The Safety Profile of Pridopidine, a Novel Sigma-1 Receptor Agonist for the Treatment of Huntington's Disease.

Background: Huntington's disease (HD) is a rare, fatal, chronic progressive neurodegenerative disorder with a significant unmet medical need for effective treatments. Pridopidine is a novel, first-in-class, highly selective and potent sigma-1 receptor (S1R) agonist in development for HD. Pridopidine has been extensively studied in adult HD across the full spectrum of disease severity and age ranges, and its safety profile has been characterized in approximately 1600 participants across multiple studies and a broad range of doses.

Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations.

Preclinical studies have shown that asparagine deprivation enhances T cell antitumour responses. Here we apply compassionate use of L-asparaginase, usually employed to treat blood malignancies, on patients with recurrent metastatic nasopharyngeal carcinoma. The use of L-asparaginase notably enhances immune-checkpoint blockade therapy in patients by strengthening CD8T cell fitness.

Temperature-Dependent Stepwise Dissociation of Methanol on Co(0001).

An atomic-level understanding of the elementary steps of catalytic reactions is crucial for a more molecularly driven catalyst design. Herein, we present a comprehensive study of temperature-dependent stepwise decomposition of methanol on a single-crystal Co(0001) surface using a series of surface science techniques and density functional theory calculation. Visualization of surface products was realized by scanning tunneling microscopy.

Mechanistic Insights into CYP199A4-Catalyzed α-Hydroxyketone Formation and Hydrogen Bond-Assisted C-C Bond Cleavage Catalyzed by the CYP199A4 F182L Mutant.

CYP199A4 is a cytochrome P450 and can catalyze the hydroxylation of 4-propionylbenzoic acid (4-pIBA) to generate α-hydroxyketone with high stereoselectivity. The F182L mutant of CYP199A4 (F182L-CYP199A4) has been shown to support the cleavage of the C-C bond between the carbonyl and hydroxyl groups of α-hydroxyketone, whereas wild-type CYP199A4 cannot. To uncover how the Phe182 regulates substrate reactivity, we conducted classical molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) MD simulations on these systems.

Double-Phase Ga-Doped InO Nanospheres and Their Self-Assembled Monolayer Film for Ultrasensitive HCHO MEMS Gas Sensors.

In the sensing field, the electronic structure of sensing materials has a great influence on the properties of the sensors. Here, by Ga doping pure rhombohedral InO (h-InO), the double-phase InO (cubic/rhombohedral InO, c/h-InO) porous nanospheres are obtained. And then Micro Electromechanical System (MEMS) gas sensors based on monolayer film are further fabricated by self-assembling the above nanospheres.

Investigation of Near-Infrared Spectroscopy for Assessing the Macroscopic Mechanical Properties of Cross-Linked Polyethylene During Thermal Aging.

The present study investigates the relationship between the near-infrared (NIR) spectral characteristics of cross-linked polyethylene (XLPE) insulation materials and their macroscopic properties, with the aim of establishing a reference framework for non-destructive material aging analysis. Accelerated thermal aging tests were conducted on samples of XLPE cables. These samples underwent Fourier-transform infrared spectroscopy (FTIR), elongation at break (EAB), and tensile strength (TS) tests.

Oxygen Vacancies Promote Formaldehyde Base-Free Reforming into Hydrogen over Cu Doping-Induced Cu-CuZnO Heterointerfaces.

Element doping is a viable strategy to regulate the metal-support interface for enhancing the catalytic performance of supported metal catalysts. Herein, Cu/ZnO:Cu-H catalysts are prepared by immobilizing Cu nanoparticles (NPs) on ZnO nanorods featuring an adjustable oxygen vacancy, in which partial Cu atoms at the Cu-ZnO interface are incorporated into the ZnO lattice to form CuZnO species. Such Cu atom doping induces the creation of distinctive Cu-CuZnO interface sites and optimizes electron transfer from ZnO to Cu NPs, thereby achieving intermediate activation and ultimately endowing the catalyst with superior performance in reforming alkali-free formaldehyde (HCHO) into hydrogen at low temperatures.

The Global Burden of Cirrhosis and Other Chronic Liver Diseases in 2021.

Background And Aim: The burden of cirrhosis and other chronic liver diseases has changed in recent years due to shifts in the contributing aetiologies. We estimated the burden of cirrhosis and other chronic liver diseases, including etiological and regional differences, across 204 countries and territories from 2010 to 2021.

Approach And Results: We analysed temporal trends in the burden of cirrhosis and other chronic liver diseases utilising data from the Global Burden of Disease Study 2021.

Theoretical Insights into Rare-Earth-Catalyst-Controlled Diastereo- and Enantioselective [3 + 2] Annulation of Aromatic Aldimines with Styrenes.

Rare-earth-catalyzed annulation reactions using alkenes via C-H activation offer an atom-efficient approach to constructing cyclic compounds. However, the mechanisms underlying these reactions remain poorly understood, limiting the rational design of related catalytic systems. Recently, Hou and Cong reported an unprecedented example of rare-earth-catalyst-controlled diastereodivergent asymmetric [3 + 2] annulation of aromatic aldimines with alkenes.

Pertussis in Southeast Asia: country-level burden and recommendations from the Global Pertussis Initiative.

The Global Pertussis Initiative met in March 2024 to discuss the burden of pertussis and prevention efforts in six Southeast Asian countries: Cambodia, Indonesia, Malaysia, Singapore, Thailand, and Vietnam. Except for Cambodia, pertussis is a notifiable disease; data accuracy varies within and between countries. Most cases in the region are diagnosed based on clinical suspicion.

Expiration CT Gas Trapping Measures with Texture-Based Radiomics Improves Association with Lung Function and Lung Function Decline in COPD.

Rationale And Objectives: Several methods quantify gas-trapping on expiration computed tomography (CT) images, but they do not consider the spatial relationship of voxels. The objective of this study was to determine if the addition of expiration CT texture-based radiomics features to existing gas-trapping measurements improves model performance for lung function, lung function decline, COPD classification and visual gas-trapping.

Materials And Methods: CanCOLD participants performed spirometry, plethysmography and CT chest imaging at full-inspiration/expiration with radiologist-assessed gas-trapping.

Measurement of Λ_{b}^{0}, Λ_{c}^{+}, and Λ Decay Parameters Using Λ_{b}^{0}→Λ_{c}^{+}h^{-} Decays.

A comprehensive study of the angular distributions in the bottom-baryon decays Λ_{b}^{0}→Λ_{c}^{+}h^{-}(h=π,K), followed by Λ_{c}^{+}→Λh^{+} with Λ→pπ^{-} or Λ_{c}^{+}→pK_{S}^{0} decays, is performed using a data sample of proton-proton collisions corresponding to an integrated luminosity of 9  fb^{-1} collected by the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV. The decay parameters and the associated charge-parity (CP) asymmetries are measured, with no significant CP violation observed. For the first time, the Λ_{b}^{0}→Λ_{c}^{+}h^{-} decay parameters are measured.

Homo-Mannich Reaction of Cyclopropanols: A Versatile Tool for Natural Product Synthesis.

ConspectusThe Mannich reaction, involving the nucleophilic addition of an enol(ate) intermediate to an imine or iminium ion, is one of the most widely used synthetic methods for the synthesis of β-amino carbonyl compounds. Nevertheless, the homo-Mannich reaction, which utilizes a homoenolate intermediate as the nucleophilic partner and provides straightforward access to the valuable γ-amino carbonyl compounds, remains underexplored. This can be largely attributed to the difficulties in generation and manipulation of the homoenolate species, despite various homoenolate equivalents that have been developed.

Monitoring Excavation-Induced Deformation of a Secant Pile Wall Using Distributed Fiber Optic Sensors.

This paper investigates the use of the BOTDA (Brillouin Optical Time-Domain Analysis) technology to monitor a large-scale bored pile wall in the field. Distributed fiber optic sensors (DFOSs) were deployed to measure internal temperature and strain changes during cement grouting, hardening, and excavation-induced deformation of a secant pile wall. The study details the geological conditions and DFOS installation process.

Molecular-level Modulation of N, S-Co-Doped Mesoporous Carbon Nanospheres for Selective Aqueous Catalytic Oxidation of Ethylbenzene.

Selective oxidation of aromatic alkanes into high value-added products through benzylic C-H bond activation is one of the main reactions in chemical industry. On account of the constantly increasing demand for mass production, efficient, eco-friendly and sustainable catalysts are urgently needed. Herein, we describe a facile and versatile emulsion-assisted interface self-assembly strategy towards molecular-level fabrication of co-doped mesoporous carbon nanospheres with controllable active N and S species.

Dual impacts of serine/glycine-free diet in enhancing antitumor immunity and promoting evasion via PD-L1 lactylation.

The effect of the serine/glycine-free diet (-SG diet) on colorectal cancer (CRC) remains unclear; meanwhile, programmed death-1 (PD-1) inhibitors are less effective for most CRC patients. Here, we demonstrate that the -SG diet inhibits CRC growth and promotes the accumulation of cytotoxic T cells to enhance antitumor immunity. Additionally, we also identified the lactylation of programmed death-ligand 1 (PD-L1) in tumor cells as a mechanism of immune evasion during cytotoxic T cell-mediated antitumor responses, and blocking the PD-1/PD-L1 signaling pathway is able to rejuvenate the function of CD8+ T cells recruited by the -SG diet, indicating the potential of combining the -SG diet with immunotherapy.

Palladium catalyzed ortho-C(sp)-H activation/cyclization of aryl amines assisted by imine and vinylacetic acid.

Palladium-catalyzed directed C - H functionalization/cyclization is an effective approach for synthesizing nitrogen heterocycles. Imine, known for its ease of installation/removal, has been extensively used in the C-H activation of aldehydes, ketones, and alkylamines. Nevertheless, it has been rarely explored in the C(sp)-H activation of aryl amines because of the generation of a strained four-membered palladacycle.

Major-auxiliary cooperative metal pairs in MOFs enable cascade oxidation of KA oil to ε-caprolactone.

Direct oxidation of KA oil (the mixture of cyclohexanone and cyclohexanol) toward ε-caprolactone is in high demand yet hard to implement in need of juggling the activation of both methyne C-H bond of cyclohexanol and α-C-C bond of cyclohexanone. Here we demonstrate that in situ formed Cu-O active site, which originates from relay reaction at Ni(II) and Cu(I) pairs in a metal-organic framework (known as NiCu-MOF-74) with O and benzaldehyde (PhCHO), efficiently oxidizes KA oil toward ɛ-caprolactone along with good stability. Mechanism investigation discloses that the auxiliary Ni(II) site first adsorbs O for abstracting formyl hydrogen in PhCHO followed by transfer of PhCO· to react with another O over the major Cu(I) site, leading to formation of Cu-O and PhCOOH.

Benzylic C-H Radical Sulfation by Persulfates.

Sulfation is a highly valuable pathological and physiological process, yet it is often underappreciated considering the rather difficult accessibility of organosulfates. O-sulfonation (O-SO), a conventional and still common way to make organosulfates, restricts its applicability to hydroxyl compounds and therein lies a major challenge of library construction. Here, we describe a benzylic C-H radical sulfation with persulfates via C-O bond formation.

Tumor draining lymph nodes connected to cold triple-negative breast cancers are characterized by Th2-associated microenvironment.

Tumor draining lymph nodes (TDLN) represent a key component of the tumor-immunity cycle. There are few studies describing how TDLNs impact lymphocyte infiltration into tumors. Here we directly compare tumor-free TDLNs draining "cold" and "hot" human triple negative breast cancers (TDLN and TDLN).

Construction of acenaphthylenes via C-H activation-based tandem penta- and hexaannulation reactions.

Acenaphthylene-containing polycyclic aromatic hydrocarbons (AN-PAHs) are noteworthy structural motifs for organic functional materials due to their non-alternant electronic structure, which increases electron affinity. However, the synthesis of AN-PAHs has traditionally required multiple sequential synthetic steps, limiting structural diversity. Herein, we present a tandem C-H penta- and hexaannulation reaction of aryl alkyl ketone with acetylenedicarboxylate.

Catalytic undirected methylation of unactivated C(sp)-H bonds suitable for complex molecules.

In pharmaceutical discovery, the "magic methyl" effect describes a substantial improvement in the pharmacological properties of a drug candidate with the incorporation of methyl groups. Therefore, to expedite the synthesis of methylated drug analogs, late-stage, undirected methylations of C(sp)-H bonds in complex molecules would be valuable. However, current methods for site-selective methylations are limited to activated C(sp)-H bonds.