Biology subjects

Weinberg, A.

Publications and source records attributed to Weinberg, A..

4 recordsLinked to original sources

bioRxiv2022

Comparative immune responses to Mycobacterium tuberculosis in people with latent infection or sterilizing protection

Tuberculosis (TB) affects 2 billion people worldwide and causes 1.5 million deaths every year. There is great need for new TB vaccines that are more efficacious than the currently licensed BCG vaccine, which provides only limited protection. Our goal was to identify potential targets for new TB vaccines by characterizing the immune responses that distinguish individuals with sterilizing protection against TB (TB-resisters), defined by presence of TB-specific immune responses and absence of latent infection, from individuals with latent TB infection (LTBI-participants). Cryopreserved peripheral blood mononuclear cells (PBMC) from 13 TB-resisters and 10 LTBI-participants were analyzed by high dimensional spectral flow cytometry after overnight M. tuberculosis (Mtb) antigenic stimulation or unstimulated control. Activation of conventional and nonconventional T cells, NK cells, and antigen presenting cells (APC) was compared between the two groups. Compared with LTBI-participants, TB-resisters had significantly higher proportions of conventional and nonconventional T cells expressing granzyme B (GranzB) and PD-1, and of polyfunctional cells in unstimulated and Mtb-stimulated conditions. Conversely LTBI-participants had higher expression of CD25, CD69, CD107a, IL10 and IFN{gamma}. An unbiased cluster analysis revealed higher frequency of recently described CD8+GMM+GranzB+ T cells in unstimulated PBMC from TB-resisters than LTBI-participants. APC activation revealed very few differences between TB-resisters and LTBI-participants. An exploratory analysis of responses in 14 BCG-recipients with minimal exposure to TB showed multiple differences with TB-resisters and LTBI-participants in PBMC activation; lower polyfunctionality of T cells and APC in Mtb-stimulated PBMC; and absence of CD8+GMM+GranzB+ T cells. We conclude that combined increased T cell expression of GranzB and checkpoint inhibitors may contribute to immune protection against TB and may be targeted by new vaccines.

immunology↗

bioRxiv2021

Molecular dynamics simulations and functional studies reveal that hBD-2 binds SARS-CoV-2 spike RBD and blocks viral entry into ACE2 expressing cells

New approaches to complement vaccination are needed to combat the spread of SARS-CoV-2 and stop COVID-19 related deaths and long-term medical complications. Human beta defensin 2 (hBD-2) is a naturally occurring epithelial cell derived host defense peptide that has antiviral properties. Our comprehensive in-silico studies demonstrate that hBD-2 binds the site on the CoV-2-RBD that docks with the ACE2 receptor. Biophysical and biochemical assays confirm that hBD-2 indeed binds to the CoV-2-receptor binding domain (RBD) (KD [~] 300 nM), preventing it from binding to ACE2 expressing cells. Importantly, hBD-2 shows specificity by blocking CoV-2/spike pseudoviral infection, but not VSV-G mediated infection, of ACE2 expressing human cells with an IC50 of 2.4{+/-} 0.1 M. These promising findings offer opportunities to develop hBD-2 and/or its derivatives and mimetics to safely and effectively use as novel agents to prevent SARS-CoV-2 infection.

biochemistry↗

bioRxiv2020

3D nanoscale analysis of bone healing around degrading Mg implants studied by X-ray scattering tensor tomography

The nanostructural adaptation of bone is crucial for its compatibility with orthopedic implants. The bones nanostructure determines its mechanical properties, however little is known about its temporal and spatial adaptation in degrading implants. This study presents insights into this adaptation by applying electron microscopy, elemental analysis, and small-angle X-ray scattering tensor-tomography (SASTT). We extend the SASTT reconstruction to multiple radii of the reciprocal space vector q, providing a 3D reciprocal-space map per voxel. Each scattering curve is spatially linked to one voxel in the volume, and properties such as the thickness of the mineral particles are quantified. This reconstruction provides information on nanostructural adaptation during healing around a degrading ZX10 magnesium implant over the course of 18 months, using a sham as control. The nanostructural adaptation process is observed to start with an initially fast interfacial organization towards the implant direction, followed by a substantial reorganization of the volume around the implant, and an adaptation in the later degradation stages. The study sheds light on the complex bone-implant interaction in 3D, allowing a more guided approach towards the design of future implant materials, which are expected to be of great interest for further clinical studies on the bone-implant interaction. TOC text and figureDegrading Magnesium implants are mechanically and chemically well adapted orthopedic implant materials and ensure a gradual load transfer during bone healing due to their degradation. The impact of the implant degradation on the bone nanostructure is however not fully understood. This study unveils the processes 3D and shows different stages of bone healing. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/375253v1_ufig1.gif" ALT="Figure 1"> View larger version (83K): org.highwire.dtl.DTLVardef@1a0ab0borg.highwire.dtl.DTLVardef@13d7486org.highwire.dtl.DTLVardef@1ad4485org.highwire.dtl.DTLVardef@6d9c86_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2018

A Cyclin A - Myb-MuvB - Aurora B network regulates the choice between mitotic cycles and polyploid endoreplication cycles.

Cells switch to polyploid endoreplication cycles during development, wound healing, and cancer. We used integrated approaches in Drosophila to determine how mitotic cycles are remodeled into endoreplication cycles, and how similar this remodeling is between developmental and induced endoreplicating cells (devECs and iECs). We found that while only devECs had a dampened E2F1 transcriptome, repression of a Cyclin A - Myb-MuvB - Aurora B mitotic network promoted endoreplication in both devECs and iECs. Cyclin A associated with and activated Myb-MuvB to induce transcription of mitotic genes, with expression of one, Aurora B, being key for mitotic commitment. Knockdown of Cyclin A, Myb, Aurora B, or downstream cytokinetic proteins induced distinct types of endoreplication, suggesting that repression of different mitotic network steps may explain the known diversity of polyploid cycles. These findings reveal how remodeling of a mitotic network promotes polyploid cycles that contribute to development, wound healing, and cancer.

developmental biology↗