Miracle-dz/UniFAR-FTUs huggingface dataset:
Metformin disposition-A 40-year-old mystery.

Metformin (N,N-dimethylbiguanide) is a first-line medication for the treatment of type 2 diabetes. It is an old drug, having been discovered in 1922 and first used in France in 1957. 1 The purpose of this commentary is to emphasise that, despite its age, aspects of its disposition remain obscure and controversial. This reflects the fact that it is a highly polar cationic compound with a log P of − 1.4 and a pKa of 12.4, which would predict that it is unlikely to cross biological mem-branes easily by passive diffusion, thereby requiring transporters for distribution and excretion, and that it would not be expected to undergo metabolism. The first studies of the pharmacokinetics of metformin were reported in 1978 – 1981 and involved both intravenous and oral administration. One of these studies 2 measured radioactivity after giv-ing 14 C-labelled drug and two used specific assays (mass fragmentography and gas chromatography, respectively). 3,4 Congruent findings from these studies were an oral bioavailability of 50% – 60% and a negligible plasma protein binding. After intravenous injection ‘ terminal ’ apparent half-lives of 1.5 – 4.5 h and of 9 – 19 h were reported based on measurement of plasma drug concentrations over 8 – 12 h after dosage and urinary excretion rates over 40 – 60 h, respec-tively. A slow accumulation in erythrocytes was observed such that whole blood drug concentrations were eventually considerable in excess of those in plasma, with a prolonged decay. 4 An extended elim-ination phase was also indicated
Primary Gliosarcoma with Extracranial Metastasis

A 69-year-old male presented with a week of worsening headache, mild dizziness and left side weakness, and the radiological work-up of his brain displayed an enhancing mass on the right frontal lobe. The tumor was totally resected. The patient was initially diagnosed with glioblastoma multiforme. His neurologic symptoms recovered after surgery. He underwent adjuvant radiotherapy with concurrent temozolomide. Approximately 7 months after surgery, the patient complained of epigastric pains. Abdominal CT scan showed multiple hepatic metastasis and multiple lymphadenopathy. Chest CT and Torso positron emission tomography-CT scans for additional metastasis study revealed multiple metastatic lesions in the right lung, left pleura, liver, lymph nodes, bones, and muscles. Percutaneous liver biopsy was performed, and associated pathology was consistent with sarcomatous component. After liver biopsy, brain tumor pathology was reviewed, which revealed typical gliomatous and sarcomatous components. The patient was therefore diagnosed with metastatic gliosarcoma. The patient was in a septic condition with aggravated pleural effusion. The patient died 9 months after the diagnosis of primary gliosarcoma.
The Combination of Oral Anticoagulant and Antiplatelet Therapies: Stay One Step Ahead

Antithrombotic drugs, which include antiplatelets and anticoagulants, are effective in prevention and treatment of many cardiovascular disorders such as acute coronary syndromes, stroke, and venous thromboembolism and are among the drugs most commonly prescribed worldwide. The advent of direct oral anticoagulants, which are safer alternatives to vitamin K antagonists and do not require laboratory monitoring, has revolutionized the treatment of nonvalvular atrial fibrillation and venous thromboembolism. The combination of oral anticoagulant and antiplatelet therapy is required in many conditions of great clinical impact such as the coexistence of atrial fibrillation and coronary artery disease, with indication to percutaneous coronary intervention. However, strategies that combine anticoagulant and antiplatelet therapies lead to a significant increase in bleeding rates and it is crucial to find the right combination in the single patient in order to optimize the ischemic and bleeding risk. The aim of this review is to explore the evidence and controversies regarding the optimal combination of anticoagulant and antiplatelet therapy through the consideration of past dogmas and new perspectives from recent clinical trials and to propose a tailored therapeutic approach, according to specific clinical scenarios and individual patient characteristics. In particular, we separately explored the clinical settings of stable and acute coronary syndromes and percutaneous revascularization in patients with atrial fibrillation.
Effect of herbicides for the control of Fimbristylis miliacea (L.) Vahl. in rice.

The experiment was conducted in the glasshouse at Universiti Putra Malaysia to determine the efficacy of herbicides with different modes of action against a Fimbristylis miliacea population and increased rice yield potentiality. Nine early post emergence herbicide treatments such as bensulfuron, cinosulfuron, pyrazosulfuron, cinosulfuron+pretilachlor+safener, 2, 4-D (amine), pretilachlor+safener, bentazone, fentrazamide+propanil and bispyribac-sodium were applied singly or in mixtures. A weed-free (hand-weeded) treatment and an unweeded treatment served as controls. The treatments were arranged in a randomized complete block design with four replications. A weed-free (hand-weeded) treatment and an unweeded treatment served as controls. The treatments were arranged in a randomized complete block design with four replications. Data on crop phytotoxicity, weed control, chlorophyll content, plant height, productive tillers, total tillers, panicle length, grains per panicle, 1000 grain weight, % filled grains per panicle, grain yield and straw biomass were recorded to evaluate efficacy of the different treatments. All tested herbicides were effective in controlling F. miliacea, but the herbicides bensulfuron and fentrazamide+propanil increased grain yield by more than 80% compared to the unweeded treatment and were comparable to the weed-free treatment.
Long-term Results of Arthroscopic Rotator Cuff Repair: A Follow-up Study Comparing Single-Row Versus Double-Row Fixation Techniques

Background: Arthroscopic rotator cuff repair (RCR) with suture anchor–based fixation techniques has replaced former open and mini-open approaches. Nevertheless, long-term studies are scarce, and lack of knowledge exists about whether single-row (SR) or double-row (DR) methods are superior in clinical and anatomic results. Purpose: To analyze long-term results after arthroscopic RCR in patients with symptomatic rotator cuff tears and to compare functional and radiographic outcomes between SR and DR repair techniques at least 10 years after surgery. Study Design: Cohort study; Level of evidence, 3. Methods: Between 2005 and 2006, 40 patients with a symptomatic full-thickness rotator cuff tear (supraspinatus tendon tear with or without a tear of the infraspinatus tendon) underwent arthroscopic RCR with either an SR repair with a modified Mason-Allen suture–grasping technique (n = 20) or a DR repair with a suture bridge fixation technique (n = 20). All patients were enrolled in a long-term clinical evaluation, with the Constant score (CS) as the primary outcome measure. Furthermore, an ultrasound examination was performed to assess tendon integrity and conventional radiographs to evaluate secondary glenohumeral osteoarthritis. Results: A total of 27 patients, of whom 16 were treated with an SR repair and 11 with a DR repair, were followed up after a mean ± SD period of 12 ± 1 years (range, 11-14 years). Five patients underwent revision surgery on the affected shoulder during follow-up period, which led to 22 patients being included. The overall CS remained stable at final follow-up when compared with short-term follow-up (81 ± 8 vs 83 ± 19 points; P = .600). An increasing number of full-thickness retears were found: 6 of 22 (27%) at 2 years and 9 of 20 (45%) at 12 years after surgery. While repair failure negatively affected clinical results as shown by the CS (P < .05), no significant difference was found between the fixation techniques (P = .456). In general, progressive osteoarthritic changes were observed, with tendon integrity as a key determinant. Conclusion: Arthroscopic RCR with either an SR or a DR fixation technique provided good clinical long-term results. Repair failure was high, with negative effects on clinical results and the progression of secondary glenohumeral osteoarthritis. While DR repair slightly enhanced tendon integrity at long-term follow-up, no clinical superiority to SR repair was found.
Distribution of [3H]α,β-methylene ATP binding sites in rat brain and spinal cord

The distribution of [3H]alpha,beta-methylene ATP ([3H]alpha,beta-MeATP) binding sites in rat brain and spinal cord was examined using autoradiography. It was shown that many structures in the CNS are densely labelled, and that the binding is displaced by both beta,gamma-methylene ATP and the P2X-purinoceptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), indicating that the binding sites are P2X-purinoceptors. Image analysis revealed that the nuclei of the thalamus have the highest density of labelling. Other densely labelled structures include: the amygdaloid, substantia nigra, cerebral cortex, hypothalamus, caudate putamen, geniculate nuclei, medial habenula and the intermediate zone of grey matter in the spinal cord. These results are consistent with the limited amount of electrophysiological evidence for the existence of P2X-purinoceptors in the CNS, and provoke the need for extensive physiological studies to establish the roles of P2X-purinoceptors in the CNS.
Identification of Erwinia carotovora from soft rot diseased plants by random amplified polymorphic DNA (RAPD) analysis.

Erwinia carotovora and pectolytic pseudomonads are the most prevalent bacteria associated with soft rot of plants. A procedure based on random amplified polymorphic DNA (RAPD) analysis was developed to distinguish these bacteria rapidly and easily. Forty bacterial strains isolated from diseased plants in the province of Quebec were used to screen RAPD primers. Two primers were chosen based on cost considerations and on their capacity to discriminate between the bacterial strains. The combination of the two primers was sufficient for adequate distinction of Erwinia carotovora from pectolytic, fluorescent Pseudomonas spp. Furthermore, E. carotovora subsps. atroseptica and carotovora could also be distinguished from each other. To simplify the identification work, a quantitative identification tool was elaborated, based on selected markers produced with the two primers. To verify the RAPD analysis accuracy, 49 additional soft rot bacteria from diseased plants were submitted to the RAPD procedure and all the identifications were in agreement with those produced by standard biochemical tests. In addition, the RAPD analysis correctly identified 25 bacteria from collections outside of Quebec.
Short- and long-term patterns of sponge diversity on a rocky tropical coast: evidence of large-scale structuring factors

The importance of a long-term ecological perspective is well documented, yet long-term data are not widely available. This paper represents the first quantitative description of sublittoral sponge assemblages over long temporal scales (6 years) along the coast of the East Pacific Ocean (Mazatlan Bay), with the goal of describing their levels of intra- and inter-annual variability, and their relationship to changing environmental conditions. It was possible to detect an apparent short-term pattern (intra-annual), with a highly diverse and stable structure, usually in the drought season, which was consistent most of the years. However, only a few species showed regular (predictable) seasonal cycles. The species per square meter (from 0.1 to 0.5), total species per sampling (14–21), and H’ diversity using loge (1.4–2) also fluctuated greatly between years, suggesting that although a consistent short-term pattern was found most of the years, the inter-annual variability was also high. The univariate and multivariate results and regression models indicated that local winds played a key role in this short-term pattern (intra-annual). During the rainy season, or during the transition between the drought and rainy season, the winds coming from the southwest (WSW) produced an increase in the net sediment movement, which was an important factor for diversity. The long-term fluctuations (annual pattern of diversity) also correlated positively with wind speed (88% of the variance observed) and with sediment deposition (69% of the variance observed). In addition, the results indicated the existence of large-scale structuring factors, as the annual pattern of diversity also was correlated positively with the Southern Oscillation (SOI) and Multivariate ENSO (MEI) indices (82% and 88% of the observed variance, for MEI and SOI, respectively). In conclusion, this study suggests that sponge assemblages in Mazatlan Bay are extremely dynamic, and changes in this community are associated with processes that occur over the short- and long-time scales (several months to several years). The significant positive relationship between wind speed and sediment deposition showed that the main factors controlling the diversity in these shallow rocky ecosystems are the winds and the swell. A high proportion of coarse sand also indicated a very high energy in the environment, which, combined with the effect of silting, abraded and removed sponges and other organisms. These features contribute to the instability of the community by producing dramatic fluctuations in species abundance and preventing competitive processes from producing a more stable community.
Lista preliminar dos anfíbios da Estação Ecológica do Taim, Rio Grande do Sul, Brasil

Out of the 67 species of amphibians known from Rio Grande do Sul, 18 were collected at the Estacao Ecologica do Taim, in the southeastern part of that State. The Leptodactylidae are the most diversified ir the area, whereas the Hylidae were the most numerous in individuais
Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors

Small molecular PD‐1 inhibitors are lacking in current immuno‐oncology clinic. PD‐1/PD‐L1 antibody inhibitors currently approved for clinical usage block interaction between PD‐L1 and PD‐1 to enhance cytotoxicity of CD8+ cytotoxic T lymphocyte (CTL). Whether other steps along the PD‐1 signaling pathway can be targeted remains to be determined. Here, we report that methylene blue (MB), an FDA‐approved chemical for treating methemoglobinemia, potently inhibits PD‐1 signaling. MB enhances the cytotoxicity, activation, cell proliferation, and cytokine‐secreting activity of CTL inhibited by PD‐1. Mechanistically, MB blocks interaction between Y248‐phosphorylated immunoreceptor tyrosine‐based switch motif (ITSM) of human PD‐1 and SHP2. MB enables activated CTL to shrink PD‐L1 expressing tumor allografts and autochthonous lung cancers in a transgenic mouse model. MB also effectively counteracts the PD‐1 signaling on human T cells isolated from peripheral blood of healthy donors. Thus, we identify an FDA‐approved chemical capable of potently inhibiting the function of PD‐1. Equally important, our work sheds light on a novel strategy to develop inhibitors targeting PD‐1 signaling axis.
Poor dietary consumption and limited sun exposure are risk factors for vitamin D deficiency in premenopausal Kuwaiti women: A cross-sectional study

Background: Low serum vitamin D levels are reported constantly among females living in the Arabian Gulf countries, presumably due to their lifestyle, which limits direct sun exposure. Because Vitamin D deficiency has been implicated in a wide range of ailments, healthy females with the deficiency might be at risk for developing many health problems. Thus, the aim was to assess lifestyle risk factors for vitamin D deficiency in healthy women in Kuwait. Methods: A total of 104, disease-free, premenopausal women were recruited for assessment of their serum 25OHD and intact PTH levels. Physical examination, blood withdrawal and interviewer-administered questionnaires were used to collect the relevant data. Associations were detected statistically using nonparametric tests and logistic regression was used to identify risk factors for vitamin D deficiency. Results: Vitamin D deficiency ( < 25 nmol/L) occurred in 84.6%, and hyperparathyroidism ( ≥ 6.9 pmol/L) occurred in 25% of women, among which all were vitamin D deficient. Significant risk factors of vitamin D deficiency were nondaily milk intake (OR:25, CI%:4.2–147), no fish intake (OR:5, CI%:1–22.8), and no weekend sun exposure (OR:8.2, CI%:1.28–52.6). Having PTH ≥ 6 pmol/L was also associated with a higher likelihood of having vitamin D deficiency. Conclusion: Vitamin D deficiency is very common in disease-free, premenopausal Kuwaiti women and can be avoided by improving food consumption and obtaining more sun exposure.
Evaluation sous serre de la tolérance à la salinité de quelques porte-greffes d'agrumes : Citrus aurantium et deux hybrides de Poncirus trifoliata (Poncirus x Citrus sinensis et Poncirus x Mandarinier sunki)

Afin de determiner les effets de la salinite sur l’intensite de la chlorose foliaire, la croissance et l’absorption de Na+ et Cl-, nous avons cultive trois porte-greffes (Citrus aurantium (C.a) ainsi que deux nouveaux hybrides de Poncirus trifoliata [P.t. x C. sinensis (PXC) et P.t. x M. sunki (PXM)]) dans des solutions nutritives contenant 0, 35 ou 70 mM NaCl pendant 30 et 60 jours. Les degâts foliaires augmentent avec la duree de traitement et la concentration en NaCl. L’intensite et la frequence de la chlorose occasionnee apres 30 jours de stress salin revelent la sensibilite du porte-greffe PXC et la tolerance de PXM. En outre, si la croissance apicale du porte-greffe C.a n’est pas affectee par 35 mM NaCl, elle est par contre stimulee chez PXM et inhibee chez PXC. La concentration 70 mM NaCl affecte plus severement la vigueur des porte-greffes et montre la tolerance de PXM et la sensibilite de PXC. D’autre part, la biomasse diminue avec le temps pour tous les traitements et les porte-greffes. Toutefois, il apparait que la concentration 35 mM NaCl est insuffisante pour la discrimination entre les porte-greffes vis-a-vis du stress salin. En revanche, a 70 mM NaCl, la reduction de la biomasse confirme la sensibilite de PXC et prouve la tolerance de PXM. Par ailleurs, les teneurs des feuilles en Cl- et Na+ sont significativement affectees par la salinite, la duree du stress et le facteur porte-greffes (PXM parait etre excluant efficace de Cl-) et elles sont correlees avec les symptomes de toxicite. En outre, la teneur en ions salins est correlee a la reduction de la biomasse de PXC. Par consequent, en plus des effets inhibiteurs des hautes concentrations de Cl- et Na+, un desequilibre d'elements nutritifs essentiels peut aussi concourir a la reduction de la croissance de ce porte-greffe sous les conditions de stress.
μ-Calpain Regulates Receptor Activator of NF-κB Ligand (RANKL)-supported Osteoclastogenesis via NF-κB Activation in RAW 264.7 Cells*

To clarify the role of calpain in the receptor activator of NF-κB ligand (RANKL)-supported osteoclastogenesis, RANKL-induced calpain activation was examined by using murine RAW 264.7 cells and bone marrow-derived monocyte/macrophage progenitors. We found that calpain activity increased in response to RANKL in both cell types based on α-spectrinolysis and that μ-calpain, rather than m-calpain, was activated during RANKL-supported osteoclastogenesis in RAW 264.7 cells. Overexpression of μ-calpain clearly augmented RANKL-supported osteoclastogenesis in RAW 264.7 cells, thereby implicating its pivotal role in this process. Cell-permeable calpain inhibitors, including calpastatin and calpeptin, were sufficient to suppress RANKL-supported osteoclastogenesis based on decreased expression of the osteoclastogenic marker, matrix metalloproteinase 9, and the generation of tartrate-resistant acid phosphatase-positive multinucleated cells in both cell types. Calpain inhibitors suppressed NF-κB activation via inhibition of the cleavage of inhibitor of NF-κB(IκBα)in RAW 264.7 cells. Taken together, our findings suggest that μ-calpain is essential to the regulation of RANKL-supported osteoclastogenesis via NF-κB activation.
POPULATION STRUCTURE, DYNAMICS, AND PRODUCTION OF THE MEDITERRANEAN MACROALGA CODIUM BURSA (CHLOROPHYCEAE)

The biochemical composition and metabolism of the balloonlike Mediterranean macroalga Codium bursa J. Agardh are strongly size dependent and constrained by the spherical geometry of its thallus. Changes in reproductive phenology, population structure, density, biomass, and production of this widespread alga were followed over an annual cycle to examine whether mortality rate was size and age dependent. Examination of size and age distributions showed the population to be in quasi‐steady state. A main recruitment event occurred in winter, with the highest gametangial densities observed in October, and the peak of recruits observed in December. The small recruits (0–2 cm in diameter) exhibited high growth (1 cm in <1 month) and mortality rates. High exponential mortality rate was also observed in the larger individuals (>12 cm, or 6 years old). Intermediate size C. bursa showed the lowest mortality rate, indicating that organisms within this size range (3–12 cm) escape advective and grazing losses that decimate small recruits and that they, unlike larger organisms, maintain an adequate physiological status. Asexual gemmation within the intermediate size classes may also contribute to maintain stable populations of this species in the NW Mediterranean littoral zone, since recruits derived from sexual reproduction experience extremely high mortality rates.
Shoutai pills improve the quality of oocytes exposed to the chemotherapeutic drug Hydroxyurea

Hydroxyurea (HU), a DNA synthesis inhibitor, is one of the most common chemotherapeutic drugs that have been widely applied to treat a variety of cancers. HU treatment exhibits severe side effects including renal toxicity, skin toxicity and embryo-toxicity. However, the influence of HU on the female gamete development has not yet fully clarified. Here, we found that HU exposure induced the degeneration of activated follicles after primordial follicle stage, resulting in the depletion of the ovarian reserve. HU exposure also led to the oocyte meiotic maturation arrest via disrupting normal spindle assembly, chromosome alignment and kinetochore-microtubule attachment. Furthermore, exposure to HU impaired the dynamics of ovastacin and Juno, two critical fertilization regulators. Notably, we illustrated that Shoutai pills (STP), a traditional Chinese medicine drug that has been commonly used for the treatment of miscarriage in China, partially restored all of the defects of oocyte development resulting from HU exposure through inhibiting the occurrence of oxidative stress-induced apoptosis. Taken together, our data not only reveal the adverse impact of HU exposure on the female gamete development, but also provide an effective strategy to prevent it, potentially contributing to the improvement of the quality of oocytes from patients treated with HU.