Pathogen hijacks programmed cell death signaling by arginine ADPR-deacylization of caspases.

Caspases are evolutionarily conserved cysteine proteases that are essential for regulating cell death and are involved in multiple development and disease processes, including immunity. Here, we show that the bacterial type III secretion system (T3SS) effector CopC (Chromobacterium outer protein C) from the environmental pathogen Chromobacterium violaceum attacks caspase-3/-7/-8/-9 by ADPR-deacylization to dysregulate programmed cell death, including apoptosis, necroptosis, and pyroptosis. This modification involves ADP-ribosylation- and deamination-mediated cyclization on Arg207 of caspase-3 by a mechanism that requires the eukaryote-specific protein calmodulin (CaM), leading to inhibition of caspase activity. The manipulation of cell death signaling by CopC is essential for the virulence of C. violaceum in a mouse infection model. CopC represents a family of enzymes existing in taxonomically diverse bacteria associated with a wide spectrum of eukaryotes ranging from humans to plants. The unique activity of CopC establishes a mechanism by which bacteria counteract host defenses through a previously unrecognized post-translational modification.

Structural insights into caspase ADPR deacylization catalyzed by a bacterial effector and host calmodulin.

Programmed cell death and caspase proteins play a pivotal role in host innate immune response combating pathogen infections. Blocking cell death is employed by many bacterial pathogens as a universal virulence strategy. CopC family type III effectors, including CopC from an environmental pathogen Chromobacterium violaceum, utilize calmodulin (CaM) as a co-factor to inactivate caspases by arginine ADPR deacylization. However, the molecular basis of the catalytic and substrate/co-factor binding mechanism is unknown. Here, we determine successive cryo-EM structures of CaM-CopC-caspase-3 ternary complex in pre-reaction, transition, and post-reaction states, which elucidate a multistep enzymatic mechanism of CopC-catalyzed ADPR deacylization. Moreover, we capture a snapshot of the detachment of modified caspase-3 from CopC. These structural insights are validated by mutagenesis analyses of CopC-mediated ADPR deacylization in vitro and animal infection in vivo. Our study offers a structural framework for understanding the molecular basis of arginine ADPR deacylization catalyzed by the CopC family.

Structural and Functional Insights into Host Death Domains Inactivation by the Bacterial Arginine GlcNAcyltransferase Effector.

Enteropathogenic E. coli NleB and related type III effectors catalyze arginine GlcNAcylation of death domain (DD) proteins to block host defense, but the underlying mechanism is unknown. Here we solve crystal structures of NleB alone and in complex with FADD-DD, UDP, and Mn2+ as well as NleB-GlcNAcylated DDs of TRADD and RIPK1. NleB adopts a GT-A fold with a unique helix-pair insertion to hold FADD-DD; the interface contacts explain the selectivity of NleB for certain DDs. The acceptor arginine is fixed into a cleft, in which Glu253 serves as a base to activate the guanidinium. Analyses of the enzyme-substrate complex and the product structures reveal an inverting sugar-transfer reaction and a detailed catalytic mechanism. These structural insights are validated by mutagenesis analyses of NleB-mediated GlcNAcylation in vitro and its function in mouse infection. Our study builds a structural framework for understanding of NleB-catalyzed arginine GlcNAcylation of host death domain.

Van der Waals Engineering of Ultrafast Carrier Dynamics in Magnetic Heterostructures.

Heterostructures composed of the intrinsic magnetic topological insulator MnBi2Te4 and its nonmagnetic counterpart Bi2Te3 host distinct surface electronic band structures depending on the stacking order and exposed termination. Here, we probe the ultrafast dynamical response of MnBi2Te4 and MnBi4Te7 following near-infrared optical excitation using time- and angle-resolved photoemission spectroscopy and disentangle surface from bulk dynamics based on density functional theory slab calculations of the surface-projected electronic structure. We gain access to the out-of-equilibrium charge carrier populations of both MnBi2Te4 and Bi2Te3 surface terminations of MnBi4Te7, revealing an instantaneous occupation of states associated with the Bi2Te3 surface layer followed by carrier extraction into the adjacent MnBi2Te4 layers with a laser fluence-tunable delay of up to 350 fs. The ensuing thermal relaxation processes are driven by phonon scattering with significantly slower relaxation times in the magnetic MnBi2Te4 septuple layers. The observed competition between interlayer charge transfer and intralayer phonon scattering demonstrates a method to control ultrafast charge transfer processes in MnBi2Te4-based van der Waals compounds.

Palladium-catalyzed Heck/aminocarbonylation of alkene-tethered carbamoyl chlorides with nitro compounds for the synthesis of carbamoyl-substituted oxindoles.

A straightforward and efficient approach for the synthesis of carbamoyl-substituted oxindoles has been developed via a palladium-catalyzed Heck cyclization and reductive aminocarbonylation reaction of alkene-tethered carbamoyl chlorides with nitro compounds. The reaction showed good compatibility toward versatile functional groups, and both nitroarenes and nitroalkanes were well tolerated. Using Mo(CO)6 as a solid CO source, without external reductants, a broad range of carbamoyl-substituted oxindoles were obtained in moderate to high yields.

Community centered public safety resilience under public emergencies: A case study of COVID-19.

During public emergencies, the level of public safety will be resilient and follow a process from decline to rise. Regarding the concept and influencing factors of public safety resilience, a three-level public safety resilience framework that includes personal, community, and government levels was proposed in this study. It provided the overall metrics that used the resistance and recovery ability to describe the dynamic characteristics of public safety resilience as well as the resilience assessment indexes on three levels. In the context of the Coronavirus Disease 2019 (COVID-19) pandemic, this study applied the proposed framework in a case study on public safety resilience at the Beihang community, Beijing, China through descriptive statistics, structural equation model, and principal component regression analysis of questionnaire data. The data analysis results showed that community resilience was the most important of the three levels of public safety resilience. In addition, community resilience could improve personal resilience, and government resilience had a positive effect on community and personal resilience. Compared with the resistance ability, the recovery ability was influenced more by the operation and improvement of the community. This study is conducive to understanding and improving public safety resilience on the personal, community, and government levels and can help relevant parties improve their ability to respond to the COVID-19 pandemic. Furthermore, the methods used in this study can be extended to other studies on public emergencies.

Gate-Tunable Anomalous Hall Effect in Stacked van der Waals Ferromagnetic Insulator-Topological Insulator Heterostructures.

The search of novel topological states, such as the quantum anomalous Hall insulator and chiral Majorana fermions, has motivated different schemes to introduce magnetism into topological insulators. A promising scheme is using the magnetic proximity effect (MPE), where a ferromagnetic insulator magnetizes the topological insulator. Most of these heterostructures are synthesized by growth techniques which prevent mixing many of the available ferromagnetic and topological insulators due to difference in growth conditions. Here, we demonstrate that MPE can be obtained in heterostructures stacked via the dry transfer of flakes of van der Waals ferromagnetic and topological insulators (Cr2Ge2Te6/BiSbTeSe2), as evidenced in the observation of an anomalous Hall effect (AHE). Furthermore, devices made from these heterostructures allow modulation of the AHE when controlling the carrier density via electrostatic gating. These results show that simple mechanical transfer of magnetic van der Waals materials provides another possible avenue to magnetize topological insulators by MPE.

Lack of tumorigenesis and protumorigenic activity of human umbilical cord mesenchymal stem cells in NOD SCID mice.

BACKGROUND: The tumorigenesis of infused umbilical cord mesenchymal stem cells (UC-MSCs) is being preclinically evaluated. METHODS: We observed tumor formation in NOD SCID mice after a single subcutaneous injection of hUC-MSCs and the effect of these cells on tumor growth in tumor-bearing mice. Three generations (P5, P7, and P10) of hUC-MSCs (1 × 107) from two donors (hUC-MSC1 and hUC-MSC2) were inoculated subcutaneously into NOD SCID mice. Subcutaneous transplantation models were established in NOD SCID mice with human cervical cancer HeLa cells (solid tumor) and human B cell lymphoma Raji cells (hematological tumor). Then, the animals were euthanized, gross dissection was performed, and tissues were collected. Various organs were observed microscopically to identify pathological changes and tumor metastasis. RESULTS: In the tumorigenesis experiment, no general anatomical abnormalities were observed. In the tumor promotion experiment, some animals in the HeLa groups experienced tumor rupture, and one animal died in each of the low- and medium-dose hUC-MSC groups. The results may have occurred due to the longer feeding time, and the tumor may have caused spontaneous infection and death. Pathological examination revealed no metastasis to distant organs in any group. In the Raji tumor model, some animals in each group experienced tumor rupture, and one animal in the medium-dose hUC-MSC group died, perhaps due to increased tumor malignancy. Thus, hUC-MSCs neither promoted nor inhibited tumor growth. No cancer cell metastasis was observed in the heart, liver, spleen, lungs, kidneys or other important organs, except that pulmonary venule metastasis was observed in 1 animal in the model group. CONCLUSIONS: Injected hUC-MSCs were not tumorigenic and did not significantly promote or inhibit solid or hematological tumor growth or metastasis in NOD SCID mice.

Anti-fatigue effects of fermented soybean protein peptides in mice.

BACKGROUND: Bioactive protein hydrolysates and peptides are believed to help counteract and ameliorate physical fatigue. Fermented soybean protein peptides (FSPPs) were prepared by protease hydrolysis and microbial fermentation. The present study aimed to evaluate the anti-fatigue properties of FSPPs. RESULTS: The forced swimming time in the FSPP group was 35.78% longer than the control group, the oxygen-resistant survival time of the FSPP group was significantly prolonged and the prolongation rate was 31.00%. In addition, FSPPs decreased the lactic acid (LD), blood urea nitrogen (BUN) and creatine kinase (CK) concentration by 27.47%, 25.93% and 21.70%, respectively, after treatment, while increasing the levels of liver glycogen and muscle glycogen by 93.35% and 67.31%, respectively. FSPPs can significantly increase gut microbiota diversity and regulate the species richness of gut microbiota. The results of real-time polymerase chain reaction (RT-PCR) and western blotting showed that FSPPs activate p-AMPK/PGC1-α and PI3K/Akt/mTOR signaling pathways. CONCLUSION: These results indicate that treatment with FSPPs induces anti-fatigue effects, which may be due to the mediating muscle protein synthesis and participation in skeletal muscle hypertrophy, providing energy for muscle cells. FSPPs may have potential applications in the food industry as functional material additives. © 2021 Society of Chemical Industry.

A Short-Term Hybrid TCN-GRU Prediction Model of Bike-Sharing Demand Based on Travel Characteristics Mining.

This paper proposes an accurate short-term prediction model of bike-sharing demand with the hybrid TCN-GRU method. The emergence of shared bicycles has provided people with a low-carbon, green and healthy way of transportation. However, the explosive growth and free-form development of bike-sharing has also brought about a series of problems in the area of urban governance, creating a new opportunity and challenge in the use of a large amount of historical data for regional bike-sharing traffic flow predictions. In this study, we built an accurate short-term prediction model of bike-sharing demand with the bike-sharing dataset from 2015 to 2017 in London. First, we conducted a multidimensional bike-sharing travel characteristics analysis based on explanatory variables such as weather, temperature, and humidity. This will help us to understand the travel characteristics of local people, will facilitate traffic management and, to a certain extent, improve traffic congestion. Then, the explanatory variables that help predict the demand for bike-sharing were obtained using the Granger causality with the entropy theory-based MIC method to verify each other. The Multivariate Temporal Convolutional Network (TCN) and Gated Recurrent Unit (GRU) model were integrated to build the prediction model, and this is abbreviated as the TCN-GRU model. The fitted coefficient of determination R2 and explainable variance score (EVar) of the dataset reached 98.42% and 98.49%, respectively. Meanwhile, the mean absolute error (MAE) and root mean square error (RMSE) were at least 1.98% and 2.4% lower than those in other models. The results show that the TCN-GRU model has strong efficiency and robustness. The model can be used to make short-term accurate predictions of bike-sharing demand in the region, so as to provide decision support for intelligent dispatching and urban traffic safety improvement, which will help to promote the development of green and low-carbon mobility in the future.

Establishment of a Systemic Inflammatory Response Syndrome Model and Evaluation of the Efficacy of Umbilical Cord Mesenchymal Stem Cell Transplantation.

Based on the characteristics of modern weapon injury, a repetitive model of traumatic systemic inflammatory response syndrome (SIRS) and an evaluation system were established. The models were treated with GFP-labeled tree shrew umbilical cord mesenchymal stem cells (UCMSCs). Forty out of 50 tree shrews were used to make a unilateral femoral comminuted fracture. Lipopolysaccharide was injected intravenously to create a traumatic SIRS model. The other 10 shrews were used as normal controls. After the model was established for 10 days, 20 tree shrews were injected intravenously with GFP-labeled UCMSCs, and 18 tree shrews were not injected as the model control group. The distribution of GFP-labeled cells in vivo was measured at 2 and 10 days after injection. Twenty days after treatment, the model group, the normal control group, and the treatment group were taken to observe the pathological changes in each tissue, and blood samples were taken for the changes in liver, renal, and heart function. Distribution of GFP-positive cells was observed in all tissues at 2 and 10 days after injection. After treatment, the HE staining results of the treatment group were close to those of the normal group, and the model group had a certain degree of lesions. The results of liver, renal, and heart function tests in the treatment group were returned to normal, and the results in the model group were abnormally increased. UCMSCs have a certain effect on the treatment of traumatic SIRS and provide a new technical solution for modern weapon trauma treatment.

Reversible engineering of topological insulator surface state conductivity through optical excitation.

Despite the broadband response, limited optical absorption at a particular wavelength hinders the development of optoelectronics based on Dirac fermions. Heterostructures of graphene and various semiconductors have been explored for this purpose, while non-ideal interfaces often limit the performance. The topological insulator (TI) is a natural hybrid system, with the surface states hosting high-mobility Dirac fermions and the small-bandgap semiconducting bulk state strongly absorbing light. In this work, we show a large photocurrent response from a field effect transistor device based on intrinsic TI Sn-Bi1.1Sb0.9Te2S (Sn-BSTS). The photocurrent response is non-volatile and sensitively depends on the initial Fermi energy of the surface state, and it can be erased by controlling the gate voltage. Our observations can be explained with a remote photo-doping mechanism, in which the light excites the defects in the bulk and frees the localized carriers to the surface state. This photodoping modulates the surface state conductivity without compromising the mobility, and it also significantly modify the quantum Hall effect of the surface state. Our work thus illustrates a route to reversibly manipulate the surface states through optical excitation, shedding light into utilizing topological surface states for quantum optoelectronics.

The Impact of Hypertension Definition Based on Two-visit Strategy on Estimate of Hypertension Burden: Results From the China Health and Nutrition Survey 1989-2011.

BACKGROUND: The diagnosis of hypertension should be based on the mean of two or more properly measured BP readings on each of two visits for clinical practice, but a one-visit strategy was applied in most epidemiological surveys. The impact of hypertension definition based on two visits on estimates of hypertension burden is unknown. This study aims to assess the impact of hypertension diagnosis based on a two-visit strategy for estimating hypertension burden in China. METHODS: The one-visit and two-visit strategies were applied to investigate the incidence of hypertension in a cohort study based on the China Health and Nutrition Survey (CHNS) 1989-2011. Additionally the prevalence of hypertension was investigated in a cross-sectional study based on the CHNS 2006-2009/2011 and the hypertension burden in China was estimated with data from the 2012-2015 China hypertension survey. RESULTS: Overall, the age-adjusted incidence of hypertension based on the two-visit strategy (1.82%; 95% confidence interval [CI], 1.74-1.90%) was 62.1% lower than estimation based on the one-visit strategy (4.80%; 95% CI, 4.68-4.93%). Similar results were found in the prevalence of hypertension (one-visit: 18.13% [95% CI, 17.34-18.92%]; two-visit: 9.47% [95% CI, 8.87-10.07%]). When the two-visit strategy was applied to the 2012-2015 China hypertension survey, the hypertension burden was predicted to be overestimated by 25.5-47.8% (based on JNC 7) and 23.5-48.2% (based on the 2017 ACC/AHA). CONCLUSION: The hypertension burden would decrease from 244.5 million persons to 127.5-182.3 million persons in China if the two-visit strategy was applied.

Auditory versus visual spatial stimulus-response mappings in tracking and discrete dual task performance: implications for human-machine interface design.

A discrete four-choice response task with auditory signal presentation and a joystick-controlled visual tracking task was used to investigate how spatial compatibility influences the dual-task performance of different display-control settings. It was found that the more incompatible the stimulus-response mapping, the longer the delay for both tasks, presumably because of the longer stimulus encoding time required for the incompatible conditions. A comparison of the findings of this study with those of past experiments on visual visual setting shows that the dual-task performance in a cross-modality (auditory visual) setting was significantly better than that in an intra-modality (visual visual) setting because of visual scanning required in the intra-modal dual tasks. However, when the locations of visual visual tasks were close enough such that ambient and focal vision was concurrently used for information processing, the dual-task performance of intra-modality (visual visual) configuration was slightly better than that of the cross-modality (auditory visual) configuration. Practitioner Summary: The effect of spatial compatibility with auditory signal presentation in multiple display-control configurations was examined in a dual-task paradigm. The results provided important and useful ergonomics design implications and consequent recommendations for intra- and cross- modal interface design. The results should facilitate human-machine system design and improve overall system performance.

Associations of fat and carbohydrate intake with becoming overweight and obese: an 11-year longitudinal cohort study.

The effects of macronutrient intake on obesity are controversial. This research aims to investigate the associations between macronutrient intake and new-onset overweight/obesity. The relationship between the consumption of carbohydrate and total fat and obesity was assessed by the multivariable Cox model in this 11-year cohort, which included 6612 adults (3291 men and 3321 women) who were free of overweight and obesity at baseline. The dietary intake was recorded using a 24-h recall method for three consecutive days. Moreover, substitution models were developed to distinguish the effects of macronutrient composition alteration from energy intake modification. During 7·5 person years (interquartile range 4·3, 10·8) of follow-up, 1807 participants became overweight or obese. After adjusting for risk factors, the hazard ratio (HR) of overweight/obesity in extreme quintiles of fat was 1·48 (quintile 5 v. quintile 1, 95 % CI 1·16, 1·89; Ptrend = 0·02) in women. Additionally, replacing 5 % of energy from carbohydrate with equivalent energy from fat was associated with an estimated 4·3 % (HR 1·043, 95 % CI 1·007, 1·081) increase in overweight/obesity in women. Moreover, dietary carbohydrate was inversely associated with overweight/obesity (quintile 5 v. quintile 1, HR 0·70, 95 % CI 0·55, 0·89; Ptrend = 0·02) in women. Total fat was related to a higher risk of overweight/obesity, whereas high carbohydrate intake was related to a lower risk of overweight/obesity in women, which was not observed in men.

Comparing the performance of conventional PCR, RTQ-PCR, and droplet digital PCR assays in detection of Shigella.

The incidence of foodborne infections caused by Shigella spp. is still very high in every year, which poses a great potential threat to public health. Conventional quantification methods based on culture techniques, biochemical, and serological identification are time-consuming and labor-intensive. To develop a more rapid and efficient detection method of Shigella spp., we compared the sensitivity and specificity of three different polymerase chain reaction (PCR) methods, including conventional PCR, quantitative real-time PCR (RTQ-PCR), and droplet digital PCR (ddPCR). Our results indicated that ddPCR method exhibited higher sensitivity, and the limit of detection was 10-5 ng/µl for genomic DNA templates, 10-1 cfu/ml for Shigella bacteria culture. In addition, we found that ddPCR was a time-saving method, which required a shorter pre-culturing time. Collectively, ddPCR assay was a reliable method for rapid and effective detection of Shigella spp.

Plain Water Intake and Association With the Risk of Overweight in the Chinese Adult Population: China Health and Nutrition Survey 2006-2011.

BACKGROUND: The prevalence of overweight is increasing dramatically worldwide. The aim of our study was to investigate the association of plain water intake (PWI) with the risk of new-onset overweight risk among Chinese adults. METHODS: A total of 3,200 adults aged 18-65 who were free of overweight at baseline were enrolled from China Health and Nutrition Survey (CHNS) cohort study in 2006-2011. The risk of new-onset overweight with different amounts of PWI per day was analyzed in this 5-year cohort. A multiple logistic regression model was used to assess the association of PWI and the risk of new-onset overweight and adjust for potential confounders. Moreover, dose-response models were developed to estimate the linear relationship. RESULTS: During 5 years of follow-up, 1,018 incident cases were identified. Our analysis indicated an inverse association of more than 4 cups of PWI per day and the risk of new-onset overweight among normal weight individuals. Compared with participants who drank 2 to 3 cups PWI, the adjusted odds ratios (OR) of overweight were 0.741 (95% confidence interval [CI], 0.599-0.916) in participants who drank 4 to 5 cups PWI, and 0.547 (95% CI, 0.435-0.687) in participants who drank more than 6 cups PWI. The dose-response analysis showed that every cup of PWI was associated with a 6.5% and 8.4% decrease in the risk of new-onset overweight among men and women, respectively. The interactions of PWI and covariates on the risk of overweight were not found. CONCLUSION: Drinking more than 4 cups (≈1 liter) per day of plain water is associated with decrease in the risk of new-onset overweight among normal-weight individuals.

N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation.

A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 µM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (koff=1.60 × 10-3 s-1) from the catalytic domain.

Trends in age of smoking initiation among the Chinese population born between 1950 and 1997.

OBJECTIVES: Smoking prevalence has significantly increased among Chinese adolescences in the past decades. The aim of our study is to investigate the trends and changing patterns in age of smoking initiation among the Chinese population. STUDY DESIGN: Pooled data from the 2006-2015 China Health and Nutrition Survey was used for analysis. A total of 10,032 adults aged ≥18 years who were born between 1950 and 1997 were separated into five birth cohorts (1950-1959, 1960-1969, 1970-1979, 1980-1989 and 1990-1997). METHODS: Age-specific (10-24 years) smoking initiation rates were calculated by gender, educational level and urbanisation. The multiple logistic models were used for estimates of changes in smoking initiation age. RESULTS: The mean age of smoking initiation decreased substantially from 22.0 years (95% confidence interval [CI]: 21.2-22.7) to 17.5 years (95% CI: 16.2-19.1) over five generations. A large decrease was seen in the initiation age group of 15-24 years in the 1980s cohort (15-19 years: odds ratio [OR] = 0.57; 95% CI: 0.19-0.97; 20-24 years: OR = 0.45; 95% CI: 0.18-0.82); a significant decrease was also found in the 1990s cohort (15-19 years: OR = 0.47; 95% CI: 0.11-0.94; 20-24 years old: OR = 0.34; 95% CI: 0.14-0.85). The peak age of smoking initiation changed from 20 years old to 18 years old over the five generations. CONCLUSIONS: The age of smoking initiation has decreased rapidly in the Chinese population in the past decades. Chinese adolescents are becoming the main target group for the tobacco marketing industry, and national legislations are urgently required.

Quantitative Analysis of Weak Antilocalization Effect of Topological Surface States in Topological Insulator BiSbTeSe2.

Quantitative analysis of the weak antilocalization (WAL) effect of topological surface states in topological insulators is of tremendous importance. The major obstacle to achieve accurate results is how to eliminate the contribution of the anisotropic magnetoconductance of bulk states when the Fermi level lies in bulk bands. Here, we demonstrate that we can analyze quantitatively and accurately the WAL effect of topological surface states in topological insulator, BiSbTeSe2 (BSTS), by measuring the anisotropic magnetoconductance. The anomalous conductance peaks induced by the WAL effect of topological surface states of BSTS together with the anisotropic magnetoconductance of bulk states have been observed. By subtracting the anisotropic magnetoconductance of bulk states, we are able to analyze the WAL effect of topological surface states using the Hikami-Larkin-Nagaoka expression. Our findings offer an alternative strategy for the quantitative exploration of the WAL effect of topological surface states in topological insulators.