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Functional differences between rodent and human PD-1 linked to evolutionary divergence.

Sci Immunol

January 2025

Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.

Mechanistic understanding of the inhibitory immunoreceptor PD-1 is largely based on mouse models, but human and mouse PD-1 share only 59.6% amino acid identity. Here, we found that human PD-1 is more inhibitory than mouse PD-1, owing to stronger interactions with the ligands PD-L1 and PD-L2 and more efficient recruitment of the effector phosphatase Shp2.

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Homozygous Familial Hypercholesterolemia Treatment: New Developments.

Curr Atheroscler Rep

January 2025

Carbohydrate and Lipid Metabolism Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa.

Purpose Of Review: Homozygous familial hypercholesterolaemia (HoFH) is characterized by marked elevation of low-density lipoprotein cholesterol (LDLC) and premature atherosclerotic cardiovascular disease. This is a review of novel pharmacological therapies to lower LDLC in patients with HoFH.

Recent Findings: Novel therapies can be broadly divided by whether their efficacy is dependent or independent of residual low-density lipoprotein receptor (LDLR) function.

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Diversity in Notch ligand-receptor signaling interactions.

Elife

January 2025

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.

The Notch signaling pathway uses families of ligands and receptors to transmit signals to nearby cells. These components are expressed in diverse combinations in different cell types, interact in a many-to-many fashion, both within the same cell (in cis) and between cells (in trans), and their interactions are modulated by Fringe glycosyltransferases. A fundamental question is how the strength of Notch signaling depends on which pathway components are expressed, at what levels, and in which cells.

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Basic Science and Pathogenesis.

Alzheimers Dement

December 2024

San Francisco VA Medical Center, University of California San Francisco, San Francisco, CA, USA.

Background: Effective disease-modifying regimens for Alzheimer's Disease (AD) remain lacking due to insufficient understanding of its pathogenic drivers. It was shown previously that upregulation of the calcium-sensing receptor (CaSR), an excitatory family C GPCR, induces neurodegeneration by interfering with the inhibitory γ-aminobutyric acid (GABA) signaling following acute brain injuries (Ann_Clin_Transl_Neurol, 1:851-66). Herein, we determined whether CaSR overexpression is causally associated with the AD.

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Background: The lateral entorhinal cortex (LEC), followed by area CA1 of hippocampus, are interconnected brain areas implicated early in Alzheimer's disease (AD). Processing of LEC input by CA1 pyramidal neurons (PNs) is critical for non-spatial memory, in which deficits are seen in early AD. How this process is affected by tauopathy is unclear.

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