Carbene-Assisted Arene Ring-Opening.

Despite the significant achievements in dearomatization and C-H functionalization of arenes, the arene ring-opening remains a largely unmet challenge and is underdeveloped due to the high bond dissociation energy and strong resonance stabilization energy inherent in aromatic compounds. Herein, we demonstrate a novel carbene assisted strategy for arene ring-opening. The understanding of the mechanism by our DFT calculations will stimulate wide application of bulk arene chemicals for the synthesis of value-added polyconjugated chain molecules.

Impact of -Glycosylation on Protein Structure and Dynamics Linked to Enzymatic C-H Activation in the Lipoxygenase.

Lipoxygenases (LOXs) from pathogenic fungi are potential therapeutic targets for defense against plant and select human diseases. In contrast to the canonical LOXs in plants and animals, fungal LOXs are unique in having appended -linked glycans. Such important post-translational modifications (PTMs) endow proteins with altered structure, stability, and/or function.

Assessing the Performance of Artificial Intelligence Models: Insights from the American Society of Functional Neuroradiology Artificial Intelligence Competition.

Background And Purpose: Artificial intelligence models in radiology are frequently developed and validated using data sets from a single institution and are rarely tested on independent, external data sets, raising questions about their generalizability and applicability in clinical practice. The American Society of Functional Neuroradiology (ASFNR) organized a multicenter artificial intelligence competition to evaluate the proficiency of developed models in identifying various pathologies on NCCT, assessing age-based normality and estimating medical urgency.

Materials And Methods: In total, 1201 anonymized, full-head NCCT clinical scans from 5 institutions were pooled to form the data set.

Bifunctional Ligand Enables Gold-Catalyzed Propargyl C-H Functionalization via Reactive Gold Allenylidene Intermediate.

Gold allenylidene species have been seldom exploited as reactive intermediates in synthetically versatile catalytic reactions. By employing alkynylbenziodoxoles as the substrates and bifunctional WangPhos as the metal ligand, this work demonstrated ready catalytic access to these intermediates of general substitution patterns and their electrophilic reactivities at the γ-carbon center with a diverse range of nucleophiles. The reaction is driven by the reductive decomposition of the benziodoxole moiety and achieves the replacement of a propargylic proton with an N/O/C-based nucleophile, hence realizing reactivity umpolung.

Antitumor Activity of a Novel LAIR1 Antagonist in Combination with Anti-PD1 to Treat Collagen-Rich Solid Tumors.

We recently reported that resistance to PD-1 blockade in a refractory lung cancer-derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1). Thus, we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. In this study, we report that LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer.

Single Cell Analysis of Treatment-Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies.

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival.

Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Clinical Guideline From the American College of Physicians.

Description: The American College of Physicians (ACP) developed this clinical guideline to update recommendations on newer pharmacologic treatments of type 2 diabetes. This clinical guideline is based on the best available evidence for effectiveness, comparative benefits and harms, consideration of patients' values and preferences, and costs.

Methods: This clinical guideline is based on a systematic review of the effectiveness and harms of newer pharmacologic treatments of type 2 diabetes, including glucagon-like peptide-1 (GLP-1) agonists, a GLP-1 agonist and glucose-dependent insulinotropic polypeptide agonist, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and long-acting insulins, used either as monotherapy or in combination with other medications.

Global Assessment of Palliative Care Need: Serious Health-Related Suffering Measurement Methodology.

Context: Inequities and gaps in palliative care access are a serious impediment to health systems especially in low- and middle-income countries and the accurate measurement of need across health conditions is a critical step to understanding and addressing the issue. Serious Health-related Suffering (SHS) is a novel methodology to measure the palliative care need and was originally developed by The Lancet Commission on Global Access to Palliative Care and Pain Relief. In 2015, the first iteration - SHS 1.

Hypoxia preconditioning increases Notch1 activity by regulating DNA methylation in vitro and in vivo.

Background: Our previous research has demonstrated that hypoxic preconditioning (HPC) can improve spatial learning and memory abilities in adult mice. Adult hippocampal neurogenesis has been associated with learning and memory. The Neurogenic locus notch homolog protein (Notch) was involved in adult hippocampal neurogenesis, as well as in learning and memory.

Sustainable Approach to Justice, Equity, Diversity, and Inclusion Through Better Quality Measurement.

The US health care industry has broadly adopted performance and quality measures that are extracted from electronic health records and connected to payment incentives that hope to improve declining life expectancy and health status and reduce costs. While the development of a quality measurement infrastructure based on electronic health record data was an important first step in addressing US health outcomes, these metrics, reflecting the average performance across diverse populations, do not adequately adjust for population demographic differences, social determinants of health, or ecosystem vulnerability. Like society as a whole, health care must confront the powerful impact that social determinants of health, race, ethnicity, and other demographic variations have on key health care performance indicators and quality metrics.

Construction of Isoquinolone Scaffolds on DNA via Rhodium(III)-Catalyzed C-H Activation.

Isoquinolone is one of the most common heterocyclic core structures in countless natural products and many bioactive compounds. Here, a highly efficient approach to synthesize isoquinolone scaffolds on DNA via rhodium(III)-catalyzed C-H activation has been described. This chemistry transformation is robust and has shown good compatibility with DNA, which is suitable for DNA-encoded library synthesis.

Identification of Multiclass Pediatric Low-Grade Neuroepithelial Tumor Molecular Subtype with ADC MR Imaging and Machine Learning.

Background And Purpose: Molecular biomarker identification increasingly influences the treatment planning of pediatric low-grade neuroepithelial tumors (PLGNTs). We aimed to develop and validate a radiomics-based ADC signature predictive of the molecular status of PLGNTs.

Materials And Methods: In this retrospective bi-institutional study, we searched the PACS for baseline brain MRIs from children with PLGNTs.

Neuropathologic changes at age 90+ related to sleep duration 19 to 40 years earlier: The 90+ Study.

Introduction: We investigated the association between sleep duration and neuropathologic changes 19 to 40 years later in oldest-old (age 90+) participants of The 90+ Study.

Methods: Participants self-reported sleep duration and underwent neuropathologic evaluation. We categorized sleep duration as < 7, 7 to 8 = reference, > 8 hours and dichotomized neuropathologic changes as present/absent.

Identification of the Thermal Activation Network in Human 15-Lipoxygenase-2: Divergence from Plant Orthologs and Its Relationship to Hydrogen Tunneling Activation Barriers.

The oxidation of polyunsaturated fatty acids by lipoxygenases (LOXs) is initiated by a C-H cleavage step in which the hydrogen atom is transferred quantum mechanically (i.e., via tunneling).

Stereoselective Construction of β-, γ-, and δ-Lactam Rings via Enzymatic C-H Amidation.

Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Methods for the asymmetric synthesis of these molecules are therefore highly desirable, particularly through the selective functionalization of unreactive aliphatic C-H bonds. Here we show the development of a strategy for the asymmetric synthesis of β-, γ-, and δ-lactams via hemoprotein-catalysed intramolecular C-H amidation reaction with readily available dioxazolone reagents.

Wnt pathway inhibition with the porcupine inhibitor LGK974 decreases trabecular bone but not fibrosis in a murine model with fibrotic bone.

G protein-coupled receptors (GPCRs) mediate a wide spectrum of physiological functions, including the development, remodeling, and repair of the skeleton. Fibrous dysplasia (FD) of the bone is characterized by fibrotic, expansile bone lesions caused by activating mutations in There are no effective therapies for FD. We previously showed that ColI(2.

In CKD, empagliflozin reduced kidney disease progression at a median 2 y, regardless of primary kidney disease type.

EMPA-KIDNEY Collaborative Group. Lancet Diabetes Endocrinol. 2024;12:51-60.

Programmed Heterocycle Synthesis Using Halomucononitriles as Pyridinimine Precursors.

Herein we report a method to convert primary amines, ubiquitous motifs found in pharmaceutical libraries, to either imidazo[1,2]pyridines or 7-alkyl azaindoles in two steps from known compounds. Using halomucononitrile reagents, we can directly access 5-bromo-6-imino-1-alkyl-1,6-dihydropyridine-2-carbonitriles (pyridinimines) in a single step from primary amines (25-93% yield) through the cyclization of transient aminomucononitrile intermediates. We then demonstrate that these compounds can be readily converted to 7-alkylazaindoles using Sonogashira cross-coupling conditions (13 examples, up to 91% yield).

Characterization of Thyroid Cancer among Hispanics in California, USA, from 2010 to 2020.

Background: Previous studies on Hispanic thyroid cancer cases show sex disparities and an increased prevalence of large tumor sizes and nodal involvement. Here, we characterized Hispanic thyroid cancer cases in California.

Methods: We identified thyroid cancer cases from 2010 to 2020 using the California Cancer Registry by sex, race/ethnicity, histology, TNM stage, tumor size, lymph node involvement, and Charlson comorbidity score.

Oxidative Transformation of Nafion-Related Fluorinated Ether Sulfonates: Comparison with Legacy PFAS Structures and Opportunities of Acidic Persulfate Digestion for PFAS Precursor Analysis.

The total oxidizable precursor (TOP) assay has been extensively used for detecting PFAS pollutants that do not have analytical standards. It uses hydroxyl radicals (HO) from the heat activation of persulfate under alkaline pH to convert H-containing precursors to perfluoroalkyl carboxylates (PFCAs) for target analysis. However, the current TOP assay oxidation method does not apply to emerging PFAS because (i) many structures do not contain C-H bonds for HO attack and (ii) the transformation products are not necessarily PFCAs.

Are all measures of liver Kp a function of F, as determined following oral dosing, or have we made a critical error in defining hepatic drug clearance?

Here we present, utilizing universally accepted relationships for hepatic clearance at steady state, that for all models of hepatic elimination the ratio of unbound liver drug concentration to unbound systemic blood concentration, Kp, is a function of or related to the hepatic bioavailability for that drug, F. According to the derivation for the well-stirred model, Kp can never exceed unity, can frequently be a function of hepatic blood flow, and is equivalent to the value of F as determined following oral dosing. For the parallel tube model, Kp will not equal F but will be a function of F and will also never be a value greater than 1.

Brain dynamics predictive of response to psilocybin for treatment-resistant depression.

Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here, we leveraged the differential outcome in responders and non-responders to psilocybin (10 and 25 mg, 7 days apart) therapy for depression-to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used large-scale brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment.