276 results match your criteria: "M.R.A.; andNational Bioenergy Center[Affiliation]"

Article Synopsis
  • Researchers analyzed genetic data from nearly 1 million individuals to create a comprehensive catalogue of human protein-coding variations, shedding light on gene function and the frequency of rare coding variants.
  • The study identified over 10 million missense and 1.1 million loss-of-function variants, discovering 1,751 novel genes with rare biallelic loss-of-function variants and 3,988 genes intolerant to these variants.
  • They estimate that 3% of people carry a clinically significant genetic variant and provide public access to their data to enhance genetic interpretation and support precision medicine.
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Molecular glues for protein-protein interactions: Progressing toward a new dream.

Cell Chem Biol

June 2024

Department of Pharmaceutical Chemistry and Small Molecule Discovery Center (SMDC), University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

The modulation of protein-protein interactions with small molecules is one of the most rapidly developing areas in drug discovery. In this review, we discuss advances over the past decade (2014-2023) focusing on molecular glues (MGs)-monovalent small molecules that induce proximity, either by stabilizing native interactions or by inducing neomorphic interactions. We include both serendipitous and rational discoveries and describe the different approaches that were used to identify them.

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Key Considerations When Targeting a Heel Spur.

Anesth Pain Med

October 2023

Department of Anesthesiology and Pain Medicine, Pain Research Center, Iran University of Medical Sciences, Tehran, Iran.

Heel spur is a common medical condition that can cause substantial discomfort and reduce the quality of life of the affected patients. When seeking treatment for a heel spur, it is important to consider the differential diagnoses and underlying medical conditions that may contribute to the symptoms. This manuscript aims to explore several distinctive diagnostic possibilities, essential factors to consider, and practical strategies for managing heel spurs.

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Classical psychedelics such as psilocybin, lysergic acid diethylamide (LSD), and -dimethyltryptamine (DMT) are showing promising results in clinical trials for a range of psychiatric indications, including depression, anxiety, and substance abuse disorder. These compounds are characterized by broad pharmacological activity profiles, and while the acute mind-altering effects can be ascribed to their shared agonist activity at the serotonin 2A receptor (5-HTR), their apparent persistent therapeutic effects are yet to be decidedly linked to activity at this receptor. We report herein the discovery of 2,5-dimethoxyphenylpiperidines as a novel class of selective 5-HTR agonists and detail the structure-activity investigations leading to the identification of LPH-5 [analogue ()-] as a selective 5-HTR agonist with desirable drug-like properties.

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Article Synopsis
  • - The study aimed to analyze medication switching patterns among Colombian MS patients, focusing on why they change their disease-modifying therapies (DMT) and how often these switches occur.
  • - Out of 701 patients, 39.5% continued their initial DMT, while the rest experienced multiple changes, with a total of 720 modifications reflecting an incidence rate of 1.09 changes yearly per patient.
  • - The study found that the primary reasons for switching DMT included disease activity, with 56.7% of changes due to relapses and 18% relating to MRI evidence of activity.
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Creative or novel behaviors in bottlenose dolphins () can be indicators of flexible thinking and problem solving. Over 50 years ago, two rough-tooth dolphins demonstrated creative novel behaviors acquired through reinforcement training in human care. Since this novel training, a variety of species have been trained to respond to this conceptual cue.

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Coagulase-negative staphylococci (CoNS) and mammaliicocci are opportunistic human and animal pathogens, often resistant to multiple antimicrobials, including methicillin. Methicillin-resistant CoNS (MRCoNS) have traditionally been linked to hospitals and healthcare facilities, where they are significant contributors to nosocomial infections. However, screenings of non-hospital environments have linked MRCoNS and methicillin-resistant mammaliicocci (MRM) to other ecological niches.

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Initial Characterization of a Transgenic Mouse with Overexpression of the Human H-Histamine Receptor on the Heart.

J Pharmacol Exp Ther

April 2024

Institute for Pharmacology and Toxicology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany (L.M.R.A., H.J., S.S., J.N., U.G.); Institute of Pharmacy, University of Regensburg, Regensburg, Germany (M.K., L.S., S.Po., S.Pi.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic (J.K., K.H.); Institute for Hematopathology, Hamburg, Germany and Scientific and Educational Resource Center for Molecular Morphology, Peoples' FriendshipUniversity of Russia, Moscow, Russia (I.B.B.); Department of Anatomy, University of Helsinki, Helsinki, Finland (C.J., P.P.); Institute of Pharmacology and Toxicology, Westfälische Wilhelms-University of Münster, Münster, Germany (U.K.).

There is a debate on whether H-histamine receptors can alter contractility in the mammalian heart. We studied here a new transgenic mouse model where we increased genetically the cardiac level of the H-histamine receptor. We wanted to know if histamine could augment or decrease contractile parameters in mice with cardiac-specific overexpression of human H-histamine receptors (H-TG) and compared these findings with those in littermate wild-type mice (WT).

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Skeletal fragility and high fracture rates are common in CKD. A key component of bone loss in CKD with secondary hyperparathyroidism is high bone turnover and cortical bone deterioration through both cortical porosity and cortical thinning. We hypothesized that RANKL drives high bone resorption within cortical bone leading to the development of cortical porosity in CKD (study 1) and that systemic inhibition of RANKL would mitigate the skeletal phenotype of CKD (study 2).

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The telescope is vital for accurate gravitational wave detection in the TianQin project. It must meet criteria like a geometric tilt-to-length (TTL) coupling noise ≤0.02√2 /µ and wavefront ≤/30.

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Feeding Value of Lupins, Field Peas, Faba Beans and Chickpeas for Poultry: An Overview.

Animals (Basel)

February 2024

Monogastric Research Centre, School of Agriculture and Environment, Massey University, Palmerston North 4442, New Zealand.

Grain legumes are fair sources of protein, amino acids and energy, and can be used as a replacement for soybean meal in poultry feed formulations as the soybean meal becomes short in supply and costly. However, a concern associated with the use of grain legumes in poultry feeding is the presence of antinutritional factors. The effective processing and utilisation of these grain legumes in poultry feeding are well documented.

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Peripheral T cell lymphomas are typically aggressive with a poor prognosis. Unlike other hematologic malignancies, the lack of target antigens to discriminate healthy from malignant cells limits the efficacy of immunotherapeutic approaches. The T cell receptor expresses one of two highly homologous chains [T cell receptor β-chain constant (TRBC) domains 1 and 2] in a mutually exclusive manner, making it a promising target.

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A Gamma-adapted subunit vaccine induces broadly neutralizing antibodies against SARS-CoV-2 variants and protects mice from infection.

Nat Commun

February 2024

Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín (UNSAM) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Martín (1650), Buenos Aires, Argentina.

In the context of continuous emergence of SARS-CoV-2 variants of concern (VOCs), one strategy to prevent the severe outcomes of COVID-19 is developing safe and effective broad-spectrum vaccines. Here, we present preclinical studies of a RBD vaccine derived from the Gamma SARS-CoV-2 variant adjuvanted with Alum. The Gamma-adapted RBD vaccine is more immunogenic than the Ancestral RBD vaccine in terms of inducing broader neutralizing antibodies.

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Background: We aimed to evaluate the precision of Alzheimer's disease (AD) and neurodegeneration biomarker measurements from venous dried plasma spots (DPS ) for the diagnosis and monitoring of neurodegenerative diseases in remote settings.

Methods: In a discovery (n = 154) and a validation cohort (n = 115), glial fibrillary acidic protein (GFAP); neurofilament light (NfL); amyloid beta (Aβ) 40, Aβ42; and phosphorylated tau (p-tau181 and p-tau217) were measured in paired DPS and ethylenediaminetetraacetic acid plasma samples with single-molecule array. In the validation cohort, a subset of participants (n = 99) had cerebrospinal fluid (CSF) biomarkers.

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Genetic variants affecting NQO1 protein levels impact the efficacy of idebenone treatment in Leber hereditary optic neuropathy.

Cell Rep Med

February 2024

IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy; Departments of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy. Electronic address:

Idebenone, the only approved treatment for Leber hereditary optic neuropathy (LHON), promotes recovery of visual function in up to 50% of patients, but we can neither predict nor understand the non-responders. Idebenone is reduced by the cytosolic NAD(P)H oxidoreductase I (NQO1) and directly shuttles electrons to respiratory complex III, bypassing complex I affected in LHON. We show here that two polymorphic variants drastically reduce NQO1 protein levels when homozygous or compound heterozygous.

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Recombinant human erythropoietin (EPO) is a biopharmaceutical frequently used in the treatment of anemia. It is a heavily glycosylated protein with a diverse and complex glycome. EPO -glycosylation influences important pharmacological parameters, prominently serum half-life.

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There is an urgent clinical need for a treatment regimen that addresses the underlying pathophysiology of ventricular arrhythmias, the leading cause of sudden cardiac death. The current report describes the design of an injectable hydrogel electrode and successful deployment in a pig model with access far more refined than any current pacing modalities allow. In addition to successful cardiac capture and pacing, analysis of surface ECG tracings and three-dimensional electroanatomic mapping revealed a QRS morphology comparable to native sinus rhythm, strongly suggesting the hydrogel electrode captures the deep septal bundle branches and Purkinje fibers.

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Machine learning-driven identification of the gene-expression signature associated with a persistent multiple organ dysfunction trajectory in critical illness.

EBioMedicine

January 2024

Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, 30322, GA, United States; Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, 30322, GA, United States.

Background: Multiple organ dysfunction syndrome (MODS) disproportionately drives morbidity and mortality among critically ill patients. However, we lack a comprehensive understanding of its pathobiology. Identification of genes associated with a persistent MODS trajectory may shed light on underlying biology and allow for accurate prediction of those at-risk.

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Glycoconjugate vaccines play a major role in the prevention of infectious diseases worldwide, with significant impact on global health, enabling the polysaccharides to induce immunogenicity in infants and immunological memory. Tetanus toxoid (TT), a chemically detoxified bacterial toxin, is among the few carrier proteins used in licensed glycoconjugate vaccines. The recombinant full-length 8MTT was engineered in with eight individual amino acid mutations to inactivate three toxin functions.

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Healthcare disparities: patients' perspectives on barriers to joint replacement.

BMC Musculoskelet Disord

December 2023

Department of Medicine, Weill Cornell Medicine, New York, NY, 10021, USA.

Objective: Racial and ethnic disparities in arthroplasty utilization are evident, but the reasons are not known. We aimed to identify concerns that may contribute to barriers to arthroplasty from the patient's perspective.

Methods: We identified patients' concerns about arthroplasty by performing a mixed methods study.

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Background: Sepsis poses a grave threat, especially among children, but treatments are limited due to clinical and biological heterogeneity among patients. Thus, there is an urgent need for precise subclassification of patients to guide therapeutic interventions.

Methods: We used clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock cohort to derive phenotypes using latent profile analyses.

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Study Objectives: Automatic sleep staging based on cardiorespiratory signals from home sleep monitoring devices holds great clinical potential. Using state-of-the-art machine learning, promising performance has been reached in patients with sleep disorders. However, it is unknown whether performance would hold in individuals with potentially altered autonomic physiology, for example under the influence of medication.

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Selective and brain-penetrant HCN1 inhibitors reveal links between synaptic integration, cortical function, and working memory.

Cell Chem Biol

March 2024

Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Hyperpolarization-activated and cyclic-nucleotide-gated 1 (HCN1) ion channels are proposed to be critical for cognitive function through regulation of synaptic integration. However, resolving the precise role of HCN1 in neurophysiology and exploiting its therapeutic potential has been hampered by minimally selective antagonists with poor potency and limited in vivo efficiency. Using automated electrophysiology in a small-molecule library screen and chemical optimization, we identified a primary carboxamide series of potent and selective HCN1 inhibitors with a distinct mode of action.

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Evaluating the impact of alternative phenotype definitions on incidence rates across a global data network.

JAMIA Open

December 2023

OHDSI Collaborators, Observational Health Data Sciences and Informatics (OHDSI), New York, NY 10027, United States.

Article Synopsis
  • The study focuses on the importance of creating accurate phenotype definitions for reliable safety research, comparing different definitions to see how they affect background incidence rates of adverse events.
  • Using data from 16 sources, the researchers analyzed 13 adverse events and discovered significant variations in incidence rates based on how phenotypes were defined, particularly with different modifications like inpatient settings.
  • The results indicated that requiring an inpatient setting significantly increased the incidence rates, showing the need to carefully evaluate definitions before using them for background rate assessments in a global context.
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