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Abstract Hepatocarcinogenesis is initiated by repeated hepatocyte death and liver damage, and the underlying mechanisms mediating cell death and the subsequent carcinogenesis remain to be fully investigated. Immunoresponsive gene 1 (IRG1) and its enzymatic metabolite itaconate are known to suppress inflammation in myeloid cells, and its expression in liver parenchymal hepatocytes is currently determined. However, the potential roles of IRG1 in hepatocarcinogenesis are still unknown. Here, using the diethylnitrosamine (DEN)-induced hepatocarcinogenesis mouse model, we found that IRG1 expression in hepatocytes was markedly induced upon DEN administration. The DEN-induced IRG1 was then determined to promote the intrinsic mitochondrial apoptosis of hepatocytes and liver damage, thus enhancing the subsequent hepatocarcinogenesis. Mechanistically, the mitochondrial IRG1 could associate and trap anti-apoptotic MCL-1 to inhibit the interaction between MCL-1 and pro-apoptotic Bim, thus promoting Bim activation and downstream Bax mitochondrial translocation, and then releasing cytochrome c and initiating apoptosis. Thus, the inducible mitochondrial IRG1 promotes hepatocyte apoptosis and the following hepatocarcinogenesis, which provides mechanistic insight and a potential target for preventing liver injury and HCC.

Abstract Background Spatial epidemiology plays an important role in public health. Yet, it is unclear whether the current university education in spatial epidemiology in China could meet the competency-oriented professional demands. This study aimed to understand the current situation of education and training, practical application, and potential demands in spatial epidemiology among public health postgraduates in China, and to assess the critical gaps in a future emerging infectious diseases (EID) pandemic preparedness and response. Methods This study was divided into three parts. The first part was a comparative study on spatial epidemiology education in international public health postgraduate training. The second part was a cross-sectional survey conducted among public health professionals. The third part was a nationwide cross-sectional survey conducted among public health postgraduates at Chinese universities from October 2020 to February 2021. Data was collected by the WeChat-based questionnaire star survey system and analyzed using the SPSS software. Results International education institutions had required public health postgraduates to master the essential knowledge and capacity of spatial epidemiology. A total of 198 public health professionals were surveyed, and they had a median of 4.00 (IQR 3.13–4.53) in demand degree of spatial epidemiology. A total of 1354 public health postgraduates were surveyed from 51 universities. Only 29.41% (15/51) of universities offered spatial epidemiology course. Around 8.05% (109/1354) of postgraduates had learned spatial epidemiology, and had a median of 1.05 (IQR 1.00–1.29) in learning degree and a median of 1.91 (IQR 1.05–2.78) in practical application degree of spatial epidemiology. To enhance professional capacity, 65.95% (893/1354) of postgraduates hoped that universities would deliver a credit-course of spatial epidemiology. Conclusions A huge unmet education and training demand in spatial epidemiology existed in the current education system of public health postgraduates in China. To enhance the competency-oriented professional capacity in preparedness and response to a future pandemic, it is urgent to incorporate the teaching and training of spatial epidemiology into the compulsory curriculum system of public health postgraduates in China.

Abstract Background Artificial intelligence (AI) tools are more effective if accepted by clinicians. We developed an AI-based clinical decision support system (CDSS) to facilitate vancomycin dosing. This qualitative study assesses clinicians' perceptions regarding CDSS implementation. Methods Thirteen semi-structured interviews were conducted with critical care pharmacists, at Mayo Clinic (Rochester, MN), from March through April 2020. Eight clinical cases were discussed with each pharmacist (N = 104). Following initial responses, we revealed the CDSS recommendations to assess participants' reactions and feedback. Interviews were audio-recorded, transcribed, and summarized. Results The participants reported considerable time and effort invested daily in individualizing vancomycin therapy for hospitalized patients. Most pharmacists agreed that such a CDSS could favorably affect (N = 8, 62%) or enhance (9, 69%) their ability to make vancomycin dosing decisions. In case-based evaluations, pharmacists' empiric doses differed from the CDSS recommendation in most cases (88/104, 85%). Following revealing the CDSS recommendations, we noted 78% (69/88) discrepant doses. In discrepant cases, pharmacists indicated they would not alter their recommendations. The reasons for declining the CDSS recommendation were general distrust of CDSS, lack of dynamic evaluation and in-depth analysis, inability to integrate all clinical data, and lack of a risk index. Conclusion While pharmacists acknowledged enthusiasm about the advantages of AI-based models to improve drug dosing, they were reluctant to integrate the tool into clinical practice. Additional research is necessary to determine the optimal approach to implementing CDSS at the point of care acceptable to clinicians and effective at improving patient outcomes.

Advancements in information technology have facilitated the emergence of mHealth apps as crucial tools for health management and chronic disease prevention. This research work focuses on mHealth apps for the management of diabetes by patients on their own. Given that China has the highest number of diabetes patients in the world, with 141 million people and a prevalence rate of 12.8% (mentioned in the Global Overview of Diabetes), the development of a usability research methodology to assess and validate the user-friendliness of apps is necessary. This study describes a usability evaluation model that combines task analysis methods and eye movement data. A blood glucose recording application was designed to be evaluated. The evaluation was designed based on the model, and the feasibility of the model was demonstrated by comparing the usability of the blood glucose logging application before and after a prototype modification based on the improvement suggestions derived from the evaluation. Tests showed that an improvement plan based on error logs and post-task questionnaires for task analysis improves interaction usability by about 24%, in addition to an improvement plan based on eye movement data analysis for hotspot movement acceleration that improves information access usability by about 15%. The results demonstrate that this study presents a usability evaluation model for mHealth apps that enables the effective evaluation of the usability of mHealth apps.

This project aimed to explore the influence of the interaction between ovotransferrin fibrils (OTF) and gum arabic (GA) on the formation mechanism, physicochemical properties, and curcumin delivery of the oleogel-in-water Pickering emulsion. Cryo-scanning electron microscopy results showed that OTF—GA complexes effectively adsorbed on the oil–water interface, generating spatial hindrance to inhibit droplet coalescence. The texture analysis also proved that OTF—GA complexes endowed oleogel-in-water Pickering emulsion with preferable springiness (0.49 ± 0.03 mm), chewiness (0.43 ± 0.07 mJ), and adhesion (0.31 ± 0.01 mJ). By exploring the coalescence stability, droplet size, and rheological properties of OTF—GA complexes–stabilized oleogel-in-water Pickering emulsion (OGPE), the higher coagulation stability, larger average droplet size (46.22 ± 0.08 μm), and stronger gel strength were observed. The microrheological results also exhibited stronger attraction between the OGPE droplets, a more pronounced solid-like structure, and a slower speed of movement than OTF-stabilized oleogel-in-water Pickering emulsion (OPE). Meanwhile, OGPE significantly enhanced the extent of lipolysis, stability, and bioaccessibility of curcumin, suggesting that it possessed superior performance as a delivery system for bioactive substances. This project provided adequate theoretical references for protein–polysaccharide complexes–stabilized oleogel-in-water Pickering emulsion, and contributed to expanding the application of oleogel-in-water Pickering emulsion in the food industry.

Background: The perception of tactile-stimulation locations is an important function of the human somatosensory system during body movements and its interactions with the surroundings. Previous psychophysical and neurophysiological studies have focused on spatial location perception of the upper body. In this study, we recorded single-trial electroencephalography (EEG) responses evoked by four vibrotactile stimulators placed on the buttocks and thighs while the human subject was sitting in a chair with a cushion. Methods: Briefly, 14 human subjects were instructed to sit in a chair for a duration of 1 h or 1 h and 45 min. Two types of cushions were tested with each subject: a foam cushion and an air-cell-based cushion dedicated for wheelchair users to alleviate tissue stress. Vibrotactile stimulations were applied to the sitting interface at the beginning and end of the sitting period. Somatosensory-evoked potentials were obtained using a 32-channel EEG. An artificial neural net was used to predict the tactile locations based on the evoked EEG power. Results: We found that single-trial beta (13–30 Hz) and gamma (30–50 Hz) waves can best predict the tactor locations with an accuracy of up to 65%. Female subjects showed the highest performances, while males’ sensitivity tended to degrade after the sitting period. A three-way ANOVA analysis indicated that the air-cell cushion maintained location sensitivity better than the foam cushion. Conclusion: Our finding shows that tactile location information is encoded in EEG responses and provides insights on the fundamental mechanisms of the tactile system, as well as applications in brain–computer interfaces that rely on tactile stimulation.

Abstract Supercapacitors have been used in a broad range of fields including electronics, transportation, and energies. Electrode materials with high capacitance and good rate performance are crucial for the future development and application of supercapacitors. Herein, we prepared N, O co‐doped defective carbon blocks (NO‐DCBs) with abundant active sites through carbonization and ball‐milling of polyimide. The as‐obtained NO‐DCBs exhibit high atomic content of N and O inherited from polyamic acid (PAA) precursor, as well as large amounts of intrinsic defects introduced by ball‐milling. Benefiting from the synergy of pseudocapacitance and electrical double‐layer capacitance provided by heteroatoms and intrinsic defects respectively, the NO‐DCBs assembled symmetric aqueous capacitor shows high capacitance of 329 F g−1 at 0.1 A g−1, good rate performance of 48% capacitance retention at 50 A g−1, and superb cycling stability. This work promotes the deep understanding of the synergy effect of functional groups and intrinsic defects for capacitive energy storage, and broadens the avenue for structural design of active sites in carbon materials.

Background Smart bracelets are increasingly used in chronic disease management, which help improve patient adherence and motivation to exercise interventions, but more evidence for their long-term effectiveness in patients with type 2 diabetes mellitus (T2DM) in the community needs to be explored. Objective To develop an intervention model for community-dwelling type 2 diabetes patients using smart bracelets, and to assess its long-term effectiveness in these patients. Methods From July to August 2018, this study selected 11 community health institutions from 11 districts of Guangzhou (one from each district) as study settings. And from each setting, 10-15 T2DM patients were selected (intervention group), and were compared to sex-matched and age-matched (+/- two years) T2DM patients (control group). The intervention was carried out from September 2018 to August 2019 in two groups, both received standardized health management services provided by the family physician team and underwent the exercise prescribed by an exercise prescriber. The intervention group additionally received health monitoring and management via wearing a smart bracelet, and set personalized exercise challenge goals under the guidance of an exercise prescriber. The score of the Chinese version of Summary of Diabetes Self-Care Activities Measure (SDSCA-C), comprehensive assessment indicators, and attainment rates of key glycemic indicators were compared between the two groups before and after the intervention. Results Ninety-two patients in the control group and 144 patients in the intervention group completed one-year intervention and follow-up. After the intervention, the subscale scores of dietary management and foot care management and the total score of SDSCA-C increased notably in the intervention group (P0.05). Two groups had no statistically significant differences in all comprehensive assessment indicators at baseline (P>0.05). After one year of intervention, besides a decrease was found in total cholesterol, apolipoprotein A1 and apolipoprotein B in both groups, a reduction was found in waist circumference in the intervention group, and in fasting plasma glucose (FPG), triacylglycerol and low-density lipoprotein cholesterol in the control group (P

Abstract Purpose To explore pediatric nurses’ challenges and effective coping strategies in caring for dying children. Methods A descriptive qualitative study was adopted. Data were collected using a semi-structured interview with ten nurses from the pediatric, pediatric emergency, and neonatology departments. Results Three themes were generated: stressors, consequences, and coping strategies. Ten sub-themes were generalized: negative emotions; helplessness; questioning rescue behavior; fear of communication; lack of workforce for night rescue; compassion fatigue; burnout; changes in life attitudes; self-regulation; leadership approval and no accountability. Conclusions Through qualitative research, nurses’ challenges and effective coping strategies in caring for dying children were found, which provides information for nurses’ career development and related policy formulation in China. Clinical relevance While there are many articles in China on hospice care, there is little research on the nurses’ experience of caring for dying children. Many studies have mentioned the adverse consequences of caring for dying children in foreign countries, leading to post-traumatic stress disorder (PTSD). However, domestic discussion of such problems is rare, and no corresponding coping strategies exist. This study explores pediatric nurses’ challenges and effective coping strategies in caring for dying children.

Abstract The Pacific Walker circulation (PWC) weakens under global warming in climate change projections, supported by a global hydrological constraint. However, the PWC has strengthened over the past decades despite ongoing global warming, and the cause has been a puzzle. Because PWC is coupled with the pattern of sea surface temperature (SST) in the tropical Pacific, quantifying the relative impact of SST pattern change and global warming on the past PWC trend is important. We show, using an atmosphere model driven by observed boundary conditions for 1979–2013 and a hypothetical uniform surface warming trend with varying magnitude, that the PWC scales with warming and weakens by 8% per °C, but this effect cannot overcome the SST pattern effect that intensifies the circulation. Further attribution experiments show that the past strengthening of PWC is explained directly by the SST warming pattern in the narrow equatorial band, about 30% of which is induced by the Indian Ocean.

Abstract Over recent decades, the Southern Ocean (SO) has experienced multi‐decadal surface cooling despite global warming. Earlier studies have proposed that recent SO cooling has been caused by the strengthening of surface westerlies associated with a positive trend of the Southern Annular Mode (SAM) forced by ozone depletion. Here we revisit this hypothesis by examining the relationships between the SAM, zonal winds and SO sea‐surface temperature (SST). Applying a low‐frequency component analysis to observations, we show that while positive SAM anomalies can induce SST cooling as previously found, this seasonal‐to‐interannual modulation makes only a small contribution to the observed long‐term SO cooling. Global climate models well capture the observed interannual SAM‐SST relationship, and yet generally fail to simulate the observed multi‐decadal SO cooling. The forced SAM trend in recent decades is thus unlikely the main cause of the observed SO cooling, pointing to a limited role of the Antarctic ozone hole.

ABSTRACT Gastrointestinal microorganisms play a crucial role in host survival and adaptation, but information on host-specific selection or environmental factors that shape the microbiome in natural populations is limited. In this study, we employed 16S rRNA gene amplicon sequencing to investigate the composition and predicted the functions of gut microbiota of two ophiuroid species (Ophiura sarsii and its subspecies O. sarsii vadicola) from cold-water habitats across three geographically distant sea areas in the Northern Pacific Ocean. We also explored the potential influence of the host and environment on the microbiota. The two ophiuroids possessed diverse microbial communities, with Proteobacteria being the most dominant phylum in all four groups. Aliivibrio was the predominant genus in O. sarsii from the Bering Sea, while Candidatus Hepatoplasma was the dominant genus in O. sarsii from the Japan Sea and O. sarsii vadicola from the Yellow Sea. Predicted bacterial functions indicated that most of the pathways with significant differences belonged to metabolism and genetic information processing. Notably, no significant difference was observed between the two coexisting ophiuroid species in the Japan Sea. The high similarity in microbial communities between O. sarsii from the Japan Sea and O. sarsii vadicola from the Yellow Sea may be attributed to their analogous ecological niche. The host and the environment jointly shape the composition of the gut microbial community. The presence of specific microorganisms supports the ecological success of ophiuroids across diverse environments, providing a foundation for host adaptation to cold-water habitats. IMPORTANCE Gastrointestinal microorganisms are critical to the survival and adaptation of hosts, and there are few studies on the differences and functions of gastrointestinal microbes in widely distributed species. This study investigated the gut microbes of two ophiuroid species (Ophiura sarsii and its subspecies O. sarsii vadicola) in cold-water habitats of the Northern Pacific Ocean. The results showed that a combination of host and environmental factors shapes the intestinal microbiota of ophiuroids. There was a high similarity in microbial communities between the two groups living in different regions, which may be related to their similar ecological niches. These microorganisms played a vital role in the ecological success of ophiuroids as the foundation for their adaptation to cold-water environments. This study revealed the complex relationship between hosts and their gut microbes, providing insights into the role they play in the adaptation and survival of marine species.

Lower limb arterial calcification (LLAC) is associated with an increased risk of mortality and it predicts poor outcomes after endovascular interventions in patients with peripheral artery disease (PAD). Detailed histological analysis of human lower artery specimens pinpointed the presence of LLAC in two distinct layers: the intima and the media. Intimal calcification has been assumed to be an atherosclerotic pathology and it is associated with smoking and obesity. It becomes instrumental in lumen stenosis, thereby playing a crucial role in disease progression. On the contrary, medial calcification is a separate process, systematically regulated and linked with age advancement, diabetes, and chronic kidney disease. It prominently interacts with vasodilation and arterial stiffness. Given that both types of calcifications frequently co-exist in PAD patients, it is vital to understand their respective mechanisms within the context of PAD. Calcification can be easily identifiable entity on imaging scans. Considering the highly improved abilities of novel imaging technologies in differentiating intimal and medial calcification within the lower limb arteries, this review aimed to describe the distinct histological and imaging features of the two types of LLAC. Additionally, it aims to provide in-depth insight into the risk factors, the effects on hemodynamics, and the clinical implications of LLAC, either occurring in the intimal or medial layers.

Objectives A well-functioning health system ensures timely routine measles vaccinations for age-appropriate children, minimising measles risk. However, there is limited knowledge about the impact of the performance of immunisation programmes in health systems on the timeliness of measles vaccination. This study aimed to identify health system barriers to timely routine measles vaccination in rural southwest China, integrating the perspectives of township vaccination professionals and village doctors.Design, setting and participants Qualitative study among township vaccination professionals and village doctors in rural Guangxi, southwest China.Methods 20 focus group discussions (FGDs) at township level and 120 in-depth interviews (IDIs) at village level, based on a four-theme framework. We used convenience sampling to recruit 60 township vaccination professionals and 120 village doctors in 2015. Instruments used were a semistructured questionnaire and interview outlines. We collected township and village-level data focusing on themes of health resources allocation, pattern of vaccination services, management and supervision of vaccination services, and perceptions of vaccination policy. The FGDs and IDIs were audio-recorded and transcribed. Braun and Clarke’s thematic analysis approach was adopted to synthesise findings into meaningful subthemes, narrative text and illustrative quotations.Results The health system barriers to timely routine vaccinations were explored across four themes. Barriers in the health resources allocation theme comprised (1) inadequacy of vaccination-related human resources (eg, lack of township vaccination professionals and lack of young village doctors), and (2) incompatible and non-identical information system of vaccination services across regions. Barriers in the pattern of vaccination services theme included inflexible vaccination services models, for example, routine vaccination services being offered monthly on fixed vaccination days, limited numbers of vaccination days per month, vaccination days being set on non-local market days, vaccination days being clustered into a specific period and absence of formal vaccination appointments. Ineffective economic incentive mechanism was identified as a barrier in the management and supervision of vaccination services theme. Low-degree participation of village doctors in routine vaccination services was identified as a barrier in the perceptions of vaccination policy theme.Conclusions We encourage policymakers and stakeholders to apply these findings to improve the timeliness of routine vaccination. Barriers to timely routine vaccination include inadequate allocation of vaccination-related resources and inflexible vaccination service delivery models. Financial and non-financial incentives should be used to retain and recruit vaccination professionals and village doctors. Strengthening information systems with unified data standards enables cross-regional data exchange. Optimising immunisation services and rationalising vaccination days could eliminate health system barriers and improve vaccination timeliness in rural China.

Human interventions mobilize massive nitrogen (N) emissions to freshwater and result in serious eutrophication impacts. Life cycle impact assessment (LCIA) provides a reliable quantitative tool to address the challenges of potential ecological impact induced by increasing nutrient inputs. However, characterization procedures that relate N emissions to ecological damage in freshwater ecosystems in LCIA methodology are still lacking. This study aims to propose a spatially explicit characterization model (1 km × 1 km) for N-induced freshwater eutrophication. A complete cause-effect chains linking the N emission with species loss endpoint impact was constructed, in which the site-specific fate factor modelling contained transfer and removal processes in terrestrial and freshwater compartments, and the mechanistic modelling of ecosystem exposure and damage effect were quantified with species loss. The eutrophication characterization was conducted with a case study in Guangzhou, China, and 1 km × 1 km spatial differentiation of eutrophication susceptibility was intuitively demonstrated, with higher values in the Pearl River Estuary area. Method comparisons and further improvements were discussed in support of model generalization and further application.

Abstract Background The COVID-19 pandemic produced unprecedented demands and rapidly changing evidence and practices within critical care settings. The purpose of this study was to identify factors and strategies that hindered and facilitated effective implementation of new critical care practices and policies in response to the pandemic. Methods We used a cross-sectional, qualitative study design to conduct semi-structured in-depth interviews with critical care leaders across the United States. The interviews were audio-taped and professionally transcribed verbatim. Guided by the Consolidated Framework for Implementation Research (CFIR), three qualitative researchers used rapid analysis methods to develop relevant codes and identify salient themes. Results Among the 17 hospitals that agreed to participate in this study, 31 clinical leaders were interviewed. The CFIR-driven rapid analysis of the interview transcripts generated 12 major themes, which included six implementation facilitators (i.e., factors that promoted the implementation of new critical care practices) and six implementation barriers (i.e., factors that hindered the implementation of new critical care practices). These themes spanned the five CFIR domains (Intervention Characteristics, Outer Setting, Inner Setting, Characteristics of Individuals, and Process) and 11 distinct CFIR constructs. Salient facilitators to implementation efforts included staff resilience, commitment, and innovation, which were supported through collaborative feedback and decision-making mechanisms between leadership and frontline staff. Major identified barriers included lack of access to reliable and transferable information, available resources, uncollaborative leadership and communication styles. Conclusions Through applying the CFIR to organize and synthesize our qualitative data, this study revealed important insights into implementation determinants that influenced the uptake of new critical care practices during COVID-19. As the pandemic continues to burden critical care units, clinical leaders should consider emulating the effective change management strategies identified. The cultivation of streamlined, engaging, and collaborative leadership and communication mechanisms not only supported implementation of new care practices across sites, but it also helped reduce salient implementation barriers, particularly resource and staffing shortages. Future critical care implementation studies should seek to capitalize on identified facilitators and reduce barriers.

This paper proposes a stochastic intestinal chemostat model considering microbial migration, intraspecific competition and stochastic perturbation. First, the extinction and persistence in mean of the intestinal microbe of the chemostat model are investigated by constructing the appropriate Lyapunov functions. Second, we explore and obtain sufficient conditions for the existence and uniqueness of an ergodic stationary distribution of the model by using ergodic theory. The results show stochastic interference has a critical impact on the extinction and sustainable survival of the intestinal microbe. Eventually, numerical simulations are carried out to verify the theoretical results.

This study investigates the airflow and thermal management of a compact electric energy storage system by using computational fluid dynamic (CFD) simulation. A porous medium model for predicting the flow resistance performance of the battery modules in a battery cabinet is developed. By studying the influence of rack shapes, the effects of heat exchanger arrangements and other parameters on the airflow and battery thermal distribution are analyzed. When applying a larger bottom air channel, the inlet flow uniformity of each battery cabin in the cabinet increases by 5%. Meanwhile, temperature standard deviation decreases by 0.18 while raising the flow rate from 3 m/s to 8 m/s, indicating better temperature uniformity in the battery cabin. When the charge–discharge ratio reaches 0.5 C, the temperature deviation of the entire cabinet significantly increases, reaching 8 K. Furthermore, a rack-level thermal management scheme is proposed to effectively reduce the thermal deviation of the container electric energy storage system and improve the overall temperature uniformity. Results reveal that the rack-level thermal management of the wavy cabinet in the electric storage container can effectively improve the thermal uniformity of the distributed battery cabin, and the overall thermal deviation is controlled within 1.0 K.

When facing problems in the aerial pursuit game, most of the current unmanned aerial vehicles (UAVs) have good maneuverability performance, but it is difficult to utilize the overload maneuverability of UAVs properly; further, UAVs tend to be more costly, and it is often difficult to effectively prevent the enemy from reaching the tailgating position behind the UAV in the aerial pursuit game. Therefore, there is a pressing need for a maneuvering algorithm that can effectively allow a UAV to quickly protect itself in a disadvantageous position, stably and effectively select a maneuver with the maneuvering algorithm, and stably and effectively establish an advantage by moving to an advantageous position. Therefore, this paper establishes a cloud model-based UAV-maneuvering aerial pursuit decision-making model based on pursuit-and-evasion game positions. Based on the evaluation of the latter, when the UAV is at a disadvantage, we use the constructed defensive maneuver expert pool to abandon the disadvantageous position. When the UAV is at an advantage, we use cloud model-based pursuit-and-evasion game maneuvering decision making to establish an advantageous position. According to the results of the simulation examples, the maneuvering decision-making method designed in this paper confirms that the UAV can quickly abandon its position and establish an advantage in case of parity or disadvantage and that it can also stably establish a tail-chasing position in case of advantage.

Crinoids, as integral echinoderms, play a crucial ecological role in benthic communities, serving as significant indicators reflecting the health of marine ecosystems. However, the phylogenetic relationships within crinoids are unclear. More molecular data can help to facilitate biodiversity assessment and elucidate evolutionary relationships by the phylogenetic tree. In this study, 13 complete mitochondrial genomes of the Crinoidea class were sequenced, annotated, and compared with other same class species available on NCBI. The results reveal five different gene order patterns among these mitochondrial genomes, indicating that crinoids have undergone gene rearrangements during evolution. The complete mitochondrial genome length of crinoids ranges from 15,772 bp to 16,850 bp. High A + T content, ranging from 64.5% to 74.2%, was observed. Additionally, our analysis of protein-coding genes highlights a preference for A + T nucleotides, along with specific start and stop codon usage, offering insights into codon bias and its implications for protein synthesis and function. The phylogenetic topology shows that the stalkless crinoid and stalked crinoid are distinct, and the phylogenetic trees generated based on maximum likelihood and Bayesian inference are almost identical at the family and order topology levels. The phylogenetic relationships of each family were fully clarified in four orders. A total of eleven positive selection sites were detected within six genes: cytb, nad2, nad3, nad4, nad4L and nad5. This study reveals the phylogenetic relationships of crinoid species, the mitochondrial gene differences, and the selective pressure on the evolution of stalked crinoids. This study significantly enhanced the crinoid mitochondrial genome database and contributed to a better understanding of the phylogenetic relationships among crinoid echinoderms.

Abstract The emergence and rapid spread of methicillin‐resistant Staphylococcus aureus (MRSA) raise a critical need for alternative therapeutic options. New antibacterial drugs and targets are required to combat MRSA‐associated infections. Based on this study, celastrol, a natural product from the roots of Tripterygium wilfordii Hook. f., effectively combats MRSA in vitro and in vivo. Multi‐omics analysis suggests that the molecular mechanism of action of celastrol may be related to Δ1‐pyrroline‐5‐carboxylate dehydrogenase (P5CDH). By comparing the properties of wild‐type and rocA‐deficient MRSA strains, it is demonstrated that P5CDH, the second enzyme of the proline catabolism pathway, is a tentative new target for antibacterial agents. Using molecular docking, bio‐layer interferometry, and enzyme activity assays, it is confirmed that celastrol can affect the function of P5CDH. Furthermore, it is found through site‐directed protein mutagenesis that the Lys205 and Glu208 residues are key for celastrol binding to P5CDH. Finally, mechanistic studies show that celastrol induces oxidative stress and inhibits DNA synthesis by binding to P5CDH. The findings of this study indicate that celastrol is a promising lead compound and validate P5CDH as a potential target for the development of novel drugs against MRSA.

Abstract Effective climate sensitivity (EffCS), commonly estimated from model simulations with abrupt 4×CO2 for 150 years, has been shown to depend on the CO2 forcing level. To understand this dependency systematically, we performed a series of simulations with a range of abrupt CO2 forcing in two climate models. Our results indicate that normalized EffCS values in these simulations are a non‐monotonic function of the CO2 forcing, decreasing between 3× and 4×CO2 in CESM1‐LE (2× and 3×CO2 in GISS‐E2.1‐G) and increasing at higher CO2 levels. The minimum EffCS value, caused by anomalously negative radiative feedbacks, arises mainly from sea‐surface temperature (SST) relative cooling in the tropical and subtropical North Atlantic. This cooling is associated with the formation of the North Atlantic Warming Hole and Atlantic Meridional Overturning Circulation collapse under CO2 forcing. Our findings imply that understanding changes in North Atlantic SST patterns is important for constraining near‐future and equilibrium global warming.

There is a lack of diagnostic performance measures associated with pulmonary embolism (PE). We aimed to explore the concept of the time to diagnostic certainty, which we defined as the time interval that elapses between first presentation of a patient to a confirmed PE diagnosis with computed tomography pulmonary angiogram (CT PA). This approach could be used to highlight variability in health system diagnostic performance, and to select patient outliers for structured chart review in order to identify underlying contributors to diagnostic error or delay. We performed a retrospective observational study at academic medical centers and associated community-based hospitals in one health system, examining randomly selected adult patients admitted to study sites with a diagnosis of acute saddle PE. One hundred patients were randomly selected from 340 patients discharged with saddle PE. Twenty-four patients were excluded. Among the 76 included patients, time to diagnostic certainty ranged from 1.5 to 310 hours. We found that 73/76 patients were considered to have PE present on admission (CT PA ≤ 48 hours). The proportion of patients with PE present on admission with time to diagnostic certainty of > 6 hours was 26% (19/73). The median (IQR) time to treatment (thrombolytics/anticoagulants) was 3.5 (2.5-5.1) hours among the 73 patients. The proportion of patients with PE present on admission with treatment delays of > 6 hours was 16% (12/73). Three patients acquired PE during hospitalization (CT PA > 48 hours). In this study, we developed and successfully tested the concept of time to diagnostic certainty for saddle PE.

Context Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, can develop into metabolic associated fatty liver disease (MAFLD). Gypenosides (GP), the main phytochemical component of Gynostemma pentaphylla (Thunb.) Makino (Cucurbitaceae), have been applied for treatment of metabolic diseases.Objective We investigate how GP modulate MAFLD-related hepatic steatosis and intestinal barrier injury.Materials and methods In cell experiments, Caco-2 cells were treated with GP (150 or 200 μmol/L, 24 h), following lipopolysaccharide (LPS) exposure (10 μg/mL, 24 h) to mimic MAFLD in vitro. In in vivo experiments, control, model and model + GP groups were set. High fructose diet/high fat (HFD/HF)-fed (12 weeks) MAFLD rats received GP treatment (300 mg/kg, 6 weeks), followed by intra-peritoneal glucose tolerance test and histopathological examination of rat liver and intestinal mucosa using haematoxylin–eosin staining.Results GP at 200 μM significantly reversed LPS-induced decreases in transepithelial electrical resistance (TER) value (25%), protein expression of occludin (two fold) and ZO-1 (four fold), and the ratio of p-AMPK to AMPK (five fold), while partially repressing LPS-induced leakage of FD4 (50%) and LPS-induced increases in the Toll-like receptor 4 (TLR4) level (50%) and the ratio of p-p65 to p65 (55%). Compared with the model rats, rats with GP treatment presented a reduction in gain of weight and glucose tolerance. In addition, GP alleviated HFD/HF-induced histopathological abnormalities in rat liver and intestinal mucosa.Conclusions GP attenuates hepatic steatosis and intestinal barrier injury in MAFLD rats via the AMPK and TLR4/nuclear factor kappa B (NF-κB) pathways, providing a potential treatment for MAFLD patients.

Abstract Background We evaluated the effects of visit‐to‐visit variability of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on macrovascular and microvascular complications among patients with type 2 diabetes. Methods A total of 11 043 patients with type 2 diabetes from primary healthcare institutions between January 2010 and June 2020 were included. The visit‐to‐visit blood pressure variability was calculated using three metrics: SD, coefficient of variation (CV), and average real variability (ARV), obtained over a 12‐month measurement period. The associations of visit‐to‐visit blood pressure variability with macrovascular and microvascular complications were evaluated using multivariate‐adjusted Cox proportional hazards models, and hazard ratio (HR) with 95% confidence interval (CI) were reported. Results There were 330 macrovascular events and 542 microvascular events. Compared to those for participants with the lowest quartile of SD of SBP and DBP, increased risks were observed in patients with the highest quartile of SD of SBP and DBP for macrovascular complications (SD‐SBP: HR = 1.78, 95% CI: 1.24–2.57; SD‐DBP: HR = 2.20, 95% CI: 1.50–3.25) and microvascular complications (SD‐SBP: HR = 1.85, 95% CI: 1.39–2.46; SD‐DBP: HR = 1.82, 95% CI: 1.36–2.44). CV and ARV of SBP and DBP also had statistically significant associations with macrovascular and microvascular complications. The optimal variability of blood pressure target was SD of SBP

Abstract Background Hepatocarcinogenesis is driven by necroinflammation or metabolic disorders, and the underlying mechanisms remain largely elusive. We previously found that retinoic acid-inducible gene-I (RIG-I), a sensor for recognizing RNA virus in innate immune cells, is mainly expressed by parenchymal hepatocytes in the liver. However, its roles in hepatocarcinogenesis are unknown, which is intensively investigated in this study. Methods DEN-induced necroinflammation-driven hepatocarcinogenesis and STAM NASH-hepatocarcinogenesis were carried out in hepatocyte-specific RIG-I knockout mice. The post-translational modification of RIG-I was determined by mass spectrometry, and specific antibodies against methylated lysine sites and the RIG-I lysine mutant mice were constructed to identify the functions of RIG-I methylation. Results We interestingly found that DEN-induced hepatocarcinogenesis was enhanced, while NASH-induced hepatocarcinogenesis was suppressed by hepatocyte-specific RIG-I deficiency. Further, IL-6 decreased RIG-I expression in HCC progenitor cells (HcPCs), which then viciously promoted IL-6 effector signaling and drove HcPCs to fully established HCC. RIG-I expression was increased by HFD, which then enhanced cholesterol synthesis and steatosis, and the in-turn NASH and NASH-induced hepatocarcinogenesis. Mechanistically, RIG-I was constitutively mono-methylated at K18 and K146, and demethylase JMJD4-mediated RIG-I demethylation suppressed IL-6-STAT3 signaling. The constitutive methylated RIG-I associated with AMPKα to inhibit HMGCR phosphorylation, thus promoting HMGCR enzymatic activity and cholesterol synthesis. Clinically, RIG-I was decreased in human hepatic precancerous dysplastic nodules while increased in NAFLD livers, which were in accordance with the data in mouse models. Conclusions Decreased RIG-I in HcPCs promotes necroinflammation-induced hepatocarcinogenesis, while increased constitutive methylated RIG-I enhances steatosis and NASH-induced hepatocarcinogenesis. JMJD4-demethylated RIG-I prevents both necroinflammation and NASH-induced hepatocarcinogenesis, which provides mechanistic insight and potential target for preventing HCC.