Parallel single-cell metabolic analysis and extracellular vesicle profiling reveal vulnerabilities with prognostic significance in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive disease with a high relapse rate. In this study, we map the metabolic profile of CD34(CD38) AML cells and the extracellular vesicle signatures in circulation from AML patients at diagnosis. CD34 AML cells display high antioxidant glutathione levels and enhanced mitochondrial functionality, both associated with poor clinical outcomes.

Epidemic Zika virus strains from the Asian lineage induce an attenuated fetal brain pathogenicity.

The 2015-2016 Zika virus (ZIKV) outbreak in the Americas revealed the ability of ZIKV from the Asian lineage to cause birth defects, generically called congenital Zika syndrome (CZS). Notwithstanding the long circulation history of Asian ZIKV, no ZIKV-associated CZS cases were reported prior to the outbreaks in French Polynesia (2013) and Brazil (2015). Whether the sudden emergence of CZS resulted from an evolutionary event of Asian ZIKV has remained unclear.

Preventive effect of Tyr-Pro, a blood-brain barrier transportable dipeptide, on memory impairment in SAMP8 mice.

In a series of studies on blood-brain barrier transportable peptides, a soybean dipeptide, Tyr-Pro, penetrated the mouse brain parenchyma after oral intake and improved short and long memory impairment in acute Alzheimer's model mice. Here, we aimed to clarify the anti-dementia effects of this peptide administered to SAMP8 mice prior to dementia onset. At the end of the 25-week protocol in 16-week-old SAMP8 mice, Tyr-Pro (10 mg/kg/day) significantly improved the reduced spatial learning ability compared with that in the control and amino acid (Tyr + Pro) groups as indicated by the results of Morris water maze tests conducted for five consecutive days.

Short tandem repeats delineate gene bodies across eukaryotes.

Short tandem repeats (STRs) have emerged as important and hypermutable sites where genetic variation correlates with gene expression in plant and animal systems. Recently, it has been shown that a broad range of transcription factors (TFs) are affected by STRs near or in the DNA target binding site. Despite this, the distribution of STR motif repetitiveness in eukaryote genomes is still largely unknown.

SEAD reference panel with 22,134 haplotypes boosts rare variant imputation and genome-wide association analysis in Asian populations.

Limited whole genome sequencing (WGS) studies in Asian populations result in a lack of representative reference panels, thus hindering the discovery of ancestry-specific variants. Here, we present the South and East Asian reference Database (SEAD) panel ( https://imputationserver.westlake.

Alcohol-induced gut microbial reorganization and associated overproduction of phenylacetylglutamine promotes cardiovascular disease.

The mechanism(s) underlying gut microbial metabolite (GMM) contribution towards alcohol-mediated cardiovascular disease (CVD) is unknown. Herein we observe elevation in circulating phenylacetylglutamine (PAGln), a known CVD-associated GMM, in individuals living with alcohol use disorder. In a male murine binge-on-chronic alcohol model, we confirm gut microbial reorganization, elevation in PAGln levels, and the presence of cardiovascular pathophysiology.

An antibody cocktail targeting two different CD73 epitopes enhances enzyme inhibition and tumor control.

CD73, an ectoenzyme responsible for adenosine production, is often elevated in immuno-suppressive tumor environments. Inhibition of CD73 activity holds great promise as a therapeutic strategy for CD73-expressing cancers. In this study, we have developed a therapeutic anti-human CD73 antibody cocktail, HB0045.

Orthogonal and multiplexable genetic perturbations with an engineered prime editor and a diverse RNA array.

Programmable and modular systems capable of orthogonal genomic and transcriptomic perturbations are crucial for biological research and treating human genetic diseases. Here, we present the minimal versatile genetic perturbation technology (mvGPT), a flexible toolkit designed for simultaneous and orthogonal gene editing, activation, and repression in human cells. The mvGPT combines an engineered compact prime editor (PE), a fusion activator MS2-p65-HSF1 (MPH), and a drive-and-process multiplex array that produces RNAs tailored to different types of genetic perturbation.

SARS-CoV-2 infection of human pluripotent stem cell-derived vascular cells reveals smooth muscle cells as key mediators of vascular pathology during infection.

Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), nearly 20% of hospitalized patients are at risk for thromboembolic events. This prothrombotic state is considered a key factor in the increased risk of stroke, which is observed clinically during both acute infection and long after symptoms clear. Here, we develop a model of SARS-CoV-2 infection using human-induced pluripotent stem cell-derived endothelial cells (ECs), pericytes (PCs), and smooth muscle cells (SMCs) to recapitulate the vascular pathology associated with SARS-CoV-2 exposure.

Structural insights into how Cas9 targets nucleosomes.

The CRISPR-associated endonuclease Cas9 derived from prokaryotes is used as a genome editing, which targets specific genomic loci by single guide RNAs (sgRNAs). The eukaryotes, the target of genome editing, store their genome DNA in chromatin, in which the nucleosome is a basic unit. Despite previous structural analyses focusing on Cas9 cleaving free DNA, structural insights into Cas9 targeting of DNA within nucleosomes are limited, leading to uncertainties in understanding how Cas9 operates in the eukaryotic genome.

Site-specific seeding of Lewy pathology induces distinct pre-motor cellular and dendritic vulnerabilities in the cortex.

Circuit-based biomarkers distinguishing the gradual progression of Lewy pathology across synucleinopathies remain unknown. Here, we show that seeding of α-synuclein preformed fibrils in mouse dorsal striatum and motor cortex leads to distinct prodromal-phase cortical dysfunction across months. Our findings reveal that while both seeding sites had increased cortical pathology and hyperexcitability, distinct differences in electrophysiological and cellular ensemble patterns were crucial in distinguishing pathology spread between the two seeding sites.

NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression.

Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane.

Rapid nongenomic estrogen signaling controls alcohol drinking behavior in mice.

Ovarian-derived estrogen can signal non-canonically at membrane-associated receptors in the brain to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high estrogen levels, but a causal role for estrogen in driving alcohol drinking has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance when estrogen was high during the estrous cycle than when it was low.

PSCA-targeted BPX-601 CAR T cells with pharmacological activation by rimiducid in metastatic pancreatic and prostate cancer: a phase 1 dose escalation trial.

Here we report results of a phase 1 multi-institutional, open-label, dose-escalation trial (NCT02744287) of BPX-601, an investigational autologous PSCA-directed GoCAR-T® cell product containing an inducible MyD88/CD40 ON-switch responsive to the activating dimerizer rimiducid, in patients with metastatic pancreatic (mPDAC) or castration-resistant prostate cancer (mCRPC). Primary objectives were to evaluate safety and tolerability and determine the recommended phase 2 dose/schedule (RP2D). Secondary objectives included the assessment of efficacy and characterization of the pharmacokinetics of rimiducid.

Mortality in Haemophilia Patients in India: A National Cohort Study.

Introduction: Mortality and morbidity in persons with haemophilia (PWH) have decreased due to improved diagnosis and treatment along with comprehensive population outreach efforts, but the impact is not uniform in different countries.

Aim: The study aims to assess all-cause and intracranial haemorrhage (ICH)-specific mortality of PWH in India.

Methods: This is a retrospective, observational, multi-centric cohort study of 1020 haemophilia patients from three centres in India.

Molecular epidemiology of invasive group B Streptococcus in South Africa, 2019-2020.

Background: Group B Streptococcus (GBS) is a leading cause of neonatal meningitis and sepsis and an important cause of disease in adults. Capsular polysaccharide and protein-based GBS vaccines are currently under development.

Methods: Through national laboratory-based surveillance, invasive GBS isolates were collected from patients of all ages between 2019 and 2020.

Environment-Organism Feedbacks Drive Changes in Ecological Interactions.

Ecological interactions are foundational to our understanding of community composition and function. While interactions are known to change depending on the environmental context, it has generally been assumed that external environmental factors are responsible for driving these dependencies. Here, we derive a theoretical framework which instead focuses on how intrinsic environmental changes caused by the organisms themselves alter interaction values.

Environmental Conditions Modulate Warming Effects on Plant Litter Decomposition Globally.

Empirical studies worldwide show that warming has variable effects on plant litter decomposition, leaving the overall impact of climate change on decomposition uncertain. We conducted a meta-analysis of 109 experimental warming studies across seven continents, using natural and standardised plant material, to assess the overarching effect of warming on litter decomposition and identify potential moderating factors. We determined that at least 5.

Physcomitrium LATERAL SUPPRESSOR genes promote formative cell divisions to produce germ cell lineages in both male and female gametangia.

The evolution of green plants from aquatic to terrestrial environments is thought to have been facilitated by the acquisition of gametangia, specialized multicellular organs housing gametes. Antheridia and archegonia, responsible for producing and protecting sperm and egg cells, undergo formative cell divisions to produce a cell to differentiate into germ cell lineages and the other cell to give rise to surrounding structures. However, the genes governing this process remain unidentified.

Impact of light dose and fluence rate on the efficacy and tolerability of topical 5-ALA photodynamic therapy for actinic keratoses: A randomized, controlled, observer-blinded intrapatient comparison study.

Background: Conventional photodynamic therapy (cPDT) is an effective treatment option for field cancerization and multiple actinic keratoses (AK). The main side effect of cPDT is pain during illumination which in severe cases might necessitate early termination of treatment. Modification of treatment parameters such as light dose and fluence rate is a promising approach to mitigate PDT-associated pain.

New tools to monitor infection and biofilms in .

Introduction: Antimicrobial resistance is a growing health problem. Pseudomonas aeruginosa is a pathogen of major concern because of its multidrug resistance and global threat, especially in health-care settings. The pathogenesis and drug resistance of depends on its ability to form biofilms, making infections chronic and untreatable as the biofilm protects against antibiotics and host immunity.

Soluble CD52 mediates immune suppression by human seminal fluid.

Seminal fluid provides for the carriage and nutrition of sperm, but also modulates immunity to prevent allo-rejection of sperm by the female. Immune suppression by seminal fluid has been associated with extracellular vesicles, originally termed prostasomes, which contain CD52, a glycosylated glycophosphoinositol-anchored peptide released from testicular epithelial cells. Previously, we reported that human T cell-derived CD52, bound to the danger-associated molecular pattern protein, high mobility group box 1 (HMGB1), suppresses T cell function via the inhibitory sialic acid-binding immunoglobulin-like lectin-10 (Siglec-10) receptor.

A retrospective description of blood and urine alterations in 386 male cats with urethral obstruction in Botucatu, São Paulo, Brazil.

Background: Urinary retention in obstructed male cats leads to changes in blood and urine compounds, which, combined with the time of obstruction, are linked to the worsening of the animal's clinical status.

Aim: This study aimed to describe the primary laboratory changes in male cats with urethral obstruction (UO).

Methods: Medical records of 386 male cats diagnosed with UO and treated at the Veterinary Teaching Hospital of the Faculty of Veterinary Medicine and Zootechnics (FMVZ), UNESP-Botucatu, between 2010 and 2020 were reviewed.

Localization is the key to action: regulatory peculiarities of lncRNAs.

To understand the transcriptomic profile of an individual cell in a multicellular organism, we must comprehend its surrounding environment and the cellular space where distinct molecular stimuli responses are located. Contradicting the initial perception that RNAs were nonfunctional and that only a few could act in chromatin remodeling, over the last few decades, research has revealed that they are multifaceted, versatile regulators of most cellular processes. Among the various RNAs, long non-coding RNAs (LncRNAs) regulate multiple biological processes and can even impact cell fate.

The role of the microbiome in allergic dermatitis-related otitis externa: a multi-species comparative review.

The external ear canal, characterized by species-specific structural and physiological differences, maintains a hostile environment that prevents microbial overgrowth and foreign body entry, supported by factors such as temperature, pH, humidity, and cerumen with antimicrobial properties. This review combines several studies on the healthy ear canal's structure and physiology with a critical approach to the potential existence of an ear microbiome. We use a comparative multi-species approach to explore how allergic conditions alter the ear canal microenvironment and cerumen in different mammalian species, promoting pathogen colonization.