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Colorectal cancer has risen to the third occurring cancer in the world. Fluorouracil (5-Fu), oxaliplatin, and cisplatin are the most effective chemotherapeutic agents for clinical chemotherapy. Nevertheless, due to chemotherapeutic drug resistance, the survival rate of patients with CRC remains very low. In this study, we used the inflammation-induced or mutation-family-inherited murine CRC models to study the anticancer and immunotherapy effects of urolithin B (UB), the final metabolite of polyphenols in the gastrointestinal tract. The label-free proteomics analysis and the gene ontology (GO) classifications were used to test and analyze the proteins affected by UB. And 16S rDNA sequencing and flow cytometry were utilized to uncover gut microbiome composition and immune defense improved by UB administration. The results indicated that urolithin B prevents colorectal carcinogenesis by remodeling gut microbial and tumor immune microenvironments, such as HLA-B, NK cells, regulatory T cells, and γδ TCR cells, and decreasing the PD-L1. The combination of urolithin B with first-line therapeutic drugs improved the colorectal intestinal hematochezia by shaping gut microbiota, providing a strategy for the treatment of immunotherapy treatment for CRC treatments. UB combined with anti-PD-1 antibody could inhibit the growth of colon cancer. Urolithin B may thus contribute to anticancer treatments and provide a high immune response microenvironment for CRC patients’ further immunotherapy.

Because it is traditionally difficult and time-consuming to identify the foramen ovale (FO) with fluoroscopy, we recently developed the H-figure method to acquire fluoroscopic view of FO with shorter procedure time and less radiation. However, the impact of such an H-figure approach on the clinical outcomes of trigeminal ganglion radiofrequency thermocoagulation (RFT) in treating idiopathic trigeminal neuralgia (ITN) remains unclear. In a 12-month follow-up retrospective cohort study, patients with ITN had fluoroscopy-guided RFT of trigeminal ganglion via either classic approach (n = 100) or H-figure approach (n = 136) to identify FO. Data of continuous variables were analyzed with a Shapiro-Wilk test for normality and subsequently with a Mann-Whitney test, and the binary data were analyzed with a χ2 test. The primary outcome was the facial pain measured by a Visual Analog Scale (VAS) 1 year after the treatment. The secondary outcomes included the quality of the fluoroscopic FO views, the threshold voltage to provoke paresthesia, the procedure time, the number of fluoroscopic images, and the facial numbness VAS. Compared with the classic approach group, the H-figure approach group was associated with better long-term pain relief after the procedure, with significantly fewer patients had pain 3 months (6.6% vs 17.0%, P = .012) and 12 months (21.3% vs 38.0%, P = .005) after the procedure, and among patients who had pain after the procedure, patients in the H-figure group had significantly less pain 6 months after the procedure (VAS median [interquartile range (IQR)]: 3 [2-6] vs 6 [4-7], P < .001). Moreover, compared to the classic approach, the H-figure approach provided better fluoroscopic view of FO, lower threshold voltage to elicit paresthesia (median [IQR]: 0.2 [0.2-0.3] vs 0.4 [0.4-0.5] V, P < .0001), with shorter procedure time (median [IQR]: 7.5 [6.0-9.0] vs 14.0 [10.0-18.0] min, P < .0001), and required fewer fluoroscopic images (median [IQR]: 4.0 [3.0-5.0] vs 8.0 [6.0-10.0], P < .0001). RFT of the trigeminal ganglion using the H-figure approach is associated with superior longer term clinical pain relief than the classic approach in treating ITN.

The question of whether narcissists are more creative than peers has attracted much scholarly attention in both psychology and organizational management sciences. Drawing from social cognitive theory, we theorized that the relationship between narcissism and creativity could be explained by individual creative self-efficacy, which depends on one's direct and vicarious experiences of creativity. Drawing from trait activation theory, we further proposed organizational valuing of creativity as a key contextual moderator that determines whether narcissism facilitates or inhibits creative self-efficacy and, in turn, creativity. We suggest that high organizational valuing of creativity will energize narcissists to put their attention and effort into both direct and vicarious experiences of creativity, enhancing their creative self-efficacy and creativity. We tested our conceptual model through a field study with data collected from 269 full-time employees working in 86 work teams. The empirical results provided support for the social cognitive explanation for the positive relationship between narcissism and creativity in the context of high organizational valuing of creativity. Our study not only resolved prior debates on the relationship between narcissism and creativity but also provided direct empirical support for social cognitive theory and the person-in-context interactionist perspective of creativity research.

Alcohol-associated liver disease (ALD) is a worldwide health problem, of which the effective treatment is still lacking. Both detrimental and protective roles of adipose tissue have been implicated in ALD. Although alcohol increases adipose tissue lipolysis to promote alcohol-induced liver injury, alcohol also activates brown adipose tissue (BAT) thermogenesis as an adaptive response in protecting against alcohol-induced liver injury. Moreover, aging and obesity are also risk factors for ALD. In the present study, we investigated the effects of autophagy receptor protein SQSTM1/p62 on adipose tissue and obesity in alcohol-induced liver injury in both young and aged mice.Young and aged whole-body SQSTM1/p62 knockout (KO) and their age-matched wild-type (WT) mice were subjected to chronic plus binge (Gao-binge) alcohol feeding. Blood, adipose and liver tissues were collected for biochemical and histologic analysis.Aged but not young SQSTM1/p62 KO mice had significantly increased body weight and fat mass compared with the matched WT mice. Gao-binge alcohol feeding induced white adipose atrophy and decreased levels of SQSTM1/p62 levels in adipose tissue in aged WT mice. SQSTM1/p62 KO aged mice were resistant to Gao-binge alcohol-induced white adipose atrophy. Alcohol feeding increased the expression of thermogenic genes in WT mouse BAT, which was significantly blunted in SQSTM1/p62 KO aged mice. Alcohol-fed aged SQSTM1/p62 KO mice showed significantly higher levels of serum alanine aminotransferase, hepatic triglyceride, and inflammation compared with young and aged WT mice fed with alcohol. Alcohol-fed SQSTM1/p62 KO mice also increased secretion of proinflammatory and angiogenic adipokines that may promote alcohol-induced liver injury.Loss of SQSTM1/p62 in aged mice leads to obesity and impairs alcohol-induced BAT adaptation, resulting in exacerbated alcohol-induced liver injury in mice.

Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase and a cellular sensor for nutrient and energy status, which is critical in regulating cell metabolism and growth by governing the anabolic (protein and lipid synthesis) and catabolic process (autophagy). Alcohol-associated liver disease (ALD) is a major chronic liver disease worldwide that carries a huge financial burden. The spectrum of the pathogenesis of ALD includes steatosis, fibrosis, inflammation, ductular reaction, and eventual hepatocellular carcinoma, which is closely associated with metabolic changes that are regulated by mTOR. In this review, we summarized recent progress of alcohol consumption on the changes of mTORC1 and mTORC2 activity, the potential mechanisms and possible impact of the mTORC1 changes on autophagy in ALD. We also discussed the potential beneficial effects and limitations of targeting mTORC1 against ALD.

Vacuole membrane protein 1 (VMP1) is an endoplasmic reticulum (ER) transmembrane protein that regulates the formation of autophagosomes and lipid droplets. Recent evidence suggests that VMP1 plays a critical role in lipoprotein secretion in zebra fish and cultured cells. However, the pathophysiological roles and mechanisms by which VMP1 regulates lipoprotein secretion and lipid accumulation in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are unknown.Liver-specific and hepatocyte-specific Vmp1 knockout mice as well as Vmp1 knock-in mice were generated by crossing Vmp1Hepatocyte-specific deletion of Vmp1 severely impaired VLDL secretion resulting in massive hepatic steatosis, hepatocyte death, inflammation and fibrosis, which are hallmarks of NASH. Mechanistically, loss of Vmp1 led to decreased hepatic levels of phosphatidylcholine and phosphatidylethanolamine as well as to changes in phospholipid composition. Deletion of Vmp1 in mouse liver also led to the accumulation of neutral lipids in the ER bilayer and impaired mitochondrial beta-oxidation. Overexpression of VMP1 ameliorated steatosis in diet-induced NASH by improving VLDL secretion. Importantly, we also showed that decreased liver VMP1 is associated with NAFLD/NASH in humans.Our results provide novel insights on the role of VMP1 in regulating hepatic phospholipid synthesis and lipoprotein secretion in the pathogenesis of NAFLD/NASH.Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis, are associated with a build-up of fat in the liver (steatosis). However, the exact mechanisms that underly steatosis in patients are not completely understood. Herein, the authors identified that the lack of a protein called VMP1 impairs the secretion and metabolism of fats in the liver and could therefore contribute to the development and progression of non-alcoholic fatty liver disease.

The outbreak of coronavirus disease 2019 (COVID-19) has affected more than 200 countries and regions to date. mRNA m6A methylation has been reported as a new therapeutic target in COVID-19 patients, and has received widespread attention. However, the effects of m6A on COVID-19 clinical features as well as the molecular characterization of m6A in real COVID-19 patients are largely unclear. We collected RNA-seq data and clinical data from 100 COVID-19 patients, and sequenced m6A-seq from peripheral blood mononuclear cells (PBMCs) of two COVID-19 patients. Using bioinformatics analysis, we found that m6A is associated with several clinical features of COVID-19 patients. Furthermore, molecular characterization of m6A of COVID-19 patients in vivo rather than cell lines is demonstrated for the first time. Our findings will be valuable for the development of novel treatment strategies for COVID-19 patients.

This paper addresses the event-triggered tracking control and filtering problem for Takagi-Sugeno fuzzy-approximation-based discrete-time nonlinear networked systems subject to the effect of denial-of-service attacks. First, the unreliability of the communication channel between the sensor and the actuator/filter is considered, and the packet loss caused by denial-of-service attacks is characterized by the binary Markov chain. Second, two novel resilient adaptive event-triggered mechanisms are proposed to resist the impact of denial-of-service attacks and discard unnecessary data packets, in which the dynamic threshold variable is designed to adjust the event-triggered condition adaptively. A problem caused by the event-triggered mechanism is that the controller or filter cannot receive the system mode signal during the trigger interval. To surmount this problem, this paper designs an estimator to compensate for unavailable system mode. Then, an adaptive event-triggered controller or filter related to the estimated mode is designed to track the desired signal. Under this framework, by constructing a membership-function-dependent Lyapunov function, the conservativeness of the stability criterion is relaxed. Finally, two examples are used to validate the applicability of the proposed approaches.

Background The study aims to investigate the clinical characteristics of early postnatal period in children with prenatal hydronephrosis (HN) in our single center for 8 years. Study design The clinical data of 1137 children with prenatal HN from 2012 to 2020 were retrospectively analyzed in our center. Variables of our study mainly included different malformations and urinary tract dilation (UTD) classification, and main outcomes were recurrent hospitalization, urinary tract infection (UTI), jaundice, and surgery. Results Among the 1137 children with prenatal HN in our center, 188 cases (16.5%) were followed-up in early postnatal period, and 110 cases (58.5%) were found malformations. The incidence of recurrent hospitalization (29.8%) and UTI (72.5%) were higher in malformation, but the incidence of jaundice (46.2%) was higher in non-malformation(P P P P Conclusion Children with prenatal HN have been found many malformations in early postnatal period, and with high-grade UTD were more prone to recurrent UTI, even to surgery. So, prenatal HN with malformations and high-grade UTD should be followed up in early postnatal period regularly.

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of preterm infants characterized by intestinal inflammation and intestinal epithelial cells (IEC) death. Evidence suggests that scattered crypt IEC apoptosis is a critical pathogenic event that subsequently leads to excessive villus necrosis in human NEC and rodent pups with experimental NEC. Necroptosis, programmed necrosis, is a proinflammatory cell death process that has been linked to several intestinal diseases. However, the critical role of necroptosis and its upstream pathways in the pathogenesis of NEC remains largely unexplored. Here, we aimed to study the linkage between scattered crypt IEC apoptosis and necroptosis during NEC development using a mouse genetic engineering approach. First, a unique triple-transgenic mouse model, 3xTg-iEAP (inducible Enterocyte specific Apoptosis Phenotype), was developed to induce IECs-specific over-expression of FasL using LoxP-Villin-Cre-mediated recombination strategy in combination with the rtTA-based regulatory system. Second, we created 3xTg-iEAPIfng-/- and 3xTg-iEAPRip3-/- mice by breeding 3xTg-iEAP with either Ifnγ knockout (KO) mice or Rip3 KO mice. The three days old neonatal pups of 3xTg-iEAP, 3xTg-iEAPIfng-/-, 3xTg-iEAPRip3-/- and littermate controls were challenged with a single dose doxycycline (Dox; 20 μg/gm, subcutaneously). Their growth was monitored on daily basis. The intestinal tissue samples were collected at different time points (8 h, 24 h, 48 h, and 72 h) and subjected to histological and qRT-PCR analysis. We confirmed that 3xTg-iEAP, 3xTg-iEAPIfng-/-, and 3xTg-iEAPRip3-/- mice developed normal, viable, and fertile, and indistinguishable from littermate controls without exposure to Dox. Treatment with Dox resulted in scattered IEC apoptosis in crypts of 3xTg-iEAP, 3xTg-iEAPIfng-/-, and 3xTg-iEAPRip3-/- mice within 8 h. Compared to littermate controls, we observed NEC-like damage with profound intestinal villus epithelial necrosis at 48 h after Dox treatment in 3xTg-iEAP mice that mimics histological features of human NEC. qRT-PCR analysis showed that the development of villus necrosis was associated with the increased expression of pro-inflammatory mediator genes and necroptosis-associated genes including Ifnγ and Rip3 in 3xTg-iEAP mice during the phase of NEC development. Interestingly, compared to 3xTg-iEAP mice, 3xTg-iEAPIfng-/- and 3xTg-iEAPRip3-/- mice displayed a lack of NEC-like incidence at 48h after Dox treatment, suggesting the crucial role of IFN-γ and RIP3 in scattered IEC apoptosis-induced NEC in our model. Taken together, the inhibition of necroptosis in IECs prevents intestinal injury during NEC. Our findings may advance knowledge in preventing or treating this devastating disorder in humans. Grants from NIH and the U.S. Department of Veterans Affairs support this work. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A Gram-stain-negative, facultative anaerobic, motile, rod-shaped and orange bacterium, designated A06T, was obtained off the coast of Weihai, PR China. Cells were 0.4–0.5×0.6–1.0 µm in size. Strain A06T grew at 20–40 °C (optimum, 33 °C), at pH 6.0–8.0 (optimum, pH 6.5–7.0) and in the presence of 0–8 % NaCl (w/v) (optimum, 2 %). Cells were oxidase and catalase positive. Menaquinone-7 was detected as the major respiratory quinone. The dominant cellular fatty acids were identified as C15:0 2-OH, iso-C15:0, anteiso-C15:0 and iso-C15:1 ω6c. The DNA G+C content of strain A06T was 46.1 mol%. The polar lipids were phosphatidylethanolamine, one aminolipid, one glycolipid and three unidentified lipids. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain A06T is a member of the family Prolixibacteraceae and exhibited the highest sequence similarity to Mangrovibacterium diazotrophicum DSM 27148T (94.3 %). Based on its phylogenetic and phenotypic characteristics, strain A06T is considered to represent a novel genus in the family Prolixibacteraceae , for which the name Gaoshiqia gen. nov. is proposed. The type species is Gaoshiqia sediminis sp. nov., with type strain A06T (=KCTC 92029T=MCCC 1H00491T). The identification and acquisition of microbial species and genes in sediments will help broaden the understanding of microbial resources and lay a foundation for its application in biotechnology. Strain A06T uses an enrichment method, so the isolation of strain A06T is of great significance to the enrichment of marine microbial resources.

The real structure and in situ evolution of catalysts under working conditions are of paramount importance, especially for bifunctional electrocatalysis. Here, we report asymmetric structural evolution and dynamic hydrogen-bonding promotion mechanism of an atomically dispersed electrocatalyst. Pyrolysis of Co/Ni-doped MAF-4/ZIF-8 yielded nitrogen-doped porous carbons functionalized by atomically dispersed Co–Ni dual-metal sites with an unprecedented N8V4 structure, which can serve as an efficient bifunctional electrocatalyst for overall water splitting. More importantly, the electrocatalyst showed remarkable activation behavior due to the in situ oxidation of the carbon substrate to form C–OH groups. Density functional theory calculations suggested that the flexible C–OH groups can form reversible hydrogen bonds with the oxygen evolution reaction intermediates, giving a bridge between elementary reactions to break the conventional scaling relationship.

Alcohol is a well-known risk factor for hepatocellular carcinoma. Autophagy plays a dual role in liver cancer, as it suppresses tumor initiation and promotes tumor progression. Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy, which is impaired in alcohol-related liver disease. However, the role of TFEB in alcohol-associated liver carcinogenesis is unknown. Liver-specific Tfeb knockout (KO) mice and their matched wild-type (WT) littermates were injected with the carcinogen diethylnitrosamine (DEN), followed by chronic ethanol feeding. We found that the numbers of both total and larger tumors increased significantly in DEN-treated mice fed with ethanol diet than in mice fed with control diet. Although the number of tumors was not different between WT and L-Tfeb KO mice fed either control or ethanol diet, the number of larger tumors was less in L-Tfeb KO mice than in WT mice. To our surprise, no differences were found in liver injury, steatosis, inflammation, ductular reaction, fibrosis, and tumor cell proliferation in DEN-treated mice fed ethanol. However, the levels of glypican 3, a marker of malignant hepatocellular carcinoma, markedly decreased in DEN-treated L-Tfeb KO mice fed ethanol in comparison to the WT mice. Our findings indicate that chronic ethanol feeding promotes DEN-initiated liver tumor development, which tends to be attenuated by genetic deletion of hepatic TFEB.

BACKGROUND AND AIMS: Increased megamitochondria formation and impaired mitophagy in hepatocytes have been linked to the pathogenesis of alcohol-associated liver disease (ALD). This study aims to determine the mechanisms by which alcohol consumption increases megamitochondria formation in the pathogenesis of ALD. APPROACH AND RESULTS: Human alcoholic hepatitis (AH) liver samples were used for electron microscopy, histology, and biochemical analysis. Liver-specific dynamin-related protein 1 (DRP1; gene name DNM1L, an essential gene regulating mitochondria fission) knockout (L-DRP1 KO) mice and wild-type mice were subjected to chronic plus binge alcohol feeding. Both human AH and alcohol-fed mice had decreased hepatic DRP1 with increased accumulation of hepatic megamitochondria. Mechanistic studies revealed that alcohol feeding decreased DRP1 by impairing transcription factor EB–mediated induction of DNM1L. L-DRP1 KO mice had increased megamitochondria and decreased mitophagy with increased liver injury and inflammation, which were further exacerbated by alcohol feeding. Seahorse flux and unbiased metabolomics analysis showed alcohol intake increased mitochondria oxygen consumption and hepatic nicotinamide adenine dinucleotide (NAD(+)), acylcarnitine, and ketone levels, which were attenuated in L-DRP1 KO mice, suggesting that loss of hepatic DRP1 leads to maladaptation to alcohol-induced metabolic stress. RNA-sequencing and real-time quantitative PCR analysis revealed increased gene expression of the cGAS–stimulator of interferon genes (STING)–interferon pathway in L-DRP1 KO mice regardless of alcohol feeding. Alcohol-fed L-DRP1 KO mice had increased cytosolic mtDNA and mitochondrial dysfunction leading to increased activation of cGAS-STING-interferon signaling pathways and liver injury. CONCLUSION: Alcohol consumption decreases hepatic DRP1 resulting in increased megamitochondria and mitochondrial maladaptation that promotes AH by mitochondria-mediated inflammation and cell injury.

Three infectious clones of radish mosaic virus (RaMV) were generated from isolates collected in mainland Korea (RaMV-Gg) and Jeju Island (RaMV-Aa and RaMV-Bb). These isolates differed in sequences and pathogenicity. Examination of the wild-type isolates and reassortants between the genomic RNA1 and RNA2 of these three isolates revealed that severe symptoms were associated with RNA1 of isolates Aa or Gg causing systemic necrosis in Nicotiana benthamiana, or with RNA1 of isolate Bb for induction of veinal necrosis and severe mosaic symptoms in radish. Reverse transcription, followed by quantitative real-time PCR (Q-RT-PCR), results from infected N. benthamiana confirmed that viral RNA2 accumulation level was correlated to RaMV necrosis-inducing ability, and that the RNA2 accumulation level was mostly dependent on the origin of RNA1. However, in radish, Q-RT-PCR results showed more similar viral RNA2 accumulation levels regardless of the ability of the isolate to induce necrosis. Phylogenetic analysis of genomic RNAs sequence including previously characterized isolates from North America, Europe, and Asia suggest possible recombination within RNA1, while analysis of concatenated RNA1+RNA2 sequences indicates that reassortment of RNA1 and RNA2 has been more important in the evolution of RaMV isolates than recombination. Korean isolate Aa is a potential reassortant between isolates RaMV-J and RaMV-TW, while isolate Bb might have evolved from reassortment between isolates RaMV-CA and RaMV-J. The Korean isolates were shown to also be able to infect Chinese cabbage, raising concerns that RaMV may spread from radish fields to the Chinese cabbage crop in Korea, causing further economic losses.

Receptor-interacting protein kinase 3 (Ripk3) is one of the critical mediators of inflammatory cytokine-stimulated signaling. Here we show that Ripk3 signaling selectively regulates both the number and the function of hematopoietic stem cells (HSCs) during stress conditions. Ripk3 signaling is not required for normal homeostatic hematopoiesis. However, in response to serial transplantation, inactivation of Ripk3 signaling prevents stress-induced HSC exhaustion and functional HSC attenuation, while in response to fractionated low doses of ionizing radiation (IR), inactivation of Ripk3 signaling accelerates leukemia/lymphoma development. In both situations, Ripk3 signaling is primarily stimulated by tumor necrosis factor-α. Activated Ripk3 signaling promotes the elimination of HSCs during serial transplantation and pre-leukemia stem cells (pre-LSCs) during fractionated IR by inducing Mlkl-dependent necroptosis. Activated Ripk3 signaling also attenuates HSC functioning and represses a pre-LSC-to-LSC transformation by promoting Mlkl-independent senescence. Furthermore, we demonstrate that Ripk3 signaling induces senescence in HSCs and pre-LSCs by attenuating ISR-mediated mitochondrial quality control.

Generating reference maps of interactome networks illuminates genetic studies by providing a protein-centric approach to finding new components of existing pathways, complexes, and processes. We apply state-of-the-art methods to identify binary protein-protein interactions (PPIs) for Drosophila melanogaster. Four all-by-all yeast two-hybrid (Y2H) screens of > 10,000 Drosophila proteins result in the ‘FlyBi’ dataset of 8723 PPIs among 2939 proteins. Testing subsets of data from FlyBi and previous PPI studies using an orthogonal assay allows for normalization of data quality; subsequent integration of FlyBi and previous data results in an expanded binary Drosophila reference interaction network, DroRI, comprising 17,232 interactions among 6511 proteins. We use FlyBi data to generate an autophagy network, then validate in vivo using autophagy-related assays. The deformed wings (dwg) gene encodes a protein that is both a regulator and a target of autophagy. Altogether, these resources provide a foundation for building new hypotheses regarding protein networks and function.

Sulfate-reducing bacteria (SRB) are essential functional microbial taxa for degrading organic matter (OM) in anoxic marine environments. However, there are little experimental data regarding how SRB regulates microbial communities. Here, we applied a top-down microbial community management approach by inhibiting SRB to elucidate their contributions to the microbial community during OM degradation. Based on the highly replicated microcosms (n = 20) of five different incubation stages, we found that many microbial community properties were influenced after inhibiting SRB, including the composition, structure, network, and community assembly processes. We also found a strong coexistence pattern between SRB and other abundant phylogenetic lineages via positive frequency-dependent selection. The relative abundances of the families Synergistaceae, Peptostreptococcaceae, Dethiosulfatibacteraceae, Prolixibacteraceae, Marinilabiliaceae, and Marinifilaceae were simultaneously suppressed after inhibiting SRB during OM degradation. A close association between SRB and the order Marinilabiliales among coexisting taxa was most prominent. They contributed to preserved modules during network successions, were keystone nodes mediating the networked community, and contributed to homogeneous ecological selection. The molybdate tolerance test of the isolated strains of Marinilabiliales showed that inhibited SRB (not the inhibitor of SRB itself) triggered a decrease in the relative abundance of Marinilabiliales. We also found that inhibiting SRB resulted in reduced pH, which is unsuitable for the growth of most Marinilabiliales strains, while the addition of pH buffer (HEPES) in SRB-inhibited treatment microcosms restored the pH and the relative abundances of these bacteria. These data supported that SRB could modify niches to affect species coexistence. IMPORTANCE Our model offers insight into the ecological properties of SRB and identifies a previously undocumented dimension of OM degradation. This targeted inhibition approach could provide a novel framework for illustrating how functional microbial taxa associate the composition and structure of the microbial community, molecular ecological network, and community assembly processes. These findings emphasize the importance of SRB during OM degradation. Our results proved the feasibility of the proposed study framework, inhibiting functional taxa at the community level, for illustrating when and to what extent functional taxa can contribute to ecosystem services.

bFGF treatment increases autophagy regulated secreted factors

Supplementary Figures from Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy

Includes legends for all supplementary figures. S1: CAFs exhibit increased LC3 puncta per cell compared to NF. S2: CAF autophagy inhibition significantly decreases HNSCC in vitro progression. S3: IL-6 and IL-8 induce fibroblast autophagy. S4: bFGF treatment increases autophagy regulated secreted factors. S5: Autophagy inhibition reduces HNSCC in combination therapy, and does not affect CAF proliferation.

Autophagy inhibition reduces HNSCC in combination therapy, and does not affect CAF proliferation

Examples of Electron Microscopy Autophagosomes

The proteasome and the autophagy systems are two evolutionarily conserved mechanisms for degrading intracellular materials. They are functionally coupled and suppression of the proteasome promotes autophagy. Although suppression of the proteasome leads to cell death, suppression of autophagy can be either prodeath or prosurvival. To understand the underlining mechanism of this dichotomy and its potential clinical implications, we treated various transformed and nontransformed human cells with proteasome inhibitors. We found that whether autophagy served a prosurvival role in this scenario was contingent on the cellular oncogenic status. Thus, autophagy suppression enhanced apoptosis induced by proteasome inhibitors in transformed cells, but not in nontransformed cells. Oncogenic transformation enhanced the ability of cells to initiate autophagy in response to stress, reflecting a stronger dependence of transformed cells on autophagy for survival. Indeed, a combined use of bortezomib, the only Food and Drug Administration–approved proteasome inhibitor for clinical use, and chloroquine, which inhibits autophagy by disturbing lysosomal functions, suppressed tumor growth more significantly than either agent alone in a xenograft model. These findings indicate that suppression of both intracellular degradation systems could constitute a novel strategy for enhanced cancer control in a tumor-specific way. [Mol Cancer Ther 2009;8(7):2036–45]

Supplementary Fig. from A coordinated action of Bax, PUMA, and p53 promotes MG132-induced mitochondria activation and apoptosis in colon cancer cells

Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs, where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL6, IL8, and other cytokines were modulated by autophagy. Notably, when HNSCC cells were cocultured with normal fibroblasts, they upregulated autophagy through IL6, IL8, and basic fibroblast growth factor. In a mouse xenograft model of HNSCC, pharmacologic inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression. Cancer Res; 77(23); 6679–91. ©2017 AACR.

CAFs exhibit increased LC3 puncta per cell compared to NF.

IL-6 and IL-8 induce fibroblast autophagy

Targeting the ubiquitin-proteasome degradation pathway has become a promising approach for cancer therapy. Previous studies have shown that proteasome inhibition leads to apoptosis in various cancer cells. The mechanism by which apoptosis occurs are not fully understood and can be cell type and/or inhibitor specific. In this study, we investigated the mechanism of mitochondrial activation by proteasome inhibitors in colon cancer cells. We found that Bax activation and mitochondria translocation were required for apoptosis induced by multiple proteasome inhibitors. In contrast, reactive oxygen species did not seem to be induced by MG132 or bortezomib and antioxidants had no effects on MG132-induced apoptosis. In contrast, treatment with MG132 or bortezomib induced a significant accumulation of p53 and PUMA. Genetic deletion of either p53 or PUMA led to a marked suppression of apoptosis induced by these inhibitors, accompanied with reduced Bax activation and cytochrome c release. Consistently, inhibition of translation by cycloheximide could also effectively abolish the accumulation of p53 and PUMA and suppress MG132-induced Bax activation and apoptosis. These findings thus strongly indicate the critical involvement of p53-, PUMA-, and Bax-mediated mitochondrial activation in proteasome inhibitor–induced apoptosis in colon cancer cells. [Mol Cancer Ther 2007;6(3):1062–9]

CAF autophagy inhibition significantly decreases HNSCC in vitro progression.