Growing evidence suggests an increasing significance for the extent of gastrointestinal tract (GIT) dysfunction in Parkinson's disease (PD). Most patients suffer from GIT symptoms, including ...dysphagia, sialorrhea, bloating, nausea, vomiting, gastroparesis, and constipation during the disease course. The underlying pathomechanisms of this α-synucleinopathy play an important role in disease development and progression, i.e., early accumulation of Lewy pathology in the enteric and central nervous systems is implicated in pharyngeal discoordination, esophageal and gastric motility/peristalsis impairment, chronic pain, altered intestinal permeability and autonomic dysfunction of the colon, with subsequent constipation. Severe complications, including malnutrition, dehydration, insufficient drug effects, aspiration pneumonia, intestinal obstruction, and megacolon, frequently result in hospitalization. Sophisticated diagnostic tools are now available that permit more detailed examination of specific GIT impairment patterns. Furthermore, novel treatment approaches have been evaluated, although high-level evidence trials are often missing. Finally, the burgeoning literature devoted to the GIT microbiome reveals its importance for neurologists. We review current knowledge about GIT pathoanatomy, pathophysiology, diagnosis, and treatment in PD and provide recommendations for management in daily practice.
We present performance results concerning the validation for anxiety level detection based on trained mathematical models using supervised machine learning techniques. The model training is based on ...biosignals acquired in a randomized controlled trial. Wearable sensors were used to collect electrocardiogram, electrodermal activity, and respiration from spider-fearful individuals. We designed and applied ten approaches for data labeling considering individual biosignals as well as subjective ratings. Performance results revealed a selection of trained models adapted for two-level (low and high) and three-level (low, medium and high) classification of anxiety using a minimal set of six features. We obtained a remarkable accuracy of 89.8% for the two-level classification and of 74.4% for the three-level classification using a short time window length of ten seconds when applying the approach that uses subjective ratings for data labeling. Bagged Trees proved to be the most suitable classifier type among the classification models studied. The trained models will have a practical impact on the feasibility study of an augmented reality exposure therapy based on a therapeutic game for the treatment of arachnophobia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Turbulent flow over a surface with streamwise-elongated rough and smooth stripes is studied by means of direct numerical simulation (DNS) in a periodic plane open channel with fully resolved ...roughness. The goal is to understand how the mean height of roughness affects the characteristics of the secondary flow formed above a spanwise heterogeneous rough surface. To this end, while the statistical properties of roughness texture as well as the width and spacing of the rough stripes are kept constant, the elevation of the smooth stripes is systematically varied in different simulation cases. Utilizing this variation, three configurations – representing protruding, recessed and an intermediate type of roughness – are analysed. In all cases, secondary flows are present and the skin friction coefficients calculated for all the heterogeneous rough surfaces are meaningfully larger than what would result from the area-weighted average of those of homogeneous smooth and rough surfaces. This drag increase appears to be linked to the strength of the secondary flow. The rotational direction of the secondary motion is shown to depend on the relative surface elevation. The present results suggest that this rearrangement of the secondary flow is linked to the spatial distribution of the spanwise-wall-normal Reynolds stress component, which carries opposing signs for protruding and recessed roughness.
Research over the last 25 years on the cell adhesion molecule L1 has revealed its pivotal role in nervous system function. Mutations of the human
L1CAM
gene have been shown to cause ...neurodevelopmental disorders such as X-linked hydrocephalus, spastic paraplegia and mental retardation. Impaired L1 function has been also implicated in the aetiology of fetal alcohol spectrum disorders, defective enteric nervous system development and malformations of the renal system. Importantly, aberrant expression of L1 has emerged as a critical factor in the development of human carcinomas, where it enhances cell proliferation, motility and chemoresistance. This discovery promoted collaborative work between tumour biologists and neurobiologists, which has led to a substantial expansion of the basic knowledge about L1 function and regulation. Here we provide an overview of the pathological conditions caused by L1 malfunction. We further discuss how the available data on gene regulation, molecular interactions and posttranslational processing of L1 may contribute to a better understanding of associated neurological and cancerous diseases.
There is a large diversity of genetically defined resistance genes in bread wheat against the powdery mildew pathogen Blumeria graminis (B. g.) f. sp. tritici. Many confer race-specific resistance to ...this pathogen, but until now only the mildew avirulence gene AvrPm3
a2/f2 that is recognized by Pm3a/f was known molecularly.
We performed map-based cloning and genome-wide association studies to isolate a candidate for the mildew avirulence gene AvrPm2. We then used transient expression assays in Nicotiana benthamiana to demonstrate specific and strong recognition of AvrPm2 by Pm2.
The virulent AvrPm2 allele arose from a conserved 12 kb deletion, while there is no protein sequence diversity in the gene pool of avirulent B. g. tritici isolates. We found one polymorphic AvrPm2 allele in B. g. triticale and one orthologue in B. g. secalis and both are recognized by Pm2. AvrPm2 belongs to a small gene family encoding structurally conserved RNase-like effectors, including Avr
a13 from B. g. hordei, the cognate Avr of the barley resistance gene Mla13.
These results demonstrate the conservation of functional avirulence genes in two cereal powdery mildews specialized on different hosts, thus providing a possible explanation for successful introgression of resistance genes from rye or other grass relatives to wheat.
Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been established as a powerful technique for the determination of metal and nonmetal distributions within biological ...systems with high sensitivity. An imaging LA-ICP-MS technique for Fe, Cu, Zn, and Mn was developed to produce large series of quantitative element maps in native brain sections of mice subchronically intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) as a model of Parkinson's disease. Images were calibrated using matrix-matched laboratory standards. A software solution allowing a precise delineation of anatomical structures was implemented. Coronal brain sections were analyzed crossing the striatum and the substantia nigra, respectively. Animals sacrificed 2 h, 7 d, or 28 d after the last MPTP injection and controls were investigated.
We observed significant decreases of Cu concentrations in the periventricular zone and the fascia dentata at 2 h and 7d and a recovery or overcompensation at 28 d, most pronounced in the rostral periventricular zone (+40%). In the cortex Cu decreased slightly to −10%. Fe increased in the interpeduncular nucleus (+40%) but not in the substantia nigra. This pattern is in line with a differential regulation of periventricular and parenchymal Cu, and with the histochemical localization of Fe, and congruent to regions of preferential MPTP binding described in the rodent brain.
The LA-ICP-MS technique yielded valid and statistically robust results in the present study on 39 slices from 19 animals. Our findings underline the value of routine micro-local analytical techniques in the life sciences and affirm a role of Cu availability in Parkinson's disease.
Quantitation in 18 animals showed a time profile of periventricular Cu paralleling the course of classical dopaminergic markers at 2 h, 7 d, and 28 d.
Abstract TASK-5 ( KCNK15 ) belongs to the acid-sensitive subfamily of two-pore domain potassium (K 2P ) channels, which includes TASK-1 and TASK-3. TASK-5 stands out as K 2P channel for which there ...is no functional data available, since it was reported in 2001 as non-functional and thus “silent”. Here we show that TASK-5 channels are indeed non-functional as homodimers, but are involved in the formation of functional channel complexes with TASK-1 and TASK-3. TASK-5 negatively modulates the surface expression of TASK channels, while the heteromeric TASK-5-containing channel complexes located at the plasma membrane are characterized by changes in single-channel conductance, Gq-coupled receptor-mediated channel inhibition, and sensitivity to TASK modulators. The unique pharmacology of TASK-1/TASK-5 heterodimers, affected by a common polymorphism in KCNK15 , needs to be carefully considered in the future development of drugs targeting TASK channels. Our observations provide an access to study TASK-5 at the functional level, particularly in malignant cancers associated with KCNK15 .
Cold‐pool‐driven convective initiation is investigated in high‐resolution, convection‐permitting simulations with a focus on the diurnal cycle and organization of convection and the sensitivity to ...grid size. Simulations of four different days over Germany were performed using the ICON‐LEM model with grid sizes from 156 to 625 m. In these simulations, we identify cold pools, cold‐pool boundaries and initiated convection. Convection is triggered much more efficiently in the vicinity of cold pools than in other regions and can provide as much as 50% of total convective initiation, in particular in the late afternoon. By comparing different model resolutions, we find that cold pools are more frequent, smaller and less intense in lower‐resolution simulations. Furthermore, their gust fronts are weaker and less likely to trigger new convection. To identify how model resolution affects this triggering probability, we use a linear causal graph analysis. In doing so, we postulate a graph structure with potential causal pathways and then apply multi‐linear regression accordingly. We find a dominant, systematic effect: reducing grid sizes directly reduces upward mass flux at the gust front, which causes weaker triggering probabilities. These findings are expected to be even more relevant for km‐scale, numerical weather prediction models. We thus expect that a better representation of cold‐pool‐driven convective initiation will improve forecasts of convective precipitation.
By comparing cold‐pool‐driven convective initiation in different, high‐resolution model simulations, we find that cold pools are more frequent, smaller, less intense and trigger less new convection in lower‐resolution simulations. We further use a linear causal graph analysis to understand how model resolution influences triggering probability. We find that reducing grid sizes directly reduces upward mass flux at the gust front, which causes weaker triggering probabilities.
To determine whether adding shear-wave (SW) elastographic features could improve accuracy of ultrasonographic (US) assessment of breast masses.
From September 2008 to September 2010, 958 women ...consented to repeat standard breast US supplemented by quantitative SW elastographic examination in this prospective multicenter institutional review board-approved, HIPAA-compliant protocol. B-mode Breast Imaging Reporting and Data System (BI-RADS) features and assessments were recorded. SW elastographic evaluation (mean, maximum, and minimum elasticity of stiffest portion of mass and surrounding tissue; lesion-to-fat elasticity ratio; ratio of SW elastographic-to-B-mode lesion diameter or area; SW elastographic lesion shape and homogeneity) was performed. Qualitative color SW elastographic stiffness was assessed independently. Nine hundred thirty-nine masses were analyzable; 102 BI-RADS category 2 masses were assumed to be benign; reference standard was available for 837 category 3 or higher lesions. Considering BI-RADS category 4a or higher as test positive for malignancy, effect of SW elastographic features on area under the receiver operating characteristic curve (AUC), sensitivity, and specificity after reclassifying category 3 and 4a masses was determined.
Median participant age was 50 years; 289 of 939 (30.8%) masses were malignant (median mass size, 12 mm). B-mode BI-RADS AUC was 0.950; eight of 303 (2.6%) BI-RADS category 3 masses, 18 of 193 (9.3%) category 4a lesions, 41 of 97 (42%) category 4b lesions, 42 of 57 (74%) category 4c lesions, and 180 of 187 (96.3%) category 5 lesions were malignant. By using visual color stiffness to selectively upgrade category 3 and lack of stiffness to downgrade category 4a masses, specificity improved from 61.1% (397 of 650) to 78.5% (510 of 650) (P<.001); AUC increased to 0.962 (P=.005). Oval shape on SW elastographic images and quantitative maximum elasticity of 80 kPa (5.2 m/sec) or less improved specificity (69.4% 451 of 650 and 77.4% 503 of 650, P<.001 for both), without significant improvement in sensitivity or AUC.
Adding SW elastographic features to BI-RADS feature analysis improved specificity of breast US mass assessment without loss of sensitivity.
The contribution of microglia to ischemic cortical stroke is of particular therapeutic interest because of the impact on the survival of brain tissue in the ischemic penumbra, a region that is ...potentially salvable upon a brain infarct. Whether or not tissue in the penumbra survives critically depends on blood flow and vessel perfusion. To study the role of microglia in cortical stroke and blood vessel stability, CX3CR1
+/GFP
mice were subjected to transient middle cerebral artery occlusion and then microglia were investigated using time-lapse two-photon microscopy in vivo. Soon after reperfusion, microglia became activated in the stroke penumbra and started to expand cellular protrusions towards adjacent blood vessels. All microglia in the penumbra were found associated with blood vessels within 24 h post reperfusion and partially fully engulfed them. In the same time frame blood vessels became permissive for blood serum components. Migration assays in vitro showed that blood serum proteins leaking into the tissue provided molecular cues leading to the recruitment of microglia to blood vessels and to their activation. Subsequently, these perivascular microglia started to eat up endothelial cells by phagocytosis, which caused an activation of the local endothelium and contributed to the disintegration of blood vessels with an eventual break down of the blood brain barrier. Loss-of-microglia-function studies using CX3CR1
GFP/GFP
mice displayed a decrease in stroke size and a reduction in the extravasation of contrast agent into the brain penumbra as measured by MRI. Potentially, medication directed at inhibiting microglia activation within the first day after stroke could stabilize blood vessels in the penumbra, increase blood flow, and serve as a valuable treatment for patients suffering from ischemic stroke.
PDF
