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Biology subjects

Xia, L.

Publications and source records attributed to Xia, L..

49 records · Page 3Linked to original sources

Modeling Changes in Probabilistic Reinforcement Learning during Adolescence

In the real world, many relationships between events are uncertain and probabilistic. Uncertainty is also likely to be a more common feature of daily experience for youth because they have less experience to draw from than adults. Some studies suggests probabilistic learning may be inefficient in youth compared to adults [1], while others suggest it may be more efficient in youth that are in mid adolescence [2, 3]. Here we used a probabilistic reinforcement learning task to test how youth age 8-17 (N = 187) and adults age 18-30 (N = 110) learn about stable probabilistic contingencies. Performance increased with age through early-twenties, then stabilized. Using hierarchical Bayesian methods to fit computational reinforcement learning models, we show that all participants performance was better explained by models in which negative outcomes had minimal to no impact on learning. The performance increase over age was driven by 1) an increase in learning rate (i.e. decrease in integration time horizon); 2) a decrease in noisy/exploratory choices. In mid-adolescence age 13-15, salivary testosterone and learning rate were positively related. We discuss our findings in the context of other studies and hypotheses about adolescent brain development. Author summaryAdolescence is a time of great uncertainty. It is also a critical time for brain development, learning, and decision making in social and educational domains. There are currently contradictory findings about learning in adolescence. We sought to better isolate how learning from stable probabilistic contingencies changes during adolescence with a task that previously showed interesting results in adolescents. We collected a relatively large sample size (297 participants) across a wide age range (8-30), to trace the adolescent developmental trajectory of learning under stable but uncertain conditions. We found that age in our sample was positively associated with higher learning rates and lower choice exploration. Within narrow age bins, we found that higher saliva testosterone levels were associated with higher learning rates in participants age 13-15 years. These findings can help us better isolate the trajectory of maturation of core learning and decision making processes during adolescence.

neuroscience↗

A potent neutralizing human antibody reveals the N-terminal domain of the Spike protein of SARS-CoV-2 as a site of vulnerability

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a global public health threat. Most research on therapeutics against SARS-CoV-2 focused on the receptor binding domain (RBD) of the Spike (S) protein, whereas the vulnerable epitopes and functional mechanism of non-RBD regions are poorly understood. Here we isolated and characterized monoclonal antibodies (mAbs) derived from convalescent COVID-19 patients. An mAb targeting the N-terminal domain (NTD) of the SARS-CoV-2 S protein, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, although it does not block the interaction between angiotensin-converting enzyme 2 (ACE2) receptor and S protein. The cryo-EM structure of the SARS-CoV-2 S protein in complex with 4A8 has been determined to an overall resolution of 3.1 Angstrom and local resolution of 3.4 Angstrom for the 4A8-NTD interface, revealing detailed interactions between the NTD and 4A8. Our functional and structural characterizations discover a new vulnerable epitope of the S protein and identify promising neutralizing mAbs as potential clinical therapy for COVID-19.

biochemistry↗

Transgenerational inheritance of abnormal spermatogenesis with Igf2/H19 epigenetic alteration in CD1 mouse induced by in utero arsenic exposure

Developmental exposure to environmental toxicants can induce transgenerational reproductive disease phenotypes through epigenetic mechanisms. However, little is known about the transgenerational effects of arsenic exposure. We hypothesize that prenatal arsenic exposure may result in impaired spermatogenesis in subsequent generations of male mice. To test our hypothesis, we treated pregnant CD-1 (F0) mice with drinking water containing sodium arsenite (85 ppm) from days 8 to 18 of gestation. Male offspring were bred with untreated female mice until the F3 generation was produced. Our results revealed that transient exposure of the F0 gestating female to arsenic can result in decreased sperm quality and histological abnormalities in testes of male offspring in the F1 and F3 generations. The overall methylation status of Igf2 DMR2 and H19 DMR was significantly lower in the arsenic-exposed group than that of the control group in both F1 and F3 generations. The relative mRNA expression levels of Igf2 and H19 in arsenic-exposed males were significantly higher than in the control males in both F1 and F3 generations. This study indicates that ancestral exposure to arsenic may result in transgenerational inheritance of an impaired spermatogenesis phenotyping involving both epigenetic alterations and the abnormal expression of Igf2 and H19.

pharmacology and toxicology↗

Temporal and state abstractions for efficient learning, transfer and composition in humans

Humans use prior knowledge to efficiently solve novel tasks, but how they structure past knowledge to enable such fast generalization is not well understood. We recently proposed that hierarchical state abstraction enabled generalization of simple one-step rules, by inferring context clusters for each rule. However, humans daily tasks are often temporally extended, and necessitate more complex multi-step, hierarchically structured strategies. The options framework in hierarchical reinforcement learning provides a theoretical framework for representing such transferable strategies. Options are abstract multi-step policies, assembled from simpler one-step actions or other options, that can represent meaningful reusable strategies as temporal abstractions. We developed a novel sequential decision making protocol to test if humans learn and transfer multi-step options. In a series of four experiments, we found transfer effects at multiple hierarchical levels of abstraction that could not be explained by flat reinforcement learning models or hierarchical models lacking temporal abstraction. We extended the options framework to develop a quantitative model that blends temporal and state abstractions. Our model captures the transfer effects observed in human participants. Our results provide evidence that humans create and compose hierarchical options, and use them to explore in novel contexts, consequently transferring past knowledge and speeding up learning.

neuroscience↗

Structural basis for the recognition of the 2019-nCoV by human ACE2

Angiotensin-converting enzyme 2 (ACE2) has been suggested to be the cellular receptor for the new coronavirus (2019-nCoV) that is causing the coronavirus disease 2019 (COVID-19). Like other coronaviruses such as the SARS-CoV, the 2019-nCoV uses the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) to engage ACE2. We most recently determined the structure of the full-length human ACE2 in complex with a neutral amino acid transporter B0AT1. Here we report the cryo-EM structure of the full-length human ACE2 bound to the RBD of the 2019-nCoV at an overall resolution of 2.9 [A] in the presence of B0AT1. The local resolution at the ACE2-RBD interface is 3.5 [A], allowing analysis of the detailed interactions between the RBD and the receptor. Similar to that for the SARS-CoV, the RBD of the 2019-nCoV is recognized by the extracellular peptidase domain (PD) of ACE2 mainly through polar residues. Pairwise comparison reveals a number of variations that may determine the different affinities between ACE2 and the RBDs from these two related viruses.

biochemistry↗

Structure of dimeric full-length human ACE2 in complex with B0AT1

Angiotensin-converting enzyme 2 (ACE2) is the surface receptor for SARS coronavirus (SARS-CoV), directly interacting with the spike glycoprotein (S protein). ACE2 is also suggested to be the receptor for the new coronavirus (2019-nCoV), which is causing a serious epidemic in China manifested with severe respiratory syndrome. B0AT1 (SLC6A19) is a neutral amino acid transporter whose surface expression in intestinal cells requires ACE2. Here we present the 2.9 [A] resolution cryo-EM structure of full-length human ACE2 in complex with B0AT1. The complex, assembled as a dimer of ACE2-B0AT1 heterodimers, exhibits open and closed conformations due to the shifts of the peptidase domains (PDs) of ACE2. A newly resolved Collectrin-like domain (CLD) on ACE2 mediates homo-dimerization. Structural modelling suggests that the ACE2-B0AT1 complex can bind two S proteins simultaneously, providing important clues to the molecular basis for coronavirus recognition and infection.

biochemistry↗

Lipid-specific labeling of enveloped viruses with quantum dots for single-virus tracking

Quantum dots (QDs) possess optical properties of superbright fluorescence, excellent photostability, narrow emission spectra, and optional colors. Labeled with QDs, single molecules/viruses can be rapidly and continuously imaged for a long time, providing more detailed information than labeled with other fluorophores. While they are widely used to label proteins in single-molecule tracking studies, QDs have rarely been used to study virus infection, mainly due to lack of accepted labeling strategies. Here, we report a general method to mildly and readily label enveloped viruses with QDs. Lipid-biotin conjugates were used to recognize and mark viral lipid membranes, and streptavidin (SA)-QD conjugates were used to light them up. Such a method allowed enveloped viruses to be labeled in 2 hours with specificity and efficiency up to 99% and 98%. The intact morphology and the native infectivity of viruses could be furthest preserved. With the aid of this QD labeling method, we lit wild-type (WT) and mutant Japanese encephalitis virus (JEV) up, tracked their infection in living Vero cells, and found that H144A and Q258A substitutions in the envelope (E) protein didnt affect the virus intracellular trafficking. The lipid-specific QD labeling method described in this study provides a handy and practical tool to readily "see" the viruses and follow their infection, facilitating the widespread use of single-virus tracking and the uncovering of complex infection mechanisms. Author summaryVirus infection in host cells is a complex process comprising a large number of dynamic molecular events. Single-virus tracking is a versatile technique to study these events. To perform this technique, viruses must be fluorescently labeled to be visible to fluorescence microscopes. Quantum dot is a kind of fluorescent tags that has many unique optical properties. It has been widely used to label proteins in single-molecule tracking studies, but rarely used to study virus infection, mainly due to lack of accepted labeling method. In this study, we developed a lipid-specific method to readily, mildly, specifically, and efficiently label enveloped viruses with quantum dots by recognizing viral envelope lipids with lipid-biotin conjugates and recognizing these lipid-biotin conjugates with streptavidin-quantum dot conjugates. Such a method is superior to the commonly used DiD/DiO labeling and the other QD labeling methods. It is not only applicable to normal viruses, but also competent to label the key protein-mutated viruses and the inactivated high virulent viruses, providing a powerful tool for single-virus tracking.

biochemistry↗

Global gene expression profile during low temperature in the brain of grass carp (Ctenopharyngodon idellus)

Grass carp is an important commercial fish widely cultured in China. Large range of temperature, in particular extremely low temperature, has dramatic effects on the aquaculture of this teleost. However, there is relatively little research on the molecular responses in the fish exposed to cold. Given the limited vision of approaches targeting individual genes, we investigated the transcriptome profiles of brain in response to cold in order to comprehensively characterize molecular mechanisms behind it. This study indicated that the estrogen signaling pathway was inhibited in brain when grass carp acclimated to low temperature, while terpenoid backbone biosynthesis pathway and steroid biosynthesis pathway were significantly activated. Such a result implied the crucial role of cholesterol in cold acclimation. Moreover, plenty of differentially expressed genes associated with spliceosomes were enriched during cooling process, which suggested alternative splicing may be involved in the regulation of biological process in acclimation to temperature changes. In researches on extremely low-temperature tolerance, we identified four genes (DUSP1, HSPA6, NR4A1 and GADD45B) associated with MAPK signaling pathway. The four genes, extensively up-regulated at 4{degrees}C and remained relatively low expression at moderate temperature, were closely related with extremely cold condition. Further examination of the candidate genes can provide insights into the mechanisms of grass carp to endure extremely low temperature in the winter.

zoology↗

The effects of carnosine pretreatment on the inflammatory response and the PI3K/Akt signaling pathway following hypoxia-ischemia in neonatal rats

An increasing number of studies have demonstrated that carnosine plays a neuroprotective role in many types of brain injury. We have previously shown that carnosine has both short-term and long-lasting neuroprotective effects in a hypoxia-ischemia(HI) rat model. In the mature brain, post-ischemia neuronal survival involves in activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, whether the activation of PI3K/Akt pathway also plays an important role in the immature brain still remain unclear.The goal of this study is to detect the effection of carnosine on inflammation response following HI, further evidencing neuroprotection of carnosine. We measured total Akt, phospho-Akt (p-AKT) and tumor necrosis factor receptor 1 (TNFR1) protein levels by western blot assay and tumor necrosis factor- (TNF-) and TNFR1 mRNA expression using real-time RT-PCR. We found the carnosine-pretreated group had statistically significant downregulation of TNF- mRNA levels 24 h after HI (P < 0.05). Similar results were observed when we measured TNFR1 mRNA levels both 24h and 72h after HI (P < 0.05). And the TNFR1 protein expression after HI was markedly decreased at 24 and 72 h post-HI in the carnosine-pretreated rats(P < 0.05). Nevertheless, the rats pretreated with carnosine showed a marked increase in p-Akt levels (P< 0.05). And the pro-apoptotic protein Bad was also examined using immunohistochemistry after 24 and 72 h of all groups. We found significantly fewer Bad-positive cells in the carnosine-pretreated group at each time point after HI (P < 0.05). These findings suggest that carnosine pretreatment inhibits the HI-induced inflammatory response, and neuroprotection mechanism of carnosine involved in activation of the PI3K/Akt signaling pathway.

neuroscience↗

A failed top-down control from prefrontal cortex to amygdala in generalized anxiety disorder: evidence from resting-state fMRI with Granger causality analysis

ObjectiveIn generalized anxiety disorder (GAD), abnormal top-down control from prefrontal cortex (PFC) to amygdala is a widely accepted hypothesis through which \"emotional dysregulation model\" may be explained. However, whether and how the PFC directly exerted abnormal top-down control on amygdala remained largely unknown. We aim to investigate the amygdala-based effective connectivity by using Granger causality analysis (GCA).\n\nMethodsThirty-five drug-naive patients with GAD and thirty-six healthy controls (HC) underwent resting-state functional MR imaging. We used seed-based Granger causality analysis to examine the effective connectivity between the bilateral amygdala and the whole brain. The amygdala-based effective connectivity was compared between the two groups.\n\nResultsIn HC, the left middle frontal gyrus exerted inhibitory influence on the right amygdala, while in GAD group, this influence was disrupted (single voxel P < 0.001, Gaussian random field corrected with P < 0.01).\n\nConclusionOur finding might provide new insight into the \"insufficient top-down control\" hypothesis in GAD.

neuroscience↗

Identification of a Nocardia seriolae secreted protein targeting host cell mitochondria and inducing apoptosis in fathead minnow (FHM) cells

Nocardia seriolae, is a Gram-positive, partially acid-fast, aerobic, and filamentous bacterium. This bacterium is the main pathogen of fish nocardiosis. A bioinformatic analysis based on the genomic sequence of the N. seriolae strain ZJ0503 showed that ORF3141 encoded a secreted protein with a signal peptide at the N-terminate which may target the mitochondria in the host cell. However, the functions of this protein and its homologs remain unknown. In this study, we experimentally tested the bioinformatic prediction on this protein. Mass spectrometry analysis of the extracellular products from N. seriolae showed that ORF3141 was a secreted protein. Subcellular localization of the ORF3141-GFP fusion protein revealed that the green fluorescence protein co-localized with the mitochondria, while ORF3141{Delta}sig-GFP (with the signal peptide deleted) fusion protein was evenly distributed in the whole cell of fathead minnow (FHM) cells. Thus, the N-terminate signal peptide had a significant impact on mitochondrial targeting. Notably, the expression of ORF3141 protein changed the distribution of mitochondria from perinuclear halo into lumps in the transfected FHM cells. In addition, apoptotic features were found in the transfected FHM cells by overexpression of ORF3141 and ORF3141{Delta}sig proteins, respectively. Quantitative assays of mitochondrial membrane potential value, caspase-3 activity and apoptosis-related gene mRNA expression suggested that cell apoptosis was induced in the transfected FHM cells. In conclusion, the ORF3141 was a secreted protein of N. seriolae that targeted host cell mitochondria and induced apoptosis in FHM cells. This protein may participate in the cell apoptosis regulation and plays an important role in the pathogenesis of N. seriolae.\n\nAuthor summaryNocardia seriolae is the causative pathogen responsible for fish nocardiosis. This facultative intercellular bacterium, adapts to survive and colonize by evading intracellular killing after being engulfed with macrophages in the host. Despite considerable economic losses caused by N. seriolae in fish infection, the pathogenic mechanism and specific virulence factor of this bacterium remain ambiguous. In this study, the characteristic of ORF3141 protein function was investigated by subcellular localization and its possible contributions on the ability of N. seriolae to induce apoptosis in transfected fathead minnow (FHM) cells was investigated. Here, we confirmed that ORF3141 was a secreted protein that targeted host cell mitochondria and induced cell apoptosis in FHM cells. Interestingly, after deleting the signal peptide, ORF3141{Delta}sig protein was evenly distributed in the whole host cell and did not co-localize with the mitochondria which could also induce cell apoptosis. Thus, the N-terminate signal peptide played an important role in mitochondrial targeting, and the domain part without the signal peptide had a critical relationship with cell apoptosis. These results demonstrated that ORF3141 mays act as a potential virulence factor that induces apoptosis in fish cells. This protein is significant to elucidate the pathogenic mechanism of N. seriolae and this study mays provide beneficial insight to prevent and treat fish nocardiosis.

pathology↗

Subset-Based Analysis using Gene-Environment Interactions for Discovery of Genetic Associations across Multiple Studies or Phenotypes

ObjectivesClassical methods for combining summary data from genome-wide association studies (GWAS) only use marginal genetic effects and power can be compromised in the presence of heterogeneity. We aim to enhance the discovery of novel associated loci in the presence of heterogeneity of genetic effects in sub-groups defined by an environmental factor.\n\nMethodsWe present a p-value Assisted Subset Testing for Associations (pASTA) framework that generalizes the previously proposed association analysis based on subsets (ASSET) method by incorporating gene-environment (G-E) interactions into the testing procedure. We conduct simulation studies and provide two data examples.\n\nResultsSimulation studies show that our proposal is more powerful than methods based on marginal associations in the presence of G-E interactions and maintains comparable power even in their absence. Both data examples demonstrate that our method can increase power to detect overall genetic associations and identify novel studies/phenotypes that contribute to the association.\n\nConclusionsOur proposed method can be a useful screening tool to identify candidate single nucleotide polymorphisms (SNPs) that are potentially associated with the trait(s) of interest for further validation. It also allows researchers to determine the most probable subset of traits that exhibit genetic associations in addition to the enhancement of power.

genetics↗

Baseline mutation profiling of 1134 samples of circulating cell-free DNA and blood cells from healthy individuals

The molecular alteration in circulating cell-free DNA (cfDNA) in plasma can reflect the status of the human body in a timely manner. Hence, cfDNA has emerged as important biomarkers in clinical diagnostics, particularly in cancer. However, somatic mutations are also commonly found in healthy individuals, which extensively interfere with the diagnostic results in cancer. This study was designed to examine the background somatic mutations in white blood cells (WBC) and cfDNA for healthy controls based on the sequencing data from 1134 samples, to understand the patterns and origin of mutations detected in cfDNA. We determined the mutation frequencies in both the WBC and cfDNA groups of the samples by a panel of 50 cancer-associated genes which covered 20K nucleotide regions using ultra-deep sequencing with average depth >40000 folds. Our results showed that most of mutations in cfDNA originated from WBC. We also observed that NPM1 gene was the most frequently mutant gene in both WBC and cfDNA. Our study highlighted the importance of sequencing both cfDNA and WBC, to improve the sensitivity and accuracy for calling cancer-related mutations from circulating tumor DNA, and shielded light on developing the early cancer diagnosis by cfDNA sequencing.

bioinformatics↗