Miracle-dz/UniFAR-FTUs huggingface dataset:
Special Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions Centella asiatica Water Extract Shows Low Potential for Cytochrome P450–Mediated Drug Interactions

Centella asiatica (CA) shows considerable promise for development as a botanical drug for cognitive decline. Its primary bioactive components include triterpene glycosides asiaticoside and madecassoside and their corresponding aglycones asiatic acid and madecassic acid. Exploration of the bioactivity of CA’s caffeoylquinic acids is ongoing. In this study, an aqueous extract of CA (CAW-R61J) was evaluated for drug interaction potential through inhibition or induction of P450 enzymes, as required by the US Food and Drug Administration. CAW-R61J was assessed for induction potential of CYP1A2, CYP2B6, and CYP3A4 using transporter-certified cryopreserved human hepatocytes in sandwich culture. Gene expression of these target P450s was quantified, and enzyme activities were determined to confirm gene expression results. No induction was observed up to 16.7 mg/ml CAW-R61J (equivalent to 1.1 mM asiaticoside, 0.8 mM madecassoside, 0.09 mM asiatic acid, and 0.12 mM madecassic acid). Reversible and time-dependent inhibitory effects of CAW-R61J on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, andCYP3A4/5wereevaluatedusinghuman livermicrosomes. CAW-R61J showedweak reversible inhibitionofmost of theP450 forms tested,with the strongest beingCYP2C9 (IC50 of 330mg/ml). CAW-R61J (£1000 mg/ml) was not a time-dependent inhibitor of any of these P450 enzymes. In summary, CAW-R61J had no, or only a weak impact, on P450 induction and inhibition in vitro. The clinical relevance of these results will depend on the in vivo concentration of CAW-R61J components achieved in humans. Plasma triterpene concentrationsmeasured in our recent clinical studies suggest minimal risk of P450-mediated drug interactions by these components. SIGNIFICANCE STATEMENT A preparation of Centella asiatica is currently under clinical development for the prevention or treatment of cognitive decline. The US Food and Drug Administration required an evaluation of its potential for drug interactionsmediated through drug-metabolizing enzymes. This in vitro study revealed minimal induction or inhibition of a range of P450 enzymes, includingCYP3A4, by theC. asiaticaextract, suggestinga low potential for drug interactions modulated by P450 metabolism.
Molecular Mechanisms of Muscle Weakness Associated with E173A Mutation in Tpm3.12. Troponin Ca2+ Sensitivity Inhibitor W7 Can Reduce the Damaging Effect of This Mutation

Substitution of Ala for Glu residue in position 173 of γ-tropomyosin (Tpm3.12) is associated with muscle weakness. Here we observe that this mutation increases myofilament Ca2+-sensitivity and inhibits in vitro actin-activated ATPase activity of myosin subfragment-1 at high Ca2+. In order to determine the critical conformational changes in myosin, actin and tropomyosin caused by the mutation, we used the technique of polarized fluorimetry. It was found that this mutation changes the spatial arrangement of actin monomers and myosin heads, and the position of the mutant tropomyosin on the thin filaments in muscle fibres at various mimicked stages of the ATPase cycle. At low Ca2+ the E173A mutant tropomyosin shifts towards the inner domains of actin at all stages of the cycle, and this is accompanied by an increase in the number of switched-on actin monomers and myosin heads strongly bound to F-actin even at relaxation. Contrarily, at high Ca2+ the amount of the strongly bound myosin heads slightly decreases. These changes in the balance of the strongly bound myosin heads in the ATPase cycle may underlie the occurrence of muscle weakness. W7, an inhibitor of troponin Ca2+-sensitivity, restores the increase in the number of myosin heads strongly bound to F-actin at high Ca2+ and stops their strong binding at relaxation, suggesting the possibility of using Ca2+-desensitizers to reduce the damaging effect of the E173A mutation on muscle fibre contractility.
Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes.

BACKGROUND Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease. METHODS In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed. RESULTS A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m2 in the allopurinol group and 67.3 ml per minute per 1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m2 (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m2 per year with allopurinol and -2.5 ml per minute per 1.73 m2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups. CONCLUSIONS We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).
Elevated Tenascin-C Serum Levels in Patients With Axial Spondyloarthritis.

This study aimed to examine serum tenascin C (TNC) in different subsets of axial spondyloarthritis (axSpA) patients. Sixty-one patients fulfilling the Assessment of SpondyloArthritis international Society classification criteria for axSpA and 20 healthy subjects (HS) were included in study. Based on imaging, patients were classified as non-radiographic (n=16) and radiographic (n=45) axSpA. TNC serum levels were determined by ELISA. Disease-related factors including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and C-reactive protein (CRP) levels, were determined. TNC levels were elevated in axSpA patients [535.3 (457.7-677.2) ng/ml] compared to HS [432.1 (329.1-565.9) ng/ml, p=0.007]. Dividing axSpA into radiographic and non-radiographic subsets, the difference in TNC was observed between the radiographic subset and HS [535.3 (434.5-677.2) vs. 432.1 (329.1-565.9) ng/ml, p=0.022]. TNC levels did not correlate with disease activity measures (serum CRP or BASDAI). Nevertheless, the weak correlation of TNC levels with different disease stages (r=0.25, p=0.025) was found, with the highest levels in patients with syndesmophytes. TNC levels are elevated across various subsets of axSpA, and although not related to systemic disease activity, TNC levels might reflect chronic structural spinal changes in axSpA patients. However, it´s specific role in bone metabolism should be elucidated in further studies.
Individualized Muscle-Tendon Assessment and Training

The interaction of muscle and tendon is of major importance for movement performance and a balanced development of muscle strength and tendon stiffness could protect athletes from overuse injury. However, muscle and tendon do not necessarily adapt in a uniform manner during a training process. The development of a diagnostic routine to assess both the strength capacity of muscle and the mechanical properties of tendons would enable the detection of muscle-tendon imbalances, indicate if the training should target muscle strength or tendon stiffness development and allow for the precise prescription of training loads to optimize tendon adaptation. This perspective article discusses a framework of individualized muscle-tendon assessment and training and outlines a methodological approach for the patellar tendon.
Molecular Cloning and Characterization of PELP1, a Novel Human Coregulator of Estrogen Receptor α

Nuclear hormone receptors (NRs) are transcription factors whose activity is regulated by ligands and by coactivators or corepressors. We report the characterization of a new NR coregulator: proline-, glutamic acid-, leucine-rich protein 1 (PELP1), a novel human protein that comprises 1,282 amino acids and is localized on chromosome 17. The primary structure of PELP1 consists of several motifs present in most transcriptional regulators including nine NR-interacting boxes (LXXLL motifs), a zinc finger, and glutamic acid- and proline-rich regions. We demonstrate that PELP1 is a coactivator of estrogen receptor α (ERα). PELP1 enhances 17β-estradiol-dependent transcriptional activation from the estrogen response element in a dose-dependent manner. PELP1 interacts with ERα and also with general transcriptional coactivators p300 and cAMP response element-binding protein-binding protein. PELP1 was differentially expressed in various human and murine tissues with the highest expression levels in the testes, mammary glands, and brain. We also provide evidence supporting the developmental regulation of PELP1 expression in murine mammary glands, the detectable expression of PELP1 in human mammary cancer cell lines, and the enhanced expression of PELP1 in human breast tumors. These findings suggest that PELP1 is a novel coregulator of ERα and may have a role in breast cancer tumorigenesis.
Determination of spatial proximity between the N-terminus and cocaine binding site of the dopamine transporter by FRET.

Amac: Dopamin tasiyicilar (DAT) dopaminin sinaptik gerialimindan ve boylelikle sinirsel iletinin cabuk sonlanmasindan sorumludur. Bu proteinler aliskanlik yapici kokain, amfetamin gibi maddelerin de etki merkezlerini olusturur. Proteinin N-ucunda bulunan Serin 7 ve 12’nin fosforilasyon bakimindan kritik amino asitler oldugu bilinmektedir. Bu calismada N-ucu ile kokain baglama bolgesi arasindaki uzaklik, yaban tip ve Ser7/12Asp ve Ser7/12Ala mutantlarinda belirlenmistir. Gerec ve Yontem: Sari-floresan protein (YFP) ve mutasyonlar DAT’in N-terminal ucuna 2-asamali PCR ile yerlestirilmistir. Dopamin geri-alim testleri yapilmis ve konfokal mikroskopta verici-agartma yontemi ile Forster rezonans enerji transferi (FRET) mesafeleri belirlenmistir. Bulgular: Tum N-ucundan YFP-etiketlenmis DAT proteinleri duzgun olarak hucre yuzeyine tasinmistir. Km degerleri sirasiyla yaban tip, Ser7/12Ala and Ser7/12/Asp mutantlari icin 0.76, 0.75 ve 1.24 mM olarak saptanmistir. FRET etkinligi yaban-tip DAT icin 0.15 olarak bulunmus ve FRET uzakligi 68.4 A olarak bulunmustur. Diger konstraktlarda FRET etkinlikleri negatiftir ve enerji transferi saptanmamistir. Sonuc: Veriler bize N-ucu bolgesinin kokain baglama bolgesi ile FRET mesafesinde oldugunu ve kritik serin rezidulerinin mutasyonlarinin (Ser7/12Asp) bu mesafeyi arttirdigini gostermektedir
Structure-Based Discovery of Dual-Target Hits for Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptors: In Silico Studies and In Vitro Confirmation

Despite extensive efforts in the development of drugs for complex neurodegenerative diseases, treatment often remains challenging or ineffective, and hence new treatment strategies are necessary. One approach is the design of multi-target drugs, which can potentially address the complex nature of disorders such as Alzheimer’s disease. We report a method for high throughput virtual screening aimed at identifying new dual target hit molecules. One of the identified hits, N,N-dimethyl-1-(4-(3-methyl-[1,2,4]triazolo[4,3-a]pyrimidin-6-yl)phenyl)ethan-1-amine (Ýmir-2), has dual-activity as an acetylcholinesterase (AChE) inhibitor and as an α7 nicotinic acetylcholine receptor (α7 nAChR) agonist. Using computational chemistry methods, parallel and independent screening of a virtual compound library consisting of 3,848,234 drug-like and commercially available molecules from the ZINC15 database, resulted in an intersecting set of 57 compounds, that potentially possess activity at both of the two protein targets. Based on ligand efficiency as well as scaffold and molecular diversity, 16 of these compounds were purchased for in vitro validation by Ellman’s method and two-electrode voltage-clamp electrophysiology. Ýmir-2 was shown to exhibit the desired activity profile (AChE IC50 = 2.58 ± 0.96 µM; α7 nAChR activation = 7.0 ± 0.9% at 200 µM) making it the first reported compound with this particular profile and providing further evidence of the feasibility of in silico methods for the identification of novel multi-target hit molecules.
Field transplantation of the freshwater bivalve Corbicula fluminea along a polymetallic contamination gradient (river Lot, France): II. Metallothionein response to metal exposure

Specimens of the Asiatic clam Corbicula fluminea were transplanted from a clean lacustrine site to four stations along a polymetallic pollution gradient in the river Lot, France, downstream from an old Zn ore treatment facility (see Part I). From April to September 1996, we studied Cd and Zn bioaccumulation and the metallothionein‐like metal‐binding protein (MT) concentrations by subsampling the cages at t = 0, 21, 49, 85, 120, and 150 d. Marked differences were observed among the four stations. At the most polluted station Riou‐Mort, MT concentrations did not increase despite very rapid metal accumulation; all mollusks died between days 49 and 85, suggesting that the metal detoxification mechanisms were overwhelmed at this station. At the next station downstream, the final levels of bioaccumulated metal after 150 d were as high as those at the Riou‐Mort station (t = 21 d), but in this case the MT concentrations also increased progressively with positive correlations between MT and metal concentrations; no mortality was observed, but a significant growth inhibition was revealed in comparison to the reference site, with a lack of correlation between MT (as a stress response) and reduced growth. Subcellular metal partitioning, as determined by size‐exclusion chromatography, revealed that most of the Cd was sequestered by MT (70% of cytosolic Cd). In contrast, most of the Zn was bound to low molecular weight proteins (70%, ≤ 6.5 kD), the MT fraction representing only 12% of cytosolic Zn. These data show the marked role of MT toward Cd bioaccumulation and toxic effects on this freshwater bivalve species.
Predicting and Promoting Human Bone Marrow MSC Chondrogenesis by Way of TGFβ Receptor Profiles: Toward Personalized Medicine

The use of human mesenchymal stromal cells (hMSCs) for cartilage regeneration has been hampered by the inherent donor variation of primary monolayer expanded cells. Although CD markers are typically used to characterize cell populations, there is no correlation between CD marker profile and functional outcomes. Therefore, we aimed to discover novel predictive MSC chondrogenesis markers. The chondrogenic potential of primary human bone marrow MSCs (hBMSCs) over multiple passages was assessed by standard pellet culture. We confirmed that the ratio of TGFβ-RI/TGFβ-RII at the time of cell recovery from the tissue culture plastic reliably predicted chondrogenic potential. Furthermore, it is possible to prospectively characterize any human BMSC cell population as responders or non-responders with respect to chondrogenic differentiation potential. Transient increase of the ratio with siRNA knockdown of TGFβ-RII reproducibly recovered the chondrogenic differentiation ability of non-responsive MSCs. Together this offers an opportunity to produce a more functionally characterized cell population for use in autologous cartilage repair therapies.
Alteration of Ecdysteroid Titre by Thyroxine and Juvenile Hormone Analogue (Methoprene) in Bombyx mori (Lepidoptera: Bombycidae)

Penelitian ini dilakukan untuk mengetahui pengaruh hormon tiroksin dan analog hormon juvenil (metopren) terhadap pola titer hormon ekdisteroid hemolimf selama instar lima Bombyx mori. Instar dua B. mori diberi pakan daun murbei yang telah diberi tiroksin dengan konsentrasi 1500 ppm. Larva kemudian dibiarkan ganti kulit sampai instar tiga dan empat tanpa perlakuan. Tujuh puluh dua jam setelah ganti kulit pada instar lima, larva disuntik sebanyak 10 μl metopren dengan konsentrasi 15 atau 25 ppm. Titer ekdisteroid hemolimf dideteksi dengan Kromatografi Cair Kinerja Tinggi. Hasil yang diperoleh menunjukkan bahwa perlakuan dengan tiroksin ataupun kombinasi tiroksin-metopren menyebabkan terjadinya perubahan pola titer ekdisteroid dibandingkan dengan kontrol. Ekdisteroid terdeteksi dua hari lebih awal pada perlakuan tiroksin dan titer ekdisteroid pada puncak tertinggi lebih tinggi jika dibandingkan dengan kontrol. Kombinasi tiroksin-metopren tampaknya menyebabkan penekanan terhadap titer ekdisteroid. Hal ini terlihat dengan terjadinya penurunan titer ekdisteroid segera setelah penyuntikan dengan metopren sebelum mencapai titer puncak tertinggi.
Workplace Interactional Demands and Work-Family Enrichment: An Investigation From the Service Sector

Emotional labor has, so far, been found to have negative consequences for service sector employees’ personal well-being. This study strives to look at the positive aspect of emotional labor in the interactive jobs. This research focuses on employees’ psychological needs fulfillment through workplace interactions. The current research is an effort to highlight the importance of workplace interactions through fulfilling the employees’ need for relatedness and personal accomplishment, which triggers positive resources that can be transferred from work domain to home domain and might induce work-family enrichment. Primary data were gathered through self-administered questionnaires. The target population was nurses working in public and private hospitals located in Faisalabad, Lahore, and Multan cities of the province of Punjab, Pakistan. This sector needs the attention of the policymakers if we want to enhance the performance of health sector employees and to improve their work-home enrichment as a healthy worker is a productive worker. Demographic characteristics of respondents have been identified through SPSS while Structural Equation Modeling (SEM) was used as multivariate data analysis tool for statistical analysis. Assessment of measurement and structural model was found satisfactory. The results showed that workplace interactional demands had a significant positive effect on work-family enrichment. Moreover, relatedness and personal accomplishment partially mediated the relationship between workplace interactional demands and work-family enrichment. The findings of the study revealed that workplace interactions are critical in fulfilling the basic psychological needs of individuals and as a result, they find themselves energized and achieve their full potential through the fulfillment of their need for relatedness and accomplishment. This energy is a valuable resource that can enrich their family life.
Depth-specific patterns in benthic-planktonic food web relationships in Lake Superior

In an investigation of the spatial characteristics of Laurentian Great Lakes food webs, we examined the trophic relationship between benthic amphipods (Diporeia) and plankton in Lake Superior. We analyzed the carbon and nitrogen stable isotope ratios of Diporeia and plankton at stations in water column depths of 4300 m. Neither δ15N nor δ13C of plankton from the upper 50 m of the water column varied significantly with station depth. Diporeia isotope ratios exhibited depth-specific patterns reflecting changes in food sources and food web relationships with plankton. Diporeia was 13C enriched at station depths of <40 m, reflecting increased dietary importance of benthic algae. There was a systematic increase in Diporeia δ15N with depth, which appeared to result from a combination of dietary shifts in the nearshore and decompositional changes in Diporeia's principal food, sedimented plankton, in deep habitats. Diporeia δ13C and δ15N together described changes in food web isotope baseline with depth. They al.
Updating Supreme Court Legitimacy: Testing the “Rule, Learn, Update” Model of Political Communication

One of the more important innovations in the study of how citizens assess the U.S. Supreme Court is the ideological updating model, which assumes that citizens grant legitimacy to the institution according to the perceived distance between themselves and the Court on a unidimensional ideological (liberal–conservative) continuum. Under this model, citizens are also said to update this calculation with every new salient Supreme Court decision. The model’s requirements, however, do not seem to square with the long-established view that Americans are largely innocent of ideology. Here, we conduct an audit of the model’s mechanisms using a series of empirical tests applied to a nationally representative sample. Our general conclusion is that the ideological updating model, especially when supplemented with the requirement that citizens must become aware of Court decisions, simply does not square with the realities of American politics. Students of Supreme Court legitimacy may therefore want to search for other theories of legitimacy updating.
Molecular characterization of genetic diversity within the Africa/Middle East/Asia Minor and Sub-Saharan African groups of the Bemisia tabaci species complex

Bemisia tabaci Gennadius is a major plant pest in many agricultural systems worldwide. It is a complex of cryptic species that differ in many ecological respects, including damage-causing potential. Monitoring the genetic composition of B. tabaci populations in the field is, therefore, essential for achieving effective control. Sequencing is costly and time consuming; thus, efficient diagnostic tools must be developed to perform epidemiological studies involving hundreds of individuals. Here, we describe a polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) method for identifying all the putative species comprising the Africa/Middle East/Asia Minor group, including those that are the most devastating crop pests. Moreover, intra-specific diversity associated with specific symbiotic bacteria known to manipulate insect host phenotypes can also be detected. In addition, this method discriminates between the Africa/Middle East/Asia Minor and the Sub-Saharan African groups, which are sympatric in some areas. This simple, reliable and cost-effective diagnostic tool is ideal for the rapid analysis of a high number of individuals and, thus, has potential applications in field contexts, where it could provide valuable baseline information for pest management programs.