Miracle-dz/UniFAR-FTUs huggingface dataset:
Receptor Clustering Is Involved in Reelin Signaling

ABSTRACT The Reelin signaling cascade plays a crucial role in the correct positioning of neurons during embryonic brain development. Reelin binding to apolipoprotein E receptor 2 (ApoER2) and very-low-density-lipoprotein receptor (VLDLR) leads to phosphorylation of disabled 1 (Dab1), an adaptor protein which associates with the intracellular domains of both receptors. Coreceptors for Reelin have been postulated to be necessary for Dab1 phosphorylation. We show that bivalent agents specifically binding to ApoER2 or VLDLR are sufficient to mimic the Reelin signal. These agents induce Dab1 phosphorylation, activate members of the Src family of nonreceptor tyrosine kinases, modulate protein kinase B/Akt phosphorylation, and increase long-term potentiation in hippocampal slices. Induced dimerization of Dab1 in HEK293 cells leads to its phosphorylation even in the absence of Reelin receptors. The mechanism for and the sites of these phosphorylations are identical to those effected by Reelin in primary neurons. These results suggest that binding of Reelin, which exists as a homodimer in vivo, to ApoER2 and VLDLR induces clustering of ApoER2 and VLDLR. As a consequence, Dab1 becomes dimerized or oligomerized on the cytosolic side of the plasma membrane, constituting the active substrate for the kinase; this process seems to be sufficient to transmit the signal and does not appear to require any coreceptor.
Should I accept this kidney?

Background. Transplant candidates frequently ask whether they should, based on information available at the time, accept a cadaver kidney or wait for a potentially better one.Methods. We analyzed 937 first and second cadaver transplants done between January 1, 1984 and December 31, 1997 to determine if information available at the time an offer is made could be used to predict long‐term graft survival.Results. By Cox regression, risk factors for worse long‐term graft survival were older donor age, cardiovascular or cerebrovascular cause of donor death, and delayed graft function (DGF). HLA‐ABDR mismatch was marginally significant. Whether DGF will occur is not known at the time of an offer, but risk factors can be determined; we found these to be older donor age and> 10% panel‐reactive antibodies (PRA) at transplantation (by Cox regression). Using these variables (PRA, ABDR mismatch, donor age, and donor cause of death) known at the time of an offer, we calculated the relative risk of worse long‐term graft survival for each subgroup ( Table 3 in manuscript). In general, older age and donor death from cardiovascular or cerebrovascular disease were associated with worse outcome. Kidneys from donors of <50 yr had the best outcome, irrespective of match.Conclusion. The data provided can be used to help guide patients as to whether they are better off accepting an offered kidney or waiting for a potentially better one. If an offer is declined, the next kidney may have a potentially worse outcome.
Epidemiology of Pretransplant EBV and CMV Serostatus in Relation to Posttransplant Non-Hodgkin Lymphoma

Background. Despite the importance of non-Hodgkin lymphoma (NHL) as a posttransplant complication, the relationship between NHL and recipient seropositivity for Epstein-Barr virus (EBV) or cytomegalovirus (CMV) is incompletely understood. Methods. Kidney, heart, and liver transplant recipients reported to the Collaborative Transplant Study with known pretransplant EBV and CMV serostatus were analyzed in terms of clinically manifest NHL. Cox multivariate regression analysis was performed to account for a wide range of possible confounders. Results. In total, 18,682 kidney, 2042 heart, and 2616 liver transplant recipients were analyzed. Regardless of age, pretransplant EBV− serostatus was significantly associated with risk of NHL in kidney transplant recipients (P<0.001). There was no significant difference in lymphoma rates according to CMV+ and CMV− serostatus among EBV− and EBV+ recipients (log-rank P=0.55 and P=0.57, respectively), but hospitalization for CMV disease during year 1 posttransplant was associated with subsequent NHL (hazard ratio [HR] 6.1; 95% confidence interval [CI] 2.0–18.4; P=0.001). EBV− serostatus was also associated with increased risk of NHL in heart transplant patients (HR 3.6; 95% CI 1.1–11.3; P=0.031) but, contrary to expectation, not in liver recipients (HR 0.6; 95% CI 0.1–1.7; P=0.32). Conclusions. In view of the striking increase in risk of NHL in EBV− kidney transplant recipients of all ages, EBV serostatus should be determined pretransplant in all age groups. CMV serostatus was not independently associated with risk of NHL after kidney transplantation. Surprisingly, in liver transplantation, the risk of NHL was virtually unaffected by EBV serostatus.
Genetic evidence that bound coagulase of Staphylococcus aureus is not clumping factor

Staphylococcus aureus Newman cells carry a surface receptor for fibrinogen called clumping factor. The bacteria also express coagulase, an extracellular protein that binds to prothrombin to form a complex with thrombinlike activity which coverts fibrinogen to fibrin. We have confirmed a recent report (M. K. Bodén and J.-I. Flock, Infect. Immun. 57:2358-2363, 1989) that coagulase can bind to fibrinogen as well as to prothrombin and also that a fraction of coagulase is firmly attached to the cell. A mutant with a deletion in the chromosomal coa gene was isolated by allelic replacement. Allelic replacement either was directly selected by electrotransformation of S. aureus R3N4220 with a nonreplicating suicide plasmid, pCOA18, carrying the delta coa::Tcr mutation or occurred after transduction of the integrated pCOA18 plasmid. The coa mutant was completely devoid of coagulase activity but interacted both with soluble fibrinogen and with solid-phase fibrinogen with the same avidity as the parental strain. This strongly suggests that the bound form of coagulase is not clumping factor and is not responsible for the adherence of S. aureus Newman to solid-phase fibrinogen. The fibrinogen binding determinant of coagulase was located in the C terminus of the protein, by analyzing truncated fusion proteins, in contrast to the prothrombin-binding region which was located in the N terminus.
Quantifying the contribution of audibility to recognition of compression-amplified speech.

OBJECTIVE The speech-recognition advantages of wide-dynamic range compression (WDRC) hearing aids are believed to be a direct result of improved audibility. The main objective of this study was to compare the relationship between increasing audibility and recognition for compression-amplified versus linearly amplified speech, using a quantitative measure of audibility. A second objective was to explore the adequacy of the Aided Articulation Index (Stelmachowicz, Lewis, Kalberer, & Creutz, 1994) in describing performance with WDRC-amplified speech. DESIGN Sixteen listeners with mild to severe sensorineural hearing loss were tested on recognition of nonsense syllables that had been digitally processed with linear or WDRC amplification. Speech recognition scores were obtained for three input levels that differed in audibility relative to the listeners' hearing thresholds. An Aided Audibility Index (AAI), ranging from 0.0 (inaudible) to 1.0 (fully audible), was calculated for each listener and condition. This importance-weighted index represents the portion of the speech signal that is available to the listener. The relationship between audibility and recognition was then examined for each type of amplification. RESULTS At low and moderate input levels, AAI values and corresponding recognition scores were higher for the compression-amplified than for the linearly amplified speech. At high input levels, AAIs and recognition scores were essentially the same for both types of amplification. Recognition scores increased monotonically as a function of the AAI for both linear and WDRC amplifiers. There was no significant difference between the functions for linearly amplified versus compression-amplified speech. In other words, a given increase in audibility resulted in the same increase in recognition for both types of amplification. CONCLUSIONS Increasing the amount of audible speech information plays the same role in recognition for compression-amplified as for linearly amplified speech. This suggests that, at least for the conditions tested here, compression does not introduce detrimental changes to the speech signal that offset the benefits of improved audibility. Accuracy of the compression-amplified AAI can be improved by substituting measured speech ranges for the estimated speech ranges used in the standard AAI calculation. In the absence of measured speech ranges, the standard AAI provides a close approximation.
Computer Simulator Training Enhances the Competency of Gastroenterology Fellows at Colonoscopy: Results of a Pilot Study

OBJECTIVES:Computer-based colonoscopy simulation (CBCS) is being utilized in endoscopy training without supporting evidence that it improves patient-based colonoscopy performance. The goal of this pilot study was to determine if CBCS training improves gastroenterology (GI) fellows' patient-based colonoscopy skills.METHODS:Competency at colonoscopy among 4 novice GI fellows who completed a 6-h CBCS curriculum was compared with 4 novice fellows who were not CBCS-trained. Measurements of competency were rendered by supervising faculty by recording “insertion time,”“depth of unassisted insertion,”“independent procedure completion,”“ability to identify endoscopic landmarks,”“inserts in a safe manner,”“adequately visualizes mucosa on withdrawal,” and “responds appropriately to patient discomfort” with each colonoscopy.RESULTS:Simulator-trained fellows outperformed traditionally trained fellows during their initial 15 colonoscopies in all performance aspects except “insertion time” (pp < 0.05). Simulator-trained fellows inserted the endoscope significantly further and reached the cecum independently nearly twice as often during this early training period. Three parameters (“depth of insertion,”“independent completion,” and “ability to identify landmarks”) demonstrated a continued advantage out to 30 colonoscopies. Beyond 30 procedures, there was no difference in the performance of the two groups.CONCLUSION:In this pilot study, a 6-h CBCS curriculum provides an early training advantage by enhancing competency at the early stages of patient-based colonoscopy. These advantages are negligible after approximately 30 patient-based procedures. CBCS-enhanced training may allow faculty to be more efficient with their colonoscopy practice.
Seven-year change in graded exercise treadmill test performance in young adults in the CARDIA study. Cardiovascular Risk Factors in Young Adults.

PURPOSE Most studies of physical fitness change have been relatively small, not population-based, and lacking in women and nonwhites. The purpose of this analysis was to evaluate the 7-yr change in physical fitness in a biracial (black and white) population of young men and women. METHODS We evaluated change in exercise treadmill test performance in a biracial (black and white) population of 1,962 young adults, ages 18-30 yr at baseline, who completed symptom-limited graded exercise treadmill tests at the baseline (1985-1986) and year 7 (1992-1993) examinations of the CARDIA study. RESULTS Mean test duration decreased 58 s (9.5%) over 7 yr (black men, 13.6% decrease, white men, 7.4%; black women, 11.1%; white women, 7.0%). Mean time to heart rate 130 (WL130), a measure of submaximal performance, decreased 31 s (11.3%) (black men, 16.9%; white men, 10.0%; black women, 12.3%; white women, 6.1%). Baseline body mass index (BMI) and physical activity were not statistically significant predictors of test duration change in any race-gender group, but change in BMI and activity were. Seven-year weight gain >20 lbs (31% of cohort) was associated with a large decrease in fitness (18.5% decrease in mean duration, 21.8% decrease in WL130). CONCLUSION These data suggest that fitness declines during young adulthood in blacks and whites and that fitness changes are related to changes in weight and physical activity.
Binding of 14-3-3β Regulates the Kinase Activity and Subcellular Localization of Testicular Protein Kinase 1*

Testicular protein kinase 1 (TESK1) is a serine/threonine kinase that phosphorylates cofilin and induces actin cytoskeletal reorganization. The kinase activity of TESK1 is stimulated by integrin-mediated signaling pathways, but the mechanism of regulation has remained unknown. By using the yeast two-hybrid system, we identified 14-3-3β to be the binding protein of TESK1. Specific interaction between TESK1 and 14-3-3β became evident in in vitro and in vivo co-precipitation assays. 14-3-3β interacts with TESK1 through the C-terminal region of TESK1 and in a manner dependent on the phosphorylation of Ser-439 within an RXXSXP motif. Binding of 14-3-3β inhibited the kinase activity of TESK1. During cell spreading on fibronectin, the TESK1/14-3-3β interaction significantly decreased, in a time course that inversely correlated with increase in TESK1 kinase activity. Thus, the dissociation of 14-3-3β from a TESK1/14-3-3β complex is likely to be involved in the integrin-mediated TESK1 activation. In HeLa cells, TESK1, together with 14-3-3β, accumulated at the cell periphery when cells were plated on fibronectin, whereas they were diffusely distributed in the cytoplasm in the case of non-stimulated cells. We propose that 14-3-3β plays important roles in regulating the kinase activity of TESK1 and localizing TESK1 to cell adhesion sites following integrin stimulation.
El estilo de liderazgo y la orientación al mercado: Su repercusión en la satisfacción en el trabajo del docente universitario

El presente trabajo pretende analizar la relacion entre los tipos de liderazgo y la orientacion al mercado en el ambito universitario asi como la repercusion de esta relacion en la satisfaccion en el trabajo del docente universitario, en un pais en desarrollo. Para ello se ha seleccionado el Centro de Estudios Superior del Estado de Sonora (Mexico), contando con una muestra de 219 docentes universitarios. Los resultados muestran que los tipos de liderazgo instrumental y compasivo, tienen una relacion directa y positiva con la orientacion al mercado; pero no asi el liderazgo participativo que, aunque tiene una relacion positiva, no es significativa. Ademas, se confirma que existe una relacion directa y positiva entre la orientacion al mercado del profesor y su satisfaccion en el trabajo.
A tetracycline controlled activation/repression system with increased potential for gene transfer into mammalian cells

Tight control of gene activity has been achieved in cells and transgenic organisms using the Tet regulatory systems. Unregulated basal transcription can, however, be observed whenever integration of target genes driven by promoters responsive to tetracycline controlled transcriptional activators (tTA, rtTA) does not occur at suitable chromosomal sites. Moreover, in viral vectors containing both the tTA coding sequence and the regulated target gene, proximity of the enhancer element driving tTA/rtTA expression to the responsive unit will lead to elevated background levels. Similarly when tTA/rtTA responsive transcription units are in a non‐integrated state as eg. , during transient expression, intrinsic residual transcription persists in their ‘off’ state, which can differ in intensity among different cell types.
In Vivo Electroporation Enhances the Immunogenicity of Hepatitis C Virus Nonstructural 3/4A DNA by Increased Local DNA Uptake, Protein Expression, Inflammation, and Infiltration of CD3+ T Cells1

The mechanisms by which in vivo electroporation (EP) improves the potency of i.m. DNA vaccination were characterized by using the hepatitis C virus nonstructural (NS) 3/4A gene. Following a standard i.m. injection of DNA with or without in vivo EP, plasmid levels peaked immediately at the site of injection and decreased by 4 logs the first week. In vivo EP did not promote plasmid persistence and, depending on the dose, the plasmid was cleared or almost cleared after 60 days. In vivo imaging and immunohistochemistry revealed that protein expression was restricted to the injection site despite the detection of significant levels of plasmid in adjacent muscle groups. In vivo EP increased and prolonged NS3/4A protein expression levels as well as an increased infiltration of CD3+ T cells at the injection site. These factors most likely additively contributed to the enhanced and broadened priming of NS3/4A-specific Abs, CD4+ T cells, CD8+ T cells, and γ-IFN production. The primed CD8+ responses were functional in vivo, resulting in elimination of hepatitis C virus NS3/4A-expressing liver cells in transiently transgenic mice. Collectively, the enhanced protein expression and inflammation at the injection site following in vivo EP contributed to the priming of in vivo functional immune responses. These localized effects most likely help to insure that the strength and duration of the responses are maintained when the vaccine is tested in larger animals, including rabbits and humans. Thus, the combined effects mediated by in vivo EP serves as a potent adjuvant for the NS3/4A-based DNA vaccine.
Is a low transfusion threshold safe in critically ill patients with cardiovascular diseases?

ObjectiveTo compare a restrictive red blood cell transfusion strategy with a more liberal strategy in volume-resuscitated critically ill patients with cardiovascular disease. SettingTwenty-two academic and three community critical care units across Canada. Study Design Randomized controlled clinical trial. Study PopulationThree hundred fifty-seven critically ill patients with cardiovascular diseases from the Transfusion Requirements in Critical Care trial who had a hemoglobin concentration of <90 g/L within 72 hrs of admission to the intensive care unit. InterventionsPatients were randomized to a restrictive strategy to receive allogeneic red blood cell transfusions at a hemoglobin concentration of 70 g/L (and maintained between 70 and 90 g/L) or a liberal strategy to receive red blood cells at 100 g/L (and maintained between 100 and 120 g/L). ResultsBaseline characteristics in the restrictive (n = 160) and the liberal group (n = 197) were comparable, except for the use of cardiac and anesthetic drugs (p < .02). Average hemoglobin concentrations (85 ± 6.2 vs. 103 ± 6.7 g/L;p < .01) and red blood cell units transfused (2.4 ± 4.1 vs. 5.2 ± 5.0 red blood cell units;p < .01) were significantly lower in the restrictive compared with the liberal group. Overall, all mortality rates were similar in both study groups, including 30-day (23% vs. 23%;p = 1.00), 60-day, hospital, and intensive care unit rates. Changes in multiple organ dysfunction from baseline scores were significantly less in the restrictive transfusion group overall (0.2 ± 4.2 vs. 1.3 ± 4.4;p = .02). In the 257 patients with severe ischemic heart disease, there were no statistically significant differences in all survival measures, but this is the only subgroup where the restrictive group had lower but nonsignificant absolute survival rates compared with the patients in the liberal group. ConclusionA restrictive red blood cell transfusion strategy generally appears to be safe in most critically ill patients with cardiovascular disease, with the possible exception of patients with acute myocardial infarcts and unstable angina.
Unequal cluster sizes for trials in English and Welsh general practice: implications for sample size calculations.

Cluster randomized trials are often used in primary care settings. In the U.K., general practices are usually the unit of allocation. The effect of variability in practice list size on sample size calculations is demonstrated using the General Medical Services Statistics for England and Wales, 1997. Summary statistics and tables are given to help design such trials assuming that a fixed proportion of patients are to be recruited from each cluster. Three different weightings of the cluster means are compared: uniform, cluster size and minimum variance weights. Minimum variance weights are shown to be superior to uniform, particularly when clusters are small, and to cluster size weights, particularly when clusters are large. Where there are large numbers of participants per cluster and cluster size weights are used, the power actually falls as more patients are recruited to large clusters. When minimum variance weights are used the increase in the design effect due to variation in list size is small, regardless of the size of intracluster correlation coefficient or the number of participants per cluster, provided there is no loss of randomized units. When the expected number of participants per practice is low a greater loss in power comes from practices which fail to recruit patients. A method to estimate the likely effect and allow for it is presented.
Solar-UV-signature mutation prefers TCG to CCG: extrapolative consideration from UVA1-induced mutation spectra in mouse skin

UVA1 exerts its genotoxicity on mammalian skin by producing cyclobutane pyrimidine dimers (CPDs) in DNA and preferentially inducing solar-UV-signature mutations, C ? T base substitution mutations at methylated CpG-associated dipyrimidine (Py-mCpG) sites, as demonstrated previously using a 364 nm laser as a UVA1 source and lacZ -transgenic mice that utilize the transgene as a mutational reporter. In the present study, we confirmed that a broadband UVA1 source induced the same mutation profiles in mouse epidermis as the UVA1 laser, generalizing the previous result from a single 364 nm to a wider wavelength range of UVA1 (340-400 nm). Combined with our previous data on the mutation spectra induced in mouse epidermis by UVB, UVA2 and solar UVR, we proved that the solar-UV-signature mutation is commonly observed in the wavelength range from UVB to UVA, and found that UVA1 induces this mutation more preferentially than the other shorter wavelength ranges. This finding indicates that the solar-UV-signature mutation-causing CPDs, which are known to prefer Py-mCpG sites, could be produced with the energy provided by the longer wavelength region of UVR, suggesting a photochemical reaction through the excitation of pyrimidine bases to energy states that can be accomplished by absorption of even low-energy UVR. On the other hand, the lower proportions of solar-UV-signature mutations observed in the mutation spectra for UVB and solar UVR indicate that the direct photochemical reaction through excited singlet state of pyrimidine bases, which can be accomplished only by high-energy UVR, is also involved in the mutation induction at those shorter wavelengths of UVR. We also found that the solar-UV signature prefers 5’-TCG-3’ to 5’-CCG-3’ as mutational target sites, consistent with the fact that UVA induces CPDs selectively at thymine-containing dipyrimidine sites and that solar UVR induces them preferably at Py-mCpG sites. However, the mutation spectrum in human p53 gene from non-melanoma skin cancers shows the opposite preference for 5’-CCG-3’ sites. This apparent discrepancy in the site preference seems to result from the lack of 5’-TCG-3’ sites mutable to missense mutations on the nontranscribed strand of human p53 gene, which should be evolutionally acquired under selective pressure from the sun.