julilili42/papers huggingface dataset:
The Pemphigus Vulgaris antigen desmoglein-3 suppresses p53 function via the YAP-Hippo pathway
2018-08-25

Abstract Desmoglein-3 (Dsg3), the Pemphigus Vulgaris (PV) antigen (PVA), plays an essential role in keratinocyte cell-cell adhesion and regulates various signaling pathways implicated in the pathogenesis the PV blistering disease. We show here that expression of Dsg3 may directly influence p53, a key transcription factor governing the response to cellular stress. Dsg3 depletion caused increased p53 and apoptosis, an effect that was further enhanced by UV and mechanical strain and reversed by Dsg3 gain-of-function studies. Analysis in Dsg3-/- mouse skin confirmed increased p53/p21/caspase-3 compared to Dsg3+/- control in vivo . This Dsg3-p53 pathway involved YAP since Dsg3 forms a complex with YAP and regulates its expression and localization. Analysis of PV patient samples detected increased p53/YAP with diffuse cytoplasmic and/or nuclear staining in cells surrounding blisters. Treatment of keratinocytes with PV sera evoked pronounced p53/YAP expression. Collectively, our findings establish a novel role for Dsg3 as an anti-stress protein, via suppression of p53 function, suggesting that this pathway, involving YAP-Hippo control of skin homeostasis, is disrupted in PV.
Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition
2018-08-27

Significance In Huntington disease (HD) gene carriers the disease-causing mutant Huntingtin (m HTT ) is already present during early developmental stages, but, surprisingly, HD patients develop clinical symptoms only many years later. While a developmental role of Huntingtin has been described, so far new therapeutic approaches targeting those early neurodevelopmental processes are lacking. Here, we show that behavioral, cellular, and molecular changes associated with m HTT in the postnatal period of genetic animal models of HD can be reverted using low-dose treatment with a histone deacetylation inhibitor. Our findings support a neurodevelopmental basis for HD and provide proof of concept that pre-HD symptoms, including aberrant neuronal differentiation, are reversible by early therapeutic intervention in vivo.
Impact of curative radiotherapy on the immune status of patients with localized prostate cancer
2018-08-27

Combination of radiotherapy with immunotherapy has become an attractive concept for the treatment of cancer. The objective of this study was to assess the effect of curative, normofractionated radiotherapy on peripheral immune lymphocytes in prostate cancer patients, in order to propose a rationale for scheduling of normofractionated radiotherapy with T-cell based immunotherapy. In a prospective study (clinicaltrials.gov: NCT01376674), eighteen patients with localized prostate cancer were treated with radiotherapy with or without hormonal therapy. Irradiation volumes encompassed prostate and, in select cases, elective pelvic nodal regions. Blood samples were collected from all patients before, during, and after radiotherapy, as well as from 6 healthy individuals as control. Normofractionated radiotherapy of prostate cancer over eight weeks had a significant influence on the systemic immune status of patients compared to healthy controls. Absolute leukocyte and lymphocyte counts decreased during treatment as did peripheral blood immune subsets (T cells, CD8<sup>+</sup> and naïve CD4<sup>+</sup> T cells, B cells). Regulatory T cells and NK cells increased. Proliferation of all immune cells except regulatory T cells increased during RT. Most of these changes were transient. Importantly, the functionality of T lymphocytes and the frequency of antigen-specific CD8<sup>+</sup> T cells were not affected during therapy. Our data indicate that combination of normofractionated radiotherapy with immunotherapy might be feasible for patients with prostate cancer. Conceptually, beginning with immunotherapy early during the course of radiotherapy could be beneficial, as the percentage of T cells is highest, the percentage of regulatory T cells is lowest, and as the effects of radiotherapy did not completely subside 3 months after end of radiotherapy.
Reflection Spectroscopy of the Black Hole Binary XTE J1752−223 in Its Long-stable Hard State
2018-08-27

Abstract We present a detailed spectral analysis of the black hole binary XTE J1752−223 in the hard state of its 2009 outburst. Regular monitoring of this source by the Rossi X-ray Timing Explorer mission provided high signal-to-noise spectra along the outburst rise and decay. During one full month this source stalled at ∼30% of its peak count rate at a constant hardness and intensity. By combining all the data in this exceptionally stable hard state, we obtained an aggregate proportional counter array spectrum (3–45 keV) with 100 million counts, and a corresponding high energy X-ray timing experiment spectrum (20–140 keV) with 5.8 million counts. Implementing a version of our reflection code with a physical model for Comptonization, we obtain tight constraints on important physical parameters for this system. In particular, the inner accretion disk is measured very close in, at R in = 1.7 ± 0.4 R g . Assuming R in = R ISCO , we find a relatively high black hole spin ( a * = 0.92 ± 0.06). Imposing a lamppost geometry, we obtain a low inclination ( i = 35° ± 4°), which agrees with the upper limit found in the radio ( i &lt; 49°). However, we note that this model cannot be statistically distinguished from a non-lamppost model with a free emissivity index, for which the inclination is markedly higher. Additionally, we find a relatively cool corona (57–70 keV) and large iron abundance (3.3–3.7 solar). We further find that properly accounting for Comptonization of the reflection emission improves the fit significantly and causes an otherwise low reflection fraction (∼0.2–0.3) to increase by an order of magnitude, in line with geometrical expectations for a lamppost corona. We compare these results with similar investigations reported for GX 339−4 in its bright hard state.
Long Noncoding RNA SSR42 Controls Staphylococcus aureus Alpha-Toxin Transcription in Response to Environmental Stimuli
2018-08-27

Staphylococcus aureus is a major cause of life-threatening infections. The bacterium expresses alpha-toxin, a hemolysin and cytotoxin responsible for many of the pathologies of S. aureus . Alpha-toxin production is enhanced by subinhibitory concentrations of antibiotics. Here, we show that this process is dependent on the long noncoding RNA, SSR42. Further, SSR42 itself is regulated by several global regulators, thereby integrating environmental and nutritional signals that modulate hemolysis of the pathogen.
Resonance compensating chirp mode for mapping the rheology of live cells by high-speed atomic force microscopy
2018-08-27

We developed resonance compensating chirp mode (RCCM), an atomic force microscopy (AFM) technique to measure the frequency dependence of the complex shear modulus of live cells over a large bandwidth (quasi-) continuously. RCCM works by applying a continuous frequency sweep (chirp) to the z-scanner and recording the resulting cantilever deflection at high speed. From this data, the frequency-resolved complex shear modulus is extracted. To reach a high maximum frequency, we iteratively shaped the chirp signal to compensate for scanner resonances. This allowed us to measure at frequencies five times higher than the resonant frequency of the scanner. Using a high-speed AFM with small cantilevers, we measured the complex shear modulus of live fibroblast cells in a continuous range between 5 Hz and 30 kHz. We found that the modulus and the loss tangent exhibit a power-law behavior throughout this frequency range. A short chirp duration of 200 ms allowed us to map live cells and generate spatially resolved images of the power-law parameters within minutes. These maps represent a unique combination of high spatial and frequency resolution, low measurement duration, and high maximum frequency.
Rare gene deletions in genetic generalized and Rolandic epilepsies
2018-08-27

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as important risk factors in brain disorders. We performed a systematic survey of rare deletions affecting protein-coding genes derived from exome data of patients with common forms of genetic epilepsies. We analysed exomes from 390 European patients (196 GGE and 194 RE) and 572 population controls to identify low-frequency genic deletions. We found that 75 (32 GGE and 43 RE) patients out of 390, i.e. ~19%, carried rare genic deletions. In particular, large deletions (>400 kb) represent a higher burden in both GGE and RE syndromes as compared to controls. The detected low-frequency deletions (1) share genes with brain-expressed exons that are under negative selection, (2) overlap with known autism and epilepsy-associated candidate genes, (3) are enriched for CNV intolerant genes recorded by the Exome Aggregation Consortium (ExAC) and (4) coincide with likely disruptive de novo mutations from the NPdenovo database. Employing several knowledge databases, we discuss the most prominent epilepsy candidate genes and their protein-protein networks for GGE and RE.
Towards the development of a tablet-based screening for cognitive symptoms of neuropsychiatric disorders
2018-08-27

Tablet-based screenings have been shown to enhance diagnostics of symptoms of neuropsychiatric disorders such as Alzheimer's or Parkinsons by providing more diagnostic data through digital media in addition to conventional paper-and-pencil tests. However, user acceptance/experience with older patients have not been systematically researched in this context. We present the design and evaluation of a tablet-based prototype of a neuropsychiatric screening of cognitive symptoms. After developing two layouts, one identical to the original pencil-and-paper test (TI), one optimized for tablets (TO), the tablet-based versions were compared with the original version in a user test (n = 20). Results showed user acceptance/experience to be positive for all versions and TO favored over the other versions. Test-retest reliability was maintained in the tablet-based versions and differences in digitizer features between healthy and cognitively impaired participants were explored.
Team Semantics for the Specification and Verification of Hyperproperties
2018-08-27

We develop team semantics for Linear Temporal Logic (LTL) to express hyperproperties, which have recently been identified as a key concept in the verification of information flow properties. Conceptually, we consider an asynchronous and a synchronous variant of team semantics. We study basic properties of this new logic and classify the computational complexity of its satisfiability, path, and model checking problem. Further, we examine how extensions of these basic logics react on adding other atomic operators. Finally, we compare its expressivity to the one of HyperLTL, another recently introduced logic for hyperproperties. Our results show that LTL under team semantics is a viable alternative to HyperLTL, which complements the expressivity of HyperLTL and has partially better algorithmic properties.
Arabidopsis RNA processing factor SERRATE regulates the transcription of intronless genes
2018-08-28

Intron splicing increases proteome complexity, promotes RNA stability, and enhances transcription. However, introns and the concomitant need for splicing extend the time required for gene expression and can cause an undesirable delay in the activation of genes. Here, we show that the plant microRNA processing factor SERRATE (SE) plays an unexpected and pivotal role in the regulation of intronless genes. Arabidopsis SE associated with more than 1000, mainly intronless, genes in a transcription-dependent manner. Chromatin-bound SE liaised with paused and elongating polymerase II complexes and promoted their association with intronless target genes. Our results indicate that stress-responsive genes contain no or few introns, which negatively affects their expression strength, but that some genes circumvent this limitation via a novel SE-dependent transcriptional activation mechanism. Transcriptome analysis of a Drosophila mutant defective in ARS2, the metazoan homologue of SE, suggests that SE/ARS2 function in regulating intronless genes might be conserved across kingdoms.
Near‐Infrared Spectroscopy as a New Tool for Neurofeedback Training: Applications in Psychiatry and Methodological Considerations
2018-08-28

Abstract Over the past decades, functional near‐infrared spectroscopy (fNIRS) has become a valuable tool in the online assessment of brain function in psychological and neuropsychiatric research. Recently, fNIRS has also been employed in the context of neurofeedback (NF), with pilot studies indicating that hemodynamic responses can be deliberately regulated and that neuroplastic changes occur over the course of several training sessions. This review article provides a comprehensive overview of the recent implementation and development of fNIRS as an NF tool; specifically, we will outline initial studies in healthy participants as well as children and adults with attention deficit hyperactivity disorder and describe new protocols aimed at reducing auditory verbal hallucinations (schizophrenic patients) and anxiety symptoms (patients with social anxiety disorder), respectively. Finally, we will discuss recent methodological developments and concerns as well as potential future perspectives. We conclude that fNIRS is a useful tool for conducting NF, especially in terms of multi‐session training. However, methodological details need to be considered when designing fNIRS‐based NF studies, and future protocols should aim at training broader network structures and implementing implicit training protocols. Finally, future studies should focus not only on (clinical) effects of fNIRS‐based NF, but also on the underlying mechanisms and activity changes in extended brain networks.
Wide Learning for Auditory Comprehension
2018-08-28

&lt;p&gt;Classical linguistic, cognitive and engineering models for speech recognition and human auditory comprehension posit representations for sounds and words that mediate between the acoustic signal and interpretation. Recent advances in automatic speech recognition have shown, using deep learning, that state-of-the-art performance is obtained without such units. We present a cognitive model of auditory comprehension based on wide rather than deep learning that was trained on 20 to 80 hours of TV news broadcasts. Just as deep network models, our model is an end-to-end system that does not make use of phonemes and phonological wordform representations. Nevertheless, it performs well on the difficult task of single word identification (model accuracy 11.37%, Mozilla DeepSpeech: 4.45%). The architecture of the model is a simple two-layered wide neural network with weighted connections between the acoustic frequency band features as inputs and lexical outcomes (pointers to semantic vectors) as outputs. Model performance shows hardly any degredation when trained on speech in noise rather than on clean speech. Performance was further enhanced by adding a second network to a standard wide network. The present word recognition module is designed to become part of a larger system modeling the comprehension of running speech.&lt;/p&gt;
Neural Response Development During Distributional Learning
2018-08-28

We investigated online electrophysiological components of distributional learning, specifically of tones by listeners of a non-tonal language. German listeners were presented with a bimodal distribution of syllables with lexical tones from a synthesized continuum based on Cantonese level tones. Tones were presented in sets of four standards (within-category tokens) followed by a deviant (across-category token). Mismatch negativity (MMN) was measured. Earlier behavioral data showed that exposure to this bimodal distribution improved both categorical perception and perceptual acuity for level tones [1]. In the present study we present analyses of the electrophysiological response recorded during this exposure, i.e. the development of the MMN response during distributional learning. This development over time is analyzed using Generalized Additive Mixed Models and results showed that the MMN amplitude increased for both within- and across-category tokens, reflecting higher perceptual acuity accompanying category formation. This is evidence that learners zooming in on phonological categories undergo neural changes associated with more accurate phonetic perception.
Effective Acoustic Cue Learning Is Not Just Statistical, It Is Discriminative
2018-08-28

&lt;p&gt;A growing statistical learning literature suggests that listeners extract statistical information from the linguistic environment. However, distributional frequency may be insufficient for important but relatively low-frequency cues. Acquisition of linguistic knowledge may rely not merely on co-occurrences but on predictive relationships between cues and their outcomes. The present study investigates effects of predictive temporal cue structure on acquisition of a non-native acoustic cue dimension.&lt;/p&gt; &lt;p&gt;During training, native English speakers saw coloured shape objects and heard spoken Min Chinese words with six different lexical tones. Tones were the only reliable cue to identifying the associated object. Words also contained a salient cue that did not discriminate between objects. Three tones occurred with high-frequency and three with low-frequency in training. The critical manipulation was the presentation order: either words, containing complex cue structure, preceded object outcomes (discriminative order) or objects preceded words (non-discriminative order).&lt;/p&gt; &lt;p&gt;Generalised linear mixed models showed accuracy was significantly higher in the discriminative order than the non-discriminative order. These results demonstrate that predictive cue structure can facilitate acquisition of a non-native cue dimension. Feedback from prediction error drives learners to ignore salient non-discriminative cues and effectively learn to use the target cue dimension.&nbsp;&lt;/p&gt;
Deep Learning for Quality Control of Subcortical Brain 3D Shape Models
2018-08-28

Abstract We present several deep learning models for assessing the morphometric fidelity of deep grey matter region models extracted from brain MRI. We test three different convolutional neural net architectures (VGGNet, ResNet and Inception) over 2D maps of geometric features. Further, we present a novel geometry feature augmentation technique based on parametric spherical mapping. Finally, we present an approach for model decision visualization, allowing human raters to see the areas of subcortical shapes most likely to be deemed of failing quality by the machine. Our training data is comprised of 5200 subjects from the ENIGMA Schizophrenia MRI cohorts, and our test dataset contains 1500 subjects from the ENIGMA Major Depressive Disorder cohorts. Our final models reduce human rater time by 46-70%. ResNet outperforms VGGNet and Inception for all of our predictive tasks.
(2S,3S)-2-Azaniumyl-4-[(1S,4aS,4bS,6S,7S,8aS,10aS)-6,7-dihydroxy-2,4b,8,8,10a-pentamethyl-1,4,4a,4b,5,6,7,8,8a,9,10,10a-dodecahydrophenanthren-1-yl]-3-methoxybutanoate–methanol–water (1/1/1)
2018-08-28

The title compound, which crystallized as a methanol and water solvate, C 24 H 41 NO 5 ·CH 4 O·H 2 O, was obtained by heterologous expression of the brasilicardin gene cluster in the bacterium Amycolatopsis japonicum . In the crystal, the components are linked by numerous hydrogen bonds, generating a three-dimensional network.
Shared Parental Leave: Exploring Variations in Attitudes, Eligibility, Knowledge and Take-up Intentions of Expectant Mothers in London
2018-08-29

Abstract In April 2015, the UK introduced Shared Parental Leave (SPL), allowing mothers to transfer their maternity leave to their partners from two weeks after the birth or adoption of a child. There has been very limited research conducted on this leave policy to date and knowledge on take-up is poor. We present findings from an in-depth survey conducted with expectant mothers in two NHS trusts in England on their knowledge, views and plans around leave after the birth of their child and examine variations across educational and ethnic groups. A total of 575 expectant mothers took part in the survey. Around 7.4 per cent of expectant mothers who were (self-)employed or in education intended to take SPL. Finances and worries over fathers’ careers were cited as the primary barriers to take up of SPL. Individual entitlement for fathers and knowing others who took SPL increased individuals’ reported intention to take SPL. Applying logistic regression models, we found that knowledge of and access to SPL is correlated with education, ethnicity and home ownership. Future research and policy design should attend to such issues to ensure equitable access across families.
GC-B Deficient Mice With Axon Bifurcation Loss Exhibit Compromised Auditory Processing
2018-08-29

Sensory axon T-like branching (bifurcation) in neurons from dorsal root ganglia and cranial sensory ganglia depends on the molecular signaling cascade involving the secreted factor C-type natriuretic peptide, the natriuretic peptide receptor guanylyl cyclase B (GC-B; also known as Npr2) and cGMP-dependent protein kinase I (cGKI, also known as PKGI). The bifurcation of cranial nerves is suggested to be important for information processing by second-order neurons in the hindbrain or spinal cord. Indeed, mice with a spontaneous GC-B loss of function mutation (<i>Npr2<sup>cn/cn</sup></i> ) display an impaired bifurcation of auditory nerve (AN) fibers. However, these mice did not show any obvious sign of impaired basal hearing. Here, we demonstrate that mice with a targeted inactivation of the GC-B gene (Npr2 <i><sup>lacZ/lacZ</sup></i> , GC-B KO mice) show an elevation of audiometric thresholds. In the inner ear, the cochlear hair cells in GC-B KO mice were nevertheless similar to those from wild type mice, justified by the typical expression of functionally relevant marker proteins. However, efferent cholinergic feedback to inner and outer hair cells was reduced in GC-B KO mice, linked to very likely reduced rapid efferent feedback. Sound-evoked AN responses of GC-B KO mice were elevated, a feature that is known to occur when the efferent axo-dendritic feedback on AN is compromised. Furthermore, late sound-evoked brainstem responses were significantly delayed in GC-B KO mice. This delay in sound response was accompanied by a weaker sensitivity of the auditory steady state response to amplitude-modulated sound stimuli. Finally, the acoustic startle response (ASR) - one of the fastest auditory responses - and the prepulse inhibition of the ASR indicated significant changes in temporal precision of auditory processing. These findings suggest that GC-B-controlled axon bifurcation of spiral ganglion neurons is important for proper activation of second-order neurons in the hindbrain and is a prerequisite for proper temporal auditory processing likely by establishing accurate efferent top-down control circuits. These data hypothesize that the bifurcation pattern of cranial nerves is important to shape spatial and temporal information processing for sensory feedback control.