Miracle-dz/UniFAR-FTUs huggingface dataset:
Performance characteristics of the adjusted r2 algorithm for determining the start of the terminal disposition phase and comparison with a simple r2 algorithm and a visual inspection method

The adjusted r2 algorithm is a popular automated method for selecting the start time of the terminal disposition phase (tz) when conducting a noncompartmental pharmacokinetic data analysis. Using simulated data, the performance of the algorithm was assessed in relation to the ratio of the slopes of the preterminal and terminal disposition phases, the point of intercept of the terminal disposition phase with the preterminal disposition phase, the length of the terminal disposition phase captured in the concentration‐time profile, the number of data points present in the terminal disposition phase, and the level of variability in concentration measurement. The adjusted r2 algorithm was unable to identify tz accurately when there were more than three data points present in a profile's terminal disposition phase. The terminal disposition phase rate constant (λz) calculated based on the value of tz selected by the algorithm had a positive bias in all simulation data conditions. Tolerable levels of bias (median bias less than 5%) were achieved under conditions of low measurement variability. When measurement variability was high, tolerable levels of bias were attained only when the terminal phase time span was 4 multiples of t1/2 or longer. A comparison of the performance of the adjusted r2 algorithm, a simple r2 algorithm, and tz selection by visual inspection was conducted using a subset of the simulation data. In the comparison, the simple r2 algorithm performed as well as the adjusted r2 algorithm and the visual inspection method outperformed both algorithms. Recommendations concerning the use of the various tz selection methods are presented.
Testicular protective effects of ellagic acid on monosodium glutamate-induced testicular structural alterations in male rats

ABSTRACT Ellagic acid (EA) has significant protective and antioxidant effects on several tissues. Monosodium glutamate (MG) is known as a flavor promoter that reversibly influences the male reproductive system. This study aims to assess the ameliorative effect of EA on oxidative stress and testicular damage induced by MG. In total, 48 male rats were included in this study and separated into six groups: control, EA (20 mg/kg), MG (low dose) (17.5 mg/kg), MG (high dose) (60 mg/kg), MG (low dose) combined with EA, and MG (high dose) combined with EA. Testicular antioxidant biomarkers [superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRx), catalase (CAT), myeloperoxidase (MPO), and xanthine oxidase (XO)] were examined. Testes were examined and scored for histological variation as an indicator of testicular damage following administration of MG alone or in combination with EA. Serum testosterone, inhibin B, 8-hydroxydeoxyguanosine (as a marker of DNA damage), and transmission electron microscope sections of the testis were evaluated, and a comet assay was performed. Results showed that administration of EA combined with MG significantly elevated the levels of enzymatic antioxidants and decreased lipid peroxidation compared with MG treatment alone. EA elevated testosterone hormone levels and thus enhanced male reproductive capacity. It is clear from the data that EA inhibits histological and ultrastructure testicular damage and improves the redox state in male rats. Graphical Abstract
Pharmaceutical Benefits of Fluticasone Propionate Association to Delivery Systems: In Vitro and In Vivo Evaluation

The objective of the present work was to characterize the ability of liposomes and cyclodextrin (CyD) complexes to modulate the in vivo profile of fluticasone (FTZ). In vitro cell compatibility tests were performed, exposing A549 cells to FTZ in the free form and FTZ associated to liposomes and complexed with CyD. The in vivo fate of a selected FTZ liposomal formulation and of several FTZ CyD complexes was achieved following intranasal instillation or pulmonary administration in BALB/c mice, respectively. For pulmonary administration, an inhalation chamber was constructed to enable the simultaneously pulmonary administration to six mice. Thirty minutes and 3 h after administration, mice were sacrificed, their blood, lungs, livers, and spleens were removed, and FTZ level was determined by HPLC using an extraction procedure. The in vitro tests revealed no toxic effects of FTZ formulations, as cellular viability was always superior to 90% for FTZ concentrations ranging from 5 to 60 µM 72 h after incubation. The in vivo biodistribution results showed that FTZ incorporated in liposomes resulted in 20 and 30 times higher accumulation in the lungs in comparison with free FTZ, at 0.5 and 3 h after i.n. administration, respectively. FTZ associated to Hydroxypropyl-γ-cyclodextrin (HP-CyD) was the complex that permitted the higher accumulation of FTZ in the lungs in comparison with the respective free form. The results also suggest that the inhalation chamber apparatus can effectively facilitate the evaluation of in vivo inhalation. The establishment of an animal model of asthma allows us to further study the therapeutic efficacy of the developed FTZ formulations.
Malt1 Protease Deficiency in Mice Disrupts Immune Homeostasis at Environmental Barriers and Drives Systemic T Cell–Mediated Autoimmunity

Key Points Autoreactive T cells drive the lethal disease in Malt1PD mice. Malt1PD mice display B cell hyperactivation to environmental Ags. IPEX-like disease occurs in Malt1PD mice despite in vitro Treg suppressive activity. The paracaspase Malt1 is a key regulator of canonical NF-κB activation downstream of multiple receptors in both immune and nonimmune cells. Genetic disruption of Malt1 protease function in mice and MALT1 mutations in humans results in reduced regulatory T cells and a progressive multiorgan inflammatory pathology. In this study, we evaluated the altered immune homeostasis and autoimmune disease in Malt1 protease-deficient (Malt1PD) mice and the Ags driving disease manifestations. Our data indicate that B cell activation and IgG1/IgE production is triggered by microbial and dietary Ags preferentially in lymphoid organs draining mucosal barriers, likely as a result of dysregulated mucosal immune homeostasis. Conversely, the disease was driven by a polyclonal T cell population directed against self-antigens. Characterization of the Malt1PD T cell compartment revealed expansion of T effector memory cells and concomitant loss of a CD4+ T cell population that phenotypically resembles anergic T cells. Therefore, we propose that the compromised regulatory T cell compartment in Malt1PD animals prevents the efficient maintenance of anergy and supports the progressive expansion of pathogenic, IFN-γ–producing T cells. Overall, our data revealed a crucial role of the Malt1 protease for the maintenance of intestinal and systemic immune homeostasis, which might provide insights into the mechanisms underlying IPEX-related diseases associated with mutations in MALT1.
Douleur Neuropathique 4 (DN4) stratifies possible and definite neuropathic pain after surgical peripheral nerve lesion

Douleur Neuropathique 4 (DN4) is a screening questionnaire to help identify neuropathic pain (NP) in clinical practice and research. We tested the accuracy of the DN4 questionnaire in stratifying possible NP (pNP) and definite NP (dNP) in patients operated for breast cancer.
Determinants of Earnout as Optimal Payment Currency in Domestic versus Cross- Border Acquisitions and Bidders’ Gains

We investigate the wealth effects of a comprehensive sample of US bidders offering contingent payments, or earnouts, as consideration for their domestic versus cross-border acquisitions. Our evidence conveys that bidders of domestic versus cross-border target firms using earnouts yield similar announcement period gains to their shareholders, irrespective of several transactionand firmspecific characteristics. We construct a logistic model to predict the ‘optimal’ use of earnouts by both bidders of domestic and cross-border target firms. We show that bidders using earnouts ‘optimally’ enjoy higher announcement period gains from bids of cross-border targets than from bids of domestic targets, consistent with our model of the choice of the optimal method of payment. Our findings also confirm that the use of earnouts in foreign bids appears much more compelling, particularly when it is used ‘optimally’, compared to the ‘optimal’ use of earnouts in domestic bids. Overall, we provide robust evidence that the use of earnouts in domestic and/or cross-border acquisitions is an effective payment mechanism that helps in significantly mitigating information asymmetry issues and valuation errors, while it enhances acquirers’ net value gains in the short-run.
Phylogenetic dispersion and diversity in regional assemblages of seed plants in China

Significance Ecological and evolutionary processes work together in the assembly of regional and local communities from available species pools based on species traits linked to ecological tolerances. Because phylogenies summarize the evolutionary history of the clades within them, phylogeny-based approaches are essential to understanding the origin of variation in species richness across environmental gradients. Here, we analyze, within a phylogenetic context, a comprehensive dataset on the distributions of seed plants in China. Specifically, we examined relationships between indices of phylogenetic structure and environment for individual clades, from taxonomic families to the root of the phylogeny of the Chinese seed plants. We found that phylogenetic niche conservatism plays an important role in the assembly of regional floras in China. Species assemble into communities through ecological and evolutionary processes. Phylogenetic niche conservatism—the tendency of species to retain ancestral ecological distributions—is thought to influence which species from a regional species pool can persist in a particular environment. We analyzed data for seed plants in China to test hypotheses about the distribution of species within regional floras. Of 16 environmental variables, actual evapotranspiration, minimum temperature of the coldest month, and annual precipitation most strongly influenced regional species richness, phylogenetic dispersion, and phylogenetic diversity for both gymnosperms (cone-bearing plants) and angiosperms (flowering plants). For most evolutionary clades at, and above, the family level, the relationships between metrics of phylogenetic dispersion (i.e., average phylogenetic distance among species), or phylogenetic diversity, and the 3 environmental variables were consistent with the tropical niche conservatism hypothesis, which predicts closer phylogenetic relatedness and reduced phylogenetic diversity with increasing environmental stress. The slopes of the relationships between phylogenetic relatedness and the 3 environmental drivers identified in this analysis were steeper for primarily tropical clades, implying greater niche conservatism, than for primarily temperate clades. These observations suggest that the distributions of seed plants across large-scale environmental gradients in China are constrained by conserved adaptations to the physical environment, i.e., phylogenetic niche conservatism.
PROX1 is a specific and dynamic marker of sacral neural crest cells in the chicken intestine

The enteric nervous system (ENS) is a complex network constituted of neurons and glial cells that ensures the intrinsic innervation of the gastrointestinal tract. ENS cells originate from vagal and sacral neural crest cells that are initially located at the border of the neural tube. In birds, sacral neural crest cells (sNCCs) first give rise to an extramural ganglionated structure (the so‐called Nerve of Remak [NoR]) and to the pelvic plexus. Later, sNCCs enter the colon mesenchyme to colonize and contribute to the intrinsic innervation of the caudal part of the gut. However, no specific sNCC marker has been described. Here, we report the expression pattern of prospero‐related homeobox 1 (PROX1) in the developing chick colon. PROX1 is a homeobox domain transcription factor that plays a role in cell type specification in various tissues. Using in situ hybridization and immunofluorescence techniques, we showed that PROX1 is expressed in sNCCs localized in the NoR and in the pelvic plexus. Then, using real‐time quantitative PCR we found that PROX1 displays a strong and highly dynamic expression pattern during NoR development. Moreover, we demonstrated using in vivo cell tracing, that sNCCs are the source of the PROX1‐positive cells within the NoR. Our results indicate that PROX1 is the first marker that specifically identifies sNCCs. This might help to better identify the role of the different neural crest cell populations in distal gut innervation, and consequently to improve the diagnosis of diseases linked to incomplete ENS formation, such as Hirschsprung's disease.
Proteomics Profiling of Swine Serum Following Lipopolysaccharide Stimulation.

RATIONALE There are no approved animal drugs for management of inflammation in swine due to lack of validated animal models. To assess efficacy, it was essential to develop proteomics approaches to identify suitable biomarkers of inflammation as presented in this study. METHODS Serum samples were collected from a group of 4 pigs prior to (baseline), and 24 and 48 h following lipopolysaccharide (LPS) stimulation to reveal proteomic changes during inflammation. Two other pigs served as untreated controls. Proteins were separated by either 1D SDS-PAGE or 2D gel electrophoresis (2DE) prior to analysis by nano flow liquid chromatography (nLC) coupled to tandem mass spectrometry. RESULTS We identified 165 proteins using SDS-PAGE, of which 47 proteins were also detected by 2DE prior to nLC-MS/MS. More than half (72%) of all characterized proteins were modulated as a result of LPS stimulation, many of which are known to be involved with innate and adaptive immunity. Pig serum samples obtained 24 h after LPS initiation of inflammation showed protein modulations of serum albumin, serotransferrin, light and heavy immunoglobulin chains (IGs), and major acute phase proteins including haptoglobin (HPT), serum amyloid A2 (SAA2), C-reactive protein (CRP), β-2-glycoprotein 1 (B-2GP1), alpha-2-HS-glycoprotein (A2HS), α-1-antitrypsin (A1AT), and α-1-acid glycoprotein (A1AG). SAA2 was distinguished from the other SAA isoforms by the unique peptide sequence of SAA2. CONCLUSIONS The results provided proteomic analysis of swine serum due to LPS stimulation and indicated the importance of SAA2, which appears to be unique and may be regarded as a potential clinical diagnostic biomarker of inflammation.
Risk of Mortality between Untreated and Treated Papillary Thyroid Cancer: A Matched Cohort Analysis

Objectives: To examine the association between treatment status and mortality risk among patients with papillary thyroid cancer (PTC). Methods: We identified 3,679 adults with PTC. Thirty-one untreated patients were matched to 155 treated patients. Hazards ratios (HR) and 95% confidence intervals (CIs) were calculated to estimate all-cause and disease-specific mortality. A low-risk subgroup was analyzed for differences in all-cause mortality. Results: The adjusted HRs (95% CIs) for all-cause mortality at 5 and 10 years were 4.2 (1.7-10.3) and 4.1 (1.9-9.4) and for disease- specific mortality were 14.1 (3.4-59.3) and 10.2 (2.9-36.4), respectively, for untreated versus treated patients. The adjusted HRs (95% CIs) for all- cause mortality was 0.7 (0.1-6.4) for low-risk untreated versus matched treated patients. Conclusions: Compared to treated patients, untreated PTC patients were at higher risk of death while low-risk untreated PTC patients had comparable rate of metastasis and no increased risk of all-cause mortality. Level of evidence: 3
Aplicação de Escala de Risco Familiar como instrumento de priorização das Visitas Domiciliares

The introduction of the Health Family Program was an attempt to reorganize the primary care in Brazil, presenting the House Visiting as an instrument peculiar to the Family Physician's activity. A family risk scale, based at the SIAB program's filling card "A", was elaborated in order to establish priorities at the visiting. This scale is based on sentinels that are seem when the first visiting is made by the Health Agent Professional (ACS). It was applied to distinct communities and microareas, showing family's graduation risk 1,2 or 3 in different proportions. The results points the relation "inhabitant vs room" as na important data in the evaluation of the risk, and the successful application of the scale as an instrument to determine priorities, both in the house visiting process, as in the health staff resources. The scale showed to be a simple and efficient instrument of analysis of the family's risk, without creating any new filling cards or burocratic stuff. The authors suggest that only the systematic use of the risk scale the Coelho Scale - as an instrument to reorganize the assistance, and posterior evaluation of it's impact at the community, can corroborate the applicability of it to the Family Physician's practice.
Chronotype, social jetlag, and time perspective

ABSTRACT The phase of entrainment (chronotype) is known to be associated with time perspective (TP), suggesting that the state of circadian system is involved in the long-term planning of human life. However, little is known regarding the influence of circadian misalignment on long-term planning ability. The aim of this study was to investigate the association between social jetlag (SJL) and TP. A total of 1064 schoolchildren and university students (mean age ± standard deviation, 19.2 ± 2.9 years; range, 15–25 years; females, 71.7%) from four cities in the Russian Federation located between 56.9 and 61.7 degrees North completed the Munich ChronoType Questionnaire, the Pittsburgh Sleep Quality Index, the Seasonal Pattern Assessment Questionnaire, and Zimbardo Time Perspective Inventory. Study participants also indicated personal data (age, sex, height weight, place of residence, and achievements). A multiple regression analysis with stepwise inclusion of predictors in the model was performed to evaluate associations between time perspective characteristics (dependent variables) and predictor variables. The change in R2 was used as the measure of effect size. Chronotype was found to be a moderate predictor of future TP (B = 0.034; ΔR2 = 0.037). In addition, sleep quality was found to be a moderate predictor of past negative (B = 0.043; ΔR2 = 0.074), present fatalistic (B = 0.021; ΔR2 = 0.035), and deviation from balanced TP (B = 0.034; ΔR2 = 0.066). Mood seasonality was a moderate predictor of present hedonistic TP (B = 0.016; ΔR2 = 0.038), and social jetlag was a weak predictor of present fatalistic (B = 0.052; ΔR2 = 0.019), future (B = −0.033; ΔR2 = 0.004), and deviation from balanced TP (B = 0.047; ΔR2 = 0.012). In conclusion, this study found a weak but significant association between social jetlag and TP in adolescents and young adults.
Characterizing the effects of in utero exposure to valproic acid on murine fetal heart development.

BACKGROUND Recently, the use of the antiepileptic drug valproic acid (VPA) for the treatment of psychiatric conditions has been on the rise. However, studies have shown that in utero VPA exposure can affect embryonic development, including being associated with congenital heart defects. One proposed mechanism of VPA-initiated teratogenicity is the inhibition of histone deacetylase, which is involved in the regulation of transcription factors that regulate cardiogenesis. Myocyte enhancing factor 2C (Mef2c), a transcription factor involved in the development of cardiac structure and cardiomyocyte differentiation, has been shown to increase in response to in utero VPA exposure, associating with contractile dysfunction and myocardial disorganization. METHODS To characterize the effects of VPA on murine heart development, pregnant CD-1 mice were dosed with 400 mg/kg of VPA on gestational day (GD) 9. Using high-resolution ultrasound, we examined the effects of VPA on cardiac contractile function on GD 14-18, with fetal hearts being harvested on GD 19 for histological analysis. Lastly, we conducted quantitative real-time polymerase chain reaction to measure the relative Mef2c gene expression in GD 16 murine hearts. RESULTS We observed structural anomalies at GD 19 in the hearts of VPA-treated mice. Additionally, our results showed alterations in measures of cardiac contractility, with a decrease or increase in cardiac contractile ability in VPA-treated mice depending on the GD and measurement taken. CONCLUSIONS These results further characterize the effects of VPA on heart development and suggest that alterations in Mef2c gene expression, at least on GD 16, do not mediate VPA-induced cardiotoxicity in CD-1 mice.
Serum microRNA expression profiling identifies serum biomarkers for HCV-related hepatocellular carcinoma.

BACKGROUND The identification of high-sensitivity biomarkers for detection of hepatocellular carcinoma (HCC) from high-risk individuals is essential. OBJECTIVE The present study was undertaken to identify and validate serum microRNAs (miRNAs) as potential biomarkers for hepatitis C virus (HCV)-related HCC. METHODS Illumina sequencing was employed to screen the expression profiles of miRNAs in serum samples of HCV-related HCC patients and liver cirrhosis (LC) patients. RT-qPCR was used to confirm the altered miRNAs between the two groups. Moreover, candidate miRNAs were examined in serum samples of 40 HCC patients, 54 LC patients, 55 patients with chronic HCV hepatitis and 45 healthy controls. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of the miRNAs for the detection of HCC. RESULTS Four miRNAs (miR-122-5p, miR-331-3p, miR-494-3p, miR-224-5p) were significantly increased and two miRNAs (miR-185-5p, miR-23b-3p) were significantly decreased in HCC patients compared to LC patients. ROC curve analysis demonstrated that the six miRNAs could be used as potential biomarkers for HCC detection. Combination of the six miRNAs could efficiently detect HCC in LC patients with the area under the ROC curve (AUC) of 0.995 and combination of the six miRNAs also provided high diagnostic accuracy (AUC = 0.961) for detection of HCC in non-HCC subjects. CONCLUSIONS The six serum miRNAs can be utilized as a surrogate and non-invasive biomarker for HCV-related HCC diagnosis.