Miracle-dz/UniFAR-FTUs huggingface dataset:
Macitentan, a double antagonist of endothelin receptors, efficiently impairs migration and microenvironmental survival signals in chronic lymphocytic leukemia

The crosstalk between chronic lymphocytic leukemia (CLL) cells and tumor microenvironment is essential for leukemic clone maintenance, supporting CLL cells survival, proliferation and protection from drug-induced apoptosis. Over the past years, the role of several soluble factors involved in these processes has been studied. CLL cells express higher levels of endothelin 1 (ET-1) and ETA receptor as compared to normal B cells. Upon ET-1 stimulation, CLL cells improve their survival and proliferation and reduce their sensitivity to the phosphoinositide-3-kinase δ inhibitor idelalisib and to fludarabine. Here, we demonstrate that CLL cells express not only ETA receptor but also ETB receptor. ET-1 acts as a homing factor supporting CLL cells migration and adhesion to microenvironmental cells. In addition, ET-1 stimulates a pro-angiogenic profile of CLL cells increasing VEGF expression through hypoxia-inducible factor-1 (HIF-1α) accumulation in CLL cells. Macitentan, a specific dual inhibitor of ETA and ETB receptors, targets CLL cells affecting leukemic cells migration and adhesion and overcoming the pro-survival and proliferation signals mediated by microenvironment. Furthermore, macitentan cooperates with ibrutinib inhibiting the BCR pathway and with ABT-199 disrupting BCL2 pathway. Our data describe the biological effects of a new drug, macitentan, able to counteract essential processes in CLL pathobiology as survival, migration, trafficking and drug resistance. These findings envision the possibility to interfere with ET receptors activity using macitentan as a possible novel therapeutic strategy for CLL patients.
Expression of Campoletis sonorensis Virus in the Parasitized Host, Heliothis virescens

Polyadenylated mRNA transcripts of the virus of Campoletis sonorensis were detected in Heliothis virescens host larvae 2 h after the larvae had been parasitized by C. sonorensis females and continued to be present in host larvae through 9 days postparasitization while C. sonorensis developed endoparasitically. cDNAs of viral transcripts present in H. virescens hybridized with only certain C. sonorensis viral DNAs.
Supplemental Vibrational Force During Orthodontic Alignment

This prospective 3-arm parallel-group randomized clinical trial investigated the effect of supplemental vibrational force on rate of orthodontic tooth alignment with fixed appliances. Eighty-one subjects (40 males, 41 females; mean age, 14.1 y) undergoing first premolar extraction-based fixed appliance treatment were randomly allocated to treatment supplemented with daily use (20 min) of a removable intraoral vibrational device (AcceleDent; OrthoAccel Technologies Inc.; n = 29), an identical nonfunctional (sham) device (n = 25), or fixed appliances only (n = 27). Mandibular study casts were taken at baseline (treatment start: placement of 0.014-in. nickel-titanium arch wire), initial alignment (0.018-in. nickel-titanium arch wire), and final alignment (0.019 x 0.025–in. stainless steel arch wire). Overall mean irregularity index in the mandibular arch at baseline was 8.5 ± 3.8 mm (95% CI, 7.6 to 9.3) with no significant difference between groups (P = 0.73). For the total sample, mean irregularity index at initial alignment was 2.7 ± 2.8 mm (95% CI, 2.2 to 3.4) with no significant difference between groups (P = 0.40). Mean time from baseline to initial alignment was 59 ± 25 d (95% CI, 54.5 to 65.6); from initial to final alignment, 150 ± 62.5 d (95% CI, 136 to 165); and baseline to final alignment, 209 ± 65 d (95% CI, 195 to 224). Kaplan-Meier analysis demonstrated that patterns of alignment were not significantly different among the 3 groups (P = 0.66). Multivariate linear regression for initial and overall alignment rates using initial irregularity index as the covariate showed no significant differences among groups. The most important influence on both initial and overall rates of alignment was initial irregularity (P = 0.1 × 10−4). This prospective randomized clinical trial found no evidence that supplemental vibrational force can significantly increase the rate of initial tooth movement or reduce the amount of time required to achieve final alignment when used in conjunction with a preadjusted edgewise fixed appliance (ClinicalTrials.gov NCT02314975).
Cationic nanoparticles induce caspase 3-, 7- and 9-mediated cytotoxicity in a human astrocytoma cell line

Abstract On a daily basis we are exposed to cationic nanoparticulates in many different ways. They are known to distribute to many organs of the body, and while some evidence suggests that these nanoparticles are toxic to cells, the mechanism of their toxicity is not clear. Here we apply a combination of biochemical and imaging techniques to study the mechanism by which amine-modified polystyrene nanoparticles induce cell death in a human brain astrocytoma cell line. Flow cytometry analysis of cells exposed to cationic nanoparticles revealed an increase in cell membrane permeability of the dyes YoPro-1 and propidium iodide, indicating onset of an apoptotic followed by a secondary necrotic response. Activation of caspases 3/7 and 9 and cleavage of poly(ADP-ribose) polymerase (PARP)-1 was also detected, providing clear molecular evidence of the apoptotic pathway induced by the nanoparticles. Transmission electron microscopy also revealed that these nanoparticles induce morphological changes in lysosomes and mitochondria, consistent with our observation of a rapid increase in the formation of reactive oxygen species in these cells. Together these results suggest that amine-modified polystyrene nanoparticles can mediate cell death through an apoptotic mechanism mediated by damage to the mitochondria.
The glucoregulatory and antilipolytic actions of insulin in abdominal obesity with normal or impaired glucose tolerance: an in vivo and in vitro study

Abstract. To evaluate the effects of obesity and impaired glucose tolerance on insulin sensitivity, we performed a euglycaemic‐hyperinsulinemic clamp at about 350 pmol 1‐1, combined with 3H‐glucose infusion, in 14 obese patients, BMI 36.5 ± 1.2 and in 12 matched controls, BMI 23.9 ± 0.4. Six obese patients had normal glucose tolerance (oNGT), and eight had impaired glucose tolerance (oIGT). The ability of insulin to inhibit lipolysis in isolated adipocytes was also studied. Insulin‐mediated glucose utilization was more severely impaired in oIGT than in oNGT with respect to the controls (621 ± 51 vs. 897 ±83 vs. 1298 ± 55 μmol m‐2 min‐1, P<0.001). Plasma gly‐cerol was higher in oIGT than in oNGT and in the controls, both fasting (238 ±12 vs. 179 ± 14 vs. 112 ± 8 μmo1 1‐1, P < 0.001) and during the clamp (175 ± 21 vs. 120 ± 12 vs. 36 ± 6/μmiol1‐1, P<0.001). The correlation between glucose utilization and the percent reduction of plasma glycerol during the clamp was significant in the study group as a whole (r = 0.809, P=0.0001), and in each of the groups separately (oIGT: r = 0.929, P = 0.002; oNGT: r = 0.943, P = 0036; controls: r = 0.902, P = 0.0001). Inhibition by insulin of noradrenaline‐stimulated lipolysis in isolated adipocytes was more severely impaired in oIGT than in oNGT compared with the controls (P < 0.001). We conclude that impaired as opposed to normal glucose tolerance in obesity is associated with more severe impairment in both glucose utilization and insulin inhibition of lipolysis.
Surface sensing and adhesion of Escherichia coli controlled by the Cpx-signaling pathway

Bacterial adhesion is an important initial step in biofilm formation, which may cause problems in medical, environmental, and industrial settings. In spite of obvious phenotypic differences between attached and planktonic cells, knowledge about the genetic basis for these differences and how adhesion-induced changes are mediated is limited. The Cpx two-component signal transduction pathway responds specifically to stress caused by disturbances in the cell envelope and activates genes encoding periplasmic protein folding and degrading factors. Here, we address the role of the Cpx-signaling pathway in sensing and responding to the physical change occurring during adhesion of Escherichia coli to surfaces. We present evidence that the expression of Cpx-regulated genes is induced during initial adhesion of E. coli to abiotic surfaces. This induction is specifically observed upon attachment of stationary-phase cells to hydrophobic surfaces. Moreover, surface-induced activity of the Cpx response requires NlpE, an outer membrane lipoprotein, which has previously been shown to induce the Cpx system when overproduced. The importance of a functional Cpx response during adhesion is further supported by the fact that a dramatically lower number of cells attach to the surface and dynamic cell–surface interactions as measured by a quartz crystal microbalance technique are altered when the CpxRA pathway is disrupted. The defects in adhesion exhibited by the cpxR and nlpE mutants were strikingly similar to those of wild-type cells in which protein synthesis was inhibited, suggesting that the Cpx pathway plays a key role in the regulation of adhesion-induced gene expression.
Ablation of the very‐long‐chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet‐induced obesity

Although saturated and monounsaturated very‐long‐chain fatty acids (VLCFAs) have long been associated with undesirable effects on health, including obesity, heart failure, and atherosclerosis, the physiological role of endogenous synthesis is largely unknown. The fatty acid elongase ELOVL3 is involved in the synthesis of C20–C24 saturated and monounsaturated VLCFAs mainly in liver, brown and white adipose tissue, and triglyceride‐rich glands such as the sebaceous and meibomian glands. Here we show that ablation of ELOVL3 leads to reduced adiponectin levels, constrained expansion of adipose tissue, and resistance against diet‐induced obesity, a situation that is more exaggerated in female mice. Both female and male knockout mice show reduced hepatic lipogenic gene expression and triglyceride content, a situation that is associated with reduced de novo fatty acid synthesis and uptake. As a consequence, the VLDL‐triglyceride level in serum is significantly reduced. Remarkably, despite increased energy expenditure, markedly reduced serum levels of leptin, and increased expression of orexigenic peptides in the hypothalamus, the Elovl3−/− mice do not compensate by increased food intake. Thus, these results reveal that C20–C22 saturated and monounsaturated VLCFAs produced by ELOVL3 are indispensable for appropriate synthesis of liver triglycerides, fatty acid uptake, and storage in adipose tissue. —Zadravec, D. , Brolinson, A. , Fisher, R. M. , Carneheim, C. , Csikasz, R. I. , Bertrand‐Michel, J., Borén, J., Guillou, H. , Rudling, M. , Jacobsson, A. Ablation of the very‐long‐chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet‐induced obesity. FASEB J. 24, 4366–4377 (2010). www.fasebj. org
Experimental Studies on Lateral Root Formation in Radish Seedling Roots: II. Analysis of the Dose-Response to Exogenous Auxin.

Application of indoleacetic acid (IAA) and other auxins causes cultured radish (Raphanus sativus L. ;Scarlet Globe') seedling root segments to produce an increased frequency (FR, no. cm(-1)) of lateral roots (LR); in the absence of auxin, segments spontaneously form about 6 LR cm(-1). A dose-response study has revealed that the increase in FR follows a biphasic Michaelis-Menten relationship with the medium concentration of the undissociated form of IAA ([IAAH](m)). The fitted curve for phase I has a maximum response level (R(max)) of 5.2 LR per centimeter above the spontaneous FR; the [IAAH](m) giving half-maximal response (C(1/2)) is 21 nanomolar. For phase II, the values for R(max) and C(1/2) are 56 LR per centimeter and 11 micromolar, respectively. The response is variable in the transition concentration region between the two phases; in that region (but not, or much less commonly, at higher or lower [IAAH](m)), LR initiation may resume or continue after the first day. At and above 100 micromolar [IAAH](m), the roots are hyperstimulated and generally fail to respond. The developmental stage of LR formed in medium with very low [IAAH](m) (10 nanomolar) is enhanced compared to LR formed in medium lacking auxin; the stage is diminished at higher auxin levels, in inverse correlation with FR. Trends in the responses to NAA and IBA were similar, but NAA required only 0.03 times the dose of IAA, while IBA required 6 times the dose of IAA. These findings may be of use in a search for possible auxin receptors involved with LR initiation.
Pre‐adult mortality in the blowfly Lucilia sericata

Abstract. Populations of the blowfly, Lucilia sericata (Meigen) (Diptera: Calliphoridae), have a considerable potential for rapid increase; the lifetime reproductive output of each adult female has been estimated to be between 130 and 172 eggs. Nevertheless, in the field, absolute population densities of this species are relatively low. To account for this difference, the levels of mortality affecting the eggs, feeding and wandering larvae and pupae of L. sericata were assessed in the field and laboratory. Percentage egg hatch was dependent on relative humidity with no egg eclosion at humidities below 50%; there was no significant effect of temperature on egg hatch. On infested sheep, the mean mortality of feeding larvae was 53%, but this ranged widely from 0% to 96%. There was no effect of atmospheric temperature or humidity on the mortality of feeding larvae in vivo. In the laboratory, only 10% of wandering larvae pupariated at 10°C. At above 20°C pupariation was consistently almost 100%. Percentage emergence increased from 0% at 10°C to about 80% between 20 and 30°C. The upper lethal temperature for pupae was approached at 35°C. Analysis of the predation of pupae in the field revealed a weak, but significant curvilinear relationship between temperature and proportionate mortality and a median mortality of 0.49% per 24 h exposure (interquartile range = 5.2%). There was no evidence of density dependence in pupal predation. Overall, it is estimated that pre‐adult mortality accounts for losses of approximately 97% of each generation, but this figure is subject to considerable variation depending on factors such as climate, time of year and host susceptibility.
Noradrenaline and adenosine triphosphate as co‐transmitters of neurogenic vasoconstriction in rabbit mesenteric artery.

The largest rami caecales of the ileocolic artery, which is a branch of the mesenteric artery, were perfused at a constant rate of flow. Either vasoconstriction (as an increase in perfusion pressure) or the release of previously incorporated [3H]‐noradrenaline was measured. Noradrenaline and ATP, but not carbachol, serotonin, adenosine, Arg‐vasopressin and neuropeptide Y, caused marked vasoconstriction. When the sympathetic vasoconstrictor axons in the arterial wall were stimulated by electrical field pulses (either 5 pulses at 10 Hz or 100 pulses at 5 Hz; 0.3 ms pulse width, 200 mA current strength), the ensuing vasoconstriction was at best slightly reduced by phentolamine, prazosin and phenoxybenzamine. The response to 100 pulses, 5 Hz was even enhanced by phentolamine and yohimbine. All antagonists except yohimbine blocked the effect of exogenous noradrenaline. Prazosin did not change the effect of exogenous ATP. alpha,beta‐Methylene‐ATP (3‐15 mumol/l) elicited transient vasoconstriction. Subsequently, responses to ATP as well as to electrical stimulation were reduced and recovered slowly. The response to noradrenaline was not changed. That part of the electrically induced vasoconstriction that remained after alpha,beta‐methylene‐ATP was almost abolished by phentolamine or prazosin. Pre‐treatment of the animals with reserpine decreased but did not prevent the electrically evoked contraction of their arteries. The reserpine‐resistant response was not changed by prazosin but was abolished by alpha,beta‐methylene‐ATP. The vasoconstriction elicited by electrical pulses was not affected by atropine or methysergide but was entirely blocked by tetrodotoxin, guanethidine or exposure to 6‐hydroxydopamine. In arteries pre‐incubated with [3H]‐noradrenaline, electrical stimulation (100 pulses at 5 Hz) increased the outflow of tritium. The evoked overflow was blocked by tetrodotoxin, not changed by alpha,beta‐methylene‐ATP (9 mumol/l) or prazosin, and enhanced by phentolamine, phenoxybenzamine and yohimbine. We conclude that, in the branch of the mesenteric artery examined, both noradrenaline and ATP or a closely related compound transmit information from sympathetic neurones to smooth muscle. An alpha‐adrenoceptor antagonist can reduce neurogenic vasoconstriction by blockade of post‐junctional alpha‐(probably alpha 1) receptors, reserpine by selective depletion of noradrenaline, and alpha,beta‐methylene‐ATP by desensitization of the post‐junctional ATP (probably P2) receptor mechanism. Noradrenaline and ATP appear to be released from the same neurone. In addition, prejunctional alpha 2‐adrenergic autoinhibition of transmitter release operates in the artery. alp
Low expression of the ClC-2 chloride channel during postnatal development: a mechanism for the paradoxical depolarizing action of GABA and glycine in the hippocampus

In early postnatal development, during the period of synapse formation, γ–aminobutyric (GABA) and glycine, the main inhibitory transmitters in the adult brain, paradoxically excite and depolarize neuronal membranes by an outward flux of chloride. The mechanisms of chloride homeostasis are not fully understood. It is known that in adult neurons intracellular chloride accumulation is prevented by a particular type of chloride channel, the ClC-2. This channel strongly rectifies in the inward direction at potentials negative to ECl thus ensuring chloride efflux. We have tested the hypothesis that in the developing hippocampus, a differential expression or regulation of ClC-2 channels may contribute to the depolarising action of GABA and glycine. We have cloned a truncated form of ClC-2 (ClC-2nh) from the neonatal hippocampus which lacks the 157 bp corresponding to exon 2. In situ hybridization experiments show that ClC-2nh is the predominant form of ClC-2 mRNA in the neonatal brain. ClC-2nh mRNA is unable to encode a full-length protein due to a frameshift, consequently it does not induce any currents upon injection into Xenopus oocytes. Low expression of the full–length ClC-2 channel, could alter chloride homeostasis, lead to accumulation of [Cl-]i and thereby contribute to the depolarizing action of GABA and glycine during early development.
Neurobehavioral performance in aluminum welders.

METHODS Twenty aluminum welders (mean age 33 years; range 21-52), who had been exposed to aluminum for an average of 8.1 years (range 2-21), were tested for tremor and reaction time and screened for neuropsychiatric symptoms in a cross-sectional study. The welders' median urinary aluminum concentration was 1.5 micromol/L (range 0. 7-4.8). Aluminum in air, measured inside the respiratory protection, was 0.9 mg/m(3) (range 0.6-3.8). The welders were compared with twenty construction workers matched for age. RESULTS Welders reported more symptoms than referents did (median 2 vs. 1; P=0.047). Although the welders as a group performed better than the referents on a tremor test, years of exposure, but not age, was predictive of poorer performance. The welders' reaction times were rapid by clinical standards (mean simple reaction time (SRT): 221 milliseconds; mean continuous performance test (CPT): 364 milliseconds). Although, as a group, they performed better than the referents, there was a statistically significant relation between longer reaction times and aluminum in air (air-Al). CONCLUSIONS The relations between hand steadiness and years exposed, and between reaction time and air-Al, could indicate slight effects from exposure to aluminum. The possibility of selection of workers with high manual skills into welding work and a possible job-related training effect, might partly serve to explain the good performance among the welders.
Prevalance of gestational diabetes mellitus in patients with gestational transient thyrotoxicosis

Abstract Objective: To investigate prevalence of gestational diabetes mellitus (GDM) in patients with gestational transient thyroxicosis (GTT). Methods: Fifty two patients with GTT and 100 age matched healthy pregnant women were included. Fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), LDL-cholesterol, HDL-cholesterol, triglyceride, thyrotrophin (TSH) and thyroid hormones were measured at thyrotoxic state in GTT patients and at 6–12th weeks of pregnancy in control group. Oral glucose tolerance test (OGTT) with 100 g glucose was performed and laboratory parameters were re-evaluated at 24–28th weeks of pregnancy in all subjects. Results: Mean age of patients with GTT was 28.46 ± 5.45 and control group was 27.78 ± 3.75(p = 0.085). Patients with GTT had significantly higher HbA1c, LDL-cholesterol and HDL-cholesterol at 6–12th weeks of pregnancy (p < 0.01, p < 0.01 and p = 0.034, respectively). TSH was negatively correlated with HbA1c and LDL-cholesterol in thyrotoxic state in GTT patients (r = −0.393, p < 0.001 and r = −0.293, p < 0.001, respectively). OGTT showed GDM in 7 (13.5%) GTT patients and 4 (4%) healthy pregnants (p = 0.047). HbA1c, LDL-cholesterol and HDL-cholesterol were higher in GTT patients compared to healthy pregnants also at 24–28th weeks of pregnancy (p < 0.001, p < 0.001 and p = 0.024). Conclusion: Although GTT is known to be a transient state that can resolve spontaneously, it might have negative effect on carbohydrate metabolism like other causes of hyperthyroidism.
THE PATHOPHYSIOLOGICAL ROLE OF PEROXYNITRITE IN SHOCK, INFLAMMATION, AND ISCHEMIA‐REPERFUSION INJURY

ABSTRACT Peroxynitrite is a reactive oxidant produced from nitric oxide (NO) and superoxide, which reacts with proteins, lipids, and DNA under conditions of inflammation and shock. Here we overview the role of peroxynitrite in circulatory shock and inflammation. Immunohistochemical and biochemical evidence demonstrate production of peroxynitrite in endotoxic and hemorrhagic shock, chronic bowel inflammation, and in various forms of ischemia-reperfusion injury. The reactivity and decomposition of peroxynitrite is determined by the chemical environment, and the ratio of superoxide versus NO. Peroxynitrite can initiate toxic oxidative reactions in vitro and in vivo. Initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane Na+/K+ ATP-ase activity, inactivation of membrane sodium channels, and other oxidative protein modifications contribute to the cytotoxic effect of peroxynitrite. In addition, peroxynitrite is a potent trigger of DNA strand breakage, with subsequent activation of the nuclear enzyme poly-ADP ribosyl synthetase, with eventual severe energy depletion of the cells. Pharmacological evidence suggests that the peroxynitrite-poly-ADP ribosyl synthetase pathway importantly contributes to the cellular injury in endotoxic shock, inflammatory pancreatic islet cell destruction, and central nervous system ischemia. The proposal that peroxynitrite is a major cytotoxic mediator would change the interpretation of previous data on the effects of NO donors, NO synthase inhibitors, and superoxide neutralizing strategies in shock and inflammation.