Disturbed intracellular folate homeostasis impairs autophagic flux and increases hepatocytic lipid accumulation.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD), a prevalent liver disorder affecting one-third of the global population, encompasses a spectrum ranging from fatty liver to severe hepatic steatosis. Both genetic and lifestyle factors, particularly diet and nutrition, contribute to its etiology. Folate deficiency, a frequently encountered type of malnutrition, has been associated with the pathogenesis of MAFLD and shown to impact lipid deposition. However, the underlying mechanisms of this relationship remain incompletely understood. We investigated the impact of disturbed folate-mediated one-carbon metabolism (OCM) on hepatic lipid metabolism both in vitro using human hepatoma cells and in vivo using transgenic fluorescent zebrafish displaying extent-, stage-, and duration-controllable folate deficiency upon induction. RESULTS: Disturbed folate-mediated one-carbon metabolism, either by inducing folate deficiency or adding anti-folate drug, compromises autophagy and causes lipid accumulation in liver cells. Disturbed folate status down-regulates cathepsin L, a key enzyme involved in autophagy, through inhibiting mTOR signaling. Interfered mitochondrial biology, including mitochondria relocation and increased fusion-fission dynamics, also occurs in folate-deficient hepatocytes. Folate supplementation effectively mitigated the impaired autophagy and lipid accumulation caused by the inhibition of cathepsin L activity, even when the inhibition was not directly related to folate deficiency. CONCLUSIONS: Disruption of folate-mediated OCM diminishes cathepsin L expression and impedes autophagy via mTOR signaling, leading to lipid accumulation within hepatocytes. These findings underscore the crucial role of folate in modulating autophagic processes and regulating lipid metabolism in the liver.

Multichannel room response equalization with a broadened control region using a linearly constrained approach and sensor interpolation.

This paper describes a room response equalization technique based on an underdetermined multichannel inverse filtering (UMIF) and linearly constrained minimum variance (LCMV) approach. Not limited to the local control at the neighborhood of the measured control points, the proposed UMIF-LCMV system is capable of widening the effective equalization area of the reproduced sound field, with a large number of interpolated control points. Specifically, a constrained optimization problem is formulated to minimize the matching error at the interpolated control points while seeking precise matching at the measured control points. In practical implementation, only the frequency responses (FRs) associated with a limited number of control points need to be measured, whereas the FRs for the interpolated points are established by using a plane wave decomposition-based sensor interpolation technique. A two-stage procedure is developed to trim down plane wave components by using the least absolute shrinkage and selection operator (LASSO) algorithm and to obtain the complex amplitudes of the principal components. Simulations and objective and subjective experiments are conducted for a system comprising a linear loudspeaker array and a linear microphone array. The results have confirmed the efficacy of the proposed system in widening the effective listening area with only limited discrete measurements.

Inhibition of Ribosomal RNA Processing 15 Homolog (RRP15) Suppressed Tumor Growth, Invasion and Epithelial to Mesenchymal Transition (EMT) of Colon Cancer.

Although ribosomal RNA processing 15 Homolog (RRP15) has been implicated in the occurrence of various cancers and is considered a potential target for cancer treatment, its significance in colon cancer (CC) is unclear. Thus, this present study aims to determine RRP15 expression and biological function in CC. The results demonstrated a strong expression of RRP15 in CC compared to normal colon specimens, which was correlated with poorer overall survival (OS) and disease-free survival (DFS) of the patients. Among the nine investigated CC cell lines, RRP15 demonstrated the highest and lowest expression in HCT15 and HCT116 cells, respectively. In vitro assays demonstrated that the knockdown of RRP15 inhibited the growth, colony-forming ability and invasive ability of the CC cells whereas its overexpression enhanced the above oncogenic function. Moreover, subcutaneous tumors in nude mice showed that RRP15 knockdown inhibited the CC growth while its overexpression enhanced their growth. Additionally, the knockdown of RRP15 inhibited the epithelial-mesenchymal transition (EMT), whereas overexpression of RRP15 promoted the EMT process in CC. Collectively, inhibition of RRP15 suppressed tumor growth, invasion and EMT of CC, and might be considered a promising therapeutic target for treating CC.

Accessory Climbing Routes Associated With More Rescue Operations Than the Main Climbing Route: A Retrospective 12-Year Report of Yushan National Park.

INTRODUCTION: This study compared the casualties and types of rescues conducted on the main climbing route (MCR) and accessory climbing routes (ACRs) in Yushan National Park (YSNP) between 2008 and 2019. METHODS: We collected the following information for all documented mountain rescue operations conducted on the MCRs and ACRs in YSNP between 2008 and 2019: accident location, casualty type, victim number, and type of rescue. The victims were categorized as to injury, illness, mortality, or no medical problem (NMP) groups according to their condition at the time of rescue. RESULTS: Two-hundred forty-four rescue operations involving 329 victims were conducted during the 12-y study period. Among them, 105 (32%) did not require medical treatment, 102 (31%) were injured, 82 (25%) were ill, and 40 (12%) were deceased. Of the 82 individuals with illness, 69 (84%) had acute altitude sickness. The accident and mortality rates on the ACRs were significantly higher than those on the MCR (P<0.001; χ2). The ACR incidents involved significantly higher percentages of helicopter-based rescues and victims in the NMP group (P<0.001). CONCLUSIONS: Acute altitude sickness accounted for most of the rescues. ACRs had higher injury and mortality rates and required more helicopter-based rescues for patients who did not have medical problems. This study may serve as a reference to reduce casualties and overuse of helicopters by educating tourists on the appropriate use of maps and the evaluation of trails in relation to weather conditions.

Differential proteomics reveals main determinants for the improved pectinase activity in UV-mutagenized Aspergillus niger strain.

OBJECTIVES: To reveal the potential mechanism and key determinants that contributed to the improved pectinase activity in Aspergillus niger mutant EIMU2, which was previously obtained by UV-mutagenesis from the wild-type A. niger EIM-6. RESULTS: Proteomic analysis for Aspergillus niger EIMU2 by two-dimensional electrophoresis demonstrated that mutant EIMU2 harbored a multiple enzyme system for the degradation of pectin, mainly constituting by main-chain-cleaving enzymes polygalacturonase, pectate lyase, pectinesterase, and some accessory enzymes rhamnogalacturonan lyase and arabinofuranosidase. Further quantitatively differential proteomic analysis revealed that the quantities of four proteins, pectinesterase, rhamnogalacturonan lyase A, DNA-directed RNA polymerase A, and a hypothetical protein in strain EIMU2 were much higher than those in EIM-6. PCR amplification, sequencing and alignment analysis of genes for the two main members of pectin-degrading enzymes, pectate lyase and polygalacturonase showed that their sequences were completely consistent in A. niger EIM-6 and mutant EIMU2. CONCLUSIONS: The result demonstrated that the improved pectinase activity by UV-mutagenesis in A. niger EIMU2 was probably contributed to the up-regulated expression of rhamnogalacturonan lyase, or pectinesterase, which resulted in the optimization of synergy amongst different components of pectin-degrading enzymes.

Electrically Pumped White-Light-Emitting Diodes Based on Histidine-Doped MoS2 Quantum Dots.

MoS2 quantum dots (QDs)-based white-light-emitting diodes (QD-WLEDs) are designed, fabricated, and demonstrated. The highly luminescent, histidine-doped MoS2 QDs synthesized by microwave induced fragmentation of 2D MoS2 nanoflakes possess a wide distribution of available electronic states as inferred from the pronounced excitation-wavelength-dependent emission properties. Notably, the histidine-doped MoS2 QDs show a very strong emission intensity, which exceeds seven times of magnitude larger than that of pristine MoS2 QDs. The strongly enhanced emission is mainly attributed to nitrogen acceptor bound excitons and passivation of defects by histidine-doping, which can enhance the radiative recombination drastically. The enabled electroluminescence (EL) spectra of the QD-WLEDs with the main peak around 500 nm are found to be consistent with the photoluminescence spectra of the histidine-doped MoS2 QDs. The enhanced intensity of EL spectra with the current increase shows the stability of histidine-doped MoS2 based QD-WLEDs. The typical EL spectrum of the novel QD-WLEDs has a Commission Internationale de l'Eclairage chromaticity coordinate of (0.30, 0.36) exhibiting an intrinsic broadband white-light emission. The unprecedented and low-toxicity QD-WLEDs based on a single light-emitting material can serve as an excellent alternative for using transition metal dichalcogenides QDs as next generation optoelectronic devices.

Monocytic thrombomodulin promotes cell adhesion through interacting with its ligand, Lewisy.

The leukocyte adhesion cascade involves multiple events that efficiently localize circulating leukocytes into the injured sites to mediate inflammatory responses. From rolling to firm adhesion, the interactions between adhesion molecules have pivotal roles in increasing the avidity of leukocytes to endothelial cells. Thrombomodulin (TM), an essential anticoagulant protein in the vasculature, is also expressed on leukocytes. We previously demonstrated that Lewisy (Ley), a specific ligand of TM, is upregulated in inflamed endothelium and is involved in leukocyte adhesion. The current study aimed to investigate whether leukocyte-expressed TM promotes cell adhesion by interacting with Ley. Using human monocytic THP-1 cells as an in vitro cell model, we showed that TM increases THP-1 cell adhesion to inflamed endothelium as well as to Ley-immobilized surface. When THP-1 adhered to activated endothelium and Ley-immobilized surface, the TM distribution became polarized. Addition of soluble Ley to a suspension of THP-1 cells with TM expression triggered an increase in the level of phosphorylated p38 mitogen-activated protein kinase (MAPK), which enabled THP-1 to adhere firmly to intercellular adhesion molecule (ICAM)-1 by activating ß2 integrins. In vivo, macrophage infiltration and neointima formation following arterial ligation-induced vascular injury were higher in wild-type TM (TMflox/flox) than in myeloid-specific TM-deficient (LysMcre/TMflox/flox) mice. Taken together, these results suggest a novel function for TM as an adhesion molecule in monocytes, where it enhances cell adhesion by binding Ley, leading to ß2 integrin activation via p38 MAPK.

A novel citrinin derivative from the marine-source fungus Penicillium citrinum.

A novel citrinin derivative, penicitrinol L (1), along with two known analogues, penidicitrinin B (2) and pennicitrinone A (3) were isolated from the marine-source fungus Penicillium citrinum. The structure of the new compound was elucidated by spectroscopic methods including one and two-dimensional NMR as well as high-resolution mass spectrometric analysis. Furthermore, compound 1 showed modest cytotoxic activity against HL-60 cell line and compound 3 showed weak cytotoxic activity against A375 cell line.

[The influence of bariatric surgery on body image in obesity patients].

BACKGROUND: Obesity is a worldwide epidemic that threats the health and body image of those who suffer from this condition. While bariatric surgery has been shown to effectively assist patients to achieve weight loss goals and to improve body image, related research on this intervention is lacking in Taiwan. PURPOSE: The purpose of this research is to investigate the effect of bariatric surgery on body image in obese patients. METHODS: This study used a longitudinal design. Data was collected from 2 hospitals located in northern and southern Taiwan. A total of 56 obese patients who had undergone bariatric surgery enrolled as participants, and the completion rate was 93.3%. Participants responded to a validated body image questionnaire immediately prior to and 3 months after bariatric surgery, with data used to assess the effects of the surgery. SPSS 20.0 software for windows was used for data analysis. RESULTS: Participant scores for body image were low on the questionnaire administered prior to surgery, with a significant negative correlation identified between body mass index (BMI) and the value of appearance (r = -.36, p < .01). After bariatric surgery, the average EWL was 42.08%, which effectively achieved expected weight loss goals. Variables including overall body image, appearance evaluation, orientation, and body satisfaction of participants were significantly improved. Only the variable of muscle tension did not improve significantly. Postoperative body image did not correlate with either BMI or EWL. CONCLUSIONS: Three months after the bariatric surgery, the body image, appearance evaluation, and physical appearance satisfaction of participants had significantly improved. However, there was no improvement in muscle tension scores. In order to improve the post-surgery body image of patients, we recommend that healthcare workers provide patients with proper expectations of bariatric surgery and teach patients appropriate muscle-tension exercises. This paper reports the relation between bariatric surgery and body image. The results provide evidence for clinical and future research in this field.

Recombinant lectin-like domain of thrombomodulin suppresses vascular inflammation by reducing leukocyte recruitment via interacting with Lewis Y on endothelial cells.

OBJECTIVE: The N-terminal lectin-like domain (domain 1 [D1]) of thrombomodulin (TM) is known to have an anti-inflammatory function. We previously showed that recombinant TM domain 1 (rTMD1) interacts with a carbohydrate molecule, Lewis Y (Le(y)), which is found to be expressed on adhesion molecules and involved in cell adhesion. Here, we tested the effect of rTMD1/Le(y) interaction on leukocyte recruitment in inflammation. APPROACH AND RESULTS: The expression of Le(y) on the surface of human umbilical vein endothelial cells was increased by tumor necrosis factor-α stimulation. Direct binding of rTMD1 to Le(y) on the cell surface was observed. rTMD1 inhibited Le(y)-mediated leukocyte adhesion on the Le(y)-immobilized flow chamber and activated endothelium under a shear flow. The following leukocyte transmigration to endothelium was also reduced by rTMD1 through binding Le(y). In vivo, treatment of rTMD1 reduced leukocyte recruitment to the inflammatory sites in carotid ligation injury and thioglycollate-induced peritonitis. rTMD1 administration in apolipoprotein E-deficient mice effectively suppressed atherosclerotic plaque formation and macrophage infiltration in atherosclerotic lesions. Increased Le(y) expression, as well as administered rTMD1, was observed in inflamed vessels. CONCLUSIONS: rTMD1 suppresses vascular inflammation by inhibiting leukocyte recruitment to endothelium through attenuating Le(y)-mediated adhesion and further protects against atherosclerosis progression. The present study provides a mechanism showing that rTMD1 can inhibit inflammation by binding to its carbohydrate ligand Le(y).

Taraxasterol protects against acetaminophen-induced hepatotoxicity by reducing liver inflammatory response and ameliorating oxidative stress in mice.

Acute liver failure is mainly caused by the overdose of acetaminophen (APAP) globally. The traditional Chinese medicinal (TCM) herb, Taraxacum, contains Taraxasterol (TAX) as one of the active components. It is a pentacyclic-triterpene compound isolated from this herb. Present work aimed to investigate the in vitro and in vivo protection effect of TAX in APAP-induced acute liver injury, and determine the potential regulatory mechamisms. The liver injury caused by APAP is attenuated by TAX, as shown by the alleviated pathological changes of mice liver and the reduced serological indexes. TAX evidently controlled the oxidative stress and liver inflammation in mice liver. In vitro studies found that TAX reversed the decrease in LO2 cell viability induced by APAP, and protected LO2 cells from APAP-induced injury. In addition, TAX reduced the secretion of inflammatory factors in RAW264.7 macrophages as induced via APAP. Besides, TAX inhibited oxidative stress in LO2 cells induced by APAP in vitro. Noteworthy, TAX enhanced protein and mRNA expressions of Nrf2 in vivo, and knockdown of Nrf2 by using adeno-associated virus (AAV)-Nrf2-KO attenuated inhibitory impact of TAX in acute liver injury induced by APAP. Also, AAV-NRF2-KO weakened the inhibitory impact of TAX against APAP-triggered liver inflammation and oxidative stress of mice liver. Moreover, TAX activated the Nrf2 signaling in APAP-induced LO2 cells, as shown by the increased nuclear Nrf2 expression together with downstream HO-1 expression in vitro. Inhibition of Nrf2 by using ML-385, anNrf2inhibitor, weakened the inhibitory effect of TAX against APAP-induced oxidative stress and cell injury in LO2 cells. Moreover, inhibition of Nrf2 attenuated anti-inflammatory effect of TAX for APAP-induced RAW264.7 cells. Collectively, TAX could protect against APAP-triggered hepatotoxicitythrough suppression of liver oxidative stress and inflammatory response in mice.

Farnesoid X receptor activation is required for the anti-inflammatory and anti-oxidative stress effects of Alisol B 23-acetate in carbon tetrachloride-induced liver fibrosis in mice.

Previous studies have shown that Alisol B 23-acetate (23ABA) had potent liver-protection effects, however, its roles and potential mechanisms in carbon tetrachloride (CCl4)-induced liver fibrosis remain to be determined. The present study aimed to investigate the effects of 23ABA on CCl4-induced liver fibrosis and tried to elucidate the underlying mechanisms by focusing on regulating of farnesoid X receptor (FXR). In vivo study found that 23ABA alleviated the CCl4-induced liver injury, and showed no obvious systemic toxicity on mice. 23ABA inhibited the collagen production, decreased sera levels of hyaluronic acid (HA) and procollagen type III (PC-III), lowered mRNA expression of α-smooth muscle actin (α-SMA), fibronectin, collagen I and collagen III in livers of mice. 23ABA inhibited the mRNA expressions and the sera levels of interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α), as well as decreased the expression of cyclooxygenase 2 (COX-2) in fibrotic livers of mice. Besides, 23ABA decreased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased glutathione (GSH) level, enhanced activities of superoxide dismutase (SOD) and glutathione reductase (GR) as well as increased mRNA expression of nuclear factor-E2-related factor 2 (Nrf2), glutamate-cysteine ligase, catalytic subunit (GCLC) and glutamate-cysteine ligase, modifier subunit (GCLM). Further study showed that the anti-liver injury and anti-fibrotic effects of 23ABA were abrogated by FXR antagonist guggulsterone (GS) in vivo. In addition, the inhibition effects of 23ABA on liver inflammation and oxidative stress were also weakened by treatment with GS in CCl4-induced fibrotic mice livers. In conclusion, the protective effects of 23ABA against CCl4-induced liver injury and fibrosis, due to FXR-mediated regulation of liver inflammation and oxidative stress.

Wumei Pill Ameliorates AOM/DSS-Induced Colitis-Associated Colon Cancer through Inhibition of Inflammation and Oxidative Stress by Regulating S-Adenosylhomocysteine Hydrolase- (AHCY-) Mediated Hedgehog Signaling in Mice.

Wumei Pill (WMP) is a traditional Chinese herbal formulation and widely used to treat digestive system diseases in clinical. S-Adenosylhomocysteine hydrolase (AHCY) can catalyze the hydrolysis of S-adenosylhomocysteine to adenosine and homocysteine in living organisms, and its abnormal expression is linked to the pathogenesis of many diseases including colorectal cancer (CRC). A previous study reported that WMP could prevent CRC in mice; however, the underlying mechanisms especially the roles of AHCY in WMP-induced anti-CRC remain largely unknown. Here, we investigated the regulatory roles and potential mechanisms of AHCY in WMP-induced anti-CRC. WMP notably alleviated the azoxymethane/dextran sulfate sodium- (AOM/DSS-) induced colitis-associated colon cancer (CAC) in mice. Besides, WMP inhibited the inflammation and oxidative stress in AOM/DSS-induced CAC mice. AHCY was high expression in clinical samples of colon cancer compared to the adjacent tissues. WMP inhibited the AHCY expression in AOM/DSS-induced CAC mice. An in vitro study found that AHCY overexpression induced cell proliferation, colony formation, invasion, and tumor angiogenesis, whereas its knockdown impaired its oncogenic function. AHCY overexpression enhanced, while its knockdown weakened the inflammation and oxidative stress in colon cancer cells. Interestingly, WMP potently suppressed the hedgehog (Hh) signaling in AOM/DSS-induced CAC mice. A further study showed that AHCY overexpression activated the Hh signaling while AHCY knockdown inactivated the Hh signaling. Moreover, activation of the Hh signaling reversed the effect of AHCY silencing on inflammation and oxidative stress in vitro. In conclusion, WMP alleviated the AOM/DSS-induced CAC through inhibition of inflammation and oxidative stress by regulating AHCY-mediated hedgehog signaling in mice. These findings uncovered a potential molecular mechanism underlying the anti-CAC effect of WMP and suggested WMP as a promising therapeutic candidate for CRC.

Podocalyxin EBP50 ezrin molecular complex enhances the metastatic potential of renal cell carcinoma through recruiting Rac1 guanine nucleotide exchange factor ARHGEF7.

Podocalyxin was initially identified in glomerular podocytes to critically maintain the structural and functional integrity of the glomerular ultrafiltrative apparatus. Lately, it has emerged as a malignant marker in tumors arising from a variety of tissue origins. By immunohistochemistry, we identified that 9.6% of renal cell carcinoma patients overexpress this protein. This subset of patients had significantly shorter disease-specific and overall survivals, and, importantly, we established podocalyxin overexpression as an independent prognostic factor for latent distant metastasis with multivariate analysis. Podocalyxin down-regulation by small interfering RNA led to defective migration in model renal tubular cells, which was corrected by re-expression of podocalyxin. The activity of the small GTPase Rac1, a well-characterized modulator of cell migration, was diminished by podocalyxin knock-down. Conversely, podocalyxin overexpression in human embryonic kidney cells up-regulated Rac1 activity, which depended on a complex formed by podocalyxin, ERM-binding phosphoprotein 50, ezrin, and ARHGEF7, a Rac1 activator. Therefore, podocalyxin can serve as a biomarker to identify renal cell carcinoma patients with higher metastatic potential for more aggressive intervention at earlier clinical stages.

Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries.

Vascular calcification is a major risk factor for cardiovascular morbidity and mortality. To develop appropriate prevention and/or therapeutic strategies for vascular calcification, it is important to understand the origins of the cells that participate in this process. In this report, we used the SM22-Cre recombinase and Rosa26-LacZ alleles to genetically trace cells derived from smooth muscle. We found that smooth muscle cells (SMCs) gave rise to osteochondrogenic precursor- and chondrocyte-like cells in calcified blood vessels of matrix Gla protein deficient (MGP(-/-)) mice. This lineage reprogramming of SMCs occurred before calcium deposition and was associated with an early onset of Runx2/Cbfa1 expression and the downregulation of myocardin and Msx2. There was no change in the constitutive expression of Sox9 or bone morphogenetic protein 2. Osterix, Wnt3a, and Wnt7a mRNAs were not detected in either calcified MGP(-/-) or noncalcified wild-type (MGP(+/+)) vessels. Finally, mechanistic studies in vitro suggest that Erk signaling might be required for SMC transdifferentiation under calcifying conditions. These results provide strong support for the hypothesis that adult SMCs can transdifferentiate and that SMC transdifferentiation is an important process driving vascular calcification and the appearance of skeletal elements in calcified vascular lesions.

China's regional public safety efficiency: a data envelopment analysis approach.

This study develops a comprehensive public safety efficiency index that includes the inputs and outputs of regional public safety. The DEA-BC2 model was used to measure the technical efficiency (TE), pure technical efficiency (PTE), and scale efficiency (SE) of public safety at 31 province-level administrative divisions (regions) in China from 2014 to 2018, and to analyze the effectiveness of public safety in each year. The findings indicate that the average TE, PTE, and SE of all regions from 2014 and 2018 were mostly redundant and ineffective. The average Malmquist index continued to decline, with the lack of technological progress identified as the main hindering factor. The public safety efficiency of 31 regions was affected by the technical progress change, pure technical efficiency change, and scale efficiency change at different periods. The findings suggest that all regions should improve the public safety inputs, better allocate various input elements and utilize public safety resources more effectively.

A bipartite signal regulates the faithful delivery of apical domain marker podocalyxin/Gp135.

Podocalyxin/Gp135 was recently demonstrated to participate in the formation of a preapical complex to set up initial polarity in MDCK cells, a function presumably depending on the apical targeting of Gp135. We show that correct apical sorting of Gp135 depends on a bipartite signal composed of an extracellular O-glycosylation-rich region and the intracellular PDZ domain-binding motif. The function of this PDZ-binding motif could be substituted with a fusion construct of Gp135 with Ezrin-binding phosphoprotein 50 (EBP50). In accordance with this observation, EBP50 binds to newly synthesized Gp135 at the Golgi apparatus and facilitates oligomerization and sorting of Gp135 into a clustering complex. A defective connection between Gp135 and EBP50 or EBP50 knockdown results in a delayed exit from the detergent-resistant microdomain, failure of oligomerization, and basolateral missorting of Gp135. Furthermore, the basolaterally missorted EBP50-binding defective mutant of Gp135 was rapidly retrieved via a PKC-dependent mechanism. According to these findings, we propose a model by which a highly negative charged transmembrane protein could be packed into an apical sorting platform with the aid of its cytoplasmic partner EBP50.

Association of the Hepatitis B Virus Large Surface Protein with Viral Infectivity and Endoplasmic Reticulum Stress-mediated Liver Carcinogenesis.

Hepatitis B is the most prevalent viral hepatitis worldwide, affecting approximately one-third of the world's population. Among HBV factors, the surface protein is the most sensitive biomarker for viral infection, given that it is expressed at high levels in all viral infection phases. The large HBV surface protein (LHBs) contains the integral pre-S1 domain, which binds to the HBV receptor sodium taurocholate co transporting polypeptide on the hepatocyte to facilitate viral entry. The accumulation of viral LHBs and its prevalent pre-S mutants in chronic HBV carriers triggers a sustained endoplasmic reticulum (ER) overload response, leading to ER stress-mediated cell proliferation, metabolic switching and genomic instability, which are associated with pro-oncogenic effects. Ground glass hepatocytes identified in HBV-related hepatocellular carcinoma (HCC) patients harbor pre-S deletion variants that largely accumulate in the ER lumen due to mutation-induced protein misfolding and are associated with increased risks of cancer recurrence and metastasis. Moreover, in contrast to the major HBs, which is decreased in tumors to a greater extent than it is in peritumorous regions, LHBs is continuously expressed during tumorigenesis, indicating that LHBs serves as a promising biomarker for HCC in people with CHB. Continuing efforts to delineate the molecular mechanisms by which LHBs regulates pathological changes in CHB patients are important for establishing a correlation between LHBs biomarkers and HCC development.

Srv2 Is a Pro-fission Factor that Modulates Yeast Mitochondrial Morphology and Respiration by Regulating Actin Assembly.

Dynamic processes such as fusion, fission, and trafficking are important in the regulation of cellular organelles, with an abundant literature focused on mitochondria. Mitochondrial dynamics not only help shape its network within cells but also are involved in the modulation of respiration and integrity. Disruptions of mitochondrial dynamics are associated with neurodegenerative disorders. Although proteins that directly bind mitochondria to promote membrane fusion/fission have been studied intensively, machineries that regulate dynamic mitochondrial processes remain to be explored. We have identified an interaction between the mitochondrial fission GTPase Dnm1/DRP1 and the actin-regulatory protein Srv2/CAP at mitochondria. Deletion of Srv2 causes elongated-hyperfused mitochondria and reduces the reserved respiration capacity in yeast cells. Our results further demonstrate that the irregular network morphology in Δsrv2 cells derives from disrupted actin assembly at mitochondria. We suggest that Srv2 functions as a pro-fission factor in shaping mitochondrial dynamics and regulating activity through its actin-regulatory effects.

Glycoproteomic identification of novel plasma biomarkers for oral cancer.

Oral cancer with high incidence rates is occurring in many countries including in India, Pakistan, Bangladesh, Sri Lanka and Taiwan. Smoking, alcoholism, and betel nut chewing are considered to be the main risk factors for oral cancer. Further, deaths from oral cancer have increased year by year. Although several oral cancer-associated biomarkers have been reported, very few useful biomarkers have been applied for early diagnosis. Therefore, the investigation of oral cancer-specific biomarkers is urgently needed. We previously investigated N-glycomes of oral cancer cells and patient plasma. We found that both mRNA levels of FUT8 and core-fucosylated glycoproteins increase in cases of oral cancer relative to normal cases. In this study we aim to discover novel core-fucosylated glycoprotein biomarkers for oral cancer diagnosis with glycoproteomic approaches. First, forty plasma samples obtained from the Human Bioinformation Bank of NCKUH were subjected to AAL (Aleuria aurantia lectin) affinity chromatography. Core-fucosylated proteins were collected and applied for LC-MS/MS followed by electrophoresis. Fourteen proteins were identified, and expression levels of proteins in plasma were verified by western blot. Expression levels of some glycoproteins were elevated in the oral cancer group, including ceruloplasmin, haptoglobin, and leucin-rich alpha-2-glycoprotein 1 (LRG1). However, levels of some glycoproteins decreased in the cancer group, including apolipoprotein A-I (apo A-I) and apolipoprotein A-IV (apo A-IV). Via ELISA analysis, we found that apo A-IV and apo A-IV/total protein ratios were decreased in plasma accompanied with cancer stages. The LRG1/total protein ratio was found to increase while plasma levels of LRG1 were not found to differ between the oral cancer plasma and normal groups. An ROC curve analysis reveals strong diagnosis performance when combining apo A-IV levels and LRG1/total protein ratios. Taken together, apo A-IV and LRG1, given their strong performance in detecting oral cancer, can serve as useful biomarkers and may be used as a useful tool for oral cancer screening and early diagnosis.