Identification of overexpressed cytokines as serum biomarkers of hepatitis C virus-induced liver fibrosis using bead-based flexible multiple analyte profiling

Hepatic inflammation is the stimulator to activate hepatic stellate cells (HSCs) and triggers fibrogenesis. Cytokines are produced during liver inflammation and maybe considered as liver fibrosis biomarker. The aim of this study was to investigate whether cytokines can be used as reliable biomarkers of liver fibrosis using flexible multi-analyte profiling (xMAP). A total of 61 chronic hepatitis C patients with different severity of liver fibrosis were enrolled. Liver biopsy was used as standard to assess the severity of fibrosis according to METAVIR classification. Afterward, 15 samples from healthy controls were analyzed and totally 50 cytokines were screened using flexible multi-analyte profiling to discover differential biomarkers. Finally, levels of protein expressions of individual stages of liver fibrosis were measured. In histological examination, the necroinflammatory score (histology activity index, HAI) was increased from F1 to F4 stage in hepatitis C virus (HCV) infected patients, indicating that inflammation was accompanied with the progression of liver fibrosis. Using flexible multi-analyte profiling, four serum cytokines, including IFN-α2 (p=0.023), GRO-α (p=0.013), SCF (p=0.047) and SDF-1α p=0.024), were identified under antibody specific recognition and elevated with HAI score. This study reveals the relationship between cytokines and liver fibrosis, and demonstrated that IFN-α2, GRO-α, SCF and SDF-1 α may be used as biomarkers to predict liver fibrosis. The overexpressed cytokines may play a role in the progression of liver fibrosis and deserves further investigation.Keywords: Cytokine, flexible multi-analyte profiling, hepatitis C virus, liver fibrosisAfrican Journal of Biotechnology Vol. 11(29), pp. 7535-7541, 29 April, 201

Lignocellulosic saccharification by a newly isolated bacterium, Ruminiclostridium thermocellum M3 and cellular cellulase activities for high ratio of glucose to cellobiose

Background: Lignocellulosic biomass is one of earth's most abundant resources, and it has great potential for biofuel production because it is renewable and has carbon-neutral characteristics. Lignocellulose is mainly composed of carbohydrate polymers (cellulose and hemicellulose), which contain approximately 75 % fermentable sugars for biofuel fermentation. However, saccharification by cellulases is always the main bottleneck for commercialization. Compared with the enzyme systems of fungi, bacteria have evolved distinct systems to directly degrade lignocellulose. However, most reported bacterial saccharification is not efficient enough without help from additional β-glucosidases. Thus, to enhance the economic feasibility of using lignocellulosic biomass for biofuel production, it will be extremely important to develop a novel bacterial saccharification system that does not require the addition of β-glucosidases. Results: In this study, a new thermophilic bacterium named Ruminiclostridium thermocellum M3, which could directly saccharify lignocellulosic biomass, was isolated from horse manure. The results showed that R. thermocellum M3 can grow at 60 °C on a variety of carbon polymers, including microcrystalline cellulose, filter paper, and xylan. Upon utilization of these substrates, R. thermocellum M3 achieved an oligosaccharide yield of 481.5 ± 16.0 mg/g Avicel, and a cellular β-glucosidase activity of up to 0.38 U/mL, which is accompanied by a high proportion (approximately 97 %) of glucose during the saccharification. R. thermocellum M3 also showed potential in degrading natural lignocellulosic biomass, without additional pretreatment, to oligosaccharides, and the oligosaccharide yields using poplar sawdust, corn cobs, rice straw, and cornstalks were 52.7 ± 2.77, 77.8 ± 5.9, 89.4 ± 9.3, and 107.8 ± 5.88 mg/g, respectively. Conclusions: The newly isolated strain R. thermocellum M3 degraded lignocellulose and accumulated oligosaccharides. R. thermocellum M3 saccharified lignocellulosic feedstock without the need to add β-glucosidases or control the pH, and the high proportion of glucose production distinguishes it from all other known monocultures of cellulolytic bacteria. R. thermocellum M3 is a potential candidate for lignocellulose saccharification, and it is a valuable choice for the refinement of bioproducts

Discovery of serum biomarkers of alcoholic fatty liver in a rodent model: C-reactive protein

<p>Abstract</p> <p>Background</p> <p>Excessive consumption of alcohol contributes to alcoholic liver disease. Fatty liver is the early stage of alcohol-related liver disease. The aim of this study was to search for specific serological biomarkers of alcoholic fatty liver (AFL) compared to healthy controls, non-alcoholic fatty liver (NAFL) and liver fibrosis in a rodent model.</p> <p>Methods</p> <p>Serum samples derived from animals with AFL, NAFL, or liver fibrosis were characterized and compared using two-dimensional differential gel electrophoresis. A matrix-assisted laser desorption ionization-time of flight tandem mass spectrometer in conjunction with mascot software was used for protein identification. Subsequently, Western blotting and flexible multi-analyte profiling were used to measure the expressions of the putative biomarkers present in the serum of animals and clinical patients.</p> <p>Results</p> <p>Eight differential putative biomarkers were identified, and the two most differentiated proteins, including upregulated C-reactive protein (CRP) and downregulated haptoglobin (Hp), were further investigated. Western blotting validated that CRP was dramatically higher in the serum of AFL compared to healthy controls and other animals with liver disease of NAFL or liver fibrosis (<it>p </it>< 0.05). Moreover, we found that CRP and Hp were both lower in liver fibrosis of TAA-induced rats and clinical hepatitis C virus-infected patients.</p> <p>Conclusion</p> <p>The results suggest that increased levels of CRP are an early sign of AFL in rats. The abnormally elevated CRP induced by ethanol can be used as a biomarker to distinguish AFL from normal or otherwise diseased livers.</p

Short term association between ozone and mortality: global two stage time series study in 406 locations in 20 countries

Objective To assess short term mortality risks and excess mortality associated with exposure to ozone in several cities worldwide. Design Two stage time series analysis. Setting 406 cities in 20 countries, with overlapping periods between 1985 and 2015, collected from the database of Multi-City Multi-Country Collaborative Research Network. Population Deaths for all causes or for external causes only registered in each city within the study period. Main outcome measures Daily total mortality (all or non-external causes only). Results A total of 45 165 171 deaths were analysed in the 406 cities. On average, a 10 μg/m 3 increase in ozone during the current and previous day was associated with an overall relative risk of mortality of 1.0018 (95% confidence interval 1.0012 to 1.0024). Some heterogeneity was found across countries, with estimates ranging from greater than 1.0020 in the United Kingdom, South Africa, Estonia, and Canada to less than 1.0008 in Mexico and Spain. Short term excess mortality in association with exposure to ozone higher than maximum background levels (70 μg/m 3) was 0.26% (95% confidence interval 0.24% to 0.28%), corresponding to 8203 annual excess deaths (95% confidence interval 3525 to 12 840) across the 406 cities studied. The excess remained at 0.20% (0.18% to 0.22%) when restricting to days above the WHO guideline (100 μg/m 3), corresponding to 6262 annual excess deaths (1413 to 11 065). Above more lenient thresholds for air quality standards in Europe, America, and China, excess mortality was 0.14%, 0.09%, and 0.05%, respectively. Conclusions Results suggest that ozone related mortality could be potentially reduced under stricter air quality standards. These findings have relevance for the implementation of efficient clean air interventions and mitigation strategies designed within national and international climate policies. © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

Short term association between ozone and mortality: global two stage time series study in 406 locations in 20 countries.

OBJECTIVE: To assess short term mortality risks and excess mortality associated with exposure to ozone in several cities worldwide. DESIGN: Two stage time series analysis. SETTING: 406 cities in 20 countries, with overlapping periods between 1985 and 2015, collected from the database of Multi-City Multi-Country Collaborative Research Network. POPULATION: Deaths for all causes or for external causes only registered in each city within the study period. MAIN OUTCOME MEASURES: Daily total mortality (all or non-external causes only). RESULTS: A total of 45 165 171 deaths were analysed in the 406 cities. On average, a 10 µg/m3 increase in ozone during the current and previous day was associated with an overall relative risk of mortality of 1.0018 (95% confidence interval 1.0012 to 1.0024). Some heterogeneity was found across countries, with estimates ranging from greater than 1.0020 in the United Kingdom, South Africa, Estonia, and Canada to less than 1.0008 in Mexico and Spain. Short term excess mortality in association with exposure to ozone higher than maximum background levels (70 µg/m3) was 0.26% (95% confidence interval 0.24% to 0.28%), corresponding to 8203 annual excess deaths (95% confidence interval 3525 to 12 840) across the 406 cities studied. The excess remained at 0.20% (0.18% to 0.22%) when restricting to days above the WHO guideline (100 µg/m3), corresponding to 6262 annual excess deaths (1413 to 11 065). Above more lenient thresholds for air quality standards in Europe, America, and China, excess mortality was 0.14%, 0.09%, and 0.05%, respectively. CONCLUSIONS: Results suggest that ozone related mortality could be potentially reduced under stricter air quality standards. These findings have relevance for the implementation of efficient clean air interventions and mitigation strategies designed within national and international climate policies

Relationships between Hematopoiesis and Hepatogenesis in the Midtrimester Fetal Liver Characterized by Dynamic Transcriptomic and Proteomic Profiles

In fetal hematopoietic organs, the switch from hematopoiesis is hypothesized to be a critical time point for organogenesis, but it is not yet evidenced. The transient coexistence of hematopoiesis will be useful to understand the development of fetal liver (FL) around this time and its relationship to hematopoiesis. Here, the temporal and the comparative transcriptomic and proteomic profiles were observed during the critical time points corresponding to the initiation (E11.5), peak (E14.5), recession (E15.5), and disappearance (3 ddp) of mouse FL hematopoiesis. We found that E11.5-E14.5 corresponds to a FL hematopoietic expansion phase with distinct molecular features, including the expression of new transcription factors, many of which are novel KRAB (Kruppel-associated box)-containing zinc finger proteins. This time period is also characterized by extensive depression of some liver functions, especially catabolism/utilization, immune and defense, classical complement cascades, and intrinsic blood coagulation. Instead, the other liver functions increased, such as xenobiotic and sterol metabolism, synthesis of carbohydrate and glycan, the alternate and lectin complement cascades and extrinsic blood coagulation, and etc. Strikingly, all of the liver functions were significantly increased at E14.5-E15.5 and thereafter, and the depression of the key pathways attributes to build the hematopoietic microenvironment. These findings signal hematopoiesis emigration is the key to open the door of liver maturation

Adolescent transport and unintentional injuries: a systematic analysis using the Global Burden of Disease Study 2019

Background: Globally, transport and unintentional injuries persist as leading preventable causes of mortality and morbidity for adolescents. We sought to report comprehensive trends in injury-related mortality and morbidity for adolescents aged 10–24 years during the past three decades. Methods: Using the Global Burden of Disease, Injuries, and Risk Factors 2019 Study, we analysed mortality and disability-adjusted life-years (DALYs) attributed to transport and unintentional injuries for adolescents in 204 countries. Burden is reported in absolute numbers and age-standardised rates per 100 000 population by sex, age group (10–14, 15–19, and 20–24 years), and sociodemographic index (SDI) with 95% uncertainty intervals (UIs). We report percentage changes in deaths and DALYs between 1990 and 2019. Findings: In 2019, 369 061 deaths (of which 214 337 [58%] were transport related) and 31·1 million DALYs (of which 16·2 million [52%] were transport related) among adolescents aged 10–24 years were caused by transport and unintentional injuries combined. If compared with other causes, transport and unintentional injuries combined accounted for 25% of deaths and 14% of DALYs in 2019, and showed little improvement from 1990 when such injuries accounted for 26% of adolescent deaths and 17% of adolescent DALYs. Throughout adolescence, transport and unintentional injury fatality rates increased by age group. The unintentional injury burden was higher among males than females for all injury types, except for injuries related to fire, heat, and hot substances, or to adverse effects of medical treatment. From 1990 to 2019, global mortality rates declined by 34·4% (from 17·5 to 11·5 per 100 000) for transport injuries, and by 47·7% (from 15·9 to 8·3 per 100 000) for unintentional injuries. However, in low-SDI nations the absolute number of deaths increased (by 80·5% to 42 774 for transport injuries and by 39·4% to 31 961 for unintentional injuries). In the high-SDI quintile in 2010–19, the rate per 100 000 of transport injury DALYs was reduced by 16·7%, from 838 in 2010 to 699 in 2019. This was a substantially slower pace of reduction compared with the 48·5% reduction between 1990 and 2010, from 1626 per 100 000 in 1990 to 838 per 100 000 in 2010. Between 2010 and 2019, the rate of unintentional injury DALYs per 100 000 also remained largely unchanged in high-SDI countries (555 in 2010 vs 554 in 2019; 0·2% reduction). The number and rate of adolescent deaths and DALYs owing to environmental heat and cold exposure increased for the high-SDI quintile during 2010–19. Interpretation: As other causes of mortality are addressed, inadequate progress in reducing transport and unintentional injury mortality as a proportion of adolescent deaths becomes apparent. The relative shift in the burden of injury from high-SDI countries to low and low–middle-SDI countries necessitates focused action, including global donor, government, and industry investment in injury prevention. The persisting burden of DALYs related to transport and unintentional injuries indicates a need to prioritise innovative measures for the primary prevention of adolescent injury. Funding: Bill &amp; Melinda Gates Foundation

Alcohol use and burden for 195 countries and territories, 1990-2016 : a systematic analysis for the Global Burden of Disease Study 2016

Background Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older. Methods Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health. Findings Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2.2% (95% uncertainty interval [UI] 1.5-3.0) of age-standardised female deaths and 6.8% (5.8-8.0) of age-standardised male deaths. Among the population aged 15-49 years, alcohol use was the leading risk factor globally in 2016, with 3.8% (95% UI 3.2-4-3) of female deaths and 12.2% (10.8-13-6) of male deaths attributable to alcohol use. For the population aged 15-49 years, female attributable DALYs were 2.3% (95% UI 2.0-2.6) and male attributable DALYs were 8.9% (7.8-9.9). The three leading causes of attributable deaths in this age group were tuberculosis (1.4% [95% UI 1. 0-1. 7] of total deaths), road injuries (1.2% [0.7-1.9]), and self-harm (1.1% [0.6-1.5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27.1% (95% UI 21.2-33.3) of total alcohol-attributable female deaths and 18.9% (15.3-22.6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0.0-0.8) standard drinks per week. Interpretation Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption.Peer reviewe

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases