Miracle-dz/UniFAR-FTUs huggingface dataset:
RANTES and IL-6 cooperate in inducing a more aggressive phenotype in breast cancer cells

Both the CC chemokine ligand 5 (CCL5/RANTES) and interleukin-6 (IL-6), released by mesenchymal stem cells (MSCs) as well as by neoplastic cells, promote breast cancer cell progression through autocrine and paracrine mechanisms. In order to assess the effects of the simultaneous overexpression of RANTES and IL-6 on the tumor cell phenotype, we overexpressed both proteins in MCF-7 and MDA-MB-231 human breast cancer cell lines. MCF-7 cells co-expressing RANTES and IL-6 had a greater ability to form colonies in soft agar, compared to cells overexpressing RANTES or IL-6. In addition, both MCF-7 and MDA-MB-231 clones co-expressing RANTES and IL-6 showed a significantly higher ability to migrate and to invade. The analysis of phosphorylated ERK1/2, AKT and STAT3 signal transduction proteins revealed that several signaling pathways are simultaneously activated in cells overexpressing both factors. Finally, the overexpression of RANTES and IL-6 in MCF-7 cells significantly increased the in vivo tumor growth. Collectively, our data suggest that the simultaneous expression of IL-6 and RANTES produces a more aggressive phenotype in breast cancer cells and provide evidence that IL-6 and RANTES might represent potential targets for novel therapeutic strategies aimed to block the tumor-stroma interaction.
Uterine Leiomyomata in Relation to Insulin-like Growth Factor-I, Insulin, and Diabetes

Background: Insulin-like growth factor-I (IGF-I) and insulin stimulate cell proliferation in uterine leiomyoma (fibroid) tissue. We hypothesized that circulating levels of these proteins would be associated with increased prevalence and size of uterine fibroids. Methods: Participants were 35-49-year-old, randomly selected members of an urban health plan who were enrolled in the study in 1996-1999. Premenopausal participants were screened for fibroids with ultrasound. Fasting blood samples were collected. Associations between fibroids and diabetes, plasma IGF-I, IGF binding protein 3 (BP3), and insulin were evaluated for blacks (n = 585) and whites (n = 403) by using multiple logistic regression. Results: IGF-I showed no association with fibroids in blacks, but in whites the adjusted odds ratios (aORs) for both mid and upper tertiles compared with the lowest tertile were 0.6 (95% confidence intervals [CI] = 0.3-1.0 and 0.4-1.1, respectively). Insulin and diabetes both tended to be inversely associated with fibroids in blacks. The insulin association was with large fibroids; aOR for the upper insulin tertile relative to the lowest was 0.4 (0.2-0.9). The aOR for diabetes was 0.5 (0.2-1.0). Associations of insulin and diabetes with fibroids were weak for whites. Binding protein 3 showed no association with fibroids. Conclusions: Contrary to our hypothesis, high circulating IGF-I and insulin were not related to increased fibroid prevalence. Instead, there was suggestion of the opposite. The inverse association with diabetes, although based on small numbers, is consistent with previously reported findings. Future studies might investigate vascular dysfunction as a mediator between hyperinsulinemia or diabetes and possible reduced risk of fibroids.
Plasma thrombospondin‐1 is increased during acute sickle cell vaso‐occlusive events and associated with acute chest syndrome, hydroxyurea therapy, and lower hemolytic rates

Platelets are activated in sickle cell disease (SCD), and particularly during vaso-occlusive episodes (VOE). Thrombospondin-1 (TSP1), a major secretory product of activated platelets, is increased in the circulation in VOE and binds to sickle red blood cells (RBC) promoting vascular adhesion. Thus, we hypothesized that TSP1 may represent a plasma biomarker of disease severity in SCD. We tested the plasma collected from patients in steady state (n = 27) and VOE (n = 14), as well as healthy controls (n = 17) at the University of Pittsburgh Medical Center (UPMC), and from patients in steady state enrolled in the walk-PHaSST clinical trial (n = 483). We found that TSP1 levels were increased in VOE in the UPMC cohort. Among steady-state patients at UPMC, TSP1 values correlated positively with lifetime history of acute chest syndrome (r = 0.72, P < 0.0001) and hemoglobin concentration (r = 0.49, P = 0.01), and negatively with markers of hemolysis, such as LDH (r = -0.50, P = 0.009). Analysis of the walk-PHaSST cohort also showed a positive association between TSP1 levels and hydroxyurea use (r = 0.14, P = 0.003), and confirmed the negative associations with the severity of hemolysis. Our results suggest that TSP1 levels are associated with more VOE, hydroxyurea use and lower rates of hemolysis. High TSP1 concentrations may indicate higher risk of the viscosity/vaso-occlusion phenotype of SCD.
Chapter 5 AMPK Regulates Microvascular Perfusion and Insulin-Induced Microvascular Recruitment Through Control Over eNOS and Endothelin-1 Activity

Rationale. Decreased tissue perfusion is an important risk factor for the development of insulin resistance and cardiovascular disease in the obese. Obesity-associated hypoadiponectinemia and subsequent decreased 5’AMP activated kinase (AMPK) activity, in particular of its α2 kinase subunit, have been linked to insulin resistance. It is, however, unknown whether and how AMPKα2 controls microvascular perfusion. Methods and Results. In isolated muscle resistance arteries (RA) of Wistar rats, effects of AMPK activation were studied, using pressure myography. Globular adiponectin (gAdn) and 5aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) increased AMPK activity in endothelium thereby enabling insulin-induced vasodilation. AMPK activation inhibited insulin-induced ERK1/2 activity, and the synergistic effects of gAdn and insulin on vascular diameter could be mimicked by inhibition of the MAPK/ERK1/2 kinase pathway. Moreover, inhibition of AMPK using compound C abolished the effect of gAdn and AICAR. In mice, genetic deletion of AMPK2 abolished the interaction between gAdn and insulin in isolated RAs.In vivo, effects of AMPK2 on muscle perfusion were studied using contrast enhanced ultrasonography (CEU) during a hyperinsulinemic euglycemic clamp. In AMPKα2-/mice but not in AMPKα2+/+ mice, hyperinsulinemia decreased skeletal muscle perfusion. This reduced muscle perfusion was associated with a 75 percent decrease in acetyl CoA carboxylase phosphorylation and a 50 percent decrease in Ser phosphorylation of eNOS. Conclusions. AMPK, and presumably the 2 isoform, controls muscle perfusion during hyperinsulinemia through stimulation of eNOS phosphorylation and inhibition of ERK1/2 phosphorylation. Our findings provide a novel mechanism linking AMPKα2 to regulation of insulin sensitivity and organ perfusion.
Profiling DRDoS Attacks with Data Analytics Pipeline

A large amount of Distributed Reflective Denial-of-Service (DRDoS) attacks are launched every day, and our understanding of the modus operandi of their perpetrators is yet very limited as we are submerged with so Big Data to analyze and do not have reliable and complete ways to validate our findings. In this paper, we propose a first analytic pipeline that enables us to cluster and characterize attack campaigns into several main profiles that exhibit similarities. These similarities are due to common technical properties of the underlying infrastructures used to launch these attacks. Although we do not have access to the ground truth and we do not know how many perpetrators are acting behind the scene, we can group their attacks based on relevant commonalities with cluster ensembling to estimate their number and capture their profiles over time. Specifically, our results show that we can repeatably identify and group together common profiles of attacks while considering domain expert's constraint in the cluster ensembles. From the obtained consensus clusters, we can generate comprehensive rules that characterize past campaigns and that can be used for classifying the next ones despite the evolving nature of the attacks. Such rules can be further used to filter out garbage traffic in Internet Service Provider networks.
Teamwork and Organizational Innovation: The Moderating Role of the HRM Context

Evidence is accumulating on the role of teams in shaping a variety of business outcomes, but our knowledge on the effect of teamwork on organizational innovation is still evolving. This study examines whether the extent to which two staff groups are organized in teams (production staff and management/administrative staff) affects organizational innovation and whether human resource management (HRM) systems, which can be of facilitating or constraining nature, enhance the teamwork/innovation relationships. Hypotheses were tested with lagged and longitudinal data derived from 18 to 45 organizations from the UK manufacturing sector. Results suggest that the more widespread the use of teamwork in organizations, the higher the level of organizational innovation. Furthermore, this effect depends, particularly for production teams, on the overall quality of the HRM systems that exist in their organizations. Teamwork/innovation relationships are further moderated (for management and administrative teams) by an HRM practice that provides teams with time for thoughtful reflection. Thus, HRM systems can be of more or less facilitating or constraining nature for teams in organizations.
How Substance Users With ADHD Perceive the Relationship Between Substance Use and Emotional Functioning

Objective: Although substance use (SU) is elevated in ADHD and both are associated with disrupted emotional functioning, little is known about how emotions and SU interact in ADHD. We used a mixed qualitative–quantitative approach to explore this relationship. Method: Narrative comments were coded for 67 persistent (50 ADHD, 17 local normative comparison group [LNCG]) and 25 desistent (20 ADHD, 5 LNCG) substance users from the Multimodal Treatment Study of Children with ADHD (MTA) adult follow-up (21.7-26.7 years-old). Results: SU persisters perceived SU positively affects emotional states and positive emotional effects outweigh negative effects. No ADHD group effects emerged. Qualitative analysis identified perceptions that cannabis enhanced positive mood for ADHD and LNCG SU persisters, and improved negative mood and ADHD for ADHD SU persisters. Conclusion: Perceptions about SU broadly and mood do not differentiate ADHD and non-ADHD SU persisters. However, perceptions that cannabis is therapeutic may inform ADHD-related risk for cannabis use.
Detecting Abnormal Word Utterances in Children With Autism Spectrum Disorders

Abnormal prosody is often evident in the voice intonations of individuals with autism spectrum disorders. We compared a machine-learning-based voice analysis with human hearing judgments made by 10 speech therapists for classifying children with autism spectrum disorders (n = 30) and typical development (n = 51). Using stimuli limited to single-word utterances, machine-learning-based voice analysis was superior to speech therapist judgments. There was a significantly higher true-positive than false-negative rate for machine-learning-based voice analysis but not for speech therapists. Results are discussed in terms of some artificiality of clinician judgments based on single-word utterances, and the objectivity machine-learning-based voice analysis adds to judging abnormal prosody.
Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior

Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT1A and 5HT2A receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments.
Effects of Various Fluoride Solutions on Enamel Erosion in vitro

The objective of this in vitro study was to investigate the effect of different fluoride solutions on enamel erosion. Human enamel specimens were pretreated with 1 of 10 different fluoride solutions (n = 20): TiF4, NaF, AmF, ZnF2, or SnF2, each at native pH (pH range: 1.2–7.8) or buffered pH (pH = 4). The control group samples received no fluoride pretreatment. All samples were then eroded by citric acid (pH 2.6) for 6 × 1 min daily over 5 days. Between the erosive cycles, the samples were stored in artificial saliva. Erosion effects were investigated by surface profilometry (n = 10), scanning electron microscopy (n = 4), and energy-dispersive X-ray spectroscopy (n = 6) after fluoride pretreatment and after erosion. To test the effects of pH only, additional experiments were carried out with fluoride-free solutions at similar pH to that of fluoride solutions. In general, AmF solution was more effective in protecting enamel erosion compared to all other fluoride agents. However, the application of native TiF4, native and buffered SnF2, and native and buffered AmF solutions also resulted in significantly less enamel loss compared to the control group. A Ti-rich coating was formed after application of native TiF4, but partially dissolved due to erosive attack. Samples pretreated with SnF2 showed a significant increase in surface tin content. Surface fluoride concentration was significantly increased by native TiF4, native and buffered AmF, buffered ZnF2, and buffered NaF application. Under the current experimental setting, the fluoride agents at lower pH had better protective potential. Highly concentrated TiF4, AmF, and SnF2 solution was effective in inhibiting erosion of enamel.
Complex History of Isolation and Gene Flow in Hoary, Olympic, and Endangered Vancouver Island Marmots

Climate change resulting in a reduction of alpine habitat is believed to pose a considerable risk to alpine-dependent species, including many marmots. Hoary marmots (Marmota caligata) range throughout much of the mountainous Pacific Northwest (PNW) and Rocky Mountains while the closely related Olympic and Vancouver Island marmots (M. olympus and M. vancouverensis, respectively) are restricted to small isolated regions of the PNW. The endemic Vancouver Island marmot is currently classified as Critically Endangered and the Olympic marmot has recently experienced dramatic population declines. Previous phylogenetic studies of PNW marmot species have had limited power as they focused on resolving interspecific relationships, implicitly assumed an absence of gene flow among currently recognized species, included relatively few individuals, and relied heavily or entirely on mitochondrial DNA. We sequenced 2 mitochondrial and 4 nuclear markers from 167 hoary, 4 Vancouver Island, and 5 Olympic marmots in order to investigate phylogenetic relationships and historic gene flow among these species. We recovered 2 monophyletic (and predominantly allopatric) mitochondrial clades of hoary marmots that are not sister groups. Instead, Vancouver Island marmots formed a monophyletic mitochondrial sister clade to 1 of the hoary marmot clades. Nuclear loci did not recover the 2 mitochondrial clades of hoary marmots and suggest that Vancouver Island marmots may have experienced mitochondrial introgression from coastal mainland hoary marmots. Additionally, our nuclear results suggest possible gene flow between hoary and Olympic marmots despite different chromosomal formulas. Rather than resolving what has previously been considered a straightforward 3-taxon phylogenetic question, our findings suggest a complicated history of rapid divergence of the 3 species followed by intermittent and possibly ongoing gene flow between hoary marmots and both Olympic and Vancouver Island marmots. These results therefore have significant implications for the conservation of the latter 2 species, both of which are conservation concerns.
Skeletal muscle satellite cells are located at a closer proximity to capillaries in healthy young compared with older men

Skeletal muscle satellite cells (SC) are instrumental in maintenance of muscle fibres, the adaptive responses to exercise, and there is an age‐related decline in SC. A spatial relationship exists between SC and muscle fibre capillaries. In the present study, we aimed to investigate whether chronologic age has an impact on the spatial relationship between SC and muscle fibre capillaries. Secondly, we determined whether this spatial relationship changes in response to a single session of resistance exercise.
Accumulation of Pax2 Transactivation Domain Interaction Protein (PTIP) at Sites of DNA Breaks via RNF8-dependent Pathway Is Required for Cell Survival after DNA Damage*

Genomic stability in eukaryotic cells is maintained by the coordination of multiple cellular events including cell cycle checkpoint, DNA repair, transcription, and apoptosis after DNA damage. Pax2 transactivation domain interaction protein (PTIP), a protein that contains six BRCT domains, has been implicated in DNA damage response. In this study we showed that recruitment of PTIP to damaged chromatin depends on DNA damage signaling proteins γH2AX·MDC1·RNF8, which in turn facilitates sustained localization of PA1 (PTIP-associated protein 1) to sites of DNA break. Similar to PTIP, depletion of PA1 increases cellular sensitivity to ionizing radiation. Furthermore, we demonstrated that the N-terminal PA1 binding domain and the C-terminal focus-localization domain of PTIP are critical for PTIP function in DNA damage repair. Interestingly, although PTIP and PA1 associate with MLL (mixed lineage leukemia) complexes and participate in transcriptional regulation, this function of PTIP·PA1 in DNA damage response is likely to be independent of the MLL complexes. Taken together, we propose that a subset of PTIP·PA1 complex is recruited to DNA damage sites via the RNF8-dependent pathway and is required for cell survival in response to DNA damage.
Emerging highly pathogenic H5 avian influenza viruses in France during winter 2015/16: phylogenetic analyses and markers for zoonotic potential

Several new highly pathogenic (HP) H5 avian influenza virus (AIV) have been detected in poultry farms from south-western France since November 2015, among which an HP H5N1. The zoonotic potential and origin of these AIVs immediately became matters of concern. One virus of each subtype H5N1 (150169a), H5N2 (150233) and H5N9 (150236) was characterised. All proved highly pathogenic for poultry as demonstrated molecularly by the presence of a polybasic cleavage site in their HA protein – with a sequence (HQRRKR/GLF) previously unknown among avian H5 HPAI viruses – or experimentally by the in vivo demonstration of an intravenous pathogenicity index of 2.9 for the H5N1 HP isolate. Phylogenetic analyses based on the full genomes obtained by NGS confirmed that the eight viral segments of the three isolates were all part of avian Eurasian phylogenetic lineage but differed from the Gs/Gd/1/96-like lineage. The study of the genetic characteristics at specific amino acid positions relevant for modulating the adaptation to and the virulence for mammals showed that presently, these viruses possess most molecular features characteristic of AIV and lack some major characteristics required for efficient respiratory transmission to or between humans. The three isolates are therefore predicted to have no significant pandemic potential.
Right and left ventricular myocardial perfusion reserves correlate with right ventricular function and pulmonary hemodynamics in patients with pulmonary arterial hypertension.

PURPOSE To evaluate the relationships of right ventricular (RV) and left ventricular (LV) myocardial perfusion reserves with ventricular function and pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH) by using adenosine stress perfusion cardiac magnetic resonance (MR) imaging. MATERIALS AND METHODS This HIPAA-compliant study was institutional review board approved. Twenty-five patients known or suspected to have PAH underwent right heart catheterization and adenosine stress MR imaging on the same day. Sixteen matched healthy control subjects underwent cardiac MR imaging only. RV and LV perfusion values at rest and at adenosine-induced stress were calculated by using the Fermi function model. The MR imaging-derived RV and LV functional data were calculated by using dedicated software. Statistical testing included Kruskal-Wallis tests for continuous data, Spearman rank correlation tests, and multiple linear regression analyses. RESULTS Seventeen of the 25 patients had PAH: 11 with scleroderma-associated PAH, and six with idiopathic PAH. The remaining eight patients had scleroderma without PAH. The myocardial perfusion reserve indexes (MPRIs) in the PAH group (median RV MPRI, 1.7 [25th-75th percentile range, 1.3-2.0]; median LV MPRI, 1.8 [25th-75th percentile range, 1.6-2.1]) were significantly lower than those in the scleroderma non-PAH (median RV MPRI, 2.5 [25th-75th percentile range, 1.8-3.9] [P = .03]; median LV MPRI, 4.1 [25th-75th percentile range, 2.6-4.8] [P = .0003]) and control (median RV MPRI, 2.9 [25th-75th percentile range, 2.6-3.6] [P < .01]; median LV MPRI, 3.6 [25th-75th percentile range, 2.7-4.1] [P < .01]) groups. There were significant correlations between biventricular MPRI and both mean pulmonary arterial pressure (mPAP) (RV MPRI: ρ = -0.59, Bonferroni P = .036; LV MPRI: ρ = -0.79, Bonferroni P < .002) and RV stroke work index (RV MPRI: ρ = -0.63, Bonferroni P = .01; LV MPRI: ρ = -0.75, Bonferroni P < .002). In linear regression analysis, mPAP and RV ejection fraction were independent predictors of RV MPRI. mPAP was an independent predictor of LV MPRI. CONCLUSION Biventricular vasoreactivity is significantly reduced with PAH and inversely correlated with RV workload and ejection fraction, suggesting that reduced myocardial perfusion reserve may contribute to RV dysfunction in patients with PAH.
Do Young Drivers Become Safer After Being Involved in a Collision?

As drivers age, their risk of being involved in a car collision decreases. The present study investigated if this trend is due, in part, to some risky drivers having a collision early in their driving lives and subsequently reducing their risky driving after that negative experience. Accelerometers and video cameras were installed in the vehicles of 16- to 17-year-old drivers (N = 254), allowing coders to measure the number of g-force events (i.e., events in which a threshold acceleration level was exceeded) per 1,000 miles and the number of collisions. Among the 41 participants who experienced a severe collision, the rate of g-force events dropped significantly in the 1st month after the collision, remained unchanged for the 2nd month, and increased significantly in the 3rd month. There were no changes in the rate of g-force events at comparable time points for the drivers not involved in a collision. Being involved in a collision led to a decrease in risky driving, but this may have been a temporary effect.