Biology subjects

Zeng, X.

Publications and source records attributed to Zeng, X..

At least 145 records · Page 8Linked to original sources

bioRxiv2023

Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (p=4.79x10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (p=1.22x10-5), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.

genomics↗

bioRxiv2023

FIREBALL: A tool to fit protein phase diagrams based on mean-field theories for polymer solutions

Biomolecular condensates form via phase transitions of condensate-specific biomacromolecules. Intrinsically disordered regions (IDRs) featuring the appropriate sequence grammar can contribute homotypic and heterotypic interactions to the driving forces for phase separation of multivalent proteins. At this juncture, experiments and computations have matured to the point where the concentrations of coexisting dense and dilute phases can be quantified for individual IDRs in complex milieus both in vitro and in vivo. For a macromolecule such as a disordered protein in a solvent, the locus of points that connects concentrations of the two coexisting phases defines a phase boundary or binodal. Often, only a few points along the binodal, especially in the dense phase, are accessible for measurement. In such cases and for quantitative and comparative analysis of parameters that describe the driving forces for phase separation, it is useful to fit measured or computed binodals to well-known mean-field free energies for polymer solutions. Unfortunately, the non-linearity of the underlying free energy functions makes it challenging to put mean-field theories into practice. Here, we present FIREBALL, a suite of computational tools designed to enable efficient construction, analysis, and fitting to experimental or computed data of binodals. We show that depending on the theory being used, one can also extract information regarding coil-to-globule transitions of individual macromolecules. Here, we emphasize the ease-of-use and utility of FIREBALL using examples based on data for two different IDRs. Statement of SignificanceMacromolecular phase separation drives the assembly of membraneless bodies known as biomolecular condensates. Measurements and computer simulations can now be brought to bear to quantify how the concentrations of macromolecules in coexisting dilute and dense phases vary with changes to solution conditions. These mappings can be fit to analytical expressions for free energies of solution to extract information regarding parameters that enable comparative assessments of the balance of macromolecule-solvent interactions across different systems. However, the underlying free energies are non-linear and fitting them to actual data is non-trivial. To enable comparative numerical analyses, we introduce FIREBALL, a user-friendly suite of computational tools that allows one to generate, analyze, and fit phase diagrams and coil-to-globule transitions using well-known theories.

biophysics↗

bioRxiv2023

Vertical transmission of African-lineage Zika virus through the fetal membranes in a rhesus Macaque (Macaca mulatta) model

Zika virus (ZIKV) can be transmitted vertically from mother to fetus during pregnancy, resulting in a range of outcomes, including severe birth defects and fetal/infant death. Potential pathways of vertical transmission in utero have been proposed but remain undefined. Identifying the timing and routes of vertical transmission of ZIKV may help us identify when interventions would be most effective. Furthermore, understanding what barriers ZIKV overcomes to effect vertical transmission may help improve models for evaluating infection by other pathogens during pregnancy. To determine the pathways of vertical transmission, we inoculated 12 pregnant rhesus macaques with an African-lineage ZIKV at gestational day 30 (term is 165 days). Eight pregnancies were surgically terminated at either seven or 14 days post-maternal infection. Maternal-fetal interface and fetal tissues and fluids were collected and evaluated with RT-qPCR, in situ hybridization for ZIKV RNA, immunohistochemistry, and plaque assays. Four additional pregnant macaques were inoculated and terminally perfused with 4% paraformaldehyde at three, six, nine, or ten days post-maternal inoculation. For these four cases, the entire fixed pregnant uterus was evaluated with in situ hybridization for ZIKV RNA. We determined that ZIKV can reach the MFI by six days post-infection and infect the fetus by ten days. Infection of the chorionic membrane and the extraembryonic coelomic fluid preceded infection of the fetus and the mesenchymal tissue of the placental villi. We did not find evidence to support a transplacental route of ZIKV vertical transmission via infection of syncytiotrophoblasts or villous cytotrophoblasts. The pattern of infection observed in the maternal-fetal interface provides evidence of vertical ZIKV transmission through the fetal membranes. Authors SummaryZika virus (ZIKV) can be vertically transmitted from mother to fetus during pregnancy resulting in adverse pregnancy outcomes. For vertical transmission to occur, ZIKV must overcome the barriers of the maternal-fetal interface, yet the exact pathway ZIKV takes remains undefined. The maternal-fetal interface consists of the maternal decidua, the placenta, and the fetal membranes. ZIKV could reach the fetus through the placenta if it can infect the layer of cells that are directly exposed to maternal blood. ZIKV could also reach the fetus by infecting the decidua and then the adjacent fetal membranes. To determine the pathways of ZIKV vertical transmission, we infected pregnant macaques and evaluated ZIKV burden in the maternal-fetal interface and fetus shortly after maternal infection. The pattern of infection observed suggests that ZIKV vertically transmits through the fetal membranes, not the placenta. This finding is significant because it challenges the assumption that vertical transmission occurs exclusively across the placenta. By including the fetal membranes in our models of vertical transmission, we can more accurately determine which pathogens can be vertically transmitted. Ultimately, this study demonstrates that fetal membranes are an essential barrier to pathogens that warrant further investigation.

pathology↗

bioRxiv2023

Transcription factor GLK2 regulates key steps of anthocyanin biosynthesis to antagonize photo-oxidative stress during greening of Arabidopsis seedlings

The greening of young seedling is light induced but vulnerable to photo-oxidative stress at the same time, due to the immature status of chloroplasts. Accumulation of anthocyanin is a protective response to high light, by absorbing excess energy and serving as antioxidant. In this work with Arabidopsis, we found that GARP family transcription factors GOLDEN2-LIKE 2 (GLK2), as a key regulator to chloroplast development, also plays an intensive role in regulating anthocyanin biosynthesis during seedling de-etiolation, especially under high light stress. We demonstrate that GLK2 positively regulates anthocyanin biosynthesis by directly activating the transcription of anthocyanin late biosynthetic genes (LBGs) as well as TRANSPARENT TESTA GLABRA 1 (TTG1) gene, which encodes a key component of the regulatory MYB-bHLH-WDR (MBW) complex (which also activates LBGs). Our data further show that GLK2 and MBW each could activate the expression of DFR gene (key LBG) independently, via distinct promoter regions. We therefore propose a multifaceted involvement of GLK2 in anthocyanin biosynthesis as an important protective measure for developing chloroplasts, against excessive light exposure during seedling photomorphogenesis.

plant biology↗

bioRxiv2023

Spin-coupled electron densities of iron-sulfur cluster imaged by in situ serial Laue diffraction

Iron-sulfur clusters are inorganic cofactors found in many proteins involved in fundamental biological processes including DNA processing. The prokaryotic DNA repair enzyme PhrB, a member of the protein family of cryptochromes and photolyases, carries a four-iron-four-sulfur cluster [4Fe4S] in addition to the catalytic cofactor flavin adenine dinucleotide (FAD) and a second pigment 6,7-dimethyl-8-ribityllumazine (DMRL). The light-induced redox reactions of this multi-cofactor protein complex were recently shown as two interdependent photoreductions of FAD and DMRL mediated by the [4Fe4S] cluster functioning as an electron cache to hold a fine balance of electrons. Here, we apply the more traditional temperature-scan cryo-trapping technique in protein crystallography and the newly developed technology of in situ serial Laue diffraction at room temperature. These diffraction methods in dynamic crystallography enable us to capture strong signals of electron density changes in the [4Fe4S] cluster that depict quantized electronic movements. The mixed valence layers of the [4Fe4S] cluster due to spin coupling and their dynamic responses to light illumination are observed directly in our difference maps between its redox states. These direct observations of the quantum effects in a protein bound iron-sulfur cluster have thus opened a window into the mechanistic understanding of metal clusters in biological systems.

biophysics↗

bioRxiv2022

CoBeL-RL: A neuroscience-oriented simulation framework for complex behavior and learning

Reinforcement learning (RL) has become a popular paradigm for modeling animal behavior, analyzing neuronal representations, and studying their emergence during learning. This development has been fueled by advances in understanding the role of RL in both the brain and artificial intelligence. However, while in machine learning a set of tools and standardized benchmarks facilitate the development of new methods and their comparison to existing ones, in neuroscience, the software infrastructure is much more fragmented. Even if sharing theoretical principles, computational studies rarely share software frameworks, thereby impeding the integration or comparison of different results. Machine learning tools are also difficult to port to computational neuroscience since the experimental requirements are usually not well aligned. To address these challenges we introduce CoBeL-RL, a closed-loop simulator of complex behavior and learning based on RL and deep neural networks. It provides a neuroscience-oriented framework for efficiently setting up and running simulations. CoBeL-RL offers a set of virtual environments, e.g. T-maze and Morris water maze, which can be simulated at different levels of abstraction, e.g. a simple gridworld or a 3D environment with complex visual stimuli, and set up using intuitive GUI tools. A range of RL algorithms, e.g. Dyna-Q and deep Q-network algorithms, is provided and can be easily extended. CoBeL-RL provides tools for monitoring and analyzing behavior and unit activity, and allows for fine-grained control of the simulation via interfaces to relevant points in its closed-loop. In summary, CoBeL-RL fills an important gap in the software toolbox of computational neuroscience.

bioinformatics↗

bioRxiv2022

Frequent first-trimester pregnancy loss in rhesus macaques infected with African-lineage Zika virus

In the 2016 Zika virus (ZIKV) pandemic, a previously unrecognized risk of birth defects surfaced in babies whose mothers were infected with Asian-lineage ZIKV during pregnancy. Less is known about the impacts of gestational African-lineage ZIKV infections. Given high human immunodeficiency virus (HIV) burdens in regions where African-lineage ZIKV circulates, we evaluated whether pregnant rhesus macaques infected with simian immunodeficiency virus (SIV) have a higher risk of African-lineage ZIKV-associated birth defects. Remarkably, in both SIV+ and SIV-animals, ZIKV infection early in the first trimester caused a high incidence (78%) of spontaneous pregnancy loss within 20 days. These findings suggest a significant risk for early pregnancy loss associated with African-lineage ZIKV infection and provide the first consistent ZIKV-associated phenotype in macaques for testing medical countermeasures.

microbiology↗

bioRxiv2022

Cerebral oxygenation and cardiac output responses during short repeated sprints exercise and modulatory effect of glucose ingestion

In this study we investigated changes in concentrations of cerebral oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb), and total haemoglobin (tHb) during repeated sprints and their relationship with cardiac output. We also examined the effect of glucose ingestion and acute hyperglycaemia on cerebral haemoglobin responses. Ten young male participants ingested either a glucose drink (70 g) or a placebo before performing a set of 10 repeated 6-second sprints on a cycle ergometer. Heart rate, stroke volume, and cardiac output were measured continuously using impedance cardiography, while changes in O2Hb, HHb, and tHb in the frontal region of the cerebral cortex were measured using near-infrared spectroscopy (NIRS). The results showed that each sprint elicited a transient increase in O2Hb and to lesser extent HHb concentrations, which was enhanced with the number of sprint repetitions and correlated with cardiac output. After each sprint, O2Hb and HHb quickly returned to baseline, while cardiac output remained elevated. At the end of the repeated sprints, O2Hb was decreased to below pre-exercise levels, while HHb and tHb were elevated. After a recovery of 10-15 min, O2Hb returned to pre-exercise values in the placebo trial, but increased to above pre-exercise values (reactive hyperaemia) in the glucose trial. Our findings suggest that short sprint exercise increases O2Hb, HHb, and tHb levels during exertion in parallel with cardiac output. However, in addition to the transient increase in cerebral haemoglobin, a progressive decline in cerebral oxygen saturation occurs during repeated sprints. Glucose ingestion does not alter cerebral haemoglobin responses to sprint exercise but appears to be associated with faster recovery of O2Hb.

physiology↗

bioRxiv2022

Proliferative Exhausted CD8 T Cells Exacerbate Long-lasting Anti-tumor Effects in Human Papillomavirus Positive Head and Neck Squamous Cell Carcinoma

The survival prognosis of human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) is largely different, and little is known about the anti-tumor mechanism of tumor-infiltrated CD8+ exhausted T cells (Tex) in HNSCC. We performed cell level multi-omics sequencing on human HNSCC samples to decipher the multi-dimensional characteristics of Tex cells. A proliferative exhausted CD8+ T cell cluster (P-Tex) which was beneficial to survival outcomes of patients with HPV-positive HNSCC was identified. Interestingly, P-Tex cells expressed CDK4 genes as high as cancer cells, which could be simultaneously inhibited by CDK4 inhibitors and might be a potential reason for the ineffectiveness of CDK4 inhibitors in treating HPV-positive HNSCC. P-Tex cells could aggregate in the antigen presenting cell niches and activate certain signaling pathways. Together, our findings suggest a promising role for P-Tex cells in the prognosis of patients with HPV-positive HNSCC by providing modest but persistent anti-tumor effects. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/513993v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1f8810forg.highwire.dtl.DTLVardef@1e11d84org.highwire.dtl.DTLVardef@58fb6aorg.highwire.dtl.DTLVardef@1e20a13_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Cultivation of widespread Bathyarchaeia reveals a novel methyltransferase system utilizing lignin-derived aromatics

Anaerobic lignin degradation is a major process in the global carbon cycle that would significantly influence estimates of carbon flux in both terrestrial and marine ecosystems. The ubiquitous Bathyarchaeia, one of the most abundant taxa in marine sediments, have been proposed to be key players in this process. However, the mechanism of Bathyarchaeial lignin degradation is unclear due to the lack of cultured strains. Here we report the cultivation of Candidatus Marisediminiarchaeum ligniniphilus DL1YTT001, a Bathyarchaeial representative from nearshore marine sediments that can grow with lignin as the sole organic carbon source under mesophilic and anaerobic conditions. Strain DL1YTT001 possesses and highly expresses a novel and specific methyltransferase system for O-demethylation of lignin-derived methoxylated aromatic compounds (ArOCH3). The key gene, methyltransferase 1 (MtgB), is not homologous to any other lineages. Enzymatic activity was confirmed through the heterologous expression of the MtgB gene, showing O-demethylation activity with guaiacol as the substrate. Considering that Bathyarchaeial lineages carrying this specific methyltransferase system are widely distributed in diverse anoxic environments, especially lignin-rich nearshore sediments, Bathyarchaeia-mediated O-demethylation is likely a key step in global anaerobic lignin remineralization.

microbiology↗

bioRxiv2022

RNAs undergo phase transitions with lower critical solution temperatures

Co-phase separation of RNAs and RNA-binding proteins is thought to drive the biogenesis of ribonucleoprotein granules. RNAs can also undergo phase transitions in the absence of proteins. However, the physicochemical driving forces of protein-free, RNA-driven phase transitions remain unclear. Here, we report that RNAs of various types undergo phase transitions with system-specific lower critical solution temperatures (LCSTs). This entropically-driven phase behavior requires Mg2+ ions and is an intrinsic feature of the phosphate backbone that is modulated by RNA bases. RNA-only condensates can additionally undergo enthalpically favorable percolation transitions within dense phases. This is enabled by a combination of Mg2+-dependent bridging interactions among phosphate groups and RNA base-stacking / base-pairing. Phase separation coupled to percolation can cause dynamical arrest of RNAs within condensates and can suppress the catalytic activity of an RNase P ribozyme. Our work highlights the need to incorporate RNA-driven phase transitions into models for RNP granule biogenesis.

biophysics↗

bioRxiv2022

HY5 Regulates GLK and GNC Transcription Factors to Orchestrate Photomorphogenesis in Arabidopsis thaliana

Light induced de-etiolation is an important aspect of seedling photomorphogenesis. GOLDEN2 LIKE (GLK) transcriptional regulators are involved in chloroplast development, but to what extent they participate in photomorphogenesis is not clear. Here we show that ELONGATED HYPOCOTYL5 (HY5) binds to GLK promoters to activate their expression, and also interacts with GLK proteins. Chlorophyll content in the de-etiolating Arabidopsis seedlings of the hy5 glk2 double mutants was lower than that in hy5 single mutant. GLKs inhibited hypocotyl elongation, and the phenotype could superimpose on the hy5 phenotype. Correspondingly, GLK2 regulates the expression of photosynthesis and cell elongation genes partially independent of HY5. Before exposed to light, the accumulation of GLK proteins was regulated by DE-ETIOLATED 1 (DET1), while also affected (especially for GLK1) transcriptionally by HY5. The enhanced etioplast development and photosystem gene expression observed in det1 mutant were attenuated in det1 glk2 double mutant. Our study reveals that GLKs act down-stream of HY5 and likely cooperate with HY5 and DET1, to orchestrate multiple developmental traits during the light-induced skotomorphogenesis to photomorphogenesis transition in Arabidopsis. One-sentence summaryGLK and GNC act downstream of HY5, and cooperate with HY5 and DET1, to regulate both chloroplast development and hypocotyl elongation during the transition from skotomorphogenesis to photomorphogenesis.

plant biology↗

bioRxiv2022

Multi-omics integrated analysis reveals a specific phenotype of CD8+ T cell may contribute to immunothromosis via Th17 response in severe and critical COVID-19

T lymphocyte reduction and immunosenescence frequently occur in severe and critical coronavirus disease 2019 (COVID-19) patients, which may cause immunothrombosis and numerous sequelae. This study integrated analyzed multi-omics data from healthy donors, pneumonia, COVID-19 patients (mild & moderate, severe, and critical), and convalescences, including clinical, laboratory test, PBMC bulk RNA-seq, PBMC scRNA-seq and TCR-seq, BAL scRNA-seq, and lung proteome. We revealed that there are certain associations among T lymphocyte reduction, CD8+ T cell senescence, Th17 immune activation, and immunothrombosis. A specific phenotype (S. P.) CD8+ T cells were identified in severe and critical COVID-19 patients in both PBMC and BAL scRNA-seq, which showed highly TCR homology with terminal effector CD8+ T cells and senescent CD8+ T cells. Pseudotime analysis showed that the S. P. CD8+ T cells were located in the transition trajectory from mild to severe disease. Which may be activated by terminal effector CD8+ T cells or senescent CD8+ T cells, thereby promoting Th17 cell differentiation. This phenomenon was absent in healthy donors, mild and moderate COVID-19 patients, or convalescences. Our findings are an important reference for avoiding the conversion of patients with mild to severe diseases and provide insight into the future prevention and control of COVID-19 and its variants.

bioinformatics↗

bioRxiv2022

Two point mutations in protocadherin-1 disrupt Andes hantavirus recognition and afford protection against lethal infection

Andes virus and Sin Nombre virus are the etiologic agents of severe hantavirus cardiopulmonary syndrome (HCPS) in the Americas for which no FDA-approved countermeasures are available. Protocadherin-1 (PCDH1), a cadherin-superfamily protein recently identified as a critical host factor for ANDV and SNV, represents a new antiviral target; however, its precise role remains to be elucidated. Here, we used computational and experimental approaches to delineate the binding surface of the ANDV glycoprotein complex on PCDH1s first extracellular cadherin repeat domain. Strikingly, a single amino acid residue in this PCDH1 surface influenced the host species-specificity of SNV glycoprotein-PCDH1 interaction and cell entry. Mutation of this, and a neighboring residue, substantially protected Syrian hamsters from pulmonary disease and death caused by ANDV. We conclude that PCDH1 is a bona fide entry receptor for ANDV and SNV whose direct interaction with hantavirus glycoproteins could be targeted to develop new interventions against HCPS.

microbiology↗

bioRxiv2022

Distinct Single-cell Immune Ecosystems Distinguish True and De Novo HBV-related Hepatocellular Carcinoma Recurrences

Revealing differential tumor immune microenvironment (TIME) characteristics between true versus de novo hepatocellular carcinoma (HCC) recurrence could help optimal development and use of immunotherapies. Here, we studied the TIME of recurrent HBV-related HCCs by 5and VDJ single-cell and bulk RNA-sequencing, flow cytometry, and multiplexed immunofluorescence. Analyses of mutational profiles, evolutionary trajectories, and clonal architecture using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The TIME of truly recurrent HCCs was characterized by an increased abundance in KLRB1+CD8+ T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+ T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed an upregulated GDF15 expression level on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited anti-tumor immunity in the TIME of truly recurrent lesions. In contrast, we found that myeloid cells crosstalk with T cells mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCC. In conclusion, our results support genomic diagnosis and immune profiling for guiding immunotherapy implementation based on the type of HCC recurrence and TIME. HighlightsO_LITruly recurrent lesions are seeded before primary tumor diagnosis, and that de novo cancer can occur earlier than the clinically used 2-year limit. C_LIO_LIScRNA-seq unravels distinct immune ecosystems in true versus de novo HCC recurrences, highlighting the need for different immunotherapy strategies for two types of HCC recurrence. C_LIO_LICD8+ T cells in de novo recurrence displayed cytotoxic and exhausted phenotypes while those in truly recurrent lesions showed a memory phenotype with weak cytotoxicity. C_LIO_LIHCC cells expressing the inhibitory molecule GDF15 were in the proximity of DCs only in truly recurrent lesions. C_LIO_LIHigh GDF15 expression level was associated with truly recurrent HCC and worse prognosis. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/494526v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@1b76bf0org.highwire.dtl.DTLVardef@10f889aorg.highwire.dtl.DTLVardef@d16b52org.highwire.dtl.DTLVardef@dceb7a_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Massive Horizontal Gene Transfer in Amphioxus Illuminates the Early Evolution of Deuterostomes

Amphioxus is considered the best-known living proxy to the chordate ancestor and an irreplaceable model organism for evolutionary studies of chordates and deuterostomes. In this study, a high-quality genome of the Beihai amphioxus, Branchiostoma belcheri beihai, was de novo assembled and annotated. Within four amphioxus genomes, twenty-eight groups of gene novelties were identified, revealing new genes that lack homologs in non-deuterostome metazoa, but share unexpectedly high similarities with those from non-metazoan species. These gene innovation events have played roles in amphioxus adaptations, including innate immunity responses, glycolysis, and regulation of calcium balance. The gene novelties related to innate immunity, such as a group of lipoxygenases and a DEAD-box helicase, boosted amphioxus immune responses. The novel genes for alcohol dehydrogenase and ferredoxin could aid in the glycolysis of amphioxus. A proximally arrayed cluster of EF-hand calcium-binding protein genes were identified to resemble those of bacteria. The copy number of this gene cluster was negatively correlated to the sea salinity of the collection region, suggesting that it may enhance their survival at different calcium concentrations. This comprehensive study collectively reveals insights into adaptive evolution of cephalochordates and provides valuable resources for research on early evolution of deuterostomes.

evolutionary biology↗

bioRxiv2022

Infection of the maternal-fetal interface and vertical transmission following low-dose inoculation of pregnant rhesus macaques (Macaca mulatta) with an African-lineage Zika virus

BackgroundCongenital Zika virus (ZIKV) infection can result in birth defects, including malformations in the fetal brain and visual system. There are two distinct genetic lineages of ZIKV: African and Asian. Asian lineage ZIKVs have been associated with adverse pregnancy outcomes in humans; however, recent evidence from experimental models suggests that African-lineage viruses can also be vertically transmitted and cause fetal harm. Methodology/Principal FindingsTo evaluate the potential for vertical transmission of African-lineage ZIKV, we inoculated nine pregnant rhesus macaques (Macaca mulatta) subcutaneously with 44 plaque- forming units of a ZIKV strain from Senegal, (ZIKV-DAK). Dams were inoculated either at gestational day 30 or 45. Following maternal inoculation, pregnancies were surgically terminated seven or 14 days later and fetal and maternal-fetal interface tissues were collected and evaluated. Infection in the dams was evaluated via plasma viremia and neutralizing antibody titers pre- and post- ZIKV inoculation. All dams became productively infected and developed strong neutralizing antibody responses. ZIKV RNA was detected in maternal-fetal interface tissues (placenta, decidua, and fetal membranes) by RT-qPCR and in situ hybridization. In situ hybridization detected ZIKV predominantly in the decidua and revealed that the fetal membranes may play a role in ZIKV vertical transmission. Infectious ZIKV was detected in the amniotic fluid of three pregnancies and one fetus had ZIKV RNA detected in multiple tissues. No significant pathology was observed in any fetus; however, we did find an increase in the occurrence of decidual vasculitis and necrosis in ZIKV-exposed pregnancies compared to gestational-age-matched controls. Conclusions/SignificanceThis study demonstrates that African-lineage ZIKV, like Asian-lineage ZIKV, can be vertically transmitted to the macaque fetus during pregnancy. The low inoculating dose used in this study suggests a low minimal infectious dose for rhesus macaques. Vertical transmission with a low dose in macaques further supports the high epidemic potential of African ZIKV strains. Author SummaryZika virus infection during pregnancy can result in adverse pregnancy outcomes including birth defects and miscarriage. There are two distinct genetic backgrounds of Zika virus: Asian-lineage and African-lineage. Currently, only Asian-lineage Zika virus is causally associated with adverse pregnancy outcomes in people. However, experimental studies have shown that African-lineage Zika virus can infect the fetus during pregnancy and cause adverse outcomes. Adverse pregnancy outcomes may not be associated with infection in people until there is an outbreak in a naive population. Thus, as African-lineage Zika virus continues to spread globally, the risk that it may pose to pregnant people remains a public health concern. In this study, we demonstrate that African-lineage Zika virus can be transmitted from the mother to the fetus during pregnancy. This study is significant because we used rhesus macaques, an animal that shares many key elements of Zika virus infection in pregnant people. This study is also significant because we inoculated pregnant macaques with a very small amount of virus, suggesting that fetal infection reported in previously published macaque studies is not limited to high-dose inoculation.

pathology↗

bioRxiv2022

WDR47 facilitates cell-specific ciliogenesis by modulating intraflagellar transport

Cilia are conserved organelles found in many cell types in eukaryotes, and their dysfunction causes defects in environmental sensing and signaling transduction; such defects are termed ciliopathies. Distinct cilia have cell-specific morphologies and exert distinct functions. However, the underlying mechanisms of cell-specific ciliogenesis and regulation are unclear. Here we identified a WD40-repeat (WDR) protein, WDR47/NMTN-1, and show that it is specifically required for ciliogenesis of AWB chemosensory neurons in C. elegans. WDR47/NMTN-1 is expressed in the AWB chemosensory neuron pair, and is localized at the basal body (BB) of the AWB cilia. Knockout of wdr47/nmtn-1 causes abnormal AWB neuron cilia morphology, structural integrity, and induces aberrant AWB-mediated aversive behaviors. We further demonstrate that wdr47/nmtn-1 deletion affects movement of intraflagellar transport (IFT) particles and their cargo delivery in AWB neurons. Our results indicate that WDR47/NMTN-1 is essential for AWB neuron ciliary morphology and function, which reveal a novel mechanism for cell-specific ciliogenesis. Since WDR47/NMTN-1 is conserved in mammals, our findings may help understand the process of cell-specific ciliogenesis and provide insights for treating ciliopathies.

developmental biology↗