Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.

Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism1-4. Glutathione peroxidase 4 (GPX4)5,6 and ferroptosis suppressor protein 1 (FSP1)7,8 constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-L-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate-the substrate and product of dihydroorotate dehydrogenase (DHODH)-attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.

A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria.

Mechanisms of defense against ferroptosis (an iron-dependent form of cell death induced by lipid peroxidation) in cellular organelles remain poorly understood, hindering our ability to target ferroptosis in disease treatment. In this study, metabolomic analyses revealed that treatment of cancer cells with glutathione peroxidase 4 (GPX4) inhibitors results in intracellular glycerol-3-phosphate (G3P) depletion. We further showed that supplementation of cancer cells with G3P attenuates ferroptosis induced by GPX4 inhibitors in a G3P dehydrogenase 2 (GPD2)-dependent manner; GPD2 deletion sensitizes cancer cells to GPX4 inhibition-induced mitochondrial lipid peroxidation and ferroptosis, and combined deletion of GPX4 and GPD2 synergistically suppresses tumor growth by inducing ferroptosis in vivo. Mechanistically, inner mitochondrial membrane-localized GPD2 couples G3P oxidation with ubiquinone reduction to ubiquinol, which acts as a radical-trapping antioxidant to suppress ferroptosis in mitochondria. Taken together, these results reveal that GPD2 participates in ferroptosis defense in mitochondria by generating ubiquinol.

Pyruvate maintains and enhances the pro-inflammatory response of microglia caused by glucose deficiency in early stroke.

Pro-inflammatory microglia mainly rely on glycolysis to maintain cytokine production during ischemia, accompanied by an increase in inducible nitric oxide synthase (iNOS) and monocarboxylate transporter 1 (MCT1). The role of energy metabolism in the pro-inflammatory response of microglia is currently unclear. In this study, we tested the response of microglia in mice after cerebral ischemia and simulated an energy environment in vitro using low glucose culture medium. The research results indicate that the expression levels of iNOS and arginase 1 (ARG1) increase in the ischemic mouse brain, but the upregulation of MCT1 expression is mainly present in iNOS positive microglia. In microglia exposed to low glucose conditions, iNOS and MCT1 levels increased, while ARG1 levels decreased. Under the same conditions, knocking down MCT1 in microglia leads to a decrease in iNOS levels, while overexpression of MCT1 leads to the opposite result. The use of NF-κB inhibitors reduced the expression levels of iNOS and MCT1 in microglia. In summary, our data indicate that pyruvate maintains and enhances the NF-κB regulated pro-inflammatory response of microglia induced by low glucose.

PPP2R1A silencing suppresses LUAD progression by sensitizing cells to nelfinavir-induced apoptosis and pyroptosis.

Lung adenocarcinoma is a major public health problem with the low 5-year survival rate (15%) among cancers. Aberrant alterations of meiotic genes, which have gained increased attention recently, might contribute to elevated tumor risks. However, systematic and comprehensive studies based on the relationship between meiotic genes and LUAD recurrence and treatment response are still lacking. In this manuscript, we first confirmed that the meiosis related prognostic model (MRPM) was strongly related to LUAD progression via LASSO-Cox regression analyses. Furthermore, we identified the role of PPP2R1A in LUAD, which showed more contributions to LUAD process compared with other meiotic genes in our prognostic model. Additionally, repression of PPP2R1A enhances cellular susceptibility to nelfinavir-induced apoptosis and pyroptosis. Collectively, our findings indicated that meiosis-related genes might be therapeutic targets in LUAD and provided crucial guidelines for LUAD clinical intervention.

Patterns and drivers of anaerobic nitrogen transformations in sediments of thermokarst lakes.

Significant attention has been given to the way in which the soil nitrogen (N) cycle responds to permafrost thaw in recent years, yet little is known about anaerobic N transformations in thermokarst lakes, which account for more than one-third of thermokarst landforms across permafrost regions. Based on the N isotope dilution and tracing technique, combined with qPCR and high-throughput sequencing, we presented large-scale measurements of anaerobic N transformations of sediments across 30 thermokarst lakes over the Tibetan alpine permafrost region. Our results showed that gross N mineralization, ammonium immobilization, and dissimilatory nitrate reduction rates in thermokarst lakes were higher in the eastern part of our study area than in the west. Denitrification dominated in the dissimilatory nitrate reduction processes, being two and one orders of magnitude higher than anaerobic ammonium oxidation (anammox) and dissimilatory nitrate reduction to ammonium (DNRA), respectively. The abundances of the dissimilatory nitrate reduction genes (nirK, nirS, hzsB, and nrfA) exhibited patterns consistent with sediment N transformation rates, while α diversity did not. The inter-lake variability in gross N mineralization and ammonium immobilization was dominantly driven by microbial biomass, while the variability in anammox and DNRA was driven by substrate supply and organic carbon content, respectively. Denitrification was jointly affected by nirS abundance and organic carbon content. Overall, the patterns and drivers of anaerobic N transformation rates detected in this study provide a new perspective on potential N release, retention, and removal upon the formation and development of thermokarst lakes.

Automatic medical specialty classification based on patients' description of their symptoms.

In China, patients usually determine their medical specialty before they register the corresponding specialists in the hospitals. This process usually requires a lot of medical knowledge for the patients. As a result, many patients do not register the correct specialty for the first time if they do not receive help from the hospitals. In this study, we try to automatically direct the patients to the appropriate specialty based on the symptoms they described. As far as we know, this is the first study to solve the problem. We propose a neural network-based model based on a hybrid model integrated with an attention mechanism. To prove the actual effect of this hybrid model, we utilized a data set of more than 40,000 items, including eight departments, such as Otorhinolaryngology, Pediatrics, and other common departments. The experiment results show that the hybrid model achieves more than 93.5% accuracy and has a high generalization capacity, which is superior to traditional classification models.

Repair of complex digital soft-tissue defects using a free composite ulnar artery perforator flap from the volar wrist.

Digital skin defects resulting from trauma are often associated with dysfunction of the digital nerve and the extensor and flexor tendons in the affected fingers. The repair of these complex tissue defects requires a graft containing multiple tissues that can be used to reconstruct the tendons and nerves and restore the skin. Such procedures can cause multiple injuries and significant damage to the donor site. The current study used a novel technique to repair complex dorsal and palmar digital soft-tissue defects. First, multiple tissues were cut and collected from the donor site. Then, part of the flexor carpi ulnaris tendon was transplanted to repair the tendon defect, and a medial antebrachial cutaneous nerve graft was used to repair the digital nerve defect. Finally, a skin flap was used to cover the skin defect. This paper reports on 31 cases of complex soft-tissue digital defects, with defect areas of 2-18 cm2 . One patient presented with a postoperative arterial crisis in the flap. All other patients recovered without experiencing a vascular crisis, flap necrosis, or wound infection. The postoperative flaps were similar in texture to the original digital skin. The sensation and the extension/flexion functions in the affected fingers recovered well. The effect on grip strength, wrist flexion, and forearm sensation was minor and the postoperative total active motion scores of the affected digits were good or excellent in 96.77% of the cases. The flap sensation recovery rate was also excellent in 83.87% of the cases. The present technique facilitates the repair of multiple dorsal and palmar digital soft-tissue, tendon and nerve defects, reduces the damage to the donor site, and significantly improves the success of surgical repair.

Lymphoid-specific helicase in epigenetics, DNA repair and cancer.

Lymphoid-specific helicase (LSH) is a member of the SNF2 helicase family of chromatin-remodelling proteins. Dysfunctions or mutations in LSH causes an autosomal recessive disease known as immunodeficiency-centromeric instability-facial anomaly (ICF) syndrome. Interestingly, LSH participates in various aspects of epigenetic regulation, including nucleosome remodelling, DNA methylation, histone modifications and heterochromatin formation. Further, LSH plays a crucial role during DNA-damage repair, specifically during double-strand break (DSB) repair, since murine LSH was shown to be essential for non-homologous end joining (NHEJ) and homologous recombination (HR). Accordingly, overexpression of LSH drives tumorigenesis and malignancy. On the other hand, LSH homologs stabilise the genome. Thus, LSH might be implemented as a biomarker for various cancer types and potential target molecule to develop therapeutic strategies against them. In this review, we focus on the role of LSH in orchestrating chromatin rearrangements, such as DNA methylation and histone modifications, as well as in DNA-damage repair. Changes in chromatin structure may facilitate gene expression signatures that cause malignant transformation. We summarise recent findings of LSH in cancers and raise critical open questions for further studies.

Lack of Associations between Endoplasmic Reticulum Aminopeptidase 2 Gene Polymorphisms and Ankylosing Spondylitis: A Meta-analysis with Trial Sequential Analysis.

BACKGROUND: Endoplasmic reticulum aminopeptidase 2 (ERAP2) gene is reported to be associated with inflammation-related diseases. Several studies have investigated the associations of ERAP2 gene polymorphisms and susceptibility to ankylosing spondylitis (AS). However, the findings of those studies were inconsistent. The aim of this study was to elucidate the associations by a meta-analysis with trial sequential analysis (TSA). METHODS: Online databases of PubMed, Web of Science, EMBASE, Cochrane Library, Wanfang, and CNKI were searched to identify eligible studies on the associations of ERAP2 gene polymorphisms and AS. Study quality was judged based on the Newcastle-Ottawa scale (NOS). Strengths of associations were presented by P-value, odds ratios (ORs), and 95% confidence intervals (95%CIs). TSA was employed to evaluate the information size and statistical power. RESULTS: A total of six studies encompassing 2774 AS patients and 4119 disease-free controls were eligible for this meta-analysis. Five studies reported rs2248374 polymorphism and three studies reported rs2549782 polymorphism. The pooled data suggested that the two polymorphisms were not significantly associated with AS susceptibility: rs2248374, A vs. G, OR = 0.94, 95%CI 0.86-1.02, P = .14; rs2549782, T vs. G, OR = 1.03, 95%CI 0.95-1.12, P = .45. TSA indicated that the sample sizes appeared to be inadequate to obtain a positive outcome. CONCLUSION: The present findings of this study do not support any evidence on the associations of rs2248374 and rs2549782 polymorphisms in the ERAP2 gene and susceptibility to AS. Additional well-designed and large-sample studies in diverse ethnicities are encouraged to validate the current findings.

Emerging mechanisms and targeted therapy of ferroptosis in cancer.

Ferroptosis is an iron- and lipid reactive oxygen species (ROS)-dependent form of programmed cell death that is distinct from other forms of regulatory cell death at the morphological, biological, and genetic levels. Emerging evidence suggests critical roles for ferroptosis in cell metabolism, the redox status, and various diseases, such as cancers, nervous system diseases, and ischemia-reperfusion injury, with ferroptosis-related proteins. Ferroptosis is inhibited in diverse cancer types and functions as a dynamic tumor suppressor in cancer development, indicating that the regulation of ferroptosis can be utilized as an interventional target for tumor treatment. Small molecules and nanomaterials that reprogram cancer cells to undergo ferroptosis are considered effective drugs for cancer therapy. Here, we systematically summarize the molecular basis of ferroptosis, the suppressive effect of ferroptosis on tumors, the effect of ferroptosis on cellular metabolism and the tumor microenvironment (TME), and ferroptosis-inducing agents for tumor therapeutics. An understanding of the latest progress in ferroptosis could provide references for proposing new potential targets for the treatment of cancers.

Large-scale evidence for microbial response and associated carbon release after permafrost thaw.

Permafrost thaw could trigger the release of greenhouse gases through microbial decomposition of the large quantities of carbon (C) stored within frozen soils. However, accurate evaluation of soil C emissions from thawing permafrost is still a big challenge, partly due to our inadequate understanding about the response of microbial communities and their linkage with soil C release upon permafrost thaw. Based on a large-scale permafrost sampling across 24 sites on the Tibetan Plateau, we employed meta-genomic technologies (GeoChip and Illumina MiSeq sequencing) to explore the impacts of permafrost thaw (permafrost samples were incubated for 11 days at 5°C) on microbial taxonomic and functional communities, and then conducted a laboratory incubation to investigate the linkage of microbial taxonomic and functional diversity with soil C release after permafrost thaw. We found that bacterial and fungal α diversity decreased, but functional gene diversity and the normalized relative abundance of C degradation genes increased after permafrost thaw, reflecting the rapid microbial response to permafrost thaw. Moreover, both the microbial taxonomic and functional community structures differed between the thawed permafrost and formerly frozen soils. Furthermore, soil C release rate over five month incubation was associated with microbial functional diversity and C degradation gene abundances. By contrast, neither microbial taxonomic diversity nor community structure exhibited any significant effects on soil C release over the incubation period. These findings demonstrate that permafrost thaw could accelerate C emissions by altering the function potentials of microbial communities rather than taxonomic diversity, highlighting the crucial role of microbial functional genes in mediating the responses of permafrost C cycle to climate warming.

Proline dehydrogenase in cancer: apoptosis, autophagy, nutrient dependency and cancer therapy.

L-proline catabolism is emerging as a key pathway that is critical to cellular metabolism, growth, survival, and death. Proline dehydrogenase (PRODH) enzyme, which catalyzes the first step of proline catabolism, has diverse functional roles in regulating many pathophysiological processes, including apoptosis, autophagy, cell senescence, and cancer metastasis. Notably, accumulated evidence demonstrated that PRODH plays complex role in many types of cancers. In this review, we briefly introduce the function of PRODH, then its expression in different types of cancer. We next discuss the regulation of PRODH in cancer, the downstream pathways of PRODH and the therapies that are under investigation. Finally, we propose novel insights for future perspectives on the modulation of PRODH.

Methanogenic Community, CH4 Production Potential and Its Determinants in the Active Layer and Permafrost Deposits on the Tibetan Plateau.

Permafrost thaw could increase methane (CH4) emissions, which largely depends on CH4 production driven by methanogenic archaea. However, large-scale evidence regarding key methanogenic taxa and their relative importance to abiotic factors in mediating methanogenesis remains limited. Here, we explored the methanogenic community, potential CH4 production and its determinants in the active layer and permafrost deposits based on soil samples acquired from 12 swamp meadow sites along a ∼1000 km permafrost transect on the Tibetan Plateau. Our results revealed lower CH4 production potential, mcrA gene abundance, and richness in the permafrost layer than those in the active layer. CH4 production potential in both soil layers was regulated by microbial and abiotic factors. Of the microbial properties, marker OTUs, rather than the abundance and diversity of methanogens, stimulated CH4 production potential. Marker OTUs differed between the two soil layers with hydrogenotrophic Methanocellales and facultative acetoclastic Methanosarcina predominant in regulating CH4 production potential in the permafrost and active layer, respectively. Besides microbial drivers, CH4 production potential increased with the carbon/nitrogen (C/N) ratio in both soil layers and was also stimulated by soil moisture in the permafrost layer. These results provide empirical evidence for model improvements to better predict permafrost carbon feedback to climate warming.

Permafrost nitrogen status and its determinants on the Tibetan Plateau.

It had been suggested that permafrost thaw could promote frozen nitrogen (N) release and modify microbial N transformation rates, which might alter soil N availability and then regulate ecosystem functions. However, the current understanding of this issue is confined to limited observations in the Arctic permafrost region, without any systematic measurements in other permafrost regions. Based on a large-scale field investigation along a 1,000 km transect and a laboratory incubation experiment with a 15 N pool dilution approach, this study provides the comprehensive evaluation of the permafrost N status, including the available N content and related N transformation rates, across the Tibetan alpine permafrost region. In contrast to the prevailing view, our results showed that the Tibetan alpine permafrost had lower available N content and net N mineralization rate than the active layer. Moreover, the permafrost had lower gross rates of N mineralization, microbial immobilization and nitrification than the active layer. Our results also revealed that the dominant drivers of the gross N mineralization and microbial immobilization rates differed between the permafrost and the active layer, with these rates being determined by microbial properties in the permafrost while regulated by soil moisture in the active layer. In contrast, soil gross nitrification rate was consistently modulated by the soil NH 4 + content in both the permafrost and the active layer. Overall, patterns and drivers of permafrost N pools and transformation rates observed in this study offer new insights into the potential N release upon permafrost thaw and provide important clues for Earth system models to better predict permafrost biogeochemical cycles under a warming climate.

Magnitude and Drivers of Potential Methane Oxidation and Production across the Tibetan Alpine Permafrost Region.

Methane (CH4) dynamics across permafrost regions is critical in determining the magnitude and direction of permafrost carbon (C)-climate feedback. However, current studies are mainly derived from the Arctic area, with limited evidence from other permafrost regions. By combining large-scale laboratory incubation across 51 sampling sites with machine learning techniques and bootstrap analysis, here, we determined regional patterns and dominant drivers of CH4 oxidation potential in alpine steppe and meadow (CH4 sink areas) and CH4 production potential in swamp meadow (CH4 source areas) across the Tibetan alpine permafrost region. Our results showed that both CH4 oxidation potential (in alpine steppe and meadow) and CH4 production potential (in swamp meadow) exhibited large variability across various sampling sites, with the median value being 8.7, 9.6, and 11.5 ng g-1 dry soil h-1, respectively. Our results also revealed that methanotroph abundance and soil moisture were two dominant factors regulating CH4 oxidation potential, whereas CH4 production potential was mainly affected by methanogen abundance and the soil organic carbon content, with functional gene abundance acting as the best explaining variable. These results highlight the crucial role of microbes in regulating CH4 dynamics, which should be considered when predicting the permafrost C cycle under future climate scenarios.

Association between IGF-1 polymorphisms and risk of osteoporosis in Chinese population: a meta-analysis.

BACKGROUND: Several studies looking into the association between insulin-like growth factor-1 (IGF-1) gene polymorphisms and osteoporosis predisposition have been conducted among Chinese population with conflicting outcomes. The present systematic review and meta-analysis was performed to appraise and synthesize the existing evidence, so as to provide a more precise and reliable association between polymorphisms in IGF-1 gene and osteoporosis. METHODS: Five electronic databases including PubMed, EMBASE, ISI Web of Science, CNKI and Wanfang were systematically searched for potential studies. Summary odds ratio (OR) and corresponding 95% confidence interval (95% CI) were calculated to evaluate the association. The best-matching genetic model of inheritance was determined using a genetic-model free approach. RESULTS: Six case-control studies comprising 2068 osteoporosis patients and 2071 healthy controls were obtained for the meta-analysis. Dominant model was confirmed to be the best-matching genetic model (TT + TC versus CC). The overall data suggested that rs35767 polymorphism was significantly associated with osteoporosis vulnerability (OR 1.21, 95% CI 1.07, 1.37; P = 0.002). When stratifying the participants and performing subgroup-analysis according to source of patients, the result suggested that rs35767 was significantly correlated to osteoporosis in post-menopausal women subgroup (OR 1.29, 95% CI 1.08, 1.54; P = 0.005), but the correlation was not established in the subgroup of both gender (OR 1.14, 95% CI 0.96, 1.35; P = 0.12). CONCLUSION: Taken together, the findings of our current study suggested a significant association between rs35767 polymorphism and risk of osteoporosis in Chinese post-menopausal women.

[Biological characteristics of an Hog1 MAPK homologous gene FoHog1 knock-out mutant of Fusarium oxysporum f. sp. cubense].

OBJECTIVE: This study was aimed to obtain a mitogen-activated protein kinase (MAPK) gene namely FoHog1 from Fusarium oxysporum f. sp. cubense and to verify its function. METHODS: We amplified FoHog1 gene by PCR and RT-PCR methods and analyzed it through bioinformatics method. PEG-mediated protoplast transformation was used to create the deletion mutants of FoHog1 gene. We analyzed different biological characteristics between knock-out strain and wild-type strain. RESULTS: FoHog1 gene encoding a putative protein of 357 amino acids and its genetic relationship with different Fusarium' s protein. Compared with the wild-type strain, FoHog1 deletion mutants have loose hyphae colony, less spores production, lower dry weight of hyphae and more sensitive to temperature, pH and osmotic stress. FoHog1 deletion mutants also have reduced colonization ability compared with the wild-type strain. CONCLUSION: FoHog1 gene participated in mycelial growth, sporulation, catabolism of sodium acetate and ammonium chloride, osmotic stress response and pathogenic process with Fusarium oxysporum f. sp. cubense Race 4.