Miracle-dz/UniFAR-FTUs huggingface dataset:
Current pharmacotherapy for the treatment of chronic hepatitis B

The virological profile of infection with the hepatitis B virus (HBV) is changing in many parts of the world from the classical hepatitis B e antigen (HBeAg)-positive serological pattern to a HBeAg-negative pattern, linked to the replacement of wild-type HBV by HBV variants with mutations in the core-promoter and in the precore region that prevent the secretion of HBeAg. The wild-type HBV disease is characterised by steady levels of alanine aminotransferase (ALT) and high HBV-DNA levels, responding relatively well to IFN treatment (3 – 5 MU/day or 10 MU every other day for 16 weeks), which induces anti-HBe seroconversion and normalises ALT levels in ∼ 30% of the adults, with a minimal risk of relapse. Pegylated-IFN appears to have superior efficacy over conventional IFN-α. Mutant-type disease (anti-HBe-positive/HBeAg-negative) is less responsive to IFN given for 6 – 12 months. This has led to the use of novel nucleoside analogues, of which the prototype is lamivudine. The response to lamivudine therapy shares with IFN a rapid decline in ALT accompanied by an improvement in histology; at variance with IFN, in HBeAg-positive chronic hepatitis B (CHB) there is delayed seroconversion to anti-HBe which accumulates over time, the switch to anti-HBs is more rare and in the long-term, the activity of the drug is abolished by the emergence of viral mutations (YMDD-motif mutants) that may rekindle the disease. The combination of IFN plus lamivudine may be more efficacious than IFN or lamivudine monotherapy. Lamivudine therapy needs to be prolonged in HBeAg-negative CHB. Short-term lamivudine-therapy is highly efficacious in preventing HBV reinfection in liver transplants. Recent data suggest that long-term IFN therapy (24 months) may achieve a response in 30% of HBeAg-negative patients. The advent of adefovir, an analogue of adenosine monophosphate, may provide a safer alternative to lamivudine in the control of HBV disease; the drug is well-tolerated and treatment raises drug-resistant mutants in < 2% of the patients over 2 years of therapy. Adefovir provides rescue therapy against YMDD mutants raised by lamivudine therapy.
Emotions in the Stock Market

Abstract The authors explore the interaction between media content and market returns and volatility. They utilize propriety investor sentiment measures developed by Thompson Reuters MarketPsych. The data are from a commercial-strength comprehensive textual analysis that provides 24-hr rolling average scores of total references in the news and social media by counting overall positive references net of negative references. The authors select 4 measures of investor sentiment that reflect both pessimism and optimism of small investors. These measures are fear, gloom, joy, and stress. The objective is twofold. First, the authors examine the ability of these sentiment measures to predict market returns. Second, they are interested in exploring the effects of these sentiment measures on market return and volatility. For this purpose, the authors utilize threshold generalized autoregressive conditional heteroskedasticity models. They explore the ability of sentiment measures to predict both the level of and change in market returns. The sentiment measure of stress has a small effect on the market return for a 1-day lag. The other 2 sentiment measures, gloom and joy, seem to play no role in predicting market returns. Furthermore, the authors find that fear among investors has a major and lasting effect on market returns and conditional volatility.
Topographical control of cell behaviour. I. Simple step cues.

The photolithographic techniques of the microelectronics industry have allowed us to fabricate patterned plastic substrata to investigate contact guidance of animal tissue cells. The reactions of cells to single steps on a substratum were examined using time-lapse videorecording and scanning electron microscopy. BHK cells and chick embryonic neural cell processes exhibited gradual inhibition of crossing steps with a concomitant increase in alignment at steps dependent on increasing step height. Comparison of these cells' reactions, with those of chick heart fibroblasts and rabbit neutrophils, at a 5 micron step revealed that the influence of topography is also dependent on cell type, the neutrophils being relatively unaffected. The presence of an adhesive difference at a series of steps altered BHK cells' reactions such that the frequency of crossing was dependent on the direction of approach to a step. Although our data are consistent with Dunn & Heath's proposal (1976) that the inflexibility of the cytoskeleton of a moving cell's protrusion is the cellular property determining such reactions to topography, we have found that, on encountering a topographical feature, the response of a cell may be predictable on a probabilistic basis, i.e. the topographical feature reduces the probability of a cell making a successful protrusion and contact in a given direction, that even the largest features tested did not act as absolute barriers to cell locomotion since a small proportion of a population of cells were able to overcome them, and that other guidance cues could significantly alter a cell's response. Even in situations where it is not the primary cue in directing cell locomotion, topographical control may be an important factor during morphogenesis since it must, at the very least, influence the efficiency of other cues.
Mapping critical residues in eukaryotic DNA-binding proteins: a plasmid-based genetic selection strategy with application to the Oct-2 POU motif.

Discrimination between allowed and disallowed amino acid substitutions provides a powerful method for analysis of protein structure and function. Site-directed mutagenesis allows specific hypotheses to be tested, but its systematic application to entire structural motifs is inefficient. This limitation may be overcome by genetic selection, which allows rapid scoring of thousands of randomly (or pseudorandomly) generated mutants. To facilitate structural dissection of DNA-binding proteins, we have designed two generally applicable bacterial selection systems: pPLUS selects for the ability of a protein to bind to a user-defined DNA sequence, whereas pMINUS selects against such binding. Complementary positive and negative selections allow rapid mapping of critical residues. To test and calibrate the systems, we have investigated the bipartite POU domain of the human B-cell-specific transcription factor Oct-2. (i) An invariant residue (Asn347) in the DNA-recognition helix of the POU-specific homeodomain (POUHD) was substituted by each of the 19 other possible amino acids. The mutant proteins each exhibited decreased specific DNA binding as defined in vivo by genetic selection and in vitro by gel retardation; relative affinities correlate with phenotypes in the positive and negative selection systems. An essential role for Asn347 in wild-type POUHD-DNA recognition is consistent with homologous Asn-adenine interactions in cocrystal structures of canonical homeodomains. (ii) Extension of pPLUS/pMINUS selection to the POU-specific subdomain (POUs) is demonstrated by analysis of mutations in its putative helix-turn-helix (HTH) element. (ABSTRACT TRUNCATED AT 250 WORDS)
High-level mobility outcomes following acquired brain injury: A preliminary evaluation

Primary objective: To evaluate the efficacy of a high-level mobility programme for people with acquired brain injury (ABI). Research design: A cohort study which evaluated the efficacy of a high-level mobility programme for people with ABI. Setting: A major rehabilitation hospital. Participants: Twenty-eight people with acquired brain injury. Experimental interventions: A 3 month high-level mobility programme conducted twice weekly consisting of strengthening exercises, pre-running and running drills and agility exercises supplemented with a gym or home exercise programme. Main outcomes and results: The primary outcome measure was the high-level mobility assessment tool (HiMAT). Participants were predominantly male and young (average age 33.2 years, range 16–72 years) with chronic ABI. HiMAT scores for the 28 participants who returned at the 3 month follow-up initially ranged from 6–44 points (mean 20.3). The 3 month follow-up scores ranged from 12–51 points (mean 29.2). The mean HiMAT score change ranged from 2–20 points (mean 8.9). Conclusions: Significant recovery in high-level mobility was achieved during a 3 month running programme. People with chronic ABI may also expect to benefit from retraining high-level mobility. Clinical trials are needed to assess the effectiveness of training programmes for high-level mobility.
Can We Reduce the Cost of Illness With More Compliant Patients? An Estimation of the Effect of 100% Compliance With Hypertension Treatment

Introduction: The current study was designed to calculate the direct cost of noncompliance of hypertensive patients to the US health system. Understanding these expenses can inform screening and education budget policy regarding expenditure levels that can be calculated to be cost-beneficial. Method: The study was conducted in 3 parts. First, a computer search of National Institutes of Health Web sites and professional society Web sites for organizations with members that treat hypertension, and a PubMed search were performed to obtain the numbers required for calculations. Second, formulas were developed to estimate the risk of noncompliance and undiagnosed hypertension. Third, risk calculations were performed using the information obtained in part 1 and the formulas developed in part 2. Results: Direct risk reduction for stroke caused by hypertension, heart attack, kidney disease, and heart disease was calculated for a 100% compliant strategy. Risk, case, and cost reduction for a 100% compliant strategy for hypertension were 32%, 8.5 million and US$ 72 billion, respectively. Discussion: Our analysis means that the society can spend up to the cost of noncompliance in screening, education, and prevention efforts in an attempt to reduce these costly and traumatic sequelae of poorly controlled hypertension in the light of published analysis.
Five things government can do to encourage local food contingency plans

Severe weather events pose significant risks to food supply chains that are reliant upon critical infrastructures such as road and rail. Can local food procurement arrangements, and contingency plans based on those arrangements, help to ameliorate food shortage in times of crisis? This article explores how governments can empower communities to this end. A broader research project provides the basis of insights and recommendations to aid policy practitioners who seek to develop food-related disaster resilience at the community level. The findings call for the following: the adoption of policies that facilitate the procurement of local food; informing council planning; facilitating shared control with those who want these changes to occur; removing the barriers to change; and utilising a suite of consultation and engagement policies to these ends. It is argued that the Australian regional context of South-East Queensland, with its inherent issues of rapid population growth, has immediate relevance to international contexts.
SGLT-1 Transport and Deglycosylation inside Intestinal Cells Are Key Steps in the Absorption and Disposition of Calycosin-7-O-β-d-Glucoside in Rats

Hydrolysis by lactase-phloridzin hydrolase (LPH) is the first and critical step in the absorption of isoflavonoid glucosides. However, the absorption characteristics of calycosin-7-O-β-d-glucoside (CG) slightly differ from other isoflavonoid glucosides. In this study, we used the rat intestinal perfusion model and performed pharmacokinetic studies and in vitro experiments to determine the factors influencing CG absorption and disposition. After oral administration of isoflavonoid glucosides, LPH was found to play minimal or no role on the hydrolysis of CG, in contrast to that of daidzin. CG was mainly transported into the small intestinal cells by sodium-dependent glucose transporter 1 (SGLT-1) as intact. This pathway could be the main mechanism underlying the high permeability of CG in the small intestine. CG was likely to be hydrolyzed in enterocytes to its aglycone calycosin by broad-specific β-glucuronides (BSβG) and glucocerebrosidase or rapidly metabolized. Calycosin was also rapidly and extensively metabolized to 3′-glucuronide in the enterocytes and liver, and the glucuronidation rates of calycosin and CG were much higher in the former. The metabolites were also transported into lumen by breast cancer resistance protein and multidrug resistance-associated protein 2. In conclusion, the enterocytes could be an important site for CG absorption, deglycosylation, and metabolism in rats. This study could contribute to the theoretical foundation and mechanism of absorption and disposition of flavonoid compounds.
The relationship between blood thiamine levels and dietary thiamine content in diabetic outpatients and healthy subjects.

Forty-six diabetic outpatients consumed (1,533 +/- 308 kcal (mean +/- SD) per day, 205 +/- 42 g of carbohydrates, 73 +/- 18 g of protein, 49 +/- 18 g of fat, and 0.05 +/- 0.34 mg of thiamine. No significant correlation was found in 46 diabetic between blood thiamine level and the intake of dietary energy, carbohydrate or thiamine. In 13 healthy subjects given prepared diets, a significant correlation was found between blood thiamine level and dietary thiamine content, thiamine content per 1,000 kcal, and 24-h urinary thiamine amount divided by urinary creatinine. When 9 healthy subjects (6 males, 3 females) consumed 1,600 kcal with 0.6 mg of thiamine for two days, their blood thiamine level was 47 +/- 29.1 ng/ml before and 29.7 +/- 7.1 ng/ml after eating the diet, showing low blood thiamine levels due to the low content of dietary thiamine. When 5 or 6 healthy female subjects consumed 1,400 kcal with 1.6 mg of thiamine or 2,000 kcal with 1.9 mg of thiamine for two days, their blood thiamine level was 45.3 +/- 4.8 ng/ml or 57.7 +/- 8.4 ng/ml before and 51.5 +/- 11.7 ng/ml or 56.4 +/- 11.7 ng/ml after eating the diets, respectively. In both diabetic outpatients and healthy subjects, a significant positive correlation was found between blood thiamine levels and dietary thiamine concentrations per 1,000 kcal, and a significant positive correlation was also found between erythrocyte transketolase activity and dietary thiamine content. (ABSTRACT TRUNCATED AT 250 WORDS)
Generation of cytokine‐induced killer cells from leukaemic samples with in vitro cytotoxicity against autologous  and allogeneic leukaemic blasts

Summary. Cytokine‐induced killer (CIK) cells are CD3+CD56+ non‐major histocompatibility complex (MHC)‐restricted immune effector cells. The present report demonstrates that it was possible to expand CIK cells obtained at diagnosis from patients with acute leukaemia. The percentage of CD3+CD56+ CIK cells generated following culture ranged between 7·6% and 65% (median of 35·3%) and these cells were able to kill the human natural killer target K562 cells. Although the same effector cells were able to lyse autologous acute myeloid leukaemia (AML) target cells, they were not able to lyse autologous acute lymphoblastic leukaemia target cells. Pre‐absorption of the CIK effector cells by K562 cells did not completely abrogate the cytotoxicity of CIK cells against autologous blasts in 9 out of 12 samples tested. Moreover, it was observed that the cytotoxicity generated by the CIK effector cells against allogeneic leukaemic blasts was similar to that against autologous blasts. The present study suggests the potential application of CIK cells in the immunotherapy of AML, either in minimal disease state, as donor lymphocyte infusion in relapse post allogeneic transplant, or in cases of chemotherapy refractory leukaemia.
Targeting macrophages with baculovirus‐produced lysosomal enzymes: implications for enzyme replacement therapy of the glycoprotein storage disorder galactosialidosis

Lysosomal storage diseases (LSDs) are monogenic disorders of metabolism caused by deficiency of hydrolytic enzymes. In several LSDs, cells of the reticuloendothelial (RE) system are the primary targets of the disease. Exogenous administration of recombinant enzymes overproduced in mammalian cells has proved effective for treating the systemic phenotype in nonneuropathic patients with LSDs. However, for the treatment of diseases with primary involvement of the RE system, the production of the therapeutic enzyme in insect cells could be an alternative and advantageous method because glycoproteins expressed in insect cells carry carbohydrates of the pauci‐mannose or core‐type. These recombinant enzymes are in principle already poised to be internalized by cells that express mannose receptors, including macrophages. Here, we demonstrate that three baculovirus‐expressed enzymes, protective protein/cathepsin A (PPCA), neuraminidase (Neu1), and β‐glucosidase, were readily taken up and restored lysosomal function in enzyme‐deficient mouse macrophages. The capacity of recombinant PPCA and Neu1 to clear the lysosomal storage in target cells was assessed in PPCA−/− mice, a model of galactosialidosis. Intravenously injected PPCA−/− mice efficiently internalized the corrective enzymes in resident macrophages of many organs. In addition, treated mice showed overall clearance of lysosomal storage in the most affected systemic organs, kidney, liver, and spleen. Our results suggest that ERT with baculovirus‐expressed enzymes might be an effective treatment for nonneuropathic patients with galactosialidosis and possibly for others with LSDs that primarily involve the RE system.
Disruption of the p16/Cyclin D1/Retinoblastoma Protein Pathway in the Majority of Human Hepatocellular Carcinomas

p16, cyclin D1 and retinoblastoma protein (pRB) regulate G1 to S transition and are commonly targeted in various cancers. However, few studies have simultaneously examined all components of the p16/cyclin D1/pRB pathway (RB pathway) in hepatocellular carcinoma (HCC). To clarify the role of the disruption of the RB pathway in HCC, we analyzed p16, pRB and cyclin D1 in 47 HCCs. Inactivation of p16 was detected in 30 of 47 HCCs (64%) by Western blot analysis and significantly correlated with hypermethylation of the promoter of this gene. pRB expression was found to be absent in 13 of 47 HCCs (28%) by immunohistochemistry. We found that 38 of 47 HCCs (81%) contained at least one inactivation in either pRB or p16. Furthermore, there was a significant inverse correlation between p16 and pRB inactivation (p = 0.041). Overexpression of cyclin D1 was detected in 5 of 47 HCCs (11%) by immunohistochemistry. The cases with cyclin D1 overexpression exhibited an advanced clinicopathological appearance and also contained inactivation of pRB and/or p16. These findings suggest that inactivation of pRB and/or p16 is a major event in human hepatocarcinogenesis, while cyclin D1 overexpression may confer additional growth advantages to the tumor in addition to pRB and/or p16 inactivation in HCC.
Chaotic Optimization Method without Initial Sampling Parameter Tuning - Empirical Comparisons of Two Approaches in Various Problems

The chaotic optimization method is a global optimization method to solve unconstrained optimization problems. Its superior search capability has been confirmed through applications to optimization problems which have high dimensional and multi-peaked objective functions. However, the chaotic optimization method has a drawback in that a parameter called initial sampling parameter has to be tuned on each optimization problem. In this study, we consider two approaches to perform the chaotic optimization method without the initial sampling parameter tuning. One is the initial sampling estimation method based on the characteristics of the chaotic optimization method. In this method, the sampling parameter at which the search trajectory bifurcates from the fixed point convergence to the two periodic solution trajectory, which is called the first bifurcating parameter, is computed from the approximation matrix to Hessian obtained by the quasi-Newton method. Then, suitable initial sampling parameter is estimated using this information. The other is the descent sign vector method. In this method, a descent sign vector extracted from a gradient vector is used as a search direction of a search point. Then, its moving distance is determined so that its search process shifts from the global search to the local search. We compare two methods and their hybrid method through numerical experiments for various optimization problems.
Financial intermediation cost, rents, and productivity: An international comparison

Calculation of the unit cost of financial intermediation for 20 countries from 1970 to 2015 has produced the following results. (i) Most countries’ unit costs decline and converge in the long run. (ii) Unit costs were much higher in the 1970s and 1980s, coinciding with high nominal rates, as confirmed by panel cointegration tests. (iii) Countries’ unit cost aggregation suggests a slight decrease in international unit cost whatever the set of hypotheses used in the calculation. (iv) The break down of unit costs into labor costs, capital costs, and profits shows that most of the decrease stems from reduced input costs. Gross operating surplus and total compensation per output tend to decline while distributed profit per output rises, suggesting increasing intermediation rents per output. (v) The productivity of labor in finance compared to other sectors tends to increase in most countries. (vi) The evidence suggests that most productivity gains have been captured by the financial sector in Canada, the UK, and the US. Elsewhere, productivity gains have benefited the nonfinancial sector through unit cost reduction. (vii) Deregulation is either negatively or not correlated with unit cost. In other words, deregulation is not related to unit cost increases. Finally, the paper discusses the consequences of those results for current debates about finance relative wage changes and inequalities.
Inhibition of the Fermentation of Propionate to Methane by Hydrogen, Acetate, and Propionate

Inhibition of the fermentation of propionate to methane and carbon dioxide by hydrogen, acetate, and propionate was analyzed with a mesophilic propionate-acclimatized sludge that consisted of numerous flocs (size, 150 to 300 μm). The acclimatized sludge could convert propionate to methane and carbon dioxide stoichiometrically without accumulating hydrogen and acetate in a propionate-minimal medium. Inhibition of propionate utilization by propionate could be analyzed by a second-order substrate inhibition model (shown below) given that the substrate saturation constant, Ks, was 15.9 μM; the substrate inhibition constant, Ki, was 0.79 mM; and the maximum specific rate of propionate utilization, qm, was 2.15 mmol/g of mixed-liquor volatile suspended solids (MLVSS) per day: qs = qmS/[Ks + S + (S2/Ki)], where qs is the specific rate of propionate utilization and S is the initial concentration of undissociated propionic acid. For inhibition by hydrogen and acetate to propionate utilization, a noncompetitive product inhibition model was used: qs = qm/[1 + (P/Kp)n], where P is the initial concentration of hydrogen or undissociated acetic acid and Kp is the inhibition constant. Kinetic analysis gave, for hydrogen inhibition, Kp(H2) = 0.11 atm (= 11.1 kPa, 71.5 μM), qm = 2.40 mmol/g of MLVSS per day, and n = 1.51 and, for acetate inhibition, Kp(HAc) = 48.6 μM, qm = 1.85 mmol/g of MLVSS per day, and n = 0.96. It could be concluded that the increase in undissociated propionic acid concentration was a key factor in inhibition of propionate utilization and that hydrogen and acetate cooperatively inhibited propionate degradation, suggesting that hydrogenotrophic and acetoclastic methanogens might play an important role in enhancing propionate degradation to methane and carbon dioxide.