Biology subjects

Zhou, J.

Publications and source records attributed to Zhou, J..

At least 19 recordsLinked to original sources

bioRxiv2026

A cognitive representation in primary visual cortex modulated by vision

Primary visual cortex (V1) is a critical substrate for mammalian vision. Traditionally, visual inputs are thought to be the main drivers of V1 activity, with internal signals playing a modulatory role. Here we show that this relationship is inverted for a large fraction of V1 neurons. In rats completing a navigation task in darkness, these neurons encoded progress along physically distinct paths with a shared turn structure. Under illumination, visual stimuli gain-modulated this path-invariant activity rather than replacing it with stimulus-driven responses. Path-invariant V1 neurons were also preferentially coordinated with hippocampal ensembles during sharp-wave ripples, linking them to a brain-wide network involved in learning. These findings establish that an internal model of the world can serve as a primary driver of activity in sensory cortex.

neuroscience↗

bioRxiv2018

CropMonitor: a scalable open-source experiment management system for distributed plant phenotyping and IoT-based crop management

BackgroundHigh-quality plant phenotyping and climate data lay the foundation of phenotypic analysis as well as genotype-by-environment interactions, which is important biological evidence not only to understand the dynamics between crop performance, genotypes, and environmental factors, but also for agronomists and farmers to monitor crops in fluctuating agricultural conditions. With the rise of Internet of Things technologies in recent years, many IoT-based remote sensing devices have been applied to phenotyping and crop monitoring that generate big plant-environment datasets every day; however, it is still technically challenging to calibrate, annotate, and aggregate big data effectively, especially when they were generated in multiple locations, and often at different scales.\n\nFindingsCropSurveyor is a PHP and SQL based server platform, which provides automated data collation, storage, device and experiment management through IoT-based sensors and distributed plant phenotyping workstations. It provides a two-component solution for monitoring biological experiments and networked devices, with interfaces specifically designed for distributed IoT devices and centralised data servers. Data transfer is performed automatically though an HTTP accessible RESTful API installed on both device-side and server-side of the CropSurveyor system, which synchronise daily representative crop growth images for quick and visual-based crop assessment, as well as detailed microclimate readings for GxE studies. CropSurveyor also supports the comparison of historical and ongoing crop performance whilst different experiments are being conducted.\n\nConclusionsAs an open-source experiment and data management system, CropSurveyor can be used to maintain and collate important crop performance and microclimate datasets captured by IoT sensors and distributed phenotyping installations. It provides near real-time environmental and crop growth monitoring in addition to historical and current data comparison through a single cloud-ready server system. Accessible both locally in the field through smart devices and remotely in an office using a PC, CropSurveyor has been used in wheat field experiments for prebreeding since 2016 and has the potential to enable scalable crop management and IoT-style agricultural practices in the near future.

plant biology↗

bioRxiv2018

A genetically encoded fluorescent sensor for rapid and specific in vivo detection ofnorepinephrine

Norepinephrine (NE) and epinephrine (Epi), two key biogenic monoamine neurotransmitters, are involved in a wide range of physiological processes. However, their precise dynamics and regulation remain poorly characterized, in part due to limitations of available techniques for measuring these molecules in vivo. Here, we developed a family of GPCR Activation-Based NE/Epi (GRABNE) sensors with a 230% peak {Delta}F/F0 response to NE, good photostability, nanomolar-to-micromolar sensitivities, sub-second rapid kinetics, high specificity to NE vs. dopamine. Viral- or transgenic- mediated expression of GRABNE sensors were able to detect electrical-stimulation evoked NE release in the locus coeruleus (LC) of mouse brain slices, looming-evoked NE release in the midbrain of live zebrafish, as well as optogenetically and behaviorally triggered NE release in the LC and hypothalamus of freely moving mice. Thus, GRABNE sensors are a robust tool for rapid and specific monitoring of in vivo NE/Epi transmission in both physiological and pathological processes.

neuroscience↗

bioRxiv2018

Dietary lysozyme supplement alters serum biochemical makers and milk metabolite profile of sows via gut microbiota

Lysozyme is an important antimicrobial agent with promising future in replacing antibiotics in livestok production. The aim of current study was to determine variations in sows gut microbiota, serum immunity and breast milk metabolite profile mediated by lysozyme supplementation.Thirty-six pregnant sows were assigned to a control group without supplementation and two treatments with 0.5 g/kg and 1.0 g/kg lysozyme provided in formula feed for 21days. Microbiota analysis based on 16s RNA high-throughput sequencing and untargeted liquid chromatography tandem mass spectrometry were applied and combined in analysis. Serum biochemical indicators and immunoglobulins were also determined. Sows received 1.0kg/t lyszoyme treatment shown significant redution in microbial diversity. Spirochaetes, Euryarchaeota and Actinobacteria significantly increased while Firmicutes showed a remarkable reduction in 1.0kg/t treated group compared with control. Pyrimidine metabolism,Purine metabolism and Amino acid related enzymes were significantly upregulated in 1.0kg/t lysozyme treated group. The richness of gram-positive bacteria were significantly down-regulated by lysozyme treatments. Serum aspartate transaminase (AST) activity was significantly un-regulated. Serum IgM levels were significantly higher in the 1.0 kg/t group compared with control, while IgA levels was significantly lower in 1.0kg/t group. Over thirty metabolites from sows breast milk including L-Glutamine,creatine and L-Arginine were sigficantly altered by lysozyme treatment. There existed crucial correlations among gut microbiota, serum immunity and breast milk metabolites where lactobacillus and prevotella may play a key role in lysozyme mediated host-microbial interactions. Overall, lysozyme supplementation could effectively improve the composition, metabolic functions and phenotypes of sows gut microbiota and it also benefit sows with better immune status and breast milk composition.\n\nImportanceEnteric infections caused by pathogens have a significant negative effect on neonatal survival and animal health in swine production. The application of antibiotics in feeds at subtherapeutic levels could improve performance and overall health and is used extensively throughout the industry. However, abuse of antibiotics is contributing to the high level of drug resistance in microbial communities and rising concerns regarding human health. Here, we revealed that lysozyme supplementation could effectively improve the composition, metabolic functions and phenotypes of sows gut microbiota and it also benefit sows with better immune status and breast milk composition. These findings confirmed that lysozyme could be a suitable alternative to antibiotics in swine production.

microbiology↗

bioRxiv2018

Selene: a PyTorch-based deep learning library for sequence-level data

To enable the application of deep learning in biology, we present Selene (https://selene.flatironinstitute.org/), a PyTorch-based deep learning library for fast and easy development, training, and application of deep learning model architectures for any biological sequences. We demonstrate how Selene allows researchers to easily train a published architecture on new data, develop and evaluate a new architecture, and use a trained model to answer biological questions of interest.

bioinformatics↗

bioRxiv2018

A general-purpose protein design framework based on mining sequence-structure relationships in known protein structures

The ability to routinely design functional proteins, in a targeted manner, would have enormous implications for biomedical research and therapeutic development. Computational protein design (CPD) offers the potential to fulfill this need, and though recent years have brought considerable progress in the field, major limitations remain. Current state-of-the-art approaches to CPD aim to capture the determinants of structure from physical principles. While this has led to many successful designs, it does have strong limitations associated with inaccuracies in physical modeling, such that a robust general solution to CPD has yet to be found. Here we propose a fundamentally novel design framework--one based on identifying and applying patterns of sequence-structure compatibility found in known proteins, rather than approximating them from models of inter-atomic interactions. Specifically, we systematically decompose the target structure to be designed into structural building blocks we call TERMs (tertiary motifs) and use rapid structure search against the Protein Data Bank (PDB) to identify sequence patterns associated with each TERM from known protein structures that contain it. These results are then combined to produce a sequence-level pseudo-energy model that can score any sequence for compatibility with the target structure. This model can then be used to extract the optimal-scoring sequence via combinatorial optimization or otherwise sample the sequence space predicted to be well compatible with folding to the target. Here we carry out extensive computational analyses, showing that our method, which we dub dTERMen (design with TERM energies): 1) produces native-like sequences given native crystallographic or NMR backbones, 2) produces sequence-structure compatibility scores that correlate with thermodynamic stability, and 3) is able to predict experimental success of designed sequences generated with other methods, and 4) designs sequences that are found to fold to the desired target by structure prediction more frequently than sequences designed with an atomistic method. As an experimental validation of dTERMen, we perform a total surface redesign of Red Fluorescent Protein mCherry, marking a total of 64 residues as variable. The single sequence identified as optimal by dTERMen harbors 48 mutations relative to mCherry, but nevertheless folds, is monomeric in solution, exhibits similar stability to chemical denaturation as mCherry, and even preserves the fluorescence property. Our results strongly argue that the PDB is now sufficiently large to enable proteins to be designed by using only examples of structural motifs from unrelated proteins. This is highly significant, given that the structural database will only continue to grow, and signals the possibility of a whole host of novel data-driven CPD methods. Because such methods are likely to have orthogonal strengths relative to existing techniques, they could represent an important step towards removing remaining barriers to robust CPD.

bioengineering↗

bioRxiv2018

Tertiary structural motif sequence statistics enable facile prediction and design of peptides that bind anti-apoptotic Bfl-1 and Mcl-1

Understanding the relationship between protein sequence and structure well enough to rationally design novel proteins or protein complexes is a longstanding goal in protein science. The Protein Data Bank (PDB) is a key resource for defining sequence-structure relationships that has supported the development of critical resources such as rotamer libraries and backbone torsional statistics that quantify the probabilities of protein sequences adopting different structures. Here, we show that well-defined, non-contiguous structural motifs (TERMs) in the PDB can also provide rich information useful for protein-peptide interaction prediction and design. Specifically, we show that it is possible to rapidly predict the binding energies of peptides to Bcl-2 family proteins as accurately as can be done with widely used structure-based tools, without explicit atomistic modeling. One benefit of a TERM-based approach is that prediction performance is less sensitive to the details of the input structure than are methods that evaluate energies using precise atomic coordinates. We show that protein design using TERM energies (dTERMen) can generate highly novel and diverse peptides to target anti-apoptotic proteins Bfl-1 and Mcl-1. 15 of 17 peptides designed using dTERMen bound tightly to their intended targets, and these peptides have just 15 - 38% sequence identity to any known native Bcl-2 family protein ligand. High-resolution structures of four designed peptides bound to their targets provided opportunities to analyze strengths and limitations of this approach. Dramatic success designing peptides using dTERMen, which comprised going from input structure to experimental validation of high-affinity binders in approximately one month, provides strong motivation for further developing TERM-based approaches to design.

biophysics↗

bioRxiv2018

5-Hydroxymethylcytosines from Circulating Cell-free DNA as Diagnostic and Prognostic Markers for Hepatocellular Carcinoma

The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC), the second-most common cause of cancer deaths worldwide. We sought to develop a clinically convenient and minimally-invasive approach that can be deployed at scale for the sensitive, specific, and highly reliable diagnosis of HCC, and to evaluate the potential prognostic value of this approach. The study cohort comprised of 2,728 subjects, including HCC patients (n = 1,208), controls (n = 965) (572 healthy individuals and 393 patients with benign lesions), as well as patients with chronic hepatitis B infection (CHB) (n =291), liver cirrhosis (LC) (n = 110), and cholangiocarcinoma (CCC) (n = 154), was recruited from three major liver cancer hospitals in Shanghai, China, from July 2016 to November 2017. Circulating cell-free DNA (cfDNA) were collected from plasma samples from these individuals before surgery or any radical treatment. Applying our 5hmC-Seal technique, the summarized 5-hydroxymethylcytosine (5hmC) profiles in cfDNA were obtained. Molecular annotation analysis suggested that the profiled 5hmC loci in cfDNA were enriched with liver tissue-derived regulatory markers (e.g., H3K4me1). We showed that a weighted diagnostic score (wd-score) based on 117 genes detected using the summarized 5hmC profiles in cfDNA accurately distinguished HCC patients from controls (AUC = 95.1%; 95% CI, 93.6-96.5%) in the validation set, markedly outperformed -fetoprotein (AFP) with superior sensitivity. The wd-scores, which not only detected early BCLC stages (e.g., Stage 0: AUC = 96.2%; 95% CI,94.1-98.4%) and small tumors (e.g., < 2 cm: AUC = 95.7%; 95% CI: 93.6-97.7%), also showed high capacity for distinguishing HCC from non-cancer patients with CHB/LC (AUC = 80.2%; 95% CI, 75.8-84.6%). Moreover, the prognostic value of 5hmC markers in cfDNA was evaluated for HCC recurrence, showing that a weighted prognostic score (wp-score) based on 16 marker genes predicted the recurrence risk (HR = 6.67; 95% CI, 2.81-15.82, p < 0.0001) in 555 patients who have been followed up after surgery. In conclusion, we have developed and validated a robust 5hmC-based diagnostic model that can be applied routinely with clinically feasible amount of cfDNA (e.g., from ~2-5 mL of plasma). Applying this new approach in the clinic could significantly improve the clinical outcomes of HCC patients, for example by early detection of those patients with surgically resectable tumors or as a convenient disease surveillance tool for recurrence.

cancer biology↗

bioRxiv2018

An \"inverse approach\" to the treatment of amblyopia

Recent laboratory finding suggest that short-term patching the amblyopic eye (i.e., inverse occlusion) results in a larger and more sustained improvement in the binocular balance compared with normal controls. In this study, we investigate the cumulative effects of the short-term inverse occlusion in adults and old children with amblyopia. A prospective cohort study of 18 amblyopes (10-35 years old; 3 with strabismus) who have been subjected to 2 hours/day of inverse occlusion for 2 months. Patients who required refractive correction or whose refractive correction needed updating were given a 2-month period of refractive adaptation. The primary outcome measure was the binocular balance which was measured using a phase combination task, the secondary outcome measures were the best corrected visual acuity which was measured with a Tumbling E acuity chart and convert to logMAR units and the stereo acuity which was measured with the Random-dot preschool stereotest. The averaged binocular gain was 0.11 in terms of the effective contrast ratio (z = -2.344, p = 0.019, 2-tailed Related samples Wilcoxon Signed Ranks Test). The average acuity gain was 0.14 logMAR equivalent (t(17) = 0.13, p < 0.001, 2-tailed paired samples t-test). The averaged stereo acuity gain was 253 arc seconds (z = -2.689, p = 0.007). Based on more recent research concerning adult ocular dominance plasticity, contrary to current practice, patching the amblyopic eye makes more sense; comparable acuity benefits, better compliance, better binocular outcome and applicable to adults as well as old children.

neuroscience↗

bioRxiv2018

Integrative analysis of Zika virus genome RNA structure reveals critical determinants of viral infectivity

Since its outbreak in 2007, Zika virus (ZIKV) has become a global health threat that causes severe neurological conditions. Here we perform a comparative in vivo structural analysis of the RNA genomes of two ZIKV strains to decipher the regulation of their infection at the RNA level. Our analysis identified both known and novel functional RNA structural elements. We discovered a functional long-range intramolecular interaction specific for the Asian epidemic strains, which contributes to their infectivity. Our findings illuminate the structural basis of ZIKV regulation and provide a rich resource for the discovery of RNA structural elements that are important for ZIKV infection.

molecular biology↗

bioRxiv2018

Ex vivo dynamics of human glioblastoma cells in a microvasculature-on-a-chip system correlates with tumor heterogeneity and subtypes

The perivascular niche (PVN) plays an essential role in brain tumor stem-like cell (BTSC) fate control, tumor invasion, and therapeutic resistance. Herein we report on the use of a microvasculature-on-a-chip system as a PVN model to evaluate the dynamics of BTSCs ex vivo from 10 glioblastoma patients. We observed that BTSCs preferentially localize in the perivascular zone. Live cell tracking revealed that the cells residing in the vicinity of microvessels had the lowest motility, while a fraction of cells on the microvessels unexpectedly possessed the highest motility and migrated over the longest distance. These results indicate that the perivascular zone is a niche for BTSCs, while the microvascular tracks are also a path for long-distance tumor cell migration and invasion. Additionally, the degree of co-localization between tumor cells and microvessels varied significantly across patients. To validate the results from our microvasculature-on-a-chip system, we used single-cell transcriptome sequencing (10 patients and 21,750 single cells in total) to identify the subtype of each tumor cell. The co-localization coefficient was found to correlate positively with proneural (stem-like) or mesenchymal (invasive) but not classical (proliferative) tumor cells. Furthermore, we found that a gene signature profile including PDGFRA correlated strongly with the \"homing\" of brain tumor cells to the PVN. Our findings demonstrated that ex vivo dynamics of human brain tumor cells in a microvasculature-on-a-chip model can recapitulate in vivo tumor cell dynamics, heterogeneity, and subtypes, representing a new route to the study of human tumor cell biology and uncover patient-specific tumor cell functions.

bioengineering↗

bioRxiv2018

Hydroxymethylated-P16 Allele Is Transcription-Inactive

Background5-Methylcytosine can be oxidized into 5-hydroxymethylcytosine (5hmC) in the genome. Methylated-P16 (P16M) can be oxidized into completely hydroxymethylated-P16 (P16H) in human cancer and precancer cells. The aim of this study is to investigate the biological function of P16H.\n\nMethodsTrue P16M and P16H were analyzed using bisulfite/TAB-based assays. A ZFP-based P16-specific dioxygenase (P16-TET) was constructed and used to induce P16H. Cell proliferation and migration were determined with a series of biological analyses.\n\nResults(A) The 5hmCs were enriched in the antisense-strand of the P16 exon-1 in HCT116 and AGS cells containing methylated-P16 alleles (P16M). (B) P16-TET induced both P16H and P16 demethylation in H1299 and AGS cells and reactivated P16 expression. Notably, P16H was only detectable in the sorted P16-TET H1299 and AGS cells that did not show P16 expression. (C) P16-TET significantly inhibited the xenograft growth derived from H1299 cells in NOD-SCID mice, but did not inhibit the growth of P16-deleted A549 control cells. P16-siRNA knockdown could rescue P16-TET-inhibited cell migration.\n\nConclusionHydroxymethylated P16 alleles are transcriptionally inactive.\n\nAUTHOR SUMMARYIt is well known that 5-methylcytosine (5mC) in genomic DNA of mammalian cells can be oxidized into 5-hydroxymethylcytosine (5hmC) and other derivates by DNA dioxygenase TETs. While conversion of 5mC to 5hmC plays an important role in active DNA demethylation through further oxidations, a certain proportion of 5hmCs remain in the genome. Although it is supposed that occurrence of 5hmCs may contribute to the flexibility of chromatin and the protection of the bivalent promoters from hypermethylation, the direct effect of 5hmCs on gene transcription is unknown. In the present study, we engineered a zinc-finger protein-based P16-specific DNA dioxygenase and used it to induce P16 hydroxymethylation and demethylation in cancer cells. Our results demonstrate, for the first time, that the hydroxymethylated P16 alleles retain transcriptionally inactive. This is supported by our recent findings that mRNAs are always transcribed only from the unmethylated P16 strands, but not from the hydroxymethylated/methylated strands in HCT116 cells, and that the risks for malignant transformation are similar for patients with the P16 methylation-positive oral epithelial dysplasia with and without P16 hydroxymethylation in a prospective study.

molecular biology↗

bioRxiv2018

High Postoperative Monocyte Predicts Worse Lung Adenocarcinoma or Squamous Cell Carcinoma Outcomes

BackgroundPeripheral monocyte count is an assessable parameter. Recently, evidence suggested an elevated preoperative monocyte counts predicting poor prognosis in malignancies. The aim of this study was to determine the prognostic effect of early postoperative (within 4 days) blood monocyte count in patients with lung adenocarcinoma or squamous cell carcinoma following lobectomy.\n\nMethodsWe retrospectively reviewed patients with operated lung adenocarcinoma or squamous cell carcinoma from 2006 to 2011 in Western China Lung Cancer database. Both the preoperative and postoperative monocyte counts were divided into two groups. Univariate analysis on disease-free survival (DFS) and overall survival (OS) was performed using the Kaplan-Meier and log-rank tests, and multivariate analysis was conducted using the Cox proportional hazards regression model.\n\nResultsThere were 433 patients enrolled in our analysis. The cut-off values were 0.375*109/L and 0.845*109/L for preoperative and early postoperative monocyte count respectively which were calculated by receiver operating characteristic curve. Two-tailed log-rank test indicated patients with an early postoperative elevated monocyte count predicted a poor DFS and OS overall (P<0.001, P<0.001, respectively) as well as in subgroup analysis. On univariate and multivariate analysis, early postoperative elevated monocyte count presented as a promising independent prognostic factor for both DFS and OS (HR=2.991, 95%CI: 2.243-3.988, P<0.001; HR=2.705, 95%CI: 1.977-3.700, P<0.001, respectively). However, no significance was detected for preoperative monocyte in multivariate analysis.\n\nConclusionsElevated early postoperative peripheral monocyte count is an independent predictor of poor prognosis for patients with operable lung adenocarcinoma or squamous cell carcinoma by lobectomy.

cancer biology↗

bioRxiv2018

Assembly of Mb-size genome segments from linked read sequencing of CRISPR DNA targets

We developed a targeted sequencing method for intact high molecular weight (HMW) DNA targets as large as 0.2 Mb. This process uses HMW DNA isolated from intact cells, custom designed Cas9-guide RNA complexes to generate 0.1 - 0.2 Mb DNA targets, electrophoretic isolation of the DNA targets and sequencing with barcode linked reads. We used alignment methods as well as local assembly of the target regions to identify haplotypes and structural variants (SVs) across multi-Megabase genomic regions. To demonstrate the performance of this approach, we designed three assays that covered a 0.2 Mb region surrounding the BRCA1 gene, a set of 40 overlapping 0.2 Mb targets covering the entire 4-Mb MHC locus, and 18 well-characterized structural variants. Using the highly characterized NA12878 genome, we achieved on-target coverage of more than 50X, while overall whole genome coverage was approximately 4X. We generated haplotypes that completely covered each targeted locus, with a maximum size of 4 Mb (for the MHC region). This method detected structural variants such as deletions and inversions with determination of the exact breakpoints and genotypes. Even breakpoints inside highly homologous segmental duplications are precisely determined with our high-quality assemblies. Overall, this is a new method to sequence large DNA segments.

genomics↗

bioRxiv2018

Molecular layer interneurons shape the spike activity of cerebellar Purkinje cells

One-sentence summaryCerebellar stellate cells and basket cells shape distinct Purkinje cell firing properties\n\nAbstractPurkinje cells receive synaptic input from several classes of interneurons. Here, we address the roles of inhibitory molecular layer interneurons in establishing Purkinje cell function in vivo. Using conditional genetics approaches in mice, we compare how the lack of stellate cell versus basket cell GABAergic neurotransmission sculpts the firing properties of Purkinje cells. We take advantage of an inducible Ascl1CreER allele to spatially and temporally target the deletion of the vesicular GABA transporter, Vgat, in developing neurons. Selective depletion of basket cell GABAergic neurotransmission increases the frequency of Purkinje cell simple spike firing and decreases the frequency of complex spike firing in adult behaving mice. In contrast, lack of stellate cell communication increases the regularity of Purkinje cell simple spike firing while increasing the frequency of complex spike firing. Our data uncover complementary roles for molecular layer interneurons in shaping the rate and pattern of Purkinje cell activity in vivo.

neuroscience↗

bioRxiv2018

Multi-protein Bridging Factor 1(Mbf1), Rps3 and Asc1 prevent stalled ribosomes from frameshifting

Stalled ribosomes in bacteria frameshift, but stalled ribosomes in eukaryotes do not frameshift and abort translation, suggesting that eukaryote-specific mechanisms might prevent frameshifting. We show that the conserved eukaryotic/archaeal protein Mbf1 acts with ribosomal proteins Rps3/uS3 and eukaryotic Asc1/RACK1 to prevent frameshifting at inhibitory CGA-CGA codon pairs in Saccharomyces cerevisiae. Mutations in RPS3 that allow frameshifting implicate eukaryotic conserved residues near the mRNA entry site. Mbf1 and Rps3 cooperate to maintain the reading frame of stalled ribosomes, while Asc1 mediates distinct events that result in aborted translation. Frameshifting occurs through a +1 shift with a CGA codon in the P site and involves competition between codons entering the A site, implying that the wobble interaction of the P site codon destabilizes translation elongation. Thus, eukaryotes have evolved unique mechanisms involving both a universally conserved ribosome component and two eukaryotic-specific proteins to maintain the reading frame at ribosome stalls.

molecular biology↗

bioRxiv2018

Accurate Prediction of Antibody Resistance in Clinical HIV-1 Isolates

Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) have promising utility in prevention and treatment of HIV-1 infection with several undergoing clinical trials. Due to high sequence diversity and mutation rate of HIV-1, viral isolates are often resistant to particular bNAbs. Resistant strains are commonly identified by time-consuming and expensive in vitro neutralization experiments. Here, we developed machine learning-based classifiers that accurately predict resistance of HIV-1 strains to 33 neutralizing antibodies. Notably, our classifiers achieved an overall prediction accuracy of 96% for 212 clinical isolates from patients enrolled in four different clinical trials. Moreover, use of the tree-based machine learning method gradient boosting machine enabled us to identify critical epitope features that distinguish between antibody resistance and sensitivity. The availability of an in silico antibody resistance predictor will facilitate informed decisions of antibody usage in clinical settings.

bioinformatics↗

bioRxiv2018

Dynamic m6A methylation facilitates mRNA triaging to stress granules

Summary blurbm6A-modification in the 5 vicinity of the coding sequence of transcripts provides a selective mechanism for triaging mRNAs to stress granules and is mediated by YTHDF3 reader protein.\n\nAbstractReversible post-transcriptional modifications on messenger RNA emerge as prevalent phenomena in RNA metabolism. The most abundant among them is N6-methyladenosine (m6A) which is pivotal for RNA metabolism and function, its role in stress response remains elusive. We have discovered that in response to oxidative stress, transcripts are additionally m6A-modified in their 5 vicinity. Distinct from that of the translationally-active mRNAs, this methylation pattern provides a selective mechanism for triaging mRNAs from the translatable pool to stress-induced stress granules. These stress-induced newly methylated sites are selectively recognized by the YTH domain family 3 (YTHDF3) reader protein, thereby revealing a new role for YTHDF3 in shaping the selectivity of stress response. Our findings describe a previously unappreciated function for RNA m6A modification in the oxidative-stress response and expand the breadth of physiological roles of m6A.

molecular biology↗