Miracle-dz/UniFAR-FTUs huggingface dataset:
Insights into the binding mode and functional components of the analgesic-antitumour peptide from Buthus martensii Karsch to human voltage-gated sodium channel 1.7 based on dynamic simulation analysis

Abstract Voltage-gated sodium (Nav) channels are transmembrane proteins composed of four homologous domains (DI–DIV) that play important roles in membrane excitability in neurons and muscles. Analgesic-antitumour peptide (AGAP) is a neurotoxin from the scorpion Buthus martensii Karsch, and has been shown to exert analgesic effect by binding on site 4 of human Nav1.7 (hNav1.7). Mechanistic details about this binding, however, remain unclear. To address this issue, we compared the binding modes of AGAP/AGAPW38G/AGAPW38F and the hNav1.7 voltage-sensing domain on DII (VSD2hNav1.7) using homology modeling, molecular docking, molecular dynamics simulation and steered molecular dynamics. Results revealed the key role of tryptophan at position 38 on the binding of AGAP to VSD2hNav1.7. Pivotal roles are played also by residues on the β-turn and negatively charged residues at the C-terminal. We further show that electrostatic interaction is the main contributor to the binding free energy of the complex. Agreement between our computational simulation findings and prior experimental data supports the accuracy of the described mechanism. Accordingly, these results can provide valuable information for designing potent toxin analgesics targeting hNav1.7 with high affinity. Communicated by Ramaswamy H. Sarma
Differential effects of BMP‐2 and TGF‐β1 on chondrogenic differentiation of adipose derived stem cells

Abstract. Objectives: This article addresses the interaction of transforming growth factor β1 (TGF‐β1) and bone morphogenic protein 2 (BMP‐2) during osteo‐chondrogenic differentiation of adipose‐derived adult stem cells (ASC). TGF‐β1 was expected to modulate the BMP‐2‐induced effects through transcriptional regulation of Dlx‐5, Msx‐2 and Runx‐2. Materials and Methods: Encapsulated ASC were cultured for 14 days in medium containing TGF‐β1 and/or BMP‐2. mRNA expression of the extracellular matrix molecules col2a1, cartilage oligomeric matrix protein, col10a1, alkaline phosphatase (AP) and transcription factors Msx‐2, Dlx‐5 and Runx‐2 was analysed. Release of glycosaminoglycans, collagen types II and X into the extracellular matrix was demonstrated. Results: BMP‐2 and TGF‐β1 induced a chondrogenic phenotype in ASC. Combined growth factor treatment had a synergistic effect on col10a1 and an additive effect on col2a1 mRNA expression. Synthesis of glycosaminoglycans was enhanced by combined growth factor treatment. Addition of TGF‐β1 inhibited BMP‐2 induced AP expression and activity and both proteins promoted chondrogenic maturation. Conclusions: Prevention of BMP‐2‐induced osteogenic transdifferentiation by TGF‐β1 seemed not to be mediated by transcriptional regulation of Dlx‐5. Due to these findings, simultaneous stimulation of ASC with BMP‐2 and TGF‐β1 seemed to be beneficial for complete differentiation of ASC into chondrocytes.
The proinflammatory effect and molecular mechanism of IL- 17 in the intestinal epithelial cell line HT-29.

PURPOSE To evaluate the proinflammatory effect and molecular mechanism of IL-17 in the intestinal epithelial cell line HT-29. METHODS After culture of HT-29 cells with IL-17 and/or TNF-(α), real-time (RT) PCR and Western blot were used to measure the gene expression level of the neutrophil chemokines CXCL1, CXCL2, CXCL5, CXCL6, IL-8 and the Th-17 chemokine CCL20, the phosphorylation level of P38 and TNF-α, and the expression level of IL-8 after treatment with P38 inhibitor. Act1 stable knockdown HT-29 cell line was established to further test the change of P38 phosphorylation after treatment with IL-17 and TNF-α. RESULTS When HT-29 cells were cultured with IL-17 and TNF-α, the expression level of neutrophil chemokines (CXCL1, CXCL2, CXCL5, CXCL6, IL-8) and Th17 chemokine (CCL20) was significantly improved (24.96±2.53, 28.47±2.87, 38.08±2.72, 33.47±2.41, 31.7±2.38, 44.37±2.73, respectively) (p<0.01). The results of Western blot showed that IL-17 obviously enhanced the phosphorylation of P38 induced by TNF-α. Compared with the control group, the expression level of IL-8 declined significantly (9.47±1.36 vs 3.06±0.67) when HT-29 was cultured together with IL-17 and TNF-α (p<0.01). P38 inhibition assay showed that P38 pathway played an essential role in IL-17 induced inflammatory response. The level of P38 phosphorylation could not be changed after treatment with IL-17 and TNF-α in Act1 stable knockdown HT-29 cell line. CONCLUSION IL-17 significantly promoted the gene expression level of TNF-α-induced neutrophil chemokines and Th17 cells chemokine. IL-17 and TNF-α have an obvious synergistic effect on P38.
The clinical and research significance of the erythrocyte sedimentation rate.

OBJECTIVES To determine normal limits for erythrocyte sedimentation rate (ESR) in rheumatology clinics based on observations from patients with noninflammatory disorders (NID); to determine the proportion of patients with osteoarthritis (OA) excluded from clinical trials because of elevated ESR; to determine the proportion of patients with rheumatoid arthritis (RA) meeting ESR criteria for remission, clinical activity, and eligibility for clinical trials; and finally, to explain elevations of ESR in OA. METHODS Cross sectional and longitudinal study of all rheumatic disease clinic outpatients with RA (N = 1,556, ESR = 12,683) and NID (N = 3,961, ESR = 5,706). RESULTS For all NID the 90th, 95th percentiles were 33, 40 for women and 23, 31 for men. For patients with OA, 21.2% of women and 8.5% of men had ESR > or = 30 mm/h. ESR in women with OA but not men with OA or those with RA were significantly associated with body mass index. Twenty-nine (29.4) percent of men and 41.6% of women with RA satisfied the ESR remission criterion. When the active disease criterion was considered (ESR > or = 28 mm/h), only 54.5% of men and 62.6% of women, on the average, have active RA. CONCLUSION The upper limit for normal ESR for women through age 60 is about 38 mm/h. A significant proportion of patients with RA with active disease will satisfy the ACR ESR criterion for remission, but only 54-63% of patients being treated in a rheumatology clinic will have active disease (ESR > or = 28 mm/h). Current use of the ESR as a criterion in clinical trials and remission criteria while based on wide clinical experience is contradictory and may not reflect actual data.
Role of Electrocorticography at Surgery for Lesion-related Frontal Lobe Epilepsy

Abstract: Background: The prognostic significance of epileptiform activity (EA) recorded intraoperatively at electrocorticography (ECOG) in patients with lesion-related frontal lobe epilepsy (FLE) is unknown. Methods: The results of ECOG performed in 22 patients with intractable FLE and a circumscribed frontal lobe structural lesion were compared with postoperative seizure control. Three patients underwent re-operation for a total of 25 cases, 23/25 with post-resection ECOG. Lesions were neoplasms (12), hamartomas (6) and arteriovenous malformations (4). Results: Outcomes were 15/25 Class I, 5/25 Class III and 5/25 Class IV (Engel classification). Class I outcome was associated with pre-excision EA recorded from ≤ 2 gyri (p < 0.05) and absence of EA, or EA limited to the resection border, at post-excision ECOG (p < 0.01). Complete lesion excision was highly correlated with Class I outcome (p < 0.001). The most significant correlations were seen when ECOG and lesionectomy variables were considered together: all 12 cases with complete lesionectomy and absent post-excision EA distant to the resection border had Class I outcome (p < 0.00015) and all 13 cases with complete lesionectomy and pre-excision EA recorded from ≤ 2 gyri had Class I outcome (p < 0.00005). Conclusions: Postoperative seizure control in lesion-related FLE is assured in the setting of complete lesion resection with pre-excision EA recorded from ≤ 2 gyri and no post-excision EA distant to the resection border; complete lesion excision is of paramount importance.
Information experiences, needs, and preferences of colonoscopy patients

Abstract Better pre-colonoscopy education may lead to improved bowel preparation, decreased anxiety, and a willingness to go direct-to-colonoscopy. We assessed information experiences, needs, and preferences of patients undergoing colonoscopy. A self-administered survey was distributed between 08/2015 and 06/2016 to patients in Winnipeg, Canada when they attended an outpatient colonoscopy. The amount, type, helpfulness, and satisfaction with information provided were analyzed. Linear and logistic regression analyses were used to assess predictors of satisfaction with various aspects of the information received, as well as overall satisfaction with the provided information. Although the majority of the 1580 respondents were satisfied with the information they received, only 68% of respondents coming for a repeat colonoscopy and 59% of those coming for first colonoscopy perceived receiving just the right amount of information from their endoscopy doctor. One quarter or less of the respondents indicated they received just the right amount of information from any source other than their colonoscopy doctor. 38% coming for a first colonoscopy and 44% coming for a repeat colonoscopy indicated they received no information from their family physician. Those coming for their first colonoscopy had a lower average score (9.7 vs 11.1; P < .001) for amount of information received (scale 0-15), were less satisfied with the information they received (P = .005) and found the information to be less clear (P = .004). Many patients going for colonoscopy in a large urban practice are inadequately informed about the various aspects of the procedure and it is worse for those going for first rather than repeat colonoscopy.
The use of telemedicine to enhance secondary care: some lessons from the front line

ABSTRACT Digital technologies such as telemedicine have the potential to transform healthcare, but uptake has only recently gained momentum secondary to national policy drivers. This paper reviews the potential benefits of telemedicine in secondary care and explores the use of video conferencing to support the hospital follow-up of older people with chronic disease, identifying a wide variety of issues that need to be addressed for successful implementation. We believe these issues will interest secondary care colleagues considering the use of telemedicine to support or substitute for some outpatient activities.
The Radical Trap 5,5-Dimethyl-1-Pyrroline N-Oxide Exerts Dose-Dependent Protection against Myocardial Ischemia-Reperfusion Injury through Preservation of Mitochondrial Electron Transport

Free radicals are important mediators of myocardial ischemia-reperfusion injury. Nitrone spin traps have been shown to scavenge free radicals. The cardioprotective effect of the spin trap, 5,5-dimethyl-1-pyrroline N-oxide (DMPO), was investigated in an isolated heart model of global ischemia and reperfusion. Rat hearts were perfused and subjected to global ischemia for 30 min followed by reperfusion with four treatment groups of varying DMPO concentration (0.5-10 mM) administered before induction of ischemia. DMPO treatment improved the recovery of left ventricular (LV) function and coronary flow over the 30-min period of reperfusion compared with untreated hearts. Enhanced recovery was observed for all doses studied but was highest with 1 mM treatment with 2.4-fold higher recovery of LV developed pressure and 37% reduction in infarct size. Superoxide was measured by tissue fluorometry using the \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}_{2}^{\overline{.}}\) \end{document} probe hydroethidine. Hearts treated with 1 mM DMPO showed a significant reduction in \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{O}_{2}^{\overline{.}}\) \end{document} production compared with control hearts both over the first 5 min of ischemia and upon reperfusion after 30 min of global ischemia. Studies of mitochondrial function demonstrated that 1 mM DMPO increased the recovery of function of complexes I, II/III, and IV after 30 min of reperfusion. Immunoblotting with antibodies against complexes I, II, and IV further revealed marked up-regulation of mitochondrial proteins, suggesting that DMPO prevents their ischemic degradation via scavenging oxygen radicals generated during ischemia/reperfusion. Thus, DMPO functions as a protective agent against ischemic and postischemic injury via radical scavenging, conferring robust dose-dependent protection with salvage of mitochondrial function and redox homeostasis.
A pan‐apicomplexan phosphoinositide‐binding protein acts in malarial microneme exocytosis

Invasion of human red blood cells by the malaria parasite Plasmodium falciparum is an essential step in the development of the disease. Consequently, the molecular players involved in host cell invasion represent important targets for inhibitor design and vaccine development. The process of merozoite invasion is a succession of steps underlined by the sequential secretion of the organelles of the apical complex. However, little is known with regard to how their contents are exocytosed. Here, we identify a phosphoinositide‐binding protein conserved in apicomplexan parasites and show that it is important for the attachment and subsequent invasion of the erythrocyte by the merozoite. Critically, removing the protein from its site of action by knock sideways preferentially prevents the secretion of certain types of micronemes. Our results therefore provide evidence for a role of phosphoinositide lipids in the malaria invasion process and provide further insight into the secretion of microneme organelle populations, which is potentially applicable to diverse apicomplexan parasites.
CBL Linker Region and RING Finger Mutations Lead to Enhanced Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Signaling via Elevated Levels of JAK2 and LYN*

Background: A subset of juvenile myelomonocytic leukemia (JMML) patients harbor mutations in the E3 ubiquitin ligase CBL. Results: CBL mutations result in increased GM-CSFR phosphorylation, elevated JAK2 and LYN levels, and enhanced survival. Conclusion: CBL JMML mutants display hypersensitive GM-CSF signaling that can be modulated via inhibition of JAK2 and/or SRC kinases. Significance: Mutation of CBL in JMML is associated with altered GM-CSF function. Juvenile myelomonocytic leukemia (JMML) is characterized by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). SHP2, NF-1, KRAS, and NRAS are mutated in JMML patients, leading to aberrant regulation of RAS signaling. A subset of JMML patients harbor CBL mutations associated with 11q acquired uniparental disomy. Many of these mutations are in the linker region and the RING finger of CBL, leading to a loss of E3 ligase activity. We investigated the mechanism by which CBL-Y371H, a linker region mutant, and CBL-C384R, a RING finger mutant, lead to enhanced GM-CSF signaling. Expression of CBL mutants in the TF-1 cell line resulted in enhanced survival in the absence of GM-CSF. Cells expressing CBL mutations displayed increased phosphorylation of GM-CSF receptor βc subunit in response to stimulation, although expression of total GM-CSFR βc was lower. This suggested enhanced kinase activity downstream of GM-CSFR. JAK2 and LYN kinase expression is elevated in CBL-Y371H and CBL-C384R mutant cells, resulting in enhanced phosphorylation of CBL and S6 in response to GM-CSF stimulation. Incubation with the JAK2 inhibitor, TG101348, abolished the increased phosphorylation of GM-CSFR βc in cells expressing CBL mutants, whereas treatment with the SRC kinase inhibitor dasatinib resulted in equalization of GM-CSFR βc phosphorylation signal between wild type CBL and CBL mutant samples. Dasatinib treatment inhibited the elevated phosphorylation of CBL-Y371H and CBL-C384R mutants. Our study indicates that CBL linker and RING finger mutants lead to enhanced GM-CSF signaling due to elevated kinase expression, which can be blocked using small molecule inhibitors targeting specific downstream pathways.
Platelet activating factor‐induced neuronal apoptosis is initiated independently of its G‐protein coupled PAF receptor and is inhibited by the benzoate orsellinic acid

The bioactive lipid mediator platelet activating factor (PAF) is recognized as a key effecter of neuronal apoptosis, yet it is not clear whether its G‐protein coupled receptor (PAFR) initiates or prevents PAF neurotoxicity. Using PAFR−/− and congenic wild‐type mice, we show that PAF triggers caspase‐3/7 activity and neuronal death in PAFR−/− but not PAFR+/+ cerebellar granule neurons. Restoring receptor expression by recombinant adenoviral infection protected cells from PAF challenge. Neuronal death was not mediated by nitric oxide or N‐methyl‐d‐aspartate receptor signaling given that N‐nitro‐l‐arginine methyl ester and MK‐801 did not inhibit PAF‐induced neuronal loss in PAFR−/− neurons. To intervene in PAFR‐independent neurotoxicity, the anti‐apoptotic actions of three structurally distinct PAF antagonists were compared to a panel of plant and fungal benzoic acid derivatives. We found that the PAF antagonist BN 52021 but not FR 49175 or CV 3988 inhibited PAFR‐independent neurotoxicity. Orsellinic acid, a fungal‐derived benzoic acid, blocked PAF‐mediated neuronal apoptosis without affecting PAFR‐mediated neuroprotection. These findings demonstrate that PAF can transduce apoptotic death in primary neurons independently of its G‐protein coupled receptor, that PAFR activation is neuroprotective, and that orsellinic acid effectively attenuates PAFR‐independent neuronal apoptosis.
One-year results and anterior segment optical coherence tomography findings of descemet stripping automated endothelial keratoplasty combined with phacoemulsification.

OBJECTIVE To report 1-year results and anterior segment optical coherence tomography findings of Descemet stripping automated endothelial keratoplasty combined with phacoemulsification in patients with cataract and Fuchs endothelial dystrophy. METHODS Twelve eyes of 11 patients with at least 1-year follow-up were retrospectively reviewed. Measured variables included best spectacle-corrected visual acuity, refractive spherical equivalent and predictability, anterior corneal keratometric values, complications, and anterior segment optical coherence tomography findings. RESULTS The mean follow-up was 14.33 months (range, 12-18 months). The best spectacle-corrected visual acuity was unchanged (8%) or improved (92%) in all eyes compared with the preoperative levels. A mean (SD) discrepancy between the targeted postoperative refraction and the actual postoperative spherical equivalent refraction (hyperopic shift) of 1.46 (0.76) diopters (D) (range, -0.05 to 3.14 D) was observed. A significant correlation existed between the ratio of central graft thickness to mean peripheral donor corneal lenticule thickness at 3 mm and induced hyperopic shift (R(2) = 0.65, P < . 001). CONCLUSIONS Descemet stripping automated endothelial keratoplasty combined with phacoemulsification and intraocular lens implantation in patients with coexisting Fuchs endothelial dystrophy and cataract improved best spectacle-corrected visual acuity without progressive time-dependent complications. A correlation exists between donor corneal lenticule shape and induced hyperopic shift.
Retinoids, Carotenoids, and Tocopherols in Breast Adipose Tissue and Serum of Benign Breast Disease and Breast Cancer Patients

Various retinoic acid (RA) isomers (all-trans, 13-cis, 11-cis, and 9-cis) as well as retinol, carotenoids, and tocopherol concentrations were determined in both serum and breast adipose tissue of 22 benign breast disease patients and 52 breast cancer patients categorized into 4 stages by malignancy. Serum RA isomers were analyzed by a newly developed sensitive method combining a high-performance liquid chromatography and a gas chromatography-mass spectrometry, and retinol, carotenoid, and tocopherol concentrations using a high-performance liquid chromatography system. The breast cancer patients showed significantly lower serum retinol, whereas significantly higher breast adipose tissue retinol concentration than those of benign breast disease patients. Although breast cancer patients showed significantly higher serum all-trans and 13-cis RA concentrations, 11-cis RA in breast adipose tissue was significantly lower in the breast cancer patients than those of benign breast disease patients and it was associated with the stage of malignancy. The current study indicates that the retinol and RA isomers in the target tissue of breast tumor patients are not reflecting their concentrations in circulation. The mechanisms of tissue specific uptake of RA isomers and their functions warrant further studies.
Development of Silicon Probe With Acute Study on In Vivo Neural Recording and Implantation Behavior Monitored by Integrated Si-Nanowire Strain Sensors

The silicon probe with highly P-doped Si electrodes was realized on 8-in Silicon on insulator wafer through standard Complementary metal-oxide semiconductor process. By leveraging the same thin Si device layer (~100 nm), the built-in piezoresistive Si-nanowires (SiNWs) configured in full-bridge structure were also equipped along the probe shank for strain sensing. After additional coatings of nanocomposite (Carbon nanotubes + Au nanoparticles) on silicon electrodes, the functionality of neural recording was validated with a low noise level (<;20 μV) during in vivo neural recording on rat brain (CA1 region). The additional capability of monitoring probe mechanical behavior was first verified through the probe buckling experiments and further examined with implantations on rat brain (S1 region). Besides the large buckling mechanics, the physiological brain micromotion (e.g., caused by respiration) was successfully picked up by integrated SiNWs strain sensors, which would provide the research platform to practically understand the correlation between the electrical neural signal and the brain micromotion.
NonO, a non-POU-domain-containing, octamer-binding protein, is the mammalian homolog of Drosophila nonAdiss

We have cloned the ubiquitous form of an octamer-binding, 60-kDa protein (NonO) that appears to be the mammalian equivalent of the Drosophila visual and courtship song behavior protein, no-on-transient A/dissonance (nonAdiss). A region unprecedently rich in aromatic amino acids containing two ribonuclear protein binding motifs is highly conserved between the two proteins. A ubiquitous form of NonO is present in all adult tissues, whereas lymphocytes and retina express unique forms of NonO mRNA. The ubiquitous form contains a potential helix-turn-helix motif followed by a highly charged region but differs from prototypic octamer-binding factors by lacking the POU DNA-binding domain. In addition to its conventional octamer duplex-binding, NonO binds single-stranded DNA and RNA at a site independent of the duplex site.
Fetal heart rate monitoring and neonatal outcome in a population of early‐ and late‐onset intrauterine growth restriction

The early‐onset intrauterine growth restriction (IUGR) is associated with severe placental insufficiency and Doppler abnormalities. The late‐onset IUGR is associated with mild placental insufficiency and normal Doppler velocimetry. The computerized cardiotocographic (cCTG) monitoring is used to evaluate the fetal well‐being in pregnancies complicated by IUGR. Our aim was to investigate the cardiotocographic characteristics of IUGR fetuses and to identify every cCTG difference between Healthy and IUGR fetuses.