Engineered heart muscle allografts for heart repair in primates and humans.

Cardiomyocytes can be implanted to remuscularize the failing heart. Challenges include sufficient cardiomyocyte retention for a sustainable therapeutic impact without intolerable side effects, such as arrhythmia and tumour growth. We investigated the hypothesis that epicardial engineered heart muscle (EHM) allografts from induced pluripotent stem cell-derived cardiomyocytes and stromal cells structurally and functionally remuscularize the chronically failing heart without limiting side effects in rhesus macaques.

Evolution of CEACAM pathogen decoy receptors in primates.

Background: CEACAM1 in leukocytes controls cell activation during inflammation. This and its expression in epithelial cells led to frequent independent appropriation of CEACAM1 as receptor by pathogens in humans and other species to gain host access and to downregulate its immune response. As a countermeasure, decoy receptors with CEACAM1-like pathogen-binding domains evolved.

Trials and tribulations of cell therapy for heart failure: an update on ongoing trials.

Heart failure (HF) remains a leading cause of mortality, responsible for 13% of all deaths worldwide. The prognosis for patients with HF is poor, with only a 50% survival rate within 5 years. A major challenge of ischaemia-driven HF is the loss of cardiomyocytes, compounded by the minimal regenerative capacity of the adult heart.

The Rate of Water Safety Team Interventions in High Diving, A Survey of Elite Athletes Performing between 2009 and 2021.

There is a paucity of sport-specific safety data on high diving. This paper describes the results of a survey of all athletes competing in elite international competitions between 2009 and 2021.Sixty-eight athletes completed surveys, representing a response rate of 80%.

Human induced pluripotent stem cells for live cell cycle monitoring and endogenous gene activation.

The fluorescence ubiquitination cell cycle inhibitor (FUCCI) has been introduced to monitor cell cycle activity in living cells, including human induced pluripotent stem cells (hiPSC) and derived cell types. We have recently developed hiPSC with stable expression of dCas9VPR for endogenous gene activation and a Citrine-tagged ACTN2 cell line to monitor sarcomere development and function in muscle cells. Here, we present dual and triple transgenic hiPSC lines developed by genomic integration of FUCCI with and without dCas9VPR into the ROSA26 and AAVS1 loci, respectively, in the previously introduced ACTN2-Citrine line.

The effect of host size on binding in host-guest complexes of cyclodextrins and polyoxometalates.

Harnessing flexible host cavities opens opportunities for the design of novel supramolecular architectures that accommodate nanosized guests. This research examines unprecedented gas-phase structures of Keggin-type polyoxometalate PWO (WPOM) and cyclodextrins (X-CD, X = α, β, γ, δ, ε, ζ) including previously unexplored large, flexible CDs. Using ion mobility spectrometry coupled to mass spectrometry (IM-MS) in conjunction with molecular dynamics (MD) simulations, we provide first insights into the binding modes between WPOM and larger CD hosts as isolated structures.

Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.

Noonan syndrome patients harboring causative variants in LZTR1 are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. In this study, we investigate the mechanistic consequences of a homozygous variant LZTR1 by using patient-specific and CRISPR-Cas9-corrected induced pluripotent stem cell (iPSC) cardiomyocytes. Molecular, cellular, and functional phenotyping in combination with in silico prediction identify an LZTR1-specific disease mechanism provoking cardiac hypertrophy.

Preclinical evaluation of CRISPR-based therapies for Noonan syndrome caused by deep-intronic variants.

Gene variants in are implicated to cause Noonan syndrome associated with a severe and early-onset hypertrophic cardiomyopathy. Mechanistically, deficiency results in accumulation of RAS GTPases and, as a consequence, in RAS-MAPK signaling hyperactivity, thereby causing the Noonan syndrome-associated phenotype. Despite its epidemiological relevance, pharmacological as well as invasive therapies remain limited.

Genome engineering of a neuronal specific, optogenetic, induced pluripotent stem cell line.

Control of neuronal activity by optogenetic tools is increasingly explored in disease modelling and optogenetics and holds great promise for regenerative therapy. To investigate neuronal connectivity with other excitable cells we established an optogenetic induced pluripotent stem cell line. The SynfChrimson line harbors a stably integrated, fast, red light-activatable channel (f-Chrimson), under the control of synapsin promotor in the AAVS1 locus.

Protocol to develop force-generating human skeletal muscle organoids.

Force generation is an essential property of skeletal muscle models in vitro. We describe a versatile 1-step procedure to direct undifferentiated human pluripotent stem cells (PSCs) into contractile skeletal muscle organoids (SMOs). Our protocol provides detailed steps for 3D casting of PSCs using either collagen-I/Matrigel- or fibrin/Geltrex-based hydrogels, SMO differentiation, and application of different culture platforms for mechanical loading and contractility analysis.

4D-Printable Photocrosslinkable Polyurethane-Based Inks for Tissue Scaffold and Actuator Applications.

4D printing recently emerges as an exciting evolution of conventional 3D printing, where a printed construct can quickly transform in response to a specific stimulus to switch between a temporary variable state and an original state. In this work, a photocrosslinkable polyethylene-glycol polyurethane ink is synthesized for light-assisted 4D printing of smart materials. The molecular weight distribution of the ink monomers is tunable by adjusting the copolymerization reaction time.

Atrial fibrillation-associated electrical remodelling in human induced pluripotent stem cell-derived atrial cardiomyocytes: a novel pathway for antiarrhythmic therapy development.

Aims: Atrial fibrillation (AF) is associated with tachycardia-induced cellular electrophysiology alterations which promote AF chronification and treatment resistance. Development of novel antiarrhythmic therapies is hampered by the absence of scalable experimental human models that reflect AF-associated electrical remodelling. Therefore, we aimed to assess if AF-associated remodelling of cellular electrophysiology can be simulated in human atrial-like cardiomyocytes derived from induced pluripotent stem cells in the presence of retinoic acid (iPSC-aCM), and atrial-engineered human myocardium (aEHM) under short term (24 h) and chronic (7 days) tachypacing (TP).

Ion mobility mass spectrometry enables the discrimination of positional isomers and the detection of conformers from cyclic oligosaccharides-metals supramolecular complexes.

Cyclic oligosaccharides are well known to interact with various metals, able to form supramolecular complexes with distinct sizes and shapes. However, the presence of various isomers in a sample, including positional isomers and conformers, can significantly impact molecular recognition, encapsulation ability and chemical reactivity. Therefore, it is crucial to have tools for deep samples probing and correlation establishments.

Two waves of evolution in the rodent pregnancy-specific glycoprotein (Psg) gene family lead to structurally diverse PSGs.

Background: The evolution of pregnancy-specific glycoprotein (PSG) genes within the CEA gene family of primates correlates with the evolution of hemochorial placentation about 45 Myr ago. Thus, we hypothesized that hemochorial placentation with intimate contact between fetal cells and maternal immune cells favors the evolution and expansion of PSGs. With only a few exceptions, all rodents have hemochorial placentas thus the question arises whether Psgs evolved in all rodent genera.

Engineering the catalytic activity of an Antarctic PET-degrading enzyme by loop exchange.

Several hydrolases have been described to degrade polyethylene terephthalate (PET) at moderate temperatures ranging from 25°C to 40°C. These mesophilic PET hydrolases (PETases) are less efficient in degrading this plastic polymer than their thermophilic homologs and have, therefore, been the subject of many protein engineering campaigns. However, enhancing their enzymatic activity through rational design or directed evolution poses a formidable challenge due to the need for exploring a large number of mutations.

Structure and function of the metagenomic plastic-degrading polyester hydrolase PHL7 bound to its product.

The recently discovered metagenomic-derived polyester hydrolase PHL7 is able to efficiently degrade amorphous polyethylene terephthalate (PET) in post-consumer plastic waste. We present the cocrystal structure of this hydrolase with its hydrolysis product terephthalic acid and elucidate the influence of 17 single mutations on the PET-hydrolytic activity and thermal stability of PHL7. The substrate-binding mode of terephthalic acid is similar to that of the thermophilic polyester hydrolase LCC and deviates from the mesophilic IsPETase.

The DZHK research platform: maximisation of scientific value by enabling access to health data and biological samples collected in cardiovascular clinical studies.

The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles.

Therapeutic efficacy of AAV-mediated restoration of PKP2 in arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy is a severe cardiac disorder characterized by lethal arrhythmias and sudden cardiac death, with currently no effective treatment. Plakophilin 2 () is the most frequently affected gene. Here we show that adeno-associated virus (AAV)-mediated delivery of PKP2 in induced pluripotent stem cell-derived cardiomyocytes restored not only cardiac PKP2 levels but also the levels of other junctional proteins, found to be decreased in response to the mutation.

Association Between Intracompartmental Pressures in the Deep Posterior Compartment of the Leg and Conservative Treatment Outcome for Exercise-Related Leg Pain in Military Service Members.

Objective: To evaluate the relationship between intracompartmental pressure (ICP) values of the deep posterior compartment and the outcomes of a comprehensive conservative outpatient treatment program in service members with chronic exercise-related leg pain.

Design: Historic cohort study.

Setting: Department of sports medicine at a military secondary care facility.

Is prehospital intubation of severely injured children in accordance with guidelines?

Background: The current German S3 guideline for polytrauma lists five criteria for prehospital intubation: apnea, severe traumatic brain injury (GCS ≤8), severe chest trauma with respiratory failure, hypoxia, and persistent hemodynamic instability. These guideline criteria, used in adults in daily practice, have not been previously studied in a collection of severely injured children. The aim of this study was to assess the extent to which the criteria are implemented in clinical practice using a multivariate risk analysis of severely injured children.

Measuring Intracompartmental Pressures in the Lower Leg: Assessing the Use of Unilateral Measurements in Patients with Bilateral Symptoms.

Unlabelled: The purpose of the present study was to evaluate whether unilateral intracompartmental pressure (ICP) measurements correctly represent the contralateral ICP value in patients suspected to have bilateral chronic exertional compartment syndrome (CECS) in the anterior compartment of the leg.

Methods: A retrospective cohort study was performed that included military service members who had been referred to a secondary care department for bilateral anterolateral exercise-related leg pain. The obtained ICP values were utilized to assess 2 possible measurement strategies to perform unilateral ICP measurements: the right-leg strategy (i.