The characteristics of intestinal microbiota in patients with type 2 diabetes and the correlation with the percentage of T-helper cells.

Background: Type 2 diabetes (T2D) is related to intestinal microflora changes and immune inflammation. We aimed to investigate the pattern of intestinal flora-systematic T helper (Th) cell linkage in T2D patients. Methods: Participants with T2D diagnosed by physicians and healthy controls were enrolled in the study. The Th1, Th2, and Th17 cells from the peripheral blood were assessed by flow cytometry. The feces were collected. The V3-V4 variable region of 16S rRNA was sequenced and analyzed using bioinformatics. Principal coordinate analysis (PCoA) and non-metric multidimensional scaling (NMDS) analysis were performed to assess the beta diversity. The linear discriminant analysis (LDA) effect size (LEfSe) method was applied to identify amicrobial taxon specific to T2D. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was conducted to identify the metabolic pathways. A network analysis was conducted by constructing a co-occurrence network. Results: The percentages of the Th1 and Th17 cells in the peripheral blood were higher in patients with T2D than in controls. Among the top 30 genera of the intestinal microbiota, the levels of Lachnospiraceae_NK4A136_group, Ruminococcaceae_UCG002, and Eubacterium_hallii_group were lower in the patients with T2D than in controls. In the LEfSe analysis, it was observed that the Lachnospiraceae and Ruminococcaceae families were significantly different between patients with T2D and controls. Moreover, the Th1/Th2 ratio was positively correlated with the abundance of the Lachnoclostridium and Ruminococcus_torques_group genera. In the network analysis, the Th1/Th2 ratio, Ruminococcaceae_UCG-002, and Lachnospiraceae_NK4A136_group were the important nodes. Conclusion: This study provided a preliminary picture of the crosstalk between the intestinal microbiome and systematic Th cells in patients with T2D. The findings of the study suggested that the network relationship among the intestinal microbiota, metabolites, and CD4+T lymphocyte immunity was unbalanced in the patients with T2D, which might have promoted the development of T2D. This presents a therapeutic opportunity to modulate gut immune reaction and then chronic inflammation by manipulating microbiome-specific Th-cell response.

Cascade electrocatalysis via AgCu single-atom alloy and Ag nanoparticles in CO2 electroreduction toward multicarbon products.

Electrocatalytic CO2 reduction into value-added multicarbon products offers a means to close the anthropogenic carbon cycle using renewable electricity. However, the unsatisfactory catalytic selectivity for multicarbon products severely hinders the practical application of this technology. In this paper, we report a cascade AgCu single-atom and nanoparticle electrocatalyst, in which Ag nanoparticles produce CO and AgCu single-atom alloys promote C-C coupling kinetics. As a result, a Faradaic efficiency (FE) of 94 ± 4% toward multicarbon products is achieved with the as-prepared AgCu single-atom and nanoparticle catalyst under ~720 mA cm-2 working current density at -0.65 V in a flow cell with alkaline electrolyte. Density functional theory calculations further demonstrate that the high multicarbon product selectivity results from cooperation between AgCu single-atom alloys and Ag nanoparticles, wherein the Ag single-atom doping of Cu nanoparticles increases the adsorption energy of *CO on Cu sites due to the asymmetric bonding of the Cu atom to the adjacent Ag atom with a compressive strain.

Primary mediastinal/thymic diffuse large B-cell lymphoma: a population-based study on incidence and survival.

Primary mediastinal large B-cell lymphoma is a rare subtype of lymphoma. The contemporary incidence of primary mediastinal large B-cell lymphoma remains unknown, and a large population-based study has not been reported. It is essential to provide guidance for further strategies in reducing the disease burden via population-based preventive initiatives. This study aims to explore the epidemiology and effect of therapeutic advances on the survival of patients with primary mediastinal large B-cell lymphoma. This population-based study was conducted using the Surveillance, Epidemiology, and End Results Program (SEER), covering the period from 1975 to 2018. A total of 774 patients in the SEER 9 and 1654 patients in the SEER 18 were analyzed. The age-adjusted incidence rate of primary mediastinal large B-cell lymphoma increased from 0.05/1,000,000 in 1975 to 2.38/1,000,000 in 2018. A significant positive linear increase in the incidence trend was found in primary mediastinal large B-cell lymphoma, with an annual percent change of 8.47% (95% confidence interval 7.7-9.2%, P < 0.001, z test). The survival in primary mediastinal large B-cell lymphoma was significantly superior to nodal diffuse large B-cell lymphoma. The incidence of PMBCL increases over the year. The survival of patients with primary mediastinal large B-cell lymphoma has improved over time.

Estimating potential illegal land development in conservation areas based on a presence-only model.

Conservation areas are facing increasing threats from anthropogenic land use activities. It is important to reasonably recognize and predict suspected illegal land development in advance. However, traditional methods easily suffer from selection bias due to the lack of accurate and reliable absence data. To tackle this problem, we have presented a novel method for estimating potential illegal land development based on the presence-only maximum entropy (MAXENT) model. The principle of MAXENT can guarantee that no additional unknown information (e.g., inaccurate pseudo-absence samples) will be introduced into the estimation procedure. This method was applied to the conservation areas in a fast-growing city, and the robustness of the MAXENT models was confirmed by the high AUC scores (over 0.80). The results indicated that the proposed method performs more effectively than the presence-absence random forest model. In addition, topographic conditions and proximity to transportation networks played dominant roles in the emergence of suspected illegal land development. Moreover, the probability map generated by MAXENT suggests that a considerable amount of forest, farmland, grassland, and water bodies will face a high degree of danger. Therefore, both superior and local governments should pay much more attention to regions with a higher potential for illegal land development. In summary, our findings are expected to support decision-making in the management and assessment of conservation areas in fast-growing regions. More importantly, the proposed method can be further applied to illegal land development estimation in many other regions.

Measuring the Non-Linear Relationship between Three-Dimensional Built Environment and Urban Vitality Based on a Random Forest Model.

Urban vitality is a major indicator used for evaluating the sustainability and attractiveness of an urban environment. Global experience indicates that urban vitality can be stimulated through a reasonable urban design. However, it remains incompletely understood in the literature which building-related indicators can substantially affect urban vitality in Asian countries. To give an insight into this question, our study took a step forward by focusing specifically on the influence of the three-dimensional built environment on urban vitality, based on which decision makers could enhance urban vitality from the perspective of vertical building design. A machine-learning-based framework was developed in this study. First, we utilized several building-related indicators to thoroughly measure the spatial characteristics of buildings at the township level. Second, the relationship between a three-dimensional built environment and urban vitality was revealed based on a combined use of the correlation method, scatter charts, and a random forest. In the random forest, both a benchmark and a new model were constructed to evaluate the importance of those building-related indicators. The results suggested that urban vitality was closely related to the three-dimensional built environment, which played an even more important role than common benchmark factors in stimulating urban vitality. The building coverage ratio, density of tall buildings, and floor area ratio were essential spatial drivers behind urban vitality. Therefore, urban designers and decision makers should not only take traditional factors into account but also carefully consider the potential influence of high-rise buildings and the outdoor thermal environment so that urban vitality can be enhanced. Our study's results can offer practical recommendations for improving urban vitality from the perspective of vertical building design. The proposed framework can also be used for measuring the potential influence of the three-dimensional built environment in other areas.

NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models.

Dengue virus (DENV) is a mosquito-borne flavivirus that poses a threat to public health, yet no antiviral drug is available. We performed a high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This chemical series was optimized to improve properties such as anti-DENV potency and solubility. The lead compound, NITD-688, showed strong potency against all four serotypes of DENV and demonstrated excellent oral efficacy in infected AG129 mice. There was a 1.44-log reduction in viremia when mice were treated orally at 30 milligrams per kilogram twice daily for 3 days starting at the time of infection. NITD-688 treatment also resulted in a 1.16-log reduction in viremia when mice were treated 48 hours after infection. Selection of resistance mutations and binding studies with recombinant proteins indicated that the nonstructural protein 4B is the target of NITD-688. Pharmacokinetic studies in rats and dogs showed a long elimination half-life and good oral bioavailability. Extensive in vitro safety profiling along with exploratory rat and dog toxicology studies showed that NITD-688 was well tolerated after 7-day repeat dosing, demonstrating that NITD-688 may be a promising preclinical candidate for the treatment of dengue.

A review of the interaction between anthocyanins and proteins.

Anthocyanins have good physiological functions, but they are unstable. The interaction between anthocyanins and proteins can improve the stability, nutritional and functional properties of the complex. This paper reviews the structural changes of complex of anthocyanins interacting with proteins from different sources. By circular dichroism (CD) spectroscopy, it was found that the contents of α-helix (from 15.90%-42.40% to 17.60%-52.80%) or ß-sheet (from 29.00%-50.00% to 29.40%-57.00%) of the anthocyanins-proteins complex increased. Fourier transform infrared spectroscopy showed that the regions of amide I (from 1627.87-1641.41 cm-1 to 1643.34-1651.02 cm-1) and amide II (from 1537.00-1540.25 cm-1 to 1539.00-1543.75 cm-1) of anthocyanins-proteins complex were shifted. Fluorescence spectroscopy showed that the fluorescence intensity of the complex decreased from 150-5100 to 40-3900 a.u. The thermodynamic analysis showed that there were hydrophobic interactions, electrostatic and hydrogen bonding interactions between anthocyanins and proteins. The kinetic analysis showed that the half-life and activation energy of the complex increased. The stability, antioxidant, digestion, absorption, and emulsification of the complex were improved. This provides a reference for the study and application of anthocyanins and proteins interactions.

Investigating the influence of three-dimensional building configuration on urban pluvial flooding using random forest algorithm.

Urban pluvial flooding has emerged as a serious threat to environmental conditions and human lives. Identifying its key drivers is crucial for the mitigation of flood risks. Although previous studies have demonstrated that pluvial flooding is caused by both natural (e.g., topography) and anthropogenic factors (e.g., land cover condition), much less effort has been devoted to investigating the potential influence of three-dimensional building configuration on pluvial flooding. To shed some light on this topic, we first analyzed the linear relationship between the density of flooding hotspots and different potential drivers in a highly-urbanized city using Pearson correlation analysis. Next, we designed two random forest-based models to quantify the importance of various building metrics. The first model considers only common drivers, while the second one also includes different types of building metrics. Results indicate that the density of buildings, building congestion degree, and building coverage ratio have exerted considerable influence on the occurrence of pluvial flooding. For example, the root relative squared error of our enhanced model (28.36%) is lower than that of the baseline model (32.58%). Our findings are expected to provide practical guidance for the mitigation of pluvial flood risks from the perspective of three-dimensional urban planning. Moreover, this methodological framework can be further applied to the analysis of flooding in many other regions.

Mapping the Interactions between the NS4B and NS3 proteins of dengue virus.

UNLABELLED: Flavivirus RNA synthesis is mediated by a multiprotein complex associated with the endoplasmic reticulum membrane, named the replication complex (RC). Within the flavivirus RC, NS4B, an integral membrane protein with a role in virulence and regulation of the innate immune response, binds to the NS3 protease-helicase. NS4B modulates the RNA helicase activity of NS3, but the molecular details of their interaction remain elusive. Here, we used dengue virus (DENV) to map the determinants for the NS3-NS4B interaction. Coimmunoprecipitation and an in situ proximity ligation assay confirmed that NS3 colocalizes with NS4B in both DENV-infected cells and cells coexpressing both proteins. Surface plasmon resonance demonstrated that subdomains 2 and 3 of the NS3 helicase region and the cytoplasmic loop of NS4B are required for binding. Using nuclear magnetic resonance (NMR), we found that the isolated cytoplasmic loop of NS4B is flexible, with a tendency to form a three-turn α-helix and two short ß-strands. Upon binding to the NS3 helicase, 12 amino acids within the cytoplasmic loop of NS4B exhibited line broadening, suggesting a participation in the interaction. Sequence alignment showed that 4 of these 12 residues are strictly conserved across different flaviviruses. Mutagenesis analysis showed that three (Q134, G140, and N144) of the four evolutionarily conserved NS4B residues are essential for DENV replication. The mapping of the NS3/NS4B-interacting regions described here can assist the design of inhibitors that disrupt their interface for antiviral therapy. IMPORTANCE: NS3 and NS4B are essential components of the flavivirus RC. Using DENV as a model, we mapped the interaction between the viral NS3 and NS4B proteins. The subdomains 2 and 3 of NS3 helicase as well as the cytoplasmic loop of NS4B are critical for the interaction. Functional analysis delineated residues within the NS4B cytoplasmic loop that are crucial for DENV replication. Our findings reveal molecular details of how flavivirus NS3 protein cooperates with NS4B within the RC. In addition, this study has established the rationale and assays to search for inhibitors disrupting the NS3-NS4B interaction for antiviral drug discovery.

Exploring the structure and function of Thermotoga maritima CorA reveals the mechanism of gating and ion selectivity in Co2+/Mg2+ transport.

The CorA family of divalent cation transporters utilizes Mg2+ and Co2+ as primary substrates. The molecular mechanism of its function, including ion selectivity and gating, has not been fully characterized. Recently we reported a new structure of a CorA homologue from Methanocaldococcus jannaschii, which provided novel structural details that offered the conception of a unique gating mechanism involving conversion of an open hydrophilic gate into a closed hydrophobic one. In the present study we report functional evidence for this novel gating mechanism in the Thermotoga maritima CorA together with an improved crystal structure of this CorA to 2.7 Å (1 Å=0.1 nm) resolution. The latter reveals the organization of the selectivity filter to be similar to that of M. jannaschii CorA and also the previously unknown organization of the second signature motif of the CorA family. The proposed gating is achieved by a helical rotation upon the binding of a metal ion substrate to the regulatory binding sites. Additionally, our data suggest that the preference of this CorA for Co2+ over Mg2+ is controlled by the presence of threonine side chains in the channel. Finally, the roles of the intracellular metal-binding sites have been assigned to increased thermostability and regulation of the gating. These mechanisms most likely apply to the entire CorA family as they are regulated by the highly conserved amino acids.