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Abstract Aims The Stress Hyperglycemia Ratio (SHR) potently predicts adverse outcomes in patients with cardiovascular and cerebrovascular diseases. However, the relationship between SHR and short-term mortality risk in patients with a first diagnosis of acute myocardial infarction (AMI) remains contentious. This study sought to understand better the relationship between SHR and short-term mortality risk in patients with a first diagnosis of AMI. Methods We conducted a cohort study using data from 1961 patients with a first diagnosis of AMI from the MIMIC-IV (version 2.2) database. Patients were divided into three groups based on SHR tertiles. The Cox proportional hazards model and a two-segmented Cox proportional hazards model were used to elucidate the nonlinear relationship between SHR in patients with a first diagnosis of AMI and mortality. Results Of the surveyed population, 175 patients (8.92%) died within 90 days, and 210 patients (10.71%) died within 180 days. After multivariate adjustments, elevated SHR levels were significantly and non-linearly associated with a higher risk of 90-day and 180-day mortality in patients with a first diagnosis of AMI, showing a J-shaped correlation with an inflection point at 0.9. Compared to participants with SHR levels below the inflection point, those with higher SHR levels had a fivefold increased risk of 90-day mortality (hazard ratio [HR] 5.74; 95% confidence interval [CI] 3.19, 10.33) and a fourfold increased risk of 180-day mortality (HR 4.56; 95% CI 2.62, 7.95). In the subgroup analysis, patients with pre-diabetes mellitus (pre-DM) and higher SHR levels had increased 90-day (HR 6.90; 95% CI 1.98, 24.02) and 180-day mortality risks (HR 5.30; 95% CI 1.96, 14.27). Conclusion In patients with a first diagnosis of AMI, there is a J-shaped correlation between SHR and 90-day and 180-day mortality, with an adverse prognostic inflection point of SHR at 0.9.

Abstract Whether Klotho plays any role in hypothyroidism is unknown. This study aimed to determine the relationship between serum Klotho levels and hypothyroidism in older adults. From the 2007 to 2012 National Health and Nutrition Examination Survey (NHANES), 1444 older adults aged 65–79 were included in this cross-sectional study. Hypothyroidism was diagnosed using participants' reports of current medications and TSH tests. Klotho was measured using an enzyme-linked immunosorbent assay. The relationship between serum Klotho levels and hypothyroidism in older people was analyzed by one-way analysis of variance, multiple linear regression models, subgroup analyses, interaction tests, smoothed curve fitting, and threshold effects. A total of 209 (14.47%) participants were identified as having hypothyroidism. Serum Klotho (ln transformation) is independently and significantly negatively associated with the risk of hypothyroidism after complete adjustment for confounders (OR = 0.49, 95% CI 0.31–0.80; P = 0.0039). The results remained stable based on subgroup analyses and interaction tests. However, we observed an inverted U-shaped curve between the two using a smoothed curve fitting in the subgroups of 70

Abstract Although in vitro experiments have demonstrated the potential of flavonoid compounds in regulating blood pressure, there is still a lack of evidence from large population studies. We conducted a cross‐sectional study using the National Health and Nutrition Examination Survey to investigate the relationship between flavonoid intake levels (natural log transformation) and hypertension events. A total of 15 752 participants aged over 20 years were included, and a weighted multivariable logistic regression analysis was performed to explore the relationship between total flavonoids, five sub types intake, and hypertension events. Smooth curve fitting was used to explore potential nonlinear relationships. Higher total flavonoids intake was associated with a lower risk of hypertension than the lowest group. The adjusted odds ratios (95% CIs) were 0.79 (0.70–0.88) for total flavonoids intake. Elevated total flavonoids intake levels were significantly and linearly associated with a lower risk of hypertension. For each unit increase in the total flavonoids intake level, the adjusted ORs for risk of hypertension decrease by 5% (OR 0.95; 95% CI, 0.92–0.98). In addition, in restricted cubic spline regression, we found that flavan‐3‐ols, anthocyanidins, and flavonols intake were linearly and negatively related to prevalence of hypertension. Flavones intake showed nonlinear associations with prevalence of hypertension with inflection points of ‐1.90. Within a certain range, a negative correlation exists between flavonoids intake and hypertension events. This finding provides insights into dietary modifications in the prevention of hypertension.

Abstract Polyethers play a crucial role in the development of anticancer drugs. To enhance the anticancer efficacy and reduce the toxicity of these compounds, thereby advancing their application in cancer treatment, herein, guided by the structure‐activity relationships of aglycone polyethers, novel aglycone polyethers are rationally redesigned with potentially improved efficacy and reduced toxicity against tumors. To realize the biosynthesis of the novel aglycone polyethers, the gene clusters and the post‐polyketide synthase tailoring pathways for aglycone polyethers endusamycin and lenoremycin are identified and subjected to combinatorial biosynthesis studies, resulting in the creation of a novel aglycone polyether termed End‐16, which demonstrates significant potential for treating bladder cancer (BLCA). End‐16 demonstrates the ability to suppress the proliferation, migration, invasion, and cellular protrusions formation of BLCA cells, as well as induce cell cycle arrest in the G1 phase in vitro. Notably, End‐16 exhibits superior inhibitory activity and fewer side effects against BLCA compared to the frontline anti‐BLCA drug cisplatin in vivo, thereby warranting further preclinical studies. This study highlights the significant potential of integrating combinatorial biosynthesis strategies with rational design to create unnatural products with enhanced pharmacological properties.

Abstract Background Zoonotic viruses cause substantial public health and socioeconomic problems worldwide. Understanding how viruses evolve and spread within and among wildlife species is a critical step when aiming for proactive identification of viral threats to prevent future pandemics. Despite the many proposed factors influencing viral diversity, the genomic diversity and structure of viral communities in East Africa are largely unknown. Results Using 38.3 Tb of metatranscriptomic data obtained via ultradeep sequencing, we screened vertebrate-associated viromes from 844 bats and 250 rodents from Kenya and Uganda collected from the wild. The 251 vertebrate-associated viral genomes of bats (212) and rodents (39) revealed the vast diversity, host-related variability, and high geographic specificity of viruses in East Africa. Among the surveyed viral families, Coronaviridae and Circoviridae showed low host specificity, high conservation of replication-associated proteins, high divergence among viral entry proteins, and frequent recombination. Despite major dispersal limitations, recurrent mutations, cocirculation, and occasional gene flow contribute to the high local diversity of viral genomes. Conclusions The present study not only shows the landscape of bat and rodent viromes in this zoonotic hotspot but also reveals genomic signatures driven by the evolution and dispersal of the viral community, laying solid groundwork for future proactive surveillance of emerging zoonotic pathogens in wildlife. Video Abstract

Abstract Background The hemoglobin glycation index (HGI) is the difference between the observed and predicted values of glycosylated hemoglobin (HbA1c), which is closely associated with a variety of poor prognoses. However, there are still no studies on the correlation between HGI and poor prognosis in patients with critical coronary artery disease. The purpose of this study was to analyze the correlation between HGI and all-cause mortality in patients with critical coronary artery disease using the MIMIC-IV database. Methods The HGI was calculated by constructing a linear regression equation between HbA1c and fasting plasma glucose (FPG). A Kaplan‒Meier survival analysis model was constructed based on the HGI quartiles to clarify the differences in all-cause mortality rates between groups, and the log-rank test was used to assess the differences between groups. The hazard ratio (HR) of HGI as a risk factor for outcome events was assessed using the Cox proportional risk model and restricted cubic spline (RCS), with the Q2 group serving as the reference group. Results A total of 5260 patients were included in this study. The 30-day mortality rate of the patients was 4.94% and the mortality rate within 365 days was 13.12%. A low HGI was significantly associated with 30-day mortality (HR, 1.96; 95% CI, (1.38, 2.78); P

Abstract Background Chronic kidney disease (decreased kidney function) is common in hypertensive patients. The SIRI is a novel immune biomarker. We investigated the correlation between the SIRI and kidney function in hypertensive patients. Methods The present study analyzed data from participants who suffered from hypertension in the NHANES from 2009 to 2018. Multivariate regression analysis and subgroup analysis were used to clarify whether the SIRI was an independent risk factor for decreased kidney function. RCSs were utilized to evaluate the correlation between the SIRI and the eGFR and between the SIRI and the ACR. In addition, we modeled the mediating effect of the SIRI on the eGFR and the ACR using blood pressure as a mediating variable. Results The highest SIRI was an independent risk factor for a decreased eGFR [odds ratio (OR) = 1.46, 95% CI (1.15, 1.86)] and an increased ACR [OR = 2.26, 95% CI (1.82, 2.82)] when the lowest quartile was used as the reference. The RCS results indicated an inverted U-shaped relationship between the SIRI and the eGFR and between the SIRI and the ACR (the inflection points were 1.86 and 3.09, respectively). The mediation effect analysis revealed that the SIRI was the main factor influencing kidney function, and diastolic blood pressure was a mediating variable. In particular, there was a fully mediating effect between the SIRI and UCr, with a mediating effect value of -0.61 (-0.90, -0.36). Conclusions The association between the SIRI and renal function in hypertensive patients was significant and was particularly dominated by the association between the SIRI and the ACR. This difference may be due to the mediating effect of diastolic blood pressure.

Objective The association between the Triglyceride-Glucose (TyG) Index and mortality rates in patients with cardiovascular disease (CVD) remains unclear. This study investigates the association between the TyG index and the incidence of all-cause and CVD-specific mortality among individuals with a history of CVD.Design Population-based cohort study.Setting Data were sourced from the US National Health and Nutrition Examination Survey (2007–2018) and linked mortality data, with follow-up continuing until 31 December 2019.Participants The study population comprised 3422 individuals aged 20 years or older with a documented history of CVD.Outcome measures We examined the association between the TyG index and the risk of all-cause and cardiovascular mortality.Results Over a median follow-up of 5.79 years, 1030 deaths occurred, including 339 due to CVD. Cox regression analysis, adjusted for multiple confounders, showed that individuals in the highest TyG index quartile, compared with those in the lowest, had HRs of 0.76 (95% CI: 0.60 to 0.96) for all-cause mortality and 0.58 (95% CI: 0.39 to 0.89) for CVD mortality. There was a significant inverse relationship between higher TyG index levels and lower mortality risks. For each unit increase in the TyG index, the adjusted HRs for all-cause and CVD mortality decreased by 18% (HR 0.82; 95% CI: 0.71 to 0.94) and 27% (HR 0.73; 95% CI: 0.57 to 0.92), respectively.Conclusions TyG index values are negatively associated with all-cause and CVD mortality risks among individuals with previous CVD. Further interventional studies are needed to clarify the impact of TyG levels on cardiovascular health.

Abstract Background The predictive utility of QTc values, calculated through various correction formulas for the incidence of postoperative major adverse cardiovascular and cerebrovascular events (MACCE) in patients experiencing acute myocardial infarction (AMI), warrants further exploration. This study endeavors to ascertain the predictive accuracy of disparate QTc values for MACCE occurrences in patients with perioperative AMI. Methods A retrospective cohort of three hundred fourteen AMI patients, comprising 81 instances of in-hospital MACCE and 233 controls, was assembled, with comprehensive collection of baseline demographic and clinical data. QTc values were derived employing the correction formulas of Bazett, Fridericia, Hodges, Ashman, Framingham, Schlamowitz, Dmitrienko, Rautaharju, and Sarma. Analytical methods encompassed comparative statistics, Spearman correlation analysis, binary logistic regression models, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Results QTc values were significantly elevated in the MACCE cohort compared to controls (P

BackgroundOur objective is to describe the current prevalence and death of ischemic heart disease (IHD) in women of childbearing age (WCBA) at the global, regional, and national levels and to analyze its temporal trends from 1990 to 2019.MethodsWCBA was defined as women aged 15–49 years. Estimates and 95% Uncertainty Intervals (UI) of IHD prevalence and death numbers for seven age groups were extracted from the 2019 Global Burden of Disease Study. The age-standardized prevalence and death rate (ASPR and ASDR) of IHD in WCBA was estimated using the direct age-standardization method. Joinpoint regression analysis was used to calculate average annual percent change (AAPC) to represent the temporal trends from 1990 to 2019.ResultsBetween 1990 and 2019, the global ASPR of IHD experienced a 3.21% increase, culminating in 367.21 (95% UI, 295.74–430.16) cases per 100,000 individuals. Conversely, the ASDR decreased to 11.11 (95% UI, 10.10–12.30) per 100,000 individuals. In 2019, among the five sociodemographic index (SDI) regions, the highest ASPR was observed in the high-middle SDI region, whereas the highest ASDR was found in the low-middle SDI region. Regionally, the Caribbean reported the highest ASPR (563.11 per 100,000 individuals; 95% UI, 493.13–643.03), and Oceania reported the highest ASDR (20.20 per 100,000 individuals; 95% UI, 13.01–31.03). At the national level, Trinidad and Tobago exhibited the highest ASPR (730.15 per 100,000 individuals; 95% UI, 633.96–840.13), and the Solomon Islands had the highest ASDR (77.77 per 100,000 individuals; 95% UI, 47.80–121.19). Importantly, over the past three decades, the global ASPR has seen a significant increase [AAPC = 0.11%, 95% Confidence Interval (CI): 0.09–0.13; P

Background: Epidemiological studies on cardiovascular diseases (CVD) among women of childbearing age (WCBA) remain scarce. Our research aims to delineate the prevalence trends of CVD within this population over the past three decades, considering age, period, and birth cohort dynamics. Methods: Estimates of CVD prevalence for WCBA, along with their 95% uncertainty intervals (UI), were extracted from the Global Burden of Diseases 2019 (GBD2019). An age-period-cohort (APC) model was utilized to assess the annual percentage change (net drifts) in overall prevalence, annual percentage changes in prevalence for individual age groups (local drifts), and fitted longitudinal age-specific rates adjusted for age effects and period/cohort relative risks (period/cohort effect). Results: In 2019, the global prevalence of CVD among WCBA was 53.42 million (95% UI: 47.77 to 60.18). Eight countries recorded a prevalence exceeding one million, accounting for 54.17% of the global CVD prevalence in WCBA. Over the past 30 years, the annual net drift in CVD prevalence among the global WCBA was 0.27% (95% CI: 0.25 to 0.29). This value was 0.01% (95% CI: 0.04 to 0.06) in regions with a high sociodemographic index (SDI) and 0.21% (95% CI: 0.19 to 0.22) in those with a low SDI. Seventy-seven countries demonstrated an increasing trend in CVD prevalence, while 53 showed a decrease, and 74 remained relatively stable. Notably, as shown in local drift, there was a rise in CVD prevalence among adolescents aged 15–19 and adults aged 40–49 in regions categorized by five distinct SDI levels. This drift varied by SDI regions. Regions with a high SDI consistently had elevated period risks throughout the study duration, while other regions had lower period risks until 2000–2004 and displayed increased adverse period risks. The prevalence in low-middle and low SDI regions manifested detrimental trends, whereas other regions demonstrated an initial decline followed by a surge in successive birth cohorts. Conclusions: Resources dedicated to CVD care for WCBA are largely insufficient, especially in low SDI regions. Thus, there is an urgent need to allocate cardiovascular healthcare resources variably across different SDI regions, aiming to diminish risks among successively younger birth cohorts. Throughout this endeavor, the formulation of targeted policies and the judicious distribution of resources are essential to reduce risks for women across all age groups.

BackgroundTo describe the burden and examine transnational inequities in overall cardiovascular disease (CVD) and ten specific CVDs across different levels of societal development.MethodsEstimates of disability-adjusted life-years (DALYs) for each disease and their 95% uncertainty intervals (UI) were extracted from the Global Burden of Diseases (GBD). Inequalities in the distribution of CVD burdens were quantified using two standard metrics recommended absolute and relative inequalities by the World Health Organization (WHO), including the Slope Index of Inequality (SII) and the relative concentration Index.ResultsBetween 1990 and 2019, for overall CVD, the Slope Index of Inequality changed from 3760.40 (95% CI: 3758.26 to 3756.53) in 1990 to 3400.38 (95% CI: 3398.64 to 3402.13) in 2019. For ischemic heart disease, it shifted from 2833.18 (95% CI: 2831.67 to 2834.69) in 1990 to 1560.28 (95% CI: 1559.07 to 1561.48) in 2019. Regarding hypertensive heart disease, the figures changed from-82.07 (95% CI: −82.56 to-81.59) in 1990 to 108.99 (95% CI: 108.57 to 109.40) in 2019. Regarding cardiomyopathy and myocarditis, the data evolved from 273.05 (95% CI: 272.62 to 273.47) in 1990 to 250.76 (95% CI: 250.42 to 251.09) in 2019. Concerning aortic aneurysm, the index transitioned from 104.91 (95% CI: 104.65 to 105.17) in 1990 to 91.14 (95% CI: 90.94 to 91.35) in 2019. Pertaining to endocarditis, the figures shifted from-4.50 (95% CI: −4.64 to-4.36) in 1990 to 16.00 (95% CI: 15.88 to 16.12) in 2019. As for rheumatic heart disease, the data transitioned from-345.95 (95% CI: −346.47 to-345.42) in 1990 to-204.34 (95% CI: −204.67 to-204.01) in 2019. Moreover, the relative concentration Index for overall CVD and each specific type also varied from 1990 to 2019.ConclusionThere’s significant heterogeneity in transnational health inequality for ten specific CVDs. Countries with higher levels of societal development may bear a relatively higher CVD burden except for rheumatic heart disease, with the extent of inequality changing over time.

Summary: As a primary target of severe acute respiratory syndrome coronavirus 2, lung exhibits heterogeneous histopathological changes following infection. However, comprehensive insight into their protein basis with spatial resolution remains deficient, which hinders further understanding of coronavirus disease 2019 (COVID-19)-related pulmonary injury. Here, we generate a region-resolved proteomic atlas of hallmark pathological pulmonary structures by integrating histological examination, laser microdissection, and ultrasensitive proteomics. Over 10,000 proteins are quantified across 71 post-mortem specimens. We identify a spectrum of pathway dysregulations in alveolar epithelium, bronchial epithelium, and blood vessels compared with non-COVID-19 controls, providing evidence for transitional-state pneumocyte hyperplasia. Additionally, our data reveal the region-specific enrichment of functional markers in bronchiole mucus plugs, pulmonary fibrosis, airspace inflammation, and alveolar type 2 cells, uncovering their distinctive features. Furthermore, we detect increased protein expression associated with viral entry and inflammatory response across multiple regions, suggesting potential therapeutic targets. Collectively, this study provides a distinct perspective for deciphering COVID-19-caused pulmonary dysfunction by spatial proteomics.

Abstract Background Serum vitamin D deficiency is common in the patients with cardiovascular disease (CVD), but the association between serum vitamin D levels and risk of all-cause mortality in patients with CVD is controversial. Objective This study aimed to understand better the association between serum 25(OH)D status and risk of all-cause mortality in patients with prior CVD. Method We conducted a cohort study using data from the National Health and Nutrition Examination Survey from 2007 to 2018 to investigate the association between serum 25(OH)D and the risk of all-cause mortality using multivariate Cox regression models, with further subgroup analyses and interactions smooth curve fitting to address possible nonlinearities. Result A total of 3220 participants with prior CVD were included in this study, with a total of 930 deaths over a median follow-up of 5.52 years, with multivariable-adjusted serum vitamin D levels after natural log transformation (4.31–4.5 ) as a reference in COX regression, and corrected HRs and 95% CIs of 1.81 (1.31, 2.50), 1.34 (1.07, 1.66), 1.28 (1.05, 1.56),1.00 (reference), 1.10 (0.89, 1.37) for all-cause mortality, respectively. Results remained robust in the stratified analysis of interactions, but a L-shaped relationship was detected. We identified an inflection point of 4.5 after multivariate adjustment through a two-stage linear regression model and recursive algorithm. Conclusion Our findings demonstrate that increasing serum 25(OH)D levels may have a L-shaped relationship with risk of all-cause mortality and that increases in serum 25(OH)D levels do not continue to reduce the risk of all-cause mortality.

The intestinal and intratumoral microbiota are closely associated with tumor progression and response to antitumor treatments. The antibacterial or tumor microenvironment (TME)-modulating approaches have been shown to markedly improve antitumor efficacy, strategies focused on normalizing the microbial environment are rarely reported. Here, we reported the development of an orally administered inulin-based hydrogel with colon-targeting and retention effects, containing hollow MnO2 nanocarrier loaded with the chemotherapeutic drug Oxa (Oxa@HMI). On the one hand, beneficial bacteria in the colon specifically metabolized Oxa@HMI, resulting in the degradation of inulin and the generation of short-chain fatty acids (SCFAs). These SCFAs play a crucial role in modulating microbiota and stimulating immune responses. On the other hand, the hydrogel matrix underwent colon microbiota-specific degradation, enabling the targeted release of Oxa and production of reactive oxygen species in the acidic TME. In this study, we have established, for the first time, a microbiota-targeted drug delivery system Oxa@HMI that exhibited high efficiency in colorectal cancer targeting and colon retention. Oxa@HMI promoted chemotherapy efficiency and activated antitumor immune responses by intervening in the microbial environment within the tumor tissue, providing a crucial clinical approach for the treatment of colorectal cancer that susceptible to microbial invasion.

Aim: This study aimed to describe the prevalence, deaths, and disability-adjusted life-years (DALYs) of hypertensive heart disease (HHD) at the global, regional, and national levels and analyze epidemiological trends. Method: We extracted global estimates of prevalence, deaths, and DALYs related to HHD in 204 countries and regions from the 2019 Global Burden of Diseases Study. Average annual percent change (AAPC) was calculated to represent temporal trends. Joinpoint regression models were used to analyze time trends from 1990 to 2019. Finally, the decomposition analysis showed the driving factors of burden changes. Results: From 1990 to 2019, the global prevalence of HHD cases increased by 138 %, reaching 18,598,025 cases (95 % uncertainty interval [UI]: 13,544,365–24,898,411). DALYs also rose by 154 %, reaching 21,508,002 (95 % UI, 16,400,051–23,899,879). The death rate increased to 14.95 (95 % UI, 11.11–16.52) per 100,000 people. Of the five sociodemographic index (SDI) regions, the prevalence rate related to HHD was the highest in the high-middle SDI region. In contrast, the death and DALY rate related to HHD were the highest in the middle SDI region. In other regions, the prevalence rate was the highest in East Asia (548.87 per 100,000 people; 95 % UI, 395.40–747.83), and the death rate was the highest in Central Europe (42.64 per 100,000 people; 95 % UI, 30.58–49.38). At the national level, the Cook Islands had the highest prevalence rate for HHD (703.08 per 100,000 people; 95 % UI, 532.87–920.72), Bulgaria had the highest death rate (75.08 per 100,000 people; 95 % UI, 46.38–92.81), and Afghanistan had the highest DALY rate (1374.12 per 100,000 people; 95 % UI, 467.17–2020.70). High body mass index, a diet high in sodium, alcohol use, lead exposure, high temperature, and low temperature were identified as risk factors for death and DALYs related to HHD in 2019. Aging and population growth were the major drivers of prevalence, death, and DALYs. Finally, over the past 30 years, the global age-standardized prevalence rate (ASPR) of HHD has significantly risen (AAPC = 0.21 %, 95 % confidence interval [CI]: 0.17–0.24; P

Zoonotic transmission of coronaviruses (CoVs) poses a serious public health threat. Swine acute diarrhea syndrome coronavirus (SADS-CoV), originating from a bat HKU2-related CoV, causes devastating swine diseases and poses a high risk of spillover to humans. Currently, licensed therapeutics that can prevent potential human outbreaks are unavailable. Identifying the cellular proteins that restrict viral infection is imperative for developing effective interventions and therapeutics. We utilized a large-scale human cDNA screening and identified transmembrane protein 53 (TMEM53) as a novel cell-intrinsic SADS-CoV restriction factor. The inhibitory effect of TMEM53 on SADS-CoV infection was found to be independent of canonical type I interferon responses. Instead, TMEM53 interacts with non-structural protein 12 (NSP12) and disrupts viral RNA-dependent RNA polymerase (RdRp) complex assembly by interrupting NSP8-NSP12 interaction, thus suppressing viral RdRp activity and RNA synthesis. Deleting the transmembrane domain of TMEM53 resulted in the abrogation of TMEM53-NSP12 interaction and TMEM53 antiviral activity. Importantly, TMEM53 exhibited broad antiviral activity against multiple HKU2-related CoVs. Our findings reveal a novel role of TMEM53 in SADS-CoV restriction and pave the way to host-directed therapeutics against HKU2-related CoV infection.

Abstract Background The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) and the Omicron variant presents a formidable challenge for control and prevention worldwide, especially for low- and middle-income countries (LMICs). Hence, taking Kazakhstan and Pakistan as examples, this study aims to explore COVID-19 transmission with the Omicron variant at different contact, quarantine and test rates. Methods A disease dynamic model was applied, the population was segmented, and three time stages for Omicron transmission were established: the initial outbreak, a period of stabilization, and a second outbreak. The impact of population contact, quarantine and testing on the disease are analyzed in five scenarios to analysis their impacts on the disease. Four statistical metrics are employed to quantify the model’s performance, including the correlation coefficient (CC), normalized absolute error, normalized root mean square error and distance between indices of simulation and observation (DISO). Results Our model has high performance in simulating COVID-19 transmission in Kazakhstan and Pakistan with high CC values greater than 0.9 and DISO values less than 0.5. Compared with the present measures (baseline), decreasing (increasing) the contact rates or increasing (decreasing) the quarantined rates can reduce (increase) the peak values of daily new cases and forward (delay) the peak value times (decreasing 842 and forward 2 days for Kazakhstan). The impact of the test rates on the disease are weak. When the start time of stage II is 6 days, the daily new cases are more than 8 and 5 times the rate for Kazakhstan and Pakistan, respectively (29,573 vs. 3259; 7398 vs. 1108). The impact of the start times of stage III on the disease are contradictory to those of stage II. Conclusions For the two LMICs, Kazakhstan and Pakistan, stronger control and prevention measures can be more effective in combating COVID-19. Therefore, to reduce Omicron transmission, strict management of population movement should be employed. Moreover, the timely application of these strategies also plays a key role in disease control. Graphical abstract

Vitamin E is one of the most widely used vitamins. In the classical commercial synthesis of vitamin E (α-tocopherol), the chemical synthesis of isophytol is the key technical barrier. Here, we establish a new process for isophytol synthesis from microbial fermented farnesene. To achieve an efficient pathway for farnesene production, Saccharomyces cerevisiae was selected as the host strain. First, β-farnesene synthase genes from different sources were screened, and through protein engineering and system metabolic engineering, a high production of β-farnesene in S. cerevisiae was achieved (55.4 g/L). This farnesene can be chemically converted into isophytol in three steps with approximately 92% yield, which is economically equal to that from the best total chemical synthesis. Furthermore, we co-produced lycopene and farnesene to reduce the cost of farnesene. A factory based on this new process was successfully operated in Hubei Province, China, in 2017, with an annual output of 30,000 tons of vitamin E. This new process has completely changed the vitamin E market due to its low cost and safety.

Severe respiratory disease coronavirus-2 (SARS-CoV-2) has been the most devastating disease COVID-19 in the century. One of the unsolved scientific questions of SARS-CoV-2 is the animal origin of this virus. Bats and pangolins are recognized as the most probable reservoir hosts that harbour highly similar SARS-CoV-2 related viruses (SARSr-CoV-2). This study identified a novel lineage of SARSr-CoVs, including RaTG15 and seven other viruses, from bats at the same location where we found RaTG13 in 2015. Although RaTG15 and the related viruses share 97.2% amino acid sequence identities with SARS-CoV-2 in the conserved ORF1b region, it only shows less than 77.6% nucleotide identity to all known SARSr-CoVs at the genome level, thus forming a distinct lineage in the Sarbecovirus phylogenetic tree. We found that the RaTG15 receptor-binding domain (RBD) can bind to ACE2 from Rhinolophus affinis, Malayan pangolin, and use it as an entry receptor, except for ACE2 from humans. However, it contains a short deletion and has different key residues responsible for ACE2 binding. In addition, we showed that none of the known viruses in bat SARSr-CoV-2 lineage discovered uses human ACE2 as efficiently as the pangolin-derived SARSr-CoV-2 or some viruses in the SARSr-CoV-1 lineage. Therefore, further systematic and longitudinal studies in bats are needed to prevent future spillover events caused by SARSr-CoVs or to understand the origin of SARS-CoV-2 better.

Tick-borne viruses (TBVs) capable of transmitting between ticks and hosts have been increasingly recognized as a global public health concern. In this study, Hyalomma ticks and serum samples from camels were collected using recorded sampling correlations in eastern Kenya. Viromes of pooled ticks were profiled by metagenomic sequencing, revealing a diverse community of viruses related to at least 11 families. Five highly abundant viruses, including three novel viruses (Iftin tick virus, Mbalambala tick virus [MATV], and Bangali torovirus [BanToV]) and new strains of previously identified viruses (Bole tick virus 4 [BLTV4] and Liman tick virus [LMTV]), were characterized in terms of genome sequences, organizations, and phylogeny, and their molecular prevalence was investigated in individual ticks. Moreover, viremia and antibody responses to these viruses have been investigated in camels. MATV, BLTV4, LMTV, and BanToV were identified as viral pathogens that can potentially cause zoonotic diseases. The transmission patterns of these viruses were summarized, suggesting three different types according to the sampling relationships between viral RNA-positive ticks and camels positive for viral RNA and/or antibodies. They also revealed the frequent transmission of BanToV and limited but effective transmission of other viruses between ticks and camels. Furthermore, follow-up surveys on TBVs from tick, animal, and human samples with definite sampling relationships are suggested. The findings revealed substantial threats from the emerging TBVs and may guide the prevention and control of TBV-related zoonotic diseases in Kenya and in other African countries.

Bats are a likely reservoir of zoonotic coronaviruses (CoVs). Here, analyzing bat CoV sequences in China, the authors find that alpha-CoVs have switched hosts more frequently than betaCoVs, identify a bat family and genus that are highly involved in host-switching, and define hotspots of CoV evolutionary diversity.

ABSTRACTIn December 2019, a novel coronavirus (2019-nCoV) caused an outbreak in Wuhan, China, and soon spread to other parts of the world. It was believed that 2019-nCoV was transmitted through respiratory tract and then induced pneumonia, thus molecular diagnosis based on oral swabs was used for confirmation of this disease. Likewise, patient will be released upon two times of negative detection from oral swabs. However, many coronaviruses can also be transmitted through oral–fecal route by infecting intestines. Whether 2019-nCoV infected patients also carry virus in other organs like intestine need to be tested. We conducted investigation on patients in a local hospital who were infected with this virus. We found the presence of 2019-nCoV in anal swabs and blood as well, and more anal swab positives than oral swab positives in a later stage of infection, suggesting shedding and thereby transmitted through oral–fecal route. We also showed serology test can improve detection positive rate thus should be used in future epidemiology. Our report provides a cautionary warning that 2019-nCoV may be shed through multiple routes.

ABSTRACTDromedary camels are important reservoir hosts of various coronaviruses, including Middle East respiratory syndrome coronavirus (MERS-CoV) that cause human infections. CoV genomes regularly undergo recombination during infection as observed in bat SARS-related CoVs. Here we report for the first time that only a small proportion of MERS-CoV receptor-binding domain positive (RBD) of spike protein positive camel sera in Kenya were also seropositive to MERS-CoV nucleocapsid (NP). In contrast, many of them contain antibodies against bat HKU8-related (HKU8r)-CoVs. Among 584 camel samples that were positive against MERS-CoV RBD, we found only 0.48 (8.22%) samples were also positive for NP. Furthermore, we found bat HKU8r-CoV NP antibody in 73 (12.5%) of the MERS-CoV RBD positive and NP negative samples, yet found only 3 (0.43%) of the HKU8r-CoV S1 antibody in the same samples. These findings may indicate co-infection with MERS-CoV and a HKU8r-CoV in camels. It may also raise the possibility of the circulation of a recombinant coronavirus virus with the spike of MERS-CoV and the NP of a HKU8r-CoV in Kenya. We failed to find molecular evidence of an HKU8r-CoV or a putative recombinant virus. Our findings should alert other investigators to look for molecular evidence of HKU8r-CoV or recombinants.

Abstract Lanthipeptides have extensive therapeutic and industrial applications. However, because many are bactericidal, traditional in vivo platforms are limited in their capacity to discover and mass produce novel lanthipeptides as bacterial organisms are often critical components in these systems. Herein, the development of a cell‐free protein synthesis (CFPS) platform that enables rapid genome mining, screening, and guided overproduction of lanthipeptides in vivo is described. For proof‐of‐concept studies, a type I lanthipeptide, nisin, is selected. Four novel lanthipeptides with antibacterial activity are identified among all nisin analogs in the National Center for Biotechnology Information (NCBI) database in a single day. Further, the CFPS platform is coupled with a screening assay for anti‐gram‐negative bacteria growth, resulting in the identification of a potent nisin mutant, M5. The titers of nisin and the nisin analog are found to be improved with CFPS platform guidance. Owing to the similarities in biosynthesis, the CFPS platform is broadly applicable to other lanthipeptides, thereby providing a universal method for lanthipeptide discovery and overproduction.

The shuttling effect of polysulfides is one of the major problems of lithium–sulfur (Li–S) batteries, which causes rapid capacity fading during cycling. Modification of the commercial separator with a functional interlayer is an effective strategy to address this issue. Herein, we modified the commercial Celgard separator of Li–S batteries with one-dimensional (1D) covalent triazine framework (CTF) and a carbon nanotube (CNT) composite as a functional interlayer. The intertwined CTF/CNT can provide a fast lithium ionic/electronic transport pathway and strong adsorption capability towards polysulfides. The Li–S batteries with the CTF/CNT/Celgard separator delivered a high initial capacity of 1314 mAh g−1 at 0.1 C and remained at 684 mAh g−1 after 400 cycles−1 at 1 C. Theoretical calculation and static-adsorption experiments indicated that the triazine ring in the CTF skeleton possessed strong adsorption capability towards polysulfides. The work described here demonstrates the potential for CTF-based permselective membranes as separators in Li–S batteries.

The majority of emerging and reemerging zoonotic viral pathogens are RNA viruses. Pathogen discovery programs of emerging infectious diseases (EIDs) in wildlife have implicated rodents and shrews as hosts of diverse human pathogens, such as hantaviruses, arenaviruses, paramyxoviruses, etc. Despite these threats, little is known about the diversity of viruses circulating among rodents and shrews in Kenya, meaning the risk of infectious disease outbreak from these small mammals could be oblivious. This study reports the first surveillance toward understanding the diversity of RNA viruses carried by rodents and shrews in areas of high-potential contact with humans in Kenya through molecular detection. A total of 617 samples comprising fecal, urine, and tissues from 138 rodents and 5 shrews were screened for eight different families of viruses using RT-PCR assays. The results highlight the presence of diverse astroviruses, paramyxoviruses, hepeviruses, and arenavirus, circulating in both wild and synanthropic Kenyan rodents and shrews. Most of the viruses detected in this study are novel strains and some belong to the families that contain important human viral pathogens. Notably, a novel arenavirus was detected in Grammomys macmillani, a rodent species newly identified to harbor arenavirus, and it potentially represent a novel arenavirus species. Our findings demonstrate the need for continued pathogen surveillance among these small mammals as well as among the vulnerable and exposed livestock and humans. This would help in development and implementation of effective preventive and control strategies on EIDs in countries with rich wildlife biodiversity like Kenya.

Abstract Epidemiological parameters for livestock diseases are often inferred from transmission experiments. However, there are several limitations inherent to the design of such experiments that limits the precision of parameter estimates. In particular, infection times and latent periods cannot be directly observed and infectious periods may also be censored. We present a Bayesian framework accounting for these features directly and employ Markov chain Monte Carlo techniques to provide robust inferences and quantify the uncertainty in our estimates. We describe the transmission dynamics using a susceptible-exposed-infectious-removed compartmental model, with gamma-distributed transition times. We then fit the model to published data from transmission experiments for foot-and-mouth disease virus (FMDV) and African swine fever virus (ASFV). Where the previous analyses of these data made various assumptions on the unobserved processes in order to draw inferences, our Bayesian approach includes the unobserved infection times and latent periods and quantifies them along with all other model parameters. Drawing inferences about infection times helps identify who infected whom and can also provide insights into transmission mechanisms. Furthermore, we are able to use our models to measure the difference between the latent periods of inoculated and contact-challenged animals and to quantify the effect vaccination has on transmission.

Bats have been identified as natural reservoirs of a variety of coronaviruses. They harbor at least 19 of the 33 defined species of alpha- and betacoronaviruses. Previously, the bat coronavirus HKU10 was found in two bat species of different suborders, Rousettus leschenaultia and Hipposideros pomona, in south China. However, its geographic distribution and evolution history are not fully investigated. Here, we screened this viral species by a nested reverse transcriptase PCR in our archived samples collected over 10 years from 25 provinces of China and one province of Laos. From 8004 bat fecal samples, 26 were found to be positive for bat coronavirus HKU10 (BtCoV HKU10). New habitats of BtCoV HKU10 were found in the Yunnan, Guangxi, and Hainan Provinces of China, and Louang Namtha Province in Laos. In addition to H. pomona, BtCoV HKU10 variants were found circulating in Aselliscus stoliczkanus and Hipposideros larvatus. We sequenced full-length genomes of 17 newly discovered BtCoV HKU10 strains and compared them with previously published sequences. Our results revealed a much higher genetic diversity of BtCoV HKU10, particularly in spike genes and accessory genes. Besides the two previously reported lineages, we found six novel lineages in their new habitats, three of which were located in Yunnan province. The genotypes of these viruses are closely related to sampling locations based on polyproteins, and correlated to bat species based on spike genes. Combining phylogenetic analysis, selective pressure, and molecular-clock calculation, we demonstrated that Yunnan bats harbor a gene pool of BtCoV HKU10, with H. pomona as a natural reservoir. The cell tropism test using spike-pseudotyped lentivirus system showed that BtCoV HKU10 could enter cells from human and bat, suggesting a potential interspecies spillover. Continuous studies on these bat coronaviruses will expand our understanding of the evolution and genetic diversity of coronaviruses, and provide a prewarning of potential zoonotic diseases from bats.

This study was aimed to screen the effective xanthine oxidase (XO) inhibitors in dietary anthocyanins from purple sweet potato and decipher the underlying mechanisms in vitro. Inhibition kinetics demonstrated that anthocyanin-rich purple sweet potato extract (APSPE) has reversible and mixed inhibitory effect on XO. Among the four fractions purified from APSPE, the fraction with highly-acylated anthocyanins showed the most powerful inhibition on XO. Molecular docking results suggested that the inhibition mechanism is the insertion of anthocyanins into the hydrophobic pocket of XO by interacting with some amino acid residues. Fluorescence and CD spectroscopy results showed that the formation of anthocyanin-XO complex is the possible quenching mechanism, which changes the secondary structure of XO. The reaction is entropy-driven and endothermic, with hydrophobic interaction being the major driving force. This study indicates that the highly-acylated dietary anthocyanins of purple sweet potato would be a promising XO inhibitor in clinical treatment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Bats, the second largest order of mammals worldwide, harbor specific characteristics such as sustaining flight, a special immune system, unique habits, and ecological niches. In addition, they are the natural reservoirs of a variety of emerging or re-emerging zoonotic pathogens. Rhabdoviridae is one of the most diverse families of RNA viruses, which consists of 20 ecologically diverse genera, infecting plants, mammals, birds, reptiles, and fish. To date, three bat-related genera are described, named Lyssavirus, Vesiculovirus, and Ledantevirus. However, the prevalence and the distribution of these bat-related rhabdoviruses remain largely unknown, especially in China. To fill this gap, we performed a large molecular retrospective study based on the real-time reverse transcription polymerase chain reaction (RT-qPCR) detection of lyssavirus in bat samples (1044 brain and 3532 saliva samples, from 63 different bat species) originating from 21 provinces of China during 2006–2018. None of them were positive for lyssavirus, but six bat brains (0.6%) of Rhinolophus bat species, originating from Hubei and Hainan provinces, were positive for vesiculoviruses or ledanteviruses. Based on complete genomes, these viruses were phylogenetically classified into three putative new species, tentatively named Yinshui bat virus (YSBV), Taiyi bat virus (TYBV), and Qiongzhong bat virus (QZBV). These results indicate the novel rhabdoviruses circulated in different Chinese bat populations.

Nanogel-based nanoplatforms have become a tremendously promising system of drug delivery. Nanogels constructed by chemical crosslinking or physical self-assembly exhibit the ability to encapsulate hydrophilic or hydrophobic therapeutics, including but not limited to small-molecule compounds and proteins, DNA/RNA sequences, and even ultrasmall nanoparticles, within their 3D polymer network. The nanosized nature of the carriers endows them with a specific surface area and inner space, increasing the stability of loaded drugs and prolonging their circulation time. Reactions or the cleavage of chemical bonds in the structure of drug-loaded nanogels have been shown to trigger the controlled or sustained drug release. Through the design of specific chemical structures and different methods of production, nanogels can realize diverse responsiveness (temperature-sensitive, pH-sensitive and redox-sensitive), and enable the stimuli-responsive release of drugs in the microenvironments of various diseases. To improve therapeutic outcomes and increase the precision of therapy, nanogels can be modified by specific ligands to achieve active targeting and enhance the drug accumulation in disease sites. Moreover, the biomembrane-camouflaged nanogels exhibit additional intelligent targeted delivery features. Consequently, the targeted delivery of therapeutic agents, as well as the combinational therapy strategy, result in the improved efficacy of disease treatments, though the introduction of a multifunctional nanogel-based drug delivery system.

A large number of SARS-related coronaviruses (SARSr-CoV) have been detected in horseshoe bats since 2005 in different areas of China. However, these bat SARSr-CoVs show sequence differences from SARS coronavirus (SARS-CoV) in different genes (S, ORF8, ORF3, etc) and are considered unlikely to represent the direct progenitor of SARS-CoV. Herein, we report the findings of our 5-year surveillance of SARSr-CoVs in a cave inhabited by multiple species of horseshoe bats in Yunnan Province, China. The full-length genomes of 11 newly discovered SARSr-CoV strains, together with our previous findings, reveals that the SARSr-CoVs circulating in this single location are highly diverse in the S gene, ORF3 and ORF8. Importantly, strains with high genetic similarity to SARS-CoV in the hypervariable N-terminal domain (NTD) and receptor-binding domain (RBD) of the S1 gene, the ORF3 and ORF8 region, respectively, were all discovered in this cave. In addition, we report the first discovery of bat SARSr-CoVs highly similar to human SARS-CoV in ORF3b and in the split ORF8a and 8b. Moreover, SARSr-CoV strains from this cave were more closely related to SARS-CoV in the non-structural protein genes ORF1a and 1b compared with those detected elsewhere. Recombination analysis shows evidence of frequent recombination events within the S gene and around the ORF8 between these SARSr-CoVs. We hypothesize that the direct progenitor of SARS-CoV may have originated after sequential recombination events between the precursors of these SARSr-CoVs. Cell entry studies demonstrated that three newly identified SARSr-CoVs with different S protein sequences are all able to use human ACE2 as the receptor, further exhibiting the close relationship between strains in this cave and SARS-CoV. This work provides new insights into the origin and evolution of SARS-CoV and highlights the necessity of preparedness for future emergence of SARS-like diseases.

Bats have been identified as a natural reservoir of a variety of coronaviruses (CoVs). Several of them have caused diseases in humans and domestic animals by interspecies transmission. Considering the diversity of bat coronaviruses, bat species and populations, we expect to discover more bat CoVs through virus surveillance. In this study, we described a new member of alphaCoV (BtCoV/Rh/YN2012) in bats with unique genome features. Unique accessory genes, ORF4a and ORF4b were found between the spike gene and the envelope gene, while ORF8 gene was found downstream of the nucleocapsid gene. All the putative genes were further confirmed by reverse-transcription analyses. One unique gene at the 3’ end of the BtCoV/Rh/YN2012 genome, ORF9, exhibits ~30% amino acid identity to ORF7a of the SARS-related coronavirus. Functional analysis showed ORF4a protein can activate IFN-β production, whereas ORF3a can regulate NF-κB production. We also screened the spike-mediated virus entry using the spike-pseudotyped retroviruses system, although failed to find any fully permissive cells. Our results expand the knowledge on the genetic diversity of bat coronaviruses. Continuous screening of bat viruses will help us further understand the important role played by bats in coronavirus evolution and transmission.

Detection of triphenylmethane dyes (TDs), especially the widely used malachite green (MG) and crystal violet (CV), plays an important role in safety control of aquatic products. There are two chromatic forms of TDs: oxidized or reduced. Usually, only one form can be detected by reported ELISA antibodies. In this article, molecular shape superimposing and quantum mechanics calculation were employed to elucidate the differences between MG, CV, and their reduced chromatic forms (leucomalachite green, LMG and leucocrystal violet, LCV). A potential hapten was rationally designed and synthesized. Polyclonal antibodies were raised through immunizing New Zealand white rabbits and BALB/C mice. We tested the cross-reactivity ratios between the hapten and TDs. The cross-reactivity ratios were correlated with the difference in surface electrostatic potential. The determination coefficients (r2) of the correlations are 0.901 and 0.813 for the rabbit and mouse antibody, respectively. According to this linear model, the significant difference in the atomic charge seemed to make it impossible to find a hapten that can produce antibodies with good cross-reactivities with both reduced and oxidized TDs.

The crystallized ligands in the Protein Data Bank (PDB) can be treated as the inverse shapes of the active sites of corresponding proteins. Therefore, the shape similarity between a molecule and PDB ligands indicated the possibility of the molecule to bind with the targets. In this paper, we proposed a shape similarity profile that can be used as a molecular descriptor for ligand-based virtual screening. First, through three-dimensional (3D) structural clustering, 300 diverse ligands were extracted from the druggable protein–ligand database, sc-PDB. Then, each of the molecules under scrutiny was flexibly superimposed onto the 300 ligands. Superimpositions were scored by shape overlap and property similarity, producing a 300 dimensional similarity array termed the “Three-Dimensional Biologically Relevant Spectrum (BRS-3D)”. Finally, quantitative or discriminant models were developed with the 300 dimensional descriptor using machine learning methods (support vector machine). The effectiveness of this approach was evaluated using 42 benchmark data sets from the G protein-coupled receptor (GPCR) ligand library and the GPCR decoy database (GLL/GDD). We compared the performance of BRS-3D with other 2D and 3D state-of-the-art molecular descriptors. The results showed that models built with BRS-3D performed best for most GLL/GDD data sets. We also applied BRS-3D in histone deacetylase 1 inhibitors screening and GPCR subtype selectivity prediction. The advantages and disadvantages of this approach are discussed.