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Human serotine transporter (hSERT) is one of the most influential drug targets, and its allosteric modulators (e.g., escitalopram) have emerged to be the next-generation medication for psychiatric disorders. However, the molecular mechanism underlying the allosteric modulation of hSERT is still elusive. Here, the simulation strategies of conventional (cMD) and steered (SMD) molecular dynamics were applied to investigate this molecular mechanism from distinct perspectives. First, cMD simulations revealed that escitalopram's binding to hSERT's allosteric site simultaneously enhanced its binding to the orthosteric site. Then, SMD simulation identified that the occupation of hSERT's allosteric site by escitalopram could also block its dissociation from the orthosteric site. Finally, by comparing the simulated structures of two hSERT-escitalopram complexes with and without allosteric modulation, a new conformational coupling between an extracellular (Arg104-Glu494) and an intracellular (Lys490-Glu494) salt bridge was identified. In summary, this study explored the mechanism underlying the allosteric modulation of hSERT by collectively applying two MD simulation strategies, which could facilitate our understanding of the allosteric modulations of not only hSERT but also other clinically important therapeutic targets.

The historically dominant SARS-CoV-2 Delta variants and the currently dominant Omicron variants carry a T492I substitution within the non-structural protein 4 (NSP4). Based on a combination ofin silicoanalyses, we predicted that the T492I mutation increases the transmissibility and adaptability of the virus. We confirmed this hypothesis by performing competition experiments in hamsters and in human airway tissue culture models. Furthermore, we show that the T492I mutation also increases the replication capacity and infectiveness of the virus, and improves its ability to evade antibody neutralization induced by previous variants. Mechanistically, the T492I mutation increases cleavage efficiency of the viral main protease NSP5 by enhancing enzyme-substrate binding, resulting in increased production of nearly all non-structural proteins processed by NSP5. Importantly, T492I mutation suppresses the viral RNA associated chemokines in monocytic macrophages, which may contribute to the attenuated pathogenicity of Omicron variants. Our results highlight the importance of the NSP4 mutation in the evolutionary dynamics of SARS-CoV-2 and identify a novel target for the development of broad-spectrum antiviral agents.

The success of protein engineering and design has extensively expanded the protein space, which presents a promising strategy for creating next-generation proteins of diverse functions. Among these proteins, the synthetic binding proteins (SBPs) are smaller, more stable, less immunogenic, and better of tissue penetration than others, which make the SBP-related data attracting extensive interest from worldwide scientists. However, no database has been developed to systematically provide the valuable information of SBPs yet. In this study, a database named ‘Synthetic Binding Proteins for Research, Diagnosis, and Therapy (SYNBIP)’ was thus introduced. This database is unique in (a) comprehensively describing thousands of SBPs from the perspectives of scaffolds, biophysical & functional properties, etc.; (b) panoramically illustrating the binding targets & the broad application of each SBP and (c) enabling a similarity search against the sequences of all SBPs and their binding targets. Since SBP is a human-made protein that has not been found in nature, the discovery of novel SBPs relied heavily on experimental protein engineering and could be greatly facilitated by in-silico studies (such as AI and computational modeling). Thus, the data provided in SYNBIP could lay a solid foundation for the future development of novel SBPs. The SYNBIP is accessible without login requirement at both official (https://idrblab.org/synbip/) and mirror (http://synbip.idrblab.net/) sites., Graphical Abstract Graphical AbstractSYNBIP is a database extensively describing a comprehensive set of synthetic binding proteins (SBPs) from the perspectives of scaffolds, biophysical & functional properties, etc.; panoramically illustrating the binding targets and broad applications of each SBP; and enabling the sequence-based similarity search against SBPs and their binding targets.

Background Microtubule-stabilizing agents have been demonstrated to modulate axonal sprouting during neuronal disease. One such agent, Epothilone D, has been used to treat spinal cord injury (SCI) by promoting axonal sprouting at the lesion site after SCI. However, the role of Epothilone D in the differentiation of neural stem cells (NSCs) in SCI repair is unknown. In the present study, we mainly explored the effects and mechanisms of Epothilone D on the neuronal differentiation of NSCs and revealed a potential new SCI treatment. Methods In vitro differentiation assays, western blotting, and quantitative real-time polymerase chain reaction were used to detect the effects of Epothilone D on NSC differentiation. Retrograde tracing using a pseudotyped rabies virus was then used to detect neuronal circuit construction. RNA sequencing (RNA-Seq) was valuable for exploring the target gene involved in the neuronal differentiation stimulated by Epothilone D. In addition, lentivirus-induced overexpression and RNA interference technology were applied to demonstrate the function of the target gene. Last, an Apol8-NSC-linear ordered collagen scaffold (LOCS) graft was prepared to treat a mouse model of SCI, and functional and electrophysiological evaluations were performed. Results We first revealed that Epothilone D promoted the neuronal differentiation of cultured NSCs and facilitated neuronal relay formation in the injured site after SCI. Furthermore, the RNA-Seq results demonstrated that Apol8 was upregulated during Epothilone D-induced neuronal relay formation. Lentivirus-mediated Apol8 overexpression in NSCs (Apol8-NSCs) promoted NSC differentiation toward neurons, and an Apol8 interference assay showed that Apol8 had a role in promoting neuronal differentiation under the induction of Epothilone D. Last, Apol8-NSC transplantation with LOCS promoted the neuronal differentiation of transplanted NSCs in the lesion site as well as synapse formation, thus improving the motor function of mice with complete spinal cord transection. Conclusions Epothilone D can promote the neuronal differentiation of NSCs by upregulating Apol8, which may provide a promising therapeutic target for SCI repair.

Tau misfolding plays a significant role in some neurodegenerative diseases such as Alzheimer's disease (AD). It is intrinsically disordered and highly soluble under normal physiological conditions. While the protein will aggregate to form paired helical filaments (PHFs) under copper homeostasis at pathological conditions, which is the main substance of neurofibrillary tangles (NFTs) in the brain of AD patients. However, the molecular mechanism underlying the copper (Cu2+) ion-induced tau misfolding is not fully understood. In this study, using the 1/2 third repeat fragment (R3 peptide) of tau protein (residues 318-335: VTSKCGSLGNIHHKPGGG) as a model, a Gaussian accelerated molecular dynamics (GaMD) method followed by efficient trajectory analysis was carried out to investigate the influences of Cu2+ on the tau about the protein fold and the free energy landscape along the simulation. The two-dimensional potential of mean force (PMF) profiles obtained from reweighting of the GaMD simulations as well as clustering analysis revealed the Cu2+ ion induced α-helix fold R3 peptide located at the low-energy wells of free energy map, which is in agreement with the reported experimental result. In contrast, there is no α-helix fold of R3 peptide that appeared during the GaMD simulation without Cu2+ ion existing. Furthermore, the definition of secondary structure of protein (DSSP) analysis indicated that the R3 peptide with Cu2+ ion forms a stable structure of the helix (Lys321-His330 interval of the peptide) at between 400 and 500 ns. Therefore, the structures and free energy profiles from GaMD simulations proposed that Cu2+ triggers the aggregation of R3 peptide into toxic PHFs through a stable α-helix fold form.

Much of the interior of the Tibetan Plateau is characterized by internal drainage, low relief topography, and high altitude. How and when this landscape formed is controversial. In this study, we use new zircon U-Pb data and low-temperature thermochronological data (apatite and zircon [U-Th/He], apatite fission track [AFT]) from the Late Cretaceous to Cenozoic Nima Basin sedimentary rocks and Xiabie granite in the adjacent Muggar Thrust hanging wall (part of the regional Shiquanhe-Gaize-Amdo thrust system), to determine the paleodrainage and timing of exhumation in the region. Individual AHe and ZHe cooling ages range from 9 to 60 Ma and 58 to 118 Ma, and the AFT ages range from 30 to 90 Ma. The thermal history derived from the Northern Nima Basin sediments and Xiabie granite require a period of exhumation between 70 and 40 Ma in the thrust fault hanging wall, and 40 and 30 Ma in the Nima Basin. Across the region, this event was followed by low rates of exhumation and the deposition of locally sourced sediment, lacustrine, and evaporitic deposits that are indicative of an internal drainage system. We suggest that the exhumation event is associated with development of thrust-elevated relief that may have disrupted the drainage network favoring the development of an endorheic system. This system, sediment accumulation, and/or post-30 Ma tectonic quiescence led to the generation of low relief topography.

Besides the environmental factors having tremendous impacts on the composition of microbial community, the host factors have recently gained extensive attentions on their roles in shaping human microbiota. There are two major types of host factors: host genetic factors (HGFs) and host immune factors (HIFs). These factors of each type are essential for defining the chemical and physical landscapes inhabited by microbiota, and the collective consideration of both types have great implication to serve comprehensive health management. However, no database was available to provide the comprehensive factors of both types. Herein, a database entitled ‘Host Genetic and Immune Factors Shaping Human Microbiota (GIMICA)’ was constructed. Based on the 4257 microbes confirmed to inhabit nine sites of human body, 2851 HGFs (1368 single nucleotide polymorphisms (SNPs), 186 copy number variations (CNVs), and 1297 non-coding ribonucleic acids (RNAs)) modulating the expression of 370 microbes were collected, and 549 HIFs (126 lymphocytes and phagocytes, 387 immune proteins, and 36 immune pathways) regulating the abundance of 455 microbes were also provided. All in all, GIMICA enabled the collective consideration not only between different types of host factor but also between the host and environmental ones, which is freely accessible without login requirement at: https://idrblab.org/gimica/, Graphical Abstract Graphical AbstractGIMICA is unique in: (i) providing both host genetic and immune factors shaping human microbiota and (ii) enabling collective consideration not only among various host factors but also between the host and environmental ones.

Cellulose and hemicelluloses were isolated from birch wood using a dilute alkaline solution and then consolidated into pellets as model compounds of cellulose and hemicelluloses in the wood cell wall. The purity of isolated cellulose and hemicelluloses was examined by Fourier-transform infrared spectroscopy and thermogravimetric analysis. The density, thermal diffusivity, heat capacity, and thermal conductivity were experimentally determined for consolidated birch powder, cellulose, and hemicelluloses in over-dry condition. The thermal degradation kinetic parameters of these materials were successfully calculated using a conversion rate step of 0.01, and the relationship with conversion rate was established. The results show that cellulose and hemicelluloses consolidated under 25 MPa had densities of 1362 kg/m3and 1464 kg/m3, respectively. The cell wall of birch powder in the oven-dry state was not collapsed under 25 MPa. The thermal diffusivity of consolidated birch powder, cellulose, and hemicelluloses linearly decreased with temperature, with values of 0.08, 0.15, and 0.20 mm2/s at room temperature, respectively. The specific heat capacity (1104, 1209, and 1305 J/(kg·K) at 22 °C, respectively) and thermal conductivity (0.09, 0.24, and 0.38 W/(m·K) at 22 °C, respectively) linearly increased with temperature, except for those for hemicelluloses which exhibited a nonlinear relationship with temperature above 120 °C, and their linear experimental prediction equations were given. Birch cellulose was more thermally stable than hemicelluloses. The thermal degradation kinetic parameters including activation energy and pre-exponential factor of birch powder, cellulose, and hemicelluloses varied with the conversion rate and calculation methods, with average activation energy in a conversion rate range of 0.02–0.15 of 123.2, 159.0, and 147.2 kJ/mol, respectively (using the Flynn–Wall–Ozawa method), for average natural logarithm pre-exponential factors of 25.0, 33.1, and 28.7 min−1, respectively. Linear and quadratic equations were fitted to describe the relationship between the kinetic parameters and conversion rates. These results give comprehensive thermal properties of the densified cellulose and hemicelluloses isolated from a specific wood.

Spontaneous formation of various buckle-delamination patterns originates from complex interaction between buckles and delamination. However the impact of large compression and delamination boundary undulation on the morphology of buckle-delamination remains a challenge especially from an analytical approach. Here, a nonlinear solution based on the Foppl–von Karman (FvK) plate theory for buckle-delamination is derived by using a coordinate transformation technique in combination with perturbation series based on Koiter expansion. The analytical results validated by finite element simulations (FEM) show that the sequential sectional profile of straight-sided (SS) blister with asymmetric secondary buckling instability exhibits a butterfly shape dependent on the compression amplitude even when the delamination boundary is straight. Besides, the wavelength for SS blister after the instability drastically changes with the compression amplitude, which is coincident with the experimental results. Our analysis further demonstrates that the elastic energy of the wavy-sided blister can be significantly lower than that of the SS blister even when the initial equi-biaxial compression is a little larger than the Euler buckling stress, significantly lower than the critical stress for secondary buckling instability of SS blisters. This result indicates an alternative mechanism that formation of telephone-cord blister may proceed first by an undulation instability of the delamination boundary.

Comparative biological studies typically require plenty of samples to ensure full representation of the given problem. A frequently-encountered question is how many samples are sufficient for a particular study. This question is traditionally assessed using the statistical power, but it alone may not guarantee the full and reproducible discovery of features truly discriminating biological groups. Two new types of statistical criteria have thus been introduced to assess sample sufficiency from different perspectives by considering diagnostic accuracy and robustness. Due to the complementary nature of these criteria, a comprehensive evaluation based on all criteria is necessary for achieving a more accurate assessment. However, no such tool is available yet. Herein, an online tool SSizer (https://idrblab.org/ssizer/) was developed and validated to enable the assessment of the sample sufficiency for a user-input biological dataset, and three statistical criteria were adopted to achieve comprehensive and collective assessment. A sample simulation based on a user-input dataset was performed to expand the data and then determine the sample size required by the particular study. In sum, SSizer is unique for its ability to comprehensively evaluate whether the sample size is sufficient and determine the required number of samples for the user-input dataset, which, therefore, facilitates the comparative and OMIC-based biological studies.

Neural stem/progenitor cell (NSPC)-based spinal cord injury (SCI) therapy is expected to bridge the lesion site by transplanting exogenous NSPCs for replacement of lost cells. The transplanted NSPCs produce a microenvironment conducive to neuronal regeneration, and ultimately, functional recovery. Although both human fetal brain- and spinal cord- derived NSPCs (hbNSPCs and hscNSPCs, respectively) have been used for SCI repair, it remains unclear whether hscNSPCs are a more appropriate stem cell source for transplantation than hbNSPCs. Therefore, in this study, we transplanted hbNSPCs or hscNSPCs into rats with complete transection SCI to monitor their differences in SCI treatment. An aligned collagen sponge scaffold (ACSS) was used here for cell retention. Aligned biomaterial scaffolds provide a support platform and favorable morphology for cell growth and differentiation, and guide axial axonal extension. The ACSS fabricated by our group has been previously reported to improve spinal cord repair by promoting neuronal regeneration and remyelination. Compared with the hbNSPC-ACSS, the hscNSPC-ACSS effectively promoted long-term cell survival and neuronal differentiation and improved the SCI microenvironment by reducing inflammation and glial scar formation. Furthermore, the transplanted hscNSPC-ACSS improved recovery of locomotor functions. Therefore, hscNSPCs appear to be a superior cell source to hbNSPCs for SCI cell therapy with greater potential clinical applications.

Vilazodone is a novel antidepressant used for the treatment of major depressive disorder (MDD) with a primary action mechanism of inhibiting the human serotonin reuptake transporter (hSERT) and acting as a 5-HT1A receptor partial agonist. The interaction between vilazodone and the 5-HT1A receptor has been reported, however, the binding mode of vilazodone in the hSERT remains elusive. In the current study, to elucidate the molecular mechanism of vilazodone binding in the hSERT, the drug and its five analogs were docked into the hSERT crystal structure as initial conformations and were sampled by 400 ns molecular dynamics (MD) simulations. Through the analysis of the profiles of protein-ligand binding free energies, interaction fingerprints, and conformational rearrangements, the binding mode of vilazodone in the hSERT was revealed. As a result, unlike the classical antidepressants located in the S1 site of the hSERT, vilazodone adopted a linear pose in the binding pocket. Its arylpiperazine fragment occupies the central site (S1) and interacts with Y95, D98, I172, Y176, F335, F341, S438, and T439, while the indole fragment extends to the allosteric site (S2) via interacting with the ionic switch (R104/E403) between the two sites. The new insights obtained are not only helpful in understanding the binding mode of vilazodone in the hSERT, but also provide valuable guidance to the discovery of novel antidepressant drugs.

Sensors for detecting glucose concentrations are crucial to medical testing. Here, we introduce silver nanoparticles (Ag NPs) uniformly distributed in space to investigate the sensing properties for detecting glucose by using the finite-different time-domain (FDTD) and experimental methods. The results show that the transmittance of dip for the proposed structural model gradually decreases as the number of Ag NPs increases, when the concentration of glucose is constant. And the transmission spectrum shows slight red shift with the increasing of the glucose concentration. Moreover, the simulation results are in agreement with the experimental results. Especially, the maximum sensitivity S=1144.07407 nm/RIU can be realized for glucose concentration variation from 0.3 to 0.4 mol/L. The research results reveal an excellent sensing property that has important application value in medical detection.

Previous work found that the cooccurring mutations R203K/G204R on the SARS-CoV-2 nucleocapsid (N) protein are increasing in frequency amongst emerging variants of concern or interest. Through a combination of in silico analyses, this study demonstrates that R203K/G204R are adaptive, while large-scale phylogenetic analyses indicate that R203K/G204R associates with the emergence of the high-transmissibility SARS-CoV-2 lineage B.1.1.7. Competition experiments suggest that the 203K/204R variants possess a replication advantage over the preceding R203/G204 variants, possibly related to ribonucleocapsid (RNP) assembly. Moreover, the 203K/204R virus shows increased infectivity in human lung cells and hamsters. Accordingly, we observe a positive association between increased COVID-19 severity and sample frequency of 203K/204R. Our work suggests that the 203K/204R mutations contribute to the increased transmission and virulence of select SARS-CoV-2 variants. In addition to mutations in the spike protein, mutations in the nucleocapsid protein are important for viral spreading during the pandemic., Graphical Abstract

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that places a heavy strain on public health. Host susceptibility to Mtb is modulated by macrophages, which regulate the balance between cell apoptosis and necrosis. However, the role of molecular switches that modulate apoptosis and necrosis during Mtb infection remains unclear. Here, we show that Mtb-susceptible mice and TB patients have relatively low miR-342-3p expression, while mice with miR-342-3p overexpression are more resistant to Mtb. We demonstrate that the miR-342-3p/SOCS6 axis regulates anti-Mtb immunity by increasing the production of inflammatory cytokines and chemokines. Most importantly, the miR-342-3p/SOCS6 axis participates in the switching between Mtb-induced apoptosis and necrosis through A20-mediated K48-linked ubiquitination and RIPK3 degradation. Our findings reveal several strategies by which the host innate immune system controls intracellular Mtb growth via the miRNA-mRNA network and pave the way for host-directed therapies targeting these pathways.

The continual spread of novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), posing a severe threat to the health worldwide. The main protease (Mpro, alias 3CLpro) of SARS-CoV-2 is a crucial enzyme for the maturation of viral particles and is a very attractive target for designing drugs to treat COVID-19. Here, we propose a multiple conformation-based virtual screening strategy to discover inhibitors that can target SARS-CoV-2 Mpro. Based on this strategy, nine Mpro structures and a protein mimetics library with 8960 commercially available compounds were prepared to carry out ensemble docking for the first time. Five of the nine structures are apo forms presented in different conformations, whereas the other four structures are holo forms complexed with different ligands. The surface plasmon resonance assay revealed that 6 out of 49 compounds had the ability to bind to SARS-CoV-2 Mpro. The fluorescence resonance energy transfer experiment showed that the biochemical half-maximal inhibitory concentration (IC50) values of the six compounds could hamper Mpro activities ranged from 0.69 ± 0.05 to 2.05 ± 0.92 μM. Evaluation of antiviral activity using the cell-based assay indicated that two compounds (Z1244904919 and Z1759961356) could strongly inhibit the cytopathic effect and reduce replication of the living virus in Vero E6 cells with the half-maximal effective concentrations (EC50) of 4.98 ± 1.83 and 8.52 ± 0.92 μM, respectively. The mechanism of the action for the two inhibitors were further elucidated at the molecular level by molecular dynamics simulation and subsequent binding free energy analysis. As a result, the discovered noncovalent reversible inhibitors with novel scaffolds are promising antiviral drug candidates, which may be used to develop the treatment of COVID-19.

The label-free proteome quantification (LFQ) is multistep workflow collectively defined by quantification tools and subsequent data manipulation methods that has been extensively applied in current biomedical, agricultural, and environmental studies. Despite recent advances, in-depth and high-quality quantification remains extremely challenging and requires the optimization of LFQs by comparatively evaluating their performance. However, the evaluation results using different criteria (precision, accuracy, and robustness) vary greatly, and the huge number of potential LFQs becomes one of the bottlenecks in comprehensively optimizing proteome quantification. In this study, a novel strategy, enabling the discovery of the LFQs of simultaneously enhanced performance from thousands of workflows (integrating 18 quantification tools with 3,128 manipulation chains), was therefore proposed. First, the feasibility of achieving simultaneous improvement in the precision, accuracy, and robustness of LFQ was systematically assessed by collectively optimizing its multistep manipulation chains. Second, based on a variety of benchmark datasets acquired by various quantification measurements of different modes of acquisition, this novel strategy successfully identified a number of manipulation chains that simultaneously improved the performance across multiple criteria. Finally, to further enhance proteome quantification and discover the LFQs of optimal performance, an online tool (https://idrblab.org/anpela/) enabling collective performance assessment (from multiple perspectives) of the entire LFQ workflow was developed. This study confirmed the feasibility of achieving simultaneous improvement in precision, accuracy, and robustness. The novel strategy proposed and validated in this study together with the online tool might provide useful guidance for the research field requiring the mass-spectrometry-based LFQ technique.

Functional annotation of protein sequence with high accuracy has become one of the most important issues in modern biomedical studies, and computational approaches of significantly accelerated analysis process and enhanced accuracy are greatly desired. Although a variety of methods have been developed to elevate protein annotation accuracy, their ability in controlling false annotation rates remains either limited or not systematically evaluated. In this study, a protein encoding strategy, together with a deep learning algorithm, was proposed to control the false discovery rate in protein function annotation, and its performances were systematically compared with that of the traditional similarity-based and de novo approaches. Based on a comprehensive assessment from multiple perspectives, the proposed strategy and algorithm were found to perform better in both prediction stability and annotation accuracy compared with other de novo methods. Moreover, an in-depth assessment revealed that it possessed an improved capacity of controlling the false discovery rate compared with traditional methods. All in all, this study not only provided a comprehensive analysis on the performances of the newly proposed strategy but also provided a tool for the researcher in the fields of protein function annotation.

Background:Despite the substantial contribution of natural products to the FDA drug approval list, the discovery of anti-cancer drugs from the huge amount of species on the planet remains looking for a needle in a haystack. Objective: Drug-productive clusters in the phylogenetic tree are thus proposed to narrow the searching scope by focusing on much smaller amount of species within each cluster, which enable prioritized and rational bioprospecting for novel drug-like scaffolds. However, the way anti-cancer nature-derived drugs distribute in phylogenetic tree has not been reported, and it is oversimplified to just focus anti-cancer drug discovery on the drug-productive clusters, since the number of species in each cluster remains too large to be managed.Objective:Drug-productive clusters in the phylogenetic tree are thus proposed to narrow the searching scope by focusing on much smaller amount of species within each cluster, which enable prioritized and rational bioprospecting for novel drug-like scaffolds. However, the way anti-cancer nature-derived drugs distribute in phylogenetic tree has not been reported, and it is oversimplified to just focus anti-cancer drug discovery on the drug-productive clusters, since the number of species in each cluster remains too large to be managed.Methods:In this study, 260 anti-cancer drugs approved in the past 70 years were comprehensively analyzed by hierarchical clustering of phylogenetic distribution.Results:207 out of these 260 drugs were derived from or inspired by the natural products isolated from 58 species. Phylogenetic distribution of those drugs further revealed that nature-derived anti-cancer drugs originated mostly from drug-productive families that tend to be clustered rather than scattered on the phylogenetic tree. Moreover, based on their productivity, drug-producing species were categorized into productive (CPS), newly emerging (CNS) and lessproductive (CLS). Statistical significances in druglikeness between drugs from CPS and CLS were observed, and drugs from CNS were found to share similar drug-like properties to those from CPS.Conclusion:This finding indicated a great raise in drug approval standard, which suggested us to focus bioprospecting on the species yielding multiple drugs and keeping productive for long period of time.

The pathogenesis of multiple sclerosis (MS) is significantly regulated by long noncoding RNAs (lncRNAs), the expression of which is substantially influenced by a number of MS-associated risk single nucleotide polymorphisms (SNPs). It is thus hypothesized that the dysregulation of lncRNA induced by genomic variants may be one of the key molecular mechanisms for the pathology of MS. However, due to the lack of sufficient data on lncRNA expression and SNP genotypes of the same MS patients, such molecular mechanisms underlying the pathology of MS remain elusive. In this study, a bioinformatics strategy was applied to obtain lncRNA expression and SNP genotype data simultaneously from 142 samples (51 MS patients and 91 controls) based on RNA-seq data, and an expression quantitative trait loci (eQTL) analysis was conducted. In total, 2383 differentially expressed lncRNAs were identified as specifically expressing in brain-related tissues, and 517 of them were affected by SNPs. Then, the functional characterization, secondary structure changes and tissue and disease specificity of the cis-eQTL SNPs and lncRNA were assessed. The cis-eQTL SNPs were substantially and specifically enriched in neurological disease and intergenic region, and the secondary structure was altered in 17.6% of all lncRNAs in MS. Finally, the weighted gene coexpression network and gene set enrichment analyses were used to investigate how the influence of SNPs on lncRNAs contributed to the pathogenesis of MS. As a result, the regulation of lncRNAs by SNPs was found to mainly influence the antigen processing/presentation and mitogen-activated protein kinases (MAPK) signaling pathway in MS. These results revealed the effectiveness of the strategy proposed in this study and give insight into the mechanism (SNP-mediated modulation of lncRNAs) underlying the pathology of MS.

Communicated by Ramaswamy H. Sarma.

Histone deacetylase 6 (HDAC6) plays a key role in a variety of neurological disorders, which makes it attractive drug target for the treatment of Alzheimer's disease, Parkinson's disease, and memory/learning impairment. The selectivity of HDAC6 inhibitors (sHDAC6Is) are widely considered to be susceptible to the sizes of their Cap group and the physicochemical properties of their linker or zinc-binding group, which makes the discovery of new sHDAC6Is extremely difficult. With the discovery of the distinct selectivity between Trichostatin A (TSA) enantiomers, the chirality residing in the connective units between TSA's Cap and linker shows a great impact on its selectivity. However, the mechanism underlining ( S)-TSA's selectivity is still elusive, and the way chirality switches the selective ( S)-TSA to nonselective ( R)-TSA is unknown. In this study, multiple computational approaches were collectively applied to explore, validate, and differentiate the binding modes of two TSA enantiomers in HDACs (especially the HDAC6) at atomic level. First, two nonconservative residues (G200/M205 and Y197/F202 in HDAC1/6) in loop3 and four conservative residues deep inside the hydrophobic binding pocket were discovered as the decisive residues of ( S)-TSA's selectivity toward HDAC6. Then, a novel mechanism underlying the selectivity of ( S)-TSA toward HDAC6 was proposed, which was composed of the trigger by two nonconservative residues F202 and M205 in HDAC6 and a subsequently improved fit of ( S)-TSA deep inside HDAC6's hydrophobic binding pocket. TSA enantiomers were used as a molecular probe to explore the mechanism underlying sHDAC6Is' selectivity in this study. Because of their decisive roles in ( S)-TSA's selectivity to HDAC6, both F202 and M205 in HDAC6 should be especially considered in the discovery of novel sHDAC6Is.

Eukaryotic elongation factor-2 kinase (eEF2K), a calcium/calmodulin-dependent protein kinase, is a potential target for treating cancer. eEF2K can reduce the binding ability of eEF2 to ribosomes by phosphorylating eEF2, thereby inhibiting peptide chain extension and negatively regulating protein synthesis, which provides a cytoprotective mechanism for the development of cancer. eEF2K has been reported to be overexpressed in various types of cancers. Therefore, it is of high importance to discover new eEF2K inhibitors for cancer therapy. Here, we proposed a three-step screening strategy to seek eEF2K inhibitors from the FDA approved drug library: homology modeling of eEF2K protein, SAR-based virtual screening, and docking-based virtual screening. Based on the screening strategy, 13 drugs with high evaluation scores were purchased to measure their binding affinity (KD) to eEF2K by using the SPR assay. The assay results suggested that 4 drugs may be potential eEF2K inhibitors, which are Pemetrexed (KD = 0.104 μM), Entecavir (KD = 2.16 μM), calcium levofolinate (KD = 11.7 μM), and Fosbretabulin (KD = 34.5 μM). To further validate whether these drugs act on eEF2K, Western blot (WB) analysis was performed, which showed that Pemetrexed and Entecavir could inhibit the eEF2K activity. Furthermore, molecular dynamics (MD) simulation was carried out to further demonstrate the interaction of eEF2K with Pemetrexed, the most bioactive drug. The specific in vitro/in vivo interaction mechanisms between these drugs and eEF2K are under investigation.

Drugs produce their therapeutic effects by modulating specific targets, and there are 89 innovative targets of first-in-class drugs approved in 2004–17, each with information about drug clinical trial dated back to 1984. Analysis of the clinical trial timelines of these targets may reveal the trial-speed differentiating features for facilitating target assessment. Here we present a comprehensive analysis of all these 89 targets, following the earlier studies for prospective prediction of clinical success of the targets of clinical trial drugs. Our analysis confirmed the literature-reported common druggability characteristics for clinical success of these innovative targets, exposed trial-speed differentiating features associated to the on-target and off-target collateral effects in humans and further revealed a simple rule for identifying the speedy human targets through clinical trials (from the earliest phase I to the 1st drug approval within 8 years). This simple rule correctly identified 75.0% of the 28 speedy human targets and only unexpectedly misclassified 13.2% of 53 non-speedy human targets. Certain extraordinary circumstances were also discovered to likely contribute to the misclassification of some human targets by this simple rule. Investigation and knowledge of trial-speed differentiating features enable prioritized drug discovery and development.

Scar tissue removal combined with biomaterial implantation is considered an effective measure to repair chronic transected spinal cord injury (SCI). However, whether more scar tissue removal surgeries could affect the treatment effects of biomaterial implantation still needs to be explored. In this study, we performed the first scar tissue removal surgery in the 3rd month and the second in the 6th month after completely removing 1 cm of spinal tissue in canines. We found that Taxol-modified linear ordered collagen scaffold (LOCS + Taxol) implantation could promote axonal regeneration, neurogenesis, and electrophysiological and functional recovery only in canines at the first scar tissue removal surgery, but not in canines at the second scar tissue removal surgery. Interestingly, we found that more endogenous neural stem cells (NSCs) around the injured site could be activated in canines with the first rather than the second scar tissue removal. Furthermore, we demonstrated that Taxol could promote the neuronal differentiation of NSCs in the myelin inhibition microenvironment through the p38 MAPK signaling pathway in vitro. Therefore, we speculated that endogenous NSC activation by the first scar tissue removal surgery and its further differentiation into neurons induced by Taxol may contribute to functional recovery in canines. Together, LOCS + Taxol implantation in combination with the first scar tissue removal provides a promising therapy for chronic long-distance transected SCI repair with the help of scar tissue removal activated endogenous NSCs.

In addition to the mutations on the spike protein (S), co-occurring mutations on nucleocapsid (N) protein are also emerging in SARS-CoV-2 world widely. Mutations R203K/G204R on N, carried by high transmissibility SARS-CoV-2 lineages including B.1.1.7 and P.1, has a rapid spread in the pandemic during the past year. In this study, we performed comprehensive population genomic analyses and virology experiment concerning on the evolution, causation and virology consequence of R203K/G204R mutations. The global incidence frequency (IF) of 203K/204R has rose up from nearly zero to 76% to date with a shrinking from August to November in 2020 but bounced later. Our results show that the emergence of B.1.1.7 is associated with the second growth of R203K/G204R mutants. We identified positive selection evidences that support the adaptiveness of 203K/204R variants. The R203K/G204R mutant virus was created and compared with the native virus. The virus competition experiments show that 203K/204R variants possess a replication advantage over the preceding R203/G204 variants, possibly in relation to the ribonucleocapsid (RNP) assemble during the virus replication. Moreover, the 203K/204R virus increased the infectivity in a human lung cell line and induced an enhanced damage to blood vessel of infected hamsters’ lungs. In consistence, we observed a positive association between the increased severity of COVID-19 and the IF of 203K/204R from in silicon analysis of global clinical and epidemic data. In combination with the informatics and virology experiment, our work suggested the contribution of 203K/204R to the increased transmission and virulence of the SARS-CoV-2. In addition to mutations on the S protein, the mutations on the N protein are also important to virus spread during the pandemic.

Tau misfolding plays a significant role in some neurodegenerative diseases such as Alzheimer's disease (AD). It is intrinsically disordered and highly soluble under normal physiological conditions. While the protein will aggregate to form paired helical filaments (PHFs) under copper homeostasis at pathological conditions, which is the main substance of neurofibrillary tangles (NFTs) in the brain of AD patients. However, the molecular mechanism underlying the copper (Cu2+) ion-induced tau misfolding is not fully understood. In this study, using the 1/2 third repeat fragment (R3 peptide) of tau protein (residues 318-335: VTSKCGSLGNIHHKPGGG) as a model, a Gaussian accelerated molecular dynamics (GaMD) method followed by efficient trajectory analysis was carried out to investigate the influences of Cu2+ on the tau about the protein fold and the free energy landscape along the simulation. The two-dimensional potential of mean force (PMF) profiles obtained from reweighting of the GaMD simulations as well as clustering analysis revealed the Cu2+ ion induced α-helix fold R3 peptide located at the low-energy wells of free energy map, which is in agreement with the reported experimental result. In contrast, there is no α-helix fold of R3 peptide that appeared during the GaMD simulation without Cu2+ ion existing. Furthermore, the definition of secondary structure of protein (DSSP) analysis indicated that the R3 peptide with Cu2+ ion forms a stable structure of the helix (Lys321-His330 interval of the peptide) at between 400 and 500 ns. Therefore, the structures and free energy profiles from GaMD simulations proposed that Cu2+ triggers the aggregation of R3 peptide into toxic PHFs through a stable α-helix fold form.

The diagenetic evolution is an important controlling factor of shale gas reservoir. In this study, based on field outcrop and drilling core data, analytical techniques including X-ray diffraction (XRD), field emission scanning electron microscope combined with a focused ion beam (FIB-FESEM), and energy dispersive spectroscopy (EDS) analysis were performed to determine diagenetic evolution of the Longmaxi Formation shale , and reveal effect of diagenetic evolution on the shale gas exploration and development in the Sichuan Basin, Southwest China. The diagenetic evolution can be divided into eodiagenesis, mesodiagenesis, and teleodiagenesis. The eodiagenesis and mesodiagenesis were subdivided into two and three evolution stages respectively both in Basin margin and center. Absorbed capacity and artificial fracturing effect of the Longmaxi Formation shale gas was related to mineral composition, which was influenced by the sediment characteristics and diagenetic evolution. Diagenetic system in the Basin margin was more open than that in Basin center due to different structural burial history. The more open diagenetic system consisting of more micro-fractures and soluble constitute (e.g. feldspar) was in favour for formation and preservation of secondary dissolved pores and organic pores in the Basin margin. The relatively closed diagenetic system with stronger compaction resulted in deformation of pore space in the central Basin due to different burial history and diagenetic evolution.

Recently, COVID-19 caused by the novel coronavirus SARS-CoV-2 has brought great challenges to the world. More and more studies have shown that severe patients may suffer from cytokine storm syndrome; however, there are few studies on its pathogenesis. Here we demonstrated that SARS-CoV-2 coding protein open reading frame 8 (ORF8) acted as a contributing factor to cytokine storm during COVID-19 infection. ORF8 could activate IL-17 signaling pathway and promote the expression of pro-inflammatory factors. Moreover, we demonstrated that treatment of IL17RA antibody protected mice from ORF8-induced inflammation. Our findings are helpful to understand the pathogenesis of cytokine storm caused by SARS-CoV-2, and provide a potential target for the development of COVID-19 therapeutic drugs., Graphical Abstract

Background Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are two important pro-inflammatory cytokines of the interleukin-6 (IL-6) family. The two cytokines mediated signaling was recently found to be closely associated with cancer and chronic inflammation, which represent promising therapeutic targets for the treatment of many solid tumors and inflammatory disease. As the most closely related members, cross-reactivity of them may result in undesired activation of off-target cells, leading to toxicity or lack of efficacy of the therapeutic effects. However, the mechanism of the cross-reactivity of OSM and LIF is not well understood. Methods In this work, protein-protein docking, molecular dynamics (MD) simulations with explicit solvent and post endpoints binding free energy (BFE) analysis were carried out to further understand the structural and energetic principles of interactions between the two cytokines and the shared receptor LIFR. Results For the first time, the simulation given a computational model of OSM-LIFR interaction, and provided significant insights into the mechanism of OSM and LIF cross-react with LIFR. The identified common features shared by OSM and LIF bind to LIFR involving 10 “conserved” residues (90% similarity) distributed at the binding site III comprised of AB loop, BC loop and D helix. In addition, 11 shared residues were identified in LIFR contribute 77.85% and 84.63% energies for OSM and LIF binding, which play a critical role in the formation of the two cytokine-receptor complexes. Moreover, the “nonconserved” residues at the same position of cytokines such as Asp41 in OSM and Pro51 in LIF as well as the three residues (Glu338, Asn201 and Glu260) in LIFR were also discovered. Conclusions These important information may facilitate the rational design of novel chemical or biological agents with less toxicity and improved efficacy.

Acquired immunodeficiency syndrome (AIDS) has been a chronic, life-threatening disease for a long time. Though, a broad range of antiretroviral drug regimens is applicable for the successful suppression of virus replication in human immunodeficiency virus type 1 (HIV-1) infected people. The mutation-induced drug resistance problems during the treatment of AIDS forced people to continuously look for new antiviral agents. HIV-1 integrase (IN) and reverse transcriptase associated ribonuclease (RT-RNase H), two pivotal enzymes in HIV-1 replication progress, have gained popularity as druggable targets for designing novel HIV-1 antiviral drugs. During the development of HIV-1 IN and/or RT-RNase H inhibitors, computer-aided drug design (CADD), including homology modeling, pharmacophore, docking, molecular dynamics (MD) simulation and binding free energy calculation, represent a significant tool to accelerate the discovery of new drug candidates and reduce costs in antiviral drug development. In this review, we summarized the recent advances in the design of single- and dual-target inhibitors against HIV-1 IN or/and RT-RNase H as well as the prediction of mutation-induced drug resistance based on computational methods. We highlighted the results of the reported literatures and proposed some perspectives on the design of novel and more effective antiviral drugs in the future.

Mesenchymal stemXin cells (MSCs) are a great cell source for bone regeneration. Although combining MSCs with growth factors and scaffolds provides a useful clinical strategy for bone tissue engineering, the efficiency of MSC osteogenic differentiation remains to be improved. Epigenetic modification is related to the differentiation ability of MSCs during osteogenic induction. In this study, we evaluate the effect of Chaetocin, an inhibitor of lysine-specific histone methyltransferases, on the differentiation of MSCs. We found that MSCs treated with Chaetocin demonstrated increased osteogenic ability and reduced adipogenic ability. The expression of osteogenic markers (Runx2 and OPN) was induced in MSCs by Chaetocin during osteogenic induction. Moveover, treatment of Chaetocin in MSCs improves Wnt/β-catenin signaling pathways and its downstream targets. Finally, we showed increased bone formation of MSC and Wnt/β-catenin signaling activity by treatment of Chaetocin using in vivo bone formation assays. Our data uncovered a critical role of Chaetocin in MSC osteogenic differentiation and provide new insights into bone tissue regeneration and repair.

Group I metabotropic glutamate receptors (mGlu(1) and mGlu(5)) are promising targets for multiple psychiatric and neurodegenerative disorders. Understanding the subtype selectivity of mGlu(1) and mGlu(5) allosteric sites is essential for the rational design of novel modulators with single- or dual-target mechanism of action. In this study, starting from the deposited mGlu(1) and mGlu(5) crystal structures, we utilized computational modeling approaches integrating docking, molecular dynamics simulation, and efficient post-trajectory analysis to reveal the subtype-selective mechanism of mGlu(1) and mGlu(5) to 10 diverse drug scaffolds representing known negative allosteric modulators (NAMs) in the literature. The results of modeling identified six pairs of non-conserved residues and four pairs of conserved ones as critical features to distinguish the selective NAMs binding to the corresponding receptors. In addition, nine pairs of residues are beneficial to the development of novel dual-target NAMs of group I metabotropic glutamate receptors. Furthermore, the binding modes of a reported dual-target NAM (VU0467558) in mGlu(1) and mGlu(5) were predicted to verify the identified residues that play key roles in the receptor selectivity and the dual-target binding. The results of this study can guide rational structure-based design of novel NAMs, and the approach can be generally applicable to characterize the features of selectivity for other G-protein-coupled receptors.

Studying the spatiotemporal dynamic changes of various cells following spinal cord injury (SCI) is of great significance for understanding the pathological processes of SCI. Changes in the characteristics of Sox9-positive cells, which are widely present in the spinal cord, have rarely been studied following SCI. We found that Sox9-positive cells were widely distributed in the central canal and parenchyma of the uninjured adult spinal cord, with the greatest distribution in the central spinal cord and relatively few cells in the dorsal and ventral sides. Ranging between 14.20% ± 1.61% and 15.60% ± 0.36% of total cells in the spinal cord, almost all Sox9-positive cells were in a quiescent state. However, Sox9-positive cells activated following SCI exhibited different characteristics according to their distance from the lesion area. In the reactive region, Sox9-positive cells highly expressed nestin and exhibited a single-branching structure, whereas in the non-reactive region, cells showed low nestin expression and a multi-branching structure. In response to SCI, a large number of Sox9-positive cells in the spinal cord parenchyma proliferated to participate in the formation of glial scars, whereas Sox9-positive cells in the central canal located near the lesion site accumulated at its broken ends through proliferation. Finally, we found that approximately 6.30% ± 0.35% of Sox9-positive cells differentiated into oligodendrocytes within two weeks after SCI. By examining the spatiotemporal dynamic changes, proliferation and differentiation characteristics of Sox9-positive cells after SCI, our findings provide a theoretical basis for understanding the pathological process of SCI.

Spinal cord injury (SCI) typically results in long-lasting functional deficits, largely due to primary and secondary wh ite matter damage at the site of injury. The transplantation of neural stem cells (NSCs) has shown promise for re-establishing communications between separated regions of the spinal cord through the insertion of new neurons between the injured axons and target neurons. However, the inhibitory microenvironment that develops after SCI often causes endogenous and transplanted NSCs to differentiate into glial cells rather than neurons. Functional biomaterials have been shown to mitigate the effects of the adverse SCI microenvironment and promote the neuronal differentiation of NSCs. A clear understanding of the mechanisms of neuronal differentiation within the injury-induced microenvironment would likely allow for the development of treatment strategies designed to promote the innate ability of NSCs to differentiate into neurons. The increased differentiation of neurons may contribute to relay formation, facilitating functional recovery after SCI. In this review, we summarize current strategies used to enhance the neuronal differentiation of NSCs through the reconstruction of the SCI microenvironment and to improve the intrinsic neuronal differentiation abilities of NSCs, which is significant for SCI repair.

Silicon (Si), germanium (Ge), and gallium arsenide (GaAs) are familiar semiconductors that always act in the role of optical dielectrics. However, these semiconductors also have plasmonic behaviors in ultraviolet (UV) ranges due to the strong interband transitions or valence electrons. And few studies are aimed at investigating plasmonic properties in the semiconductor at the nanoscale. In this work, we discuss UV plasmonics and sensing properties in single and dimer Si, Ge, and GaAs triangular prism meta-antenna systems. The results show that obvious local surface plasmon resonances (LSPRs) can be realized in the proposed triangular prism meta-antennas, and the resonant wavelength, electromagnetic field distribution, surface charge distribution, and surface current density can be effectively tuned by structural and material parameters. In addition, we also find that the Si triangular prism meta-antenna shows more intense plasmonic responses in UV ranges than that in the Ge or GaAs triangular prism nanostructures. Especially, the phase difference between the triangular prism nanostructure and light source can effectively regulate the symbol and value of the surface charge. Moreover, the great enhancement of electric field can be seen in the dimer triangular prism meta-antennas when the distance of the gap is gnm, especially g=1 nm. The most interesting result is that the maximum of refractive index sensitivity s and figure of merit (FoM) are greatly enlarged in dimer triangular prism meta-antennas. Particularly, the sensitivity can reach up to 215 nm/RIU in the dimer GaAs triangular prism meta-antennas, which is improved more than one order of magnitude. These research results may play important roles in applications of the photo detecting, plasmonic sensing and disinfecting in UV ranges.

Intracellular survival of Mycobacterium tuberculosis results in bacterial proliferation and the spread of infection in lungs, consequently deteriorating the conditions of tuberculosis (TB) patients. This research discovers a new immune escape pathway of M. tuberculosis by modulating host miR-325-3p expression, thus leading to the intracellular survival of M. tuberculosis. These findings make a contribution to the understanding of the immune escape of M. tuberculosis, and they provide a theoretical basis for the development of therapeutic approaches for drug-resistant TB., Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that poses threats to the public. M. tuberculosis survives in macrophages by escaping from immune surveillance and clearance, which exacerbates the bacterial proliferation. However, the molecular mechanisms of this immune escape have not yet been fully understood. Using multiple cell and mouse models, we found that microRNA-325-3p (miR-325-3p) is upregulated after M. tuberculosis infection and Mir325-deficient mice show resistance to M. tuberculosis. We demonstrated that miR-325-3p directly targets LNX1, an E3 ubiquitin ligase of NEK6, and that this hampers the proteasomal degradation of NEK6 in macrophages. The abnormal accumulation of NEK6 leads to the activation of STAT3 signaling, thus inhibiting the process of apoptosis and promoting the intracellular survival of M. tuberculosis. Our findings not only reveal a new immune escape pathway of M. tuberculosis but also may provide new insights into the development of therapeutic approaches for drug-resistant TB.

We investigate Fano resonances and sensing enhancements in a simple Au/TiO2 hybrid metasurface through the finite-different time-domain (FDTD) simulation and coupled mode theory (CMT) analysis. The results show that the Fano resonance in the proposed simple metasurface is caused by the destructive interaction between the surface plasmon polaritons (SPPs) and the local surface plasmon resonances (LSPRs), the quality factor and dephasing time for the Fano resonance can be effectively tuned by the thickness of Au and TiO2 structures, the length of each unit in x and y directions, as well as the structural defect. In particular, single Fano resonance splits into multiple Fano resonances caused by a stub-shaped defect, and multiple Fano resonances can be tuned by the size and position of the stub-shaped defect. Moreover, we also find that the sensitivity in the Au/TiO2 hybrid metasurface with the stub-shaped defect can reach up to 330 nm/RIU and 535 nm/RIU at the Fano resonance 1 and Fano resonance 2, which is more than three times as sensitive in the Au/TiO2 hybrid metasurface without the stub-shaped defect, and also higher than that in the TiO2 metasurface reported before. These results may provide further understanding of Fano resonances and guidance for designing ultra-high sensitive refractive index sensors.

Knowledge of the geological history of the Tibetan plateau is critical to understanding crustal deformation process, and the plateau’s influence on climate. However, the timing of Tibetan plateau development remains controversial. The Nima Basin along the Jurassic-Cretaceous Bangong Suture in central Tibet provides well-dated records of exhumation in this area. Here, we present detrital zircon U-Pb, apatite U-Th/He (AHe) and apatite fission track data (AFT) from upper Cretaceous and Oligocene red sandstones and conglomerates in the Nima Basin, as well as from the Xiabie granite in the hanging wall of the basin-bounding Muggar Thrust. 4 granite conglomerate clasts from the above yield zircon U-Pb ages ranging between 114-122 Ma, which likely come from the Xiabie granite. 7 granitoid/sandstone conglomerate clasts yield AHe ages ranging from 21-58 Ma, while AFT ages range from 34-83 Ma. Thermal history inversion modelling for five of the above samples show a consistent rapid cooling from 100 ℃ to 30 ℃ between 50-40 Ma, the cooling rate decreased significantly after 40 Ma. Implications of these data, integrated in the context of previously published data for the wider region (e.g. Rohrmann et al. 2012; Haider et al., 2013; Li et al., 2019) will be discussed. ReferenceRohrmann, A et al., 2012, Thermochronologic evidence for plateau formation in central Tibet by 45 Ma: Geology, v. 40, p. 187-190.Haider, V. L et al., 2013, Cretaceous to Cenozoic evolution of the northern Lhasa Terrane and the Early Paleogene development of peneplains at Nam Co, Tibetan Plateau: Journal of Asian Earth Sciences, v. 70-71, p. 79-98.Li, H. A et al., 2019, The formation and expansion of the eastern Proto-Tibetan Plateau: Insights from low-temperature thermochronology: Journal of Asian Earth Sciences, v. 183, 103975.

Therapeutics targeting cytokines such as the oncostatin M (OSM)-mediated inflammation represent a potential strategy for the treatment of inflammatory bowel disease (IBD). Despite the investigation of the specific role of the interactions between OSM and the receptor (OSMR) in IBD pathogenesis, the 3D structure of the OSM–OSMR complex remains elusive. In this work, the interaction mode between OSM and OSMR at atomic level was predicted by computational simulation approach. The interaction domain of the OSMR was built with the homology modeling method. The near-native structure of the OSM–OSMR complex was obtained by docking, and long-time scale molecular dynamics (MD) simulation in an explicit solvent was further performed to sample the conformations when OSM binds to the OSMR. After getting the equilibrated states of the simulation system, per-residue energy contribution was calculated to characterize the important residues for the OSM–OSMR complex formation. Based on these important residues, eight residues (OSM: Arg100, Leu103, Phe160, and Gln161; OSMR: Tyr214, Ser223, Asp262, and Trp267) were identified as the “hot spots” through computational alanine mutagenesis analysis and verified by additional MD simulation of R100A (one of the identified “hotspots”) mutant. Moreover, six cavities were detected at the OSM–OSMR interface through the FTMap analysis, and they were suggested as important binding sites. The predicted 3D structure of the OSM–OSMR complex and the identified “hot spots” constituting the core of the binding interface provide helpful information in understanding the OSM–OSMR interactions, and the detected sites serve as promising targets in designing small molecules to block the interactions.

We study dual-Fano resonances and its sensing properties in a crossed ring-shaped metasurface by use of the finite-different time-domain (FDTD) simulation. The results show that the dual-Fano resonances in the proposed crossed ring-shaped metasurface are caused by the interaction among three local surface plasmon resonances (LSPRs), and the spectra of dual-Fano resonances can be tuned by the radius of the circular ring (CR) nanostructure, the distance between the center of the two CRs in x direction, and the polarization of the incident light. Interestingly, single Fano resonance splits into dual-Fano resonances in the case of asymmetric ring structure arrangement or non-y-axis polarized incident or the distance d

The Qiangtang Basin is the largest Mesozoic marine hydrocarbon-bearing basin in China. Investigating its tectonic and sedimentary evolution is therefore relevant for hydrocarbon exploration. Here we present a detailed stratigraphic and sedimentological analysis of five Jurassic stratigraphic sections in the North Qiangtang Basin. Nineteen facies associations were identified and allowed us to reconstruct changes of water-depth. The North Qiangtang Basin experienced two transgressive-regressive cycles during the Jurassic. The first cycle started in the mid-Jurassic (Bajocian-Bathonian), with braided-river and floodplain sediments passing up-section to tidal flat and eventually inner-to mid-ramp deposits. Tidal-flat deposition resumed during the Callovian. The second cycle began in the Late Jurassic (Oxfordian) with transgressive inner-to mid-ramp sediments followed by a shallowing-upward trend during the late Oxfordian, leading again to tidal-flat sedimentation in the Kimmeridgian-Tithonian. Petrographic analysis and detrital-zircon geochronology indicate provenance constantly from the Hoh Xil-Songpan Ganzi terrane, Kunlun arc, and central Qiangtang. Because Jurassic magmatic activity and active syn-depositional faults have not been reported, and steady detrital supply indicates a stable tectonic environment, eustatic change is inferred to represent the principal control on sedimentary evolution in the North Qiangtang Basin during the Jurassic. A comparison with the Amu Darya Basin in central Asia, characterized by similar sedimentological conditions and distribution of reservoir and source rocks, emphasizes the importance of eustatic control for the development of the source-reservoir-seal system of the North Qiangtang Basin.