Biology subjects

De, A.

Publications and source records attributed to De, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Spike antibodies targeting GRP78 predispose to cardiovascular complications compared to Dengue

One major aftermath of COVID-19 pandemic is cardiovascular consequences. SARS-CoV-2 binds to ACE2 and downregulates vasodilation. Dengue favors hypotension by weakening endothelial glycocalyx leading to plasma leakage. C1q levels, immune complexes (ICs), and proteomic profiles in serum samples from 52 COVID-19 and 19 pre-pandemic Dengue cases were studied. Unlike Dengue, COVID-19 serums showed elevated coagulation proteins promoting vaso-occlusion and peripheral artery diseases. The stress-induced chaperone and atherosclerosis marker, GRP78 (gene/ protein) was found upregulated upon SARS-CoV-2 spike expression in cardiac/ lung cell lines. Elevated GRP78 levels were also observed in serum samples from COVID-19-diagnosed individuals and subjects with myocardial infarction (MI) in post COVID-era. Surprisingly, spike antibodies (Abs) showed cross-binding to GRP78 and possibly contributed to the observed higher-level ICs in COVID-19 serums (cardiovascular embolism?). Co-localization studies showed that spike Abs (analogous to pro-atherosclerotic GRP78 auto-Abs) could directly bind to upregulated cellular GRP78 (type II hypersensitivity?). Both pathways could worsen vascular injury and atherosclerosis, leading to cardiac complications in COVID-19 cases with narrowed vessels.

microbiology↗

bioRxiv2026

Influenza virus Non Structural protein 1 (NS1) Chaperones Nucleoprotein (NP) Oligomerization to Coordinate Ribonucleoprotein Assembly and Genome Replication

Influenza virus nucleoprotein (NP) co-transcriptionally enwraps viral genomic/antigenomic RNAs to assemble viral ribonucleoprotein complexes (RNPs), while the non-structural protein-1 (NS1) is classically recognized as an antagonist of host antiviral responses. Although NP-NS1 interaction has long been reported, the molecular basis of this protein-protein interaction and its relevance in the virus life cycle remain elusive. Here, we define the NP-NS1 interaction interface and uncover a noncanonical role of NS1 in regulating RNP assembly and viral genome replication. Using integrated biochemical, biophysical, and structural analyses, we demonstrate that the RNA-binding domain (RBD) of NS1 directly engages the NP tail-loop, conferring high affinity for monomeric NP. Functional assays reveal that a cytoplasm-restricted NS1 variant acts as an NP-specific chaperone by stabilizing monomeric NP through sequestration of its intrinsically flexible tail-loop and by scaffolding NP-NP interactions. During influenza virus infection, phosphorylation at the homotypic interface restricts NP in a replication-competent monomeric state. Cytoplasmic NS1 recruits these phosphorylated monomeric NPs into assembling RNPs, thereby facilitating viral genome replication and virus propagation. Collectively, our findings establish NS1 as a selective cytoplasmic chaperone of NP and reveal a novel regulatory axis governing influenza virus RNP biogenesis and replication.

molecular biology↗

bioRxiv2026

Control of cortical population activity with patterned microstimulation

Closed-loop control of cortical activity is a central goal in systems neuroscience and clinical neuromodulation, but most approaches either rely on detailed circuit models that are unattainable in vivo or on open-loop stimulation tuned by trial and error. Here we introduce REACHable manifold Control (REACH-Ctrl), a data-driven brain-computer interface that achieves real-time control of population spiking activity using patterned microstimulation and multi-electrode recordings. REACH-Ctrl learns a finite-horizon controllability map directly from short training epochs in which random multi-electrode pulse sequences are delivered through a subset of electrodes while recording evoked responses. From these input-output data, it identifies the "reachable manifold" of population states and computes low-current microstimulation sequences that steer activity toward designated targets, without explicit knowledge of the underlying connectivity or dynamics. We test REACH-Ctrl in macaque prefrontal cortex, demonstrating high control accuracy, robust across sessions and stimulation parameters. Geometric analyses showed that multi-pulse sequences traverse a well-defined reachable manifold with substantial, but incomplete, overlap with the intrinsic neural activity manifold, revealing both on- and off-manifold components of control. Encoding models further revealed that, in our weak-stimulation regime, population responses to multi-electrode sequences are well approximated by the linear sum of localized "stimulation fields" with modest history dependence, explaining the success of our linear control approach. These results demonstrate precise, sample-efficient control of cortical population activity with clinically relevant microstimulation hardware, and provide a general blueprint for designing perturbations for sparsely observed neural circuits.

neuroscience↗

bioRxiv2026

Cytosolic interaction with RNA-helicase DDX39A titrates viral RNA G-quadruplex mediated α-Synuclein amyloidogenesis

Amyloid aggregates of -Synuclein are hallmark of Parkinsons Disease (PD) and related neurodegenerative diseases. -Synuclein, being an non-canonical RNA-binding protein (RBP), associates with other RBPs within cytosolic RNA-protein granules to modulate mRNA-stability. Conversely, mRNA G-quadruplexes (rG4s) expedite -Synuclein amyloidogenesis. However, spatiotemporal control on -Synuclein amyloidogenesis by other RBPs remains unexplored. Here, we report that RNA-dependent cytosolic interaction with DEAD-box RNA-helicase DDX39A decelerates -Synuclein amyloidogenesis. Viral infections transiently elevate rG4s in cytoplasm. Perturbing interactions between Synuclein and DDX39A using viral rG4s from H1N1-influenza and SARS-CoV-2 genomes expedites intracellular amyloidogenesis. Conversely, DDX39A overexpression alleviates -Synuclein amyloidogenesis in mouse primary neurons triggered by SARS-CoV-2 infection. We demonstrate that while DDX39A unwinds viral rG4s to mitigate -Synuclein sol-gel transition, its reciprocal cooperative phase separation with -Synuclein enhances the helicases rG4-unwinding activity. We propose that accelerated -Synuclein amyloidogenesis represents a trade-off within this RNA-protein interaction equilibrium, contributing to the viral etiology of PD.

biochemistry↗

bioRxiv2025

Population-level temporal decoding and dynamical structure in frontostriatal circuits during decision making

Perceptual decisions unfold over time, requiring neural circuits to evaluate sensory evidence, track elapsed time, and commit to an action. To investigate how these computations are distributed across corticostriatal circuits, we recorded large-scale neural population activity using Neuropixels probes in the rat frontal orienting field (FOF) and anterior dorsal striatum (ADS) during a free-response auditory change detection task. Both regions exhibited structured, highly dynamic population activity during task performance. Using single-trial population decoding, we found that both FOF and ADS robustly encoded retrospective time from stimulus onset and prospective time preceding the decision report. Using a new approach to analyze temporal encoding to identify the dynamical structure supporting decoding, we found that time encoding could be decomposed into two primary dynamical motifs: monotonic ramp-like trajectories and transient bump-like trajectories. While these modes were similarly expressed during early evidence evaluation, FOF exhibited more pronounced decision-aligned changes near the time of the decision report, possibly reflecting a state transition at commitment. Population geometry analyses further revealed stable low-dimensional subspaces during evidence evaluation that transitioned at decision commitment, with significantly larger subspace changes in FOF than ADS. Together, these results reveal a common dynamical framework during evidence evaluation across corticostriatal circuits, while identifying a selective reorganization of FOF dynamics associated with decision commitment.

neuroscience↗

bioRxiv2025

Single Cell RNA Sequencing and Spatial Profiling Identify Mechanisms of Neonatal Brain Hemorrhage Development and Resolution

Precise control of cell-cell communication networks within brain neurovascular units (NVUs) promotes normal tissue physiology, and dysregulation of these networks can lead to pathologies including intracerebral hemorrhage (ICH). The cellular and molecular mechanisms underlying ICH development and subsequent tissue repair processes remain poorly understood. Here we employed quantitative single cell RNA sequencing coupled with spatial in situ gene expression profiling to characterize NVU signaling pathways associated with ICH in neonatal mouse brain tissue. The initial stages of ICH pathogenesis are characterized by downregulation of extracellular matrix (ECM)-associated signaling factors (Adamtsl2, Htra3, and Lama4) that functionally connect to canonical TGF{beta} activation and signaling in vascular endothelial cells. Conversely, the progressive resolution of ICH involves upregulation of neuroinflammatory signaling networks (Gas6 and Axl) alongside activation of iron metabolism pathway components (Hmox1, Cp, and Slc40a1) in astrocytes and microglial cells. Integrated computational modeling identifies additional ligand-receptor signaling networks between perivascular glial cells and endothelial cells during both ICH pathogenesis and resolution. Collectively, these findings illuminate the molecular signaling networks that promote NVU maturation and provide novel mechanistic insights into the pathways controlling ICH pathogenesis and repair.

developmental biology↗

bioRxiv2025

Towards model-based design of causal manipulations of brain circuits with high spatiotemporal precision

Recent advancements in neurotechnology enable precise spatiotemporal patterns of micros- timulations with single-cell resolution. The choice of perturbation sites must satisfy two key criteria: efficacy in evoking significant responses and selectivity for the desired target effects. This choice is currently based on laborious trial-and-error procedures, unfeasible for sequences of multi-site stimulations. Efficient methods to design complex perturbation patterns are ur- gently needed. Can we design a spatiotemporal pattern of stimulation to steer neural activity and behavior towards a desired target? We outline a method for achieving this goal in two steps. First, we identify the most effective perturbation sites, or hubs, only based on short observations of spontaneous neural activity. Second, we provide an efficient method to design multi-site stimulation patterns by combining approaches from nonlinear dynamical systems, control theory and data-driven methods. We demonstrate the feasibility of our approach using multi-site stimulation patterns in recurrent network models.

neuroscience↗

bioRxiv2025

PLGA Soya Lecithin Based Hybrid Nanocomposite for Targeted Topical Delivery of Resveratrol in Psoriasis Management

Psoriasis is a recurring autoimmune-driven inflammatory skin disorder characterised by red, scaly, dry skin patches, keratinocyte hyperproliferation and infiltration of inflammatory cells, impacting millions globally. Patients with psoriasis often require repeated treatments with corticosteroids, which are often associated with significant side effects and comorbidities. Therefore, there is a growing need for advanced nanomedicine-based therapeutic approaches. Resveratrol (RSV), a plant-derived polyphenol, has shown promising anti-inflammatory and antioxidant properties for the treatment and management of psoriasis. However, its therapeutic potential is limited due to its poor solubility, low stability, and reduced skin penetration. To overcome these challenges, we have developed dual-carrier conjugated nanoparticles (RSVNPL) composed of soya lecithin and poly(lactic-co-glycolic acid) (PLGA). To further enhance its ease of application and prolong skin residence time, RSVNPL was incorporated into a carbomer 974P-based hydrogel system, forming RSVNPGel. Our formulation demonstrated improved physicochemical properties, including enhanced spreadability, superior skin adhesiveness and stability. Ex vivo skin permeation studies confirmed a significantly higher accumulation of RSV in the epidermis and dermis compared to free drugs. In vivo, efficacy was investigated using imiquimod (IMQ)-induced psoriatic mouse model, where RSVNPGel treatment led to a notable reduction in epidermal thickness, inflammatory cell infiltration, and key histopathological features associated with psoriasis. Additionally, serum biochemical analysis and organ histology established the biocompatibility and safety of the formulation. Overall, RSVNPGel presents a promising nanocarrier-based strategy for the effective topical management of psoriasis, enhancing RSV delivery and therapeutic efficacy while minimizing systemic exposure. Research HighlightsO_LIHybrid nanoparticles composite of soya lecithin and PLGA were developed for RSV delivery. C_LIO_LIThe formulation enhanced skin penetration, retention and created a better skin adhesive profile in psoriatic lesions. C_LIO_LISignificant anti-psoriatic effects were achieved in a preclinical model. C_LIO_LIThe system showed excellent safety and biocompatibility. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/648585v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@e28c4corg.highwire.dtl.DTLVardef@1690c80org.highwire.dtl.DTLVardef@1b3e4bforg.highwire.dtl.DTLVardef@16ec0ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Development of Bioisosteric Iboga-alkaloids as Antinociceptive and Anxiolytic Agents with Neuroprotective Effects

The clinical importance of iboga alkaloids lies in their efficacy in reversing drug addiction and modulating drug tolerance. However, due to safety concerns, their use is restricted to appropriate medical supervision. These alkaloids often cause severe hallucinogenic effects due to differential binding to various brain receptors and cardiotoxicity by blocking the human ether-a-go-go-related gene (hERG) potassium channel. To create safer analogs, our group previously synthesized various benzofuran-containing iboga analogs with good opioid binding selectivity and excellent antinociceptive property. However, the present manuscript disclosed a step-economical and cost-effective synthesis of modified ibogaine/ibogamine analogs (C1, C2, C3 & C4) with bio-isosteric replacement of the indole scaffold with a benzofuran moiety, and comparing their antinociceptive/anxiolytic activity with their natural counterparts. Among the synthesized iboga analogs, the Endo-iboga analogs (C2 & C4, epimers of C1 and C3, respectively) not only exhibited superior anti-inflammatory and oxidative stress-relieving activity, but also effectively improved restricted locomotor activity in a formalin-induced acute pain model in mice. These Endo-iboga analogs significantly elevated the levels of inhibitory neurotransmitters (GABA and dopamine) and brain-derived neurotrophic factor (BDNF) compared to their Exo-counterparts or previously published benzofuran-containing iboga analogs lacking the tetrahydroazepine ring. Amongst, C2 and C4, the latter exhibited superior cardiac safety profile in C2C12 cells (IC50 = 235 {micro}M) and showed no adverse effects on rat hearts during in vivo ECG tests, indicated by no significant QTc prolongation. Overall, the development of bioisosteric iboga analogs, particularly C4, demonstrated significant potential for acute pain management without notable cardiotoxicity, representing a breakthrough in pain therapy innovation.

physiology↗

bioRxiv2024

In Situ Single-Cell Spatial Profiling of Matrisome Gene Expression in Glioblastoma

The human brain contains a rich milieu of extracellular matrix (ECM) components that are often dysregulated in pathologies including the malignant cancer glioblastoma (GBM). Here, we have used in situ single-cell spatial transcriptomic platforms to map the expression patterns of nearly 400 ECM genes in normal brain and GBM samples. Our analysis identifies at least four different GBM cell populations with unique ECM expression profiles that show spatial enrichment in distinct intratumor regions. Spatial mapping also demonstrates largely non-overlapping expression signatures of various ECM components in GBM stromal cell types, particularly in vascular endothelial cells and reactive microglia/macrophages. Comparisons of GBM (IDH1 wild type) versus lower-grade II and III astrocytoma samples (IDH1 R132H) identifies differential expression of key ECM components, including elevated levels of select ECM glycoproteins (IGFBP2 and MGP) and ECM-affiliated proteins (ANXA1 and ANXA2). In addition, we detect spatially enriched expression of COL8A1 (collagen), LUM (proteoglycan), and POSTN (ECM glycoprotein) in perivascular stromal cells in GBM but not in lower grade tumors. Computational analysis of putative ligand-receptor interactions reveals novel ECM communication networks between cancer cells and stromal components, particularly in regions of GBM microvascular proliferation and pseudopalisading necrosis. In summary, this comprehensive spatial map provides new insights into microenvironmental control of GBM initiation and progression and identifies potential therapeutic targets in the ECM.

cancer biology↗

bioRxiv2024

Transcutaneous delivery of disease specific PI3K/Akt/mTOR inhibitor based hybrid nanoparticles in hydrogel system for the management of psoriasis: Insights from in vivo studies

We have reported robust and scalable lipid polymeric conjugated hybrid nanoparticles comprised of phospholipid shell and polymeric core that combine the benefit of both polymeric and lipid nanoparticles. Rapamycin, a PI3K/Akt/mTORC1 inhibitor, was encapsulated inside the lipid-polymeric conjugated spherical-shaped hybrid nanoparticles (RPMN), having an encapsulation efficiency of {approx} 83% and particle size {approx} 277.6 nm. Further, RPMN was converted into the carpool-based hydrogel system (RPMNGel), which enhanced release kinetics, long-term stability and skin residence time. Specifically, in an in-vivo imiquimod-induced psoriatic model, RPMNGel showed high accumulation and deeper penetration inside the epidermis, slowly diffusing away inside the psoriatic skin without causing any side effect to normal skin. This leads to longer and sustained retention over more than three days without being affected by sweat, humidity or wiping due to adherence between the stratum corneum and epidermis. Similarly, the cumulative PASI score was also reduced from 10.25 to 1.75 on day 7 in the group treated with RPMNGel. Overall, RPMNGel has a potential role in treating and managing psoriasis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/599287v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1366d88org.highwire.dtl.DTLVardef@51255forg.highwire.dtl.DTLVardef@16ca71dorg.highwire.dtl.DTLVardef@4f93e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Fmp40 ampylase regulates cell survival upon oxidative stress by controlling Prx1 and Trx3 oxidation

Reactive oxygen species (ROS), play important roles in cellular signaling, nonetheless are toxic at higher concentrations. Cells have many interconnected, overlapped or backup systems to neutralize ROS, but their regulatory mechanisms remain poorly understood. Here, we reveal an essential role for mitochondrial AMPylase Fmp40 from budding yeast in regulating the redox states of mitochondrial 1-Cys peroxiredoxin, Prx1, which is the only protein shown to neutralize H2O2 with the oxidation of the mitochondrial glutathione and Trx3, thioredoxin, directly involved in the reduction of Prx1. Deletion of FMP40 impacts a cellular response to H2O2 treatment that leads to programmed cell death (PCD) induction and an adaptive response involving up or down regulation of genes encoding, among others the catalase Cta1, PCD inducing factor Aif1, and mitochondrial redoxins Trx3 and Grx2. This ultimately perturbs the reduced glutathione and NADPH cellular pools. We further demonstrated that Fmp40 AMPylates Prx1, Trx3, and Grx2 in vitro and interacts with Trx3 in vivo. AMPylation of the threonine residue 66 in Trx3 is essential for this proteins proper endogenous level of and its precursor forms maturation under oxidative stress conditions. Additionally, we showed the Grx2 involvement in the reduction of Trx3 in vivo. Taken together, Fmp40, through control of the reduction of mitochondrial redoxins, regulates the hydrogen peroxide, GSH and NADPH signaling influencing the programmed cell death execution. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/590396v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@2bae9borg.highwire.dtl.DTLVardef@1d46514org.highwire.dtl.DTLVardef@1380c2aorg.highwire.dtl.DTLVardef@a6bad9_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

Common population codes produce extremely nonlinear neural manifolds

Populations of neurons represent sensory, motor and cognitive variables via patterns of activity distributed across the population. The size of the population used to encode a variable is typically much greater than the dimension of the variable itself, and thus the corresponding neural population activity occupies lower-dimensional subsets of the full set of possible activity states. Given population activity data with such lower-dimensional structure, a fundamental question asks how close the low-dimensional data lies to a linear subspace. The linearity or non-linearity of the low-dimensional structure reflects important computational features of the encoding, such as robustness and generalizability. Moreover, identifying such linear structure underlies common data analysis methods such as Principal Component Analysis. Here we show that for data drawn from many common population codes the resulting point clouds and manifolds are exceedingly nonlinear, with the dimension of the best-fitting linear subspace growing at least exponentially with the true dimension of the data. Consequently, linear methods like Principal Component Analysis fail dramatically at identifying the true underlying structure, even in the limit of arbitrarily many data points and no noise.

neuroscience↗

bioRxiv2022

HepaCAM Suppresses Glioblastoma Stem Cell Invasion in the Brain

Glioblastoma (GBM) is a malignant brain cancer that contains sub-populations of highly invasive tumor cells that drive progression and recurrence after surgery and radiochemotherapy. The exact mechanisms that enable GBM cells to disperse from the main tumor mass and navigate throughout the brain microenvironment remain largely unknown. As a result, there is a lack of effective strategies to block cancer cell invasive growth in primary and recurrent GBM. Here we report that hepatocyte cell adhesion molecule (hepaCAM), which is normally expressed in perivascular astrocytes, plays central roles in controlling the invasive growth features of GBM cells. Genetically targeting HEPACAM induces a transition from GBM cell proliferation/self-renewal to invasion. Increased invasion is due, in part, to an activation of focal adhesion signaling pathways and enhanced GBM cell adhesion to the extracellular matrix (ECM) in the brain microenvironment. Transcriptional profiling of GBM cells reveals various HEPACAM-regulated genes with links to polarity and invasion. Collectively, these data show that hepaCAM balances ECM adhesion and signaling pathways to control cancer cell proliferation versus invasion in the brain parenchyma. Targeting select components of the hepaCAM pathway may be an effective way to block tumor progression and recurrence in patients with GBM.

cancer biology↗

bioRxiv2022

Genomic analysis unveils the role of genome degradation events and gene flux in the emergence and persistence of S. Paratyphi A lineages

Paratyphoid fever caused by S. Paratyphi A is endemic in parts of Asia and Sub-Saharan Africa. The proportion of enteric fever cases caused by S. Paratyphi A has substantially increased, yet only limited data is available on the population structure and genetic diversity of this serovar. We examined the phylogenetic distribution and evolutionary trajectory of S. Paratyphi A isolates collected as part of the Indian enteric fever surveillance study "Surveillance of Enteric Fever in India (SEFI)." In the study period (2017-2020), S. Paratyphi A comprised 17.6% (441/2503) of total enteric fever cases in India, with the isolates highly susceptible to all the major antibiotics used for treatment except fluoroquinolones. Phylogenetic analysis clustered the global S. Paratyphi A collection into seven lineages (A-G), and the present study isolates were distributed in lineages A, C and F. Our analysis documented that the genome degradation events and gene acquisitions or losses play a major role in the evolution of new S. Paratyphi A lineages/sub-lineages. A total of 10 pseudogene-forming mutations possibly associated with the emergence of lineages were identified. Pan-genome analysis identified the insertion of P2/PSP3 phage and acquisition of IncX1 plasmid during the selection in 2.3.2/2.3.3 and 1.2.2 genotypes, respectively. We also identified that the six characteristic missense mutations associated with the lipopolysaccharide (LPS) biosynthesis genes of S. Paratyphi A confer only a low structural impact and would therefore have minimal impact on vaccine effectiveness. Since S. Paratyphi A is human restricted, high levels of genetic drift are not expected unless these bacteria transmit to naive hosts. However, public-health investigation and intervention by means of genomic surveillance would be continually needed to avoid S. Paratyphi A serovar becoming a public health threat similar to the S. Typhi of today.

genomics↗

bioRxiv2022

Development of Non-invasive ABPP-BRET Platform Technology Enable Real-Time Detection of Post-Translational Modification and Target Engagement with Absolute Specificity in Living Systems

Non-invasive, real-time, longitudinal imaging of protein functions in living systems with unprecedented specificity is one of the critical challenges of modern biomedical research. Despite several advancements, it is estimated that nearly 35% of the human proteome is not completely characterized. Therefore, the development of new technologies is imperative for shining more light on so-called "dark proteomes". Towards that goal, here we report a platform fusion technology called activity-based protein profiling-bioluminescence resonance energy transfer (ABPP-BRET). This method provides an opportunity to study the post-translational modification of a target protein in real-time in living systems in a longitudinal manner with a high spatio-temporal resolution. This semi-synthetic BRET biosensor method is used for target engagement studies and further for inhibitor profiling in live cells. The simplicity of this method coupled with the critical physical distance dependent BRET read-out turned out to be a powerful method, thus pushing the activity-based protein profiling technology to the next level.

cell biology↗

bioRxiv2021

A species-specific signature residue in the PB2 subunit of the bat influenza virus polymerase restricts viral RNA synthesis.

Bat influenza A viruses (H17N10 and H18N11) are genetically distant from conventional influenza A viruses and replicates poorly in non-bat hosts species. However, the reason behind the lower replication fitness of these viruses are yet to be elucidated. In this work, we have identified species-specific signature residues, present in viral PB2 protein, which is a major determinant of polymerase fitness in human, avian and bat cell lines. Through extensive sequence and structural comparison between the bat and non-bat influenza virus RNA polymerases, we have identified a previously uncharacterized PB2-282 residue, which is serine in bat virus PB2 protein but harbours highly conserved glutamic acid in conventional influenza A viruses. Introduction of these bat specific signatures in the polymerase of a human adapted strain of influenza A/H1N1 virus drastically reduces its polymerase activity and replication efficiency in cell lines of human, bat and canine origin. In contrast, introduction of the human specific signatures in bat virus PB2 (H17N10), significantly enhances its function in the context of a chimeric RNA polymerase. Interestingly, the PB2-282 resides within an evolutionary conserved "S-E-S" motif present across different genera of influenza viruses but is replaced with a "S-S-T" motif in bat influenza viruses, indicating that this E to S transition may serve as a species-specific adaptation signature that modulates the activity of bat virus polymerase in other host species. ImportanceRecent isolation of influenza A like viruses (H17N10 and H18N11) in bats raised concerns about their potential of zoonotic transmission in human. Here we present species-specific signature residues present in the bat influenza virus polymerase, which may act as critical modulators of bat virus propagation in non-bat host species. We utilize bioinformatics based comparative analysis followed by functional screening in order to identify the PB2-282nd position, which harbors a highly conserved glutamic acid in conventional influenza A viruses, but contains an unusual serine in case of bat influenza viruses. Human adapted polymerase, harboring bat specific signature (PB2-S282) performs poorly, while bat PB2 protein harboring human specific signature (PB2-E282) shows increased fitness in human cells. Together, our data identifies novel species-specific signatures present within the influenza virus polymerase that may serve as a key factor in the adaptation of influenza viruses from bat to non-bat host species and vice versa.

microbiology↗

bioRxiv2021

Coding of chromatic spatial contrast by macaque V1 neurons

Color perception relies on spatial comparisons of chromatic signals, but how the brain performs these comparisons is poorly understood. Here, we show that many V1 neurons compare signals across their receptive fields (RF) using a common principle. We estimated the spatial-chromatic RFs of each neuron, and then measured neural selectivity to customized colored edges that were sampled using a novel closed-loop technique. We found that many double-opponent (DO) cells, which have spatially and chromatically opponent RFs, responded to chromatic contrast as a weighted sum, akin to how simple cells respond to luminance contrast. Other neurons integrated chromatic signals non-linearly, confirming that linear signal integration is not an obligate property of V1 neurons. The functional similarity of DO and simple cells suggests a common underlying neural circuitry, promotes the construction of image-computable models for full-color image representation, and sheds new light on V1 complex cells.

neuroscience↗