Miracle-dz/UniFAR-FTUs huggingface dataset:
DNMT3B overexpression contributes to aberrant DNA methylation and MYC-driven tumor maintenance in T-ALL and Burkitt’s lymphoma

Aberrant DNA methylation is a hallmark of cancer. However, our understanding of how tumor cell-specific DNA methylation patterns are established and maintained is limited. Here, we report that in T-cell acute lymphoblastic leukemia (T-ALL) and Burkitt’s lymphoma the MYC oncogene causes overexpression of DNA methyltransferase (DNMT) 1 and 3B, which contributes to tumor maintenance. By utilizing a tetracycline-regulated MYC transgene in a mouse T-ALL (EμSRα-tTA;tet-o-MYC) and human Burkitt’s lymphoma (P493-6) model, we demonstrated that DNMT1 and DNMT3B expression depend on high MYC levels, and that their transcription decreased upon MYC-inactivation. Chromatin immunoprecipitation indicated that MYC binds to the DNMT1 and DNMT3B promoters, implicating a direct transcriptional regulation. Hence, shRNA-mediated knock-down of endogenous MYC in human T-ALL and Burkitt’s lymphoma cell lines downregulated DNMT3B expression. Knock-down and pharmacologic inhibition of DNMT3B in T-ALL reduced cell proliferation associated with genome-wide changes in DNA methylation, indicating a tumor promoter function during tumor maintenance. We provide novel evidence that MYC directly deregulates the expression of both de novo and maintenance DNMTs, showing that MYC controls DNA methylation in a genome-wide fashion. Our finding that a coordinated interplay between the components of the DNA methylating machinery contributes to MYC-driven tumor maintenance highlights the potential of specific DNMTs for targeted therapies.
A Thy1-CFP DBA/2J mouse line with cyan fluorescent protein expression in retinal ganglion cells

Abstract A DBA/2J (D2) transgenic mouse line with cyan fluorescent protein (CFP) reporter expression in ganglion cells was developed for the analysis of ganglion cells during progressive glaucoma. The Thy1-CFP D2 (CFP-D2) line was created by congenically breeding the D2 line, which develops pigmentary glaucoma, and the Thy1-CFP line, which expresses CFP in ganglion cells. Microsatellite marker analysis of CFP-D2 progeny verified the genetic inclusion of the D2 isa and ipd loci. Specific mutations within these loci lead to dysfunctional melanosomal proteins and glaucomatous phenotype in D2 mice. Polymerase chain reaction analysis confirmed the inclusion of the Thy1-CFP transgene. CFP-fluorescent ganglion cells, 6–20 μm in diameter, were distributed in all retinal regions, CFP processes were throughout the inner plexiform layer, and CFP-fluorescent axons were in the fiber layer and optic nerve head. Immunohistochemistry with antibodies to ganglion cell markers NF-L, NeuN, Brn3a, and SMI32 was used to confirm CFP expression in ganglion cells. Immunohistochemistry with antibodies to amacrine cell markers HPC-1 and ChAT was used to confirm weak CFP expression in cholinergic amacrine cells. CFP-D2 mice developed a glaucomatous phenotype, including iris disease, ganglion cell loss, attrition of the fiber layer, and elevated intraocular pressure. A CFP-D2 transgenic line with CFP-expressing ganglion cells was developed, which has (1) a predominantly D2 genetic background, (2) CFP-expressing ganglion cells, and (3) age-related progressive glaucoma. This line will be of value for experimental studies investigating ganglion cells and their axons in vivo and in vitro during the progressive development of glaucoma.
Differential Modulation of Xenobiotic-Metabolizing Enzymes in Rats Following Single and Concurrent Exposure to Chlorpyrifos, Arsenic, and Ascorbic Acid

The present study was undertaken to evaluate the subacute toxicity of arsenic (As) and chlorpyrifos (CPF) alone or in combination. In addition, the ameliorative effect of ascorbic acid on As and/or CPF-induced hepatic microsomal xenobiotic metabolizing enzymes in rats was examined. Rats were divided into 9 groups of 6 animals each: control (deionized water), vehicle control (groundnut oil), ascorbic acid (100 mg/kg body weight), As (40 ppm in water), CPF (5 mg/kg body weight), As (40 ppm) + CPF (5 mg/kg body weight), As + ascorbic acid, CPF + ascorbic acid, and As + CPF + ascorbic acid. After 28 d of exposure, rats were sacrificed and liver was extracted for isolation of hepatic microsomes. Exposure to As or CPF alone as well as both of these in combination significantly altered microsomal proteins and activity of phase I and phase II xenobiotic-metabolizing enzymes. Cytochrome P-450 and cytochrome b 5 levels and activities of aniline p-hydroxylase (APH) and uridine diphosphate glucuronosyltransferase (UGT) were significantly decreased in groups treated with As, CPF, and As plus CPF, while glutathione S-transferase (GST) was not markedly altered. Enzymatic activity of aminopyrine N-demethylase (ANDM) was also significantly reduced in As- and CPF-only groups. Co-administration of ascorbic acid effectively countered the As- and CPF-induced alterations in xenobiotic-metabolizing enzymes.
cAMP signalling of Bordetella adenylate cyclase toxin through the SHP‐1 phosphatase activates the BimEL‐Bax pro‐apoptotic cascade in phagocytes

The adenylate cyclase toxin‐hemolysin (CyaA, ACT or AC‐Hly) plays a key role in virulence of Bordetella pertussis. CyaA penetrates myeloid cells expressing the complement receptor 3 (αMβ2 integrin CD11b/CD18) and subverts bactericidal capacities of neutrophils and macrophages by catalysing unregulated conversion of cytosolic ATP to the key signalling molecule adenosine 3',5'‐cyclic monophosphate (cAMP). We show that the signalling of CyaA‐produced cAMP hijacks, by an as yet unknown mechanism, the activity of the tyrosine phosphatase SHP‐1 and activates the pro‐apoptotic BimEL‐Bax cascade. Mitochondrial hyperpolarization occurred in human THP‐1 macrophages within 10 min of exposure to low CyaA concentrations (e.g. 20 ng ml−1) and was accompanied by accumulation of BimEL and association of the pro‐apoptotic factor Bax with mitochondria. BimEL accumulation required cAMP/protein kinase A signalling, depended on SHP‐1 activity and was selectively inhibited upon small interfering RNA knockdown of SHP‐1 but not of the SHP‐2 phosphatase. Moreover, signalling of CyaA‐produced cAMP inhibited the AKT/protein kinase B pro‐survival cascade, enhancing activity of the FoxO3a transcription factor and inducing Bim transcription. Synergy of FoxO3a activation with SHP‐1 hijacking thus enables the toxin to rapidly trigger a persistent accumulation of BimEL, thereby activating the pro‐apoptotic programme of macrophages and subverting the innate immunity of the host.
Assessing equivalence or non‐inferiority in screening tests with paired and independent binomial endpoints through confidence intervals for the odds ratio

The confidence interval (CI) on the population average (PA) odds ratio (OR) is a useful measure of agreement among different diagnostic methods when no gold standard is available. It can be calculated by the repeated measures logistic regression procedure (GENMOD, SAS). We compare the width of CIs from paired and independent samples with an identical number of measurements and an identical probability of positive response among them. For two and three diagnostic methods with binomial endpoints, the best performing sampling strategy is analytically described. The asymptotic formulae of the ratio of the CI widths for paired and independent samples are provided. We numerically study the dependence of the width of the CIs on the number of positive concordant outcomes. The width of CIs from independent samples is an increasing function of the sample size with a saturation asymptote and rather weak dependence on the argument. The width of CIs from paired samples is a decreasing function of the sample size with a saturation asymptote and significant dependence on the argument when the sample size is small. If curves for paired and independent samples intersect, a critical sample size exists. At this point, a small change in the sample size can reverse the choice of the best performing sampling policy. We numerically validated the robustness of the critical point to variations of the conditional OR. Published in 2005 by John Wiley & Sons, Ltd.
Factors Associated with Six-Month Outcome of Pediatric Stroke

Background Pediatric stroke outcome studies are often cross sectional in design. Prospective information regarding the clinical course following diagnosis is lacking, but may inform clinical management beyond the acute period. Aims To describe the outcome of arterial ischemic stroke in infants, children and adolescents at one-month and six-months post-stroke across health domains, and explore the relationship between lesion characteristics and early outcome with six-month adaptive behavior. Methods A single center prospective longitudinal study at a tertiary level children's hospital. Recruitment was undertaken from December 2007 to January 2012. Participants were children aged birth to 18 years presenting acutely with first diagnosed arterial ischemic stroke. Lesion characteristics on brain imaging were classified. Children were grouped according to age at diagnosis for analysis (neonates vs. those aged >30 days). Results In 50 children with a median age of 47 months at diagnosis, sensorimotor impairments were most evident upon neurological examination acutely, especially in the older children. At both one-month and six-months motor functioning was significantly impaired in the older age group but no significant cognitive or language sequelae were identified. Lesion characteristics alone were not associated with six-month adaptive behavior outcomes. Conclusions For patients surviving arterial ischemic stroke, the most significant clinical consequences both acutely and at six-months, are sensorimotor impairments, particularly evident in the older children. In contrast cognitive or language sequelae were not identified. Long-term surveillance is required to describe clinical course and rehabilitation needs, particularly for neonates and infants.
Evaluation of white blood cell concentration, plasma fibrinogen concentration, and an agar gel immunodiffusion test for early identification of foals with Rhodococcus equi pneumonia.

OBJECTIVE To evaluate WBC concentration, plasma fibrinogen concentration, and an agar gel immunodiffusion (AGID) test for early identification of Rhodococcus equi-infected foals. DESIGN Prospective study. ANIMALS 162 foals from a farm with enzootic R equi infection. PROCEDURE Blood samples were obtained from each foal at 4-week intervals for measurement of WBC and plasma fibrinogen concentrations and at 2-week intervals for detection of anti-R equi antibody by an AGID assay. Diagnostic performance of WBC and fibrinogen concentrations was assessed by use of receiver operating characteristic curve analysis. For each assay, sensitivity, specificity, and predictive values were calculated at various cutoff points; bacteriologic culture of R equi from a tracheobronchial aspirate was used as the reference standard test. RESULTS Diagnostic performance of WBC concentration was significantly higher than that of fibrinogen concentration. Sensitivity and specificity of measurement of WBC concentration at a cutoff of 13,000 cells/microL were 95.2 and 61.2%, respectively; at a cutoff of 15,000 cells/microL, sensitivity was 78.6% and specificity was 90.8%. When a positive test result was used as the cutoff, sensitivity of the AGID assay was 62.5% and specificity was 53.8%. CONCLUSION AND CLINICAL RELEVANCE Monitoring WBC concentration is a useful approach for early detection of infected foals on farms with a high prevalence of R equi pneumonia. In contrast, serologic surveillance by use of an AGID assay is of little benefit for that purpose.
Ultrafast pulse-amplitude modulation with a femtojoule silicon photonic modulator

Ultrahigh-speed optical interconnects are essential to future cloud computing. Further increase in optical transmission speed has been hindered by power consumption and limited bandwidth resources, for which integrated optical transceivers using advanced modulation formats, such as pulse-amplitude modulation (PAM), are a promising solution. We report 80 Gb/s PAM operation of a silicon microring modulator (MRM) with an ultralow power consumption below 7 fJ/bit. We also report the first demonstration of PAM-8 modulation of MRMs in the Gb/s order, achieving error-free capability at 45 Gb/s, using 1 fJ/bit. To the best of our knowledge, these results feature the lowest power consumption, per transmitted bit, ever demonstrated at such high data rates. We further demonstrate PAM data transmission up to 64 Gb/s over 5 km. Simultaneous achievement of ultrafast modulation and ultralow power consumption is a critical step toward next-generation optical interconnects.
Long-term quantitative evaluation of liver transplantation in familial amyloid polyneuropathy (Portuguese V30M)

Familial amyloid polyneuropathy (FAP) is associated with massive endoneurial and extracellular deposition of amyloid, which is formed from a mutated transthyretin (TTR) protein. Ninety percent of TTR protein is produced in liver. Liver transplantation (LT) is the only treatment that can halt FAP clinical progression. We studied 35 LT patients. The mean age of the first symptoms was 36.6 years (ranging from 27 to 56), 19 were males, and 16 females, they underwent LT after a mean time of 5 years of symptomatic disease. Fifteen patients followed for more than 24 months after LT had periodic evaluations with clinical and neurophysiological scores (CS and NS). Ten were first evaluated before LT (mean follow-up time of 44 months after LT), and 5 were evaluated only after LT (for a mean time of 41 months). Five patients were followed periodically before LT (mean time of 44 months) to study the natural course of this condition. The mortality rate was of 14% in the first 6 months and was related to known complications of the surgery. No deaths occurred in the period 6 months to 1 year after LT. Five patients (14%) died 1-2 years after LT, 4 of whom were transplanted in advance stages. in the survival group, CS tended to stabilize shortly after LT and to remain invariable later on. The NS progressed in the first year following LT, and subsequently it did not increase significantly. LT changed the natural course of FAP-I.
Temporal and intrapopulation variation in prey choice of wintering geese determined by stable isotope analysis.

1. Individual variability in prey preferences can have marked effects on many demographic parameters from individual survival and fecundity to the vital rates of entire populations. A population level response is ultimately determined by individual prey choices; however, the effect of individual dietary choice is often overlooked. 2. We determined prey choice by individual consumers, light-bellied Brent geese Branta bernicla, during the overwintering period. Two hundred and eighty-one individuals were sampled at distinct temporal points over two winters. Stable isotopic ratios of carbon and nitrogen for blood cells and blood plasma, from each sampled individual were measured. Isotopic ratios for potential prey items were also measured. 3. Delta15N and delta13C for blood samples were both significantly different between sample months. Generally we found a decrease in both isotopic ratios during the course of the winter. All potential prey items were also isotopically distinct. Multisource mixing models (isosource) were used to determine the range of possible contribution to the diet of individuals. 4. During early winter, diet consisted almost exclusively of sea grass Zostera spp. The level of Zostera spp. in the diet dropped until mid-winter, and was supplemented by the utilization of green algae Ulva lactuca, and Enteromorpha spp. , and terrestrial grasses. Terrestrial grass comprised an increasing proportion of the diet in late winter, representing virtually the exclusive food source by April. 5. By examining intrapopulation variability in resource utilization we highlight a number of ecologically important factors not addressed by previous population level studies.
Canadians' willingness to receive care from physician assistants.

OBJECTIVE To determine the willingness of Canadians to accept treatment from physician assistants (PAs). DESIGN Respondents were asked to be surrogate patients or parents under 1 of 3 conditions selected at random. Two scenarios involved injury to themselves, with the third involving injury to their children. The wait time for a physician was assumed to be 4 hours, whereas to explore the sensitivity of patients' preferences for a range of times, PA wait times were 30 minutes, 1 hour, and 2 hours. SETTING Vancouver, BC. PARTICIPANTS Two hundred twenty-nine mothers attending a hospital with their children. MAIN OUTCOME MEASURES The main outcome measure was the proportion of individuals in each scenario who were willing to be treated by PAs for at least one of the time trade-off options offered. A secondary outcome was the proportion of individuals who changed their answers when the waiting time to see the PA varied. RESULTS Regardless of the scenarios, 99% of participants opted for PAs under the personal circumstances; 96% opted for PAs when the issue involved their children. The choice favouring the PA persisted, albeit at slightly lower proportions, as the difference in wait time between PAs and physicians decreased (85% and 67% for a difference in PA and physician wait time of 3 and 2 hours, respectively). CONCLUSION These findings suggest that British Columbians are willing to be treated by PAs under most circumstances, whether this includes themselves or their children. The high level of willingness to be treated by PAs demonstrates public confidence in PA care, and suggests that the use of PAs in Canadian emergency departments or clinics is a viable policy response to decreasing primary care capacity.
In vivo proton MR spectroscopy of the breast using the total choline peak integral as a marker of malignancy.

OBJECTIVE The purpose of our study was to use the total choline-containing compound (tCho) peak integral as a marker of malignancy in breast MR spectroscopy (MRS). SUBJECTS AND METHODS Forty-eight single-voxel water- and fat-suppressed 1.5-T MRS measurements were performed in 42 patients, obtaining both absolute tCho peak integral and tCho peak integral normalized for the volume of interest (VOI). Our reference standard was histology for lesions with BI-RADS category 4 and 5 and histology or at least a 2-year follow-up for findings with BI-RADS 2 and 3 and normal glands. Receiver operating characteristic (ROC) analysis, Mann-Whitney U test, and Spearman's rank correlation were used. RESULTS Three of 48 measurements (6%) failed. Of the remaining 45 spectra, 18 nonmalignant tissues showed no tCho peak, eight nonmalignant tissues showed a tCho peak integral from 0.99 to 9.03 arbitrary units (AU), and 19 malignant lesions showed a tCho peak integral from 1.26 to 19.80 AU. The diameter of nonmalignant tissues was 16.9 +/- 7.4 mm; that of malignant lesions was 15.3 +/- 6.9 mm (p = 0.308). At ROC analysis, the optimal threshold was 1.90 AU for absolute tCho peak, with 0.895 (17/19) sensitivity, 0.923 (24/26) specificity, and an AUC (area under the curve) of 0.917 (95% CI, 0.822-1.000); the optimal threshold was 0.85 AU/mL for the normalized tCho peak integral with 0.842 (16/19) sensitivity, 0.885 (23/26) specificity, and an AUC of 0.941 (0.879-1.000) (p = 0.470). A negative correlation (p = 0.011) was found between the VOI and the normalized tCho peak integral of malignant tissues. CONCLUSION Breast MRS using tCho peak integral reaches a high level of diagnostic performance.
A new biometric-based security framework for cloud storage

Cloud computing is a paradigm that is redrawing the information technology landscape by outsourcing the computation and data storage services to public cloud service providers. Over the last years, cloud storage services revealed an unprecedented opportunity for Internet users to profit from online storage services. Thanks to their enriched toolbox for file sharing and syncing, cloud storage platforms provide organizations and individuals with a reliable and cost-effective collaborative workspace. However, in addition to the traditional security issues, cloud storage services introduce new security concerns that are mainly related to the insecure state in which the files are while being synchronized. Recent publications highlighted the significant impact of the security flaws that exist in the syncing protocols used by the most popular cloud storage application. In this paper, we consider the Man in the Cloud (MitC) attack demonstrated in 2015 which allows accessing the files stored in a private repository without the possession of the authentication and authorization credentials. To address this issue, we propose a biometric-based framework for cloud storage services aiming to impede intruders from launching MitC attacks. Our framework is based on our previously published technique to combine chaotic maps and fuzzy extractors. The experiments performed on real biometric features confirm the potential brought by our framework to implement strong authentication in cloud storage applications.
Changes in the default mode network in the prefrontal lobe, posterior cingulated cortex and hippocampus of heroin users

The default mode network is associated with senior cognitive functions in humans. In this study, we performed independent component analysis of blood oxygenation signals from 14 heroin users and 13 matched normal controls in the resting state through functional MRI scans. Results showed that the default mode network was significantly activated in the prefrontal lobe, posterior cingulated cortex and hippocampus of heroin users, and an enhanced activation signal was observed in the right inferior parietal lobule (P < 0.05, corrected for false discovery rate). Experimental findings indicate that the default mode network is altered in heroin users.
High‐pass filtering surface EMG in an attempt to better represent the signals detected at the intramuscular level

Surface electromyography (EMG) is often used to represent activation profiles of the underlying musculature. The purpose of this study was to assess the potential of high‐pass (HP) filtering to improve the matching of surface EMG signals to those signals recorded intramuscularly. EMG was recorded at the skin surface over the infraspinatus and supraspinatus muscles as well as from fine‐wire electrodes placed in the infraspinatus, supraspinatus, and teres minor muscles. The surface EMG signals were HP‐filtered at 18 cutoff frequencies (0–510 HZ in 30 HZ increments), and the time‐histories were correlated with the signals from the wire electrodes. HP filtering did not significantly alter the correlated muscle activation waveform relationship between the surface and wire signals until cutoffs reached 240 HZ. HP filtering of the surface signals did not improve the representation of the muscle fiber‐level activation profile, but the results suggest that enough information resides in the high‐frequency components of the signal to reproduce the activation time–history profile of the muscle. Muscle Nerve, 2010