841 non-Hispanic White [NHW]); 108,195 non-Hispanic Black [NHB]; 25,560 Hispanic; 16,346 other race/ethnicity).

Advancing the genetic engineering toolbox by combining AsCas12a knock-in mice with ultra-compact screening.

Cas12a is a next-generation gene editing tool that enables multiplexed gene targeting. Here, we present a mouse model that constitutively expresses enhanced Acidaminococcus sp. Cas12a (enAsCas12a) linked to an mCherry fluorescent reporter.

Versatile nitrate-respiring heterotrophs are previously concealed contributors to sulfur cycle.

Heterotrophic denitrifiers play crucial roles in global carbon and nitrogen cycling. However, their inability to oxidize sulfide renders them vulnerable to this toxic molecule, which inhibits the key enzymatic reaction responsible for reducing nitrous oxide (NO), thereby raising greenhouse gas emissions. Here, we applied microcosm incubations, community-isotope-corrected DNA stable-isotope probing, and metagenomics to characterize a cohort of heterotrophic denitrifiers in estuarine sediments that thrive by coupling sulfur oxidation with denitrification through chemolithoheterotrophic metabolism.

Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer.

Mechanisms related to tumor evasion from NK cell-mediated immune surveillance remain enigmatic. Dickkopf-1 (DKK1) is a Wnt/β-catenin inhibitor, whose levels correlate with breast cancer progression. We find DKK1 to be expressed by tumor cells and cancer-associated fibroblasts (CAFs) in patient samples and orthotopic breast tumors, and in bone.

Oncolytic reprogramming of tumor microenvironment shapes CD4 T-cell memory via the IL6ra-Bcl6 axis for targeted control of glioblastoma.

Oncolytic viruses (OVs) emerge as a promising cancer immunotherapy. However, the temporal impact on tumor cells and the tumor microenvironment, and the nature of anti-tumor immunity post-therapy remain largely unclear. Here we report that CD4 T cells are required for durable tumor control in syngeneic murine models of glioblastoma multiforme after treatment with an oncolytic herpes simplex virus (oHSV) engineered to express IL-12.

Upregulated FoxO1 promotes arrhythmogenesis in mice with heart failure and preserved ejection fraction.

Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in male HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias.