Design and Synthesis of Topoisomerases-Histone Deacetylase Dual Targeted Quinoline-Bridged Hydroxamates as Anticancer Agents.

The multifactorial nature of cancer requires treatment that involves simultaneous targeting of associated overexpressed proteins and cell signaling pathways, possibly leading to synergistic effects. Herein, we present a systematic study that involves the simultaneous inhibition of human topoisomerases (hTopos) and histone deacetylases (HDACs) by multitargeted quinoline-bridged hydroxamic acid derivatives. These compounds were rationally designed considering pharmacophoric features and catalytic sites of the cross-talk proteins, synthesized, and assessed for their anticancer potential.

Design, Synthesis, and Pharmacological Evaluation of Nonsteroidal Tricyclic Ligands as Modulators of GABA Receptors.

GABA receptors (GABARs) are the major elements of inhibitory neurotransmission in the central nervous system (CNS). They are established targets for regulation by endogenous brain neuroactive steroids (NASs) such as pregnanolone. However, the complexity of de novo synthesis of NAS derivatives has hindered attempts to circumvent the principal limitations of using endogenous NASs, including selectivity and limited oral bioavailability.

The chromatin remodeler ADNP regulates neurodevelopmental disorder risk genes and neocortical neurogenesis.

Although chromatin remodelers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), the roles of these complexes during brain development are in many cases unclear. Here, we focused on the recently discovered ChAHP chromatin remodeling complex. The zinc finger and homeodomain transcription factor ADNP is a core subunit of this complex, and de novo mutations lead to intellectual disability and autism spectrum disorder.

An Activin Receptor-Like Kinase 1-governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases.

The biology centered around the TGF-beta type I receptor Activin Receptor-Like Kinase (ALK)1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation.

Identification of Butyrylcholinesterase-Derived Small Molecule Peptides Indicative of Novichok Nerve Agent Exposures.

Novichok nerve agents, such as A-230, A-232, and A-234, were classified as Schedule 1 chemicals under the Chemical Weapons Convention (CWC) by the Organisation for the Prohibition of Chemical Weapons (OPCW) following poisoning incidents in 2018. As a result, the production, storage, and use of these chemicals are strictly prohibited by CWC signatory nations. The identification of biomarkers indicating Novichok exposure in humans is crucial for prompt detection and response to potential incidents involving these banned chemical weapons.

Epigenetics in the modern era of crop improvements.

Epigenetic mechanisms are integral to plant growth, development, and adaptation to environmental stimuli. Over the past two decades, our comprehension of these complex regulatory processes has expanded remarkably, producing a substantial body of knowledge on both locus-specific mechanisms and genome-wide regulatory patterns. Studies initially grounded in the model plant Arabidopsis have been broadened to encompass a diverse array of crop species, revealing the multifaceted roles of epigenetics in physiological and agronomic traits.

Pulmonary granuloma formation during latent infection in C3HeB/FeJ mice involves progression through three immunological phases.

is a fungal pathogen that can cause lethal disease in immunocompromised patients. Immunocompetent host immune responses, such as formation of pulmonary granulomas, control the infection and prevent disseminated disease. Little is known about the immunological conditions establishing the latent infection granuloma in the lungs.

Mechanically Robust Bismuth-Embedded Carbon Microspheres for Ultrafast Charging and Ultrastable Sodium-Ion Batteries.

Advancements in the development of fast-charging and long-lasting microstructured alloying anodes with high volumetric capacities are essential for enhancing the operational efficiency of sodium-ion batteries (SIBs). These anodes, however, face challenges such as declined cyclability and rate capability, primarily due to mechanical degradation reduced by significant volumetric changes (over 252%) and slow kinetics of sodium-ion storage. Herein, we introduce a novel anode design featuring densely packed bismuth (Bi) embedded within highly conductive carbon microspheres to overcome the aforementioned challenges.

Highly Tension-Strained Copper Concentrates Diluted Cations for Selective Proton-Exchange Membrane CO2 Electrolysis.

Electrolysis of carbon dioxide (CO2) in acid offers a promising route to overcome CO2 loss in alkaline and neutral electrolytes, but requires concentrated alkali cations (typical ≥3 M) to mitigate the trade-off between low pH and high hydrogen evolution reaction (HER) rate, causing salt precipitation. Here we report a strategy to resolve this problem by introducing tensile strain in a copper (Cu) catalyst, which can selectively reduce CO2 to valuable multicarbon products, particularly ethylene, in a pH 1 electrolyte with 1 M potassium ions. We find that the tension-strained Cu creates an electron-rich surface that concentrates diluted potassium ions, contributing to CO2 activation and HER suppression.

Clinical utility of plasma p-tau217 in identifying abnormal brain amyloid burden in an Asian cohort with high prevalence of concomitant cerebrovascular disease.

Introduction: Using an Asian cohort with high prevalence of concomitant cerebrovascular disease (CeVD), we evaluated the performance of a plasma immunoassay for tau phosphorylated at threonine 217 (p-tau217) in detecting amyloid beta positivity (Aβ+) on positron emission tomography and cognitive decline, based on a three-range reference, which stratified patients into low-, intermediate-, and high-risk groups for Aβ+.

Methods: Brain amyloid status (Aβ- [n = 142] vs Aβ+ [n = 73]) on amyloid PET scans was assessed along with the plasma ALZpath p-tau217 assay to derive three-range reference points for PET Aβ+ based on 90% sensitivity (lower threshold) and 90% specificity (upper threshold).

Results: Plasma p-tau217 (area under the curve [AUC] = 0.

AAPM Truth-based CT (TrueCT) reconstruction grand challenge.

Background: This Special Report summarizes the 2022, AAPM grand challenge on Truth-based CT image reconstruction.

Purpose: To provide an objective framework for evaluating CT reconstruction methods using virtual imaging resources consisting of a library of simulated CT projection images of a population of human models with various diseases.

Methods: Two hundred unique anthropomorphic, computational models were created with varied diseases consisting of 67 emphysema, 67 lung lesions, and 66 liver lesions.

HIF1α Plays a Crucial Role in the Development of TFE3-Rearranged Renal Cell Carcinoma by Orchestrating a Metabolic Shift Toward Fatty Acid Synthesis.

Tumor development often requires cellular adaptation to a unique, high metabolic state; however, the molecular mechanisms that drive such metabolic changes in TFE3-rearranged renal cell carcinoma (TFE3-RCC) remain poorly understood. TFE3-RCC, a rare subtype of RCC, is defined by the formation of chimeric proteins involving the transcription factor TFE3. In this study, we analyzed cell lines and genetically engineered mice, demonstrating that the expression of the chimeric protein PRCC-TFE3 induced a hypoxia-related signature by transcriptionally upregulating HIF1α and HIF2α.

Reductive Removal of Antimony from Wastewater by a UV/Sulfite Process: Targeted Recovery of Strategic Metalloid Antimony.

The removal of antimony from wastewater using traditional methods such as adsorption and membrane filtration generates large amounts of antimony-containing hazardous wastes, posing significant environmental threats. This study proposed a new treatment strategy to reductively remove and recover antimony from wastewater using an advanced UV/sulfite reduction process in the form of valuable strategic metalloid antimony (Sb(0)), thus preventing hazardous waste generation. The results indicated that more than 99.

Early Versus Delayed Antihypertensive Treatment After Acute Ischemic Stroke by Hypertension History.

Background: We performed a prespecified subgroup analysis of the CATIS-2 trial (China Antihypertensive Trial in Acute Ischemic Stroke II) to compare the effect of early versus delayed antihypertensive treatment on death and disability in patients with and without medical history of hypertension.

Methods: CATIS-2 is a multicenter randomized clinical trial conducted in 106 hospitals in China. The trial randomized 4810 patients with acute ischemic stroke within 24 to 48 hours of symptom onset and elevated systolic blood pressure between 140 and <220 mm Hg to receive antihypertensive treatment immediately after randomization or to discontinue antihypertensive medications for 7 days and then receive treatment on day 8.

Small mammals and associated infections in China: a systematic review and spatial modelling analysis.

Background: As natural reservoirs of diverse pathogens, small mammals are considered a key interface for guarding public health due to their wide geographic distribution, high density and frequent interaction with humans.

Methods: All formally recorded natural occurrences of small mammals (Order: Rodentia, Eulipotyphla, Lagomorpha, and Scandentia) and their associated microbial infections in China were searched in the English and Chinese literature spanning from 1950 to 2021 and geolocated. Machine learning models were applied to determine ecological drivers for the distributions of 45 major small mammal species and two common rodent-borne diseases (RBDs), and model-predicted potential risk locations were mapped.

Ischemia during exercise stress testing, an indication of coronary vasomotor dysfunction?

Background: Recently it has been suggested that coronary microvascular dysfunction (CMD) may explain the high false-positive rate of exercise electrocardiographic stress testing (EST). However, patients with angina but non-obstructive coronary artery disease (ANOCA) present with a broader spectrum of coronary vasomotor dysfunction (CVDys), namely coronary artery spasm (CAS), CMD or a combination of both. We aim to investigate the diagnostic value of EST for the entire CVDys spectrum.

Intestinal epithelial cell NCoR deficiency ameliorates obesity and metabolic syndrome.

Nuclear receptor corepressor (NCoR1) interacts with various nuclear receptors and regulates the anabolism and catabolism of lipids. An imbalance in lipid/energy homeostasis is also an important factor in obesity and metabolic syndrome development. In this study, we found that the deletion of NCoR1 in intestinal epithelial cells (IECs) mainly activated the nuclear receptor PPAR and attenuated metabolic syndrome by stimulating thermogenesis.

Development of a bacteria-nanosapper for the active delivery of ZIF-8 particles containing therapeutic genes for cancer immune therapy.

Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment (TME). Some bacteria exhibit spontaneous chemotaxis toward the anaerobic and immune-suppressive TME, which makes them ideal natural vehicles for cancer gene therapy. Here, we conjugated ZIF-8 metal-organic frameworks encapsulating eukaryotic murine interleukin 2 () expression plasmid onto the surface of VNP20009, an attenuated strain with well-documented anti-cancer activity, and constructed a TME-targeted delivery system named /ZIF-8@.

Comparison of Jinzhen oral liquid and ambroxol hydrochloride and clenbuterol hydrochloride oral solution in the treatment of acute bronchitis in children: A multicenter, non-inferiority, prospective, randomized controlled trial.

The comparison between traditional Chinese medicine Jinzhen oral liquid (JZOL) and Western medicine in treating children with acute bronchitis (AB) showed encouraging outcomes. This trial evaluated the efficacy and safety of the JZOL for improving cough and expectoration in children with AB. 480 children were randomly assigned to take JZOL or ambroxol hydrochloride and clenbuterol hydrochloride oral solution for 7 days.

Identification of USP2 as a novel target to induce degradation of KRAS in myeloma cells.

Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation. In this study, we identify ubiquitin-specific protease 2 (USP2) as a novel deubiquitinating enzyme of KRAS in multiple myeloma (MM). Specifically, we demonstrate that gambogic acid (GA) forms a covalent bond with the cysteine 284 residue of USP2 through an allosteric pocket, inhibiting its deubiquitinating activity.

Prognostic significance of immune reconstitution following CD19 CAR T-cell therapy for relapsed/refractory B-cell lymphoma.

Immune deficits after CD19 chimeric antigen receptor (CAR) T-cell therapy can be long-lasting, predisposing patients to infections and non-relapse mortality. In B-cell non-Hodgkin lymphoma (B-NHL), the prognostic impact of immune reconstitution (IR) remains ill-defined, and detailed cross-product comparisons have not been performed to date. In this retrospective observational study, we longitudinally characterized lymphocyte subsets and immunoglobulin levels in 105 B-NHL patients to assess patterns of immune recovery arising after CD19 CAR-T.

Global Perspectives on Returning Genetic Research Results in Parkinson Disease.

Background And Objectives: In the era of precision medicine, genetic test results have become increasingly relevant in the care of patients with Parkinson disease (PD). While large research consortia are performing widespread research genetic testing to accelerate discoveries, debate continues about whether, and to what extent, the results should be returned to patients. Ethically, it is imperative to keep participants informed, especially when findings are potentially actionable.

Fluoride binding-modulated supramolecular chirality of urea-containing triarylamine and its photo-manifestation.

In recent years, the regulation of anion-mediated chiral assemblies has gained significant interest. This study investigated the modulation of supramolecular chiroptical signals and chiral assembled structures in a triarylamine system containing a urea moiety through fluoride ion-urea bond interactions, aiming to understand the chiral sense amplification in supramolecular assemblies. Chiral triarylamine derivatives containing urea or amide units were synthesized and the self-assemblies were examined in the absence and presence of fluoride ions.