Assessment of Hsp90β-selective inhibitor safety and on-target effects.

The heat shock protein 90 (Hsp90) family of molecular chaperones mediates the folding and activation of ~ 400 client proteins, many of which contribute to oncogenesis. As a result, Hsp90 pan-inhibitors, which inhibit all four Hsp90 isoforms, have been investigated in the clinic for the treatment of cancer. Unfortunately, detrimental side effects were observed and hindered the clinical development of pan-Hsp90 inhibitors.

Polydopamine grafting polyether ether ketone to stabilize growth factor for efficient osteonecrosis repair.

This study examines the biocompatibility, osteogenic potential, and effectiveness of polyether ether ketone (PEEK) composites for treating osteonecrosis, seeking to establish a theoretical basis for clinical application. A range of PEEK composite materials, including sulfonated polyether ether ketone (SPEEK), polydopamine-sulfonated polyether ether ketone (SPEEK-PDA), bone-forming peptide-poly-dopamine-sulfonated polyether ether ketone (SPEEK-PDA-BFP), and vascular endothelial growth factor-poly-dopamine-sulfonated polyether ether ketone (SPEEK-PDA-VEGF), were constructed by concentrated sulfuric acid sulfonation, polydopamine modification and grafting of bioactive factors. The experiments involved adult male New Zealand rabbits aged 24-28 weeks and weighing 2.

Salicylic acid confers cadmium tolerance in wheat by regulating photosynthesis, yield and ionic homeostasis.

Wheat (Triticum aestivum L.) productivity and quality can be threatened by soil cadmium (Cd) contamination, posing a concern to food security. Salicylic acid (SA) is an endogenously produced signaling molecule that activates the defense system imparting abiotic stress tolerance in plants.

Convergent evidence for the temperature-dependent emergence of silicification in terrestrial plants.

Research on silicon (Si) biogeochemistry and its beneficial effects for plants has received significant attention over several decades, but the reasons for the emergence of high-Si plants remain unclear. Here, we combine experimentation, field studies and analysis of existing databases to test the role of temperature on the expression and emergence of silicification in terrestrial plants. We first show that Si is beneficial for rice under high temperature (40 °C), but harmful under low temperature (0 °C), whilst a 2 °C increase results in a 37% increase in leaf Si concentrations.

Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia.

ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukemia (ALL) associated with favorable prognosis, but the optimal therapy for this subtype remains unclear. Profiling the genomic and pharmacological landscape of 194 pediatric ETV6::RUNX1 ALL cases, we uncover two transcriptomic clusters, C1 (61%) and C2 (39%). Compared to C1, the C2 subtype features higher white blood cell counts and younger age at diagnosis, as well as better early treatment responses.

Elucidating the potential of EGFR mutated NSCLC and identifying its multitargeted inhibitors.

Lung cancer is the leading cause of cancer-related fatalities globally, accounting for the highest mortality rate among both men and women. Mutations in the epidermal growth factor receptor (EGFR) gene are frequently found in non-small cell lung cancer (NSCLC). Since curcumin and CB[2]UN support various medicinal applications in drug delivery and design, we investigated the effect of curcumin and CB[2]UN-based drugs in controlling EGFR-mutant NSCLC through a dodecagonal computational approach.

Gemistocytic tumor cells programmed for glial scarring characterize T cell confinement in IDH-mutant astrocytoma.

Isocitrate dehydrogenase 1/2 mutant (IDHmt) astrocytoma is considered a T cell-deprived tumor, yet little is known regarding the phenotypes underlying T cell exclusion. Using bulk, single nucleus and spatial RNA and protein profiling, we demonstrate that a distinct spatial organization underlies T cell confinement to the perivascular space (T cell cuff) in IDHmt astrocytoma. T cell cuffs are uniquely characterized by a high abundance of gemistocytic tumor cells (GTC) in the surrounding stroma.

Sucrose-preferring gut microbes prevent host obesity by producing exopolysaccharides.

Commensal bacteria affect host health by producing various metabolites from dietary carbohydrates via bacterial glycometabolism; however, the underlying mechanism of action remains unclear. Here, we identified Streptococcus salivarius as a unique anti-obesity commensal bacterium. We found that S.

Single cell profiling of circulating autoreactive CD4 T cells from patients with autoimmune liver diseases suggests tissue imprinting.

Autoimmune liver diseases (AILD) involve dysregulated CD4 T cell responses against liver self-antigens, but how these autoreactive T cells relate to liver tissue pathology remains unclear. Here we perform single-cell transcriptomic and T cell receptor analyses of circulating, self-antigen-specific CD4 T cells from patients with AILD and identify a subset of liver-autoreactive CD4 T cells with a distinct B-helper transcriptional profile characterized by PD-1, TIGIT and HLA-DR expression. These cells share clonal relationships with expanded intrahepatic T cells and exhibit transcriptional signatures overlapping with tissue-resident T cells in chronically inflamed environments.

Comparison of mNGS with conventional methods for diagnosis of cryptococcal meningitis: a retrospective study.

The application of metagenomic next-generation sequencing (mNGS) in the diagnosis of cryptococcal meningitis is relatively under characterized. Here, we retrospectively evaluated data from cryptococcal meningitis patients who were tested using mNGS and/or routine testing, including fungal culture, India ink staining, and cryptococcal antigen (CrAg) testing. The performance of mNGS was then assessed.

The mycobacterial ABC transporter IrtAB employs a membrane-facing crevice for siderophore-mediated iron uptake.

The mycobacterial ABC transporter IrtAB features an ABC exporter fold, yet it imports iron-charged siderophores called mycobactins. Here, we present extensive cryo-EM analyses and DEER measurements, revealing that IrtAB alternates between an inward-facing and an outward-occluded conformation, but does not sample an outward-facing conformation. When IrtAB is locked in its outward-occluded conformation in nanodiscs, mycobactin is bound in the middle of the lipid bilayer at a membrane-facing crevice opening at the heterodimeric interface.

In situ osteogenic activation of mesenchymal stem cells by the blood clot biomimetic mechanical microenvironment.

Blood clots (BCs) play a crucial biomechanical role in promoting osteogenesis and regulating mesenchymal stem cell (MSC) function and fate. This study shows that BC formation enhances MSC osteogenesis by activating Itgb1/Fak-mediated focal adhesion and subsequent Runx2-mediated bone regeneration. Notably, BC viscoelasticity regulates this effect by modulating Runx2 nuclear translocation.

Distinct bacteria display genus and species-specific associations with mycobionts in paramo lichens in Colombia.

Lichens are complex symbiotic systems where fungi interact with an extracellular arrangement of one or more photosynthetic partners and an indeterminate number of other microbes. Recently, specific lichen-microbial community associations have been proposed. In this study, we aimed to characterize the differences in bacteria associated with closely related lichens, under a defined set of environmental conditions in Colombian paramos.

Subcellular mitochondrial heterogeneity enables opposing metabolic demands.

Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell.

Blood Lactate as a Metabolic Biomarker of Anaerobic Vocal Capacity: A Pilot Study.

Purpose: Blood lactate concentration is commonly used to assess metabolic demand and skeletal muscle training response. The objective of the pilot study was to investigate if a change in blood lactate was detectable in an anaerobically designed vocal demand task vocal capacity anaerobic task (VCAT) and determine if the developed vocal demand task may assess the anaerobic capacity of the voice musculature, like anaerobic power tests commonly used in applied exercise science.

Methods: A prospective repeated measures study quantified blood lactate concentration preVCAT and postVCAT in vocally healthy adults.

MuSK regulates neuromuscular junction Nav1.4 localization and excitability.

The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly, the function of the NMJ is to transduce nerve action potentials into muscle fiber action potentials (MFAPs). Efficient neuromuscular transmission requires both cholinergic signaling, responsible for generation of endplate potentials (EPPs), and excitation, the amplification of the EPP by postsynaptic voltage-gated sodium channels (Nav1.

K1 channels enable myelinated axons to transmit spikes reliably without spiking ectopically.

Action potentials (spikes) are regenerated at each node of Ranvier during saltatory transmission along a myelinated axon. The high density of voltage-gated sodium channels required by nodes to reliably transmit spikes increases the risk of ectopic spike generation in the axon. Here we show that ectopic spiking is avoided because K1 channels prevent nodes from responding to slow depolarization; instead, axons respond selectively to rapid depolarization because K1 channels implement a high-pass filter.

An Open-Source 3D-Printable Platform for Testing Head-Fixed Cognitive Flexibility in Rodents.

The study of the neural circuitry underlying complex mammalian decision-making, particularly cognitive flexibility, is critical for understanding psychiatric disorders. To test cognitive flexibility, as well as potentially other decision-making paradigms involving multimodal sensory perception, we developed FlexRig, an open-source, modular behavioral platform for use in head-fixed mice. FlexRig enables the administration of tasks relying upon olfactory, somatosensory, and/or auditory cues and employing left and right licking as a behavior readout and reward delivery mechanism.

Valorization of Macroalgal Hydrolysate for the Production of Lipids and DHA by Marine Microbes.

The present study aimed to explore the potential of macroalgal hydrolysate to serve as an economical substrate for the growth of the oleaginous microbes Aspergillus sp. SY-70, Rhizopus arrhizus SY-71 and Aurantiochytrium sp. YB-05 for lipid and DHA production under laboratory conditions.

Lobectomy Increases Postoperative Pulmonary Artery Enlargement to a Greater Extent than Segmentectomy.

Purpose: The underlying mechanism why segmentectomy has demonstrated the non-inferiority to lobectomy in several randomized trials remains unclear. Computed tomography (CT)-measured pulmonary artery (PA) enlargement reflects PA pressure and predicts the prognosis of certain respiratory diseases. We compared the preoperative and postoperative PA diameter to the ascending aorta diameter (PA/A) ratio, investigating its impact on right ventricular function in lung resection.

Usefulness of Artificial Pneumothorax during Totally Endoscopic Off-Pump Left Atrial Appendage Closure and Surgical Ablation.

Purpose: In totally endoscopic off-pump left atrial appendage (LAA) closure and surgical ablation, securing the operative field is sometimes difficult in some patients because of a narrow working space caused by an elevated diaphragm or ventricles. In this study, we aimed to investigate the effectiveness of a method that facilitates securing the operative field using an artificial pneumothorax.

Methods: We analyzed 71 consecutive patients who underwent totally endoscopic off-pump LAA closure and bilateral pulmonary vein isolation.

Prognostic Value of Coronary Angiography-Derived Index of Microcirculatory Resistance in Patients With Intermediate Coronary Stenosis.

Background: The association between coronary microcirculation and clinical outcomes in patients with intermediate stenosis remains unclear.

Objectives: The aim of this study was to assess the prognostic significance of angiography-derived index of microcirculatory resistance (angio-IMR) in patients with intermediate coronary stenosis.

Methods: This post hoc analysis included 1,658 patients from the FLAVOUR (Fractional Flow Reserve and Intravascular Ultrasound for Clinical Outcomes in Patients with Intermediate Stenosis) trial, with angio-IMR measured in each vessel exhibiting intermediate stenosis.

Mental Well-being in Menopause.

The hormonal changes that accompany the transition to menopause are disruptive to most women, and for some, mental health maybe adversely affected. Depressive symptoms and major depression are the best-studied conditions in association with menopause, but anxiety, executive function, and comorbid pre-existing psychiatric conditions all influence the symptomatology that women will experience during this phase of their lives. The epidemiology, diagnosis, and evidence-based treatment guidelines for perimenopausal patients are discussed.

Characterization and Localization of Focal Atrial Tachycardia in Patients With Adult Congenital Heart Disease.

Background: In patients with structurally normal hearts, algorithms using surface electrocardiographic P-wave morphology are helpful to predict focal atrial tachycardia (FAT) location. However, these algorithms have not been formally assessed in patients with adult congenital heart disease (ACHD).

Objectives: This study sought to assess the efficacy of FAT-location prediction algorithms in an adult population of patients with ACHD.

Risk Factors and Mechanisms for Diabetes in Pancreatitis.

Diabetes (DM) can occur as a complication of acute, acute recurrent, or chronic pancreatitis, affecting more than 30% of adults with chronic pancreatitis. Data on the pathophysiology and management are limited, especially in pediatric population. Proposed mechanisms include insulin deficiency, insulin resistance, decreased pancreatic polypeptide, and possible beta-cell autoimmunity (in a small subset).