Biology subjects

Zhao, K.

Publications and source records attributed to Zhao, K..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Sex Differences in Sleep Phenotypes in the BACHD Mouse Model of Huntington's Disease

Sleep and circadian rhythm disturbances are common features of Huntingtons disease (HD). HD is an autosomal dominant neurodegenerative disorder that affects men and women in equal numbers, but some epidemiological studies as well as preclinical work indicate there may be sex differences in disease progression. Since sex differences in HD could provide important insights to understand cellular and molecular mechanism(s), we used the bacterial artificial chromosome transgenic mouse model of HD (BACHD) to examine whether sex differences in sleep/wake cycles are detectable in an animal model of the disease. Electroencephalography/electromyography (EEG/EMG) was used to measure sleep/wake states and polysomnographic patterns in young adult (12 week-old) male and female wild-type and BACHD mice. Our findings show that male, but not female, BACHD mice exhibited increased variation in phases of the rhythms as compared to age and sex matched wild-types. For both Rapid-eye movement (REM) and Non-rapid eye movement (NREM) sleep, genotypic and sex differences were detected. In particular, the BACHD males spent less time in NREM and exhibited a more fragmented sleep than the other groups. Both male and female BACHD mice exhibited significant changes in delta but not in gamma power compared to wild-type mice. Finally, in response to a 6-hrs sleep deprivation, both genotypes and sexes displayed predicted homeostatic responses to sleep loss. These findings suggest that females are relatively protected early in disease progression in this HD model. Significance StatementSleep and circadian rhythm disturbances are common features of Huntingtons disease (HD). Using an animal model of HD and EEG measures of sleep, we found that the males were more vulnerable to sleep/wake architecture alterations and sleep fragmentation. Homeostatic recovery from sleep loss did not appear to be altered at this stage of the disease. These findings raise the possibility that sex-specific factors play a role in the HD symptom progression and that hormone-based treatments may have therapeutic utility.

neuroscience↗

bioRxiv2023

Pathfinder: protein folding pathway prediction based on conformational sampling

The study of protein folding mechanism is a challenge in molecular biology, which is of great significance for revealing the movement rules of biological macromolecules, understanding the pathogenic mechanism of folding diseases, and designing protein engineering materials. Based on the hypothesis that the conformational sampling trajectory contain the information of folding pathway, we propose a protein folding pathway prediction algorithm named Pathfinder. Firstly, Pathfinder performs large-scale sampling of the conformational space and clusters the decoys obtained in the sampling. The heterogeneous conformations obtained by clustering are named seed states. Then, a resampling algorithm that is not constrained by the local energy basin is designed to obtain the transition probabilities of seed states. Finally, protein folding pathways are inferred from the maximum transition probabilities of seed states. The proposed Pathfinder is tested on our developed test set (34 proteins). For 5 widely studied proteins, we correctly predicted their folding pathways. For 25 partial biological experiments proteins, we predicted folding pathways could be further verified. For the other 4 proteins without biological experiment results, potential folding pathways were predicted to provide new insights into protein folding mechanism. The results reveal that structural analogs may have different folding pathways to express different biological functions, homologous proteins may contain common folding pathways, and -helices may be more prone to early protein folding than {beta}-strands.

bioinformatics↗

bioRxiv2023

Protein multiple conformations prediction using multi-objective evolution algorithm

MotivationWith the breakthrough of AlphaFold2 and the publication of AlphaFold DB, the protein structure prediction has made remarkable progress, which may further promote many potential applications of proteomics in all areas of life. However, it should be noted that AlphaFold2 models tend to represent only a single static structure, and accurately predicting multiple conformations remains a challenge. Therefore, it is essential to develop methods for predicting multiple conformations, which enable us to gain knowledge of multiple conformational states and the broader conformational landscape to better understand the mechanism of action. ResultsIn this work, we proposed a multiple conformational states folding method using the distance-based multi-objective evolutionary algorithm framework, named MultiSFold. First, a multi-objective energy landscape with multiple competing constraints generated by deep learning is constructed. Then, an iterative modal exploration and exploitation strategy based on multi-objective optimization, geometric optimization and structural similarity clustering is designed to perform conformational sampling. Finally, the final population is generated using a loop-specific perturbation strategy to adjust the spatial orientations. MultiSFold was compared with state-of-the-art methods on a developed benchmark testset containing 81 proteins with two representative conformational states. Based on the proposed metric, the success ratio of MultiSFold predicting multiple conformations was 70.4% while that of AlphaFold2 was 9.88%, which may indicate that conformational sampling combined with knowledge gained through deep learning has the potential to produce conformations spanned the range between two experimental structures. In addition, MultiSFold was tested on 244 human proteins with low structural accuracy in AlphaFold DB to test whether it could further improve the accuracy of static structures. The experimental results demonstrate that the TM-score of MultiSFold is 2.97% and 7.72% higher than that of AlphaFold2 and RoseTTAFold, respectively, supporting our hypothesis that multiple competing optimization objectives can further assist conformational search to improve prediction accuracy.

bioinformatics↗

bioRxiv2023

A longitudinal resource for population neuroscience of school-age children and adolescents in China

During the past decade, cognitive neuroscience has been calling for population diversity to address the challenge of validity and generalizability, ushering in a new era of population neuroscience. The developing Chinese Color Nest Project (devCCNP, 2013-2022), a ten-year pilot stage of the lifespan CCNP (2013-2032), is an ongoing project focusing on brain-mind development. The project aims to create and share a large-scale, longitudinal and multimodal dataset of typically developing children and adolescents (ages 6.0-17.9 at enrolment) in the Chinese population. The devCCNP houses not only phenotypes measured by demographic, biophysical, psychological and behavioural, cognitive, affective, and ocular-tracking assessments but also neurotypes measured with magnetic resonance imaging (MRI) of brain morphometry, resting-state function, naturalistic viewing function and diffusion structure. This Data Descriptor introduces the first data release of devCCNP including a total of 864 visits from 479 participants. Herein, we provided details of the experimental design, sampling strategies, and technical validation of the devCCNP resource. We demonstrate and discuss the potential of a multicohort longitudinal design to depict normative brain growth curves from the perspective of developmental population neuroscience. The devCCNP resource is shared as part of the "Chinese Data-sharing Warehouse for In-vivo Imaging Brain" in the Chinese Color Nest Project (CCNP) - Lifespan Brain-Mind Development Data Community (https://www.scidb.cn/en/c/ccnp) at the Science Data Bank. Design TypesO_LIAccelerated longitudinal design C_LIO_LIBrain-mind development C_LIO_LIPopulation imaging C_LIO_LIBrain chart C_LIO_LIRepeated measure C_LI MeasurementsO_LIPsychological behaviours C_LIO_LIBiophysical and physical measures C_LIO_LIIntelligence quotient measure C_LIO_LINeuroimaging C_LI Sample Characteristic - OrganismO_LIHomo sapiens C_LI Sample Characteristic - EnvironmentO_LISchool- and community-based sample C_LI Sample Characteristic - LocationO_LIChongqing and Beijing, China C_LI DurationO_LI10 years (2013-2022) C_LI

neuroscience↗

bioRxiv2023

NDC80 status pinpoints mitotic kinase inhibitors as emerging therapeutic options in clear cell renal cell carcinoma

[~]30% of clear cell renal cell carcinoma (ccRCC) patients present with metastatic disease at the time of diagnosis, causing a dire 5-year survival rate of 13%. Whereas anti-PD-1 immunotherapy has improved survival, a strong need remains for new therapeutic options. Using integrated network analysis, we identified the mitotic regulator NDC80 as a predictor of ccRCC progression. Overexpression of NDC80 fosters the malignant phenotype by promoting cell cycle progression through S phase as well as boosting glycolysis and mitochondrial respiration. Despite high levels of immune infiltration, particularly derived from tumor resident CD8+ T cells with an exhausted phenotype, NDC80 defines a class of ccRCCs that poorly respond to immune checkpoint blockade. Instead, bioinformatics identified NDC80-high ccRCCs as sensitive to inhibitors of mitotic kinases, PLK1 and AURK, therapeutic approaches we validated in cell lines and mouse xenograft studies. Thus, NDC80 status pinpoints mitotic kinase inhibitors as promising therapeutic options in difficult-to-treat ccRCCs.

cancer biology↗

bioRxiv2023

Modification of social cheating facilitates the stabilization and chronic infection of polymorphic Pseudomonas aeruginosa population

Chronic infection of the common bacterial pathogen Pseudomonas aeruginosa frequently leads to the coexistence of heterogeneous individuals to engage in several group behaviors. However, further evolution of the polymorphic P. aeruginosa population, including the dynamic change of social cooperation and its impact on host immune system, still remain elusive. We show that the evolution of P. aeruginosa in the patients with chronic obstructive pulmonary disease frequently selects the isolates deficient in producing the costly and sharable extracellular products for nutrient acquisition. The evolution of polymorphic P. aeruginosa population is mainly concentrated on modifying the adaptability of lasR mutants, which are typical cheaters in the competition of quorum-sensing-controlled extracellular proteases. Importantly, lasR mutants with varying degrees of evolution interact with wild-type P. aeruginosa in a framework termed cascaded public goods game to compete for extracellular proteases and siderophores, and thus perpetuate social cooperation under different conditions. Finally, we find that a polymorphic population comprised of lasR-intact P. aeruginosa and evolved lasR-mutant can minimize the host immune fluctuation for persistent colonization. This study demonstrates the multistage evolution and complex interaction of P. aeruginosa in adaptation to host lungs, and provides an explanation for the success of cooperation in public goods game.

microbiology↗

bioRxiv2022

Assigning functionality to cysteines by base editing of cancer dependency genes

Chemical probes are lacking for most human proteins. Covalent chemistry represents an attractive strategy for expanding the ligandability of the proteome, and chemical proteomics has revealed numerous electrophile-reactive cysteines on diverse proteins. Determining which of these covalent binding events impact protein function, however, remains challenging. Here, we describe a base-editing strategy to infer the functionality of cysteines by quantifying the impact of their missense mutation on cell proliferation. We show that the resulting atlas, which covers >13,800 cysteines on >1,750 cancer dependency proteins, correctly predicts the essentiality of cysteines targeted by cancer therapeutics and, when integrated with chemical proteomic data, identifies essential, ligandable cysteines on >110 cancer dependency proteins. We further demonstrate how measurements of reactivity in native versus denatured proteomes can discriminate essential cysteines amenable to chemical modification from those buried in protein structures, providing a valuable resource to prioritize the pursuit of small-molecule probes with high function-perturbing potential.

systems biology↗

bioRxiv2022

Structural basis of sRNA RsmZ regulation of Pseudomonas aeruginosa virulence

Pseudomonas aeruginosa is an opportunistic human pathogen that poses threats to hospitalized immunocompromised patients 1. A non-coding small RNA (sRNA) from the repressor of secondary metabolites (Rsm) system, RsmZ, sequesters the global repressor protein RsmA to regulate downstream gene expressions that reprogram virulence repertoires associated with acute and chronic P. aeruginosa infections 2,3. Molecular insights into the full-length RsmZ architecture remain elusive, leading to the lack of understanding of RsmZ binding to RsmA and subsequent modulations of gene expressions. Here we use cryo-electron microscopy (cryo-EM) to resolve structures of the full-length RsmZ in complexes with RsmA, in which five stem-loops (SLs) and one single-stranded junction carrying the GGA binding sites in RsmZ form three pairs of clamps, each binding to a RsmA homodimer. Disruptions of the base-pairings in all stems of RsmZ significantly reduced the binding affinity to RsmA by 17-fold, which resulted in enhanced RsmA downregulation of gene expressions and phenotypes associated to both acute and chronic virulence of P. aeruginosa. Double mutations that rescued these stems of RsmZ restored the binding to RsmA by more than 5-fold, and recovered the corresponding phenotypes. Our results reveal the molecular mechanism of RsmZ regulation of P. aeruginosa virulence and suggest RsmZ as a potential target for the development of new antimicrobial agents.

microbiology↗

bioRxiv2022

Research on protein structure prediction and folding based on novel remote homologs recognition

Recognition of remote homologous structures is a necessary module in AlphaFold2 and is also essential for the exploration of protein folding pathways. Here, we developed a new method, PAthreader, which identifies remote homologous structures based on the three-track alignment of distance profiles and structure profiles originated from PDB and AlphaFold DB by deep learning. Based on the identified templates, we further enhanced state-of-the-art modelling method and explored protein folding pathways based on the residue frequency distribution of homologs and the secondary structure. The results show that the average accuracy of templates identified by PAthreader is 11.6% higher than those of HHsearch on 551 nonredundant proteins. In terms of structure modelling, PAthreader improves the performance of AlphaFold2 and ranks first in CAMEO blind test for the last three months. Furthermore, we explored protein folding pathways for 37 proteins. The results are almost consistent with biological experiments for 7 proteins, and the remaining 30 human proteins have yet to be verified by biological experiments, revealing that folding information can be exploited from remote homologous structures.

bioinformatics↗

bioRxiv2022

Network-based hub biomarker discovery for glaucoma

Glaucoma is an optic neuropathy, and the leading cause of irreversible blindness worldwide. However, the early detection of glaucoma remains challenging as chronic forms of glaucoma remain largely asymptomatic until considerable irreversible visual field deficits have ensued. Thus, biomarkers that facilitate early diagnosis and treatment for patients with a high risk of progression are critical. Network medicine approaches can be useful in identifying key relationships and important biomolecules for complex diseases. In this paper, we identified several hub biomarkers/drug targets for the diagnosis, treatment and prognosis for glaucoma and explored their associations for glaucoma based on human disease-biomarker and disease-target-drug networks. These results were verified by text-mining and genomic/epidemiology data. We also predicted the new application of BMP1 and MMP9 to diagnose glaucoma and confirm the theory of hub biomarkers with multiple clinical applications. Further, relevant pivotal pathways (regulation of the multicellular organismal process, regulation of localisation, and cytoplasmic vesicle for biomarkers; signal transduction and developmental process for targets) for these hub biomolecules were discovered, which may be foundations for future biomarker and drug target prediction for glaucoma. In conclusion, based on complex networks, hub biomolecules, essential pathways, and close diseases were identified for glaucoma in diagnosis, treatment and prognosis.

bioinformatics↗

bioRxiv2022

Roles of the distinct N-terminal amino acid between H3 and H3.3 in Drosophila male germline stem cell lineage

Adult stem cells undergo asymmetric cell divisions to produce two daughter cells with distinct cell fates: one capable of self-renewal and the other committed for differentiation. Mis-regulation of this delicate balance can lead to cancer and tissue degeneration. During asymmetric division of Drosophila male germline stem cells (GSCs), preexisting (old) and newly synthesized histone H3 are differentially segregated whereas old and new histone variant H3.3 are more equally inherited. However, what underlies these distinct inheritance patterns remains unknown. Here, we report that the N-terminal tails of H3 and H3.3 are critical for their inheritance patterns, as well as GSC maintenance and proper differentiation. H3 and H3.3 differ at the 31st position in their N-termini with Alanine for H3 and Serine for H3.3. By swapping these two amino acids, we generated two mutant histones (i.e., H3A31S and H3.3S31A). Upon expressing them in the early-stage germline, we identified opposing phenotypes: over-population of early-stage germ cells in the H3A31S-expressing testes and significant germ cell loss in testes expressing the H3.3S31A. Asymmetric H3 inheritance is disrupted in the H3A31S-expressing GSCs, due to mis-incorporation of old histones between sister chromatids during DNA replication. Furthermore, H3.3S31A mutation accelerates old histone turn-over in the GSCs. Finally, using a modified Chromatin Immunocleavage assay on early-stage germ cells, we found that H3A31S has an enhanced occupancy at the promoters and transcription starting sites than H3, while H3.3S31A is more enriched at transcriptionally silent intergenic regions compared to H3.3. Overall, these results suggest that the 31st amino acids for both H3 and H3.3 are critical for their proper genomic occupancy and function. Together, our findings indicate a critical role for the different amino acid composition of the N-terminal tails between H3 and H3.3 in an endogenous stem cell lineage, and provide insights into the importance of proper histone inheritance in specifying cell fates and regulating cellular differentiation.

developmental biology↗

bioRxiv2022

Functional hierarchy among different Rab27 effectors involved in secretory granule exocytosis

The Rab27 effectors play versatile roles in regulated exocytosis. In pancreatic beta cells, exophilin-8 anchors granules in the peripheral actin cortex, whereas granuphilin and melanophilin mediate granule fusion with and without stable docking to the plasma membrane, respectively. However, it is unknown whether these coexisting effectors function in parallel or in sequence to support the whole insulin secretory process. Here, we investigate their functional relationship by comparing the exocytic phenotypes in beta cells simultaneously lacking two effectors with those lacking one of them. Analyses of prefusion profiles by total internal reflection fluorescence microscopy indicate that melanophilin exclusively functions downstream of exophilin-8 to mobilize granules for fusion from the actin network to the plasma membrane after stimulation. The two effectors are physically linked via the exocyst complex. Downregulation of the exocyst component affects granule exocytosis only in the presence of exophilin-8. Exophilin-8 also promotes fusion of granules stably docked to the plasma membrane mediated by granuphilin, although it is dispensable for granule residence beneath the plasma membrane. The current study presents the first diagram for multiple intracellular paths of granule exocytosis and for functional hierarchy among different Rab27 effectors in the same cell.

cell biology↗

bioRxiv2022

Improved model quality assessment using sequence and structural information by enhanced deep neural networks

Protein model quality assessment plays an important role in protein structure prediction, protein design, and drug discovery. In this work, DeepUMQA2, a substantially improved version of DeepUMQA for protein model quality assessment, is proposed. First, sequence features containing protein co-evolution information and structural features reflecting family information are extracted to complement model-dependent features. Second, a novel backbone network based on triangular multiplication update and axial attention mechanism is designed to enhance information exchange between inter-residue pairs. On CASP13 and CASP14 datasets, the performance of DeepUMQA2 increases by 20.5% and 20.4% compared with DeepUMQA, respectively (measured by top 1 loss). Moreover, on the three-month CAMEO dataset (March 11 to June 04, 2022), DeepUMQA2 outperforms DeepUMQA by 15.5% (measured by local AUC0,0.2) and ranks first among all competing server methods in CAMEO blind test. Experimental results show that DeepUMQA2 outperforms state-of-the-art model quality assessment methods, such as ProQ3D-LDDT, ModFOLD8, DeepAccNet, Atom_ProteinQA, and QMEAN3.

bioinformatics↗

bioRxiv2022

Causal contributions to sensory-based decision-making by cell-type specific circuits in the tail striatum

The striatum comprises distinct types of neurons giving rise to the direct and indirect basal ganglia pathways and local circuits. A large amount of work has been focusing on cell-type specific striatal circuits in the context of movement control, proposing several models on their functional roles. But it remains to be elucidated how the cell-type specific striatal circuits contribute to decision-making behavior and whether the existing models apply. Here, we investigate the causal roles of the cell-type specific circuits in the posterior tail of the dorsal striatum (TS) of mice in an auditory-guided decision-making behavior. Transient unilateral activation of the direct- or indirect-pathway striatal spiny projection neurons (dSPNs or iSPNs) both biased decisions in opposite directions. These effects, however, were not due to a direct influence on movement, but was specific to the decision period preceding action execution. Optogenetic inactivation of dSPNs and iSPNs revealed their opposing causal contributions to decisions. At the local circuit level, simutaneous optical recording and manipulation of dSPNs and iSPNs revealed their antagnizing interactions. Inactivation of PV interneurons, a common inhibitory input to both dSPNs and iSPNs, facilitated contraversive choices, supporting a causal contribution of coordinated striatal circuits. Using a neural circuit model, we further demonstrated the computational implemenation of the causal circuit mechanism. Our results indicate that while the causal roles of the cell-type specific striatal circuits in decision-making largely agree with classic models in movement control, they show decision task-related specificity involving local circuit coordination.

neuroscience↗

bioRxiv2022

Development of Equine Polyclonal Antibodies as a Broad-Spectrum Therapy Against SARS-CoV-2 Variants

The Coronavirus disease 19 (COVID-19) pandemic has accumulated over 550 million confirmed cases and more than 6.34 million deaths worldwide. Although vaccinations has largely protected the population through the last two years, the effect of vaccination has been increasingly challenged by the emerging SARS-CoV-2 variants. Although several therapeutics including both monoclonal antibodies and small molecule drugs have been used clinically, high cost, viral escape mutations, and potential side effects have reduced their efficacy. There is an urgent need to develop a low cost treatment with wide-spectrum effect against the novel variants of SARS-CoV-2. Here we report a product of equine polyclonal antibodies that showed potential broad spectrum neutralization effect against the major variants of SARS-CoV-2. The equine polyclonal antibodies were generated by horse immunization with the receptor binding domain (RBD) of SARS-CoV-2 spike protein and purified from equine serum. A high binding affinity between the generated equine antibodies and the RBD was observed. Although designed against the RBD of the early wild type strain sequenced in 2020, the equine antibodies also showed a highly efficient neutralization capacity against the major variants of SARS-CoV-2, including the recent BA.2 Omicron variant (IC50 =1.867g/ml) in viral neutralization assay in Vero E6 cells using live virus cultured. The broad-spectrum neutralization capacity of the equine antibodies was further confirmed using pseudovirus neutralization assay covering the major SARS-CoV-2 variants including wild type, alpha, beta, delta, and omicron, showing effective neutralization against all the tested strains. Ex vivo reconstructed human respiratory organoids representing nasal, bronchial, and lung epitheliums were employed to test the treatment efficacy of the equine antibodies. Antibody treatment protected the human nasal, bronchial, and lung epithelial organoids against infection of the novel SARS-CoV-2 variants challenging public health, the Delta and Omicron BA.2 isolates, by reducing >95% of the viral load. The equine antibodies were further tested for potential side effects in a mouse model by inhalation and no significant pathological feature was observed. Equine antibodies, as a mature medical product, have been widely applied in the treatment of infectious diseases for more than a century, which limits the potential side effects and are capable of large scale production at a low cost. A cost-effective, wide-spectrum equine antibody therapy effective against the major SARS-CoV-2 variants can contribute as an affordable therapy to cover a large portion of the world population, and thus potentially reduce the transmission and mutation of SARS-CoV-2.

immunology↗

bioRxiv2022

Hi-TrAC reveals fractal nesting of super-enhancers

Eukaryotic genome spatial folding plays a key role in genome function. Decoding the principles and dynamics of 3D genome organization depends on improving technologies to achieve higher resolution. Chromatin domains have been suggested as regulatory micro-environments, whose identification is crucial to understand the genome architecture. We report here that our recently developed method, Hi-TrAC, which specializes in detecting chromatin loops among genomic accessible regulatory regions, allows us to examine active domains with limited sequencing depths at a high resolution. Hi-TrAC can detect active sub-TADs with a median size of 100kb, most of which harbor one or two cell specifically expressed genes and regulatory elements such as super-enhancers organized into nested interaction domains. These active sub-TADs are characterized by highly enriched signals of histone mark H3K4me1 and chromatin-binding proteins, including Cohesin complex. We show that knocking down core subunit of the Cohesin complex using shRNAs in human cells or decreasing the H3K4me1 modification by deleting the H3K4 methyltransferase Mll4 gene in mouse Th17 cells disrupted the sub-TADs structure. In summary, Hi-TrAC serves as a compatible and highly responsive approach to studying dynamic changes of active sub-TADs, allowing us more explicit insights into delicate genome structures and functions. Highlights- Hi-TrAC detects active sub-TADs with a median size of 100 kb. - Hi-TrAC reveals a block-to-block interaction pattern between super-enhancers, and fractal structures within super-enhancers. - Active sub-TADs are disrupted by the knockdown of RAD21. - Active sub-TADs interaction densities are decreased by the knockout of Mll4.

genomics↗

bioRxiv2022

Inferring CTCF insulators and anchored loops across human tissues and cell types

CCCTC-binding factor (CTCF) is a transcription regulator which is involved in many cellular processes. How CTCF recognizes DNA sequence to exert chromosome barrier or enhancer blocking effects remains to be fully interrogated. Despite many computational tools were developed to predict CTCF-mediated loops qualitatively or quantitatively, few could specially evaluate the regulatory potential of DNA sequence at CTCF binding sites (CBSs) and how it affects chromatin loop formation. Here, we developed a deep learning model, DeepAnchor, to precisely characterize the binding patterns for different types of CBSs. By incorporating base-wise genomic/epigenomic features, we revealed distinct chromatin and sequence features for CTCF-mediated insulation and looping at a high resolution, such as two sequence motifs flanking the core CTCF motif at loop-associated CBSs. Besides, we leveraged the predicted anchor score to optimize the loop extrusion model and achieved the best performance in predicting CTCF-anchored loops. We established a compendium of context-specific CTCF-anchored loops across 52 human tissue/cell types and found that genomic disruption of CTCF-anchored loops may represent a general causal mechanism of disease pathogenesis. These computational models, together with the established resource, could facilitate the mechanistic research on how the CTCF-mediated cis-regulatory elements (CREs) shapes context-specific gene regulation in cell development and disease progression.

bioinformatics↗

bioRxiv2022

A causal role of the human left temporoparietal junction in computing social influence during goal-directed learning

The human temporoparietal junction (TPJ) is a brain area crucial for processing social information. Although brain stimulation studies have started to explore the causal function of TPJ under social contexts, few have explicitly considered bilateral TPJ as target regions. Here, leveraging non-invasive continuous theta-burst stimulation (cTBS) and hierarchical Bayesian computational modeling, we tested whether left or right TPJ (with vertex as control) is causally involved in how dissenting choices by others influence individuals choice adjustments in goal-directed learning. In our social learning paradigm, participants (N = 31) first made their private decision, and then were allowed to re-adjust their choices after observing choices of four other players. Behaviorally, we show that disruption of the left, but not the right TPJ, weakened participants choice adjustment and delayed their response speed when confronted with dissenting information from the other players. Computationally, disrupting activity in the left TPJ attenuated the degree of computing social influence during choice adjustment, whereas the extent to which how observational learning from others choices was integrated into direct learning remained intact. Together, our results provide evidence for the causal role of left TPJ in social influence during goal-directed learning and shed light on the relational function (with respect to oneself) of the TPJ in social cognition.

neuroscience↗