Biology subjects

Abbasi, S.

Publications and source records attributed to Abbasi, S..

5 recordsLinked to original sources

bioRxiv2023

Intrinsic neural timescales attenuate information transfer along the uni-transmodal hierarchy

The brains intrinsic timescales are organized in a hierarchy with shorter timescales in sensory regions and longer ones in associative regions. This timescale hierarchy overlaps with the timing demands of sensory information. Our question was how does this timescale hierarchy affect information transfer. We used a model of the timescale hierarchy based on connected excitatory and inhibitory populations across the cortex. We found that a hierarchy of information transfer follows the hierarchy of timescales with higher information transfer in sensory areas while it is lower in associative regions. Probing the effect of changes in timescale hierarchy on information transfer, we changed various model parameters which all, through, the loss of hierarchy, induced increased information transfer. Finally, the steepness of the timescale hierarchy relates negatively to total information transfer. Human MEG data confirmed our results. In sum, we demonstrate a key role of the brains timescale hierarchy in mediating information transfer.

neuroscience↗

bioRxiv2023

Cutaneous jet-injection of naked mRNA vaccine induces robust immune responses without systemic vaccine spillage

Naked mRNA-based vaccines may reduce the reactogenicity associated with delivery carriers, but their effectiveness has been suboptimal against infectious diseases. Herein, we aimed to enhance their efficacy by using a pyro-drive liquid jet injector that precisely controls pressure to widely disperse mRNA solution in the skin. The jet injection boosted naked mRNA delivery efficiency in the mouse skin. Mechanistic analyses indicate that dendritic cells, upon uptake of antigen mRNA in the skin, migrate to the draining lymph nodes for antigen presentation. Additionally, the jet injector activated innate immune responses in the skin, presumably by inducing physical stress, thus serving as a physical adjuvant. From a safety perspective, our approach, utilizing naked mRNA, restricted mRNA distribution solely to the injection site, preventing systemic pro-inflammatory reactions following vaccination. Ultimately, the jet injection of naked mRNA encoding SARS-CoV-2 spike protein elicited robust humoral and cellular immunity, providing protection against SARS-CoV-2 infection in mice. Furthermore, our approach induced plasma activity of neutralizing SARS-CoV-2 in non-human primates, comparable to that observed in mice, with no detectable systemic reactogenicity.

bioengineering↗

bioRxiv2022

Cell-specific occupancy dynamics between the pioneer-like factor Opa/ZIC and Ocelliles/OTX regulate early head development in embryos

During development, embryonic patterning systems direct a set of initially uncommitted pluripotent cells to differentiate into a variety of cell types and tissues. A core network of transcription factors, such as Zelda/POU5F1, Odd-paired (Opa)/ZIC and Ocelliless (Oc)/OTX, are conserved across animals. While Opa is essential for a second wave of zygotic activation after Zelda, it is unclear whether Opa drives head cell specification past gastrulation onset, in the Drosophila embryo. Our hypothesis is that Opa and Oc are interacting with distinct cis-regulatory regions for shaping cell fates in the embryonic head. Using super-resolution microscopy and epigenomic meta-analysis of single cell RNAseq datasets we find that opas and ocs overlapping expression domains are dynamic in the head region, with both factors being simultaneously transcribed at the blastula stage. However, analysis of single-embryo RNAseq data reveals a subgroup of Opa-bound genes to be Opa-independent in the cellularized embryo. Interrogation of these genes against Oc ChIPseq combined with in situ data, suggests that Opa is competing with Oc for the regulation of a subgroup of genes later in gastrulation. Specifically, we find that Oc binds to late, head-specific enhancers independently and activates them in a head-specific wave of zygotic transcription, suggesting distinct roles for Oc in the blastula and gastrula stages.

developmental biology↗

bioRxiv2022

Tethering designer short double-stranded RNA to mRNA for co-delivery of molecularly-targeted adjuvants and antigens towards cancer vaccination

Integrating antigen-encoding mRNA and immunostimulatory adjuvant into a single formulation is a promising approach to potentiating the efficacy of mRNA vaccines. Here, we developed a scheme based on RNA engineering to integrate adjuvancy directly into antigen-encoding mRNA strands without hampering the ability to express antigen proteins. Short double-stranded RNA (dsRNA) was designed to target retinoic acid-inducible gene-I (RIG-I), an innate immune receptor, for effective cancer vaccination and then tethered onto mRNA strand via hybridization. Tuning the dsRNA structure and microenvironment by changing its length and sequence enabled the determination of the structure of dsRNA-tethered mRNA efficiently stimulating RIG-I. Eventually, the formulation loaded with dsRNA-tethered mRNA of the optimal structure effectively activated mouse and human dendritic cells and drove them to secrete a broad spectrum of proinflammatory cytokines without increasing the secretion of anti-inflammatory cytokines. Notably, the immunostimulating intensity was tunable by modulating the number of dsRNA along mRNA strand, which prevents excessive immunostimulation. Versatility in the applicable formulation is a practical advantage of the dsRNA-tethered mRNA. Its formulation with three existing systems, i.e., anionic lipoplex, ionizable lipid-based lipid nanoparticles, and polyplex micelles, induced appreciable cellular immunity in the mice model. Of particular interest, dsRNA-tethered mRNA encoding ovalbumin (OVA) formulated in anionic lipoplex used in clinical trials exerted a significant therapeutic effect in the mouse lymphoma (E.G7-OVA) model. In conclusion, the system developed here provides a simple and robust platform to supply the desired intensity of immunostimulation in various formulations of mRNA cancer vaccines.

bioengineering↗

bioRxiv2021

Synthetic repertoires derived from convalescent COVID-19 patients enable discovery of SARS-CoV-2 neutralizing antibodies and a novel quaternary binding modality

The ongoing evolution of SARS-CoV-2 into more easily transmissible and infectious variants has sparked concern over the continued effectiveness of existing therapeutic antibodies and vaccines. Hence, together with increased genomic surveillance, methods to rapidly develop and assess effective interventions are critically needed. Here we report the discovery of SARS-CoV-2 neutralizing antibodies isolated from COVID-19 patients using a high-throughput platform. Antibodies were identified from unpaired donor B-cell and serum repertoires using yeast surface display, proteomics, and public light chain screening. Cryo-EM and functional characterization of the antibodies identified N3-1, an antibody that binds avidly (Kd,app = 68 pM) to the receptor binding domain (RBD) of the spike protein and robustly neutralizes the virus in vitro. This antibody likely binds all three RBDs of the trimeric spike protein with a single IgG. Importantly, N3-1 equivalently binds spike proteins from emerging SARS-CoV-2 variants of concern, neutralizes UK variant B.1.1.7, and binds SARS-CoV spike with nanomolar affinity. Taken together, the strategies described herein will prove broadly applicable in interrogating adaptive immunity and developing rapid response biological countermeasures to emerging pathogens.

synthetic biology↗