Visible-Light-Mediated Deaminative Alkylation of Primary Amines with Silacarboxylic Acids via Isonitrile Formation.

The functionalization of the C-N bond of amines is a straightforward strategy for the construction of complex scaffolds or for the late-stage functionalization of pharmaceuticals. Herein, we describe a photoredox-catalyzed strategy for the deaminative alkylation of primary amine-derived isonitriles that provides unnatural amino acid derivatives under mild conditions. The use of silacarboxylic acids as silyl radical precursors enables the generation of carbon-centered radicals that allow the construction of Csp-Csp bonds via a Giese-type addition, avoiding the undesired hydrodeamination product.

Trityl isocyanide as a general reagent for visible light mediated photoredox-catalyzed cyanations.

A photoredox catalytic strategy has been developed to enable the functionalization of a variety of commercially available, structurally different radical precursors by the use of a bench-stable isonitrile as an efficient cyanating reagent. Specifically, a radical-based reaction has provided a mild and convenient procedure for the cyanation of primary, secondary and tertiary radicals derived from widely accessible sp-hybridized carboxylic acids, alcohols and halides under visible light irradiation. The reaction tolerates a variety of functional groups and it represents a complementary method for the cyanation of structurally different scaffolds that show diverse native functionalities, expanding the scope of previously reported methodologies.

CYB5R3 overexpression exhibits sexual dimorphism: Mitochondrial and metabolic adaptations in transgenic female mice during calorie restriction.

There is a pressing need to develop new strategies for enhancing health in the elderly and preventing the rise in age-related diseases. Calorie restriction without malnutrition (CR) stands among the different antiaging interventions. Lifelong CR leads to increased expression and activity of plasma membrane CYB5R3, and male mice overexpressing CYB5R3 exhibit some beneficial adaptations that are also seen with CR.

Cytochrome b reductase 3 overexpression and dietary nicotinamide riboside supplementation promote distinctive mitochondrial alterations in distal convoluted tubules of mouse kidneys during aging.

The kidney undergoes structural and physiological changes with age, predominantly studied in glomeruli and proximal tubules. However, limited knowledge is available about the impact of aging and anti-aging interventions on distal tubules. In this study, we investigated the effects of cytochrome b reductase 3 (CYB5R3) overexpression and/or dietary nicotinamide riboside (NR) supplementation on distal tubule mitochondria.

Exploring candidate biomarkers for rheumatoid arthritis through cardiovascular and cardiometabolic serum proteome profiling.

Introduction: RA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related biological pathways.

Methods: This study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25).

New advances in genomics and epigenetics in antiphospholipid syndrome.

APS patients exhibit a wide clinical heterogeneity in terms of the disease's origin and progression. This diversity can be attributed to consistent aPL profiles and other genetic and acquired risk factors. Therefore, understanding the pathophysiology of APS requires the identification of specific molecular signatures that can explain the pro-atherosclerotic, pro-thrombotic and inflammatory states observed in this autoimmune disorder.

Decoding clinical and molecular pathways of liver dysfunction in Psoriatic Arthritis: Impact of cumulative methotrexate doses.

Background: The occurrence of liver abnormalities in Psoriatic Arthritis (PsA) has gained significant recognition. Identifying key factors at the clinical and molecular level can help to detect high-risk patients for non-alcoholic fatty liver disease in PsA.

Objectives: to investigate the influence of PsA and cumulative doses of methotrexate on liver function through comprehensive in vivo and in vitro investigations.

Clinical features and immune mechanisms directly linked to the altered liver function in patients with rheumatoid arthritis.

Background: The aim of this study was to explore the impact of arthritis on liver function using different approaches in vivo and in vitro.

Methods: A cross-sectional study was performed on 330 non-obese/non-T2DM subjects: 180 RA patients, 50 NAFLD non-RA patients, and 100 healthy donors (HDs). A longitudinal study was conducted on 50 RA patients treated with methotrexate for six months.

Sex-specific metabolic adaptations in transgenic mice overexpressing cytochrome b reductase-3.

Cytochrome b reductase 3 (CYB5R3) activates respiratory metabolism in cellular systems and exerts a prolongevity action in transgenic mice overexpressing this enzyme, mimicking some of the beneficial effects of calorie restriction. The aim of our study was to investigate the role of sex on metabolic adaptations elicited by CYB5R3 overexpression, and how key markers related with mitochondrial function are modulated in skeletal muscle, one of the major contributors to resting energy expenditure. Young CYB5R3 transgenic mice did not exhibit the striking adaptations in carbon metabolism previously detected in older animals.

The thrombus proteome in stroke reveals a key role of the innate immune system and new insights associated with its etiology, severity, and prognosis.

Background: Nowadays little is known about the molecular profile of the occluding thrombus of patients with ischemic stroke.

Objectives: To analyze the proteomic profile of thrombi in patients who experienced an ischemic stroke in order to gain insights into disease pathogenesis.

Methods: Thrombi from an exploratory cohort of patients who experienced a stroke were obtained by thrombectomy and analyzed by sequential window acquisition of all theoretical spectra-mass spectrometry.

Preclinical Characterization of Pharmacologic NAD Boosting as a Promising Therapeutic Approach in Rheumatoid Arthritis.

Objective: We analyzed NAD metabolism in patients with rheumatoid arthritis (RA), its association with disease activity and clinical outcomes of RA, and the therapeutic potential of pharmacologic NAD boosting.

Methods: Our study included 253 participants. In the first cohort, comprising 153 RA patients and 56 healthy donors, we assessed NAD levels and NAD -related gene pathways.

Characterization of the inflammatory proteome of synovial fluid from patients with psoriatic arthritis: Potential treatment targets.

Objectives: 1) To characterize the inflammatory proteome of synovial fluid (SF) from patients with Psoriatic Arthritis (PsA) using a high-quality throughput proteomic platform, and 2) to evaluate its potential to stratify patients according to clinical features.

Methods: Inflammatory proteome profile of SF from thirteen PsA patients with active knee arthritis were analyzed using proximity extension assay (PEA) technology (Olink Target 96 Inflammation panel). Four patients with OA were included as control group.

Splicing machinery is profoundly altered in systemic lupus erythematosus and antiphospholipid syndrome and directly linked to key clinical features.

Objectives: To characterize the splicing machinery (SM) of leukocytes from primary antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome with lupus (APS + SLE) patients, and to assess its clinical involvement.

Methods: Monocytes, lymphocytes and neutrophils from 80 patients (22 APS, 35 SLE and 23 APS + SLE) and 50 HD were purified, and 45 selected SM components were evaluated by qPCR-microfluidic array. Relationship with clinical features and underlying regulatory mechanisms were assessed.

Nonalcoholic fatty liver disease in inflammatory arthritis: Relationship with cardiovascular risk.

Liver disease is one of the most important causes of morbidity and mortality worldwide whose prevalence is dramatically increasing. The first sign of hepatic damage is inflammation which could be accompanied by the accumulation of fat called non-alcoholic fatty liver disease (NAFLD), causing damage in the hepatocytes. This stage can progress to fibrosis where the accumulation of fibrotic tissue replaces healthy tissue reducing liver function.

Pathogenic mechanisms involving the interplay between adipose tissue and auto-antibodies in rheumatoid arthritis.

We aimed to evaluate the association between adipose tissue (AT) dysfunction, autoimmunity, and disease activity in rheumatoid arthritis (RA). A cross-sectional study including 150 RA patients and 50 healthy donors and longitudinal study with 122 RA patients treated with anti-tumor necrosis factor (TNF)-α, anti-interleukin 6 receptor (IL6R) or anti-CD20 therapies for 6 months were carried out. experiments with human AT and adipocyte and macrophage cell lines were performed.

A ribbon graph derivation of the algebra of functional renormalization for random multi-matrices with multi-trace interactions.

We focus on functional renormalization for ensembles of several (say ) random matrices, whose potentials include multi-traces, to wit, the probability measure contains factors of the form for certain noncommutative polynomials in the matrices. This article shows how the "algebra of functional renormalization"-that is, the structure that makes the renormalization flow equation computable-is derived from ribbon graphs, only by requiring the one-loop structure that such equation (due to Wetterich) is expected to have. Whenever it is possible to compute the renormalization flow in terms of -invariants, the structure gained is the matrix algebra with entries in , being the free algebra generated by the Hermitian matrices of size (the flowing random variables) with multiplication of homogeneous elements in given, for each , by which, together with the condition for each complex , fully define the symbol .

On Multimatrix Models Motivated by Random Noncommutative Geometry II: A Yang-Mills-Higgs Matrix Model.

We continue the study of fuzzy geometries inside Connes' spectral formalism and their relation to multimatrix models. In this companion paper to Pérez-Sánchez (Ann Henri Poincaré 22:3095-3148, 2021, arXiv:2007.10914), we propose a gauge theory setting based on noncommutative geometry, which-just as the traditional formulation in terms of almost-commutative manifolds-has the ability to also accommodate a Higgs field.

miR-374a-5p regulates inflammatory genes and monocyte function in patients with inflammatory bowel disease.

MicroRNAs are critical regulators of gene expression controlling cellular processes including inflammation. We explored their role in the pathogenesis of inflammatory bowel disease (IBD) and identified reduced expression of miR-374a-5p in IBD monocytes that correlated with a module of up-regulated genes related to the inflammatory response. Key proinflammatory module genes, including for example TNFα, IL1A, IL6, and OSM, were inversely correlated with miR-374a-5p and were validated in vitro.

The clinical and molecular cardiometabolic fingerprint of an exploratory psoriatic arthritis cohort is associated with the disease activity and differentially modulated by methotrexate and apremilast.

Objectives: (1) To evaluate clinical and molecular cardiovascular disease (CVD) signs and their relationship with psoriatic arthritis (PsA) features and (2) to identify a clinical patient profile susceptible to benefit from methotrexate (MTX) and/or apremilast regarding CVD risk.

Methods: This cross-sectional study included 100 patients with PsA and 100 age-matched healthy donors. In addition, an exploratory cohort of 45 biologically naïve patients treated for 6 months with apremilast, MTX or combined therapy according to routine clinical practice was recruited.

Molecular Changes in the Adipose Tissue Induced by Rheumatoid Arthritis: Effects of Disease-Modifying Anti-Rheumatic Drugs.

Disease severity, progression and response to therapy might be worse in obese rheumatoid arthritis (RA) patients, but paradoxically, obesity also might protect from radiographic joint damage. Thus, the intricate relationship between obesity and RA needs urgent clarification. The aim of this study was to assess the influence of obesity on the onset and development of RA and to determine whether arthritis could modify the adipose tissue biology and whether conventional Disease Modifying Anti-Rheumatic Drugs (cDMARDs) can modulate these alterations.

Splicing machinery is impaired in rheumatoid arthritis, associated with disease activity and modulated by anti-TNF therapy.

Objectives: To characterise splicing machinery (SM) alterations in leucocytes of patients with rheumatoid arthritis (RA), and to assess its influence on their clinical profile and therapeutic response.

Methods: Leucocyte subtypes from 129 patients with RA and 29 healthy donors (HD) were purified, and 45 selected SM elements (SME) were evaluated by quantitative PCR-array based on microfluidic technology (Fluidigm). Modulation by anti-tumour necrosis factor (TNF) therapy and underlying regulatory mechanisms were assessed.

Anti-dsDNA Antibodies Increase the Cardiovascular Risk in Systemic Lupus Erythematosus Promoting a Distinctive Immune and Vascular Activation.

Objective: Systemic lupus erythematosus (SLE) is associated to boosted atherosclerosis development and a higher cardiovascular disease risk. This study aimed to delineate the role of anti-double stranded DNA (anti-dsDNA) antibodies on the molecular profile and the activity of immune and vascular cells, as well as on their enhanced cardiovascular risk.

Approach And Results: Eighty SLE patients were included.

Potential Role and Impact of Peripheral Blood Mononuclear Cells in Radiographic Axial Spondyloarthritis-Associated Endothelial Dysfunction.

Endothelial dysfunction (ED) is well known as a process that can lead to atherosclerosis and is frequently presented in radiographic axial spondyloarthritis (r-axSpA) patients. Here, we investigated cellular and molecular mechanisms underlying r-axSpA-related ED, and analyzed the potential effect of peripheral blood mononuclear cells (PBMCs) in promoting endothelial injury in r-axSpA. A total of 30 r-axSpA patients and 32 healthy donors (HDs) were evaluated.