julilili42/papers huggingface dataset:
Discovery of functional non-coding conserved regions in the α-synuclein gene locus
2014-12-08

<ns4:p>Several single nucleotide polymorphisms (SNPs) and the Rep-1 microsatellite marker of the α-synuclein (<ns4:italic>SNCA</ns4:italic>) gene have consistently been shown to be associated with Parkinson’s disease, but the functional relevance is unclear. Based on these findings we hypothesized that conserved cis-regulatory elements in the<ns4:italic>SNCA</ns4:italic>genomic region regulate expression of<ns4:italic>SNCA</ns4:italic>, and that SNPs in these regions could be functionally modulating the expression of<ns4:italic>SNCA</ns4:italic>, thus contributing to neuronal demise and predisposing to Parkinson’s disease.</ns4:p><ns4:p>In a pair-wise comparison of a 206kb genomic region encompassing the<ns4:italic>SNCA</ns4:italic>gene, we revealed 34 evolutionary conserved DNA sequences between human and mouse. All elements were cloned into reporter vectors and assessed for expression modulation in dual luciferase reporter assays. We found that 12 out of 34 elements exhibited either an enhancement or reduction of the expression of the reporter gene. Three elements upstream of the<ns4:italic>SNCA</ns4:italic>gene displayed an approximately 1.5 fold (p&lt;0.009) increase in expression. Of the intronic regions, three showed a 1.5 fold increase and two others indicated a 2 and 2.5 fold increase in expression (p&lt;0.002). Three elements downstream of the<ns4:italic>SNCA</ns4:italic>gene showed 1.5 fold and 2.5 fold increase (p&lt;0.0009). One element downstream of<ns4:italic>SNCA</ns4:italic>had a reduced expression of the reporter gene of 0.35 fold (p&lt;0.0009) of normal activity.</ns4:p><ns4:p>Our results demonstrate that the<ns4:italic>SNCA</ns4:italic>gene contains cis-regulatory regions that might regulate the transcription and expression of<ns4:italic>SNCA</ns4:italic>. Further studies in disease-relevant tissue types will be important to understand the functional impact of regulatory regions and specific Parkinson’s disease-associated SNPs and its function in the disease process.</ns4:p>
A Bayesian model for identifying hierarchically organised states in neural population activity
2014-12-08

Neural population activity in cortical circuits is not solely driven by external inputs, but is also modulated by endogenous states. These cortical states vary on multiple time-scales and also across areas and layers of the neocortex. To understand information processing in cortical circuits, we need to understand the statistical structure of internal states and their interaction with sensory inputs. Here, we present a statistical model for extracting hierarchically organized neural population states from multi-channel recordings of neural spiking activity. We model population states using a hidden Markov decision tree with state-dependent tuning parameters and a generalized linear observation model. Using variational Bayesian inference, we estimate the posterior distribution over parameters from population recordings of neural spike trains. On simulated data, we show that we can identify the underlying sequence of population states over time and reconstruct the ground truth parameters. Using extracellular population recordings from visual cortex, we find that a model with two levels of population states outperforms a generalized linear model which does not include state-dependence, as well as models which only including a binary state. Finally, modelling of state-dependence via our model also improves the accuracy with which sensory stimuli can be decoded from the population response.
Cognitive state monitoring and the design of adaptive instruction in digital environments: lessons learned from cognitive workload assessment using a passive brain-computer interface approach
2014-12-09

According to Cognitive Load Theory (CLT), one of the crucial factors for successful learning is the type and amount of working-memory load (WML) learners experience while studying instructional materials. Optimal learning conditions are characterized by providing challenges for learners without inducing cognitive over- or underload. Thus, presenting instruction in a way that WML is constantly held within an optimal range with regard to learners' working-memory capacity might be a good method to provide these optimal conditions. The current paper elaborates how digital learning environments, which achieve this goal can be developed by combining approaches from Cognitive Psychology, Neuroscience, and Computer Science. One of the biggest obstacles that needs to be overcome is the lack of an unobtrusive method of continuously assessing learners' WML in real-time. We propose to solve this problem by applying passive Brain-Computer Interface (BCI) approaches to realistic learning scenarios in digital environments. In this paper we discuss the methodological and theoretical prospects and pitfalls of this approach based on results from the literature and from our own research. We present a strategy on how several inherent challenges of applying BCIs to WML and learning can be met by refining the psychological constructs behind WML, by exploring their neural signatures, by using these insights for sophisticated task designs, and by optimizing algorithms for analyzing electroencephalography (EEG) data. Based on this strategy we applied machine-learning algorithms for cross-task classifications of different levels of WML to tasks that involve studying realistic instructional materials. We obtained very promising results that yield several recommendations for future work.
An EEG/EOG-based hybrid brain-neural computer interaction (BNCI) system to control an exoskeleton for the paralyzed hand
2014-12-09

Abstract The loss of hand function can result in severe physical and psychosocial impairment. Thus, compensation of a lost hand function using assistive robotics that can be operated in daily life is very desirable. However, versatile, intuitive, and reliable control of assistive robotics is still an unsolved challenge. Here, we introduce a novel brain/neural-computer interaction (BNCI) system that integrates electroencephalography (EEG) and electrooculography (EOG) to improve control of assistive robotics in daily life environments. To evaluate the applicability and performance of this hybrid approach, five healthy volunteers (HV) (four men, average age 26.5±3.8 years) and a 34-year-old patient with complete finger paralysis due to a brachial plexus injury (BPI) used EEG (condition 1) and EEG/EOG (condition 2) to control grasping motions of a hand exoskeleton. All participants were able to control the BNCI system (BNCI control performance HV: 70.24±16.71%, BPI: 65.93±24.27%), but inclusion of EOG significantly improved performance across all participants (HV: 80.65±11.28, BPI: 76.03±18.32%). This suggests that hybrid BNCI systems can achieve substantially better control over assistive devices, e.g., a hand exoskeleton, than systems using brain signals alone and thus may increase applicability of brain-controlled assistive devices in daily life environments.
Learned self-regulation of the lesioned brain with epidural electrocorticography
2014-12-09

Introduction: Different techniques for neurofeedback of voluntary brain activations are currently being explored for clinical application in brain disorders. One of the most frequently used approaches is the self-regulation of oscillatory signals recorded with electroencephalography (EEG). Many patients are, however, unable to achieve sufficient voluntary control of brain activity. This could be due to the specific anatomical and physiological changes of the patient’s brain after the lesion, as well as to methodological issues related to the technique chosen for recording brain signals.
Transverse mixing in three-dimensional nonstationary anisotropic heterogeneous porous media
2014-12-09

Groundwater plumes originating from continuously emitting sources are typically controlled by transverse mixing between the plume and reactants in the ambient solution. In two-dimensional domains, heterogeneity causes only weak enhancement of transverse mixing in steady-state flows. In three-dimensional domains, more complex flow patterns are possible because streamlines can twist. In particular, spatially varying orientation of anisotropy can cause steady-state groundwater whirls. We analyze steady-state solute transport in three-dimensional locally isotropic heterogeneous porous media with blockwise anisotropic correlation structure, in which the principal directions of anisotropy differ from block to block. For this purpose, we propose a transport scheme that relies on advective transport along streamlines and transverse-dispersive mass exchange between them based on Voronoi tessellation. We compare flow and transport results obtained for a nonstationary anisotropic log-hydraulic conductivity field to an equivalent stationary field with identical mean, variance, and two-point correlation function disregarding the nonstationarity. The nonstationary anisotropic field is affected by mean secondary motion and causes neighboring streamlines to strongly diverge, which can be quantified by the two-particle semivariogram of lateral advective displacements. An equivalent kinematic descriptor of the flow field is the advective folding of plumes, which is more relevant as precursor of mixing than stretching. The separation of neighboring streamlines enhances transverse mixing when considering local dispersion. We quantify mixing by the flux-related dilution index, which is substantially larger for the nonstationary anisotropic conductivity field than for the stationary one. We conclude that nonstationary anisotropy in the correlation structure has a significant impact on transverse plume deformation and mixing. In natural sediments, contaminant plumes most likely mix more effectively in the transverse directions than predicted by models that neglect the nonstationarity of anisotropy.
Quantification of riboflavin, flavin mononucleotide, and flavin adenine dinucleotide in mammalian model cells by CE with LED‐induced fluorescence detection
2014-12-09

Cultured mammalian cells essential are model systems in basic biology research, production platforms of proteins for medical use, and testbeds in synthetic biology. Flavin cofactors, in particular flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), are critical for cellular redox reactions and sense light in naturally occurring photoreceptors and optogenetic tools. Here, we quantified flavin contents of commonly used mammalian cell lines. We first compared three procedures for extraction of free and noncovalently protein‐bound flavins and verified extraction using fluorescence spectroscopy. For separation, two CE methods with different BGEs were established, and detection was performed by LED‐induced fluorescence with limit of detections (LODs 0.5–3.8 nM). We found that riboflavin (RF), FMN, and FAD contents varied significantly between cell lines. RF (3.1–14 amol/cell) and FAD (2.2–17.0 amol/cell) were the predominant flavins, while FMN (0.46–3.4 amol/cell) was found at markedly lower levels. Observed flavin contents agree with those previously extracted from mammalian tissues, yet reduced forms of RF were detected that were not described previously. Quantification of flavins in mammalian cell lines will allow a better understanding of cellular redox reactions and optogenetic tools.
Reticulocyte haemoglobin content as a marker of iron deficiency
2014-12-09

Objective To evaluate reticulocyte haemoglobin content (CHr), compared with ferritin, transferrin saturation (TS) and mean corpuscular volume (MCV), as a marker of iron deficiency (ID). Design Retrospective analysis of clinically indicated blood samples taken between February 2010 and October 2012. Setting Single-centre neonatal care unit. Patients 210 very preterm (gestational age &lt;32 weeks) or very low birthweight infants (birth weight &lt;1500 g) at 3–4 months corrected age. Main outcome measures Complete blood count, CHr, ferritin and TS determined as part of a standard follow-up examination. To detect the optimal CHr cut-off, ID was defined by the presence of more than two of the following three criteria: MCV &lt;75 fL, TS &lt;10%, ferritin &lt;30 μg/L. Results 210 preterm infants were included at a corrected age of (median (IQR)) 3.5 (3.0–4.0) months and with a CHr of 29.7 (28.6–30.7) pg. There were correlations between CHr and MCV (r=0.54, p &lt;0.0001) and between CHr and TS (r=0.44, p &lt;0.0001). There were 27 (13.4%) iron-deficient infants, and two infants (1%) fulfilled criteria of ID-anaemia. CHr was lower in infants with ID (26.4 (23.8–28.7) pg) than in those without (29.9 (29.0–30.8) pg, p &lt;0.0001). The optimal CHr cut-off for detecting ID was 29 pg (sensitivity 85%, specificity 73%). Areas under the receiver operating characteristic curve for detection of ID tended to be higher for CHr compared with ferritin (0.92 vs 0.75), TS (0.90 vs 0.82) and MCV (0.81 vs 0.72). Conclusions CHr seems to be a suitable marker for latent ID in preterm infants at 3–4 months corrected age and may be superior to ferritin, TS and MCV.
Decoding upper limb residual muscle activity in severe chronic stroke
2014-12-09

Abstract Objective Stroke is a leading cause of long‐term motor disability. Stroke patients with severe hand weakness do not profit from rehabilitative treatments. Recently, brain‐controlled robotics and sequential functional electrical stimulation allowed some improvement. However, for such therapies to succeed, it is required to decode patients' intentions for different arm movements. Here, we evaluated whether residual muscle activity could be used to predict movements from paralyzed joints in severely impaired chronic stroke patients. Methods Muscle activity was recorded with surface‐electromyography ( EMG ) in 41 patients, with severe hand weakness (Fugl‐Meyer Assessment [ FMA ] hand subscores of 2.93 ± 2.7), in order to decode their intention to perform six different motions of the affected arm, required for voluntary muscle activity and to control neuroprostheses. Decoding of paretic and nonparetic muscle activity was performed using a feed‐forward neural network classifier. The contribution of each muscle to the intended movement was determined. Results Decoding of up to six arm movements was accurate (&gt;65%) in more than 97% of nonparetic and 46% of paretic muscles. Interpretation These results demonstrate that some level of neuronal innervation to the paretic muscle remains preserved and can be used to implement neurorehabilitative treatments in 46% of patients with severe paralysis and extensive cortical and/or subcortical lesions. Such decoding may allow these patients for the first time after stroke to control different motions of arm prostheses through muscle‐triggered rehabilitative treatments.
Parallel detection of ancient pathogens via array-based DNA capture
2014-12-09

DNA capture coupled with next generation sequencing is highly suitable for the study of ancient pathogens. Screening for pathogens can, however, be meticulous when assays are restricted to the enrichment of single organisms, which is common practice. Here, we report on an array-based DNA capture screening technique for the parallel detection of nearly 100 pathogens that could have potentially left behind molecular signatures in preserved ancient tissues. We demonstrate the sensitivity of our method through evaluation of its performance with a library known to harbour ancient Mycobacterium leprae DNA. This rapid and economical technique will be highly useful for the identification of historical diseases that are difficult to characterize based on archaeological information alone.
Lactate as a Novel Quantitative Measure of Viability in Schistosoma mansoni Drug Sensitivity Assays
2014-12-09

ABSTRACT Whole-organism compound sensitivity assays are a valuable strategy in infectious diseases to identify active molecules. In schistosomiasis drug discovery, larval-stage Schistosoma allows the use of a certain degree of automation in the screening of compounds. Unfortunately, the throughput is limited, as drug activity is determined by manual assessment of Schistosoma viability by microscopy. To develop a simple and quantifiable surrogate marker for viability, we targeted glucose metabolism, which is central to Schistosoma survival. Lactate is the end product of glycolysis in human Schistosoma stages and can be detected in the supernatant. We assessed lactate as a surrogate marker for viability in Schistosoma drug screening assays. We thoroughly investigated parameters of lactate measurement and performed drug sensitivity assays by applying schistosomula and adult worms to establish a proof of concept. Lactate levels clearly reflected the viability of schistosomula and correlated with schistosomulum numbers. Compounds with reported potencies were tested, and activities were determined by lactate assay and by microscopy. We conclude that lactate is a sensitive and simple surrogate marker to be measured to determine Schistosoma viability in compound screening assays. Low numbers of schistosomula and the commercial availability of lactate assay reagents make the assay particularly attractive to throughput approaches. Furthermore, standardization of procedures and quantitative evaluation of compound activities facilitate interassay comparisons of potencies and, thus, concerted drug discovery approaches.
Long-term change in the cyclotron line energy in Hercules X-1
2014-12-09

\\n Aims. We investigate the long-term evolution of the cyclotron resonance scattering feature (CRSF) in the spectrum of the binary X-ray pulsar <ext-link ext-link-type="aoi">Her X-1</ext-link> and present evidence of a true long-term decrease in the centroid energy Ecyc of the cyclotron line in the pulse phase averaged spectra from 1996 to 2012. \\n Methods. Our results are based on repeated observations of Her X-1 by those X-ray observatories capable of measuring clearly beyond the cyclotron line energy of ~40 keV; these are RXTE, INTEGRAL, Suzaku, and NuSTAR. We consider results based on our own successful observing proposals as well as results from the literature. \\n Results. The historical evolution of the pulse phase averaged CRSF centroid energy Ecyc since its discovery in 1976 is characterized by an initial value around 35 keV, an abrupt jump upwards to beyond ~40 keV between 1990 and 1994, and an apparent decay thereafter. Much of this decay, however, was found to be due to an artifact, namely a correlation between Ecyc and the X-ray luminosity Lx discovered in 2007. In observations after 2006, however, we now find a statistically significant true decrease in the cyclotron line energy. At the same time, the dependence of Ecyc on X-ray luminosity is still valid with an increase of ~5% in energy for a factor of two increase in luminosity. We also report on the first evidence of a weak dependence of Ecyc on phase of the 35 d precessional period, which manifests itself not only in the modulation of the X-ray flux, but also in the systematic variation in the shape of the 1.24 s pulse profile. One of our motivations for repeatedly observing Her X-1, namely the suspicion that the cyclotron line energy may be gradually decreasing after its strong upward jump in the early 1990s, is finally confirmed. A decrease in Ecyc by 4.2 keV over the 16 years from 1996 to 2012 can either be modeled by a linear decay, or by a slow decay until 2006 followed by a more abrupt decrease thereafter. \\n Conclusions. The observed timescale for the decrease in Ecyc of a few decades is too short for a decay of the global magnetic field. We speculate that the physical reason could be connected to a geometric displacement of the cyclotron resonant scattering region in the polar field or to a true physical change in the magnetic field configuration at the polar cap by the continued accretion. In the second scenario, the upward jump in Ecyc observed around 1991 may have been due to a relatively fast event in which the polar magnetic field rearranged itself after releasing part of the accumulated material to larger areas of the neutron star surface. \\n
Clinical, Environmental, and Serologic Surveillance Studies of Melioidosis in Gabon, 2012–2013
2014-12-09

Burkholderia pseudomallei, an environmental gram-negative bacillus, is the causative agent of melioidosis and a bio-threat agent. Reports of B. pseudomallei isolation from soil and animals in East and West Africa suggest that melioidosis might be more widely distributed than previously thought. Because it has been found in equatorial areas with tropical climates, we hypothesized that B. pseudomallei could exist in Gabon. During 2012-2013, we conducted a seroprevalance study in which we set up microbiology facilities at a large clinical referral center and prospectively screened all febrile patients by conducting blood cultures and testing for B. pseudomallei and related species; we also determined whether B. pseudomallei could be isolated from soil. We discovered a novel B. pseudomallei sequence type that caused lethal septic shock and identified B. pseudomallei and B. thailandensis in the environment. Our data suggest that melioidosis is emerging in Central Africa but is unrecognized because of the lack of diagnostic microbiology facilities.
Modulation of Immune Responses by Histone Deacetylase Inhibitors
2014-12-09

Recent studies have demonstrated that histone deacetylase (HDAC) inhibitors (HDACi) have potential immunomodulatory activity since they affect the immune surveillance by regulating the production of cytokines, alter the activity and function of macrophages and dendritic cells (DC), regulate the transcription of a variety of immune-stimulating genes, and can modulate the activity of immune effector cells of both the innate and adaptive immune system. Besides their immunostimulatory activity, HDACi can induce growth arrest and cell death, and modulate a subset of cellular functions such as cell motility or differentiation. This makes HDACi interesting therapeutic candidates for the treatment of a variety of human diseases like cancer, autoimmune, and graft versus host diseases. Besides these, HDACs have been shown to be involved in virus replication and pathogenesis, and it was recently shown that HDACi provide therapeutic effects in the treatment of oncogenic virus infections and associated malignancies. This review will further give information about the different families of HDACs and their opponents, the histone acetylases (HATs), about the classes and function of specific HDACi, and their use in the treatment of human diseases.
Screening ancient tuberculosis with qPCR: challenges and opportunities
2014-12-09

The field of ancient DNA (aDNA) has rapidly accelerated in recent years as a result of new methods in next-generation sequencing, library preparation and targeted enrichment. Such research is restricted, however, by the highly variable DNA preservation within different tissues, especially when isolating ancient pathogens from human remains. Identifying positive candidate samples via quantitative PCR (qPCR) for downstream procedures can reduce reagent costs, increase capture efficiency and maximize the number of sequencing reads of the target. This study uses four qPCR assays designed to target regions within the Mycobacterium tuberculosis complex (MTBC) to examine 133 human skeletal samples from a wide geographical and temporal range, identified by the presence of skeletal lesions typical of chronic disseminated tuberculosis. Given the inherent challenges working with ancient mycobacteria, strict criteria must be used and primer/probe design continually re-evaluated as new data from bacteria become available. Seven samples tested positive for multiple MTBC loci, supporting them as strong candidates for downstream analyses. Using strict and conservative criteria, qPCR remains a fast and effective screening tool when compared with screening by more expensive sequencing and enrichment technologies.