Biology subjects

Shi, Z.

Publications and source records attributed to Shi, Z..

At least 163 records · Page 9Linked to original sources

bioRxiv2020

Inhibition of SARS-CoV-2 infection (previously 2019-nCoV) by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be confirmed. Therefore, we herein used a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed plasma membrane fusion capacity superior to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. We then generated a series of lipopeptides and found that the EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than that of EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, potently inhibiting replication of 4 live human coronaviruses, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by currently circulating SARS-CoV-2 and emerging SARSr-CoVs.

microbiology↗

bioRxiv2020

Structure-based drug design, virtual screening and high-throughput screening rapidly identify antiviral leads targeting COVID-19

A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1-4. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these inhibit Mpro with IC50 values ranging from 0.67 to 21.4 M. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available.

biochemistry↗

bioRxiv2020

CandiHap: a toolkit for haplotype analysis for sequence of samples and fast identification of candidate causal gene(s) in genome-wide association study

Genome-wide association study (GWAS) is widely used to identify genes involved in plants, animals and human complex traits. Generally, the identified SNP is not necessarily the causal variant, but it is rather in linkage disequilibrium (LD). One key challenge for GWAS results interpretation is to rapidly identify causal genes and provide profound evidence on how they affect the trait. Researches want to identify candidate causal variants from the most significant SNPs of GWAS in any species and on their local computer, while to complete these tasks are to be time-consuming, laborious and prone to errors and omission. To our knowledge, so far there is no tool available to solve the challenge for GWAS data very quickly. Based on the standard VCF (variant call format) format, CandiHap is developed to fast preselection candidate causal SNPs and gene(s) from GWAS by integrating LD result, SNP annotation, haplotype analysis and traits statistics of haplotypes. Investigators can specify genes or linkage regions based on GWAS results, linkage disequilibrium (LD), and predicted candidate causal gene(s). It supported Windows, Mac and Linux computers and servers in graphical interface and command line, and applied to any other plant, animal or bacteria species. The source code of CandiHap tool is freely available at https://github.com/xukaili/CandiHap

bioinformatics↗

bioRxiv2020

Lower Soil Carbon Loss Due to Persistent Microbial Adaptation to Climate Warming

Soil microbial respiration is an important source of uncertainty in projecting future climate and carbon (C) cycle feedbacks. Despite intensive studies for two decades, the magnitude, direction, and duration of such feedbacks are uncertain, and their underlying microbial mechanisms are still poorly understood. Here we examined the responses of soil respiration and microbial community structure to long-term experimental warming in a temperate grassland ecosystem. Our results indicated that the temperature sensitivity of soil microbial respiration (i.e., Q10) persistently decreased by 12.0{+/-}3.7% across 7 years of warming. Integrated metagenomic and functional analyses showed that microbial community adaptation played critical roles in regulating respiratory acclimation. Incorporating microbial functional gene abundance data into a microbially-enabled ecosystem model significantly improved the modeling performance of soil microbial respiration by 5-19%, compared to the traditional non-microbial model. Model parametric uncertainty was also reduced by 55-71% when gene abundances were used. In addition, our modeling analyses suggested that decreased temperature sensitivity could lead to considerably less heterotrophic respiration (11.6{+/-}7.5%), and hence less soil C loss. If such microbially mediated dampening effects occur generally across different spatial and temporal scales, the potential positive feedback of soil microbial respiration in response to climate warming may be less than previously predicted.

ecology↗

bioRxiv2020

Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody

The newly identified 2019 novel coronavirus (2019-nCoV) has caused more than 800 laboratory-confirmed human infections, including 25 deaths, posing a serious threat to human health. Currently, however, there is no specific antiviral treatment or vaccine. Considering the relatively high identity of receptor binding domain (RBD) in 2019-nCoV and SARS-CoV, it is urgent to assess the cross-reactivity of anti-SARS-CoV antibodies with 2019-nCoV spike protein, which could have important implications for rapid development of vaccines and therapeutic antibodies against 2019-nCoV. Here, we report for the first time that a SARS-CoV-specific human monoclonal antibody, CR3022, could bind potently with 2019-nCoV RBD (KD of 6.3 nM). The epitope of CR3022 does not overlap with the ACE2 binding site within 2019-nCoV RBD. Therefore, CR3022 has the potential to be developed as candidate therapeutics, alone or in combination with other neutralizing antibodies, for the prevention and treatment of 2019-nCoV infections. Interestingly, some of the most potent SARS-CoV-specific neutralizing antibodies (e.g., m396, CR3014) that target the ACE2 binding site of SARS-CoV failed to bind 2019-nCoV spike protein, indicating that the difference in the RBD of SARS-CoV and 2019-nCoV has a critical impact for the cross-reactivity of neutralizing antibodies, and that it is still necessary to develop novel monoclonal antibodies that could bind specifically to 2019-nCoV RBD.

microbiology↗

bioRxiv2020

Ensemble perception in the time domain: evidence in favor of logarithmic encoding of time intervals

Although time perception is based on the internal representation of time, whether the subjective timeline is scaled linearly or logarithmically remains an open issue. Evidence from previous research is mixed: while the classical internal-clock model assumes a linear scale with scalar variability, there is evidence that logarithmic timing provides a better fit to behavioral data. A major challenge for investigating the nature of the internal scale is that the retrieval process required for time judgments may involve a remapping of the subjective time back to the objective scale, complicating any direct interpretation of behavioral findings. Here, we used a novel approach, requiring rapid intuitive ensemble averaging of a whole set of time intervals, to probe the subjective timeline. Specifically, observers task was to average a series of successively presented, auditory or visual, intervals in the time range 300-1300 ms. Importantly, the intervals were taken from three sets of durations, which were distributed such that the arithmetic mean (from the linear scale) and the geometric mean (from the logarithmic scale) were clearly distinguishable. Consistently across the three sets and the two presentation modalities, our results revealed subjective averaging to be close to the geometric mean, indicative of a logarithmic timeline underlying time perception.

neuroscience↗

bioRxiv2020

Diversified Learning Environment Alleviates Learning Impairment Caused by Contextual Stress

Environment is capable of affecting our learning ability. Existing studies reported that learning ability can be enhanced by enriched environment and impaired by stressful context. However, it is still unclear whether diversified environment can reverse or ameliorate the learning difficulty caused by stressful context. In this study, several behavioral tasks were designed to test the role of diversified environment in active avoidance learning. In the present study, sound-cued active avoidance (two-way shuttle box) acted as learning paradigm. Multiple shuttle boxes with the identical size but different designs were employed to mimic diversified environment in learning tasks. Mild but inevitable foot shocking was adopted to increase animals stress to certain context. To quantify the depression/anxiety level of animals, open field test, forced swimming test, light-dark box test, and elevated plus maze were performed. The following findings were reported. First, diversified learning environment could improve learning ability in active avoidance, as manifested by higher successful rate and sharper learning curve. Second, elevating the stress level of animal to a certain context could noticeably reduce its performance in active avoidance learning. Third, the learning impairment attributed to stressful context can be improved by training in diversified environments. Thus, as revealed from the results, learning impairment caused by stressful context can be alleviated by diversified learning environment which may facilitate further medical and education applications.

animal behavior and cognition↗

bioRxiv2020

DNA damage induced during mitosis undergoes DNA repair synthesis

Understanding the mitotic DNA damage response (DDR) is critical to our comprehension of cancer, premature aging and developmental disorders which are marked by DNA repair deficiencies. In this study we use a micro-focused-laser to induce DNA damage in selected mitotic chromosomes to study the subsequent repair response. Our findings demonstrate that (1) mitotic cells are capable of DNA repair as evidenced by DNA synthesis at damage sites, (2) Repair is attenuated when DNA-PKcs and ATM are simultaneously compromised, (3) Laser damage may permit the observation of previously undetected DDR proteins when damage is elicited by other methods in mitosis, and (4) Twenty five percent of mitotic DNA-damaged cells undergo a subsequent mitosis. Together these findings suggest that mitotic DDR is more complex than previously thought and may involve factors from multiple repair pathways that are better understood in interphase.

cell biology↗

bioRxiv2019

The human mitochondrial 12S rRNA m4C methyltransferase METTL15 is required for proper mitochondrial function

Mitochondrial DNA (mtDNA) gene expression is coordinately regulated pre- and post-transcriptionally, and its perturbation can lead to human pathologies. Mitochondrial ribosomal RNAs (mt-rRNAs) undergo a series of nucleotide modifications following release from polycistronic mitochondrial RNA (mtRNA) precursors, which is essential for mitochondrial ribosomal biogenesis. Cytosine N4 methylation (m4C) at position 839 of the 12S small subunit (SSU) mt-rRNA was identified decades ago, however, its biogenesis and function have not been elucidated in details. Here we demonstrate that human Methyltransferase Like 15 (METTL15) is responsible for 12S mt-rRNA methylation at C839 (m4C839) both in vivo and in vitro. We tracked the evolutionary history of RNA m4C methyltransferases and revealed the difference in substrates preference between METTL15 and its bacterial ortholog rsmH. Additionally, unlike the very modest impact on ribosome upon loss of m4C methylation in bacterial SSU rRNA, we found that depletion of METTL15 specifically causes severe defects in mitochondrial ribosome assembly, which leads to an impaired translation of mitochondrial protein-coding genes and a decreased mitochondrial respiration capacity. Our findings point to a co-evolution of methylatransferase specificities and modification patterns in rRNA with differential impact on prokaryotic ribosome versus eukaryotic mitochondrial ribosome.

molecular biology↗

bioRxiv2019

IL-22 induced cell extrusion and IL-18-induced pyroptosis prevent and cure rotavirus infection

Administration of bacterial flagellin elicits production of TLR5-mediated IL-22 and NLRC4-mediated IL-18 that act in concert to cure and prevent rotavirus (RV) infection. This study investigated the mechanism by which these cytokines act to impede this virus. Although IL-18 and IL-22 induce each others expression, we found that IL-18 and IL-22 both impeded RV independently of each other and did so by distinct mechanisms, in both cases via activation of their cognate receptors in intestinal epithelial cells (IEC). IL-22 drove IEC proliferation and migration toward villus tips, which resulted in increased extrusion of highly differentiated IEC that serve as the site of RV replication. In contrast, IL-18 induced pyroptotic death of RV-infected IEC thus directly interrupting the RV replication cycle, resulting in spewing of incompetent virus into the intestinal lumen and causing a rapid drop in levels of RV-infected IEC. Together, these actions resulted in rapid and complete expulsion of RV, even in hosts with severely compromised immune systems. These results suggest that IL-18/22 might be a means of treating viral infections that preferentially target short-lived epithelial cells.

immunology↗

bioRxiv2019

Distinct gut metagenomics and metaproteomics signatures in prediabetics and treatment-naïve type 2 diabetics

BackgroundThe gut microbiota plays important roles in modulating host metabolism. Previous studies have demonstrated differences in the gut microbiome of T2D and prediabetic individuals compared to healthy individuals, with distinct disease-related microbial profiles being reported in groups of different age and ethnicity. However, confounding factors such as anti-diabetic medication hamper identification of the gut microbial changes in disease development.\n\nMethodWe used a combination of in-depth metagenomics and metaproteomics analyses of faecal samples from treatment-naive type 2 diabetic (TN-T2D, n=77), pre-diabetic (Pre-DM, n=80), and normal glucose tolerant (NGT, n=97) individuals to investigate compositional and functional changes of the gut microbiota and the faecal content of microbial and host proteins in Pre-DM and treatment-naive T2D individuals to elucidate possible host-microbial interplays characterising different disease stages.\n\nFindingsWe observed distinct differences characterizing the gut microbiota of these three groups and validated several key features in an independent TN-T2D cohort. We also demonstrated that the content of several human antimicrobial peptides and pancreatic enzymes differed in faecal samples between three groups, such as reduced faecal level of antimicrobial peptides and pancreatic enzymes in TN-T2D.\n\nInterpretationOur findings suggest a complex, disease stage-dependent interplay between the gut microbiota and the host and emphasize the value of metaproteomics to gain further insight into interplays between the gut microbiota and the host.\n\nFundingNational Key Research and Development Program of China, No. 2017YFC0909703, Shenzhen Municipal Government of China, No. JCYJ20170817145809215, and National Natural Science Foundation of China, No. 31601073.

microbiology↗

bioRxiv2019

Age-dependent sexual dimorphism in the adult human gut microbiota

A decade of studies has established the importance of the gut microbiome in human health. In spite of sex differences in the physiology, lifespan, and prevalence of many age-associated diseases, sex and age disparities in the gut microbiota have been little studied. Here we show age-related sex differences in the adult gut microbial composition and functionality in two community-based cohorts from Northern China and the Netherlands. Consistently, women harbour a more diverse and stable microbial community across broad age ranges, whereas men exhibit a more variable gut microbiota strongly correlated with age. Reflecting the sex-biased age-gut microbiota interaction patterns, sex differences observed in younger adults are considerably reduced in the elderly population. Our findings highlight the age- and sex-biased differences in the adult gut microbiota across two ethnic population and emphasize the need for considering age and sex in studies of the human gut microbiota.

genomics↗

bioRxiv2019

Nonobese subjects of Bacteroides and Prevotella enterotypes responded differentially to calorie restriction intervention

Calorie restriction (CR), which has the potential effect to weight loss and blood amino acids, has been demonstrated to associate with gut microbiota in human, especially in obese individuals. However, studies for simultaneously evaluating enterotype-dependent impacts of CR on the gut microbiota and blood amino acids in nonobese individuals are still limited.\n\nHere, 41 nonobese individuals received a 3-week CR diet with approximately 50% fewer calories than normal diet. We measured their BMI and blood amino acid concentration, along with the gut microbiota before and after the intervention. In this trial, 28 Enterotype Bacteroides (ETB) subjects and 13 Enterotype Prevotella (ETP) subjects were identified before the intervention. Short-term CR dietary intervention decreased the body mass index (BMI) in most subjects but varied in subjects with different enterotypes. ETP subjects exhibited significantly higher BMI loss ratio than the ETB subjects. CR additionally induced substantial enterotype-independent changes in blood amino acids, but only minor changes in gut microbial composition.\n\nWe further built a prediction model based on baseline relative abundances of 7 gut microbial species showing high performance in predicting CR-associated BMI loss ratio. Among them, the relative abundance of ETB-enriched Clostridium bolteae and C. ramosum were negatively correlated with BMI loss ratio while the relative abundance of Dorea longicatena which was slightly enriched in ETP subjects, was positively correlated with BMI loss ratio.\n\nTogether, our work points out that the individual variation of BMI loss after CR could be partially correlated with different microbial composition and highlights the potential application for microbiome stratification in personalized nutrition intervention.

microbiology↗

bioRxiv2018

Seedling leaves allocate lower fractions of nitrogen to photosynthetic apparatus in nitrogen fixing trees (Dalbergia odorifera and Erythrophleum fordii) than in non-nitrogen fixing trees (Betula alnoides and Castanopsis hystrix) in subtropical China

Photosynthetic-nitrogen use efficiency (PNUE) is a useful trait to characterize leaf economics, physiology, and strategy. In this study, we investigated the differences in PNUE, leaf nitrogen (N) allocation, and mesophyll conductance (gm) in Dalbergia odorifera and Erythrophleum fordii (N-fixing trees), and Betula alnoides and Castanopsis hystrix (non-N-fixing trees). Seedlings of the four species were cultured in pots and received the same nutrient solution, water volume, and light. LiCor-6400 was used to determine fluorescence yield, photosynthetic response to light, and intercellular CO2 concentration (Ci). N allocation fractions in the photosynthetic apparatus were calculated according to Niinemets and Tenhunen method; gm was calculated according to variable J, EDO, and A-Ci curve fitting methods. PNUE of D. odorifera and E. fordii were significantly lower than those of B. alnoides and C. hystrix because of their allocation of a lower fraction of leaf N to Rubisco (PR) and bioenergetics (PB). Mesophyll conductance had a significant positive correlation with PNUE in D. odorifera, E. fordii, and B. alnoides. The fraction of leaf N to cell wall (PCW) had a significant negative correlation with PR in B. alnoides and C. hystrix. We conclude that B. alnoides and C. hystrix optimized their leaf N allocation toward photosynthesis, with the trade-off being N allocation to the cell wall and Rubisco. Thus, these two species may have a higher competitive ability in natural ecosystems with fertile soil.

ecology↗

bioRxiv2018

Probability cueing of singleton-distractor locations in visual search: priority-map- or dimension-based inhibition?

Observers can learn the likely locations of salient distractors in visual search, reducing their potential to capture attention (Ferrante et al., 2018; Sauter et al., 2018a; Wang & Theeuwes, 2018a). While there is agreement that this involves positional suppression of the likely distractor location(s), it is contentious at which stage of search guidance the suppression operates: the supra-dimensional priority map or feature-contrast signals within the distractor dimension. On the latter account, advocated by Sauter et al., target processing should be unaffected by distractor suppression when the target is defined in a different (non-suppressed) dimension to the target. At odds with this, Wang and Theeuwes found strong suppression not only of the (color) distractor, but also of the (shape) target when it appeared at the likely distractor location. Adopting their paradigm, the present study ruled out that increased cross-trial inhibition of the single frequent (frequently inhibited) as compared to any of the rare (rarely inhibited) distractor locations is responsible for this target-location effect. However, a reduced likelihood of the target appearing at the frequent vs. a rare distractor location contributes to this effect: removing this negative bias abolished the cost to target processing with increasing practice, indicative of a transition from priority-map- to dimension-based - and thus a flexible locus of - distractor suppression.\n\nPublic Significance StatementDistraction by a salient visual stimulus outside the focus of the task at hand occurs frequently. The present study examined whether and how knowledge of the likely location(s) where the distractors occur helps the observer to mitigate distraction. The results confirmed that observers can learn to suppress distracting stimuli at likely locations. Further, they showed that, the suppression may occur at different levels in the hierarchically organized visual system where the priorities of which objects to be attended in the environment are determined.

neuroscience↗

bioRxiv2018

150 years of research on Vierordt’s law - Fechner’s fault?

150 years ago, the physiologist Karl Vierordt discovered one type of systematic errors in time perception - an overestimation of long durations and underestimation of short durations, now known as Vierordt's law. Here we review the original study in its historical context and ask whether Vierordt's law is a result of an unnatural experimental randomization protocol. Using iterative Bayesian updating, we simulated the original results with astonishing accuracy. To validate whether the experimental protocol matters, we compared duration reproduction from two sequences with the same sampled distribution and found that trial-wise variation determines the reproduction error. We conclude that Vierordt's law is caused by an unnatural yet widely used experimental protocol.

neuroscience↗

bioRxiv2018

What you see depends on what you hear: temporal averaging and crossmodal integration

In our multisensory world, we often rely more on auditory information than on visual input for temporal processing. One typical demonstration of this is that the rate of auditory flutter assimilates the rate of concurrent visual flicker. To date, however, this auditory dominance effect has largely been studied using regular auditory rhythms. It thus remains unclear whether irregular rhythms would have a similar impact on visual temporal processing; what information is extracted from the auditory sequence that comes to influence visual timing; and how the auditory and visual temporal rates are integrated together in quantitative terms. We investigated these questions by assessing, and modeling, the influence of a task-irrelevant auditory sequence on the type of \"Ternus apparent motion\": group motion versus element motion. The type of motion seen critically depends on the time interval between the two Ternus display frames. We found that an irrelevant auditory sequence preceding the Ternus display modulates the visual interval, making observers perceive either more group motion or more element motion. This biasing effect manifests whether the auditory sequence is regular or irregular, and it is based on a summary statistic extracted from the sequential intervals: their geometric mean. However, the audiovisual interaction depends on the discrepancy between the mean auditory and visual intervals: if it becomes too large, no interaction occurs - which can be quantitatively described by a partial Bayesian integration model. Overall, our findings reveal a crossmodal perceptual averaging principle that may underlie complex audiovisual interactions in many everyday dynamic situations.

neuroscience↗

bioRxiv2018

Inter-trial effects in visual pop-out search: Factorial comparison of Bayesian updating models

Many previous studies on visual search have reported inter-trial effects, that is, observers respond faster when some target property, such as a defining feature or dimension, or the response associated with the target repeats versus changes across consecutive trial episodes. However, what processes drive these inter-trial effects is still controversial. Here, we investigated this question using a combination of Bayesian modeling of belief updating and evidence accumulation modeling in perceptual decision-making. In three visual singleton ( pop-out) search experiments, we explored how the probability of the response-critical states of the search display (e.g., target presence/absence) and the repetition/switch of the target-defining dimension (color/ orientation) affect reaction time distributions. The results replicated the mean reaction time (RT) inter-trial and dimension repetition/switch effects that have been reported in previous studies. Going beyond this, to uncover the underlying mechanisms, we used the Drift-Diffusion Model (DDM) and the Linear Approach to Threshold with Ergodic Rate (LATER) model to explain the RT distributions in terms of decision bias (starting point) and information processing speed (evidence accumulation rate). We further investigated how these different aspects of the decision-making process are affected by different properties of stimulus history, giving rise to dissociable inter-trial effects. We approached this question by (i) combining each perceptual decision making model (DDM or LATER) with different updating models, each specifying a plausible rule for updating of either the starting point or the rate, based on stimulus history, and (ii) comparing every possible combination of trial-wise updating mechanism and perceptual decision model in a factorial model comparison. Consistently across experiments, we found that the (recent) history of the response-critical property influences the initial decision bias, while repetition/switch of the target-defining dimension affects the accumulation rate, likely reflecting an implicit top-down modulation process. This provides strong evidence of a disassociation between response- and dimension-based inter-trial effects.

neuroscience↗