bioRxiv Science⌕ Search

Biology subjects

Zhang, T.

Publications and source records attributed to Zhang, T..

At least 469 records · Page 26Linked to original sources

Endotaxis: A Universal Algorithm for Mapping, Goal-Learning, and Navigation

An animal entering a new environment typically faces three challenges: explore the space for resources, memorize their locations, and navigate towards those targets as needed. Experimental work on exploration, mapping, and navigation has mostly focused on simple environments - such as an open arena [68], a pond [42], or a desert [44] - and much has been learned about neural signals in diverse brain areas under these conditions [12, 54]. However, many natural environments are highly structured, such as a system of burrows, or of intersecting paths through the underbrush. Similarly, for many cognitive tasks, a sequence of simple actions can give rise to complex solutions. Here we propose an algorithm that learns the structure of a complex environment, discovers useful targets during exploration, and navigates back to those targets by the shortest path. It makes use of a behavioral module common to all motile animals, namely the ability to follow an odor to its source [4]. We show how the brain can learn to generate internal "virtual odors" that guide the animal to any location of interest. This endotaxis algorithm can be implemented with a simple 3-layer neural circuit using only biologically realistic structures and learning rules. Several neural components of this scheme are found in brains from insects to humans. Nature may have evolved a general mechanism for search and navigation on the ancient backbone of chemotaxis.

neuroscience↗

Top2a promotes the development of social behavior via PRC2 and H3K27me3

Human infants exhibit innate social behaviors at birth, yet little is understood about the embryonic development of sociality. We screened 1120 known drugs and found that embryonic inhibition of topoisomerase II (Top2a) resulted in lasting social deficits in zebrafish. In mice, prenatal Top2 inhibition caused behavioral defects related to core symptoms of autism, including impairments in social interaction and communication. Mutation of Top2a in zebrafish caused downregulation of a set of genes highly enriched for genes associated with autism in humans. Both the Top2a-regulated and autism-associated gene sets possess binding sites for polycomb repressive complex 2 (PRC2), a regulatory complex responsible for H3K27 trimethylation. Moreover, both gene sets are highly enriched for H3K27me3. Inhibition of PRC2 component Ezh2 rescued social deficits caused by Top2 inhibition. Therefore, Top2a is a key component of an evolutionarily conserved pathway that promotes the development of social behavior through PRC2 and H3K27me3.

animal behavior and cognition↗

Mechanical stimulation promotes enthesis injury repair by mobilizing Prx1+ cells via ciliary TGF-β signaling

Proper mechanical stimulation can improve rotator cuff enthsis injury repair. However, the underlying mechanism of mechanical stimulation promoting injury repair is still unknown. In this study, we found that Prx1+ cell was essential for murine rotator cuff enthesis development identified by single-cell RNA sequence and involved in the injury repair. Proper mechanical stimulation could promote the migration of Prx1+ cells to enhance enthesis injury repair. Meantime, TGF-{beta} signaling and primary cilia played an essential role in mediating mechanical stimulation signaling transmission. Proper mechanical stimulation enhanced the release of active TGF-{beta}1 to promote migration of Prx1+ cells. Inhibition of TGF-{beta} signaling eliminated the stimulatory effect of mechanical stimulation on Prx1+ cell migration and enthesis injury repair. In addition, knockdown of Pallidin to inhibit TGF-{beta}R2 translocation to the primary cilia or deletion of IFT88 in Prx1+ cells also restrained the mechanics-induced Prx1+ cells migration. These findings suggested that mechanical stimulation could increase the release of active TGF-{beta}1 and enhance the mobilization of Prx1+ cells to promote enthesis injury repair via ciliary TGF-{beta} signaling.

cell biology↗

Effects of short-term salinity exposure on haemolymph osmolality, gill morphology and Na+/K+ - ATPase activity in Solenaia oleivora

In order to explore the physiological reaction to hyperosmotic environment, Solenaia oleivora were exposed to 2.23{per thousand} salinity. In 48h, the hemolymph osmolality kept increasing, and the hemolymph protein concentration increased in the first 6h and then decreased significantly, while the free amino acid content increased in the first 24h and then kept stable (P < 0.05). The activity of Na+/K+-ATPase at 0h was significantly higher than other times in most organs except intestine, which was highest at 3h (P < 0.05). The ions concentration were also influenced. The concentration of Na+ rose in haemolymph, axe foot and intestine, but decreased in gill and hepatopancreas. In hemolymph, gill, hepatopancreases and adductor muscle, the K+ concentration was the highest at 0h, while in axe foot and intestine, it showed a positive tendency. The concentration of Cl- in haemolymph, adductor muscle, intestine and axe foot were positively correlated with treatment time, while hepatopancreas showed opposite tendency. High salinity stress caused a difference in the gill histological structure, the gill structure shrunk, the gill lamellas space and shrinking degree showed an enlarging trend with salinity treatment time.

animal behavior and cognition↗

Large-scale miRNA-Target Data Analysis to Discover miRNA Co-regulation Network of Abiotic Stress Tolerance in Soybeans

Although growing evidence shows that microRNA (miRNA) regulates plant growth and development, miRNA regulatory networks in plants are not well understood. Current experimental studies cannot characterize miRNA regulatory networks on a large scale. This information gap provides a good opportunity to employ computational methods for global analysis and to generate useful models and hypotheses. To address this opportunity, we collected miRNA-target interactions (MTIs) and used MTIs from Arabidopsis thaliana and Medicago truncatula to predict homologous MTIs in soybeans, resulting in 80,235 soybean MTIs in total. A multi-level iterative bi-clustering method was developed to identify 483 soybean miRNA-target regulatory modules (MTRMs). Furthermore, we collected soybean miRNA expression data and corresponding gene expression data in response to abiotic stresses. By clustering these data, 37 MTRMs related to abiotic stresses were identified including stress-specific MTRMs and shared MTRMs. These MTRMs have gene ontology (GO) enrichment in resistance response, iron transport, positive growth regulation, etc. Our study predicts soybean miRNA-target regulatory modules with high confidence under different stresses, constructs miRNA-GO regulatory networks for MTRMs under different stresses and provides miRNA targeting hypotheses for experimental study. The method can be applied to other biological processes and other plants to elucidate miRNA co-regulation mechanisms.

plant biology↗

Azacytidine targeting SARS-CoV-2 viral RNA as a potential treatment for COVID-19

The COVID-19 pandemic is a global health disaster. Moreover, emerging mutated virus strains present an even greater challenge for existing vaccines and medications. One possible solution is to design drugs based on the properties of virus epigenome, which are more common among coronaviruses. Here, we reported an FDA-approved drug for myelodysplastic syndrome, azacytidine (5Aza), limited virus infection and protected mice against SARS-CoV-2. We demonstrated that this antiviral effect is related to 5Aza incorporation into viral RNA, which disrupt m5C RNA methylation modification profile. This work suggests that targeting viral epigenomes is a viable therapeutic strategy, potentially opening new pathways for treating COVID-19.

microbiology↗

ROS signalling requires uninterrupted electron flow and is lost during ageing in flies

Mitochondrial Reactive Oxygen Species (mtROS) are cellular messengers essential for cellular homeostasis. In response to stress, reverse electron transport (RET) by respiratory complex I generates high levels of mtROS. Suppression of ROS produced via RET (ROS-RET) reduces survival under stress, while activation of ROS-RET extends lifespan in basal conditions. Here, we demonstrate that ROS-RET signalling requires increased electron entry and uninterrupted electron flow through the electron transport chain (ETC). We found that ROS-RET is abolished in old fruit flies where electron flux is reduced. Instead, mitochondria in aged flies produce consistently high levels of mtROS. Finally, we demonstrate that in young flies reduction of electron exit from the ETC, but not electron entry, phenocopies mtROS generation observed in old individuals. Our results define the mechanism by which ROS signalling is lost during ageing. HighlightsO_LIROS-RET signalling requires an uninterrupted flow of electrons through the ETC. C_LIO_LIROS-RET signalling fails during ageing, with mitochondria producing persistently high levels of ROS. C_LIO_LIInterruption of ROS-RET signalling compromises stress adaptation in old flies. C_LIO_LIReducing electron exit suppresses ROS-RET signalling and phenocopies ROS production observed in old mitochondria. C_LI

physiology↗

Elamipretide (SS-31) Treatment Attenuates Age-Associated Post-Translational Modifications of Heart Proteins

It has been demonstrated that elamipretide (SS-31) rescues age-related functional deficits in the heart but the full set of mechanisms behind this have yet to be determined. We investigated the hypothesis that elamipretide influences post-translational modifications to heart proteins. The S-glutathionylation and phosphorylation proteomes of mouse hearts were analyzed using shotgun proteomics to assess the effects of aging on these post-translational modifications and the ability of the mitochondria-targeted drug elamipretide to reverse age-related changes. Aging led to an increase in oxidation of protein thiols demonstrated by increased S-glutathionylation of cysteine residues on proteins from Old (24 months old at the start of the study) mouse hearts compared to Young (5-6 months old). This shift in the oxidation state of the proteome was almost completely reversed by 8-weeks of treatment with elamipretide. Many of the significant changes that occurred were in proteins involved in mitochondrial or cardiac function. We also found changes in the mouse heart phosphoproteome that were associated with age, some of which were partially restored with elamipretide treatment. Parallel reaction monitoring of a subset of phosphorylation sites revealed that the unmodified peptide reporting for Myot S231 increased with age, but not its phosphorylated form and that both phosphorylated and unphosphorylated forms of the peptide covering cMyBP-C S307 increased, but that elamipretide treatment did not affect these changes. These results suggest that changes to thiol redox state and phosphorylation status are two ways in which age may affect mouse heart function, which can be restored by treatment with elamipretide.

cell biology↗

A method for simultaneously monitoring phloem and xylem reconnections in grafted watermelon seedlings

Grafting is an effective way to increase watermelon tolerance to biotic and abiotic stresses. However, the survival of grafted seedlings largely depends on successful graft formation. Therefore, understanding the graft formation process, particularly the vascular reconnection process is of critical importance. This study found that lignin in watermelon stem shows strong auto-fluorescence under blue-light excitation which makes blue-light excited fluorescent tracers (FTs) such as 5(6)-carboxy fluorescein diacetate (CFDA) become unsuitable for assaying vascular connectivity in watermelon. In contrast, UV-light excited esculin and red-light excited acid fuchsin were proved to be efficient FTs for monitoring the phloem and xylem connectivity, respectively, in self-grafted watermelon. Furthermore, a combined application of esculin to the scion cotyledon and acid fuchsin to the rootstock root enabled simultaneous monitoring of the phloem and xylem connectivity in individual self-grafted watermelon seedlings. In addition, this method is also applicable in investigating the phloem and xylem reconnections in self-grafted melon and cucumber, and heterograft of watermelon, melon and cucumber onto pumpkin rootstock. Based on this established method, we found that phloem and xylem reconnections are not timely separated in self-grafted watermelon. Furthermore, low temperature and removal of the rootstock cotyledons both delayed the vascular reconnection process in watermelon. In conclusion, this new method provides a convenient, accurate and rapid way to analyze the vascular connectivity not only in watermelon, but also in other cucurbit crops.

plant biology↗

Genome-wide RNA structure changes during human neurogenesis drive gene regulatory networks

The distribution, dynamics and function of RNA structures in human development is under- explored. Here, we systematically assayed RNA structural dynamics and its relationship with gene expression, translation and decay during human neurogenesis. We observed that the human ESC transcriptome is globally more structurally accessible than that of differentiated cells; and undergo extensive RNA structure changes, particularly in the 3UTR. Additionally, RNA structure changes during differentiation is associated with translation and decay. We also identified stage-specific regulation as RBP and miRNA binding, as well as splicing is associated with structure changes during early and late differentiation, respectively. Further, RBPs serve as a major factor in structure remodelling and co-regulates additional RBPs and miRNAs through structure. We demonstrated an example of this by showing that PUM2-induced structure changes on LIN28A enable miR-30 binding. This study deepens our understanding of the wide-spread and complex role of RNA-based gene regulation during human development.

molecular biology↗

Untangling Microbiota Diversity and Assembly Patterns in the World's Largest Water Diversion Canal

Large water diversion projects are important constructions for reallocation of human-essential water resources. Deciphering microbiota dynamics and assembly mechanisms underlying canal water ecosystem services especially during long-distance diversion is the prerequisite for water quality monitoring, biohazard warning and sustainable management. Using a 1432-km canal of the South-to-North Water Diversion Projects as a model system, we answer three central questions: how bacterial and micro-eukaryotic communities spatio-temporally develop, how much ecological stochasticity contributes to microbiota assembly, and which immigrating populations better survive and navigate across the canal. We applied quantitative ribosomal RNA gene sequence analyses to investigate canal water microbial communities sampled over a year, as well as null model- and neutral model-based approaches to disentangle the microbiota assembly processes. Our results showed clear microbiota dynamics in community composition driven by seasonality more than geographic location, and seasonally dependent influence of environmental parameters. Overall, bacterial community was largely shaped by deterministic processes, whereas stochasticity dominated micro-eukaryotic community assembly. We defined a local growth factor (LGF) and demonstrated its innovative use to quantitatively infer microbial proliferation, unraveling taxonomically dependent population response to local environmental selection across canal sections. Using LGF as a quantitative indicator of immigrating capacities, we also found that most micro-eukaryotic populations (82%) from the source lake water sustained growth in the canal and better acclimated to the hydrodynamical water environment than bacteria (67%). Taxa inferred to largely propagate include Limnohabitans sp. and Cryptophyceae, potentially contributing to water auto-purification. Combined, our work poses first and unique insights into the microbiota assembly patterns and dynamics in the worlds largest water diversion canal, providing important ecological knowledge for long-term sustainable water quality maintenance in such a giant engineered system.

microbiology↗

Lineage-specific regulatory changes in the pathological cardiac remodeling of hypertrophy cardiomyopathy unraveled by single-nucleus RNA-seq and spatial transcriptomics

BACKGROUNDHypertrophy cardiomyopathy (HCM) is the most common cardiac genetic disorder with the histopathological features of cardiomyocyte hypertrophy and cardiac fibrosis. The pathological remodeling that occurs in the myocardium of HCM patients may ultimately progress to heart failure and death. A thorough understanding of the cell type-specific changes in the pathological cardiac remodeling of HCM is crucial for developing successful medical therapies to prevent or mitigate the progression of this disease. METHODSWe performed single-nucleus RNA-seq of the cardiac tissues from 10 HCM patients and 2 healthy donors, and conducted spatial transcriptomic assays of 4 cardiac tissue sections from 3 HCM patients. Comparative analyses were performed to explore the lineage-specific changes in expression profile, subpopulation composition and intercellular communication in the cardiac tissues of HCM patients. Based on the results of independent analyses including pseudotime ordering, differential expression analysis, and differential regulatory network analysis, we prioritized candidate therapeutic targets for mitigating the progression to heart failure or attenuating the cardiac fibrosis in HCM. Using the spatial transcriptomic data, we examined the spatial activity patterns of the key candidate genes, pathways and subpopulations. RESULTSUnbiased clustering of 55,122 nuclei from HCM and healthy conditions revealed 9 cell lineages and 28 clusters. Significant expansion of vascular-related lineages and contraction of cardiomyocytes, fibroblasts and myeloid cells in HCM were observed. The transcriptomic dynamics during the transition towards the failing state of cardiomyocytes in HCM were uncovered. Candidate target genes for mitigating the progression to heart failure in HCM were obtained such as FGF12, IL31RA, BDNF, S100A1, CRYAB and PROS1. The transcriptomic dynamics underlying the fibroblast activation were also uncovered, and candidate targets for attenuating the cardiac fibrosis in HCM were obtained such as RUNX1, MEOX1, AEBP1, LEF1 and NRXN3. CONCLUSIONSWe provided a comprehensive analysis of the lineage-specific regulatory changes in HCM. Our analysis identified a vast array of candidate therapeutic target genes and pathways to prevent or attenuate the pathological remodeling of HCM. Our datasets constitute a valuable resource to examine the lineage-specific expression changes of HCM at single-nucleus and spatial resolution. We developed a web-based interface (http://snsthcm.fwgenetics.org/) for further exploration.

pathology↗

Mutations in PIKFYVE cause autosomal dominant congenital cataract

Congenital cataract, an ocular disease predominantly occurring within the first decade of life, is one of the leading causes of blindness in children. Through whole exome sequencing of a Chinese family with congenital cataract, we identified a disease-causing mutation (p.G1943E) in PIKFYVE, which affecting the PIP kinase domain of the PIKfyve protein. We demonstrated that heterozygous/homozygous disruption of PIKfyve kinase domain, instead of overexpression of PIKFYVEG1943E in zebrafish mimicked the cataract defect in human patients, suggesting that haploinsufficiency, rather than dominant-negative inhibition of PIKfyve activity caused the disease. Phenotypical analysis of pikfyve zebrafish mutants revealed that loss of Pikfyve caused aberrant vacuolation (accumulation of Rab7+Lc3+ amphisomes) in lens cells, which was significantly alleviated by treatment with the V-ATPase inhibitor bafilomycin A1 (Baf-A1). Collectively, we identified PIKFYVE as a novel causative gene for congenital cataract and demonstrated the potential application of Baf-A1 in treatment of congenital cataract.

genomics↗

SARS-CoV-2 Infects Syncytiotrophoblast and Activates Inflammatory Responses in the Placenta

SARS-CoV-2 infection during pregnancy leads to an increased risk of adverse pregnancy outcomes. Although the placenta itself can be a target of virus infection, most neonates are virus free and are born healthy or recover quickly. Here, we investigated the impact of SARS-CoV-2 infection on the placenta from a cohort of women who were infected late during pregnancy and had tested nasal swab positive for SARS-CoV-2 by qRT-PCR at delivery. SARS-CoV-2 genomic and subgenomic RNA was detected in 23 out of 54 placentas. Two placentas with high virus content were obtained from mothers who presented with severe COVID-19 and whose pregnancies resulted in adverse outcomes for the fetuses, including intrauterine fetal demise and a preterm delivered baby still in newborn intensive care. Examination of the placental samples with high virus content showed efficient SARS-CoV-2 infection, using RNA in situ hybridization to detect genomic and replicating viral RNA, and immunohistochemistry to detect SARS-CoV-2 nucleocapsid protein. Infection was restricted to syncytiotrophoblast cells that envelope the fetal chorionic villi and are in direct contact with maternal blood. The infected placentas displayed massive infiltration of maternal immune cells including macrophages into intervillous spaces, potentially contributing to inflammation of the tissue. Ex vivo infection of placental cultures with SARS-CoV-2 or with SARS-CoV-2 spike (S) protein pseudotyped lentivirus targeted mostly syncytiotrophoblast and in rare events endothelial cells. Infection was reduced by using blocking antibodies against ACE2 and against Neuropilin 1, suggesting that SARS-CoV-2 may utilize alternative receptors for entry into placental cells.

cell biology↗

Dissection of N-, O- and glycosphingolipid glycosylation changes in PaTu-S pancreatic adenocarcinoma cells upon TGF-β challenge

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and high mortality. Transforming growth factor-{beta} (TGF-{beta}) plays a key role in tumor progression, which is often associated with aberrant glycosylation. How PDAC cells respond to TGF-{beta} and the role of glycosylation therein is, however, not well known. Here, we investigated the TGF-{beta}-mediated response and glycosylation changes in SMAD4-deficient PaTu-8955S (PaTu-S) cell line. PaTu-S cells responded to TGF-{beta} by upregulating SMAD2 phosphorylation and target gene expression. TGF-{beta} induced expression of the mesenchymal marker N-cadherin, but did not significantly affect epithelial marker E-cadherin expression. The differences of N-glycans, O-glycans and glycosphingolipid (GSL) glycans in PaTu-S cells with TGF-{beta} stimulation were examined. TGF-{beta} treatment primarily induced N-glycome aberrations involving elevated levels of branching, core fucosylation, and sialylation in PaTu-S cells, in line with TGF-{beta}-induced changes in the expression of glycosylation-related genes. In addition, we observed differences in O- and GSL-glycosylation profiles after TGF-{beta} treatment, including lower levels of sialylated Tn antigen, and neoexpression of globosides. Furthermore, SOX4 expression was upregulated upon TGF-{beta} stimulation, and its depletion blocked the TGF-{beta}-induced N-glycomic changes. Thus, our study provides a mechanism by which TGF-{beta}-induced N-glycosylation changes in SOX4 dependent and SMAD4 independent manner in pancreatic cancer cells. Our results open up avenues to study the relevance of glycosylation in TGF-{beta} signaling in SMAD4 inactivated PDAC.

cancer biology↗

Metagenome-genome-wide association studies reveal human genetic impact on the oral microbiome

The oral microbiota contains billions of microbial cells, which could contribute to diseases in a number of body sites. Challenged by eating, drinking and dental hygiene on a daily basis, the oral microbiota is regarded as highly dynamic. Here, we report significant human genomic associations with the oral metagenome from more than 1,915 individuals, for both the tongue dorsum and saliva. We identified five genetic loci associated with oral microbiota at study-wide significance (p < 3.16 x 10-11). Four of the five associations were well replicated in an independent cohort of 1,439 individuals: rs1196764 at APPL2 with Prevotella jejuni, Oribacterium uSGB 3339 and Solobacterium uSGB 315; rs3775944 at the serum uric acid transporter SLC2A9 with Oribacterium uSGB 1215, Oribacterium uSGB 489 and Lachnoanaerobaculum umeaense; rs4911713 near OR11H1 with species F0422 uSGB 392; and rs36186689 at LOC105371703 with Eggerthia. Further analyses confirmed 84% (386/455 for tongue dorsum) and 85% (391/466 for saliva) of genetic-microbiota associations including 6 genome-wide significant associations mutually validated between the two niches. Human genetics accounted for at least 10% of oral microbiome compositions between individuals. Machine learning models showed that polygenetic risk score dominated over oral microbiome in predicting predisposing risk of dental diseases such as dental calculus and gingival bleeding. These findings indicate that human genetic differences are one explanation for a stable or recurrent oral microbiome in each individual.

genetics↗

Mechanical vibration patterns elicit behavioral transitions and habituation in crawling Drosophila larvae

How animals respond to repeatedly applied stimuli, and how animals respond to mechanical stimuli in particular, are important questions in behavioral neuroscience. We study adaptation to repeated mechanical agitation using the Drosophila larva. Vertical vibration stimuli elicit a discrete set of responses in crawling larvae: continuation, pause, turn, and reversal. Through high-throughput larva tracking, we characterize how the likelihood of each response depends on vibration intensity and on the timing of repeated vibration pulses. By examining transitions between behavioral states at the population and individual levels, we investigate how the animals habituate to the stimulus patterns. We identify time constants associated with desensitization to prolonged vibration, with re-sensitization during removal of a stimulus, and additional layers of habituation that operate in the overall response. Known memory-deficient mutants exhibit distinct behavior profiles and habituation time constants. An analogous simple electrical circuit suggests possible neural and molecular processes behind adaptive behavior.

animal behavior and cognition↗

A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses

Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN polymorphisms are associated with Alzheimers disease (AD). PGRN is highly expressed in the microglia near A{beta} plaques and influences plaque dynamics and microglial activation. However, the detailed mechanisms remain elusive. Here we report that PGRN deficiency reduces human APP and A{beta} levels in the young male but not female mice. PGRN deficient microglia exhibit increased expression of markers associated with microglial activation, including CD68, Galectin-3, TREM2 and GPNMB, specifically near A{beta} plaques. In addition, PGRN loss leads to up-regulation of lysosome proteins and an increase in the nuclear localization of TFE3, a transcription factor involved in lysosome biogenesis. Cultured PGRN deficient microglia show enhanced nuclear translocation of TFE3 and inflammation in response to A{beta} fibril treatment. Taken together, our data revealed a sex- and age-dependent effect of PGRN on amyloid metabolism and a role of PGRN in regulating lysosomal activities and inflammation in plaque-associated microglia, which may contribute to the disease mechanism associated with PGRN polymorphisms in AD.

neuroscience↗