Miracle-dz/UniFAR-FTUs huggingface dataset:
Mitochondrial D-loop Polymorphisms and Mitochondrial DNA Content in Childhood Acute Lymphoblastic Leukemia

The mitochondrial displacement loop (D-loop) controls mitochondrial expression, with mutations and mitochondrial DNA (mtDNA) content linked to oncogenesis. We investigated D-loop polymorphisms and mtDNA content in childhood acute lymphoblastic leukemia (ALL). The D-loop was sequenced in 251 children: precursor B ALL (n=114), with 76 paired remission/relapse samples; T-ALL (n=24); cord blood controls (n=113). The mtDNA copy number was analyzed using real-time quantitative polymerase chain reaction for 92 controls and 54 ALL patients at diagnosis and remission. Polymorphisms around H-strand replication origin (nucleotides 150 to 199) and conserved sequence block II (nucleotides 299 to 317) were associated with leukemia biology and treatment response. T-ALL patients were more likely to have longer nt303 poly-C tract. T199C polymorphism was associated with increased risk of ALL in Malays; T152C was more frequent in good responders. There was no difference in mtDNA content between diagnostic ALL samples and controls; however, there was significant decrease in mtDNA content after treatment, especially in samples with OH polymorphisms. Somatic mutations were found in 13% (9 of 76) of patients, suggesting a link to leukemogenesis. Our results suggest that polymorphisms impacting transcriptional control could affect mtDNA replication. Decrease in mtDNA content after treatment may confer susceptibility to chemotherapy and be a clue to the good prognosis of childhood ALL.
Combination Drug Scheduling Defines a “Window of Opportunity” for Chemopotentiation of Gemcitabine by an Orally Bioavailable, Selective ChK1 Inhibitor, GNE-900

Checkpoint kinase 1 (ChK1) is a serine/threonine kinase that functions as a central mediator of the intra-S and G2–M cell-cycle checkpoints. Following DNA damage or replication stress, ChK1-mediated phosphorylation of downstream effectors delays cell-cycle progression so that the damaged genome can be repaired. As a therapeutic strategy, inhibition of ChK1 should potentiate the antitumor effect of chemotherapeutic agents by inactivating the postreplication checkpoint, causing premature entry into mitosis with damaged DNA resulting in mitotic catastrophe. Here, we describe the characterization of GNE-900, an ATP-competitive, selective, and orally bioavailable ChK1 inhibitor. In combination with chemotherapeutic agents, GNE-900 sustains ATR/ATM signaling, enhances DNA damage, and induces apoptotic cell death. The kinetics of checkpoint abrogation seems to be more rapid in p53-mutant cells, resulting in premature mitotic entry and/or accelerated cell death. Importantly, we show that GNE-900 has little single-agent activity in the absence of chemotherapy and does not grossly potentiate the cytotoxicity of gemcitabine in normal bone marrow cells. In vivo scheduling studies show that optimal administration of the ChK1 inhibitor requires a defined lag between gemcitabine and GNE-900 administration. On the refined combination treatment schedule, gemcitabine's antitumor activity against chemotolerant xenografts is significantly enhanced and dose-dependent exacerbation of DNA damage correlates with extent of tumor growth inhibition. In summary, we show that in vivo potentiation of gemcitabine activity is mechanism based, with optimal efficacy observed when S-phase arrest and release is followed by checkpoint abrogation with a ChK1 inhibitor. Mol Cancer Ther; 12(10); 1968–80. ©2013 AACR.
Bootstrapping trust in software defined networks

Software-Defined Networking (SDN) is a novel architectural model for cloud network infrastructure, improving resource utilization, scalability and administration. SDN deployments increasingly rely on virtual switches executing on commodity operating systems with large code bases, which are prime targets for adversaries attacking the network infrastructure. We describe and implement TruSDN, a framework for bootstrapping trust in SDN infrastructure using Intel Software Guard Extensions (SGX), allowing to securely deploy SDN components and protect communication between network endpoints. We introduce ephemeral flow-specific preshared keys and propose a novel defense against cuckoo attacks on SGX enclaves. TruSDN is secure under a powerful adversary model, with a minor performance overhead. (Less)
Risk factors for Buruli ulcer disease (Mycobacterium ulcerans Infection): results from a case-control study in Ghana.

BACKGROUND Morbidity due to Buruli ulcer disease (BUD), a cutaneous infection caused by Mycobacterium ulcerans, has been increasingly recognized in rural West Africa. The source and mode of transmission remain unknown. METHODS To identify BUD risk factors, we conducted a case-control study in 3 BUD-endemic districts in Ghana. We enrolled case patients with clinically diagnosed BUD and obtained skin biopsy specimens. M. ulcerans infection was confirmed by at least 1 of the following diagnostic methods: histopathologic analysis, culture, polymerase chain reaction, and Ziehl-Neelsen staining of a lesion smear. We compared characteristics of case patients with confirmed BUD with those of age- and community-matched control subjects using conditional logistic regression analysis. RESULTS Among 121 case patients with confirmed BUD, leg lesions (49%) or arm lesions (36%) were common. Male case patients were significantly more likely than female case patients to have lesions on the trunk (25% vs. 6%; P = .009). Multivariable modeling among 116 matched case-control pairs identified wading in a river as a risk factor for BUD (odds ratio [OR], 2.69; 95% confidence interval [CI], 1.27-5.68; P = .0096). Wearing a shirt while farming (OR, 0.27; 95% CI, 0.11-0.70; P = .0071), sharing indoor living space with livestock (OR, 0.36; 95% CI, 0.15-0.86; P = .022), and bathing with toilet soap (OR, 0.41; 95% CI, 0.19-0.90; P = .026) appeared to be protective. BUD was not significantly associated with penetrating injuries (P = .14), insect bites near water bodies (P = .84), bacille Calmette-Guerin vaccination (P = .33), or human immunodeficiency virus infection (P = .99). CONCLUSIONS BUD is an environmentally acquired infection strongly associated with exposure to river areas. Exposed skin may facilitate transmission. Until transmission is better defined, control strategies in BUD-endemic areas could include covering exposed skin.
prosodie du "français fédéral". Étude de la vitesse d'articulation et de l'accentuation en français L1 et L2.

The aim of this study is to examine some prosodic features of a variety of L2 French commonly called "français fédéral", which is a variety of French spoken by people who have a Swiss German dialect as L1. We compared the data of 4 groups of 4 speakers: 2 groups of French native speakers (from Neuchâtel in Switzerland and from Paris) and 2 groups of 4 Swiss German French speakers (from Bern and Zurich but living in Neuchâtel for at least 20 years). The data were semi-automatically processed. We examined two prosodic properties: articulation rate and accentuation. Our findings suggest that: (i) native speakers from Paris articulate faster than native speakers from Neuchâtel; (ii) non-native speakers articulate as fast as the native speakers of the corresponding variety; (iii) "français fédéral" shares several features with a lexical accentuation system rather than with a supra-lexical accentuation system.
Needle-track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis.

We congratulate Silva et al ( Gut 2008; 57 :1592–6) for addressing an important issue in the management of patients with suspected hepatocellular carcinoma (HCC). We agree with the authors that biopsy of liver lesions should not be performed indiscriminately and that they should be undertaken preferably within or at least only after consultation with a liver transplant centre. Some HCCs can be managed successfully with resection. However, our own series of 85 patients showed that biopsy of such lesions, almost exclusively being carried out before referral almost halved the patients’ chance of disease free survival at 5 years post-resection (52% vs 24%). 1 We agree that a …
Perception de l'horizon visuel en milieu d'hyperpesanteur : Rôle des systèmes oculomoteur, otolithique et somesthésique

Les deplacements a bord de vehicules de locomotion induisent souvent des stimulations sensorielles a l'origine d'illusions perceptives. Ces perceptions erronees de la position du corps ont ete decrites dans la litterature sous le terme de desorientation spatiale, dont l'origine est principalement consideree comme otolithique. En effet, lors d'une acceleration lineaire constante vers l'avant, le vecteur resultant de l'acceleration imposee et de la gravite n'est plus aligne par rapport a la verticale gravitaire. Comme tout autre accelerometre physique, le systeme otolithique ne peut differencier la gravite de toute autre acceleration lineaire et va ainsi integrer ce vecteur resultant, appele acceleration gravito-inertielle (AGI), comme la nouvelle verticale. Parmi les incidences comportementales les plus connues figurent les illusions d'elevation et oculogravique. Ces illusions se traduisent par une perception visuelle erronee de la position des objets en milieu d'hyperpesanteur. Ce travail doctoral s'interesse i) aux sources d'informations sensorielles determinantes dans les illusions perceptives en milieu d'hyperpesanteur, ii) aux differences inter-individuelles dans l'estimation de l'horizon visuel, et iii) au role des references egocentree et exocentree impliquees dans les illusions d'elevation et oculogravique. Nos resultats experimentaux mettent en evidence : (1) le role fondamental de l'intensite gravito-inertielle dans la perception de l'horizon visuel, (2) l'effet couple de l'orientation corporelle et de la perception visuelle egocentree dans l'estimation de l'horizon visuel, (3) l'explication en termes otolithiques des differences inter-individuelles consequentes a la modulation de l'intensite gravito-inertielle, (4) l'apport des informations somesthesiques, notamment pour l'illusion oculogravique. L'ensemble des travaux rapportes dans cette these suggere une approche sensorielle en termes otolithique et somesthesique, ainsi qu'une approche individuelle de la perception de l'horizon visuel gravitaire.
Localised retinal nerve fibre layer defects in chronic experimental high pressure glaucoma in rhesus monkeys

AIM To evaluate prospectively in an experimental model of chronic high pressure glaucoma whether the concept of a mainly diffuse pattern of optic nerve damage holds true for high pressure glaucoma. METHODS The study comprised nine eyes of nine rhesus monkeys (Macaca mulatta) with a mean age of 17.7 (SD 3.1) years (range 13–23 years). Experimental glaucoma was produced by multiple applications of argon laser to the trabecular meshwork. Applanation tonometry was regularly performed and fundus photographs, which were taken serially, were used for retinal nerve fibre layer (RNFL) assessment and morphometric optic disc analysis. Six monkeys, in which arterial hypertension and atherosclerosis had additionally been induced several years before elevation of intraocular pressure, did not show any sign of diffuse loss or localised defects of the RNFL before initiation of glaucoma. RESULTS Compared with the same eyes at baseline, localised RNFL defects had developed in eight (89%) eyes. It included all three eyes (100%) of the monkeys without arterial hypertension/arteriosclerosis, and five of the six monkeys (83%) with arterial hypertension/arteriosclerosis. Four eyes had multiple localised RNFL defects. In all eyes, diffuse RNFL loss was additionally present. CONCLUSIONS Besides diffuse loss of RNFL, localised RNFL defects were present in almost all eyes of monkeys with chronic experimental high pressure glaucoma. Challenging the concept that a mostly diffuse type of optic neuropathy occurs in high pressure glaucoma, the results suggest that, in high pressure glaucoma, at least a mixture of localised and diffuse pattern of optic nerve damage prevails.
The Role of Airway Secretions in COPD—Clinical Applications

It has been established that mucus hypersecretion and decreased mucus clearance contribute to the morbidity of chronic obstructive pulmonary disease (COPD). Indeed, the classic definition of chronic bronchitis relies on determining the frequency and duration of sputum expectoration. Despite the well recognized importance of this symptom, there are few therapies routinely used to decrease the sputum production or to improve clearance. There are fewer well conducted clinical trials of existing medications and this has led many regulatory agencies, notably the Food and Drug Administration (FDA), to refuse to register these medications or approve their sale. Similarly, airway clearance devices and chest physical therapy have not been well studied in COPD. Carefully conducted studies of interventions to improve airway clearance, similar to those done in cystic fibrosis (CF), may help us to identify effective therapies and possibly novel diagnostic tests for the management of COPD.
Validation of a Diagnostic Score for the Diagnosis of Autoinflammatory Diseases in Adults

Most autoinflammatory disorders typically come out in the pediatric population, although a limited number of patients may experience disease onset during adulthood. To date, a late disease onset has been described only in familial Mediterranean fever, caused by mutations in the MEFV gene, and in tumor necrosis factor receptor-associated periodic syndrome, caused by mutations in the TNFRSF1A gene. The relative rarity and lack of information on adult-onset autoinflammatory diseases make it likely that mutations will be found in an even smaller percentage of cases. With the aim of improving the genetic diagnosis in adults with suspected autoinflammatory disorders, we recently identified a set of variables related to the probability of detecting gene mutations in MEFV and TNFRSF1A and, in addition, we have also proposed a diagnostic score for identifying those patients at high risk of carrying mutations in these genes. In the present study we evaluated the preliminary score sensitivity and specificity on a wider number of patients in order to validate the goodness of fit of the model. Two hundred and nineteen consecutive patients with a clinical history of periodic fever attacks were screened for mutations in MEFV and TNFRSF1A genes; detailed information about family/personal history and clinical manifestations were also collected. For the validation of the score we considered data both from the 110 patients used to build the preliminary diagnostic score and from the additional 219 patients enrolled in the present study, for a total number of 329 patients. Early age at disease onset, positive family history for recurrent fever episodes, thoracic pain, abdominal pain and skin rash, which are the variables that had previously been shown to be significantly associated with a positive genetic test result (12), were used for validation. On univariate analysis the associations with a positive genetic test were: age at onset (odds ratio [OR] 0.43, p=0.003), positive family history for recurrent fever episodes (OR 5.81, p<0.001), thoracic pain (OR 3.17, p<0.001), abdominal pain (OR 3.80, p<0.001) and skin rash (OR 1.58, p=0.103). The diagnostic score was calculated using the linear combination of the estimated coefficients of the logistic multivariate model (cut-off equals to 0.24) revealing good sensitivity (0.778) and good specificity (0.718). In conclusion, our score may serve in the diagnostic evaluation of adult patients presenting with recurrent fever episodes suspected of having an autoinflammatory disorder, helping identify the few subjects among them who may be carriers of mutations in MEFV and TNFRSF1A genes.
A two-step mechanism for the interaction of estradiol with rat uterus.

During the past ten years much information has been accumulated concerning the interaction of tritilated estrogens with hormone-dependent tissues. Their striking affinity for estradiol, both in vivo'-5 and in vitro,6-9 first suggested that such target tissues as uterus, vagina, and anterior pituitary possess unique components called "estrogen receptors. " Strong but reversible association of hormone with receptor, without chemical transformation of the steroid molecule, appears to be a primary step in the uterotrophic process, not affected by such inhibitors of early estrogen response as puromycin or actinomycin D.1 The interaction of estradiol with target tissues involves two distinct phenomena uptake and retention; the latter process, but not the former, becomes saturated in vivo if the hormone administered exceeds the physiological level. 1 Centrifugal fractionation experiments"0-14 demonstrate two sites of estrogen binding in uterine cells. As confirmed by autoradiography,1' 16 most estradiol, both in endometrium and in myometrium, resides in the nuclei, but a certain amount is bound to a macromolecular substance appearing in the supernatant fraction. Toft and Gorski'7 made the important observation that the radioactive estradiol-receptor complex in the supernatant fraction can be characterized by ultracentrifugation in sucrose density gradients where it migrates with a sedimentation coefficient of 9.5S; disruption of the complex by proteases but not by nucleases suggests that the receptor substance is a protein. We have confirmed these findings and have observed further8-20 that a different estradiol-receptor complex, sedimenting at about 5S, cani be extracted from uterine nuclei by cold 0.3 Ml KC1, which solubilizes little uterine DNA.2' Although the 9.5S complex does not appear to be a simple aggregate of the 5S, the two receptor substances show many similar characteristics, discussed in more detail elsewhere.22 An important difference is the ability of the 9.5S complex to form spontaneously on addition of tritiated estradiol to supernatant fraction;'9 20, 23 the 5S complex is not produced by adding estradiol to nuclear extract,24 although it can be formed in the whole homogenate. This paper presents evidence that the 9.5S receptor is extranuclear and involved in estrogen uptake, whereas the nuclear 5S complex, probably responsible for hormone retention and growth initiation, is formed from the 9.5S complex by a process which consumes 9.5S receptor and which is retarded at low temperature. Materials and Methods. -These investigations used estradiol-6, 7-H3 (spec. act. 57.4 c/mmole), KRH buffer (pH 7.3, Krebs-Ringer-Henseleit-glucose, containing in gm/liter: NaCl, 8.0; KCI, 0.20; Na2HPO4 7H20, 1.73; KH2PO4, 0.20; CaC12, 0.10; MgC12, 0.048; and glucose, 1.0), and Tris-EDTA buffer (pH 7.4, 0.01 Al 2-amino-2-hydroxymethyl-1,3-propanediol plus 0.0015 M4 ethylenediaminetetraacetic acid, disodium salt).
Reducing the Stress of Coordination: Sharing Travel Time Information Between Contacts on Mobile Phones

We explore the everyday use of a new abstraction for mo-bile location-sharing. By sharing the travel time between contacts calculated for walking, transit, and driving, we have enabled users to more easily coordinate meeting up and planning family obligations. Specifically, our participants reported that the information helped to lower the stress of these activities and provided reassurance of the arrival times of their close friends and family. In this paper, we describe our system, motivate its design, and explore results from a 20-user, 21-day field trial showing the use-fulness of the abstraction as well as attitudes towards privacy when sharing travel times with close friends or family.
Expression, Purification, and Spectroscopic Characterization of Human Thromboxane Synthase*

Thromboxane A2(TXA2) is a potent inducer of vasoconstriction and platelet aggregation. Large scale expression of TXA2 synthase (TXAS) is very useful for studies of the reaction mechanism, structural/functional relationships, and drug interactions. We report here a heterologous system for overexpression of human TXAS. The TXAS cDNA was modified by replacing the sequence encoding the first 28 amino acid residues with a CYP17 amino-terminal sequence and by adding a polyhistidine tag sequence prior to the stop codon; the cDNA was inserted into the pCW vector and co-expressed with chaperonins groES and groEL in Escherichia coli. The resulting recombinant protein was purified to electrophoretic homogeneity by affinity, ion exchange, and hydrophobic chromatography. UV-visible absorbance (UV-Vis), magnetic circular dichroism (MCD), and electron paramagnetic resonance (EPR) spectra indicate that TXAS has a typical low spin cytochrome P450 heme with an oxygen-based distal ligand. The UV-Vis and EPR spectra of recombinant TXAS were essentially identical to those of TXAS isolated from human platelets, except that a more homogenous EPR spectrum was observed for the recombinant TXAS. The recombinant protein had a heme:protein molar ratio of 0.7:1 and a specific activity of 12 μmol of TXA2/min/mg of protein at 23 °C. Furthermore, it catalyzed formation of TXA2, 12-hydroxy-5,8,10-heptadecatrienoic acid, and malondialdehyde in a molar ratio of 0.94:1.0:0.93. Spectral binding titrations showed that bulky heme ligands such as clotrimazole bound strongly to TXAS (K d ∼0.5 μm), indicating ample space at the distal face of the heme iron. Analysis of MCD and EPR spectra showed that TXAS was a typical low spin hemoprotein with a proximal thiolate ligand and had a very hydrophobic distal ligand binding domain.
Integration of International Service Learning in Developing Countries within Occupational Therapy Education: Process and Implications

ABSTRACT International service learning (ISL) is included in an increasing number of courses at post-secondary levels of education, including programs which educate future occupational therapy practitioners. There is a limited amount of literature and research concerning best practices for course-based occupational therapy education featuring ISL experiences, in particular within developing countries. The purpose of this paper is to (a) to review key literature on ISL, (b) explicate key elements which can help design course-based ISL experiences; and (c) suggest areas for further research and development of course-based ISL. The seven elements of focus that provide a base to guide occupational therapy educators who create ISL courses with an immersion component in a country with a developing economy are discussed, as well as future challenges and possibilities when providing occupational therapy services to a global society.