Miracle-dz/UniFAR-FTUs huggingface dataset:
E46K α-synuclein pathological mutation causes cell-autonomous toxicity without altering protein turnover or aggregation

Significance α-Synuclein (aSyn) plays a key role in neurodegenerative disorders known as “synucleinopathies. “ By tracking individual primary neurons overexpressing wild-type and mutant aSyn versions we have determined how pathological hallmarks like alterations in aSyn expression and stability, aggregation, or serine 129 phosphorylation (PS129) contribute to neuronal death. We have found that the E46K mutant displayed the highest toxicity. Neurotoxicity was independent of aggregation but correlated with PLK2-dependent PS129. Surprisingly, inhibiting PS129 did not affect neuronal survival, suggesting that this modification is an epiphenomenon. Finally, we set up an assay to score for cell-autonomous and nonautonomous toxicity. While we identified a minor non–cell-autonomous component restricted to proximal neurons, E46K toxicity was mostly cell autonomous. α-Synuclein (aSyn) is the main driver of neurodegenerative diseases known as “synucleinopathies,” but the mechanisms underlying this toxicity remain poorly understood. To investigate aSyn toxic mechanisms, we have developed a primary neuronal model in which a longitudinal survival analysis can be performed by following the overexpression of fluorescently tagged WT or pathologically mutant aSyn constructs. Most aSyn mutations linked to neurodegenerative disease hindered neuronal survival in this model; of these mutations, the E46K mutation proved to be the most toxic. While E46K induced robust PLK2-dependent aSyn phosphorylation at serine 129, inhibiting this phosphorylation did not alleviate aSyn toxicity, strongly suggesting that this pathological hallmark of synucleinopathies is an epiphenomenon. Optical pulse-chase experiments with Dendra2-tagged aSyn versions indicated that the E46K mutation does not alter aSyn protein turnover. Moreover, since the mutation did not promote overt aSyn aggregation, we conclude that E46K toxicity was driven by soluble species. Finally, we developed an assay to assess whether neurons expressing E46K aSyn affect the survival of neighboring control neurons. Although we identified a minor non–cell-autonomous component spatially restricted to proximal neurons, most E46K aSyn toxicity was cell autonomous. Thus, we have been able to recapitulate the toxicity of soluble aSyn species at a stage preceding aggregation, detecting non–cell-autonomous toxicity and evaluating how some of the main aSyn hallmarks are related to neuronal survival.
Channel State Information-Based Detection of Sybil Attacks in Wireless Networks

Single authentication mechanisms and broadcast characteristics of wireless networks make the Access Point (AP) vulnerable to spoofing attacks and Sybil attacks. However, Sybil attacks seriously affect network performance. Sybil nodes act with different identity, and prevent the normal clients from transmission. In this paper, a self-adaptive MUSIC algorithm is proposed, which improves the accuracy of the angle of the indoor wireless device by eliminating the phase offset in channel state information (CSI), and designs different types’ detection algorithm of Sybil attacks and spoofing attacks based on different Sybil attack models. And we experiment on mobile and commercial WiFi devices. The average detection error of angle is below 6.3°. After combining analysis of received signal strength indicator (RSSI), our detection algorithm can effectively detect whether the nodes launched by Sybil attacks, and the identity of other clients disguised by spoofing attacks. According to the experimental results, the scheme can distinguish the Sybil clients and the normal clients accurately, and the average success rate of the Sybil attack detection system is 98.5%.
Transcriptional and cellular effects of benzotriazole UV stabilizers UV‐234 and UV‐328 in the freshwater invertebrates Chlamydomonas reinhardtii and Daphnia magna

Benzotriazole ultra violet stabilizers (BZT‐UVs) are compounds used in many applications and products to prevent photochemical degradation. Despite their widespread presence in aquatic ecosystems and persistence in the environment, there are very limited data on their effects and toxicity, and their modes of action remain largely unknown. The objectives of the present study were to evaluate the chronic effects of 2 BZT‐UVs, 2‐(2H‐benzotriazol‐2‐yl)‐4,6‐bis(1‐methyl‐1‐phenylethyl)phenol (UV‐234) and 2‐(2H‐benzotriazol‐2‐yl)‐4,6‐di‐tert‐pentylphenol (UV‐328), on the freshwater green algae Chlamydomonas reinhardtii and the freshwater crustacean Daphnia magna. Organisms were exposed to 0.01 and 10 μg/L of UV‐234, UV‐328, as well as a mixture of the 2 compounds. Life‐history endpoints (viability, reproduction, and growth) and oxidative stress–related biomarkers (gene transcription, reactive oxygen species [ROS] production, and lipid peroxidation) were measured. Daphnia magna growth, reproduction, and gene transcription were not impacted by 21‐d individual or mixed exposure. After 96‐h of exposure, no differences were observed on the cellular viability of C. reinhardtii for either of the 2 BZT‐UVs. In the algae, results showed increased ROS production in response to UV‐328 and lipid peroxidation following exposure to UV‐234. Synergistic effects of the 2 BZT‐UVs were evident at the transcriptional level with 2 to 6 times up‐regulation of glutathione peroxidase (gpx) in response to the mixture for all treatment conditions. The transcription of superoxide dismutase (sod), catalase (cat), and ascorbic peroxidase (apx) was also regulated by UV‐234 and UV‐328 in the green algae, most likely as a result of ROS production and lipid peroxidation. Results from the present study suggest potential impacts of UV‐234 and UV‐328 exposure on the antioxidant defense system in C. reinhardtii. Environ Toxicol Chem 2017;36:3333–3342. © 2017 Crown in the Right of Canada. Published by Wiley Periodicals Inc., on behalf of SETAC.
Role of plasmalemmal caveolae in signal transduction.

Caveolae are specialized plasmalemmal microdomains originally studied in numerous cell types for their involvement in the transcytosis of macromolecules. They are enriched in glycosphingolipids, cholesterol, sphingomyelin, and lipid-anchored membrane proteins, and they are characterized by a light buoyant density and resistance to solubilization by Triton X-100 at 4°C. Once the identification of the marker protein caveolin made it possible to purify this specialized membrane domain, it was discovered that caveolae also contain a variety of signal transduction molecules. This includes G protein-coupled receptors, G proteins and adenylyl cyclase, molecules involved in the regulation of intracellular calcium homeostasis, and their effectors including the endothelial isoform of nitric oxide synthase, multiple components of the tyrosine kinase-mitogen-activated protein kinase pathway, and numerous lipid signaling molecules. More recent work has indicated that caveolae further serve to compartmentalize, modulate, and integrate signaling events at the cell surface. This specialized plasmalemmal domain warrants direct consideration in future investigations of both normal and pathological signal transduction in pulmonary cell types.
Analytical validation of a next generation sequencing liquid biopsy assay for high sensitivity broad molecular profiling

Circulating tumor DNA (ctDNA) analysis is being incorporated into cancer care; notably in profiling patients to guide treatment decisions. Responses to targeted therapies have been observed in patients with actionable mutations detected in plasma DNA at variant allele fractions (VAFs) below 0.5%. Highly sensitive methods are therefore required for optimal clinical use. To enable objective assessment of assay performance, detailed analytical validation is required. We developed the InVisionFirst™ assay, an assay based on enhanced tagged amplicon sequencing (eTAm-Seq™) technology to profile 36 genes commonly mutated in non-small cell lung cancer (NSCLC) and other cancer types for actionable genomic alterations in cell-free DNA. The assay has been developed to detect point mutations, indels, amplifications and gene fusions that commonly occur in NSCLC. For analytical validation, two 10mL blood tubes were collected from NSCLC patients and healthy volunteer donors. In addition, contrived samples were used to represent a wide spectrum of genetic aberrations and VAFs. Samples were analyzed by multiple operators, at different times and using different reagent Lots. Results were compared with digital PCR (dPCR). The InVisionFirst assay demonstrated an excellent limit of detection, with 99.48% sensitivity for SNVs present at VAF range 0.25%-0.33%, 92.46% sensitivity for indels at 0.25% VAF and a high rate of detection at lower frequencies while retaining high specificity (99.9997% per base). The assay also detected ALK and ROS1 gene fusions, and DNA amplifications in ERBB2, FGFR1, MET and EGFR with high sensitivity and specificity. Comparison between the InVisionFirst assay and dPCR in a series of cancer patients showed high concordance. This analytical validation demonstrated that the InVisionFirst assay is highly sensitive, specific and robust, and meets analytical requirements for clinical applications.
Dynamics of Bacterial Colonization With Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis During Symptomatic and Asymptomatic Viral Upper Respiratory Tract Infection

Abstract Background Virus is detected in about 80% of upper respiratory tract infections (URTIs) in children and is also detectable in the nasopharynx of 30% of asymptomatic children. The effect of asymptomatic viral infection on the dynamics of bacterial density and colonization of the nasopharynx has not been reported. The current study was performed to assess the presence and density of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the nasopharynx of 4–7-year-old children during URTI and when well. Methods Nasal samples were obtained during 4 surveillance periods when children were asymptomatic and whenever they had symptoms of URTI. Respiratory viruses and bacterial pathogens were identified and quantified using polymerase chain reaction. Results The proportion of children colonized with all 3 bacteria was higher during visits for acute URTI than during asymptomatic surveillance visits. Mean bacterial densities were significantly higher at all visits for all 3 pathogens when a virus was detected. The differences between the means were 1.0, 0.4, and 0.7 log10 colony-forming unit equivalents per milliliter for S. pneumoniae, H. influenzae, and M. catarrhalis, respectively, compared with visits in which virus was not detected. The percentage of children colonized and density were also higher at asymptomatic visits in which virus was detected than at visits in which virus was not detected. Conclusion The density and frequency of colonization with S. pneumoniae, H. influenzae, and M. catarrhalis in nasal wash samples increase during periods of both symptomatic and asymptomatic viral infection. Increases in bacterial colonization observed during asymptomatic viral infection were nearly the same magnitude as when children were symptomatic.
Dscam1 Forms a Complex with Robo1 and the N-Terminal Fragment of Slit to Promote the Growth of Longitudinal Axons

The Slit protein is a major midline repellent for central nervous system (CNS) axons. In vivo, Slit is proteolytically cleaved into N- and C-terminal fragments, but the biological significance of this is unknown. Analysis in the Drosophila ventral nerve cord of a slit allele (slit-UC) that cannot be cleaved revealed that midline repulsion is still present but longitudinal axon guidance is disrupted, particularly across segment boundaries. Double mutants for the Slit receptors Dscam1 and robo1 strongly resemble the slit-UC phenotype, suggesting they cooperate in longitudinal axon guidance, and through biochemical approaches, we found that Dscam1 and Robo1 form a complex dependent on Slit-N. In contrast, Robo1 binding alone shows a preference for full-length Slit, whereas Dscam1 only binds Slit-N. Using a variety of transgenes, we demonstrated that Dscam1 appears to modify the output of Robo/Slit complexes so that signaling is no longer repulsive. Our data suggest that the complex is promoting longitudinal axon growth across the segment boundary. The ability of Dscam1 to modify the output of other receptors in a ligand-dependent fashion may be a general principle for Dscam proteins.
Optimal Design Analysis of the Thickness of Shrink-Fit Holder

A calculation scheme to gain the relationship between the thickness of shrink-fit holder and thermodynamic properties. Based on the theoretical analysis of fitting molder between shrink-fit holder and tool, then the thermodynamic properties of the shrink-fit holder and cutting tool such as contact pressure, equivalent stress and deformation are analyzed at different thickness of shrink-fit holder in static, under cutting force and inducting heating by using the finite element software ANSYS. The results show that the total contact pressure and maximum equivalent stress increased and the minimum thermal displacement difference decreased with the increase of holder thickness. Under the action of cutting force, the contact stress on the tool holder no longer uniformed and the maximum contact stress significantly increased, cutting tool also deformed. Finally a method to determine the reasonable holder thickness is given and it has a practical guiding significance for the design and selection of the shrink-fit tool holder.
FANCI-FANCD2 stabilizes the RAD51-DNA complex by binding RAD51 and protects the 5′-DNA end

The FANCI-FANCD2 (I-D) complex is considered to work with RAD51 to protect the damaged DNA in the stalled replication fork. However, the means by which this DNA protection is accomplished have remained elusive. In the present study, we found that the I-D complex directly binds to RAD51, and stabilizes the RAD51-DNA filament. Unexpectedly, the DNA binding activity of FANCI, but not FANCD2, is explicitly required for the I-D complex-mediated RAD51-DNA filament stabilization. The RAD51 filament stabilized by the I-D complex actually protects the DNA end from nucleolytic degradation by an FA-associated nuclease, FAN1. This DNA end protection is not observed with the RAD51 mutant from FANCR patient cells. These results clearly answer the currently enigmatic question of how RAD51 functions with the I-D complex to prevent genomic instability at the stalled replication fork.
A Two-Stage Approach for Word Spotting in Graphical Documents

Presence of multi-oriented characters, connected characters with graphical lines, intersection of text and symbols with graphical lines/curves etc. are very common in graphical documents. As a result word spotting in graphical documents is still a challenging task that we try to solve (partially) in this paper. The proposed approach proceeds in two stages. In the first stage, recognition of isolated components is done using rotation invariant features and an SVM classifier. The characters having good recognition score and match in the query string are first selected for initial spotting. Because of structural complexity of graphical documents as well as of touching components, we may miss some of the query characters during initial spotting in some documents. In that case, based on the position, size and orientation of the recognized characters in the input document image, regions where missing characters may be located (candidate regions) are defined. In the second stage, Scale Invariant Feature Transform (SIFT) is used to find those missing characters in the candidate regions for possible spotting. Finally, using the position, size, orientation as well as intercharacter gap information of the recognized components, spotting is validated. Experimental results demonstrate that the method is efficient to locate a query word in multi-oriented and/or touching graphical documents.
Effects of aging on in vivo synthesis of skeletal muscle myosin heavy-chain and sarcoplasmic protein in humans.

A decline in muscle mass and contractile function are prominent features of the sarcopenia of old age. Because myosin heavy chain is an important contractile protein, it was hypothesized that synthesis of this protein decreases in sarcopenia. The fractional synthesis rate of myosin heavy chain was measured simultaneously with rates of mixed muscle and sarcoplasmic proteins from the increment of [13C]leucine in these proteins purified from serial needle biopsy samples taken from 24 subjects (age: from 20 to 92 yr) during a primed continuous infusion ofl-[1-13C]leucine. A decline in synthesis rate of mixed muscle protein ( P < 0.01) and whole body protein ( P < 0.01) was observed from young to middle age with no further change with advancing age. An age-related decline of myosin heavy-chain synthesis rate was also observed ( P < 0.01), with progressive decline occurring from young, through middle, to old age. However, sarcoplasmic protein synthesis did not decline with age. Myosin heavy-chain synthesis rate was correlated with measures of muscle strength ( P < 0.05), circulating insulin-like growth factor I ( P < 0.01), and dehydroepiandrosterone sulfate ( P < 0.05) in men and women and free testosterone levels in men ( P < 0.01). A decline in the synthesis rate of myosin heavy chain implies a decreased ability to remodel this important muscle contractile protein and likely contributes to the declining muscle mass and contractile function in the elderly.
DEPENDENCE RELATIONS IN GENE ONTOLOGY: A PRELIMINARY STUDY

The functional interpretation of microarray experiments requires computerized methods that exploit similarities between gene products with respect to their Gene Ontology (GO) annotations. While GO already represents taxonomic and meronomic relations, our objective is to identify associative relations across Gene Ontology hierarchies. The expected benefit of this effort is that these additional relations can be used to produce more consistent annotations. As a first step toward this goal, we analyze dependence relations between GO terms, first in a set of 23 gene products involved in enterocyte differentiation and later in GOA. Our approach takes into account ontological, lexical, and statistical aspects of dependence. Preliminary results suggest the interest of combining these three approaches for accurately identifying ontological and functional dependence relations in GO.
What Persons with Chronic Health Conditions Need to Maintain or Return to Work—Results of an Online-Survey in Seven European Countries

Chronic health conditions represent the major share of the disease burden in Europe and have a significant impact on work. This study aims to: (1) identify factors that have a negative or positive impact on the work lives of persons with chronic health conditions; (2) explore the needs of these persons to maintain a job or return to work and (3) compare these results with respect to these persons’ occupational status. An online survey was performed in seven European countries. Open-ended survey questions were analyzed using qualitative methods. In total, 487 participants with six chronic health conditions participated. The majority of participants named work-related aspects (such as career development, stress at the workplace, work structure and schedule as well as workload), support of others and attitudes of others as being the factors positively and negatively impact their work lives the most. Our study shed light on the importance of changing the attitudes of supervisors and co-workers to counteract stigmatization of persons with chronic health conditions in the workplace. In conclusion, this study provides a basis for developing new strategies of integration and reintegration at work for persons with chronic health conditions in European countries.
iNOS expression in human intestinal microvascular endothelial cells inhibits leukocyte adhesion.

Increased nitric oxide (NO) production by inducible nitric oxide synthase (iNOS) has been associated with intestinal inflammation, including human inflammatory bowel disease. However, NO can downregulate endothelial activation and leukocyte adhesion, critical steps in the inflammatory response. Using primary cultures of human intestinal microvascular endothelial cells (HIMEC), we determined the role of NO in the regulation of HIMEC activation and interaction with leukocytes. Both nonselective ( N G-monomethyl-l-arginine) and specific ( N-iminoethyl-l-lysine) competitive inhibitors of iNOS significantly increased binding of leukocytes by HIMEC activated with cytokines and lipopolysaccharide. Increased adhesion was reversible with the NOS substratel-arginine and was not observed in human umbilical vein endothelial cells (HUVEC). Activation of HIMEC significantly upregulated HIMEC iNOS expression and NO production. NOS inhibitors did not augment cell adhesion molecule levels in activated HIMEC but did result in sustained increases in intracellular reactive oxygen species. In addition, antioxidant compounds reversed the effect of NOS inhibitors on HIMEC-leukocyte interaction. Taken together, these data suggest that after HIMEC activation, iNOS-derived NO is an endogenous antioxidant, downregulating leukocyte binding and potentially downregulating intestinal inflammation.
Image Generation and Translation with Disentangled Representations

Generative models have made significant progress in the tasks of modeling complex data distributions such as natural images. The introduction of Generative Adversarial Networks (GANs) and auto-encoders lead to the possibility of training on big data sets in an unsupervised manner. However, for many generative models it is not possible to specify what kind of image should be generated and it is not possible to translate existing images into new images of similar domains. Furthermore, models that can perform image-to-image translation often need distinct models for each domain, making it hard to scale these systems to multiple domain image-to-image translation. We introduce a model that can do both, controllable image generation and image-to-image translation between multiple domains. We split our image representation into two parts encoding unstructured and structured information respectively. The latter is designed in a disentangled manner, so that different parts encode different image characteristics. We train an encoder to encode images into these representations and use a small amount of labeled data to specify what kind of information should be encoded in the disentangled part. A generator is trained to generate images from these representations using the characteristics provided by the disentangled part of the representation. Through this we can control what kind of images the generator generates, translate images between different domains, and even learn unknown data-generating factors while only using one single model.
RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.