Zinc-based Polyoxometalate Nanozyme Functionalized Hydrogels for optimizing the Hyperglycemic-Immune Microenvironment to Promote Diabetic Wound Regeneration.

BACKGROUND: In diabetic wounds, hyperglycemia-induced cytotoxicity and impaired immune microenvironment plasticity directly hinder the wound healing process. Regulation of the hyperglycemic microenvironment and remodeling of the immune microenvironment are crucial. RESULTS: Here, we developed a nanozymatic functionalized regenerative microenvironmental regulator (AHAMA/CS-GOx@Zn-POM) for the effective repair of diabetic wounds. This novel construct integrated an aldehyde and methacrylic anhydride-modified hyaluronic acid hydrogel (AHAMA) and chitosan nanoparticles (CS NPs) encapsulating zinc-based polymetallic oxonate nanozyme (Zn-POM) and glucose oxidase (GOx), facilitating a sustained release of release of both enzymes. The GOx catalyzed glucose to gluconic acid and (H2O2), thereby alleviating the effects of the hyperglycemic microenvironment on wound healing. Zn-POM exhibited catalase and superoxide dismutase activities to scavenge reactive oxygen species and H2O2, a by-product of glucose degradation. Additionally, Zn-POM induced M1 macrophage reprogramming to the M2 phenotype by inhibiting the MAPK/IL-17 signaling diminishing pro-inflammatory cytokines, and upregulating the expression of anti-inflammatory mediators, thus remodeling the immune microenvironment and enhancing angiogenesis and collagen regeneration within wounds. In a rat diabetic wound model, the application of AHAMA/CS-GOx@Zn-POM enhanced neovascularization and collagen deposition, accelerating the wound healing process. CONCLUSIONS: Therefore, the regenerative microenvironment regulator AHAMA/CS-GOx@Zn-POM can achieve the effective conversion of a pathological microenvironment to regenerative microenvironment through integrated control of the hyperglycemic-immune microenvironment, offering a novel strategy for the treatment of diabetic wounds.

Psychosocial profiles influencing healthy dietary behaviors among adolescents in Shandong Province, China: a cross-sectional study.

Objectives: We aimed to assess the influence of psychosocial profiles on dietary behaviors among school-aged adolescents in China. Methods: A cross-sectional study was conducted involving 7,862 adolescents from 100 schools in Shandong, China. Psychosocial profiles and dietary behaviors were assessed using the Junior High School Students' Psychosocial Profiles Questionnaire (JPPQ) and the Chinese Diet Quality Questionnaire (DQQ), respectively. Linear regression models were used to investigate the association between adolescents' psychosocial profiles and dietary behaviors. Results: The mean age of the participants was 13.18 ± 1.15 years; 48.5% of them were boys. The majority of participants (97.90%) were Han Chinese, and approximately half of the participants (50.90%) resided in rural areas. After adjusting for sociodemographic characteristics and family computer and Internet ownership and usage, healthy dietary behavior was positively correlated with higher psychosocial profile scores (p < 0.05). The stratified analysis results revealed that the group with the highest psychosocial profile score was associated with an increased overall global dietary reference (GDR) score in "households without a family computer and Internet" ( ß : 5.357, 95% Cl: 4.931-5.784, p < 0.05). Conclusion: Good psychosocial profiles exhibit a positive influence on healthy dietary behaviors. Therefore, policymakers should focus on Internet usage to maximize the positive effects on global youth health behaviors.

Gasdermin C promotes Stemness and Immune Evasion in Pancreatic Cancer via Pyroptosis-Independent Mechanism.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic and lethal disease. Gasdermins are primarily associated with necrosis via membrane permeabilization and pyroptosis, a lytic pro-inflammatory type of cell death. In this study, GSDMC upregulation during PDAC progression is reported. GSDMC directly induces genes related to stemness, EMT, and immune evasion. Targeting Gsdmc in murine PDAC models reprograms the immunosuppressive tumor microenvironment, rescuing the recruitment of anti-tumor immune cells through CXCL9. This not only results in diminished tumor initiation, growth and metastasis, but also enhances the response to KRASG12D inhibition and PD-1 checkpoint blockade, respectively. Mechanistically, it is discovered that ADAM17 cleaves GSDMC, releasing nuclear fragments binding to promoter regions of stemness, metastasis, and immune evasion-related genes. Pharmacological inhibition of GSDMC cleavage or prevention of its nuclear translocation is equally effective in suppressing GSDMC's downstream targets and inhibiting PDAC progression. The findings establish GSDMC as a potential therapeutic target for enhancing treatment response in this deadly disease.

The association between the number of food kinds and risk of depression in U.S. adults.

BACKGROUND: The association between the number of food kinds and the risk of depression in adults was examined. METHODS: According to the inclusion and exclusion criteria, a total of 4593 adults were included in the study. The number of food kinds was collected via 24‒hour dietary recalls. Depression was assessed using the Patient Health Questionnaire‒9. Logistic regression and restricted cubic spline models were applied to assess the association between the number of food kinds and the risk of depression. RESULTS: This study included 4593 study participants, 451 of whom were diagnosed with depression. The revised advantage ratios (with corresponding confidence intervals) for the prevalence of depression among individuals in the fourth quartiles of the number of food kinds (Q4) in comparison to the lowest quartile (Q1) were determined to be 0.59 (0.36‒0.96), respectively. According to our subgroup analyses, the number of food kinds was negatively associated with the risk of depression in females, participants aged 18‒45 and 45‒65 years, and participants with a body mass index (BMI) of 25 to 24.9 kg/m2. According to our dose‒response analysis, the number of food kinds was linearly associated with the risk of depression (Pfor nonlinear=0.5896). CONCLUSION: The risk of depression exhibited a linear and negative correlation with the number of food kinds. The results indicated that a diversified diet was an effective nonpharmacological approach that deserved further generalization.

Cancer therapy resistance mediated by cancer-associated fibroblast-derived extracellular vesicles: biological mechanisms to clinical significance and implications.

Cancer-associated fibroblasts (CAFs) are a diverse stromal cell population within the tumour microenvironment, where they play fundamental roles in cancer progression and patient prognosis. Multiple lines of evidence have identified that CAFs are critically involved in shaping the structure and function of the tumour microenvironment with numerous functions in regulating tumour behaviours, such as metastasis, invasion, and epithelial-mesenchymal transition (EMT). CAFs can interact extensively with cancer cells by producing extracellular vesicles (EVs), multiple secreted factors, and metabolites. Notably, CAF-derived EVs have been identified as critical mediators of cancer therapy resistance, and constitute novel therapy targets and biomarkers in cancer management. This review aimed to summarize the biological roles and detailed molecular mechanisms of CAF-derived EVs in mediating cancer resistance to chemotherapy, targeted therapy agents, radiotherapy, and immunotherapy. We also discussed the therapeutic potential of CAF-derived EVs as novel targets and clinical biomarkers in cancer clinical management, thereby providing a novel therapeutic strategy for enhancing cancer therapy efficacy and improving patient prognosis.

Multifunctional Human-Computer Interaction System Based on Deep Learning-Assisted Strain Sensing Array.

Continuous and reliable monitoring of gait is crucial for health monitoring, such as postoperative recovery of bone joint surgery and early diagnosis of disease. However, existing gait analysis systems often suffer from large volumes and the requirement of special space for setting motion capture systems, limiting their application in daily life. Here, we develop an intelligent gait monitoring and analysis prediction system based on flexible piezoelectric sensors and deep learning neural networks with high sensitivity (241.29 mV/N), quick response (66 ms loading, 87 ms recovery), and excellent stability (R2 = 0.9946). The theoretical simulations and experiments confirm that the sensor provides exceptional signal feedback, which can easily acquire accurate gait data when fitted to shoe soles. By integrating high-quality gait data with a custom-built deep learning model, the system can detect and infer human motion states in real time (the recognition accuracy reaches 94.7%). To further validate the sensor's application in real life, we constructed a flexible wearable recognition system with human-computer interaction interface and a simple operation process for long-term and continuous tracking of athletes' gait, potentially aiding personalized health management, early detection of disease, and remote medical care.

Correlation between Vegetable and Fruit Intake and Cognitive Function in Older Adults: A Cross-Sectional Study in Chongqing, China.

OBJECTIVE: To explore the correlation between different types of vegetable and fruit intake and cognitive function among the older adults in Chongqing, China, and to provide a scientific basis for developing efficient lifestyle interventions for the prevention of Mild Cognitive Impairment (MCI). METHOD: Approximately 728 older adults in urban and rural areas of Chongqing were surveyed using face-to-face questionnaires. Cognitive function was assessed with the Montreal Cognitive Assessment-Basic (MoCA-B) scale, and the vegetable and fruit intake groups were investigated with the Simple Food Frequency Counting Survey Scale. Binary logistic regression was used to explore the effect of the vegetable and fruit intake group on cognitive function. Subgroup analysis was used to demonstrate the robustness of the results. RESULT: Of the 728 participants in the study, 36.40% were likely to have MCI, which is higher than the national average for this condition. After adjusting for confounders, compared to the Q1 group, fruit and root vegetable intake was a protective factor for MCI, showing a dose-response relationship (p < 0.05). Only lower intake (Q2) of total vegetables, medium intake (Q2, Q3) of solanaceous vegetables, and medium-high intake (Q2, Q4) of fungi and algae was protective against MCI, whereas the leafy vegetables showed no relation to MCI. Apart from this, participants who were older, female, unmarried, non-smoking, and engaged in physical labor, and who had an average monthly income of less than 3000 RMB were more likely to suffer from cognitive impairment. CONCLUSION: This suggested that the fruit-intake groups and some vegetable-intake groups showed a protective effect on cognitive function, and might behave differently depending on their different intake and demographic characteristics. A sensible, healthy diet can help prevent MCI.

Communication between cancer cell subtypes by exosomes contributes to nasopharyngeal carcinoma metastasis and poor prognosis.

Background: Intratumor heterogeneity is common in cancers, with different cell subtypes supporting each other to become more malignant. Nasopharyngeal carcinoma (NPC), a highly metastatic cancer, shows significant heterogeneity among its cells. This study investigates how NPC cell subtypes with varying metastatic potentials influence each other through exosome-transmitted molecules. Methods: Exosomes were purified and characterized. MicroRNA expression was analyzed via sequencing and qRT-PCR. The effects of miR-30a-5p on migration, invasion, and metastasis were evaluated in vitro and in vivo. Its impact on desmoglein glycoprotein (DSG2) was assessed using dual-luciferase assays and Western blotting. Immunohistochemistry (IHC) and statistical models linked miR-30a-5p/DSG2 levels to patient prognosis. Results: Different NPC cell subtypes transmit metastatic potential via exosomes. High-metastatic cells enhance the migration, invasion, and metastasis of low-metastatic cells through exosome-transmitted miR-30a-5p. Plasma levels of exosomal miR-30a-5p are reliable indicators of NPC prognosis. miR-30a-5p may promote metastasis by targeting DSG2 and modulating Wnt signaling. Plasma exosomal miR-30a-5p inversely correlates with DSG2 levels, predicting patient outcomes. Conclusion: High-metastatic NPC cells can increase the metastatic potential of low-metastatic cells through exosome-transmitted miR-30a-5p, which is a valuable prognostic marker assessable via liquid biopsy.

Solving the Asymmetric Doping for Wide-Gap Semiconductors by Host Functionalization: Quantum Engineering Strategy.

Asymmetric doping of wide-gap semiconductors has long been a major challenge, hindering their wider applications. Despite numerous attempts to address this issue through engineering doping levels, the results were still inconclusive. In this work, we propose a quantum engineering strategy based on the state-of-the-art spin-polarized HSE06 hybrid functional method. The local band offset between the host and quantum structures can considerably compensate for the large carrier activation energy (Ea). We chose the system of the AlN host embedded by GaN quantum dots as an example to validate the feasibility of this strategy. The Ea of Si (n-type) and Be (p-type) dopants can be reduced from 222 and 404 meV to negative values and 2 meV, respectively. Therefore, electron and hole density can be increased to more than 1019 and 1020 cm-3, respectively. We also tested potential dopants (C and Ge for the n-type, Mg and Ca for the p-type), and the technique is equally effective. This mechanism can also be used to understand the experimental observations of the superlattice doping strategy. Overall, our study demonstrates that the quantum engineering strategy provides a potential solution to overcome the asymmetric doping problem for universal wide-gap semiconductors and supports a feasible pathway for more efficient devices in the future.

The activation of autophagy by molecular hydrogen is functionally associated with osmotic tolerance in Arabidopsis.

The role of molecular hydrogen (H2) in autophagy during inflammatory response is controversial in mammalian cells. Although the stimulation of H2 production in response to osmotic stress was observed in plants, its synthetic pathway and the interrelationship between its induction and plant autophagy remain unclear. Here, the induction of autophagy was observed in Arabidopsis upon osmotic stress, assessing by the autophagosome formation and autophagy-related genes expression. Above responses were intensified by H2 fumigation. Meanwhile, the reduction in seedling growth and roots vigor was obviously abolished, accompanied by reestablishing redox balance. These H2 responses were markedly impaired in T-DNA knockout lines atg2, atg5, and atg18. Further evidence showed that the increased endogenous H2 synthesis by genetic manipulation, not only stimulated autophagosome formation, but also triggered various plant responses toward osmotic stress. By contrast, these responses were obviously abolished by the disruption of endogenous H2 synthesis with the addition of 2,6-dichloroindophenol sodium salt. Together, the integrated genetic and molecular evidence clearly illustrated the requirement of autophagy activation in H2 control of plant osmotic tolerance.

Environmental Persistent Free Radicals in highly polluted soils and the association with polycyclic aromatic compounds.

Environmental persistent free radicals (EPFRs), as emerging contaminants in environment, can induce oxidative stress causing severe adverse health outcomes. The formation of EPFRs is thought to be associated with the transformation of aromatic compounds like polycyclic aromatic hydrocarbons (PAHs). Herein this study firstly evaluated EPFRs in industrial soils being highly polluted by PAHs, and explored its associated with PAHs, with the modification of soil organic matter content. Soil EPFRs from two industrial plants were 4.1 × 1016 and 4.5 × 1016 spins/g, respectively, that were significantly higher than the levels in the surrounding areas. Carbon-centered EPFRs account for approximately 80% inside the plant, but outside the plants, nearly 50-70% of EPFRs were carbon-centered with adjacent heteroatoms. As one important precursor of EPFRs, PAHs exhibited a significantly positive correlation with EPFRs in industrial soils (p < 0.05), explaining 40%-60% of the variation in EPFRs concentration in the present study. The relationship between soil organic matter and EPFRs concentration normalized by PAHs forms an inverted V-shape, suggesting an inhibition effect of soil organic matter on the EPFR formation potentials from PAHs, that is worthy to be further examed in future laboratory and field experiments.

MDD brain network analysis based on EEG functional connectivity and graph theory.

Background: Existing studies have shown that the brain network of major depression disorder (MDD) has abnormal topologies. However, constructing reliable MDD brain networks is still an open problem. New method: This paper proposed a reliable MDD brain network construction method. First, seven connectivity methods are used to calculate the correlation between channels and obtain the functional connectivity matrix. Then, the matrix is binarized using four binarization methods to obtain the EEG brain network. Besides, we proposed an improved binarization method based on the criterion of maximizing differences between groups: the adaptive threshold (AT) method. The AT can automatically set the optimal binarization threshold and overcome the artificial influence of traditional methods. After that, several network metrics are extracted from the brain network to analyze inter-group differences. Finally, we used statistical analysis and Fscore values to compare the performance of different methods and establish the most reliable method for brain network construction. Results: In theta, alpha, and total frequency bands, the clustering coefficient, global efficiency, local efficiency, and degree of the MDD brain network decrease, and the path length of the MDD brain network increases. Comparison with existing methods: The results show that AT outperforms the existing binarization methods. Compared with other methods, the brain network construction method based on phase-locked value (PLV) and AT has better reliability. Conclusions: MDD has brain dysfunction, particularly in the frontal and temporal lobes.

Immunoproteasome acted as immunotherapy 'coffee companion' in advanced carcinoma therapy.

Immunoproteasome is a specialized form of proteasome which plays a crucial role in antigen processing and presentation, and enhances immune responses against malignant cells. This review explores the role of immunoproteasome in the anti-tumor immune responses, including immune surveillance and modulation of the tumor microenvironment, as well as its potential as a target for cancer immunotherapy. Furthermore, we have also discussed the therapeutic potential of immunoproteasome inhibitors, strategies to enhance antigen presentation and combination therapies. The ongoing trials and case studies in urology, melanoma, lung, colorectal, and breast cancers have also been summarized. Finally, the challenges facing clinical translation of immunoproteasome-targeted therapies, such as toxicity and resistance mechanisms, and the future research directions have been addressed. This review underscores the significance of targeting the immunoproteasome in combination with other immunotherapies for solid tumors and its potential broader applications in other diseases.

CTC-derived pancreatic cancer models serve as research tools and are suitable for precision medicine approaches.

Pancreatic ductal adenocarcinoma (PDAC) poses significant clinical challenges, often presenting as unresectable with limited biopsy options. Here, we show that circulating tumor cells (CTCs) offer a promising alternative, serving as a "liquid biopsy" that enables the generation of in vitro 3D models and highly aggressive in vivo models for functional and molecular studies in advanced PDAC. Within the retrieved CTC pool (median 65 CTCs/5 mL), we identify a subset (median content 8.9%) of CXCR4+ CTCs displaying heightened stemness and metabolic traits, reminiscent of circulating cancer stem cells. Through comprehensive analysis, we elucidate the importance of CTC-derived models for identifying potential targets and guiding treatment strategies. Screening of stemness-targeting compounds identified stearoyl-coenzyme A desaturase (SCD1) as a promising target for advanced PDAC. These results underscore the pivotal role of CTC-derived models in uncovering therapeutic avenues and ultimately advancing personalized care in PDAC.

Efficacy, safety, and prognostic modeling in neoadjuvant immunotherapy for esophageal squamous cell carcinoma.

OBJECTIVE: To evaluate the safety and efficacy of neoadjuvant immunotherapy in patients with esophageal squamous cell carcinoma (ESCC) and construct a prognostic model. METHODS: Clinical data were retrospectively collected from patients with locally advanced ESCC who received neoadjuvant immunotherapy and chemotherapy. The primary endpoints were major pathologic remission rate and disease-free survival, and secondary endpoints were treatment-related adverse events and perioperative complications. Correlates affecting pathological response were analyzed using univariate and multivariate logistic regression, survival-related variables were screened by Boruta and least absolute shrinkage and selection operator Cox regression analysis. A nomogram was constructed and utilized to test the predictive efficacy of the treatment with receiver operating characteristic curve and decision curve analysis. RESULTS: A total of 181 patients were enrolled, of whom 119 (66 %) patients received 3-4 cycles of treatment. Treatment-related adverse events occurred in 65.2 % of the patients, with 13.3 % experiencing severe complications. Major pathological remission rate was achieved in 68 (37.6 %) patients, with no significant difference between the treatment cycle groups (P=0.925). The nomogram included pathologic TNM stage, lymphovascular invasion, post-treatment and post-surgery albumin levels, and post-treatment systemic immune-inflammation index. One-year disease-free survival area under the curve was 0.86 (95 %CI, 0.75-0.97) in the derivation cohort and 0.75 (95 %CI, 0.50-0.99) in the validation cohort, with good calibration performance. CONCLUSIONS: Pathological staging combined with albumin level and systemic immune-inflammation index could be a superior predictor of survival prognosis in ESCC patients receiving neoadjuvant immunotherapy. The findings of this study yield new evidence regarding the efficacy and safety of neoadjuvant immunotherapy in ESCC and provide a tool for identifying patients at risk of recurrence.

Hierarchically Micro-, Meso-, and Macro-Porous MOF Nanosystems for Localized Cross-Scale Dual-Biomolecule Loading and Guest-Carrier Cooperative Anticancer Therapy.

Mass transfer of bulky molecules, e.g., bioenzymes, particularly for cross-scale multibiomolecules, imposes serious challenges for microporous metal-organic frameworks (MOFs). Here, we create a hierarchically porous MOF heterostructure featuring highly region-ordered micro-, meso-, and macro-pores by growing a microporous ZIF-8 shell onto a hollow Prussian blue core through an epitaxial growth strategy. This allows for localized loading of large bioenzyme glucose oxidase (GOx) and small drug 5-fluorouracil (5-FU) within specific pores simultaneously and triggers unique guest-carrier cooperative anticancer capabilities. The stable ZIF-8 outer layer effectively blocks the core pores, preventing the undesired leakage of GOx into normal tissues. The acidity-induced ZIF-8 degradation gradually releases Zn2+ and loaded 5-FU for chemotherapy under acidic tumor microenvironments. With the loss of the shielding effect of the ZIF-8 coating, the released GOx depletes intratumoral glucose (Glu) for starvation therapy. Notably, an accelerated cascade reaction occurs between ZIF-8 decomposition and GOx release, facilitated by the modulator factor of Glu. This culminates in the realization of synergistic cancer therapy, as comprehensively demonstrated by in vitro and in vivo experiments, as well as transcriptome sequencing analyses. Our work not only introduces a hierarchically porous MOF heterostructure with highly region-ordered pores but also provides a perspective for guest-carrier cooperative anticancer therapy.

Polysaccharide nanosystems for osteoarthritis therapy: Mechanisms, combinations, and future directions.

Osteoarthritis (OA) represents a chronic degenerative joint ailment characterized by the gradual breakdown of cartilage, inflicting substantial physical and economic burdens, especially among the elderly. Given the incomplete understanding of OA's pathogenesis, there is an increasing need to develop targeted therapeutic strategies and preventive measures. Conventional pharmaceutical interventions, such as non-steroidal anti-inflammatory drugs, steroids, and opioids, though effective, are often accompanied by notable adverse effects, thus emphasizing the urgency in seeking safer and more efficient therapeutic alternatives. The rapid evolution of nanotechnology has opened the door to various nanosystems for drug delivery, offering a promising avenue to mitigate these side effects. Of particular interest, recent research has shed light on the significant potential of polysaccharide-based nanosystems in the context of OA therapy, demonstrating their capability to counter inflammation, oxidative stress, regulate chondrocyte metabolism and proliferation, and protect cartilage. Therefore, in this review, we provide an in-depth examination of the role of polysaccharide nanosystems in OA, focusing on summarizing these findings based on different mechanisms of action. Furthermore, this review explores the application of combined polysaccharide nanosystems in OA, aiming to establish a foundation for the utilization of novel drug delivery nanoplatforms in OA treatment, ultimately expanding therapeutic options for this debilitating condition.

Wafer-Scale Growth and Transfer of High-Quality MoS2 Array by Interface Design for High-Stability Flexible Photosensitive Device.

Transition metal disulfide compounds (TMDCs) emerges as the promising candidate for new-generation flexible (opto-)electronic device fabrication. However, the harsh growth condition of TMDCs results in the necessity of using hard dielectric substrates, and thus the additional transfer process is essential but still challenging. Here, an efficient strategy for preparation and easy separation-transfer of high-uniform and quality-enhanced MoS2 via the precursor pre-annealing on the designed graphene inserting layer is demonstrated. Based on the novel strategy, it achieves the intact separation and transfer of a 2-inch MoS2 array onto the flexible resin. It reveals that the graphene inserting layer not only enhances MoS2 quality but also decreases interfacial adhesion for easy separation-transfer, which achieves a high yield of ≈99.83%. The theoretical calculations show that the chemical bonding formation at the growth interface has been eliminated by graphene. The separable graphene serves as a photocarrier transportation channel, making a largely enhanced responsivity up to 6.86 mA W-1, and the photodetector array also qualifies for imaging featured with high contrast. The flexible device exhibits high bending stability, which preserves almost 100% of initial performance after 5000 cycles. The proposed novel TMDCs growth and separation-transfer strategy lightens their significance for advances in curved and wearable (opto-)electronic applications.

Exploring Paleogene Tibet's warm temperate environments through target enrichment and phylogenetic niche modelling of Himalayan spiny frogs (Paini, Dicroglossidae).

The Cenozoic topographic development of the Himalaya-Tibet orogen (HTO) substantially affected the paleoenvironment and biodiversity patterns of High Asia. However, concepts on the evolution and paleoenvironmental history of the HTO differ massively in timing, elevational increase and sequence of surface uplift of the different elements of the orogen. Using target enrichment of a large set of transcriptome-derived markers, ancestral range estimation and paleoclimatic niche modelling, we assess a recently proposed concept of a warm temperate paleo-Tibet in Asian spiny frogs of the tribe Paini and reconstruct their historical biogeography. That concept was previously developed in invertebrates. Because of their early evolutionary origin, low dispersal capacity, high degree of local endemism, and strict dependence on temperature and humidity, the cladogenesis of spiny frogs may echo the evolution of the HTO paleoenvironment. We show that diversification of main lineages occurred during the early to Mid-Miocene, while the evolution of alpine taxa started during the late Miocene/early Pliocene. Our distribution and niche modelling results indicate range shifts and niche stability that may explain the modern disjunct distributions of spiny frogs. They probably maintained their (sub)tropical or (warm)temperate preferences and moved out of the ancestral paleo-Tibetan area into the Himalaya as the climate shifted, as opposed to adapting in situ. Based on ancestral range estimation, we assume the existence of low-elevation, climatically suitable corridors across paleo-Tibet during the Miocene along the Kunlun, Qiangtang and/or Gangdese Shan. Our results contribute to a deeper understanding of the mechanisms and processes of faunal evolution in the HTO.

L-Alanyl-L-Glutamine Alleviated Ischemia-Reperfusion Injury and Primary Graft Dysfunction in Rat Lung Transplants.

BACKGROUND: Concern of ischemia-reperfusion injury reduces utilization of donor lungs. We hypothesized adding L-alanyl-L-glutamine (L-AG) to preservation solution may protect donor lungs from ischemia-reperfusion injury through its multiple cytoprotective effects. METHODS: A lung transplantation cell culture model was used on human lung epithelial cells and pulmonary microvascular endothelial cells, and the effects of adding different concentrations of L-AG on basic cellular function were tested. Rat donor lungs were preserved at 4 °C with 8 mmol/L L-AG for 12 h followed by 4 h reperfusion or monitored for 3 d. Lung function, lung histology, inflammation, and cell death biomarker were tested. Computerized tomography scan was used and metabolomic analysis was performed on lung tissues. RESULTS: Cold preservation with L-AG improved cell viability and inhibited apoptosis in cell culture. Rat donor lungs treated with L-AG during cold storage showed decreased peak airway pressure, higher dynamic compliance and oxygenation ability, reduced lung injury, apoptosis, and oxidative stress during reperfusion. L-AG treatment significantly changed 130 metabolites during reperfusion, with enhanced amino acid biosynthesis and tricarboxylic acid cycle. Furthermore, cold storage with L-AG decreased primary graft dysfunction grade, improved oxygenation, reduced pulmonary atelectasis, sign of infection, and pneumothorax in a rat left lung transplant 3-d survival model. CONCLUSIONS: Adding L-AG to cold preservation solution reduced lung injury and alleviated primary graft dysfunction by inhibiting inflammation, oxidative stress, and cell death with modified metabolic activities.