Search

The Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded ORF50 protein is a potent transcriptional activator essential for triggering KSHV lytic reactivation. Despite extensive studies, little is known about whether ORF50 possesses the ability to repress gene expression or has an antagonistic action to cellular transcription factors. Previously, we demonstrated that human oncoprotein MDM2 can promote the degradation of ORF50 protein. Herein, we show that abundant ORF50 expression in cells can conversely downregulate MDM2 expression via repressing both the upstream (P1) and internal (P2) promoters of the MDM2 gene. Deletion analysis of the MDM2 P1 promoter revealed that there were two ORF50-dependent negative response elements located from −102 to −63 and from −39 to +1, which contain Sp1-binding sites. For the MDM2 P2 promoter, the ORF50-dependent negative response element was identified in the region from −110 to −25, which is coincident with the location of two known p53-binding sites. Importantly, we further demonstrated that overexpression of Sp1 or p53 in cells indeed upregulated MDM2 expression; however, coexpression with ORF50 protein remarkably reduced the Sp1- or p53-mediated MDM2 upregulation. Collectively, our findings propose a reciprocal negative regulation between ORF50 and MDM2 and uncover that ORF50 decreases MDM2 expression through repressing Sp1- and p53-mediated transactivation.

The structure of lincomycin A consists of the unusual eight-carbon thiosugar core methyllincosamide (MTL) decorated with a pendent N-methylprolinyl moiety. Previous studies on MTL biosynthesis have suggested GDP-ᴅ-erythro-α-ᴅ-gluco-octose and GDP-ᴅ-α-ᴅ-lincosamide as key intermediates in the pathway. However, the enzyme-catalyzed reactions resulting in the conversion of GDP-ᴅ-erythro-α-ᴅ-gluco-octose to GDP-ᴅ-α-ᴅ-lincosamide have not yet been elucidated. Herein, a biosynthetic subpathway involving the activities of four enzymes—LmbM, LmbL, CcbZ, and CcbS (the LmbZ and LmbS equivalents in the closely related celesticetin pathway)—is reported. These enzymes catalyze the previously unknown biosynthetic steps including 6-epimerization, 6,8-dehydration, 4-epimerization, and 6-transamination that convert GDP-ᴅ-erythro-α-ᴅ-gluco-octose to GDP-ᴅ-α-ᴅ-lincosamide. Identification of these reactions completes the description of the entire lincomycin biosynthetic pathway. This work is significant since it not only resolves the missing link in octose core assembly of a thiosugar-containing natural product but also showcases the sophistication in catalytic logic of enzymes involved in carbohydrate transformations.

Metallothionein (MT) is a protein with function of heavy metal detoxification. However, studies about how single nucleotide polymorphisms (SNPs) of MT genes influence lead nephropathy are relatively scarce. Therefore, our aim is to investigate the association between blood lead levels and renal biomarkers and to study whether this association is influenced by the combination of MT1A and MT2A SNPs. Blood lead, urinary uric acid (UA), and urinary N-acetyl-beta-d-glucosaminidase (NAG) levels were analyzed from 485 participants. Genotyping were performed on MT1A SNPs (rs11640851 and rs8052394) and MT2A SNPs (rs10636 and rs28366003). The combined MT1A 2A SNPs were divided into 16 groups. Among renal biomarkers, urinary UA was negatively significant associated with the time-weighted index of cumulative blood lead (TWICL), while urinary NAG was positively significant with TWICL. Furthermore, the association between urinary UA and TWICL was significantly modified by group 6 of combined SNPs (MT1A 2 A SNPs combination were AAAGGGAA, ACAGGGAA, and ACGGGGAA). In conclusion, the negative association of urinary UA and TWICL is modified by group 6, which means participants of group 6 are more susceptible to lead nephrotoxicity.

Background Association between smoking and sleep apnea is well-known from previous studies. However, the influence of secondhand smoke (SHS), which is a potential risk factor of obstructive sleep apnea (OSA), remains unclear. Our aim was to investigate the relationship between SHS and OSA using a meta-analysis. Materials and methods For the meta-analysis, searches were performed in MEDLINE, EMBASE, and Web of Science databases on January 10, 2022, by combining various keywords including “SHS exposure” and “OSA”. Data were extracted using defined inclusion and exclusion criteria. Fixed-effects model meta-analyses were used to pool risk ratio (RR) estimates with their 95% confidence intervals (CI). I2 was used to assess heterogeneity. Moreover, we performed subgroup meta-analyses of children-adults, and smoker fathers and mothers. Results In total, 267 articles were obtained through an electronic search. Twenty-six articles were included in our analysis according to the inclusion and exclusion criteria. We found evidence of an association between SHS exposure and possible OSA (RR 1.64, 95% CI 1.44–1.88). The results of the subgroup analyses showed that children passive smokers (RR 1.84, 95% CI 1.60–2.13) were at greater risks of possible OSA than adult passive smokers (RR 1.35, 95% CI 1.21–1.50). Also, significant differences were observed in mothers with smoking exposure (RR 2.61, 95% CI 1.62–4.21, p p = 0.06). Short conclusion. Our meta-analysis confirmed that SHS exposure is significantly associated with OSA. In the subgroup analyses, the association of SHS and possible OSA was significant in both children and adults, as well as in smoker mothers and fathers.

We used gastric cancer cell line AGS and clinical samples to investigate the roles of mitochondrial DNA (mtDNA) alterations and mitochondrial respiratory dysfunction in gastric adenocarcinoma (GAC). A total of 131 clinical samples, including 17 normal gastric mucosa (N-GM) from overweight patients who had received sleeve gastrectomy and 57 paired non-cancerous gastric mucosae (NC-GM) and GAC from GAC patients who had undergone partial/subtotal/total gastrectomy, were recruited to examine the copy number and D310 sequences of mtDNA. The gastric cancer cell line AGS was used with knockdown (KD) mitochondrial transcription factor A (TFAM) to achieve mitochondrial dysfunction through a decrease of mtDNA copy number. Parental (PT), null-target (NT), and TFAM-KD-(A/B/C) represented the parental, control, and TFAM knocked-down AGS cells, respectively. These cells were used to compare the parameters reflecting mitochondrial biogenesis, glycolysis, and cell migration activity. The median mtDNA copy numbers of 17 N-GM, 57 NC-GM, and 57 GAC were 0.058, 0.055, and 0.045, respectively. The trend of decrease was significant (p = 0.030). In addition, GAC had a lower mean mtDNA copy number of 0.055 as compared with the paired NC-GM of 0.078 (p < 0.001). The mean mtDNA copy number ratio (mtDNA copy number of GAC/mtDNA copy number of paired NC-GM) was 0.891. A total of 35 (61.4%) GAC samples had an mtDNA copy number ratio ≤0.804 (p = 0.017) and 27 (47.4%) harbored a D310 mutation (p = 0.047), and these patients had shorter survival time and poorer prognosis. After effective knockdown of TFAM, TFAM-KD-B/C cells expressed higher levels of hexokinase II (HK-II) and v-akt murine thymoma viral oncogene homolog 1 gene (AKT)-encoded AKT, but lower levels of phosphorylated pyruvate dehydrogenase (p-PDH) than did the NT/PT AGS cells. Except for a higher level of p-PDH, the expression levels of these proteins remained unchanged in TFAM-KD-A, which had a mild knockdown of TFAM. Compared to those of NT, TFAM-KD-C had not only a lower mtDNA copy number (p = 0.050), but also lower oxygen consumption rates (OCR), including basal respiration (OCRBR), ATP-coupled respiration (OCRATP), reserve capacity (OCRRC), and proton leak (OCRPL)(all with p = 0.050). In contrast, TFAM-KD-C expressed a higher extracellular acidification rate (ECAR)/OCRBR ratio (p = 0.050) and a faster wound healing migration at 6, 12, and 18 h, respectively (all with p = 0.050). Beyond a threshold, the decrease in mtDNA copy number, the mtDNA D310 mutation, and mitochondrial dysfunction were involved in the carcinogenesis and progression of GACs. Activation of PDH might be considered as compensation for the mitochondrial dysfunction in response to glucose metabolic reprogramming or to adjust mitochondrial plasticity in GAC.

Primary biliary cholangitis (PBC) is a chronic liver autoimmune disease with augmented T helper (Th) 1 and corresponding cytokine IFN-γ immune responses. Using 2-octynoic acid (2-OA) coupled to OVA (2-OA-OVA)-induced mouse models of autoimmune cholangitis (inducible chemical xenobiotic models of PBC), our previous study demonstrated that overexpression of IFN-γ in the model mice enhanced liver inflammation upon disease initiation, but subsequently led to the suppression of chronic inflammation with an increase in interleukin-30 (IL-30) levels. In this study, we investigated whether IL-30 had an immunosuppressive function and whether it could be part of an immune therapeutic regimen for PBC, by treating model mice with murine IL-30-expressing recombinant adeno-associated virus (AAV-mIL-30). We first defined the effects of AAV-mIL-30 in vivo by administering it to a well-known concanavalin A (ConA)-induced hepatitis model of mice and found that AAV-mIL-30 reduced the numbers of activated CD25+CD4+ T cells and the levels of serum IFN-γ and IL-12. In autoimmune cholangitis, decreased numbers of activated CD4+ T cells and Foxp3+ regulatory T cells were noted in the mice treated with AAV-mIL-30 at 3 weeks after the 2-OA-OVA immunization. Treatment with IL-30 did not change the features of autoimmune cholangitis including autoantibodies, cell infiltration, and collagen deposition in the liver at 11 weeks of examination. However, increased levels of cytokines and chemokines were observed. These results suggest that IL-30 suppresses not only CD4+ T cells but also regulatory T cells. Additionally, the administration of IL-30 did not suppress liver inflammation in the murine model of PBC.

Pulmonary lymphoepithelioma-like carcinoma (LELC) is a distinct type of Epstein-Barr virus (EBV)-associated non-small cell carcinoma characterized by a syncytial growth pattern with heavy lymphocytic infiltration. We recently identified a group of non-small cell carcinomas, which are also associated with EBV but lack significant lymphocytic infiltration. These EBV-associated pulmonary carcinomas with low lymphocytic infiltration morphologically resemble nonkeratinizing squamous cell carcinoma, but their patient characteristics are more similar to those of LELC, including female sex and nonsmoking status. To clarify the relationships between these disease entities, in this study, we explored the molecular characteristics of the EBV-associated carcinomas with low lymphocytic infiltration using whole-exome sequencing and compared their molecular profiles with those of classic LELC and pulmonary squamous cell carcinoma. We demonstrate that the molecular characteristics of EBV-associated carcinomas with low lymphocytic infiltration are highly similar to those of classic LELC. Both show low tumor mutational burden, lack of commonly mutated driver genes in other types of non-small cell lung cancer, similar mutational signature involving APOBEC-related mutations, and enrichment of CD274 (programmed death-ligand 1) amplification. These molecular characteristics are very different from those of pulmonary squamous cell carcinoma. The unique patient demographics and molecular characteristics shared by EBV-associated carcinomas with low lymphocytic infiltration and classic LELC suggest that these tumors represent one single disease entity defined by EBV association. This study supports the proposal for the usage of the term "EBV-associated pulmonary carcinoma" to encompass the entire morphologic spectrum of this distinct EBV-associated disease entity.

The links of air pollutants to health hazards have been revealed in literature and inflammation responses might play key roles in the processes of diseases. WBC count is one of the indexes of inflammation, however the literature reveals inconsistent opinions on the relationship between WBC counts and exposure to air pollutants. The goal of this population-based observational study was to examine the associations between multiple air pollutants and WBC counts. This study recruited community subjects from Kaohsiung city. WBC count, demographic and health hazard habit data were collected. Meanwhile, air pollutants data (SO2, NO2, CO, PM10, and O3) were also obtained. Both datasets were merged for statistical analysis. Single- and multiple-pollutants models were adopted for the analysis. A total of 10,140 adults (43.2% males, age range, 33~86 years old) were recruited. Effects of short-term ambient concentrations (within one week) of CO could increase counts of WBC, neutrophils, monocytes, and lymphocytes. However, SO2 could decrease counts of WBC, neutrophils, and monocytes. Gender, BMI, and smoking could also contribute to WBC count increases, though their effects are minor when compared to CO. Air pollutants, particularly SO2, NO2 and CO, may thus be related to alterations of WBC counts, and this would imply air pollution has an impact on human systematic inflammation.

The present study aimed to use event-related potentials with the stop-signal task to investigate the effects of trait anxiety on inhibitory control, error monitoring, and post-error adjustments. The stop-signal reaction time (SSRT) was used to evaluate the behavioral competence of inhibitory control. Electrophysiological signals of error-related negativity (ERN) and error positivity (Pe) were used to study error perception and error awareness, respectively. Post-error slowing (PES) was applied to examine the behavioral adjustments after making errors. The results showed that SSRT and PES did not differ significantly between individuals with high trait anxiety (HTA) and those with low trait anxiety (LTA). However, individuals with HTA demonstrated reduced ERN amplitudes and prolonged Pe latencies than those with LTA. Prolonged Pe latencies were also significantly associated with poorer post-error adjustments. In conclusion, HTA led to reduced cortical responses to error monitoring. Furthermore, inefficient conscious awareness of errors might lead to maladaptive post-error adjustments.

Objectives Work is often a barrier for women to continue breastfeeding after they have given birth. Breastfeeding support is an important part of workplace health promotion. We investigated the implementation of breastfeeding promotion and gender equality polices in workplaces with the Taiwan Badge of Accredited Healthy Workplace. Methods Our samples consisted of 1648 corporations with the badge of Accredited Healthy Workplace issued by the Bureau of Health Promotion from 2007 to 2008. Concomitantly, 2000 corporations without accreditation were randomly selected from the National Business Directory as the control group. Data were collected from self‐administered questionnaires. Logistic regression was used to examine the association with breast‐feeding promotion and other variables in Taiwanese workplaces. Results Members of accredited group of 1089/1648 (66.1%) and the control group of 526/2000 (26.3%) responded to the questionnaire. The accredited companies had more mother‐friendly settings, including breastfeeding policies and documents, appropriate breastmilk preserving equipment and settings in the workplace. In the accredited group, breastfeeding rate of mothers returning to work after giving birth was 64.3% in 2008 (1 year after giving birth) and 60.4% in 2009 (1 year after giving birth), while the rate of the control group was 59.1% in 2008 and 51% in 2009. Conclusion Accredited corporations are better at breastfeeding support than those of the control group. This might be related to the company size, location, and the implementation of tobacco control and/or occupational health promotion policies, which may increase awareness of healthy workplaces and influence maternal protection positively.

Background Listening to music can be a noninvasive method for reducing the anxiety level without any adverse effects. The aim of this study was to explore whether music can reduce anxiety and to compare two different styles of music, informal classical music and light music, to ascertain the more effective style of music in reducing anxiety in patients undergoing colonoscopy without sedation. Methods This study enrolled 138 patients who underwent colonoscopy without sedation during a general health examination from February 2009 to January 2015. The patients were randomly assigned to a group that did not listen to music, a group that listened to music by David Tolley, or a group that listened to music by Kevin Kern. The State-Trait Anxiety Inventory was used to evaluate the status of anxiety. Results A trend test for mild anxiety was performed on the patients in the three groups, and a significant trend was noted ( p =0.017 for all patients; p =0.014 for analysis by sex). Multivariate analysis for mild anxiety on the patients in each group was also performed in this study, and music by Kevin Kern was found to have the lowest odds ratio (Odds ratio=0.34, p =0.045). Conclusion Listening to music, especially music by Kevin Kern, reduced the level of anxiety in patients undergoing colonoscopy examination without sedation.

Chemische Reaktionen, die zu Ehren ihrer wahren oder zumindest wahrgenommenen Entdecker benannt sind, werden als “Namensreaktionen” bezeichnet. Dieser Aufsatz ist eine Zusammenstellung von biologischen Beispielen fur benannte chemische Reaktionen. Der Schwerpunkt liegt dabei auf Reaktionsarten und Katalysemechanismen, die die chemische Diversitat in der Biosynthese von Naturstoffen wie auch Parallelen zur organischen Synthesechemie veranschaulichen. Enzymatische Katalysemechanismen werden soweit moglich im Kontext mit den entsprechenden Mechanismen in der Synthese beschrieben, und fur derzeit noch untersuchte Reaktionen werden mechanistische Hypothesen diskutiert. Der Aufsatz ist nach Reaktionsarten gegliedert, z. B. Kondensation, Reduktion und Oxidation, Substitution, Carboxylierung, Radikal-vermittelte Reaktionen und Umlagerungen, und diese sind anhand der Namensreaktionen weiter unterteilt.

This study aimed to investigate the performance of innovative and traditional cardiometabolic indices, including body mass index (BMI), waist circumference (WC), Chinese visceral adiposity index (CVAI), visceral adiposity index, lipid accumulation product, a body shape index (ABSI), body roundness index, conicity index (CI), triglyceride-glucose (TyG) index, TyG-BMI, and TyG-WC, in estimating atherosclerotic cardiovascular disease (ASCVD) risk in 3143 Taiwanese adults aged 20–79 years. Elevated 10-year ASCVD risk was defined as ≥7.5% using the Pooled Cohort Equations. The performance of different indices in estimating elevated ASCVD risk was assessed by receiver operating characteristic (ROC) curves. In multivariate-adjusted logistic regression analyses, all cardiometabolic indices (p-value &lt, 0.001) were significantly associated with elevated ASCVD risk in both genders, except for ABSI and CI in women. In particular, CVAI had the largest area under the curve (AUC) in men (0.721) and women (0.883) in the ROC analyses. BMI had the lowest AUC in men (0.617), while ABSI had the lowest AUC in women (0.613). The optimal cut-off value for CVAI was 83.7 in men and 70.8 in women. CVAI performed best among various cardiometabolic indices in estimating elevated ASCVD risk. CVAI may be a reliable index for identifying people at increased risk of ASCVD.

Chronic infection by hepatitis C virus (HCV) is a major risk factor for the development of hepatocellular carcinoma (HCC). Despite the clear clinical importance of virus-associated HCC, the underlying molecular mechanisms remain largely unclarified. Oxidative stress, in particular, DNA lesions associated with oxidative damage, plays a major role in carcinogenesis, and is strongly linked to the development of many cancers, including HCC. However, in identifying hepatocytes with HCV viral RNA, estimates of the median proportion of HCV-infected hepatocytes have been found as high as 40% in patients with chronic HCV infection. In order to explore the gene alternation and association between different viral loads of HCV-infected cells, we established a method to dissect high and low viral load cells and examined the expression of DNA damage-related genes using a quantitative polymerase chain reaction array. We found distinct expression patterns of DNA damage-related genes between high and low viral load cells. This study provides a new method for future study on virus-associated gene expression research.

Lincosamides such as lincomycin A, celesticetin, and Bu-2545, constitute an important group of antibiotics. While these natural products are characterized by a thiooctose linked to a L-proline residue, they differ with regards to modification of the thioacetal moiety, the pyrrolidine ring, and the octose core. Herein we report that the pyridoxal 5′-phosphate-dependent enzyme CcbF is a decarboxylating deaminase that converts a cysteine S-conjugated intermediate in the celesticetin biosynthetic pathway to an aldehyde product. In contrast, the homologous enzyme LmbF from the lincomycin biosynthetic pathway catalyzes C–S bond cleavage of the same intermediate to afford a thioglycoside. Moreover, we show that downstream methyltransferases, Ccb4 and LmbG, convert the resulting aldehyde and thiol intermediates into a variety of methylated lincosamide compounds including Bu-2545. The substrates used in these studies are the β-anomers of the natural substrates. The findings reported herein not only provide insight into how the biosynthetic pathway of lincosamide antibiotics can bifurcate to generate different lincosamides, but also reveal the promiscuity of enzymes involved.

Liver is an immunologically tolerogenic organ, while, autoreactive immune cells mediated autoimmune hepatitis (AIH) is observed. Suppression of the hyper-reactive immune responses may restore the tolerance of liver. IL-37, an emerging IL-1 family cytokine with anti-inflammatory effects on innate and adaptive immunity, shows benefit on many autoimmune diseases. We proposed IL-37 could inhibit immune responses and improve AIH. IL-37 expressing adeno-associated virus (AAV-IL-37) successfully dampened the activation of macrophages in vitro. We next analyzed the effect of IL-37 in Con A-induced autoimmune hepatitis mouse model. Surprisingly, the liver histopathology showed more necrotic hepatocytes and infiltrating immune cells in AAV-IL-37 treated Con A mice than in control mice. Higher levels of serum IFN-γ in IL-37-expressing Con A mice were observed. Moreover, expression of inflammation-related mRNA in the liver were also highly induced with AAV-IL-37 treatment. Among hepatic lymphoid cells, NK and NKT cells were particularly increased in IL-37 treated Con A mice. The frequency of IFN-γ-secreting NK cells was also significantly increased. Further, CCL5, a chemoattractant for NK cells, was significantly elevated in the serum of AAV-IL-37 injected Con A mice. These results suggest that IL-37 worsen liver inflammation instead of relieving the disease. Of note, there was no obvious inflammation in AAV-IL-37 treated naïve mice, suggesting the proinflammatory effect of IL-37 in Con A treated mice resulted from the inflamed liver microenvironment. In conclusion, IL-37 aggravated liver inflammation in Con A induced hepatitis through recruiting NK cells and elevating the IFN-γ secretion of NK cells.

The immunomodulatory effect of IL-10 as an immunosuppressive and anti-inflammatory cytokine is well known. Taking advantage of our established mouse model of autoimmune cholangitis using 2-octynoic acid conjugated ovalbumin (2-OA-OVA) induction, we compared liver pathology, immune cell populations and antimitochondrial antibodies between IL-10 knockout and wild type mice immunized with 2-OA-OVA. At 10 weeks post immunization, portal inflammation and fibrosis were more severe in 2-OA-OVA immunized IL-10 knockout mice than in wild type mice. This was accompanied by significant higher levels of collagen I and III expression, T, NK and NKT subsets in liver and IgG anti-mitochondrial autoantibodies (AMA) compared to 2-OA-OVA immunized wild type mice, suggesting that endogenous IL-10 is necessary for the maintenance of immune tolerance in primary biliary cholangitis (PBC). Further, we investigated whether administration of exogenous IL-10 could prevent PBC by administration of IL-10 expressing recombinant adeno-associated virus (AAV-IL-10) either 3 days before or 3 weeks after the establishment of liver pathology. Interestingly, administration of AAV-IL-10 resulted in increased liver inflammation and fibrosis, accompanied by increases in IFN-γ in liver CD4(+) T cell, granzyme B, FasL, and CD107a in liver CD8(+) T and NKT cells, and granzyme B and FasL in liver NK cells of AAV-IL-10 administered mice compared with control mice. Furthermore, administration of AAV-IL-10 significantly increased levels of proinflammatory cytokines and chemokines (IFN-γ, TNF-α, CXCL9 and CXCL10) and collagen I and III production in naive mice, together with increase in immune cell infiltration and collagen deposition in the liver, suggesting a role of IL-10 in fibrosis. In conclusion, our data demonstrate that endogenous IL-10 is critical in the maintenance of immune tolerance but exogenous administration of IL-10 exacerbates liver inflammation and fibrosis. Furthermore, the distinctive presence of inflammatory immune cell populations and collagen expression in AAV-IL-10 treated naive mice cautions against the clinical use of exogenous IL-10 in patients with autoimmune cholangitis.

Introduction Lead in blood can stimulate lipid oxidation in phosphatidylcholine and increase peroxidation in lipids. Metallothionein (MT) is a cysteine rich protein that can influence the detoxification of heavy metals and scavenge oxidative stress for free radicals. One of the most expressive functional genes in humans is the MT2A gene. This study aims to determine if the association of the blood lead level and lipid biomarkers was influenced by MT2A polymorphisms. Methods We recruited 677 participants after informed consent was obtained. All of the samples collected were analysed for lipid biomarkers and blood lead levels and were genotyped for MT2A polymorphisms by RT-PCR. A short questionnaire collected the medical history and alcohol and cigarette consumption information. The data were used for descriptive analyses and linear regression models. Result The investigation revealed that lead elevated concentration increased low-density lipoprotein cholesterol (LDL-C) and decreased high-density lipoprotein cholesterol (HDL-C) by multiple linear models. The carriers of the rs10636 GC-rs28366003 AA genetic combination may be less susceptive to lead elevated concentration on HDL-C than other types. Conclusion In conclusion, the association of the blood lead level and HDL-C may be modified by the MT2A genetic combination: the rs10636 GC-rs28366003 AA genotype could play a protective role in lead elevated concentration on HDL-C in humans.

Introduction Lead toxicity plays an important role in public health. It causes multiple organs damage, and nephrotoxicity is included. Metallothionein (MT) is a cysteine-rich, low molecular weight protein with function of heavy metal detoxification. However, study about how the MT1A and MT2A single nucleotide polymorphisms (SNPs) influence the lead nephropathy is relatively scarce. Our aim is to investigate the association of blood lead levels and renal biomarkers in chronic lead exposure, and to study whether the association was influenced by MT1A2A SNPs. Methods Blood samples were collected from 485 participants during their annual health examination after informed consent letters were obtained. The blood lead level,urinary creatinine, urinary uric acid, and urinary N-acetyl-beta-d-glucosaminidase (NAG) were measured and analysed. DNA was extracted and used for real-time PCRgenotyping two MT1A SNPs (rs11640851 and rs8052394) and two MT2A SNPs (rs10636 and rs28366003). The MT1A2A SNPs combination was dividedinto 16 groups. Data were treated for descriptive analysis, one-way ANOVA, and multiple linear regressions by SPSS. Results Urine uric acid had significantly negative association with time-weighted index of cumulative blood lead (TWICL) after adjusting other potential confounders except 16 groups of MT1A2A SNPs combination. Moreover, the association was modified by 16 groups of SNPs combination. For urine uric acid, group 6th and group 12th were more susceptible to lead toxicity, while group 5th was lesssusceptible to lead toxicity. On the other hand, urinary NAG was positively associated with TWICL no matter whether the 16 groups were adjusted or not. Conclusion Urinary uric acid and urinary NAG might be considered as proper indicators of lead nephrotoxicity. Moreover, MT1A2A combination 16 groups were modifiers in the relationship between urinary uric acid and TWICL. The group 5th was positive association while group 6th and 12th were negative association with TWICL on urinary uric acid

Biliary tract intraductal tubulopapillary neoplasms (BT-ITPNs) and intraductal papillary mucinous neoplasms (BT-IPMNs) are rare and poorly described. Herein, we examined the magnetic resonance imaging (MRI) features of BT-ITPNs and BT-IPMNs and correlated them with key gross and microscopic pathological findings. We retrospectively identified five patients with definitive pathological findings of BT-ITPN and available diagnostic MRI findings. Key MRI features were correlated to the gross and microscopic pathology and compared to those of BT-IPMNs (19 patients). All BT-ITPNs showed ductal dilatation and visible intraductal soft tissue with peribiliary liver parenchyma enhancement. One BT-ITPN patient had synchronous lung metastases, and another showed rapid tumor growth rate. The intraductal soft tissue proportion of BT-ITPNs was significantly more than that of BT-IPMNs (p < 0.05). CA-199 level was elevated in 60% of BT-ITPN cases. The overall combined 1-year and 3-year survival rates in the BT-ITPN group was 100% and 40%, and in the BT-IPMN group was 100% and 58%, respectively. A high intraductal soft tissue proportion, a lack of intraluminal mucin, and immunohistochemical absence of MUC5AC are radiological and pathological characteristics that differentiate BT-ITPN from BT-IPMN. Although rare, BT-ITPN should be suspected when solid intraductal soft tissue and peribiliary liver parenchyma enhancement are present, particularly if the bile duct upstream and downstream of the lesion have a normal diameter, without mucin. Owing to the aggressive nature of the tumor, recognition of these features may indicate the need for more aggressive treatment in selected patients.

We investigated the role of mitochondrial function in the invasiveness of human colorectal cancer (CRC) cell lines, using paired primary SW480 and metastatic SW620 cells, and appraised the clinical relevance of the alteration of mtDNA copy number in 33 pairs of CRC specimens after surgical resection. Suppression of mitochondrial function was achieved by the exposure of cells to oligomycin A (OA) or by knockdown of mitochondrial transcriptional factor A (TFAM) to evaluate their effects on energy metabolism, reactive oxygen species, protein expression levels of epithelial-mesenchymal transition (EMT) markers and invasive activity of CRC cells. We found that SW620 cells expressed higher levels of TFAM and mitochondrial DNA (mtDNA)-encoded NADH dehydrogenase subunit 6 (ND6) and cytochrome c oxidase subunit II (COX-II) and nuclear DNA-encoded NADH ubiquinone oxidoreductase subunit A9 (NDUFA9), iron-sulfur protein subunit B of succinate dehydrogenase (SDHB), ubiquinol‑cytochrome c reductase core protein I/II (UQCRC1/2) and cytochrome c oxidase subunit IV (COX-IV) when compared with the SW480 cells. The mtDNA copy number, ADP-triggered oxygen consumption rate (OCR) and respiratory control ratio (RCR) of succinate-supported respiration in the SW620 cells were higher than those noted in the SW480 cells. The intracellular levels of H2O2 and O2-• in the SW620 cells were lower than levels noted in the SW480 cells. Moreover, SW620 cells displayed lower protein levels of hexokinase II (HK-II), glucose 6-phosphate isomerase (GPI) and lactate dehydrogenase (LDH), and lower lactate production rate, and expressed higher levels of EMT markers N-cadherin, vimentin and Snail, and showed higher Transwell migration and invasion activities as compared with the SW480 cells. After OA treatment, SW620 cells exhibited a decrease in OCR and RCR of succinate-supported respiration, an increase in lactate production rate and intracellular levels of H2O2 and O2-•. Moreover, the level of vimentin and Transwell migration activity of the SW620 cells were decreased. After TFAM knockdown, the protein levels of TFAM, ND6 and COX-II, and mtDNA copy number, OCR and RCR of succinate-supported respiration in the SW620-KD#4 and SW620-KD#5 cells were all lower than those noted in the SW620‑Control cells. By contrast, the protein level of HK-II, lactate production rate, the intracellular levels of H2O2 and O2-• in the SW620-KD#4 and SW620-KD#5 cells were all higher than those noted in the SW620-Control cells. Subsequently, both SW620-KD#4 and SW620-KD#5 cells had lower Transwell invasion activity than did the SW620-Control cells. Furthermore, we found that deeper invasion (P=0.025) and longer tumor length (P=0.069) were associated with higher mtDNA copy ratios in the 33 pairs of CRC specimens obtained from surgical resection. Taken together, we conclude that higher mtDNA copy number and mitochondrial function may confer an invasive advantage to CRCs.

Chemical reactions that are named in honor of their true, or at least perceived, discoverers are known as "name reactions". This Review is a collection of biological representatives of named chemical reactions. Emphasis is placed on reaction types and catalytic mechanisms that showcase both the chemical diversity in natural product biosynthesis as well as the parallels with synthetic organic chemistry. An attempt has been made, whenever possible, to describe the enzymatic mechanisms of catalysis within the context of their synthetic counterparts and to discuss the mechanistic hypotheses for those reactions that are currently active areas of investigation. This Review has been categorized by reaction type, for example condensation, nucleophilic addition, reduction and oxidation, substitution, carboxylation, radical-mediated, and rearrangements, which are subdivided by name reactions.

Background Lead in blood can stimulate lipid oxidation in phosphatidylcholine and increase peroxidation in lipids. Metallothionein (MT) is a cysteine-rich protein that can influence the detoxification of heavy metals and scavenge oxidative stress for free radicals. One of the most expressive functional genes in humans is the MT2A gene. Objective This study aims to determine if the association of the blood lead level and lipid biomarkers was influenced by MT2A polymorphisms. Methods We recruited 677 participants after informed consent was obtained. All the samples collected were analyzed for lipid biomarkers and blood lead levels and were genotyped for MT2A polymorphisms by reverse transcription polymerase chain reaction. A short questionnaire collected the medical history and alcohol and cigarette consumption information. The data were used for descriptive analyses and linear regression models. Results The investigation revealed that lead elevated concentration increased low-density lipoprotein cholesterol and decreased high-density lipoprotein cholesterol (HDL-C) by multiple linear models. The carriers of the rs10636 GC-rs28366003 AA genetic combination may be less susceptive to lead elevated concentration on HDL-C than other types. Conclusion In conclusion, the association of the blood lead level and HDL-C may be modified by the MT2A genetic combination: the rs10636 GC-rs28366003 AA genotype could play a protective role in lead elevated concentration on HDL-C in humans.

The purpose of this study was to investigate the potential risk factors for the reactivation of the replication of hepatitis B virus (HBV) and hepatitis C virus (HCV) after transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma. Forty-four hepatocellular carcinoma patients treated by TACE using epirubicin plus mitomycin C were studied. Serum HBV DNA ( n =17) and HCV RNA ( n =27) levels were measured 1 day before and 3 months after TACE. Plasma concentrations of chemotherapeutic agents were determined at 1 hour and 72 hours after TACE. A total of 29 patients ( n =13 for chronic hepatitis Band n =16 for chronic hepatitis C) showed significant changes of the viral loads after TACE. Patients with increased viral loads after TACE were older ( p =0.041), had higher incidence of pre-TACE white blood cell counts being less than normal limit ( p =0.023), and had higher plasma mitomycin C concentrations ( p =0.039) than those in patients with decreased viral loads. Analysis by multiple logistic regressions using age, decreased or normal pre-TACE white blood cell counts, mitomycin C concentrations >3.95ng/mL adopted by receiver operating characteristic curve ( p =0.037), and epirubicin concentrations have shown that decreased pre-TACE white blood cell counts was the only significant factor associated with increased viral loads after TACE ( p =0.048). In conclusion, patients with decreased pre-TACE white blood cell counts have a potential risk for the reactivation of the replication of HBV or HCV after TACE.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major causes of liver disease in Taiwan and have a great impact on the health of this country. This study investigated the seroprevalence of HBV and HCV in southern Taiwan. Screening programs were performed from September 1999 to August 2005 for community-based surveillance of liver disease. A total of 28,797 adults from southern Taiwan, including Kaohsiung City (n = 14,036), Kaohsiung County (n = 7,713), and Pingtung County (n = 7,048) were participated. The mean age was 50.3 ± 14.6 years (range, 20-97 years), with 41.0% were men. Hepatitis B surface antigen (HBsAg), antibody to HCV (anti-HCV), and liver function tests were performed. Among the 28,797 adults, the prevalence of HBsAg(+) was 15.1% and that for anti-HCV(+) was 8.6%. The seroprevalence of HBsAg in Kaohsiung County was 18.2%, which was higher than in Kaohsiung City (14.7%, p < 0.001) or Pingtung County (12.5%, p < 0.001). The seroprevalence of anti-HCV in Kaohsiung County was 17.2%, which was higher than in the other regions (Kaohsiung City = 5.8%, p < 0.001; Pingtung County = 4.6%, p < 0.001). The prevalence of dual HBsAg and anti-HCV was 1.1% (323 patients). Tzukuan Township in Kaohsiung County was endemic for HBsAg (19.1%, 1,026/5,375 patients), anti-HCV (22.4%, 1,203/5,375 patients), and dual HBsAg/anti-HCV (3.6%, 191/5,375 patients). Subjects with anti-HCV(+) were older and had higher alanine transaminase levels than their HBsAg(+) counterparts (p < 0.001 and p < 0.001, respectively). The current study shows the epidemiological characteristics of HBV and HCV infections among adults in southern Taiwan. Viral hepatitis infections remain widely endemic in this region.

Background Limited data support the notion that lipid ratios are risk factors for nonalcoholic fatty liver disease (NAFLD). We evaluated the association between lipid ratios and NAFLD. Methods This was a large population, cross-sectional, retrospective study. Data on NAFLD severity, blood pressure, fasting glucose, total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) levels were obtained from 44,767 examinees at single health checkup center. The enrollees were stratified into four subgroups based on their TC/HDL-C and TG/HDL-C ratios. We used multivariate analyses to evaluate the odds between lipid ratios and NAFLD. Results The prevalence rate of fatty liver in this study was 53.76%. In the baseline subgroup with the lowest TC/HDL-C and TG/HDL-C ratios, the prevalence of NAFLD, hypertension, and diabetes was lower than that of the other three subgroups. Patients with higher lipid ratios had a significantly greater risk for advanced NAFLD. Conclusions Adults with high TC/HDL-C or TG/HDL-C ratios, or both, have a greater risk for NAFLD, especially advanced NAFLD.

In order to process large numbers of explicit knowledge documents such as patents in an organized manner, automatic document categorization and search are required. In this paper, we develop a document classification and search methodology based on neural network technology that helps companies manage patent documents more effectively. The classification process begins by extracting key phrases from the document set by means of automatic text processing and determining the significance of key phrases according to their frequency in text. In order to maintain a manageable number of independent key phrases, correlation analysis is applied to compute the similarities between key phrases. Phrases with higher correlations are synthesized into a smaller set of phrases. Finally, the back-propagation network model is adopted as a classifier. The target output identifies a patent document’s category based on a hierarchical classification scheme, in this case, the international patent classification (IPC) standard. The methodology is tested using patents related to the design of power hand-tools. Related patents are automatically classified using pre-trained neural network models. In the prototype system, two modules are used for patent document management. The automatic classification module helps the user classify patent documents and the search module helps users find relevant and related patent documents. The result shows an improvement in document classification and identification over previously published methods of patent document management.

Lincomycin A is a clinically useful antibiotic isolated from Streptomyces lincolnensis. It contains an unusual methylmercapto-substituted octose, methylthiolincosamide (MTL). While it has been demonstrated that the C8 backbone of MTL moiety is derived from D-fructose 6-phosphate and D-ribose 5-phosphate via a transaldol reaction catalyzed by LmbR, the subsequent enzymatic transformations leading to the MTL moiety remain elusive. Here, we report the identification of GDP-D-erythro-α-D-gluco-octose (GDP-D-α-D-octose) as a key intermediate in the MTL biosynthetic pathway. Our data show that the octose 1,8-bisphosphate intermediate is first converted to octose 1-phosphate by a phosphatase, LmbK. The subsequent conversion of the octose 1-phosphate to GDP-D-α-D-octose is catalyzed by the octose 1-phosphate guanylyltransferase, LmbO. These results provide significant insight into the lincomycin biosynthetic pathway, because the activated octose likely serves as the acceptor for the installation of the C1 sulfur appendage of MTL.

Carbohydrates serve many structural and functional roles in biology. While the majority of monosaccharides are characterized by the chemical composition (CH2O)n, modifications including deoxygenation, C-alkylation, amination, O- and N-methylation, which are characteristic of many sugar appendages of secondary metabolites, are not uncommon. Interestingly, some sugar molecules are formed via modifications including amine oxidation, sulfur incorporation, and “high-carbon” chain attachment. Most of these unusual sugars have been identified over the past several decades as components of microbially produced natural products, although a few high-carbon sugars are also found in the lipooligosaccharides of the outer cell walls of Gram-negative bacteria. Despite their broad distribution in nature, these sugars are considered “rare” due to their relative scarcity. The biosynthetic steps that underlie their formation continue to perplex researchers to this day and many questions regarding key transformations remain unanswered. This review will focus on our current understanding of the biosynthesis of unusual sugars bearing oxidized amine substituents, thio-functional groups, and high-carbon chains.

Supported by maturing information and communication technology (ICT) technologies, the medical care industry entered its digitization age. However, medical information is highly confidential and involves privacy; even legitimate access can cause privacy infringements. Under the current medical administration system, no established application systems conform to the IRB (Institutional review board) to protect privacy in human subject research. To prevent the privacy of research subjects from being disclosed unintentionally, and to meet the “need-to-know” demands of information management, this study proposes an intelligent privacy-preserving administration tool (iPAT) designed to facilitate human subject research. This study provides the principle and feasibility of iPAT that are introduced and verified through a use case conducted by the head of the research project.

Digitizing medical information is an emerging trend that employs information and communication technology (ICT) to manage health records, diagnostic reports, and other medical data more effectively, in order to improve the overall quality of medical services. However, medical information is highly confidential and involves private information, even legitimate access to data raises privacy concerns. Medical records provide health information on an as-needed basis for diagnosis and treatment, and the information is also important for medical research and other health management applications. Traditional privacy risk management systems have focused on reducing reidentification risk, and they do not consider information loss. In addition, such systems cannot identify and isolate data that carries high risk of privacy violations. This paper proposes the Hiatus Tailor (HT) system, which ensures low re-identification risk for medical records, while providing more authenticated information to database users and identifying high-risk data in the database for better system management. The experimental results demonstrate that the HT system achieves much lower information loss than traditional risk management methods, with the same risk of re-identification.

A novel compound, N⁶-(4-hydroxybenzyl)adenosine, isolated from Gastrodia elata and which has been shown to be a potential therapeutic agent for preventing and treating neurodegenerative disease, was found to target both the adenosine A(2A) receptor (A(2A) R) and the equilibrative nucleoside transporter 1 (ENT1). As A(2A) R and ENT1 are proximal in the synaptic crevice of striatum, where the mutant huntingtin aggregate is located, the dual-action compounds that concomitantly target these two membrane proteins may be beneficial for the therapy of Huntington's disease. To design the desired dual-action compounds, pharmacophore models of the A(2A) R agonists and the ENT1 inhibitors were constructed. Accordingly, potentially active compounds were designed and synthesized by chemical modification of adenosine, particularly at the N⁶ and C⁵' positions, if the predicted activity was within an acceptable range. Indeed, some of the designed compounds exhibit significant dual-action properties toward both A(2A) R and ENT1. Both pharmacophore models exhibit good statistical correlation between predicted and measured activities. In agreement with competitive ligand binding assay results, these compounds also prevent apoptosis in serum-deprived PC12 cells, rendering a crucial function in neuroprotection and potential utility in the treatment of neurodegenerative diseases.

Serum deprivation-induced neuronal-like PC12 cell apoptosis was used as an ischemic/hypoxic model to screen neuroprotective compounds from the rhizomes of Gastrodia elata, a traditional Chinese medicine. Two active compounds, bis(4-hydroxybenzyl)sulfide (1) and N6-(4-hydroxybenzyl)adenine riboside (2), together with 15 known compounds were obtained from the active fraction. Compound 2 was further elucidated by chemical synthesis. Compounds 1 and 2 potently prevented PC12 cell apoptosis in concentration-dependent manners with EC50 values of 7.20 microM and 3.7 x 10-8 M, respectively, and IC50 values of 42.90 microM (Ki 24.10 microM) and 4.660 microM (Ki 2.620 microM), respectively, in an adenosine A2A receptor binding assay.

Carbohydrates serve many structural and functional roles in biology. While the majority of monosaccharides are characterized by the chemical composition: (CH2O)n, modifications including deoxygenation, C-alkylation, amination, O- and N-methylation, which are characteristic of many sugar appendages of secondary metabolites, are not uncommon. Interestingly, some sugar molecules are formed via modifications including amine oxidation, sulfur incorporation, and “high-carbon” chain attachment. Most of these unusual sugars have been identified over the past several decades as components of microbially produced natural products, although a few high-carbon sugars are also found in the lipooligosaccharides of the outer cell walls of Gram-negative bacteria. Despite their broad distribution in nature, these sugars are considered “rare” due to their relative scarcity. The biosynthetic steps that underlie their formation continue to perplex researchers to this day and many questions regarding key transformations remain unanswered. This review will focus on our current understanding of the biosynthesis of unusual sugars bearing oxidized amine substituents, thio-functional groups, and high-carbon chains.

Objectives The epidemiologic characteristics of metabolic syndrome (MS) and insulin resistance should be an important task for health promotion in workers. Methods Analysing 3100 data (female: 1125, male: 1975) aged 31.5±12.1 years from completely decoding health surveillance bank. HOMA-IR as insulin sensitivity index was calculated by (Insulin (μU/ml) X Glucose (mmol/l)/22.5). MS was defined on updated NCEP/ATP III criteria modified for Asians. Results The prevalence of MSin our group was 12%. The 75th percentile of HOMA-IR in non-diabetic cases was 1.88. Diabetes mellitus (DM) was the most significant predictor for MS (10.4 vs 69%, OR=12.0–31.1). In non-diabetic, the major factors were HOMA-IR≥1.88 (4.7 vs 27.6%, OR=6.1–10.1), age, sex (=4.5%,=13.8%, OR=2.5-4.7), hypertension (6.6 vs 35.7%, OR=6.0–10.1), abnormal liver function GPT≥1.3X (8.5 vs 34.7%, OR=4.2–7.8), central obesity (5.2 vs 33.5%, OR=7.1–11.8), body mass index(BMI) (normal (18.5≥BMI Conclusions High prevalence of MS was noted in workers and it predicts insulin resistance.

Objectives To understand prevalence of occupation-related disease and promote the recognition of occupation hazard exposure for hairdresser and cosmetologist. Methods Anonymous questionaires were surveilled in 467 female and 46 male workers of aged 15 to 64 (33.9±10.4 y)in Kaohsiung City. Results Overwork daily hours in 86%, burnout in 30%, and work satisfaction in 57% could be noted. More frequent in fatigue and low satisfaction was in younger workers. There were work-related asthma (n=6), rhinitis (n=19), hand eczema (7.2%), hand injury (3.7%), carpal tunnel syndrome (CTS) (3.5%), neck-shoulder pain (22.2%), low back pain (9.7%). Skin disorder occurred more in hair-washing (p=0.013), injury (p=0.004) and CTS (p=0.013) in hair cutting and design, neck-shoulder pain (p=0.006) and low back pain (p=0.04) also in hair-designers. Near 15% to 20% of workers did not know about irritant/allergic components in products for hair-washing, colour agents, nail agents, and did not wear protective masks or gloves. More than 30% knew nothing about chemical exposure in their workplace and health-hazard effect. Eighty percent of workers knew the risk of trasmission of turberculosis, but less than 60% had protective practice. Most (90%) knew the viral-trasmission hazards of blood-contaminated instruments and sterile procedures, but no protective measures during chemical sterilisation. Less knowledge about chemical hazards and opposition against mask-wearing could be noted in older workers, trainees, and employees than bosses or managers. About 60% thought their pain came from work-related condition, but their work-station was not ergonomically suitable. Conclusions Highly prevalent overwork and occupation-related disorders were noted. Education program to promote recognition of chemical hazards and protective measures should be reinforced.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report a novel dual-function compound, N(6)-(4-hydroxybenzyl)adenine riboside (designated T1-11) which activates the A(2A)R and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A(2A)R and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A(2A)R knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A(2A)R in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD. CONCLUSIONS/SIGNIFICANCE: The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases.

Pyreno[2,1-b]pyrrole and its dimeric derivative display excellent selectivity and sensitivity for detection of fluoride ion, in comparison with chloride, bromide, iodide, acetate, dihydrogen phosphate, hydrogen sulfate, perchlorate, nitrate, and thiocyanate ions. The hydrogen bonding with fluoride ion, both in formation and in subsequent dissociation, provides remarkable colorimetric and fluorescent changes in the visible region that are advantageous for real-time and on-site application. Detailed NMR and dynamic fluorescence spectroscopic analyses establish the associated mechanism.