Miracle-dz/UniFAR-FTUs huggingface dataset:
Relative contribution of cytochromes P-450 and flavin-containing monoxygenases to the metabolism of albendazole by human liver microsomes.

AIMS Albendazole (ABZ; methyl 5-propylthio-1H-benzimidazol-2-yl carbamate) is a broad spectrum anthelmintic whose activity resides both in the parent compound and its sulphoxide metabolite (ABS). There are numerous reports of ABZ metabolism in animals but relatively few in humans. We have investigated the sulphoxidation of ABZ in human liver microsomes and recombinant systems. METHODS The specific enzymes involved in the sulphoxidation of ABZ were determined by a combination of approaches; inhibition with an antiserum directed against cytochrome P450 reductase, the effect of selective chemical inhibitors on ABZ sulphoxidation in human liver microsomes, the capability of expressed CYP and FMO to mediate the formation of ABS, regression analysis of the rate of metabolism of ABZ to ABS in human liver microsomes against selective P450 substrates and regression analysis of the rate of ABS sulphoxidation against CYP expression measured by Western blotting. RESULTS Comparison of Vmax values obtained following heat inactivation (3min at 45 degrees C) of flavin monoxygenases (FMO), chemical inhibition of FMO with methimazole and addition of an antiserum directed against cytochrome P450 reductase indicate that FMO and CYP contribute approximately 30% and 70%, respectively, to ABS production in vitro. Comparison of CLint values suggests CYP is a major contributor in vivo. A significant reduction in ABZ sulphoxidation (n = 3) was seen with ketoconazole (CYP3 A4; 32-37%), ritonavir (CYP3 A4: 34-42%), methimazole (FMO: 28-49%) and thioacetamide (FMO; 32-35%). Additive inhibition with ketoconazole and methimazole was 69 +/- 8% (n = 3). ABS production in heat - treated microsomes (3 min at 45 degrees C) correlated significantly with testosterone 6beta-hydroxylation (CYP3A4; P < 0.05) and band intensities on Western blots probed with an antibody selective for 3A4 (P < 0.05). Recombinant human CYP3 A4, CYP1A2 and FMO3 produced ABS in greater quantities than control microsomes, with those expressing CYP3A4 producing threefold more ABS than those expressing CYP1A2. Kinetic studies showed the Km values obtained with both CYP3A4 and FMO3 were similar. CONCLUSIONS We conclude that the production of ABS in human liver is mediated via both FMO and CYP, principally CYP3A4, with the CYP component being the major contributor.
Laparoscopic versus open radical prostatectomy in high prostate volume cases: impact on oncological and functional results

ABSTRACT Background and objective: To prospectively compare the laparoscopic versus open approach to RP in cases with high prostate volume and to evaluate a possible different impact of prostate volume. Materials and Methods: From March 2007 to March 2013 a total of 120 cases with clinically localized prostate cancer (PC) and a prostate volume>70cc identified for radical prostatectomy (RP), were prospectively analyzed in our institute. Patients were offered as surgical technique either an open retropubic or an intraperitoneal laparoscopic (LP) approach. In our population, 54 cases were submitted to LP and 66 to open RP. We analyzed the association of the surgical technique with perioperative, oncological and postoperative functional parameters. Results: In those high prostate volume cases, the surgical technique (laparoscopic versus open) does not represent a significant independent factor able to influence positive surgical margins rates and characteristics (p=0.4974). No significant differences (p>0.05) in the overall rates of positive margins was found, and also no differences following stratification according to the pathological stage and nerve sparing (NS) procedure. The surgical technique was able to significantly and independently influence the hospital stay, time of operation and blood loss (p<0.001). On the contrary, in our population, the surgical technique was not a significant factor influencing all pathological and 1-year oncological or functional outcomes (p>0.05). Conclusions: In our prospective non randomized analysis on high prostate volumes, the laparoscopic approach to RP is able to guarantee the same oncological and functional results of an open approach, maintaining the advantages in terms of perioperative outcomes.
Pressure pain sensitivity: A new method of stress measurement in patients with ischemic heart disease

Abstract Background. Chronic stress is prevalent in patients with ischemic heart disease (IHD) and worsens the long-term prognosis. Chronic stress is vaguely defined, but is associated with depressive symptoms, reduced psychological wellbeing, and reduced quality of life (QOL). Stress seems to induce hyperalgesia.The aim of the present study was to evaluate hyperalgesia by pressure pain sensitivity (PPS) in patients with IHD, and compare PPS to questionnaires measuring depressive symptoms, reduced psychological wellbeing, and QOL as markers of stress. Design. A cross-sectional study of 361 subjects with IHD. Methods. PPS was measured on the sternum, and compared to the questionnaires: Clinical stress symptoms score (CSS), Major Depression Inventory (MDI), WHO-5 Wellbeing Index, and SF-36 QOL score. Results. PPS correlated to CSS (r = 0.20, p < 0.001), MDI (r = 0.14, p = 0.02), SF-36 mental component summary score (MCS) (r = − 0.10, p = 0.049), SF-36 physical component summary score (PCS) (r = − 0.17, p = 0.001), and self-perceived stress level (r = 0.15, p = 0.006). CSS correlated similarly (r = 0.5–0.7, all p < 0.001). Comparing subjects within the lowest vs. highest tertiles of PPS and CSS, the mean MDI score was 4 vs. 15, WHO-5 was 77 vs. 53, SF-36 PCS was 53 vs. 43, and SF-36 MCS was 58 vs. 46; all p < 0.001. Conclusions. PPS reflected to a modest degree markers of chronic stress in IHD. PPS and CSS together might be useful as easy-to use tools for evaluating these markers in IHD patients.
Correlation between concentration of cholinesterases and the resistance of animals to organophosphorus compounds.

The molar concentrations of the catalytic sites of serum cholinesterase (ChE--EC 3.1.1.8.) and cholinesterases (ChEs-acetylcholinesterase (AChE)--EC 3.1. 1.7. and ChE) from brain and perfused liver of male birds, rats, swine and sheep were determined. A positive correlation between the molar concentrations of the catalytic sites of ChEs and the resistance of the animals to some organophosphorus compounds (OPhCs) was found. In addition, the present study also showed that the difference of the molar concentrations of catalytic sites of ChEs in the brain, blood serum and liver can cause varied resistance to some OPhCs.
Stage-Specific Effects of Androgens and Estradiol-17beta on the Development of Late Primary and Early Secondary Ovarian Follicles of Coho Salmon (Oncorhynchus kisutch) In Vitro1

ABSTRACT An in vitro system was used to analyze the effects of sex steroids on the development of primary (late perinucleolar stage) and early secondary, previtellogenic (early cortical alveolus stage) ovarian follicles of coho salmon cultured for up to 21 days. Late perinucleolar-stage follicles increased significantly in size after 7 days of treatment with low concentrations of 11-ketotestosterone (11-KT), a nonaromatizable androgen. An androgen receptor antagonist (flutamide) inhibited this growth-promoting effect, and the highest concentration resulted in atresia of follicles, implicating androgens as survival factors at this stage. Testosterone (T) was less effective than 11-KT in promoting growth, but blocking aromatization with exemestane resulted in a growth response similar to that of 11-KT. Estradiol-17beta (E2) had no effect on growth at this stage. After 21 days of culture, E2 was the most potent steroid in increasing the number of follicles containing cortical alveoli and the number of cortical alveoli within those follicles. At the early cortical alveolus stage, low doses of E2 promoted growth and strongly stimulated synthesis of cortical alveoli, actions that were inhibited by an estrogen receptor antagonist (tamoxifen). 11-KT displayed moderate growth-promoting effects, and 11-KT and T stimulated moderate to substantial increases in abundance of cortical alveoli. This study shows that the predominant role of androgens is the promotion of growth of late perinucleolar-stage follicles, while E2 stimulates both the growth and accumulation of cortical alveoli in early cortical alveolus-stage follicles.
Immunomodulatory effects of selenium and vitamin E on alterations in T lymphocyte subsets induced by T-2 toxin

Abstract Context: T-2 toxin, a potent mycotoxin, has serious effects on immune system. Objective: Here, the effects of a sublethal dose of this toxin on T lymphocyte sub-population levels and the potential protective effects from treatment with selenium or vitamin E were studied. Materials and methods: After having determined the sublethal dose of the T-2 toxin in Balb/c mice hosts, the post-injection kinetics of changes in T lymphocyte sub-population (CD3+, CD4+ and CD8+ cells) profiles were analyzed via flow cytometry. For these studies, the selenium and vitamin E were either provided to the mice before or concurrent with the toxin. Results: The results show that after a sublethal dose of T-2 alone, the number of CD8+ T-lymphocytes was significantly decreased at 12 h and normalized at 48 h. In contrast, level of CD3+ and CD4+ T-lymphocytes were significantly increased at 24 h and returned to normal after 48 h. When selenium was injected into the mice 24 h before or concurrent with the T-2, the effects on CD8+ cells were mitigated. Oddly, only when the selenium was given with the toxin could the effects on the CD3+ and CD4+ cells be altered. Vitamin E, when injected 24 h before or concurrent with the T-2 toxin, was only able to impact upon the CD8+ lymphocyte alterations induced by the toxin. Conclusions: Compared with vitamin E, it seems that selenium could assert an important effect against the immunotoxic effects of T-2 toxin against T lymphocytes.
Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome

Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is characterized by deficient cognition and inevitable development of the Alzheimer disease (AD) type pathology during aging. Here we used JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), to examine the effects of chronic MAGL inhibition on the behavioral, biochemical, and synaptic properties of aged Ts65Dn mice, a genetic model of DS. In both Ts65Dn mice and their normosomic (2N) controls, JZL184-treatment increased brain levels of 2-arachidonoylglycerol (2-AG) and decreased levels of its metabolites such as arachidonic acid, prostaglandins PGD2, PGE2, PGFα, and PGJ2. Enhanced spontaneous locomotor activity of Ts65Dn mice was reduced by the JZL184-treatement to the levels observed in 2N animals. Deficient long-term memory was also improved, while short-term and working types of memory were unaffected. Furthermore, reduced hippocampal long-term potentiation (LTP) was increased in the JZL184-treated Ts65Dn mice to the levels observed in 2N mice. Interestingly, changes in synaptic plasticity and behavior were not observed in the JZL184-treated 2N mice suggesting that the treatment specifically attenuated the defects in the trisomic animals. The JZL184-treatment also reduced the levels of Aβ40 and Aβ42, but had no effect on the levels of full length APP and BACE1 in both Ts65Dn and 2N mice. These data show that chronic MAGL inhibition improves the behavior and brain functions in a DS model suggesting that pharmacological targeting of MAGL may be considered as a perspective new approach for improving cognition in DS.
Proteasome inhibitors and IMiDs can overcome some high‐risk cytogenetics in multiple myeloma but not gain 1q21

Chromosomal aberrations have significant prognostic importance in multiple myeloma (MM). However, proteasome inhibitors (PI) and IMiDs may partly overcome the poor prognostic impact of some of them. In this study, we investigated a population‐based consecutive cohort newly diagnosed patients with MM admitted during a defined time period to hospitals in Denmark, Norway, and Sweden. The impact of treatment modality on the prognostic importance of specific chromosomal aberration was investigated, with special reference to gain 1q21. The median follow‐up of patients still alive at analysis was 40 months for the high‐dose (HDT)‐treated ones and 29 months for the whole population. Three hundred forty‐seven patients with a known 1q21 status were included in this study. The 347 patients were divided into three groups, that is, 119 patients with the 1q21 gain, 105 patients with other aberrations (OA), that is, del(13q), del(17p), t(4,14), and/or (14;16), and 123 patients with no aberrations (NA). The groups were compared in terms of overall survival (OS), time to progression (TTP), and response. The 3‐yr OS for patients with gain 1q21 was 60% compared to patients with OA 74% and NO 82% (gain 1q21 vs. NO P < 0.001; gain 1q21 vs. OA P = 0.095). If treated with PI or IMiDs, the 3‐yr OS was 58% for patients with gain 1q21 compared to patients with OA 78% and NO 78%, respectively (P = 0.041, P = 0.140). In HDT patients, the 3‐yr OS was 69% for patients with gain 1q21 compared to patients with OA 84% and NO 88%, respectively (P < 0.008, P = 0.600). Thus, neither HDT nor using PI or IMiDs could overcome the poor prognostic impact of gain 1q21, while these drugs and HDT seemed to improve OS in patients with OA, approaching the survival in NO. Further, gain 1q21 appears to be one of the most important poor prognostic chromosomal aberrations in multiple myeloma with current treatments. Trials using new drugs or allogeneic transplantation are warranted.
Working capital financing, firm performance and financial constraints

Purpose The purpose of this paper is to examine the relationship between working capital financing and firm performance for a sample of 437 non-financial Indian companies. In addition, this study examines the impact of financial constraints on working capital financing–performance relationship. Design/methodology/approach The study is based on secondary financial data of 437 non-financial Indian companies obtained from Capitaline database, pertaining to a period of 10 years (2007–2016). This study employs two-step generalized method of moments techniques to arrive at results. Findings Results of the study confirm the inverted U-shape relationship between working capital financing and firm performance. In addition, the authors also found that the firms that are likely to be less financially constrained can finance greater proportion of working capital using short-term debt. Originality/value This study contributes to the scant existing literature by testing the impact of financial constraints on the relationship between working capital financing and firm performance, representing a typical emerging market in India.
A computer model for the growth and differentiation of a fungal colony on solid substrate

Mold growth and differentiation are closely related to the formation of secondary products. In solid‐substrate fermentations this interrelationship is often more completely realized than in submerged cultures. Solid substrate reactions are used commercially in a limited manner in the western world, but are relatively common in Asia. Basic studies in solid‐substrate fermentation should yield results applicable to all types of commercial mold fermentations for the production of a secondary product. This paper presents a relatively simple model for the growth of a mold colony on a solid surface with a defined medium utilizing glucose. Unlike submerged cultures the model must account for both cellular differentiation and the spatial heterogeneity in the system. Model parameters were estimated independently using literature values. The results of the simulation studies suggest that mass transfer limitations are at least partially responsible for the proliferation of differentiated structures on solid substrates as compared to liquid cultures. Since the concentration profile depends on the depth of the substratum, conditions that enhance conidia production can be achieved by controlling the depth of the solid medium.
Pregnancy outcome after previous stillbirth resulting from causes other than maternal conditions and fetal abnormalities.

BACKGROUND An adequate fetomaternal circulatory system may be compromised by a variety of disturbances leading to stillbirth. The purpose of this study was to assess subsequent pregnancy outcome in women with a history of stillbirth as a result of causes other than maternal conditions and fetal abnormalities. METHODS Ninety-two deliveries after stillbirth were identified among 11,910 deliveries of parous women recorded in the birth registry at Kuopio, Finland. Using logistic regression, pregnancy outcome measures were compared with those of a parous healthy obstetric population (n = 11,818). RESULTS Women with a history of stillbirth as a result of causes other than maternal conditions and fetal abnormalities were older than their unaffected controls (32.4 yr vs 30.3 yr). Stillbirth in an earlier pregnancy was associated with a significantly higher (p < 0.001) frequency of placental abruption in subsequent pregnancy (5.4% vs 0.7%). A history of stillbirth was predictive of preterm delivery (OR = 2.25) and low-birthweight infants (OR = 2.70). No recurrence was reported. CONCLUSIONS Pregnancy with a history of stillbirth as a result of causes other than maternal conditions and fetal abnormalities is a moderate risk state, with prematurity and low-birthweight rates somewhat higher than those in the general population. The overall probability of a favorable outcome is good. These findings may be useful in counseling pregnant women with a history of stillbirth.
The expression of presenilin 1 enhances carcinogenesis and metastasis in gastric cancer

Presenilin 1 (PS-1, encoded by PSEN1) is a part of the gamma− (γ−) secretase complex. Mutations in PSEN1 cause the majority of cases of familial Alzheimer's disease (FAD). Although in recent years PS-1 has been implicated as a tumor enhancer in various cancers, nothing is known regarding its role in gastric cancer (GC). In the present study, we investigate the role and clinical significance of PS-1 in GC. We observed that PS-1 was significantly upregulated and amplified in GC tissues and cell lines, and its aberrant expression was positively correlated with lymph node metastasis and with poor overall survival. Furthermore, PS-1 promoted tumor invasion and metastasis of GC both in vitro and vivo without affecting the proliferation of GC cells (MGC-803 and MKN-45). The results of treatment with the γ-secretase inhibitor DAPT were consistent with the outcomes of PS-1 silencing. PS-1/γ-secretase cleaves E-cadherin and releases its bound protein partner, β-catenin, from the actin cytoskeleton, thereby allowing it to translocate into the nucleus and to activate the TCF/LEF-1 transcriptional activator, which may promote GC invasion and metastasis. In conclusion, PS-1 promotes invasion and metastasis in GC and may represent a novel prognostic biomarker and potential therapeutic target for GC treatment.
A Systematic Review of Cognitive Behavioral Therapy and Behavioral Activation Apps for Depression

Depression is a common mental health condition for which many mobile apps aim to provide support. This review aims to identify self-help apps available exclusively for people with depression and evaluate those that offer cognitive behavioural therapy (CBT) or behavioural activation (BA). One hundred and seventeen apps have been identified after searching both the scientific literature and the commercial market. 10.26% (n = 12) of these apps identified through our search offer support that seems to be consistent with evidence-based principles of CBT or BA. Taking into account the non existence of effectiveness/efficacy studies, and the low level of adherence to the core ingredients of the CBT/BA models, the utility of these CBT/BA apps are questionable. The usability of reviewed apps is highly variable and they rarely are accompanied by explicit privacy or safety policies. Despite the growing public demand, there is a concerning lack of appropiate CBT or BA apps, especially from a clinical and legal point of view. The application of superior scientific, technological, and legal knowledge is needed to improve the development, testing, and accessibility of apps for people with depression.
Joint exploration model based light field image coding: A comparative study

The recent light field imaging technology has been attracting a lot of interests due to its potential applications in a large number of areas including Virtual Reality, Augmented Reality (VR/AR), Teleconferencing, and E-learning. Light Field (LF) data is able to provide rich visual information such as scene rendering with changes in depth of field, viewpoint, and focal length. However, Light Field data usually associates to a critical problem — the massive data. Therefore, compressing LF data is one of the main challenges in LF research. In this context, we present in this paper a comparative study for compressing LF data with not only the widely used image/video coding standards, such as JPEG-2000, H.264/AVC, HEVC and Google/VP9 but also with the most recent image/video coding solution, the Joint Exploration Model. In addition, this paper also proposes a LF image coding flow, which can be used as a benchmark for future LF compression evaluation. Finally, the compression efficiency of these coding solutions is thoroughly compared throughout a rich set of test conditions.
Presence of a Plant-like Proton-pumping Pyrophosphatase in Acidocalcisomes of Trypanosoma cruzi*

The vacuolar-type proton-translocating pyrophosphatase (V-H+-PPase) is an enzyme previously described in detail only in plants. This paper demonstrates its presence in the trypanosomatid Trypanosoma cruzi. Pyrophosphate promoted organellar acidification in permeabilized amastigotes, epimastigotes, and trypomastigotes of T. cruzi. This activity was stimulated by K+ ions and was inhibited by Na+ ions and pyrophosphate analogs, as is the plant activity. Separation of epimastigote extracts on Percoll gradients yielded a dense fraction that contained H+-PPase activity measured both by proton uptake and phosphate release but lacked markers for mitochondria, lysosomes, glycosomes, cytosol, and plasma membrane. Antiserum raised against specific sequences of the plant V-H+-PPase cross-reacted with a T. cruziprotein, which was also detectable in the dense Percoll fraction. The organelles in this fraction appeared by electron microscopy to consist mainly of acidocalcisomes (acidic calcium storage organelles). This identification was confirmed by x-ray microanalysis. Immunofluorescence and immunoelectron microscopy indicated that the V-H+-PPase was located in the plasma membrane and acidocalcisomes of the three different forms of the parasite. Pyrophosphate was able to drive calcium uptake in permeabilized T. cruzi. This uptake depended upon a proton gradient and was reversed by a specific V-H+-PPase inhibitor. Our results imply that the phylogenetic distribution of V-H+-PPases is much wider than previously perceived but that the enzyme has a unique subcellular location in trypanosomes.