Neonatal systemic gene therapy restores cardiorespiratory function in a rat model of Pompe disease.

Absence of functional acid-α-glucosidase (GAA) leads to early-onset Pompe disease with cardiorespiratory and neuromuscular failure. A novel Pompe rat model ( ) was used to test the hypothesis that neonatal gene therapy with adeno-associated virus serotype 9 (AAV9) restores cardiorespiratory neuromuscular function across the lifespan. Temporal vein administration of AAV9-DES-GAA or sham (saline) injection was done on post-natal day 1; rats were studied at 6-12 months old.

YKL-40, cardiovascular events, and mortality in individuals recently diagnosed with type 2 diabetes: A Danish cohort study.

Aims: We investigated the association of the inflammatory biomarker YKL-40 with cardiovascular events (CVEs) and mortality in individuals with type 2 diabetes.

Methods: We followed 11,346 individuals recently diagnosed with type 2 diabetes for up to 14 years. Baseline YKL-40 levels (measured in 9,010 individuals) were grouped into percentiles (0-33 %, 34-66 %, 67-90 %, and 91-100 %) and analyzed continuously (per 1 SD log increment), with comparisons to CRP (measured in 9,644 individuals).

Room-Temperature Deposition of δ-NiGa Thin Films and Nanoparticles via Magnetron Sputtering.

Magnetron sputtering is a versatile method for investigating model system catalysts thanks to its simplicity, reproducibility, and chemical-free synthesis process. It has recently emerged as a promising technique for synthesizing δ-NiGa thin films. Physically deposited thin films have significant potential to clarify certain aspects of catalysts by eliminating parameters such as particle size dependence, metal-support interactions, and the presence of surface ligands.

Antibodies against SARS-CoV-2 spike protein in the cerebrospinal fluid of COVID-19 patients and vaccinated controls: a multicentre study.

Introduction: SARS-CoV-2 antibodies in the cerebrospinal fluid (CSF) of COVID-19 patients possibly reflect blood-cerebrospinal fluid barrier (BCB) disruption due to systemic inflammation. However, some studies indicate that CSF antibodies signal a neurotropic infection. Currently, larger studies are needed to clarify this, and it is unknown if CSF antibodies appear solely after infection or also after COVID-19 vaccination.

The DLEU2/miR-15a/miR-16-1 cluster shapes the immune microenvironment of chronic lymphocytic leukemia.

The development and progression of chronic lymphocytic leukemia (CLL) depend on genetic abnormalities and on the immunosuppressive microenvironment. We have explored the possibility that genetic drivers might be responsible for the immune cell dysregulation that shapes the protumor microenvironment. We performed a transcriptome analysis of coding and non-coding RNAs (ncRNAs) during leukemia progression in the Rag2γ MEC1-based xenotransplantation model.

Targeting IL-11R/EZH2 signaling axis as a therapeutic strategy for osteosarcoma lung metastases.

Lung metastases are the primary cause of death for osteosarcoma (OS) patients. We recently validated interleukin-11 receptor α (IL-11Rα) as a molecular target for the inhibition of OS lung metastases. Since there is no clinically approved antibody against this receptor, we sought to identify downstream targets that mediate the effects of IL-11Rα signaling.

Chemogenetic stimulation of phrenic motor output and diaphragm activity.

Impaired respiratory motor output contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We investigated if expressing designer receptors exclusively activated by designer drugs (DREADDs) in the mid-cervical spinal cord could effectively stimulate phrenic motor output to increase diaphragm activation. Two primary questions were addressed: 1) does effective DREADD-mediated diaphragm activation require focal expression in phrenic motoneurons (vs.

Low-grade inflammation in persons with recently diagnosed type 2 diabetes: The role of abdominal adiposity and putative mediators.

Aims: To determine the magnitude of the association between abdominal adiposity and low-grade inflammation in persons with recently diagnosed type 2 diabetes (T2D) and to determine to what extent this association is mediated by low physical activity level, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, hypertension, and comorbidities.

Materials And Methods: We measured waist circumference, clinical characteristics, and inflammatory markers i.e.

V2a neurons restore diaphragm function in mice following spinal cord injury.

The specific roles that different types of neurons play in recovery from injury is poorly understood. Here, we show that increasing the excitability of ipsilaterally projecting, excitatory V2a neurons using designer receptors exclusively activated by designer drugs (DREADDs) restores rhythmic bursting activity to a previously paralyzed diaphragm within hours, days, or weeks following a C2 hemisection injury. Further, decreasing the excitability of V2a neurons impairs tonic diaphragm activity after injury as well as activation of inspiratory activity by chemosensory stimulation, but does not impact breathing at rest in healthy animals.

Co-clinical Trial of Novel Bispecific Anti-HER2 Antibody Zanidatamab in Patient-Derived Xenografts.

Unlabelled: Zanidatamab is a bispecific human epidermal growth factor receptor 2 (HER2)-targeted antibody that has demonstrated antitumor activity in a broad range of HER2-amplified/expressing solid tumors. We determined the antitumor activity of zanidatamab in patient-derived xenograft (PDX) models developed from pretreatment or postprogression biopsies on the first-in-human zanidatamab phase I study (NCT02892123). Of 36 tumors implanted, 19 PDX models were established (52.

Estimation of epidemiological cut-off values for eight antibiotics used for treatment of bovine mastitis caused by Streptococcus uberis and Streptococcus dysgalactiae subsp. dysgalactiae.

Interpretive criteria for antimicrobial susceptibility testing are lacking for most antimicrobials used for bovine streptococcal mastitis. The objectives of this study were to determine (tentative) epidemiological cut-off ((T)ECOFF) values for clinically relevant antibiotics used for treatment of bovine mastitis, and to estimate the proportion of acquired resistance (non-wild-types) in Streptococcus dysgalactiae subsp. dysgalactiae and Streptococcus uberis.

Automated de Novo Design of Olefin Metathesis Catalysts: Computational and Experimental Analysis of a Simple Thermodynamic Design Criterion.

Methods for computational de novo design of inorganic molecules have paved the way for automated design of homogeneous catalysts. Such studies have so far relied on correlation-based prediction models as fitness functions (figures of merit), but the soundness of these approaches has yet to be tested by experimental verification of de novo-designed catalysts. Here, a previously developed criterion for the optimization of dative ligands L in ruthenium-based olefin metathesis catalysts RuCl(L)(L')(═CHAr), where Ar is an aryl group and L' is a phosphine ligand dissociating to activate the catalyst, was used in de novo design experiments.

Differential expression of the inflammatory ciita gene may be accompanied by altered bone properties in intact sex steroid-deficient female rats.

Objective: The class II transactivator (CIITA), encoded by the CIITA gene, controls expression of immune response regulators, which affect bone homeostasis. Previously, we investigated a functional CIITA polymorphism in elderly women. Women carrying the allele associated with lower CIITA levels displayed higher bone mineral density (BMD), but also higher bone loss.

Executive functions and ADHD symptoms predict educational functioning in children with ADHD: A two-year longitudinal study.

The aim of this two-year longitudinal study was to investigate whether deficits in executive functions (EF) predict impaired everyday functioning after two years in children and adolescents with ADHD. A sample of 135 participants with and without ADHD were assessed with neuropsychological tests of EF and parent ratings of everyday functioning with the Child Behavior Checklist at baseline (M = 11.6, SD = 2.

BubbleDrive, a low-volume incubation chamber for acute brain slices.

Acute brain slices are a common and useful preparation in experimental neuroscience. A wide range of incubation chambers for brain slices exists but only a few are designed with very low volumes of the bath solution in mind. Such chambers are necessary when high-cost chemicals are to be added to the solution or when small amounts of substances released by the slice are to be collected for analysis.

Characteristics and long-term prognosis of Danish residents with a positive intrathecal antibody index test for herpes simplex virus or varicella-zoster virus compared with individuals with a positive cerebrospinal fluid PCR: a nationwide cohort study.

Objectives: We compared characteristics and outcomes of individuals who in the cerebrospinal fluid (CSF) were positive for herpes simplex virus (HSV) or varicella-zoster virus (VZV)-intrathecal antibody index test ([AI]-positive) vs. individuals who were PCR-positive for HSV type 1 (HSV1), type 2 (HSV2), and for VZV.

Methods: Nationwide cohort study of all Danish residents with positive CSF-AI or -PCR for HSV or VZV (1995-2021).

SARS-CoV-2 and autoantibodies in the cerebrospinal fluid of COVID-19 patients: prospective multicentre cohort study.

Disease mechanisms underlying neurological and neuropsychiatric symptoms after coronavirus disease 2019 (COVID-19), termed neuro-COVID, are poorly understood. Investigations of the cerebrospinal fluid (CSF) for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antibodies, as well as autoantibodies against neuronal surface antigens, could improve our understanding in that regard. We prospectively collected CSF and blood from patients investigated by lumbar puncture for neurological or neuropsychiatric symptoms during or after COVID-19.

Distinct effects of AMPAR subunit depletion on spatial memory.

Pharmacological studies established a role for AMPARs in the mammalian forebrain in spatial memory performance. Here we generated global GluA1/3 double knockout mice () and conditional knockouts lacking GluA1 and GluA3 AMPAR subunits specifically from principal cells across the forebrain (). In both models, loss of GluA1 and GluA3 resulted in reduced hippocampal GluA2 and increased levels of the NMDAR subunit GluN2A.

Increased membrane Ca permeability drives astrocytic Ca dynamics during neuronal stimulation at excitatory synapses.

Astrocytes are intricately involved in the activity of neural circuits; however, their basic physiology of interacting with nearby neurons is not well established. Using two-photon imaging of neurons and astrocytes during higher frequency stimulation of hippocampal CA3-CA1 Schaffer collateral (Scc) excitatory synapses, we could show that increasing levels of released glutamate accelerated local astrocytic Ca elevation. However, blockage of glutamate transporters did not abolish this astrocytic Ca response, suggesting that astrocytic Ca elevation is indirectly associated with an uptake of extracellular glutamate.

Mucopolysaccharidosis type IIIB: a current review and exploration of the AAV therapy landscape.

Mucopolysaccharidoses type IIIB is a rare genetic disorder caused by mutations in the gene that encodes for N-acetyl-alpha-glucosaminidase. This results in the aggregation of heparan sulfate polysaccharides within cell lysosomes that leads to progressive and severe debilitating neurological dysfunction. Current treatment options are expensive, limited, and presently there are no approved cures for mucopolysaccharidoses type IIIB.

Adipogenic and SWAT cells separate from a common progenitor in human brown and white adipose depots.

Adipocyte function is a major determinant of metabolic disease, warranting investigations of regulating mechanisms. We show at single-cell resolution that progenitor cells from four human brown and white adipose depots separate into two main cell fates, an adipogenic and a structural branch, developing from a common progenitor. The adipogenic gene signature contains mitochondrial activity genes, and associates with genome-wide association study traits for fat distribution.

Danish Citizens' Expectations for mHealth Prescription.

Use of mHealth in Denmark is growing, and prescription structures for mHealth apps are a political goal. In this pilot survey study, respondents generally perceive their mHealth use as beneficial, which correlates with their frequency of use. Willingness to substitute traditional treatments for prescribed mHealth varies based on type of substituted treatment.

Mesomeric Acceleration Counters Slow Initiation of Ruthenium-CAAC Catalysts for Olefin Metathesis (CAAC = Cyclic (Alkyl)(Amino) Carbene).

Ruthenium catalysts bearing cyclic (alkyl)(amino)carbene (CAAC) ligands can attain very high productivities in olefin metathesis, owing to their resistance to unimolecular decomposition. Because the propagating methylidene species RuCl(CAAC)(=CH) is extremely susceptible to bimolecular decomposition, however, turnover numbers in the metathesis of terminal olefins are highly sensitive to catalyst concentration, and hence loadings. Understanding how, why, and how rapidly the CAAC complexes partition between the precatalyst and the active species is thus critical.

Enabling Molecular-Level Computational Description of Redox and Proton-Coupled Electron Transfer Reactions of Samarium Diiodide.

Samarium diiodide (SmI, Kagan's reagent) is a one-electron reductant with applications ranging from organic synthesis to nitrogen fixation. Highly inaccurate relative energies of redox and proton-coupled electron transfer (PCET) reactions of Kagan's reagent are predicted by pure and hybrid density functional approximations (DFAs) when only scalar relativistic effects are accounted for. Calculations including spin-orbit coupling (SOC) show that the SOC-induced differential stabilization of the Sm(III) versus the Sm(II) ground state is little affected by ligands and solvent, and a standard SOC correction derived from atomic energy levels is thus included in the reported relative energies.