Miracle-dz/UniFAR-FTUs huggingface dataset:
MI-DRA 3D: New Model for Reconstruction of US FDA Drug-target Network and Theoretic-experimental Studies of Rasagiline Derivatives Inhibitors of AChE

The Neurodegenerative diseases have been increasing in the last years. Many of the drug candidates to be used in the treatment of neurodegenerative disease present specific 3D structural features. One important protein in this sense is the acetylcholinesterase (AChE); which is the target of many Alzheimer's dementia drugs. Consequently, the prediction of Drug-Proteins Interactions (DPIs/nDPIs) between new drug candidates with specific 3D structure and targets it is about the major importance. For it, we can use Quantitative Structure-Activity Relationships (QSAR) models to carry out rational DPIs prediction. Unfortunately, many previous QSAR models developed to predict DPIs take into consideration only 2D structural information and codify the activity against only one target. To solve this problem we can develop one 3D multi-target QSAR (3D MtQSAR) models. In this communication, we introduce the technique MI-DRA 3D a new predictor for DPIs based two different well-known software. We use the software MARCH-INSIDE (MI) and DRAGON to calculate 3D structural parameters for drugs and targets respectively. Both classes of 3D parameters were used as input to train Artificial Neuronal Network (ANN) algorithms using as benchmark datasets the complex network (CN) formed by all DPIs between US FDA approved drugs and their targets. The entire dataset was downloaded from Drug Bank. The best 3D Mt-QSAR predictor found is one ANN of type Multilayer Perceptron (MLP) with profile MLP 37:37-24-1:1. This MLP classifies correctly 274 out of 321 DPIs (Sensitivity = 85.35%) and 1041 out of 1190 nDPIs (Specificity = 87.48%), corresponding to training Accuracy = 87.03%. We validated the model with external predicting series with Sensitivity = 84.16% (542/644 DPIs; Specificity = 87.51% (2039/2330 nDPIs) and Accuracy = 86.78%. The new CNs of DPIs reconstructed from US FDA can be used to explore large DPIs databases in order to discover both new drugs and/or targets. We carried out theoretic-experimental studies to illustrate the practical use of MI-DRA 3D. First, we reported the prediction and pharmacological assay of 22 different rasagiline derivatives with possible AChE inhibitory activity.
Saturation of 1047- and 1064-nm Absorption in ${\hbox {Cr}}^{4+}$:YAG Crystals

To investigate the physical mechanism of the saturation process in Cr4+:YAG crystals we solved the three coupled rate equations which describe the saturable absorber. We experimentally verified this model using two lasers with nanosecond pulses and continuous-wave radiation. We used crystalline and ceramic Cr4+-doped YAG saturable absorbers with various initial transmissions. The ratio between the ground and the excited-state absorption cross section at 1064 nm was measured to be between 3.8 plusmn 0.2 and 4.7 plusmn 0.2 for crystalline and 3.6 plusmn 0.1 for ceramic Cr4+:YAG. The ratio between the above named cross sections at 1047 nm was found to be 6.2 plusmn 0.2 for both crystalline and ceramic Cr4+:YAG. With these results the ground-state and the excited-state absorption cross sections at 1047 nm were calculated to be (9.55plusmn0.01)times10-19 cm2 and (1.54plusmn0.03)times10-19 cm2, respectively
Qualitative and Quantitative Assessment of Technical Skills in Percutaneous Coronary Intervention: In Vivo Porcine Studies

<italic>Objective:</italic> Technical skill assessment plays an important role in the professional development of an interventionalist in percutaneous coronary intervention (PCI). However, most of the traditional assessment methods are time consuming and subjective. This paper aims to develop objective assessment techniques. <italic>Methods:</italic> In this study, a natural-behavior-based assessment framework is proposed to qualitatively and quantitatively assess technical skills in PCI. <italic>In vivo</italic> porcine studies were conducted to deliver a medical guidewire to two target coronaries of left circumflex arteries by six novice and four expert interventionalists. Simultaneously, four types of natural behaviors (i.e., hand motion, proximal force, muscle activity, and finger motion) were acquired from the subjects’ dominant hand and arm. The features extracted from the behaviors of different skill-level groups were compared using the Mann–Whitney U-test for effective behavior selection. The effective ones were further applied in the Gaussian-mixture-model-based qualitative assessment and Mahalanobis-distance-based quantitative assessment. <italic>Results:</italic> The qualitative assessment achieves an accuracy of 92% to distinguish the novice and expert attempts, which is significantly higher than that of using single guidewire motions. Furthermore, the quantitative assessment can assign objective and effective scores for all attempts, indicating high correlation (<inline-formula><tex-math notation="LaTeX">$R$</tex-math></inline-formula> <inline-formula><tex-math notation="LaTeX">$=$</tex-math></inline-formula> 0.9225) to those obtained by traditional methods. <italic>Conclusion:</italic> The objective, effective, and comprehensive assessment of technical skills can be provided by qualitatively and quantitatively analyzing interventionalists’ natural behaviors in PCI. <italic>Significance:</italic> This paper suggests a novel approach for the technical skill assessment and the promising results demonstrate the great importance and effectiveness of the proposed method for promoting the development of objective assessment techniques.
An IL-1 Cytokine Member, IL-33, Induces Human Basophil Activation via Its ST2 Receptor1

Basophils are thought to play pivotal roles in allergic inflammation through rapid release of chemical mediators in addition to sustained production of Th2 cytokines, including IL-4. A newly identified cytokine, IL-33, has been recognized as one of the key cytokines enhancing Th2-balanced immune regulation through its receptor, ST2. The present study was conducted to elucidate whether IL-33 acts directly on, and affects the functions of, human basophils. Real-time PCR analysis showed that basophils express transcripts for ST2. The expression levels were significantly higher compared with eosinophils and neutrophils, and treatment with IL-33 significantly up-regulated basophil ST2 mRNA expression. Expressions of IL-4 and IL-13 mRNA were also up-regulated by IL-33, and there was also enhanced secretion of IL-4 protein. IL-33 increased the surface levels of basophil CD11b expression and enhanced basophil adhesiveness. Although IL-33 failed to directly induce degranulation or attract basophils, it exerted priming effects on basophils. It enhanced degranulation in response to IgE-crosslinking stimulus and also enhanced basophil migration toward eotaxin without changing surface CCR3. Also, IL-33 synergistically enhanced IL-4 production and CD11b expression by IL-3-stimulated basophils. Neutralization using Ab specific for ST2 significantly diminished the enhancing effects of IL-33 on both basophil CD11b expression and migration toward eotaxin, indicating that IL-33 signals via ST2 expressed on basophils. This study revealed that IL-33 potently regulates migration and activation of human basophils. IL-33 may be a key cytokine in the pathogenesis of Th2-dominant inflammation by acting not only on lymphocytes but also on effector cells such as basophils.
Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome

Evidence of distinct disease propagating stem cells in myelodysplastic syndrome (MDS) has emerged in recent years. However, immunophenotypic characterization of these cancer stem cells remains sparse. In acute myeloid leukaemia (AML), we have previously described aberrant expression of the C‐type lectin domain family 12, member A (CLEC12A) as a stable and reliable marker of leukaemia blasts and as a tool for assessing minimal residual disease. Furthermore, CLEC12A has been proposed as a promising marker of leukaemic stem cells in AML. The role of CLEC12A in MDS, however, remains to be elucidated. In this study, we found CLEC12A aberrantly expressed on the CD34+CD38− cell compartment in 71% (22/31) of MDS patients, distributed across all Revised International Prognostic Scoring System risk groups. We showed that the CD34+CD38−CLEC12A+ cells were indeed malignant and possessed functional stem cell properties in the long‐term colony‐initiating cell assay. As opposed to reported findings in AML, we showed that cancer stem cells from MDS samples derived from both CLEC12A positive and negative CD34+CD38− subpopulations. Due to the absence of CLEC12A on normal haematopoietic stem cells, CLEC12A stem cell immunophenotyping may contribute to diagnosing and monitoring MDS patients and could furthermore add knowledge about disease propagating cells in MDS.
Transfer of Intracellular HIV Nef to Endothelium Causes Endothelial Dysfunction

With effective antiretroviral therapy (ART), cardiovascular diseases (CVD) are emerging as a major cause of morbidity and death in the aging HIV-infected population. To address whether HIV-Nef, a viral protein produced in infected cells even when virus production is halted by ART, can lead to endothelial activation and dysfunction, we tested Nef protein transfer to and activity in endothelial cells. We demonstrated that Nef is essential for major endothelial cell activating effects of HIV-infected Jurkat cells when in direct contact with the endothelium. In addition, we found that Nef protein in endothelial cells is sufficient to cause apoptosis, ROS generation and release of monocyte attractant protein-1 (MCP-1). The Nef protein-dependent endothelial activating effects can be best explained by our observation that Nef protein rapidly transfers from either HIV-infected or Nef-transfected Jurkat cells to endothelial cells between these two cell types. These results are of in vivo relevance as we demonstrated that Nef protein induces GFP transfer from T cells to endothelium in CD4.Nef. GFP transgenic mice and Nef is present in chimeric SIV-infected macaques. Analyzing the signal transduction effects of Nef in endothelial cells, we found that Nef-induced apoptosis is mediated through ROS-dependent mechanisms, while MCP-1 production is NF-kB dependent. Together, these data indicate that inhibition of Nef-associated pathways may be promising new therapeutic targets for reducing the risk for cardiovascular disease in the HIV-infected population.
Zinc Content in the Diet Affects the Activity of Cu/ZnSOD, Lipid Peroxidation and Lipid Profile of Spontaneously Hypertensive Rats

The present study focused on the effect of Zn containing diets on the activity of superoxide dismutase (Cu/ZnSOD), systolic blood pressure (SBP), lipid peroxides (ROOH) and lipids (LDL, HDL, triglycerides and cholesterol) in male spontaneously hypertensive rats (SHR). Three experimental groups of animals were studied: a control (G1-40 mg), and two with zinc-supplemented diets (G2-100 and G3-160 mg Zn/kg lab chow). The diets were introduced at the beginning of the development of hypertension (2 months after birth) and the animals were fed for 8 weeks. The activity of CuZnSOD in erythrocytes was determined by spectrophotometry with the use of RANSOD kit (RANDOX Laboratories Ltd., UK). Atomic-absorption spectrometry was used to determine Zn and Cu concentrations in the rat’s sera. A significantly increased Cu/ZnSOD activity was found in G3 compared with rats fed with control diet G. (p = 0.020). SBP was significantly decreased in G3 in relation to G. (p = 0.0048). The lipid hydroperoxide concentration was significantly decreased in G3 compared with G. (p = 0.016) and G. (p = 0.005). Zinc supplement affected lipids profile by decreasing LDL and increasing HDL. The present data suggest that Zn concentration in the diet plays an important role in the regulation of SBP and can be a critical nutrient for maintenance of anti-oxidative events in SHR.
VSE++: Improving Visual-Semantic Embeddings with Hard Negatives

We present a new technique for learning visual-semantic embeddings for cross-modal retrieval. Inspired by hard negative mining, the use of hard negatives in structured prediction, and ranking loss functions, we introduce a simple change to common loss functions used for multi-modal embeddings. That, combined with fine-tuning and use of augmented data, yields significant gains in retrieval performance. We showcase our approach, VSE++, on MS-COCO and Flickr30K datasets, using ablation studies and comparisons with existing methods. On MS-COCO our approach outperforms state-of-the-art methods by 8.8% in caption retrieval and 11.3% in image retrieval (at R@1).
Chinese Graduate Students at North American Universities: Learning Challenges and Coping Strategies

The paper investigated four Chinese graduate students’ perceptions of the challenges they face and the coping strategies they use in their English academic learning at two North American universities. They reported experiencing the following seven major challenges in their academic learning: 1) financial difficulties; 2) problems in using English for academic purposes; 3) frustrations in becoming a permanent resident; 4) difficulty in adapting to the classroom learning environment; 5) lack of critical thinking skills; 6) acculturation problems; and 7) loneliness and academic anxiety. For each of the seven challenges they have developed corresponding coping strategies.
Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers

A distinct group of breast cancers, called “basal” or “triple-negative” (TN) cancers express both basal cytokeratins and the epidermal growth factor receptor, but fail to express estrogen receptors, progesterone receptors or HER2 and have stem-like or mesenchymal features. They are particularly aggressive, are frequently chemo-resistant, with p53 mutation, up-regulation of IL-6 and Stat3. Because TN cells are particularly sensitive to the anti-diabetic agent metformin, we hypothesized that it may target JAK2/Stat3 signaling. The effects of metformin upon Stat3 expression and activation were examined in four human TN cell lines. Metformin’s effects were also studied in sublines with forced over-expression of constitutively active (CA) Stat3, as well as lines with stable knockdown of Stat3. Metformin inhibited Stat3 activation (P-Stat3) at Tyr705 and Ser727 and downstream signaling in each of the four parental cell lines. CA-Stat3 transfection attenuated, whereas Stat3 knockdown enhanced, the effects of metformin upon growth inhibition and apoptosis induction. A Stat3 specific inhibitor acted synergistically with metformin in reducing cell growth and inducing apoptosis. An mTOR inhibitor showed no significant interaction with metformin. In summary, Stat3 is a critical regulator of metformin action in TN cancer cells, providing the potential for enhancing metformin’s efficacy in the clinical setting.
Contribution of Homeostatic Chemokines CCL19 and CCL21 and Their Receptor CCR7 to Coronary Artery Disease

Objective— Our aim was to identify the role of the homeostatic chemokines CCL19 and CCL21 and their common receptor CCR7 in atherogenesis and to study the relationships between CCL19, CCL21, and CCR7 gene variants and coronary artery disease in a Chinese Han population. Approach and Results— Immunohistochemical analysis of samples with atherosclerosis of various stages showed increased CCL19, CCL21, and CCR7 expression in atherosclerotic coronary plaques compared with nonatherosclerotic controls. Expression levels increased in positive correlation with coronary lesion stage. Cell adhesion assays confirmed that CCL19 promoted monocyte adhesion, which was induced by CCR7, to human umbilical vein endothelial cells, an effect partially antagonized by atorvastatin. After the human umbilical vein endothelial cells were treated with CCR7-neutralizing antibody, both CCL19- and CCL21-induced monocyte to human umbilical vein endothelial cell migration and CCL19-induced monocyte to human umbilical vein endothelial cell adhesion were abolished. The associations between genetic variants of CCL19, CCL21, CCR7, and coronary artery disease in a Chinese Han population were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The following single nucleotide polymorphisms were associated with coronary artery disease: CCL19 rs2227302, CCL21 rs2812377, and CCR7 rs588019. Individuals with the CCL19 rs2227302 T allele or CCL21 rs2812377 G allele had higher plasma CCL19 levels than those with C/C genotype and higher CCL21 levels than those with T/T genotype in both case and control subjects. Conclusion— CCL19/CCL21–CCR7 is a novel homeostatic chemokine system that modulates human monocyte adhesion and migration, promoting atherogenesis. It is associated with coronary artery disease risk in Chinese Han individuals. These data suggest that the CCL19/CCL21–CCR7 axis plays an important role in atherosclerosis progression.
Differential Diagnosis of Immunoglobulin G4-associated Cholangitis From Cholangiocarcinoma

Background and Aim: Immunoglobulin G4-associated cholangitis (IAC) shares many similar symptoms with cholangiocarcinoma (CCA). However, the treatment and the prognosis are substantially different. This study aimed to identify the important markers for the differential diagnosis of these 2 diseases. Methods: Thirty IAC patients and 275 CCA patients were reviewed retrospectively for their clinical symptoms, serological tests, and imaging characteristics. Posttreatment responses were also studied. Results: IgG4 had 100% specificity for IAC at a cutoff of 6 times the upper normal limit. IAC patients had a significantly higher incidence of weight loss (P=0.025) and a higher level of weight loss (P=0.008) than CCA patients. The positive rates of biological markers CA199, CA242, and CEA in CCA and IAC were 81.5% versus 42.9%, 45.5% versus 4.5%, and 29.2% versus 7.1%, respectively. Levels of these tumor markers in CCA were significantly higher than in IAC (P<0.05). The thickened wall [17/18 (94.4%) vs. 3/10 (30%), P=0.001] and the occupying lesion on the bile duct [1/18 (5.6%) vs. 8/10 (80%), P<0.001] were found to be significantly different in IAC and CCA, respectively, by endoscopic ultrasonography. Autoimmune pancreatitis was the most frequently observed comorbidity of IAC (25/30). All IAC patients respond positively to steroid treatment. Conclusions: Increased tumor markers, 6-fold higher levels of serum IgG4, and other organs’ involvement could be the reference factors for a differential diagnosis of IAC and CCA. Endoscopic ultrasonography might be an effective imaging tool for diagnosis, although clinical signs and symptoms of IAC and CCA are similar. Experimental steroid treatment can be useful in the diagnosis for certain difficult cases.
Antituberculosis nanodelivery system with controlled-release properties based on para-amino salicylate–zinc aluminum-layered double-hydroxide nanocomposites

We report the intercalation and characterization of para-amino salicylic acid (PASA) into zinc/aluminum-layered double hydroxides (ZLDHs) by two methods, direct and indirect, to form nanocomposites: PASA nanocomposite prepared by a direct method (PASA-D) and PASA nanocomposite prepared by an indirect method (PASA-I). Powder X-ray diffraction, Fourier-transform infrared spectroscopy, and thermogravimetric analysis revealed that the PASA drugs were accommodated within the ZLDH interlayers. The anions of the drug were accommodated as an alternate monolayer (along the long-axis orientation) between ZLDH interlayers. Drug loading was estimated to be 22.8% and 16.6% for PASA-D and PASA-I, respectively. The in vitro release properties of the drug were investigated in physiological simulated phosphate-buffered saline solution of pH 7.4 and 4.8. The release followed the pseudo-second-order model for both nanocomposites. Cell viability (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide [MTT] assays) was assessed against normal human lung fibroblast MRC-5 and 3T3 mouse fibroblast cells at 24, 48, and 72 hours. The results showed that the nanocomposite formulations did not possess any cytotoxicity, at least up to 72 hours.
Comparison of the Different Approaches to Saphenous Nerve Block

Background:The authors compared the efficacy of the different approaches to saphenous nerve block. Methods:The following approaches to saphenous nerve block were compared in 10 volunteers: perifemoral, transsartorial, block at the medial femoral condyle, below-the-knee field block, and blockade at the level of the medial malleolus. Each volunteer underwent all five blocks, and the interval between blocks was 3–7 days. The sequence of injection was randomized by Latin square design. Sensory blockade at the medial aspects of the leg and foot and the strength of the anterior thigh muscles were noted. Results:The transsartorial, perifemoral, and below-the-knee field block approaches were more effective than block at the medial femoral condyle in providing sensory anesthesia to the medial aspect of the leg. The transsartorial approach was more effective than block at the medial femoral condyle and below-the-knee field block in providing sensory anesthesia to the medial aspect of the foot. Compared with the perifemoral approach, the transsartorial approach did not cause weakness of the hip flexors and the knee extensors. In volunteers with partial numbness in the medial aspect of the foot, supplemental block of the medial dorsal cutaneous branch of the superficial peroneal nerve resulted in complete sensory blockade. Conclusions:Sensory blockade in the medial aspects of the leg and foot is best achieved with the transsartorial approach. In some subjects, supplementary block of the medial dorsal cutaneous branch of the superficial peroneal nerve may have to be performed to assure complete numbness of the medial aspect of the foot.