Miracle-dz/UniFAR-FTUs huggingface dataset:
Nucleoside transporters, bcl‐2 and apoptosis in CLL cells exposed to nucleoside analogues in vitro

The purine nucleoside analogues fludarabine (Fl) and chlorodeoxyadenosine (2‐CdA) are considered to be cell cycle specific agents which require DNA synthesis for cytotoxicity. However, their efficacy in the treatment of CLL, an indolent lymphoid malignancy suggests additional mechanisms of action. Like cytosine arabinoside (AraC), Fl and 2‐CdA gain access to the cell via a specific nucleoside transporter (NST) protein. To investigate the mode of action of these drugs in CLL, we used a fluorescent ligand for the NST (5‘‐(SAENTA‐ x 8)‐fluorescein) and 3‐colour flow cytometry to determine NST expression on CD5+/CD19+ B‐cells from the peripheral blood (PB) of patients with CLL. NST levels on these cells was found to be not significantly different from normal control lymphocytes (mean = 485±425) vs. (mean = 553±178). Exposure to varying concentrations (0, 3 μM and 30 μM) of Fl and 2‐CdA, however, resulted in an upregulation of NST (mean = 1552±775 with 30 μM FL; mean = 3392±2197 with 30 μM 2‐CdA) after 48 h. “Large” lymphoid cells (not present in normal PB) were found to express significantly more NST (mean = 2540±2861) and have a higher proliferative capacity than “small” cells (mean = 357±517 NST/cell). Incubation of CLL cells with Fl (n = 6) and 2‐CdA (n = 8) in vitro over 48 h also resulted in an increase in the proportion of cells in S‐phase (0 μM = 0.2±0.1; 30 μM FL = 2.4±2.0; 30 μM 2‐CdA = 3.3±1.3) and a significant increase in morphologically identifiable apoptosis. Apoptosis was confirmed by flow cytometric DNA analysis (0 μM = 13±8%; 30 μM FL = 40±20%; 30 μM 2‐CdA = 48±11%). In situ hybridization using a biotinylated cDNA bcl‐2 probe demonstrated that bcl‐2 mRNA expression was markedly decreased in treated cells after 24 h. These studies have demonstrated that: (1) NST expression on CLL lymphocytes is low; (2) in vitro exposure to the analogues increases both the level of NST expression and the % cells in S‐phase; (3) exposure to the analogues downregulates bcl‐2 expression and increases apoptosis.
Presence of Active and Inactive Molecules of a Cell Wall-Associated Proteinase in Lactobacillus helveticus CP790

Monoclonal antibodies against a cell wall-associated 45-kDa proteinase from Lactobacillus helveticus CP790 were prepared and used for an immunoblotting analysis of the cell wall extract of CP790. They were found to react with an unidentified 46-kDa protein as well as the 45-kDa proteinase. The 46-kDa protein was copurified with the 45-kDa proteinase by affinity column chromatography using antibody-fixed Sepharose and sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then extracted from the gels. An elution profile of the cyanogen bromide digest of the purified 46-kDa protein obtained by reversed-phase high-performance liquid chromatography was identical to that of the 45-kDa proteinase except for one peak. An analysis of the N-terminal 21-amino-acid sequence revealed that the 46-kDa protein possesses an extra 7 amino acids at the N terminus of the 45-kDa proteinase. The 46-kDa protein was produced at constant levels during fermentation in a skim milk medium, while the 45-kDa protein was mainly observed in the middle of the exponential phase of growth and was produced in proportion to the proteinase activity. Moreover, only the 46-kDa protein was detected in the crude extract of L. helveticus CP791, a variant strain of CP790 defective in proteinase activity. These data strongly suggest that the 46-kDa protein is a precursor, inactive form of the 45-kDa proteinase.
Apolipoprotein E genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease.

IMPORTANCE Several studies suggest that the apolipoprotein E (APOE) ε4 allele modulates cerebrospinal fluid (CSF) levels of β-amyloid 42 (Aβ42). Whether this effect is secondary to the association of the APOE ε4 allele with cortical Aβ deposition or whether APOE ε4 directly influences CSF levels of Aβ42 independently of Aβ pathology remains unknown. OBJECTIVE To evaluate whether the APOE genotype affects the diagnostic accuracy of CSF biomarkers for Alzheimer disease (AD), in particular Aβ42 levels, and whether the association of APOE ε4 with CSF biomarkers depends on cortical Aβ status. DESIGN, SETTING, AND PARTICIPANTS We collected data from 4 different centers in Sweden, Finland, and Germany. Cohort A consisted of 1345 individuals aged 23 to 99 years with baseline CSF samples, including 309 with AD, 287 with prodromal AD, 399 with stable mild cognitive impairment, 99 with dementias other than AD, and 251 controls. Cohort B included 105 nondemented younger individuals (aged 20-34 years) with CSF samples available. Cohort C included 118 patients aged 60 to 80 years with mild cognitive symptoms who underwent flutemetamol F 18 ([18F]flumetamol) positron emission tomography amyloid imaging and CSF tap. EXPOSURES Standard care. MAIN OUTCOMES AND MEASURES Cerebrospinal fluid levels of Aβ42 and total and phosphorylated tau in relation to the APOE ε2/ε3/ε4 polymorphism in different diagnostic groups and in cases with or without cortical uptake of [18F]flutemetamol. RESULTS The CSF levels of Aβ42 but not total and phosphorylated tau were lower in APOE ε4 carriers compared with noncarriers irrespective of diagnostic group (cohort A). Despite this, CSF levels of Aβ42 differed between participants with AD when compared with controls and those with stable mild cognitive impairment, even when stratifying for APOE genotype (P < .001 to P = .006). Multiple binary logistic regression revealed that CSF levels of Aβ42 and APOE ε4 genotype were independent predictors of AD diagnosis. In cohort B, APOE ε4 carrier status did not influence CSF levels of Aβ42. Moreover, when stratifying for cortical uptake of [18F]flutemetamol in cohort C, APOE ε4 genotype did not influence CSF levels of Aβ42. This result was replicated in a cohort with individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) using carbon 11-labeled Pittsburgh Compound B scanning. CONCLUSIONS AND RELEVANCE Cerebrospinal fluid levels of Aβ42 are strongly associated with the diagnosis of AD and cortical Aβ accumulation independent of APOE genotype. The clinical cutoff for CSF levels of Aβ42 should be the same for all APOE genotypes.
Development and validation of a clinical risk score to predict mortality after percutaneous coronary intervention

Objective To develop and validate a contemporary clinical risk score to predict mortality after percutaneous coronary intervention (PCI). Methods Using data collected from patients undergoing PCI at the South Yorkshire Cardiothoracic Centre, Sheffield, UK, between January 2007 and September 2013, a risk score was developed to predict mortality. Logistic regression was used to evaluate the effect of each variable upon 30-day mortality. A backwards stepwise logistic regression model was then used to build a predictive model. The results were validated both internally and externally with data from Manchester Royal Infirmary, UK. 30-Day mortality status was determined from the UK Office of National Statistics. Results The development data set comprised 6522 patients from Sheffield. Five risk factors, including cardiogenic shock, procedural urgency, history of renal disease, diabetes mellitus and age, were statistically significant to predict 30-day mortality. The risk score was validated internally on a further 3290 patients from Sheffield and externally on 3230 patients from Manchester. The discrimination of the model was high in the development (C-statistic=0.82, 95% CI 0.79 to 0.85), internal (C-statistic=0.81, 95% CI 0.76 to 0.86) and external (C statistics=0.90, 95% CI 0.87 to 0.93) cohorts. There was no significant difference between observed and predicted mortality in any group. Conclusion This contemporary risk score reliably predicts 30-day mortality after PCI using a small number of clinical variables obtainable prior to the procedure, without knowledge of the coronary anatomy.
Endovascular reconstruction by means of stent placement in symptomatic intracranial atherosclerotic stenosis

Abstract Objective: Patients with intracranial atherosclerosis who fail antithrombotic therapy have a poor prognosis. The high rate of recurrent stroke warrants testing alternative treatments such as intracranial angioplasty. Methods: We present our experience in the treatment of 104 patients (age range, 54–82 years; mean age, 67 years) with symptomatic intracranial atherosclerotic stenoses despite medical therapy who underwent stent-assisted angioplasty. Patient records were retrospectively analysed for location and degree of stenosis, regimen of antiplatelet agents, devices used, procedure-related complications and adverse events. Clinical (Modified Rankin Scale) and radiographic outcomes were obtained 24 hours, 1 month and 3–6 months after treatment. Sixty-five lesions (62.5%) were located in the posterior circulation. Mean stenosis was 75.4%. Results: In all patients, the angiographic degree of stenosis was reduced to less than 30%. One stent was implanted in 66 patients (63%), and two or more in 38 patients (37%). Modified Rankin Scale (mR) was 1–2 in 67.5% of the cases, 3–4 in 25.9%, 5 in 2.8%, 6 in 3.8%. Procedural morbidity was 5.7% and procedural mortality was 3.8%. Angiographic follow-up was available in 58 patients (55.7%) and the restenosis rate was 12.5%. Discussion: In selected patients, endovascular revascularization of intracranial arteries by means of stent-assisted angioplasty is technically feasible, effective and safe.
Distribution pattern of MRI abnormalities within the knee and wrist of juvenile idiopathic arthritis patients: signature of disease activity.

OBJECTIVE The aim of this study in clinically active juvenile idiopathic arthritis (JIA) was to assess the frequency and distribution pattern of synovitis as hallmark of disease and additional soft-tissue and bony abnormalities on MRI in the knee and wrist as two target joints. MATERIALS AND METHODS MRI datasets of 153 clinically active JIA patients (110 with knee and 43 with wrist involvement) were evaluated independently by two readers for the presence of literature-based imaging features: "synovial hypertrophy," "bone marrow changes," "bone erosions," "tenosynovitis" (only in the wrist), and "cartilage lesions" (only in the knee) in accordance with validated definitions and scoring locations. RESULTS Synovial hypertrophy was most frequently observed--both in the knee and in the wrist (61.8-65.1% of cases). For the knee, the most frequently involved locations were the cruciate ligaments (46/183 locations [25.1%] affected with synovial hypertrophy) and medial patella (18/62 locations [29.0%] with bone marrow changes). Cartilage lesions and bone erosions were rare (5.5-7.3% of cases). For the wrist, most frequently involved were the radiocarpal joint (21/64 locations [32.8%] with synovial hypertrophy), lunate (7/46 locations [15.2%] with bone marrow changes), and capitate or triquetrum (6/28 locations [21.4%] with bone erosions). Tenosynovitis was a common wrist-specific feature (46.5% of cases). MRI showed no abnormalities in a subgroup of patients with clinically active knee (23.6%) and wrist (16.3%) involvement. CONCLUSION The distribution pattern of MRI abnormalities in the knee and wrist of active JIA patients provides a practical tool to detect a signature of JIA disease activity in target joints.
Reconstructed adeno-associated virus with the extracellular domain of murine PD-1 induces antitumor immunity.

BACKGROUND The negative signaling provided by interactions of the co-inhibitory molecule, programmed death-1 (PD-1), and its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), is a critical mechanism contributing to tumor evasion; blockade of this pathway has been proven to enhance cytotoxic activity and mediate antitumor therapy. Here we evaluated the anti-tumor efficacy of AAV-mediated delivery of the extracellular domain of murine PD-1 (sPD-1) to a tumor site. MATERIAL AND METHODS An rAAV vector was constructed in which the expression of sPD-1, a known negative regulator of TCR signals, is driven by human cytomegalovirus immediate early promoter (CMV-P), using a triple plasmid transfection system. Tumor-bearing mice were then treated with the AAV/sPD1 construct and expression of sPD-1 in tumor tissues was determined by semi quantitative RT-PCR, and tumor weights and cytotoxic activity of splenocytes were measured. RESULTS Analysis of tumor homogenates revealed sPD-1 mRNA to be significantly overexpressed in rAAV/sPD-1 treated mice as compared with control levels. Its use for local gene therapy at the inoculation site of H22 hepatoma cells could inhibit tumor growth, also enhancing lysis of tumor cells by lymphocytes stimulated specifically with an antigen. In addition, PD-1 was also found expressed on the surfaces of activated CD8+ T cells. CONCLUSION This study confirmed that expression of the soluble extracellular domain of PD-1 molecule could reduce tumor microenvironment inhibitory effects on T cells and enhance cytotoxicity. This suggests that it might be a potential target for development of therapies to augment T-cell responses in patients with malignancies.
Analysis of complex decision problems based on cumulative prospect theory

Complex risky decision problems involve sequences of decisions and random events.The choice at a given stage depends on the decisions taken in the previous stages, as well as on the realizations of the random events that occurred earlier. In the analysis of such situations, decision trees are used, and the criterion for choosing the optimal decision is to maximize the expected monetary value. Complex risky decision problems involve sequences of decisions and random events.The choice at a given stage depends on the decisions taken in the previous stages, as well as on the realizations of the random events that occurred earlier. In the analysis of such situations, decision trees are used, and the criterion for choosing the optimal decision is to maximize the expected monetary value. Unfortunately, this approach often does not reflect the actual choices of individual decision makers. In descriptive decision theory, the criterion of maximizing the expected monetary value is replaced by a subjective valuation that takes into account the relative outcomes and their probabilities. This paper presents a proposal to use the principles of cumulative prospect theory to analyse complex decision problems. The concept of a certainty equivalent is used to make it possible to compare risky and non-risky alternatives.
Community Aged Care: What Is the Evidence for Effects on Service Use and Costs?

Abstract Objective: To evaluate the effects of case management in community aged care (CMCAC) interventions on service use and costs. Method: Five databases were searched from inception to 2011 July to include randomized control trials and comparative observational English studies. Results were summarized by using the best-evidence synthesis approach. Results: Twenty-one studies were included. Available studies supported improvements in clients’ use of case management services (all of the four studies), some community services (8 of the 10) and nursing home admission and stay (around one half), delay of nursing home placement (all of the two studies), and achieving cost neutrality (8 of the 11). The effects on medical care utilization were varying. Discussion: In general, these positive effects justify the further development and refinement of CMCAC programs. Result applicability is limited by only including English studies. Cost studies applying a societal perspective, and full economic appraisals where appropriate are warranted.
Pedunculopontine nucleus in the squirrel monkey: Cholinergic and glutamatergic projections to the substantia nigra

The distribution and chemospecificity of the pedunculonigral neurons have been studied in squirrel monkeys (Saimiri sciureus)with cholera toxin subunit B (CTb) and fluorogold (FG) as retrograde tracers combined with immunohistochemistry for choline acetyltransferase (ChAT), glutamate, and the calcuium binding protein calbindin D‐28k. The injection of either CTb or FG into the substantia nigra produces prominent retrograde cell labeling in the mesopontine tegmentum. Labeled neurons are particularly numerous at the level of the decussation of the superior cerebellar peduncle, where they abound principally in the pars dissipata of the pedunculopontine nucleus (PPN). A significant proportion of retrogradely labeled neurons in the PPN display ChAT immunoreactivity. Whithin the entire PPN, approximately 25% of the retrogradley labeled neurons express ChAT immunoreactivity, but proportions of doubly labeled neurons are about 35%, 25% in the rostral, middle, and caudal thirds of the PPn, respectively. These doubly labeled neurons are scattered among numerous retrogradely labeled neurons that are ChAT‐negative and whose number increases along the rostrocaudal extent of the PPN. Several retrogradely labeled neurons in the PPN display glutamate immunoreactivity, but very few express calbindin. This study provides the first direct evedence for the involvement of cholinergic and glutamatergic neurons in the pedunculonigral projection in primates. Furthermore, the fact that some neurons of the PPN display bothe ChAT and glutamate immunoreactivity indicates that single neurons in the mesopontine tegmentum may exert a two‐fold effect upon dopaminergic neurons of the substantia nigra. This dual cholinergic and glutamatergic pedunculonigral projection may play a crucial role in the functional organization of primate basal ganglia. © 1994 Wiley‐Liss, Inc.
Revealing Shared and Distinct Gene Network Organization in Arabidopsis Immune Responses by Integrative Analysis1

Multiscale network analysis shows a robust gene network architecture in effector-triggered immunity of Arabidopsis. Pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) are two main plant immune responses to counter pathogen invasion. Genome-wide gene network organizing principles leading to quantitative differences between PTI and ETI have remained elusive. We combined an advanced machine learning method and modular network analysis to systematically characterize the organizing principles of Arabidopsis (Arabidopsis thaliana) PTI and ETI at three network resolutions. At the single network node/edge level, we ranked genes and gene interactions based on their ability to distinguish immune response from normal growth and successfully identified many immune-related genes associated with PTI and ETI. Topological analysis revealed that the top-ranked gene interactions tend to link network modules. At the subnetwork level, we identified a subnetwork shared by PTI and ETI encompassing 1,159 genes and 1,289 interactions. This subnetwork is enriched in interactions linking network modules and is also a hotspot of attack by pathogen effectors. The subnetwork likely represents a core component in the coordination of multiple biological processes to favor defense over development. Finally, we constructed modular network models for PTI and ETI to explain the quantitative differences in the global network architecture. Our results indicate that the defense modules in ETI are organized into relatively independent structures, explaining the robustness of ETI to genetic mutations and effector attacks. Taken together, the multiscale comparisons of PTI and ETI provide a systems biology perspective on plant immunity and emphasize coordination among network modules to establish a robust immune response.
Improving surgical reduction in radial fractures using a ‘dowel’ pinning technique in miniature and toy breed dogs

Summary Objectives: A retrospective approach was used to detail and evaluate a ‘dowel’ pinning technique in distal radial fractures in miniature and toy breed dogs. Methods: Medical records and radiographs from 2003–2009 of miniature and toy breed dog radial fractures were examined. Sixty cases were divided into two groups: 51 radial fractures repaired with a ‘dowel’ pinning and external skeletal fixation (ESF) and nine radial fractures repaired with closed reduction and ESF. Each dog was evaluated and radiographic images were obtained at presentation, postoperatively, and at 1, 2, 4, 8, and 12 weeks postoperatively. Signalment, reduction, alignment, time to clinical bone healing and ESF removal, and implant morbidity were determined for each group. Results: Radial fractures repaired with a ‘dowel’ pin and ESF had improved reduction compared to closed reduction and ESF alone (p <0.0001 as evaluated with lateral radiographs and p <0.0004 with cranial/caudal radiographs). Both surgical groups resulted in good clinical outcome with low morbidity, however it was observed that the time to clinical union and ESF removal was an average of 2.5 weeks less with closed reduction technique compared to the open reduction and ‘dowel’ pinning technique (p <0.031). Clinical Significance: Incorporating a ‘dowel’ pin to the surgical repair enhances the reduction of distal radial fractures in miniature and toy breed dogs and results in excellent clinical outcomes but causes a small delay in bone healing.
Genetic and statistical properties of residual feed intake.

Residual feed intake is defined as the difference between actual feed intake and that predicted on the basis of requirements for production and maintenance of body weight. Formulas were developed to obtain genetic parameters of residual feed intake from knowledge of the genetic and phenotypic parameters of the component traits. Genetic parameters of residual feed intake were determined for a range of heritabilities (h2 = .1, .3, or .5) for component traits of feed intake and production, and genetic (rg = .1, .5, or .9) and environmental (re = .1, .5, or .9) correlations between them. Resulting heritability of residual feed intake ranged from . 03 to . 84 and the genetic correlation between residual feed intake and production ranged from -. 90 to . 87. Heritability of residual feed intake depends considerably on the environmental correlation between feed intake and production. Residual feed intake based on phenotypic regression of feed intake on production usually contains a genetic component due to production. Residual feed intake based on genotypic regression of feed intake on production is genetically independent of production and its use is equivalent to use of a selection index restricted to hold production constant. Multiple-trait selection on residual feed intake, based on either phenotypic or genetic regressions, and production is equivalent to multiple-trait selection on feed intake and production. Residual energy intake in dairy cattle was examined as an example. Heritability of residual energy intake based on genotypic regression was close to zero and indicated that measurement of feed intake provides little additional genetic information over and above that provided by milk production and body weight. The principles outlined in this study have broader application than just to residual feed intake and apply to any trait that is defined as a linear function of other traits.
Efficient segmentation of large‐area skin images: an overview of image processing *

Background/aims: This paper is the first of a series describing research and development performed by the SPOTS project towards automating the process of monitoring pigmented lesions for change over time. A comprehensive overview of digital image processing techniques used for the systematic approach to segmentation of large‐area skin images, including the description and classification of skin features, is presented.