Biology subjects

Singh, S.

Publications and source records attributed to Singh, S..

At least 433 records · Page 24Linked to original sources

bioRxiv2020

An evolutionarily diverged mitochondrial protein controls biofilm growth and virulence in Candida albicans

A forward genetic screening approach identified orf19.2500, as a gene controlling Candida albicans biofilm dispersal and biofilm detachment. Three-dimensional (3-D) protein modeling and bioinformatics revealed that orf19.2500 is a conserved mitochondrial protein, structurally similar to, but functionally diverged from, the squalene/phytoene synthases family. The C. albicans orf19.2500 is distinguished by three evolutionarily acquired stretches of amino acid inserts, absent from all other eukaryotes except a small number of ascomycete fungi. Biochemical assays showed that orf19.2500 is required for the assembly and activity of the NADH ubiquinone oxidoreductase Complex I of the respiratory electron transport chain, and was thereby named NDU1. NDU1 is essential for respiration and growth on alternative carbon sources, important for immune evasion, required for virulence in a mouse model of hematogenously disseminated candidiasis, and for potentiating resistance to antifungal drugs. Our study is the first report on a protein that sets the Candida-like fungi phylogenetically apart from all other eukaryotes, based solely on evolutionary "gain" of new amino acid inserts that are also the functional hub of the protein.

microbiology↗

bioRxiv2020

Breast tumors escape endocrine therapy by ER-independent mechanisms triggered by the coordinated activities of HER2/HER3 and deacetylated FOXA1

Hormone-resistance in ER positive breast cancer is associated with high HER2 activity. Yet, the interplay between HER2 and FOXA1 in hormone resistant tumors is not elucidated. Now, we demonstrate that hormone resistant tumors have increased HER2 expression and that FOXA1 mediates the signals of HER2/3 in an Estrogen Receptor independent manner. Our in vitro and in vivo experiments reveal that HER2/HER3 triggers FOXA1 binding at chromatin regions of ER-regulated genes associated with poor prognosis, facilitating their expression and leading to ER-independent growth. Furthermore, our study supports that FOXA1 acetylated by the acetyltransferase EP300 is retained at ER chromatin regions, which enables ER function. By contrast, HER2/3 activation hinders FOXA1 acetylation and facilitates FOXA1 binding at non-ER interacting regions enriched towards poor prognosis genes. Moreover, FOXA1 deacetylation confers insensitivity to anti-ER drugs inhibitory effect in ER positive cells. These results elucidate how post-translational modifications of FOXA1 control transcription independently of ER in hormone-resistant tumors with enhanced HER2/3 signaling.

cancer biology↗

bioRxiv2020

Emergence and expansion of highly infectious spike:D614G mutant SARS-CoV-2 in central India

COVID 19 has emerged as global pandemic with largest damage to the economy and human psyche. The genomic signature deciphered during the ongoing pandemic period is valuable to understand the virus evolutionary patterns and spread across the globe. Increased availability of genome information of circulating strain in our country will enable to generate selective details in virulent and non virulent markers to prophylaxis and therapeutic interventions. The first case of SARS CoV-2 was detected in Chambal region of Madhya Pradesh state in mid of March 2020 followed by multiple introduction events and expansion of COVID-19 cases within 3 months in this region. We analyzed around 5000 COVID -19 suspected samples referred to Defence Research and Development Establishment, Gwalior, Madhya Pradesh. A total of 136 cases were found positive over a span of three months period this includes virus introduction to region and further spread. Whole genome sequences employing Oxford nanopore technology were deciphered for 26 SARS-CoV-2 circulating in 10 different districts in Madhya Pradesh State of India. The region witnessed index cases with multiple travel history responsible for introduction of COVID-19 followed by remarkable expansion of virus. The genome wide substitutions including in important viral proteins were observed. The detailed phylogenetic analysis revealed the circulating SARS-CoV-2 clustered in multiple clades A2a, A4 and B. The cluster wise segregation was observed suggesting multiple introduction links and evolution of virus in the region. This is the first comprehensive details of whole genome sequence analysis from central India region, which will add genome wide knowledge towards diagnostic and therapeutic interventions.

molecular biology↗

bioRxiv2020

Computationally validated SARS-CoV-2 CTL and HTL Multi-Patch Vaccines designed by reverse epitomics approach, shows potential to cover large ethnically distributed human population worldwide

BackgroundThe SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is a positive-sense single-stranded RNA coronavirus responsible for the ongoing 2019-2020 COVID-19 outbreak. The highly contagious COVID-19 disease has spread to 216 countries in less than six months. Though several vaccine candidates are being claimed, an effective vaccine is yet to come. In present study we have designed and theoretically validated novel Multi-Patch Vaccines against SARS-CoV-2. MethodologyA novel reverse epitomics approach, "overlapping-epitope-clusters-to-patches" method is utilized to identify multiple antigenic regions from the SARS-CoV-2 proteome. These antigenic regions are here termed as "Ag-Patch or Ag-Patches", for Antigenic Patch or Patches. The identification of Ag-Patches is based on clusters of overlapping epitopes rising from a particular region of SARS-CoV-2 protein. Further, we have utilized the identified Ag-Patches to design Multi-Patch Vaccines (MPVs), proposing a novel methodology for vaccine design and development. The designed MPVs were analyzed for immunologically crucial parameters, physiochemical properties and cDNA constructs. ResultsWe identified 73 CTL (Cytotoxic T-Lymphocyte), 49 HTL (Helper T-Lymphocyte) novel Ag-Patches from the proteome of SARS-CoV-2. The identified Ag-Patches utilized to design MPVs cover 768 (518 CTL and 250 HTL) overlapping epitopes targeting different HLA alleles. Such large number of epitope coverage is not possible for multi-epitope vaccines. The large number of epitopes covered implies large number of HLA alleles targeted, and hence large ethnically distributed human population coverage. The MPVs:Toll-Like Receptor ectodomain complex shows stable nature with numerous hydrogen bond formation and acceptable root mean square deviation and fluctuation. Further, the cDNA analysis favors high expression of the MPVs constructs in human cell line. ConclusionHighly immunogenic novel Ag-Patches are identified from the entire proteome of SARS CoV-2 by a novel reverse epitomics approach. We conclude that the novel Multi-Patch Vaccines could be a highly potential novel approach to combat SARS-CoV-2, with greater effectiveness, high specificity and large human population coverage worldwide. O_FIG O_LINKSMALLFIG WIDTH=187 HEIGHT=200 SRC="FIGDIR/small/284992v1_ufig1.gif" ALT="Figure 1"> View larger version (84K): org.highwire.dtl.DTLVardef@176f27org.highwire.dtl.DTLVardef@82a4fcorg.highwire.dtl.DTLVardef@11db43forg.highwire.dtl.DTLVardef@12495b2_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOABSTRACT FIGURE:C_FLOATNO A Multi-Patch Vaccine design to combat SARS-CoV-2 and a method to prepare thereof. Multi-Patch Vaccine designing to combat SARS-CoV-2 infection by reverse epitomics approach, "Overlapping-epitope-clusters-to-patches" method. C_FIG

immunology↗

bioRxiv2020

SOCS1/SOCS3 Immune Axis Modulates Synthetic Perturbations in IL6 Biological Circuit for Dynamical Cellular Response

Macrophage phenotype plays a crucial role in the pathogenesis of Leishmanial infection. Pro-inflammatory cytokines are the key regulators that eliminate the infection induced by Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Suppressor of cytokine signaling (SOCS) is a well-known negative feedback regulator of JAK/STAT pathway. However, change in expression levels of SOCS in correlation with the establishment of infection is not well understood. Mathematical modeling of IL6 signaling pathway have helped identified the role of SOCS1 in establishment of infection. Furthermore, the ratio of SOCS1 and SOCS3 has been quantified both in silico as well as in vitro, indicating an immune axis which governs the macrophage phenotype during L. major infection. The ability of SOCS1 protein to inhibit the JAK/STAT1 signaling pathway and thereby decreasing pro-inflammatory cytokine expression makes it a strong candidate for therapeutic intervention. Using synthetic biology approaches, peptide based immuno-regulatory circuit have been designed to target the activity of SOCS1 which can restore pro-inflammatory cytokine expression during infection.

systems biology↗

bioRxiv2020

Prenatal Stress Dysregulates Resting-State Functional Connectivity and Sensory Motifs

Prenatal stress (PS) can impact fetal brain structure and function and contribute to higher vulnerability to neurodevelopmental and neuropsychiatric disorders. To understand how PS alters evoked and spontaneous neocortical activity and intrinsic brain functional connectivity, mesoscale voltage imaging was performed in adult C57BL/6NJ mice that had been exposed to auditory stress on gestational days 12-16, the age at which neocortex is developing. PS mice had a four-fold higher basal corticosterone level and reduced amplitude of cortical sensory-evoked responses to visual, auditory, whisker, forelimb, and hindlimb stimuli. Relative to control animals, PS also led to a general reduction of resting-state functional connectivity, as well as reduced inter-modular connectivity, enhanced intra-modular connectivity, and altered frequency of auditory and forelimb spontaneous sensory motifs. These resting-state changes resulted in a cortical connectivity pattern featuring disjoint but tight modules and a decline in network efficiency. The findings demonstrate that cortical connectivity is sensitive to PS and exposed offspring may be at risk for adult stress-related neuropsychiatric disorders.

neuroscience↗

bioRxiv2020

Antioxidant nanozyme counteracts HIV-1 by modulating intracellular redox potential

Reactive oxygen species (ROS) regulates the proliferation of human immunodeficiency virus (HIV-1) and Mycobacterium tuberculosis (Mtb) inside the infected immune cells. However, the application of this knowledge to develop therapeutic strategies remained unsuccessful due to unfavorable consequences of manipulating cellular antioxidant systems that respond to ROS. Here, we show that vanadium pentoxide (V2O5) nanosheets functionally mimic the activity of natural glutathione peroxidase (GPX) to mitigate ROS associated with HIV-1 infection without triggering detrimental changes in cellular physiology. Using genetic reporters of glutathione (GSH) redox potential (EGSH; Grx1-roGFP2) and H2O2 (Orp1-roGFP2), we showed that V2O5-nanosheets catalyze GSH-dependent neutralization of ROS in HIV-1 infected cells. Notably, V2O5-nanosheets uniformly blocked HIV-1 reactivation, multiplication, and impaired survival of drug-resistant Mtb during HIV-TB co-infection. Mechanistically, V2O5-nanosheets suppressed HIV-1 by affecting the expression of pathways coordinating redox balance, virus transactivation (e.g., NF-{kappa}B and FOS), inflammation, and apoptosis. Importantly, a combination of V2O5-nanosheets with a pharmacological inhibitor of NF-{kappa}B (BAY11-7082) abrogated activation of HIV-1 from latency. Lastly, V2O5-nanosheets counteracted ROS, disease pathophysiology, and virus expression in HIV-1 transgenic mice. Our data successfully revealed the usefulness of V2O5-nanosheets against human pathogens and suggest nanozymes as future platforms to develop interventions against infectious diseases. Significance StatementRedox stress, such as those caused by the deregulation of the antioxidant glutathione, promotes the multiplication of human immunodeficiency virus-1 (HIV-1) and Mycobacterium tuberculosis (Mtb). Here we present a vanadium pentoxide (V2O5)-based antioxidant nanozyme that targets cells infected with HIV-1. The nanozyme, by mimicking the activity of glutathione peroxidase, reprograms redox signaling to subvert HIV-1 from monocytes, lymphocytes, and HIV-1 transgenic mice. Treatment with nanozyme bolsters the antiviral potential of immune cells by reducing the expression of genes involved in virus activation, inflammation, and apoptosis. The nanozyme also inhibited the proliferation of Mtb, which is a major cause of lethality in HIV patients. These V2O5-based nanozymes may be applied to numerous human pathogens where redox signaling contributes to disease progression.

bioengineering↗

bioRxiv2020

Uncovering the geometry of color space with magnetoencephalography (MEG)

The geometry that describes the relationship among colors is unsettled despite centuries of study. Here we present a new approach, using multivariate analyses of direct measurements of brain activity obtained with magnetoencephalography to reverse-engineer the geometry of the neural representation of color space. The analyses depend upon determining similarity relationships among the neural responses to different colors and assessing how these relationships change in time. To evaluate the approach, we relate patterns of neural activity to universal patterns in color naming. Control experiments showed that responses to color words could not decode activity elicited by color stimuli. The results suggest that three patterns of color naming can be accounted for by decoding the similarity relationships in the neural representation of color: the association of warm colors such as reds and oranges with "light" and cool colors such as blues and greens with "dark"; the greater precision among all languages in naming warm colors compared to cool colors; and the preeminence of red.

neuroscience↗

bioRxiv2020

An equivalence of prokaryotic pore forming proteins of Plasmodium triggers cellular dysfunction responsible for malaria pathogenesis

Severe malaria caused by Plasmodium falciparum poses a major global health problem with high morbidity and mortality. The P. falciparum harbours a family of pore forming proteins (PFPs), known as perforin like proteins (PLPs), which are structurally equivalent to prokaryotic PFPs. These PLPs are secreted from the parasites and by interacting to host cells they contribute to disease pathogenesis. The severe malaria pathogenesis is associated with dysfunction of various barrier cells including endothelial cells. A number of factors, including PLPs, secreted by parasite contribute to the host cell dysfunction. Here in, we tested the hypothesis that the PLPs mediate dysfunction of barrier cells and might have a role in disease pathogenesis. We analysed various dysfunction in barrier cells following rPLP2 exposure and demonstrate that it causes an increase in intracellular Ca2+ levels. Additionally, rPLP2 exposed barrier cells displayed features of cell death including Annexin/PI positivity, depolarized mitochondrial membrane potential and ROS generation. We further performed the time lapse video microscopy of barrier cells and found the treatment of rPLP2 triggers their membrane blebbing. The cytoplasmic localization of HMGB1, a marker of necrosis, further confirmed the necrotic type of cell death. This study highlights the role of parasite factor PLP in endothelial dysfunction and provides a rational for the design of adjunct therapies against severe malaria.

cell biology↗

bioRxiv2020

Multinomial Convolutions for Joint Modeling of Sequence Motifs and Enhancer Activities

Massively parallel reporter assays (MPRAs) have enabled the study of transcriptional regulatory mechanisms at an unprecedented scale and with high quantitative resolution. However, this realm lacks models that can discover sequence-specific signals de novo from the data and integrate them in a mechanistic way. We present MuSeAM (Multinomial CNNs for Sequence Activity Modeling), a convolutional neural network that overcomes this gap. MuSeAM utilizes multinomial convolutions that directly model sequence-specific motifs of protein-DNA binding. We demonstrate that MuSeAM fits MPRA data with high accuracy and generalizes over other tasks such as predicting chromatin accessibility and prioritizing potentially functional variants.

systems biology↗

bioRxiv2020

Single-dose intranasal vaccination elicits systemic and mucosal immunity against SARS-CoV-2

A safe and durable vaccine is urgently needed to tackle the COVID19 pandemic that has infected >15 million people and caused >620,000 deaths worldwide. As with other respiratory pathogens, the nasal compartment is the first barrier that needs to be breached by the SARS-CoV-2 virus before dissemination to the lung. Despite progress at remarkable speed, current intramuscular vaccines are designed to elicit systemic immunity without conferring mucosal immunity. We report the development of an intranasal subunit vaccine that contains the trimeric or monomeric spike protein and liposomal STING agonist as adjuvant. This vaccine induces systemic neutralizing antibodies, mucosal IgA responses in the lung and nasal compartments, and T-cell responses in the lung of mice. Single-cell RNA-sequencing confirmed the concomitant activation of T and B cell responses in a germinal center-like manner within the nasal-associated lymphoid tissues (NALT), confirming its role as an inductive site that can lead to long-lasting immunity. The ability to elicit immunity in the respiratory tract has can prevent the initial establishment of infection in individuals and prevent disease transmission across humans.

immunology↗

bioRxiv2020

Biodiversity and Antimicrobial Potential of Bacterial Endophytes from Halophyte Salicornia brachiata

Untapped natural habitats like halophytes, marsh land, and marine environment are suitable arena for chemical ecology between plants and microbes having environmental impact. Endophytes constitute an ecofriendly option for the promotion of plant growth and to serve as sustainable resources of novel bioactive natural products. The present study focusing on biodiversity of bacterial endophytes from Salicornia brachiata, led to isolation of around 350 bacterial endophytes. Phylogenetic analysis of 63 endophytes revealed 13 genera with 29 different species, belonging to 3 major groups: Firmicutes, Proteobacteria and Actinobacteria. 30% isolates belonging to various genera demonstrated broad-spectrum antibacterial and antifungal activities against a panel of human, plant, and aquatic infectious agents. An endophytic isolate Bacillus amyloliquefaciens 5NPA-1, exhibited strong in-vitro antibacterial activity against human pathogen S. aureus and phytopathogen X. campestris. Investigation through LC-MS/MS-based molecular networking and bioactivity-guided purification led to the identification of three bioactive compounds belonging to lipopeptide class on the basis of 1H- and 13C-NMR and MS analysis. To our knowledge, this is the first report studying bacterial endophytic biodiversity of Salicornia brachiata and isolation of bioactive compounds from its endophyte. Overall, the present study provides insights into the diversity of endophytes associated with the plants from the extreme environment as rich source of metabolites with remarkable agricultural applications and therapeutic properties.

microbiology↗

bioRxiv2020

KDM6B promotes oncogenic CDK4/6-pRB-E2F pathway via maintaining enhancer activation in high-risk neuroblastoma

The H3K27me2/me3 histone demethylase KDM6B is over-expressed in neuroblastoma and is essential to neuroblastoma cell survival. While the KDM6B inhibitor, GSK-J4, has shown activity in in vitro and in vivo preclinical models, the mechanism of action remains poorly defined. We demonstrate that genetic and pharmacologic inhibition of KDM6B downregulates the pRB-E2F transcriptome and MYCN expression. Chemical genetic analyses show that high expression of the E2F transcriptome is positively correlated with sensitivity of cancer cells to GSK-J4. Mechanistically, inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and GSK-J4. A gene signature targeted by KDM6B inhibition is associated with poor survival of patients with neuroblastoma regardless of the MYCN status. These data indicate that KDM6B activity promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.

cancer biology↗

bioRxiv2020

Docosahexaenoic acid (DHA), a nutritional supplement, modulates steroid insensitivity in asthma

Asthmatics with poor steroid responsiveness are now found to use health services at higher frequency and contribute to socio-economic burden disproportionately. We have previously shown that a ω-6 fatty acid metabolite leads to a severe and steroid insensitive asthma-like condition in mice. Here, we investigated the role of retinoid-x-receptor gamma (RXRγ) and Docosahexaenoic acid (DHA), a ω3 fatty acid rexinoid ligand of RXR, on the features of steroid insensitivity in asthmatic condition. RXRγ was found to be reduced in the lungs of human asthmatics and mice with steroid insensitive allergic airway inflammation. RXRγ knockdown in naïve mice led to spontaneous asthma like features whereas RXRγ knockdown in allergic mice led to steroid insensitive asthma features. We observed while RXRγ binds to the glucocorticoid receptor (GR) gene and regulates its transcription, DHA increases the GRα expression in human bronchial epithelial cells and reverses the steroid insensitive features in mice with allergic airway inflammation. Docosahexaenoic acid (DHA), a ligand of RXR, was reduced in the sera of steroid-insensitive asthmatics. We conclude that DHA may prove to be a promising steroid sensitizing agent for the treatment of steroid insensitive asthmatics.Summary The molecular regulation of glucocorticoid receptor by retinoid-x-receptor gamma (RXRgama) has an implication in steroid insensitive asthma as we found that Docosahexaenoic acid (DHA), a nutritional supplement and natural ligand of RXRgamma, improves steroid sensitivity in steroid insensitive mice model of asthma and DHA levels are found to be low in steroid insensitive asthmatic patients.Competing Interest StatementThe authors have declared no competing interest.Abbreviations usedAAIAllergic airway inflammationAHRAirway hyper-responsivenessATRAAll-trans retinoic acidAUArbitrary unitsBALBronchoalveolar lavageBEAS-2BHuman bronchial epithelial cellsCECockroach allergen extractChIPChromatin Immunoprecipitation9CRA9-cis retinoic acidDEXDexamethasoneDHADocosahexaenoic acidDMSODimethyl sulfoxideELISAEnzyme-linked immunosorbent assayGAPDHGlyceraldehyde 3-phosphate dehydrogenaseGLucGaussia luciferaseGRαGlucocorticoid receptor alphaGREGlucocorticoid receptor elementH & EHaematoxylin and eosinIFNγInterferon gammaIgEImmunoglobulinE ILInterleukinKCKeratinocyte chemoattractant15-LOX15-lipoxygenaseMCF-7Human breast adenocarcinoma cell lineMCP1-αMonocyte chemoattractant protein1-αNF-κBNuclear Factor kappa-light-chain-enhancer of activated B cellsO.EOverexpressionOVAOvalbuminp38-MAPKp38 mitogen-activated protein kinasePBSPhosphate buffered salineRARRetinoic acid receptorPDTCPyrrolidinedithiocarbamateRXRERexinoid receptor elementRXRγRetinoid-x-receptor gamma13-S-HODE13-hydroxyoctadecadienoic acidSEMStandard error meansiRNASmall interfering RNASTAT-6Signal transducer and activator of transcription 6ThT helperVEHVehicleView Full Text

immunology↗

bioRxiv2020

Citizen Scientists Create an Exascale Computer to Combat COVID-19

SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression, and replication, which depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate an unprecedented 0.1 seconds of the viral proteome. Our simulations capture dramatic opening of the apo Spike complex, far beyond that seen experimentally, which explains and successfully predicts the existence of cryptic epitopes. Different Spike homologues modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also observe dramatic conformational changes across the proteome, which reveal over 50 cryptic pockets that expand targeting options for the design of antivirals. All data and models are freely available online, providing a quantitative structural atlas.

biophysics↗

bioRxiv2020

Temporal dynamics of the neural mechanisms for encoding hue and luminance contrast uncovered by magnetoencephalography

Hue and luminance contrast are basic visual features, yet the timing of the neural computations that extract them, and whether they depend on common neural circuits, is not well established. Using multivariate analyses of magnetoencephalography data, we show that hue and luminance-contrast polarity can be decoded from MEG data and, with lower accuracy, both features can be decoded across changes in the other feature. These results are consistent with the existence of both common and separable neural mechanisms. The decoding time course is earlier and more temporally precise for luminance polarity than hue, a result that does not appear to depend on task, suggesting that luminance contrast is an updating signal that separates visual events. Meanwhile, cross-temporal generalization is slightly greater for representations of hue compared to luminance polarity, providing a neural correlate of the preeminence of hue in perceptual grouping and memory. Finally, decoding of luminance polarity varies depending on the hues used to obtain training and testing data; the pattern of results suggests that luminance contrast is mediated by both L-M and S cone sub-cortical mechanisms.

neuroscience↗

bioRxiv2020

The SARS-CoV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA

The SARS-CoV-2 nucleocapsid (N) protein is an abundant RNA binding protein critical for viral genome packaging, yet the molecular details that underlie this process are poorly understood. Here we combine single-molecule spectroscopy with all-atom simulations to uncover the molecular details that contribute to N protein function. N protein contains three dynamic disordered regions that house putative transiently-helical binding motifs. The two folded domains interact minimally such that full-length N protein is a flexible and multivalent RNA binding protein. N protein also undergoes liquid-liquid phase separation when mixed with RNA, and polymer theory predicts that the same multivalent interactions that drive phase separation also engender RNA compaction. We offer a simple symmetry-breaking model that provides a plausible route through which single-genome condensation preferentially occurs over phase separation, suggesting that phase separation offers a convenient macroscopic readout of a key nanoscopic interaction.

biophysics↗

bioRxiv2020

PROTECTIVE ANTIBODIES AGAINST HPIV3 INFECTION

Human parainfluenza virus type III (HPIV3) is a common respiratory pathogen that afflicts children and can be fatal in vulnerable populations, including the immunocompromised. Unfortunately, an effective vaccine or therapeutic is not currently available, resulting in tens of thousands of hospitalizations per year. In an effort to discover a protective antibody against HPIV3, we screened the B cell repertoires from peripheral blood, tonsils, or spleen from healthy children and adults. These analyses yielded five monoclonal antibodies that potently neutralized HPIV3 in vitro. These HPIV3 neutralizing antibodies targeted two non-overlapping epitopes of the HPIV3 F protein, with most targeting the apex. Importantly, prophylactic administration of one of these antibodies, named PI3-E12, resulted in potent protection against HPIV3 infection in cotton rats. Additionally, PI3-E12 could also be used therapeutically to suppress HPIV3 in immunocompromised animals. These results demonstrate the potential clinical utility of PI3-E12 for the prevention or treatment of HPIV3 in both immunocompetent and immunocompromised individuals.

immunology↗