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Abstract The ability to image adoptively transferred T cells in the body and to eliminate them to avoid toxicity will be vital for chimeric antigen receptor (CAR) T cell therapy, particularly against solid tumors with higher risk of off-tumor toxicity. Previously, we have demonstrated the utility of somatostatin receptor 2 (SSTR2) for CAR T cell imaging, illustrating the expansion and contraction of CAR T cells in tumor as well as off-tumor expansion. Using intercellular adhesion molecule 1 (ICAM-1)-specific CAR T cells that secrete interleukin (IL)-12 as a model, herein we examined the potential of SSTR2 as a safety switch when combined with the SSTR2-specific maytansine-octreotate conjugate PEN-221. Constitutive secretion of IL-12 led to continuous expansion of CAR T cells after rapid elimination of tumors, causing systemic toxicity in mice with intact MHC expression. Treatment with PEN-221 rapidly reduced the abundance of CAR T cells, decreasing the severity of xenogeneic graft-versus-host disease (GvHD), and prolonged survival. Our study supports the development of SSTR2 as a single genetic marker for CAR T cells that is readily applicable to humans both for anatomical detection of T cell distribution and an image-guided safety switch for rapid elimination of CAR T cells.

Drought is one of the main environmental factors affecting plant survival and growth. Atraphaxis bracteata is a common desert plant mainly utilized in afforestation and desertification control. This study analyzed the morphological, physiological and molecular regulatory characteristics of different organs of A. bracteata under drought stress. The results showed that with the intensification of drought stress, the height, root length and leaf area of A. bracteata seedlings decreased, while the content of osmotic substances and antioxidant enzyme activity increased. Furthermore, a total of 63 907 non-redundant transcript sequences, of which 55 574 transcripts were annotated, 248 178 FLNC sequences, 107 112 high-quality consistent sequences and 291 314 CCSs were obtained from Iso-Seq. Meanwhile, a total of 2 039 AS events, 22 919 SSR, 40 404 CDS and 5 902 lncRNA were also obtained. The RNA-Seq analysis results revealed that a total of 2 821, 3 907 and 5 532 DETs were identified from roots, stems and leaves, respectively, and which had significantly enrichment in "circadian rhythm-plant" and "starch and sucrose metabolism" pathway. These results would be great significance for further research on the stress resistance of A. bracteata and these DETs function., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Recently, a new bacterial disease was detected on cucumber stalks. In order to study the pathogenesis of this disease, the pathogenic bacteria were isolated and identified on the basis of morphological and molecular characteristics, and further analyzed for pathogenicity and antagonistic evaluation. Pathogenicity analysis showed that HlJ-3 caused melting decay and cracking in cucumber stems, and the strain reisolated from re-infected cucumber stalks was morphologically identical to HlJ-3 colonies, which is consistent with the Koch's postulates. The pathogenic strain HlJ-3 was identified as having similar morphological characteristics to Bacillus subtilis. Meanwhile, its internal transcribed spacer sequence (ITS) and DNA gyrase A subunit (gyrA) were both more than 99% homologous and clustered on the same branch with B. subtilis. Therefore, combined with morphological and molecular biological features, strain HlJ-3 was identified as B. subtilis. In addition, B. subtilis, which has a wide range of hosts, was able to infest other common crop species, including potato, tomato, pepper, melon, and radish. Furthermore, antagonistic evaluation confirmed that strain HlJ-3 strongly inhibited the mycelial growth of Colletotrichum coccodes and Alternaria tenuissima in vitro, with antagonistic effects of 69.92% and 68.08%, respectively. In conclusion, our results showed that strain HlJ-3 is B. subtilis, which is pathogenic to cucumber in vivo and can infect plants of Solanaceae, Cucurbitaceae and Brassicaceae with a wide range of hosts. In addition, this strain has good biocontrol effects against C. coccodes and A. tenuissima in vitro. The findings of this research will help to prevent and control the occurrence of this pathogen and regulate its use as a biocontrol agent., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Research involving plants: The plant material collected for this test, as well as the plants for the test, complied with the relevant laws and regulations. Reprints and permissions information: is available at www.nature.com/reprints . Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional afliations., (© 2025. The Author(s).)

Although the proof-of-concept (POC) phase is critical for the success of translational medical research (TMR), its use remains limited, and clinicians are frequently uncertain about how to seek assistance from POC teams when experiencing difficulties with TMR. Therefore, this study explored clinicians' awareness of POC and the supportive reference services offered by POC teams. We distributed an internet-based questionnaire to 702 clinicians who conducted TMR between August 2022 and March 2023. Descriptive statistics, chi-square test, Wilcoxon rank sum test, Kruskal-Wallis rank sum test, and stepwise logistic regression analysis were applied. Clinicians' awareness of POC was low (69.23%). However, young clinicians (aged 21-30 years) with a higher educational level than their colleagues, good understanding of POC, reliance on the hospital's TMR policy and serviceability, and need or great need for services to identify suitable technology, literature, and intelligence services were likely to choose 'agree' over 'disagree' regarding the ability for POC services to help solve difficulties with TMR. Favourable conditions should be created to encourage clinicians to fully use POC services, and clinicians should actively acquire POC knowledge to enhance their understanding of the value of POC services in TMR. Notably, promoting the establishment of POC centres or platforms at the national level would facilitate the use of POC services by clinicians conducting TMR., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval and consent to participate: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Committee on Ethics of Medicine, Navy Medical University, PLA. All participants were informed of the study aims and provided informed consent electronically. Consent for publication: Not applicable., (© 2024. The Author(s).)

Indocyanine green (ICG) is a diagnostic dye commonly used in medical imaging and liver function monitoring. Given its widespread use, there is a need for detailed evaluations of its adverse drug reactions in real-world settings. As the comprehensive overview of its safety profile is very limited, this study aimed to analyze the adverse events (AEs) associated with ICG using data from the Food and Drug Administration Adverse Event Reporting System (FAERS). Data between 2004Q1 and 2023Q4 were extracted from the FAERS database. Signal detection was performed using various disproportionality analysis algorithms, including reporting odds ratio (ROR), proportional reporting ratio, Bayesian confidence propagation neural network, and multiitem gamma Poisson shrinker. During the study period, a total of 62 ICG-related AEs were reported in the FAERS database. Significant clinical adverse reactions included anaphylactic shock (ROR: 92.10, 95% confidence interval (CI): 37.71-224.96), procedural hypotension (ROR: 1397.27, 95% CI: 443.31-4404.08), and urticaria (ROR: 10.88, 95% CI: 4.02-29.42). This study provides valuable insights into the safety profile of ICG, highlighting the need for further monitoring to ensure its safe clinical use in clinical practice. Ongoing pharmacovigilance and large-scale studies are warranted to fully understand the potential risks associated with ICG., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Data sharing statement: The FAERS database, utilized for this research, is publicly accessible through the FDA’s official website. The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. Ethics statement: No ethical approval is required for studies using publicly available data from FAERS., (© 2024. The Author(s).)

A large-scale conversion of apple orchards into farmland has occurred in the tableland region of the Chinese Loess Plateau due to the aging of apple trees and the increase in pests and diseases. However, the impact of this conversion on soil desiccation recovery and soil nutrient transportation remains unclear, posing a new challenge for sustainable agricultural development in the region. The study employed the space-time substitution approach to select a long-standing orchard and croplands that has been growing maize for 1-, 3-, 5-, and 10-years post-orchard conversion as sampling sites, to investigate the effects of recovery durations of orchard-to-cropland conversion on deep soil water recharge and residual nitrate dynamics, as well as the key factors driving these changes. The results indicated that within 5 years, the conversion led to a rapid recharge of desiccated deep soil (6-9 m), followed by a stable and slow increase in subsequent years. The annual soil water recovery rate in the deep soil was as high as 5.90 mm m -1  a -1 . While, the increased water input also caused rapid leaching and accumulation of nitrate in the deep soil, with its peak depth increasing significantly from 3.4 m to 7.0 m over time (R 2  = 0.92). Soil water was identified as the key factor influencing nitrate leaching, with a correlation coefficient of 0.48 (P < 0.05). In conclusion, orchard-to-cropland conversion effectively replenished the deep soil water in the short term but also accelerated soil nitrate leaching. Therefore, while large-scale conversion of orchards to farmland is undertaken, it is crucial to acknowledge the trade-off relationship involving the recharge of deep soil water and the subsequent increase in deep nitrogen leaching. The findings of this study hold significant implication for the management of water and nutrient resources after the conversion of orchards to farmland, highlighting the necessity to mitigate nitrogen leaching while soil water is being restored., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Our study aimed to investigate the association between RFM and kidney stones, focusing specifically on the mediating role of high-density lipoprotein cholesterol (HDL-C). We performed a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) covering the years 2007 to 2018. Our analytical approach included multivariate logistic regression modeling, subgroup analysis, generalized additive modeling (GAM), smoothed curve fitting, and receiver operating characteristic (ROC) curve, as well as mediation analysis to assess the association between RFM and kidney stones. Finally, we categorized RFM into normal and elevated groups to conduct a sensitivity analysis. This study involved 29,712 participants, with a kidney stone prevalence of 9.88%. We discovered a positive association between RFM and kidney stones (OR = 1.41 per SD increment, 95% CI: 1.24, 1.60). Subgroup analysis revealed a consistent positive association across all subgroups, with a notably higher likelihood of developing kidney stones in young adulthood (P for interaction < 0.05). The smooth curve fitting shows that RFM is nonlinearly and positively correlated with the prevalence of kidney stones. Additionally, HDL-C was found to be negatively associated with kidney stones. Importantly, HDL-C demonstrated a significant mediating effect, with a mediation ratio of 13.52%. ROC analysis indicated that RFM (AUC = 0.616) provided better diagnostic accuracy than traditional measures such as BMI (AUC = 0.565) and WC (AUC = 0.599). Furthermore, the sensitivity analysis further supports the robustness of our findings. RFM is nonlinearly and positively correlated with the prevalence of kidney stones, with HDL cholesterol playing a significant mediating role in this relationship. However, further studies are needed to confirm these associations and explore potential mechanisms., (© 2024. The Author(s).)

The glycocalyx is a complex layer of carbohydrate and protein molecules that surrounds the cell membrane of many types of mammalian cells. It serves several important functions, including cell adhesion and communication, and maintain cell shape and stability, especially in the case of erythrocytes. Alteration of glycocalyx composition represents a cardiovascular health threatening. For example, in diabetes mellitus glycocalyx of erythrocytes and of endothelial cells is known to be impaired, a potential source of blood occlusion in microcirculation, which may lead to blindness, and renal failure of patients. The impact of glycocalyx impairment on erythrocyte aggregation remains a largely unexplored research area. We conduct here in vitro-experiments in microfluidic devices in order to investigate erythrocytes aggregation incubated with amylase, an enzyme that partially breaks down glycocalyx molecules. It is found that incubation of erythrocytes by amylase leads to a dramatic increase of their aggregation and stability and alters the aggregates morphologies. Confocal microscopy analysis reveals a significant degradation of the glycocalyx layer, correlated with enhanced erythrocytes aggregation. An increased erythrocyte aggregation in vivo should affect oxygen and other metabolites delivery to organs and tissues. This study brings new elements about elucidation of microscopic origins of erythrocyte aggregation and their potential impact on cardiovascular pathologies., (© 2024. The Author(s).)

Background: Both lipid metabolism and obesity are crucial factors in osteoporosis, influencing the relevance of the cardiometabolic index (CMI), a new body fat index incorporating obesity and lipid metrics. Our study aims to explore the relationship between CMI and lumbar spine bone mineral density (BMD) and the mediating role of body fat percentage., Methods: Utilizing the National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2018, we conducted a cross-sectional analysis. We employed multiple linear regression models, subgroup analyses, generalized additive models (GAM), smooth curve fitting, and mediation analysis to evaluate the linear and nonlinear relationships between CMI and lumbar spine BMD., Results: The study involved 5,124 participants with an average lumbar spine BMD of 1.03 ± 0.15 g/cm 2 . We identified a negative correlation between CMI and lumbar spine BMD (β = -0.015; 95% CI: -0.023, -0.008). Nonlinear associations were evident, with inflection points at CMI values of 1.12 and 2.86. Subgroup analyses showed consistent negative correlations across all categories without significant differences (p for interaction > 0.05). Moreover, body fat percentage negatively correlated with BMD (β = -0.005; 95% CI: -0.006, -0.004) and mediated 9.41% of the relationship between CMI and BMD., Conclusion: Increased CMI levels are associated with lower lumbar spine BMD, with body fat percentage significantly mediating this relationship. This underscores the importance of managing body composition in the context of bone health, highlighting CMI's potential utility in osteoporosis risk assessment., (© 2024. The Author(s).)

This study aimed to investigate whether metabolic dysfunction-associated fatty liver disease (MAFLD) defined by the fatty liver index (FLI) affects the decline in kidney function and whether this relationship is still observed in MAFLD defined by ultrasonography (USG). A retrospective cohort study was conducted using de-identified data from participants who received health checkups at Samsung Changwon Hospital between 2002 and 2018. The primary and secondary exposures were the presence of FLI- and USG-defined MAFLD, respectively. The primary outcome was 5-years slope of eGFR. The secondary outcome was a rapid decline in kidney function, defined as a 5-years slope of estimated glomerular filtration rate (eGFR) of less than - 3 mL/min/1.73 m 2 per year. A total of 37,500 participants were included in the analysis. Participants with FLI-defined MAFLD had a larger decline in 5-year eGFR slope than those without FLI-defined MAFLD (beta coefficients - 0.11; 95% CI - 0.14 to - 0.08). Participants with FLI-defined MAFLD had a higher risk of rapid kidney function decline than those without FLI-defined MAFLD (odds ratio 1.33; 95% confidence intervals (CIs) 1.05-1.69). However, USG-defined MAFLD was less related to kidney function decline. In conclusion, the presence of FLI-defined MAFLD was associated with larger and faster kidney function decline., (© 2024. The Author(s).)

To explore the molecular pathogenesis of pulmonary arterial hypertension (PAH) and identify potential therapeutic targets, we performed transcriptome sequencing of lung tissue from mice with hypoxia-induced pulmonary hypertension. Our Gene Ontology analysis revealed that "extracellular matrix organization" ranked high in the biological process category, and matrix metallopeptidases (MMPs) and other proteases also played important roles in it. Moreover, compared with those in the normoxia group, we confirmed that MMPs expression was upregulated in the hypoxia group, while the hub gene Timp1 was downregulated. Crocin, a natural MMP inhibitor, was found to reduce inflammation, decrease MMPs levels, increase Timp1 expression levels, and attenuate hypoxia-induced pulmonary hypertension in mice. In addition, analysis of the cell distribution of MMPs and Timp1 in the human lung cell atlas using single-cell RNAseq datasets revealed that MMPs and Timp1 are mainly expressed in a population of fibroblasts. Moreover, in vitro experiments revealed that crocin significantly inhibited myofibroblast proliferation, migration, and extracellular matrix deposition. Furthermore, we demonstrated that crocin inhibited TGF-β1-induced fibroblast activation and regulated the pulmonary arterial fibroblast MMP2/TIMP1 balance by inhibiting the TGF-β1/Smad3 signaling pathway. In summary, our results indicate that crocin attenuates hypoxia-induced pulmonary hypertension in mice by inhibiting TGF-β1-induced myofibroblast activation., (© 2024. The Author(s).)

Millimeter-wave (mmWave) massive multiple-input multiple-output non-orthogonal multiple access (MIMO-NOMA) is proven to be a primary technique for sixth-generation (6G) wireless communication networks. However, the great increase in users and antennas brings challenges for interference suppression and resource allocation for mmWave massive MIMO-NOMA systems. This study proposes a spectrum-efficient and fast convergence deep reinforcement learning (DRL)-based resource allocation framework to optimize user grouping and allocation of subchannel and power. First, an enhanced K-means grouping algorithm is proposed to reduce the multi-user interference and accelerate the convergence. Then, a dueling deep Q-network (DQN) structure is proposed to perform subchannel allocation, which further improves the convergence speed. Moreover, a deep deterministic policy gradient (DDPG)-based power resource allocation algorithm is designed to avoid the performance loss caused by power quantization and improve the system's achievable sum-rate. The simulation results demonstrate that our proposed scheme outperforms other neural network-based algorithms in terms of convergence performance, and can achieve higher system capacity compared with the greedy algorithm, the random algorithm, the RNN algorithm, and the DoubleDQN algorithm., (© 2024. The Author(s).)

The ground state search of the Ising model can be used to solve many combinatorial optimization problems. Under the current computer architecture, an Ising ground state search algorithm suitable for hardware computing is necessary for solving practical problems. Inspired by the potential energy conversion of the springs, we propose the Spring-Ising Algorithm, a point convolutional neural network algorithm for ground state search based on the spring vibration model. Spring-Ising Algorithm regards the spin as a moving mass point connected to a spring and establishes the equation of motion for all spins. Spring-Ising Algorithm can be mapped on AI chips through the basic structure of the neural network for fast and efficient parallel computing. The algorithm has shown promising results in solving the Ising model and has been tested in the recognized test benchmark K2000. The optimal results of this algorithm after 10,000 steps of iteration are 2.9% of all results. The algorithm introduces the concept of dynamic equilibrium to achieve a more detailed local search by dynamically adjusting the weight of the Ising model in the spring oscillation model. Spring-Ising Algorithm offers the possibility to calculate the Ising model on a chip which focuses on accelerating neural network calculations., (© 2024. The Author(s).)

Transarterial chemoembolisation (TACE) is a standard therapy for hepatocellular carcinoma (HCC). However, adverse events, including abdominal pain, are common. This study aimed to investigate and verify the feasibility of a nomogram model to predict severe abdominal pain after first conventional TACE (cTACE) among patients with HCC. Patients with HCC treated with cTACE between October 28, 2019, and August 5, 2022, at a single centre were enrolled (n = 216). Patients were divided into training and validation cohorts (ratio, 7:3). A visual analogue scale score between 7 and 10 was considered severe abdominal pain. A total of 127 (58.8%) patients complained of severe abdominal pain after first cTACE treatment. The nomogram considered age and tumour number and size. The nomogram demonstrated good discrimination, with a C-index of 0.749 (95% confidence interval [CI], 0.617, 0.881). Further, the C-index in the validation cohort reached 0.728 (95% CI 0.592, 0.864). The calibration curves showed ideal agreement between the prediction and real observations, and the nomogram decision curve analysis performed well. The nomogram model can provide an accurate prediction of severe abdominal pain in patients with HCC after first cTACE, aiding in the personalization of pain management and providing novel insights into hospital nursing., (© 2023. The Author(s).)

High-density lipoprotein (HDL) therapy has demonstrated beneficial effects in acute stroke and acute myocardial infarction models by reducing infarct size. In this study, we investigated the inhibitory effects of reconstituted HDL (rHDL) on neointimal hyperplasia and elucidated its underlying mechanism using a balloon injury rat model. Our finding revealed a significant 37% reduction in the intima to media ratio in the arteries treated with 80 mg/kg rHDL compared to those subjected to injury alone (p < 0.05), indicating a specific inhibition of neointimal hyperplasia. In vivo analysis further supported the positive effects of rHDL by demonstrating a reduction in smooth muscle cell (SMC) proliferation and an increase in endothelial cell (EC) proliferation. Additionally, rHDL treatment led to decreased infiltration of leukocytes and downregulated the expression of matrix metallopeptidase 9 (MMP9) in the neointimal area. Notably, rHDL administration resulted in decreased expression of VCAM1 and HIF1α, alongside increased expression of heme oxygenase 1 (HO1) and heat shock protein 27 (HSP27). Overexpression of HSP27 and HO1 effectively inhibited SMC proliferation. Moreover, rHDL-mediated suppression of injury-induced HIF1α coincided with upregulation of HSP27. Interestingly, HSP27 and HO1 had varying effects on the expression of chemokine receptors and rHDL did not exert significant effect on chemokine receptor expression in THP1 cells. These findings underscore the distinct roles of HSP27 and HO1 as potential regulatory factors in the progression of restenosis. Collectively, our study demonstrates that rHDL exerts a potent anti-neointimal hyperplasia effect by reducing leukocytes infiltration and SMC proliferation while promoting EC proliferation., (© 2023. The Author(s).)

The continued spread of Candida auris in healthcare facilities has increased the demand for widely available screening to aid in containment and inform treatment options. Current methods of detection can be unreliable and require bulky and expensive instruments to lyse and identify fungal pathogens. Here, we present a quick, low-cost, instrument-free method for lysis of C. auris suitable for streamlined sample processing with polymerase chain reaction (PCR) detection. Chemical, thermal, and bead beating lysis techniques were evaluated for lysis performance and compatibility with nucleic acid extraction and downstream PCR reactions. Using only 10 s of manual shaking with glass beads, this method demonstrated a limit of detection (LOD) of C. auris at 500 colony forming units per mL, a 20-fold improvement compared to the LOD without manual shaking, and a 60-fold reduction in time compared to common fungal lysis kits, all while maintaining repeatability and reproducibility across multiple users. This work highlights a simple method for increasing sensitivity and reducing turnaround time of PCR-based C. auris detection and exhibits promise for integration into point-of-care platforms towards real-time triage of colonized patients., (© 2023. The Author(s).)

Prophylactic pharmacotherapy for health care in patients with high risk of cardiac arrest (CA) is an elusive and less explored strategy. Melatonin has possibilities used as a daily nutraceutical to trigger the cellular adaptation. We sought to find the effects of long-term daily prophylactic supplement with melatonin on the victim of CA. Rats were divided into sham, CA, and melatonin + CA (Mel + CA) groups. The rats in the Mel + CA group received daily IP injection of melatonin 100 mg/kg for 14 days. CA was induced by 8 min asphyxia and followed by manual cardiopulmonary resuscitation. The endpoint was 24 h after resuscitation. Survival, neurological outcome, and hippocampal mitochondrial integrity, dynamics and function were assessed. Survival was significantly higher in the Mel + CA group than the CA group (81 vs. 42%, P = 0.04). Compared to the CA group, neurological damage in the CA1 region and the level of cytochrome c, cleaved caspase-3 and caspase-9 in the Mel + CA group were decreased (P < 0.05). Mitochondrial function and integrity were protected in the Mel + CA group compared to the CA group, according to the results of mitochondrial swelling, ΔΨm, ROS production, oxygen consumption rate, and respiratory control rate (P < 0.05). Melatonin increased SIRT3 and downregulated acetylated CypD. The mitochondrial dynamics and autophagy were improved in the Mel + CA group (P < 0.05). Long-term daily prophylactic supplement with melatonin buy the time from brain injury after CA., (© 2023. The Author(s).)

This study evaluated changes in the peripheral blood immune cell population in patients with advanced thyroid cancer receiving lenvatinib treatment to confirm the immune-modulatory effect of lenvatinib. After obtaining informed consent from patients, we prospectively collected 20 ml of whole blood at 2-3 months intervals 2-4 times from each patient; peripheral blood mononuclear cells (PBMCs) were separated, and the Maxpar Direct Immune Profiling Assay was performed. A total of 10 patients were enrolled, and 31 blood samples were obtained. The median age of patients was 65 years, and all patients showed durable responses to the lenvatinib treatment. When we compared the PBMC profiles between the pre-treatment, on-treatment, and off-treatment samples, the peripheral natural killer (NK) cell proportion differed significantly. The proportion of NK cells among total live cells significantly increased from 9.3 ± 4.5 (%) in the pre-treatment samples to 20.8 ± 7.9 (%) in the on-treatment samples (P = 0.009) and decreased to 13.3 ± 3.1 (%) in the off-treatment samples (P = 0.07). There was a significant increase in the peripheral NK cell population with lenvatinib treatment in advanced thyroid cancer patients. This finding confirms the immune-modulatory effect of lenvatinib., (© 2023. Springer Nature Limited.)

Exploring the evolution of urban elements can improve understanding of the developmental process of city and drive such development into a better direction. However, the non-linearity and complexity of changes in urban elements have brought great challenges to understanding this process. In this paper, we propose a cross-diffusion partial differential equation based on ecological dynamics to simulate the evolutionary process of urban elements from the microscopic viewpoint. The interaction between urban elements is simulated by constructing a non-linear and spatiotemporal change equation, and the main influence between elements is evaluated by the key parameters in the discussed equation. Our model is first experimented to time-series data on population density and housing prices to analyzes the interaction of these two elements in the evolution process. We then extend the model to label data, land cover data, to obtain a quantitative expression of the interaction between different land types in the process of urban land cover change., (© 2023. The Author(s).)

Injection of fillers for soft tissue augmentation can lead to a variety of complications, among which vascular occlusion caused by intravascular injection of filler will induce severe or permanent damage. The treatment strategies for intravascular embolization caused by injection include warm compress application, but the exact beneficial effects of this therapy have not been confirmed. The purpose of this study is to construct an intravascular injection embolism model and observe the effectiveness of warm and cold compress through a randomized, controlled trial. Thirty rabbit's sixty ears were randomly divided into warm compress group, cold compress group, and control group. Polymethyl methacrylate (PMMA) was slowly injected into the central ear artery (CEA) to cause vascular embolism. Warm compress and cold compress treatment were performed respectively. The vascular recanalization and other related indexes were observed at 30 min, 1 day, and 7 days after injection, and the tissue necrosis was analyzed at 7 days. In the early stage of vascular embolization, warm compress can immediately promote vascular dilatation, blood circulation and partial blood flow recovery. One day after intravascular injection, warm compress can reduce intravascular embolization and reduce the incidence of tissue necrosis. At 7 days after intravascular injection, the vessels in the cold compress and control groups were still embolized while the percentage of recanalization in the warm compress group was 47.4% (P < 0.000). Early-stage warm compress after intravascular PMMA injection is conducive to recanalization of vascular embolization and reducing tissue necrosis., (© 2023. The Author(s).)

The causal association between education and cervical spondylosis may be mediated partly through risk factors of cardiovascular disease. The identification of the protective effect of education and the evaluation of risk factors will help to optimize disease prevention at both clinical and public health levels. In this study, we applied several different Mendelian randomization (MR) methods to identify which cardiovascular factors underlie the clustering of cervical spondylosis with cardiovascular disease, and the degree to which these mediate an effect of education. Univariable MR analyses provided evidence supporting a protective effect of genetically predicted education on cervical spondylosis risk, and MVMR further identified the direct effect of education level. Our results also provided evidence supporting the detrimental effects of BMI and smoking on cervical spondylosis risk, with evidence that the effect of education is mediated through BMI and smoking. The proportions of the effect of education mediated through BMI and smoking were 12% and 3%, respectively. These findings highlight education, obesity, and smoking as common mechanisms underlying the clustering of cervical spondylosis with risk factors of cardiovascular disease, which might represent clinical and public health targets for reducing multi-morbidity and the burden of these common conditions., (© 2023. The Author(s).)

Abnormal coagulation and increased risk of thrombosis are some of the symptoms associated with COVID-19 severity. Anti-phospholipid antibodies (aPLs) present in critically ill COVID-19 patients contribute to systemic thrombosis. The aim of this study was to identify key common genes to characterize genetic crosstalk between COVID-19 and antiphospholipid syndrome (APS) using bioinformatics analysis and explore novel mechanisms of immune-mediated thrombosis in critically ill COVID-19 patients. The transcriptome data of mononuclear cells from severe COVID-19 patients and APS patients were evaluated to obtain the common genes. The protein-protein interaction network and cytoHubba module analysis in Cytoscape software were used to find the associated hinge genes and hub genes. Among the common differentially expressed genes, TIMELESS depletion was identified only in patients with severe COVID-19 and not in patients with mild COVID-19, and it was validated with the GSE159678 dataset. Functional analyses using gene ontology terms and the Kyoto Encyclopedia of Genes and Genomes pathway suggested that TIMELESS might contribute to the production of antiphospholipid antibody and thrombosis in both COVID-19 and APS patients. The potential role of TIMELESS and autophagy genes in momonuclear cells were further investigated, and GSK3B was found to be associated with TIMELESS. Autophagy targeting agents have a therapeutic potential against COVID-19 and thrombogenesis in APS, which may be related to the role of autophagy genes in the modification of circadian clock proteins. Interference with TIMELESS and other genes associated with it to regulate autoantibody expression may be a potential strategy for immunotherapy against thrombogenesis in severe COVID-19 patients., (© 2022. The Author(s).)

Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1) is believed to function as a tumor suppressor, while Phosphoinositide-3-Kinase Regulatory Subunit 2 (PIK3R2) as a tumor driver. However, there is no systematic pan-cancer analysis of them. The pan-cancer study comprehensively investigated the gene expression, genetic alteration, DNA methylation, and prognostic significance of PIK3R1 and PIK3R2 in 33 different tumors based on the TIMER, GEPIA, UALCAN, HPA, cBioPortal, and Kaplan-Meier Plotter database. The results indicated that PIK3R1 is lowly expressed in most tumors while PIK3R2 is highly expressed in most tumors, and abnormal gene expression may be related to promoter methylation. Moreover, not only mutations, downregulation of PIK3R1 and upregulation of PIK3R2 were found to be detrimental to the survival of most cancer patients as well. Furthermore, the expression of both PIK3R1 and PIK3R2 was associated with the level of immune infiltration in multiple tumors, such as breast invasive carcinoma. Our study conducted a comparatively comprehensive analysis of the role of PIK3R1 and PIK3R2 in a variety of cancers, contributing to further study of their potential mechanisms in cancer occurrence and progression. Our findings suggested that PIK3R1 and PIK3R2 could serve as prognostic markers for several cancers., (© 2022. The Author(s).)

This paper aimed to investigate the characteristics of female HPV infection in the Shangcheng District, Hangzhou city, China. The retrospective study was designed to analyze the HPV prevalence rate of 22,382 women receiving physical examinations from 2016 to 2020 in the Shangcheng District of Hangzhou city in China. A commercial kit was designed to detect the HPV genotypes. Trends were examined for age-specific groups (≤ 30 years, 31-44 years, 45-54 years, 55-64 years,  ≥ 65 years). A receiver operating characteristic (ROC) analysis was used to assess the correlation of age classification in high risk HPV (HR-HPV) infection. 22.41% (5015/22,382) of samples were HPV positive, 91.28% (4578/5015) of HPV positive women were infected by HR-HPV. The most prevalent HR-HPV genotypes were 16, 52, 18, 58, 56, and 51. The trend of HPV prevalence showed the significant differences in age-specific groups (χ 2  = 164.70, P < 0.001). Moreover, the areas under ROC curve (AUC) was 0.712 in 55-64 years group which showed a strong contribution of age classification for HR-HPV infection. This study provided baseline data on the prevalence characteristics of HPV infection and the critical age group of HR-HPV prevalence rate was 55-64 y among the samples receiving physical examinations., (© 2021. The Author(s).)

Materials performance can be significantly degraded due to bubble generation. In this work, the bubble growth process is elaborated in Cu by atomistic modeling to bridge the gap of experimental observations. Upon continuous He implantation, bubble growth is accommodated first by nucleation of dislocation network from bubble surface, then formation of dissociated prismatic dislocation loop (DPDL), and final DPDL emission in [Formula: see text] directions. As the DPDL is found capable of collecting He atoms, this process is likely to assist the formation of self-organized bubble superlattice, which has been reported from experiments. Moreover, the pressurized bubble in solid state manifests the shape of an imperfect octahedron, built by Cu [Formula: see text] surfaces, consistent with experiments. These atomistic details integrating experimental work fill the gap of mechanistic understanding of athermal bubble growth in Cu. Importantly, by associating with nanoindentation testings, DPDL punching by bubble growth arguably applies to various FCC (face-centered cubic) metals such as Au, Ag, Ni, and Al.

The development of insects is critically affected by temperature, which therefore plays an important role in the control of stored grain pests. Extreme temperature stress conditions lead to biological responses in mites, such as the synthesis of heat shock proteins. Tyrophagus putrescentiae (Tp) is a pest mite in stored grain that has negative effects on both economy and health. Since T. putrescentiae population dynamics are strongly influenced by temperature, in the present study we have cloned the cDNA of HSP70 and HSP90 (referred to as TpHSP70-1, TpHSP70-2 and TpHSP90) and determined their expression by fluorescence real time quantitative PCR. TpHSP70 and TpHSP90 showed high homology with similar genes in other species and the open reading frames of TpHSP70-1, TpHSP70-2 and TpHSP90 encoded proteins of 665, 661 and 718 amino acid residues, respectively. Under thermal stress, expression of TpHsp70-1 and TpHsp90 was up-regulated at higher temperatures, suggesting their role in the defense against thermal stress.

Experimental and clinical studies over the past two decades have provided overwhelming evidence that human cancers, including prostate cancer (PCa), harbor cancer stem cells (CSCs) that sustain tumor growth, drive tumor progression and mediate therapy resistance and tumor relapse. Recent studies have also implicated NUMB as a PCa suppressor and an inhibitor of PCa stem cells (PCSCs); however, exactly how NUMB functions in these contexts remains unclear. Here, by employing bioinformatics analysis and luciferase assays and by conducting rescue experiments, we first show that NUMB is directly targeted by microRNA-9-5p (miR-9-5p), an oncogenic miR associated with poor prognosis in many malignancies. We further show that miR-9-5p levels are inversely correlated with NUMB expression in CD44 + PCSCs. miR-9-5p reduced NUMB expression and inhibited numerous PCSC properties including proliferation, migration, invasion as well as self-renewal. Strikingly, overexpression of NUMB in CD44 + PCSCs overcame all of the above PCSC properties enforced by miR-9-5p. Taken together, our results suggest that inhibiting the expression of the oncomiR miR-9-5p and overexpressing NUMB may represent novel therapeutic strategies to target PCSCs and PCa metastasis.

Coronary artery abnormalities (CAAs) are a severe complication of Kawasaki disease (KD) that may lead to cardiovascular events. Given the evidence that brachial artery flow-mediated dilation (FMD) decreases in children after the onset of KD, we hypothesized that it could be an early marker of CAA development in the acute stage and investigated its relationship with variation in the coronary artery diameter. A total of 326 sex- and age-matched children were enrolled, including 120 with KD, 109 febrile children and 97 healthy controls. In this study, FMD was significantly decreased in the KD group compared with the febrile and healthy groups. FMD was lower in the CAA group than in the no coronary artery abnormality group. The comparison of FMD showed an obvious difference among the CAA subgroups. The FMD in the coronary aneurysm (CA) group showed a strong negative correlation with the pretreatment maximum coronary artery Z-score (preZmax). While preZmax was 2.5, the receiver operating characteristic curve indicated an optimal cutoff point of 3.44% for FMD. FMD ≤ 3.44% could be considered as a signal of coronary lesions in acute stage of KD.

The prominent vessel sign (PVS) on susceptibility-weighted imaging (SWI) is not displayed in all cases of acute ischemia. We aimed to investigate the factors associated with the presence of PVS in stroke patients. Consecutive ischemic stroke patients admitted within 24 h from symptom onset underwent emergency multimodal MRI at admission. Associated factors for the presence of PVS were analyzed using univariate analyses and multivariable logistic regression analyses. A total of 218 patients were enrolled. The occurrence rate of PVS was 55.5%. Univariate analyses showed significant differences between PVS-positive group and PVS-negative group in age, history of coronary heart disease, baseline NIHSS scores, total cholesterol, hemoglobin, anterior circulation infarct, large vessel occlusion, and cardioembolism. Multivariable logistic regression analyses revealed that the independent factors associated with PVS were anterior circulation infarct (odds ratio [OR] 13.7; 95% confidence interval [CI] 3.5-53.3), large vessel occlusion (OR 123.3; 95% CI 33.7-451.5), and cardioembolism (OR 5.6; 95% CI 2.1-15.3). Anterior circulation infarct, large vessel occlusion, and cardioembolism are independently associated with the presence of PVS on SWI.

Labile organic carbon (LOC) fractions and related enzyme activities in soils are considered to be early and sensitive indicators of soil quality changes. We investigated the influences of fertilization and residue incorporation on LOC fractions, enzyme activities, and the carbon pool management index (CPMI) in a 10-year field experiment. The experiment was composed of three treatments: (1) no fertilization (control), (2) chemical fertilizer application alone (F), and (3) chemical fertilizer application combined with incorporation of wheat straw residues (F + R). Generally, the F + R treatment led to the highest concentrations of the LOC fractions. Compared to the control treatment, the F + R treatment markedly enhanced potential activities of cellulase (CL), β-glucosidase (BG), lignin peroxidase (LiP), and manganese peroxidase (MnP), but decreased laccase (LA) potential activity. Partial least squares regression analysis suggested that BG and MnP activities had a positive impact on the light-fraction organic carbon (LFOC), permanganate-oxidizable carbon (POXC), and dissolved organic carbon (DOC) fractions, whereas laccase activity had a negative correlation with those fractions. In addition, the F + R treatment significantly increased the CPMI compared to the F and control treatments. These results indicated that combining fertilization with crop residues stimulates production of LOC and could be a useful approach for maintaining sustainable production capacity in lime concretion black soils along the Huai River region of China.

This study was to investigate the correlation of vagal activity with coronary artery lesion (CAL) in Kawasaki disease (KD) children, and assess the predictive value of heart rate deceleration capacity (DC) for CAL in acute phase of KD.50 KD children with CAL, 130 KD children without CAL, 30 children with acute upper respiratory infection and 100 healthy children were recruited and indicators reflecting vagal activity including DC were measstuogram. KD children with CAL showed decreased vagal activity with significantly lower values of DC. DC was negatively correlated with levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) in KD children. DC was a usable cardiac electrophysiological index to predict CAL in children with KD, with an area under the receiver operating characteristic curve (AUC) of 0.741. The cut-off value of DC for predicting CAL in KD children was 4.37 ms. DC was an independent predictor of CAL in children with KD, evaluated by multiple logistic regression analysis, KD children with DC ≤ 4.37 ms had an increased risk of CAL, with odds ratios (OR) of 5.94. Our study illustrates DC could be used to predict CAL in acute phase of KD.

Synthetic biology is advancing into a new phase where real-world applications are emphasized. There is hence an urgent need for mathematical modeling that can quantitatively describe the behaviors of genetic devices in natural, fluctuating environments. We utilize an integrative circuit-host modeling framework to examine the dynamics of a genetic switch and its host cell in varying environments. For both steady-state and transient cases, we find increasing nutrient reduces the bistability region of the phase space and eventually drives the switch from bistability to monostability. In response, cellular growth and proteome partitioning experience the same transition. Antibiotic perturbations cause the similar circuit and host responses as nutrient variations. However, one difference is the trend of growth rate, which augments with nutrient but declines with antibiotic levels. The framework provides a mechanistic scheme to account for both the dynamic and static characteristics of the circuit-host system upon environmental perturbations, underscoring the intimacy of gene circuits and their hosts and elucidating the complexity of circuit behaviors arising from environmental variations.

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain cancer whose median survival time is under one year. The possible roles of the two most common DIPG associated cytoplasmic ACVR1 receptor kinase domain mutants, G328V and R206H, are reexamined in the context of new biochemical results regarding their intrinsic relative ATPase activities. At 37 °C, the G328V mutant displays a 1.8-fold increase in intrinsic kinase activity over wild-type, whereas the R206H mutant shows similar activity. The higher G328V mutant intrinsic kinase activity is consistent with the statistically significant longer overall survival times of DIPG patients harboring ACVR1 G328V tumors. Based on the potential cross-talk between ACVR1 and TβRI pathways and known and predicted off-targets of ACVR1 inhibitors, we further validated the inhibition effects of several TβRI inhibitors on ACVR1 wild-type and G328V mutant patient tumor derived DIPG cell lines at 20-50 µM doses. SU-DIPG-IV cells harboring the histone H3.1K27M and activating ACVR1 G328V mutations appeared to be less susceptible to TβRI inhibition than SF8628 cells harboring the H3.3K27M mutation and wild-type ACVR1. Thus, inhibition of hidden oncogenic signaling pathways in DIPG such as TβRI that are not limited to ACVR1 itself may provide alternative entry points for DIPG therapeutics.

Neuroinflammation is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS), but only limited data are available on systematic peripheral and central immune cell profiles in ALS. We studied detailed immune profiles of 73 ALS patients and 48 healthy controls (controls) in peripheral blood by fluorescence-activated cell sorting as well as cytokine expression profiles in serum. In a subgroup of 16 ALS patients and 10 controls we additionally studied cerebrospinal fluid (CSF) samples. In peripheral blood, T cell subtypes presented a shift towards pro-inflammatory Th 1 and Th 17 cells whereas anti-inflammatory Th2 and T regulatory cells were decreased. Important players in innate immunity including distinct monocyte (Mo) and natural killer (NK) cell subtypes were changed in ALS patients compared to controls. Pro-inflammatory serum cytokines such as interleukin (IL)-1 beta, IL-6 and interferon-gamma (IFN-gamma) were increased and the anti-inflammatory cytokine IL-10 was decreased. Correlation analysis revealed moderate negative correlations between Th1 and Th17 to the ALS functional rating scale revised (ALSFRS-R) and to forced vital capacity. In CSF samples, no relevant alteration of the immune profile was found. In conclusion, the immune profile in ALS was shifted towards a Th1/Th17 cell-mediated pro-inflammatory immune response and correlated to disease severity and progression. Large prospective studies are needed to confirm these findings.

The field of genome editing was founded on the establishment of methods, such as the clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated protein (CRISPR/Cas) system, used to target DNA double-strand breaks (DSBs). However, the efficiency of genome editing also largely depends on the endogenous cellular repair machinery. Here, we report that the specific modulation of targeting vectors to provide 3' overhangs at both ends increased the efficiency of homology-directed repair (HDR) in embryonic stem cells. We applied the modulated targeting vectors to produce homologous recombinant mice directly by pronuclear injection, but the frequency of HDR was low. Furthermore, we combined our method with the CRISPR/Cas9 system, resulting in a significant increase in HDR frequency. Thus, our HDR-based method, enhanced homologous recombination for genome targeting (eHOT), is a new and powerful method for genome engineering.

Despite the growing attentions dedicated to the harvesting of acoustic energy that is a clean and renewable yet usually wasted energy source, the long wavelength of airborne sound still poses fundamental limits on the miniaturization of harvester devices and hinders practical applications. Here we present an ultrathin and planar acoustic energy harvester with rigidity. We propose a distinctive metasurface-based mechanism that reduces the effective wavelength to produce extraordinarily strong local energy within deep-subwavelength dimension and enable high-efficiently harvesting energy of incident airborne sound with considerably long wavelength. Our design idea is implemented by a foldy-structured metasurface capable of confining low-frequency energy within narrow channel at resonance, with a piezoelectric plate judiciously placed to converse acoustic to electric energy. The resulting device is downscaled to as thin as λ/63 while keeping flat shape and mechanical rigidity. We analytically derive the effective acoustical parameter of the unit cell, and verify the theoretical predictions via numerical simulations which shows the generation of the maximum output power at the prescribed working frequency. Our design with compactness and rigidity makes an important step towards the miniaturization and integration of acoustic energy harvesters and may have far-reaching implication in diverse applications ranging from microelectronic device design to wireless and self-powered active sensing.

Retinal hypoperfusion injury is the pathophysiologic basis of ocular ischemic syndrome (OIS) which often leads to severe visual loss. In this study, we aimed to establish a rat model of retinal chronic hypoperfusion by bilateral common carotid artery occlusion (BCCAO) and observe changes in the retinal function and morphology. We found that model rats showed retinal arteriosclerosis, slight dilated retinal vein, small hemangiomas, hemorrhages, vascular segmental filling, and nonperfused areas after 2 weeks of BCCAO. In the model rats, the retinal circulation time was significantly prolonged by fluorescein fundus angiography (FFA), the latency of a and b waves was delayed and the amplitude was decreased significantly at each time point by electroretinogram (ERG), and the perfusion of the eyes continued to reduced. Morphologic and ultrastructural changes covered that the retinal ganglion cells (RGCs) presented obvious apoptosis and the thickness in the retinal layers were significantly thinner. Collectively, these findings suggested that BCCAO induced retinal hypoperfusion injury in the model rats, thus providing an ideal animal model for the study of OIS.

The yeast metabolic cycle (YMC) is a fascinating example of biological organization, in which cells constrain the function of specific genetic, protein and metabolic networks to precise temporal windows as they grow and divide. However, understanding the intracellular origins of the YMC remains a challenging goal, as measuring the oxygen oscillations traditionally associated with it requires the use of synchronized cultures growing in nutrient-limited chemostat environments. To address these limitations, we used custom-built microfluidic devices and time-lapse fluorescence microscopy to search for metabolic cycling in the form of endogenous flavin fluorescence in unsynchronized single yeast cells. We uncovered robust and pervasive metabolic cycles that were synchronized with the cell division cycle (CDC) and oscillated across four different nutrient conditions. We then studied the response of these metabolic cycles to chemical and genetic perturbations, showing that their phase synchronization with the CDC can be altered through treatment with rapamycin, and that metabolic cycles continue even in respiratory deficient strains. These results provide a foundation for future studies of the physiological importance of metabolic cycles in processes such as CDC control, metabolic regulation and cell aging.

Unambiguous subunit assignment in a multicomponent complex is critical for thorough understanding of the machinery and its functionality. The eukaryotic group II chaperonin TRiC/CCT folds approximately 10% of cytosolic proteins and is important for the maintenance of cellular homeostasis. TRiC consists of two rings and each ring has eight homologous but distinct subunits. Unambiguous subunit identification of a macromolecular machine such as TRiC through intermediate or low-resolution cryo-EM map remains challenging. Here we present a yeast internal-subunit eGFP labeling strategy termed YISEL, which can quickly introduce an eGFP tag in the internal position of a target subunit by homologous recombination, and the tag labeled protein can be expressed in endogenous level. Through this method, the labeling efficiency and tag-occupancy is ensured, and the inserted tag is usually less mobile compared to that fused to the terminus. It can also be used to bio-engineer other tag in the internal position of a protein in yeast. By applying our YISEL strategy and combined with cryo-EM 3D reconstruction, we unambiguously identified all the subunits in the cryo-EM map of TRiC, demonstrating the potential for broad application of this strategy in accurate and efficient subunit identification in other challenging complexes.

Circulating miRNAs are proposed as a biomarker of heart disease. This study evaluated whether circulating miRNAs could be used as a biomarker for childhood dilated cardiomyopathy (CDCM). A total of 28 participants were enrolled in a discovery set, including patients with CDCM (n = 16) and healthy children (n = 12). The cardiac function of patients with CDCM was characterized by echocardiography and serum miRNA profiles of all participants were assessed by miRNA sequencing. After miRNA profiling, we quantitatively confirmed 148 regulated miRNAs in patients with CDCM compared with healthy subjects, and none were downregulated. Validation of candidate miRNAs was assessed by quantitative real-time polymerase chain reaction in other patients with CDCM (n = 30) and healthy controls (n = 16). A unique signature comprising mir-142-5p, mir-143-3p, mir-27b-3p, and mir-126-3p differentiated patients with CDCM from healthy subjects. Importantly, we observed an increase in mir-126-3p or let-7g in parallel with a robust decrease in the ejection fraction in patients with CDCM, which could differentiate heart failure patients from non-heart failure patients with CDCM. Moreover, mir-126-3p and let-7g were significantly negatively associated with the left ventricular ejection fraction. This study shows that a signature of four serum miRNAs may be a potential biomarker for diagnosing CDCM and assessing heart failure.

Oxidized low-density lipoprotein (ox-LDL)-induced vascular endothelial damage is a key event in early atherosclerosis. Safflower has been used to treat atherosclerotic heart disease in China for many years, but its molecular basis remains unclear. Hydroxysafflor yellow A (HSYA) is the main active ingredient of aqueous safflower extract. We identified the proteins involved in HSYA activity against ox-LDL-induced endothelial injury using isobaric tags for relative and absolute quantification-coupled two-dimensional liquid chromatography-tandem mass spectrometry. HSYA (1, 5, or 25 μM) alleviated ox-LDL-induced endothelial damage in a dose-dependent manner. We quantitated approximately 2700 protein species, of which 77 were differentially expressed following HSYA treatment. Most protein changes were related to structural molecules, metabolic enzymes, and proteins involved in signal transduction. Several differentially expressed proteins were further validated by western blot analysis. We also analysed the role of the mitochondrial membranous voltage-dependent anion-selective channel protein 2 (VDAC2) in HSYA treatment using small interfering RNA. VDAC2 functioned as a downstream anti-apoptosis effector during HSYA treatment of ox-LDL-induced endothelial impairment. These results further our understanding of the mechanisms responsible for the effects of HSYA.

Although α-synuclein (αSyn) has been linked to Parkinson's disease (PD), the mechanisms underlying the causative role in PD remain unclear. We previously proposed a model for a transportable microtubule (tMT), in which dynein is anchored to a short tMT by LIS1 followed by the kinesin-dependent anterograde transport; however the mechanisms that produce tMTs have not been determined. Our in vitro investigations of microtubule (MT) dynamics revealed that αSyn facilitates the formation of short MTs and preferentially binds to MTs carrying 14 protofilaments (pfs). Live-cell imaging showed that αSyn co-transported with dynein and mobile βIII-tubulin fragments in the anterograde transport. Furthermore, bi-directional axonal transports are severely affected in αSyn and γSyn depleted dorsal root ganglion neurons. SR-PALM analyses further revealed the fibrous co-localization of αSyn, dynein and βIII-tubulin in axons. More importantly, 14-pfs MTs have been found in rat femoral nerve tissue, and they increased approximately 19 fold the control in quantify upon nerve ligation, indicating the unconventional MTs are mobile. Our findings indicate that αSyn facilitates to form short, mobile tMTs that play an important role in the axonal transport. This unexpected and intriguing discovery related to axonal transport provides new insight on the pathogenesis of PD.

The protective effects of Kisspeptin on heat-induced oxidative stress in rats were investigated by using a combination of biochemical parameters and metabonomics. Metabonomic analyses were performed using gas chromatography/mass spectrometry in conjunction with multivariate and univariate statistical analyses. At the end point of the heat stress experiment, histological observation, ultrastructural analysis and biochemical parameters were measured. Metabonomic analysis of liver tissue revealed that Kisspeptin mainly attenuated the alteration of purine metabolism and fatty acid metabolism pathways. Futhermore, Kisspeptin also increased the levels of GSH, T-AOC as well as SOD activities, and upregulated MDA levels. These results provide important mechanistic insights into the protective effects of Kisspeptin against heat-induced oxidative stress.

Chronic pancreatitis (CP) is a fibro-inflammatory disease leading to pain, maldigestion, and pancreatic insufficiency. No therapeutic options exist due to a limited understanding of the biology of CP pathology. Recent findings implicate pancreatic stellate cells (PSC) as prominent mediators of inflammatory and fibrotic processes during CP. Here, we utilized primary and immortalized PSC obtained from mice and patients with CP or pancreatic cancer to examine the effect of Jak/STAT and MAPK pathway inhibition in vitro. The well-characterized caerulein model of CP was used to assess the therapeutic efficacy of Jak1/2 inhibition in vivo. Treatment of cultured PSC with the Jak1/2 inhibitor ruxolitinib reduced STAT3 phosphorylation, cell proliferation, and expression of alpha-smooth muscle actin (α-SMA), a marker of PSC activation. Treatment with the MAPK inhibitor, MEK162, had less consistent effects on PSC proliferation and no impact on activation. In the caerulein-induced murine model of CP, administration of ruxolitinib for one week significantly reduced biomarkers of inflammation and fibrosis. These data suggest that the Jak/STAT pathway plays a prominent role in PSC proliferation and activation. In vivo treatment with the Jak1/2 inhibitor ruxolitinib reduced the severity of experimental CP, suggesting that targeting Jak/STAT signaling may represent a promising therapeutic strategy for CP.