Miracle-dz/UniFAR-FTUs huggingface dataset:
Evolution of spatial expression pattern

Summary How can complex patterns of gene expression evolve? Understanding the near‐precise repeatability of morphology created by animal development, through the interactions between morphogens and networks of transcription factors, is one of the most difficult outstanding problems in developmental biology. Spatial patterns are created in part by interactions between transcription factors and their DNA targets. Here we simulate the evolution of such interactions to compare the success and the evolvability of simple and complex gene networks in reaching a desired spatial pattern of expression along an embryo. We find that adding more genes to a network makes only a slight difference to evolvability. Expression patterns can evolve within a few hundred mutational events, and some simulations show partial redundancy. However, there is wide variation between simulations, with both simple and complex networks being liable to reach evolutionary “dead ends” that can only be escaped by means of an advantageous combination of individually deleterious mutations.
Interleukin-2 activity in patients with extensive small-cell lung cancer: a phase II trial of Cancer and Leukemia Group B.

BACKGROUND Chemotherapy may induce overall (complete plus partial) response rates of more than 50% and complete response rates up to 25% in extensive small-cell lung cancer (stage IIIB or IV), but survival is generally limited to 8-12 months. Interleukin-2 (IL-2) has demonstrated activity against this disease in vitro and has produced regression in melanoma and renal cell carcinoma. PURPOSE The purpose of this study was to determine in a prospective, nonblinded, phase II trial the activity of IL-2 in patients with extensive small-cell lung cancer who had not achieved complete remission with chemotherapy. METHODS The 68 patients eligible for the study were initially treated with at least one dose of combination chemotherapy with cisplatin, doxorubicin, cyclophosphamide, and etoposide (PACE). Of the 50 who did not obtain complete remission with PACE, 24 who had measurable or evaluable disease and whose medical condition allowed further therapy were treated with IL-2. Beginning 3 weeks after the last dose of PACE, IL-2 was administered intravenously at 4.5 million Nutley units/m2 per day as a continuous infusion for 96 hours, followed by a 3-day rest. The planned duration of therapy was 8 weeks. RESULTS Of the 24 patients eligible to receive IL-2, four (17%) with measurable disease or evaluable but not measurable disease obtained a complete response after IL-2 therapy; one (4%) patient had a partial response. The overall response rate was 21%. Complete responses continued for 8, 9, and more than 11 months in three patients; the remaining patient developed acute myelomonocytic leukemia while in complete remission approximately 8 months after the start of IL-2 therapy. Only five of the 24 patients were able to complete the planned 8 weeks of IL-2 therapy. Therapy was discontinued in 11 patients because of life-threatening side effects, in six because of disease progression, and in two who withdrew from the study, probably related to IL-2 toxicity. CONCLUSIONS These results indicate that IL-2 has some activity in extensive small-cell lung cancer and suggest that IL-2 is not cross-resistant with PACE therapy. IMPLICATIONS Further studies are needed to define the optimum timing, dose, and schedule of IL-2 and to determine whether the agent has a role in the therapy of small-cell lung cancer.
A Chemometric Analysis for Evaluation of Early-Stage Cartilage Degradation by Infrared Fiber-Optic Probe Spectroscopy

In vivo identification of early-stage cartilage degradation could positively impact disease progression in osteoarthritis, but to date remains a challenge. The primary goal of this study was to develop an infrared fiber-optic probe (IFOP) chemometric method using partial least squares (PLS1) to objectively determine the degree of cartilage degradation. Arthritic human tibial plateaus (N = 61) were obtained during knee replacement surgery and analyzed by IFOP. IFOP data were collected from multiple regions of each specimen and the cartilage graded according to the Collins Visual Grading Scale of 0, 1, 2, or 3. These grades correspond to cartilage morphology that displayed normal, swelling or softening, superficially slight fibrillation, and deeper fibrillation or serious fibrillation, respectively. The model focused on detecting early cartilage degradation and therefore utilized data from grades 0, 1, and 2. The best PLS1 calibration utilized the spectral range 1733–984 cm−1, and independent validation of the model utilizing 206 spectra to create a model and 105 independent test spectra resulted in a correlation between the predicted and actual Collins grade of R2 = 0.8228 with a standard error of prediction of 0.258 with a PLS1 rank of 15 PLS factors. A preliminary PLS1 calibration that utilized a cross-validation technique to investigate the possibility of correlation with histological tissue grade (33 spectra from 18 tissues) resulted in R2 = 0.8408 using only eight PLS factors, a very encouraging outcome. Thus, the groundwork for use of IFOP-based chemometric determination of early cartilage degradation has been established.
Potential Selective Inhibitors against Rv0183 of Mycobacterium tuberculosis Targeting Host Lipid Metabolism

Tuberculosis is the second leading infectious killer with 9 million new cases in 2009. Extensive use of pathogen’s lipid metabolism especially in utilizing the host lipids and virulence highlights the importance of exported lipid‐catabolizing enzymes. Current study aims to emphasize the importance of Rv0183, an exported monoacylglycerol lipase, involved in metabolizing the host cell membrane lipids. Sequence analysis and homology modeling shows Rv0183 is highly conserved throughout mycobacterial species even in Mycobacterium leprae and also significantly divergent from mammalian lipases. Additionally, employing virtual screening using NCI diversity set and ZINC database with criteria of molecules with higher predicted free energy of binding toward Rv0183 than human lipase, potential inhibitors have been identified for Rv0183. A tautomer of ZINC13451138, known inhibitor for HIV‐1 integrase is the best hit with difference in free energy of binding of 8.72 kcal/mol. The sequence and structure analysis were helpful in identifying the ligand binding sites and molecular function of the mycobacterial specific monoacylglycerol lipase. Rv0183 represents a suitable and promising drug target and is also a step towards understanding dormancy development and reactivation, thereby addressing pathogen’s drug resistance. Experimental studies on the discovered potential inhibitors in this virtual screen should further validate the therapeutic utility of Rv0183.
Inhibition of Glucosyltransferase Activity by Antisera to Known Serotypes of Streptococcus mutans

Using a recently developed assay for glucosyltransferase activity based on 14C-glucose incorporation into an alcohol-insoluble polysaccharide, we were able to study inhibition by antibody of this enzyme activity. Rabbit antibody was relatively specific for the strain of Streptoccus mutans from which the enzyme was obtained. Absorption studies showed that neither removal of antibodies directed to dextran nor absorption with intact bacteria offset the enzyme-inhibitory capacity of these sera, whereas absorption with partially purified enzyme did result in removal of the inhibitory capacity.
Patients with Crohn's Disease with High Body Mass Index Present More Frequent and Rapid Loss of Response to Infliximab

Background: Infliximab (IFX) is effective in inducing and maintaining remission in patients with luminal and anoperineal Crohn's disease (CD). However, treatment failure within 12 months after initiating IFX is observed in a significant proportion of patients. The aim of the present study was to determine whether the body mass index (BMI) affects response to IFX during the first year of treatment in patients with CD. Methods: All patients with luminal CD who began IFX between January 2010 and May 2014 were prospectively included. BMI was calculated before IFX treatment was begun, and patients were divided into 3 groups: normal BMI (BMI < 25 kg/m2), overweight patients (BMI of 25.0–30 kg/m2), and obese patients (BMI > 30.0 kg/m2). The primary outcome was to evaluate the rate and delay of IFX optimization during the first year of treatment among normal weight, overweight, and obese patients. Results: One hundred forty patients were included. Demographic and clinical characteristics at IFX initiation were comparable among the 3 groups. Within 12 months after the initiation of IFX, the rate of IFX optimization was significantly higher in overweight and obese patients than in the normal BMI group: 52%, 56%, and 20%, respectively (P = 0.0002). The median time until optimization of IFX was significantly shorter in overweight and obese patients than in the normal BMI group: 7, 7, and 10 months, respectively (P = 0.03). A BMI >25 kg/m2 was significantly associated with IFX optimization within 12 months on multivariate analysis. Conclusion: This is the first study to show that optimization of IFX is more frequent and faster in obese and overweight patients with CD and occurs within 12 months after beginning IFX, suggesting that an induction regimen with higher doses of IFX and a tight control of IFX concentrations may be needed in these patients.
Underlying cause discovered for a prior idiopathic AMI

The authors previously reported on an active, young male with normal coronaries who sustained an acute myocardial infarction (AMI). The acute cause was a coronary thrombus; however, the cause of this thrombus and a definitive diagnosis remained elusive for 18 months until a new series of events, including symptoms of breathlessness, dizziness and collapse led to acute hospital admission. CT scan revealed numerous deep venous thromboses in the right leg and bilateral pulmonary emboli (PE). Acute pharmacological thrombolysis eliminated breathlessness and significantly reduced the risk of mortality. Clinical consensus suggests a coagulopathy, requiring indefinite treatment with Warfarin. In young individuals presenting with AMI, lifestyle, personal, family and clinical history should be considered and coronary artery disease should not be assumed until further tests have eliminated coagulopathy. In those presenting with breathlessness and a history which includes AMI, a CT scan is indicated to eliminate concerns of venous thromboembolism generally and PE specifically where untreated survival times are short.
Neisseria meningitidis tonB, exbB, and exbD genes: Ton-dependent utilization of protein-bound iron in Neisseriae

We have recently cloned and characterized the hemoglobin (Hb) receptor gene, hmbR, from Neisseria meningitidis. To identify additional proteins that are involved in Hb utilization, the N. meningitidis Hb utilization system was reconstituted in Escherichia coli. Five cosmids from N. meningitidis DNA library enabled a heme-requiring (hemA), HmbR-expressing mutant of E. coli to use Hb as both porphyrin and iron source. Nucleotide sequence analysis of DNA fragments subcloned from the Hb-complementing cosmids identified four open reading frames, three of them homologous to Pseudomonas putida, E. coli, and Haemophilus influenzae exbB, exbD, and tonB genes. The N. meningitidis TonB protein is 28.8 to 33.6% identical to other gram-negative TonB proteins, while the N. meningitidis ExbD protein shares between 23.3 and 34.3% identical amino acids with other ExbD and TolR proteins. The N. meningitidis ExbB protein was 24.7 to 36.1% homologous with other gram-negative ExbB and TolQ proteins. Complementation studies indicated that the neisserial Ton system cannot interact with the E. coli FhuA TonB-dependent outer membrane receptor. The N. meningitidis tonB mutant was unable to use Hb, Hb-haptoglobin complexes, transferrin, and lactoferrin as iron sources. Insertion of an antibiotic cassette in the 3' end of the exbD gene produced a leaky phenotype. Efficient usage of heme by N. meningitidis tonB and exbD mutants suggests the existence of a Ton-independent heme utilization mechanism. E. coli complementation studies and the analysis of N. meningitidis hmbR and hpu mutants suggested the existence of another Hb utilization mechanism in this organism.
La medición del desempeño ante la innovación mediante el uso de indicadores y macroindicadores

Los diagnosticos de innovacion tratan de aproximarse al comportamiento empresarial ante diferentes aspectos de la innovacion. Este trabajo ofrece una metodologia de medicion a partir de los resultados de un diagnostico de innovacion realizado sobre una muestra de empresas valencianas pertenecientes al sector iluminacion. Se propone una agregacion a dos niveles. En primer lugar, las variables originales se resumen en una serie de indicadores, los cuales, a su vez, se agrupan nuevamente de forma consistente hasta obtener 3 macro-indicadores que nos informan sobre la estrategia de innovacion, los resultados de su actividad de innovacion y la propension a la colaboracion tecnologica con otros agentes.
Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops.

OBJECTIVE The development of bronchopulmonary dysplasia (BPD) often has been attributed to injury from mechanical ventilation and supplemental oxygen. Early lung inflammation in infants with BPD has been thought to be secondary to these factors. The purpose of this study was to evaluate whether preexisting (prenatal) inflammation may be a primary causative factor in the development of BPD. METHODS Intubated newborns of less than 2,000 g birth weight were prospectively enrolled. The presence or absence of chorioamnionitis was documented. Lung inflammation was evaluated on days 1, 2, and 4 of intubation by assaying concentrations of interleukin 1 beta (IL-1 beta), thromboxane B2, leukotriene B4, and prostaglandin E2 in tracheal lavages. Infants in whom BPD developed were compared with those in whom it did not using these measures. RESULTS Fifty-three infants were enrolled; 41 survived. Thirty-eight had respiratory distress syndrome; 15 were intubated for other diagnoses. Infants prenatally exposed to chorioamnionitis were less likely to present with respiratory distress syndrome; however, chorioamnionitis was significantly associated with both the presence of IL-1 beta from the first day of intubation and the development of BPD. Tracheal lavage concentrations of IL-1 beta were higher in infants in whom BPD developed. Thromboxane B2 concentrations were similar on day 1 but were higher on days 2 and 4 in infants in whom BPD developed. CONCLUSIONS In this study, intubated infants weighing less than 2,000 g at birth in whom BPD developed had increased exposure to inflammation prenatally (chorioamnionitis) and evidence of increased lung inflammation from the first postnatal day. We speculate that chorioamnionitis may accelerate lung maturation but that it also causes lung inflammation and subsequent lung injury in intubated infants, fostering the development of BPD.
Race Performance and Exercise Intensity of Male Amateur Mountain Runners During a Multistage Mountain Marathon Competition Are Not Dependent on Muscle Strength Loss or Cardiorespiratory Fitness

Abstract Gatterer, H, Schenk, K, Wille, M, Raschner, C, Faulhaber, M, Ferrari, M, and Burtscher, M. Race performance and exercise intensity of male amateur mountain runners during a multistage mountain marathon competition are not dependent on muscle strength loss or cardiorespiratory fitness. J Strength Cond Res 27(8): 2149–2156, 2013—The aims of this study were to quantify the cardiorespiratory fitness level of amateur mountain runners and to characterize the related cardiorespiratory and muscular strain during a multistage competition. Therefore, 16 male amateur participants performed an incremental treadmill test before the Transalpine-Run 2010. Besides race time, heart rate (HR) was monitored using portable HR monitors during all stages, and countermovement jump ability was assessed after each stage. Overall race time and race times of the single stages were not related to any of the cardiorespiratory fitness parameters assessed during the incremental treadmill test (e.g., V[Combining Dot Above]O2max, ventilatory threshold). Average HR during the first stage was 81 ± 7% of the maximal HR and decreased to 73 ± 6% during the following stages. Creatine kinase activity as an indirect marker of muscle damage and strain amounted to 1,100 ± 619 U·L−1 after the third stage and was related to the decrease in the mean HR between stage 1 and stage 2 (r = −0.616, p < 0.05). Jump ability decreased continuously in the course of the race but was not related to exercise intensity. In conclusion, this study showed that race performance during a multistage mountain marathon does not depend on cardiorespiratory fitness parameters determined in the laboratory. Furthermore, the mean HR decreased after the first stage and remained constant during the following stages independent of the decreased muscle strength. We interpret these data to mean that performance differences were a result of insufficient recovery after the first day of multistage mountain running and the different individual pacing strategies. It is worth mentioning that also other factors, not determined in this investigation, could be responsible for the present outcomes (e.g., nutrition, genetics, psychological and environmental factors, or different training programs).
Channel-Aligned Multiuser Two-Way Relaying Scheme With Finite Feedforward

We consider a multiuser two-way amplify-and-forward relay channel with finite feedforward (FF) of the beamforming weights. The relay decides the beamforming weights of the users based on the full channel knowledge and feeds the beamforming information to the users through the band-limited FF channels. Assuming random vector quantization (RVQ), the performance analysis of the finite-FF system is presented. Similar to the multiuser broadcast channel, the average sum rate saturates at a high SNR with a fixed-size codebook. The scaling rate of the codebook size necessary to overcome the saturation and to follow up the multiplexing gain is presented. Supporting simulation results are presented.
Core Conflictual Relationship Themes of Men and Women Who are Violent toward Their Partners

The Core Conflictual Relationship Themes of men and women violent toward their partners and entering psychotherapy, students violent toward their partners, and nonviolent students (n = 84; n = 14 in each of the six groups) were compared. Men and women entering psychotherapy more often had negative Wish elements than others. The wish element was “to be loved” for 11 of the 14 student women violent toward their partners and 5 of the 14 nonviolent student women.
Naturally occurring methylation inhibitor: DNA hypomethylation and hemoglobin synthesis in human K562 cells

A naturally occurring methylation inhibitor isolated from rabbit liver and named methinin inhibits a number of methyltransferases. Methinin is a low-molecular-weight compound (1,400) that has an active amine group. This compound inhibits the DNA methyltransferase of human erythroleukemia cells (K562) in vitro. When the K562 cells were grown in medium containing methinin, fetal hemoglobin was produced. Small but detectable amounts of adult hemoglobin were also produced. Methinin was not toxic to these cells. The overall rate of genomic DNA methylation was reduced by 60% in cells grown in medium containing methinin. Southern blots of genomic DNA from methinin-treated cells and untreated cells hybridized to a 32P-labeled globin gene probe showed that one site in the globin gene region was hypomethylated. Methinin is a naturally occurring compound which inhibits DNA methylation both in vitro and in vivo.
Recurrent Systemic Pneumococcal Disease in Children

Background: Recurrent systemic pneumococcal infection usually occurs in immunocompromised patients and patients with underlying conditions. Methods: Between 1993 and 2006, investigators at 8 pediatric hospitals prospectively identified cases of invasive pneumococcal disease (IPD) and retrospectively documented demographics and clinical information. Antibiotic susceptibility was determined for penicillin and ceftriaxone by microbroth dilution. Isolates were serotyped and molecular relatedness determined using pulse field gel electrophoresis (PFGE). Results: Four thousand sixty-seven children were diagnosed with IPD over 12.3 years. One hundred and 8 episodes of recurrent disease were seen in 90 children (2.6%); 75 experienced 2 infections, 12 experienced 3 infections and 3 experienced 4 infections. Fourteen of the 15 children with >2 episodes of infection had underlying conditions. The mean duration between 1st and 2nd infection was 22.9 weeks for children with no known underlying condition and 43.0 weeks for children with an underlying condition (P = 0.001). Seventy episodes of IPD among the 90 patients were caused by a different serotype or a different genotype as demonstrated by the PFGE. Sixteen children had intervals <30 days between infections; 7 were caused by different strains. Conclusions: Approximately 80% of the children with recurrent invasive pneumococcal disease had underlying conditions. Seven of 16 children with recurrent infection <30 days apart were caused by acquisition of a new strain. Relapse of infection requires documentation that the pneumococcal isolates are not only the same serotype but also have the same PFGE patterns.
The Roche European American Cataract Trial (REACT): A randomized clinical trial to investigate the efficacy of an oral antioxidant micronutrient mixture to slow progression of age-related cataract

context Funding surgery worldwide for age-related cataract (ARC), a leading cause of blindness, is a huge economic burden. Non-surgical means of slowing ARC progression could benefit patients and reduce this burden. objective To determine if a mixture of oral antioxidant micronutrients [mg/day] (ß-carotene [18], vitamin C [750], and vitamin E [600]) would modify progression of ARC. design REACT was a multi-centered, prospective, double-masked, randomized, placebo-controlled, 3-year trial. setting Consecutive adult American and English outpatients with early ARC were recruited. patients Four-hundred-and-forty-five patients were eligible; 297 were randomized; 231 (78%) were followed for two years; 158 (53%) were followed for three years; 36 (12%) were followed for four years. Twelve patients died during the trial (9 on vitamins; 3 on placebo (p = 0.07)). There were no serious safety issues. intervention After a three-month placebo run-in, patients were randomized by clinical center to the vitamin or placebo groups and followed every four months. main outcome measure Cataract severity was documented with serial digital retroillumination imagery of the lens; progression was quantified by image analysis assessing increased area of opacity. This measure of area, ‘increase % pixels opaque’ (IPO), was the main outcome measure. results There were no statistically significant differences between the treatment groups at baseline. The characteristics of dropouts and the mean follow-up times by treatment group were the same. After two years of treatment, there was a small positive treatment effect in U.S. patients (p = 0.0001); after three years a positive effect was apparent (p = 0.048) in both the U.S. and the U.K. groups. The positive effect in the U.S. group was even greater after three years: (IPO = 0.389 (vitamin) vs. IPO = 2.517 (placebo); p = 0.0001). There was no statistically significant benefit of treatment in the U.K. group. In spite of nearly perfect randomization into treatment groups, the U.S. and U.K. cohorts differed significantly. conclusion Daily use of the afore-mentioned micronutrients for three years produced a small deceleration in progression of ARC.