Parametric polymorphism - universally

In the 1980s, John Reynolds postulated that a parametrically polymorphic function is an ad-hoc polymorphic function satisfying a uniformity principle. This allowed him to prove that his set-theoretic semantics has a relational lifting which satisfies the Identity Extension Lemma and the Abstraction Theorem. However, his definition (and subsequent variants) have only been given for specific models. In contrast, we give a model-independent axiomatic treatment by characterising Reynolds' definition via a universal property, and show that the above results follow from this universal property in the axiomatic setting

Kub5-Hera(RPRD1B) deficiency promotes “BRCAness” and vulnerability to PARP inhibition in BRCA-proficient breast cancers

Purpose: Identification of novel strategies to expand the use of PARP inhibitors beyond BRCA deficiency is of great interest in personalized medicine. Here, we investigated the unannotated role of Kub5-Hera(RPRD1B) (K-H) in homologous recombination (HR) repair and its potential clinical significance in targeted cancer therapy. Experimental Design: Functional characterization of K-H alterations on HR repair of double-strand breaks (DSB) were assessed by targeted gene silencing, plasmid reporter assays, immunofluorescence, and Western blots. Cell survival with PARP inhibitors was evaluated through colony-forming assays and statistically analyzed for correlation with K-H expression in various BRCA1/2 nonmutated breast cancers. Gene expression microarray/qPCR analyses, chromatin immunoprecipitation, and rescue experiments were used to investigate molecular mechanisms of action. Results: K-H expression loss correlates with rucaparib LD50 values in a panel of BRCA1/2 nonmutated breast cancers. Mechanistically, K-H depletion promotes BRCAness, where extensive upregulation of PARP1 activity was required for the survival of breast cancer cells. PARP inhibition in these cells led to synthetic lethality that was rescued by wild-type K-H reexpression, but not by a mutant K-H (p.R106A) that weakly binds RNAPII. K-H mediates HR by facilitating recruitment of RNAPII to the promoter region of a critical DNA damage response and repair effector, cyclin-dependent kinase 1 (CDK1). Conclusions: Cancer cells with low K-H expression may have exploitable BRCAness properties that greatly expand the use of PARP inhibitors beyond BRCA mutations. Our results suggest that aberrant K-H alterations may have vital translational implications in cellular responses/survival to DNA damage, carcinogenesis, and personalized medicine. (C) 2018 AACR

Scleral Thickness in Human Eyes

Purpose: To obtain information about scleral thickness in different ocular regions and its associations. Methods: The histomorphometric study included 238 human globes which had been enucleated because of choroidal melanomas or due to secondary angle-closure glaucoma. Using light microscopy, anterior-posterior pupil-optic nerve sections were measured. Results: In the non-axially elongated group (axial length #26 mm), scleral thickness decreased from the limbus (0.5060.11 mm) to the ora serrata (0.4360.14 mm) and the equator (0.4260.15 mm), and then increased to the midpoint between posterior pole and equator (0.6560.15 mm) and to the posterior pole (0.9460.18 mm), from where it decreased to the peri-optic nerve region (0.8660.21 mm) and finally the peripapillary scleral flange (0.3960.09 mm). Scleral thickness was significantly lower in the axially elongated group (axial length.26 mm) than in the non-axially elongated group for measurements taken at and posterior to the equator. Scleral thickness measurements of the posterior pole and of the peripapillary scleral flange were correlated with lamina cribrosa thickness measurements. Scleral thickness measurements at any location of examination were not significantly (all P.0.10) correlated with corneal thickness measurements. Scleral thickness was statistically independent of age, gender and presence of glaucoma. Conclusions: In non-axially elongated eyes, the sclera was thickest at the posterior pole, followed by the peri-optic nerv

Tracking the Expression of Annoyance in Call Centers

Machine learning researchers have dealt with the identification of emo- tional cues from speech since it is research domain showing a large number of po- tential applications. Many acoustic parameters have been analyzed when searching for cues to identify emotional categories. Then classical classifiers and also out- standing computational approaches have been developed. Experiments have been carried out mainly over induced emotions, even if recently research is shifting to work over spontaneous emotions. In such a framework, it is worth mentioning that the expression of spontaneous emotions depends on cultural factors, on the particu- lar individual and also on the specific situation. In this work, we were interested in the emotional shifts during conversation. In particular we were aimed to track the annoyance shifts appearing in phone conversations to complaint services. To this end we analyzed a set of audio files showing different ways to express annoyance. The call center operators found disappointment, impotence or anger as expression of annoyance. However, our experiments showed that variations of parameters derived from intensity combined with some spectral information and suprasegmental fea- tures are very robust for each speaker and annoyance rate. The work also discussed the annotation problem arising when dealing with human labelling of subjective events. In this work we proposed an extended rating scale in order to include anno- tators disagreements. Our frame classification results validated the chosen annota- tion procedure. Experimental results also showed that shifts in customer annoyance rates could be potentially tracked during phone callsSpanish Mineco under grant TIN2014- 54288-C4-4-R H2020 EU under Empathic RIA action number 769872

A nodulo-cystic eumycetoma caused by Pyrenochaeta romeroi in a renal transplant recipient: A case report

<p>Abstract</p> <p>Introduction</p> <p><it>Pyrenochaeta romeroi </it>(<it>P. romeroi</it>) is a saprophytic fungus found in soil and plants. The fungal spores can be introduced into deeper tissues by trauma. It causes eumycetoma, which affects skin and subcutaneous tissues.</p> <p>Case presentation</p> <p>A 57-year-old South Asian man presented with a painless, nodular lesion (1 cm × 0.5 cm) on the left knee. He had had a renal transplant eight months earlier for end-stage renal failure. The patient was on tacrolimus, mycophenolate mofetil and prednisolone for immunosuppression. The lesion had progressed dramatically (to 5 cm × 5 cm) despite antibiotic treatment. The size and location of the lesion was severely affecting his quality of life, so an excision biopsy was performed. Nuclear ribosomal repeat-region sequencing confirmed the causative organism as <it>P. romeroi</it>. An <it>in vitro </it>antifungal susceptibility test demonstrated that <it>P. romeroi </it>was sensitive to voriconazole. Following a successful surgical removal, voriconazole was continued orally for two months.</p> <p>Conclusion</p> <p>To the best of our knowledge, we are reporting the first case of Eumycetoma caused by <it>P. romeroi </it>in a renal transplant recipient. Physicians should be aware of this rare fungal disease in transplant recipients. We recommend a combination of medical and surgical management in these immunosuppressed patients.</p

The effect of a preoperative subconjuntival injection of dexamethasone on blood–retinal barrier breakdown following scleral buckling retinal detachment surgery: a prospective randomized placebo-controlled double blind clinical trial

textabstractBackground: Blood-retinal barrier breakdown secondary to retinal detachment and retinal detachment repair is a factor in the pathogenesis of proliferative vitreoretinopathy (PVR). We wished to investigate whether an estimated 700 to 1000 ng/ml subretinal dexamethasone concentration at the time of surgery would decrease the blood-retinal barrier breakdown postoperatively. Methods: Prospective, placebo-controlled, double blind clinical trial. In 34 patients with rhegmatogenous retinal detachment scheduled for conventional scleral buckling retinal detachment surgery, a subconjunctival injection of 0.5 ml dexamethasone diphosphate (10 mg) or 0.5 ml placebo was given 5-6 hours before surgery. Differences in laser flare photometry (KOWA) measurements taken 1, 3 and 6 weeks after randomisation between dexamethasone and placebo were analysed using mixed model ANOVA, while correcting for the preoperative flare measurement. Results: Six patients did not complete the study, one because of recurrent detachment within 1 week, and five because they missed their postoperative laser flare visits. The use of dexamethasone resulted in a statistically significant decrease in laser flare measurements at the 1-week postoperative visit. Conclusion: The use of a preoperative subconjunctival injection of dexamethasone decreased 1-week postoperative blood-retina barrier breakdown in patients undergoing conventional scleral buckling retinal detachment surgery. This steroid priming could be useful as a part of a peri-operative regime that would aim at decreasing the incidence of PVR

Phenoloxidase activity acts as a mosquito innate immune response against infection with semliki forest virus

Several components of the mosquito immune system including the RNA interference (RNAi), JAK/STAT, Toll and IMD pathways have previously been implicated in controlling arbovirus infections. In contrast, the role of the phenoloxidase (PO) cascade in mosquito antiviral immunity is unknown. Here we show that conditioned medium from the Aedes albopictus-derived U4.4 cell line contains a functional PO cascade, which is activated by the bacterium Escherichia coli and the arbovirus Semliki Forest virus (SFV) (Togaviridae; Alphavirus). Production of recombinant SFV expressing the PO cascade inhibitor Egf1.0 blocked PO activity in U4.4 cell- conditioned medium, which resulted in enhanced spread of SFV. Infection of adult female Aedes aegypti by feeding mosquitoes a bloodmeal containing Egf1.0-expressing SFV increased virus replication and mosquito mortality. Collectively, these results suggest the PO cascade of mosquitoes plays an important role in immune defence against arboviruses

Temperature influence on DXA measurements: bone mineral density acquisition in frozen and thawed human femora

<p>Abstract</p> <p>Background</p> <p>Determining bone mineral density (BMD) with dual-energy x-ray absorptiometry (DXA) is an established and widely used method that is also applied prior to biomechanical testing. However, DXA is affected by a number of factors. In order to delay decompositional processes, human specimens for biomechanical studies are usually stored at about -20°C; similarly, bone mineral density measurements are usually performed in the frozen state. The aim of our study was to investigate the influence of bone temperature on the measured bone mineral density.</p> <p>Methods</p> <p>Using DXA, bone mineral density measurements were taken in 19 fresh-frozen human femora, in the frozen and the thawed state. Water was used to mimic the missing soft tissue around the specimens. Measurements were taken with the specimens in standardized internal rotation. Total-BMD and single-BMD values of different regions of interest were used for evaluation.</p> <p>Results</p> <p>Fourteen of the 19 specimens showed a decrease in BMD after thawing. The measured total-BMD of the frozen specimens was significantly (1.4%) higher than the measured BMD of the thawed specimens.</p> <p>Conclusion</p> <p>Based on our findings we recommend that the measurement of bone density, for example prior to biomechanical testing, should be standardized to thawed or frozen specimens. Temperature should not be changed during measurements. When using score systems for data interpretation (e.g. T- or Z-score), BMD measurements should be performed only on thawed specimens.</p

Mice expressing a human KATP channel mutation have altered channel ATP sensitivity but no cardiac abnormalities

AIMS/HYPOTHESIS: Patients with severe gain-of-function mutations in the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, have neonatal diabetes, muscle hypotonia and mental and motor developmental delay-a condition known as iDEND syndrome. However, despite the fact that Kir6.2 forms the pore of the cardiac K(ATP) channel, patients show no obvious cardiac symptoms. The aim of this project was to use a mouse model of iDEND syndrome to determine whether iDEND mutations affect cardiac function and cardiac K(ATP) channel ATP sensitivity. METHODS: We performed patch-clamp and in vivo cine-MRI studies on mice in which the most common iDEND mutation (Kir6.2-V59M) was targeted to cardiac muscle using Cre-lox technology (m-V59M mice). RESULTS: Patch-clamp studies of isolated cardiac myocytes revealed a markedly reduced K(ATP) channel sensitivity to MgATP inhibition in m-V59M mice (IC(50) 62 μmol/l compared with 13 μmol/l for littermate controls). In vivo cine-MRI revealed there were no gross morphological differences and no differences in heart rate, end diastolic volume, end systolic volume, stroke volume, ejection fraction, cardiac output or wall thickening between m-V59M and control hearts, either under resting conditions or under dobutamine stress. CONCLUSIONS/INTERPRETATION: The common iDEND mutation Kir6.2-V59M decreases ATP block of cardiac K(ATP) channels but was without obvious effect on heart function, suggesting that metabolic changes fail to open the mutated channel to an extent that affects function (at least in the absence of ischaemia). This may have implications for the choice of sulfonylurea used to treat neonatal diabetes