The Relevance of the Type of Ventricular Arrhythmia in Titin-Related Dilated Cardiomyopathy: A Multicenter Study.

Background: Truncating titin variants (TTNtvs) are the most prevalent cause of inherited dilated cardiomyopathy. Occurrence of different ventricular arrhythmia (VA) subtypes, including premature ventricular complexes (PVCs), nonsustained ventricular tachycardia (NSVT), and sustained monomorphic VT (SMVT), has been reported.

Objectives: The aim of this study was to analyze the prognostic relevance of distinct VA subtypes among TTNtv carriers and their underlying arrhythmogenic substrates.

Feature selection methods affect the performance of scRNA-seq data integration and querying.

The availability of single-cell transcriptomics has allowed the construction of reference cell atlases, but their usefulness depends on the quality of dataset integration and the ability to map new samples. Previous benchmarks have compared integration methods and suggest that feature selection improves performance but have not explored how best to select features. Here, we benchmark feature selection methods for single-cell RNA sequencing integration using metrics beyond batch correction and preservation of biological variation to assess query mapping, label transfer and the detection of unseen populations.

[Problematic digital media use and health literacy among schoolchildren in Germany. Findings of the 2022 HBSC Study].

Background: The digital life of children and young people is characterised by frequent use of social media and digital games. Previous research has demonstrated detrimental health effects of problematic media use. However, links with health literacy (HL) have received little attention, although frameworks suggest health literacy to be a determinant of health behaviour.

TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial.

Background: M6223 is an intravenous (IV), Fc-competent, fully human, antagonistic, anti-T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) antibody. Bintrafusp alfa (BA) is a bifunctional fusion protein that simultaneously blocks nonredundant immunosuppressive TGF-β and PD-(L)1 pathways.

Methods: This first-in-human, dose-escalation study in patients with advanced solid tumors (N=58; aged ≥18 years, ECOG PS≤1) evaluated M6223 alone (Part 1A, n=40; M6223 10-2400 mg every 2 weeks, n=32; M6223 2400 mg every 3 weeks, n=8) or with BA (Part 1B, n=18; M6223 300-1600 mg with BA 1200 mg; both every 2 weeks, intravenous).

Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor.

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of the T cell receptor signaling pathway and is therefore a target of interest for immunooncology. Nonselective HPK1 inhibitors may affect other kinase components of T cell activation, blunting the beneficial impact of enhanced T cell activity that results from HPK1 inhibition itself. Here, we report the discovery of pyrazine carboxamide HPK1 inhibitors and their optimization through structure-based drug design to afford a highly selective HPK1 inhibitor, compound (AZ3246).

The IL-23/Th17 pathway inhibitors in the treatment of psoriasis and the risk of skin malignancies: a review.

Psoriasis and psoriatic arthritis are chronic inflammatory conditions that constitute a significant global health burden due to their prevalence and impact on quality of life. A deeper comprehension of psoriasis and psoriatic arthritis pathogenesis has recently led to the emergence of novel classes of biologics targeting the IL-23/Th17 pathway. The specific role of interleukin-12, -23, and -17 in cancer as either promoters or inhibitors is under investigation in various studies.

Constraint of Different Knee Implant Designs Under Anterior-Posterior Shear Forces and Internal-External Rotation Moments in Human Cadaveric Knees.

Instability remains one of the most common indications for revision after total knee arthroplasty. To gain a better understanding of how an implant will perform in vivo and support surgeons in selecting the most appropriate implant design for an individual patient, it is crucial to evaluate the implant constraint within clinically relevant ligament and boundary conditions. Therefore, this study investigated the constraint of three different implant designs (symmetrical implants with and without a post-cam mechanism and an asymmetrical medial-stabilized implant) under anterior-posterior shear forces and internal-external rotation moments at different flexion angles in human cadaveric knees using a six-degrees-of-freedom joint motion simulator.

Ni-Catalyzed Enantioselective Desymmetrization: Development of Divergent Acyl and Decarbonylative Cross-Coupling Reactions.

Ni-catalyzed asymmetric reductive cross-coupling reactions provide rapid and modular access to enantioenriched building blocks from simple electrophile precursors. Reductive coupling reactions that can diverge through a common organometallic intermediate to two distinct families of enantioenriched products are particularly versatile but underdeveloped. Here, we describe the development of a bis(oxazoline) ligand that enables the desymmetrization of -anhydrides.

Translational and clinical comparison of whole genome and transcriptome to panel sequencing in precision oncology.

Precision oncology offers new cancer treatment options, yet sequencing methods vary in type and scope. In this study, we compared whole-exome/whole-genome (WES/WGS) and transcriptome sequencing (TS) with broad panel sequencing by resequencing the same tumor DNA and RNA as well as normal tissue DNA for germline assessment, from 20 patients with rare or advanced tumors, who were originally sequenced by WES/WGS ± TS within the DKFZ/NCT/DKTK MASTER program from 2015 to 2020. Molecular analyses resulted in a median number of 2.

Additively manufactured ready-to-use platform using conductive recycled PLA for ketamine sensing.

The use of 3D-printed electrodes is reported fabricated from in-house conductive filament composed of a mixture of recycled poly (lactic acid) (rPLA), graphite (Gpt), and carbon black (CB) for fast detection of the abused drug ketamine. Firstly, the performance of these electrodes was evaluated in comparison to 3D-printed electrodes produced employing a commercially available conductive filament. After a simple pretreatment step (mechanical polishing), the new 3D-printed electrodes presented better performance than the electrodes produced from commercial filament in relation to peak-to-peak separation of the redox probe [Fe(CN)]/ (130 mV and 759 mV, respectively), charge transfer resistance (R = 1.

Exploration of Novel Biomarkers for Neurodegenerative Diseases Using Proteomic Analysis and Ligand-Binding Assays.

Background/objectives: Neurodegenerative diseases are a major cause of morbidity and mortality worldwide, and their public health burden continues to increase. There is an urgent need to develop reliable and sensitive biomarkers to aid the timely diagnosis, disease progression monitoring, and therapeutic development for neurodegenerative disorders. Proteomic screening strategies, including antibody microarrays, are a powerful tool for biomarker discovery, but their findings should be confirmed using quantitative assays.

Synthesis of Lewis Acid-Base Adducts Between Potassium Dihydrogenpnictogenides and Group 13 Lewis Acids.

Lewis acid-base adducts between potassium dihydrogenpnictogenides [K(18c6)PnH] (Pn=P, As) and Trialkylgallanes (GaMe, GaEt, GatBu) as well as BH were synthesized. In the course of these investigations, we were able to fully characterize a row of compounds of the type [K(18c6)(thf)][PnH(ER)] (E=B: R=H; E=Ga: R=Me, Et, tBu). Based on the successful syntheses of these species, we also synthesized several compounds of the composition [K(18c6)(thf)][Pn(SiMe)(ER)] (n=1, 2) starting from [KPn(SiMe)] (Pn=P and As) and ER (E=B, Al, In: R=Me; E=Ga: R=Me, Et, tBu).

Kinematic Patterns of Different Loading Profiles Before and After Total Knee Arthroplasty: A Cadaveric Study.

One of the major goals of total knee arthroplasty (TKA) is to restore the physiological function of the knee. In order to select the appropriate TKA design for a specific patient, it would be helpful to understand whether there is an association between passive knee kinematics intraoperatively and during complex activities, such as ascending stairs. Therefore, the primary objective of this study was to compare the anterior-posterior (AP) range of motion during simulated passive flexion and stair ascent at different conditions in the same knees using a six-degrees-of-freedom joint motion simulator, and secondary, to identify whether differences between TKA designs with and without a post-cam mechanism can be detected during both activities, and if one design is superior in recreating the AP translation of the native knee.

Nuclear pleomorphism in canine cutaneous mast cell tumors: Comparison of reproducibility and prognostic relevance between estimates, manual morphometry, and algorithmic morphometry.

Variation in nuclear size and shape is an important criterion of malignancy for many tumor types; however, categorical estimates by pathologists have poor reproducibility. Measurements of nuclear characteristics can improve reproducibility, but current manual methods are time-consuming. The aim of this study was to explore the limitations of estimates and develop alternative morphometric solutions for canine cutaneous mast cell tumors (ccMCTs).

Insights into the electronic structure of non-steroidal anti-inflammatory drugs: soft X-ray study of fenoprofen, ketoprofen and methyl salicylate in the gas phase.

The valence and core electronic structure of three non-steroidal anti-inflammatory drugs (methyl salicylate, fenoprofen and ketoprofen) have been studied by photoelectron and soft X-ray absorption spectroscopy, supported by theoretical calculations of the molecular and electronic structure. The conformational landscape has been explored for sixteen low-energy conformers of fenoprofen and ketoprofen, and the energies of both compounds fall into two groups with steric similarities, separated by about 3 kJ mol. Valence band photoelectron spectra agree with previous results, and the spectra have been calculated using two approaches.

Long-term effectiveness of an ultra-rapid rollout vaccination campaign with BNT162b2 on the incidence of SARS-CoV-2 infection.

In 2021, an ultra-rapid rollout vaccination campaign in the Schwaz district, Tyrol, Austria, delivered the COVID-19 vaccine BNT162b2 to 66.9% of eligible residents (dose 1: March 11-16, dose 2: April 8-13). Alongside the campaign, we recruited 11,955 residents into the prospective study REDUCE, of whom 3,859 participated in a booster vaccination initiative (November 20-28, 2021).

Single-molecule dynamic structural biology with vertically arranged DNA on a fluorescence microscope.

The intricate interplay between DNA and proteins is key for biological functions such as DNA replication, transcription and repair. Dynamic nanoscale observations of DNA structural features are necessary for understanding these interactions. Here we introduce graphene energy transfer with vertical nucleic acids (GETvNA), a method to investigate DNA-protein interactions that exploits the vertical orientation adopted by double-stranded DNA on graphene.

Search for the Exclusive W Boson Hadronic Decays W^{±}→π^{±}γ, W^{±}→K^{±}γ and W^{±}→ρ^{±}γ with the ATLAS Detector.

A search for the exclusive hadronic decays W^{±}→π^{±}γ, W^{±}→K^{±}γ, and W^{±}→ρ^{±}γ is performed using up to 140  fb^{-1} of proton-proton collisions recorded with the ATLAS detector at a center-of-mass energy of sqrt[s]=13  TeV. If observed, these rare processes would provide a unique test bench for the quantum chromodynamics factorization formalism used to calculate cross sections at colliders. Additionally, at future colliders, these decays could offer a new way to measure the W boson mass through fully reconstructed decay products.

Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise.

In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls.

FGFR4 Is Required for Concentric Growth of Cardiac Myocytes during Physiologic Cardiac Hypertrophy.

Fibroblast growth factor (FGF) 23 is a bone-derived hormone that promotes renal phosphate excretion. Serum FGF23 is increased in chronic kidney disease (CKD) and contributes to pathologic cardiac hypertrophy by activating FGF receptor (FGFR) 4 on cardiac myocytes, which might lead to the high cardiovascular mortality in CKD patients. Increases in serum FGF23 levels have also been observed following endurance exercise and in pregnancy, which are scenarios of physiologic cardiac hypertrophy as an adaptive response of the heart to increased demand.