Miracle-dz/UniFAR-FTUs huggingface dataset:
Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity

Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1-f ]purinediones with the aim to obtain multi-target drugs that block human A1 and A2A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A1 ARs, e.g., 15d (PSB-18339, 8-m-bromobenzyl-substituted) displayed a Ki value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A2A AR affinity. The 8-phenethyl derivative 20h was selective for the A2A AR (Ki 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A1 and A2A ARs with equal potency (Ki A1, 180 nM; A2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blocked all three targets, A1 ARs (Ki 396 nM), A2A ARs (Ki 1,620 nM), and MAO-B (IC50 106 nM) with high selectivity vs. the other subtypes (A2B and A3 ARs, MAO-A), and can thus be considered as a multi-target drug. Our findings were rationalized by molecular docking studies based on previously published X-ray structures of the protein targets. The new drugs have potential for the treatment of neurodegenerative diseases, in particular Parkinson's disease.
The human leukemia virus HTLV-1 alters the structure and transcription of host chromatin in cis

Chromatin looping controls gene expression by regulating promoter-enhancer contacts, the spread of epigenetic modifications, and the segregation of the genome into transcriptionally active and inactive compartments. We studied the impact on the structure and expression of host chromatin by the human retrovirus HTLV-1. We show that HTLV-1 disrupts host chromatin structure by forming loops between the provirus and the host genome; certain loops depend on the critical chromatin architectural protein CTCF, which we recently showed binds to the HTLV-1 provirus. Finally, we show that the provirus causes two distinct patterns of abnormal transcription of the host genome in cis: bidirectional transcription in the host genome immediately flanking the provirus, and clone-specific transcription in cis at non-contiguous loci up to >300 kb from the integration site. We conclude that HTLV-1 causes insertional mutagenesis up to the megabase range in the host genome in >104 persistently-maintained HTLV-1+ T-cell clones in vivo.
Low Birth Weight Impairs Acquisition of Spatial Memory Task in Pigs

In commercial pig farming, an increasing number of low birth weight (LBW) piglets are born, due to selection for large litter sizes. While LBW piglets have a higher risk of pre-weaning mortality, a considerable number of these piglets survive to slaughter age. In humans, LBW is a risk factor for long-term cognitive impairments. In pigs, studies examining the post-weaning effects of LBW on cognition have reported contradictory results. Therefore, the current study aimed to assess the effects of LBW on cognitive development in pigs using an improved study design, by (1) testing a larger sample size than previous studies, (2) assessing acute and chronic stress responses to account for a potential altered stress response in LBW pigs, and (3) testing both female and male pigs to account for potential confounding effects of sex. Learning and memory of 20 LBW pigs and 20 normal birth weight (NBW) pigs, both groups consisting of 10 females and 10 males, were compared using a spatial holeboard task. In this task, pigs had to learn and remember the locations of hidden food rewards. After a pig had successfully acquired the task, it was presented with two successive reversal phases during which it was presented with a new configuration of reward locations. The holeboard allows for simultaneous assessment of working and reference memory, as well as measures of motivation, exploration, and behavioral flexibility. Mixed model ANOVAs revealed a transiently impaired reference memory performance of LBW pigs, implying they had more difficulty learning their reward configuration in the holeboard. Also, LBW piglets showed increased pre-weaning hair cortisol concentrations compared to their NBW siblings. No other effects of LBW were found. Sex had no direct or interaction effects on any measures of holeboard performance or stress. It is possible that the enriched housing conditions applied during our study had an ameliorating effect on our pigs' cognitive development. Overall, our results suggest LBW has a negative effect on post-weaning cognitive performance in pigs. This could have welfare consequences as cognitive skills are required for pigs to learn how to correctly respond to their environment.
Lower Renal Function Is Associated With Derangement of 11-β Hydroxysteroid Dehydrogenase in Type 2 Diabetes

Abstract Context Derangement of 11-β hydroxysteroid dehydrogenase type 1 and type 2 (11β-HSD1 and 11β-HSD2), which regulate intracellular cortisol production, has been suggested in both type 2 diabetes (T2D) and chronic kidney disease (CKD). However, activity of 11β-HSD enzymes in patients with T2D and CKD has never been assessed. Objectives To compare 11β-HSD activities between patients with T2D and healthy controls, and assess whether in T2D, renal function is associated with 11β-HSD activities. Design Cross-sectional analysis in the Diabetes and Lifestyle Cohort Twente (DIALECT-1). Setting Referral center for T2D. Patients Patient with T2D [n = 373, age 64 ± 9 years, 58% men, 26% of patients estimated glomerular filtration rate (eGFR) <60 mL/min·1.73 m2] and healthy controls (n = 275, age 53 ± 11 years, 48% men). Mean Outcome Measure We measured cortisol, cortisone, and metabolites [tetrahydrocortisol (THF), allo-THF (aTHF), and tetrahydrocortisone (THE)] in 24-hour urine samples. Whole body 11β-HSD and 11β-HSD2 activities were calculated as the urinary (THF + aTHF)/THE and cortisol/cortisone ratios, respectively. Results Patients with T2D had a higher (THF + aTHF)/THE ratio [1.02 (0.84 to 1.27) vs 0.94 (0.79 to 1.0), P < 0.001] and cortisol/cortisone ratio [0.70 (0.58 to 0.83) vs 0.63 (0.54 to 0.74), P < 0.001] than healthy controls. In T2D, lower eGFR was associated with a higher (THF + aTHF)/THE ratio (β = −0.35, P < 0.001), and a higher cortisol/cortisone ratio (β = −0.16, P = 0.001). Conclusions In this real-life secondary care setting of patients with T2D, 11β-HSD enzymes activities were shifted to higher intracellular cortisol production in T2D, which was further aggravated in patients with CKD. Prospective analyses are warranted to investigate causality of these associations.
Biological therapies for eosinophilic asthma

ABSTRACT Introduction: Severe uncontrolled asthma is by definition refractory to traditional therapies or can be controlled only with therapies that have intolerable side effects. Monoclonal antibodies that target interleukin (IL)-5/IL-5Rα, IgE, and IL-4Rα have shown favorable results in clinical trials, including reductions in asthma exacerbations and other important clinical outcomes. These biological agents offer treatment alternatives to patients with uncontrolled severe eosinophilic asthma. Areas covered: This article reviews how the shifting emphasis toward identifying distinct asthma phenotypes has led to the approval of biological therapies that preferentially benefit patients with severe eosinophilic asthma. The clinical trials that led to the approval of these biologic treatments are discussed in detail. Expert opinion: Biologic therapies targeting the IL-5, IgE, IL-4/IL-13 signaling pathways have been successful in clinical trials in subjects with severe eosinophilic asthma. Some of these agents have also been successful regardless of peripheral blood eosinophil counts. These treatments have shown a relatively favorable safety profile in clinical trials, although long-term safety data for some of these agents are limited. Due to the high costs associated with these medications, they should be reserved for select patients where they yield a therapeutic and pharmacoeconomic advantage.
AT 101 induces early mitochondrial dysfunction and HMOX1 (heme oxygenase 1) to trigger mitophagic cell death in glioma cells

ABSTRACT In most cases, macroautophagy/autophagy serves to alleviate cellular stress and acts in a pro-survival manner. However, the effects of autophagy are highly contextual, and autophagic cell death (ACD) is emerging as an alternative paradigm of (stress- and drug-induced) cell demise. AT 101 ([-]-gossypol), a natural compound from cotton seeds, induces ACD in glioma cells as confirmed here by CRISPR/Cas9 knockout of ATG5 that partially, but significantly rescued cell survival following AT 101 treatment. Global proteomic analysis of AT 101-treated U87MG and U343 glioma cells revealed a robust decrease in mitochondrial protein clusters, whereas HMOX1 (heme oxygenase 1) was strongly upregulated. AT 101 rapidly triggered mitochondrial membrane depolarization, engulfment of mitochondria within autophagosomes and a significant reduction of mitochondrial mass and proteins that did not depend on the presence of BAX and BAK1. Conversely, AT 101-induced reduction of mitochondrial mass could be reversed by inhibiting autophagy with wortmannin, bafilomycin A1 and chloroquine. Silencing of HMOX1 and the mitophagy receptors BNIP3 (BCL2 interacting protein 3) and BNIP3L (BCL2 interacting protein 3 like) significantly attenuated AT 101-dependent mitophagy and cell death. Collectively, these data suggest that early mitochondrial dysfunction and HMOX1 overactivation synergize to trigger lethal mitophagy, which contributes to the cell killing effects of AT 101 in glioma cells. Abbreviations: ACD, autophagic cell death; ACN, acetonitrile; AT 101, (-)-gossypol; BAF, bafilomycin A1; BAK1, BCL2-antagonist/killer 1; BAX, BCL2-associated X protein; BH3, BCL2 homology region 3; BNIP3, BCL2 interacting protein 3; BNIP3L, BCL2 interacting protein 3 like; BP, Biological Process; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; CC, Cellular Component; Con, control; CQ, chloroquine; CRISPR, clustered regularly interspaced short palindromic repeats; DMEM, Dulbecco’s Modified Eagle Medium; DTT, 1,4-dithiothreitol; EM, electron microscopy; ER, endoplasmatic reticulum; FACS, fluorescence-activated cell sorting; FBS, fetal bovine serum; FCCP, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; GO, Gene Ontology; HAcO, acetic acid; HMOX1, heme oxygenase 1; DKO, double knockout; LC-MS/MS, liquid chromatography coupled to tandem mass spectrometry; LPL, lipoprotein lipase, MEFs, mouse embryonic fibroblasts; mPTP, mitochondrial permeability transition pore; MTG, MitoTracker Green FM; mt-mKeima, mito-mKeima; MT-ND1, mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1; PBS, phosphate-buffered saline; PE, phosphatidylethanolamine; PI, propidium iodide; PRKN, parkin RBR E3 ubiquitin protein ligase; SDS, sodium dodecyl sulfate; SQSTM1/p62, sequestome 1; STS, staurosporine; sgRNA, single guide RNA; SILAC, stable isotope labeling with amino acids in cell culture; TFA, trifluoroacetic acid, TMRM, tetramethylrhodamine methyl ester perchlorate; WM, wortmannin; WT, wild-type
miR-155-5p Promotes Progression of Acute Respiratory Distress Syndrome by Inhibiting Differentiation of Bone Marrow Mesenchymal Stem Cells to Alveolar Type II Epithelial Cells

Background We investigated whether microRNA-155-5p is involved in the differentiation of bone marrow mesenchymal stem cells (BMSCs) into alveolar type II epithelial (AT II) cells by regulating the Wnt signaling pathway, thus participating in the development of acute respiratory distress syndrome (ARDS). Material/Methods Serum levels of microRNA-155-5p in 50 ARDS patients and 50 normal controls were detected by quantitative real-time PCR (qRT-PCR). Marrow mesenchymal stem cells (MCSs) were isolated from mouse bone marrow and identified by flow cytometry. Subsequently, the effect of microRNA-155-5p on differentiation of BMSCs into AT II cells was evaluated by detecting the expression levels of AT II-specific genes. The expression levels of proteins in the Wnt signaling pathway after overexpression or knockdown of microRNA-155-5p were detected by Western blot. Results Serum levels of microRNA-155-5p in ARDS patients were significantly higher than that in normal controls. Expression levels of AT II-specific genes were enhanced after downregulating microRNA-155-5p in BMSCs. MicroRNA-155-5p overexpression showed the opposite result. Furthermore, microRNA-155-5p inhibited the expression levels of proteins in the Wnt signaling pathway. Conclusions MicroRNA-155-5p can attenuate the differentiation of BMSCs into AT II cells by inhibiting the Wnt signaling pathway, thus promoting the progression of ARDS.
In-situ Stochastic Training of MTJ Crossbar based Neural Networks

Owing to high device density, scalability and non-volatility, Magnetic Tunnel Junction-based crossbars have garnered significant interest for implementing the weights of an artificial neural network. The existence of only two stable states in MTJs implies a high overhead of obtaining optimal binary weights in software. We illustrate that the inherent parallelism in the crossbar structure makes it highly appropriate for in-situ training, wherein the network is taught directly on the hardware. It leads to significantly smaller training overhead as the training time is independent of the size of the network, while also circumventing the effects of alternate current paths in the crossbar and accounting for manufacturing variations in the device. We show how the stochastic switching characteristics of MTJs can be leveraged to perform probabilistic weight updates using the gradient descent algorithm. We describe how the update operations can be performed on crossbars both with and without access transistors and perform simulations on them to demonstrate the effectiveness of our techniques. The results reveal that stochastically trained MTJ-crossbar NNs achieve a classification accuracy nearly same as that of real-valued-weight networks trained in software and exhibit immunity to device variations.
Barriers and Facilitators to Effective Mental Health Care in Correctional Settings

It is estimated that one third to one half of the 2.3 million individuals inside U.S. jails and prisons have a mental illness in contrast to 18.3% of the general population. The implications of this on training mental health professionals to provide efficacious treatment inside correctional facilities, as well as planning for the rehabilitation and reintegration of incarcerated individuals, are significant and numerous. This article will present a brief history and overview of mental health services in the U.S. correctional system, as well as a discussion of the barriers to and potential facilitators of providing effective care in the future.
Is progression of coronary artery calcification influenced by modality of renal replacement therapy? A systematic review

ABSTRACT Background Progression of coronary artery calcification is an important marker for cardiovascular morbidity in end-stage renal disease patients. Therefore, we reviewed the evidence on coronary artery calcification progression in different renal replacement therapies. Methods MEDLINE (PubMed), Embase and TRIP databases were searched from 1999 – 2016. Additionally, bibliographies were searched by hand and citation tracking of key publications was performed. Prospective studies were included that examined coronary artery calcification with two or more multislice computed tomography scans ≥6 months apart in patients 18–75 years old receiving any renal replacement therapy, including kidney transplantation. Reporting of separate scores for different modalities was required. Two researchers extracted data independently with pilot-tested forms and assessed the risk of bias using a validated tool. Results We identified 29 eligible studies that assessed coronary artery calcification progression in end-stage renal disease patients, of which 19 studies evaluated haemodialysis and 8 kidney transplantation. Evidence on progression in peritoneal dialysis (three studies) and nocturnal haemodialysis (one study) was limited. Meta-analysis was not possible due to diverse reporting methods of coronary artery calcification scores and definitions of progression. Median coronary artery calcification scores were considerably higher in haemodialysis cohorts at baseline, presumably due to a generally higher age and dialysis vintage. Median coronary artery calcification progressed universally. Visual inspection suggested the least progression in kidney transplant recipients. Conclusions There is insufficient evidence to compare the influence of renal replacement therapies on coronary artery calcification progression. We advocate the adoption of a standardized reporting method of coronary artery calcification progression.
Prognostic Implication of BCR-ABL Fusion Transcript Variants in Chronic Myeloid Leukemia (CML) Treated with Imatinib. A First of Its Kind Study on CML Patients of Kashmir

Background: The prognostic significance of the common BCR-ABL transcripts like e13a2 (b2a2) and e14a2 (b3a2) in Chronic myeloid leukemia (CML) has been reported from patients treated with different tyrosine kinase inhibitors but its impact on clinical response and overall survival remains still unexplored. The aim of this study was to evaluate the prognostic significance of different transcript types in a cohort of CML patients treated with imatinib. Methods: A total 42 confirmed cases of Chronic Myeloid Leukemia (CML) patients were recruited into our cohort study and a multiplex Reverse Transcriptase-Polymerase Chain Reaction technique (RT-PCR) was used to detect 3 main transcript types ‘e1a2’, ‘e13a2’, and ‘e14a2’ found in CML. Results: Only two types of transcripts e13a2 (b2a2) and e14a2 (b3a2) were detected in our CML patients and none had the e1a2 type. All the patients were RT-PCR positive for either e13a2 or e14a2 fusion transcript demonstrating 100% concordance with their Ph+ve cytogenetic status at baseline. TLC count (range of 201-600x103/µl) and platelet count (range of 201-900x103/µl) at baseline were found to be associated more with the e14a2 (b3a2) than the e13a2 (b2a2) transcript type (p-value: 0.001). The two transcripts found did not relate significantly towards sex, age-group or indicated spleen size ranges as well as percentage ranges of blast cells. Conclusion: We conclude that there is no overall prognostic implication of either the e13a2 or the e14a2 transcript type across the spectrum of indicated clinical parameters evaluated. Even the overall survival analysis of the two transcript types revealed no prognostic association whatsoever.
Improved Exact Methods for Solving No-Wait Flowshop Scheduling Problems With Due Date Constraints

The no-wait flowshop scheduling problem with hard due date constraints is critical to operations in many industries, such as plastic, chemical, and pharmaceutical manufacturing. However, to date, there is a lack of effective optimization algorithms for this NP-hard problem. This paper develops a new mixed integer linear programming (MILP) model and a two-phase enumeration algorithm to improve the best-so-far exact methods for solving this problem with the objective of minimizing the makespan. A comprehensive computational experiment is performed to compare the performances of the discussed exact methods. The computational results demonstrate that the proposed MILP model and the two-phase enumeration algorithm significantly outperform the best-so-far optimization methods, and the (sub-) optimal solutions to several unsolved instances from the literature are reported.
Effects of environmental temperature and dietary zinc on egg production performance, egg quality and antioxidant status and expression of heat-shock proteins in tissues of broiler breeders

Abstract To investigate the effects of environmental temperature and dietary Zn on egg production performance, egg quality and antioxidant status, as well as expression of heat-shock proteins (HSP) in tissues, of laying broiler breeders, we used a completely randomised design with a 2×3 factorial arrangement of treatments. The two environmental temperatures were normal (21±1°C, NT) and high (32±1°C, HT). The three dietary Zn sources were a Zn-unsupplemented basal diet (CON), and the basal diet supplemented with 110 mg Zn/kg as either the inorganic Zn sulphate (iZn) or the organic Zn proteinate with a moderate chelation strength (oZn). HT decreased (P<0·002) egg weight, laying rate, eggshell strength, thickness and weight, but increased (P≤0·05) rectal temperature, broken egg rate, misshapen egg rate, feed:egg ratio, Cu Zn superoxide dismutase activities in liver and pancreas, as well as metallothionein (MT) level in pancreas, and HSP70 mRNA levels in liver and pancreas of laying broiler breeders. Broiler breeders fed the oZn diet had higher (P<0·04) Zn content in the liver, as well as MT levels in the liver and pancreas, compared with those fed the CON diet. Under HT, broiler breeders fed the oZn diet had higher (P<0·05) Zn content in the pancreas compared with those fed the iZn and CON diets. The results from this study indicated that HT impaired egg production performance and eggshell quality possibly because of the disturbed redox balance and HSP homoeostasis, whereas the oZn is more available than the iZn for pancreatic Zn of heat-stressed laying broiler breeders.
ZnO Nanoparticles: A Promising Anticancer Agent

Nanoparticles, with their selective targeting capabilities and superior efficacy, are becoming increasingly important in modern cancer therapy and starting to overshadow traditional cancer therapies such as chemotherapy radiation and surgery. ZnO nanoparticles, with their unique properties such as biocompatibility, high selectivity, enhanced cytotoxicity and easy synthesis, may be a promising anticancer agent. Zinc, as one of the major trace elements of the human body and co-factor of more than 300 mammalian enzymes, plays an important role in maintaining crucial cellular processes including oxidative stress, DNA replication, DNA repair, cell cycle progression and apoptosis. Thus, it is evident that an alteration in zinc levels in cancer cells can cause a deleterious effect. Research has shown that low zinc concentration in cells leads to the initiation and progression of cancer and high zinc concentration shows toxic effects. Zinc-mediated protein activity disequilibrium and oxidative stress through reactive oxygen species (ROS) may be the probable mechanism of this cytotoxic effect. The selective localization of ZnO nanoparticles towards cancer cells due to enhanced permeability and retention (EPR) effect and electrostatic interaction and selective cytotoxicity due to increased ROS present in cancer cells show that ZnO nanoparticles can selectively target and kill cancer cells, making them a promising anticancer agent.