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This article explores determinants of effective communication for crisis responses across functional sub-systems at diverse public organisation levels. That is done by analysing WHO and IPCC statements on COVID-19 and climate change, and governmental responses, drawing on Denmark as a pilot case. A functional sub-system is constituted by binary codes, embodying the sub-system’s key logic. Sub-systems respond to information triggering their logics. The analysis shows that with an emphasis on effective governance and the delivery of health care, the WHO was effective in generating governmental action on COVID-19. By contrast, the IPCC’s extensive deployment of the true/false logic of science is less effective for activating governmental response. Addressing public governance and relevance of Luhmann’s systems theory, our findings suggest that decision-makers can be prompted into action through deployment of arguments that connect to governments’ logic. This finding holds potential for improving communication between scientific and governance agencies for crisis responses. Este artículo explora los factores determinantes de una comunicación eficaz para responder a las crisis a través de subsistemas funcionales en diversos niveles de organizaciones públicas. Para ello se analizan las declaraciones de la OMS y el IPCC sobre la COVID-19 y el cambio climático, así como las respuestas gubernamentales, tomando Dinamarca como caso piloto. Un subsistema funcional está constituido por códigos binarios, que encarnan la lógica clave del subsistema. Los subsistemas responden a la información que activa su lógica. El análisis muestra que, al hacer hincapié en la gobernanza eficaz y la prestación de asistencia sanitaria, la OMS fue eficaz a la hora de generar medidas gubernamentales en relación con la COVID-19. En cambio, el amplio despliegue de la lógica de la ciencia verdadero/falso por parte del IPCC es menos eficaz para activar la respuesta gubernamental. En lo que respecta a la gobernanza pública y la relevancia de la teoría de sistemas de Luhmann, nuestros resultados insinúan que el despliegue de argumentos que conecten con la lógica de los gobiernos puede inducir a la acción a los responsables de tomar decisiones. Este hallazgo puede mejorar la comunicación entre los organismos científicos y de gobierno en las respuestas a las crisis.

The solution-treated second-generation single crystal (SX) superalloys underwent hot isostatic pressing (HIP) at 1316 °C and 105 MPa for varying durations. This study investigates the effect of HIP on micropores and stress-rupture behavior under conditions of 980 °C and 250 MPa. The results illustrate that the application of HIP treatment significantly reduces the porosity and volume of micropores, thereby increasing the rupture life of the alloys. With the disappearance of micropores, the crack initiation site shifts from the micropores to the γ/γʹ interface, resulting in reduced crack dimensions and decelerated propagation. Consequently, the smaller size of cracks in HIPed specimens slow down fracture. Nonetheless, the crack propagation pattern remains consistent: cracks expand perpendicular to the stress axis, connecting with cracks at other heights via secondary cracks along the direction.

Abstract Recent advances in spatial transcriptomics (ST) techniques provide valuable insights into cellular interactions within the tumor microenvironment (TME). However, most analytical tools lack consideration of histological features and rely on matched single-cell RNA sequencing data, limiting their effectiveness in TME studies. To address this, we introduce the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI), an end-to-end framework that maps cancer cells and TME components, stratifies cell types and states, and analyzes cell co-localization. By integrating spatial transcriptomics, cell morphology, and curated gene signatures, METI enhances our understanding of the molecular landscape and cellular interactions within the tissue. We evaluate the performance of METI on ST data generated from various tumor tissues, including gastric, lung, and bladder cancers, as well as premalignant tissues. We also conduct a quantitative comparison of METI with existing clustering and cell deconvolution tools, demonstrating METI’s robust and consistent performance.

Abstract Parkinson’s disease (PD) exhibits heterogeneity in terms of symptoms and prognosis, likely due to diverse neuroanatomical alterations. This study employs a contrastive deep learning approach to analyze Magnetic Resonance Imaging (MRI) data from 932 PD patients and 366 controls, aiming to disentangle PD-specific neuroanatomical alterations. The results reveal that these neuroanatomical alterations in PD are correlated with individual differences in dopamine transporter binding deficit, neurodegeneration biomarkers, and clinical severity and progression. The correlation with clinical severity is verified in an external cohort. Notably, certain proteins in the cerebrospinal fluid are strongly associated with PD-specific features, particularly those involved in the immune function. The most notable neuroanatomical alterations are observed in both subcortical and temporal regions. Our findings provide deeper insights into the patterns of brain atrophy in PD and potential underlying molecular mechanisms, paving the way for earlier patient stratification and the development of treatments to slow down neurodegeneration.

Electric vehicle (EV) is more environmental-friendly than gasoline vehicle because the main power is not petrol. For the heating system, the waste heat generated by engines is recycled to heat the cabin of gasoline ones, while the EV need extra electric energy consumption for heating the cabin which decreases the driving range. Personal comfort system (PCS) has been reported that it is an alternative technique to improve occupant thermal comfort and indirectly save building heating energy. This study aims to investigate the occupants’ thermal sensation under four heating modes in the EV cabin in winter, including no heating, only PCS, only air conditioning, and both air conditioning and PCS. The field survey is conducted in a parked EV with 12 subjects. Three thermal comfort indexes (PMV, SET*, and operative temperature Top) are used and assessed for their applicability in the thermal environment of the EV. Results show that the thermal environment in the cabin is non-uniform and dynamic with the air conditioning mode, while the PCS mode just slightly affects the temperature differences inside. Meanwhile, the subjects’ thermal sensations cannot maintain neutral or warmer under the PCS mode only. The results of PMV are lower than the subjects’ actual thermal sensation votes (TSV), while the results of SET* and Top show significant linear relationships with the TSV for the correlation coefficients above 0.80. Compare to the air conditioning mode, the neutral SET* and neutral Top are decreased by 2.7 °C and 1.6 °C under the mode with PCS and air conditioning, respectively. The findings indicate that PCS not only has a positive effect on improving the cabin environment and occupant's thermal sensation but also has the potential to lower the setting temperature of air conditioner of EVs in winter.

An improved weighted expectile average estimator for the regression coefficient has been obtained based on the covariate balancing propensity score (CBPS), when the responses of linear models are missing at random. The asymptotic normality of the proposed method has been proved, and the estimation effect of the method is further illustrated by numerical simulation.

Abstract We explored physiological effects of the sodium-glucose co-transporter-2 inhibitor empagliflozin on intact experimentally hypertrophic murine hearts following transverse aortic constriction (TAC). Postoperative drug (2–6 weeks) challenge resulted in reduced late Na+ currents, and increased phosphorylated (p-)CaMK-II and Nav1.5 but not total (t)-CaMK-II, and Na+/Ca2+ exchanger expression, confirming previous cardiomyocyte-level reports. It rescued TAC-induced reductions in echocardiographic ejection fraction and fractional shortening, and diastolic anterior and posterior wall thickening. Dual voltage- and Ca2+-optical mapping of Langendorff-perfused hearts demonstrated that empagliflozin rescued TAC-induced increases in action potential durations at 80% recovery (APD80), Ca2+ transient peak signals and durations at 80% recovery (CaTD80), times to peak Ca2+ (TTP100) and Ca2+ decay constants (Decay30–90) during regular 10-Hz stimulation, and Ca2+ transient alternans with shortening cycle length. Isoproterenol shortened APD80 in sham-operated and TAC-only hearts, shortening CaTD80 and Decay30–90 but sparing TTP100 and Ca2+ transient alternans in all groups. All groups showed similar APD80, and TAC-only hearts showed greater CaTD80, heterogeneities following isoproterenol challenge. Empagliflozin abolished or reduced ventricular tachycardia and premature ventricular contractions and associated re-entrant conduction patterns, in isoproterenol-challenged TAC-operated hearts following successive burst pacing episodes. Empagliflozin thus rescues TAC-induced ventricular hypertrophy and systolic functional, Ca2+ homeostatic, and pro-arrhythmogenic changes in intact hearts.

Abstract Background Cholestasis is a common yet severe complication that occurs during the advancement of liver metastasis. However, how cholestasis impacts the development, treatment, and tumor microenvironment (TME) of liver metastasis remains to be elucidated. Methods Extrahepatic and intrahepatic cholestatic mouse models with liver metastasis were established to detect the differential expression levels of genes, infiltration of immune cells and change in bile acid-associated metabolites by using RNA-Sequencing, flowcytometry, and liquid chromatography and mass spectrometry. Western blot was applied to neutrophils under the stimulation of primary bile acids (BAs) in vitro to study the mechanism of phenotypic alteration. In vitro coculture of BA-treated neutrophils with CD8+ T cells were performed to study the immune-suppressive effect of phenotypic-altered neutrophils. Clinical samples collected from colorectal cancer patients with liver metastasis and cholestasis were applied to RNA-Seq. Results Compared to non-cholestatic mice, the progression of liver metastasis of cholestatic mice was significantly accelerated, which was associated with increased neutrophil infiltration and T-cell exclusion. Both neutrophils and T cells expressed higher immunosuppressive markers in the cholestatic mouse model, further indicating that an immunosuppressive tumor microenvironment was induced during cholestasis. Although neutrophils deletion via anti-Ly6G antibody partially hindered liver metastasis progression, it reduced the overall survival of mice. Tauro-β-muricholic acid (Tβ-MCA) and Glycocholic acid (GCA), the two most abundant cholestasis-associated primary BAs, remarkably promoted the expression of Arg1 and iNOS on neutrophils via p38 MAPK signaling pathway. In addition, BAs-pretreated neutrophils significantly suppressed the activation and cytotoxic effects of CD8+ T cells, indicating that the immunosuppressive phenotype of neutrophils was directly induced by BAs. Importantly, targeting BA anabolism with Obeticholic acid (OCA) under cholestasis effectively suppressed liver metastasis progression, enhanced the efficacy of immune checkpoint blockade, and prolonged survival of mice. Conclusions Our study reveals the TME of cholestasis-associated liver metastasis and proposes a new strategy for such patients by targeting bile acid anabolism. Graphical Abstract Schematic model depicting the proposed mechanism of cholestasis-mediated progression of colorectal liver metastasis. As cholestasis progresses, excessive primary bile acids that accumulate in the liver intoxicates hepatocytes, which lead to exacerbated release of chemokines, particularly CXCL2 and CXCL5. Neutrophils are then accumulated by CXCL2 and CXCL5 and undergo an immunosuppressive-phenotypic alteration induced by direct stimulation of BAs via activating the p38 MAPK signaling pathway, which eventually led to the dysfunction of T cells and progression of LM. Targeting bile acid anabolism can effectively restore the immune-activated microenvironment and prevent the progression of LM.

Abstract Background L-theanine is a unique non-protein amino acid in tea that is widely used as a safe food additive. We investigated the cardioprotective effects and mechanisms of L-theanine in myocardial ischemia-reperfusion injury (MIRI). Methods The cardioprotective effects and mechanisms of L-theanine and the role of Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling were investigated in MIRI mice using measures of cardiac function, oxidative stress, and apoptosis. Results Administration of L-theanine (10 mg/kg, once daily) suppressed the MIRI-induced increase in infarct size and serum creatine kinase and lactate dehydrogenase levels, as well as MIRI-induced cardiac apoptosis, as evidenced by an increase in Bcl-2 expression and a decrease in Bax/caspase-3 expression. Administration of L-theanine also decreased the levels of parameters reflecting oxidative stress, such as dihydroethidium, malondialdehyde, and nitric oxide, and increased the levels of parameters reflecting anti-oxidation, such as total antioxidant capacity (T-AOC), glutathione (GSH), and superoxide dismutase (SOD) in ischemic heart tissue. Further analysis showed that L-theanine administration suppressed the MIRI-induced decrease of phospho-JAK2 and phospho-STAT3 in ischemic heart tissue. Inhibition of JAK2 by AG490 (5 mg/kg, once daily) abolished the cardioprotective effect of L-theanine, suggesting that the JAK2/STAT3 signaling pathway may play an essential role in mediating the anti-I/R effect of L-theanine. Conclusions L-theanine administration suppresses cellular apoptosis and oxidative stress in part via the JAK2/STAT3 signaling pathway, thereby attenuating MIRI-induced cardiac injury. L-theanine could be developed as a potential drug to alleviate cardiac damage in MIRI.

Abstract As the severity of global climate change escalates, carbon peak and carbon neutrality have emerged as international imperatives. Green taxation, a crucial fiscal strategy promoting the transition to a green low-carbon economy, demands thorough investigation regarding its efficacy and operational mechanisms. Predominantly, existing research has concentrated on the macroeconomic implications of green taxes, while their influence on regional green growth and innovation remains underexplored. This paper delineates green taxation in both a broad and narrow sense, elucidating its essence and potential in stimulating regional green progress and innovation. Utilizing panel data from 30 provinces in China spanning 2004 to 2021, a bidirectional fixed-effects model was developed for empirical analysis. Moreover, an impact mechanism model was constructed to delve into how green taxation specifically affects regional green development and innovation. Findings reveal that green taxation significantly fosters regional green growth and markedly enhances green innovation. Nonetheless, due to the resource crowding-out effect, it adversely impacts the comprehensive innovation capabilities of regional enterprises. This insight offers a fresh perspective on the paradoxical effects of green taxation, underscoring the necessity for a balanced approach in policy design and implementation. Drawing on these conclusions, the paper presents tailored policy recommendations.

IntroductionThe primary objective of our study was to evaluate the first use of a novel intracardiac echocardiography (ICE) catheter in human subjects. This study aimed to assess its practicality, image clarity, and guidance role during electrophysiology procedures.MethodsTwo patients underwent procedures using the novel ICE catheter. Post-procedure evaluations were conducted by four operators, who assessed the imaging quality and overall performance of the catheter. Anatomical and blood test results were also analyzed to determine the safety and impact on internal cardiac structures.ResultsBoth patients were discharged one day after the procedure without any complications. The novel ICE catheter provided comparable imaging quality to existing commercial catheters. The catheter's advanced design allowed for detailed imaging at short distances, essential for accurate diagnosis and treatment planning. Moreover, it successfully navigated complex anatomical structures like the atrial septum and left atrial appendage.DiscussionThese preliminary studies indicate that the novel ICE catheter achieves a level of safety and effectiveness comparable to previously available commercial catheters. The findings highlight its potential to meet current clinical needs, particularly in sophisticated anatomic interventions. Despite the prolonged thrombin time after anticoagulant administration, both types of ICE catheters were non-damaging to cardiac structures during routine operations. The study underscores the importance of using trans-septal large inner diameter sheaths to minimize complications when advancing the catheter into the left atrium.

Non-ST-segment elevation acute myocardial infarction (NSTEMI) is a life-threatening clinical emergency with a poor prognosis. However, there are no individualized nomogram models to identify patients at high risk of NSTEMI who may undergo death. The aim of this study was to develop a nomogram for in-hospital mortality in patients with NSTEMI to facilitate rapid risk stratification of patients. A total of 774 non-diabetic patients with NSTEMI were included in this study. Least Absolute Shrinkage and Selection Operator regression was used to initially screen potential predictors. Univariate and multivariate logistic regression (backward stepwise selection) analyses were performed to identify the optimal predictors for the prediction model. The corresponding nomogram was constructed based on those predictors. The receiver operating characteristic curve, GiViTI calibration plot, and decision curve analysis (DCA) were used to evaluate the performance of the nomogram. The nomogram model consisting of six predictors: age (OR = 1.10; 95% CI: 1.05-1.15), blood urea nitrogen (OR = 1.06; 95% CI: 1.00-1.12), albumin (OR = 0.93; 95% CI: 0.87-1.00), triglyceride (OR = 1.41; 95% CI: 1.09-2.00), D-dimer (OR = 1.39; 95% CI: 1.06-1.80), and aspirin (OR = 0.16; 95% CI: 0.06-0.42). The nomogram had good discrimination (area under the curve (AUC) = 0.89, 95% CI: 0.84-0.94), calibration, and clinical usefulness. In this study, we developed a nomogram model to predict in-hospital mortality in patients with NSTEMI based on common clinical indicators. The proposed nomogram has good performance, allowing rapid risk stratification of patients with NSTEMI.

Abstract Marine animals equipped with sensors provide vital information for understanding their ecophysiology and collect oceanographic data on climate change and for resource management. Existing methods for attaching sensors to marine animals mostly rely on invasive physical anchors, suction cups, and rigid glues. These methods can suffer from limitations, particularly for adhering to soft fragile marine species such as squid and jellyfish, including slow complex operations, unreliable fixation, tissue trauma, and behavior changes of the animals. However, soft fragile marine species constitute a significant portion of ocean biomass (>38.3 teragrams of carbon) and global commercial fisheries. Here we introduce a soft hydrogel-based bioadhesive interface for marine sensors that can provide rapid (time 160 J m−2), and non-invasive adhesion on various marine animals. Reliable and rapid adhesion enables large-scale, multi-animal sensor deployments to study biomechanics, collective behaviors, interspecific interactions, and concurrent multi-species activity. These findings provide a promising method to expand a burgeoning research field of marine bio-sensing from large marine mammals and fishes to small, soft, and fragile marine animals.

Arsenic, a naturally occurring metal-like chemical element, is one of the 10 chemicals of major public concerns listed by the World Health Organization as harmful to the environment and human health. It can enter the human body through breathing, intaking food, drinking water, skin exposure, and other ways, and long-term exposure to arsenic can cause cancer of multiple organs and impaired function of multiple systems. Epigenetic mechanisms play an important role in arsenic-induced health effects, and research suggested that the carcinogenicity of arsenic may be associated with epigenetic changes. Previous studies focused on the effects of arsenic on DNA methylation modification. In recent years, research showed that 5-hydroxymethylcytosine (5-hmC), an intermediate of active demethylation of DNA, can act as a sensitive epigenetic mark and play a crucial role as a "bridge" between arsenic exposure and health effects. Based on the latest research progress on the role of DNA hydroxymethylation in the health effects associated with arsenic exposure, this article briefly described the relationship between the health effects of arsenic exposure and DNA hydroxymethylation, summarized the possible mechanisms of DNA hydroxymethylation in the health effects associated with arsenic exposure, and provided a scientific basis for preventing and treating the health effects associated with arsenic exposure.

Abstract Brain structural changes in Parkinson’s disease (PD) are progressive throughout the disease course. Changes in surface morphology with disease progression remain unclear. This study aimed to assess the volumetric and shape changes of the subcortical nuclei during disease progression and explore their association with clinical symptoms. Thirty-four patients and 32 healthy controls were enrolled. The global volume and shape of the subcortical nuclei were compared between patients and controls at baseline. The volume and shape changes of the subcortical nuclei were also explored between baseline and 2 years of follow-up. Association analysis was performed between the volume of subcortical structures and clinical symptoms. In patients with PD, there were significantly atrophied areas in the left pallidum and left putamen, while in healthy controls, the right putamen was dilated compared to baseline. The local morphology of the left pallidum was correlated with Mini Mental State Examination scores. The left putamen shape variation was negatively correlated with changes in Unified Parkinson’s Disease Rating Scale PART III scores. Local morphological atrophy of the putamen and pallidum is an important pathophysiological change in the development of PD, and is associated with motor symptoms and cognitive status in patients with PD.

Abstract AURKA is an established target for cancer therapy; however, the efficacy of its inhibitors in clinical trials is hindered by differential response rates across different tumor subtypes. In this study, we demonstrate AURKA regulates amino acid synthesis, rendering it a vulnerable target in KEAP1-deficient non-small cell lung cancer (NSCLC). Through CRISPR metabolic screens, we identified that KEAP1-knockdown cells showed the highest sensitivity to the AURKA inhibitor MLN8237. Subsequent investigations confirmed that KEAP1 deficiency heightens the susceptibility of NSCLC cells to AURKA inhibition both in vitro and in vivo, with the response depending on NRF2 activation. Mechanistically, AURKA interacts with the eIF2α kinase GCN2 and maintains its phosphorylation to regulate eIF2α-ATF4-mediated amino acid biosynthesis. AURKA inhibition restrains the expression of asparagine synthetase (ASNS), making KEAP1-deficient NSCLC cells vulnerable to AURKA inhibitors, in which ASNS is highly expressed. Our study unveils the pivotal role of AURKA in amino acid metabolism and identifies a specific metabolic indication for AURKA inhibitors. These findings also provide a novel clinical therapeutic target for KEAP1-mutant/deficient NSCLC, which is characterized by resistance to radiotherapy, chemotherapy, and targeted therapy.

Abstract Wastewater surveillance has proven a cost-effective key public health tool to understand a wide range of community health diseases and has been a strong source of information on community levels and spread for health departments throughout the SARS- CoV-2 pandemic. Studies spanning the globe demonstrate the strong association between virus levels observed in wastewater and quality clinical case information of the population served by the sewershed. Few of these studies incorporate the temporal dependence present in sampling over time, which can lead to estimation issues which in turn impact conclusions. We contribute to the literature for this important public health science by putting forward time series methods coupled with statistical process control that (1) capture the evolving trend of a disease in the population; (2) separate the uncertainty in the population disease trend from the uncertainty due to sampling and measurement; and (3) support comparison of sub-sewershed population disease dynamics with those of the population represented by the larger downstream treatment plant. Our statistical methods incorporate the fact that measurements are over time, ensuring correct statistical conclusions. We provide a retrospective example of how sub-sewersheds virus levels compare to the upstream wastewater treatment plant virus levels. An on-line algorithm supports real-time statistical assessment of deviations of virus level in a population represented by a sub-sewershed to the virus level in the corresponding larger downstream wastewater treatment plant. This information supports public health decisions by spotlighting segments of the population where outbreaks may be occurring.

Abstract Post-COVID-19 syndrome may be associated with the abnormal immune status. Compared with the unexposed age-matched elder group, PD-1 in the CD8+ T cells from recovered COVID-19 patients was significantly lower. IFN-γ in the plasma of COVID-19 convalescent patients was increased, which inhibited PD-1 expression in CD8+ T cells from COVID-19 convalescent patients. scRNA-seq bioinformatics analysis revealed that AKT/GSK3β may regulate the INF-γ/PD-1 axis in CD8+ T cells from COVID-19 convalescent patients. In parallel, an IFN-γ neutralizing antibody reduced AKT and increased GSK3β in PBMCs. An AKT agonist (SC79) significantly decreased p-GSK3β. Moreover, AKT decreased PD-1 on CD8+ T cells, and GSK3β increased PD-1 on CD8+ T cells according to flow cytometry analysis. Collectively, we demonstrated that recovered COVID-19 patients may develop long COVID. Increased IFN-γ in the plasma of recovered Wuhan COVID-19 patients contributed to PD-1 downregulation on CD8+ T cells by regulating the AKT/GSK3β signaling pathway.

Abstract Tissue adhesives are promising alternatives to sutures and staples for joining tissues, sealing defects, and immobilizing devices. However, existing adhesives mostly take the forms of glues or hydrogels, which offer limited versatility. We report a direct-ink-write 3D printable tissue adhesive which can be used to fabricate bioadhesive patches and devices with programmable architectures, unlocking new potential for application-specific designs. The adhesive is conformable and stretchable, achieves robust adhesion with wet tissues within seconds, and exhibits favorable biocompatibility. In vivo rat trachea and colon defect models demonstrate the fluid-tight tissue sealing capability of the printed patches, which maintained adhesion over 4 weeks. Moreover, incorporation of a blood-repelling hydrophobic matrix enables the printed patches to seal actively bleeding tissues. Beyond wound closure, the 3D printable adhesive has broad applicability across various tissue-interfacing devices, highlighted through representative proof-of-concept designs. Together, this platform offers a promising strategy toward developing advanced tissue adhesive technologies.

Abstract Background Patients with myocardial infarction (MI) frequently experience a heightened incidence of depression, thereby increasing the risk of adverse cardiovascular events. Consequently, early detection and intervention in depressive symptoms among patients with MI are imperative. Shexiang Baoxin Pills (SBP), a Chinese patent medicine employed for the treatment of MI, exhibits diverse mechanisms targeting this condition. Nevertheless, its therapeutic efficacy on postmyocardial infarction depressive symptoms remains unclear. The aim of this study is to investigate the effectiveness and mechanism of SBP in managing depression during acute myocardial infarction (AMI). Methods A rat model combining MI and depression was established, and the rats were randomly divided into four groups: the model (MOD) group, SBP group, Fluoxetine (FLX) group, and Sham group. After 28 days of drug intervention, cardiac function was assessed using echocardiography while behavior was evaluated through sucrose preference test (SPT), forced swimming test (FST), and open‐field test (OFT). Additionally, levels of inflammatory factors in serum and hippocampus were measured along with NLRP3 inflammasome‐related protein expression via Western blotting and immunofluorescence. Results SBP can enhance cardiac function in rats with AMI and depression, while significantly ameliorating depressive‐like behavior. Compared to the Sham group, levels of IL‐1β, IL‐18, TNF‐α, and other inflammatory factors were markedly elevated in the MOD group. However, expressions of these inflammatory factors were reduced to varying degrees following treatment with SBP or FLX. Analysis of NLRP3 inflammasome‐related proteins in the hippocampus revealed a significant upregulation of IL‐1β, IL‐18, NLRP3, ASC, caspase‐1, and GSDMD in the MOD group; conversely, these measures were significantly attenuated after SBP intervention. Conclusion We have observed a significant amelioration in depression‐like behavior upon SBP administration during the treatment of AMI, suggesting that this effect may be attributed to the inhibition of NLRP3‐mediated pyroptosis. (The main findings are summarized in the graphical abstract in the supplementary file.)

Abstract Objective To analyze the efficacy and adverse effects of anti‐PD‐1 immune checkpoint inhibitors aimed at nasopharyngeal carcinoma (NPC). Methods During the first stage of the study, using 40 patients with stage III/IVa NPC treated with anti‐PD‐1 immune checkpoint inhibitors in combination with chemoradiotherapy as a first‐line treatment (observation group) and 70 patients with NPC treated with chemoradiotherapy alone (control group). In the second stage of the study, 88 patients with NPC treated with immune checkpoint inhibitors were grouped according to the number of lines of immunotherapy, the number of times, and the types of application. Results Observation of the short‐term effects in the first stage indicated that the objective response rate (ORR) of the observation group and the control group against primary foci of NPC was 75.0% versus 40.0%; the mortality rate of the observation group was much lower than that of the control group. The overall first‐line treatment evaluation of the observation vs. control groups were as follows: ORR (67.5% vs. 38.6%); median PFS (17.52 vs. 17.21 months); and median OS (18.68 vs. 18.14 months), respectively (p

The drug development process is poised for significant transformation due to the rapid advancement of modern biological and information technologies, such as artificial intelligence (AI). As these new technologies and concepts infiltrate every stage of drug development, the efficiency and success rate of research and development are expected to improve substantially. Traditional Chinese medicine (TCM), a time-honored therapeutic system encompassing herbal medicine, acupuncture, and qigong, will also be profoundly impacted by these advancements. Over the next decade, Traditional Chinese medicine research will encounter both opportunities and challenges as it integrates with modern technologies and concepts. By 2035, TCM is anticipated to merge with modern medicine through a more contemporary and open research and development model, providing substantial support for treating a broader spectrum of diseases.

Abstract Nickel–rich layered oxides of LiNi1–x–yCoxMn(Al)yO2 (where 1–x–y>0.6) are considered promising cathode active materials for lithium‐ion batteries (LIBs) due to their high reversible capacity and energy density. However, the widespread application of NCM(A) is limited by microstructural degradation caused by the anisotropic shrinkage and expansion of primary particles during the H2→H3 phase transition. In this mini–review, we comprehensively discuss the formation of microcracks, subsequent material degradation, and related alleviation strategies in nickel–rich layered NCM(A). Firstly, theories on microcracks′ formation and evolution mechanisms are presented and critically analyzed. Secondly, recent advancements in mitigation strategies to prevent degradation in Ni–rich NCM/NCA are highlighted. These strategies include doping, surface coating, structural optimization, and morphology engineering. Finally, we provide an outlook and perspective to identify promising strategies that may enable the practical application of Ni–rich NCM/NCA in commercial settings.

Background: Whether there is hypothalamic degeneration in Parkinson's disease (PD) and its association with clinical symptoms and pathophysiological changes remains controversial. Objectives: We aimed to quantify microstructural changes in hypothalamus using a novel deep learning-based tool in patients with PD and those with probable rapid-eye-movement sleep behavior disorder (pRBD). We further assessed whether these microstructural changes associated with clinical symptoms and free thyroxine (FT4) levels. Methods: This study included 186 PD, 67 pRBD, and 179 healthy controls. Multi-shell diffusion MRI were scanned and mean kurtosis (MK) in hypothalamic subunits were calculated. Participants were assessed using Unified Parkinson's Disease Rating Scale (UPDRS), RBD Questionnaire-Hong Kong (RBDQ-HK), Hamilton Depression Rating Scale (HAMD), and Activity of Daily Living (ADL) Scale. Additionally, a subgroup of PD (n = 31) underwent assessment of FT4. Results: PD showed significant decreases of MK in anterior-superior (a-sHyp), anterior-inferior (a-iHyp), superior tubular (supTub), and inferior tubular hypothalamus when compared with healthy controls. Similarly, pRBD exhibited decreases of MK in a-iHyp and supTub. In PD group, MK in above four subunits were significantly correlated with UPDRS-I, HAMD, and ADL. Moreover, MK in a-iHyp and a-sHyp were significantly correlated with FT4 level. In pRBD group, correlations were observed between MK in a-iHyp and UPDRS-I. Conclusions: Our study reveals that microstructural changes in the hypothalamus are already significant at the early neurodegenerative stage. These changes are associated with emotional alterations, daily activity levels, and thyroid hormone levels.

Deep vein thrombosis (DVT) is one of the common complications after joint replacement, which seriously affects the quality of life of patients. We systematically searched nine databases, a total of eleven studies on prediction models to predict DVT after knee/hip arthroplasty were included, eight prediction models for DVT after knee/hip arthroplasty were chosen and compared. The results of network meta-analysis showed the XGBoost model (SUCRA 100.0%), LASSO (SUCRA 84.8%), ANN (SUCRA 72.1%), SVM (SUCRA 53.0%), ensemble model (SUCRA 40.8%), RF (SUCRA 25.6%), LR (SUCRA 21.8%), GBT (SUCRA 1.1%), and best prediction performance is XGB (SUCRA 100%). Results show that the XGBoost model has the best predictive performance. Our study provides suggestions and directions for future research on the DVT prediction model. In the future, well-designed studies are still needed to validate this model.

ObjectiveTo investigate the correlation between programmed death ligand 1(PD-L1), tumor mutation burden (TMB) and the short-term efficacy and clinical characteristics of anti-PD-1 immune checkpoint inhibitor combination chemotherapy in NSCLC patients. The efficacy of the prediction model was evaluated.MethodsA total of 220 NSCLC patients receiving first-line treatment with anti-PD-1 immune checkpoint inhibitor combined with chemotherapy were retrospectively collected. The primary endpoint was short-term efficacy ORR. The correlation between short-term efficacy, PD-L1, TMB, and clinical characteristics using χ2 test or t-test was evaluated. Screen the independent prognostic factors using univariate and multivariate logistic regression analyses, and construct a nomogram prediction model using the “rms” package in R software. Using receiver operating characteristic (ROC) curve analysis to evaluate the independent Prognostic factors and the prediction model. Using decision curve analysis (DCA) to verify the superiority of the prediction model.ResultsThe mean values of PD-L1, TMB, neutrophils, lymphocytes, neutrophil-to-lymphocyte ratio, and albumin were the highest in the ORR group, PD-L1 expression and TMB correlated with epidermal growth factor receptor expression. Multivariate analyses showed that PD-L1, TMB, and neutrophil were independent prognostic factors for ORR. The area under the ROC curve (AUC) values of the ROC constructed based on these three indicators were 0.7104, 0.7139, and 0.7131, respectively. The AUC value under the ROC of the nomogram model was 0.813. The DCA of the model showed that all three indicators used together to build the prediction model of the net return were higher than those of the single indicator prediction model.ConclusionPD-L1, TMB, and neutrophils are independent prognostic factors for short-term efficacy. The nomogram prediction model constructed using these three indicators can further improve predictive efficacy of ICIs in patients with NSCLC.

Abstract Bone regeneration for large, critical-sized bone defects remains a clinical challenge nowadays. Guided bone regeneration (GBR) is a promising technique for the repair of multiple bone defects, which is widely used in oral and maxillofacial bone defects but is still unsatisfied in the treatment of long bone defects. Here, we successfully fabricated a bilayer mineralized collagen/collagen (MC/Col)-GBR membrane with excellent osteoinductive and barrier function by coating the MC particles prepared via in situ biomimetic mineralization process on one side of a sheet-like pure collagen layer. The aim of the present study was to investigate the physicochemical properties and biological functions of the MC/Col film, and to further evaluate its bone regeneration efficiency in large bone defect repair. Fourier-transform infrared spectra and X-ray diffraction patterns confirmed the presence of both hydroxyapatite and collagen phase in the MC/Col film, as well as the chemical interaction between them. stereo microscope, scanning electron microscopy and atomic force microscope showed the uniform distribution of MC particles in the MC/Col film, resulting in a rougher surface compared to the pure Col film. The quantitative analysis of surface contact angle, light transmittance and tensile strength demonstrated that the MC/Col film have better hydrophilicity, mechanical properties, light-barrier properties, respectively. In vitro macrophage co-culture experiments showed that the MC/Col film can effectively inhibit macrophage proliferation and fusion, reducing fibrous capsule formation. In vivo bone repair assessment of a rabbit critical segmental radial defect proved that the MC/Col film performed better than other groups in promoting bone repair and regeneration due to their unique dual osteoinductive/barrier function. These findings provided evidence that MC/Col film has a great clinical potential for effective bone defect repair. Graphic abstract

Abstract Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson’s disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics. Using a brain-first mouse model of PD, we demonstrate αSyn trafficking from the brain to the ileum of male mice. Immunohistochemistry revealed that the ileal αSyn aggregations are contained within CD11c+ cells. Using single-cell RNA sequencing, we demonstrate that ileal CD11c+ cells are microglia-like and the same subtype of cells is activated in the brain and ileum of PD mice. Moreover, by utilizing mice expressing the photo-convertible protein, Dendra2, we show that CD11c+ cells traffic from the brain to the ileum. Together these data provide a mechanism of αSyn trafficking between the brain and gut.

Abstract Background People with hypertension have a higher risk of developing Parkinson’s disease (PD), epidemiological evidence suggests that multiple antihypertensives may affect the occurrence and development of PD with inconsistent results. With multisource data, we sought to determine whether specific antihypertensive classes elevated or reduced the risk for PD. Methods We used a mixed methods approach that combines 4 methodologies. First, we conducted a disproportionality analysis using the reports causing adverse events in the US Food and Drug Administration Adverse Events Reporting System (FAERS) to explore the effect of different classes of antihypertensive medications on the risk of PD; based on the findings from FAERS, a meta-analysis and a UK Biobank cohort analysis were used to further assess the association of drug use with PD; finally, we employed Mendelian randomization (MR) analysis to validate the causal relationship between the drug target and the occurrence of PD. Results In the disproportionality analysis using the FAERS (N = 187,266), nonselective beta-adrenoceptor blockers (NBBs) were demonstrated to have a significant association with PD (reporting odds ratio (ROR) = 3.13; 95% CI 2.33–4.22). In the meta-analysis of 12 studies with 12,183,809 participants, PD risk was elevated in NBBs (RR, 1.64; 95% CI, 1.19–2.09) when stratified by subtypes of BBs. Among the 105,763 participants included in the cohort analysis using data from the UK Biobank, individuals who used NBBs had a significantly increased risk of PD compared to nonusers (HR, 1.47; 95% CI 1.04–2.06). The MR analysis revealed a significant association between higher expression of the β2 adrenergic receptor (ADRB2) gene, a drug target blocked by NBBs, and a reduced risk of PD (OR, 0.85; 95% CI 0.73–0.99). Conclusions Our comprehensive study indicated that regular NBB use is associated with an increased risk of PD. In light of the detrimental effects of NBBs on PD, some people should choose alternative antihypertensive treatments.

Cymbidium faberi Rolfe is one of the traditional Chinese orchids with important ornamental value, and the cultivation of Cymbidium faberi Rolfe mutant strains with different appearances is essential to increase its economic value. However, at present, their acquisition largely relies on natural mutation. The objectives of this research were to mutagenize Cymbidium faberi Rolfe protocorm-like bodies (PLBs) and shoots in vitro using sodium azide (NaN3) and to screen and evaluate mutants in the mutagenized seedlings using morphological characteristics. Cymbidium faberi Rolfe PLBs and shoots were used as mutagenic materials. Mutations were induced by the addition of 0.0 (control), 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 mg·L−1 and 0.0 (control), 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, and 10.0 mg·L−1 NaN3 to a shoot-growth-inducing medium. The mortality rates of the PLBs and shoots increased with an increase in the NaN3 concentration. At 14 d of co-cultivation, the PLBs and shoots were most efficiently mutagenized with 1.5 mg·L−1 and 4.0 mg·L−1 NaN3, respectively. After the explants were cultured for 3 months, changes in leaf and flower morphology were observed in some mutants: shorter and thicker leaves, shorter node length, reduced height, and mid-translucent leaves compared with controls. Some Cymbidium faberi Rolfe bloomed prematurely, with single flowers with large, thick petal sepals and small inflorescences. Colors included light green throughout, with some exhibiting purple stamens. This suggests that NaN3 can effectively mutagenize Cymbidium faberi Rolfe PLBs and shoots to satisfy people’s demand for this plant’s ornamental properties while increasing its economic value.

In this study, the neuroprotective potential of tanshinone IIA (TIIA)-modified mesenchymal stem cells (MSC) were investigated using a murine model of lipopolysaccharide (LPS)-induced neuroinflammation. The cognitive performance of the mice was assessed using the Y-maze and Morris water maze tests, while immunofluorescence and Western blot analyses were employed to evaluate the hippocampal expression of pertinent markers and inflammatory factors, respectively. The results from the behavioral experiments demonstrated discernible differences in learning and memory abilities between the model group and the control group (P

Abstract This study examined the levels of soluble CD146 (sCD146) in plasma samples from patients with chronic obstructive pulmonary disease (COPD) and assessed the relationship between sCD146 and the severity of COPD. A total of 97 COPD patients were recruited from 20 medical centers in Jiangsu, China, including 13 stable subjects and 84 exacerbated subjects. The plasma sCD146 level in exacerbated subjects (28.77 ± 10.80 ng/mL) was significantly lower than that in stable subjects (38.84 ± 15.00 ng/mL). In the high sCD146 group, the proportion of subjects with modified Medical Research Council (mMRC) scores of 0–1 was higher, the proportion of subjects with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 4 was lower, and the proportion of subjects with ≥1 hospitalizations in the past year was lower. The plasma sCD146 level was negatively correlated with the COPD Assessment Test (CAT) score (r = −0.2664, p = 0.0087). Logistic regression analysis showed that sCD146 was an independent risk factor for acute exacerbation of COPD (AECOPD). Receiver operating characteristic (ROC) analysis suggested that sCD146 combined with sex, age, pulmonary function, and acute exacerbations in the past year had clinical value for the accurate identification of AECOPD, with an area under the ROC curve (AUC) of 0.908 (95% CI: 0.810–1.000, p

BackgroundObesity and dyslipidemia, major global health concerns, have been linked to psoriasis, but previous studies faced methodological limitations and their shared genetic basis remains unclear. This study examines various obesity-related and lipidemic traits as potential contributors to psoriasis development, aiming to clarify their genetic associations and potential causal links.MethodsSummary statistics from genome-wide association studies (GWAS) conducted for obesity-related traits (body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-hip ratio adjusted for the body mass index (WHRadjBMI)) and lipidemic traits (high-density lipoprotein (HDL), LDL, triglyceride (TG), total Cholesterol (TC), apolipoprotein A1 (apoA1), apolipoprotein B (apoB), and apolipoprotein E (apoE)) and psoriasis, all in populations of European ancestry, were used. We quantified genetic correlations, identified shared loci and explored causal relationship across traits.ResultsWe found positive genetic correlation between BMI and psoriasis (rg=0.22, p=2.44×10-18), and between WHR and psoriasis (rg=0.19, p=1.41×10-12). We further found the positive genetic correlation between psoriasis and WHRadjBMI(rg=0.07, p=1.81×10-2) the genetic correlation, in while the effect of BMI was controlled for. We identified 14 shared loci underlying psoriasis and obesity-related traits and 43 shared loci between psoriasis and lipidemic traits via cross-trait meta-analysis. Mendelian randomization (MR) supported the causal roles of BMI (IVW OR=1.483, 95%CI=1.333-1.649), WHR (IVW OR=1.393, 95%CI=1.207-1.608) and WHRadjBMI (IVW OR=1.18, 95%CI=1.047-1.329) in psoriasis, but not observe any significant association between lipidemic traits and the risk of psoriasis. Genetic predisposition to psoriasis did not appear to affect the risk of obesity and lipidemic traits.ConclusionsAn intrinsic link between obesity-related traits and psoriasis has been demonstrated. The genetic correlation and causal role of obesity-related traits in psoriasis highlight the significance of weight management in both the prevention and treatment of this condition.

Background: Parkinson's disease (PD) patients exhibit an imbalance between neuronal activity and perfusion, referred to as abnormal neurovascular coupling (NVC). Nevertheless, the underlying molecular mechanism and how levodopa, the standard treatment in PD, regulates NVC is largely unknown. Material and methods: A total of 52 drug-naïve PD patients and 49 normal controls (NCs) were enrolled. NVC was characterized in vivo by relating cerebral blood flow (CBF) and amplitude of low-frequency fluctuations (ALFF). Motor assessments and MRI scanning were conducted on drug-naïve patients before and after levodopa therapy (OFF/ON state). Regional NVC differences between patients and NCs were identified, followed by an assessment of the associated receptors/transporters. The influence of levodopa on NVC, CBF, and ALFF within these abnormal regions was analyzed. Results: Compared to NCs, OFF-state patients showed NVC dysfunction in significantly lower NVC in left precentral, postcentral, superior parietal cortex, and precuneus, along with higher NVC in left anterior cingulate cortex, right olfactory cortex, thalamus, caudate, and putamen (P-value

Abstract Objective To determine whether white matter hyperintensity (WMH) volumes in specific regions are associated with Parkinson's disease (PD) compared to non‐PD controls, and to assess their impact on motor signs through cross‐sectional and longitudinal analyses. Methods A total of 50 PD participants and 47 age‐ and gender‐matched controls were enrolled. All PD participants were followed up for at least 2 years. To detect regions of greater WMH in the PD, the WMH volume of each region was compared with the corresponding region in the control group. Linear regression and linear mixed effects models were respectively used for cross‐sectional and longitudinal analyses of the impact of increases in WMH volume on motor signs. Results The PD group had greater WMH volume in the occipital region compared with the control group. Cross‐sectional analyses only detected a significant correlation between occipital WMH volume and motor function in PD. Occipital WMH volume positively correlated with the severity of tremor, and gait and posture impairments, in the PD group. During the follow‐up period, the participants' motor signs progressed and the WMH volumes remained stable, no longitudinal association was detected between them. The baseline occipital WMH volume cannot predict the progression of signs after adjustment for baseline disease duration and the presence of vascular risk factors. Interpretation PD participants in this study were characterized by greater WMH at the occipital region, and greater occipital WMH volume had cross‐sectional associations with worse motor signs, while its longitudinal impact on motor signs progression was limited.

Abstract The association of various air pollutants exposure during adolescence with blood pressure (BP) in young adulthood is uncertain. We intended to evaluate the long‐term association of individual and joint air pollutants exposure during adolescence with BP in young adulthood. This cross‐sectional study of incoming students was conducted in five geographically disperse universities in China during September and October 2018. Mean concentrations of particulate matter with diameters ≤2.5 μm (PM2.5), ≤10 μm (PM10), nitrogen dioxides (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3) at participants’ residential addresses during 2013–2018 were collected from the Chinese Air Quality Reanalysis dataset. Generalized linear mixed models (GLM) and quantile g‐computation (QgC) models were utilized to estimate the association between individual and joint air pollutants exposure and systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP). A total of 16,242 participants were included in the analysis. The GLM analyses showed that PM2.5, PM10, NO2, CO, and SO2 were significantly positively associated with SBP and PP, while O3 was positively associated with DBP. The QgC analyses indicated that long‐term exposure to a mixture of the six air pollutants had a significant positive joint association with SBP and PP. In conclusion, air pollutant co‐exposure during adolescence may influence BP in young adulthood. The findings of this study emphasized the impacts of multiple air pollutants interactions on potential health and the need of minimizing pollution exposures in the environment.

Abstract Increasing evidence suggests that Parkinson’s disease (PD) exhibits disparate spatial and temporal patterns of progression. Here we used a machine-learning technique—Subtype and Stage Inference (SuStaIn) — to uncover PD subtypes with distinct trajectories of clinical and neurodegeneration events. We enrolled 228 PD patients and 119 healthy controls with comprehensive assessments of olfactory, autonomic, cognitive, sleep, and emotional function. The integrity of substantia nigra (SN), locus coeruleus (LC), amygdala, hippocampus, entorhinal cortex, and basal forebrain were assessed using diffusion and neuromelanin-sensitive MRI. SuStaIn model with above clinical and neuroimaging variables as input was conducted to identify PD subtypes. An independent dataset consisting of 153 PD patients and 67 healthy controls was utilized to validate our findings. We identified two distinct PD subtypes: subtype 1 with rapid eye movement sleep behavior disorder (RBD), autonomic dysfunction, and degeneration of the SN and LC as early manifestations, and cognitive impairment and limbic degeneration as advanced manifestations, while subtype 2 with hyposmia, cognitive impairment, and limbic degeneration as early manifestations, followed later by RBD and degeneration of the LC in advanced disease. Similar subtypes were shown in the validation dataset. Moreover, we found that subtype 1 had weaker levodopa response, more GBA mutations, and poorer prognosis than subtype 2. These findings provide new insights into the underlying disease biology and might be useful for personalized treatment for patients based on their subtype.

Abstract Background The prevalence of type 2 diabetes mellitus (T2DM) currently was increased in some countries of the world like China. However, the epidemiological trends of T2DM attributable to non-high body mass index (BMI) remain unclear. Thus, we aimed to describe the burden of T2DM attributable to non-high BMI. Methods To estimate the burden of T2DM attributable to non-high BMI, data from the Global Burden of Disease Study 2019 were used to calculate the deaths and disability-adjusted life years (DALYs) by age, sex, year, and location. The estimated annual percentage change (EAPC) was applied in the analysis of temporal trends in T2DM from 1990 to 2019. Results Globally in 2019, the number of death cases and DALYs of T2DM attributable to non-high BMI accounted for 57.9% and 48.1% of T2DM-death from all risks, respectively. Asia accounted for 59.5% and 63.6% of the global non-high-BMI-related death cases and DALYs of T2DM in 2019, respectively. From 1990 to 2019, regions in the low-income experienced a rise in DALYs attributable to non-high BMI. As compared to other age groups, older participants had higher deaths and DALYs of T2DM attributable to non-high BMI. The death and DALY rates of T2DM due to non-high BMI were higher in males and people in regions with low socio-demographic index (SDI) countries. Conclusions The burden of T2DM attributable to non-high BMI is higher in the elderly and in people in regions with low- and middle-SDI, resulting in a substantial burden on human health and the social cost of healthcare.

Abstract Hepatocellular carcinoma (HCC) is one of the most lethal tumor types worldwide. Glycosylation has shown promise in the study of tumor mechanisms and treatment. The glycosylation status of HCC and the underlying molecular mechanisms are still not fully elucidated. Using bioinformatic analysis we obtained a more comprehensive characterization of glycosylation of HCC. Our analysis presented that high glycosylation levels might correlate with tumor progression and poor prognosis. Subsequent Experiments identified key molecular mechanisms for ST6GALNAC4 promoting malignant progression by inducing abnormal glycosylation. We confirmed the contribution of ST6GALNAC4 to proliferation, migration, and invasion in vitro and in vivo. Mechanistic studies revealed that ST6GALNAC4 may be induced abnormal TGFBR2 glycosylation, resulting in the higher protein levels of TGFBR2 and TGF $$\beta$$ β pathway increased activation. Our study also provided a further understand of immunosuppressive function of ST6GALNAC4 through T antigen-galectin3+ TAMs axis. This study has provided one such possibility that galectin3 inhibitors might be an acceptable treatment choice for HCC patients with high T antigen expression.

ABSTRACT: Misregulation of spermatogenesis transcription factors (TF) in hybrids can lead to misexpression, which is a mechanism for hybrid male sterility (HMS). We used dzo (male offspring of Bos taurus ♂ × Bos grunniens ♀) in bovines to investigate the relationship of the key TF with HMS via RNA sequencing and assay for transposase-accessible chromatin with high-throughput sequencing analyses. RNA sequencing showed that the widespread misexpression in dzo was associated with spermatogenesis-related genes and somatic or progenitor genes. The transition from leptotene or zygotene spermatocytes to pachytene spermatocytes may be the key stage for meiosis arrest in dzo. The analysis of TF-binding motif enrichment revealed that the male meiosis-specific master TF MYB proto-oncogene like 1 (MYBL1, known as A-MYB) motif was enriched on the promoters of downregulated pachytene spermatocyte genes in dzo. Assay for transposase-accessible chromatin with high-throughput sequencing revealed that TF-binding sites for MYBL1, nuclear transcription factor Y, and regulatory factor X were enriched in the low-chromatin accessibility region of dzo. The target genes of the MYBL1-binding motif were associated with meiosis-specific genes and significantly downregulated in dzo testis. The transcription factor MYBL1 may be the candidate master regulator for pachytene spermatocyte genes dysregulated in interspecific HMS dzo. This study reported that a few upstream TF regulation changes might exert a cascading effect downstream in a regulatory network as a mechanism for HMS.

Mixed micelles (MMs), as a new targeted drug delivery system with high adjustability, have been widely studied in biomedicines. In order to study whether mixtures containing two different molecules have excellent targeted anti-tumor effect, MMs based on D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and triblock copolymer P84 were prepared, and the characterization, cell endocytosis, and exocytosis of P84/TPGS MMs were observed. Paclitaxel (PTX), a classical anti-tumor drug, was selected as a model compound to explore its anti-tumor effect in vivo. The results showed that P84/TPGS MMs had better stability, suitably distributed particle size, good cell endocytosis, and tumor sphere permeability, which could improve the permeability of PTX in the tumor site and effectively inhibit the growth of H22 tumor in mice. In conclusion, P84/TPGS MMs is a potential micelle carrier system of cancer targeting, needing further investigation.

Objective: Placenta previa is a health issue during pregnancy when the placenta wholly or partially covers the opening of the uterus. It can result in bleeding during pregnancy or after delivery, and preterm delivery. This study aimed to investigate the risk factors correlated with poorer childbirth outcomes of placenta previa. Materials and methods: Between May 2019 and January 2021, pregnant women diagnosed with placenta previa in our hospital were enrolled. Outcomes were postpartum hemorrhage after childbirth, and lower Apgar score and preterm delivery of the neonate. Laboratory blood examination data preoperatively were collected from medical records. Results: A total of 131 subjects were included, with a median age 31 years. Multivariate analysis showed that fibrinogen reduced risk for postpartum hemorrhage (adjusted odds ratio (aOR): 0.45, 95% confidence interval (CI): 0.26–0.79, p = 0.005). Homocysteine (aOR: 0.73, 95% CI: 0.54–0.99, p = 0.04) reduced the risk while D-dimer (aOR: 1.19, 95% CI: 1.02–1.37, p = 0.02) increased the risk for low Apgar score. Age (aOR: 0.86, 95% CI: 0.77–0.96, p = 0.005) decreased the risk but history of full-term pregnancy more than twice (aOR: 8.58, 95% CI: 2.32–31.71, p = 0.001) increased the risk for preterm delivery. Conclusion: The findings suggest that poorer childbirth outcomes in pregnant women with placenta previa are associated with young age, history of full-term pregnancy, and preoperative concentrations of low fibrinogen, low homocysteine and high D-dimer. This provides obstetricians adjunctive information for early screening of high-risk population and relevant treatment arrangement in advance.

Linkage disequilibrium (LD) is a fundamental concept in genetics; critical for studying genetic associations and molecular evolution. However, LD measurements are only reliable for common genetic variants, leaving low-frequency variants unanalyzed. In this work, we introduce cumulative LD (cLD), a stable statistic that captures the rare-variant LD between genetic regions, which reflects more biological interactions between variants, in addition to lack of recombination. We derived the theoretical variance of cLD using delta methods to demonstrate its higher stability than LD for rare variants. This property is also verified by bootstrapped simulations using real data. In application, we find cLD reveals an increased genetic association between genes in 3D chromatin interactions, a phenomenon recently reported negatively by calculating standard LD between common variants. Additionally, we show that cLD is higher between gene pairs reported in interaction databases, identifies unreported protein-protein interactions, and reveals interacting genes distinguishing case/control samples in association studies.

Objectives To explore the association between non-high-density lipoprotein (non-HDL) and mortality risk, both short-term and long-term, in Chinese people.Design A prospective cohort study.Setting The National Basic Public Health Service (BPHS) in China.Participants Including 621 164 elderly individuals around Hunan Province who underwent healthcare management receiving check-ups in China BPHS from 2010 to 2020. Exclusion criteria: (1) missing information on gender; (2) missing records of lipid screening; (3) missing information on key covariates; and (4) missing records of comorbidities (cardiovascular disease, hypertension, diabetes, cancer.)Primary and secondary outcome measures The study’s primary endpoint was all-cause and cause-specific mortality, sourced from Hunan’s CDC(Center for Disease Control and Prevention)-operated National Mortality Surveillance System, tracking participants until 24 February 2021.Results 26 758 (4.3%) deaths were recorded, with a median follow-up of 0.83 years. Association between non-HDL and mortality was non-linear after multivariable adjustment, with the optimum concentration (OC) being 3.29 and 4.85 mmol/L. Compared with OC, the risk increased by 1.12-fold for non-HDL

Neonatal thrombocytopenia is one of the common hematological abnormalities in neonates, especially premature infants. Platelet transfusion is an effective method of treating neonatal thrombocytopenia, but its threshold selection and timing are controversial. Recent findings support the use of a lower platelet transfusion threshold (25×109/L) in neonates and highlight the potential harm that may arise from liberal blood transfusion strategy. In current clinical practice, the volume of neonatal platelet transfusion greatly exceeds that routinely used in adults, but there are significant functional differences between neonatal and adult platelets, and platelets may mediate several immune and inflammatory responses in multiple ways. In this paper, based on the recent developments of evidence-based medical evidence of neonatal platelet transfusion, we summarized the pathophysiological basis of neonatal restrictive blood transfusion strategy, platelet transfusion with different ABO blood types, and the pathogenesis and potential mechanism of adverse events related to platelet transfusion.

Abstract Background Understanding the stoichiometric characteristics and nutrient allocation strategies of dominant tree species in montane forest systems can provide a basis for decision-making in relation to montane system management. Therefore, according to precipitation and temperature gradients, we selected three typical areas in the Qilian Mountains on the eastern margin of the Qinghai-Tibet Plateau to analyse the spatial relations of plant-soil stoichiometric characteristics and nutrient allocation strategies of plant tissues for Qinghai spruce (Picea crassifolia) along different environmental gradients. Results 1) The plant and soil stoichiometric characteristics had similar spatial patterns. The C content of plants and soils tended to decrease with increasing latitude, and the N and P contents and the N:P ratio tended to increase with increasing latitude. 2) The stoichiometric characteristics of the plant tissues also interacted with each other and showed synergistic trade-offs. Nutrient allocation in the eastern section of the Qilian Mountains was similar to that in the western section, while more N and P in the plant stems were allocated to maintain plant growth in the relatively arid western Sect. 3) The nutrient allocation strategies in the plant tissues were mainly regulated by soil and climate. Conclusions Information on plant-soil stoichiometric characteristics along different gradients can help us better understand the nutrient patterns and dynamics of forest ecosystems under arid and semiarid conditions at a wide geographic scale from the perspective of plant nutrient partitioning.

PDC bit has become the preferred type of drill bits in the field of oil and gas exploration. The ever-increasing performance requirements of PDC bits, especially the drilling efficiency, have brought great challenges to the drill bits. The improvement of the drill bit working face structure is crucial to the efficient rock breaking of PDC bits. However, this brings great difficulties to the manufacture of drill bits. 3D printing technology is a new type of rapid prototyping technology which has the advantages of manufacturing any complex shape structures, personalized customization and creative design. It is an inevitable trend to apply 3D printing technology to the production of PDC bits. This paper focuses on the basic principles of 3D printing technologies currently used to prepare PDC bits, including photolithography (SLA), fused deposition (FDM), selective laser sintering (SLS), selective laser melting (SLM) and three dimensional printing (3DP), etc. And then it summarizes the research progress of the existing 3D printing technology in the manufacture of PDC and PDC bits, and gives an outlook on the development of 3D printing PDC and PDC bits in the future.

Dear Editor, In our subsequent study after the receipt of the article, it was found that the P84Ms carrier had certain cytotoxicity. As can be seen from the Figure 1 and Figure 2, compared with the cells in the control group, after incubation with different prepare preparations, the single carrier group Micelles-Blank and Mixed Micelles-Blank could inhibit the growth of the cells. However, the cytotoxicity data in the paper did not set Micelles-Blank and Mixed Micelles-Blank groups, which was also an oversight of our design at that time. Hence it is hard to say whether the therapeutic effect of the preparation is due to the toxicity of the carrier or the therapeutic effect of the drug in this article Therefore, the statement in the article that the carrier is safe and effective may be wrong. So the article needs to be withdrawn, and we will further modify the carrier in the future to reduce its toxicity.

As the largest lake in South China, Wanlv Lake is also an important drinking water source for Guangdong and Hong Kong and is responsible for water supplying of more than 40 million people in the Guangdong-Hong Kong-Macao Greater Bay Area. The study of fish diversity in Wanlv Lake can help us to effectively understand the changes and states of its aquatic ecosystem and provide scientific basis for natural ecological protection, biodiversity, sustainable use and scientific management of fishery resources. However, research on the lake’s fish is scarce. The high throughput environmental DNA metabarcoding technology (eDNA technology) of the mitochondrial 12S rRNA gene sequence was herein used to conduct a preliminary exploration of Wanlv Lake fish diversity. A total of 10 sampling sites were set up to monitor fish diversity and analyze the composition and richness of the species. The results revealed a total of 83 genera in 42 families and 17 orders of fish in the lake, with the highest proportion found in Cypriniformes (38 species), accounting for 45.24% of the total. Five alien species and eight rare and endangered species were also detected. The proportion of invasive species was 5.95%, and the combined proportion of rare and endangered species was 9.52%. The results indicated that Wanlv Lake serves as an important drinking water source, and overall, the condition of fish is satisfactory. However, proactive measures should be implemented to control the overpopulation of invasive species, as their unchecked proliferation may lead to a decline in species abundance, particularly among endangered species. This was the first overall assessment report on fish of the Wanlv Lake via 12S rRNA; the results herein lay a foundation for water quality assessment of Wanlv Lake as a drinking water source.

Wetlands in the arid zone of northwest China have ecological values such as climate regulation, water conservation, and biodiversity maintenance. However, in the context of global warming and economic development, the degree of natural and human interference in the wetlands has been increasing, and wetland health problems are becoming increasingly severe. The current comparative research on the ecosystem health evaluation of natural and constructed wetlands and their sustainable development in the arid zone of northwest China is not perfect, so we selected the natural (Dunhuang Xihu Wetland) and constructed wetlands (Suzhou District Wetland) as research objects. The ecosystem health evaluation system has been developed from 5 levels of the drive, pressure, state, impact, and response (DPSIR). The ecological health status and impact factors were evaluated for the two wetlands using socioeconomic data combined with remote sensing technology from 2000 to 2019. The results showed that 1) the ecological health of natural and constructed wetlands was in a medium healthy state, and the ecological health values of the wetlands showed a trend of decreasing and then increasing from 2000 to 2019, with 2005 as the turning point. The ecological health status of natural wetlands (0.46) was better than that of constructed wetlands (0.42). 2) The main reasons for the degradation of constructed wetlands (-3.20%) were the urban population expansion and blind agricultural reclamation of wetlands, while the degradation of natural wetlands (-6.45%) was dominated by extreme climatic conditions and overuse of water resources. These results provide case support and a theoretical basis for the conservation management and sustainable development of wetland ecosystems in the arid zone.