EXPLORING CRITICAL HOST-PATHOGENS INTERACTIONS DURING CITROBACTER RODENTIUM LETHAL INFECTION IN IMMUNOCOMPROMISED HOSTS

Attaching/Effacing(A/E) pathogens include Enteropathogenic Escherichia coli (EPEC) and Enterohemorrhagic E. coli (EHEC), which cause gastroenteritis and are significant causes of foodborne diseases worldwide. Citrobacter rodentium (CR), as the murine equivalent, produces the same characteristic A/E lesions. While CR causes self-limiting infection in immunocompetent hosts, the morbidity and mortality are significantly higher in immunocompromised hosts. In the infection cycle of CR, the pathogen senses the changes of external environment and expresses an array of virulence factors. However, the adaptation process and critical host-pathogen interactions under immunocompromised conditions remain elusive. We utilized the infection of wild-type CR in interleukin-22 (Il-22) knockout (Il22-/-) mice as a model to dissect the crucial host-pathogen interactions during CR infection in immunocompromised hosts associated with severe symptoms and mortality. Previous studies from our lab utilizing RNA-sequencing (RNA-seq) analysis of gene transcription in host-adapted CR derived from the infected Il22-/- mice and in vitro culture reveal a substantial number of genes upregulated in the host-adapted CR. Among them, several genes were significantly upregulated in host-adapted CR, indicating that they might function as important virulence factors accounting for the infection-caused severe symptoms and lethality, including bioF, fepA, and Rod_48101. Here, we generated chromosomal knockout strains of bioF, fepA, and Rod_48101 and assessed the impacts of deletions of these genes on CR proliferation in vitro and virulence in vivo. Our results demonstrate that deletion of these genes does not impair the proliferation of CR in vitro. Meanwhile, infections with ΔfepA, ΔbioF, and ΔRod-48101 strains still result in severe body weight loss and high mortality in the infected Il22-/- mice, as does by wild-type CR. Therefore, our findings suggest that bioF, fepA, and Rod_48101 is dispensable for CR virulence in the immunocompromised Il22-/- mice. The dramatic upregulation of these genes is most likely the consequences of, rather than the causative triggers for the severe inflammatory responses resulting in mortality during CR infection in Il22-/- mice. Our results also indicate a complex host-pathogen interactions and bacterial virulence regulatory mechanisms during A/E pathogen infections in immunocompromised hosts associated with severe symptoms and outcomes, which are worthy of further investigations

Evaluating staggered working hours using a multi-agent-based Q-learning model

Staggered working hours has the potential to alleviate excessive demands on urban transport networks during the morning and afternoon peak hours and influence the travel behavior of individuals by affecting their activity schedules and reducing their commuting times. This study proposes a multi-agent-based Q-learning algorithm for evaluating the influence of staggered work hours by simulating travelers’ time and location choices in their activity patterns. Interactions among multiple travelers were also considered. Various types of agents were identified based on real activity–travel data for a mid-sized city in China. Reward functions based on time and location information were constructed using Origin–Destination (OD) survey data to simulate individuals’ temporal and spatial choices simultaneously. Interactions among individuals were then described by introducing a road impedance function to formulate a dynamic environment in which one traveler’s decisions influence the decisions of other travelers. Lastly, by applying the Q-learning algorithm, individuals’ activity–travel patterns under staggered working hours were simulated. Based on the simulation results, the effects of staggered working hours were evaluated on both a macroscopic level, at which the space–time distribution of the traffic volume in the network was determined, and a microscopic level, at which the timing of individuals’ leisure activities and their daily household commuting costs were determined. Based on the simulation results and experimental tests, an optimal scheme for staggering working hours was developed

Cellular Automata Based Modeling for Evaluating Different Bus Stop Designs in China

A cellular automaton model is proposed to simulate mixed traffic flow composed of motor vehicles and bicycles near bus stops. Three typical types of bus stops which are common in China are considered in the model, including two types of curbside bus stops and one type of bus bay stops. Passenger transport capacity of three types of bus stops, which is applied to evaluate the bus stop design, is calculated based on the corresponding traffic flow rate. According to the simulation results, the flow rates of both motor vehicles and bicycles exhibit phase transition from free flow to the saturation one at the critical point. The results also show that the larger the interaction between motor vehicle and bicycle flow is near curbside bus stops, the more the value of saturated flows drops. Curbside bus stops are more suitable when the conflicts between two flows are small and the inflow rate of motor vehicles is low. On the contrary, bus bay stops should be applied due to their ability to reduce traffic conflicts. Findings of this study can provide useful suggestions on bus stop selection considering different inflow rate of motor vehicles and bicycles simultaneously

Methylation-mediated silencing of PTPRD induces pulmonary hypertension by promoting pulmonary arterial smooth muscle cell migration via the PDGFRB/PLCγ1 axis

OBJECTIVE: Pulmonary hypertension is a lethal disease characterized by pulmonary vascular remodeling and is mediated by abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Platelet-derived growth factor BB (PDGF-BB) is the most potent mitogen for PASMCs and is involved in vascular remodeling in pulmonary hypertension development. Therefore, the objective of our study is to identify novel mechanisms underlying vascular remodeling in pulmonary hypertension. METHODS: We explored the effects and mechanisms of PTPRD downregulation in PASMCs and PTPRD knockdown rats in pulmonary hypertension induced by hypoxia. RESULTS: We demonstrated that PTPRD is dramatically downregulated in PDGF-BB-treated PASMCs, pulmonary arteries from pulmonary hypertension rats, and blood and pulmonary arteries from lung specimens of patients with hypoxic pulmonary arterial hypertension (HPAH) and idiopathic PAH (iPAH). Subsequently, we found that PTPRD was downregulated by promoter methylation via DNMT1. Moreover, we found that PTPRD knockdown altered cell morphology and migration in PASMCs via modulating focal adhesion and cell cytoskeleton. We have demonstrated that the increase in cell migration is mediated by the PDGFRB/PLCγ1 pathway. Furthermore, under hypoxic condition, we observed significant pulmonary arterial remodeling and exacerbation of pulmonary hypertension in heterozygous PTPRD knock-out rats compared with the wild-type group. We also demonstrated that HET group treated with chronic hypoxia have higher expression and activity of PLCγ1 in the pulmonary arteries compared with wild-type group. CONCLUSION: We propose that PTPRD likely plays an important role in the process of pulmonary vascular remodeling and development of pulmonary hypertension in vivo

Efficacy and safety of inclisiran in stroke or cerebrovascular disease prevention: a systematic review and meta-analysis of randomized controlled trials

Aims: As the impact of inclisiran in stroke prevention in atherosclerotic cardiovascular disease (ASCVD) patients or those at high risk of ASCVD is still unclear, we conducted a systematic review and meta-analysis of randomized controlled trials (RCT) to quantify the effectiveness of inclisiran in stroke prevention in these patients.Methods: Literature research was conducted in four electronic databases (PubMed, EMBASE, Web of Science, CENTRAL) and two clinical trials registers (ClinicalTrials.gov, WHO ICTRP) from the inception of the study to 17 October 2022, and was updated by the end of the study on 5 January 2023. Two authors independently screened the studies, extracted the data, and assessed the bias. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB 2). The intervention effect was estimated by calculating risk ratio (RR), weighted mean difference (WMD), and 95% confidence interval (CI) with R 4.0.5. Sensitivity analysis by changing meta-analysis model was also performed to test the robustness of the pooled results. If this was not possible, a descriptive analysis was conducted.Results: Four RCTs (n = 3,713 patients) were rated as high-risk bias. Meta-analysis of three RCTs (ORION-9, ORION-10, and ORION-11) showed that inclisiran reduced myocardial infarction (MI) risk by 32% (RR = 0.68, 95%CI = 0.48–0.96) but did not reduce stroke (RR = 0.92, 95%CI = 0.54–1.58) and major cardiovascular events (MACE) (RR = 0.81, 95%CI = 0.65–1.02) risk. Sensitivity analysis results were stable. Safety was similar to the placebo group but had frequent injection-site reactions (RR = 6.56, 95%CI = 3.83–11.25), which were predominantly mild or moderate. A descriptive analysis of one RCT (ORION-5) was conducted due to different study designs, and suggested that inclisiran might be given semiannually from the beginning.Conclusion: Inclisiran is not beneficial for stroke or MACE prevention in ASCVD or patients at high risk of ASCVD but is associated with the reduction of MI. Given the limited number and quality of the available studies and the lack of a standardized definition for cardiovascular events, further studies are essential for confirming the results

CRAFTS for Fast Radio Bursts : extending the dispersion-fluence relation with new FRBs detected by FAST

We report three new FRBs discovered by the Five-hundred-meter Aperture Spherical radio Telescope (FAST), namely FRB 181017.J0036+11, FRB 181118, and FRB 181130, through the Commensal Radio Astronomy FAST Survey (CRAFTS). Together with FRB 181123, which was reported earlier, all four FAST-discovered FRBs share the same characteristics of low fluence (1000 pc cm(-3)), consistent with the anticorrelation between DM and fluence of the entire FRB population. FRB 181118 and FRB 181130 exhibit band-limited features. FRB 181130 is prominently scattered (tau(s) 8 ms) at 1.25 GHz. FRB 181017.J0036+11 has full-bandwidth emission with a fluence of 0.042 Jy ms, which is one of the faintest FRB sources detected so far. CRAFTS has started to build a new sample of FRBs that fills the region for more distant and fainter FRBs in the fluence-DME diagram, previously out of reach of other surveys. The implied all-sky event rate of FRBs is 1.24(-0.90)(+1.94) x 5 sky(-1) day(-1) at the 95% confidence interval above 0.0146 Jy ms. We also demonstrate here that the probability density function of CRAFTS FRB detections is sensitive to the assumed intrinsic FRB luminosity function and cosmological evolution, which may be further constrained with more discoveries

Comprehensive Bibliometric Analysis of the Kynurenine Pathway in Mood Disorders: Focus on Gut Microbiota Research

Background: Emerging evidence implicates the dysregulated kynurenine pathway (KP), an immune-inflammatory pathway, in the pathophysiology of mood disorders (MD), including depression and bipolar disorder characterized by a low-grade chronic pro-inflammatory state. The metabolites of the KP, an important part of the microbiota-gut-brain axis, serve as immune system modulators linking the gut microbiota (GM) with the host central nervous system.Aim: This bibliometric analysis aimed to provide a first glimpse into the KP in MD, with a focus on GM research in this field, to guide future research and promote the development of this field.Methods: Publications relating to the KP in MD between the years 2000 and 2020 were retrieved from the Scopus and Web of Science Core Collection (WoSCC), and analyzed in CiteSpace (5.7 R5W), biblioshiny (using R-Studio), and VOSviewer (1.6.16).Results: In total, 1,064 and 948 documents were extracted from the Scopus and WoSCC databases, respectively. The publications have shown rapid growth since 2006, partly owing to the largest research hotspot appearing since then, “quinolinic acid.” All the top five most relevant journals were in the neuropsychiatry field, such as Brain Behavior and Immunity. The United States and Innsbruck Medical University were the most influential country and institute, respectively. Journal co-citation analysis showed a strong tendency toward co-citation of research in the psychiatry field. Reference co-citation analysis revealed that the top four most important research focuses were “kynurenine pathway,” “psychoneuroimmunology,” “indoleamine 2,3-dioxygenase,” and “proinflammatory cytokines,” and the most recent focus was “gut-brain axis,” thus indicating the role of the KP in bridging the GM and the host immune system, and together reflecting the field’s research foundations. Overlap analysis between the thematic map of keywords and the keyword burst analysis revealed that the topics “Alzheimer’s disease,” “prefrontal cortex,” and “acid,” were research frontiers.Conclusion: This comprehensive bibliometric study provides an updated perspective on research associated with the KP in MD, with a focus on the current status of GM research in this field. This perspective may benefit researchers in choosing suitable journals and collaborators, and aid in the further understanding of the field’s hotspots and frontiers, thus facilitating future research

CRAFTS for Fast Radio Bursts Extending the dispersion-fluence relation with new FRBs detected by FAST

We report three new FRBs discovered by the Five-hundred-meter Aperture Spherical radio Telescope (FAST), namely FRB 181017.J0036+11, FRB 181118 and FRB 181130, through the Commensal Radio Astronomy FAST Survey (CRAFTS). Together with FRB 181123 that was reported earlier, all four FAST-discovered FRBs share the same characteristics of low fluence ($\leq$0.2 Jy ms) and high dispersion measure (DM, $>1000$ \dmu), consistent with the anti-correlation between DM and fluence of the entire FRB population. FRB 181118 and FRB 181130 exhibit band-limited features. FRB 181130 is prominently scattered ($\tau_s\simeq8$ ms) at 1.25 GHz. FRB 181017.J0036+11 has full-bandwidth emission with a fluence of 0.042 Jy ms, which is one of the faintest FRB sources detected so far. CRAFTS starts to built a new sample of FRBs that fills the region for more distant and fainter FRBs in the fluence-$\rm DM_E$ diagram, previously out of reach of other surveys. The implied all sky event rate of FRBs is $1.24^{+1.94}_{-0.90} \times 10^5$ sky$^{-1}$ day$^{-1}$ at the $95\%$ confidence interval above 0.0146 Jy ms. We also demonstrate here that the probability density function of CRAFTS FRB detections is sensitive to the assumed intrinsic FRB luminosity function and cosmological evolution, which may be further constrained with more discoveries.Comment: 9 Pages, 4 Plots and 1 Table. The Astrophysical Journal Letter Accepte

Selective disrupted gray matter volume covariance of amygdala subregions in schizophrenia

ObjectiveAlthough extensive structural and functional abnormalities have been reported in schizophrenia, the gray matter volume (GMV) covariance of the amygdala remain unknown. The amygdala contains several subregions with different connection patterns and functions, but it is unclear whether the GMV covariance of these subregions are selectively affected in schizophrenia.MethodsTo address this issue, we compared the GMV covariance of each amygdala subregion between 807 schizophrenia patients and 845 healthy controls from 11 centers. The amygdala was segmented into nine subregions using FreeSurfer (v7.1.1), including the lateral (La), basal (Ba), accessory-basal (AB), anterior-amygdaloid-area (AAA), central (Ce), medial (Me), cortical (Co), corticoamygdaloid-transition (CAT), and paralaminar (PL) nucleus. We developed an operational combat harmonization model for 11 centers, subsequently employing a voxel-wise general linear model to investigate the differences in GMV covariance between schizophrenia patients and healthy controls across these subregions and the entire brain, while adjusting for age, sex and TIV.ResultsOur findings revealed that five amygdala subregions of schizophrenia patients, including bilateral AAA, CAT, and right Ba, demonstrated significantly increased GMV covariance with the hippocampus, striatum, orbitofrontal cortex, and so on (permutation test, P< 0.05, corrected). These findings could be replicated in most centers. Rigorous correlation analysis failed to identify relationships between the altered GMV covariance with positive and negative symptom scale, duration of illness, and antipsychotic medication measure.ConclusionOur research is the first to discover selectively impaired GMV covariance patterns of amygdala subregion in a large multicenter sample size of patients with schizophrenia