Miracle-dz/UniFAR-FTUs huggingface dataset:
Leber Congenital Amaurosis Associated with AIPL1: Challenges in Ascribing Disease Causation, Clinical Findings, and Implications for Gene Therapy

Leber Congenital Amaurosis (LCA) and Early Childhood Onset Severe Retinal Dystrophy are clinically and genetically heterogeneous retinal disorders characterised by visual impairment and nystagmus from birth or early infancy. We investigated the prevalence of sequence variants in AIPL1 in a large cohort of such patients (n = 392) and probed the likelihood of disease-causation of the identified variants, subsequently undertaking a detailed assessment of the phenotype of patients with disease-causing mutations. Genomic DNA samples were screened for known variants in the AIPL1 gene using a microarray LCA chip, with 153 of these cases then being directly sequenced. The assessment of disease-causation of identified AIPL1 variants included segregation testing, assessing evolutionary conservation and in silico predictions of pathogenicity. The chip identified AIPL1 variants in 12 patients. Sequencing of AIPL1 in 153 patients and 96 controls found a total of 46 variants, with 29 being novel. In silico analysis suggested that only 6 of these variants are likely to be disease-causing, indicating a previously unrecognized high degree of polymorphism. Seven patients were identified with biallelic changes in AIPL1 likely to be disease-causing. In the youngest subject, electroretinography revealed reduced cone photoreceptor function, but rod responses were within normal limits, with no measurable ERG in other patients. An increasing degree and extent of peripheral retinal pigmentation and degree of maculopathy was noted with increasing age in our series. AIPL1 is significantly polymorphic in both controls and patients, thereby complicating the establishment of disease-causation of identified variants. Despite the associated phenotype being characterised by early-onset severe visual loss in our patient series, there was some evidence of a degree of retinal structural and functional preservation, which was most marked in the youngest patient in our cohort. This data suggests that there are patients who have a reasonable window of opportunity for gene therapy in childhood.
ANALISIS DE LA MORFOLOGIA DE LA ONDA T DURANTE INCREMENTOS EN LA DISPERSION DE LA REPOLARIZACION VENTRICULAR

La medición de incrementos en la dispersión del intervalo QT (DIQT), es utilizada como índice marcador de arritmias ventriculares severas. Sin embargo, hay estudios que sugieren que el aumento de la DIQT podría deberse a fenómenos en la proyección del vector cardíaco en las derivaciones electrocardiográficas y/o a una incorrecta determinación del fin de la repolarización ventricular (RV). Nuestro objetivo fue encontrar marcadores sobre el electrocardiograma (ECG) que representasen verdaderos incrementos de la dispersión de la RV, a partir de un modelo experimental de corazón aislado de conejo con múltiples electrodos. Se analizaron los ECG mediante Descomposición en Valores Singulares (SVD) y por la medición de parámetros que caracterizan la morfología y duración de las ondas de la RV. Se concluyó que los índices morfológicos de la onda T, en particular su duración, discriminan notablemente mejor incrementos en la dispersión de la RV que las componentes obtenidas al aplicar SVD.
Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12

Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether, 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.
Work satisfaction of the self-employed

Studies on segregation in employment are suggestive of higher levels of job satisfaction in female-dominated occupational settings. This research investigates whether this effect is replicated in self-employment. We explore whether satisfaction differentials are related to differences in autonomy and working hours. Our hypotheses are tested using data from the European Social Survey. The final sample consists of 1079 males and 326 females. Our research suggests that differences in job satisfaction among self-employed men and women should not be attributed to gender but to gender composition of sector. Our study contributes to our understanding of gender within a sectoral perspective and the significance of work autonomy and level of working hours to improve work satisfaction of the self-employed.
What is the best method of surgical training?: A report of America's leading senior surgeons.

OBJECTIVES To characterize the career choices and developments made by leading senior surgeons in this country and to examine hypothetically whether application of a short tracking program would have hindered their career decisions. DESIGN A survey pertaining to each surgeon's career, decisions, and opinions concerning surgical training. SETTING AND PARTICIPANTS Senior surgeons of regional and national surgical societies. MAIN OUTCOME MEASURE Survey responses. RESULTS A total of 352 surveys (41.4%) were received. Respondents answered that the most common reasons for choosing a specialty were role models or mentors (56%), research (51%), and available patient population (23%). The 2 most common stages in a career at which the respondents became interested in a specialty, or an area of expertise, were at the junior residency level (when the specialty was chosen) and at the assistant professor level (when a more specific topic within the specialty was chosen). The most common stage at which the group believed they acquired their expertise was also at the assistant professor level. Seventy-one percent of respondents believed broad training was superior to a short tracking system, although none had participated in shortened surgical training. CONCLUSIONS Most leading senior surgeons in this country still believe that broad surgical training is superior and should be maintained. Because career specialties in this surveyed group were generally chosen in early residency, a hypothetical application of the short tracking system would have still allowed for these important decisions to be made. Also, it seems likely that specialty and career development would not have been hindered because "expertization" mostly occurred after training was completed. Regardless of training method, a role model or mentor seems most important in career choices and developments.
A Prospective Study of Symptomatic Gallstones in Women: Relation With Oral Contraceptives and Other Risk Factors

Objective: To examine the relation between oral contraceptives (OCs), body mass index (BMI), weight change, alcohol use, parity, smoking, and symptomatic gallstones in women less than 45 years of age. Methods: In this prospective study, associations between the various self-reported exposures and symptomatic gallstones were assessed in 96,211 female United States nurses with 425 cases of gallstones, using multiple logistic regression. Results: We found little relation between ever-use of OCs and symptomatic gallstones (relative risk [RR] 1.2, 95% confidence interval [CI] 0.9-1.6), although there was a modest elevation in risk for long-term use (RR 1.5, 95% CI 1.0-2.2 for 10-14 years; RR 1.6,95% CI 1.0-2.4 for 15 or more years). There was also an increased risk in current users of OCs (RR 1.6, 95% CI 1.1-2.4). The risk of symptomatic gallstones increased with increasing BMI and weight gain since age 18. Women with four or more births had an elevated risk of symptomatic gallstones (RR 2.0, 95% CI 1.3-3.2), and current cigarette smokers had a slightly higher risk than never-smokers (RR 1.3, 95% CI 1.0-1.7). The risk decreased with increasing alcohol intake. Conclusion: We found no substantial increase in the risk of symptomatic gallstones among ever-OC users, although current and long-term users had somewhat elevated risks. Body mass index remains the strongest predictor of symptomatic gallstones among young women.
Primary Blast-Induced Changes in Akt and GSK3β Phosphorylation in Rat Hippocampus

Traumatic brain injury (TBI) due to blast from improvised explosive devices has been a leading cause of morbidity and mortality in recent conflicts in Iraq and Afghanistan. However, the mechanisms of primary blast-induced TBI are not well understood. The Akt signal transduction pathway has been implicated in various brain pathologies including TBI. In the present study, the effects of simulated primary blast waves on the phosphorylation status of Akt and its downstream effector kinase, glycogen synthase kinase 3β (GSK3β), in rat hippocampus, were investigated. Male Sprague-Dawley (SD) rats (350–400 g) were exposed to a single pulse shock wave (25 psi; ~7 ms duration) and sacrificed 1 day, 1 week, or 6 weeks after exposure. Total and phosphorylated Akt, as well as phosphorylation of its downstream effector kinase GSK3β (at serine 9), were detected with western blot analysis and immunohistochemistry. Results showed that Akt phosphorylation at both serine 473 and threonine 308 was increased 1 day after blast on the ipsilateral side of the hippocampus, and this elevation persisted until at least 6 weeks postexposure. Similarly, phosphorylation of GSK3β at serine 9, which inhibits GSK3β activity, was also increased starting at 1 day and persisted until at least 6 weeks after primary blast on the ipsilateral side. In contrast, p-Akt was increased at 1 and 6 weeks on the contralateral side, while p-GSK3β was increased 1 day and 1 week after primary blast exposure. No significant changes in total protein levels of Akt and GSK were observed on either side of the hippocampus at any time points. Immunohistochemical results showed that increased p-Akt was mainly of neuronal origin in the CA1 region of the hippocampus and once phosphorylated, the majority was translocated to the dendritic and plasma membranes. Finally, electrophysiological data showed that evoked synaptic N-methyl-d-aspartate (NMDA) receptor activity was significantly increased 6 weeks after primary blast, suggesting that increased Akt phosphorylation may enhance synaptic NMDA receptor activation, or that enhanced synaptic NMDA receptor activation may increase Akt phosphorylation.
Perioperative Antibiotic Therapy for Penetrating Injuries of the Abdomen

From 1979 through 1981, 152 patients with penetrating injuries of the intra-abdominal gastrointestinal tract were placed on one of three different perioperative antibiotic regimens in a prospective randomized fashion. The three regimens were A) cefamandole 2 grams every 4 hours, B) cefoxitin 2 grams every 6 hours, and C) ticarcillin 3 grams every 4 hours and tobramycin 1.5 mg/kg every 8 hours. Antibiotics were administered intravenously before and for 48 hours following surgical exploration and repair. The three treatment groups were similar with respect to age, average number of organ injuries, and distribution of organ injuries. Cefoxitin-treated patients experienced uneventful recoveries more often than cefamandole-treated patients (94% vs. 80.3%, p less than 0.05) when the incidence of gram-negative wound infection and intra-abdominal abscess formation was considered, while the number of patients who experienced uneventful recoveries in the ticarcillin-tobramycin group was not statistically different from the other two groups of patients. Bacteroides fragilis was isolated from three of the six abscesses occurring in the cefamandole-treated group, while no anaerobes were isolated from abscesses in patients treated with either of the other two regimens. The results of this study suggest that the most effective perioperative antibiotic regimen for patients with penetrating gastrointestinal wounds should possess activity against both aerobic and anaerobic flora of the bowel.
Tripin/hSgo2 recruits MCAK to the inner centromere to correct defective kinetochore attachments

hSgo2 (previously annotated as Tripin) was recently reported to be a new inner centromere protein that is essential for centromere cohesion (Kitajima et al., 2006). In this study, we show that hSgo2 exhibits a dynamic distribution pattern, and that its localization depends on the BUB1 and Aurora B kinases. hSgo2 is concentrated at the inner centromere of unattached kinetochores, but extends toward the kinetochores that are under tension. This localization pattern is reminiscent of MCAK, which is a microtubule depolymerase that is believed to be a key component of the error correction mechanism at kinetochores. Indeed, we found that hSgo2 is essential for MCAK to localize to the centromere. Delocalization of MCAK accounts for why cells depleted of hSgo2 exhibit kinetochore attachment defects that go uncorrected, despite a transient delay in the onset of anaphase. Consequently, these cells exhibit a high frequency of lagging chromosomes when they enter anaphase. We confirmed that hSgo2 is associated with PP2A, and we propose that it contributes to the spatial regulation of MCAK activity within inner centromere and kinetochore.
Thyroid dysfunction in multi-transfused iron loaded thalassemia patients.

Seventy-two transfusion-dependent iron loaded thalassemia patients were investigated for thyroid dysfunction by estimating circulating thyroid hormones (T4 and T3) and basal thyroid stimulating hormone (TSH). They were also evaluated for their liver function (biochemically) and iron overload by estimating serum ferritin. Thyroid failure (hypothyroidism) was documented in 14 patients (19.4%). In all, 3 groups were seen, i.e. Group 1: Normal T4, T3, TSH (58 patients: 80.6%); Group 2: Compensated hypothyroidism characterized by normal T4, T3 and raised TSH (9 patients: 12.5%); Group 3: Decompensated hypothyroidism characterized by decreased T4 and increased TSH (5 patients: 6.9%). Interestingly, impaired thyroid function could not be correlated with age, amount of blood transfused, liver dysfunction or degree of iron overload. It is postulated that an inter-play between chronic hypoxia, liver dysfunction and iron overload may be responsible for the thyroid damage.
Comparison of renal function markers in Kuwaiti patients with sickle cell disease

Background: Proteinuria is a common manifestation of renal disease which is a significant cause of morbidity in patients with sickle cell disease (SCD). Objective: To evaluate and compare cystatin C, β2-microglobulin, and creatinine as markers of renal disease in relation to the degree of proteinuria and other complications of SCD. Methods: 24 h urine collections were used for estimation of urine protein and creatinine clearance in 59 patients with SCD. Results were correlated with plasma cystatin C, β2-microglobulin, creatinine, glomerular filtration rate (GFR; derived from plasma creatinine by Cockcroft-Gault, MDRD formulae, and calculated cystatin C clearance), and clinical and haematological variables. Results: Comparing the different methods of GFR, the proportion of patients with hyperfiltration (GFR >140 ml/min) were 30.5% (MDRD), 44.1% (Cockcroft-Gault), and 10.2 % (calculated cystatin C clearance). Cystatin C was the most consistent marker of hyperfiltration. The endogenous markers of GFR showed an increasing trend with increasing proteinuria, but haematological variables were not correlated with cystatin C, β2-microglobulin, or plasma creatinine. Urine protein excretion was correlated with age (r = 0.33) and significant proteinuria was present in 13.6% of patients. Patients with proteinuria had lower haemoglobin concentration (p = 0.027) than those without proteinuria but HbF was not related to the degree of proteinuria or to markers of GFR. Conclusions: Markers of GFR show variable ability to identify hyperfiltration in patients with SCD, but cystatin C is the best endogenous marker. Proteinuria is associated with age, haemoglobin, and abnormalities of GFR. Routine screening is recommended to allow for early detection and intervention.
R 2 0 1 6 / 0 4 Copula – based Specification of vector MEMs

The Multiplicative Error Model (Engle (2002)) for nonnegative valued processes is specified as the product of a (conditionally autoregressive) scale factor and an innovation process with nonnegative support. A multivariate extension allows for the innovations to be contemporaneously correlated. We overcome the lack of sufficiently flexible probability density functions for such processes by suggesting a copula function approach to estimate the parameters of the scale factors and of the correlations of the innovation processes. We illustrate this vector MEM with an application to the interactions between realized volatility, volume and the number of trades. We show that significantly superior realized volatility forecasts are delivered in the presence of other trading activity indicators and contemporaneous correlations.
An alternating fixpoint tailored to magic programs

We study applying the magic-sets transformation technique to Datalog programs with negation that may not have 2-valued well-founded models. In this general setting we encounter the problem that the well-founded model of the original program does not always agree with the well-founded model of the magic program derived by commonly used left-to-right sips on the query. In order to fix this disagreement we present a novel method that is obtained by slightly and naturally tailoring Van Gelder's alternating fixpoint technique [16] to a magic program.
Functional role of internal water molecules in rhodopsin revealed by x-ray crystallography

Activation of G protein-coupled receptors (GPCRs) is triggered and regulated by structural rearrangement of the transmembrane heptahelical bundle containing a number of highly conserved residues. In rhodopsin, a prototypical GPCR, the helical bundle accommodates an intrinsic inverse-agonist 11-cis-retinal, which undergoes photo-isomerization to the all-trans form upon light absorption. Such a trigger by the chromophore corresponds to binding of a diffusible ligand to other GPCRs. Here we have explored the functional role of water molecules in the transmembrane region of bovine rhodopsin by using x-ray diffraction to 2.6 Å. The structural model suggests that water molecules, which were observed in the vicinity of highly conserved residues and in the retinal pocket, regulate the activity of rhodopsin-like GPCRs and spectral tuning in visual pigments, respectively. To confirm the physiological relevance of the structural findings, we conducted single-crystal microspectrophotometry on rhodopsin packed in our three-dimensional crystals and show that its spectroscopic properties are similar to those previously found by using bovine rhodopsin in suspension or membrane environment.
On Probabilistic Term Rewriting Martin Avanzini

We study the termination problem for probabilistic term rewrite systems. We prove that the interpretation method is sound and complete for a strengthening of positive almost sure termination, when abstract reduction systems and term rewrite systems are considered. Two instances of the interpretation method—polynomial and matrix interpretations—are analyzed and shown to capture interesting and nontrivial examples when automated. We capture probabilistic computation in a novel way by means of multidistribution reduction sequences, thus accounting for both the nondeterminism in the choice of the redex and the probabilism intrinsic in firing each rule.
An extensible probe architecture for network protocol performance measurement

This paper describes the architecture, implementation, and application of Windmill, a passive network protocol performance measurement tool. Windmill enables experimenters to measure a broad range of protocol performance metrics both by reconstructing application‐level network protocols and by exposing the underlying protocol layers' events. Windmill is split into three functional components: a dynamically compiled Windmill Protocol Filter (WPF), a set of abstract protocol modules, and an extensible experiment engine. To demonstrate Windmill's utility, we present the results from several experiments. The first set of experiments validates a possible cause for the correlation between Internet routing instability and network bandwidth usage. The second set of experiments highlights Windmill's ability to act as a driver for a complementary active Internet measurement infrastructure, its ability to perform online data reduction, and the non‐intrusive measurement of a closed system. Copyright © 2003 John Wiley & Sons, Ltd.
Correlation of breath ammonia with blood urea nitrogen and creatinine during hemodialysis

We have spectroscopically determined breath ammonia levels in seven patients with end-stage renal disease while they were undergoing hemodialysis at the University of California, Los Angeles, dialysis center. We correlated these measurements against simultaneously taken blood samples that were analyzed for blood urea nitrogen (BUN) and creatinine, which are the accepted standards indicating the level of nitrogenous waste loading in a patient's bloodstream. Initial levels of breath ammonia, i.e., at the beginning of dialysis, are between 1,500 ppb and 2,000 ppb (parts per billion). These levels drop very sharply in the first 15–30 min as the dialysis proceeds. We found the reduction in breath ammonia concentration to be relatively slow from this point on to the end of dialysis treatment, at which point the levels tapered off at 150 to 200 ppb. For each breath ammonia measurement, taken at 15–30 min intervals during the dialysis, we also sampled the patient's blood for BUN and creatinine. The breath ammonia data were available in real time, whereas the BUN and creatinine data were available generally 24 h later from the laboratory. We found a good correlation between breath ammonia concentration and BUN and creatinine. For one of the patients, the correlation gave an R2 of 0.95 for breath ammonia and BUN correlation and an R2 of 0.83 for breath ammonia and creatinine correlation. These preliminary data indicate the possibility of using the real-time breath ammonia measurements for determining efficacy and endpoint of hemodialysis.