17,837 results match your criteria: "The Scripps Research Institute.[Affiliation]"

Rab11 family interacting protein 4 (Rab11-FIP4) regulates endocytic trafficking. A possible role for Rab11-FIP4 in the regulation of lysosomal function has been proposed, but its precise function in the regulation of cellular homeostasis is unknown. By mRNA array and protein analysis, we found that Rab11-FIP4 is downregulated in the lysosomal storage disease cystinosis, which is caused by genetic defects in the lysosomal cystine transporter, cystinosin.

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  • The study focuses on humanizing camelid-derived variable domain heavy chain antibodies (VHHs), addressing challenges like immunogenicity, stability, and affinity reduction, especially through changes in crucial structural regions.
  • Researchers systematically exchanged key residues in VHHs targeting NKp30 with human equivalents, then characterized the variants for binding affinity, yield, and purity using methods such as crystal structure determination and AlphaFold2 predictions.
  • The study emphasizes the importance of specific sequence motifs and non-canonical disulfide bonds in VHHs, contributing to better understanding their structural determinants to aid in their design and optimization for therapeutic use.
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Widely distributed in nature, sulfated glycan epitopes play important roles in diverse pathophysiological processes. However, due to their structural complexity, the preparation of glycan epitopes with structurally defined sulfation patterns is challenging, which significantly hampers the detailed elucidation of their biological functions at the molecular level. Here, we introduce a strategy for site-specific chemical sulfation of glycan epitopes, leveraging enzymatic sialylation and desialylation processes to precisely control the regio-specificity of sulfation of disaccharide or trisaccharide glycan backbones.

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Cancer treatment has been rapidly transformed by the development of immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1. However, many patients fail to respond, especially those with an immunosuppressive tumor microenvironment (TME), suggesting the existence of additional immune checkpoints that act through orthogonal mechanisms. Sialic acid-binding immunoglobulin-like lectin (Siglec)-7 and -9 are newly designated glycoimmune checkpoints that are abundantly expressed by tumor-infiltrating myeloid cells.

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Pioneer transcription factors (TFs) bind to and open closed chromatin, facilitating engagement by other regulatory factors involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation in cells. Here, we report the chemical proteomic discovery of electrophilic compounds that stereoselectively and site-specifically bind the pioneer TF forkhead box protein A1 (FOXA1) at a cysteine (C258) within the forkhead DNA-binding domain.

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The kidneys act as finely tuned sensors to maintain physiological homeostasis. Both sympathetic and sensory nerves modulate kidney function through precise neural control. However, how the kidneys are innervated during development to support function remains elusive.

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Catalyst-Controlled Chemoselective γ-C(sp)-H Lactonization of Carboxylic Acid: Methyl versus Methylene.

J Am Chem Soc

October 2024

Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.

Despite recent advances in ligand-enabled C(sp)-H functionalization of native substrates, controlling chemoselectivity in the presence of methyl and methylene C(sp)-H bonds remains a significant challenge. Herein, we report the first example of the Pd(II)-catalyzed chemoselective lactonization of γ-methyl and methylene C(sp)-H bonds of carboxylic acids. Exclusive chemoselectivity of methyl or methylene γ-lactonization was achieved by using two different classes of Quinoline-Pyridone ligands.

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The impact of small molecules in human biology are manifold; not only are they critical regulators of physiological processes, but they also serve as probes to investigate biological pathways and leads for therapeutic development. Identifying the protein targets of small molecules, and where they bind, is critical to understanding their functional consequences and potential for pharmacological use. Over the past two decades, chemical proteomics has emerged as a go-to strategy for the comprehensive mapping of small molecule-protein interactions.

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Perineuronal nets (PNNs), a specialized form of extra cellular matrix (ECM), surround numerous neurons in the CNS and allow synaptic connectivity through holes in its structure. We hypothesize that PNNs serve as gatekeepers that guard and protect synaptic territory and thus may stabilize an engram circuit. We present high-resolution and 3D EM images of PNN-engulfed neurons in mice brains, showing that synapses occupy the PNN holes and that invasion of other cellular components is rare.

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Article Synopsis
  • Fibrosis, especially idiopathic pulmonary fibrosis (IPF), is linked to abnormal healing processes in the lungs that can lead to organ failure, with no current cure.
  • The study investigates activated myofibroblasts (aMYFs), their different subtypes, and their roles in lung repair and damage using genetic and transcriptomic analysis in mice, as well as human data.
  • Findings reveal that aMYFs can be categorized into four distinct groups, with a specific subset linked to both the progression and resolution of fibrosis, suggesting new potential treatment targets for managing IPF.
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RNA ensembles from in vitro to in vivo: Toward predictive models of RNA cellular function.

Curr Opin Struct Biol

December 2024

The Scripps Research Institute, Department of Integrative Structural and Computational Biology, La Jolla, CA, USA. Electronic address:

Article Synopsis
  • * Understanding RNA ensembles involves analyzing free energy landscapes, which show the relative stability of different conformations and the barriers between them.
  • * Recent research indicates that while RNA behavior varies in cellular contexts compared to in vitro, integrating quantitative measurements with computational methods can enhance predictions of RNA function and lead to new biological insights.
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Epidemiological data indicate a strong association between alcohol use disorder (AUD) and neuropathic pain. Genetically-selected Marchigian Sardinian alcohol-preferring (msP) rats exhibit a high preference for alcohol compared with their background strain (Wistar rats), but their sensitivity to mechanical allodynia after chronic alcohol exposure is unknown. The present study compared the development of mechanical allodynia between "low, non-pathological drinker" Wistar rats and "high drinker" msP rats using the two-bottle choice (2BC) free-access procedure.

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Power and sample size calculations for testing the ratio of reproductive values in phylogenetic samples.

Am J Epidemiol

October 2024

Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Carolina Population Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Article Synopsis
  • The accuracy of pathogen sequence data analysis relies heavily on the number and type of sequences included in the sample, impacting the conclusions drawn from phylogenetic studies.
  • There is a lack of clear guidance on designing effective studies for phylogenetic inference, specifically regarding how to determine which individuals are more likely to spread pathogens.
  • The study introduces a new estimator for measuring differential pathogen transmission among individuals, provides sample size calculations, and offers an R package called phylosamp for practical implementation and validation of the method.
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Advancing stem cell technologies for conservation of wildlife biodiversity.

Development

October 2024

Department of Biochemistry, University of Cambridge, Hopkins Building, Downing Site, Tennis Court Road, Cambridge CB2 1QW, UK.

Article Synopsis
  • Wildlife biodiversity helps keep ecosystems healthy and strong.
  • Scientists study this diversity to learn more about life and how it started.
  • Due to the rapid loss of various species, immediate action is needed from conservationists, and new techniques like stem cell technologies could help protect animal diversity.
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  • DiDBiT is a new proteomic technique that enhances the detection of newly synthesized proteins by 20 times compared to traditional methods.
  • The new method, DiDBiT-TMT, allows for the quantification of these proteins across multiple conditions and replicates in a single experiment.
  • Using DiDBiT-TMT on brain slices, researchers found distinct differences in newly synthesized proteins following different treatments, suggesting unique molecular processes at play in response to chemical long-term potentiation and norepinephrine.
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  • HIV-1 envelope glycoprotein (Env) structure affects the immune response, with "closed" forms evading certain antibodies while "open" forms are vulnerable to others.
  • Infected CD4+ T cells show that downmodulation of CD4 occurs before HIV-1 mRNA expression, and these cells mainly express "closed" Envs, resistant to non-neutralizing antibodies (nnAbs).
  • The study challenges the effectiveness of nnAbs in targeting productively infected cells for HIV-1 treatment, as attempts with nnAbs did not reduce viral replication in humanized mouse models.
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Electrophysical cardiac remodeling at the molecular level: Insights into ryanodine receptor activation and calcium-induced calcium release from a stochastic explicit-particle model.

Biophys J

November 2024

Computational Neurobiology Lab, The Salk Institute of Biological Studies, La Jolla, California; Department of Chemistry and Biochemistry, The University of California San Diego, La Jolla, California. Electronic address:

We present the first-ever, fully discrete, stochastic model of triggered cardiac Ca dynamics. Using anatomically accurate subcellular cardiac myocyte geometries, we simulate the molecular players involved in Ca handling using high-resolution stochastic and explicit-particle methods at the level of an individual cardiac dyadic junction. Integrating data from multiple experimental sources, the model not only replicates the findings of traditional in silico studies and complements in vitro experimental data but also reveals new insights into the molecular mechanisms driving cardiac dysfunction under stress and disease conditions.

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  • Break-induced replication (BIR) is a highly mutagenic process that needs tight regulation, and this study reveals the critical role of the protein 53BP1 in controlling BIR after double strand breaks (DSBs).
  • Loss of 53BP1 leads to increased hyperrecombination that activates BIR, which is connected to specific DNA synthesis processes on single-stranded DNA (ssDNA) overhangs, resulting in larger genome deletions and instability.
  • The findings suggest that targeting the interaction between 53BP1 and BIR could open up new avenues for cancer treatment.
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The histone methyltransferase enhancer of zeste homolog 2 (EZH2) plays important roles in T-cell differentiation, proliferation, and function. Previous studies have demonstrated that genetic deletion of EZH2 in CD8+ or total T cells impairs their antiviral and antitumor activities, cytokine production, and ability to expand upon rechallenge. Contrary to the detrimental role of deleting T cell-intrinsic EZH2, in this study, we demonstrated that transient inhibition of EZH2 in T cells prior to the phenotypic onset of exhaustion with a clinically approved inhibitor, tazemetostat (Taz), delayed their dysfunctional progression and preserved T-cell stemness and polyfunctionality but had no negative impact on cell proliferation.

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An effective human immunodeficiency virus 1 (HIV-1) vaccine will most likely have to elicit broadly neutralizing antibodies (bNAbs) to overcome the sequence diversity of the envelope glycoprotein (Env). So far, stabilized versions of Env, such as SOSIP trimers, have been able to induce neutralizing antibody (NAb) responses, but those responses are mainly strain-specific. Here we attempted to broaden NAb responses by using a multivalent vaccine and applying a number of design improvements.

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Broadly potent spike-specific human monoclonal antibodies inhibit SARS-CoV-2 Omicron sub-lineages.

Commun Biol

October 2024

Centre for Translational Medicine and Parasitology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The continuous emergence of SARS-CoV-2 variants of concern has rendered many therapeutic monoclonal antibodies (mAbs) ineffective. To date, there are no clinically authorized therapeutic antibodies effective against the recently circulating Omicron sub-lineages BA.2.

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The ISA Nomenclature Committee met at the XIX International Symposium of Amyloidosis in Rochester, MN, 27 May 2024. The in-person event was followed by many electronic discussions, resulting in the current updated recommendations. The general nomenclature principles are unchanged.

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MEF2C is a critical transcription factor in neurodevelopment, whose loss-of-function mutation in humans results in MEF2C haploinsufficiency syndrome (MHS), a severe form of autism spectrum disorder (ASD)/intellectual disability (ID). Despite prior animal studies of MEF2C heterozygosity to mimic MHS, MHS-specific mutations have not been investigated previously, particularly in a human context as hiPSCs afford. Here, for the first time, we use patient hiPSC-derived cerebrocortical neurons and cerebral organoids to characterize MHS deficits.

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