Miracle-dz/UniFAR-FTUs huggingface dataset:
Intérêt et importance de la pharmacovigilance dans le suivi et l'amélioration des données sur les interactions médicamenteuses : caractérisation de plus de 700 cas de diagnostics iatrogènes médicamenteux analysés par le Centre régional de Pharmacovigilance Marseille-Provence-Corse

L’etude des interactions medicamenteuses (IAM) lors des essais cliniques et les donnees relatives aux IAM responsables d’effets indesirables medicamenteux (EIM) disponibles dans la litterature sont limitees. L’objectif de cette etude est de determiner les caracteristiques des cas d’EIM suspectes d’etre dus a des IAM. Une etude retrospective des cas de PV d’IAM enregistres par le centre regional de pharmacovigilance Marseille-Provence-Corse, du 01/01/2010 au 31/12/2016 inclus, a ete realisee. Le referentiel national des IAM, Thesaurus des IAM, a ete utilise pour l’analyse des IAM et les classifications MedDRA et ATC ont ete utilisees dans l’analyse des EIM et des molecules impliquees. Au total, 767 cas de diagnostics iatrogenes medicamenteux ont ete analyses. La population de patient ayant exprimee un EIM suite a une IAM est majoritairement constituee de personnes âgees (plus de 50%, avec une mediane d’âge de la population a 76 ans). Les EIM les plus frequemment releves sont principalement lies a des saignements ou une insuffisance renale aigue. Les associations de medicaments sont principalement des associations de medicaments de meme classe pharmacotherapeutique, et 42% sont des associations d’antithrombotiques. La fluindione est la molecule la plus frequemment retrouvee. Concernant les IAM, le processus pharmacodynamique reste principalement implique (plus de 75% des IAM analysees). Le niveau de contrainte majoritairement retrouve est le niveau de contrainte « a prendre en compte » (APEC) avec 33.3% des IAM referencees. Les IAM a faible niveau de contrainte (APEC et « precaution d’emploi ») sont les plus frequemment retrouvees concernant plus de 60% des IAM referencees responsables d’EIM. Les IAM sont responsable d’EIM qui peuvent etre grave. Les IAM PD ne doivent pas etre sous-estimees et les IAM de faible niveau de contrainte ne doivent pas etre negligees. Enfin des IAM non referencees ont pu etre mises en evidence dans cette etude, d’ou l’interet de la PV dans l’amelioration des connaissances sur les medicaments, notamment les IAM.
Investigating immunological and metabolic pathways involved in the pathogenesis of chronic liver disease

Chronic liver disease affects a large number of people with a rising incidence, and is characterized by the development of liver fibrosis, eventually resulting in cirrhosis, Treatment options for end-stage liver disease are limited and liver cirrhosis represents the main risk factor for hepatocellular carcinoma (HCC), highlighting the need for novel therapeutic approaches. In this thesis, metabolic as well as immunological pathways contributing to the development of liver fibrosis and subsequent HCC have been investigated. Hepatic stellate cells (HSCs) are considered as the key players in fibrosis development, as their activation results in excessive extracellular matrix deposition, leading to the establishment of liver fibrosis. In addition, tumour-stromal interactions between HSCs and HCC play a role in HCC pathogenesis, and are therefore considered as a potential target for novel HCC therapy. In this thesis, the role of the AMPK pathway in tumour-stromal interactions between HSCs and HCC has been investigated, with a special focus on pharmacologically targeting AMPK in both HSCs and HCC. Moreover, the development of liver fibrosis and cirrhosis is accompanied by a chronic inflammatory immune response, fostering a pro-fibrogenic environment, especially in the context of autoimmune liver disease (AILD). Mucosal-associated invariant T cells (MAIT cells) are a recently discovered subset of innate like T cells that represent up to 40% of all liver lymphocytes. Besides being crucial for anti-microbial defence, MAIT cells contribute to autoimmune diseases and are thought to play an important role in tissue inflammation in the liver, as they secrete pro-inflammatory cytokines upon activation. Therefore, the role of MAIT cells for the development of liver fibrosis in AILD was explored. More specifically, the MAIT cell subset was characterized in human patients with AILD, and mechanisms of MAIT cell activation, as well as MAIT cell – HSC interactions were investigated.
Crystal structure of the TreS:Pep2 complex, initiating α-glucan synthesis in the GlgE pathway of mycobacteria

A growing body of evidence implicates the mycobacterial capsule, the outermost layer of the mycobacterial cell envelope, in modulation of the host immune response and virulence of mycobacteria. Mycobacteria synthesize the dominant capsule component, α(1→4)-linked glucan, via three interconnected and potentially redundant metabolic pathways. Here, we report the crystal structure of the Mycobacterium smegmatis TreS:Pep2 complex, containing trehalose synthase (TreS) and maltokinase (Pep2), which converts trehalose to maltose 1-phosphate as part of the TreS:Pep2–GlgE pathway. The structure, at 3.6 Å resolution, revealed that a diamond-shaped TreS tetramer forms the core of the complex and that pairs of Pep2 monomers bind to opposite apices of the tetramer in a 4 + 4 configuration. However, for the M. smegmatis orthologues, results from isothermal titration calorimetry and analytical ultracentrifugation experiments indicated that the prevalent stoichiometry in solution is 4 TreS + 2 Pep2 protomers. The observed discrepancy between the crystallized complex and the behavior in the solution state may be explained by the relatively weak affinity of Pep2 for TreS (Kd 3.5 μm at mildly acidic pH) and crystal packing favoring the 4 + 4 complex. Proximity of the ATP-binding site in Pep2 to the complex interface provides a rational basis for rate enhancement of Pep2 upon binding to TreS, but the complex structure appears to rule out substrate channeling between the active sites of TreS and Pep2. Our findings provide a structural model for the trehalose synthase:maltokinase complex in M. smegmatis that offers critical insights into capsule assembly.
Transposition of IS4 Family Insertion Sequences ISTeha3, ISTeha4, and ISTeha5 into the arc Operon Disrupts Arginine Deiminase System in Tetragenococcus halophilus

Insertion sequences play important roles in bacterial evolution and are frequently utilized in mutagenesis systems. However, the intrinsic insertion sequences of tetragenococci are not well characterized. Here, we identified three active insertion sequences of T. halophilus by transposition into the region around the arc operon. This report provides an example of insertion sequence-mediated generation and evolution of T. halophilus and primary information about their characteristics. ABSTRACT Tetragenococcus halophilus, a halophilic lactic acid bacterium, is often used as a starter culture in the manufacturing of soy sauce. T. halophilus possesses an arginine deiminase system, which is responsible for the accumulation of citrulline, the main precursor of the potential carcinogen ethyl carbamate. In this study, we generated five derivatives lacking arginine deiminase activity from T. halophilus NBRC 12172 by UV irradiation. Using these derivatives as a fermentation starter prevented arginine deimination in soy sauce. DNA sequence analysis of the derivatives revealed that novel IS4 family insertion sequences, designated ISTeha3, ISTeha4, and ISTeha5, were transposed into the region around the arginine deiminase (arc) operon in the mutants. These insertion sequences contain a single open reading frame encoding a putative transposase and 13- to 15-bp inverted repeats at both termini, which are adjacent to 7- to 9-bp duplications of the target sequence. Investigation of wild strains isolated from soy sauce mash incapable of arginine deimination also indicated that insertion sequences are involved in the disruption of the arginine deiminase system in T. halophilus. IMPORTANCE Insertion sequences play important roles in bacterial evolution and are frequently utilized in mutagenesis systems. However, the intrinsic insertion sequences of tetragenococci are not well characterized. Here, we identified three active insertion sequences of T. halophilus by transposition into the region around the arc operon. This report provides an example of insertion sequence-mediated generation and evolution of T. halophilus and primary information about their characteristics.
Synergistic Action of Gefitinib and GSK41364A Simultaneously Loaded in Ratiometrically-Engineered Polymeric Nanoparticles for Glioblastoma Multiforme

Glioblastoma Multiforme is a deadly cancer of glial cells with very low survival rates. Current treatment options are invasive and have serious side effects. Single drug treatments make the tumor refractory after a certain period. Combination therapies have shown improvements in treatment responses against aggressive forms of cancer and are becoming a mainstay in the management of cancer. The purpose of this study is to design a combinatorial treatment regimen by engineering desired ratios of two different small molecule drugs (gefitinib and GSK461364A) in a single carrier that can reduce off-target effects and increase their bioavailability. Synergistic effects were observed with our formulation when optimal ratios of gefitinib and GSK461364A were loaded in poly (lactic-co-glycolic) acid and polyethylene glycol (PLGA-PEG) nanoparticles and tested for efficacy in U87-malignant glioma (U87-MG) cells. Combination nanoparticles proved to be more effective compared to single drug encapsulated nanoparticles, free drug combinations, and the mixture of two single loaded nanoparticles, with statistically significant values at certain ratios and drug concentrations. We also observed drastically reduced clonogenic potential of the cells that were treated with free drugs and nanoparticle combinations in a colony forming assay. From our findings, we conclude that the combination of GSK461364A and higher concentrations of gefitinib when encapsulated in nanoparticles yield synergistic killing of glioma cells. This study could form the basis for designing new combination treatments using nanoparticles to deliver multiple drugs to cancer cells for synergistic effects.
Interspecific scaling of blood flow rates and arterial sizes in mammals

ABSTRACT This meta-study investigated the relationships between blood flow rate (Q̇; cm3 s−1), wall shear stress (τw; dyn cm−2) and lumen radius (ri; cm) in 20 named systemic arteries of nine species of mammals, ranging in mass from 23 g mice to 652 kg cows, at rest. In the dataset, derived from 50 studies, lumen radius varied between 3.7 µm in a cremaster artery of a rat and 11.2 mm in the aorta of a human. The 92 logged data points of and ri are described by a single second-order polynomial curve with the equation: . The slope of the curve increased from approximately 2 in the largest arteries to approximately 3 in the smallest ones. Thus, da Vinci's rule () applies to the main arteries and Murray's law () applies to the microcirculation. A subset of the data, comprising only cephalic arteries in which is fairly constant, yielded the allometric power equation: . These empirical equations allow calculation of resting perfusion rates from arterial lumen size alone, without reliance on theoretical models or assumptions on the scaling of wall shear stress in relation to body mass. As expected, of individual named arteries is strongly affected by body mass; however, of the common carotid artery from six species (mouse to horse) is also sensitive to differences in whole-body basal metabolic rate, independent of the effect of body mass. Summary: Blood flow rates determine artery sizes in mammals, independent of body mass.
Task Engagement and the Vigilance Decrement Revisited: Expanding Upon the Work of Joel S. Warm Using a Semantic Vigilance Paradigm

Objective: The goal of the present study is twofold: (1) demonstrate the importance of measuring and understanding the relationship between task engagement and vigilance performance, and (2) celebrate the work of Joel S. Warm and expand upon his previous research in two semantic vigilance paradigms. Background: The importance of measuring task engagement in cognitive and sensory vigilance tasks has been well documented. But to date, our understanding of the effects of task engagement on semantic vigilance performance is limited. Method: Seventy-three participants completed either a standard semantic vigilance task or a lure semantic vigilance task. Participants also completed subjective measures of workload and stress. Results: The results indicated that changes in task engagement are associated with correct detection performance. Changes in task engagement may be related to individual differences in the distress associated with performing semantic vigilance tasks. Conclusion: In line with the work of Warm and his colleagues (Dember, Warm, Bowers, & Lanzetta, 1984), participants who reported increased task engagement after the vigil outperformed their peers who noted decreased task engagement upon conclusion of the task. Participants reporting increases in engagement with the semantic vigilance tasks also reported significantly greater distress pretask, but not posttask. Instead, increases in postvigil distress were driven by the task to which participants were assigned, not task engagement. Application: The present study has several implications for applied settings that involve long duration semantic processing or semantic target identification. Such real-world tasks include aviation, cyber threat detection and analysis, driving, and reading.
Outcome of male circumcision: A comparison between plastibell and dorsal slit methods

Introduction: Circumcision is the surgical removal of the skin covering the glans penis (prepuce). Circumcision is performed worldwide, among many tribe and races. It is the commonest surgical procedure done in males. It is perform by both trained and non-trained medical personal. Aims and Objective: To compare the outcome of circumcision done by dorsal slit and plastibell methods. Methods and Materials: A prospective study was done over 1 year period. A structured questionnaire was used to collect data. It was a cross-sectional analytical study with sample size of 120 patients divided in to 2 study groups. Group A had dorsal slit while group B had plastibell type of circumcision. Results: The age of circumcision varies between 7days to 10 years. The average duration of the procedure was 12minutes for dorsal slit and 7 minutes, with estimated blood loss of 7mls and 4mls in the two methods. The most common complications observed in our study are surgical site infection, post operative haemorrhage, and delayed separation of the ring. While surgical site infection is more in plastibell method, post operative haemorrhage was found to be commoner in dorsal slit method. Conclusion: Our study showed that plastibell has an obvious advantage of shorter time of procedure, lower risk of post operative bleeding compared to the conventional dorsal slit method of circumcision.
Interactions between WUSCHEL- and CYC2-like Transcription Factors in Regulating the Development of Reproductive Organs in Chrysanthemum morifolium

Chrysanthemum morifolium is a gynomonoecious plant that bears both female zygomorphic ray florets and bisexual actinomorphic disc florets in the inflorescence. This sexual system is quite prevalent in Asteraceae, but poorly understood. CYCLOIDEA (CYC) 2 subclade transcription factors, key regulators of flower symmetry and floret identity in Asteraceae, have also been speculated to function in reproductive organs and could be an entry point for studying gynomonoecy. However, the molecular mechanism is still unclear. On the other hand, the Arabidopsis WUSCHEL (WUS) transcription factor has been proven to play a vital role in the development of reproductive organs. Here, a WUS homologue (CmWUS) in C. morifolium was isolated and characterized. Overexpression of CmWUS in A. thaliana led to shorter siliques and fewer stamens, which was similar to CYC2-like genes reported before. In addition, both CmWUS and CmCYC2 were highly expressed in flower buds during floral organ differentiation and in the reproductive organs at later development stages, indicating their involvement in the development of reproductive organs. Moreover, CmWUS could directly interact with CmCYC2d. Thus, our data suggest a collaboration between CmWUS and CmCYC2 in the regulation of reproductive organ development in chrysanthemum and will contribute to a further understanding of the gynomonoecious sexual system in Asteraceae.
Chronological Aging Standard Curves of Telomere Length and Mitochondrial DNA Copy Number in Twelve Tissues of C57BL/6 Male Mouse

The changes in telomere length and mitochondrial DNA copy number (mtDNAcn) are considered to be aging markers. However, many studies have provided contradictory or only fragmentary information about changes of these markers in animal models, due to inaccurate analysis methods and a lack of objective aging standards. To establish chronological aging standards for these two markers, we analyzed telomere length and mtDNAcn in 12 tissues—leukocytes, prefrontal cortex, hippocampus, pituitary gland, adrenal gland, retina, aorta, liver, kidney, spleen, skeletal muscle, and skin—from a commonly used rodent model, C57BL/6 male mice aged 2–24 months. It was found that at least one of the markers changed age-dependently in all tissues. In the leukocytes, hippocampus, retina, and skeletal muscle, both markers changed age-dependently. As a practical application, the aging marker changes were analyzed after chronic immobilization stress (CIS) to see whether CIS accelerated aging or not. The degree of tissue-aging was calculated using each standard curve and found that CIS accelerated aging in a tissue-specific manner. Therefore, it is expected that researchers can use our standard curves to objectively estimate tissue-specific aging accelerating effects of experimental conditions for least 12 tissues in C57BL/6 male mice.
Using a Novel Student-centered Teaching Method to Improve Pharmacy Student Learning

Objective. To improve students’ learning and develop their learning skills in pharmacy education. Methods. A novel teaching method composed of Self-study, Test, Question and Discussion (STQD) sessions uses self-, peer-, co-learning, active learning, inductive teaching, and formative assessment to promote student-centered teaching in pharmacy education. STQD has been implemented within courses focusing on instrumental analysis and analytical chemistry. In a four-year study, qualitative and quantitative approaches were used to evaluate the effectiveness of STQD in facilitating students’ learning. Results. Students positively evaluated their experience in STQD class with an overall mean and standard deviation of 4.35 (0.64) in a 5-point Likert scale, where a score of 1 is "strongly disagree" and a score of 5 is "strongly agree. " The final examination results showed students’ average score in an STQD class was higher than students’ average score in a traditional class. Most students indicated that the STQD improved their learning ability, communication ability and facilitated their learning. Conclusion. The use of STQD in an integrated basic science curriculum has the potential to develop students' learning skills and improve their learning in pharmacy education.
Prion and Prion-Like Protein Strains: Deciphering the Molecular Basis of Heterogeneity in Neurodegeneration

Increasing evidence suggests that neurodegenerative disorders share a common pathogenic feature: the presence of deposits of misfolded proteins with altered physicochemical properties in the Central Nervous System. Despite a lack of infectivity, experimental data show that the replication and propagation of neurodegenerative disease-related proteins including amyloid-β (Aβ), tau, α-synuclein and the transactive response DNA-binding protein of 43 kDa (TDP-43) share a similar pathological mechanism with prions. These observations have led to the terminology of “prion-like” to distinguish between conditions with noninfectious characteristics but similarities with the prion replication and propagation process. Prions are considered to adapt their conformation to changes in the context of the environment of replication. This process is known as either prion selection or adaptation, where a distinct conformer present in the initial prion population with higher propensity to propagate in the new environment is able to prevail over the others during the replication process. In the last years, many studies have shown that prion-like proteins share not only the prion replication paradigm but also the specific ability to aggregate in different conformations, i.e., strains, with relevant clinical, diagnostic and therapeutic implications. This review focuses on the molecular basis of the strain phenomenon in prion and prion-like proteins.
PENGARUH PEMBERIAN LEAFLET DAN PENJELASAN TERHADAP PENGETAHUAN IBU MENGENAI PELAKSANAAN METODE KANGURU PADA BAYI BERAT LAHIR RENDAH

Latar belakang: Bayi berat lahir rendah (BBLR) merupakan salah satu penyebab kematian neonatus di Indonesia.Perawatan metode kanguru (PMK) merupakan perawatan untuk BBLR. Untuk menurunkan kejadian kematian neonatal perlu dilakukan usaha preventif melalui penyuluhan guna meningkatkan pengetahuan ibu mengenai PMK pada BBLR. Penyuluhan menggunakan metode ceramah sudah sering dilakukan, sebaliknya pendekatan individu dengan menggunakan leaflet jarang dilakukan sehingga penelitian ini perlu dilaksanakan. Tujuan: Menganalisis pengaruh pemberian leaflet dan penjelasan terhadap pengetahuan ibu mengenai pelaksanaan metode kanguru pada BBLR. Metode: Penelitian ini menggunakan desain quasi eksperimental dengan kelompok pretest posttest. Subjek penelitian merupakan ibu dari bayi dengan BBLR di RSUP Dr. Kariadi Semarang yang dipilih secara consecutive sampling dari bulan Maret hingga Mei 2016. Peneliti memberikan kuesioner yang telah diuji validitas sebagai pretest dan kemudain subjek diberikan leaflet dan penjelasan. Posttest dilakukan satu hari setelah subjek diberikan leaflet dan penjelasan. Hasil: Pengetahuan pre-intervensi bernilai minimal 5, median 8 dan maksimal 11, sedangkan skor minimal 10, median 16, maksimal 19 didapatkan pada post-intervensi. Diperoleh nilai p = 0,000 ( p <0,05) pada perbedaan pengetahuan sebelum dan sesudah pemberian leaflet . Simpulan: Terdapat perbedaan yang bermakna secara statistik antara pengetahuan ibu mengenai PMK dan setelah penyuluhan menggunakan leaflet.
Assessing Regional Differences in Green Innovation Efficiency of Industrial Enterprises in China

Green technology innovation is an important means to break out of the constraints of resources and the environment, enhance the competitiveness of enterprises, and achieve the upgrading of industrial structures, and promote high-quality economic growth. In order to realize the overall improvement of the green technology innovation capability of Chinese enterprises, it is necessary to measure the efficiency of industrial enterprises’ green technology innovation and explore their regional differences. In this paper, from the perspective of a two-stage innovation value chain, by introducing the industrial carbon emissions per unit of Gross Domestic Product (GDP) and the “three wastes” pollutants into the research framework of green technology innovation efficiency, we established a novel green innovation efficiency evaluation indicator system for industrial enterprises. Furthermore, we used a two-stage network DEA with shared input to measure the efficiency of regional enterprises’ green technology innovation and explored the regional differences in industrial enterprises’ green technology R&D and the efficiency of green technology achievement transformation. Finally, we provide some suggestions for improving China’s industrial enterprises’ green innovation efficiency, so that they can ameliorate the significant regional imbalances and differences and realize high-quality economic growth.