Activation of locus coeruleus noradrenergic neurons rapidly drives homeostatic sleep pressure.

Homeostatic sleep regulation is essential for optimizing the amount and timing of sleep for its revitalizing function, but the mechanism underlying sleep homeostasis remains poorly understood. Here, we show that optogenetic activation of locus coeruleus (LC) noradrenergic neurons immediately increased sleep propensity following a transient wakefulness, contrasting with many other arousal-promoting neurons whose activation induces sustained wakefulness. Fiber photometry showed that repeated optogenetic or sensory stimulation caused a rapid reduction of calcium activity in LC neurons and steep declines in noradrenaline/norepinephrine (NE) release in both the LC and medial prefrontal cortex (mPFC).

DNA damage response mutations enhance the antitumor efficacy of ATR and PARP inhibitors in cholangiocarcinoma cell lines.

Cholangiocarcinoma (CCA) is a biliary tract carcinoma that is challenging to treat due to its heterogeneity and limited treatment options. Genetic alterations in DNA damage response (DDR) pathways and homologous recombination (HR) defects are common in CCA. This has prompted interest in the use of ataxia telangiectasia and Rad3-related protein (ATR) and poly(ADP-ribose) polymerase (PARP) inhibitors to treat CCA.

ABO isoagglutinin titers in group "O" blood donors.

Background: High titers of anti-A and anti-B are considered to be one reason for hemolytic transfusion reactions and ABO hemolytic disease in fetus and neonates. There is no consensus for critical ABO antibody titers to guide transfusion or transplant decisions. Implementation of ABO titer measurement can favor reduction in transfusion reactions in nongroup "O" recipients.

Transfusion medicine hackathon: Nurturing the innovative ideas to revolutionize voluntary blood donation.

Background And Objective: Blood transfusion is an essential component of health care. However, several issues can hamper the promotion and sustainability of voluntary blood donation programs. This article is about a hackathon in the field of transfusion medicine that was designed to stimulate original ideas to promote voluntary blood donation.

Evaluating the Effectiveness of Shockwave Lithotripsy vs Ureteroscopic Lithotripsy for Treatment of Renal Stones: A Prospective Cohort Study.

Background: Renal stones are a prevalent condition requiring effective treatment strategies. This study evaluates the comparative effectiveness of shockwave lithotripsy (SWL) and ureteroscopic lithotripsy (URSL) in treating renal stones in a Pakistani cohort, focusing on stone clearance, recurrence, and complications.

Methods: This prospective cohort study involved 250 patients aged 18-55 diagnosed with renal stones.

Casticin reduces rosacea-related inflammation by inhibiting mast cell activation via Mas-related G protein-coupled receptor X2.

Background: Rosacea is a chronic inflammatory disease characterized by persistent erythema, papules, and pustules, mainly on the skin of the face. Rosacea is difficult to treat; therefore, identifying new treatments is crucial. Mas-related G protein-coupled receptor X2 (MRGPRX2)-mediated mast cell (MC) activation is essential in the pathogenesis of rosacea.

Resetting of the Human Circadian Melatonin Rhythm by Ambient Hypoxia.

Circadian clocks in the body drive daily cycles in physiology and behavior. A master clock in the brain maintains synchrony with the environmental day-night cycle and uses internal signals to keep clocks in other tissues aligned. Work in cell cultures uncovered cyclic changes in tissue oxygenation that may serve to reset and synchronize circadian clocks.

Safety and efficacy of trifluridine/tipiracil +/- bevacizumab plus XB2001 (anti-IL-1α antibody): a single-center phase 1 trial.

In the tumour microenvironment, IL-1α promotes neoangiogenesis, matrix remodelling, tumour proliferation, chemoresistance, and metastases. Highly expressed in human colorectal cancers, IL-1α is associated with poor prognosis. XB2001, a fully human monoclonal antibody neutralizing IL-1α, was evaluated for safety and preliminary efficacy with trifluridine/tipiracil (FTD/TPI) and bevacizumab in metastatic colorectal cancer patients previously treated with oxaliplatin- and irinotecan-based chemotherapies.

Encoding of cerebellar dentate neuron activity during visual attention in rhesus macaques.

The role of cerebellum in controlling eye movements is well established, but its contribution to more complex forms of visual behavior has remained elusive. To study cerebellar activity during visual attention we recorded extracellular activity of dentate nucleus (DN) neurons in two non-human primates (NHPs). NHPs were trained to read the direction indicated by a peripheral visual stimulus while maintaining fixation at the center, and report the direction of the cue by performing a saccadic eye movement into the same direction following a delay.

Transformation-Guided Genome Mining Provides Access to Brominated Lanthipeptides.

Natural product biosynthesis is nature's tinkering ground for developing new enzymes that can achieve chemical transformations that are outside the purview of traditional chemical catalysis. Herein we describe a genome mining approach that leads to the discovery of a halogenase that regioselectively brominates a tryptophan side chain indole for a macrocyclic peptide substrate, enabling downstream chemical arylation by Suzuki-Miyaura coupling. The halogenase was found to prefer a macrocyclic peptide substrate over a linear peptide.

Reconstitution of synaptic junctions orchestrated by teneurin-latrophilin complexes.

Synapses are organized by trans-synaptic adhesion molecules that coordinate assembly of pre- and postsynaptic specializations, which, in turn, are composed of scaffolding proteins forming liquid-liquid phase-separated condensates. Presynaptic teneurins mediate excitatory synapse organization by binding to postsynaptic latrophilins; however, the mechanism of action of teneurins, driven by extracellular domains evolutionarily derived from bacterial toxins, remains unclear. In this work, we show that only the intracellular sequence, a dimerization sequence, and extracellular bacterial toxin-derived latrophilin-binding domains of Teneurin-3 are required for synapse organization, suggesting that teneurin-induced latrophilin clustering mediates synaptogenesis.

Mechanisms and rationales of SAM homeostasis.

S-Adenosylmethionine (SAM) is the primary methyl donor for numerous cellular methylation reactions. Its central role in methylation and involvement with many pathways link its availability to the regulation of cellular processes, the dysregulation of which can contribute to disease states, such as cancer or neurodegeneration. Emerging evidence indicates that intracellular SAM levels are maintained within an optimal range by a variety of homeostatic mechanisms.

Left ventricular elastance with resting volumetric transthoracic echocardiography identifies different phenotypes in heart failure with preserved ejection fraction: A retrospective analysis of a multicenter prospective observational study.

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity including patients with different phenotypes of near normal, normal, and supernormal left ventricular (LV) function.

Objectives: To assess the value of resting LV elastance (also known as force) with transthoracic echocardiography (TTE) to identify HFpEF phenotypes.

Methods: In a prospective, observational, multicenter study, 2380 HFpEF patients were recruited from July 2016 to May 2024.

Molecular Determinants of Optical Modulation in ssDNA-Carbon Nanotube Biosensors.

Most traditional optical biosensors operate through molecular recognition, where ligand binding causes conformational changes that lead to optical perturbations in the emitting motif. Optical sensors developed from single-stranded DNA-functionalized single-walled carbon nanotubes (ssDNA-SWCNTs) have started to make useful contributions to biological research. However, the mechanisms underlying their function have remained poorly understood.

Single cell derived multicellular meristem: insights into male-to-hermaphrodite conversion and de novo meristem formation in ceratopteris.

Land plants alternate between asexual sporophytes and sexual gametophytes. Unlike seed plants, ferns develop free-living gametophytes. Gametophytes of the model fern Ceratopteris exhibit two sex types: hermaphrodites with pluripotent meristems and males lacking meristems.

KW2478 and Cisplatin Synergistically Anti-colorectal Cancer by Targeting PI3K/AKT/mTOR Pathway.

Objective: The objective of this study is to examine the impact of KW-2478 combined with DDP on colorectal cancer cells both in vitro and in vivo and to elucidate the molecular mechanism of KW-2478 in colorectal cancer.

Methods: qRT-PCR and Western blot were employed to assess HSP90 mRNA and protein expression in normal intestinal epithelial and colorectal cancer cells. DLD-1 and HCT116 were selected for the experiment.

Cardio-Obstetrics Practice in Latin America: A Regional Survey of General Cardiologists.

Background: Cardiovascular (CV) disease is a leading cause of death in pregnant women globally, especially in low- and middle-income countries including Latin America (LATAM), where there is lack of data on how cardiologists are trained in cardio-obstetrics (CO) and the practice patterns in the care of pregnant patients.

Objectives: The authors aimed to identify CO competency and practice patterns among LATAM general cardiologists.

Methods: An anonymous cross-sectional Google-based electronic survey was sent via email to clinical cardiologists through local American College of Cardiology chapters and CV societies.

Optimal chemokine receptors for enhancing immune cell trafficking in adoptive cell therapy.

Recently, a strategy involving the engineering of chemokine receptors on immune cells was developed to optimize adoptive cell therapy (ACT) for solid tumors. Given the variability in chemokine secretion among different tumor types, identifying and modulating the appropriate chemokine receptors is crucial. In this study, we utilized extensive RNA sequencing data from both tumor tissues from The Cancer Genome Atlas and normal tissues from Genotype-Tissue Expression to investigate the expression profiles of chemokines.

Super-photostable organic dye for long-term live-cell single-protein imaging.

Organic dyes play a crucial role in live-cell imaging because of their advantageous properties, such as photostability and high brightness. Here we introduce a super-photostable and bright organic dye, Phoenix Fluor 555 (PF555), which exhibits an order-of-magnitude longer photobleaching lifetime than conventional organic dyes without the requirement of any anti-photobleaching additives. PF555 is an asymmetric cyanine structure in which, on one side, the indole in the conventional Cyanine-3 is substituted with 3-oxo-quinoline.

Massively parallel characterization of transcriptional regulatory elements.

The human genome contains millions of candidate cis-regulatory elements (cCREs) with cell-type-specific activities that shape both health and many disease states. However, we lack a functional understanding of the sequence features that control the activity and cell-type-specific features of these cCREs. Here we used lentivirus-based massively parallel reporter assays (lentiMPRAs) to test the regulatory activity of more than 680,000 sequences, representing an extensive set of annotated cCREs among three cell types (HepG2, K562 and WTC11), and found that 41.

De novo designed proteins neutralize lethal snake venom toxins.

Snakebite envenoming remains a devastating and neglected tropical disease, claiming over 100,000 lives annually and causing severe complications and long-lasting disabilities for many more. Three-finger toxins (3FTx) are highly toxic components of elapid snake venoms that can cause diverse pathologies, including severe tissue damage and inhibition of nicotinic acetylcholine receptors, resulting in life-threatening neurotoxicity. At present, the only available treatments for snakebites consist of polyclonal antibodies derived from the plasma of immunized animals, which have high cost and limited efficacy against 3FTxs.

Challenges and insights of transferring animal maze studies principles to human spatial learning research.

Maze tasks, originally developed in animal research, have become a popular method for studying human cognition, particularly with the advent of virtual reality. However, these experiments frequently rely on simplified environments and tasks, which may not accurately reflect the complexity of real-world situations. Our pilot study aims to transfer a multi-alternative maze with a complex task structure, previously demonstrated to be useful in studying animal cognition, to studying human spatial cognition.