Miracle-dz/UniFAR-FTUs huggingface dataset:
SCORE: A computational approach to the identification of cis-regulatory modules and target genes in whole-genome sequence data

A large fraction of the information content of metazoan genomes resides in the transcriptional and posttranscriptional cis-regulatory elements that collectively provide the blueprint for using the protein-coding capacity of the DNA, thus guiding the development and physiology of the entire organism. As successive whole-genome sequencing projects—–including those of mice and humans—are completed, we have full access to the regulatory genome of yet another species. But our ability to decipher the cis-regulatory code, and hence to link genes into regulatory networks on a global scale, is currently very limited. Here we describe SCORE (Site Clustering Over Random Expectation), a computational method for identifying transcriptional cis-regulatory modules based on the fact that they often contain, in statistically improbable concentrations, multiple binding sites for the same transcription factor. We have carried out a Drosophila genomewide inventory of predicted binding sites for the Notch-regulated transcription factor Suppressor of Hairless [Su(H)] and found that the fly genome contains highly nonrandom clusterings of Su(H) sites over a broad range of sequence intervals. We found that the most statistically significant clusters are very heavily enriched in both known and logical targets of Su(H) binding and regulation. The utility of the SCORE approach was validated by in vivo experiments showing that proper expression of the novel gene Him in adult muscle precursor cells depends both on Su(H) gene activity and sequences that include a previously unstudied cluster of four Su(H) sites, indicating that Him is a likely direct target of Su(H).
Use of a MeSH-based index of faculty research interests to identify faculty publications: an IAIMSian study of precision, recall, and data reusability

OBJECTIVE To determine whether MEDLINE searches based on an existing automated faculty research interest index or on author name entities can be used to automate construction of accurate online lists of faculty publications. METHODS Curricula vitae (CVs) for 36 faculty members were selected at random. Their lists of journal publications were used to determine recall and precision of two MEDLINE search strategies. OUTCOME Most faculty publications in the CVs (86%) were indexed in MEDLINE. The research-interest-enhanced MEDLINE searches retrieved citations in the CVs that were also in MEDLINE with a recall of 0.53 and precision of 0.85. For every 10 citations in the research interest-enhanced search, on average 8.5 were in the CVs. The name entity searches retrieved a higher proportion of citations in the CVs (recall 0.94, precision 0.59) with a higher rate of citations not in the CVs: For every 10 citations in the faculty name searches, 7.3 citations were in the CVs. Name commonness or clinical or basic sciences appointment did not change these results. CONCLUSION MEDLINE searches, especially those based on research interests, can be used to populate faculty publication lists with high rates of accuracy. Author based searches can also be used, but they retrieve a higher proportion of irrelevant citations. This study confirms a successful instance of data reusability and integration at a large health academic sciences institution.
Invasive Staphylococcus aureus strains are highly variable in PFGE patterns, agr group and exoprotein production

In the present study, we have investigated 37 invasive Staphylococcus aureus strains (collected between 1997 and 2005) from 33 human episodes of septicaemia causing either endocarditis or vertebral osteomyelitis. All S. aureus strains were typed using pulsed field gel electrophoresis (PFGE), and most strains belonged to any of 4 different PFGE clusters. There was no correlation between any of the PFGE clusters with site of infection. All strains showed highly different expression patterns of extracellular proteins, i.e. we found a vast variation in the number of proteins and amount of individual proteins expressed by the different strains. There was no correlation between any cluster of exoprotein patterns with endocarditis or with vertebral osteomyelitis. We did not find any correlation between agr group and endocarditis, as previously reported. On the other hand, a correlation between some of the PFGE clusters with a certain agr group was found. Known risk factors for S. aureus infections were observed in a majority of the patients.
Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group.

PURPOSE To investigate whether radiotherapy can be reduced without loss of efficacy from extended field (EF) to involved field (IF) after four cycles of chemotherapy. PATIENTS AND METHODS Between 1993 and 1998, patients with newly diagnosed early-stage unfavorable HD were enrolled onto this multicenter study. Patients were randomly assigned to receive cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) + doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for two cycles followed by radiotherapy of 30 Gy EF + 10 Gy to bulky disease (arm A) or 30 Gy IF + 10 Gy to bulky disease (arm B). RESULTS Of 1,204 patients randomly assigned to treatment, 1,064 patients were informative and eligible for the arm comparison (532 patients in arm A; 532 patients in arm B). The median observation time was 54 months. Five years after random assignment, the overall survival (OSran) for all eligible patients was 91% and freedom from treatment failure (FFTFran) was 83%. Survival rates at 5 years after start of radiotherapy revealed no differences for arms A and B, respectively, in terms of FFTF (85.8% and 84.2%) and OS at 5 years (90.8% and 92.4%). There also were no differences between arms A and B, respectively, in terms of complete remission (98.5% and 97.2%), progressive disease (0.8% and 1.9%), relapse (6.4% and 7.7%), death (8.1% and 6.4%), and secondary neoplasia (4.5% and 2.8%). In contrast, acute side effects including leukopenia, thrombocytopenia, nausea, gastrointestinal toxicity, and pharyngeal toxicity were more frequent in the EF arm. CONCLUSION Radiotherapy volume size reduction from EF to IF after COPP + ABVD chemotherapy for two cycles produces similar results and less toxicity in patients with early-stage unfavorable HD.
Antiproliferative activity of interferon α and retinoic acid in SiHa carcinoma cells: The role of cell adhesion

Several lines of evidence have demonstrated that IFNs could be relevant in the treatment of certain neoplastic diseases such as carcinomas. In particular, IFN‐α, in addition to the anti‐proliferative and cytostatic effects, was demonstrated to be capable of inducing cell death by apoptosis both in vivo and in vitro. Numerous protocols have also been proposed which consider the association of IFN‐α with other drugs. Among these are retinoids, a class of compounds capable of inducing inhibition of cell growth and differentiation. We address the question here by analyzing the role of cell adhesion in susceptibility to IFN‐α, RA and their combination of a human cell line derived from a squamous carcinoma of the cervix, the Bcl‐2‐negative SiHa cell line. In this context, cytoskeleton components and several surface molecules playing a role in cell substrate and cell‐to‐cell relationships have been evaluated. We found that RA treatment is capable of improving stress fiber formation, decreasing cell detachment and increasing cell‐adhesion capability. However, no variations in the ability to adhere to specific extracellular‐matrix molecules were found in RA‐treated cells. No quantitative changes were detected in integrins involved as receptors for extracellular matrix molecules (VLA1‐VLA5) or in other cell‐adhesion‐associated molecules (e.g., CD44). By contrast, 2 important molecules involved in cell‐adhesion processes appeared to be up‐regulated by RA exposure: focal adhesion kinase and E‐cadherin, involved in adhesion plaque formation and cell‐to‐cell contacts, respectively. Keeping in mind the importance of adhesion properties in the cell‐growth pathway, our findings could be of interest in the study of carcinoma‐cell proliferation and metastatic potential. Int. J. Cancer 76:531–540, 1998. © 1998 Wiley‐Liss, Inc.
Iron-catalyzed reactions in organic synthesis.

A new iron(III) halide-promoted aza-Prins cyclization between γ,δ-unsaturated tosylamines and aldehydes provides six-membered azacycles in good to excellent yields. The process is based on the consecutive generation of γ-unsaturated-iminium ion and further nucleophilic attack by the unsaturated carbon−carbon bond. Homoallyl tosylamine leads to trans-2-alkyl-4-halo-1-tosylpiperidine as the major isomer. In addition, the alkyne aza-Prins cyclization between homopropargyl tosylamine and aldehydes gives 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines as the only cyclic products. The piperidine ring is widely distributed throughout Nature, e.g., in alkaloids,1 and is an important scaffold for drug discovery, being the core of many pharmaceutically significant compounds.2,3 The syntheses of these type of compounds have been extensively studied in the development of new drugs containing six-membered-ring heterocycles.4 Reactions between N-acyliminium ions and nucleophiles, also described as amidoalkylation or Mannich-type condensations, have been frequently used to introduce substituents at the R-carbon of an amine.5 There are several examples that involve an intramolecular attack of a nucleophilic olefin into an iminium cation for the construction of a heterocyclic ring system.6 Traditionally, the use of hemiaminals or their derivatives as precursors of N-acyliminium intermediates has been a common two-step strategy in these reactions.6a Among this type of cyclization is the aza-Prins cyclization,7 which uses alkenes as intramolecular nucleophile. However, cy† X-ray analysis. E-mail address: malopez@ull.es. (1) (a) Fodor, G. B. ; Colasanti, B. Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W. , Ed.; Wiley: New York, 1985; Vol. 23, pp 1-90. (b) Baliah, V. ; Jeyarama, R. ; Chandrasekaran, L. Chem. ReV. 1983, 83, 379-423. (2) Watson, P. S. ; Jiang, B. ; Scott, B. Org. Lett. 2000, 2, 3679-3681. (3) Horton, D. A. ; Bourne, G. T. ; Smythe, M. L. Chem. ReV. 2003, 103, 893-930. (4) Buffat, M. G. P. Tetrahedron 2004, 60, 1701-1729 and references therein. (5) Speckamp, W. N. ; Moolenaar, M. J. Tetrahedron 2000, 56, 3187- 3856 and references therein. (6) (a) Hiemstra, H. ; Speckamp, W. N. In ComprehensiVe Organic Synthesis; Trost, B. M. , Fleming, O. , Heathcock, C. H. , Eds.; Pergamon: New York, 1991; Vol. 2, pp 1047-1081. (b) Speckamp, W. N. ; Hiemstra, H. Tetrahedron 1985, 41, 4367-4416. (7) (a) Dobbs, A. P.; Guesne, S. J. J.; Hursthouse, M. B. ; Coles, S. J. Synlett 2003, 11, 1740-1742. (b) Dobbs, A. P.; Guesne, S. J. J.; Martinove, S. ; Coles, S. J.; Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880-7883. (c) Hanessian, S. ; Tremblay, M. ; Petersen, F. W. J. Am. Chem. Soc. 2004, 126, 6064-6071 and references therein. (d) Dobbs, A. P.; Guesne, S. J. Synlett 2005, 13, 2101-2103. ORGANIC
Spread of an emerging Mycobacterium tuberculosis drug-resistant strain in the western Cape of South Africa.

BACKGROUND South Africa has a high burden of drug-resistant tuberculosis (TB). METHODS Routine drug susceptibility testing was performed prospectively over a 2-year period on Mycobacterium tuberculosis isolates in two health districts of the Western Province, South Africa. A cluster of drug-resistant strains that shared a rare mutation in katG315 was found in 64 of the 450 cases identified as having been infected with drug-resistant TB. Isolates belonging to this cluster were phenotypically and genotypically characterised. Epidemiological and clinical characteristics were used to identify mechanisms leading to the acquisition and spread of this drug-resistant strain. RESULTS An outbreak of an emerging non-Beijing drug-resistant strain infecting 64 pulmonary tuberculosis (PTB) cases was identified. This previously undetected genotype (now designated DRF150) is characterised by five IS6110 insertions, specific spoligotypes and high levels of resistance to the first-line TB medications isoniazid, streptomycin and rifampicin. In 45% of the cases it is also resistant to ethambutol and pyrazinamide. Key factors leading to the development and spread of this drug-resistant genotype were inappropriate chemotherapy, poor adherence to treatment and prolonged periods of infectiousness due to delays in susceptibility testing. CONCLUSIONS Molecular markers allowed early identification of an emerging non-Beijing drug-resistant strain.
β1‐integrins dominate cell traffic of leukemic cells in human bone‐marrow stroma

Migration patterns of leukemic cells in bone marrow are largely regulated by cell contacts between leukemic cells and stromal cells or extra‐cellular matrix. The mechanism of this interaction with bone‐marrow stromal cells was studied in a human in vitro model. Migration behavior of erythroleukemia cell line K562, derived from a patient with chronic myeloid leukemia, was compared with that of the erythroleukemia cell line HEL92.1. 7 and the promyelocytic leukemia cell line HL60 from acute leukemias. Interaction varied between low binding affinity (K562) to intensive cell interaction (HEL92.1.7) followed by invasion into the stromal cell monolayer. Some of the HL60 cells adhered to stromal cells, while the remainder migrated into the stromal cell monolayer. The role of adhesion molecules in these cell interactions was determined. Distinct expression of β1‐integrins ICAM‐I, CD44 and VCAM‐I was detected on the different cell lines. Inhibition studies pointed to a dominant role of VLA‐4‐ and VLA‐5‐mediated interactions. K562 lacked VLA‐4 and a low affinity of the VLA‐5 on these cells resulted in an absence of binding to the bone‐marrow stroma. These results indicate the VLA‐5/fibronectin, VLA‐4/fibronectin and the VLA‐4/VCAM‐I interaction pathways between leukemic cells and bone‐marrow stroma. © 1996 Wiley‐Liss, Inc.
Translational readthrough of the PDE2 stop codon modulates cAMP levels in Saccharomyces cerevisiae

The efficiency of translation termination in yeast can vary several 100‐fold, depending on the context around the stop codon. We performed a computer analysis designed to identify yeast open reading frames (ORFs) containing a readthrough motif surrounding the termination codon. Eight ORFs were found to display inefficient stop codon recognition, one of which, PDE2, encodes the high‐affinity cAMP phosphodiesterase. We demonstrate that Pde2p stability is very impaired by the readthrough‐dependent extension of the protein. A 20‐fold increase in readthrough of PDE2 was observed in a [PSI+] as compared with a [psi–] strain. Consistent with this observation, an important increase in cAMP concentration was observed in suppressor backgrounds. These results provide a molecular explanation for at least some of the secondary phenotypes associated with suppressor backgrounds.
Electrocardiographic and Electrophysiologic Effects of Dexmedetomidine on Children

Dexmedetomidine (DEX) is a highly selective alpha‐2‐adrenergic agonist approved for short‐term sedation and monitored anesthesia care in adults. Its effects on the electrocardiography and cardiac conduction tissue are not well described in the literature. Therefore, we aimed to characterize the electrocardiographic and electrophysiologic effects of DEX in children.
Regulation by Rab3A of an endogenous modulator of neurotransmitter release at mouse motor nerve endings

Rab3A, a small GTP‐binding protein attached to synaptic vesicles, has been implicated in several stages in the process of neurosecretion, including a late stage occurring just prior to the actual release of neurotransmitter. The inhibitory neuromodulator adenosine also targets a late step in the neurosecretory pathway. We thus compared neuromuscular junctions from adult Rab3A−/‐ mutant mice with those from wild‐type mice with respect to: (a) the basic electrophysiological correlates of neurotransmitter release at different stimulation frequencies, and (b) the actions of exogenous and endogenous adenosine on neurotransmitter release in normal calcium solutions. Neither the spontaneous quantal release of acetylcholine (ACh) nor basal evoked ACh release (0.05 Hz) differed between the mutant and wild‐type mice. At 50‐100 Hz stimulation (10‐19 stimuli), facilitation of release was observed in the mutant mice but not in wild‐type, followed by a depression of ACh release in both strains. ACh release at the end of the stimulus train in the mutant mouse was approximately double that of the wild‐type mouse. The threshold concentration for inhibition of ACh release by exogenous adenosine was over 20‐fold lower in the mutant mouse than in the wild‐type mouse. The adenosine A1 receptor antagonist 8‐cyclopentyltheophylline (CPT) increased ACh release (0.05‐1 Hz stimulation) in the mutant mouse under conditions in which it had no effect in the wild‐type mouse. CPT had no effect on the pattern of responses recorded during repetitive stimulation in either strain. The results suggest that Rab3A reduces the potency of adenosine as an endogenous mediator of neuromuscular depression.
Recent advances in pharmacokinetic extrapolation from preclinical data to humans

The early characterisation of drug metabolism and pharmacokinetic (DMPK) properties of new chemical entities plays a key role in the pharmaceutical industry’s effort to reduce attrition. Specifically, a major goal of early DMPK studies is to accurately predict the behaviour of new chemical entities in humans, thus allowing likely failures to be terminated rapidly and resource to be placed on molecules most likely to succeed. The present review summarises progress over the past several years in the key technologies used in the pharmaceutical industry to achieve these goals: namely, in vivo, in vitro and in silico/computational tools. The limitations of the various assays are discussed, with attention also given to likely future directions in this field.
Use of transtympanic round window electrocochleography for threshold estimations in children.

OBJECTIVE This study aimed to evaluate the efficacy of round window electrocochleography for the estimation of hearing thresholds in difficult-to-test children. STUDY DESIGN The study was a retrospective analysis. SETTING A standard day-stay operating room was used. PATIENTS Round window electrocochleography was performed on 198 children between January 1993 and January 1996. INTERVENTION The intervention was diagnostic. MAIN OUTCOME MEASURE Clinically reliable pure-tone audiograms were obtained in 101 patients (50.9%) for comparisons of electrocochleography and behavioral thresholds. RESULTS The mean differences between electrocochleography and behavioral thresholds at 0.5, 1, 2, and 4 kHz were less than 6 dB. Ninety-seven percent of the results were within +30 to -30 dB, and approximately 86% of the results were within +20 to -20 dB. Good correlation coefficients of 0.83, 0.84, 0.91 and 0.88 were found between electrocochleography and behavioral thresholds at 0.5, 1, 2, and 4 kHz, respectively. Only 2 of 395 ears were complicated postoperatively by suppurative otitis media. There were no anesthetic complications. CONCLUSION Round window electrocochleography can be used in conjunction with other audiometric methods for threshold estimations in the difficult-to-test children and as part of the preoperative assessment for cochlear implantation.
Siblings in the context of anorexia nervosa.

BACKGROUND Sibling relationships may be relevant to the development of anorexia nervosa (AN), yet little research has focused on this aspect of the disorder. METHOD A narrative study of four women in various stages of recovery from AN is described and results relevant to sibling relationships are presented, enriched by published anecdotes and case studies. RESULTS The anorexic interviewees described much antagonism and rivalry and little warmth and intimacy between themselves and their siblings. They seemed to feel they did not belong sufficiently in their families and other social settings despite a strong desire to belong. LIMITATIONS The sample is small, reports subjective and retrospective and no control group was included. CONCLUSIONS It is suggested that anorexic girls often feel emotionally isolated from and misunderstood by siblings, who may have much to contribute to the process of therapy and recovery.
Extracting Semantic Frames from Thai Medical-Symptom Unstructured Text with Unknown Target-Phrase Boundaries

Due to the limitations of language-processing tools for the Thai language, pattern-based information extraction from Thai documents requires supplementary techniques. Based on sliding-window rule application and extraction filtering, we present a framework for extracting semantic information from medical-symptom phrases with unknown boundaries in Thai unstructured-text information entries. A supervised rule learning algorithm is employed for automatic construction of information extraction rules from hand-tagged training symptom phrases. Two filtering components are introduced: one uses a classification model to predict rule application across a symptom-phrase boundary based on instantiation features of rule internal wildcards, the other uses weighted classification confidence to resolve conflicts arising from overlapping extractions. In our experimental study, we focus our attention on two basic types of symptom phrasal descriptions: one is concerned with abnormal characteristics of some observable entities and the other with human-body locations at which primitive symptoms appear. The experimental results show that the filtering components improve precision while preserving recall satisfactorily.