Miracle-dz/UniFAR-FTUs huggingface dataset:
Nature Genetics Advance Online Publication a N a Ly S I S Identification of Significantly Mutated Regions across Cancer Types Highlights a Rich Landscape of Functional Molecular Alterations

Cancer sequencing studies have primarily identified cancer driver genes by the accumulation of protein-altering mutations. An improved method would be annotation independent, sensitive to unknown distributions of functions within proteins and inclusive of noncoding drivers. We employed density-based clustering methods in 2 tumor types to detect variably sized significantly mutated regions (SMRs). SMRs reveal recurrent alterations across a spectrum of coding and noncoding elements, including transcription factor binding sites and untranslated regions mutated in up to ~5% of specific tumor types. SMRs demonstrate spatial clustering of alterations in molecular domains and at interfaces, often with associated changes in signaling. Mutation frequencies in SMRs demonstrate that distinct protein regions are differentially mutated across tumor types, as exemplified by a linker region of PIK3CA in which biophysical simulations suggest that mutations affect regulatory interactions. The functional diversity of SMRs underscores both the varied mechanisms of oncogenic misregulation and the advantage of functionally agnostic driver identification. In cancer, driver mutations alter functional elements of diverse nature and size. For example, melanoma drivers include hyperacti-vating mutations mapping to single amino acid residues (for example, BRAF Val600; ref. 1), inactivating mutations along tumor-suppressor exons (for example, in PTEN 1) and regulatory mutations (for example, in the TERT promoter 2). Cancer genomics projects such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) have substantially expanded our understanding of the landscape of somatic alterations by identifying frequently mutated protein-coding genes 3–5. However, these studies have focused little attention on systematically analyzing the positional distribution of coding mutations or characterizing noncoding alterations 6. Algorithms to identify cancer driver genes often examine non-synonymous-to-synonymous mutation rates across the gene body or recurrently mutated amino acids called mutation hotspots 5 , as observed in BRAF 7 , IDH1 (ref. 8) and DNA polymerase ε (encoded by POLE) 9. Yet, these analyses ignore recurrent alterations in the vast intermediate scale of functional coding elements, such as those affecting protein subunits or interfaces. Moreover, where mutation clustering within genes has been examined 10–12 , analyses have employed windows of fixed length or identified clusters of non-synonymous mutations, assuming that driver mutations exclusively influence protein sequence and ignoring the importance of exon-embedded regulatory elements 13–18. A significant proportion of regulatory elements in the genome are located proximal to or even in exons 15,19 , suggesting that many may be captured by whole-exome sequencing. Efforts to characterize noncoding regulatory variation …
2017-00176-PhD Position / Predictive Security Monitoring for Large-Scale Cyber-Physical Systems

A propos d'Inria Inria, institut de recherche dédié au numérique, promeut « l'excellence scientifique au service du transfert technologique et de la société ». Inria emploie 2700 collaborateurs issus des meilleures universités mondiales, qui relèvent les défis des sciences informatiques et mathématiques. Son modèle ouvert et agile lui permet d’explorer des voies originales avec ses partenaires industriels et académiques. Inria répond ainsi efficacement aux enjeux pluridisciplinaires et applicatifs de la transition numérique. Inria est à l'origine de nombreuses innovations créatrices de valeur et d'emplois.
Increasing short-term cardiomyocyte progenitor cell (CMPC) survival by necrostatin-1 did not further preserve cardiac function.

AIMS One of the main limitations for an effective cell therapy for the heart is the poor cell engraftment after implantation, which is partly due to a large percentage of cell death in the hostile myocardium. In the present study, we investigated the utilization of necrostatin-1 (Nec-1) as a possible attenuator of cell death in cardiomyocyte progenitor cells (CMPCs). METHODS AND RESULTS In a mouse model of myocardial infarction, survival of CMPCs 3 days after intra-myocardial injection was 39 ± 9% higher in cells pretreated with the Nec-1 compound. However, the increase in cell number was not sustained over 28 days, and did not translate into improved cardiac function (ejection fraction %, 20.6 ± 2.1 vs. 21.4 ± 2.5 for vehicle and Nec-1-treated CMPC, respectively). Nonetheless, Nec-1 rescued CMPCs remained functionally competent. CONCLUSION A pharmacological pretreatment approach to solely enhance cell survival on the short term does not seem to be effective strategy to improve cardiac cell therapy with CMPCs.
Effect of in vitro exposure time on comet assay results

Some mutagens are inactivated rapidly by components included in culture media, especially by serum. Long incubation periods may not be appropriate for the comet assay because DNA lesions may be repaired during the time that mutagens are inactivated, leading to false negative results. We questioned how the exposure period of Chinese hamster ovary cells to 8 unstable mutagens affected outcome of the assay.Although the longest biological half-life of the test mutagens was 1.98 h, four were positive following 0.5—24 h incubations while other four were positive only when the incubation period was ≤ 4 h, suggesting that the DNA damage was repaired and the mutagens were inactivated. The rapid inactivation of mutagens in the medium did not affect whether the outcome of the comet assay was positive or negative when cells were exposed for 1—4 h. Based on these results, we concluded that long exposure should not be employed for the compounds that are unstable in culture media, and appropriate incubation time should be determined for them individually.
War Sailor syndrome.

One third of the Norwegian sailors in the merchant navy, who survived World War II, are today disabled and on invalid pension. The majority suffer from a syndrome which is very similar to that present in the concentration camp survivors. The syndrome falls into two parts, the one consisting of non-neurotic anxiety repeating the terrors of war time, the other being a brain-organic one. This last part has in a few cases been confirmed by neuroradiology and neuropsychology. This is taken as an indicator that prolonged stress, as constant fear of death, may cause brain damage without physical trauma.
Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

Alzheimer’s disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid β (Aβ), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aβ is dysregulated, which leads to the accumulation and aggregation of Aβ. Metabolism of Aβ and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.
Radial Flow Assay Using Gold Nanoparticles and Rolling Circle Amplification to Detect Mercuric Ions

A novel colorimetric assay employing oligonucleotide-conjugated gold nanoparticle (AuNP probes) and rolling circle amplification (RCA) was developed for simple detection of mercuric ions (Hg2+). The thymine-Hg2+-thymine (T-Hg2+-T) coordination chemistry makes our detection system selective for Hg2+. In the presence of Hg2+, the thymine 12-mer oligonucleotide is unable to act as a primer for RCA due to the formation of T-Hg2+-T before the RCA reaction. However, in the absence of Hg2+, DNA coils as RCA products are generated during the RCA reaction, and is further labeled with AuNP probes. Colorimetric signals that depend on the amount of DNA coil-AuNP probe complexes were generated by drop-drying the reaction solution on nitrocellulose-based paper. As the reaction solution spread radially because of capillary action, the complexes formed a concentric red spot on the paper. The colorimetric signals of the red spots were rapidly measured with a portable spectrophotometer and determined as the ΔE value, which indicates the calculated color intensity. Our assay displays great linearity (detection limit: 22.4 nM), precision, and reproducibility, thus demonstrating its utility for Hg2+ quantification in real samples. We suggest that our simple, portable, and cost-effective method could be used for on-site Hg2+ detections.
A comparative study of the incidence of in-hospital cardiopulmonary resuscitation on Monday–Wednesday and Thursday–Sunday

Abstract Because most medical staff work from Monday–Friday, it is possible that they are relatively more fatigued and less capable of providing emergency supportive services on Thursday–Sunday (Thu–Sun) than on Monday–Wednesday (Mon–Wed). In this study, we aimed to analyze the incidence of in-hospital cardiopulmonary resuscitation (CPR) to determine if it differed between Thu–Sun and Mon–Wed. This retrospective observational study of in-hospital CPR was performed during 2012 to 2016 among inpatients at the Seoul National University Bundang Hospital. The primary outcome was the incidence of in-hospital CPR per 1000 inpatients in the Mon–Wed and Thu–Sun periods. Secondary outcomes included differences in the CPR incidence by time of day and season. In the study, 1195 cases of in-hospital CPR were included. The incidence of in-hospital CPR per 1000 inpatients was significantly higher on Thu–Sun (mean: 0.595, 95% confidence interval [CI]: 0.564–0.626) than on Mon–Wed (mean: 0.505, 95% CI: 0.474–0.536, P < .001). There were no seasonal variations in the incidence of in-hospital CPR. However, in-hospital CPR was most frequently performed between 16:00 and 24:00, and the return of spontaneous circulation (ROSC) rate was the lowest among cases that occurred between 0:00 and 8:00. In addition, the ROSC rate was lowest among female patients, patients with cardiac arrest, and after in-hospital CPR performed on a Sunday. The incidence of in-hospital CPR per 1000 inpatients was significantly higher on Thu–Sun than on Mon–Wed. No seasonal variations were observed in the incidence of in-hospital CPR, but the data suggest circadian variations and differences in ROSC rates.
Residence Time Distribution in a High Shear Twin Screw Extruder

Abstract The residence time distributions (RTD) of a high shear twin screw extruder were measured by an on–line UV fluorescence device. First, by increasing throughput (Q) and screw speed (N), a decrease of the complex viscosity of the studied polypropylene (PP) was observed, revealing chain scissions. It was associated to high viscous dissipation taking place during extrusion, and more particularly under high shear conditions. Then the impact of these experimental conditions on the RTD was carried out. As expected, an increase of usual throughputs and screw speeds decrease mostly the RTD characteristic data. In this study industrial rate have been studied: throughput varied from 1.5 up to 22 kg h−1 and screw speed varied from 200 min−1 up to 1 200 min−1. However, by increasing the screw speed over usual values (from 500 up to 1 200 min−1), the variation of some experimental RTD characteristics were unexpected. Indeed, the slope of the shape of the experimental RTD function E(t) changed significantly. This phenomenon will be called lag or delay time. This result was only observed at low throughputs and high screw rotation speeds. To finish, a modeling software of twin screw extrusion process was used to compare experimental and calculated results. For usual processing conditions (up to 700 min−1), the simulation predicts nicely the experimental RTDs. However, at high screw speed (N > 800 min−1) and moderate throughput (Q = 4 kg h−1), the simulation fails to predict the RDT delay time. Hence, some side effects apparently occurred during high shear extrusion at low throughputs.
Syndromic Hearing Loss: A Brief Review of Common Presentations and Genetics

Abstract Congenital hearing loss is one of the most common birth defects worldwide, with around 1 in 500 people experiencing some form of severe hearing loss. While over 400 different syndromes involving hearing loss have been described, it is important to be familiar with a wide range of syndromes involving hearing loss so an early diagnosis can be made and early intervention can be pursued to maximize functional hearing and speech-language development in the setting of verbal communication. This review aims to describe the presentation and genetics for some of the most frequently occurring syndromes involving hearing loss, including neurofibromatosis type 2, branchio-oto-renal syndrome, Treacher Collins syndrome, Stickler syndrome, Waardenburg syndrome, Pendred syndrome, Jervell and Lange-Nielsen syndrome, Usher syndromes, Refsum disease, Alport syndrome, MELAS, and MERRF.
Symposium on glaucoma The Association for Research in Ophthalmology and the National Society for the Prevention of Blindness Hyperosmotic agents in glaucoma

Hyperosmotic agents lower intraocidar pressure by creating an osmotic gradient between the blood and the ocular fluids. Factors affecting the osmotic gradient are described. The currently used hyperosmotic agents are discussed, and the advantages and disadvantages of each are mentioned. Oral glycerol is the agent of choice in most cases of glaucoma, but it may produce nausea and vomiting in many patients. Isosorbide, a new hyperosmotic drug, tends to have fewer side effects than glycerol. Mannitol remains the most effective intravenously administered hyperosmotic agent. These drugs are of greatest value in the acute glaucomas and make the management of these diseases much safer and more effective.
Understanding Spreading Depression from Headache to Sudden Unexpected Death

Spreading depression (SD) is a neurophysiological phenomenon characterized by abrupt changes in intracellular ion gradients and sustained depolarization of neurons. It leads to loss of electrical activity, changes in the synaptic architecture, and an altered vascular response. Although SD is often described as a unique phenomenon with homogeneous characteristics, it may be strongly affected by the particular triggering event and by genetic background. Furthermore, SD may contribute differently to the pathogenesis of widely heterogeneous clinical conditions. Indeed, clinical disorders related to SD vary in their presentation and severity, ranging from benign headache conditions (migraine syndromes) to severely disabling events, such as cerebral ischemia, or even death in people with epilepsy. Although the characteristics and mechanisms of SD have been dissected using a variety of approaches, ranging from cells to human models, this phenomenon remains only partially understood because of its complexity and the difficulty of obtaining direct experimental data. Currently, clinical monitoring of SD is limited to patients who require neurosurgical interventions and the placement of subdural electrode strips. Significantly, SD events recorded in humans display electrophysiological features that are essentially the same as those observed in animal models. Further research using existing and new experimental models of SD may allow a better understanding of its core mechanisms, and of their differences in different clinical conditions, fostering opportunities to identify and develop targeted therapies for SD-related disorders and their worst consequences.
A computational design tool for compliant mechanisms

We present a computational tool for designing compliant mechanisms. Our method takes as input a conventional, rigidly-articulated mechanism defining the topology of the compliant design. This input can be both planar or spatial, and we support a number of common joint types which, whenever possible, are automatically replaced with parameterized flexures. As the technical core of our approach, we describe a number of objectives that shape the design space in a meaningful way, including trajectory matching, collision avoidance, lateral stability, resilience to failure, and minimizing motor torque. Optimal designs in this space are obtained as solutions to an equilibrium-constrained minimization problem that we solve using a variant of sensitivity analysis. We demonstrate our method on a set of examples that range from simple four-bar linkages to full-fledged animatronics, and verify the feasibility of our designs by manufacturing physical prototypes.
A Reference Compensation Current Control strategy for Grid-Connected Inverter of Three-Phase Distributed Generators

Renewable energy resources (RES) are being increasingly connected in distribution systems by utilizing power electronic converters. However, the extensive use of power electronics has resulted in a rise in power quality (PQ) concerns faced by the utility. A novel control strategy implementing reference compensation current was proposed in this paper. So that these grid-connected inverters can achieve maximum benefits when they were installed in 3-phase 4-wire distribution systems. The inverter is controlled to perform as a multi-function device by incorporating active power filter functionality. The inverter can thus be utilized as: 1) power converter to transfer active power from RES to the grid, and 2) load reactive power demand support; 3) current harmonics compensation at PCC; and 4) current unbalance and neutral current compensation in case of 3-phase 4-wire system. Moreover, with adequate control of grid-interfacing inverter, all the four objectives can be accomplished either individually or simultaneously. Simulation and experimental results show the validity and capability of the novel proposed control strategy. DOI : http://dx.doi. org/10.11591/telkomnika.v12i5. 4918
The Non-Destructive Evaluation Of Composites And Other Materials By Thermal Pulse Video Thermography

The detection of sub-surface defects and structures, by thermal pulse video compatible thermal imagers, ie beginning to complement the slower methods of ultrasonic scanning and in some applications to surpass them. In principal a short pulse of radiation is emitted from a xenon flash tube and is absorbed by the surface of the material under inspection. This energy diffuses as heat through the material and sub-surface features are revealed as variations in surface temperature, either on the far face or near face, by a scanning infra-red camera. The promise of thermal pulse thermography lies in its ability to inspect materials for defects and quality with great speed and without physical contact. Other methods of applying heat are currently being investigated.
The cholinergic system in the cerebellum: from structure to function

Abstract The cerebellar cholinergic system belongs to the third type of afferent nerve fiber system (after the climbing and mossy fibers), and has important modulatory effects on cerebellar circuits and cerebellar-mediated functions. In this report, we review the cerebellar cholinergic system, including cholinergic origins and innervations, acetylcholine receptor expression and distributions, cholinergic modulations of neuronal firing and synaptic plasticity, the cholinergic role in cerebellar-mediated integral functions, and cholinergic changes during development and aging. Because some motor and mental disorders, such as cerebellar ataxia and autism, are accompanied with cerebellar cholinergic disorders, we also discuss the correlations between cerebellar cholinergic dysfunctions and these disorders. The cerebellar cholinergic input plays an important role in the modulation of cerebellar functions; therefore, cholinergic abnormalities could induce physiological dysfunctions.
Is the occurrence of a temporal pterygium really so rare?

The author, in keeping with the data quoted in literature, confirms that a temporal pterygium is rare. Out of 1,388 Arab patients with pterygia, only 33 (2.4%) had temporal pterygia. The other statement, i.e. that temporal pterygium rarely occurs without a nasal one, is also confirmed. This was found only in one case (0.08%) out of the total number of people afflicted by pterygium.
Elasticity of multilayers II. Strips, coatings and sandwiches

In multilayer structures the elastic constants vary with one coordinate. Applied stresses (caused by external loading) or internal stresses (caused by dislocations) might be present. We calculate the elastic fields in layered strips of finite thickness, and layered half spaces, either loaded or clamped, with and without a dislocation in the interior. The same is done for layered coatings on a homogeneous half space, and a layered strip sandwiched between two homogeneous half spaces. Completeness of the eigenfunctions used is proven.
A new business model of custom software development for agile software development

In this paper, we propose a new business model for custom software development industry utilizing agile software development to embrace changes. Traditional business model usually does not work well with agile software development because it mandate up-front man-month estimation based on a fixed scope. Our new model proposes a solution with two notable features; fixed monthly subscription and weekly agreement of what to provide. We successfully applied the new business model to more than 20 cases over 3 years and this paper describes one of them.
FoxO3 hastens autophagy and shrinks the heart but does not curtail pathological hypertrophy in adult mice.

This editorial refers to ‘FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model’ by T.G. Schips et al . , doi:10.1093/cvr/cvr144 The FoxO subfamily of Forkhead box transcription factors regulate many target genes that are involved in diverse cellular processes. FoxO proteins show partial functional redundancy due to the conserved DNA-binding domain, but also exhibit isoform specificity with regard to cellular function.1 Three of the four FoxO isoforms—FoxO1, FoxO3, and FoxO4, but not FoxO6—are expressed in the heart. The biological functions of FoxO proteins in the heart have been mainly revealed by studies on FoxO1 and FoxO3 using either cultured cardiomyocytes or loss-of-function animal models. Combined loss of FoxO1 and FoxO3 in the heart does not affect cardiac development,1 suggesting functional redundancy of FoxO proteins in regulating cardiac development. Indeed, loss of all three FoxO isoforms is required for an oncogenic phenotype in mice.2 So far, a viable animal model of FoxO gain-of-function is lacking, hindering a better understanding on the pathophysiological significance of FoxO proteins in adult hearts. Schips et al . 3 report the first mouse model of cardiac-specific and temporally controllable …