Fault-Tolerant Consensus of Multiagent Systems With Prescribed Performance.

This article studies the fault-tolerant consensus problem with the guaranteed transient performance of multiagent systems (MASs) subject to unknown time-varying actuator faults and disturbances. The general actuator faults, including both multiplicative and additive time-varying faults, are considered in such a problem for the first time. Both single-integrator modeled agents and double-integrator modeled agents are investigated. The transient performance is ensured in the sense that position errors between each pair of neighboring agents are guaranteed within certain user-defined time-varying performance bounds. Adaptive laws are designed to estimate information about faults and disturbances. For MASs with additive faults, the proposed controllers ensure errors asymptotically converge to zero with guaranteed transient performance. For MASs with both multiplicative faults and additive faults, the proposed controllers ensure errors converge to a residual set without asymptotic convergence but still with guaranteed transient performance. Two simulation examples are provided to evaluate the proposed schemes.

Effect of Sb Content on the Microstructure and Mechanical Properties of Eutectic SnPb Solder.

SnPb solder was widely used in electronic packaging for aerospace devices due to its high reliability. However, its creep resistance is poor and can be improved by adding alloying elements. The effects of Sb content on the microstructure, tensile, and creep properties of eutectic SnPb solder were investigated. Sb addition effectively improved the mechanical properties of the SnPb solder. When Sb content exceeds 1.7 wt.%, SbSn intermetallic compounds (IMCs) occurred. And increasing the Sb content increased the tensile strength. Furthermore, Sb addition decreased the steady-state creep rate and increased the stress exponent n, suggesting that the creep resistance had been enhanced, which may be attributed to the hindrance of dislocation movement by SbSn IMCs, as well as the reduction in phase boundaries, which consequently reduced grain boundary sliding.

Improvement of PbSn Solder Reliability with Ge Microalloying-Induced Optimization of Intermetallic Compounds Growth.

PbSn solders are used in semiconductor devices for aerospace or military purposes with high levels of reliability requirements. Microalloying has been widely adopted to improve the reliability for Pb-free solders, but its application in PbSn solders is scarce. In this article, the optimization of PbSn solder reliability with Ge microalloying was investigated using both experimental and calculation methods. Intermetallic compounds (IMC) growth and morphologies evolution during reliability tests were considered to be the main factors of device failure. Through first-principle calculation, the growth mechanism of interfacial Ni3Sn4 was discussed, including the formation of vacancies, the Ni-vacancies exchange diffusion and the dominant Ni diffusion along the [1 0 0] direction. The doping of Ge in the cell increased the exchange energy barrier and thus inhibited the IMC development and coarsening trend. In three reliability tests, only 0.013 wt% Ge microalloying in Pb60Sn40 was able to reduce IMC thickness by an increment of 22.6~38.7%. The proposed Ge microalloying method in traditional PbSn solder could yield a prospective candidate for highly reliable applications.

EBUS-TBLC increase the diagnosis rate in different type of peripheral pulmonary lesions.

Background and objective: Recently, endobronchial ultrasonography with guide sheath-guided (EBUS-GS) has been increasingly used in the diagnosis of peripheral pulmonary lesions (PPLs) from human natural orifice. However, the diagnostic rate is still largely dependent on the location of the lesion and the probe. Here, we reported a new procedure to improve the diagnostic rate of EBUS-transbronchial lung cryobiopsy (EBUS-TBLC), which performed under general anesthesia with laryngeal mask airway (LMA) in all of the patients. This study retrospectively evaluated the diagnosis of PPLs with 'blind-ending' type (Type I) and 'pass-through' type procedures (Type II) of EBUS-GS-TBLB or EBUS-TBLC respectively. Methods: Retrospective review of 136 cases performed by EBUS-GS-TBLB or EBUS-TBLC for PPLs over 2 years. Results: A total of 126 cases EBUS-GS-TBLB or EBUS-TBLC were performed during the study period. Among them, 66 (52.4%) were performed Type I and 60 (47.6%) were performed Type II. Clinical baseline characteristics did not differ between two groups. The overall diagnosis rate of 126 patients with EBUS-GS-TBLB or EBUS-TBLC was 73% (92/126), and different method type have significant influence on the diagnostic yield (P = 0.012, x2 = 4.699). Among them, diagnostic yields for Type I with forceps biopsy (n=34), Type I with cryobiopsy (n=32), Type II with forceps biopsy (n=30), and Type II with cryobiopsy (n=30) were 72.5%, 64.5%, 70.4% and 74.2% respectively (Figure 2A). The study further compared the outcomes of different procedures in concentric and eccentric lesion. Diagnostic yields for Type I with eccentric (n=30), Type I with concentric (n=36), Type II with eccentric (n=34), and Type II with concentric (n=26) were 58.2%, 76.9%, 60.2% and 74.8%, respectively (P < 0.05). The incidence of complications in 126 patients was 2.6%. Conclusion: EBUS-GS-TBLB and EBUS-TBLC both are very safe and highly diagnostic technique; different method types have significant influence on the diagnostic yield. Moreover, Type II procedure has higher diagnostic yield. In addition, Type I with eccentric had the lowest diagnosis yield.

Molecular mechanism for target recognition, dimerization, and activation of Pyrococcus furiosus Argonaute.

The Argonaute nuclease from the thermophilic archaeon Pyrococcus furiosus (PfAgo) contributes to host defense and represents a promising biotechnology tool. Here, we report the structure of a PfAgo-guide DNA-target DNA ternary complex at the cleavage-compatible state. The ternary complex is predominantly dimerized, and the dimerization is solely mediated by PfAgo at PIWI-MID, PIWI-PIWI, and PAZ-N interfaces. Additionally, PfAgo accommodates a short 14-bp guide-target DNA duplex with a wedge-type N domain and specifically recognizes 5'-phosphorylated guide DNA. In contrast, the PfAgo-guide DNA binary complex is monomeric, and the engagement of target DNA with 14-bp complementarity induces sufficient dimerization and activation of PfAgo, accompanied by movement of PAZ and N domains. A closely related Argonaute from Thermococcus thioreducens adopts a similar dimerization configuration with an additional zinc finger formed at the dimerization interface. Dimerization of both Argonautes stabilizes the catalytic loops, highlighting the important role of Argonaute dimerization in the activation and target cleavage.

Identification of key biomarkers in ischemic stroke: single-cell sequencing and weighted co-expression network analysis.

PURPOSE: At present, there is a lack of accurate early diagnostic markers for ischemic stroke. METHODS: By using dimensionality reduction cluster analysis, differential expression analysis, weighted co-expression network analysis, protein-protein interaction network analysis, cell heterogeneity and key pathogenic genes were identified in ischemic stroke. Immunomicroenvironment analysis was used to explore the immune landscape and immune associations of key genes in ischemic stroke. The analysis platform we use is R software (version 4.0.5). PCR experiments were used to verify the expression of key genes. RESULTS: Single cell sequencing data in ischemic stroke can be annotated as fibroblast cells, pre-B cell CD34, neutrophils cells, bone marrow (BM), keratinocytes, macrophage, neurons and mesenchymal stem cells (MSC). By the intersection of differential expression analysis and WGCNA analysis, 385 genes were obtained. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that these genes were highly correlated with multiple functions and pathways. Protein-protein interaction network analysis revealed that MRPS11 and MRPS12 were key genes, both of which were down-regulated in ischemic stroke. The Pseudo-time series analysis found that the expression of MRPS12 decreased gradually with the differentiation of pre-B cell CD34 cells in ischemic stroke, suggesting that the downregulation of MRPS12 expression may play an important role in ischemic stroke. At last, PCR showed that MRPS11 and MRPS12 were significantly down-regulated in peripheral blood of patients with ischemic stroke. CONCLUSIONS: Our study provides a reference for the study of pathogenesis and key targets of ischemic stroke.

The impact of global, regional, and national population ageing on disability-adjusted life years and deaths associated with diabetes during 1990-2019: A global decomposition analysis.

AIMS: To understanding the net regional, national, and economic effect of global population ageing on diabetes and its trends during 1990 and 2019 worldwide. METHODS: We employed a decomposition method to estimate the impact of population ageing on diabetes-related disability-adjusted life years (DALYs) and total deaths in 204 countries from 1990 to 2019 at the global, regional, and national level. This method separated the net effect of population ageing from population growth and changes in mortality. RESULTS: Globally, population ageing has become the major contributor to diabetes-related deaths since 2013. The increases in diabetes-related deaths attributed to population ageing exceeding the decreases in mortality change. Population ageing produced an additional 0.42 million diabetes-related deaths and 14.95 million DALYs from 1990 to 2019. At the regional level, population ageing is associated with the increases in diabetes-related deaths in 18 out of 22 regions. The highest increase in diabetes-related deaths attributed to population ageing occurred in men in East Asia (136.31%) and women in Central Latin America (118.58%). The proportion of diabetes-related deaths and DALYs attributable to population ageing showed a bell-shaped relationship with sociodemographic index (SDI) and peaked at high-middle-SDI countries. CONCLUSIONS: The decreases in diabetes-related deaths attributed to mortality change exceeded the increases attributed to population ageing between 1990 and 2019 globally and regionally. The diabetes-related deaths in high-middle-SDI countries were most impacted by population ageing.

New perspective on exploring the predictive factors of blood pressure reduction during CPAP treatment in people with severe OSA and hypertension: a prospective observational study.

BACKGROUND: The predictive factors of blood pressure (BP) response to continuous positive airway pressure (CPAP) in obstructive sleep apnoea (OSA) are still being explored. We aimed to assess the antihypertensive effect of CPAP considering the obstructive respiratory event-triggered BP surge profiles in 130 subjects with severe OSA and untreated hypertension. METHODS: Nocturnal BP was monitored continuously and synchronised with polysomnography. Event-triggered BP surge profiles were studied: BP surge as the value of event-related systolic BP (SBP) elevation; BP index as the number of BP surge events of ≥10 mm Hg per hour. Patients were then divided into two groups according to the median BP index (high and low BP surge groups) and assigned to 4 weeks of CPAP. Changes in BPs and plasma biomarkers were compared. After the initial evaluation, patients with a better BP response in the high BP surge group were then followed up for the second evaluation at 24 months. RESULTS: Overall, a modest decrease was observed in both office and asleep BPs at the 4-week follow-up; however, BPs dropped more markedly in patients in the high BP surge group than those in the low BP surge group, in both office SBP (5.3 mm Hg vs 2.2 mm Hg, p=0.003) and diastolic BP (4.0 mm Hg vs 1.2 mm Hg, p<0.001), especially the asleep SBP (9.0 mm Hg vs 2.1 mm Hg, p<0.001). For 30 cases in the high BP surge group, optimal BP control was achieved in 60.0% of patients and BP<140/90 mm Hg reached up to 83.3% after 24 months of CPAP. Linear regression revealed that BP index was significantly associated with BP decrease during CPAP treatment. CONCLUSIONS: Our results suggested that high event-triggered BP surge was a sensitive predictor of BP response to CPAP in patients with severe OSA and untreated hypertension. TRIAL REGISTRATION NUMBER: Clinical Trials.gov Identifier: NCT03246022; https://clinicaltrials.gov/ct2/show/NCT03246022?term=NCT+03246022&draw=2&rank=1.

Gestational and Postpartum Complications in Patients with First Trimester Thyrotoxicosis: A Prospective Multicenter Cohort Study from Northeast China.

Objective: Gestational transient thyrotoxicosis (GTT) and Graves' disease (GD) are the most common causes of hyperthyroidism during pregnancy. However, few studies have compared pregnancy outcomes of patients who had GTT with those who had GD in the first trimester of pregnancy. Methods: We conducted a prospective multicenter cohort study in China. Participants received questionnaires, physical examinations, and underwent measurements of thyrotropin (TSH), free thyroxine (fT4), thyroid peroxidase antibody (TPOAb), TSH receptor antibody (TRAb), and urinary iodine in the first trimester. The patients diagnosed with either GTT or GD and normal thyroid function (NTF) group were followed until delivery. The thyroid function and pregnancy outcomes were reported. Results: A total of 125 pregnant women with thyrotoxicosis and 246 age-matched pregnant women with NTF were included. (1) The thyroid function of the GTT group returned to normal range in the third trimester, but was consistently abnormal in the GD group. (2) The incidence of gestational diabetes mellitus (GDM) in the GTT group (11.5%, 9/78) was significantly higher than that in NTF group (4.9%, 12/246) (p = 0.037). The incidence of premature delivery in the GD untreated (30.8%, 8/26, p = 0.002) and treated groups (28.6%, 6/21, p = 0.008) was both, respectively, higher than that in the NTF group (7.7%, 19/246). Miscarriage (15.4%, 4/26 vs. 3.7%, 9/246, p = 0.026) and gestational hypertension (19.2%, 5/26 vs. 3.3%, 8/246, p = 0.004) were more prevalent in the GD untreated group than in the NTF group. (3) The presence of positive TRAb and positive TPOAb in the first trimester were independent risk factors for miscarriage (odds ratio [OR] = 5.23, confidence interval [CI] = 1.11-24.78, p = 0.037) and low birth weight infants (OR = 7.76, CI = 1.23-48.86, p = 0.029), respectively. Conclusion: In conclusion, pregnancy outcomes appear variable, according to the etiology of first trimester thyrotoxicosis. GTT appears to be associated with GDM. GD appears to be associated with an increased risk of premature delivery, gestational hypertension, and miscarriage. The diagnosis of GTT and GD patients during early pregnancy and appropriate treatment of GD patients may be associated with improved pregnancy outcomes.

A bacterial Argonaute from Tepiditoga spiralis with the ability of RNA guided plasmid cleavage.

The eukaryotic Argonaute proteins (eAgos) play an important role in the RNA interference pathway. The function and mechanism of prokaryotic Argonaute proteins (pAgos) in vivo are still unclear although the structure of pAgos and eAgos are highly homologous. Most of the reported pAgos have a preference for 5'P-gDNA, but MpAgo originated from bacteria Marinitoga piezophila preferentially uses 5'OH-gRNA to target DNA and RNA. To enrich our knowledge of this type of Argonaute proteins, here we report an Argonaute protein derived from Tepiditoga spiralis (TsAgo). Like MpAgo, TsAgo has a preference for 5'OH-gRNA. Meanwhile, TsAgo has DNA and RNA cleavage activity in presence of Mn2+ and Mg2+, and TsAgo has catalytic activity at 37-70 °C. In addition, TsAgo can tolerate mismatches in the 5'-end and 3'-tail regions of guides but is sensitive to mismatches in the 5'-seed and central regions of guides, especially the central region. Furthermore, the EMSA assay reveals that TsAgo exhibits a stronger binding affinity for 5'OH-gRNA than 5'P-gRNA which is consistent with its cleavage activity. Moreover, the structural modeling analysis demonstrates that like MpAgo, TsAgo has an ordered α5 at the C terminus of the PIWI domain which may hinder to binding of 5' phosphate. Importantly, we find that TsAgo can target and cut plasmid DNA in vitro at 60 °C under the direction of RNA guides. These studies broaden our understanding of pAgos, and demonstrate that TsAgo can be regarded as an RNA-guided programmable nuclease for cleaving plasmids.

A bacterial Argonaute with efficient DNA and RNA cleavage activity guided by small DNA and RNA.

Argonaute proteins are widespread in prokaryotes and eukaryotes with diversified catalytic activities. Here, we describe an Argonaute from Marinitoga hydrogenitolerans (MhAgo) with all eight cleavage activities. Utilization of all four types of guides and efficient cleavage of single-stranded DNA (ssDNA) and RNA targets are revealed. The preference for the 5'-terminus nucleotides of 5'P guides, but no obvious preferences for that in 5'OH guides, is further uncovered. Moreover, the cleavage efficiency is heavily impaired by mismatches in the central and 3'-supplementary regions of guides, and the affinity between guides or guides/target duplex and MhAgo is proved as one of the factors affecting cleavage efficiency. Structural and mutational analyses imply some unknown distinctive structural features behind the cleavage activity of MhAgo. Meanwhile, 5'OH-guide RNA (gRNA)-mediated plasmid cleavage activity is unveiled. Conclusively, MhAgo is versatile, and its biochemical characteristics improve our understanding of pAgos and the pAgo-based techniques.

Prototheca bovis induces autophagy in bovine mammary epithelial cells via the HIF-1α and AMPKα/ULK1 pathway.

Prototheca bovis, a highly contagious pathogen, causes bovine mastitis, resulting in premature culling of affected cows and severe economic losses. Infection with P. bovis caused oxidative stress and apoptosis in bovine mammary epithelial cells (bMECs); however, mechanisms underlying P. bovis-induced autophagy remain unclear. Therefore, the autophagy flux induced by P. bovis in bMECs was analyzed by Western blot and laser scanning confocal microscopy. Expression levels of proteins in the HIF-1α and AMPKα/ULK1 pathway, including HIF-1α, AMPKα, p-AMPKα, ULK1, p-ULK1, mTOR, and p-mTOR, plus expression of autophagy-related genes including SQSTM1/p62, Atg5, Beclin1, and LC3II/LC3I, were quantified with Western blot. Infection with P. bovis induced autophagosomes and LC3 puncta in bMECs that were detected using transmission electron microscopy and laser scanning confocal microscopy, respectively. In addition, lysosome-associated proteins Rab7 and LAMP2a, and lysosomal activity were measured with Western blot and laser scanning confocal microscopy. Infection with P. bovis induced an unobstructed autophagic flux, increased protein expression of LC3II/LC3I, and decreased SQSTM1/p62 protein expression at 6 hpi. Furthermore, P. bovis upregulated protein expression in the HIF-1α and AMPKα/ULK1 pathway and increased the ratio of LC3II/LC3I, implying autophagy was activated in bMECs. However, deletion of AMPKα or ULK1 decreased LC3II/LC3I expression levels and LC3 puncta numbers, suggesting that autophagy was inhibited in bMECs. Additionally, deficiency of HIF-1α decreased protein expression of AMPKα and ULK1 as well as LC3 puncta numbers, and autophagy induced by P. bovis was also inhibited in bMECs. At 6 hpi, lysosome-associated protein Rab7 was decreased and LAMP2a was increased, indicating normal autophagy. In contrast, at 12 hpi, expression of Rab7 and LAMP2a proteins indicated that autophagy was inhibited in bMECs at that time. Therefore, we confirmed that P. bovis infection induced autophagy in bMECs via the HIF-1α and AMPKα/ULK1 pathway, with involvement of lysosome-associated protein Rab7 and LAMP2a.

CHK2 Promotes Metabolic Stress-Induced Autophagy through ULK1 Phosphorylation.

Reactive oxygen species (ROS) act as a signaling intermediate to promote cellular adaptation to maintain homeostasis by regulating autophagy during pathophysiological stress. However, the mechanism by which ROS promotes autophagy is still largely unknown. Here, we show that the ATM/CHK2/ULK1 axis initiates autophagy to maintain cellular homeostasis by sensing ROS signaling under metabolic stress. We report that ULK1 is a physiological substrate of CHK2, and that the binding of CHK2 to ULK1 depends on the ROS signal and the phosphorylation of threonine 68 of CHK2 under metabolic stress. Further, CHK2 phosphorylates ULK1 on serine 556, and this phosphorylation is dependent on the ATM/CHK2 signaling pathway. CHK2-mediated phosphorylation of ULK1 promotes autophagic flux and inhibits apoptosis induced by metabolic stress. Taken together, these results demonstrate that the ATM/CHK2/ULK1 axis initiates an autophagic adaptive response by sensing ROS, and it protects cells from metabolic stress-induced cellular damage.

Whole-Cell Display of Phosphotransferase in Escherichia coli for High-Efficiency Extracellular ATP Production.

Adenosine triphosphate (ATP), as a universal energy currency, takes a central role in many biochemical reactions with potential for the synthesis of numerous high-value products. However, the high cost of ATP limits industrial ATP-dependent enzyme-catalyzed reactions. Here, we investigated the effect of cell-surface display of phosphotransferase on ATP regeneration in recombinant Escherichia coli. By N-terminal fusion of the super-folder green fluorescent protein (sfGFP), we successfully displayed the phosphotransferase of Pseudomonas brassicacearum (PAP-Pb) on the surface of E. coli cells. The catalytic activity of sfGFP-PAP-Pb intact cells was 2.12 and 1.47 times higher than that of PAP-Pb intact cells, when the substrate was AMP and ADP, respectively. The conversion of ATP from AMP or ADP were up to 97.5% and 80.1% respectively when catalyzed by the surface-displayed enzyme at 37 °C for only 20 min. The whole-cell catalyst was very stable, and the enzyme activity of the whole cell was maintained above 40% after 40 rounds of recovery. Under this condition, 49.01 mg/mL (96.66 mM) ATP was accumulated for multi-rounds reaction. This ATP regeneration system has the characteristics of low cost, long lifetime, flexible compatibility, and great robustness.

Transplantion of predominant Lactobacilli from native hens to commercial hens could indirectly regulate their ISC activity by improving intestinal microbiota.

In poultry, HyLine (HL) Hens are known for their excellent laying performance. However, ZhenNing (ZN) Hens, a native chicken breed in China, are known for their unique flavour. The intestinal mucosa, which is the main organ for nutrient absorption, could affect livestock product quality. In ZN Hens' intestinal mucosa, we found more villus wrinkles, larger villus circumference and higher amino acid transporters mRNA abundance compared with HL Hens. Among three laying periods of ZN Hens, in the intestinal lumen, Lactobacillus salivarius (L. sa.), Lactobacillus agilis (L. ag.) and Lactobacillus aviarius were the predominant species in the laying peak period. Furthermore, multiple-antibiotics feeding in ZN Hens and predominant Lactobacillus feeding in HL Hens suggested that these Lactobacilli could indeed increase villus wrinkles and improve intestinal absorption. In HL Hens, L. sa. + L. ag. treatment could promote organoids budding in vitro, and promote epithelial proliferation in vivo. Collectively, the unique intestinal mucosa morphology in ZN Hens was due to the high abundance of intestinal L. sa. and L. ag. Transplant these Lactobacilli to HL Hens could increase their intestinal probiotics abundance, fine adjust the intestinal stem cell function and promote the epithelial proliferation, in turn, increase villus winkles and mucosal absorption area.

Co-overexpression of RIOK1 and AKT1 as a prognostic risk factor in glioma.

Glioblastoma multiforme (GBM) is one of the most frequent primary malignancies of the brain. Although the treatment strategy has significantly improved, patient prognosis remains poor. In vitro studies have shown that the right open reading frame kinase 1/protein kinase B (RIOK1-AKT) signaling pathway plays an important role in the malignant phenotype of glioma cells. This study aimed to investigate the co-expression of RIOK1 and ATK in glioma tissues and its clinical significance. Compared with normal tissues, RIOK1 and AKT1 expression were significantly upregulated in glioma tissues. In addition, patients with higher World Health Organization staging grades had increased RIOK1 and AKT1 expression levels, and RIOK1 and AKT1 expression were positively correlated. Notably, both RIOK1 and AKT1 expressions were correlated with poor prognosis. In vitro experiments showed that silencing RIOK1 inhibited the proliferation, migration, and invasion of glioma cell lines by suppressing AKT and c-Myc expression. These results indicate that the RIOK1-AKT1 axis could play an important role in GBM progression.

Bacteria-Mediated Tumor Therapy via Photothermally-Programmed Cytolysin A Expression.

By leveraging the ability of bacteria to express therapeutic protein cytolysin A (ClyA) through plasmid transformation, a thermally-activated biohybrid (TAB@Au) is constructed by biomineralizing gold nanoparticles (AuNPs) on the E. coli surface. Due to the feature of anaerobic bacteria homing to tumor microenvironments, the bacteria-based antitumor vehicles can be efficaciously accumulated at tumor sites. Under NIR laser irradiation, the biomineralized AuNPs harvest transdermal photons and convert them into local heat for photothermal therapy. After that, the produced heat elicits the expression of ClyA for killing tumor cells. In vitro and in vivo experiments verify the conception that the current therapeutic modality greatly inhibits the proliferation of tumor cells. In terms of the spatial specificity and non-invasiveness of NIR laser, the bacteria-based phototherapy represents an appealing way for tumor therapy.

ATM at the crossroads of reactive oxygen species and autophagy.

Reactive oxygen species (ROS) are generally small, short-lived and highly reactive molecules, initially thought to be a pathological role in the cell. A growing amount of evidence in recent years argues for ROS functioning as a signaling intermediate to facilitate cellular adaptation in response to pathophysiological stress through the regulation of autophagy. Autophagy is an essential cellular process that plays a crucial role in recycling cellular components and damaged organelles to eliminate sources of ROS in response to various stress conditions. A large number of studies have shown that DNA damage response (DDR) transducer ataxia-telangiectasia mutated (ATM) protein can also be activated by ROS, and its downstream signaling pathway is involved in autophagy regulation. This review aims at providing novel insight into the regulatory mechanism of ATM activated by ROS and its molecular basis for inducing autophagy, and revealing a new function that ATM can not only maintain genome homeostasis in the nucleus, but also as a ROS sensor trigger autophagy to maintain cellular homeostasis in the cytoplasm.

Paneth cells mediated the response of intestinal stem cells at the early stage of intestinal inflammation in the chicken.

The rapid renewal and repair of the intestinal mucosa are based on intestinal stem cells (ISC), which are located at the crypt bottom. Paneth cells are an essential component in the crypt, which served as the niche for ISC development. However, in the chicken, how the function of Paneth cells changes during intestinal inflammation is unclear and is the key to understand the mechanism of mucosal repair. In the present study, 36 HyLine White chickens (7 d of age, n = 6) were randomly divided into 1 control and 5 lipopolysaccharide (LPS) injection groups. The chickens were injected (i.p.) with PBS in the control group, however, were injected (i.p.) with LPS (10 mg/kg BW) in the LPS injection groups, which would be sampled at 5 time points (1 h postinjection [hpi], 2 hpi, 4 hpi, 6 hpi, and 8 hpi). Results showed that tumor necrosis factor-α mRNA transcription in duodenal tissue increased gradually since 1 hpi, peaked at 4 hpi, and then reduced remarkably, indicating that 4 hpi of LPS was the early stage of intestinal inflammation. Meanwhile, the MUC2 expression in duodenal tissue was dramatically reduced since 1 hpi of LPS. The ISC marker, Lgr5 and Bmi1, in the duodenal crypt were reduced from 1 hpi to 4 hpi and elevated later. Accordingly, the hydroethidine staining showed that the reactive oxygen species level, which drives the differentiation of ISC, in the duodenal crypt reduced obviously at 1 hpi and recovered gradually since 4 hpi. The analysis of Paneth cells showed that many swollen mitochondria appeared in Paneth cells at 4 hpi of LPS. Meanwhile, the Lysozyme transcription in the duodenal crypt was substantially decreased since 1 hpi of LPS. However, the Wnt3a and Dll1 in duodenal crypt decreased at 1 hpi of LPS, then increased gradually. In conclusion, Paneth cells were impaired at the early stage of intestinal inflammation, then recovered rapidly. Thus, the ISC activity was reduced at first and recovery soon.

Hypoxia-autophagy axis induces VEGFA by peritoneal mesothelial cells to promote gastric cancer peritoneal metastasis through an integrin α5-fibronectin pathway.

BACKGROUND: Peritoneal metastasis (PM) is an important pathological process in the progression of gastric cancer (GC). The metastatic potential of tumor and stromal cells is governed by hypoxia, which is a key molecular feature of the tumor microenvironment. Mesothelial cells also participate in this complex and dynamic process. However, the molecular mechanisms underlying the hypoxia-driven mesothelial-tumor interactions that promote peritoneal metastasis of GC remain unclear. METHODS: We determined the hypoxic microenvironment in PM of nude mice by immunohistochemical analysis and screened VEGFA by human growth factor array kit. The crosstalk mediated by VEGFA between peritoneal mesothelial cells (PMCs) and GC cells was determined in GC cells incubated with conditioned medium prepared from hypoxia-treated PMCs. The association between VEGFR1 and integrin α5 and fibronectin in GC cells was enriched using Gene Set Enrichment Analysis and KEGG pathway enrichment analysis. In vitro and xenograft mouse models were used to evaluate the impact of VEGFA/VEGFR1 on gastric cancer peritoneal metastasis. Confocal microscopy and immunoprecipitation were performed to determine the effect of hypoxia-induced autophagy. RESULTS: Here we report that in the PMCs of the hypoxic microenvironment, SIRT1 is degraded via the autophagic lysosomal pathway, leading to increased acetylation of HIF-1α and secretion of VEGFA. Under hypoxic conditions, VEGFA derived from PMCs acts on VEGFR1 of GC cells, resulting in p-ERK/p-JNK pathway activation, increased integrin α5 and fibronectin expression, and promotion of PM. CONCLUSIONS: Our findings have elucidated the mechanisms by which PMCs promote PM in GC in hypoxic environments. This study also provides a theoretical basis for considering autophagic pathways or VEGFA as potential therapeutic targets to treat PM in GC.