Miracle-dz/UniFAR-FTUs huggingface dataset:
Phase 1 Studies to Define the Safety, Tolerability, and Pharmacokinetic and Pharmacodynamic Profiles of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone in Healthy Volunteers

Apararenone is a long‐acting, nonsteroidal mineralocorticoid receptor antagonist (MRA). The safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of single‐ and multiple‐dose apararenone were assessed in 3 phase 1 randomized, double‐blind studies in 223 healthy adults. Study 1 assessed the PK, safety/tolerability, and PD of single‐dose apararenone (3.75–640 mg) and multiple‐dose apararenone (10–40 mg/day on days 1–14, 320 mg loading dose on day 1 + 10 mg/day on days 2–14, or 40–320 mg loading dose on day 1 + 2.5–20 mg/day on days 2–14) in Caucasian and Black men and women. Study 2 assessed the PK and safety of single‐dose apararenone (5–320 mg) in healthy Japanese men. Study 3 assessed the PK, PD, and safety/tolerability of single‐dose apararenone (160 or 640 mg) or eplerenone (200 mg; only for 160 mg of apararenone), each after fludrocortisone challenge in Caucasian men. In studies 1 and 2, an approximately dose‐proportional increase was observed in PK parameters over the apararenone dose range of 3.75–40 mg; at higher doses, a less than dose‐proportional increase was observed. Food, sex, age, and race had no apparent effect on apararenone PK. A long half‐life was seen for apararenone and its principal metabolite; in addition, the exposure of the metabolite was lower than that of apararenone. Apararenone suppressed the decrease in urinary sodium and potassium ion ratio that occurs after loading with fludrocortisone. These studies support the mechanism of action of apararenone as an MRA, and further clinical development is warranted.
Organosulphur Compounds Induce Apoptosis and Cell Cycle Arrest in Cervical Cancer Cells via Downregulation of HPV E6 and E7 Oncogenes.

BACKGROUND The quest for strong, safe and cost-effective natural antiproliferative agents that could reduce cancer have been focused now a day. In this regard, the organosulfur compounds from garlic (AlliumsativumL.), like diallyl sulfide (DAS) and diallyl disulfide (DADS), have been shown to exhibit potent antiproliferative and anticancer properties in many studies. However, the potential of these compounds against viral oncoproteins in cervical cancer has not been fully elucidated yet. OBJECTIVE The objective of this study was to analyze the antiproliferative and apoptotic properties of DADS and DAS in HPV16+ human cervical cancer Caski cell line. METHODS Caski (cervical cancer cells) were cultured and followed by the treatment of various concentrations of organosulphur compounds (DADS and DAS), cell viability was measured by MTT assay. The apoptotic assay was performed by DAPI and Hoechst3342 staining. Reactive Oxygen Species (ROS) was estimated by DCFDA staining protocol. The distributions of cell cycle and apoptosis (FITC-Annexin V assay) were analyzed by flow cytometry. Finally, gene expression analysis was performed via quantitative real time PCR. RESULTS Our results showed that DAS and DADS exerted significant antiproliferative effect on Caski cells by reducing the cell viability and inducing a dose-related increment in intracellular ROS production along with apoptosis in Caski cells. DAS and DADS also induced cellcycle arrest in G0/G1 phase, which was supported by the downregulation of cyclin D1 and CDK4 and upregulation of CDK inhibitors p21WAF1/CIP1 and p27KIP1 in Caski cells. Additionally, DAS and DADS lead to downregulation of viral oncogene E6 and E7 and restoration of p53 function. CONCLUSION Thus, this study confirms the efficacy of both the organosulfur compounds DADS and DAS against cervical cancer cells.
TransBorrow: genome-guided transcriptome assembly by borrowing assemblies from different assemblers

RNA-seq technology is widely used in various transcriptomic studies and provides great opportunities to reveal the complex structures of transcriptomes. To effectively analyze RNA-seq data, we introduce a novel transcriptome assembler, TransBorrow, which borrows the assemblies from different assemblers to search for reliable subsequences by building a colored graph from those borrowed assemblies. Then, by seeding reliable subsequences, a newly designed path extension strategy accurately searches for a transcript-representing path cover over each splicing graph. TransBorrow was tested on both simulated and real data sets and showed great superiority over all the compared leading assemblers.
LncRNA SNHG15 predicts poor prognosis in uveal melanoma and its potential pathways.

AIM To evaluate the role of long noncoding RNA (lncRNA) SNHG15 and its potential pathways in uveal melanoma (UM). METHODS The SNHG15 mRNA expression level and corresponding clinicopathological characteristics of 80 patients with UM were obtained from the Cancer Genome Atlas (TCGA) database and further analyzed. The SPSS 24.0 statistical software package was used for statistical analyses. To investigate the potential function of SNHG15 in UM, we conducted in-depth research on Gene Set Enrichment Analysis (GSEA). RESULTS The univariate analysis revealed that the age, tumor diameter, pathological type, extrascleral extension, cancer status, and high expression of SNHG15 were statistical risk factors for death from all causes. The multivariate analysis suggested that the mRNA expression level of SNHG15 was an independent risk factor for death from all causes, as was age and pathological type. Kaplan-Meier survival analysis confirmed that UM patients with high SNHG15 expression might have a poor prognosis. In addition, SNHG15 was significantly differentially expressed in the different groups of tumor pathologic stage, metastasis and living status. Besides, the logistic regression analysis indicated that high SNHG15 expression group in UM was significantly associated with cancer status, pathologic stage, metastasis, and living status. Moreover, the GSEA indicated the potential pathways regulated by SNHG15 in UM. CONCLUSION Our research suggests that SNHG15 may play a vital role as a potential marker in UM that predicts poor prognosis. Besides, GSEA indicates the underlying signaling pathways enriched differentially in SNHG15 high expression phenotype.
Developmental Changes in Dendritic Spine Morphology in the Striatum and Their Alteration in an A53T α-Synuclein Transgenic Mouse Model of Parkinson’s Disease

Abstract The aging process is accompanied by various neurophysiological changes, and the severity of neurodegenerative disorders such as Parkinson’s disease (PD) increases with aging. However, the precise neuroanatomical changes that accompany the aging process in both normal and pathologic conditions remain unknown. This is in part because there is a lack of high-resolution imaging tool that has the capacity to image a desired volume of neurons in a high-throughput and automated manner. In the present study, focused ion beam/scanning electron microscopy (FIB/SEM) was used to image striatal neuropil in both wild-type (WT) mice and an A53T bacterial artificial chromosome (BAC) human α-synuclein (A53T-BAC-SNCA) transgenic (Tg) mouse model of PD, at 1, 3, 6, and 22 months of age. We demonstrated that spine density gradually decreases, and average spine head volume gradually increases with age in WT mice, suggesting a homeostatic balance between spine head volume and spine density. However, this inverse relationship between spine head volume and spine density was not observed in A53T-BAC-SNCA Tg mice. Taken together, our data suggest that PD is accompanied by an abnormality in the mechanisms that control synapse growth and maturity.
Activity of indolyl-3-acetic acid oxidase and peroxidase in roots of carrot infested with Meloidogyne hapla Chiuu.

IAA-oxidase and peroxidase activity was measured in storage and side roots of healthy and M. hapla infested carrots of two sultivars. Cultivar 'Perfekcja' is sensitive whereas cv. 'Slendero' is tolerant to the northern root-knot ne-matode. 3-, 4-, and 5-month-old plants were subjected to analyses. In M. hapla infested plants of both cultivars IAA-oxidase inhibitors accumulated. Kinetics of IAA oxidation in vivo were the same in healthy and infested plants. IAA-oxidase activity in vitro was inhibited in crude extracts of the infested tissues, the inhibition being prevented by PVP. Peroxidase activity increased in secondary phloem and decreased in galled side roots of both cultivars when compared with healthy controls. In galled side roots of the youngest 3-month-old plants peroxidase activity was not decreased. IAA-oxidase inhibitors accumulated in the infested roots.It is concluded that M. hapla has no direct effect on IAA-oxidase. Degree of tolerance to nematodes is correlated with the ratio of IAA-oxidase inhibitors to IAA-oxidase rather than with the absolute activity of IAA-oxidase.
Compensatory gain of crossbred heifers supplemented in pastures under evaluation hormonal profile and blood parameters

The objective of this experiment was to verify the effect of nutritional management that alternates periods of energy/protein restriction and refeeding of grazing crossbred heifers during their prepuberty on the hormonal profile and blood parameters. The study was conducted at Princesa do Mateiro farm in Ribeirao do Largo, in the southwest region of the state of Bahia. Twenty crossbred heifers 5/8 Dairy Guzerat x 3/8 Dutch with an average age of 12 months and average body weight of 187 ± 13.74 kg were used at the beginning of the experiment. It lasted 238 days, 14 out of them were for the animals’ adaptation. The animals were kept in rotational grazing of Brachiariabrizantha cv. Marandu pastures and randomly assigned to two treatments: Control (T100) = animals receiving concentrate supplement to supply 100% of the nutrients requirement to gain 750 g day-1 of live weight and Compensatory Nutrition (CN). The animals of the CN treatment alternated periods of Restriction (T80) = receiving concentrate supplement to meet 80% of the demand for nutrients of the (T100) and periods of Refeeding (T120) = getting concentrate supplement to supply 120% of the nutrient requirements of the (T100 The final plasma concentrations of IGF-I, glucose and urea were higher (P 0.05). There were positive correlations (P<0.05) between IGF-I, insulin, glucose and cholesterol, and a negative correlation (P<0.05) between IGF-I and urea. There were also positive correlation (P<0.05) between insulin and glucose and positive correlation (P<0.05) between glucose and cholesterol. There was a negative correlation (P<0.05) of the urea with cholesterol, progesterone and protein. Progesterone also showed a positive correlation (P<0.05) with the protein.
Down-regulation of tenascin-C inhibits breast cancer cells development by cell growth, migration, and adhesion impairment

Tenascin-C (TNC) is an extracellular matrix (ECM) glycoprotein that plays an important role in cell proliferation, migration, and tumour invasion in various cancers. TNC is one of the main protein overexpressed in breast cancer, indicating a role for this ECM molecule in cancer pathology. In this study we have evaluated the TNC loss-off-function in breast cancer cells. In our approach, we used dsRNA sharing sequence homology with TNC mRNA, called ATN-RNA. We present the data showing the effects of ATN-RNA in MDA-MB-231 cells both in monolayer and three-dimensional culture. Cells treated with ATN-RNA were analyzed for phenotypic alterations in proliferation, migration, adhesion, cell cycle, multi-caspase activation and the involvement in epithelial to mesenchymal transition (EMT) processes. As complementary analysis the oncogenomic portals were used to assess the clinical implication of TNC expression on breast cancer patient’s survival, showing the TNC overexpression associated with a poor survival outcome. Our approach applied first in brain tumors and then in breast cancer cell lines reveals that ATN-RNA significantly diminishes the cell proliferation, migration and additionally, reverses the mesenchymal cells phenotype to the epithelial one. Thus, TNC could be considered as the universal target in different types of tumors, where TNC overexpression is associated with poor prognosis.
Therapeutic Effect of Diminazene Aceturate on Parasitic Blood Fluke Schistosoma mansoni Infection

Praziquantel is currently the only drug available to treat schistosomiasis, a disease of enormous public health significance caused by a blood fluke of the genus Schistosoma. Diminazene, a drug approved by the FDA, has been successfully used to treat diseases caused by blood protozoan parasites. In this study, we evaluated the antiparasitic properties of diminazene against Schistosoma mansoni ex vivo and in mice harboring either chronic or early S. mansoni infections. ABSTRACT Praziquantel is currently the only drug available to treat schistosomiasis, a disease of enormous public health significance caused by a blood fluke of the genus Schistosoma. Diminazene, a drug approved by the FDA, has been successfully used to treat diseases caused by blood protozoan parasites. In this study, we evaluated the antiparasitic properties of diminazene against Schistosoma mansoni ex vivo and in mice harboring either chronic or early S. mansoni infections. In vitro, we monitored phenotypic and tegumental changes as well as the effects of the drug on pairing and egg production. In mice infected with either adult (chronic infection) or immature (early infection) worms, diminazene was administered intraperitoneally (10 to 100 mg/kg of body weight) or by oral gavage (100 to 400 mg/kg), and we studied the influence of the drug on worm burden and egg production. Liver and spleen pathologies and serum aminotransferase levels were also analyzed. In vitro, 50% effective concentrations (EC50) and EC90 revealed that diminazene is able to kill both immature and adult parasites, and its effect was time and concentration dependent. In addition, confocal laser scanning microscopy showed morphological alterations in the teguments of schistosomes. In an animal model, the influence of the drug on worm burden, egg production, hepatomegaly, and splenomegaly depended on the dosing regimen applied and the route of administration. Diminazene also caused a significant reduction in aminotransferase levels. Comparatively, diminazene treatment was more effective in chronic infection than in early infection. In tandem, our study revealed that diminazene possesses anthelmintic properties and inhibits liver injury caused by Schistosoma eggs.
The clinical characteristics of pregnant women with epilepsy in China.

BACKGROUND Epilepsy during pregnancy and puerperium is infrequent, and it can induce severe complications and poor prognosis. Pregnancy in women with epilepsy (WWE) is usually uneventful. Previous studies have mainly focused on the effects of different treatments on prognosis. However, few articles have addressed if different epilepsy types were associated with a higher incidence of seizure breakthrough/recurrence and pregnancy outcomes. METHODS In the present study, based on a unique sample with a low incidence of epilepsy, we evaluated the main clinical characteristics of epilepsy patients. RESULTS Mean age of pregnant WWE was 29.95±4.65 (range, 21-42) years. Pregnancies were at a mean gestational age of 33.80±9.14 (range, 7-41) weeks, and 88.24% (52/61) of WWE were in their third trimester. There was 9.84% (6/61) of pregnant WWE underwent abortion or induced labor in midpregnancy to ensure maternal safety. There was 75.41% (46/61) of pregnant WWE using antiepileptic drugs (AEDs), of which 52.46% (32/61) were taking a single AED and 22.95% (14/61) were using multiple AEDs. There was 47.54% (29/61) of WWE experiencing seizures during their pregnancy. We found that the type of epilepsy did not affect seizures during pregnancy or the prognosis. However, more pregnant WWE with hypertensive disorder had seizures compared with pregnant WWE without hypertensive disorder. CONCLUSIONS The study highlighted a novel direction for effectively improving seizures during pregnancy and the prognosis of pregnancy-associated epilepsy.
INF1 is a novel microtubule and actin cytoskeleton cross-linking protein

Formin proteins, characterized by two conserved formin homology (FH) domains, play an important role in cytoskeletal regulation and dynamics. The FH domains are most commonly implicated with the polymerization of F-actin and more recently with the stabilization of microtubules. Inverted formin 1 (INF1) is an atypical formin that has its FH1 and FH2 domains in its N-terminus. The C-terminus of INF 1 contains five conserved regions unlike any other sequence found in the database. In this study, we demonstrate that INF1 discreetly associates with microtubules via a unique bipartite microtubule-binding domain (MTBD) in the C-terminus. Additionally, similar to the diaphanous related formin mDia, INF1 induces microtubule stabilization and acetylation. Expression of the MTBD alone, and not the FH2 domain, is sufficient to induce microtubule stabilization. However, in the absence of the MTBD, the N-terminus induces microtubule stabilization dependent on the presence of both the FH1 and the FH2 domains. In addition, knockdown of INF 1 protein in NIH 3T3 fibroblasts results in a dramatic loss of acetylated microtubules suggesting INF1 is required for MT acetylation in these cells. Furthermore, we show that INF1 is not regulated by auto-inhibition, but is constitutively active both in vivo and in vitro. Our overexpression results suggest the INF1 C-terminus contains a putative regulatory domain targeted by an unknown inhibitory factor. Finally, we show that INF1 is capable of bundling both microtubules and F-actin simultaneously, implying that INF1 is a cytoskeletal cross-linking protein that could play an important role in cell polarity, cell migration and other cytoskeletal dependent processes.
Early Life Experiences and Trajectories of Cognitive Development

We explore how multiple early life experiences differentiate patterns of cognitive development over the first 5 years of life in 5 low- and middle-income settings. BACKGROUND: Multiple factors constrain the trajectories of child cognitive development, but the drivers that differentiate the trajectories are unknown. We examine how multiple early life experiences differentiate patterns of cognitive development over the first 5 years of life in low-and middle-income settings. METHODS: Cognitive development of 835 children from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) multisite observational cohort study was assessed at 6, 15, 24 (Bayley Scales of Infant and Toddler Development), and 60 months (Wechsler Preschool and Primary Scale of Intelligence). Markers of socioeconomic status, infection, illness, dietary intake and status, anthropometry, and maternal factors were also assessed. Trajectories of development were determined by latent class-mixed models, and factors associated with class membership were examined by discriminant analysis. RESULTS: Five trajectory groups of cognitive development are described. The variables that best discriminated between trajectories included presence of stimulating and learning resources in the home, emotional or verbal responsivity of caregiver and the safety of the home environment (especially at 24 and 60 months), proportion of days (0–24 months) for which the child had diarrhea, acute lower respiratory infection, fever or vomiting, maternal reasoning ability, mean nutrient densities of zinc and phytate, and total energy from complementary foods (9–24 months). CONCLUSIONS: A supporting and nurturing environment was the variable most strongly differentiating the most and least preferable trajectories of cognitive development. In addition, a higher quality diet promoted cognitive development while prolonged illness was indicative of less favorable patterns of development.
The scoring systems in predicting short-term outcomes in patients with hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND Hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening syndrome characterized by acute and severe hepatic insults with high short-term mortality. This study aimed to compare the scoring systems which were used to predict short-term outcomes for HBV-ACLF patients. METHODS A total of 529 patients diagnosed as HBV-ACLF were retrospectively analyzed and randomly divided, at a ratio of 3:1, into derivation cohort (n=397) and validation cohort (n=132). Univariate and multivariate analyses were performed to determine the discriminative abilities of the ALBI grade in predicting 30-day and 90-day mortality. The area under the receiver operating characteristic (AUC) curves was used to evaluate the accuracy of models. RESULTS The survival was associated with lower ALBI score, MELD score and CLIF-C ACLF score than death. In the derivation cohort, elevated ALBI score was related to worse prognosis (30-day mortality: HR =3.452; 90-day mortality: HR =3.822), increased MELD score was associated with worse overall survival (30- day mortality: HR =1.073; 90-day mortality: HR =1.082), and increased CLIF-C ACLF score was associated with worse overall survival (30-day mortality: HR =1.061; 90-day mortality: HR =1.065). The multivariate analyses identified the ALBI score, MELD score and CLIF-C ACLF score as independent prognostic predictors. The results of validation cohort validated these findings. CONCLUSIONS Our study revealed that both the ALBI score, MELD score and CLIF-C ACLF score could predict 30- and 90-day mortality of HBV-ACLF accurately. Elevated ALBI score, MELD score and CLIF-C ACLF score were associated with worse prognosis.
A cryptic tubulin-binding domain links MEKK1 to curved tubulin protomers

Significance The protein kinase MEKK1 activates stress-signaling pathways in response to various cellular stressors, including chemotherapies that disrupt dynamics of the tubulin cytoskeleton. We show that MEKK1 contains a previously uncharacterized domain that can preferentially bind to the curved tubulin heterodimer—which is found in soluble tubulin and at sites of microtubule assembly and disassembly. Mutations that interfere with MEKK1−tubulin binding disrupt microtubule networks in migrating cells and are enriched in patient-derived tumor sequences. These results suggest that MEKK1−tubulin binding may be relevant to cancer progression, and the efficacy of microtubule-disrupting chemotherapies that require the activity of MEKK1. The MEKK1 protein is a pivotal kinase activator of responses to cellular stress. Activation of MEKK1 can trigger various responses, including mitogen-activated protein (MAP) kinases, NF-κB signaling, or cell migration. Notably, MEKK1 activity is triggered by microtubule-targeting chemotherapies, among other stressors. Here we show that MEKK1 contains a previously unidentified tumor overexpressed gene (TOG) domain. The MEKK1 TOG domain binds to tubulin heterodimers—a canonical function of TOG domains—but is unusual in that it appears alone rather than as part of a multi-TOG array, and has structural features distinct from previously characterized TOG domains. MEKK1 TOG demonstrates a clear preference for binding curved tubulin heterodimers, which exist in soluble tubulin and at sites of microtubule polymerization and depolymerization. Mutations disrupting tubulin binding decrease microtubule density at the leading edge of polarized cells, suggesting that tubulin binding may play a role in MEKK1 activity at the cellular periphery. We also show that MEKK1 mutations at the tubulin-binding interface of the TOG domain recur in patient-derived tumor sequences, suggesting selective enrichment of tumor cells with disrupted MEKK1–microtubule association. Together, these findings provide a direct link between the MEKK1 protein and tubulin, which is likely to be relevant to cancer cell migration and response to microtubule-modulating therapies.