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Abstract Aim This study aimed to discover risk factors for death in patients with critical COVID-19 infection in order to identify patients with a higher risk of death at an early stage. Methods We retrospectively analyzed the clinical data of patients with critical COVID-19 infection from April 2022 to June 2022. Data were collected from the electronic medical records. Propensity matching scores were used to reduce the effect of confounding factors, such as patient baseline variables. Independent risk factors affecting patient prognosis were assessed using univariate logistic regression and multivariate logistic regression analysis. Restricted cubic spline curves were used to assess the relationship between independent and dependent variables. Results The data of 132 patients with critical COVID-19 infection were included in the study. Of the 132 patients, 79 survived and 53 died. Among laboratory indicators, patients who died had higher proportions of abnormalities in procalcitonin, aspartate aminotransferase (AST), creatinine, cardiac troponin I, and myoglobin. Univariate and multivariate logistic regression analyses suggested that abnormal AST (OR = 4.98, P = 0.02), creatinine (OR = 7.93, P = 0.021), and myoglobin (OR = 103.08, P = 0.002) were independent risk factors for death. After correction for AST and creatinine, a linear relationship between myoglobin and risk of death in patients was found using restricted cubic splines. Conclusion High myoglobin level is an independent risk factor for death and is therefore a prognostic marker in elderly patients with severe COVID-19 infection.

Abstract We leverage machine learning approaches to adapt nanopore sequencing basecallers for nucleotide modification detection. We first apply the incremental learning (IL) technique to improve the basecalling of modification-rich sequences, which are usually of high biological interest. With sequence backbones resolved, we further run anomaly detection (AD) on individual nucleotides to determine their modification status. By this means, our pipeline promises the single-molecule, single-nucleotide, and sequence context-free detection of modifications. We benchmark the pipeline using control oligos, further apply it in the basecalling of densely-modified yeast tRNAs and E.coli genomic DNAs, the cross-species detection of N6-methyladenosine (m6A) in mammalian mRNAs, and the simultaneous detection of N1-methyladenosine (m1A) and m6A in human mRNAs. Our IL-AD workflow is available at: https://github.com/wangziyuan66/IL-AD .

Polypyrimidine tract-binding protein 1 (PTBP1) plays an essential role in splicing and post-transcriptional regulation. Moreover, PTBP1 has been implicated as a causal factor in tumorigenesis. However, the involvement of PTBP1 in cellular senescence, a key biological process in aging and cancer suppression, remains to be clarified. Here, it is shown that PTBP1 is associated with the facilitation of tumor growth and the prognosis in lung adenocarcinoma (LUAD). PTBP1 exhibited significantly increased expression in various cancer types including LUAD and showed consistently decreased expression in multiple cellular senescence models. Suppression of PTBP1 induced cellular senescence in LUAD cells. In terms of molecular mechanisms, the silencing of PTBP1 enhanced the skipping of exon 3 in F-box protein 5 (FBXO5), resulting in the generation of a less stable RNA splice variant, FBXO5-S, which subsequently reduces the overall FBXO5 expression. Additionally, downregulation of FBXO5 was found to induce senescence in LUAD. Collectively, these findings illustrate that PTBP1 possesses an oncogenic function in LUAD through inhibiting senescence, and that targeting aberrant splicing mediated by PTBP1 has therapeutic potential in cancer treatment.

Abstract It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of frailty. Here, we conducted a prospective study to evaluate the feasibility and benefits of dynamic frailty-tailored therapy (DynaFiT) in elderly patients. Patients with newly diagnosed MM (aged ≥ 65 years) received eight induction cycles of bortezomib, lenalidomide, and dexamethasone (daratumumab was recommended for frail patients), with treatment intensity adjusted according to longitudinal changes in the frailty category (IMWG-FI) at each cycle. Of 90 patients, 33 (37%), 16 (18%), and 41 (45%) were fit, intermediate fit, and frail at baseline, respectively. Of 75 patients who had geriatric assessment at least twice, 28 (37%) experienced frailty category changes at least once. At analysis, 15/26 (58%) frail patients improved (27% became fit and 31% became intermediate fit), 4/15 (27%) intermediate fit patients either improved or deteriorated (two for each), and 6/30 (20%) fit patients deteriorated. During induction, 34/90 (38%) patients discontinued treatment, including 10/33 (30%) fit, 4/16 (25%) intermediate fit, and 20/41 (49%) frail; 14/40 (35%) frail patients discontinued treatment within the first two cycles, mainly because of non-hematologic toxicity (mostly infections). For fit, intermediate-fit, and frail patients, the overall response rate was 100%, 93%, and 73%, respectively; one-year overall survival was 90%, 75%, and 54%, respectively. Therefore, the individualized DynaFiT is feasible and promising for heterogeneous elderly patients.

Land subsidence, marked by a decline in surface elevation, poses a significant threat to urban infrastructure and safety. Accurate subsidence information and a reliable prediction model are crucial for prevention and control. In this study, we used persistent scatterer interferometric synthetic aperture radar (PS-InSAR) technology to obtain long-term land subsidence data and analyzed subsidence characteristics in Decheng District. By integrating hydrogeological and groundwater data, we developed a three-dimensional groundwater flow and one-dimensional compaction model through numerical simulation. Furthermore, the subsidence data monitored by PS-InSAR were used to further constrain and validate the model. The evolution trend of land subsidence under different groundwater exploitation scenarios was predicted and analyzed. The results showed that from May 2017 to December 2021, the cumulative maximum subsidence in Decheng District reached −173 mm. The subsidence area is mainly concentrated in the northern area, and its subsidence center is near Qiaoyuan Town. According to the Land Subsidence Prevention and Control Plan of Dezhou City, Shandong Province (2018–2025), we set up different groundwater mining scenarios with the goal that the rate of land subsidence in the key prevention and control area is less than 35 mm/yr in 2025.The Fluid-solid coupled model prediction analysis results indicated that a 30% reduction in groundwater exploitation is reasonable.

Abstract Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity in obese male mice. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.

ObjectiveParent-child relationship is critical for children’s well-being. In China, the large number of left-behind children (LBC, one or both parents leaving for work for at least 6 months) raises public concern. Although LBC often report poor mental health status and higher alienation towards parents, the dynamic trend of subjective well-being in this population, as well as the prediction of alienation towards parents on LBC’s subjective well-being, remain unrevealed. This study aimed to examine the dynamic trend of subjective well-being in Chinese LBC and further explore the predictional influence of alienation towards parents, with resilience as a potential mediator.MethodsWe recruited 916 rural LBC in China and investigated them at five waves (baseline, and 1, 3, 6, and 12 months later) using Inventory of Alienation towards Parents (IAP), Resilience Scale for Chinese Adolescents (RSCA) and Subjective Happiness Scale (SHS). We used hierarchical linear modeling (HLM) for analysis.ResultsAt baseline, no significant differences were found in the scores of alienation towards parents, resilience, and subjective well-being on gender, grade, or type of LBC. A significant correlation existed between the scores of alienation towards parents, resilience, and subjective well-being. HLM showed a linear increase in the subjective well-being of rural LBC. Alienation toward both mother and father negatively predicted the developmental trajectory of children’s subjective well-being over 12 months. Moreover, resilience partially mediated this prediction.ConclusionThis study is among the first to reveal that alienation towards parents predicts the developmental trajectory of later LBC’s subjective well-being, with resilience as a mediator. These findings warrant the necessity of paying attention to alienation toward parents to ensure the mental health of LBC, giving valuable guidance to parents, schools and governments.

BackgroundEarly prediction of prognosis may help early treatment measures to reduce mortality in critically ill coronavirus disease (COVID-19) patients. The study aimed to develop a mortality prediction model for critically ill COVID-19 patients.MethodsThis retrospective study analyzed the clinical data of critically ill COVID-19 patients in an intensive care unit between April and June 2022. Propensity matching scores were used to reduce the effect of confounding factors. A predictive model was built using logistic regression analysis and visualized using a nomogram. Calibration and receiver operating characteristic (ROC) curves were used to estimate the accuracy and predictive value of the model. Decision curve analysis (DCA) was used to examine the value of the model for clinical interventions.ResultsIn total, 137 critically ill COVID-19 patients were enrolled; 84 survived, and 53 died. Univariate and multivariate logistic regression analyses revealed that aspartate aminotransferase (AST), creatinine, and myoglobin levels were independent prognostic factors. We constructed logistic regression prediction models using the seven least absolute shrinkage and selection operator regression-selected variables (hematocrit, red blood cell distribution width-standard deviation, procalcitonin, AST, creatinine, potassium, and myoglobin; Model 1) and three independent factor variables (Model 2). The calibration curves suggested that the actual predictions of the two models were similar to the ideal predictions. The ROC curve indicated that both models had good predictive power, and Model 1 had better predictive power than Model 2. The DCA results suggested that the model intervention was beneficial to patients and patients benefited more from Model 1 than from Model 2.ConclusionThe predictive model constructed using characteristic variables screened using LASSO regression can accurately predict the prognosis of critically ill COVID-19 patients. This model can assist clinicians in implementing early interventions. External validation by prospective large-sample studies is required.

This study emphasises the growing relevance of hydrogen as a green energy source in meeting the growing need for sustainable energy solutions. It foregrounds the importance of assessing the environmental consequences of hydrogen-generating processes for their long-term viability. The article compares several hydrogen production processes in terms of scalability, cost-effectiveness, and technical improvements. It also investigates the environmental effects of each approach, considering crucial elements such as greenhouse gas emissions, water use, land needs, and waste creation. Different industrial techniques have distinct environmental consequences. While steam methane reforming is cost-effective and has a high production capacity, it is coupled with large carbon emissions. Electrolysis, a technology that uses renewable resources, is appealing but requires a lot of energy. Thermochemical and biomass gasification processes show promise for long-term hydrogen generation, but further technological advancement is required. The research investigates techniques for improving the environmental friendliness of hydrogen generation through the use of renewable energy sources. Its ultimate purpose is to offer readers a thorough awareness of the environmental effects of various hydrogen generation strategies, allowing them to make educated judgements about ecologically friendly ways. It can ease the transition to a cleaner hydrogen-powered economy by considering both technological feasibility and environmental issues, enabling a more ecologically conscious and climate-friendly energy landscape.

Background: Synchronizing a TMS pulse with a person's underlying EEG rhythm can modify the brain's response. It is unclear if synchronizing rTMS trains might boost the antidepressant effect of TMS. In this first-in-human trial, we demonstrated that a single TMS pulse over the prefrontal cortex produces larger effects in the anterior cingulate depending on when it is fired relative to the individual's EEG alpha phase. Objective/hypotheses: We had three hypotheses. 1) It is feasible to synchronize repetitive TMS (rTMS) delivery to a person's preferred prefrontal alpha phase in each train of every session during a 30-visit TMS depression treatment course. 2) EEG-synchronized rTMS would produce progressive entrainment greater than unsynchronized (UNSYNC) rTMS. And 3) SYNC TMS would have better antidepressant effects than UNSYNC (remission, final Hamilton Depression Rating

Existing cleaning devices for edible sunflower have a low cleaning efficiency, high cleaning loss rate, and high impurity rate; therefore, a wind-sieve-type cleaning device for edible sunflower harvesting was designed. According to the characteristics of dislodged objects, a vibrating screen for the device was designed, and the dislodged edible sunflower objects in the device were used for a mechanical analysis of the force conditions to determine the displacement of the different edible sunflower objects dislodged by the action of airflow. Using FLUENT-DEM gas–solid coupling simulation technology, the velocity of the flow field, the velocity vector, and the trajectory of the dislodged objects inside the cleaning device were analyzed, and the law of motion applied to the airflow and the dislodged objects inside the device was clarified. According to the results of the coupled simulation analysis, the key factors affecting the operation of the cleaning device were wind speed, vibration frequency, and amplitude. Based on the key factors of wind speed, vibration frequency, and amplitude, an orthogonal rotary combination test was carried out with the loss rate and impurity rate of cleaned grains as the evaluation indexes, and the test parameters were optimized to obtain the optimal combination of operating parameters of the device, which were as follows: wind speed: 30 m·s−1; vibration frequency: 8.44 Hz; and amplitude: 41.35 mm. With this combination of parameters, the seed loss rate and impurity rate reached 3.47% and 6.17%, respectively. Based on the optimal combination of operating parameters, a validation test was performed, and the results of this test were compared with the results of the test bench using this combination of parameters. The results show that the relative errors of the loss rate and impurity rate between the bench test and the simulation test were 3.45% and 3.07%, respectively, which are less than 5%, proving the reliability of the simulation analysis and the reasonableness of the design of the test bench.

Summary: T cell infiltration into white adipose tissue (WAT) drives obesity-induced adipose inflammation, but the mechanisms of obesity-induced T cell infiltration into WAT remain unclear. Our single-cell RNA sequencing reveals a significant impact of adipose stem cells (ASCs) on T cells. Transplanting ASCs from obese mice into WAT enhances T cell accumulation. C-C motif chemokine ligand 5 (CCL5) is upregulated in ASCs as early as 4 weeks of high-fat diet feeding, coinciding with the onset of T cell infiltration into WAT during obesity. ASCs and bone marrow transplantation experiments demonstrate that CCL5 from ASCs plays a crucial role in T cell accumulation during obesity. The production of CCL5 in ASCs is induced by tumor necrosis factor alpha via the nuclear factor κB pathway. Overall, our findings underscore the pivotal role of ASCs in regulating T cell accumulation in WAT during the early phases of obesity, emphasizing their importance in modulating adaptive immunity in obesity-induced adipose inflammation.

Abstract In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess axon collaterals within the globus pallidus (GPe) (bridging collaterals), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches in mice to dissect the roles of dSPN GPe collaterals in motor function. We find that dSPNs projecting to the SNr send synchronous motor-related information to the GPe via axon collaterals. Inhibition of native activity in dSPN GPe terminals impairs motor activity and function via regulation of Npas1 neurons. We propose a model by which dSPN GPe axon collaterals (striatopallidal Go pathway) act in concert with the canonical terminals in the SNr to support motor control by inhibiting Npas1 neurons.

Background: The communication through coherence model posits that brain rhythms are synchronized across different frequency bands and that effective connectivity strength between interacting regions depends on their phase relation. Evidence to support the model comes mostly from electrophysiological recordings in animals while evidence from human data is limited. Methods: Here, an fMRI-EEG-TMS (fET) instrument capable of acquiring simultaneous fMRI and EEG during noninvasive single pulse TMS applied to dorsolateral prefrontal cortex (DLPFC) was used to test whether prefrontal EEG alpha phase moderates TMS-evoked top-down influences on subgenual, rostral and dorsal anterior cingulate cortex (ACC). Six runs (276 total trials) were acquired in each participant. Phase at each TMS pulse was determined post-hoc using single-trial sorting. Results were examined in two independent datasets: healthy volunteers (HV) (n = 11) and patients with major depressive disorder (MDD) (n = 17) collected as part of an ongoing clinical trial. Results: In both groups, TMS-evoked functional connectivity between DLPFC and subgenual ACC (sgACC) depended on the EEG alpha phase. TMS-evoked DLPFC to sgACC fMRI-derived effective connectivity (EC) was modulated by EEG alpha phase in healthy volunteers, but not in the MDD patients. Top-down EC was inhibitory for TMS pulses during the upward slope of the alpha wave relative to TMS timed to the downward slope of the alpha wave. Prefrontal EEG alpha phase dependent effects on TMS-evoked fMRI BOLD activation of the rostral anterior cingulate cortex were detected in the MDD patient group, but not in the healthy volunteer group. Discussion: Results demonstrate that TMS-evoked top-down influences vary as a function of the prefrontal alpha rhythm, and suggest potential clinical applications whereby TMS is synchronized to the brain's internal rhythms in order to more efficiently engage deep therapeutic targets.

Abstract Recent evidence shows that programs targeting the socio-emotional dimensions of entrepreneurship—e.g., resilience, personal initiative, and empathy—are more highly correlated with success along with key business metrics, such as sales and survival, than programs with a narrow, technical bent—e.g., accounting and finance. We argue that programs designed to foster socio-emotional skills are effective in improving entrepreneurship outcomes because they improve the students’ ability to regulate their emotions. They enhance the individuals’ disposition to make more measured, rational decisions. We test this hypothesis studying a randomized controlled trial (RCT, RCT ID: AEARCTR-0000916) of an entrepreneurship program in Chile. We combine administrative data, surveys, and neuro-psychological data from lab-in-the-field measurements. A key methodological contribution of this study is the use of the electroencephalogram (EEG) to quantify the impact of emotional responses. We find that the program has a positive and significant impact on educational outcomes and, in line with the findings of other studies in the literature, we find no impact on self-reported measures of socio-emotional skills (e.g., grit and locus of control) and creativity. Our novel insight comes from the finding that the program has a significant impact on neurophysiological markers, decreasing arousal (a proxy of alertness), valence (a proxy for withdrawal from or approachability to an event or stimuli), and neuro-psychological changes to negative stimuli.

Since the outbreak of COVID-19, mask-wearing has become a widespread phenomenon. Even after the pandemic, people continue to maintain the habit of wearing masks in their daily lives. While existing research has explored how mask-wearing can influence wearers’ behavior in everyday life, its effects in the workplace have received less attention. Drawing on self-perception theory, this study examined the positive effect of mask-wearing in the workplace on wearers’ voice behavior via psychological safety. An online experiment (N = 291) using a within-subject manipulation of wearing masks supported our hypotheses. This study uncovered the positive psychological and behavioral consequences of mask-wearing beyond its benefits in people’s health conditions and everyday life.

Core analysis is an accurate and direct method for finding the physical properties of oil and natural gas reservoirs. However, in some cases coring is time consuming and difficult, and only cuttings with the drilling fluid can be obtained. It is important to determine whether cuttings can adequately represent formation properties such as porosity, permeability, and pore size distribution (PSD). In this study, seven limestone samples with different sizes were selected (Cubes: 4 × 4 × 4 cm, 4 × 4 × 2 cm, 4 × 2 × 2 cm and 2 × 2 × 2 cm, Core: diameter of 2.5 cm and a length of 5 cm, Cuttings: 1–1.7 mm and 4.7–6.75 mm in diameter), and low-field nuclear magnetic resonance (NMR) measurements were performed on these samples to obtain porosity, PSD, and permeability. The results showed that the porosity of cubes and cuttings with different sizes are consistent with cores, which is about 1%. Whereas the PSDs and permeabilities of the two cutting samples (less than in size 6.75 mm) differ significantly within cores. It is suggested that interparticle voids and mechanical pulverization during sample preparation have a negligible effect on porosity and a larger effect on PSD and permeability. Combined with factors such as wellbore collapse and mud contamination suffered in the field, it is not recommended to use cuttings with a particle size of less than 6.75 mm to characterize actual extra-low porosity and extra-low permeability formation properties.

Introduction: Critically ill patients who receive mechanical ventilation after endotracheal intubation commonly experience discomfort and pressure. The major sedative drugs that are currently used in clinical practice present with many complications, such as hypotension, bradycardia, and respiratory depression. Ciprofol (HSK3486), which is a newly developed structural analog of propofol, is a short-acting gamma-aminobutyric acid (GABA) receptor agonist, and its mechanism of action is sedation or anesthesia by enhancing GABA-mediated chloride influx. The high efficacy of ciprofol for short-term sedation is comparable to that of propofol, and it has a relatively low incidence of adverse effects and high level of safety, which has been confirmed by multiple clinical studies. However, few studies have examined its safety and efficacy for long-term sedation. The purpose of the study is to evaluate the efficacy and safety of ciprofol for long-term sedation in mechanically ventilated patients.Methods: A prospective, single-center, double-blind, randomized, propofol-controlled, non-inferiority trial is proposed. The study will enroll 112 mechanically ventilated patients hospitalized in the intensive care unit (ICU) of the Shanghai Fourth People’s Hospital affiliated with Tongji University based on the inclusion and exclusion criteria of the study, and randomly assign them to a group sedated with either ciprofol or propofol. The primary outcome is the percentage of time spent under target sedation, and secondary outcomes include drug dose, number of cases requiring additional dextrometropine, incidence of systolic blood pressure 180 mmHg, incidence of diastolic blood pressure 100 mmHg, incidence of heart rate 120 bpm, inflammatory indicators, blood lipid levels, liver and kidney functions, nutritional indicators, ventilator-free days within the 7-day period after enrollment, 28-day mortality, ICU stay duration, and hospitalization costs.Discussion: We hypothesize that the efficacy and safety of ciprofol for long-term sedation in mechanically ventilated ICU patients will not be inferior to that of propofol.Trial registration: Chinese Clinical Trials Registry identifier ChiCTR2200066951.

The presence of water, competing with methane for the space, weakens the ability of methane adsorption and diffusion in coal dramatically. The study on the occurrence of water in coal has direct effects on coalbed methane exploitation. In this study, NMR technology was used to obtain water vapor adsorption curves, moreover, the surface adsorption, water cluster formation and pore filling of water in coal pores of coal samples were characterized. Meanwhile, the method based on NMR was first used to quantify the water in different occurrence state in coal pores. The results show that modified BET model can not fit the data in all the pressure history of high rank coal with well-developed micropores and mesopores. Moreover, for pores in high-rank anthracite coal, adsorption water is mainly the indirect adsorption water, and for pores of low-rank bituminous coal, the proportion of direct adsorption water is 50%.

Water distribution can affect the storage and transport of methane in coal. There are many reports involving the distribution of water and methane in coal, but the microscopic mechanism of water-methane interaction is still unclear. In this study, realistic molecular structure models of bituminous and anthracite coals were constructed based on the chemical structures of two coal samples. And the chemical structures were analyzed by solid-state nuclear magnetic resonance, Fourier-transform infrared, and X-photoelectron spectroscopy. Then slit-pore models with different pore sizes were constructed based on the molecular structures to simulate the methane-water interaction in bituminous and anthracite coals. Results show that water molecules tend to form water bridges and water films in the pores of bituminous and anthracite coals, respectively. The significant displacement of pre-adsorbed water by methane was observed through simulation. It is found that the water molecules on the pore surface and the interfaces of small-size water bridges are more easily displaced by methane. In the larger pores, methane molecules mainly drive water molecules to agglomerate larger water bridges in bituminous coal. While methane molecules mainly drive water molecules to cover the pore surface and form a thicker water film in anthracite coal. This study provides new insights into the microscopic distribution and interaction mechanism of fluids in coal.

Contrary to the commonly assumed local segregation in mixed halide perovskite alloys, this work reveals the nonlocal nature of the “segregation”, a macroscopic/mesoscopic scale oscillatory charge displacement.

Objective The purposes of the study were to investigate the detailed association of serum uric acid (SUA) with visceral fat area (VFA) and body fat percentage (BFP) as calculated by bioelectrical impedance analysis (BIA) and build non-invasive diagnosis models of hyperuricaemia by combining obesity-related indicators, age and sex.Method A total of 19 343 adults were included. Multivariable regression analysis models were employed to analyse the association of SUA with VFA and BFP. Receiver operating characteristic curves were generated to diagnose hyperuricaemia in adults.Results After fully adjusting for covariates, SUA was positively associated with VFA, BFP and body mass index (BMI) with βs of 0.447, 2.522 and 4.630 (95% CI= (0.412 to 0.482), (2.321 to 2.723) and (4.266 to 4.994)). After stratification by gender, this association persists (p

BackgroundTo a great extent, genetic factors contribute to the susceptibility to type 1 diabetes (T1D) development, and by triggering immune imbalance, Toll-like receptor (TLR) 9 is involved in the development of T1D. However, there is a lack of evidence supporting a genetic association between polymorphisms in the TLR9 gene and T1D.MethodsIn total, 1513 individuals, including T1D patients (n=738) and healthy control individuals (n=775), from the Han Chinese population were recruited for an association analysis of the rs352140 polymorphism of the TLR9 gene and T1D. rs352140 was genotyped by MassARRAY. The allele and genotype distributions of rs352140 in the T1D and healthy groups and those in different T1D subgroups were analyzed by the chi-squared test and binary logistic regression model. The chi-square test and Kruskal−Wallis H test were performed to explore the association between genotype and phenotype in T1D patients.ResultsThe allele and genotype distributions of rs352140 were significantly different in T1D patients and healthy control individuals (p=0.019, p=0.035). Specifically, the T allele and TT genotype of rs352140 conferred a higher risk of T1D (OR=1.194, 95% CI=1.029-1.385, p=0.019, OR=1.535, 95% CI=1.108-2.126, p=0.010). The allele and genotype distributions of rs352140 were not significantly different between childhood-onset and adult-onset T1D and between T1D with a single islet autoantibody and T1D with multiple islet autoantibodies (p=0.603, p=0.743). rs352140 was associated with T1D susceptibility according to the recessive and additive models (p=0.015, p=0.019) but was not associated with T1D susceptibility in the dominant and overdominant models (p=0.117, p=0.928). Moreover, genotype-phenotype association analysis showed that the TT genotype of rs352140 was associated with higher fasting C-peptide levels (p=0.017).ConclusionIn the Han Chinese population, the TLR9 polymorphism rs352140 is associated with T1D and is a risk factor for susceptibility to T1D.

Abstract Functional capacities of lead halide perovskites are strongly dependent on their morphology, crystallographic texture, and internal ultrastructure on the nano‐ and the meso‐scale. In the last decade, significant efforts are directed towards the development of novel synthesis routes that would overcome the morphological constraints provided by the physical and crystallographic properties of these materials. In contrast, various living organisms, such as unicellular algae, have the ability to mold biogenic crystals into a vast variety of intricate nano‐architectured shapes while keeping their single crystalline nature. Here, using the cell wall of the dinoflagellate L. granifera as a model, sustainably harvested biogenic calcite is successfully transformed into nano‐structured perovskites. Three variants of lead halide perovskites CH3NH3PbX3 are generated with X = Cl−, Br− and I−; exhibiting emission peak‐wavelength ranging from blue, to green, to near‐infrared, respectively. The approach can be used for the mass production of nano‐architectured perovskites with desired morphological, textural and, consequently, physical properties exploiting the numerous templates provided by calcite forming unicellular organisms.

Birthplace, as a proxy for environmental exposures (e.g., diet), may influence metabolomic profiles and influence risk of cancer. This secondary analysis investigated metabolomic profile differences between foreign and U.S.-born Mexican-origin (MO) Hispanic men to shed light on potential mechanisms through which foreign- and U.S.-born individuals experience differences in cancer risk and risk factors. Plasma samples from MO Hispanic men ( N = 42) who participated in a previous lifestyle intervention were collected pre-and post-intervention. Metabolomic profiles were characterized from samples using ultra performance liquid chromatography–quadrupole time of flight mass spectrometry (UPLC-QTOF). Models were visualized using supervised orthogonal projections to latent structures–discriminant analysis (OPLS-DA). Progenesis QI was used for peak integration and metabolite identification. Plasma metabolomic profiles differed between foreign- and U.S.-born pre-intervention (R2 = .65) and post-intervention (R2 = .62). Metabolomic profiles differed pre- versus post-intervention (R2 = .35 and R2 = .65) for the foreign- and U.S.-born group, respectively. Both endogenous metabolites and dietary components characterized differences between foreign- and U.S.-born participants pre- and post-intervention. Plasma metabolomic profiles from MO Hispanic men differed by birthplace. These results advance our understanding of relevant exposures that may affect cancer risk among MO Hispanic men born abroad or in the United States.

Background: Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation modality that can treat depression, obsessive-compulsive disorder, or help smoking cessation. Research suggests that timing the delivery of TMS relative to an endogenous brain state may affect efficacy and short-term brain dynamics. Objective: To investigate whether, for a multi-week daily treatment of repetitive TMS (rTMS), there is an effect on brain dynamics that depends on the timing of the TMS relative to individuals’ prefrontal EEG quasi-alpha rhythm (between 6 and 13 Hz). Method: We developed a novel closed-loop system that delivers personalized EEG-triggered rTMS to patients undergoing treatment for major depressive disorder. In a double blind study, patients received daily treatments of rTMS over a period of six weeks and were randomly assigned to either a synchronized or unsynchronized treatment group, where synchronization of rTMS was to their prefrontal EEG quasi-alpha rhythm. Results: When rTMS is applied over the dorsal lateral prefrontal cortex (DLPFC) and synchronized to the patient's prefrontal quasi-alpha rhythm, patients develop strong phase entrainment over a period of weeks, both over the stimulation site as well as in a subset of areas distal to the stimulation site. In addition, at the end of the course of treatment, this group's entrainment phase shifts to be closer to the phase that optimally engages the distal target, namely the anterior cingulate cortex (ACC). These entrainment effects are not observed in the group that is given rTMS without initial EEG synchronization of each TMS train. Conclusions: The entrainment effects build over the course of days/weeks, suggesting that these effects engage neuroplastic changes which may have clinical consequences in depression or other diseases.

Bieber et al use intestinal monolayers derived from fresh murine crypts as a model system to study drug toxicity. Testing 48 oncology drugs with known gastrointestinal toxicity as a proof of concept, they discover differential responses in cells from large and small intestine, increasing our mechanistic understanding of intestinal drug toxicity.

Accumulation and activation of immunocytes in adipose tissues are essential to obesity-induced inflammation and insulin resistance. Chemokines are pivotal for the recruitment of immunocytes in adipose tissue during obesity. Chemokine (C-C motif) ligand 5 (CCL5) plays a vital role in the recruitment of immunocytes to sites of inflammation. CCL5 expression level is increased in obese adipose tissue from humans and mice. However, the role of CCL5 in obesity-induced adipose inflammation remains unclear. Our study found that the CCL5 expression level was increased in the epididymal white adipose tissue (eWAT) of obese mice, particularly in CD8+ T cells. CCL5 knockout (KO) mice exhibited better glucose tolerance than wild-type (WT) mice under lean conditions. In contrast, CCL5 KO mice were more insulin resistant and had severe hepatic steatosis than WT mice under obese conditions. Increased T cells in adipose tissue heaven adipose inflammation in obese CCL5 KO mice. The compensatory increased T cell-associated chemokines may account for increased T cell content in the eWAT of obese CCL5 KO mice. These findings imply that CCL5 deficiency exacerbates adipose inflammation and impairs insulin sensitivity in the metabolic tissues of obese mice.

Paternal environmental inputs can influence various phenotypes in offspring, with important implications for basic biology and public health. Here the authors show that Ang-mediated biogenesis of 5′-tsRNAs in sperm contributes to paternal inflammation-induced metabolic disorders in offspring.

BackgroundType 1 diabetes mellitus (T1DM) is caused by immune cell-mediated β-cell dysfunction. In recent decades, N6-methyladenosine (m6A) has attracted widespread attention in the scientific research field because it plays vital roles in the pathogenesis of immunity-related diseases, including autoimmune diseases. However, neither the m6A modification profile nor the potential role it plays in T1DM pathogenesis has been investigated to date.Materials and MethodsAn m6A mRNA epitranscriptomic microarray analysis was performed to analyze m6A regulator expression patterns and m6A methylation patterns in immune cells of T1DM patients (n=6) and healthy individuals (n=6). A bioinformatics analysis was subsequently performed to explore the potential biological functions and signaling pathways underlying T1DM pathogenesis. Furthermore, mRNA expression and m6A methylation levels were subsequently verified by qRT–PCR and methylated RNA immunoprecipitation–qPCR (MeRIP–qPCR), respectively, in the T1DM and healthy groups (n=6 per group).ResultsAmong the multiple m6A regulators, METTL3 and IGF2BP2 had significantly downregulated expression, and YTHDC1 and HNRNPA2B1 had significantly upregulated expression in the T1DM group relative to the healthy group. The microarray analysis revealed 4247 differentially methylated transcripts, including 932 hypermethylated and 3315 hypomethylated transcripts, and 4264 differentially expressed transcripts, including 1818 upregulated transcripts and 2446 downregulated transcripts in the T1DM group relative to the healthy group. An association analysis between methylation and gene expression demonstrated that the expression of 590 hypermethylated transcripts was upregulated, and that of 1890 hypomethylated transcripts was downregulated. Pearson correlation analysis showed significant correlations between the expression levels of differentially expressed m6A regulators and the methylation levels of differentially methylated transcripts and significant correlations between the expression levels of differentially expressed m6A regulators and that of differentially expressed transcripts. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that differentially methylated transcripts were involved in pathways related to immunity, including some closely associated with T1DM.ConclusionsOur study presents m6A regulator expression patterns and m6A methylation patterns of immune cells in T1DM, showing that the m6A mark and m6A regulators are promising targets for T1DM diagnosis and treatment.

ObjectivesLong-time separation with parents during early life, such as left-behind children (LBC, one or both of whose parents are leaving for work for at least a period of 6 months), may contribute to high alienation toward parents and endanger their mental health (e.g., depression). However, the dynamic status of depression and potential prediction of alienation on depression in LBC remained largely unknown. This study aimed to examine the dynamic status of depression, prediction of alienation toward parents on later depression in rural LBC, and a potential mediation of life-events.MethodsA total of 877 LBC in rural areas of China were recruited and surveyed at five time-points (baseline, T0: 1-month, T1: 3-months, T2: 6-months, T3: 12-months, T4) with the Inventory of Alienation Toward Parents, Childhood Depression Inventory, and Adolescent Self-Rating Life-Events Checklist. The Hierarchical Linear Model (HLM) and Hayes's PROCESS macro model were conducted to estimate the developmental trend and hierarchical predictors of depression.ResultsThe left-behind children aged 9-years old experienced higher depression than the children with other ages. At baseline, the children in the family atmosphere of frequent quarrels and compulsive parenting style reported a higher level of alienation toward parents, life-events, and depression. Alienation toward parents, life-events, and depression were positively and moderately correlated with each other (r = 0.14 ~ 0.64). The HLM model depicted a linear decline in depression, alienation, and life-events with an average rate of 0.23, 0.24, and 0.86, respectively, during the five time-points. Also, T0 alienation toward parents and T0 life-events positively predicted the developmental trajectory of depression over time, and T0 life-events positively predicted the descendant rate of depression. Notably, life-events mediated the prediction of baseline alienation toward parents on T4 depression in LBC.ConclusionThis study is among the first to reveal that alienation toward parents predicts the developmental trajectory of later depression in LBC. The findings that life-events mediate the prediction of alienation on later depression further suggest the importance of family and social factors in the occurrence of depression in LBC. The findings warrant the necessity to consider the family and social factors when evaluating and reducing risks for mental health problems in LBC, i.e., relationship with parents (especially alienation toward parents) and life-events need further attention.

Various studies have revealed the association of metabolic diseases with inflammation. Mitochondria are key organelles involved in metabolic regulation and important drivers of inflammation. However, it is uncertain whether the inhibition of mitochondrial protein translation results in the development of metabolic diseases, such that the metabolic benefits related to the inhibition of mitochondrial activity remain unclear. Mitochondrial methionyl-tRNA formyltransferase (Mtfmt) functions in the early stages of mitochondrial translation. In this study, we reveal that feeding with a high-fat diet led to the upregulation of Mtfmt in the livers of mice and that a negative correlation existed between hepatic Mtfmt gene expression and fasting blood glucose levels. A knockout mouse model of Mtfmt was generated to explore its possible role in metabolic diseases and its underlying molecular mechanisms. Homozygous knockout mice experienced embryonic lethality, but heterozygous knockout mice showed a global reduction in Mtfmt expression and activity. Moreover, heterozygous mice showed increased glucose tolerance and reduced inflammation, which effects were induced by the high-fat diet. The cellular assays showed that Mtfmt deficiency reduced mitochondrial activity and the production of mitochondrial reactive oxygen species and blunted nuclear factor-κB activation, which, in turn, downregulated inflammation in macrophages. The results of this study indicate that targeting Mtfmt-mediated mitochondrial protein translation to regulate inflammation might provide a potential therapeutic strategy for metabolic diseases.

Background and AimsThe NLRP3 gene is reportedly associated with several autoimmune diseases. However, in the Chinese Han population, whether NLRP3 polymorphisms are associated with type 1 diabetes (T1D) is unclear. Therefore, this study examined the associations of rs3806265 and rs4612666 of the NLRP3 gene with T1D susceptibility and the clinical characteristics of Chinese Han T1D patients.MethodsIn total, 510 classic T1D patients and 531 healthy controls from the Chinese Han population were recruited for a case-control study. rs3806265 and rs4612666 of the NLRP3 gene were genotyped by MassARRAY. Logistic regression analysis and the chi-square test were used to compare the distributions of the alleles and genotypes of rs3806265 and rs4612666. The relationships between rs3806265 and rs4612666 and the clinical characteristics of T1D patients were analyzed by Kruskal-Wallis one-way ANOVA. Student’s t test was used to analyze normally distributed data. Bonferroni correction was used for multiple comparisons.Results1) rs3806265 was associated with glutamic acid decarboxylase antibody (GADA) titers (P = 0.02), and patients with the CC genotype had higher GADA titers than patients with the TT genotype. 2) rs4612666 was also associated with GADA titers (P=0.041). Compared with patients with the CC genotype, patients with the TT genotype had higher GADA titers. 3) rs3806265 and rs4612666 of the NLRP3 gene were not significantly associated with T1D susceptibility under different genetic models.Conclusionrs3806265 and rs4612666 of the NLRP3 gene were significantly associated with GADA titers in Chinese Han T1D patients.

PurposeTo compare visual outcomes and corneal optical quality after small incision lenticule extraction (SMILE), wavefront-optimized (WFO) FS-LASIK, and topography-guided customized ablation treatment (TCAT) FS-LASIK for myopia.MethodsThis prospective case-series study included 283 eyes of 283 myopic patients who underwent SMILE or FS-LASIK. There were 102, 100, and 81 eyes in the SMILE group, WFO group and TCAT group, respectively. The tomography system (Sirius) was used to measure corneal aberrations and optical quality.ResultsAt postoperative 1 and 6 months, there were no significant differences in uncorrected distance visual acuity and corrected distance visual acuity among the three groups (P > 0.05). Postoperative manifest refractive spherical equivalent was similar among the groups (P > 0.05). There was statistically significant difference in cylinder at 1 month among the three groups, with the highest mean value in TCAT group (P < 0.05). The corneal optical path difference, root mean square of corneal astigmatism and strehl ratio were the most superior in the TCAT group at postoperative 1 and 6 months (P < 0.05).ConclusionSMILE, WFO FS-LASIK, and TCAT FS-LASIK provided similar visual results. The corneal visual quality after TCAT FS-LASIK was the best.

Th1 cell activation is considered a key mediator of the pathogenesis of type 1 diabetes. Targeting IL-12-induced Th1 cell differentiation seems to be an effective way to block the development of type 1 diabetes. However, given the critical function of Th1 in the immune system, the potential side effects hinder the application of anti-Th1 therapy in the treatment of type 1 diabetes. To identify safe anti-Th1 treatment(s), we screened the FDA-approved tyrosine kinase inhibitor (TKI) drug library using an IL-12-induced Th1 differentiation cell model. We found that among the TKIs with little effect on T cell viability, sorafenib is the top contender for the inhibition of Th1 differentiation. Treatment of NOD mice with sorafenib significantly impeded the development of type 1 diabetes and ameliorated insulitis, which coincided with a specifically decreased accumulation of Th1 cell population in the pancreas but not in peripheral immune organs. Mechanistically, sorafenib indirectly inhibited janus kinase 2 (JAK2) activity and blocked IL-12-induced phosphorylations of JAK2 and signal transducer and activator of transcription 4 (STAT4). Since sorafenib is classified as an FDA-approved drug, it serves as a preliminary lead point for additional experimentation and may be a promising therapy for type 1 diabetes in humans.

Multibranched horizontal well is an important means to develop low permeability reservoirs. Fishbone multibranched horizontal well has the advantages of increasing drainage area, reducing drilling number, utilizing existing wells, and saving oilfield development cost, especially for marginal oilfield exploitation. The morphological structure of fishbone multibranched horizontal well is very complex, so the numerical simulation study is of great significance to guide the production of fishbone multibranched horizontal well. In this paper, the numerical model is established for fishbone multibranched horizontal well in the oil reservoir. The finite element method is used to numerically solve the mathematic model. The oil well production can be achieved by using the material balance method. Sensitivity analysis is made on the important reservoir and well-type factors that affect the production behavior and transient pressure distribution of fishbone multibranched horizontal well. It is concluded that the effective reservoir thickness and flowing bottomhole pressure have great influence on the productivity, but the influence of heterogeneity is not obvious. The length of main wellbore has great effect on the productivity in the early stage. Fishbone multibranched horizontal wells should be placed in the middle of the reservoir to increase productivity. Branch length, branch angle, branch number, and branch spacing are important parameters affecting the productivity of fishbone multibranched horizontal well. The variation of these parameters has obvious influence on the stimulation effect in the early stage of production, but the influence degree is different. Under the premise of drilling technology and drilling safety, the comprehensive impact of these four factors on productivity should be considered simultaneously. The presented model and obtained results not only enrich production behavior analysis of fishbone multibranched horizontal well but also have significance on formulation of stimulation measures and efficient low permeability reservoir development.

The fault diagnosis is always a key issue in the security field of marine propulsion system. There are obvious problems like the unsteady working of sensors, distortion of original data, and ambivalent feature information from marine shafting’s vibration or motion. It is therefore critical to develop a more effective method to identify the fault information so that the safety of marine propulsion system can be pre-estimated. Hence, a composite method which is based on the ensemble empirical mode decomposition (EEMD) and coupled with the autocorrelation method (AM), the fast Fourier transform (FFT), is mixed and applied to identify the fault information of marine shafting during its operating by hull vibration. The contrastive analysis of the three methods and fault feature study are then conducted to assess the effectiveness of the proposed method thoroughly and validated by the author previously. The research indicates that the composite method is available to fault diagnosis of marine shafting by hull vibration which coupled the shafting vibration with fault feature.

Objective: The outbreak of coronavirus disease 2019 (COVID-19), declared as a major public health emergency, has had profound effects on public mental health especially emotional status. Due to professional requirements, medical staff are at a higher risk of infection, which might induce stronger negative emotions. This study aims to reveal the emotional status of Chinese frontline medical staff in the early epidemic period to better maintain their mental health, and provide adequate psychological support for them.Methods: A national online survey was carried out in China at the early stage of the COVID-19 epidemic. In total, 3025 Chinese frontline medical staff took part in this investigation which utilized a general information questionnaire, the Emotion Regulation Questionnaire (ERQ), and the Berkeley Expressivity Questionnaire (BEQ).Results: At the early stage of COVID-19, anxiety was the most common negative emotion of Chinese medical staff, followed by sadness, fear, and anger, mainly at a mild degree, which declined gradually over time. Nurses had the highest level of negative emotions compared with doctors and other healthcare workers. Women experienced more fear than men, younger and unmarried medical staff had more anxiety and fear compared with elders and married ones. Risk perception and emotional expressivity increased negative emotions, cognitive reappraisal reduced negative emotions, while negative emotions led to more avoidant behavior and more physical health disturbances, in which negative emotions mediated the effect of risk perception on avoidant behavior tendency in the model test.Conclusion: Chinese frontline medical staff experienced a mild level of negative emotions at the early stage of COVID-19, which decreased gradually over time. The findings suggest that during the epidemic, nurses' mental health should be extensively attended to, as well as women, younger, and unmarried medical staff. To better ensure their mental health, reducing risk perception and improving cognitive reappraisal might be important, which are potentially valuable to form targeted psychological interventions and emotional guidance under crisis in the future.

Objective: To investigate the association between susceptibility to type 1 diabetes mellitus (T1DM) and polymorphisms (rs1143627 and rs1143643) in the interleukin 1 beta (IL1B) gene in the Chinese Han population.Methods: The Meso Scale Discovery (MSD) method was used to detect the concentration of IL-1β in 24 T1DM patients and 27 healthy controls. MassARRAY was used to analyze the polymorphisms in the IL1B gene in 510 patients with classic T1DM and 531 healthy controls. The general data of the T1DM patients and healthy controls were compared by the chi-square test and Mann-Whitney U test. The chi-square test and logistic regression were used to analyze the frequency distributions of alleles and genotypes of polymorphisms in the IL1B gene. The Kruskal-Wallis H test and chi-square test were used for the genotype-phenotype analysis of rs1143627 and rs1143643 in the IL1B gene.Results: ① The concentration of IL-1β in T1DM patients was significantly higher than that in healthy controls. ② rs1143627 and rs1143643 in the IL1B gene were significantly correlated with the positivity rates for IA-2A and ZnT8A; genotype GG at rs1143627 and genotype CC at rs1143643 in the case group showed lower positivity rates for IA-2A and ZnT8A. ③ There was no significant difference in the genotypes or allele frequencies at rs1143627 (GG/GA/AA) or rs1143643 (CC/CT/TT) between the case group and control group (p > 0.05). ④ rs1143627 and rs1143643 were not found to be linked to T1DM susceptibility under different genetic models.Conclusion: rs1143627 and rs1143643 in the IL1B gene correlate with the positivity rate of IA-2A and ZnT8A in Chinese Han individuals with T1DM.

Populations used to create warfarin dose prediction algorithms largely lacked participants reporting Hispanic or Latino ethnicity. While previous research suggests nonlinear modeling improves warfarin dose prediction, this research has mainly focused on populations with primarily European ancestry. We compare the accuracy of stable warfarin dose prediction using linear and nonlinear machine learning models in a large cohort enriched for US Latinos and Latin Americans (ULLA). Each model was tested using the same variables as published by the International Warfarin Pharmacogenetics Consortium (IWPC) and using an expanded set of variables including ethnicity and warfarin indication. We utilized a multiple linear regression model and three nonlinear regression models: Bayesian Additive Regression Trees, Multivariate Adaptive Regression Splines, and Support Vector Regression. We compared each model’s ability to predict stable warfarin dose within 20% of actual stable dose, confirming trained models in a 30% testing dataset with 100 rounds of resampling. In all patients (n = 7,030), inclusion of additional predictor variables led to a small but significant improvement in prediction of dose relative to the IWPC algorithm (47.8 versus 46.7% in IWPC, p = 1.43 × 10−15). Nonlinear models using IWPC variables did not significantly improve prediction of dose over the linear IWPC algorithm. In ULLA patients alone (n = 1,734), IWPC performed similarly to all other linear and nonlinear pharmacogenetic algorithms. Our results reinforce the validity of IWPC in a large, ethnically diverse population and suggest that additional variables that capture warfarin dose variability may improve warfarin dose prediction algorithms.

Elucidating the characteristics of continuous oil spill fires for different slope conditions can provide important theoretical support for the prevention of, and rescue strategies during, oil spill fire accidents. For this research, we conducted experiments to observe the spread and burning process of continuous oil spill fires under different slope conditions. The changes in physical attributes, such as flame spread rate, burning rate, heat convection at the bottom surface, and flame feedback radiation, were analyzed for the different slope conditions. The results showed that the shrinking phase becomes difficult to see, and the steady phase disappears when the slope increases in the spread and burning process. When the slope increases, the spread speed and spread area increase, and burning rate decreases. Compared with a non-burning process, the resistance to spread decreases in the burning process. We show that the slope directly affects the spreading process, and indirectly affects the burning process.