Miracle-dz/UniFAR-FTUs huggingface dataset:
Long-term exposures to low doses of cobalt nanoparticles induce cell transformation enhanced by oxidative damage

Abstract A weak aspect of the in vitro studies devoted to get information on the toxic, genotoxic and carcinogenic properties of nanomaterials is that they are usually conducted under acute-exposure and high-dose conditions. This makes difficult to extrapolate the results to human beings. To overcome this point, we have evaluated the cell transforming ability of cobalt nanoparticles (CoNPs) after long-term exposures (12 weeks) to sub-toxic doses (0.05 and 0.1 µg/mL). To get further information on whether CoNPs-induced oxidative DNA damage is relevant for CoNPs carcinogenesis, the cell lines selected for the study were the wild-type mouse embryonic fibroblast (MEF Ogg1+/+) and its isogenic Ogg1 knockout partner (MEF Ogg1−/−), unable to properly eliminate the 8-OH-dG lesions from DNA. Our initial short-term exposure experiments demonstrate that low doses of CoNPs are able to induce reactive oxygen species (ROS) and that MEF Ogg1−/− cells are more sensitive to CoNPs-induced acute toxicity and oxidative DNA damage. On the other hand, long-term exposures of MEF cells to sub-toxic doses of CoNPs were able to induce cell transformation, as indicated by the observed morphological cell changes, significant increases in the secretion of metalloproteinases (MMPs) and anchorage-independent cell growth ability, all cancer-like phenotypic hallmarks. Interestingly, such changes were significantly dependent on the cell line used, the Ogg1−/− cells being particularly sensitive. Altogether, the data presented here confirms the potential carcinogenic risk of CoNPs and points out the relevance of ROS and Ogg1 genetic background on CoNPs-associated effects.
Effect of positive end-expiratory pressure after porcine unilateral left lung transplant.

OBJECTIVES To evaluate the effects of 2 different levels of positive end-expiratory pressure on pigs who had unilateral lung transplants. MATERIALS AND METHODS A left lung transplant was performed in 12 pigs. The animals were randomized into 2 groups based on positive end-expiratory pressure: group 1 (5 cm H(2)O) and group 2 (10 cm H(2)O). Hemodynamics, gas exchange, and respiratory mechanics were measured before and after surgery. Cytokines, oxidative stress, and histologic scores were assessed in the lung tissue of each pig. RESULTS Pigs in group 2 exhibited a significantly higher mean heart rate (P = .006), static compliance (P = .001), lower mean arterial pressure (P = .003), and airway resistance (P = .001) than did pigs in group 1. There were no postoperative differences between the groups in concentrations of thiobarbituric acid reactive substances, superoxide dismutase, and interleukin 8. At the end of the observation period, pigs in group 2 had higher levels of thiobarbituric acid reactive substances (P = .001) and interleukin 8 (P = .05), and pigs in group 1 had higher levels of superoxide dismutase (P = .05) than they did at baseline. CONCLUSIONS After unilateral lung transplant, higher positive end-expiratory pressure was associated with improved respiratory mechanics, a negative effect on hemodynamics, a stronger inflammatory response, and increased production of reactive oxygen species, but no effect on gas exchange.
Genetic Expression in Heterozygous Replicative Form Molecules of φX174

Heterozygous replicative form molecules of bacteriophage φX174 deoxyribonucleic acid (DNA) have been constructed in vitro. These are composed of viral strands extracted from purified preparations of phage bearing ts mutations and complementary strands of either half length or full length synthesized with purified DNA polymerase, in vitro, on DNA from am3 phage. In infections with such heterozygous DNA, involving mutations in each of four different cistrons, phage with the genotype of the complementary strand comprised 1 to 20% of the total phage produced by a spheroplast population. From single-burst analysis of the progeny from DNA heterozygous in one cistron (B), it appears that those phage with the genotype of the complementary strand arise as major components in a small proportion of the infected cells rather than comprising a minor component in most cells. The implications of such a pattern of expression are discussed with respect to mechanisms of phage DNA synthesis.
Impact of migraine attacks on the blood-brain barrier.

BACKGROUND Cortical spreading depression can cause migraine attack, and up-regulate matrix metalloproteinase-9 (MMP-9) expression in animal. This study aimed to determine the impact on the structure and function of the blood-brain barrier by measuring plasma MMP-9 levels in patients at the acute and late stages of migraine attacks in order to elucidate the pathological mechanisms involved. METHODS We recruited a case-control cohort of 38 adult migraine patients and 20 age- and gender-matched healthy control subjects. Five milliliter blood samples were collected at the acute and late stages of migraine (days 1 - 7), and also from the control subjects. Solid phase double antibody sandwich enzyme-linked immunosorbent assay was used to determine plasma MMP-9 levels. Statistical analysis was performed using the SAS version 9.1. RESULTS Initial plasma MMP-9 levels of migraine patients were significantly higher than those of controls ((12.612 ± 0.016) µg/L vs. (6.069 ± 0.023) µg/L, respectively, P < 0.05). High MMP-9 expression was observed during days 1 - 6 of migraine attacks, with highest expression occurring on day 3 ((17.524 ± 0.035) µg/L). During attacks, MMP-9 levels were similar in migraine patients with and without aura (P > 0.05); in addition, levels were not correlated with degree of headache pain (P > 0.05). CONCLUSIONS We hypothesize that migraine could lead to increased plasma MMP-9 levels resulting in blood-brain barrier damage. MMP-9 levels increase during days 1 - 6 of migraine attacks, peaking on day 3. Therefore, MMP-9 could be used as a biological marker to guide treatment of migraine attacks.
Everolimus: an update on the mechanism of action, pharmacokinetics and recent clinical trials.

BACKGROUND A growing body of evidence suggests that everolimus might offer effective immunosuppressive activity together with antiproliferative effects that may address some of the unmet needs in the long-term therapeutic management of the post-transplant patient. OBJECTIVE To summarize the emerging evidence for employing everolimus-based immunosuppression. METHODS A systematic review was conducted of the Medline, Embase and Renal Health Library (Cochrane Collaboration) databases, and of the summary publications from international transplant meetings and congresses during 2000-2008. RESULTS This article summarizes this analysis, with special focus on the pharmacokinetic characteristics of everolimus and on the results of its use in renal transplantation. Some data has also been included about the efficacy of the drug in other solid organ transplantation and in tumours. CONCLUSIONS Everolimus is an immunosuppressant drug with proven efficacy in transplantation. When used in combination with cyclosporin, better results are obtained in renal function with low cyclosporin doses. Adverse events related to this drug are frequent and lead to moderate dropout rates.
p14ARF Induces G2 Cell Cycle Arrest in p53- and p21-deficient Cells by Down-regulating p34cdc2 Kinase Activity*

The human INK4a gene locus encodes two structurally unrelated tumor suppressor proteins, p16INK4a and p14ARF. Although primarily proposed to require a functional p53·Mdm-2 signaling axis, recently p14ARF has been implicated in p53-independent cell cycle regulation. Here we show that p14ARF preferentially induces a G2 arrest in tumor cells lacking functional p53 and/or p21. Expression of p14ARF impaired mitotic entry and enforced a primarily cytoplasmic localization of p34cdc2 that was associated with a decrease in p34cdc2 kinase activity and reduced p34cdc2 protein expression. A direct physical interaction between p14ARF and p34cdc2 was, nevertheless, ruled out by lack of co-immunoprecipitation. The p14ARF-induced depletion of p34cdc2 was associated with impaired cdc25C phosphatase expression and a prominent shift to inhibitory Tyr-15-phosphorylation in G2-arrested cells lacking either p53, p21, or both. Finally, reconstitution of p34cdc2 using a constitutively active, phosphorylation-deficient p34cdc2AF mutant alleviated this p14ARF-induced G2 arrest, thereby allowing cell cycle progression. Taken together, these data indicate that p14ARF arrests cells lacking functional p53/p21 in the G2 phase of the cell cycle by targeting p34cdc2 kinase. This may represent an important fail-safe mechanism by which p14ARF protects p53/p21-deficient cells from unrestrained proliferation.
Reliability and Validity of a Simple Measure for Assessing the Social Skills of People with Schizophrenia Necessary for Seeking and Securing a Job

The literature shows that social and vocational impairments are common problems among people with schizophrenia. However, assessment instruments available for measuring social competence of people with schizophrenia in the workplace are limited. This article describes a two-part measure developed and validated based on a model (Tsang & Pearson, 1996) for assessing social skills necessary for seeking and maintaining a job for people with schizophrenia. The measure consists of a 10 item self-administered checklist and a role-play exercise. The self-administered checklist measures clients' perceived competence in handling work-related social situations. The role-play exercise assesses the social skills necessary for job acquisition and maintenance in two simulated situations (participating in a simulated job interview and requesting urgent leave from work). Cronbach alpha coefficients (self-administered checklist: .80 (n=140); role-play test: . 96 (n=60)) show that both parts had good internal consistency. In addition, correlation coefficients show that the self-administered checklist has acceptable test-retest reliability (.35 to .78), and the role-play exercise has good interrater reliability (.77 to .90). The concurrent validity is also shown to be good for both parts of the measure using the method of contrasted groups. It is suggested that this measure is suitable for use by clinicians, rehabilitation administrators and researchers. Application of the instrument in other countries is discussed. Finally, further research is suggested.
Modelled in vivo HIV Fitness under drug Selective Pressure and Estimated Genetic Barrier Towards Resistance are Predictive for Virological Response

Background A method has been developed to estimate a fitness landscape experienced by HIV-1 under treatment selective pressure as a function of the genotypic sequence thereby also estimating the genetic barrier to resistance. Methods We evaluated the performance of two estimated fitness landscapes (nelfinavir [NFV] and zidovudine [AZT] plus lamivudine [3TC]) to predict week 12 viral load (VL) change for 176 treatment change episodes (TCEs) and probability of week 48 virological failure for 90 TCEs, in treatment experienced patients starting these drugs in combination. Results A higher genetic barrier for AZT plus 3TC, (quantified per additional mutation required to develop resistance against these drugs) was associated with a 0.54 (95% confidence interval [CI] 0.30–0.77) larger log10 VL reduction at 12 weeks (P<0.0001) and a 0.39 (95% CI 0.23–0.66) lower odds of virological failure at 48 weeks (P=0.0005), in analyses adjusting for the pre-TCE VL and the exact time-lag between the TCE and the date of determining response VL. The strength of these associations was comparable with those seen with expert interpretation systems (Rega, ANRS and HIVDB). A higher genetic barrier to NFV resistance was the only genotypic predictor that tended to be associated with a 0.19 (95% CI 0–0.39) higher log10 VL reduction at 12 weeks (P=0.05) and a 0.63 (95% CI 0.36–1.09) lower odds of virological failure at 48 weeks (P=0.10) per additional mutation. Conclusions These results suggest that an estimated genetic barrier derived from fitness landscapes may contribute to an improvement of predicted treatment outcome for NFV and this approach should be explored for other drugs.
Passive Immunization of Neonatal Mice against Pneumocystis carinii f. sp. muris Enhances Control of Infection without Stimulating Inflammation

ABSTRACT Pneumocystis carinii is an opportunistic fungal pathogen that causes life-threatening pneumonia in immunocompromised individuals. Infants appear to be particularly susceptible to infection with Pneumocystis. We have previously shown that there is a significant delay in clearance of the organisms from the lungs of neonatal mice compared to adults. Since alveolar macrophages are the effector cells responsible for killing and clearance of Pneumocystis, we have examined alveolar macrophage activity in neonatal mice. We found that alveolar macrophage activation is delayed about 1 week in Pneumocystis-infected neonates compared to adults. Opsonization of the organism by Pneumocystis-specific antibody resulted in increased clearance of the organism in neonatal mice; however, there was decreased expression of activation markers on neonatal alveolar macrophages and reduced levels of cytokines associated with macrophage activation. Mice born to immunized dams had significant amounts of Pneumocystis-specific immunoglobulin G in their lungs and serum at day 7 postinfection, whereas mice born to naïve dams had merely detectable levels. This difference correlated with enhanced Pneumocystis clearance in mice born to immunized dams. The increase in specific antibody, however, did not result in significant inflammation in the lungs, as no differences in numbers of activated CD4+ cells were observed. Furthermore, there was no difference in cytokine or chemokine concentrations in the lungs of pups born to immune compared to naïve dams. These findings indicate that specific antibody plays an important role in Pneumocystis clearance from lungs of infected neonates; moreover, this process occurs without inducing inflammation in the lungs.
Lamotrigine reduces painful diabetic neuropathy

Objective: To study the efficacy of lamotrigine in relieving the pain associated with diabetic neuropathy. Methods: The authors randomly assigned 59 patients to receive either lamotrigine (titrated from 25 to 400 mg/day) or placebo over a 6-week period. Primary outcome measure was self-recording of pain intensity twice daily with a 0 to 10 numerical pain scale (NPS). Secondary efficacy measures included daily consumption of rescue analgesics, the McGill Pain Questionnaire (MPQ), the Beck Depression Inventory (BDI), the Pain Disability Index (PDI), and global assessment of efficacy and tolerability. Results: Twenty-four of 29 patients (83%) receiving lamotrigine and 22 of 30 (73%) patients receiving placebo completed the study. Daily NPS in the lamotrigine-treated group was reduced from 6.4 ± 0.1 to 4.2 ± 0.1 and in the control group from 6.5 ± 0.1 to 5.3 ± 0.1 (p < 0.001 for lamotrigine doses of 200, 300, and 400 mg). The results of the MPQ, PDI, and BDI remained unchanged in both groups. The global assessment of efficacy favored lamotrigine treatment over placebo, and the adverse events profile was similar in both groups. Conclusions: Lamotrigine is effective and safe in relieving the pain associated with diabetic neuropathy.
Activation of human cancer/testis antigen gene, XAGE‐1, in tumor cells is correlated with CpG island hypomethylation

Expression of the XAGE‐1 antigen is restricted to germ cells of the testis and a variety of neoplastic tissues. To date, the molecular mechanism for regulating expression of this cancer/testis antigen gene has been unknown. To evaluate methylation as a potential mechanism for regulating expression of this gene, we first correlated gene methylation status (measured by sequencing of bisulfide‐modified DNA and COBRA) to expression of XAGE‐1 mRNA in normal and cancerous cells. This analysis revealed dense methylation of the CpG island in the XAGE‐1 gene promoter for the normal and cancerous cells that do not express this gene but loss of this methylation in normal testis, cancer cell lines and the primary gastric cancers where the gene is highly expressed. Further supporting the role of methylation in regulating expression of XAGE‐1 were observations that treatment of 2 heavily methylated cell lines, SNU620 and HT29, with 5′‐aza‐deoxycytidine resulted in demethylation of XAGE‐1 promoter and corresponding expression of this gene. Finally, we cloned various segments of the CpG‐rich XAGE‐1 gene promoter linked to a luciferase reporter construct and transiently transfected this construct into HCT116 cells. These experiments confirmed transcriptional regulatory activity for the promoter region that incorporates the CpG island and demonstrated that in vitro methylation of this island results in loss of promoter activity. Collectively, these studies indicate that XAGE‐1 expression in normal and cancerous tissues is regulated by methylation of the CpG island in the gene promoter. © 2005 Wiley‐Liss, Inc.
Rural-Urban Differences in Reasons for Living

Objective: The suicide rate in Australia is cause for concern, especially the increase in attempted and completed suicides in rural and regional locations. The present study examined reasons for choosing not to commit suicide as a function of residential location. Method: The study involved 655 Victorian residents from four population-based strata; urban, regional city, regional town, and rural. Results: Results from the Reasons for Living Inventory revealed significant differences as a function of residential location. Overall, residents in rural locations reported having significantly more to live for than their urban counterparts. Further analysis of six reasons for living (child, family, moral, social, coping and death-related concerns) showed a pattern whereby residents in rural locations reported having the most to live for, followed by regional residents, and urban residents who reported having the least to live for. Conclusions: These findings are in contrast to increase of suicide rates in rural areas, and highlight the need for a greater understanding of the mechanisms underlying suicidal behaviour.
Decreased platelet function in aortic valve stenosis: high shear platelet activation then inactivation.

OBJECTIVE--To elucidate the mechanism of the bleeding tendency observed in patients with aortic valve stenosis. DESIGN--A prospective study of high and low shear platelet function tests in vitro in normal controls compared with that in patients with severe aortic valve stenosis with a mean (SD) systolic gradient by Doppler of 75 (18) mm Hg before and at least 4 months after aortic valve replacement. SETTING--District general hospital. RESULTS--The patients showed reduced retention in the high shear platelet function tests. (a) Platelet retention in the filter test was 53.6 (12.6)% in patients with aortic valve stenosis and 84.8 (9.6)% in the controls (P < 0.001). (b) Retention in the glass bead column test was 49.8 (19.2) in the patients and 87.4 (8.7) in the controls (P < 0.001). (c) The standard bleeding time was longer in the patients (P < 0.06). Results of the high shear tests (a, b, and c) after aortic valve replacement were within the normal range. The platelet count was low but within the normal range before surgery and increased postoperatively (P < 0.01). There were no differences in the results of standard clotting tests, plasma and intraplatelet von Willebrand's factor, or in 15 platelet aggregation tests using five agonists between patients with aortic valve stenosis and controls. CONCLUSIONS--The high shear haemodynamics of aortic valve stenosis modify platelet function in vivo predisposing to a bleeding tendency. This abnormality of platelet function is detectable only in vitro using high shear tests. The abnormal function is reversed by aortic valve replacement. High shear forces in vitro activate and then inactivate platelets. By the same mechanisms aortic valve stenosis seems to lead to high shear damage in vivo, resulting in a clinically important bleeding tendency in some patients.
Local and Global Structural Properties of the HIV-MN V3 Loop (*)

Studies of the feasibility of a subunit vaccine to protect against human immunodeficiency virus (HIV) infection have principally focused on the third variable (V3) loop. The principal neutralizing determinant (PND) of HIV-1 is located inside the V3 loop of the surface envelope glycoprotein, gp120. However, progress toward a PND-based vaccine has been impeded by the amino acid sequence variability in the V3 loops of different HIV isolates. Theoretical studies revealed that the variability in sequence and structure of the V3 loop is confined to the N- and C-terminal sides of the conserved GPG crest. This leaves three regions of the V3 loop conserved both in sequence and secondary structure. We present the results of NMR studies that test the validity of our theoretical predictions. Structural studies are reported for the HIV-V3 loop (HIV-MN) in the linear and cyclic (S-S-bridged) forms. For the V3 loop sequence of the HIV-MN isolate, the three conserved secondary structural elements are as underlined below: Finally, the conformational requirement of the PND in the V3 loop-antibody interaction is tested by monitoring the monoclonal antibody binding to the HIV-MN V3 loop in the linear and cyclic forms by enzyme-linked immunosorbent assay. The binding data reveal that the cyclic V3 loop is a better ligand for the monoclonal antibodies than the linear form although the latter has the same sequence. This means that the monoclonal antibodies recognize the PNDs as conformational epitopes.
Trajectory Tracking With Prescribed Performance for Underactuated Underwater Vehicles Under Model Uncertainties and External Disturbances

This paper addresses the tracking control problem of 3-D trajectories for underactuated underwater robotic vehicles. Our recent theoretical results on the prescribed performance control of fully actuated nonlinear systems are innovatively extended on the control of the most common types of underactuated underwater vehicles, namely, the torpedo-like (i.e., vehicles actuated only in surge, pitch, and yaw) and the unicycle-like (i.e., vehicles actuated only in surge, heave, and yaw). The main contributions of this paper concentrate on: 1) the reduced design complexity; 2) the increased robustness against system uncertainties; 3) the prescribed transient and steady-state performance; and 4) the minimal tracking information requirements. A comparative simulation study points out the intriguing performance properties of the proposed method, while its applicability is experimentally verified using a small unicycle-like underactuated underwater vehicle in a test tank.