Mechanisms of a novel regulatory light chain-dependent cardiac myosin inhibitor.

Hypertrophic cardiomyopathy (HCM) is a genetic disease of the heart characterized by thickening of the left ventricle (LV), hypercontractility, and impaired relaxation. HCM is caused primarily by heritable mutations in sarcomeric proteins, such as β myosin heavy chain. Until recently, medications in clinical use for HCM did not directly target the underlying contractile changes in the sarcomere.

Split intein-mediated protein trans-splicing to express large dystrophins.

Gene replacement using adeno-associated virus (AAV) vectors is a promising therapeutic approach for many diseases. However, this therapeutic modality is challenged by the packaging capacity of AAVs (approximately 4.7 kilobases), limiting its application for disorders involving large coding sequences, such as Duchenne muscular dystrophy, with a 14 kilobase messenger RNA.

Genome-wide mapping of G-quadruplex DNA: a step-by-step guide to select the most effective method.

The development of methods that enabled genome-wide mapping of DNA G-quadruplex structures in chromatin has played a critical role in providing evidence to support the formation of these structures in living cells. Over the past decade, a variety of methods aimed at mapping G-quadruplexes have been reported in the literature. In this critical review, we have sought to provide a technical overview on the relative strengths and weaknesses of the genomics approaches currently available, offering step-by-step guidance to assessing experimental needs and selecting the most appropriate method to achieve effective genome-wide mapping of DNA G-quadruplexes.

Echocardiography to Assess Cardiac Structure and Function in Genetic Cardiomyopathies.

Rodents are the most common experimental models used in cardiovascular research including studies of genetic cardiomyopathies. Genetic cardiomyopathies are characterized by changes in cardiac structure and function. Echocardiography allows for relatively inexpensive, non-invasive, reliable, and reproducible assessment of these changes.

Factors affecting endoscopic third ventriculostomy success in adults.

Background: Endoscopic third ventriculostomy (ETV) is a standard treatment in hydrocephalus of certain aetiologies. The most widely used predictive model is the ETV success score. This is frequently used to predict outcomes following ETV in adult patients; however, this was a model developed in paediatric patients with often distinct aetiologies of hydrocephalus.

Danicamtiv Increases Myosin Recruitment and Alters Cross-Bridge Cycling in Cardiac Muscle.

Background: Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Danicamtiv is a novel myosin activator with promising preclinical data that is currently in clinical trials. While it is known that danicamtiv increases force and cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies regarding its mode of action are lacking.

Cell based dATP delivery as a therapy for chronic heart failure.

Transplanted human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) improve ventricular performance when delivered acutely post-myocardial infarction but are ineffective in chronic myocardial infarction/heart failure. 2'-deoxy-ATP (dATP) activates cardiac myosin and potently increases contractility. Here we engineered hPSC-CMs to overexpress ribonucleotide reductase, the enzyme controlling dATP production.

Danicamtiv increases myosin recruitment and alters the chemomechanical cross bridge cycle in cardiac muscle.

Unlabelled: Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Detailed mechanism of action of these agents can help predict potential unwanted affects and identify patient populations that can benefit most from them. Danicamtiv is a novel myosin activator with promising preclinical data that is currently in clinical trials.

Correcting dilated cardiomyopathy with fibroblast-targeted p38 deficiency.

Inherited mutations in contractile and structural genes, which decrease cardiomyocyte tension generation, are principal drivers of dilated cardiomyopathy (DCM)- the leading cause of heart failure . Progress towards developing precision therapeutics for and defining the underlying determinants of DCM has been cardiomyocyte centric with negligible attention directed towards fibroblasts despite their role in regulating the best predictor of DCM severity, cardiac fibrosis . Given that failure to reverse fibrosis is a major limitation of both standard of care and first in class precision therapeutics for DCM, this study examined whether cardiac fibroblast-mediated regulation of the heart's material properties is essential for the DCM phenotype.

dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.

Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown.

Mechanistic insights into consumption of the food additive xanthan gum by the human gut microbiota.

Processed foods often include food additives such as xanthan gum, a complex polysaccharide with unique rheological properties, that has established widespread use as a stabilizer and thickening agent. Xanthan gum's chemical structure is distinct from those of host and dietary polysaccharides that are more commonly expected to transit the gastrointestinal tract, and little is known about its direct interaction with the gut microbiota, which plays a central role in digestion of other dietary fibre polysaccharides. Here we show that the ability to digest xanthan gum is common in human gut microbiomes from industrialized countries and appears contingent on a single uncultured bacterium in the family Ruminococcaceae.

MBNL1 drives dynamic transitions between fibroblasts and myofibroblasts in cardiac wound healing.

Dynamic fibroblast to myofibroblast state transitions underlie the heart's fibrotic response. Because transcriptome maturation by muscleblind-like 1 (MBNL1) promotes differentiated cell states, this study investigated whether tactical control of MBNL1 activity could alter myofibroblast activity and fibrotic outcomes. In healthy mice, cardiac fibroblast-specific overexpression of MBNL1 transitioned the fibroblast transcriptome to that of a myofibroblast and after injury promoted myocyte remodeling and scar maturation.

Climate Mitigation through Biological Conservation: Extensive and Valuable Blue Carbon Natural Capital in Tristan da Cunha's Giant Marine Protected Zone.

Carbon-rich habitats can provide powerful climate mitigation if meaningful protection is put in place. We attempted to quantify this around the Tristan da Cunha archipelago Marine Protected Area. Its shallows (<1000 m depth) are varied and productive.

Syringomyelia: diagnosis and management.

In the pre-MR era syringomyelia often presented late, as a crippling neurological disorder. Today, most cases are diagnosed earlier, with less pronounced deficits. We are therefore presented with new challenges, including understanding the significance of various presenting symptoms, knowing when surgery might help and being aware of other treatments that could benefit someone living with the effects of syringomyelia, or its underlying cause.

Accelerating vein-to-vein cell therapy workflows with new bioanalytical strategies.

Cell therapies represent a new era of treatment modalities for cancer. Through agile bioprocessing and bioengineering, patient-derived T-cells can be directed toward cancer biomarkers to impart a more robust and targeted immune response. In order to avoid delays in critical treatment timeframes, new bioanalytical tools are needed to accelerate, streamline, and maximize the throughput of T-cell bioprocessing.

Out of hours magnetic resonance imaging for suspected cauda equina syndrome: lessons from a comparative study across two centres.

Background: Cauda equina syndrome, a rare but disabling spinal surgical emergency, requires prompt investigation, ideally using magnetic resonance imaging as patients may require decompressive surgery. Out of hours access to magnetic resonance imaging is only routinely available in major trauma centres and neurosurgical units. Patients in regional hospitals with suspected cauda equina syndrome may require transfer for diagnostic imaging.

Symptom outcome after craniovertebral decompression for Chiari type 1 malformation without syringomyelia.

Background: Specific symptom outcomes after craniovertebral decompression for patients with Chiari type 1 malformation, without accompanying syringomyelia, are not well characterised and poorly reported.

Methods: We performed a retrospective review of all patients diagnosed with Chiari type 1, without syringomyelia, who underwent craniovertebral decompression in our unit.

Results: We identified 129 individuals with a minimum of 2 years' follow-up.

Experience with revision craniovertebral decompression in adult patients with Chiari malformation type 1, with or without syringomyelia.

Background: Craniovertebral decompression is performed for symptomatic Chiari malformation type 1, with or without syringomyelia. In a few patients the symptoms and/or syrinx persist or recur, in which case revision surgery may be offered. The aim of this study was to examine the cause of failure of primary surgery and to assess the outcomes for revision cranio-vertebral decompression.

Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts.

Dilated cardiomyopathy (DCM) is often associated with sarcomere protein mutations that confer reduced myofilament tension-generating capacity. We demonstrated that cardiac twitch tension-time integrals can be targeted and tuned to prevent DCM remodeling in hearts with contractile dysfunction. We employed a transgenic murine model of DCM caused by the D230N-tropomyosin (Tm) mutation and designed a sarcomere-based intervention specifically targeting the twitch tension-time integral of D230N-Tm hearts using multiscale computational models of intramolecular and intermolecular interactions in the thin filament and cell-level contractile simulations.

Increasing Fatty Acid Oxidation Prevents High-Fat Diet-Induced Cardiomyopathy Through Regulating Parkin-Mediated Mitophagy.

Background: Increased fatty acid oxidation (FAO) has long been considered a culprit in the development of obesity/diabetes mellitus-induced cardiomyopathy. However, enhancing cardiac FAO by removing the inhibitory mechanism of long-chain fatty acid transport into mitochondria via deletion of acetyl coenzyme A carboxylase 2 (ACC2) does not cause cardiomyopathy in nonobese mice, suggesting that high FAO is distinct from cardiac lipotoxicity. We hypothesize that cardiac pathology-associated obesity is attributable to the imbalance of fatty acid supply and oxidation.

Challenges to Neurosurgery During the Coronavirus Disease 2019 (COVID-19) Pandemic.

The coronavirus disease 2019 pandemic has presented a massive burden to most health care systems across the globe. The demand for intensive care unit capacity in particular has increased significantly, and hospitals in most affected regions have struggled to cope. The focus of health care activity has shifted to the pandemic, with a negative impact on the management of other conditions.

The implementation of an external ventricular drain care bundle to reduce infection rates.

The main complication of external ventricular drains (EVD) is infection. Implementation of evidence-based guidelines for central venous catheter (CVC) care resulted in significant declines in infections. We tested a comparable approach to EVD infection rates.

Cardiac myosin activation with 2-deoxy-ATP via increased electrostatic interactions with actin.

The naturally occurring nucleotide 2-deoxy-adenosine 5'-triphosphate (dATP) can be used by cardiac muscle as an alternative energy substrate for myosin chemomechanical activity. We and others have previously shown that dATP increases contractile force in normal hearts and models of depressed systolic function, but the structural basis of these effects has remained unresolved. In this work, we combine multiple techniques to provide structural and functional information at the angstrom-nanometer and millisecond time scales, demonstrating the ability to make both structural measurements and quantitative kinetic estimates of weak actin-myosin interactions that underpin sarcomere dynamics.