Biology subjects

Zhong, J.

Publications and source records attributed to Zhong, J..

At least 91 records · Page 5Linked to original sources

bioRxiv2024

Discriminative histone imputation using chromatin accessibility

Histone modifications (HMs) play a pivot role in various biological processes, including transcription, replication and DNA repair, significantly impacting chromatin structure. These modifications underpin the molecular mechanisms of cell-specific gene expression and complex diseases. However, annotating HMs across different cell types solely using experimental approaches is impractical due to cost and time constraints. Herein, we present dHICA (discriminative histone imputation using chromatin accessibility), a novel deep learning framework that integrates DNA sequences and chromatin accessibility data to predict multiple HM tracks. Employing the Transformer architecture alongside dilated convolutions, dHICA boasts an extensive receptive field and captures more cell-type-specific information. dHICA not only outperforms state-of-the-art baselines but also achieves superior performance in cell-specific loci and gene elements, aligning with biological expectations. Furthermore, dHICAs imputations hold significant potential for downstream applications, including chromatin state segmentation and elucidating the functional implications of SNPs. In conclusion, dHICA serves as an invaluable tool for advancing the understanding of chromatin dynamics, offering enhanced predictive capabilities and interpretability.

bioinformatics↗

bioRxiv2023

Paternal genomic resources from the YanHuang cohort suggested a Weakly-Differentiated Multi-source Admixture model for the formation of Hans founding ancestral lineages

The large-scale human genome revolution and rapidly advanced statistical innovation have updated our understanding of the fine-scale and complex genetic structure, the entire landscape of genetic diversity and the evolutionary trajectories of spatiotemporally different ancients and ethnolinguistically diverse modern populations. Recent ancient DNA research provided a detailed and complex admixture picture of ancient Europeans but limited insights into East Asians as the few available genomes. Y-chromosome variations in the male-specific regions, served as molecular archaeological tool, have unique evolutionary features that can be utilized to reconstruct the origin and subsequent interaction of ancient East Asian paternal lineages. We launched the YanHuang cohort using our designed highest-resolution capture sequencing panel to explore the detailed evolutionary trajectory of the Han Chinese, one of the largest ethnic groups in the world. We reported one of the largest uniparental genomic resources and observed multiple founding paternal lineages dominant in ancient western Eurasian, Siberian and East Asian participating in the formation of the gene pool of the Han Chinese. We identified fine-scale paternal genetic structure correlated with different patterns of ancient population interaction and geographical mountain barriers (Qinling-Huaihe line and Nanling Mountains), suggesting isolation-enhanced and admixture-introduced genetic differentiation enhanced the complexity of the Han Chinese genomic diversity. We observed a strong direct correlation between the frequency of multiple founding lineages of the Han Chinese and the proportion of subsistence-related ancestry sources related to western pastoralists, Holocene Mongolian Plateau people and ancient East Asians, reflecting the ancient migration events contributed to our identified patterns of Chinese paternal genomic diversity. We finally provided one novel and the most plausible admixture-by-admixture model, the Weakly-Differentiated Multi-Source Admixture model, as the major genetic mechanism to illuminate our observed pattern of complex interactions of multiple ancestral sources and landscape of the Han Chinese paternal genetic diversity. Generally, we presented one large-scale uniparental genomic resource from the YanHuang cohort, portrayed one novel admixture formation model and presented the entire genomic landscape with multiple ancestral sources related to ancient herders, hunter-gatherers and farmers who participated in the ancestral formation of the Han Chinese.

evolutionary biology↗

bioRxiv2023

Cartography of the developability landscapes of native and human-engineered antibodies

Designing effective monoclonal antibody (mAb) therapeutics faces a multi-parameter optimization challenge known as "developability", which reflects an antibodys ability to progress through development stages based on its physicochemical properties. While natural antibodies may provide valuable guidance for mAb selection, we lack a comprehensive understanding of natural developability parameter (DP) plasticity (redundancy, predictability, sensitivity) and how the DP landscapes of human-engineered and natural antibodies relate to one another. These gaps hinder fundamental developability profile cartography. To chart natural and engineered DP landscapes, we computed 40 sequence- and 46 structure-based DPs of over two million native and human-engineered single-chain antibody sequences. We found lower redundancy among structure-based compared to sequence-based DPs. Sequence DP sensitivity to single amino acid substitutions varied by antibody region and DP, and structure DP values varied across the conformational ensemble of antibody structures. Sequence DPs were more predictable than structure-based ones across different machine-learning tasks and embeddings, indicating a constrained sequence-based design space. Human-engineered antibodies were localized within the developability and sequence landscapes of natural antibodies, suggesting that human-engineered antibodies explore mere subspaces of the natural one. Our work quantifies the plasticity of antibody developability, providing a fundamental resource for multi-parameter therapeutic mAb design.

bioinformatics↗

bioRxiv2023

Quantitative Learning of Cellular Features From Single-cell Transcriptomics Data Facilitates Effective Drug Repurposing

In this study, we have devised a computational framework SuperFeat that allows for the training of a machine learning model and evaluate the canonical cellular states/features in pathological tissues that underlie the progression of disease. This framework also enables the identification of potential drugs that target the presumed detrimental cellular features. This framework was constructed on the basis of an artificial neural network with the gene expression profiles serving as input nodes. The training data comprised single-cell RNA-seq datasets that encompassed the specific cell lineage during the developmental progression of cell features. A few models of the canonical cancer-involved cellular states/features were tested by such framework. Finally, we have illustrated the drug repurposing pipeline, utilizing the training parameters derived from the adverse cellular states/features, which has yielded successful validation results both in vitro and in vivo. SuperFeat is accessible at https://github.com/weilin-genomics/rSuperFeat.

cell biology↗

bioRxiv2023

Dynamic atP5CS2 Filament Facilitates Substrate Channeling

In plants, the rapid accumulation of proline is a common response to combat abiotic stress. Delta-1-pyrroline-5-carboxylate synthase (P5CS) is a rate-limiting enzyme in proline synthesis, catalyzing the initial two-step conversion from glutamate to proline. Here, we determine the first structure of plant P5CS. Our results show that Arabidopsis thaliana P5CS2 (atP5CS2) can form enzymatic filaments in a substrate-sensitive manner. The destruction of atP5CS filaments by mutagenesis leads to a significant reduction in enzymatic activity. Furthermore, separate activity tests on two domains reveals that filament-based substrate channeling is essential for maintaining the high catalytic efficiency of atP5CS. Our study demonstrates the unique mechanism for the efficient catalysis of P5CS, shedding light on the intricate mechanisms underlying plant proline metabolism and stress response. Therefore these findings provide potential avenues for crop genetically modified breeding.

biochemistry↗

bioRxiv2023

Nifuroxazide enhances radiotherapy efficacy against hepatocellular carcinoma by upregulating PD-L1 degradation via the ubiquitin-proteasome pathway

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

immunology↗

bioRxiv2023

Ancient farmer and steppe pastoralist-related founding lineages contributed to the complex landscape of episodes in the diversification of Chinese paternal lineages

Ancient DNA advances have reported the complex genetic history of Eurasians, but how the knowledge of ancient subsistence strategy shifts and population movements influenced the fine-scale paternal genetic structure in East Asia has not been assessed. Here, we reported one integrated Y-chromosome genomic database of 15,530 people, including 1753 ancient people and newly-reported 919 individuals genotyped using our recently-developed targeted sequencing YHSeqY3000 panel, to explore Chinese genomic diversity, population evolutionary tracts and their genetic formation mechanism. We identified four major ancient technological innovations and population movements that shaped the landscape of Chinese paternal lineages. First, the expansion of millet farmers and early East Asians from the Yellow River Basin carrying the major O2/D subclades promoted the formation of the Sino-Tibetan peoples major composition and accelerated the Tibetan Plateaus permanent occupation. Second, rice farmers dispersal from the Yangtze River Valley carrying O1 and some sublineages of O2 contributed significantly to Tai-Kadai, Austronesian, Hmong-Mien, Austroasiatic people and southern Han Chinese. Third, Siberian-related paternal lineages of Q and C originated and boomed from Neolithic hunter-gatherers from the Mongolian Plateau and the Amur River Basin and significantly influenced the gene pools of northern Chinese. Fourth, western Eurasian-derived J, G and R lineages initially spread with Yamnaya steppe pastoralists and other proto-Indo-European people and further widely dispersed via the trans-Eurasian cultural communication along the Eurasian Steppe and the ancient Silk Road, remaining genetic trajectories in northwestern Chinese. Our work provided comprehensive modern and ancient genetic evidence to illuminate the impact of population interaction from the ancient farmer or herder-based societies on the genetic diversity patterns of modern people, revised our understandings of ancestral sources of Chinese paternal lineages, underscored the scientific imperative of the large-scale genomic resources of dense spatiotemporal underrepresented sampling populations to understand human evolutionary history.

genetics↗

bioRxiv2023

Timing the Evolution of Phosphorus-Cycling 1 Enzymes Through Geological Time

SUMMARY PARAGRAPHPhosphorus plays a crucial role in controlling biological productivity, but geological estimates of phosphate concentrations in the Precambrian ocean, during lifes origin and early evolution, vary over several orders of magnitude1-10. While reduced phosphorus species may have served as alternative substrates to phosphate11, their bioavailability on the early Earth remains unknown. Here, we reconstruct the phylogenomic record of life on Earth and find that phosphate transporting genes (pnas) evolved in the mid-Archean (ca. 3.2 Ga) and are consistent with phosphate concentrations above modern levels (>3 M). The first gene optimized for low phosphate levels (pstS; <1 M) appeared around 2.9 Ga. Most enzymatic pathways for metabolising reduced phosphorus emerged and expanded across the tree of life in the Neoarchean to Paleoproterozoic (ca. 2.6 to 1.8 Ga). This includes phosphonate-catabolising CP-lyases, phosphite-oxidising pathways and hypophosphite-oxidising pathways. CP-lyases are particularly abundant in dissolved phosphate concentrations below 0.1 M. Our results thus indicate declining phosphate levels through the Archean, possibly linked to increasing deposition of phosphate-scavenging iron oxides, which may have limited productivity. However, reduced phosphorus species did not become widely used until after the Paleoproterozoic Great Oxidation Event (2.3 Ga), possibly linked to an expansion of the biosphere at that time.

evolutionary biology↗

bioRxiv2023

Aminomutation catalyzed by CO2 self-sufficient cascade amino acid decarboxylases

Molecular editing of an amino group from -position of amino acids to its {beta}-position is of scientific interest and could be economically appealing. Here we reconstructed an in vitro biotransformation pathway composed of two cascade decarboxylases, i.e., aspartate {beta}-decarboxylase and aspartate -decarboxylase, and implemented molecular editing to change -alanine into {beta}-alanine. In it, we discovered a new reaction of aspartate {beta}-decarboxylase that can fix CO2 directly. This cascade enzymatic pathway enabled an aminomutation reaction with 100% carbon atom economy. This work presented the first CO2-fixing biological reaction catalyzed by the amino acid decarboxylases and demonstrated a new means for the molecular editing of -amino acids.

biochemistry↗

bioRxiv2023

Acquired Cross-resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC paralogs

Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here we present a pre-clinical system that recapitulates acquired cross-resistance in SCLC, developed from 51 patient-derived xenografts (PDXs). Each model was tested for in vivo sensitivity to three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These functional profiles captured hallmark clinical features, such as the emergence of treatment-refractory disease after early relapse. Serially derived PDX models from the same patient revealed that cross-resistance was acquired through a MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that this was not unique to one patient, as MYC paralog amplifications on ecDNAs were recurrent among cross-resistant models derived from patients after relapse. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC. SIGNIFICANCESCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC.

cancer biology↗

bioRxiv2023

Mammalian PIWI-piRNA-target complexes reveal features for broad and efficient target-silencing

The PIWI-interacting RNA (piRNA) pathway is an adaptive defense system wherein piRNAs guide PIWI-family Argonaute proteins to recognize and silence ever-evolving selfish genetic elements and ensure genome integrity. Driven by this intensive host-pathogen arms race, piRNA pathway and its targeted transposons have co-evolved rapidly in a species-specific manner, but how the piRNA pathway specifically adapts to target silencing in mammals remains elusive. Here, we show that mouse MILI and human HILI piRISCs bind and cleave targets more efficiently than their invertebrate counterpart from sponge Ephydatia fluviatilis. The inherent functional differences comport with structural features identified by cryo-EM studies of piRISCs. In the absence of target, MILI and HILI piRISCs adopt a wider nucleic-acid-binding channel and display an extended prearranged piRNA seed as compared to EfPiwi piRISC, consistent with their ability to capture targets more efficiently than EfPiwi piRISC. In the presence of target, the seed gate--which enforces seed-target fidelity in microRNA RISC--adopts a relaxed state in mammalian piRISC, revealing how MILI and HILI tolerate seed-target mismatches to broaden the target spectrum. A vertebrate-specific lysine distorts the piRNA seed, shifting the trajectory of the piRNA-target duplex out of the central cleft and toward the PAZ lobe. Functional analyses reveal that this lysine promotes target binding and cleavage. Our study therefore provides a molecular basis for the piRNA targeting mechanism in mouse and human, and suggests that mammalian piRNA machinery can achieve broad target silencing using a limited supply of piRNA species.

molecular biology↗

bioRxiv2023

Distinguished biological adaptation architecture aggravated population differentiation of Tibeto-Burman-speaking people inferred from 500 whole genome data from 39 populations

Tibeto-Burman (TB) people have tried to adapt to the hypoxic, cold and high-UV high-altitude Tibetan Plateau and complex disease exposure in the lowland wet and hot rainforest since the late Paleolithic period. However, the full landscape of genetic history and biological adaptation of geographically diverse TB people and their interaction mechanism remained unknown. We generated a whole-genome-based meta-database of 500 individuals from 39 TB populations from East Asia and Southeast Asia and presented a comprehensive landscape of genetic diversity, admixture history and differentiated adaptative features of geographically different TB people. We identified geography/language-related genetic differentiation among Tibetan Plateau, Tibetan-Yi-Corridor (TYC) and Southeast Asian TB people, consistent with their differentiated admixture process with incoming or indigenous ancestral source populations. A robust genetic connection between TYC people and ancient YR people supported the Northern origin hypothesis of TB people. We reported population substructure-related differentiated biological adaptative signatures between highland Tibetans and lowland TB people and between geographically different Lolo speakers. Highland adaptative EPAS1 and EGLN variants riched in Tibetans but lacked in TYC people whose adaptation is associated with the physical features and skin pigmentation (EDAR and SLC24A5), hepatic alcohol metabolism (ALDH9A1), regulation of cell-cell adhesion of muscle cells (CTNNA3) and immune/fat metabolism-related adaptative signature. TB-related genomic resources provided new insights into the genetic basis of phenotype differences and better reference for the anthropologically-informed sampling design in biomedical and genomic cohort research.

genetics↗

bioRxiv2023

CytoSIP: An annotated structural atlas for interactions involving cytokine or cytokine receptor

Cytokines primarily interact with specific cytokine receptors on the cell surface as essential signal transduction pathways in many physiological and pathological processes. Therapeutic agents targeting cytokine-cytokine receptor (CK-CKR) interactions lead to the disruption in cellular signaling function and have been demonstrated effective in the treatment of many diseases including tumors. However, a lack of universal and quick access to annotated structural surface regions on CK/CKR has limited the progress of a structure-driven approach to the development of targeted macromolecular drugs and precision medicine therapeutics. Herein we develop CytoSIP (Single nucleotide polymorphisms (SNPs), Interface, and Phenotype), a rich internet application based on a database of atomic interactions around hotspots in experimentally determined CK/CKR structural complexes. The content of the CytoSIP database includes the following key features: (1) SNPs on CK/CKR; (2) interactions involving CK/CKR at the domain level, including CK/CKR interfaces, oligomeric interfaces, epitopes, or other drug targeting surfaces; and (3) diseases and phenotypes associated with CK/CKR or SNPs. The database introduces a unique tri-level SIP data model to link genetic variants (atomic level) to disease phenotypes (organism level) using protein structure (complexes) as an underlying framework (molecule level). Moreover, CytoSIP implements screening criteria and tools to allow customized selection of relevant subset of CK/CKR for the study of interest. This reduces the time and resources needed to interrogate large datasets and allows rapid screening of cytokines and cytokine receptor proteins interfaces for hotspots targeted drug design and any other specific cellular signaling/function mechanisms and their correlation to pathologies. The CytoSIP framework crafted herein bridges CK/CKR genotype with phenotype, facilitating not only the panoramic investigation of the context-dependent crosstalk between CK/CKR but also the development of targeted therapeutic agents. CytoSIP portal website is publicly accessible at https://CytoSIP.biocloud.top.

immunology↗

bioRxiv2023

Insulin-like Growth Factor-1 Supplementation Promotes Kidney Development and Alleviate Renal Inflammation in Preterm Pigs

BackgroundPreterm birth and its associated complications cause disruption of normal prenatal renal development, leading to postnatal kidney injury and failure. Preterm infants are deficient in insulin-like growth factor 1 (IGF-1), a critical growth factor that stimulates tissue perfusion and development. Using necrotizing enterocolitis-sensitive preterm pigs as a model for preterm infants, we investigated whether IGF-1 supplementation during early life could improve kidney development and health. MethodsCaesarean-delivered preterm pigs were allocated into two groups, either consistently receiving vehicle or IGF-1 immediately after birth for 5, 9 or 19 days. Postnatal age-matched term pigs were selected and served as term control on postnatal day (PND) 5, 9, and 19. Blood, urine and kidney tissue were collected for biochemical, histological and gene expression analyses. ResultsPreterm pigs showed impaired kidney development and increased kidney insults, as indicated by reduced average glomerular area, increased abnormal glomeruli percentage and increased markers of renal injury and inflammation compared to term pigs. IGF-1 supplementation significantly reduced the abnormal glomeruli percentage, renal injury and inflammation related markers, and up-regulated certain maturation-related genes on PND5. ConclusionIGF-1 supplementation supports kidney maturation and restoration of kidney insults after preterm birth in the early life of newborns. ImpactO_LIPreterm birth disrupts kidney development in preterm pigs. C_LIO_LIPreterm birth leads to kidney injury and inflammation in preterm pigs. C_LIO_LIIGF-1 supplementation might promote kidney maturation and alleviate preterm birth associated kidney injury and inflammation in preterm pigs. C_LI

physiology↗

bioRxiv2023

Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia

Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be fully elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited lipid dysmetabolism and deficits in phagocytosis, a critical microglia function. Our cumulative data implicate an effect of ALS-linked PFN1 on the autophagy pathway, including enhanced binding of mutant PFN1 to the autophagy signaling molecule PI3P, as an underlying cause of defective phagocytosis in ALS-PFN1 iMGs. Indeed, phagocytic processing was restored in ALS-PFN1 iMGs with Rapamycin, an inducer of autophagic flux. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and highlight microglia vesicular degradation pathways as potential therapeutic targets for these disorders.

neuroscience↗

bioRxiv2023

Use of Artificial Intelligence for Automated Detection and Surveillance of Red Imported Fire Ants Nests

The red imported fire ant, Solenopsis invicta Buren is a destructive invasive species that has spread around the world. Early detection of S. invicta nests is critical for effective monitoring and control in invaded regions. This study presents a novel surveillance system for S. invicta nests combining artificial intelligence and robotic dogs. The system was designed with intelligent recognition algorithms to accurately identify S. invicta nests. With a precision rate of 95%, the system yielded efficient detection of S. invicta nests with increased sensitivity and low missing and false discovery rates, which can aid or even replace humans in locating and delivering pesticides to fire ant nests in open fields to effective control of this invasive pest.

ecology↗

bioRxiv2023

GbyE: A New Genome Wide Association and Prediction Model based on Genetic by Environmental Interaction

Nowadays, studies on genetic by environment interactions (GxE) are receiving increasing attention because of its theoretical and practical importance in explaining individual behavioral traits. Use information from different environments to improve the statistical power of genome-wide association and prediction in the hope of obtaining individuals with better breeding value is the most expedient way. However, there are significant challenges when performing genome-wide association studies (GWAS) and genomic selection (GS) using multiple environments or traits, mainly because most diseases and quantitative traits have numerous associated loci with minimal effects. Therefore, this study constructed a new genotype design model program (GbyE) for genome-wide association and prediction using Kronecker product, which can enhance the statistical power of GWAS and GS by utilizing the interaction effects of multiple environments or traits. The data of 282 maize, 354 yaks and 255 peaches were used to evaluate the power of the model at different levels of heritability and genetic correlation. The results show that GbyE can provide higher statistical power for the traditional GWAS and GS models in any heritability and genetic correlation, and can detect more real loci. In addition, GbyE has increased statistical power to three Bayesian models (BRR, BayesA, and BayesCpi). GbyE can make full use of multiple environment or trait informations to increase the statistical power of the model, which can help us understand the GxE and provide a method for predicting association loci for complex traits.

bioinformatics↗

bioRxiv2023

Multi-species atlas resolves an axolotl limb development and regeneration paradox

Humans and other tetrapods are considered to require apical-ectodermal-ridge, AER, cells for limb development, and AER-like cells are suggested to be re-formed to initiate limb regeneration. Paradoxically, the presence of AER in the axolotl, the primary regeneration model organism, remains controversial. Here, by leveraging a single-cell transcriptomics-based multi-species atlas, composed of axolotl, human, mouse, chicken, and frog cells, we first established that axolotls contain cells with AER characteristics. Surprisingly, further analyses and spatial transcriptomics revealed that axolotl limbs do not fully re-form AER cells during regeneration. Moreover, the axolotl mesoderm displays part of the AER machinery, revealing a novel program for limb (re)growth. These results clarify the debate about the axolotl AER and the extent to which the limb developmental program is recapitulated during regeneration.

developmental biology↗