Miracle-dz/UniFAR-FTUs huggingface dataset:
Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer.

PURPOSE No effective systemic therapy exists for patients with metastatic low-grade serous (LGS) ovarian cancers. BRAF and KRAS mutations are common in serous borderline (SB) and LGS ovarian cancers, and MEK inhibition has been shown to induce tumor regression in a minority of patients; however, no correlation has been observed between mutation status and clinical response. With the goal of identifying biomarkers of sensitivity to MEK inhibitor treatment, we performed an outlier analysis of a patient who experienced a complete, durable, and ongoing (> 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor. PATIENTS AND METHODS Next-generation sequencing was used to analyze this patient's tumor as well as an additional 28 SB/LGS tumors. Functional characterization of an identified novel alteration of interest was performed. RESULTS Analysis of the extraordinary responder's tumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. Functional characterization demonstrated that this mutant induced extracellular signal-regulated kinase pathway activation, promoted anchorage-independent growth and tumor formation in mice, and retained sensitivity to selumetinib. Analysis of additional LGS/SB tumors identified mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions, one of whom achieved an ongoing complete response to MEK inhibitor-based combination therapy. CONCLUSION Alterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with LGS ovarian cancer. Next-generation sequencing analysis revealed deletions and fusions that are not detected by older sequencing approaches. These findings, coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional clinical studies of MEK inhibitors in this disease.
Preoperative Evaluation of Patient Anatomy to Increase Success of Robotics-Assisted Bypass Surgery

Objective Robotics-assisted endoscopic atraumatic coronary artery bypass has been shown to be effective in reducing surgical morbidity and length of hospital stay. Unfortunately, the criteria for selecting eligible patients for this procedure are still primitive. This has motivated the use of preoperative computed tomography scans to establish patient eligibility. The objective of this study is to establish which image measurements can be correlated to procedure success. Methods A retrospective study was performed in 144 patients who underwent robotics-assisted coronary bypass surgery. After an initial set of 55 patients, preoperative computed tomography scans of the other patients were used to obtain patient specific measurements: the lateral distance between the midline of the sternum to the left anterior descending coronary artery and its depth from the skin surface, anteroposterior diameter of the thoracic cavity, and the transverse diameter of the thoracic cavity. The procedures were rated as successful if completed in a minimally invasive manner. Different combinations of the variables were evaluated and correlated with success. Results A strong correlation was found between success rate and the ratio of the lateral distance to the transverse diameter in the female patients only (0.532, P = 0.006). A ratio of less than 0.20 significantly increased the occurrence of conversion during this procedure in female cases. Conclusions The lateral distance of the left anterior descending coronary artery from the midline divided by the transverse thoracic width of a female patient shows a significant correlation with procedure success. No significant correlations were found for male patients.
Evaluation of a current doubler IPT pickup controller for materials handling applications

This paper evaluates a new current doubler pickup controller for materials handling IPT applications and compares it with the conventional boost controller. The current doubling capability and switching regulation of the controller were presented. While the component count of the current doubler is slightly higher than the boost controller, most of its components require half the current rating of the boost controller. Assuming that the boost controller requires two devices in parallel to handle the high currents at high power applications, the current doubler will have a lower component count. Simulations showed that the current doubler controller has a higher efficiency of 95.4 % compared to the boost controller's 93.9 % at 5 kW. A current doubler controller prototype was built and the measured efficiency at 5 kW was 94.4 %. The measured results matches well with simulation and this shows that the current doubler controller is comparable with the conventional boost controller and is an alternative pickup controller.
AP‐3 Adaptor Functions in Targeting P‐Selectin to Secretory Granules in Endothelial Cells

P‐selectin, a cell adhesion protein participating in the early stages of inflammation, contains multiple sorting signals that regulate its cell surface expression. Targeting to secretory granules regulates delivery of P‐selectin to the cell surface. Internalization followed by sorting from early to late endosomes mediates rapid removal of P‐selectin from the surface. We show here that the P‐selectin cytoplasmic domain bound AP‐2 and AP‐3 adaptor complexes in vitro. The amino acid substitution L768A, which abolishes endosomal sorting and impairs granule targeting of P‐selectin, reduced binding of AP‐3 adaptors but not AP‐2 adaptors. Turnover of P‐selectin was 2.4‐fold faster than turnover of transferrin receptor in AP‐3‐deficient mocha fibroblasts, similar to turnover of these two proteins in AP‐3‐competent cells, demonstrating that AP‐3 function is not required for endosomal sorting. However, sorting P‐selectin to secretory granules was defective in endothelial cells from AP‐3‐deficient pearl mice, demonstrating a role for AP‐3 adaptors in granule assembly in endothelial cells. P‐selectin sorting to platelet α‐granules was normal in pearl mice, consistent with earlier evidence that granule targeting of P‐selectin is mechanistically distinct in endothelial cells and platelets. These observations establish that AP‐3 adaptor functions in assembly of conventional secretory granules, in addition to lysosomes and the ‘lysosome‐like’ secretory granules of platelets and melanocytes.
Genome-wide parametric linkage analyses of 644 bipolar pedigrees suggest susceptibility loci at chromosomes 16 and 20

Objective Our aim is to map chromosomal regions that harbor loci that increase susceptibility to bipolar disorder. Methods We analyzed 644 bipolar families ascertained by the National Institute of Mental Health Human Genetics Initiative for bipolar disorder. The families have been genotyped with microsatellite loci spaced every approximately 10 cM or less across the genome. Earlier analyses of these pedigrees have been limited to nonparametric (model-free) methods and thus, information from unaffected subjects with genotypes was not considered. In this study, we used parametric analyses assuming dominant and recessive transmission and specifying a maximum penetrance of 70%, so that information from unaffecteds could be weighed in the linkage analyses. As in previous linkage analyses of these pedigrees, we analyzed three diagnostic categories: model 1 included only bipolar I and schizoaffective, bipolar cases (1565 patients of whom approximately 4% were schizoaffective, bipolar); model 2 included all individuals in model 1 plus bipolar II patients (1764 total individuals); and model 3 included all individuals in model 2 with the addition of patients with recurrent major depressive disorder (2046 total persons). Results Assuming dominant inheritance the highest genome-wide pair-wise logarithm of the odds (LOD) score was 3.2 with D16S749 using model 2 patients. Multipoint analyses of this region yielded a maximum LOD score of 4.91. Under recessive transmission a number of chromosome 20 markers were positive and multipoint analyses of the area gave a maximum LOD of 3.0 with model 2 cases. Conclusion The chromosome 16p and 20 regions have been implicated by some studies and the data reported herein provide additional suggestive evidence of bipolar susceptibility genes in these regions.
Isolation and Characterization of Serum Extracellular Vesicles (EVs) from Atlantic Salmon Infected with Piscirickettsia Salmonis

Secretion of extracellular vesicles (EVs) is a common feature of both eukaryotic and prokaryotic cells. Isolated EVs have been shown to contain different types of molecules, including proteins and nucleic acids, and are reported to be key players in intercellular communication. Little is known, however, of EV secretion in fish, or the effect of infection on EV release and content. In the present study, EVs were isolated from the serum of healthy and Piscirickettsia salmonis infected Atlantic salmon in order to evaluate the effect of infection on EV secretion. P. salmonis is facultative intracellular bacterium that causes a systemic infection disease in farmed salmonids. EVs isolated from both infected and non-infected fish had an average diameter of 230–300 nm, as confirmed by transmission electron microscopy, nanoparticle tracking, and flow cytometry. Mass spectrometry identified 180 proteins in serum EVs from both groups of fish. Interestingly, 35 unique proteins were identified in serum EVs isolated from the fish infected with P. salmonis. These unique proteins included proteasomes subunits, granulins, and major histocompatibility class I and II. Our results suggest that EV release could be part of a mechanism in which host stimulatory molecules are released from infected cells to promote an immune response.
Optimizing the test power for a radiation retention model in the human body

The model that describes the retention in lungs of radioisotope particles is studied in this paper, considering the situation of an accident in facilities that handle radioactive materials. Optimal times to make the bioassays are computed for D‐ and c‐optimality, and efficiencies for the computed designs are provided and compared. Moreover, the test power is checked by means of simulations and replications. After that the inverse of the Fisher information matrix is compared to an estimation of the covariance matrix of the parameters. Finally, a study taking into consideration the randomness of the designs space is performed. Copyright © 2009 John Wiley & Sons, Ltd.
Long-term benefit of enzyme replacement therapy in Pompe disease

Objective: To determine the effect of enzyme replacement therapy (ERT) after 5 years and to identify predictors for a favorable response because few data are available on the long-term efficacy of ERT in Pompe disease. Methods: We included 102 adult patients with Pompe disease in a nationwide, prospective cohort study. We assessed muscle strength (manual muscle testing with Medical Research Council [MRC] grading, handheld dynamometry [HHD]), muscle function (6-minute walk test, Quick Motor Function Test), daily life activities (Rasch-Built Pompe-Specific Activity [R-PAct] Scale), and pulmonary function (forced vital capacity [FVC] in upright and supine positions, maximum inspiratory and expiratory pressures) at 3- to 6-month intervals before and after the start of ERT. Data were analyzed with linear mixed-effects models for repeated measurements. Results: Median follow-up duration was 6.1 years (range 0.4–7.9 years), of which 5.0 years (range 0.2–7.3 years) were during ERT. Treated patients had better muscle strength (MRC sum score +6.6 percentage points [pp]; HHD sum score +9.6 pp, both p < 0.0001), activity levels (R-PAct +10.8 pp, p < 0.002), and pulmonary function (FVC upright +7.3 pp, FVC supine +7.6 pp, both p < 0.0003) than expected for their untreated disease course. Walking distance improved (416 vs 376 m at baseline, p = 0.03). The largest increase was seen during the first 2 to 3 years of treatment. Response to treatment was similar between groups regardless of sex, age, or disease duration. Conclusions: Long-term ERT positively affects muscle strength, pulmonary function, and daily life activities in adult patients with Pompe disease, with a peak effect at ≈2 to 3 years of treatment. Classification of evidence: This study provides Class IV evidence that for patients with Pompe disease, long-term ERT positively affects muscle strength, pulmonary function, and daily life activities.
Dystrophin Expression in Muscles of Duchenne Muscular Dystrophy Patients After High-Density Injections of Normal Myogenic Cells

A clinical trial was conducted to test a new protocol of normal muscle precursor cell (MPC) allotransplantation in skeletal muscles of patients with Duchenne muscular dystrophy (DMD). Cultured MPCs obtained from one of the patient's parents were implanted in 0.25 or 1 cm3 of a Tibialis anterior in 9 patients with DMD. MPC injections were placed 1 to 2 mm from each other, and a similar pattern of saline injections was done in the contralateral muscle. The patients were immunosuppressed with tacrolimus. Muscle biopsies were performed at the injected sites 4 weeks later. In the biopsies of the cell-grafted sites, there were myofibers expressing donor's dystrophin in 8 patients. The percentage of myofibers expressing donor's dystrophin varied from 3.5% to 26%. Evidence of small myofiber neoformation was observed in some patients. Donor-derived dystrophin transcripts were detected by reverse transcriptase-polymerase chain reaction in the cell-grafted sites in all patients. The protocol of immunosuppression was sufficient to obtain these results, although it is not certain whether acute rejection was efficiently controlled in all the cases. In conclusion, intramuscular allotransplantation of normal MPCs can induce the expression of donor-derived dystrophin in skeletal muscles of patients with DMD, although this expression is restricted to the sites of MPC injection.
Linking disease associations with regulatory information in the human genome

Genome-wide association studies have been successful in identifying single nucleotide polymorphisms (SNPs) associated with a large number of phenotypes. However, an associated SNP is likely part of a larger region of linkage disequilibrium. This makes it difficult to precisely identify the SNPs that have a biological link with the phenotype. We have systematically investigated the association of multiple types of ENCODE data with disease-associated SNPs and show that there is significant enrichment for functional SNPs among the currently identified associations. This enrichment is strongest when integrating multiple sources of functional information and when highest confidence disease-associated SNPs are used. We propose an approach that integrates multiple types of functional data generated by the ENCODE Consortium to help identify “functional SNPs” that may be associated with the disease phenotype. Our approach generates putative functional annotations for up to 80% of all previously reported associations. We show that for most associations, the functional SNP most strongly supported by experimental evidence is a SNP in linkage disequilibrium with the reported association rather than the reported SNP itself. Our results show that the experimental data sets generated by the ENCODE Consortium can be successfully used to suggest functional hypotheses for variants associated with diseases and other phenotypes.
Dynamics of chromosomes and microtubules visualized by multiple‐wavelength fluorescence imaging in living mammalian cells: effects of mitotic inhibitors on cell cycle progression

Mitotic events are accomplished by a coordinated interaction of molecular components within a cell. The continuous observation of specific molecular components in individual living cells provides a unique opportunity to examine the temporal and spatial coordination of these components. In order to be able to observe dynamic events in living mammalian cells, we have developed a computerized fluorescence microscope system.
The evolution of business ethics research in the realm of tourism and hospitality: A bibliometric analysis

Purpose This paper aims to illustrate how business ethics research is progressing in the tourism and hospitality (T/H) industries and suggest a research agenda. Design/methodology/approach This study applies bibliometric analysis to articles related to business ethics topics in the T/H fields published between 1995 and 2014 in six, nine and five leading hospitality-, tourism- and business ethics-oriented journals, respectively. Findings This study provides a broad view on business ethics research in the T/H fields based on leading authors, institutions, themes and methods used over the past two decades. Research limitations/implications This study assesses the progress of business ethics research in the hospitality and tourism fields. Only articles published in select, prominent Social Sciences Citation Index journals were analyzed. Practical implications This analysis focuses on published articles related to business ethics in the T/H fields. As such, it facilitates researchers, academic scholars and professionals in contributing to the field more effectively and advancing scientific progress in the literature. It aids practitioners by evaluating the extent to which scholars have investigated key issues in the field. Originality/value This study is the first to utilize bibliometric analysis to assess business ethics research focusing on T/H activities published in leading tourism, hospitality and business ethics journals.
Horizontal cell receptive fields are reduced in connexin57‐deficient mice

Horizontal cells are coupled by gap junctions; the extensive coupling of the horizontal cells is reflected in their large receptive fields, which extend far beyond the dendritic arbor of the individual cell. In the mouse retina, horizontal cells express connexin57 (Cx57). Tracer coupling of horizontal cells is impaired in Cx57‐deficient mice, which suggests that the receptive fields of Cx57‐deficient horizontal cells might be similarly reduced. To test this hypothesis we measured the receptive fields of horizontal cells from wildtype and Cx57‐deficient mice. First, we examined the synaptic connections between horizontal cells and photoreceptors: no major morphological alterations were found. Moreover, horizontal cell spacing and dendritic field size were unaffected by Cx57 deletion. We used intracellular recordings to characterize horizontal cell receptive fields. Length constants were computed for each cell using the cell's responses to concentric light spots of increasing diameter. The length constant was dependent on the intensity of the stimulus: increasing stimulus intensity reduced the length constant. Deletion of Cx57 significantly reduced horizontal cell receptive field size. Dark resting potentials were strongly depolarized and response amplitudes reduced in Cx57‐deficient horizontal cells compared to the wildtype, suggesting an altered input resistance. This was confirmed by patch‐clamp recordings from dissociated horizontal cells; mean input resistance of Cx57‐deficient horizontal cells was 27% lower than that of wildtype cells. These data thus provide the first quantification of mouse horizontal cell receptive field size and confirm the unique role of Cx57 in horizontal cell coupling and physiology.
A cautionary tale about control variables in IV estimation

Many instrumental variable (IV) regressions include control variables to justify (conditional) independence of the instrument and the potential outcomes. The plausibility of conditional IV independence crucially depends on the timing when the control variables are determined. This paper systemically works through different IV models and discusses the (conditions for the) satisfaction of conditional IV independence when controlling for covariates measured (a) prior to the instrument, (b) after the treatment, or (c) both. To illustrate these identification issues, we consider an empirical application using the Vietnam War draft risk as instrument either for veteran status or education to estimate the effects of these variables on labor market and health outcomes.
Comparison of predicted body fat percentage from anthropometric methods and from impedance in university students

The objective of the present study was to compare different methods for evaluating body fat percentage (BF%) (anthropometric methods and bioelectrical impedance analysis) in university students. Subjects were 653 healthy students whose mean age, body height, body weight and BMI were 21·1 (SD 2·5) years, 166·0 (SD 8·4) cm, 62·8 (SD 11·0) kg and 22·7 (SD 3·1) kg/m2, respectively. Results showed that BMI is a poor predictor of body fatness since the sensitivity was low in comparison with the reference method (Siri equation). The lowest values of BF% were obtained using the reference method (Siri equation) (21·8 (SD 6·8)%). The two methods with the highest agreement were Siri and Lean (mean difference, −0·5), followed by Brozek (mean difference, −1·4) and Deurenberg (mean difference, −1·5). The largest mean difference for BF% was between Siri and impedance (−4·5). Although the methods and/or equations used in the present study have been commonly utilised to estimate BF% in young adults, the results must be interpreted with caution in the diagnosis and monitoring of overweight and obesity.
Age differences in major depression: results from the National Comorbidity Survey Replication (NCS-R)

Background Although depression appears to decrease in late life, this could be due to misattribution of depressive symptom to physical disorders that increase in late life. Method We studied age differences in major depressive episodes (MDE) in the National Comorbidity Survey Replication, a national survey of the US household population. DSM-IV MDE was defined without organic exclusions or diagnostic hierarchy rules to facilitate analysis of co-morbidity. Physical disorders were assessed with a standard chronic conditions checklist and mental disorders with the WHO Composite International Diagnostic Interview (CIDI) version 3.0. Results Lifetime and recent DSM-IV/CIDI MDE were significantly less prevalent among respondents aged ⩾65 years than among younger adults. Recent episode severity, but not duration, was also lower among the elderly. Despite prevalence of mental disorders decreasing with age, co-morbidity of hierarchy-free MDE with these disorders was either highest among the elderly or unrelated to age. Co-morbidity of MDE with physical disorders, in comparison, generally decreased with age despite prevalence of co-morbid physical disorders usually increasing. Somewhat more than half of respondents with 12-month MDE received past-year treatment, but the percentage in treatment was lowest and most concentrated in the general medical sector among the elderly. Conclusions Given that physical disorders increase with age independent of depression, their lower associations with MDE in old age argue that causal effects of physical disorders on MDE weaken in old age. This result argues against the suggestion that the low estimated prevalence of MDE among the elderly is due to increased confounding with physical disorders.