Miracle-dz/UniFAR-FTUs huggingface dataset:
The effect of rider weight and additional weight in Icelandic horses in tölt: part I. Physiological responses

This study examined the effect of increasing BW ratio (BWR) between rider and horse, in the BWR range common for Icelandic horses (20% to 35%), on heart rate (HR), plasma lactate concentration (Lac), BWR at Lac 4 mmol/l (W4), breathing frequency (BF), rectal temperature (RT) and hematocrit (Hct) in Icelandic horses. In total, eight experienced school-horses were used in an incremental exercise test performed outdoors on an oval riding track and one rider rode all horses. The exercise test consisted of five phases (each 642 m) in tölt, a four-beat symmetrical gait, at a speed of 5.4±0.1 m/s (mean±SD), where BWR between rider (including saddle) and horse started at 20% (BWR20), was increased to 25% (BWR25), 30% (BWR30), and 35% (BWR35) and finally decreased to 20% (BWR20b). Between phases, the horses were stopped (~5.5 min) to add lead weights to specially adjusted saddle bags and a vest on the rider. Heart rate was measured during warm-up, the exercise test and after 5, 15 and 30 min of recovery and blood samples were taken and BF recorded at rest, and at end of each of these aforementioned occasions. Rectal temperature was measured at rest, at end of the exercise test and after a 30-min recovery period. Body size and body condition score (BCS) were registered and a clinical examination performed on the day before the test and for 2 days after. Heart rate and BF increased linearly (P<0.05) and Lac exponentially (P<0.05) with increasing BWR. The W4 was 22.7±4.3% (individual range 17.0% to 27.5%). There was a positive correlation between back BCS and W4 (r=0.75; P=0.032), but no other correlations between body measurements and W4 were found. Hematocrit was not affected by BWR (P>0.05), but negative correlations (P<0.05) existed between body size measurements and Hct. While HR, Hct and BF recovered to values at rest within 30 min, Lac and RT did not. All horses had no clinical remarks on palpation and at walk 1 and 2 days after the test. In conclusion, increasing BWR from 20% to 35% resulted in increased HR, Lac, RT and BF responses in the test group of experienced adult Icelandic riding horses. The horses mainly worked aerobically until BWR reached 22.7%, but considerable individual differences (17.0% to 27.5%) existed that were not linked to horse size, but to back BCS.
TSC2 regulates microRNA biogenesis via mTORC1 and GSK3&bgr;

Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by germline inactivating mutations of TSC1 or TSC2. In TSC-associated tumors of the brain, heart, skin, kidney and lung, inactivation of both alleles of TSC1 or TSC2 leads to hyperactivation of the mTORC1 pathway. The TSC/mTORC1 pathway is a key regulator of cellular processes related to growth, proliferation and autophagy. We and others have previously found that mTORC1 regulates microRNA biogenesis, but the mechanisms are not fully understood. Microprocessor, a multi-protein complex including the nuclease Drosha, processes the primary miR transcript. Using a dual-luciferase reporter, we found that inhibition of mTORC1 or downregulation of Raptor decreased Microprocessor activity, while loss of TSC2 led to a striking increase (∼5-fold) in Microprocessor activity. To determine the global impact of TSC2 on microRNAs we quantitatively analyzed 752 microRNAs in Tsc2-expressing and Tsc2-deficient cells. Out of 259 microRNAs expressed in both cell lines, 137 were significantly upregulated and 24 were significantly downregulated in Tsc2-deficient cells, consistent with the increased Microprocessor activity. Microprocessor activity is known to be regulated in part by GSK3β. We found that total GSK3β levels were higher in Tsc2-deficient cells, and the increase in Microprocessor activity associated with Tsc2 loss was reversed by three different GSK3β inhibitors. Furthermore, mTOR inhibition increased the levels of phospho-GSK3β (S9), which negatively affects Microprocessor activity. Taken together these data reveal that TSC2 regulates microRNA biogenesis and Microprocessor activity via GSK3β.
Polymorphisms of miR‐146a, miR‐149, miR‐196a2, and miR‐499 are associated with osteoporotic vertebral compression fractures in Korean postmenopausal women

Genetic factors have been shown to be a small but significant predictor for osteoporosis and osteoporotic fracture risk. We performed a case–control association study to determine the association between miR‐146a, miR‐149, miR‐196a2, and miR‐499 polymorphisms and osteoporotic vertebral compression fracture (OVCF) susceptibility. In total, 286 unrelated postmenopausal Korean women (57 with OVCFs, 55 with non‐OVCFs, and 174 healthy controls) were recruited. All subjects underwent dual energy X‐ray absorptiometry to determine BMD at the lumbar spine and femoral neck. We focused on four single nucleotide polymorphisms (SNPs) of pre‐miRNA sequences including miR‐146aC>G (rs2910164), miR‐149T>C (rs2292832), miR‐196a2T>C (rs11614913), and miR‐499A>G (rs3746444). Genotype frequencies of these four SNPs were determined using polymerase chain reaction‐restriction fragment length polymorphism analysis. The TT genotype of miR‐149aT>C was less frequent in subjects with OVCFs, suggesting a protective effect against OVCF risk (Odds ratio [OR], 0.435; 95% confidence interval [CI], 0.22–0.85, p = 0.014), whereas the miR‐146aCG/ miR‐196a2TC combined genotype was more frequent in OVCF patients (OR, 5.163; 95%CI, 1.057–25.21, p = 0.043), suggesting an increase in OVCF risk. Additionally, combinations of miR‐146a, ‐149, ‐196a2, and ‐449 showed a significant association with increased prevalence of OVCFs in postmenopausal women. In particular, the miR‐146aG/‐149T/‐196a2C/‐449G allele combination was significantly associated with an increased risk of OVCF (OR, 35.01; 95% CI, 1.919–638.6, p = 0.001). Our findings suggest that the TT genotype of miR‐149aT>C may contribute to decreased susceptibility to OVCF in Korean postmenopausal women. Conversely, the miR‐146aCG/ miR‐196a2TC combined genotype and the miR‐146aG/‐149T/‐196a2C/‐449G allele combination may contribute to increased susceptibility to OVCF. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:244–253, 2018.
Contradicting interplay between insulin-like growth factor-1 and miR-486-5p in primary NK cells and hepatoma cell lines with a contemporary inhibitory impact on HCC tumor progression

Abstract In this study, an impaired natural killer (NK) cell cytolytic activity in 135 hepatocellular carcinoma (HCC) patients parallel to a reduced expression level of insulin-like growth factor (IGF)-1 in NK cells of HCC patients has been revealed. Ectopic expression of miR-486-5p, a direct upstream regulator of IGF-1, restored the endogenous level of IGF-1 in NK cells of HCC patients, thus augmenting its cytolytic activity against Huh7 cells in an opposite manner to the IGF-1 siRNAs. Unorthodoxly, over-expression of miR-486-5p in target hepatocytes resulted in the repression of IGF-1, suppression of Huh7 cells proliferation and viability in a similar pattern to the IGF-1 siRNAs. Therefore, this study highlights a potential role of IGF-1 in modulating cytolytic potential of NK cells of HCC patients. miR-486-5p acts in a cell-specific manner, differentially modulating IGF-1 expression in NK cells and their target hepatocytes with a contemporary inhibitory impact on HCC progression.
Exploring the Pivotal Role of the CK2 Hinge Region Sub-Pocket in Binding with Tricyclic Quinolone Analogues by Computational Analysis

Protein kinase CK2 has been considered as an attractive therapeutic target of cancer therapy. The tricyclic quinoline compound CX-4945 is the first representative of CK2 inhibitors used in human clinical trials. The binding of non-2,6-naphtyridine substituted compounds 27e (IC50 > 500 nM) and 27h (IC50 > 1000 nM) to CK2 is abolished. However, the unbinding mechanisms due to the key pharmacophore group replacement of compounds 27e and 27h are unveiled. In the present work, combined computational analysis was performed to investigate the underlying structural basis of the low-affinity of two systems. As indicated in the results, the loss of hydrogen bonds between the non-2,6-naphtyridine and the hinge region destroyed the proper recognition of the two complexes. Besides, the allosteric mechanisms between the deviated ligands and the changed regions (G-loop, C-loop and β4/β5 loop) are proposed. Furthermore, energetic analysis was evaluated by detailed energy calculation and residue-based energy decomposition. More importantly, the summary of known polar pharmacophore groups elucidates the pivotal roles of hinge region sub-pocket in the binding of CK2 inhibitors. These results provide rational clues to the fragment-based design of more potent CK2 inhibitors.
Evaluation Of Experimental ProceduresFor Confined Concrete Columns Using3D Finite Element Analyses

This paper presents the results of the early stages of both a continuing experimental work on the square confined concrete columns and their 3D finite element modeling based on the isotropic damage theory in order to establish a realistic approach for the confinement pressure. Based on the axial behavior of four RC columns with a 200 mm square cross section tested under concentric loading, existing experimental data and procedures in the literature are evaluated. As demonstrated from the comparison of the FE analysis and the test results, obtaining a uniform axial loading and deformation state is questionable.
Proximal Junctional Kyphosis Prevention Strategies: A Video Technique Guide.

BACKGROUND Proximal junctional kyphosis (PJK) is a well-recognized complication in patients undergoing posterior instrumented fusion procedures for adult spinal deformity. Strategies that reduce rates of PJK have the potential to improve the safety of these operations and decrease cost by eliminating the need for revision surgery. OBJECTIVE To present a set of surgical techniques that can decrease rates of PJK in adults undergoing surgery for spinal deformity. METHODS We summarize the use of vertebroplasty, transverse process hooks, terminal rod contouring, and ligament augmentation as means to reduce rates of PJK. RESULTS We present PJK prevention strategies and a video technique guide that are safe, technically feasible, and add minimal operative time to these surgical procedures. When applied to appropriate high-risk patients, these techniques have the potential to dramatically reduce rates of PJK, which improves quality of life and decreases the cost associated with this treating adult spinal deformity. CONCLUSION PJK prevention strategies represent a critical area for improvement in surgery for adult spinal deformity. We present a summary of techniques that are safe, feasible, and add minimal time to the overall procedure. These techniques warrant investigation in a thoughtful, prospective manner, but are supported by existing data and compelling biomechanical rationale. Our hope is that these strategies can be applied, particularly in high-risk patients, to help reduce rates of PJK.
Adding glucose to food and solutions to enhance fructose absorption is not effective in preventing fructose‐induced functional gastrointestinal symptoms: randomised controlled trials in patients with fructose malabsorption

BACKGROUND In healthy individuals, the absorption of fructose in excess of glucose in solution is enhanced by the addition of glucose. The present study aimed to assess the effects of glucose addition to fructose or fructans on absorption patterns and genesis of gastrointestinal symptoms in patients with functional bowel disorders. METHODS Randomised, blinded, cross-over studies were performed in healthy subjects and functional bowel disorder patients with fructose malabsorption. The area-under-the-curve (AUC) was determined for breath hydrogen and symptom responses to: (i) six sugar solutions (fructose in solution) (glucose; sucrose; fructose; fructose + glucose; fructan; fructan + glucose) and (ii) whole foods (fructose in foods) containing fructose in excess of glucose given with and without additional glucose. Intake of fermentable short chain carbohydrates (FODMAPs; fermentable, oligo-, di-, monosaccharides and polyols) was controlled. RESULTS For the fructose in solution study, in 26 patients with functional bowel disorders, breath hydrogen was reduced after glucose was added to fructose compared to fructose alone [mean (SD) AUC 92 (107) versus 859 (980) ppm 4 h-1 , respectively; P = 0.034). Glucose had no effect on breath hydrogen response to fructans (P = 1.000). The six healthy controls showed breath hydrogen patterns similar to those with functional bowel disorders. No differences in symptoms were experienced with the addition of glucose, except more nausea when glucose was added to fructose (P = 0.049). In the fructose in foods study, glucose addition to whole foods containing fructose in excess of glucose in nine patients with functional bowel disorders and nine healthy controls had no significant effect on breath hydrogen production or symptom response. CONCLUSIONS The absence of a favourable response on symptoms does not support the concomitant intake of glucose with foods high in either fructose or fructans in patients with functional bowel disorders.
5-hydroxymethylation of the EBV genome regulates the latent to lytic switch

Significance Epstein–Barr virus (EBV) normally establishes a lytic infection in differentiated epithelial cells. However, in the abnormal context of nasopharyngeal carcinoma (NPC), EBV latently infects undifferentiated epithelial cells. Here we demonstrate that the EBV genome can become 5-hydroxymethylated and that this DNA modification affects EBV lytic reactivation. We find that 5-hydroxymethylcytosine accumulates during differentiation of normal epithelial cells but not in EBV+ NPCs. Furthermore, we show that ten–eleven translocation (TET) enzymes dysregulate lytic viral reactivation by altering the 5-methylcytosine and 5-hydroxymethylcytosine state of lytic promoters. These data suggest that loss of TET activity may promote cellular hypermethylation and alter EBV gene regulation in NPC tumors. Latent Epstein–Barr virus (EBV) infection and cellular hypermethylation are hallmarks of undifferentiated nasopharyngeal carcinoma (NPC). However, EBV infection of normal oral epithelial cells is confined to differentiated cells and is lytic. Here we demonstrate that the EBV genome can become 5-hydroxymethylated and that this DNA modification affects EBV lytic reactivation. We show that global 5-hydroxymethylcytosine (5hmC)-modified DNA accumulates during normal epithelial-cell differentiation, whereas EBV+ NPCs have little if any 5hmC-modified DNA. Furthermore, we find that increasing cellular ten–eleven translocation (TET) activity [which converts methylated cytosine (5mC) to 5hmC] decreases methylation, and increases 5hmC modification, of lytic EBV promoters in EBV-infected cell lines containing highly methylated viral genomes. Conversely, inhibition of endogenous TET activity increases lytic EBV promoter methylation in an EBV-infected telomerase-immortalized normal oral keratinocyte (NOKs) cell line where lytic viral promoters are largely unmethylated. We demonstrate that these cytosine modifications differentially affect the ability of the two EBV immediate-early proteins, BZLF1 (Z) and BRLF1 (R), to induce the lytic form of viral infection. Although methylation of lytic EBV promoters increases Z-mediated and inhibits R-mediated lytic reactivation, 5hmC modification of lytic EBV promoters has the opposite effect. We also identify a specific CpG-containing Z-binding site on the BRLF1 promoter that must be methylated for Z-mediated viral reactivation and show that TET-mediated 5hmC modification of this site in NOKs prevents Z-mediated viral reactivation. Decreased 5-hydroxymethylation of cellular and viral genes may contribute to NPC formation.
The relative efficacy and safety of targeted agents used in combination with chemotherapy in treating patients with untreated advanced gastric cancer: a network meta-analysis

Gastric cancer is one of the leading mortal causes. Targeted therapy is a new type of cancer treatment, which precisely identifies and attacks cancer cells and significantly reduces side effects. In this network meta-analysis, we focused on the efficacy and safety of 12 targeted agents on gastric cancer among a total of 8,405 patients from 24 trials. Hazard ratio (HR) with 95% credible interval (CrI) were calculated for primary outcomes, including overall survival (OS) and progression-free survival (PFS), while odds ratio (OR) with 95% CrI were calculated for secondary outcomes. Surface under the cumulative ranking curve (SUCRA) were calculated to illustrate the rank probability of various agents for different outcomes. Compared with other analyzed treatments, ramucirumab is outstanding in survival outcomes. However, higher risk of hematological events should be noted during its application. Lapatinib is also efficacious in progression reduction, while it is always combined with severe gastrointestinal events. Trastuzumab is proposed for its high efficacy in improving survival rate and safety, which is proper for most patients. In conclusion, trastuzumab was recommended as the optimal targeted agent combined with chemotherapy for gastric cancer patients.
Viability of Lucilia sericata maggots after exposure to wound antiseptics

After debridement and before dressing a wound with maggots of calliphorid flies, one frequently performed step is the application of antiseptics to the prepared wound bed. However, the concomitant application of antiseptic agents during maggot therapy is regarded controversial as antiseptics may interfere with maggots' viability. In this experimental in vitro study, the viability of fly maggots was investigated after exposure to various antiseptics frequently used in wound care. Here, we show that Lucilia sericata fly maggots can survive up to an hour's exposure to wound antiseptics such as octenidine, povidone‐iodine or polihexanide. Concomitant short‐term application of wound antiseptics together with maggots on wound beds is tolerated by larvae and does not impair their viability.
Cdc37 facilitates cell survival of colorectal carcinoma via activating the CDK4 signaling pathway

Cell division cycle 37 (Cdc37) is an important partner for heat shock protein 90 (HSP90), assisting in molecular chaperone activities, particularly with regard to the regulation of protein kinases. Given its influence on cell growth pathways, Cdc37 has been discussed as a potential intermediate in carcinogenesis. However, to date, the potential functional roles and molecular mechanisms by which Cdc37 regulates cell survival in colorectal carcinoma (CRC) remain unclear. Here, we investigated the expression of Cdc37 and its clinical significance in CRC, and systematically explored the role and the underlying mechanism of Cdc37 in CRC cell survival both in vitro and in vivo. Our results showed that Cdc37 was remarkably up‐regulated in CRC, which facilitated cell survival mainly by promoting cell proliferation, G1‐S transition, and inhibiting cell apoptosis. Our data further indicated that Cdc37 increased the stability of cyclin‐dependent kinase 4 (CDK4) to activate the retinoblastoma 1 (RB1) signaling pathway, followed by increased expression of Bcl‐2 and Bcl‐xL, which ultimately promoted cell survival in CRC. Moreover, knockdown of CDK4 reversed the Cdc37‐mediated effect in promoting the progression of CRC. Our findings showed that Cdc37 played a critical role in promoting CRC cell survival by increasing CDK4 stability to activate the RB1 signaling pathway. Thereby, Cdc37 might serve as a potential therapeutic target in CRC patients.
Quorum‐sensing inhibition abrogates the deleterious impact of Pseudomonas aeruginosa on airway epithelial repair

Chronic Pseudomonas aeruginosa lung infections are associated with progressive epithelial damage and lung function decline. In addition to its role in tissue injury, the persistent presence of P. aeruginosa–secreted products may also affect epithelial repair ability, raising the need for new antivirulence therapies. The purpose of our study was to better understand the outcomes of P. aeruginosa exoproducts exposure on airway epithelial repair processes to identify a strategy to counteract their deleterious effect. We found that P. aeruginosa exoproducts significantly decreased wound healing, migration, and proliferation rates, and impaired the ability of directional migration of primary non–cystic fibrosis (CF) human airway epithelial cells. Impact of exoproducts was inhibited after mutations in P. aeruginosa genes that encoded for the quorum‐sensing (QS) transcriptional regulator, LasR, and the elastase, LasB, whereas impact was restored by LasB induction in ΔlasR mutants. P. aeruginosa purified elastase also induced a significant decrease in non‐CF epithelial repair, whereas protease inhibition with phosphoramidon prevented the effect of P. aeruginosa exoproducts. Furthermore, treatment of P. aeruginosa cultures with 4‐hydroxy‐2,5‐dimethyl‐3(2H)furanone, a QS inhibitor, abrogated the negative impact of P. aeruginosa exoproducts on airway epithelial repair. Finally, we confirmed our findings in human airway epithelial cells from patients with CF, a disease featuring P. aeruginosa chronic respiratory infection. These data demonstrate that secreted proteases under the control of the lasR QS system impair airway epithelial repair and that QS inhibitors could be of benefit to counteract the deleterious effect of P. aeruginosa in infected patients. —Ruffin, M. , Bilodeau, C. , Maillé, É. , LaFayette, S.L. , McKay, G.A. , Trinh, N.T. N. , Beaudoin, T. , Desrosiers, M. ‐Y. , Rousseau, S. , Nguyen, D. , Brochiero, E. Quorum‐sensing inhibition abrogates the deleterious impact of Pseudomon asaeruginosa on airway epithelial repair. FASEBJ. 30, 3011–3025 (2016). www.fasebj. org
Endometrial Cancer Risk Factors, Hormone Receptors, and Mortality Prediction

Background: Endometrial tumors arise from a hormonally responsive tissue. Defining subtypes by hormone receptor expression might better inform etiology and prediction of patient outcomes. We evaluated the potential role of tumor estrogen receptor (ER) and progesterone receptor (PR) expression to define endometrial cancer subtypes. Methods: We measured semi-continuous ER and PR protein expression in tissue specimens from 360 endometrial primary tumors from the Nurses' Health Study. To explore the impact of different definitions of marker positivity, we dichotomized ER and PR expression at different cut points in increments of 5% positive cells. Logistic regression was used to estimate associations between endometrial cancer risk factors, such as body mass index, with dichotomous ER or PR status. Reclassification statistics were used to assess whether adding dichotomous ER or PR status to standard prognostic factors of stage, grade, and histologic type would improve endometrial cancer-specific mortality prediction. Results: Compared with not being obese, obesity increased the odds of having an ER-positive tumor at cut points of 0% to 20% [maximum OR, 2.92; 95% confidence interval (CI), 1.34–6.33] as well as the odds of having a PR-positive tumor at cut points of 70% to 90% (maximum OR, 2.53; 95% CI, 1.36–4.68). Adding dichotomous tumor ER or PR status to the panel of standard predictors did not improve both model discrimination and calibration. Conclusions: Obesity may be associated with greater endometrial tumor expression of ER and PR. Adding either marker does not appear to improve mortality prediction beyond the standard predictors. Impact: Body mass index might explain some of the biological variation among endometrial tumors. Cancer Epidemiol Biomarkers Prev; 26(5); 727–35. ©2017 AACR.