AAV8 gene therapy reverses cardiac pathology and prevents early mortality in a mouse model of Friedreich's ataxia.

Friedreich's ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progresses to heart failure and death. The potential to reverse or prevent progression of the cardiac phenotype of FRDA was investigated in a mouse model of FRDA, using an adeno-associated viral vector (AAV8) containing the coding sequence of the gene.

Prevalence of Immunomodulator Use as Combination Therapy With Vedolizumab or Ustekinumab in Inflammatory Bowel Disease.

Introduction: The benefit of adding an immunomodulator to vedolizumab and ustekinumab remains unclear and may compromise the safety of these biologics. We evaluated the prevalence and predictors of immunomodulator use with vedolizumab or ustekinumab in patients with inflammatory bowel disease in a large longitudinal cohort.

Methods: Clinical information was ascertained from electronic medical records of patients enrolled in TARGET-IBD, a prospective longitudinal observational cohort of patients with inflammatory bowel disease (IBD) at 34 sites.

High-dimensional analysis of 16 SARS-CoV-2 vaccine combinations reveals lymphocyte signatures correlating with immunogenicity.

The range of vaccines developed against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) provides a unique opportunity to study immunization across different platforms. In a single-center cohort, we analyzed the humoral and cellular immune compartments following five coronavirus disease 2019 (COVID-19) vaccines spanning three technologies (adenoviral, mRNA and inactivated virus) administered in 16 combinations. For adenoviral and inactivated-virus vaccines, heterologous combinations were generally more immunogenic compared to homologous regimens.

Increased chest CT derived bone and muscle measures capture markers of improved morbidity and mortality in COPD.

Background: Chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging and is associated with comorbid conditions including osteoporosis and sarcopenia. These extrapulmonary conditions are highly prevalent yet frequently underdiagnosed and overlooked by pulmonologists in COPD treatment and management. There is evidence supporting a role for bone-muscle crosstalk which may compound osteoporosis and sarcopenia risk in COPD.

Intratumourally injected alum-tethered cytokines elicit potent and safer local and systemic anticancer immunity.

Anti-tumour inflammatory cytokines are highly toxic when administered systemically. Here, in multiple syngeneic mouse models, we show that the intratumoural injection of recombinantly expressed cytokines bound tightly to the common vaccine adjuvant aluminium hydroxide (alum) (via ligand exchange between hydroxyls on the surface of alum and phosphoserine residues tagged to the cytokine by an alum-binding peptide) leads to weeks-long retention of the cytokines in the tumours, with minimal side effects. Specifically, a single dose of alum-tethered interleukin-12 induced substantial interferon-γ-mediated T-cell and natural-killer-cell activities in murine melanoma tumours, increased tumour antigen accumulation in draining lymph nodes and elicited robust tumour-specific T-cell priming.

On the Ability of Nickel Complexes Derived from Tripodal Aminopyridine Ligands to Catalyze Arene Hydroxylations.

The development of catalysts for the selective hydroxylation of aromatic C-H bonds is an essential challenge in current chemical research. The accomplishment of this goal requires the discovery of powerful metal-based oxidizing species capable of hydroxylating inert aromatic bonds in a selective manner, avoiding the generation of non-selective oxygen-centered radicals. Herein we show an investigation on the ability of nickel(ii) complexes supported by tripodal tetradentate aminopyridine ligands to catalyze the direct hydroxylation of benzene to phenol with H₂O₂ as oxidant.

Bioinspired Non-Heme Iron Complexes: The Evolution of Facial Ligand Design.

Iron-containing metalloenzymes that contain the 2-His-1-Carboxylate facial triad at their active site are well known for their ability to activate molecular oxygen and catalyse a broad range of oxidative transformations. Many of these reactions are synthetically challenging, and developing small molecular iron-based catalysts that can achieve similar reactivity and selectivity remains a long-standing goal in homogeneous catalysis. This review focuses on the development of bioinspired facial ligands that model the 2-His-1-Carboxylate facial triad to a greater degree of structural accuracy than many of the polydentate -donor ligands commonly used in this field.

Novel Mutations and Decreased Expression of the Epigenetic Regulator in Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in and 16 other genes; however, these mutations occur in <25% of patients with idiopathic PAH and are rare in PAH associated with connective tissue diseases. Preclinical studies suggest epigenetic dysregulation, including altered DNA methylation, promotes PAH.

Physician Versus Nonphysician Instruction: Evaluating an Expert Curriculum-Competent Facilitator Model for Simulation-Based Central Venous Catheter Training.

Introduction: Healthcare simulation supports educational opportunities while maintaining patient safety. To reduce costs and increase the availability of training, a randomized controlled study evaluated central venous catheter (CVC) insertion training in the simulation laboratory with nonphysician competent facilitators (NPCFs) as instructors.

Method: A group of learners naive to central line placement participated in a blended curriculum consisting of interactive online materials and simulation-based training.

COMPASS-CP: An Electronic Application to Capture Patient-Reported Outcomes to Develop Actionable Stroke and Transient Ischemic Attack Care Plans.

Background Patient-reported outcomes (PROs) are clinical tools that measure patients' goals of care and assess patient-reported physical, mental, and social well-being. Despite their value in advancing patient-centered care, routine use of PROs in stroke management has lagged. As part of the pragmatic COMPASS (Comprehensive Post-Acute Stroke Services) trial, we developed COMPASS-Care Plan (CP), a clinician-facing application that captures and analyzes PROs for stroke and transient ischemic attack patients discharged home and immediately generates individualized electronic CP.

US Molecular Imaging of Acute Ileitis: Anti-Inflammatory Treatment Response Monitored with Targeted Microbubbles in a Preclinical Model.

Purpose To evaluate whether dual-selectin-targeted US molecular imaging allows longitudinal monitoring of anti-inflammatory treatment effects in an acute terminal ileitis model in swine. Materials and Methods The Institutional Animal Care and Use Committee approved all animal studies. Fourteen swine with chemically induced acute terminal ileitis (day 0) were randomized into the following groups: (a) an anti-inflammatory treatment group (n = 8; meloxicam, 0.

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery.

Background: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy.

Methods: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%).

On-chip intermediate LED-IF-based detection for the control of electromigration in multichannel networks.

Monitoring analytes during the transfer step from the first to the second dimension in multidimensional electrophoretic separations is crucial to determine and control the optimal time point for sample transfer and thus to avoid band broadening or unwanted splitting of the sample band with consequent sample loss. A spatially resolved intermediate on-chip LED-induced fluorescence detection system was successfully implemented for a hybrid capillary-chip glass interface. The setup includes a high-power 455-nm LED prototype as an excitation light source and a linear light fiber array consisting of 23 light fibers with a diameter of 100 μm for spatially resolved fluorescence detection in combination with a push-broom imager for hyperspectral detection.

Genetic Variation in the 11β-hydroxysteroid-dehydrogenase 1 Gene Determines NAFLD and Visceral Obesity.

Context/objective: Acute pharmacological inhibition of 11β-hydroxysteroid-dehydrogenase 1 (11β-HSD1), which converts cortisone into the much more potent cortisol in peripheral tissues, results in reduction of total, visceral, and liver fat but not insulin resistance. We now investigated whether lifelong alterations of 11β-HSD1 activity similarly affect these cardiometabolic risk parameters by studying single-nucleotide polymorphisms (SNPs) in the 11β-HSD1-coding gene (HSD11B1).

Design/methods: Liver fat content was measured by H-magnetic resonance spectroscopy and total and visceral fat mass by H-magnetic resonance tomography in 327 subjects.

Comparison of the acute ultraviolet photoresponse in congenic albino hairless C57BL/6J mice relative to outbred SKH1 hairless mice.

Hairless albino Crl:SKH1-Hr(hr) mice are commonly utilized for studies in which hair or pigmentation would introduce an impediment to observational studies. Being an outbred strain, the SKH1 model suffers from key limitations that are not seen with congenic mouse strains. Inbred and congenic C57BL/6J mice are commonly utilized for modified genetic mouse models.

Rapid and body weight-independent improvement of endothelial and high-density lipoprotein function after Roux-en-Y gastric bypass: role of glucagon-like peptide-1.

Background: Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight loss-independent manner. The present study investigated in rats and patients whether obesity-induced endothelial and high-density lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1-dependent mechanism.

Facial triad modelling using ferrous pyridinyl prolinate complexes: synthesis and catalytic applications.

A series of new chiral pyridinyl prolinate (RPyProR) ligands and their corresponding Fe(II) triflate and chloride complexes are reported. The ligands possess an NN'O coordination motif, as found in the active site of non-heme iron enzymes with the so-called 2-His-1-carboxylate facial triad. The coordination behaviour of these ligands towards iron turned out to be dependent on the counter ion (chloride or triflate), the crystallization conditions (coordinating or non-coordinating solvents) and the presence of substituents on the ligand.

Making Fe(BPBP)-catalyzed C-H and C[double bond, length as m-dash]C oxidations more affordable.

The limited availability of catalytic reaction components may represent a major hurdle for the practical application of many catalytic procedures in organic synthesis. In this work, we demonstrate that the mixture of isomeric iron complexes [Fe(OTf)2(mix-BPBP)] (mix-1), composed of Λ-α-[Fe(OTf)2(S,S-BPBP)] (S,S-1), Δ-α-[Fe(OTf)2(R,R-BPBP)] (R,R-1) and Δ/Λ-β-[Fe(OTf)2(R,S-BPBP)] (R,S-1), is a practical catalyst for the preparative oxidation of various aliphatic compounds including model hydrocarbons and optically pure natural products using hydrogen peroxide as an oxidant. Among the species present in mix-1, S,S-1 and R,R-1 are catalytically active, act independently and represent ca.