Publications by authors named "Amir Zilberstein"
Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cell types and their heterogeneity within the human liver, but the spatial organization at single-cell resolution has not yet been described. Here we apply multiplexed error robust fluorescent in situ hybridization (MERFISH) to map the zonal distribution of hepatocytes, spatially resolve subsets of macrophage and mesenchymal populations, and investigate the relationship between hepatocyte ploidy and gene expression within the healthy human liver. Integrating spatial information from MERFISH with the more complete transcriptome produced by single-nucleus RNA sequencing (snRNA-seq), also reveals zonally enriched receptor-ligand interactions.
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- The study investigates how genetic variation impacts gene expression in various brain cell types and subtypes using single-nucleus RNA sequencing from 424 older individuals.
- Researchers identified thousands of eGenes (genes with expression influenced by genetic variants) in different cell types and subtypes, revealing that some eGenes are unique to specific subtypes.
- Notably, a variant affecting APOE expression in microglia is linked to cerebral amyloid angiopathy, and findings were connected to diseases like Alzheimer's, schizophrenia, and Parkinson's through genome-wide association studies.
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- - We studied 1,130 E3 ligases and their roles in the inflammatory response of primary dendritic cells using Perturb-seq, revealing their significant impact on different types of dendritic cells and macrophages.
- - E3 ligases and their adaptors work together but interact with different substrate recognition adaptors, influencing various processes in dendritic cell development and function.
- - A deep learning model named comβVAE was developed to predict outcomes of new E3 ligase combinations, showing that the E3 regulatory network is linked to genetic variations and abnormal gene expression in immune-related human diseases.
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- SARS-CoV-2 infection results in varying immune responses, with neutralizing antibodies generally protecting against reinfection.
- The study investigated mild cases linked to a single event, revealing sex-specific differences in T cell responses and their correlation with antibody levels, particularly in males.
- Additionally, single-cell immunoprofiling indicated variations in type I IFN signaling that may influence antibody production, emphasizing the importance of sex-based factors in immune responses to SARS-CoV-2.
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- Non-genetic factors play a crucial role in why some cancer therapies fail, allowing a subset of cancer cells to enter a reversible drug-tolerant state.
- Researchers developed a tool called Watermelon to trace the origins and behaviors of these resistant cancer cell populations, revealing that cycling and non-cycling persisters come from different lineages with unique metabolic and transcriptional activities.
- The study found that certain gene programs related to antioxidants and fatty acid metabolism support the ability of these persisters to proliferate, highlighting potential new targets for therapies to improve treatment outcomes and reduce cancer recurrence.
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- This study examines the pathophysiology of COVID-19 by analyzing single-cell and spatial atlases from various organ autopsy samples of individuals who died from the virus.
- Findings revealed significant changes in lung tissue, including impaired tissue regeneration and inflammation, indicating how SARS-CoV-2 affects different cell types.
- The research provides crucial insights into the biological impact of severe COVID-19, aiding in the development of potential new treatments.
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- The SARS-CoV-2 pandemic has led to over 1 million deaths worldwide, primarily due to severe lung injuries and multiple organ failures, but there is limited understanding of the immune responses involved in COVID-19.
- Researchers collected and analyzed over 420 tissue samples from various organs of 17 COVID-19 victims, utilizing advanced techniques like RNA sequencing to map out cellular changes related to their illness.
- Significant findings include alterations in lung tissue cell types, such as the increase of specific progenitor cells and myofibroblasts, indicating impaired tissue repair and failed regenerative processes in severely damaged lungs.
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- - The organization of cells into periodic patterns is essential for the proper function of various organs, and this process is typically facilitated by intercellular signaling.
- - This study examines how the arrangement of hair cells and supporting cells in the organ of Corti (part of the mammalian ear) shifts from a disordered state to an ordered checkerboard pattern, attributing this change to mechanical forces rather than signaling mechanisms.
- - Through time-lapse imaging of mouse cochlear tissue and mechanical modeling, the research shows that the transition to an ordered pattern is driven by global shear forces and local repulsion among hair cells, likening this process to phenomena observed in materials like polymers and granular substances.
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- Atypical cadherins Fat and Dachsous (Ds) are key players in establishing planar cell polarity (PCP) in various tissues, but their feedback mechanisms were not well understood.
- Researchers created a synthetic biology platform using mammalian cells with human Fat4 and Ds1 to investigate these feedbacks.
- Findings show that Fat4-Ds1 complexes form at cell boundaries and are more stable, highlighting that these localized feedback mechanisms contribute to the polarization necessary for PCP.
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- Cells change shape during development, which can affect how they communicate with each other, especially in Notch signaling that guides neighboring cells' fates.
- Researchers used micropatterning and a specialized assay to discover that the area of contact between two cells directly influences their signaling, with larger contact areas promoting stronger signals.
- Mathematical models suggest that this signaling relationship can lead to smaller cells being more likely to become signal-producing cells, as observed in the developing chick inner ear, where smaller precursor cells for hair cells had different characteristics compared to non-hair cells.
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- Notch signaling is crucial for coordinating cell differentiation across various organisms, but the impact of receptor and ligand distribution on signaling is not well understood.
- By using live-cell imaging and mathematical modeling, researchers studied the behavior of the Notch ligand Delta-like 1 (Dll1) in mammalian cells, revealing significant variability in its diffusion rates among different cells.
- The findings indicate that the dynamics of membrane distribution and cell shape can significantly influence cell-to-cell signaling, highlighting the importance of these factors in biological processes.
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- The PCP pathway is crucial for the proper development and orientation of cochlear hair cells, which are essential for hearing, and involves the movement of a primary cilium called kinocilium.
- Mutations in the GPSM2/LGN gene, linked to hearing loss in both humans and mice, disrupt kinocilium migration and lead to severe malformations in hair cells.
- Despite the presence of truncated GPSM2/LGN proteins in mutant mice, which show misorientation and structural issues, the core PCP proteins remain polarized, indicating a specific role for GPSM2/LGN in localizing key signaling molecules involved in cell polarity and function.
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- NF-κB plays a crucial role in immune response and cell survival, and its deregulation is linked to chronic inflammation and cancer, impacting genes like IκBα and A20 that help regulate it.
- DSIF, when functional, helps process mRNA for these genes, but its knockdown leads to reduced protein levels of IκBα and A20 while extending NF-κB activation.
- The study finds that a significant portion of IκBα and A20 mRNA is improperly processed and retained in the nucleus, highlighting the importance of DSIF in mRNA processing during hypophosphorylated elongation.
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- The regulation of corticotropin-releasing hormone (CRH) is essential for an animal's response to stress, with its dysregulation linked to psychiatric disorders in humans.
- Researchers found that the hypothalamic transcription factor Orthopedia affects CRH expression and the splicing factor Ataxin 2-Binding Protein-1 (A2BP1/Rbfox-1) during stress in mice and zebrafish.
- The study highlighted that alternative splicing of the PAC1 receptor, influenced by stress, is necessary for proper CRH regulation and adaptive stress responses, identifying a key biochemical pathway involved in this process.
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- PGC-1α is a coactivator that plays a crucial role in regulating energy expenditure, and its absence in mice leads to obesity and increased food intake.
- Research indicates that PGC-1α directly influences the expression of the neuropeptide oxytocin in the hypothalamus, which is involved in appetite control.
- In zebrafish models, knocking down PGC-1α reduces oxytocin levels but can be restored by reintroducing PGC-1α or oxytocin, highlighting PGC-1α's essential role in stimulating oxytocin production related to energy intake.
Localizing the source of an epileptic seizure using noninvasive EEG suffers from inaccuracies produced by other generators not related to the epileptic source. The authors isolated the ictal epileptic activity, and applied a source localization algorithm to identify its estimated location. Ten ictal EEG scalp recordings from five different patients were analyzed.
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- - The A20 gene, a target of NF-kappaB, is controlled by the elongation factor DSIF through two different mechanisms before and after NF-kappaB activation.
- - Before activation, DSIF inhibits A20's transcription elongation via an element called ELIE, while after NF-kappaB activation, the regulation shifts from ELIE to NF-kappaB controlling DSIF.
- - Experiments showed that the E-box protein USF1 binds to ELIE and is displaced during NF-kappaB induction, emphasizing its role in regulating transcription under different conditions.
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- - NF-kappaB transcription factors play a crucial role in activating genes that are essential for the immune response, inflammation, and cell survival, interacting with transcription elongation factors P-TEFb and DSIF.
- - The study reveals that NF-kappaB regulates different target genes through either P-TEFb or DSIF depending on the type of core promoter (TATA or TATA-less) and enhancer present in the gene.
- - The conversion of a TATA-less promoter to a TATA promoter shifts regulatory control from DSIF to P-TEFb, with RNA polymerase II phosphorylation by P-TEFb facilitating this change, thereby linking transcription initiation and elongation processes.
Article Synopsis
- A20 is a gene targeted by NF-kappaB that has a unique regulation process, showing repression at the elongation stage of transcription before being stimulated.
- The study identifies that the DRB sensitivity-inducing factor (DSIF) is responsible for this elongation repression, which is influenced by a negative promoter element called ELIE.
- After NF-kappaB stimulation, the regulation of DSIF changes, revealing a complex interaction between transcription factors and the elongation process for A20 and another related gene, IkappaBalpha.