CD39hi identifies an exhausted tumor-reactive CD8+ T cell population associated with tumor progression in human gastric cancer.

The ectonucleotidase CD39 has been regarded as a promising immune checkpoint in solid tumors. However, the expression of CD39 by tumor-infiltrating CD8+ T cells as well as their potential roles and clinical implications in human gastric cancer (GC) remain largely unknown. Here, we found that GC-infiltrating CD8+ T cells contained a fraction of CD39hi cells that constituted about 6.6% of total CD8+ T cells in tumors. These CD39hi cells enriched for GC-infiltrating CD8+ T cells with features of exhaustion in transcriptional, phenotypic, metabolic and functional profiles. Additionally, GC-infiltrating CD39hiCD8+ T cells were also identified for tumor-reactive T cells, as these cells expanded in vitro were able to recognize autologous tumor organoids and induced more tumor cell apoptosis than those of expanded their CD39int and CD39-CD8+ counterparts. Furthermore, CD39 enzymatic activity controlled GC-infiltrating CD39hiCD8+ T cell effector function, and blockade of CD39 efficiently enhanced their production of cytokines IFN-γ and TNF-α. Finally, high percentages of GC-infiltrating CD39hiCD8+ T cells correlated with tumor progression and independently predicted patients' poor overall survival. These findings provide novel insights into the association of CD39 expression level on CD8+ T cells with their features and potential clinical implications in GC, and empowering those exhausted tumor-reactive CD39hiCD8+ T cells through CD39 inhibition to circumvent the suppressor program may be an attractive therapeutic strategy against GC.

Modelling the impact of human behavior using a two-layer Watts-Strogatz network for transmission and control of Mpox.

PURPOSE: This study aims to evaluate the effectiveness of mitigation strategies and analyze the impact of human behavior on the transmission of Mpox. The results can provide guidance to public health authorities on comprehensive prevention and control for the new Mpox virus strain in the Democratic Republic of Congo as of December 2023. METHODS: We develop a two-layer Watts-Strogatz network model. The basic reproduction number is calculated using the next-generation matrix approach. Markov chain Monte Carlo (MCMC) optimization algorithm is used to fit Mpox cases in Canada into the network model. Numerical simulations are used to assess the impact of mitigation strategies and human behavior on the final epidemic size. RESULTS: Our results show that the contact transmission rate of low-risk groups and susceptible humans increases when the contact transmission rate of high-risk groups and susceptible humans is controlled as the Mpox epidemic spreads. The contact transmission rate of high-risk groups after May 18, 2022, is approximately 20% lower than that before May 18, 2022. Our findings indicate a positive correlation between the basic reproduction number and the level of heterogeneity in human contacts, with the basic reproduction number estimated at 2.3475 (95% CI: 0.0749-6.9084). Reducing the average number of sexual contacts to two per week effectively reduces the reproduction number to below one. CONCLUSION: We need to pay attention to the re-emergence of the epidemics caused by low-risk groups when an outbreak dominated by high-risk groups is under control. Numerical simulations show that reducing the average number of sexual contacts to two per week is effective in slowing down the rapid spread of the epidemic. Our findings offer guidance for the public health authorities of the Democratic Republic of Congo in developing effective mitigation strategies.

Pelvic floor muscle strength and influencing factors based on vaginal manometry among healthy women at different life stages: A multicentre cross-sectional study.

OBJECTIVE: To assess pelvic floor muscle (PFM) strength and influencing factors among healthy women at different life stages. DESIGN: Multicentre cross-sectional study. SETTING: Fourteen hospitals in China. POPULATION: A total of 5040 healthy women allocated to the following groups (with 1680 women per group): premenopausal nulliparous, premenopausal parous and postmenopausal. METHODS: The PFM strength was evaluated by vaginal manometry. Multivariate logistic regression was used to determine the influencing factors for low PFM strength. MAIN OUTCOME MEASURES: Maximum voluntary contraction pressure (MVCP). RESULTS: The median MVCP values were 36, 35 and 35 cmH2O in premenopausal nulliparous (aged 19-51 years), premenopausal parous (aged 22-61 years), and postmenopausal (aged 40-86 years) women, respectively. In the premenopausal nulliparous group, physical work (odds ratio, OR 2.05) was the risk factor for low PFM strength, which may be related to the chronic increased abdominal pressure caused by physical work. In the premenopausal parous group, the number of vaginal deliveries (OR 1.28) and diabetes (OR 2.70) were risk factors for low PFM strength, whereas sexual intercourse (<2 times per week vs. none, OR 0.55; ≥2 times per week vs. none, OR 0.56) and PFM exercise (OR 0.50) may have protective effects. In the postmenopausal group, the number of vaginal deliveries (OR 1.32) and family history of pelvic organ prolapse (POP) (OR 1.83) were risk factors for low PFM strength. CONCLUSIONS: Physical work, vaginal delivery, diabetes and a family history of POP are all risk factors for low PFM strength, whereas PFM exercises and sexual life can have a protective effect. The importance of these factors varies at different stages of a woman's life.

Exendin-4 alleviates myocardial ischemia reperfusion injury by enhancing autophagy through promoting nuclear translocation of TFEB.

Ischemia-reperfusion (I/R) injury (IRI) is a common clinical consequence of myocardial infarction. Exendin-4 is a glucagon-like peptide-1 (GLP-1) analog that has been demonstrated to alleviate myocardial IRI. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in myocardial IRI. However, whether exendin-4 exerts a protective effect on myocardial IRI by modulating autophagy remains elusive. Herein, we investigated the effect of exendin-4 on autophagic flux and explored the underlying molecular mechanisms. Our data revealed that the autophagic flux was blocked in the human ventricular cardiomyocyte cell lines (AC16) subjected to oxygen glucose deprivation/reoxygenation (OGD/R) in vitro. Exendin-4 pre-treatment markedly restored the blocked autophagic flux induced by OGD/R through promoting nuclear translocation of TFEB and transcription of genes involving autophagy initiation, the effect of which was reversed by TFEB knockdown. The restoration of autophagic flux contributed to multiple beneficial effects of exendin-4 in cardiomyocytes, including reduction of oxidative stress, preservation of mitochondrial network as well as inhibition of cytochrome c leakage from mitochondrial permeability transition pore (MPTP) and the resulting apoptosis. Moreover, the administration of exendin-4 reduced infarct size and preserved cardiac function through its anti-apoptosis and antioxidative effects in vivo. These results shed some light on understanding the novel mechanism of exendin-4 as a protective agent against myocardial IRI.

The Effectiveness and Safety of Intrapartum or Postpartum Catheterization in the Prevention of Postpartum Urinary Retention: A Scoping Review.

INTRODUCTION AND HYPOTHESIS: Catheterization is a common treatment for postpartum urinary retention (PUR); however, its application before diagnosis of PUR remains unclear. The aim was to give an overview of the existing literature on the effectiveness and safety of intrapartum or postpartum catheterization in the prevention of PUR. METHODS: This scoping review followed a methodological framework. PubMed, the Cochrane Library, Embase, Web of Science, the China National Knowledge Infrastructure, WanFang, the China Science and Technology Journal Database, and the China Biomedical Literature Database were searched from the inception of each database to 21 May 2023. RESULTS: The search revealed 16 studies examining three different catheterization methodologies, including 12 intrapartum studies. Ten studies concluded that intrapartum or postpartum catheterization prevented PUR, two of which were only for overt or covert PUR. In 4 out of 13 experimental studies, no significant difference was found: one for intrapartum catheterization versus routine nursing, the other for intrapartum or postpartum intermittent versus indwelling catheterization. However, one found that postpartum disposable catheterization after ineffective targeted care reduced the incidence of PUR compared with indwelling catheterization. One out of the 3 case-control studies concluded that prenatal catheterization ≥2 times was a risk factor for PUR. CONCLUSIONS: Based on the findings in this scoping review, catheterization prior to the diagnosis of PUR appears to play a role in preventing PUR and is safe. Preliminary evidence is accumulating on the effectiveness of three types of catheterization methods in preventing PUR, but more comprehensive studies are needed to establish these findings.

Risk factor analysis and risk prediction study of obesity in steelworkers: model development based on an occupational health examination cohort dataset.

BACKGROUND: Obesity is increasingly recognized as a grave public health concern globally. It is associated with prevalent diseases including coronary heart disease, fatty liver, type 2 diabetes, and dyslipidemia. Prior research has identified demographic, socioeconomic, lifestyle, and genetic factors as contributors to obesity. Nevertheless, the influence of occupational risk factors on obesity among workers remains under-explored. Investigating risk factors specific to steelworkers is crucial for early detection, prediction, and effective intervention, thereby safeguarding their health. METHODS: This research utilized a cohort study examining health impacts on workers in an iron and steel company in Hebei Province, China. The study involved 5469 participants. By univariate analysis, multifactor analysis, and review of relevant literature, predictor variables were found. Three predictive models-XG Boost, Support Vector Machine (SVM), and Random Forest (RF)-were employed. RESULTS: Univariate analysis and cox proportional hazard regression modeling identified age, gender, smoking and drinking habits, dietary score, physical activity, shift work, exposure to high temperatures, occupational stress, and carbon monoxide exposure as key factors in the development of obesity in steelworkers. Test results indicated accuracies of 0.819, 0.868, and 0.872 for XG Boost, SVM, and RF respectively. Precision rates were 0.571, 0.696, and 0.765, while recall rates were 0.333, 0.592, and 0.481. The models achieved AUCs of 0.849, 0.908, and 0.912, with Brier scores of 0.128, 0.105, and 0.104, log losses of 0.409, 0.349, and 0.345, and calibration-in-the-large of 0.058, 0.054, and 0.051, respectively. Among these, the Random Forest model demonstrated superior performance. CONCLUSIONS: The research indicates that obesity in steelworkers results from a combination of occupational and lifestyle factors. Of the models tested, the Random Forest model exhibited superior predictive ability, highlighting its significant practical application.

Global analysis of an age-structured tuberculosis model with an application to Jiangsu, China.

Diagnostic delay for TB infected individuals and the lack of TB vaccines for adults are the main challenges to achieve the goals of WHO by 2050. In order to evaluate the impacts of diagnostic delay and vaccination for adults on prevalence of TB, we propose an age-structured model with latent age and infection age, and we incorporate Mycobacterium TB in the environment and vaccination into the model. Diagnostic delay is indicated by the age of infection before receiving treatment. The threshold dynamics are established in terms of the basic reproduction number R 0 . When R 0 < 1 , the disease-free equilibrium is globally asymptotically stable, which means that TB epidemic will die out; When R 0 = 1 , the disease-free equilibrium is globally attractive; there exists a unique endemic equilibrium and the endemic equilibrium is globally attractive when R 0 > 1 . We estimate that the basic reproduction number R 0 = 0.5320 (95% CI (0.3060, 0.7556)) in Jiangsu Province, which means that TB epidemic will die out. However, we find that the annual number of new TB cases by 2050 is 1,151 (95%CI: (138, 8,014)), which means that it is challenging to achieve the goal of WHO by 2050. To this end, we evaluate the possibility of achieving the goals of WHO if we start vaccinating adults and reduce diagnostic delay in 2025. Our results demonstrate that when the diagnostic delay is reduced from longer than four months to four months, or 20% adults are vaccinated, the goal of WHO in 2050 can be achieved, and 73,137 (95%CI: (23,906, 234,086)) and 54,828 (95%CI: (15,811, 206,468)) individuals will be prevented from being infected from 2025 to 2050, respectively. The modeling approaches and simulation results used in this work can help policymakers design control measures to reduce the prevalence of TB.

Commonality and diversity in tRNA substrate recognition in t6A biogenesis by eukaryotic KEOPSs.

N 6-Threonylcarbamoyladenosine (t6A) is a universal and pivotal tRNA modification. KEOPS in eukaryotes participates in its biogenesis, whose mutations are connected with Galloway-Mowat syndrome. However, the tRNA substrate selection mechanism by KEOPS and t6A modification function in mammalian cells remain unclear. Here, we confirmed that all ANN-decoding human cytoplasmic tRNAs harbor a t6A moiety. Using t6A modification systems from various eukaryotes, we proposed the possible coevolution of position 33 of initiator tRNAMet and modification enzymes. The role of the universal CCA end in t6A biogenesis varied among species. However, all KEOPSs critically depended on C32 and two base pairs in the D-stem. Knockdown of the catalytic subunit OSGEP in HEK293T cells had no effect on the steady-state abundance of cytoplasmic tRNAs but selectively inhibited tRNAIle aminoacylation. Combined with in vitro aminoacylation assays, we revealed that t6A functions as a tRNAIle isoacceptor-specific positive determinant for human cytoplasmic isoleucyl-tRNA synthetase (IARS1). t6A deficiency had divergent effects on decoding efficiency at ANN codons and promoted +1 frameshifting. Altogether, our results shed light on the tRNA recognition mechanism, revealing both commonality and diversity in substrate recognition by eukaryotic KEOPSs, and elucidated the critical role of t6A in tRNAIle aminoacylation and codon decoding in human cells.

RNA granule-clustered mitochondrial aminoacyl-tRNA synthetases form multiple complexes with the potential to fine-tune tRNA aminoacylation.

Mitochondrial RNA metabolism is suggested to occur in identified compartmentalized foci, i.e. mitochondrial RNA granules (MRGs). Mitochondrial aminoacyl-tRNA synthetases (mito aaRSs) catalyze tRNA charging and are key components in mitochondrial gene expression. Mutations of mito aaRSs are associated with various human disorders. However, the suborganelle distribution, interaction network and regulatory mechanism of mito aaRSs remain largely unknown. Here, we found that all mito aaRSs partly colocalize with MRG, and this colocalization is likely facilitated by tRNA-binding capacity. A fraction of human mitochondrial AlaRS (hmtAlaRS) and hmtSerRS formed a direct complex via interaction between catalytic domains in vivo. Aminoacylation activities of both hmtAlaRS and hmtSerRS were fine-tuned upon complex formation in vitro. We further established a full spectrum of interaction networks via immunoprecipitation and mass spectrometry for all mito aaRSs and discovered interactions between hmtSerRS and hmtAsnRS, between hmtSerRS and hmtTyrRS and between hmtThrRS and hmtArgRS. The activity of hmtTyrRS was also influenced by the presence of hmtSerRS. Notably, hmtSerRS utilized the same catalytic domain in mediating several interactions. Altogether, our results systematically analyzed the suborganelle localization and interaction network of mito aaRSs and discovered several mito aaRS-containing complexes, deepening our understanding of the functional and regulatory mechanisms of mito aaRSs.

Molecular basis for human mitochondrial tRNA m3C modification by alternatively spliced METTL8.

METTL8 has recently been identified as the methyltransferase catalyzing 3-methylcytidine biogenesis at position 32 (m3C32) of mitochondrial tRNAs. METTL8 also potentially participates in mRNA methylation and R-loop biogenesis. How METTL8 plays multiple roles in distinct cell compartments and catalyzes mitochondrial tRNA m3C formation remain unclear. Here, we discovered that alternative mRNA splicing generated several isoforms of METTL8. One isoform (METTL8-Iso1) was targeted to mitochondria via an N-terminal pre-sequence, while another one (METTL8-Iso4) mainly localized to the nucleolus. METTL8-Iso1-mediated m3C32 modification of human mitochondrial tRNAThr (hmtRNAThr) was not reliant on t6A modification at A37 (t6A37), while that of hmtRNASer(UCN) critically depended on i6A modification at A37 (i6A37). We clarified the hmtRNAThr substrate recognition mechanism, which was obviously different from that of hmtRNASer(UCN), in terms of requiring a G35 determinant. Moreover, SARS2 (mitochondrial seryl-tRNA synthetase) interacted with METTL8-Iso1 in an RNA-independent manner and modestly accelerated m3C modification activity. We further elucidated how nonsubstrate tRNAs in human mitochondria were efficiently discriminated by METTL8-Iso1. In summary, our results established the expression pattern of METTL8, clarified the molecular basis for m3C32 modification by METTL8-Iso1 and provided the rationale for the involvement of METTL8 in tRNA modification, mRNA methylation or R-loop biogenesis.

The complete mitochondrial genome of cattle tick clade C reveals the genetic relationship within Rhipicephalus microplus complex.

Cattle ticks (Rhipicephalus microplus) are important economic ectoparasites causing direct and indirect damage to cattle and leading to severe economic losses in cattle husbandry. It is common knowledge that R. microplus is a species complex including five clades; however, the relationships within the R. microplus complex remain unresolved. In the present study, we assembled the complete mitochondrial genome of clade C by next-generation sequencing and proved its correctness based on long PCR amplification. It was 15,004 bp in length and consisted of 13 protein genes, 22 transfer genes, and two ribosomal genes located in the two strains. There were two copies of the repeat region (pseudo-nad1 and tRNA-Glu). Data revealed that cox1, cox2, and cox3 genes were conserved within R. microplus with small genetic differences. Ka/Ks ratios suggested that 12 protein genes (excluding nad6) may be neutral selection. The genetic and phylogenetic analyses indicated that clade C was greatly close to clade B. Findings in the current study provided more data for the identification and differentiation of the R. microplus complex and made up for the lack of information about R. microplus clade C.

Exploring the seasonality and optimal control strategy of HIV/AIDS epidemic in China: The impact of seasonal testing.

In this work, we investigate how the seasonal variation in the number of individuals who are tested for an HIV antibody in outpatient clinics affects the HIV transmission patterns in China, which has not been well studied. Based on the characteristics of outpatient testing data and reported cases, we establish a periodic infectious disease model to study the impact of seasonal testing on HIV transmission. The results indicate that the seasonal testing is a driving factor for the seasonality of new cases. We demonstrate the feasibility of ending the HIV/AIDS epidemic. We find that the diagnostic rates related to testing play a crucial role in controlling the size of the epidemic. Specifically, when considering minimizing both infected individuals and diagnostic rates, the level of attention paid to undiagnosed infected individuals is always positively correlated with the optimal diagnostic rates, while the optimal diagnostic rates are negatively correlated with the size of the epidemic at the terminal time.

A new coumarin and a new flavonoid from Ochrocarpus longifolius.

A new coumarin (1) and a new flavonoid (2) were isolated from the air-dried flower buds of Ochrocarpus longifolius, together with ten known compounds (3-12). The structures of two new compounds were established by 1D and 2D NMR and MS data. In addition, the new compound 2 showed significant proliferation inhibitory activity on Eca-109 and MGC-803 cells. The results of this study may enrich the diversity of compounds from O. longifolius and provide a basis for further research on its natural products and pharmacological activities.

Facile Fabrication of Hollow Nanoporous Carbon Architectures by Controlling MOF Crystalline Inhomogeneity for Ultra-Stable Na-Ion Storage.

Hollow nanoporous carbon architectures (HNCs) present significant utilitarian value for a wide variety of applications. Facile and efficient preparation of HNCs has long been pursued but still remains challenging. Herein, we for the first time demonstrate that single-component metal-organic frameworks (MOFs) crystals, rather than the widely reported hybrid ones which necessitate tedious operations for preparation, could enable the facile and versatile syntheses of functional HNCs. By controlling the growth kinetics, the MOFs crystals (STU-1) are readily engineered into different shapes with designated styles of crystalline inhomogeneity. A subsequent one-step pyrolysis of these MOFs with intraparticle difference can induce a simultaneous self-hollowing and carbonization process, thereby producing various functional HNCs including yolk-shell polyhedrons, hollow microspheres, mesoporous architectures, and superstructures. Superior to the existing methods, this synthetic strategy relies only on the complex nature of single-component MOFs crystals without involving tedious operations like coating, etching, or ligand exchange, making it convenient, efficient, and easy to scale up. An ultra-stable Na-ion battery anode is demonstrated by the HNCs with extraordinary cyclability (93 % capacity retention over 8000 cycles), highlighting a high level of functionality of the HNCs.

Multiple Accessible Redox-Active Sites in a Robust Covalent Organic Framework for High-Performance Potassium Storage.

Covalent organic framework (COF) materials with porous character and robust structure have significant applied implications for K-ion battery (KIB) anodes, but they are limited by the low reversible capacity and inferior rate capability. Here, based on theoretical calculations, we identified that a porous bulk COF featuring numerous pyrazines and carbonyls in the π-conjugated periodic skeleton could provide multiple accessible redox-active sites for high-performance potassium storage. Its porous structure with a surface-dominated storage mechanism enabled the fast and stable storage of K-ions. Its insolubility in organic electrolytes and small volumetric change after potassiation ensured a robust electrode for stable cycling. As a KIB anode, this bulk COF demonstrated an unprecedentedly outstanding combination of reversible capacity (423 mAh g-1 at 0.1 C), rate capability (185 mAh g-1 at 10 C), and cyclability. The theoretical simulation and comprehensive characterizations confirmed the active sites are contributed by C═O, C═N, and the cation-π effect.

Activation of the Chemokine Receptor CCR1 and Preferential Recruitment of Gαi Suppress RSV Replication: Implications for Developing Novel Respiratory Syncytial Virus Treatment Strategies.

Respiratory syncytial virus (RSV) is a major pathogen that can cause acute respiratory infectious diseases of the upper and lower respiratory tract, especially in children, elderly individuals, and immunocompromised people. Generally, following viral infection, respiratory epithelial cells secrete cytokines and chemokines to recruit immune cells and initiate innate and/or adaptive immune responses. However, whether chemokines affect viral replication in nonimmune cells is rarely clear. In this study, we detected that chemokine CCL5 was highly expressed, while expression of its receptor, CCR1, was downregulated in respiratory epithelial cells after RSV infection. When we overexpressed CCR1 on respiratory epithelial cells in vivo or in vitro, viral load was significantly suppressed, which can be restored by the neutralizing antibody for CCR1. Interestingly, the antiviral effect of CCR1 was not related to type I interferon (IFN-I), apoptosis induction, or viral adhesion or entry inhibition. In contrast, it was related to the preferential recruitment and activation of the adaptor Gαi, which promoted inositol 1,4,5-triphosphate receptor type 3 (ITPR3) expression, leading to inhibited STAT3 phosphorylation; explicitly, phosphorylated STAT3 (p-STAT3) was verified to be among the important factors regulating the activity of HSP90, which has been previously reported to be a chaperone of RSV RNA polymerase. In summary, we are the first to reveal that CCR1 on the surface of nonimmune cells regulates RSV replication through a previously unknown mechanism that does not involve IFN-I induction. IMPORTANCE Our results revealed a novel mechanism by which RSV escapes innate immunity. That is, although it induces high CCL5 expression, RSV might attenuate the binding of CCL5 by downregulating the expression of CCR1 in respiratory epithelial cells to weaken the inhibitory effect of CCR1 on HSP90 activity and thereby facilitate RSV replication in nonimmune cells. This study provides a new target for the development of co-antiviral inhibitors against other components of the host and co-molecular chaperone/HSP90 and provides a scientific basis for the search for effective broad-spectrum antiviral drugs.

Efficient modulation of cellular phosphorus components in response to phosphorus deficiency in the dinoflagellate Karenia mikimotoi.

IMPORTANCE: Dinoflagellates are the most common phytoplankton group and account for more than 75% of harmful algal blooms in coastal waters. In recent decades, dinoflagellates seem to prevail in phosphate-depleted waters. However, the underlying acclimation mechanisms and competitive strategies of dinoflagellates in response to phosphorus deficiency are poorly understood, especially in terms of intracellular phosphorus modulation and recycling. Here, we focused on the response of intracellular phosphorus metabolism to phosphorus deficiency in the model dinoflagellate Karenia mikimotoi. Our work reveals the strong capability of K. mikimotoi to efficiently regulate intracellular phosphorus resources, particularly through membrane phospholipid remodeling and miRNA regulation of energy metabolism. Our research improved the understanding of intracellular phosphorus metabolism in marine phytoplankton and underscored the advantageous strategies of dinoflagellates in the efficient modulation of internal phosphorus resources to maintain active physiological activity and growth under unsuitable phosphorus conditions, which help them outcompete other species in coastal phosphate-depleted environments.

Protective role for C3aR in experimental chronic pyelonephritis.

Emerging evidence suggest that C3aR plays important roles in homeostasis, host defense and disease. Although it is known that C3aR is protective in several models of acute bacterial infections, the role for C3aR in chronic infection is largely unknown. Here we show that C3aR is protective in experimental chronic pyelonephritis. Global C3aR deficient (C3ar-/- ) mice had higher renal bacterial load, more pronounced renal histological lesions, increased renal apoptotic cell accumulation, tissue inflammation and extracellular matrix deposition following renal infection with uropathogenic E. coli (UPEC) strain IH11128, compared to WT control mice. Myeloid C3aR deficient (Lyz2-C3ar-/- ) mice exhibited a similar disease phenotype to global C3ar-/- mice. Pharmacological treatment with a C3aR agonist reduced disease severity in experimental chronic pyelonephritis. Furthermore, macrophages of C3ar-/- mice exhibited impaired ability to phagocytose UPEC. Our data clearly demonstrate a protective role for C3aR against experimental chronic pyelonephritis, macrophage C3aR plays a major role in the protection, and C3aR is necessary for phagocytosis of UPEC by macrophages. Our observation that C3aR agonist curtailed the pathology suggests a therapeutic potential for activation of C3aR in chronic infection.

Vaccine hesitancy promotes emergence of new SARS-CoV-2 variants.

The successive emergence of SARS-CoV-2 mutations has led to an unprecedented increase in COVID-19 incidence worldwide. Currently, vaccination is considered to be the best available solution to control the ongoing COVID-19 pandemic. However, public opposition to vaccination persists in many countries, which can lead to increased COVID-19 caseloads and hence greater opportunities for vaccine-evasive mutant strains to arise. To determine the extent that public opinion regarding vaccination can induce or hamper the emergence of new variants, we develop a model that couples a compartmental disease transmission framework featuring two strains of SARS-CoV-2 with game theoretical dynamics on whether or not to vaccinate. We combine semi-stochastic and deterministic simulations to explore the effect of mutation probability, perceived cost of receiving vaccines, and perceived risks of infection on the emergence and spread of mutant SARS-CoV-2 strains. We find that decreasing the perceived costs of being vaccinated and increasing the perceived risks of infection (that is, decreasing vaccine hesitation) will decrease the possibility of vaccine-resistant mutant strains becoming established by about fourfold for intermediate mutation rates. Conversely, we find increasing vaccine hesitation to cause both higher probability of mutant strains emerging and more wild-type cases after the mutant strain has appeared. We also find that once a new variant has emerged, perceived risk of being infected by the original variant plays a much larger role than perceptions of the new variant in determining future outbreak characteristics. Furthermore, we find that rapid vaccination under non-pharmaceutical interventions is a highly effective strategy for preventing new variant emergence, due to interaction effects between non-pharmaceutical interventions and public support for vaccination. Our findings indicate that policies that combine combating vaccine-related misinformation with non-pharmaceutical interventions (such as reducing social contact) will be the most effective for avoiding the establishment of harmful new variants.

Transmission risk assessment of HIV/AIDS epidemic resulting from sexual transmission in China, 2013-2017.

To estimate the risk of human immunodeficiency virus (HIV) infection through sexual transmission in China from 2013 to 2017 accurately, we divide the total population into three groups, namely, men who have sex with men (MSM) group; non-marital and commercial sex group: female sex workers (FSW) and their clients (FSWC); non-marital and non-commercial sex group: general women (GW) and general men (GM). First, the risks of HIV infection among men who have contacts with infected men or infected women decrease annually. Second, the number of contacts between susceptible FSWC and infected FSW per unit time is greater than that between susceptible MSM and infected MSM, and also greater than that between susceptible FSW and infected FSWC, which suggests that the intervention for commercial sex of heterosexual men should be strengthened. Third, the effective reproduction numbers of the MSM group and non-commercial sex group decrease annually, while the effective reproduction number of the commercial sex group decreases first, then increases, because the risk of women being infected by men decreases first, then increases. Additionally, the effective reproduction number of the commercial sex group exceeds that of the MSM group after 2015, which indicates that commercial sex contributes more and more to the HIV/AIDS epidemic.