Miracle-dz/UniFAR-FTUs huggingface dataset:
Association between DNA strand breaks and specific DNA adducts in murine hepatocytes following in vivo and in vitro exposure to N-hydroxy-2-acetylaminofluorene and N-acetoxy-2-acetylaminofluorene.

N-hydroxy-2-acetylaminofluorene (N-OH-AAF) and N-acetoxy-2-acetylaminofluorene (N-OAc-AAF) have previously been shown to induce dose-dependent DNA strand breaks in primary hepatocytes from mice and rats. In an attempt to determine the relationship between the extent of DNA strand breaks and the formation of specific DNA-carcinogen bound adducts in murine liver, the capability of N-OH-AAF and N-OAc-AAF to induce both DNA single strand breaks and adduct formation in in vivo and in primary hepatocytes was measured. N-OH-AAF induced a low level of DNA damage in F344 rats (10 mg/kg, i.p.) and in B6 mice (40 mg/kg, i.p.) 4 h after treatment. The DNA adducts identified in vivo were N-(guanin-8-yl)-2-acetylaminofluorene (Gua-C8-AAF) 55% versus 11%, N-(guanin-8-yl)-2-aminofluorene (Gua-C8-AF) 34% versus 67% and 3-(guanin-N2-yl)-2-acetylaminofluorene (Gua-N2-AAF) 11% versus 10%, respectively, for rat and mouse liver. An additional unknown adduct (12%) was detected in mouse liver. Dose dependent DNA binding and formation of individual DNA adducts were observed in rat and mouse primary hepatocytes following 1 h exposure to [ring-3H]-N-OH-AAF (0.1-20 microM) and [ring-3H]-N-OAc-AAF (5-20 microM). The patterns of DNA adducts in mouse and rat primary hepatocytes exposed to N-OH-AAF and N-OAc-AF were similar to those obtained in liver following in vivo treatment with N-OH-AAF. The deacetylase inhibitor, paraoxon (10(-4) M) completely inhibited DNA damage induced by N-OH-AAF in mouse and partially in rat hepatocytes while DNA damage caused by N-OAc-AAF was only partially inhibited by paraoxon (10(-4) M) in both species. Parallel experiments showed that paraoxon, at low concentration (10(-6) M), did not alter either the level of DNA binding or the pattern of adduct formation in rat hepatocytes treated with N-OH-AAF (20 microM). However, at 10(-4) M paraoxon partially blocked DNA binding (60%) and the formation of Gua-C8-AAF (95%) and Gua-N2-AAF (80%) while Gua-C8-AF was increased two-fold. In mouse hepatocytes paraoxon pretreatment (10(-4) M) inhibited the formation of Gua-C8-AF by 70% following exposure to N-OH-AAF (20 microM). Gua-C8-AAF and Gua-N2-AAF were also inhibited but only at 10(-4) M paraoxon. (ABSTRACT TRUNCATED AT 400 WORDS)
Peripheral refraction measurement: does it matter if one turns the eye or the head?

It has been suggested that, following eye movements, the changing pressures exerted by the extraocular muscles and the lids might distort the shape of the eyeball and alter refraction across the visual field. To confirm or refute this hypothesis, the pattern of monocular peripheral refraction in the right eyes of 10 healthy young adults was measured either by turning the eye to fixate a series of horizontally spaced targets or by turning the head to view the same targets while maintaining central fixation and the eye in its primary position. In each case a fixed Shin‐Nippon autorefractor was used to measure peripheral refraction at 5° intervals over the central ±30° of the visual field. The duration of any eye turn was ≤1 min. Repeated‐measures analysis showed no significant differences between the spherical equivalents of peripheral refraction measured under the two conditions (p = 0.223). A further study of five subjects involving 2.5‐min periods of fixation with an eye or head turn of 25° also showed no significant refractive differences. Thus, within the conditions of the study (eye‐turn durations and field angles ≤2.5 min and 30° respectively), the results fail to confirm the occurrence of large differences in peripheral refraction when measurements are made with eye turn rather than head turn.
Genetically-engineered mesenchymal stem cells transfected with human HCN1 gene to create cardiac pacemaker cells

Objective To test the proof-of-principle that genetically-engineered mesenchymal stem cells (MSCs) transfected with the human hyperpolarization-activated cyclic nucleotide-gated channel 1 (hHCN1) gene can be modified to become cardiac pacemaker cells. Methods MSCs were transfected with the hHCN1 gene using lentiviral-based transfection. The expressed pacemaker current (If) in hHCN1-transfected MSCs was recorded using whole-cell patch-clamp analysis. The effect of the hHCN1-transfected MSCs on cardiomyocyte excitability was determined by coculturing the MSCs with neonatal rabbit ventricular myocytes (NRVM). The spontaneous action potentials of the NRVM were recorded by whole-cell current-clamp analysis. Results A high level time- and voltage-dependent inward hyperpolarization current that was inhibited by 4 mM caesium chloride was detected in hHCN1-transfected MSCs, suggesting that the HCN1 proteins acted as If channels in MSCs. The mean ± SE beating frequency in NRVMs cocultured with control MSCs transfected with the pcDNA3 plasmid control was 82 ± 8 beats/min (n = 5) compared with 129 ± 11 beats/min (n = 5) in NRVMs cocultured with hHCN1-transfected MSCs. Conclusions Genetically-engineered MSCs transfected with the hHCN1 gene can be modified to become cardiac pacemaker cells.
Entorhinal inputs to hippocampal CA1 and dentate gyrus in the rat: a current-source-density study.

1. Laminar profiles of the average evoked potentials and current-source-density analysis were used to study the input provided by the medial perforant path (PP) to the hippocampus in the urethan-anesthetized rat. 2. Stimulation of the PP activated an early latency sink in the middle molecular layer of the dentate gyrus (DG) and in the stratum lacunosum-moleculare in CA1. The DG current sink was generated by excitatory synaptic currents activated by the PP on dentate granule cells. In the normal rat, the peak current sink in the DG was typically five times greater than that of CA1. However, the CA1 sink could be distinguished from the DG sink in several ways: 1) it peaked when the DG sink was subsiding; 2) it showed paired-pulse facilitation, whereas the DG sink did not; and 3) in rats in which the DG was lesioned by local colchicine injection, the DG sink was reduced much more than the CA1 sink. 3. The PP afferents to CA1 required a slightly higher stimulus threshold (> 100 microA) for activation than those projecting to the DG granule cells (< 30 microA). The onset latency of the early CA1 sink (2.5 +/- 0.2 ms, mean +/- SE) was also slightly longer than that of the DG sink (1.7 +/- 0.1 ms), suggesting that the axons of entorhinal layer III cells that project to CA1 have a slightly lower conduction velocity than the axons of the layer II cells that project to the DG. 4. The short-latency current sink activated by the PP in the distal dendritic layers of CA1 was likely provided by excitatory currents at the distal apical dendrites of CA1 pyramidal cells. The accompanying current source was mainly confined to stratum radiatum and appeared not to involve the cell body layer. Thus the electrotonic current spread may not be effective enough to depolarize the cell body or axon hillock. Contribution of interneurons to the above source-sink profile is possible, with the provision that these interneurons must have dendritic processes that span strata radiatum and lacunosum moleculare. 5. Extracellular field recordings provided no evidence that PP evoked a short-latency (< 9 ms) CA1-generated population spike, even with the use of micropipettes filled with mM bicuculline. Similarly, unit recordings in CA1 revealed only long-latency (9-17 ms) unit firing after PP stimulation, corresponding to a late, di/trisynaptic excitation of CA1 via the Schaffer collaterals. (ABSTRACT TRUNCATED AT 400 WORDS)
Prolonged QRS duration: a new predictor of adverse outcome in idiopathic pulmonary arterial hypertension.

BACKGROUND A prolonged QRS duration ( ≥ 120 milliseconds) predicts outcomes in patients with left-sided heart failure, but the impact in idiopathic pulmonary arterial hypertension (IPAH) and right-sided heart failure is unknown. We assessed the prognostic value of a prolonged ECG QRS duration in patients with IPAH in China. METHODS We retrospectively analyzed the initial 12-lead ECG for QRS duration in 212 consecutive patients with IPAH seen at our center between 2007 and 2009. Patients were divided according to QRS duration < 120 milliseconds or ≥ 120 milliseconds. The baseline characteristics and survival of the two groups were compared. RESULTS Thirty-five patients with IPAH (16.5%) had a QRS duration ≥ 120 milliseconds, including 21 (9.9%) with right bundle-branch block and 14 (6.6%) with nonspecific intraventricular conduction delay. Prolongation of the QRS duration was associated with a worse World Health Organization functional class and 6-min walk test distance and higher serum uric acid when compared with patients with normal QRS duration (P < .05). Prolonged QRS duration was an independent predictor of mortality and was associated with a 2.5-fold increased risk of death (P = .024). CONCLUSION Prolongation of the QRS duration is associated with clinical severity in patients with IPAH. In addition, QRS prolongation has an independent association with cardiopulmonary mortality and could be a new predictor of adverse outcome in patients with IPAH.
Knockdown of Ron Kinase Inhibits Mutant Phosphatidylinositol 3-Kinase and Reduces Metastasis in Human Colon Carcinoma*

Abnormal accumulation and activation of receptor tyrosine kinase Ron (recepteur d'origine nantais) has been demonstrated in a variety of primary human cancers. We show that RNA interference-mediated knockdown of Ron kinase in a highly tumorigenic colon cancer cell line led to reduced proliferation as compared with the control cells. Decreased Ron expression sensitized HCT116 cells to growth factor deprivation stress-induced apoptosis as reflected by increased DNA fragmentation and caspase 3 activation. In addition, cell motility was decreased in Ron knockdown cells as measured by wound healing assays and transwell assays. HCT116 cells are heterozygous for gain of function mutant PIK3CA H1047R. Analysis of signaling proteins that are affected by Ron knockdown revealed that phosphatidylinositol 3-kinase (PI3K) activity of the mutant PI3K as well as AKT phosphorylation was substantially reduced in the Ron knockdown cells compared with the control cells. Moreover, we demonstrated in vivo that knockdown of Ron expression significantly reduced lung metastasis as compared with the control cells in the orthotopic models. In summary, our results demonstrate that Ron plays an essential role in maintaining malignant phenotypes of colon cancer cells through regulating mutant PI3K activity. Therefore, targeting Ron kinase could be a potential strategy for colon cancer treatment, especially in patients bearing gain of function mutant PI3K activity.
Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training.

BACKGROUND The absence (deletion allele [D]) of a 287-base pair marker in the ACE gene is associated with higher ACE levels than its presence (insertion allele [I]). If renin-angiotensin systems regulate left ventricular (LV) growth, then individuals of DD genotype might show a greater hypertrophic response than those of II genotype. We tested this hypothesis by studying exercise-induced LV hypertrophy. METHODS AND RESULTS Echocardiographically determined LV dimensions and mass (n=140), electrocardiographically determined LV mass and frequency of LV hypertrophy (LVH) (n=121), and plasma brain natriuretic peptide (BNP) levels (n=49) were compared at the start and end of a 10-week physical training period in male Caucasian military recruits. Septal and posterior wall thicknesses increased with training, and LV mass increased by 18% (all P<.0001). Response magnitude was strongly associated with ACE genotype: mean LV mass altered by +2.0, +38.5, and +42.3 g in II, ID and DD, respectively (P<.0001). The prevalence of electrocardiographically defined LVH rose significantly only among those of DD genotype (from 6 of 24 before training to 11 of 24 after training, P<.01). Plasma brain natriuretic peptide levels rose by 56.0 and 11.5 pg/mL for DD and II, respectively (P<.001). CONCLUSIONS Exercise-induced LV growth in young males is strongly associated with the ACE I/D polymorphism.
Glut2‐dependent glucose‐sensing controls thermoregulation by enhancing the leptin sensitivity of NPY and POMC neurons

The physiological contribution of glucose in thermoregulation is not completely established nor whether this control may involve a regulation of the melanocortin pathway. Here, we assessed thermoregulation and leptin sensitivity of hypothalamic arcuate neurons in mice with inactivation of glucose transporter type 2 (Glut2)‐dependent glucose sensing. Mice with inactivation of Glut2‐dependent glucose sensors are cold intolerant and show increased susceptibility to food deprivation‐induced torpor and abnormal hypothermic response to intracerebroventricular administration of 2‐deoxy‐D‐glucose compared to control mice. This is associated with a defect in regulated expression of brown adipose tissue uncoupling protein I and iodothyronine deiodinase II and with a decreased leptin sensitivity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons, as observed during the unfed‐to‐refed transition or following i.p. leptin injection. Sites of central Glut‐2 expression were identified by a genetic tagging approach and revealed that glucose‐sensitive neurons were present in the lateral hypothalamus, the dorsal vagal complex, and the basal medulla but not in the arcuate nucleus. NPY and POMC neurons were, however, connected to nerve terminals from Glut2‐expressing neurons. Thus, our data suggest that glucose controls thermoregulation and the leptin sensitivity of NPY and POMC neurons through activation of Glut2‐dependent glucose‐sensing neurons located outside of the arcuate nucleus. —Mounien, L. , Marty, N. , Tarussio, D. , Metref, S. , Genoux, D. , Preitner, F. , Foretz, M. , Thorens, B. Glut2‐dependent glucosesensing controls thermoregulation by enhancing the leptin sensitivity of NPY and POMC neurons. FASEB J. 24, 1747–1758 (2010). www.fasebj. org
Molecular epidemiology of methicillin-resistant Staphylococcus aureus from bacteraemia in northern Italy.

BACKGROUND Vancomycin is frequently used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia; reduced susceptibility to vancomycin is therefore disturbing. METHODS molecular epidemiological analysis of 81 MRSA bacteraemia isolates collected during 2002-10 in the province of Bolzano, northern Italy was performed. MICs of a range of antimicrobials were determined by agar microdilution, screening for hGISA was by Macro-Etest and Etest GRD and confirmed by PAP-AUC with vancomycin and teicoplanin. All isolates were characterised by toxin gene profiling, agr, spa, and SCCmec-typing; MLST and PFGE were carried out on representative strains. RESULTS The dominant clones identified were ST8-MRSA-IVc (55%) and ST228- and ST111-MRSA-I (25%); most of the latter two lineages (19/20; 95%) were GISA or PAP-AUC confirmed hGISA. One ST8-MRSA-IVc isolate harboured ccrA2B2 together with ccrA4B4. The remainder were diverse genotypically and belonged to MLST clonal complexes 1, 22, 45 and 398. CONCLUSIONS Diverse lineages of MRSA were identified as causing bacteraemia in a province in northern Italy. The association of a specific genotype with the hGISA and GISA phenotypes among representatives of the second most common lineage identified is of clinical concern.
First trimester screening with free β‐hCG, PAPP‐A and nuchal translucency in pregnancies conceived with assisted reproduction

To evaluate the effect of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) on free beta‐human chorionic gonadotrophin (β‐hCG), pregnancy‐associated plasma protein A (PAPP‐A) and nuchal translucency (NT).
Analgesia following Arthroscopic Knee Surgery. A Controlled Study of Intra-articular Morphine, Bupivacaine or Both Combined

In a double-blind, randomised controlled trial, we studied 40 patients who received one of four intra-articular injections at the end of arthroscopic surgery. Each group contained ten patients. The patients in Group 1 received normal saline 25 ml; those in Group 2 received bupivacaine 0.25% 25 ml; those in Group 3 received morphine 5 mg in normal saline 25 ml; and those in Group 4 received a combination of bupivacaine 0.5% 12.5 ml and 5 mg of morphine made up to 25 ml with normal saline to produce the same bupivacaine concentration as Group 2. At the time the patient awoke, and 30min, Ihr, Ihr 30min, 2hr, 4hr, 8hr, 12hr, and 24hr postoperatively, pain was assessed using a visual analogue scale. The need for supplementary analgesic agents in the first 24 hours was recorded. All pain scores were significantly lower (P< 0.05) in Groups 2, 3 and 4 compared with the control group with the exception of Group 2 at 24 hours. Pain scores were significantly lower (P<0.05) for Group 2 compared with Group 3 for the first 90 minutes postoperatively. At 4, 8, 12 and 24 hours postoperatively the pain scores were significantly lower (P<0.05%) for Group 3 compared with Group 2. Group 4 had the lowest pain scores over the recorded period compared with the other groups. The need for supplemental analgesia was significantly lower (P<0.05) in the treatment Groups 2, 3 and 4 compared to the control Group 1. There was no significant difference in supplemental analgesic requirements between Groups 2, 3 and 4. A combination of bupivacaine and morphine injected intra-articularly following arthroscopy provided superior analgesia compared with that achieved by either drug alone.
Microvascular blood flow and stasis in transgenic sickle mice: Utility of a dorsal skin fold chamber for intravital microscopy

Vascular inflammation, secondary to ischemia–reperfusion injury, may play an essential role in vaso‐occlusion in sickle cell disease (SCD). To investigate this hypothesis, dorsal skin fold chambers (DSFCs) were implanted on normal and transgenic sickle mice expressing human α and βs/βs‐Antilles globin chains. Microvessels in the DSFC were visualized by intravital microscopy at baseline in ambient air and after exposure to hypoxia–reoxygenation. The mean venule diameter decreased 9% (P < 0.01) in sickle mice after hypoxia–reoxygenation but remained constant in normal mice. The mean RBC velocity and wall shear rate decreased 55% (P < 0.001) in sickle but not normal mice after hypoxia–reoxygenation. None of the venules in normal mice became static at any time during hypoxia–reoxygenation; however, after 1 hr of hypoxia and 1 hr of reoxygenation, 11.9% of the venules in sickle mice became static (P < 0.001). After 1 hr of hypoxia and 4 hr of reoxygenation, most of the stasis had resolved; only 3.6% of the subcutaneous venules in sickle mice remained static (P = 0.01). All of the venules were flowing again after 24 hr of reoxygenation. Vascular stasis could not be induced in the subcutaneous venules of sickle mice by tumor necrosis factor alpha (TNF‐α). Leukocyte rolling flux and firm adhesion, manifestations of vascular inflammation, were significantly higher at baseline in sickle mice compared to normal (P < 0.01) and increased 3‐fold in sickle (P < 0.01), but not in normal mice, after hypoxia–reoxygenation. Plugs of adherent leukocytes were seen at bifurcations at the beginning of static venules. Misshapen RBCs were also seen in subcutaneous venules. Am. J. Hematol. 77:117–125, 2004. © 2004 Wiley‐Liss, Inc.
Biological Maturation and Physical Activity in South Korean Adolescent Girls.

INTRODUCTION/PURPOSE To examine whether body fatness (i.e., body mass index and percent body fat) and psychosocial correlates of physical activity (PA) mediate the relationships between pubertal status and PA and sedentary behavior (SB) among South Korean adolescent girls. METHODS Pubertal status, body fatness, sport competence, perceived barriers to PA, self-efficacy, parental support for PA, self-reported and step-determined PA, and self-reported SB were assessed among 236 South Korean adolescent girls (mean age = 13.56 ± 1.2 yr). RESULTS A direct association was identified between pubertal status and PA in all models; more advanced pubertal status predicted lower PA among South Korean adolescents (b = -0.51 to -0.57; P < 0.001). Indirect effects on the pubertal status-PA relationship were also found: body fatness, perceived barriers to PA, and self-efficacy mediated the relationship between pubertal status and PA. Parental support for PA did not moderate the relationship between maturation and PA. SB was not associated with pubertal status. CONCLUSIONS This study found mediated effects of body fatness, and psychosocial correlates (i.e., perceived barriers to PA, self-efficacy) on the relationship between maturity and PA among South Korean adolescent girls. Efforts to promote PA among South Korean adolescent girls should focus on reducing perceived barriers to PA, and increasing self-efficacy by providing more opportunities to have positive, and enjoyable experiences in PA among early-maturing girls.
Molecular Determinants of Malignant Brain Cancers: From Intracellular Alterations to Invasion Mediated by Extracellular Vesicles

Malignant glioma cells invade the surrounding brain parenchyma, by migrating along the blood vessels, thus promoting cancer growth. The biological bases of these activities are grounded in profound alterations of the metabolism and the structural organization of the cells, which consequently acquire the ability to modify the surrounding microenvironment, by altering the extracellular matrix and affecting the properties of the other cells present in the brain, such as normal glial-, endothelial- and immune-cells. Most of the effects on the surrounding environment are probably exerted through the release of a variety of extracellular vesicles (EVs), which contain many different classes of molecules, from genetic material to defined species of lipids and enzymes. EV-associated molecules can be either released into the extracellular matrix (ECM) and/or transferred to neighboring cells: as a consequence, both deep modifications of the recipient cell phenotype and digestion of ECM components are obtained, thus causing cancer propagation, as well as a general brain dysfunction. In this review, we first analyze the main intracellular and extracellular transformations required for glioma cell invasion into the brain parenchyma; then we discuss how these events may be attributed, at least in part, to EVs that, like the pawns of a dramatic chess game with cancer, open the way to the tumor cells themselves.