A Molecular Coordination Strategy for Regulating the Interface of MoS2 Field Effect Transistors.

Chemically modifying monolayer two-dimensional transition metal dichalcogenides (TMDs) with organic molecules provides a wide range of possibilities to regulate the electronic and optoelectronic performance of both materials and devices. However, it remains challenging to chemically attach organic molecules to monolayer TMDs without damaging their crystal structures. Herein, we show that the Mo atoms of monolayer MoS2 (1L-MoS2) in defect states can coordinate with both catechol and 1,10-phenanthroline (Phen) groups, affording a facile route to chemically modifying 1L-MoS2. Through the design of two isomeric molecules (LA2 and LA5) comprising catechol and Phen groups, we show that attaching organic molecules to Mo atoms via coordinative bonds has no negative effect on the crystal structure of 1L-MoS2. Both theoretical calculation and experiment results indicate that the coordinative strategy is beneficial for (i) repairing sulfur vacancies and passivating defects; (ii) achieving a long-term and stable n-doping effect; and (iii) facilitating the electron transfer. Field effect transistors (FETs) based on the coordinatively modified 1L-MoS2 show high electron mobilities up to 120.3 cm2 V-1 s-1 with impressive current on/off ratios over 109. Our results indicate that coordinatively attaching catechol- or Phen-bearing molecules may be a general method for the nondestructive modification of TMDs.

Impact of omitting the intravenous heparin bolus on outcomes of leadless pacemaker implantation.

BACKGROUND: Early guidance recommended a bolus of intravenous heparin at the beginning of leadless pacemaker (LP) implantation procedures. However, due to concern about bleeding complications, more recent practice has tended toward omitting the bolus and only running a continuous heparin infusion through the introducer sheath. The impact of omitting the heparin bolus on procedural outcomes is not clear. METHODS: We reviewed all Medtronic Micra LP implants at our institution from 9/2014 to 9/2022. The decision to bolus with heparin was at operator discretion. RESULTS: Among 621 LP implants, 326 received an intravenous heparin bolus, 243 did not, and 52 patients were excluded because heparin bolus status could not be confirmed. There was a trend toward more frequent omission of the heparin bolus with more recent implants. Median follow-up after LP implant was 14.3 (interquartile range [IQR]: 8.4-27.9) months. There was no difference between heparin bolus and no bolus groups in the number of device deployments/recaptures (1.42 ± 0.81 vs. 1.31 ± 0.66, p = .15). Implant-related adverse events were also similar between heparin bolus and no bolus groups: access-site hematoma requiring intervention (7 vs. 5, p = .99), pseudoaneurysm (1 vs. 1, p = .99), cardiac perforation (1 vs. 1, p = .99), intraprocedural device thrombus formation (2 vs. 4, p = .41), 30-day rehospitalization (21 vs. 15, p = .98), and 30-day all-cause mortality (16 vs. 14, p = .70). There was one additional nonfatal cardiac perforation in a patient who was excluded due to unknown heparin bolus status. Regarding device electrical parameters between heparin bolus and no bolus groups, there were no significant differences at the time of implant: pacing capture threshold 0.5 ± 0.4 vs. 0.5 ± 0.3, p = .10; pacing impedance 739.9 ± 226.4 vs. 719.1 ± 215.4, p = .52; R wave sensing 11.7 ± 5.7 vs. 12.0 ± 5.4, p = .34). Long-term device performance was also similar between groups. CONCLUSION: Omission of the systemic heparin bolus at the time of LP implantation appears safe in appropriately selected patients. Heparin bolus may still be considered in long cases requiring multiple device deployments or in patients at high risk for thrombotic complications.

MRI-based automated machine learning model for preoperative identification of variant histology in muscle-invasive bladder carcinoma.

OBJECTIVES: It is essential yet highly challenging to preoperatively diagnose variant histologies such as urothelial carcinoma with squamous differentiation (UC w/SD) from pure UC in patients with muscle-invasive bladder carcinoma (MIBC), as their treatment strategy varies significantly. We developed a non-invasive automated machine learning (AutoML) model to preoperatively differentiate UC w/SD from pure UC in patients with MIBC. METHODS: A total of 119 MIBC patients who underwent baseline bladder MRI were enrolled in this study, including 38 patients with UC w/SD and 81 patients with pure UC. These patients were randomly assigned to a training set or a test set (3:1). An AutoML model was built from the training set, using 13 selected radiomic features from T2-weighted imaging, semantic features (ADC values), and clinical features (tumor length, tumor stage, lymph node metastasis status), and subsequent ten-fold cross-validation was performed. A test set was used to validate the proposed model. The AUC of the ROC curve was then calculated for the model. RESULTS: This AutoML model enabled robust differentiation of UC w/SD and pure UC in patients with MIBC in both training set (ten-fold cross-validation AUC = 0.955, 95% confidence interval [CI]: 0.944-0.965) and test set (AUC = 0.932, 95% CI: 0.812-1.000). CONCLUSION: The presented AutoML model, that incorporates the radiomic, semantic, and clinical features from baseline MRI, could be useful for preoperative differentiation of UC w/SD and pure UC. CLINICAL RELEVANCE STATEMENT: This MRI-based automated machine learning (AutoML) study provides a non-invasive and low-cost preoperative prediction tool to identify the muscle-invasive bladder cancer patients with variant histology, which may serve as a useful tool for clinical decision-making. KEY POINTS: • It is important to preoperatively diagnose variant histology from urothelial carcinoma in patients with muscle-invasive bladder carcinoma (MIBC), as their treatment strategy varies significantly. • An automated machine learning (AutoML) model based on baseline bladder MRI can identify the variant histology (squamous differentiation) from urothelial carcinoma preoperatively in patients with MIBC. • The developed AutoML model is a non-invasive and low-cost preoperative prediction tool, which may be useful for clinical decision-making.

Placental inflammatory injury induced by chlorinated polyfluorinated ether sulfonate (F-53B) through NLRP3 inflammasome activation.

Chlorinated polyfluorinated ether sulfonate, commercially known as F-53B, has been associated with adverse birth outcomes. However, the reproductive toxicology of F-53B on the placenta remains poorly understood. To address this gap, we examined the impact of F-53B on placental injury and its underlying molecular mechanisms in vivo. Pregnant C57BL/6 J female mice were randomly allocated to three groups: the control group, F-53B 0.8 µg/kg/day group, and F-53B 8 µg/kg/day group. After F-53B exposure through free drinking water from gestational day (GD) 0.5-14.5, the F-53B 8 µg/kg/day group exhibited significant increases in placental weights and distinctive histopathological alterations, including inflammatory cell infiltration, heightened syncytiotrophoblast knots, and a loosened trophoblastic basement membrane. Within the F-53B 8 µg/kg/day group, placental tissue exhibited increased apoptosis, as indicated by increased caspase3 activation. Furthermore, F-53B potentially induced the NF-κB signaling pathway activation through IκB-α phosphorylation. Subsequently, this activation upregulated the expression of inflammatory cytokines and components of the NLRP3 inflammasome, including activated caspase1, IL-1ß, IL-18, and cleaved gasdermin D (GSDMD), ultimately leading to pyroptosis in the mouse placenta. Our findings reveal a pronounced inflammatory injury in the placenta due to F-53B exposure, suggesting potential reproductive toxicity at concentrations relevant to the human population. Further toxicological and epidemiological investigations are warranted to conclusively assess the reproductive health risks posed by F-53B.

Plasma miR-203a-3p as a Novel Predictor of Dementia in Patients with Parkinson's Disease.

The early detection of cognitive decline in Parkinson's disease is important for providing drug therapy and non-pharmacological management. The circulating microRNAs present in plasma are promising biomarkers of PD with dementia (PDD) due to their critical roles in synaptic plasticity and the regulation of neurodegeneration-associated proteins. In this study, we aimed to identify plasma microRNAs that may differentiate PD with or without cognitive impairment. Global microRNA expression was obtained from a discovery set of 123 participants who were divided into four groups, namely normal controls (HC), PD with no dementia (PDND), PD with mild cognitive impairment (PD-MCI), and PDD, using next-generation sequencing. The BOLD selector was used for microRNA candidate selection. Six miRNAs, namely miR-203a-3p, miR-626, miR-662, miR-3182, miR-4274, and miR-4295, were clustered as potential candidates for use in identifying PDND from PD-MCI. Another independent cohort of 120 participants was further recruited in a validation step in order to detect candidate microRNAs via droplet digital PCR (ddPCR), which was used for its high sensitivity in detecting low miRNA concentrations. Our results show that the ratio of miR-203a-3p/miR-16-5p, in which miR-16-5p was used as a reference control miRNA, was significantly increased in PDD compared to that seen in PD-MCI and PDND individually, and was negatively correlated with the MoCA scores (r = -0.237, p = 0.024) in patients with PD. However, there was no significant difference in the ratio of miR-203a-3p/miR-16-5p between HC and PDND, PD-MCI, or PDD individually. The ROC curve of the logistic regression model, factoring in the variables of age, the ratio of miR-203a-3p/miR-16-5p, and the UPDRS III score, demonstrated an AUC of 0.883. Our findings suggest that the ratio of miR-203a-3p/miR-16-5p, used with age and motor score, could be a predictor of dementia among PD patients.

Changes in source composition of wet nitrate deposition after air pollution control in a typical area of Southeast China.

In recent years, China has adopted numerous policies and regulations to control NOx emissions to further alleviate the adverse impacts of NO3--N deposition. However, the variation in wet NO3--N deposition under such policies is not clear. In this study, the southeastern area, with highly developed industries and traditional agriculture, was selected to explore the variation in NO3--N deposition and its sources changes after such air pollution control through field observation and isotope tracing. Results showed that the annual mean concentrations of NO3--N in precipitation were 0.67 mg L-1 and 0.54 mg L-1 in 2014-2015 and 2021-2022, respectively. The average wet NO3--N depositions in 2014-2015 and 2021-2022 was 7.76 kg N ha-1 yr-1 and 5.03 kg N ha-1 yr-1, respectively, indicating a 35% decrease. The δ15N-NO3- and δ18O-NO3- values were lower in warm seasons and higher in cold seasons, and both showed a lower trend in 2021-2022 compared with 2014-2015. The Bayesian model results showed that the NOx emitted from coal-powered plants contributed 53.6% to wet NO3--N deposition, followed by vehicle exhaust (22.9%), other sources (17.1%), and soil emissions (6.4%) during 2014-2015. However, the contribution of vehicle exhaust (33.3%) overpassed the coal combustion (32.3%) and followed by other sources (25.4%) and soil emissions (9.0%) in 2021-2022. Apart from the control of air pollution, meteorological factors such as temperature, precipitation, and solar radiation are closely related to the changes in atmospheric N transformation and deposition. The results suggest phased achievements in air pollution control and that more attention should be paid to the control of motor vehicle exhaust pollution in the future, at the same time maintaining current actions and supervision of coal-powered plants.

Effective evaluations of community nursing on rehabilitation for stroke survivors: A meta-analysis.

BACKGROUND: Long-term rehabilitation of stroke survivors is often difficult and new tools to improve quality of life should be proposed. Community nursing can be a cost-effective tool to positively impact the lives of stroke survivors. This meta-analysis aimed to comprehensively evaluate the effects of community nursing on rehabilitation for stroke survivors. METHODS: The Cochrane Library, PubMed, Web of Science, CINAHL Plus, Embase, PEDro, China Knowledge Resource Integrated Database (CNKI), WANFANG, and WEIPU databases were comprehensively searched from their inception to April 18, 2023. The revised Cochrane risk-of-bias tool for RCTs(RoB 2 tool) was used to assess the quality of the included studies. Meta-analysis was conducted using the Stata 12.0 software package and Review Manager v5.3 software. RESULTS: A total of 25 randomized controlled trials with 2537 participants were included in the meta-analysis. Compared with the control group, community nursing combined with routine nursing had a significantly superior effect on the Barthel Index(BI), Fugl-Meyer(FMA), National Institutes of Health Stroke Scale(NIHSS), Self-rating Anxiety Scale(SAS), and Self-rating Depression Scale(SDS) scores for stroke survivors (BI: MD: 18.48, 95 % CI [16.87, 20.08], P < 0.00001; FMA: MD: 12.61, 95 % CI [10.44, 14.78], P < 0.00001; NIHSS: MD: -2.94, 95 % CI [-3.50, -2.37], P < 0.00001; SAS: MD: -8.19; 95 % CI: [-9.46, -6.92], P < 0.00001; SDS: MD: -6.46 95 % CI [-7.23, -5.70], P < 0.00001). Subgroup analysis demonstrated that routine nursing, health education, exercise rehabilitation nursing and psychological nursing combined with different community nursing measures were significant in rehabilitation for stroke survivors and there was no heterogeneous in the studies of each subgroup(P > 0.1, I2 < 50 %). CONCLUSION: This meta-analysis demonstrated that community nursing combined with routine nursing might improve activities of daily living, motor function and nerve function, and relieve anxiety and depression in stroke survivors. Overall, community nursing had a significant effect on rehabilitation of stroke survivors. However, this study still has limitations such as the overestimation effects caused by the sample size and the risk of bias caused by interventions. Future research will attempt to overcome these limitations and comprehensively assess the effect of community nursing on the rehabilitation of stroke survivors.

Prenatal exposure of diabetes and progestin-mediated autistic biomarker in peripheral blood mononuclear cells.

Despite the importance of early diagnosis and intervention, the diagnosis of autism spectrum disorders (ASDs) remains delayed as it is mostly based on clinical symptoms and abnormal behaviours appearing after 2 years of age. Identification of autistic markers remains a top priority in achieving an early and effective ASD diagnosis. We have previously reported that prenatal exposure of hormones or diabetes triggers epigenetic changes and oxidative stress, resulting in gene suppression with autism-like behaviours in offspring. Here, a potential biomarker for ASD diagnosis was established through gene analysis in peripheral blood mononuclear cells (PBMCs). The study from in vivo mouse showed that prenatal hormone exposure or maternal diabetes suppresses mRNA expression of estrogen-related receptor α (ERRα), superoxide dismutase 2 (SOD2), G protein-coupled estrogen receptor (GPER) and retinoic acid-related orphan receptor α (RORA) in the brain as well as oxidative stress and mitochondrial dysfunction, subsequently triggering autism-like behaviour in mouse offspring. Also, similar gene suppression was found in hematopoietic stem cells (HSCs) and PBMC, with inherited epigenetic changes being identified on the related promoters. The human case-control study found that mRNA levels of ERRα, SOD2, GPER and RORA were significantly reduced in PBMC from ASD subjects (n = 132) compared with typically developing (n = 135) group. The receiver operating characteristic curve showed a .869 ± .021 of area under the curve for ASD subjects with 95% confidence interval of .829-.909, together with 1.000 of sensitivity and .856 of specificity. In conclusion, the combined mRNA expression in PBMC based on prenatal factor exposure-mediated gene suppression could be a potential biomarker for ASD diagnosis.

Lipid Membrane Alterations in Tumor Spheroids Revealed by Fluorescence Lifetime Microscopy Imaging.

Three-dimensional (3D) cultured tumor spheroid models, as one type of in vitro model, have been proven to have more physiological similarities to in vivo animal models than cells in 2D cultures. Tumor spheroids have been widely used in preclinical experiments of anticancer drug treatments, providing reliable data in pathogenetic research. Currently, different 3D cell culture conditions, even in the same cell line, generate heterogeneous spheroids in morphology and size, resulting in different growth rates or drug-killing responses. Therefore, the measurement and evaluation of the properties of tumor spheroids have become highly demanding tasks with huge challenges. For functional characterization of tumor spheroids, the microenvironment sensitivity and quantitative properties of the fluorescence lifetime microscopy imaging (FLIM) technique have great advantages for improving the reliability of cell physiological testing. In this paper, we have proposed a FLIM-based approach to observe the lipid components labeled with Nile red of cells in both 3D and 2D cultures. The imaging data and analysis provided basic information on the sizes, morphologies, and cell membrane fluorescence lifetime values of the tumor spheroids. FLIM data showed that the microenvironment of the cell membrane in the 3D model was largely altered compared to that in the 2D culture. Next, a series of parameters that may influence the lipid components of tumor cells and tumor spheroids were tested by FLIM, including pH, viscosity, and polarity. The results showed that pH and viscosity contributed little to the change in fluorescence lifetime values, while the change in cell membrane polarity was the main cause of the alterations in fluorescence lifetime data, suggesting that cell membrane polarity should be considered a marker in distinguishing tumor spheroids from cellular physiological status. In conclusion, this FLIM-based testing process has been proven to be a quantitative method for measuring the differences between the cells of the 3D model from the 2D cultured cells with satisfactory sensitivity and accuracy, providing a high potential standard assay in the quality evaluation and control of tumor spheroids for future anticancer drug development.

The ubiquitin-binding protein MdRAD23D1 mediates drought response by regulating degradation of the proline-rich protein MdPRP6 in apple (Malus domestica).

RAD23 (RADIATION SENSITIVE23) proteins are a group of UBL-UBA (ubiquitin-like-ubiquitin-associated) proteins that shuttle ubiquitylated proteins to the 26S proteasome for breakdown. Drought stress is a major environmental constraint that limits plant growth and production, but whether RAD23 proteins are involved in this process is unclear. Here, we demonstrated that a shuttle protein, MdRAD23D1, mediated drought response in apple plants (Malus domestica). MdRAD23D1 levels increased under drought stress, and its suppression resulted in decreased stress tolerance in apple plants. Through in vitro and in vivo assays, we demonstrated that MdRAD23D1 interacted with a proline-rich protein MdPRP6, resulting in the degradation of MdPRP6 by the 26S proteasome. And MdRAD23D1 accelerated the degradation of MdPRP6 under drought stress. Suppression of MdPRP6 resulted in enhanced drought tolerance in apple plants, mainly because the free proline accumulation is changed. And the free proline is also involved in MdRAD23D1-mediated drought response. Taken together, these findings demonstrated that MdRAD23D1 and MdPRP6 oppositely regulated drought response. MdRAD23D1 levels increased under drought, accelerating the degradation of MdPRP6. MdPRP6 negatively regulated drought response, probably by regulating proline accumulation. Thus, "MdRAD23D1-MdPRP6" conferred drought stress tolerance in apple plants.

Outcomes of leadless pacemaker implantation after cardiac surgery and transcatheter structural valve interventions.

INTRODUCTION: Permanent pacing indications are common after cardiac surgery and transcatheter structural valve interventions. Leadless pacemakers (LPs) have emerged as a useful alternative to transvenous pacemakers. However, current commercially available LPs are unable to provide atrial pacing or cardiac resynchronization and relatively little is known about LP outcomes after cardiac surgery and transcatheter valve interventions. METHODS: This retrospective study included patients who received a Micra VR (MicraTM MC1VR01) or Micra AV (MicraTM MC1AVR1) (Medtronic) leadless pacemaker following cardiac surgery or transcatheter structural valve intervention between September 2014 and September 2022. Device performance and clinical outcomes, including ventricular pacing burden, ejection fraction, and need for conversion to transvenous pacing systems, were evaluated during follow-up. RESULTS: A total of 78 patients were included, of whom 40 received a Micra VR LP implant, and 38 received a Micra AV LP implant. The mean age of the cohort was 65.9 ± 17.9 years, and 48.1% were females. The follow-up duration for the entire cohort was 1.3 ± 1.1 years: 1.6 ± 1.3 years for the Micra VR group and 0.8 ± 0.5 years for the Micra AV group. Among the cohort, 50 patients had undergone cardiac surgery and 28 underwent transcatheter structural valve interventions. Device electrical performance was excellent during follow-up, with a small but clinically insignificant increase in ventricular pacing threshold and a slight decrease in pacing impedance. The mean right ventricle pacing (RVP) burden significantly decreased over time in the entire cohort (74.3% ± 37.2% postprocedure vs. 47.7% ± 40.6% at last follow-up, p < .001), and left ventricle ejection fraction (LVEF) showed a modest but significant downward trend during follow-up (55.0% ± 10.6% vs. 51.5% ± 11.2% p < .001). Patients with Micra VR implants had significantly reduced LVEF during follow-up (54.1% ± 11.9% vs. 48.8% ± 11.9%, p = .003), whereas LVEF appeared stable in the Micra AV group during follow-up (56.1% ± 9.0% vs. 54.6% ± 9.7%, p = .06). Six patients (7.7%) required conversion to transvenous pacing systems, four who required cardiac resynchronization for drop in LVEF with high RVP burden and two who required dual-chamber pacemakers for symptomatic sinus node dysfunction. CONCLUSION: Leadless pacemakers provide a useful alternative to transvenous pacemakers in appropriately selected patients after cardiac surgery and transcatheter structural valve interventions. Device performance is excellent over medium-term follow-up. However, a significant minority of patients require conversion to transvenous pacing systems for cardiac resynchronization or atrial pacing support, demonstrating the need for close electrophysiologic follow-up in this cohort.

Myofiber directs macrophages IL-10-Vav1-Rac1 efferocytosis pathway in inflamed muscle following CTX myoinjury by activating the intrinsic TGF-ß signaling.

BACKGROUND: To explore the role of skeletal muscle specific TGF-ß signaling on macrophages efferocytosis in inflamed muscle caused by Cardiotoxin (CTX) injection. METHODS: CTX myoinjury was manipulated in TGF-ßr2flox/flox (control) mice or transgenic mice with TGF-ß receptor 2 (TGF-ßr2) being specifically deleted in skeletal muscle (SM TGF-ßr2-/-). Gene levels of TGF-ß signal molecules, special inflammatory mediators in damaged muscle or in cultured and differentiated myogenic precursor cells (MPC-myotubes) were monitored by transcriptome microarray or qRT-PCR. TGF-ß pathway molecules, myokines and embryonic myosin heavy chain in regenerating myofibers, the phenotype and efferocytosis of macrophages were evaluated by immunofluorescence, immunoblotting, Luminex, or FACS analysis. In vitro apoptotic cells were prepared by UV-irradiation. RESULTS: In control mice, TGF-ß-Smad2/3 signaling were significantly up-regulated in regenerating centronuclear myofibers after CTX-myoinjury. More severe muscle inflammation was caused by the deficiency of muscle TGF-ß signaling, with the increased number of M1, but the decreased number of M2 macrophages. Notably, the deficiency of TGF-ß signaling in myofibers dramatically affected on the ability of macrophages to conduct efferocytosis, marked by the decreased number of Annexin-V-F4/80+Tunel+ macrophages in inflamed muscle, and the impaired uptake of macrophages to PKH67+ apoptotic cells transferred into damaged muscle. Further, our study suggested that, the intrinsic TGF-ß signaling directed IL-10-Vav1-Rac1 efferocytosis signaling in muscle macrophages. CONCLUSIONS: Our data demonstrate that muscle inflammation can be suppressed potentially by activating the intrinsic TGF-ß signaling in myofibers to promote IL-10 dependent-macrophages efferocytosis. Video Abstract.

Equity and trends in general practitioners' allocation in China: based on ten years of data from 2012 to 2021.

BACKGROUND: General practitioners (GP) are the gatekeepers of residents' health, 2021 is the 10th year of the establishment of the GP system in China. This study aims to assess the equity and trends of GP allocation in China from 2012 to 2021, summarize the efforts and progress of GPs in China during the decade, predict the development trend of GPs in mainland China in the next 5 years to provide a reference for regional health planning and rational allocation of GPs in China. METHODS: Data from 2012 to 2021 on GPs in 22 provinces, 5 autonomous regions, and 4 municipalities directly under the central government in mainland China (excluding Hong Kong, Macao, and Taiwan) are collected by us. Gini coefficient, Lorenz curve and health resource agglomeration degree (HRAD) were used to analyze the equity of the allocation of GPs in China from different dimensions, a Grey prediction model was used to forecast the number of GPs in 2022-2026. RESULTS: The number of GPs in mainland China increased from 109 794 to 434 868 from 2012 to 2021, with 3.08 GPs per 10 000 people in 2021. The Gini coefficient of GPs allocation by population in China decreased from 0.312 to 0.147 from 2012 to 2021, while the Gini coefficient of geographic dimension remained between 0.700 and 0.750. Compared with the degree of curvature of the Lorenz curve in the geographic dimension, the degree of curvature of the population and economic dimension were smaller. In 2021, the HRAD in the Eastern region was 4.618, the Central region was 1.493, with different degrees of imbalance among regions, the HRAD/PAD (population agglomeration degree) in the Eastern, Central and Western regions were 1.196, 0.880 and 0.821, respectively. GPs in the Eastern region is still concentrated, while the Central and Western regions were at a similar level, GPs were more scarce. The GM (1,1) model predicts that the number of GPs in mainland China will reach about 720 000 in 2026, the number of GPs per 10 000 people will reach 4.9. CONCLUSION: After a decade of development, the number of GPs in China has increased significantly. It has reached the goal of the GP system when it was first established. However, the equity of the geographical dimension, both in terms of Gini coefficient and HRAD, has great differences between different regions. The average Gini coefficient at the geographic dimension is 0.723. The average HRAD index was 4.969 in the East and 0.293 in the West. The Western region has the problem of insufficient GP allocation in both population and geographical dimension. In the future, the number of GPs in China will continue to grow rapidly with the support of policies. The "2030" goal, proposed in 2018, is expected to be achieved by 2026. Due to certain factors (such as COVID-19), the actual situation may be different from the predicted results.

IRE1α arm of unfolded protein response in muscle-specific TGF-ß signaling-mediated regulation of muscle cell immunological properties.

Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are involved in various muscle pathological states. The IRE1α arm of UPR can affect immunological properties of myofiber through restraining p38 mitogen-activated protein kinases (MAPK) activation under inflammatory milieu. However, the relevant pathway molecules regulating the initiation of the IRE1α arm in myofiber remain unclear. In this work, expression of transforming growth factor-beta (TGF-ß) and TGF-ß receptor II (TGF-ßr2), and UPR pathway activation were examined in cardiotoxin (CTX)-damaged mouse muscle, which revealed the activation of TGF-ß signaling and UPR in CTX-damaged muscle and in regenerating myofibers. Using control or transgenic mice with TGF-ßr2 deleted in skeletal muscle (SM TGF-ßr2-/-) and the derived primary differentiating myogenic precursor cells (MPCs) treated with/without ERS activator or inhibitor, IRE1α pathway inhibitor, or TGF-ß signaling activator, this study further revealed an essential role of intrinsic TGF-ß signaling in regulating muscle cell to express inflammation-related molecules including H-2Kb, H2-Eα, TLR3, and special myokines. TGF-ß signaling prompted UPR IRE1α arm and restrained p38 MAPK activation in myofiber under inflammatory milieu. This study uncovers a previously unrecognized function of TGF-ß signaling acting as an upstream factor controlling myofiber immune capacities in the inflamed state through the UPR-IRE1α-p38 MAPK pathway.

A study of primary health care service efficiency and its spatial correlation in China.

BACKGROUND: China's primary health care system has undergone major changes since the new round of medical reform in 2009, but the current status of primary health care institution service efficiency is still unsatisfactory. The purpose of this study is to compare and evaluate the China's primary health care institution service efficiency and provide a reference for improving the efficiency and promoting the development of primary health care institution. METHODS: Based on panel data of 31 provinces (municipalities directly under the central government and autonomous regions) in mainland China from 2011 to 2020, using the super efficiency slack-based measure-data envelopment analysis model, to analyze the data from a static perspective, and the changes in the efficiency of primary health care services were analyzed from a dynamic perspective by using the Malmquist index method. Spatial autocorrelation analysis method was used to verify the spatial correlation of primary health care service efficiency among various regions. RESULTS: The number of Primary health care institutions increased from 918,000 in 2011 to 970,000 in 2020. The average primary health care institution service efficiency in the northeastern region including Jilin (0.324), Heilongjiang (0.460), Liaoning (0.453) and northern regions such as Shaanxi (0.344) and Neimenggu (0.403) was at a low level, while the eastern coastal regions such as Guangdong (1.116), Zhejiang (1.211), Shanghai (1.402) have higher average service efficiency levels. The global Moran's I showed the existence of spatial autocorrelation, and the local Moran's I index suggested that the problem of uneven regional development was prominent, showing a contiguous regional distribution pattern. Among them, H-H (high-efficiency regions) were mainly concentrated in Jiangsu, Anhui and Shanghai, and L-L regions (low-efficiency regions) were mostly in northern and northeastern China. CONCLUSION: The service efficiency of primary health care institution in China showed a rising trend in general, but the overall average efficiency was still at a low level, and there were significant geographical differences, which showed a spatial distribution of "high in the east and low in the west, high in the south and low in the north". The northwestern region, after receiving relevant support, has seen a rapid development of primary health care, and its efficiency was steadily improving and gradually reaching a high level. The average primary health care institution service efficiency in the northeastern region including the northern region of China was at a low level, while the average efficiency in the eastern coastal region and some economically developed regions was high, which also verifies the dependence and high symbiosis of primary health care institution service efficiency on regional economy.

Muscle cytotoxicity and immuno-reactivity analysis of the porous carbon nanospheres fabricated by high temperature calcination.

Carbon-based nanomaterials have a high specific surface area, biocompatibility, and controlled mesopore structures. These characteristics make carbon nanospheres excellent carriers for drugs, biological dyes, photosensitizers, etc. Nevertheless, little is known about the impact of topological features on the surface of carbon nanomaterials on their in vivo immunoreactivity. In this study, we fabricated mesoporous carbon nanoparticles (MCNs) and solvent-processable carbon vesicles (CVs) by high-temperature calcination. The hematoxylin and eosin (H&E) staining suggested CVs' relatively poor dispersion capacity compared to MCNs and carbon precursors (CPs), leading to more severe muscle inflammation and necrosis. Immunostaining and Fluorescence Activated Cell Sorter (FACS) analysis further showed that both MCNs and CVs triggered a transient immune response in transplanted muscle and muscle-draining lymph nodes, but did not alter muscle resistance to exogenous viruses. In conclusion, this study provides insights into how carbon nanoparticles modulate the activation of immune responses in vivo.

An Efficient Synthesis of Naphtho[2,3-b]furan-4,9-diones via Visible-Light-Mediated [3+2] Cycloaddition Reaction.

Naphtho[2,3-b]furan-4,9-dione is an important privileged structural motif which is present in natural products, drugs, and drug candidates. Herein, visible-light-mediated [3+2] cycloaddition reaction for the synthesis of naphtho[2,3-b]furan-4,9-diones and dihydronaphtho[2,3-b]furan-4,9-diones has been developed. Under environmentally friendly conditions, a variety of title compounds were delivered in good yields. This new protocol shows excellent regioselectivity and remarkable functional group tolerance. This approach provides a powerful, green, efficient, and facile means to expand the structural diversity of naphtho[2,3-b]furan-4,9-diones and dihydronaph-tho[2,3-b]furan-4,9-diones as promising scaffolds for novel drug discovery.

Key technology of HX-NGS adsorption for treating organic matter in orchid carbon wastewater.

In this article, COD, volatile phenol and ammonia nitrogen concentrations of the wastewater from semicarbon are reported as 38,000; 6,400 and 5,700 mg/L, respectively. According to the field test, when the pH of the wastewater is 9, the field test temperature is 20 °C, the adsorption time is 30 min and the optimal dosing ratio of nitrogen-doped gasification slag (HX-NGS) to the wastewater is 1:4, HX-NGS has the best removal effect on COD, volatile phenol and ammonia nitrogen in the wastewater from the semicarbon. The removal rates of COD, volatile phenol and ammonia nitrogen are 94, 91 and 85%, respectively, and the concentrations of the remaining COD, volatile phenol and ammonia nitrogen are 2,280, 576 and 855 mg/L, respectively, after regeneration, the material HX-NGS has a good effect on the treatment of the wastewater from the semicarbon. The reuse rate of the adsorption material is at least eight times. The adsorption effect of the material HX-NGS conforms to the mechanism law of dynamics and thermodynamics.

Regenerating myofiber directs Tregs and Th17 responses in inflamed muscle through the intrinsic TGF-ß signaling-mediated IL-6 production.

Transforming growth factor-ß (TGF-ß) is considered to be an important immune regulatory cytokine. However, it remains unknown whether and how the muscle fiber specific-TGF-ß signaling is directly involved in intramuscular inflammatory regulation by affecting T cells. Here, we addressed these in a mouse tibialis anterior muscle Cardiotoxin injection-induced injury repair model in muscle creatine kinase (MCK)-Cre control or transgenic mice with TGF-ß receptor II (TGF-ßr2) being specifically deleted in muscle cells (SM TGF-ßr2-/-). In control mice, TGF-ß2 and TGF-ßr2 were found significantly upregulated in muscle after the acute injury. In mutant mice, deficiency of TGF-ß signaling in muscle cells caused more serious muscle inflammation, with the increased infiltration of macrophages and CD4+ T cells at the degeneration stage (D4) and the early stage of regeneration (D7) after myoinjury. Notably, the loss of TGF-ß signaling in myofibers dramatically affected CD4+ T cell function and delayed T cells withdrawal at the later stage of muscle regeneration (D10 and D15), marked by the elevated Th17, but the impaired Tregs response. Furthermore, in vivo and in vitro, the intrinsic TGF-ß signaling affected immune behaviors of muscle cells and directed CD4+ T cells differentiation by impairing IL-6 production and release. It suggests that local muscle inflammation can be inhibited potentially by directly activating the TGF-ß signaling pathway in muscle cells to suppress Th17, but induce Tregs responses. Thus, according to the results of this study, we found a new idea for the control of local acute inflammation in skeletal muscle.NEW & NOTEWORTHY Myofiber mediates muscle inflammatory response through activating the intrinsic TGF-ß signaling. The specific TGF-ß signaling activation contributes to myofiber IL-6 production and directs muscle-specific Th17 and Treg cell responses.

Thoracic radiotherapy may improve the outcome of extensive stage small cell lung carcinoma patients treated with first-line immunotherapy plus chemotherapy.

OBJECTIVE: Immunotherapy plus etoposide and platinum (EP)-based chemotherapy is the standard of care for patients with extensive stage-small cell lung carcinoma (ES-SCLC). In the era of immunotherapy, the role of thoracic radiotherapy for ES-SCLC remains unclear. METHODS: We retrospectively included ES-SCLC patients treated with first-line EP-based chemotherapy plus atezolizumab or durvalumab at Taichung Veterans General Hospital to evaluate the prognostic role and safety of thoracic radiotherapy. RESULTS: A total of 22 patients were included. The median age was 64 years and most of them were male and smokers. Sixteen patients (72.7%) received durvalumab, while the other 6 patients (27.3%) underwent atezolizumab treatment. Among these patients, 11 (50.0%) had a history of thoracic radiotherapy. There was no significant difference in baseline characteristics between patients with and without thoracic radiotherapy. In the overall population, the objective response rate to immunotherapy plus chemotherapy was 73.7%. The progression-free survival and overall survival were 6.0 months (95% CI: 4.0-7.9) and 13.8 months (95% CI: 8.0-19.6), respectively. The overall survival was significantly longer in patients with thoracic radiotherapy (not-reached [NR] [95% CI NR-NR] vs. 9.6 months [95% CI 2.5-16.6]), respectively ( P value by log-rank test <0.001). Both multivariate analysis and subgroup analysis specifically comparing patients with consolidative thoracic radiotherapy and patients with clinical benefits to systemic therapy who did not undergo thoracic radiotherapy indicated that thoracic radiotherapy improved survival. CONCLUSION: The real-world efficacy of EP-based chemotherapy plus atezolizumab or durvalumab was comparable with that of clinical trials. Thoracic radiotherapy may improve the outcome of ES-SCLC.