Miracle-dz/UniFAR-FTUs huggingface dataset:
Interaction between FOG-1 and the Corepressor C-Terminal Binding Protein Is Dispensable for Normal Erythropoiesis In Vivo

ABSTRACT The hematopoietic, zinc-finger protein FOG-1 is essential for the development of the erythroid and megakaryocytic lineages. FOG-1's function in hematopoiesis is dependent on its ability to interact with the transcription factor GATA-1. FOG-1 has also been observed to interact with the corepressor molecule C-terminal binding protein (CtBP) through a peptide motif shared by all FOG family members. In this study, we confirmed that FOG-1 and CtBP interact by coimmunoprecipitation. We further demonstrate that a FOG-1 mutant unable to interact with CtBP has increased erythropoietic (but not megakaryocytic) rescue (relative to the wild type) of a FOG-1−/− cell line. To analyze further the physiological role of the FOG-1-CtBP interaction, we generated knock-in mice that express a FOG-1 variant unable to bind CtBP. Surprisingly, these mice are normal and fertile. Furthermore, erythropoiesis at all stages of development is normal in these mice. Erythrocyte production is similar in mutant and wild-type mice even under conditions of erythropoietic stress stimulated by either exogenously added erythropoietin or phenylhydrazine-induced anemia. Thus, despite conservation of the FOG-CtBP interaction site, the in vivo function of FOG-1 in erythroid development is not affected by its inability to interact with the corepressor CtBP.
Strategic decision support for the bi-objective location-arc routing problem

This article develops an intelligent decision support tool for a complex supply chain management problem. In order to solve the bi-objective Location-Arc Routing Problem (LARP) facilities have to be located and routes must be determined simultaneously. The first objective is the minimization of the total costs which are the fixed cost of opening the facility, the fixed cost for the vehicles as well as the travelled distances. Additionally, a second objective related to a service aspect is investigated: the total sum of the delivery times for servicing the required demands. This idea arises since e.g. in a snow plowing application lead times for satisfying the required demands play an important role for the safety of people using the road network. To the best of our knowledge, this paper presents the first study devoted to the bi-objective LARP. The trade-off between the proposed objectives is investigated on adapted benchmark instances.
Structural Basis for Inflammation-driven Shedding of CD163 Ectodomain and Tumor Necrosis Factor-α in Macrophages*

Background: ADAM17 mediates shedding of CD163 and tumor necrosis factor-α (TNF-α) during inflammation. Results: Similar substrate sequence motifs in proTNF-α and CD163 are essential for ADAM17-mediated cleavage. Conclusion: The structural basis for shedding of CD163 and TNF-α is disclosed. Significance: The data provide new molecular information on the inflammatory response and explain evolution of a regulatory mechanism for CD163 expression. The haptoglobin-hemoglobin receptor CD163 and proTNF-α are transmembrane macrophage proteins subjected to cleavage by the inflammation-responsive protease ADAM17. This leads to release of soluble CD163 (sCD163) and bioactive TNF-α. Sequence comparison of the juxtamembrane region identified similar palindromic sequences in human CD163 (1044Arg-Ser-Ser-Arg) and proTNF-α (78Arg-Ser-Ser-Ser-Arg). In proTNF-α the Arg-Ser-Ser-Ser-Arg sequence is situated next to the previously established ADAM17 cleavage site. Site-directed mutagenesis revealed that the sequences harbor essential information for efficient cleavage of the two proteins upon ADAM17 stimulation. This was further evidenced by analysis of mouse CD163 that, like CD163 in other non-primates, does not contain the palindromic CD163 sequence in the juxtamembrane region. Mouse CD163 resisted endotoxin- and phorbol ester-induced shedding, and ex vivo analysis of knock-in of the Arg-Ser-Ser-Arg sequence in mouse CD163 revealed a receptor shedding comparable with that of human CD163. In conclusion, we have identified an essential substrate motif for ADAM17-mediated CD163 and proTNF-α cleavage in macrophages. In addition, the present data indicate that CD163, by incorporation of this motif in late evolution, underwent a modification that allows for an instant down-regulation of surface CD163 expression and inhibition of hemoglobin uptake. This regulatory modality seems to have coincided with the evolution of an enhanced hemoglobin-protecting role of the haptoglobin-CD163 system in primates.
The growth, characteristics, and future of online CME

Introduction: Physician use of online continuing medical education (CME) is growing, but there are conflicting data on the uptake of online CME and few details on this market. Methods: Analyses of 11 years of data from the Accreditation Council for Continuing Medical Education (ACCME) and a survey of 272 publicly available CME Web sites. Results: The data suggest that online CME was 6.9%–8.8% of CME consumed in 2008. If previous exponential growth continues, online CME is likely to be 50% of all CME consumed within 7–10 years. Most (60%) online CME is produced by medical publishing and education companies. The online CME marketplace is consolidating, with 16% of surveyed sites providing 76% of available credits. Currently, 70% of online CME is offered at $10 or less per credit. Most online CME uses low‐technology educational approaches, such as pure text and repurposed live lectures. Discussion: Online CME use is growing rapidly and is likely to be half of all CME consumed by practicing physicians within a few years. The pattern is consistent with Christensen's model of “disruptive innovation,” whereby an innovative technology eventually displaces an incumbent technology by first providing a relatively low‐quality, low‐cost product that meets the needs of unserved customers. The technologies being developed for online CME may facilitate broader changes in medical education as well.
A Planned Prospective, Randomized, Placebo-Controlled Multicenter Trial Assessing the Effect of Helicobacter pylori Eradication on the Healing of Iatrogenic Ulcer after Endoscopic Resection of Gastric Neoplasm.

BACKGROUND/AIMS Helicobacter pylori eradication may facilitate the healing of iatrogenic ulcer after endoscopic resection of gastric neoplasm. This study involved designing a randomized, double-blinded, placebo-controlled, multicenter trial, performed by the Korean College of Helicobacter and Upper Gastrointestinal Research and the Medical Research Collaboration Center, Seoul National University Hospital. METHODS We intend to enroll up to 232 patients H. -pylori-positive patients who have gastric adenoma or early gastric cancer after endoscopic resection. The enrolled patients are being randomly allocated to the H. -pylori-eradication-plus-proton-pump-inhibitor group or the placebo-plus-proton-pump-inhibitor group based on their histology results and the size of the resected specimen. After random allocation, the iatrogenic ulcer size and stage are evaluated at 4- and 8-week follow-ups (with a window of ±7 days). The primary end point is the healing rate of the ulcer by stage, and the secondary end point is the rate of ulcer size reduction, relief rate from ulcer-related symptoms, and adverse-event rates. RESULTS More than 90% of the target subjects have already been enrolled into the study and are receiving ongoing periodic monitoring by the Medical Research Collaboration Center. CONCLUSIONS Completion of the study should reveal whether H. pylori eradication can facilitate the healing of ulcer after endoscopic resection in Korea.
Increased expression of nitric oxide synthase in human lung transplants after nitric oxide inhalation1

Background. The effects of the ischemia-reperfusion process of organ transplantation on nitric oxide (NO) synthase (NOS) in humans are unknown. The effects of NO inhalation on endogenous NOS expression and activity are controversial. The authors hypothesized that NO inhalation may affect ischemia-reperfusion–induced alterations of the endogenous NOS system. Methods. The authors performed lung biopsy on patients in a randomized phase II clinical trial of NO inhalation during lung transplantation. After lung implantation, 20 ppm of NO or placebo gas was administered 10 min after the start of reperfusion. Lung tissues were collected from 20 patients (NO, n=9; placebo, n=11) after cold and warm ischemia, 1 hr and 2 hr after reperfusion. The protein levels of NOS isoforms were analyzed by Western blotting and the total NOS activity was measured. Results. The protein levels of inducible NOS did not change significantly in either of the groups. In contrast, during the 2-hr reperfusion period, constitutive NOS (neuronal NOS [nNOS] and endothelial NOS) tended to decrease in the placebo group, but gradually increased in the NO group. After 2 hr of reperfusion, the nNOS protein in the NO group was significantly higher than that in the placebo group (P <0.05). However, the total NOS activity remained at low levels in both groups. Conclusions. NO inhalation-induced increase of constitutive NOS proteins indicates the interaction between inhaled NO molecules and lung tissues. However, the activity of these newly synthesized NOS proteins remains suppressed during the ischemia-reperfusion period of lung transplantation.
Feasibility of Partial A2 and A4 Pulley Excision: Residual Pulley Strength

We investigated residual digital flexor pulley strengths after 75% excision of the A2 and A4 pulleys. For direct pull-off tests, A2 and A4 pulleys from cadaveric fingers were tested by pulling on a loop of flexor digitorum profundus tendon through the pulley. For functional loading tests, fingers were positioned with the metacarpophalangeal joint flexed to 90° for A2 testing, and with the proximal interphalangeal joint in 90° flexion for A4 testing (with all other joints in full extension). Excision of 75% of A2 and A4 pulleys reduced pulley strengths determined by both testing methods. For the functional loading tests, which are more clinically relevant, mean tendon forces at failure after partial excision of A2 and A4 pulleys were 224 and 131 N respectively, which is sufficient to withstand flexor tendon forces expected during activities of daily living.
High efficiency of mutation detection in type 1 stickler syndrome using a two‐stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1

Stickler syndrome is a genetically heterogenous disorder that affects the ocular, skeletal, and auditory systems. To date three genes, COL2A1, COL11A1, and COL11A2, encoding the heterotypic type II/XI collagen fibrils present in vitreous and cartilage have been shown to have mutations that result in Stickler syndrome. As systemic features in this disorder are variable we have used an ophthalmic examination to differentiate those patients with a membranous vitreous phenotype associated with mutations in COL2A1, from other patients who may have mutations in other genes. Gene amplification and exon sequencing was used to screen 50 families or sporadic cases with this membranous phenotype, for mutations in COL2A1. Mutations were detected in 47 (94%) cases consisting of 166 affected and 78 unaffected individuals. We also demonstrate that the predominantly ocular form of type 1 Stickler syndrome is not confined to mutations in the alternatively spliced exon 2. Using splicing reporter constructs we demonstrate that a mutant GC donor splice site in intron 51 can be spliced normally; this contributed to the predominantly ocular phenotype in the family in which it occurred. Hum Mutat 27(7), 696–704, 2006. © 2006 Wiley‐Liss, Inc.
Hippocampal Abnormalities in an MR Imaging Series of Patients with Tuberous Sclerosis

BACKGROUND AND PURPOSE: Hippocampal abnormalities are known as highly epileptogenic precursor lesions in the general population, primarily manifesting as MTS. The purpose of this study was to evaluate the occurrence of hippocampal abnormalities on MR imaging in patients with TS to explore the possible underlying mechanisms of the abnormalities and to identify the relationship between an abnormal HF and epilepsy. MATERIALS AND METHODS: We studied MR images and clinical data from 31 patients with TS. The MR imaging protocol was identical for all patients and included tilted coronal images of their temporal lobes. The diagnosis of TSC was made according to established criteria. The HFs of the patients were evaluated from coronal images according to size, morphology, and signal intensity. The data were submitted to statistical analysis, and P values ≤ . 05 were considered significant. RESULTS: We found HF abnormalities in 5 patients. Four had typical MTS, and 1 had HIMAL. We found a positive correlation between childhood febrile seizures and MTS in patients with TS. We also confirmed that patients with altered hippocampi had a tendency to exhibit more cortical tubers. CONCLUSIONS: Analysis of this series of patients demonstrated the presence of HF abnormalities, mainly MTS in patients with TS. We also found that the occurrence of febrile seizures during the first year of life appears to be one of the determining factors for MTS development in these patients.
Relation classification using revised convolutional neural networks

Relation classification plays an important part in the structuralization of text data via information extraction. Lately, neural network-based methods have been applied to relation classification, which use neural networks to encode and extract features from the input text. As convolution neural network based method can extract high-level features through convolution filters, it achieves competitive performance with other complex-structured networks by only using a standard convolution layer, a pooling layer, and a regression layer. However, it failed to capture the hierarchical and syntax information of sentence. Inspired by this, We introduce the hierarchical convolutional layers and dependency embedding to the CNN based methods. The hierarchical convolution layers capture the detail feature and high-level hierarchical features and concatenate these features as the sentence representation. The dependency embeddings help CNN capture the dependency structure in the window size, which improve the classification results. Experiments verify that the revised relation classification method provide state-of-the-art performance, even without additional artificial features.
Comparative Virus Replication and Host Innate Responses in Human Cells Infected with Three Prevalent Clades (2.3.4, 2.3.2, and 7) of Highly Pathogenic Avian Influenza H5N1 Viruses

ABSTRACT Highly pathogenic avian influenza H5N1 virus clades 2.3. 4, 2.3. 2, and 7 are the dominant cocirculating H5N1 viruses in poultry in China. However, humans appear to be clinically susceptible mostly to the 2.3. 4 virus clade. Here, we demonstrated that A549 cells and human macrophages infected with clade 2.3. 4 viruses produced significantly more viruses than those infected with the other two clades. Likewise, clade 2.3. 4-infected macrophages caused the most severe cellular damage and strongest proinflammatory response.
Complete pipeline for Infinium(®) Human Methylation 450K BeadChip data processing using subset quantile normalization for accurate DNA methylation estimation.

BACKGROUND Huge progress has been made in the development of array- or sequencing-based technologies for DNA methylation analysis. The Illumina Infinium(®) Human Methylation 450K BeadChip (Illumina Inc., CA, USA) allows the simultaneous quantitative monitoring of more than 480,000 CpG positions, enabling large-scale epigenotyping studies. However, the assay combines two different assay chemistries, which may cause a bias in the analysis if all signals are merged as a unique source of methylation measurement. MATERIALS & METHODS We confirm in three 450K data sets that Infinium I signals are more stable and cover a wider dynamic range of methylation values than Infinium II signals. We evaluated the methylation profile of Infinium I and II probes obtained with different normalization protocols and compared these results with the methylation values of a subset of CpGs analyzed by pyrosequencing. RESULTS We developed a subset quantile normalization approach for the processing of 450K BeadChips. The Infinium I signals were used as 'anchors' to normalize Infinium II signals at the level of probe coverage categories. Our normalization approach outperformed alternative normalization or correction approaches in terms of bias correction and methylation signal estimation. We further implemented a complete preprocessing protocol that solves most of the issues currently raised by 450K array users. CONCLUSION We developed a complete preprocessing pipeline for 450K BeadChip data using an original subset quantile normalization approach that performs both sample normalization and efficient Infinium I/II shift correction. The scripts, being freely available from the authors, will allow researchers to concentrate on the biological analysis of data, such as the identification of DNA methylation signatures.
The predictive ability of blood pressure in elderly trial patients

Objectives: To assess the impact of the blood pressure (BP) profile on cardiovascular risk in the Medical Research Council (UK) elderly trial; investigate whether the effects of hypertensive drugs in reducing event rates are solely a product of systolic pressure reduction. Methods: Using longitudinal BP data from 4396 hypertensive patients, the general trend over time was estimated using a first-stage multilevel model. We then investigated how BP acted alongside other BP-related covariates in a second-stage ‘time-to-event’ statistical model, assessing risk for stroke events and coronary heart disease (CHD). Differences in outcome prediction between diuretic, &bgr;-blocker and placebo treatment arms were investigated. Results: The &bgr;-blocker arm experienced comparatively poor control of current SBP, episodic peaks and variability in BP levels. After adjusting for the mean level, variability in SBP over time was significant: risk ratio was 1.15 [95% confidence interval (CI): 1.01–1.31] across all patients for stroke events. The risk ratio for current SBP was 1.36 (95% CI: 1.16–1.58). Current DBP and variability in DBP also predicted stroke independently: risk ratios was 1.43 and 1.18, respectively. The risk factors exhibited weaker associations with CHD risk; only the highest measured value and variability in SBP showed a statistically significant association: risk ratios were 1.26 and 1.16, respectively. Conclusion: Individual risk characterization could be augmented with additional prognostic information, besides current SBP, including current diastolic pressure, temporal variability over and above general trends and historical measurements.
Whose Hands Are in the Finnish Cookie Jar?

Web cookies are ubiquitously used to track and profile the behavior of users. Although there is a solid empirical foundation for understanding the use of cookies in the global world wide web, thus far, limited attention has been devoted for country-specific and company-level analysis of cookies. To patch this limitation in the literature, this paper investigates persistent third-party cookies used in the Finnish web. The exploratory results reveal some similarities and interesting differences between the Finnish and the global web---in particular, popular Finnish web sites are mostly owned by media companies, which have established their distinct partnerships with online advertisement companies. The results reported can be also reflected against current and future privacy regulation in the European Union.
Prader–Willi syndrome and Tay–Sachs disease in association with mixed maternal uniparental isodisomy and heterodisomy 15 in a girl who also had isochromosome Xq

Malsegregation of chromosomes during reproduction can result in uniparental disomy when associated with trisomy rescue, monosomy rescue or gamete complementation. Pathogenicity stemming from uniparental disomy in liveborns results from imprinting disorders or autozygosity for autosomal recessive disorders. We report on a girl with Prader–Willi syndrome and Tay–Sachs disease resulting from maternal uniparental disomy of chromosome 15. The child also had an isochromosome Xq. To further characterize the etiology of the aberrant chromosome 15 and the isochromosome Xq, SNP loci from both chromosomes were assessed in the proband and parents, and genome‐wide DNA methylation analysis was performed. SNP and DNA methylation analysis confirmed maternal uniparental heterodisomy around the Prader–Willi locus, while the region around the HEXA locus showed maternal uniparental isodisomy. This result is consistent with trisomy rescue of a maternal meiosis l error in a chromosome 15 with two meiotic recombinations. SNP analysis of the X chromosomes is consistent with a maternal origin for the isochromosome. © 2014 Wiley Periodicals, Inc.
Variation of mood and empathy during internship.

CONTEXT Internship is a time of great transition, during which mood disturbances are common. However, variations in mood and empathy levels throughout the internship year have not been investigated. OBJECTIVE To examine mood patterns and changes in empathy among internal medicine residents over the course of the internship year. DESIGN Cohort study of interns involving completion of survey instruments at 4 points: time 1 (June 2000; Profile of Mood States [POMS] and Interpersonal Reactivity Index [IRI]), times 2 and 3 (November 2000 and February 2001; POMS), and time 4 (June 2001; POMS and IRI). SETTING Internal medicine residency program at a university-based medical center. PARTICIPANTS Sixty-one interns. MAIN OUTCOME MEASURES Baseline scores of mood states and empathy; trends in mood states and empathy over the internship year. RESULTS Response rates for time 1 were 98%; for time 2, 72%; for time 3, 79%; and for time 4, 79%. Results of the POMS revealed that physicians starting their internship exhibit less tension, depression, anger, fatigue, and confusion and have more vigor than general adult and college student populations (P<.001 for all). Results of the IRI showed better baseline scores for perspective taking (P<.001) and empathic concern (P =.007) and lower scores for personal distress (P<.001) among interns compared with norms. Five months into internship, however, POMS scores revealed significant increases in the depression-dejection (P<.001), anger-hostility (P<.001), and fatigue-inertia (P<.001) scales, as well as an increase in IRI personal distress level (P<.001). These increases corresponded with decreases in the POMS vigor-activity scores (P<.001) and IRI empathic concern measures (P =.005). Changes persisted throughout the internship period. CONCLUSIONS We found that, in this sample, enthusiasm at the beginning of internship soon gave way to depression, anger, and fatigue. Future research should be aimed at determining whether these changes persist beyond internship.