Biology subjects

Yang, Z.

Publications and source records attributed to Yang, Z..

At least 433 records · Page 24Linked to original sources

bioRxiv2022

Hiplot: a comprehensive and easy-to-use web service boosting publication-ready biomedical data visualization

Modern web techniques provide an unprecedented opportunity for leveraging complex biomedical data generating in clinical, omics, and mechanism experiments. Currently, the functions for carrying out publication-ready biomedical data visualization represent primary technical hurdles in the state-of-art omics-based web services, whereas the demand for visualization-based interactive data mining is ever-growing. Here, we propose an easy-to-use web service, Hiplot (https://hiplot.com.cn), equipping with comprehensive and interactive biomedical data visualization functions (230+) including basic statistics, multi-omics, regression, clustering, dimensional reduction, meta-analysis, survival analysis, risk modeling, etc. We used the demo and real datasets to demonstrate the usage workflow and the core functions of Hiplot. It permits users to conveniently and interactively complete a few specialized visualization tasks that previously could only be done by senior bioinformatics or biostatistics researchers. A modern web client with efficient user interfaces and interaction methods has been implemented based on the custom components library and the extensible plugin system. The versatile output can also be produced in different environments via using the cross-platform portable command-line interface (CLI) program, Hctl. A switchable view between the editable data table and the file uploader/path selection could facilitate data importing, previewing, and exporting, while the plumber-based response strategy significantly reduced the time costs for generating basic scientific graphics. Diversified layouts, themes/styles, and color palettes in this website allow users to create high-quality and publication-ready graphics. Researchers devoted to both life and data science may benefit from the emerging web service.

bioinformatics↗

bioRxiv2022

Differential expression of Nanog 3UTR and coding region mRNA components defines an embryonic stem cell niche

Differential expression of mRNA coding sequences (CDSs) and 3untranslated regions (UTRs) is widespread, yet whether these domains contribute independently to cellular function remains unclear. Here, using Nanog as a model, we find that Nanog mRNA domain usage is spatially organized in mouse and human pluripotent cells and in the blastocyst, with cells enriched in 3UTR transcripts marking colony borders and cells enriched for the Nanog CDS located interior. Functional perturbation reveals a marked asymmetry between mRNA domains. Loss of the Nanog 3UTR leads to defects in colony architecture, cell spreading and morphogenetic behavior, accompanied by decreased extracellular matrix modeling gene expression and ROCK dependent cytoskeletal organization. In contrast, deletion of the Nanog CDS primarily disrupts epithelial polarity-associated transcriptional programs and the expression of chromatin regulators, consistent with a dominant role for the Nanog protein in transcriptional and epigenetic control. These domain specific effects are not redundant but instead reflect separable regulatory activities encoded within a single transcript. Together, these findings demonstrate that distinct regions of a single mRNA can encode separable and asymmetric biological functions, revealing mRNA domain usage as a distinct regulatory layer through which genes can encode multiple biological outputs beyond protein coding capacity.

developmental biology↗

bioRxiv2022

Development of a ferritin-based nanoparticle vaccine against the SARS-CoV-2 Omicron variant

A new SARS-CoV-2 variant named Omicron (B.1.1.529) discovered initially in South Africa has recently been proposed as a variant of concern (VOC) by the World Health Organization, because of its high transmissibility and resistance to current vaccines and therapeutic antibodies. Therefore, rapid development of vaccines against prevalent variants including Omicron is urgently needed for COVID-19 prevention. Here, we designed a self-assembling ferritin-based nanoparticle (FNP) vaccine against the SARS-CoV-2 Omicron variant. The purified Fc-RBDOmicron automatically formed a dimer depending on the nature of the Fc tag, thus assembling onto the nanoparticles by the Fc-protein A tag interaction (FNP-Fc-RBDOmicron). The results of hACE2-transgenic mice immunization showed that SARS-CoV-2 Omicron RBD-specific IgG titer induced by FNP-Fc-RBDOmicron was much higher than that by Fc-RBDOmicron. Consistently, the sera showed a higher neutralizing activity against SARS-CoV-2 Omicron BA.1 and BA.2 in the FNP-Fc-RBDOmicron immunized mice, indicating that immunization of a self-assembling ferritin-based nanoparticle vaccine offers a robust humoral immune response against Omicron variants. This study offers a great potential for the quick response of the emerging SARS-CoV-2 variants and affords versatility to develop universal vaccines against other emerging and reemerging coronaviruses in the future.

microbiology↗

bioRxiv2022

Seasonality but not photoperiodism affects susceptibility of the two-spotted spider mite, Tetranychus urticae Koch (Acari: Tetranychidae) to pesticides

Understanding how endogenous and exogenous factors such as annual seasonal rhythm and photoperiodism affect the toxicity of pesticides can help design integrated pest management strategies. The two-spotted spider mite Tetranychus urticae Koch (Acari: Tetranychidae), a worldwide phytophagous pest species distributed in areas with different time zones, is a good model to explore how the photoperiodism and seasonality affect the pesticide toxicity. In this study, we conducted a laboratory experiment from March 2017 to November 2018 where spider mites were reared at three photoperiod regimes in environmentally controlled incubators. The toxicities of two acaricides, propargite and diafenthiruon, were measured on T. urticae every month. To determine potential mechanisms underlying the changes in the acaricide toxicity, we measured body size and total GSTs activity with the toxicity measurements in 2018. Our results showed that the toxicities of the two acaricides were not significantly different among the three photoperiod regimes. However, both had a consistent trend along the season which increased in the spring and summer and decreased in the winter in all photoperiod regimes for two consecutive years, suggesting seasonality be an endogenous factor affecting the susceptibility of the spider mites to pesticide. Pearsons correlation analyses showed only the body size had a weak negative correlation with the acaricide toxicities, suggesting a minor contribution to the higher toxicity from the smaller size of T. urticae. Our study is the first to show that seasonality can have an endogenous effect on the pesticide toxicity, and the results can inform practical insights into the pest management strategies.

zoology↗

bioRxiv2022

Proteogenomics analysis to identify acquired resistance-specific alterations in melanoma PDXs on MAPKi therapy

Therapeutic approaches to treat melanoma include small molecule drugs that target activating protein mutations in pro-growth signaling pathways like the MAPK pathway. While beneficial to the approximately 50% of patients with activating BRAFV600 mutation, mono- and combination therapy with MAPK inhibitors is ultimately associated with acquired resistance. To better characterize the mechanisms of MAPK inhibitor resistance in melanoma, we utilize patient-derived xenografts and apply proteogenomic approaches leveraging genomic, transcriptomic, and proteomic technologies that permit the identification of resistance-specific alterations and therapeutic vulnerabilities. A specific challenge for proteogenomic applications comes at the level of data curation to enable multi-omics data integration. Here, we present a proteogenomic approach that uses custom curated databases to identify unique resistance-specific alternations in melanoma PDX models of acquired MAPK inhibitor resistance. We demonstrate this approach with a NRASQ61L melanoma PDX model from which resistant tumors were developed following treatment with a MEK inhibitor. Our multi-omics strategy addresses current challenges in bioinformatics by leveraging development of custom curated proteogenomics databases derived from individual resistant melanoma that evolves following MEK inhibitor treatment and is scalable to comprehensively characterize acquired MAPK inhibitor resistance across patient-specific models and genomic subtypes of melanoma.

bioinformatics↗

bioRxiv2022

A Robust and Automated Spike Sorting Method based on the Density Peaks

ObjectiveSpike sorting is a fundamental step in extracting single-unit activity from neural ensemble recordings, which play an important role in basic neuroscience and neurotechnologies. A few algorithms have been applied in spike sorting. However, when noise level or waveform similarity becomes relatively high, their robustness still faces a big challenge. ApproachIn this study, we propose a spike sorting method combining Linear Discriminant Analysis (LDA) and Density Peaks (DP) for feature extraction and clustering. Relying on the joint optimization of LDA and DP: DP provides more accurate classification labels for LDA, LDA extracts more discriminative features to cluster for DP, and the algorithm achieves high performance after iteration. We first compared the proposed LDA-DP algorithm with several algorithms on one publicly available simulated dataset and one real rodent neural dataset with different noise levels. We further demonstrated the performance of the LDA-DP method on a real neural dataset from non-human primates with more complex distribution characteristics. Main resultsThe results show that our LDA-DP algorithm extracts a more discriminative feature subspace and achieves better cluster quality than previously established methods in both simulated and real data. Especially in the neural recordings with high noise levels or waveform similarity, the LDA-DP still yields a robust performance with automatic detection of the number of clusters. SignificanceThe proposed LDA-DP algorithm achieved high sorting accuracy and robustness to noise, which offers a promising tool for spike sorting and facilitates the following analysis of neural population activity.

neuroscience↗

bioRxiv2022

dbDEMC 3.0: Functional Exploration of Differentially Expressed miRNAs in Cancers of Human and Model Organisms

microRNAs (miRNAs) are important regulators in gene expression. The deregulation of miRNA expression is widely reported in the transformation from physiological to pathological state of cells. A large amount of differentially expressed miRNAs (DEMs) have been identified in various human cancers by using high-throughput technologies, such as microarray and miRNA-seq. Through mining of published researches with high-throughput experiment information, the database of differentially expressed miRNAs in human cancers (dbDEMC) was constructed with the aim of providing a systematic resource for the storage and query of the DEMs. Here we report an update of the dbDEMC to version 3.0, containing two-fold more data entries than the previous version, now including also data from mouse and rat. The dbDEMC 3.0 contains 3,268 unique DEMs in 40 different cancer types. The current datasets for differential expression analysis have expanded to 9 generalized categories. Moreover, the current release integrates functional annotations of DEMs obtained from experimentally validated targets. The annotations can greatly benefit integrative analysis of DEMs. In summary, dbDEMC 3.0 provides a valuable resource for characterizing molecular functions and regulatory mechanisms of DEMs in human cancers. The dbDEMC 3.0 is freely accessible at https://www.biosino.org/dbDEMC.

bioinformatics↗

bioRxiv2022

Anatomical connectivity profile development constrains medial-lateral topography in the dorsal prefrontal cortex

The prefrontal cortex (PFC) is a highly variable, evolutionarily expanded brain region that is engaged in multiple cognitive processes. The subregions of the PFC mature relatively late compared with other brain regions, and the maturation times vary between these subregions. Among these, the dorsomedial and dorsolateral prefrontal cortex (dmPFC and dlPFC) share a parallel topographic pattern of functional connectivity, while participating in different types of complex behaviors. However, the developmental trajectories of the two areas remain obscure. In this study, we uncovered differences in the developmental trends of the dmPFC and dlPFC. These differences were mainly caused by structural and functional changes in the medial area of the superior frontal gyrus (SFG). The developmentally different arealization patterns were verified using multiple parcellation approaches with multimodal data, including structural magnetic resonance imaging (sMRI), diffusion MRI (dMRI), resting state functional MRI (rfMRI), and a publicly available transcriptomic dataset. Human brain gene expression data was also used to perform downstream analyses, which could inform us about the potential biological mechanisms underlying the developmentally different arealizations. Furthermore, behavioral analyses hinted at the effects of regionalization on ontogeny. In brief, this study revealed a tendency toward a medial-lateral prefrontal division and can provide a fuller understanding of the potential underlying genetic underpinnings as well as of the potential effects on developmental behavior.

neuroscience↗

bioRxiv2022

The impact of multigenerational high-fat diet feeding on the gut microbiome and host metabolism

Although human genetics partially explain the heritability of obesity and type 2 diabetes (T2D), the human gut microbiome also plays a significant role. While changes in human genetics at the population level occur only after many generations, the gut microbiome evolves over a shorter time span. The gut microbiome is also vertically transmitted across generations, therefore, changes in one generation can be passed on to subsequent generations. However, it is unknown whether the gut microbiome influences natural selection of its host under obesogenic pressure. Here, we show that C57BL/6 mice fed a high-fat diet (60% fat, HFD) over four generations develop resistance to obesity and the metabolic syndrome (MetS). Unexpectedly, the mice were increasingly leaner as well as more glucose tolerant and insulin sensitive across generations. This phenomenon was attributed to the most obese mice not yielding progenies, whereas the leanest mice successfully reproduced, and their offspring were also resistant to obesity. In other words, a population bottleneck was observed. Because all the mice were nearly genetically identical inbred C57BL/6J mice, the large variation in body weight gain in response to HFD feeding was likely independent of genetics. We explored whether microbial factors enriched in obesity-resistant mice promote healthier host metabolic phenotypes under HFD feeding, thereby contributing to the heterogeneity in body weight gain and providing an adaptive advantage to the host. Pearson correlation analysis revealed that body weight gain was positively correlated with Lactococcus lactis, as well as negatively correlated with Lactobacillus johnsonii and pathways for coenzyme A biosynthesis, amino acid biosynthesis (lysine, isoleucine, valine), and nucleotide biosynthesis (adenosine, guanosine). Overall, we observed multigenerational adaptation in the gut microbiome correlated with improved metabolism, yet further studies are needed to validate that these adaptations drive metabolic health.

microbiology↗

bioRxiv2021

Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody

The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies has been limited by the continuous emergence of viral variants, and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly conserved regions on Omicron variant RBD recognized by broadly neutralizing antibodies. Based on this finding, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant RBD as revealed by Cryo-EM structures. This inhalable antibody exhibited exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. The structures also deciphered an uncommon cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.

immunology↗

bioRxiv2021

5-aminolevulinic acid-photodynamic therapy ameliorates cutaneous granuloma by killing drug-resistant Mycobacterium marinum

BackgroundAlthough 5-aminolevulinic acid photodynamic therapy (ALA-PDT) has been extensively used to treat to various skin disease, the application of ALA-PDT on cutaneous infection caused by Mycobacterium marinum (M. marinum), especially by drug-resistant M. marinum is still not clear. ObjectivesWe evaluated the therapeutic efficacy of ALA-PDT on M. marinum in a mouse infection model and tested its killing effect on M. marinum in vitro. Finally, we investigated the clinical effect of ALA-PDT in treating cutaneous granuloma caused by drug-resistant M. marinum. Materials and methodsWe isolated total 9 strains of M. marinum from patients and confirmed by morphological and molecular approaches. The strains were identified by anti-mycobacterial susceptibility. Then we evaluated the killing effect of ALA-PDT on M. marinum in vitro and in a mouse model to observe the antimycobacterial effect of ALA-PDT. Therapeutic efficacy was further assessed in patients with cutaneous granuloma caused by drug-resistant M. marinum. ResultsWe demonstrated that the ALA-PDT directly killed M. marinum in vitro. The paws cutaneous lesions of mice caused by M. marinum were fully recovered 2 weeks after ALA-PDT treatment. However, there was no significant difference for immune cells in peripheral blood before and after ALA-PDT therapy. Finally, ALA-PDT proved to be effective in treat two patients with cutaneous infection caused by drug-resistant M. marinum. ConclusionsThe results suggest that ALA-PDT is effective in treating M. marinum cutaneous infections by killing M. marinum directly, independent of systemic immune responses. The data highlight the ALA-PDT as a promising therapeutic choice for M. marinum infection, especially for drug-resistant strains.

microbiology↗

bioRxiv2021

The SPEECHLESS-induced stomatal increase is required for the salt tolerance of oil palm

Oil palm is the most productive oil producing plant. Salt stress leads to growth damage and decrease in yield of oil palm. However, the physiological responses of oil palm to salt stress and their underlying mechanisms are not clear. RNA-Seq for leaf samples from young palms challenged under three levels of salts (100, 250 and 500 mM NaCl) and control for 14 days was conducted. Diverse signalling pathways were involved in responses to different levels of salt stress. All the three levels of salt stress activated EgSPCH expression and induced stomatal density of oil palm, which was contrasting to that in Arabidopsis. Under strong salt stress group, oil palm removed excessive salt via stomata. Overexpression of EgSPCH in Arabidopsis increased the stomatal production but lowered the salt tolerance. These data suggest that in oil palm, salt activates EgSPCH to generate more stomata in response to salt stress. Our results shed a light on the cellular response to salt stress of oil palm and provide new insights into the mechanisms of different salt-induced stomatal development between halophytes and glycophytes.

plant biology↗

bioRxiv2021

Significant cross-species gene flow detected in the Tamias quadrivittatus group of North American chipmunks

In the past two decades genomic data have been widely used to detect historical gene flow between species in a variety of plants and animals. The Tamias quadrivittatus group of North America chipmunks, which originated through a series of rapid speciation events, are known to undergo massive amounts of mitochondrial introgression. Yet in a recent analysis of targeted nuclear loci from the group, no evidence for cross-species introgression was detected, indicating widespread cytonuclear discordance. The study used heuristic methods that analyze summaries of the multilocus sequence data to detect gene flow, which may suffer from low power. Here we use the full likelihood method implemented in the Bayesian program BPP to reanalyze these data. We take a stepwise approach to constructing an introgression model by adding introgression events onto a well-supported binary species tree. The analysis detected robust evidence for multiple ancient introgression events affecting the nuclear genome, with introgression probabilities reaching 65%. We estimate population parameters and highlight the fact that species divergence times may be seriously underestimated if ancient cross-species gene flow is ignored in the analysis. Our analyses highlight the importance of using adequate statistical methods to reach reliable biological conclusions concerning cross-species gene flow.

evolutionary biology↗

bioRxiv2021

Serum Amyloid A promotes Acetaminophen-induced liverinjury by damaging sinusoidal endothelial cell and exacerbating platelet aggregation in liver

BackgroundAcetaminophen (APAP) is the most commonly used non-prescription antipyretic and analgesic drugs. Overuse of APAP can cause hepatotoxicity. Liver sinusoidal endothelial cells (LSECs) damage is an important early event in APAP-induced liver injury. Serum amyloid A (SAA) is an acute phase protein that mainly produced by hepatocytes, and promotes endothelial dysfunction via a pro-inflammatory and pro-thrombotic effect in atherosclerosis and renal disease. However, the role of SAA in APAP-induced liver injury remains unclear. MethodsIn this study, we used neutralizing antibody (anti-SAA) or antagonistic small peptide derived from sequence of human SAA1/2 (SAA-pep) to block the functional activity of Saa1/2 in mouse serum. Immunohistochemistry staining, Evans blue and platelet adhesion assays were performed to examine the liver damage, the integrity of sinusoidal endothelium and platelets accumulation in APAP-induce liver injury. ResultsOur study showed that in the early stage of APAP-induced acute liver injury in mice, the intrahepatic and serum Saa1/2 levels were significantly increased within 24 hours, and then gradually reduced to normal level from 3 days. Neutralization of Saa1/2 by antibodies or peptides effectively prevented the destruction of hepatic sinusoids, reduced the intrahepatic hemorrhage and platelet accumulation in liver, as well as increased the survival rate of mice treated with lethal dose of APAP. In vitro experiments showed that Saa1/2 aggravated LSECs death induced by APAP. Moreover, Saa1/2 promoted platelets adhesion on LSECs via Tlr2/Vcam-1 axis. ConclusionOur findings suggest that Saa1/2 promotes APAP-induced liver injury by damaged LSECs and exacerbated platelets aggregation. This study provides a potential target for intervention of acute liver injury/failure caused by hepatotoxic drugs such as APAP.

pharmacology and toxicology↗

bioRxiv2021

A novel Phytophthora sojae effector PsFYVE1 modulates transcription and alternative splicing of immunity related genes by targeting host RZ-1A protein

Oomycete pathogens secrete many effectors to manipulate plant immunity and promote infection. However, relatively few effector types have been well characterized. In this study, members of a FYVE domain-containing protein family that is highly expanded in oomycetes were systematically identified, and one secreted protein, PsFYVE1, was selected for further study. PsFYVE1 enhanced Phytophthora infection in Nicotiana benthamiana and was necessary for P. sojae virulence. The FYVE domain of PsFYVE1 had PI3P-binding activity that depended on four conservative amino acid residues. Furthermore, PsFYVE1 targeted RNA-binding proteins RZ-1A/1B/1C in N. benthamiana and soybean, and silencing of NbRZ-1A/1B/1C genes attenuates plant immunity. NbRZ-1A was associated with spliceosome that included three important components, NbGRP7, NbGRP8, and NbU1-70K. Notably, PsFYVE1 could disrupt NbRZ-1A-NbGRP7 interaction. RNA-seq and subsequent experimental analysis demonstrated that PsFYVE1 and NbRZ-1A not only co-regulated transcription of NbHCT, NbEIN2, and NbSUS4 genes but also modulated pre-mRNA alternative splicing (AS) of the NbNSL1 gene, which participated in plant immunity. Collectively, these findings indicate that the FYVE domain-containing protein family includes potential new effector types and also highlight that plant pathogen effectors can regulate plant immunity related genes at both transcription and AS levels to promote disease. Author summaryMany plant pathogenic oomycetes secrete effector proteins into plants to facilitate infection. Discovering potential repertoire of novel effectors and corresponding molecular mechanisms are major themes in the study of oomycete-plant interactions. Here, we characterized a FYVE domain-containing protein (PsFYVE1) in P. sojae. PsFYVE1 carries a functional secretory signal peptide and is a virulence-essential effector for P. sojae infection. We demonstrated that PsFYVE1 interacted with a class of plant RNA-binding proteins, including soybean GmRZ-1A/1B/1C and N. benthamiana NbRZ-1A/1B/1C. Silencing of NbRZ-1A/1B/1C proteins increased Phytophthora infection and suppressed plant defense. Furthermore, NbRZ-1A interacted with the spliceosome components, and PsFYVE1 disrupted association between NbRZ-1A and spliceosome component NbGRP7. We examined the global transcription and alternative splicing (AS) changes regulated by PsFYVE1 and NbRZ-1A, which indicated that PsFYVE1 and NbRZ-1A co-regulated transcription and pre-mRNA AS of immunity-related genes. Thus, this study identifies a novel virulence-related effector from P. sojae and a class of positive regulators of plant immunity, and reveals a detailed mechanism of effector-medicated transcription and AS regulation during pathogen-plant interactions.

pathology↗

bioRxiv2021

Deep-BGCpred: A unified deep learning genome-mining framework for biosynthetic gene cluster prediction

Natural products produced by microorganisms constitute an important source of essential pharmaceuticals, including antimicrobial and anti-tumor drugs. These bioactive molecules are microbial secondary metabolites synthesized by co-localized genes termed Biosynthetic Gene Clusters (BGCs). The rapid increase of microbial genomics resources, due to the availability of high-throughput sequencing technologies, has spurred the development of computational methods for microbial genome mining for BGC discovery. Current machine learning methods, however, have limited successes in uncovering novel BGCs due to an excessive number of false positives in their predictions. To this end, we propose Deep-BGCpred, a framework that effectively addresses the aforementioned issue by improving a deep learning model termed DeepBGC. The new model embeds multi-source protein family domains and employs a stacked Bidirectional Long Short-Term Memory model to boost accuracy for BGC identifications. In particular, it integrates two customized strategies, sliding window strategy and dual-model serial screening, to improve the models performance stability and reduce the number of false positive in BGC predictions. We compare the proposed model against other well-established methods on common benchmarks and achieve new state-of-the-art results with convincing evidences. We expect that researchers working on genome mining for natural products may be greatly benefited from our newly proposed method, Deep-BGCpred.

bioinformatics↗

bioRxiv2021

Cbln1 regulates axon growth and guidance in multiple neural regions

The accurate construction of neural circuits requires the precise control of axon growth and guidance, which is regulated by multiple growth and guidance cues during early nervous system development. It is generally thought that the growth and guidance cues that control the major steps of axon guidance have been defined. Here, we describe cerebellin-1 (Cbln1) as a novel cue that controls diverse aspects of axon growth and guidance throughout the central nervous system (CNS). Cbln1 has previously been shown to function in late neural development to influence synapse organization. Here we find that Cbln1 has an essential role in early neural development. Cbln1 is expressed on the axons and growth cones of developing commissural neurons and functions in an autocrine manner to promote axon growth. Cbln1 is also expressed in intermediate target tissues and functions as an attractive guidance cue. We find that these functions of Cbln1 are mediated by neurexin-2 (Nrxn2), which functions as the Cbln1 receptor for axon growth and guidance. In addition to the developing spinal cord, we further show that Cbln1 functions in diverse parts of the CNS with major roles in cerebellar parallel fiber growth and retinal ganglion cell axon guidance. Despite the prevailing role of Cbln1 as a synaptic organizer, our study discovers a new and unexpected function for Cbln1 as a general axon growth and guidance cue throughout the nervous system. Impact statementDespite the prevailing role of Cbln1 as a synaptic organizer, our study discovers a new and unexpected function for Cbln1 as a general axon growth and guidance cue throughout the nervous system.

neuroscience↗

bioRxiv2021

Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer

Broadly-neutralizing antibodies (bNAbs) against HIV-1 Env can protect from infection. We characterize Ab1303 and Ab1573, heterologously-neutralizing CD4-binding site (CD4bs) antibodies, isolated from sequentially-immunized macaques. Ab1303/Ab1573 binding is observed only when Env trimers are not constrained in the closed, prefusion conformation. Fab-Env cryo-EM structures show that both antibodies recognize the CD4bs on Env trimer with an occluded-open conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4. The occluded-open Env trimer conformation includes outwardly-rotated gp120 subunits, but unlike CD4-bound Envs, does not exhibit V1V2 displacement, 4-stranded gp120 bridging sheet, or co-receptor binding site exposure. Inter-protomer distances within trimers measured by double electron-electron resonance spectroscopy suggest an equilibrium between occluded-open and closed Env conformations, consistent with Ab1303/Ab1573 binding stabilizing an existing conformation. Studies of Ab1303/Ab1573 demonstrate that CD4bs neutralizing antibodies that bind open Env trimers can be raised by immunization, thereby informing immunogen design and antibody therapeutic efforts.

immunology↗