Biology subjects

Qin, S.

Publications and source records attributed to Qin, S..

At least 91 records · Page 5Linked to original sources

bioRxiv2021

Cell-to-cell variability in inducible Caspase9-mediated cell death

iCasp9 suicide gene has been widely used as a promising killing strategy in various cell therapies. However, different cells show significant heterogeneity in response to apoptosis inducer, posing challenges in clinical applications of killing strategy. The cause of the heterogeneity remains elusive so far. Here, by simultaneously monitoring the dynamics of iCasp9 dimerization, Caspase3 activation and cell fate in single cells, we found that the heterogeneity was mainly due to cell-to-cell variability in initial iCasp9 expression and XIAP/Caspase3 ratio. Moreover, multiple-round drugging cannot increase the killing efficiency. Instead, it will place selective pressure on protein levels, especially on the level of initial iCasp9, leading to drug resistance. We further show this resistance can be largely eliminated by combinatorial drugging with XIAP inhibitor at the end, but not at the beginning, of the multiple-round treatments. Our results unveil the source of cell fate heterogeneity and drug resistance in iCasp9-mediated cell death, which may enlighten better therapeutic strategies for optimized killing.

cell biology↗

bioRxiv2021

Long-term stress and trait anxiety alter brain network balance in dynamic decisions during working memory

Long-term stress has a profound impact on the human brain and cognition, and trait anxiety influences stress-induced adaptive and maladaptive effects. However, the neurocognitive mechanisms underlying long-term stress and trait anxiety interactions remain elusive. Here we investigated how long-term stress and trait anxiety interact to affect dynamic decisions during working-memory (WM) by altering functional brain network balance. In comparison to controls, male participants under long-term stress experienced higher psychological distress and exhibited faster evidence accumulation but had a lower decision-threshold during WM. This corresponded with hyper-activation in the anterior insula, less WM-related deactivation in the default-mode network, and stronger default-mode network decoupling with the frontoparietal network. Critically, high trait anxiety under long-term stress led to slower evidence accumulation through higher WM-related frontoparietal activity, and increased decoupling between the default-mode and frontoparietal networks. Our findings provide neurocognitive evidence for long-term stress and trait anxiety interactions on executive functions with (mal)adaptive changes.

neuroscience↗

bioRxiv2021

Effects of short-term plasticity in early olfactory information processing in Drosophila

In Drosophila, olfactory information received by the olfactory receptor neurons (ORNs) is first processed by an incoherent feed forward neural circuit in the antennal lobe (AL) that consists of ORNs (input), the inhibitory local neurons (LNs), and projection neurons (PNs). This "early" olfactory information process has two important characteristics. First, response of a PN to its cognate ORN is normalized by the overall activity of other ORNs, a phenomenon termed "divisive normalization". Second, PNs respond strongly to the onset of ORN activities, but they adapt to prolonged or continuously increasing inputs. Despite the importance of these characteristics for learning and memory, their underlying mechanism remains not fully understood. Here, we develop a circuit model for describing the ORN-LN-PN dynamics by including key features of neuron-neuron interactions, in particular short-term plasticity (STP) and presynaptic inhibition (PI). Our model shows that STP is critical in shaping PNs steady-state response properties. By fitting our model to experimental data quantitatively, we found that strong and balanced short-term facilitation (STF) and short-term depression (STD) in STP is crucial for the observed nonlinear divisive normalization in Drosophila. By comparing our model with the observed adaptive response to time-varying signals quantitatively, we find that both STP and PI contribute to the highly adaptive response with the latter being the dominant factor for a better fit with experimental data. Our model not only helps reveal the mechanisms underlying two main characteristics of the early olfactory process, it can also be used to predict the PN responses to arbitrary time-dependent signals and to infer microscopic properties of the circuit (such as the strengths of STF and STD) from the measured input-output relation.

neuroscience↗

bioRxiv2021

Electrophysiological signatures of hierarchical learning

Human perception and learning is thought to rely on a hierarchical generative model that is continuously updated via precision-weighted prediction errors (pwPEs). However, the neural basis of such cognitive process and how it unfolds during decision making, remain poorly understood. To investigate this question, we combined a hierarchical Bayesian model (i.e., Hierarchical Gaussian Filter, HGF) with electrophysiological (EEG) recording, while participants performed a probabilistic reversal learning task in alternatingly stable and volatile environments. Behaviorally, the HGF fitted significantly better than two control, non-hierarchical, models. Neurally, low-level and high-level pwPEs were independently encoded by the P300 component. Low-level pwPEs were reflected in the theta (4-8 Hz) frequency band, but high-level pwPEs were not. Furthermore, the expressions of high-level pwPEs were stronger for participants with better HGF fit. These results indicate that the brain employs hierarchical learning, and encodes both low- and high-level learning signals separately and adaptively.

neuroscience↗

bioRxiv2021

Pharmacological targeting of a PWWP domain demonstrates cooperative control of NSD2 localization

NSD2 is the primary enzyme responsible for the dimethylation of lysine 36 of histone 3 (H3K36me2), a mark associated with active gene transcription and intergenic DNA methylation. In addition to a methyltransferase domain, NSD2 harbors two PWWP and five PHD domains believed to serve as chromatin reading modules, but their exact function in the regulation of NSD2 activity remains underexplored. Here we report a first-in-class chemical probe targeting the N-terminal PWWP (PWWP1) domain of NSD2. UNC6934 binds potently (Kd of 91 {+/-} 8 nM) to PWWP1, antagonizes its interaction with nucleosomal H3K36me2, and selectively engages endogenous NSD2 in cells. Crystal structures show that UNC6934 occupies the canonical H3K36me2-binding pocket of PWWP1 which is juxtaposed to the DNA-binding surface. In cells, UNC6934 induces accumulation of endogenous NSD2 in the nucleolus, phenocopying the localization defects of NSD2 protein isoforms lacking PWWP1 as a result of translocations prevalent in multiple myeloma. Mutation of other NSD2 chromatin reader domains also increases NSD2 nucleolar localization, and enhances the effect of UNC6934. Finally we identified two C-terminal nucleolar localization sequences in NSD2 that appear to drive nucleolar accumulation when one or more chromatin reader domains are disabled. These data support a model in which NSD2 chromatin engagement is achieved in a cooperative manner and subcellular localization is controlled by multiple competitive structural determinants. This chemical probe and the accompanying negative control, UNC7145, will be useful tools in defining NSD2 biology.

cell biology↗

bioRxiv2021

Development of Large-Scale Brain Network Dynamics in Children

Functional brain networks require dynamic reconfiguration to support flexible cognitive function. However, the developmental principles shaping brain network dynamics remain poorly understood. Here, we report the longitudinal development of large-scale brain network dynamics during childhood and adolescence, and its connection with gene expression profiles. Using a multilayer network model, we show the temporally varying modular architecture of child brain networks, with higher network switching primarily in the association cortex and lower switching in the primary regions. This topographical profile exhibits progressive maturation, which manifests as reduced modular dynamics, particularly in the transmodal (e.g., default-mode and frontoparietal) and sensorimotor regions. These developmental refinements mediate age-related enhancements of global network segregation and are linked with the expression profiles of genes associated with the enrichment of ion transport and nucleobase-containing compound transport. These results highlight a progressive stabilization of brain dynamics, which expand our understanding of the neural mechanisms that underlie cognitive development.

neuroscience↗

bioRxiv2021

Weight loss response following lifestyle intervention associated with baseline gut metagenomic signature in humans

We report a weight-loss response analysis on a small cohort of individuals (N=25) selected from a larger population (N[~]5,000) enrolled in a commercial scientific wellness program, which included healthy lifestyle coaching. Each individual had baseline data on blood metabolomics, blood proteomics, clinical labs, lifestyle questionnaires, and stool metagenomes. A subset of these participants (N=15) lost at least 10% of their body weight within a 6-12 month period and saw significant improvement in metabolic health markers ( weight loss group), while another subset of individuals (N=10) undergoing the same lifestyle intervention showed no change in BMI over the same timeframe ( no weight loss group). Only a single baseline blood analyte, a metabolite linked to fried food consumption, was (negatively) associated with weight loss, but a large number of baseline stool metagenomic features, including complex polysaccharide and protein degradation genes, stress-response genes, respiration-related genes, cell wall synthesis genes, and gut bacterial replication rates, were significantly associated with weight loss after explicitly controlling for baseline BMI. Together, these results provide a set of baseline gut microbiome functional features that are associated with weight loss outcomes.

microbiology↗

bioRxiv2021

Positive and Neutral Updating Reconsolidate Aversive Episodic Memories via Different Routes

Aversive memories are long-lasting and prone to have adverse effects on our emotional wellbeing and mental health. Yet, how to remedy the maladaptive effects of aversive memories remains elusive. Using memory reactivation and emotional updating manipulations, we investigated how positive and neutral emotion updates aversive memories for reconsolidation in humans. We found that positive updating after reactivation was equivalent to neutral updating in altering true memories of the aversive story, but introduced more false memory. Moreover, an additional 12 hours of sleep reconsolidation did not further enlarge true memory differences, but attenuated the effect of reactivation and updating on false memory. Interestingly, the neutral rather than the positive updating reduced the emotional arousal of the aversive memory 24 hours later. Our findings provide novel insights into real-world therapeutic applications regarding how updating with positive and neutral emotion may reshape aversive memories, especially when taking wake- and sleep-filled reconsolidation into account.

neuroscience↗

bioRxiv2020

Convergent evolution of distinct immune sensor systems for fungal polygalacturonases in Brassicaceae

Plant pattern recognition receptors (PRRs) facilitate recognition of microbial surface patterns and mediate activation of plant immunity. Arabidopsis thaliana RLP42, a leucine-rich repeat (LRR) receptor protein (LRR-RP), senses fungal endopolygalacturonases (PGs) through a ternary complex comprising RLP42, the adapter kinase SOBIR1, and SERK proteins. Several fungal PGs harbor a conserved 9-amino acid fragment pg9(At), which is sufficient to activate RLP42-dependent plant immunity. Domain swap experiments using RLP42 and paralogous RLP40 sequences revealed a dominant role of the island domain (ID) for ligand binding and PRR complex assembly. Involvement of the ID in plant receptor function is reminiscent of plant phytosulfokine (PSK) perception through the receptor, PSKR, a LRR receptor kinase. Sensitivity to pg9(At), which is restricted to A. thaliana, exhibits notable accession specificity as active RLP42 alleles were found in only 16 of 52 accessions tested. Arabidopsis arenosa and Brassica rapa, two Brassicaceae species closely related to A. thaliana, perceive plant immunogenic PG fragments pg20(Aa) or pg36(Bra), which are distinct from pg9(At). Our study unveils unprecedented complexity and dynamics of PG pattern recognition receptor evolution within a single plant family. PG perception systems may have evolved rather independently as a result of convergent evolution even among closely related species.

plant biology↗

bioRxiv2020

Dynamic integration and segregation of amygdala subregional functional circuits linking to physiological arousal

The dynamical organization of brain networks is essential to support human cognition and emotion for rapid adaption to ever-changing environment. As the core nodes of emotion-related brain circuitry, the basolateral amygdala (BLA) and centromedial amygdala (CMA) as two major amygdalar nuclei, are recognized to play distinct roles in affective functions and internal states, via their unique connections with cortical and subcortical structures in rodents. However, little is known how the dynamical organization of emotion-related brain circuitry reflects internal autonomic responses in humans. Using resting-state functional magnetic resonance imaging (fMRI) with K-means clustering approach in a total of 79 young healthy individuals (cohort 1: 42; cohort 2: 37), we identified two distinct states of BLA- and CMA-based intrinsic connectivity patterns, with one state (integration) showing generally stronger BLA- and CMA-based intrinsic connectivity with multiple brain networks, while the other (segregation) exhibiting weaker yet dissociable connectivity patterns. In an independent cohort 2 of fMRI data with concurrent recording of skin conductance, we replicated two similar dynamic states and further found higher skin conductance level in the integration than segregation state. Moreover, machine learning-based Elastic-net regression analyses revealed that time-varying BLA and CMA intrinsic connectivity with distinct network configurations yield higher predictive values for spontaneous fluctuations of skin conductance level in the integration than segregation state. Our findings highlight dynamic functional organization of emotion-related amygdala nuclei circuits and networks and its links to spontaneous autonomic arousal in humans.

neuroscience↗

bioRxiv2020

The selfish nature in interpersonal exchange among adolescents: imposing the kind and submitting to the exploitative

Cooperation is essential for success in society. Research consistently showed that adolescents are less cooperative than adults, which is often attributed to underdeveloped mentalizing that limits their expectations of others. However, the internal computations underlying this reduced cooperation remain largely unexplored. This study compared cooperation between adolescents and adults using a repeated Prisoners Dilemma Game. Adolescents cooperated less than adults, particularly after their partners cooperation. Computational modeling revealed that adults increased their intrinsic reward for reciprocating when their partner continued cooperating, a pattern absent in adolescents. Both computational modeling and self-reported ratings showed that adolescents did not differ from adults in building expectations of their partners cooperation. Therefore, the reduced cooperation appears driven by a lower intrinsic reward for reciprocity, reflecting a stronger motive to prioritize self-interest, rather than a deficiency in predicting others cooperation in social learning. These findings provide insights into the developmental trajectory of cooperation from adolescence to adulthood.

animal behavior and cognition↗

bioRxiv2020

Brain preparedness: The proactive role of the cortisol awakening response

Upon awakening from nighttime sleep, the stress hormone cortisol exhibits a burst in the morning within 30-minutes in humans. This cortisol awakening response (CAR) is thought to prepare the brain for upcoming challenges. Yet, the neurobiological mechanisms underlying the CAR-mediated preparation function remains unknown. Using blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI) with a dedicated prospective design and pharmacological manipulation, we investigated this proactive mechanism in humans across two fMRI studies. In Study 1, we found that a robust CAR was predictive of less hippocampal and prefrontal activity, though enhanced functional coupling between those regions and facilitated working memory performance, during a demanding task later in the afternoon. These results implicate the CAR in proactively promoting brain preparedness based on improved neural efficiency. To address the causality of this proactive effect, we conducted a second study (Study 2) in which we suppressed the CAR with a double blind, placebo controlled, randomized design using Dexamethasone. We found that pharmacological suppression of CAR mirrored the proactive effects from Study 1. Dynamic causal modeling analyses further revealed a reduction of prefrontal top-down modulation over hippocampal activity when performing a cognitively demanding task in the afternoon. These findings establish a causal link between the CAR and its proactive role in optimizing brain functional networks involved in neuroendocrine control and memory.

neuroscience↗

bioRxiv2020

Emotional tagging retroactively promotes memory integration through rapid neural reactivation and reorganization

Neutral events preceding emotional experiences are thought to be better remembered by tagging them as significant to simulate future event predictions. Yet, the neurobiological mechanisms how emotion transforms initially mundane events into strong memories remain unclear. By two behavioral and one fMRI studies with adapted sensory preconditioning paradigm, we show rapid neural reactivation and reorganization underlying emotion-tagged retroactive memory enhancement. Behaviorally, emotional tagging enhanced initial memory for neutral associations across the three studies. Neurally, emotional tagging potentiated reactivation of overlapping neural traces in the hippocampus and stimulus-relevant neocortex. Moreover, it induced large-scale hippocampal-neocortical reorganization supporting such retroactive benefit, as characterized by enhanced hippocampal-neocortical coupling modulated by the amygdala during online processing, and a shift from stimulus-relevant neocortex to transmodal prefrontal-parietal areas during offline post-tagging rest. Together, emotional tagging retroactively promotes associations between past neutral events through stimulating rapid reactivation of overlapping representations and reorganizing related memories into an integrated network.

neuroscience↗

bioRxiv2020

An ABA Synthesis Enzyme Allele OsNCED2 Promotes the Aerobic Adaption in Upland Rice

There are two ecotypes, upland rice and irrigate rice, during its evolution in rice. Upland rice exhibits aerobic adaptive phenotype via its stronger root system and more rapid drought responses compared with its counterpart, irrigated rice. We assessed the functional variation and applications of the aerobic adaptive allele OsNCED2T cloned from IRAT104 which is a cultivar of upland rice. OsNCED2-overexpressing transgenic rice and OsNCED2T-NILs exhibited significantly higher ABA contents at the seedling and reproductive stages, which can improve root development (RD) and drought tolerance (DT) to promote aerobic adaptation in upland rice. RNA-Seq-based expression profiling of transgenic versus wild-type rice identified OsNCED2-mediated pathways that regulate RD and DT. Meanwhile, OsNCED2-overexpressing rice exhibited significantly increased reactive oxygen species (ROS)-scavenging abilities and transcription levels of many stress- and development-related genes, which regulate RD and DT. A SNP mutation (C to T) from irrigated rice to upland rice, caused the functional variation of OsNCED2, and the enhanced RD and DT mediated by this site under aerobic conditions could promote higher yield of upland rice. These results show that OsNCED2T, through ABA synthesis, positively modulates RD and DT which confers aerobic adaptation in upland rice and might serve as a novel gene for breeding aerobic adaptive or water-saving rice.

plant biology↗

bioRxiv2020

Rapid Neural Reorganization during Retrieval Practice Predicts Subsequent Long-term Retention and False Memory

Active retrieval can induce changes to the strength and content of a memory, yielding enhanced or distorted subsequent recall. But how consolidation influences these retrieval-induced seemingly contradictory outcomes remains unknown. Here we show rapid neural reorganization over eight runs of retrieval practice predicted subsequent recall. Behaviorally, retrieval practice boosted memory following a 24-hour (long-term) but not a 30-minute delay, and increased false memory at both delays. Long-term retention gains were predicted by multi-voxel representation distinctiveness in the posterior parietal cortex that increased progressively over retrieval practice. False memory was predicted by unstable representation distinctiveness in the medial temporal lobe during retrieval practice. Memory-related neural networks gradually reconfigured over retrieval practice, with the ventrolateral and medial prefrontal cortex acting as hubs for functional connections that predicted long-term retention gains and false memory outcomes respectively. Our findings demonstrate dynamic neural reorganization during retrieval practice, through which memories are arranged into discrete yet malleable representations for subsequent consolidation.

neuroscience↗

bioRxiv2020

T606-phosphorylated Kaiso interacting with 14-3-3 and p120ctn is sequestered in the cytoplasm of human cells

It is well known that Kaiso protein encoded by ZBTB33 gene is a transcription repressor and that Kaiso-P120ctn interaction increases the shift of Kaiso from the nucleus into the cytoplasm. However, the regulatory mechanisms of Kaiso compartmentalization are far from clear. Here, we reported that AKT1 could phosphorylate 606-threonine residue (T606) within the RSSTIP motif of Kaiso in the cytoplasm. The T606-phosphorylated Kaiso (pT606-Kaiso) could directly bind to 14-3-3 family proteins and the depletion of T606 phosphorylation by T606A mutation abolished most of the Kaiso-14-3-3 binding. In addition, the Kaiso-P120ctn interaction was essential for the pT606-Kaiso accumulation in the cytoplasm. Notably, enforced 14-3-3{sigma} (SFN) overexpression could increase the pT606-Kaiso accumulation in the cytoplasm and de-repress the transcription of Kaiso target gene CDH1. Decreased amounts of both pT606-Kaiso and CDH1 proteins were frequently observed in human gastric cancer tissues relative to paired normal controls. The mRNA levels of 14-3-3{sigma} and Kaiso target gene CDH1 were positively and significantly correlated with each other in bioinformatics analyses using publicly available RNA-seq datasets for human normal tissues (n=11688, r=0.60, p<0.001) in the GTEx project and for cancer cell lines (n=1156, r=0.41, p<0.001) in the CCLE project. Furthermore, Kaiso T606A mutant (unable to be phosphorylated) significantly increased the migration and invasion of cancer cells in vitro as well as boosted the growth of these cells in vivo. In conclusion, Kaiso could be phosphorylated by AKT1 at the T606 and the pT606-Kaiso accumulates in the cytoplasm through binding to 14-3-3/P120ctn that de-represses the expression of Kaiso target gene CDH1 in normal tissues. Decreased Kaiso phosphorylation may contribute to the development of gastrointestinal cancer. The status of Kaiso phosphorylation is a determinant factor for the role of Kaiso in the development of cancer.

molecular biology↗

bioRxiv2020

Internal state configures olfactory behavior and early sensory processing in Drosophila larva

Animals exhibit different behavioral responses to the same sensory cue depending on their state at a given moment in time. How and where in the brain are sensory inputs combined with internal state information to select an appropriate behavior? Here we investigate how food deprivation affects olfactory behavior in Drosophila larvae. We find that certain odors reliably repel well-fed animals but attract food-deprived animals. We show that feeding state flexibly alters neural processing in the first olfactory center, the antennal lobe. Food deprivation differentially modulates two separate output pathways that are required for opposing behavioral responses. Uniglomerular projection neurons mediate odor attraction and show elevated odor-evoked activity in the food-deprived state. A multiglomerular projection neuron mediates odor aversion and receives odor-evoked inhibition in the food-deprived state. The switch between these two pathways is regulated by the lone serotonergic neuron in the antennal lobe, CSD. Our findings demonstrate how flexible behaviors can arise from state-dependent circuit dynamics in an early sensory processing center.

neuroscience↗

bioRxiv2019

Identification of a small molecule antagonist for the Tudor domain of SMN

Survival of motor neuron (SMN), a Tudor-domain-containing protein, plays an important role in diverse biological pathways via recognition of symmetrically dimethylated arginine (Rme2s) on proteins by its Tudor domain, and deficiency of SMN leads to the motor neuron degenerative disease spinal muscular atrophy (SMA). Here we report a potent and selective antagonist with a 4-iminopyridine scaffold targeting the Tudor domain of SMN. Our structural and mutagenesis studies indicate that the sandwich stacking interactions of SMN and compound 1 play a critical role in selective binding to SMN. Various on-target engagement assays support that compound 1 recognizes SMN specifically in a cellular context. In cell studies display that the SMN antagonist prevent the interaction of SMN with R1810me2s of DNA-directed RNA polymerase II subunit POLR2A and results in transcription termination and R-loop accumulation, mimicking depletion of SMN. Thus, in addition to the antisense, RNAi and CRISPR/Cas9 techniques, the potent SMN antagonist could be used as an efficient tool in understanding the biological functions of SMN and molecular etiology in SMA.

biochemistry↗