118 results match your criteria: "Novartis Institutes for BioMedical Research (NIBR)[Affiliation]"

Macrophages regulate metabolic homeostasis in health and disease. Macrophage colony-stimulating factor (CSF1)-dependent macrophages contribute to homeostatic control of the size of the liver. This study aimed to determine the systemic metabolic consequences of elevating circulating CSF1.

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Variants of uncertain significance (VUS) in CTLA4 are frequently identified in patients with antibody deficiency or immune dysregulation syndromes including, but not limited to, patients with multi-organ autoimmunity and autoinflammation. However, to ascertain the diagnosis of CTLA4 insufficiency, the functional relevance of each variant needs to be determined. Currently, various assays have been proposed to assess the functionality of CTLA4 VUS, including the analysis of transendocytosis, the biological function of CTLA4 to capture CD80 molecules from antigen presenting cells.

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Article Synopsis
  • The study evaluated an algorithmic testing approach in hematopathology to enhance cost-effectiveness in test selection at Brigham and Women's Hospital and Dana-Farber Cancer Institute, especially for expensive molecular assays.
  • Researchers developed standard ordering protocols (SOPs) for 17 disease categories, comparing data from six months of beta testing to actual testing practices, along with two years of prospective data from a community site.
  • Results showed a massive improvement in test concordance after implementing SOPs, with a decrease in overordered tests and significant potential annual savings of over $1.3 million, indicating that algorithmic testing can streamline procedures without compromising vital information.
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Interactions between communities of the gut microbiome and with the host could affect the onset and progression of metabolic associated fatty liver disease (MAFLD), and can be useful as new diagnostic and prognostic biomarkers. In this study, we performed a multi-omics approach to unravel gut microbiome signatures from 32 biopsy-proven patients (10 simple steatosis -SS- and 22 steatohepatitis -SH-) and 19 healthy volunteers (HV). Human and microbial transcripts were differentially identified between groups (MAFLD vs.

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Mild cognitive impairment (MCI) is characterized by an abnormal decline in mental and cognitive function compared with normal cognitive aging. It is an underlying condition of Alzheimer's disease (AD), an irreversible neurodegenerative disease. In recent years, neuroinflammation has been investigated as a new leading target that contributes to MCI progression into AD.

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Alzheimer's disease (AD) and other neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD) are associated with progressive cognitive, motor, affective and consequently functional decline considerably affecting Activities of Daily Living (ADL) and quality of life. Standard assessments, such as questionnaires and interviews, cognitive testing, and mobility assessments, lack sensitivity, especially in early stages of neurodegenerative diseases and in the disease progression, and have therefore a limited utility as outcome measurements in clinical trials. Major advances in the last decade in digital technologies have opened a window of opportunity to introduce digital endpoints into clinical trials that can reform the assessment and tracking of neurodegenerative symptoms.

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Article Synopsis
  • * Research shows that neuroinflammatory lesions in mouse spinal cords lead to significant energy deficits in axons, impacting mitochondrial performance and enzyme levels in the tricarboxylic acid (TCA) cycle.
  • * Enhancing the expression of specific TCA cycle enzymes can help restore energy balance in affected neurons, indicating a potential therapeutic target for treating energy deficiencies in MS.
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Article Synopsis
  • The discussion on industrial Medicinal Chemistry highlighted the growth in the chemical modality space, shifting from small molecules to tackle more complex targets.
  • The importance of drug design now includes considerations for environmental sustainability alongside traditional optimization techniques.
  • Future Medicinal Chemists will need to excel in synthetic chemistry while also acquiring knowledge in data sciences and teamwork skills to navigate the evolving landscape influenced by biotech and digital companies.
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Lafora disease is a rare, fatal form of progressive myoclonus epilepsy characterized by continuous neurodegeneration with epileptic seizures, characterized by the intracellular accumulation of aberrant polyglucosan granules called Lafora bodies. Several works have provided numerous evidence of molecular and cellular alterations in neural tissue from experimental mouse models deficient in either laforin or malin, two proteins related to the disease. Oxidative stress, alterations in proteostasis, and deregulation of inflammatory signals are some of the molecular alterations underlying this condition in both KO animal models.

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Long-acting injectable (LAI) delivery technologies have enabled the development of several pharmaceutical products that improve patient health by delivering therapeutics from weeks to months. Over the last decade, due to its good biocompatibility, formulation tunability, wide range of degradation rates, and extensive clinical studies, polyester-based LAI technologies including poly(lactic-co-glycolic acid) (PLGA) have made substantial progress. Herein, we discuss PLGA properties with seminal approaches in the development of LAIs, the role of molecular dynamic simulations of polymer-drug interactions, and their effects on quality attributes.

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Intercellular communication is crucial for collective regulation of cellular behaviors. While clustering T cells have been shown to mutually control the production of key communication signals, it is unclear whether they also jointly regulate their availability and degradation. Here we use newly developed reporter systems, bioinformatic analyses, protein structure modeling and genetic perturbations to assess this.

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Expanding the use of methods that refine, reduce, and replace (3Rs) the use of animals in research is fundamental for both ethical and scientific reasons. The mission of the 3Rs Translational and Predictive Sciences Leadership Group (3Rs TPS LG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) is to promote sharing and integration of science and technology to advance the 3Rs in the discovery and development of new medicines, vaccines, medical devices, and health care products for humans and animals. The 3Rs TPS LG is dedicated to identifying opportunities for member companies to share practices, enhance learning, promote discussions, and advance the 3Rs across the industry.

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Identification of bacterial pathogens in formalin fixed, paraffin embedded (FFPE) tissue samples is limited to targeted and resource-intensive methods such as sequential PCR analyses. To enable unbiased screening for pathogens in FFPE tissue samples, we established a whole genome sequencing (WGS) method that combines shotgun sequencing and metagenomics for taxonomic identification of bacterial pathogens after subtraction of human genomic reads. To validate the assay, we analyzed more than 100 samples of known composition as well as FFPE lung autopsy tissues with and without histological signs of infections.

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Background: Coessentiality networks derived from CRISPR screens in cell lines provide a powerful framework for identifying functional modules in the cell and for inferring the roles of uncharacterized genes. However, these networks integrate signal across all underlying data and can mask strong interactions that occur in only a subset of the cell lines analyzed.

Results: Here, we decipher dynamic functional interactions by identifying significant cellular contexts, primarily by oncogenic mutation, lineage, and tumor type, and discovering coessentiality relationships that depend on these contexts.

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Ultra-high-diversity factorizable libraries for efficient therapeutic discovery.

Genome Res

September 2022

Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

The successful discovery of novel biological therapeutics by selection requires highly diverse libraries of candidate sequences that contain a high proportion of desirable candidates. Here we propose the use of computationally designed factorizable libraries made of concatenated segment libraries as a method of creating large libraries that meet an objective function at low cost. We show that factorizable libraries can be designed efficiently by representing objective functions that describe sequence optimality as an inner product of feature vectors, which we use to design an optimization method we call stochastically annealed product spaces (SAPS).

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Bioorthogonal chemistry can facilitate the development of fluorescent probes that can be used to sensitively and specifically detect the presence of biological targets. In this study, such an assay was developed to evaluate the uptake and delivery of antimicrobials into , building on and extending previous work which utilised more resource intensive LCMS detection. The bacteria were genetically engineered to express streptavidin in the periplasmic or cytoplasmic compartments, which was used to localise a bioorthogonal probe (BCN-biotin).

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Tears in the rotator cuff are challenging to repair because of the complex, hypocellular, hypovascular, and movement-active nature of the tendon and its enthesis. Insulin-like Growth Factor-1 (IGF-1) is a promising therapeutic for this repair. However, its unstable nature, short half-life, and ability to disrupt homeostasis has limited its clinical translation.

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Therapeutic potential of macrophage colony-stimulating factor in chronic liver disease.

Dis Model Mech

April 2022

Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland 4102, Australia.

Resident and recruited macrophages control the development and proliferation of the liver. We have previously shown in multiple species that treatment with a macrophage colony stimulating factor (CSF1)-Fc fusion protein initiated hepatocyte proliferation and promoted repair in models of acute hepatic injury in mice. Here, we investigated the impact of CSF1-Fc on resolution of advanced fibrosis and liver regeneration, using a non-resolving toxin-induced model of chronic liver injury and fibrosis in C57BL/6J mice.

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Krabbe Disease (KD) is an autosomal metabolic disorder that affects both the central and peripheral nervous systems. It is caused by a functional deficiency of the lysosomal enzyme, galactocerebrosidase (GALC), resulting in an accumulation of the toxic metabolite, psychosine. Psychosine accumulation affects many different cellular pathways, leading to severe demyelination.

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Towards the sustainable discovery and development of new antibiotics.

Nat Rev Chem

October 2021

Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), and Department of Pharmacy, Saarland University Campus E8.1, Saarbrücken, Germany.

An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics.

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Purpose: This first-in-human study (NCT02947152) evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of HKT288, a first-in-class CDH6-targeting antibody-drug conjugate (ADC).

Experimental Design: HKT288 was administered intravenously (IV) every 3 weeks until patients experienced unacceptable toxicity or progressive disease (PD). The starting dose of 0.

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Towards the sustainable discovery and development of new antibiotics.

Nat Rev Chem

August 2021

Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), and Department of Pharmacy, Saarland University Campus E8.1, Saarbrücken, Germany.

An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics.

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Regulated control of gene therapies by drug-induced splicing.

Nature

August 2021

Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

So far, gene therapies have relied on complex constructs that cannot be finely controlled. Here we report a universal switch element that enables precise control of gene replacement or gene editing after exposure to a small molecule. The small-molecule inducers are currently in human use, are orally bioavailable when given to animals or humans and can reach both peripheral tissues and the brain.

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