Production of Exopolysaccharides from Submerged Culture of Antrodia Camphorata S-29

Antrodia camphorata is a unique mushroom of Taiwan, which has been used as a natural therapeutic ingredient in Traditional Chinese Medicine (TCM) for protection of diverse health related conditions. Polysaccharides produced from A. camphorata have attracted much attention of research due to cytotoxic activity and miscellaneous activities. In this paper, we report on the fermentation conditions species-specific exopolysaccharides (EPS) from A. camphorata in submerged culture. A favorable medium for EPS production was obtained only by single-factor experiment, where Glucose and Yeast-Extracts were identified to be the most suitable carbon and nitrogen sources, with the concentration of 40 g/L and 5.0 g/L respectively. Zinc sulphate was identified to be the best salt source with the concentration of 0.4g/l. Initial pH and inoculum size for mycelial growth and EPS yield were 6.0 and 15% respectively. The maximum EPS production was 0.474 g/L in shake-flask culture, which is higher than the baseline media that was 0.351 g/L. This study provides the baseline information about production conditions for this specific specie which is crucial data to know before any further studies as it determines the properties and quantity of the desired produced specie. Keywords: A. camphorata; Exopolysaccharide; Sub­merged culture

Determination of bupropion and hydroxybupropion by LC-MS/MS in rat and its application to assessment of CYP2B6 activity

A selective and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for quantitation of bupropion (BUP) and its metabolite hydroxybupropion (HBUP) in rat plasma and urine using carbamazepine as an internal standard. Chromatographic separation was achieved on a SB-C18 column at 30 °C, using the gradient elution of 0.1 % formic acid in water and acetonitrile. Calibration plots were linear over range of 10-2000 ng/mL for BUP and 5-1000 ng/mL for HBUP in rat plasma. The intra- and inter-run relative standard deviations of the assay were less than 10 % for both BUP and HBUP. The effects of tolbutamide on cytochrome P450-mediated metabolism of BUP were studied by the validated method above. The results revealed that tolbutamide had signigicantly decreased the rate of BUP hydroxylation.Colegio de Farmacéuticos de la Provincia de Buenos Aire

TRAF3 Negatively Regulates Platelet Activation and Thrombosis

CD40 ligand (CD40L), a member of the tumor necrosis factor (TNF) superfamily, binds to CD40, leading to many effects depending on target cell type. Platelets express CD40L and are a major source of soluble CD40L. CD40L has been shown to potentiate platelet activation and thrombus formation, involving both CD40-dependent and -independent mechanisms. A family of proteins called TNF receptor associated factors (TRAFs) plays key roles in mediating CD40L-CD40 signaling. Platelets express several TRAFs. It has been shown that TRAF2 plays a role in CD40L-mediated platelet activation. Here we show that platelet also express TRAF3, which plays a negative role in regulating platelet activation. Thrombin- or collagen-induced platelet aggregation and secretion are increased in TRAF3 knockout mice. The expression levels of collagen receptor GPVI and integrin αIIbβ3 in platelets were not affected by deletion of TRAF3, suggesting that increased platelet activation in the TRAF3 knockout mice was not due to increased expression platelet receptors. Time to formation of thrombi in a FeCl3-induced thrombosis model was significantly shortened in the TRAF3 knockout mice. However, mouse tail-bleeding times were not affected by deletion of TRAF3. Thus, TRAF3 plays a negative role in platelet activation and in thrombus formation in vivo

ARNOLD: A Benchmark for Language-Grounded Task Learning With Continuous States in Realistic 3D Scenes

Understanding the continuous states of objects is essential for task learning and planning in the real world. However, most existing task learning benchmarks assume discrete(e.g., binary) object goal states, which poses challenges for the learning of complex tasks and transferring learned policy from simulated environments to the real world. Furthermore, state discretization limits a robot's ability to follow human instructions based on the grounding of actions and states. To tackle these challenges, we present ARNOLD, a benchmark that evaluates language-grounded task learning with continuous states in realistic 3D scenes. ARNOLD is comprised of 8 language-conditioned tasks that involve understanding object states and learning policies for continuous goals. To promote language-instructed learning, we provide expert demonstrations with template-generated language descriptions. We assess task performance by utilizing the latest language-conditioned policy learning models. Our results indicate that current models for language-conditioned manipulations continue to experience significant challenges in novel goal-state generalizations, scene generalizations, and object generalizations. These findings highlight the need to develop new algorithms that address this gap and underscore the potential for further research in this area. See our project page at: https://arnold-benchmark.github.ioComment: The first two authors contributed equally; 20 pages; 17 figures; project availalbe: https://arnold-benchmark.github.io

Determination of free cyclosporine A with a LC-MS/MS method: Application to C2 monitoring in rabbits

Cyclosporine A (CsA) is a cyclic peptide widely used as an immunosuppressant. Therapeutic drug monitoring (TDM) of CsA is becoming mandatory for transplant patients who received CsA therapy in the routine clinical practice because of large individual variability, dose-related toxicity and the risk of acute rejection. In this study, a rapid, sensitive, and selective LC-MS/MS method was developed and validated for the quantitative analysis of free CsA (fCsA), a better indicator for the prediction of efficacy and safety of CsA-based therapy. Following ultrafiltration for fCsA, chromatographic separation was performed on an Agilent Zorbax SB-C18 column (100 mm x 2.1 mm, 3.5 μm ) with acetonitrile and 0.1 % ammonium hydroxide in water (85:15, v/v) as the mobile phases. The compounds were quantified by positive electrospray ionization tandem mass spectrometry. Selectivity, linearity, accuracy, precision, recovery, and stability were evaluated during method validation. The validated method was applied to a single blood concentration measurement 2 h after CsA administration (C2) measurement study of fCsA after an oral administration of a single 15 mg/kg intravenous dose of CsA to six rabbits.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Synthesis of Fluorescent Carbon Dots by Gastrointestinal Fluid Treatment of Mongolia Har Gabur

Har Gabur is the carbide obtained from pig manure by burning. The fluorescent carbon dots (CDs) of Har Gabur were successfully synthesized through simulating the digestion process of human gastrointestinal tract. Transmission Electron Microscope (TEM) analysis showed that the average size of the prepared Har Gabur CDs was 4 nm, with good solubility in water and strong fluorescence under UV irradiation. The X-ray and Raman results showed that the Har Gabur CDs were mainly composed of oxygen “O” and carbon “C” elements, in the forms of “C=O” and “C-O.” The bond energy results showed that the nitrogen “N” atom presented as “C-N” form, which indicated that Har Gabur CDs also contain “N.” In photobleaching assay, Har Gabur CDs showed excellent light stability compared with ordinary organic dye, fluorescein, and Rhodamine B. The fluorescence intensity of Har Gabur CDs was fairly stable within a wide pH range of 3–10. When L-lysine and L-cysteine were applied for the passivation stage, the relative quantum yields were improved by 1.53 and 3.68 times, respectively. Finally, the fluorescence properties of Har Gabur CDs were tested in cells and zebrafish, illustrating that Har Gabur CD has potential in the application of biological labeling and imaging

Glycomics Analysis of Mammalian Heparan Sulfates Modified by the Human Extracellular Sulfatase HSulf2

The Sulfs are a family of endosulfatases that selectively modify the 6O-sulfation state of cell-surface heparan sulfate (HS) molecules. Sulfs serve as modulators of cell-signaling events because the changes they induce alter the cell surface co-receptor functions of HS chains. A variety of studies have been aimed at understanding how Sulfs modify HS structure, and many of these studies utilize Sulf knockout cell lines as the source for the HS used in the experiments. However, genetic manipulation of Sulfs has been shown to alter the expression levels of HS biosynthetic enzymes, and in these cases an assessment of the fine structural changes induced solely by Sulf enzymatic activity is not possible. Therefore, the present work aims to extend the understanding of substrate specificities of HSulf2 using in vitro experiments to compare HSulf2 activities on HS from different organ tissues.To further the understanding of Sulf enzymatic activity, we conducted in vitro experiments where a variety of mammalian HS substrates were modified by recombinant human Sulf2 (HSulf2). Subsequent to treatment with HSulf2, the HS samples were exhaustively depolymerized and analyzed using size-exclusion liquid chromatography-mass spectrometry (SEC-LC/MS). We found that HSulf2 activity was highly dependent on the structural features of the HS substrate. Additionally, we characterized, for the first time, the activity of HSulf2 on the non-reducing end (NRE) of HS chains. The results indicate that the action pattern of HSulf2 at the NRE is different compared to internally within the HS chain.The results of the present study indicate that the activity of Sulfs is dependent on the unique structural features of the HS populations that they edit. The activity of HSulf2 at HS NREs implicates the Sulfs as key regulators of this region of the chains, and concomitantly, the protein-binding events that occur there

Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

As mortality rates decline, life expectancy increases, and populations age, non-fatal outcomes of diseases and injuries are becoming a larger component of the global burden of disease. The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016

Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Measurement of changes in health across locations is useful to compare and contrast changing epidemiological patterns against health system performance and identify specific needs for resource allocation in research, policy development, and programme decision making. Using the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we drew from two widely used summary measures to monitor such changes in population health: disability-adjusted life-years (DALYs) and healthy life expectancy (HALE). We used these measures to track trends and benchmark progress compared with expected trends on the basis of the Socio-demographic Index (SDI). METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2016. We calculated DALYs by summing years of life lost and years of life lived with disability for each location, age group, sex, and year. We estimated HALE using age-specific death rates and years of life lived with disability per capita. We explored how DALYs and HALE differed from expected trends when compared with the SDI: the geometric mean of income per person, educational attainment in the population older than age 15 years, and total fertility rate. FINDINGS: The highest globally observed HALE at birth for both women and men was in Singapore, at 75·2 years (95% uncertainty interval 71·9-78·6) for females and 72·0 years (68·8-75·1) for males. The lowest for females was in the Central African Republic (45·6 years [42·0-49·5]) and for males was in Lesotho (41·5 years [39·0-44·0]). From 1990 to 2016, global HALE increased by an average of 6·24 years (5·97-6·48) for both sexes combined. Global HALE increased by 6·04 years (5·74-6·27) for males and 6·49 years (6·08-6·77) for females, whereas HALE at age 65 years increased by 1·78 years (1·61-1·93) for males and 1·96 years (1·69-2·13) for females. Total global DALYs remained largely unchanged from 1990 to 2016 (-2·3% [-5·9 to 0·9]), with decreases in communicable, maternal, neonatal, and nutritional (CMNN) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). The exemplars, calculated as the five lowest ratios of observed to expected age-standardised DALY rates in 2016, were Nicaragua, Costa Rica, the Maldives, Peru, and Israel. The leading three causes of DALYs globally were ischaemic heart disease, cerebrovascular disease, and lower respiratory infections, comprising 16·1% of all DALYs. Total DALYs and age-standardised DALY rates due to most CMNN causes decreased from 1990 to 2016. Conversely, the total DALY burden rose for most NCDs; however, age-standardised DALY rates due to NCDs declined globally. INTERPRETATION: At a global level, DALYs and HALE continue to show improvements. At the same time, we observe that many populations are facing growing functional health loss. Rising SDI was associated with increases in cumulative years of life lived with disability and decreases in CMNN DALYs offset by increased NCD DALYs. Relative compression of morbidity highlights the importance of continued health interventions, which has changed in most locations in pace with the gross domestic product per person, education, and family planning. The analysis of DALYs and HALE and their relationship to SDI represents a robust framework with which to benchmark location-specific health performance. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform health policies, health system improvement initiatives, targeted prevention efforts, and development assistance for health, including financial and research investments for all countries, regardless of their level of sociodemographic development. The presence of countries that substantially outperform others suggests the need for increased scrutiny for proven examples of best practices, which can help to extend gains, whereas the presence of underperforming countries suggests the need for devotion of extra attention to health systems that need more robust support. FUNDING: Bill & Melinda Gates Foundation

Population and fertility by age and sex for 195 countries and territories, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017

Background: Population estimates underpin demographic and epidemiological research and are used to track progress on numerous international indicators of health and development. To date, internationally available estimates of population and fertility, although useful, have not been produced with transparent and replicable methods and do not use standardised estimates of mortality. We present single-calendar year and single-year of age estimates of fertility and population by sex with standardised and replicable methods. Methods: We estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods. We based the estimates on the demographic balancing equation, with inputs of fertility, mortality, population, and migration data. Fertility data came from 7817 location-years of vital registration data, 429 surveys reporting complete birth histories, and 977 surveys and censuses reporting summary birth histories. We estimated age-specific fertility rates (ASFRs; the annual number of livebirths to women of a specified age group per 1000 women in that age group) by use of spatiotemporal Gaussian process regression and used the ASFRs to estimate total fertility rates (TFRs; the average number of children a woman would bear if she survived through the end of the reproductive age span [age 10–54 years] and experienced at each age a particular set of ASFRs observed in the year of interest). Because of sparse data, fertility at ages 10–14 years and 50–54 years was estimated from data on fertility in women aged 15–19 years and 45–49 years, through use of linear regression. Age-specific mortality data came from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 estimates. Data on population came from 1257 censuses and 761 population registry location-years and were adjusted for underenumeration and age misreporting with standard demographic methods. Migration was estimated with the GBD Bayesian demographic balancing model, after incorporating information about refugee migration into the model prior. Final population estimates used the cohort-component method of population projection, with inputs of fertility, mortality, and migration data. Population uncertainty was estimated by use of out-of-sample predictive validity testing. With these data, we estimated the trends in population by age and sex and in fertility by age between 1950 and 2017 in 195 countries and territories. Findings: From 1950 to 2017, TFRs decreased by 49\ub74% (95% uncertainty interval [UI] 46\ub74–52\ub70). The TFR decreased from 4\ub77 livebirths (4\ub75–4\ub79) to 2\ub74 livebirths (2\ub72–2\ub75), and the ASFR of mothers aged 10–19 years decreased from 37 livebirths (34–40) to 22 livebirths (19–24) per 1000 women. Despite reductions in the TFR, the global population has been increasing by an average of 83\ub78 million people per year since 1985. The global population increased by 197\ub72% (193\ub73–200\ub78) since 1950, from 2\ub76 billion (2\ub75–2\ub76) to 7\ub76 billion (7\ub74–7\ub79) people in 2017; much of this increase was in the proportion of the global population in south Asia and sub-Saharan Africa. The global annual rate of population growth increased between 1950 and 1964, when it peaked at 2\ub70%; this rate then remained nearly constant until 1970 and then decreased to 1\ub71% in 2017. Population growth rates in the southeast Asia, east Asia, and Oceania GBD super-region decreased from 2\ub75% in 1963 to 0\ub77% in 2017, whereas in sub-Saharan Africa, population growth rates were almost at the highest reported levels ever in 2017, when they were at 2\ub77%. The global average age increased from 26\ub76 years in 1950 to 32\ub71 years in 2017, and the proportion of the population that is of working age (age 15–64 years) increased from 59\ub79% to 65\ub73%. At the national level, the TFR decreased in all countries and territories between 1950 and 2017; in 2017, TFRs ranged from a low of 1\ub70 livebirths (95% UI 0\ub79–1\ub72) in Cyprus to a high of 7\ub71 livebirths (6\ub78–7\ub74) in Niger. The TFR under age 25 years (TFU25; number of livebirths expected by age 25 years for a hypothetical woman who survived the age group and was exposed to current ASFRs) in 2017 ranged from 0\ub708 livebirths (0\ub707–0\ub709) in South Korea to 2\ub74 livebirths (2\ub72–2\ub76) in Niger, and the TFR over age 30 years (TFO30; number of livebirths expected for a hypothetical woman ageing from 30 to 54 years who survived the age group and was exposed to current ASFRs) ranged from a low of 0\ub73 livebirths (0\ub73–0\ub74) in Puerto Rico to a high of 3\ub71 livebirths (3\ub70–3\ub72) in Niger. TFO30 was higher than TFU25 in 145 countries and territories in 2017. 33 countries had a negative population growth rate from 2010 to 2017, most of which were located in central, eastern, and western Europe, whereas population growth rates of more than 2\ub70% were seen in 33 of 46 countries in sub-Saharan Africa. In 2017, less than 65% of the national population was of working age in 12 of 34 high-income countries, and less than 50% of the national population was of working age in Mali, Chad, and Niger. Interpretation: Population trends create demographic dividends and headwinds (ie, economic benefits and detriments) that affect national economies and determine national planning needs. Although TFRs are decreasing, the global population continues to grow as mortality declines, with diverse patterns at the national level and across age groups. To our knowledge, this is the first study to provide transparent and replicable estimates of population and fertility, which can be used to inform decision making and to monitor progress. Funding: Bill & Melinda Gates Foundation