Biology subjects

Hoffmann, J.

Publications and source records attributed to Hoffmann, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Aging, HIV Status, and Sex Differentially Influence Antiretroviral Therapy Disposition Pathways in Rectosigmoid Tissue and Peripheral Blood Mononuclear Cells

People living with human immunodeficiency virus (HIV) are increasingly surviving into older age due to the effectiveness of antiretroviral (ARV) therapy (ART), creating a growing population in whom age-related changes may influence treatment outcomes. Although aging is known to affect drug disposition, the molecular mechanisms by which aging alters ARV pharmacology remain incompletely understood, particularly within tissue compartments, including the rectosigmoid region of the colon, that serve as sites of HIV transmission and persistence. To address this knowledge gap, we used proteomics by liquid chromatography-mass spectrometry (LC-MS) to evaluate the impact of age and HIV status on proteins and pathways relevant to ARV disposition in peripheral blood mononuclear cells (PBMC) and rectosigmoid colon tissue obtained from young (18-50) HIV-seronegative adults, older (65-80) HIV-seronegative adults, and older virally suppressed people living with HIV. We found that aging and HIV infection differentially influenced proteins predominantly within nucleos(t)ide reverse transcriptase inhibitor (NRTI) pathways, in rectosigmoid tissue and PBMC. HIV-associated effects to the proteome were more prominent in PBMC, whereas aging produced broader alterations in ARV disposition-related proteins in rectosigmoid tissue, including proteins involved in drug transport, intracellular drug activation, dephosphorylation, and nucleotide homeostasis. Several age-associated changes were further influenced by biologic sex, suggesting that aging may not affect ARV disposition uniformly across populations. To place these findings within a broader context, pathway analyses were performed that identified extensive tissue-specific remodeling associated with aging and HIV infection involving drug disposition, immune regulation, cellular metabolism, and disease-related pathways. Notably, aging was associated with alterations in pathways relevant to nucleotide metabolism and gastrointestinal tissue function, suggesting that processes beyond traditional drug transport and metabolism pathways may contribute to variability in ARV disposition with advancing age. Together, these findings identify aging as an important modifier of pathways that regulate ARV disposition within compartments relevant to HIV transmission and persistence. While the clinical consequences of our findings are unknown, these data provide a mechanistic foundation for future studies investigating whether age-associated changes influence the effectiveness of ART and HIV pre-exposure prophylaxis in older adults.

pharmacology and toxicology↗

bioRxiv2026

DarHTG is a tripartite phage defence system for purine DNA base ADP-ribosylation

Bacteria evolved a variety of phage defence strategies to combat the constant onslaught of viral threats. DarTG toxin-antitoxin systems provide phage defence by ADP-ribosylation of bases in single-stranded DNA which interferes with viral replication and aborts phage infection. Here, we describe DarHTG, a system widespread among bacteria, that combines DarTG with a non-processive superfamily I helicase functioning as co-toxin for DarT and thereby enabling the ADP-ribosylation of double-stranded DNA. We identified two such DarHTG subclasses which catalyse the ADP-ribosylation of adenosine and guanosine bases, respectively, and reverse these modifications with structurally unique ARH superfamily antitoxins. Thus, DarHTG antitoxins expand the known macromolecular target spectrum of the ARH enzyme class to nucleic acids. These DarHTG systems confer resistance to a broad range of bacteriophages and can be triggered by the highly charged tails of viral single-stranded DNA-binding proteins, which occlude the active site of the ARH antitoxin.

microbiology↗

bioRxiv2025

AlterNet: Alternative splicing-aware gene regulatory networkinference

Gene regulatory networks (GRNs) help decode biological systems by identifying how genes interact and regulate cellular processes. However, conventional GRN inference methods operate at the gene-level, overlooking transcript-level variability introduced by alternative splicing (AS). In this work, we present AlterNet, the first GRN inference and annotation pipeline which considers isoform of transcription factors as distinct regulators in a GRN. AlterNet builds on the GRNBoost2 inference algorithm, and includes a transcript plausibility and annotation workflow. We applied AlterNet to expression data from heart tissue, including samples from donors with normal heart function and from patients with different types of cardiomyopathy. The resulting isoform-level GRNs uncovered highly relevant regulatory interactions not detectable at the gene-level. Overall, AlterNet infers transcript-level regulatory network which enable the discovery of novel, biologically relevant regulatory interactions that remain hidden in gene-level GRNs. The source code of AlterNet is available on GitHub https://github.com/bionetslab/AlterNet, and can be installed as a Python package.

bioinformatics↗

bioRxiv2025

A modified oncolytic measles virus exhibits strong immunotherapeutic potential through RIG-I activation by defective viral genomes

Oncolytic viruses can destroy tumors directly or by activating antitumor immunity, but balancing safety with potent immune stimulation remains challenging. Here, we show that deletion of the measles virus C protein, a key viral antagonist of innate immunity, reprograms the live-attenuated vaccine strain into a RIG-I-driven cancer immunotherapy. The resulting virus, MVdeltaC, accumulates defective viral genomes that activate RIG-I/MAVS signaling and trigger robust type I interferon and pro-inflammatory cytokine responses. MVdeltaC kills tumor cells more rapidly and efficiently than the parental virus and induces hallmarks of immunogenic cell death, including HMGB1 release and dendritic cell maturation. Intratumoral administration in immunocompetent mice bearing syngeneic neuroblastoma induced complete tumor regression in 90% of animals and established long-term antitumor memory. Antitumor responses were dependent on CD8 T and NK cells and were further enhanced by anti-CTLA-4 therapy or CD4 T-cell depletion. Prior measles immunization accelerated tumor clearance, indicating vaccine-boosted responses. MVdeltaC also controlled the growth of human mesothelioma, melanoma, and triple-negative breast cancer xenografts and patient-derived tumors in immunodeficient models. These findings establish MVdeltaC as a clinically ready, broad-spectrum immunotherapeutic that links RIG-I activation through defective viral genome generation to elicit potent and durable antitumor immunity. IMPACT StatementA modified measles virus lacking a viral innate immunity antagonist triggers potent antitumor responses via RIG-I sensing of defective viral genomes, revealing a new strategy for cancer immunotherapy.

immunology↗

bioRxiv2025

TFEB and TFE3 have cell-type specific expression in the brain and divergent roles in neurons

Lysosomal dysfunction occurs in many neurodegenerative diseases, including Parkinsons disease, and activating TFEB to enhance lysosomal biogenesis is a promising therapeutic strategy. To understand TFEB physiology in cells of the brain, we characterised TFEB expression using iPSC-derived models, and transcriptomic analysis of human and mouse brain tissue. Surprisingly, TFEB expression at the RNA and protein level was restricted to glia, whereas the related transcription factor, TFE3, was expressed ubiquitously. We identified HDAC1/2/3 as transcriptional repressors of neuronal TFEB and found the brain-penetrant HDAC inhibitor ACY-738 derepressed TFEB expression and enhanced TFE3 nuclear translocation in iPSC-dopaminergic neurons (iPSC-DaNs). We delineated the role of each transcription factor by genetic manipulation in iPSC-DaNs to reveal divergent roles in which TFEB activates mitochondrial biogenesis, whereas TFE3 enhances lysosomal biogenesis. Finally, we show TFE3 activation corrects the lysosomal dysfunction associated with GBA-N370S and SNCA-Triplication mutations in Parkinsons patient-derived iPSC-DaNs, demonstrating therapeutic utility in neurodegeneration.

cell biology↗

bioRxiv2025

Universal bacterial clade dynamics dominate under predation despite altered phenotypes and mutation targets

Recent studies have revealed bacterial genome-wide evolution to be complex and dynamic even in a constant environment, characterized by the emergence of new clades competing or temporarily coexisting as each clade undergoes evolutionary change. Previous studies on predator-prey dynamics tracking simple ecological and phenotypic metrics have shown predation to fundamentally alter prey evolution, facilitating defense evolution followed by coevolution and frequency dependent selection between defended and undefended prey genotypes. Here we sought to consolidate these fields by examining genome-wide evolution in five bacterial prey species separately subjected to long-term evolution under ciliate predation. We hypothesized that the presence of predation could change the pattern of clonal dynamics, for example, by more frequently producing selective sweeps if predation-defense-related mutations are under strong selection. For all species, we found mutational signals of prey adaptation, with phenotypic data and genomic mutation targets demonstrating changes in composition between the experimental treatments. Intriguingly, despite higher variant counts, overall temporal clade dynamics across the coevolved prey species were strikingly similar to those of bacteria evolving alone, with constant emergence, competition and quasi-stable coexistence of clades. This study shows that long-term molecular evolution in bacterial prey under predation is more interesting and less predictable than we might expect based on existing coevolutionary theories.

evolutionary biology↗

bioRxiv2025

Multi-System Dysregulation in Placental Malaria Contributes to Adverse Perinatal Outcomes in Mice

Sequestration of Plasmodium parasites in the placental vasculature causes increased morbidity and mortality in pregnant compared to non-pregnant patients in malaria- endemic regions. In this study, outbred pregnant CD1 mice with semi allogeneic fetuses were infected with transgenic Plasmodium berghei or mock-inoculated by mosquito bite at either embryonic day (E) 6 (first trimester-equivalent) or 10 (second trimester- equivalent) and compared with non-pregnant females. P. berghei-infected mosquitoes had greater biting avidity for E10 dams than uninfected mosquitoes, which was not apparent for E6 dams nor non-pregnant females. Infected E10 dams had greater numbers of parasites than E6 dams in the uterus and spleen, but not in the blood or liver. While parasites were found in placentas, no parasites were present in fetuses. Maternal infection at E6 caused greater maternal morbidity, with greater rates of fetal reabsorption and stillbirths than at E10. Infection at E10 caused adverse offspring outcomes, including growth restriction. To identify possible mechanisms of adverse offspring outcomes, E10 dams were euthanized during peak parasitemia (8 days post infection), and outcomes were compared with mock-infected dams. P. berghei caused significant systemic maternal immune activation with elevated circulating lymphocytes, eosinophils, and neutrophils and splenic cytokine concentrations. P. berghei infection at E10 increased corticosterone and decreased progesterone concentrations, which could contribute to adverse perinatal outcomes through immunomodulation. There were limited changes in the maternal fecal microbiome after P. berghei infection. Mosquito bite infection of outbred dams with P. berghei causes placental malaria and provides a novel, tractable model to investigate therapeutic treatments.

microbiology↗

bioRxiv2024

Canonical and non-canonical PRC1 differentially contribute to the regulation of neural stem cell fate

Neocortex development is characterized by sequential phases of neural progenitor cell (NPC) expansion, neurogenesis and gliogenesis. Polycomb-mediated epigenetic mechanisms are known to play important roles in regulating the lineage potential of NPCs during development. The composition of Polycomb Repressive Complex 1 (PRC1) is highly diverse in mammals and was hypothesized to contribute to context-specific regulation of cell fate. Here, we have performed side-by-side comparison of the role of canonical PRC1.2/1.4 and non-canonical PRC1.3/1.5, all of which are expressed in the developing neocortex, in NSC proliferation and differentiation. We found that the deletion of Pcgf2/4 in NSCs led to a strong reduction in proliferation and to altered lineage fate, both during the neurogenic and gliogenic phase, whereas Pcgf3/5 played a minor role. Mechanistically, genes encoding stem cell and neurogenic factors were bound by PRC1 and differentially expressed upon Pcgf2/4 deletion. Thus, rather than different PRC1 sub-complexes contributing to different phases of neural development, we found that canonical PRC1 played a more significant role in NSC regulation during proliferative, neurogenic and gliogenic phases compared to non-canonical PRC1.

developmental biology↗

bioRxiv2024

Sexually dimorphic effects of Amylin 1 receptor activation in trigeminovascular neurons

BackgroundMigraine is more prevalent in women, and although the mechanisms involved in this disparity remain poorly understood, an interaction between the trigeminovascular system and cycling estrogen levels in biologically-predisposed women has been suggested. We investigated the role of amylin 1 (AMY1) receptor activation in the modulation of the trigeminal nociceptive system in female rats across the estrous cycle in cycle stages with falling and rising estrogen levels and compared these to the responses in males. MethodsWe recorded neuronal activity in vivo within the trigeminocervical complex (TCC) and examined the effects of targeting AMY1 receptors on ongoing spontaneous and dural stimulus-evoked firing rates of trigeminovascular neurons. The selective AMY1 receptor agonist pramlintide and AMY1 receptor antagonist AC 187 were used. Estrous cycle stages were identified via cytology from vaginal smears. ResultsAdministration of pramlintide increased the spontaneous activity and dural stimulus-evoked neuronal responses in the TCC, only during falling estrogen phases of the female estrous cycle. Moreover, the administration per se of AC 187 decreased spontaneous evoked firing rates of central trigeminovascular neurons in females and males, whereas pretreatment with AC 187 prevented pramlintide-induced increases in spontaneous activity and dural stimulus-evoked responses in females with falling estrogen levels. ConclusionAMY1 receptors modulate the trigeminal nociceptive system. The facilitating effect is most pronounced in female rats during falling estrogen phases of the estrous cycle. Our data also supports selective AMY1 receptor antagonists as potentially effective targets for the treatment of migraine.

neuroscience↗

bioRxiv2023

Integration of ζ-deficient CARs into the CD3-zeta gene conveys potent cytotoxicity in T and NK cells

I.Chimeric antigen receptor (CAR)-reprogrammed immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in non-physiological regulation of CAR-signaling and limits their accessibility due to logistical challenges, high costs and biosafety requirements. Here, we propose a novel approach utilizing CRISPR-Cas gene editing to redirect T cells and natural killer (NK) cells with CARs. By transferring shorter, truncated CAR-transgenes lacking a main activation domain into the human CD3{zeta} (CD247) gene, functional CAR fusion-genes are generated that exploit the endogenous CD3{zeta} gene as the CARs activation domain. Repurposing this T/NK-cell lineage gene facilitated physiological regulation of CAR-expression and reprogramming of various immune cell types, including conventional T cells, TCR{gamma}/{delta} T cells, regulatory T cells, and NK cells. In T cells, CD3{zeta} in-frame fusion eliminated TCR surface expression, reducing the risk of graft-versus-host disease in allogeneic off-the-shelf settings. CD3{zeta}-CD19-CAR-T cells exhibited comparable leukemia control to T cell receptor alpha constant (TRAC)-replaced and lentivirus-transduced CAR-T cells in vivo. Tuning of CD3{zeta}-CAR-expression levels significantly improved the in vivo efficacy. Compared to TRAC-edited CAR-T cells, integration of a Her2-CAR into CD3{zeta} conveyed similar in vitro tumor lysis but reduced susceptibility to activation-induced cell death and differentiation, presumably due to lower CAR-expression levels. Notably, CD3{zeta} gene editing enabled reprogramming of NK cells without impairing their canonical functions. Thus, CD3{zeta} gene editing is a promising platform for the development of allogeneic off-the-shelf cell therapies using redirected killer lymphocytes. Key pointsO_LIIntegration of {zeta}-deficient CARs into CD3{zeta} gene allows generation of functional TCR-ablated CAR-T cells for allogeneic off-the-shelf use C_LIO_LICD3{zeta}-editing platform allows CAR reprogramming of NK cells without affecting their canonical functions C_LI

immunology↗

bioRxiv2023

Primate-expressed EPIREGULIN promotes basal progenitor proliferation in the developing neocortex

Neocortex expansion during evolution is linked to higher numbers of neurons thought to result from increased proliferative capacity and neurogenic potential of basal progenitor cells (BPs) during development. Here we show that EREG, encoding the growth factor EPIREGULIN, is expressed in the human developing neocortex and in gorilla organoids, but not in the mouse neocortex. Addition of EPIREGULIN to the mouse neocortex increases proliferation of BPs via EGFR-mediated signaling, whereas ablation of EREG in human cortical organoids reduces BP proliferation. Addition of EPIREGULIN to cortical organoids promotes a further increase in proliferation of gorilla but not human BPs. Finally, we identify putative cis-regulatory elements that may contribute to inter-species differences in EREG expression. Overall, our results suggest that species-specific expression of EPIREGULIN may contribute to increased neocortex size in primates by providing a pro-proliferative signal to BPs in the subventricular zone progenitor niche.

developmental biology↗

bioRxiv2023

Phenotypic drought stress prediction of European beech (Fagus sylvatica) by genomic prediction and remote sensing

Current climate change species response models usually not include evolution. We integrated remote sensing with population genomics to improve phenotypic response prediction to drought stress in the key forest tree European beech (Fagus sylvatica L.). We used whole-genome sequencing of pooled DNA from natural stands along an ecological gradient from humid-cold to warm-dry climate. We phenotyped stands for leaf area index (LAI) and moisture stress index (MSI) for the period 2016-2022. We predicted this data with matching meteorological data and a newly developed genomic population prediction score in a Generalised Linear Model. Model selection showed that addition of genomic prediction decisively increased the explanatory power. We then predicted the response of beech to future climate change under evolutionary adaptation scenarios. A moderate climate change scenario would allow persistence of adapted beech forests, but not worst-case scenarios. Our approach can thus guide mitigation measures, such as allowing natural selection or proactive evolutionary management.

evolutionary biology↗

bioRxiv2023

DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts

Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A) drive clonal hematopoiesis of indeterminate potential (CHIP) and are associated with adverse prognosis in patients with heart failure (HF). The interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential interaction partners of CHIP-mutated monocytes using combined transcriptomic data from peripheral blood mononuclear cells of HF patients with and without CHIP and the cardiac tissue. We demonstrate that CHIP augments macrophage-to-cardiac fibroblasts interactions. Mechanistically, the secretome of DNMT3A-silenced monocytes leads to myofibroblast activation, partially through epidermal growth factor (EGFR) signaling. Harboring DNMT3A CHIP-driver mutations is associated with increased cardiac interstitial fibrosis in mice and patients, and, thereby, may contribute to the poor outcome. These findings not only identify a novel pathway of DNMT3A CHIP-driver mutation-induced instigation and progression of HF, but may also provide a rationale for the development of new anti-fibrotic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/521766v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@10a365aorg.highwire.dtl.DTLVardef@176807borg.highwire.dtl.DTLVardef@ed3f47org.highwire.dtl.DTLVardef@1d572b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2021

Antibiofilm agents with therapeutic potential against enteroaggregative Escherichia coli

BackgroundEnteroaggregative Escherichia coli (EAEC) is a predominant but neglected enteric pathogen implicated in infantile diarrhoea and nutrient malabsorption. There are no non-antibiotic approaches to dealing with persistent infection by these exceptional colonizers, which form copious biofilms. We screened the Medicines for Malaria Venture Pathogen Box for chemical entities that inhibit EAEC biofilm formation. MethodologyWe used two EAEC strains, 042 and MND005E, in a medium-throughput crystal violet-based antibiofilm screen. Hits were confirmed in concentration-dependence, growth kinetic and time course assays and activity spectra were determined against a panel of genome-sequenced EAEC. Antibiofilm activity against isogenic EAEC mutants, molecular docking simulations and comparative genomic analysis were used to identify the mechanism of action of one hit. Principal findingsIn all, five compounds (1.25%) reproducibly inhibited biofilm accumulation by at least one strain by 30-85% while inhibiting growth by under 10%. Hits exhibited at least 10-fold greater antibiofilm activity than nitazoxanide, the only known EAEC biofilm inhibitor. Reflective of known EAEC heterogeneity, only one hit was active against both screen isolates, but three hits showed broad antibiofilm activity against a larger panel of strains. Mechanism of action studies point to the EAEC anti-aggregation protein (Aap), dispersin, as the target of compound MMV687800. ConclusionsThis study identified five compounds not previously described as anti-adhesins or Gram-negative antibacterials with significant and specific EAEC antibiofilm activity. One molecule, MMV687800, targets the EAEC Aap. In vitro small-molecule inhibition of EAEC colonization opens a way to new therapeutic approaches to preventing and treating EAEC infection. Author summaryDiarrhoea accounts for over half a million deaths in children under five annually. It additionally contributes to childhood malnutrition as well as growth and development deficiencies, particularly in low-income countries. Enteroaggregative Escherichia coli (EAEC) causes diarrhoea that is often persistent and can also contribute to growth deficiencies in young children. EAEC is a neglected pathogen that is often resistant to antimicrobial drugs. Small molecules that block EAEC colonization may hold the key to interfering with EAEC disease without promoting antimicrobial resistance. We screened the Medicines for Malaria Ventures Pathogen Box for chemicals that can interfere with EAEC biofilm formation, a key colonization indicator. Our screen identified five biofilm-inhibiting molecules that did not interfere with bacterial viability and therefore are unlikely to exert strong pressure for resistance. Molecular biology and computational investigations point to the EAEC anti-aggregative protein, also known as dispersin, as a possible target for one of these hit molecules. Optimizing EAEC antibiofilm hits will create templates that can be employed for resolving EAEC diarrhoea and related infections.

microbiology↗

bioRxiv2021

In-depth immunophenotyping with mass cytometry during TB treatment reveals non-canonical T-cell subsets associated with sputum culture conversion.

Tuberculosis (TB) is a difficult-to-treat infection because of multidrug regimen requirements based on drug susceptibility profiles and treatment observance issues. TB cure is defined by mycobacterial sterilization, technically complex to systematically assess. We hypothesized that microbiological outcome was associated with stage-specific immune changes in peripheral whole blood during TB treatment. The T-cell phenotypes of treated TB patients were prospectively characterized in a blinded fashion using mass cytometry after Mycobacterium tuberculosis (Mtb) antigen stimulation, and then correlated to sputum culture status. At two months of treatment, cytotoxic and terminally differentiated CD8+ T-cells were under-represented and naive CD4+ T-cells were over-represented in positive-versus negative-sputum culture patients, regardless of Mtb drug susceptibility. At treatment completion, an antigen-driven T-cell immune shift towards differentiated subpopulations was associated with TB cure. Overall, we identified specific T-cell profiles associated with slow sputum converters, which brings new insights in TB prognostic biomarker research designed for clinical application. SummaryIn patients treated for pulmonary TB, high-dimensional immune profiling with mass cytometry revealed that Mycobacterium tuberculosis culture conversion is associated with newly characterized peripheral CD8+ T-cell phenotypes. This paves the way for new immune biomarkers associated with mycobacterial sterilization.

immunology↗

bioRxiv2021

Breaking the Crosstalk of the Cellular Tumorigenic Network in NSCLC by a Highly Effective Drug Combination

Non-small cell lung cancer (NSCLC) is commonly diagnosed at advanced stages limiting treatment options. Although, targeted therapy has become integral part of NSCLC treatment therapies often fail to improve patients prognosis. Based on previously published criteria for selecting drug combinations for overcoming resistances, NSCLC patient-derived xenograft (PDX) tumors were treated with a low dose combination of cabozantinib, afatinib, plerixafor and etoricoxib. All PDX tumors treated, including highly therapy-resistant adeno-and squamous cell carcinomas without identifiable driver mutations, were completely suppressed by this drug regimen, leading to an ORR of 81% and a CBR of 100%. The application and safety profile of this low dose therapy regimen was well manageable in the pre-clinical settings. Overall, this study provides evidence of a relationship between active paracrine signaling pathways of the cellular tumorigenic network, which can be effectively targeted by a low-dose multimodal therapy to overcome therapy resistance and improve prognosis of NSCLC.

cancer biology↗

bioRxiv2021

Local density determines nuclear movements during syncytial blastoderm formation in a cricket

Animal embryos pass through an early stage called the blastoderm, in which cells are arranged in a continuous layer at the periphery of the embryo. Despite the broad evolutionary conservation of this embryonic stage, the cellular behaviours that lead to blastoderm formation vary across animals, and the mechanisms that regulate these behaviours are poorly understood. In most insects, pre-blastoderm development begins as a syncytium: that is, many nuclei divide and move throughout the single shared cytoplasm of the embryo. Then these syncytial nuclei must move from their scattered positions within the cytoplasm to form a single layer at the cortex. Recent work showed that in the fruit fly Drosophila melanogaster, some of these early nuclear movements are caused by pulses of cytoplasmic flows that are coupled to synchronous divisions. Here, we show that the cricket Gryllus bimaculatus has an altogether different solution to the problem. We quantified nuclear dynamics during the period of syncytial cleavages and movements that lead to blastoderm formation in G. bimaculatus embryos with transgenically labeled nuclei. We found that: (1) cytoplasmic flows were unimportant for nuclear movement, and (2) division cycles, nuclear speeds, and the directions of nuclear movement were not synchronized across the embryo as in D. melanogaster, but instead were heterogeneous in space and time. Moreover, several aspects of nuclear divisions and movements were correlated with local nuclear density. We show that previously proposed models for the movement of D. melanogaster syncytial nuclei cannot explain the behaviours of G. bimaculatus syncytial nuclei. We introduce a novel geometric model based on asymmetric local pulling forces on nuclei, which recapitulates the density-dependent nuclear speeds and orientations of unperturbed G. bimaculatus embryos, without invoking the common paradigms of localized polarity cues or cell lineage as determinants of nuclear activity. Our model also accurately predicts nuclear behavior in embryos physically manipulated to contain regions of atypical nuclear densities. We show that this model can be used to generate falsifiable predictions about the dynamics of blastoderm formation in other insect species.

developmental biology↗

bioRxiv2020

A SARS-CoV-2 neutralizing antibody protects from lung pathology in a COVID-19 hamster model

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC50 of 3.1 ng/ml. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 [A] revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.

immunology↗