Biology subjects

Lv, Z.

Publications and source records attributed to Lv, Z..

49 records · Page 3Linked to original sources

bioRxiv2020

New Measures of Visual Scanning Efficiency and Cognitive Effort

Visual scanning plays an important role in sampling visual information from the surrounding environments for a lot of everyday sensorimotor tasks, such as walking and car driving. In this paper, we consider the problem of visual scanning mechanism underpinning sensorimotor tasks in 3D dynamic environments. We exploit the use of eye tracking data as a behaviometric, for indicating the visuo-motor behavioral measures in the context of virtual driving. A new metric of visual scanning efficiency (VSE), which is defined as a mathematical divergence between a fixation distribution and a distribution of optical flows induced by fixations, is proposed by making use of a widely-known information theoretic tool, namely the square root of Jensen-Shannon divergence. Based on the proposed efficiency metric, a cognitive effort measure (CEM) is developed by using the concept of quantity of information. Psychophysical eye tracking studies, in virtual reality based driving, are conducted to reveal that the new metric of visual scanning efficiency can be employed very well as a proxy evaluation for driving performance. In addition, the effectiveness of the proposed cognitive effort measure is demonstrated by a strong correlation between this measure and pupil size change. These results suggest that the exploitation of eye tracking data provides an effective behaviometric for sensorimotor activity.

neuroscience↗

bioRxiv2020

Ebselen derivatives are very potent dual inhibitors of SARS-CoV-2 proteases - PLpro and Mpro in in vitro studies

Proteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. SARS-CoV-2 main protease (Mpro, 3CLpro) and papain-like protease (PLpro) are responsible for viral polyprotein cleavage - a process crucial for viral survival and replication. Recently it was shown that 2-phenylbenzisoselenazol-3(2H)-one (ebselen), an organoselenium anti-inflammatory small-molecule drug, is a potent, covalent inhibitor of both the proteases and its potency was evaluated in enzymatic and anti-viral assays. In this study, we screened a collection of 23 ebselen derivatives for SARS-CoV-2 PLpro and Mpro inhibitors. Our studies revealed that ebselen derivatives are potent inhibitors of both the proteases. We identified three PLpro and four Mpro inhibitors superior to ebselen. Our work shows that ebselen constitutes a promising platform for development of new antiviral agents targeting both SARS-CoV-2 PLpro and Mpro.

biochemistry↗

bioRxiv2020

Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody

The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we reported a humanized monoclonal antibody, H014, efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nM level by engaging the S receptor binding domain (RBD). Importantly, H014 administration reduced SARS-CoV-2 titers in the infected lungs and prevented pulmonary pathology in hACE2 mouse model. Cryo-EM characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a novel conformational epitope, which is only accessible when the RBD is in open conformation. Biochemical, cellular, virological and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncover broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19. One sentence summaryA potent neutralizing antibody conferred protection against SARS-CoV-2 in an hACE2 humanized mouse model by sterically blocking the interaction of the virus with its receptor.

biophysics↗

bioRxiv2020

Rapid development of an inactivated vaccine for SARS-CoV-2

The COVID-19 pandemic caused by SARS-CoV-2 has brought about an unprecedented crisis, taking a heavy toll on human health, lives as well as the global economy. There are no SARS-CoV-2-specific treatments or vaccines available due to the novelty of this virus. Hence, rapid development of effective vaccines against SARS-CoV-2 is urgently needed. Here we developed a pilot-scale production of a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc), which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats and non-human primates. These antibodies potently neutralized 10 representative SARS-CoV-2 strains, indicative of a possible broader neutralizing ability against SARS-CoV-2 strains circulating worldwide. Immunization with two different doses (3g or 6 g per dose) provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without any antibody-dependent enhancement of infection. Systematic evaluation of PiCoVacc via monitoring clinical signs, hematological and biochemical index, and histophathological analysis in macaques suggests that it is safe. These data support the rapid clinical development of SARS-CoV-2 vaccines for humans. One Sentence SummaryA purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc) confers complete protection in non-human primates against SARS-CoV-2 strains circulating worldwide by eliciting potent humoral responses devoid of immunopathology

microbiology↗

bioRxiv2020

Plastome phylogenomic study of Gentianeae (Gentianaceae): widespread gene tree discordance and its association with evolutionary rate heterogeneity of plastid genes

BackgroundPlastome-scale data have been prevalent in reconstructing the plant Tree of Life. However, phylogenomic studies currently based on plastomes rely primarily on maximum likelihood (ML) inference of concatenated alignments of plastid genes, and thus phylogenetic discordance produced by individual plastid genes has generally been ignored. Moreover, structural and functional characteristics of plastomes indicate that plastid genes may not evolve as a single locus and are experiencing different evolutionary forces, yet the genetic characteristics of plastid genes within a lineage remain poorly studied. ResultsWe sequenced and annotated ten plastome sequences of Gentianeae. Phylogenomic analyses yielded robust relationships among genera within Gentianeae. We detected great variation of gene tree topologies and revealed more than half of the genes, including one (atpB) of the three widely used plastid markers (rbcL, atpB and matK) in phylogenetic inference of Gentianeae, are likely contributing to phylogenetic ambiguity of Gentianeae. Estimation of nucleotide substitution rates showed extensive rate heterogeneity among different plastid genes and among different functional groups of genes. Comparative analysis suggested that the ribosomal protein (RPL and RPS) genes and the RNA polymerase (RPO) genes have higher substitution rates and genetic variations in Gentianeae. Our study revealed that just one (matK) of the three (matK, ndhB and rbcL) widely used markers show high phylogenetic informativeness (PI) value. Due to the high PI and lowest gene-tree discordance, rpoC2 is advocated as a promising plastid DNA barcode for taxonomic studies of Gentianeae. Furthermore, our analyses revealed a positive correlation of evolutionary rates with genetic variation of plastid genes, but a negative correlation with gene-tree discordance under purifying selection. ConclusionsOverall, our results demonstrate the heterogeneity of nucleotide substitution rates and genetic characteristics among plastid genes providing new insights into plastome evolution, while highlighting the necessity of considering gene-tree discordance into phylogenomic studies based on plastome-scale data.

evolutionary biology↗

bioRxiv2019

Exfoliated near infrared fluorescent CaCuSi4O10 nanosheets with ultra-high photostability and brightness for biological imaging

Imaging of complex (biological) samples in the near infrared (nIR) range of the spectrum is beneficial due to reduced light scattering, absorption, phototoxicity and autofluorescence. However, there are only few near infrared fluorescent materials known and suitable for biomedical applications. Here, we exfoliate the layered pigment CaCuSi4O10 (known as Egyptian Blue, EB) via facile tip sonication into nanosheets (EB-NS) with ultra-high nIR fluorescence stability and brightness. The size of EB-NS can be tailored by tip sonication to diameters < 20 nm and heights down to 1 nm. EB-NS fluoresce at 910 nm and the total fluorescence intensity scales with the number of Cu2+ ions that serve as luminescent centers. Furthermore, EB-NS display no bleaching and ultra-high brightness compared to other nIR fluorophores. The versatility of EB-NS is demonstrated by in vivo single-particle tracking and microrheology measurements in developing Drosophila embryos. Additionally, we show that EB-NS can be uptaken by plants and remotely detected in a low cost stand-off detection setup despite strong plant background fluorescence. In summary, EB-NS are a highly versatile, bright, photostable and biocompatible nIR fluorescent material that has the potential for a wide range of bioimaging applications both in animal and plant systems.

biophysics↗

bioRxiv2019

Two C-terminal sequence variations determine differential neurotoxicity between human and mouse α-synuclein

-Synuclein (aSyn) aggregation is thought to play a central role in neurodegenerative disorders termed synucleinopathies, including Parkinsons disease (PD). Mouse aSyn contains a threonine residue at position 53 that mimics the human familial PD substitution A53T, yet in contrast to A53T patients, mice show no evidence of aSyn neuropathology even after aging. Here we studied the neurotoxicity of human A53T, mouse aSyn, and various human-mouse chimeras in cellular and in vivo models as well as their biochemical properties relevant to aSyn pathobiology. We report that mouse aSyn is less neurotoxic than the human A53T variant as a result of inhibitory effects of two C-terminal amino acid substitutions on membrane-induced aSyn aggregation and aSyn-mediated vesicle permeabilization. Our findings highlight the importance of membrane-induced self-assembly in aSyn neurotoxicity and suggest that inhibiting this process by targeting the C-terminal domain could slow neurodegeneration in PD and other synucleinopathy disorders.

neuroscience↗

bioRxiv2019

An emergent flow of the nuclear array in syncytial embryos

Many aspects in tissue morphogenesis are attributed to the collective behavior of the participating cells. Yet, the mechanism for emergence of dynamic tissue behavior is not understood completely. Here we report the "yo-yo"-like nuclear drift movement in Drosophila syncytial embryo displays typical emergent feature of collective behavior, which is associated with pseudo-synchronous nuclear division cycle. We uncover the direct correlation between the degree of asynchrony of mitosis and the nuclear collective movement. Based on experimental manipulations and numerical simulations, we find the ensemble of spindle elongation, rather than a nucleus own spindle, is the main driving force for its drift movement. The cortical F-actin acts as viscoelastic medium to dampen the movements and plays a critical role in restoring the nuclear positions after a mitosis cycle. Our study provides insights into how the interactions between cytoskeleton as individual elements leads to collective movement of the nuclear array on a macroscopic scale.

developmental biology↗

bioRxiv2019

Spontaneous Self-assembly of Amyloid β (1-40) into Dimers

The self-assembly and fibrillation of amyloid {beta} (A{beta}) proteins is the neuropathological hallmark of Alzheimers disease. However, the molecular mechanism of how disordered monomers assemble into aggregates remains largely unknown. In this work, we characterize the assembly of A{beta} (1-40) monomers into dimers using long-time molecular dynamics simulations. Upon interaction, the monomers undergo conformational transitions, accompanied by change of the structure, leading to the formation of a stable dimer. The dimers are primarily stabilized by interactions in the N-terminal region (residues 5-12), in the central hydrophobic region (residues 16-23), and in the C-terminal region (residues 30-40); with inter-peptide interactions focused around the N- and C- termini. The dimers do not contain long {beta}-strands that are usually found in fibrils.

biophysics↗

bioRxiv2018

Preliminary Study of the Potential Mechanism of CTSD in the Aging Process of Sepiella japonica: Fundamental Function Analysis

Cathepsin D, a kind of endopeptidase, can degrade peptides and proteins in lysosomes, which are involved in cell apoptosis. Previous transcriptome analysis of optic glands of Sepiella japonica across four growth stages, expression of a cathepsin D-like segment was found to be significantly different. Based on the complete cDNA sequence of S. japonica, the CTSD gene (also called sjCTSD, GenBank accession no. KY745896.1) was cloned using RACE amplification; this gene is 1389 bp in length and encodes proteins composed of 393 amino acids. Spatio-temporal expression profiles of the sjCTSD gene were determined using qPCR assays, which showed that the expression levels of sjCTSD constantly increased across four growth stages in 9 of 11 tissues that were investigated. In the optic glands, as well as pancreas and liver cells, sjCTSD expression levels sharply increased during the post-spawning phase. To investigate the potential role of the sjCTSD gene in aging progress, we constructed the prokaryotic expression vector of pET28a/sjCTSD. After induced by IPTG, the recombinant protein sjCTSD was obtained in the form of inclusion bodies, with a molecular size of approximately 40.3 kDa, the inclusion body of sjCTSD can be converted to soluble protein through the denaturation and renaturation. The results of functional experiments showed that sjCTSD could degrade bovine hemoglobin under acidic conditions, and inhibit the growth of Escherichia coli and Vibrio alginolyticus, which was speculated that the increased expression of sjCTSD may help inhibit the invasion of pathogenic bacteria with the immune function of cuttlefish declines during the aging process. To a certain extent, these results indicated the potential functional role of the sjCTSD gene in the aging process of S. japonica. This study provides insights to further understand the roles of lysosomal proteins on anti-aging effects in S. japonica and other cephalopoda species.

genetics↗

bioRxiv2018

Molecular Detection of H.pylori Antibiotic-Resistant Genes and Bioinformatics Predictive Analysis

To explore the mutation characteristics of H.pylori resistance-related genes to antibiotics of clarithromycin, levofloxacin and metronidazole. 23S rRNA, gyrA, gyrB, rdxA and frxA genes were amplified and sequenced, respectively. Their structural alteration after mutation was predicted using bioinformatics software. In the clarithromycin-resistant strains, the mutation rate in site A2143G was 74.2% (n=23). The mutations in sites C1883T, C2131T and T2179G might cause structural alteration. In the levofloxacin-resistant strains, the mutation rates in 87 (N to K/I) and 91 (D to N/Y/G) of gyrA were 28.6% (n=16) and 12.5% (n =7), respectively. Meanwhile, one of the mutation strains in site 91 was accompanied by D99N variation. Additionally, a D143E mutation was found in one drug-resistant strain. Some changes of tertiary structure occurred after these mutations. The mutation types of RdxA protein consisted of protein truncation caused by premature stop codons (n=26, 33.3%), frameshift mutations (n=8, 10.3%), FMN-binding sites (n=16, 20.5%) and the others (n=11, 14.1%). Predictive analysis showed that mutations in the first three groups and the A118S of the last group could lead to structural alteration. Our study suggested the clarithromycin-resistant sites of H.pylori were mainly located in A2143G of 23S rRNA. C1883T, C2131T and T2179G might also be related to resistance. Levofloxacin resistance was mainly based on the amino acid changes in 87 and 91 sites of gyrA. The new sites D99N and D143E might also be associated with resistance. Metronidazole resistance was related to RdxA protein truncation, frameshift, and FMN binding. The new site A118S might also be linked to drug resistance.

microbiology↗

bioRxiv2018

Phospholipid membranes promote the early stage assembly of α-synuclein aggregates

Development of Parkinsons disease is associated with spontaneous self-assembly of -synuclein (-syn). Efforts aimed at understanding this process have produced little clarity and the mechanism remains elusive. We report a novel effect of phospholipid bilayers on the catalysis of -syn aggregation from monomers. We directly visualized -syn aggregation on supported lipid bilayers using time-lapse atomic force microscopy. We discovered that -syn assemble in aggregates on bilayer surfaces even at the nanomolar concentration of monomers in solution. The efficiency of the aggregation process depends on the membrane composition, being highest for a negatively charged bilayer. Furthermore, assembled aggregates can dissociate from the surface, suggesting that on-surface aggregation can be a mechanism by which pathological aggregates are produced. Computational modeling revealed that interaction of -syn with bilayer surface changes the protein conformation and its affinity to assemble into dimers, and these properties depend on the bilayer composition. A model of the membrane-mediated aggregation triggering the assembly of neurotoxic aggregates is proposed.

neuroscience↗

bioRxiv2017

A "molecular guillotine" reveals an interphase function of Kinesin-5

Motor proteins are important for transport and force generation in a variety of cellular processes and morphogenesis. Here we design a general strategy for conditional motor mutants by inserting a protease cleavage site at the \"neck\" between the head domain and the stalk of the motor protein, making the protein susceptible to proteolytic cleavage at the neck by the corresponding protease. To demonstrate the feasibility of this approach, we inserted the cleavage site of TEV protease into the neck of the tetrameric motor Kinesin-5. Application of TEV protease led to a specific depletion and functional loss of Kinesin-5 in Drosophila embryos. By this, we revealed that Kinesin-5 stabilized the microtubule network during interphase in syncytial embryos. The \"molecular guillotine\" can potentially be applied to many motor proteins due to the conserved structures of kinesin, dynein and myosin with accessible necks.\n\nAuthor summaryWe design a general strategy for conditional motor mutants by inserting a protease cleavage site between head and stalk domain of the motor protein, making it susceptible to specific proteolytic cleavage. We demonstrate the feasibility of the approach with the motor Kinesin-5 and the protease TEV in Drosophila embryos. This approach can potentially be applied to motor proteins kinesin, dynein and myosin due to the conserved structures.

developmental biology↗