Drp1 is a dynamin-like GTPase that mediates mitochondrial and peroxisomal division in a process dependent on self-assembly and coupled to GTP hydrolysis. Despite the link between Drp1 malfunction and human disease, the molecular details of its membrane activity remain poorly understood. Here we reconstituted and directly visualized Drp1 activity in giant unilamellar vesicles. We quantified the effect of lipid composition and GTP on membrane binding and remodeling activity by fluorescence confocal microscopy and flow cytometry. In contrast to other dynamin relatives, Drp1 bound to both curved and flat membranes even in the absence of nucleotides. We also found that Drp1 induced membrane tubulation that was stimulated by cardiolipin. Moreover, Drp1 promoted membrane tethering dependent on the intrinsic curvature of the membrane lipids and on GTP. Interestingly, Drp1 concentrated at membrane contact surfaces and, in the presence of GTP, formed discrete clusters on the vesicles. Our findings support a role of Drp1 not only in the formation of lipid tubes but also on the stabilization of tightly apposed membranes, which are intermediate states in the process of mitochondrial fission.
Corrupted gradient directions (GD) in diffusion weighted images may seriously affect reliability of diffusion tensor imaging (DTI)-based comparisons at the group level. In the present study we employed a quality control (QC) algorithm to eliminate corrupted gradient directions from DTI data. We then assessed effects of this procedure on comparisons between Huntington disease (HD) subjects and controls at the group level.
The recent discovery of active brown fat in human adults has led to renewed interest in the role of this key metabolic tissue. This is particularly true for neurodegenerative conditions like Huntington disease (HD), an adult-onset heritable disorder with a prominent energy deficit phenotype. Current methods for imaging brown adipose tissue (BAT) are in limited use because they are equipment-wise demanding and often prohibitively expensive. This prompted us to explore how a standard MRI set-up can be modified to visualize BAT in situ by taking advantage of its characteristic fat/water content ratio to differentiate it from surrounding white fat. We present a modified MRI protocol for use on an 11.7 T small animal MRI scanner to visualize and quantify BAT in wild-type and disease model laboratory mice. In this application study using the R6/2 transgenic mouse model of HD we demonstrate a significantly reduced BAT volume in HD mice vs. matched controls (n = 5 per group). This finding provides a plausible structural explanation for the previously described temperature phenotype of HD mice and underscores the significance of peripheral tissue pathology for the HD phenotype. On a more general level, the results demonstrate the feasibility of MR-based BAT imaging in rodents and open the path towards transferring this imaging approach to human patients. Future studies are needed to determine if this method can be used to track disease progression in HD and other disease entities associated with BAT abnormalities, including metabolic conditions such as obesity, cachexia, and diabetes.
We recently published that platelet-activating factor receptor (PAFr) is upregulated on the epithelium of the proximal airways of current smokers and also in bronchial epithelial cells exposed to cigarette smoke extract. These treated cells also showed upregulation of Streptococcus pneumoniae adhesion. Bacterial wall phosphorylcholine specifically binds to PAFr expressed on airway epithelium, thus facilitating adherence and tissue invasion, which may be relevant to chronic obstructive pulmonary disease (COPD). Moreover, the use of inhaled corticosteroids (ICS) in COPD patients is associated with an increased risk of invasive respiratory pneumococcal infections.
The relative distribution of non-Hodgkin lymphoma (NHL) subtypes differs markedly around the world. The aim of this study was to report this distribution in Algeria. A panel of four hematopathologists classified 197 consecutive cases according to the World Health Organization classification, including 87.3% B-cell and 12.7% T- or natural killer (NK)-cell NHLs. This series was compared with similar cohorts from Western Europe (WEU) and North America (NA). Algeria had a significantly higher frequency of diffuse large B-cell lymphoma (DLBCL: 52.8%) and a lower frequency of follicular lymphoma (FL: 13.2%) compared with WEU (DLBCL: 32.2%; FL: 20.0%) and NA (DLBCL: 29.3%; FL: 33.6%). The frequency of mantle cell lymphoma was lower in Algeria (2.5%) compared with WEU (8.3%). Smaller differences were also found among the NK/T-cell lymphomas. In conclusion, we found important differences between Algeria and Western countries, and further epidemiologic studies are needed to explain these differences.
In amyotrophic lateral sclerosis (ALS), cognition is affected. Cortical atrophy in frontal and temporal areas has been associated with the cognitive profile of patients. Additionally, reduced metabolic turnover and regional cerebral blood flow in frontal areas indicative of reduced neural activity have been reported for ALS. We hypothesize that functional connectivity in non-task associated functional default mode network (DMN) is associated with cognitive profile and white matter integrity. This study focused on specific cognitive tasks known to be impaired in ALS such as verbal fluency and attention, and the relationship with functional connectivity in the DMN and white matter integrity. Nine patients and 11 controls were measured with an extensive neuropsychological battery. Resting-state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data were acquired. Results showed that ALS patients performed significantly worse in attention and verbal fluency task. Patients showed increased functional connectivity in parahippocampal and parietal areas of the non-task associated DMN compared to controls. The more pronounced the cognitive deficits, the stronger the increase in functional connectivity in those areas. White matter integrity was reduced in frontal areas in the patients. In conclusion, increased connectivity in the DMN in parahippocampal and parietal areas might represent recruitment of accessory brain regions to compensate for dysfunctional frontal networks.
N-terminal signal peptides are a hallmark of the vast majority of soluble secretory proteins that are transported along the endoplasmic reticulum/Golgi-dependent pathway. They are recognized by signal recognition particle, a process that initiates membrane translocation into the lumen of the endoplasmic reticulum followed by vesicular transport to the cell surface and release into the extracellular space. Beyond this well-established mechanism of protein secretion from eukaryotic cells, a number of extracellular proteins with critical physiological functions in immune surveillance and tissue organization are known to be secreted in a manner independent of signal recognition particle. Such processes have collectively been termed "unconventional protein secretion" and, while known for more than two decades, their underlying mechanisms are only beginning to emerge. Different types of unconventional secretory mechanisms have been described with the best-characterized example being based on direct translocation of cytoplasmic proteins across plasma membranes. The aim of this review is to critically assess our current knowledge of this type of unconventional secretion focusing on fibroblast growth factor 2 (FGF2) as the most established example.
For decades, Aggregatibacter actinomycetemcomitans has been considered the most likely etiologic agent in aggressive periodontitis. Implementation of DNA-based microbiologic methodologies has considerably improved our understanding of the composition of subgingival biofilms, and advanced open-ended molecular techniques even allow for genome mapping of the whole bacterial spectrum in a sample and characterization of both the cultivable and not-yet-cultivable microbiota associated with periodontal health and disease. Currently, A. actinomycetemcomitans is regarded as a minor component of the resident oral microbiota and as an opportunistic pathogen in some individuals. Its specific JP2 clone, however, shows properties of a true exogenous pathogen and has an important role in the development of aggressive periodontitis in certain populations. Still, limited data exist on the impact of other microbes specifically in aggressive periodontitis. Despite a wide heterogeneity of bacteria, especially in subgingival samples collected from patients, bacteria of the red complex in particular, and those of the orange complex, are considered as potential pathogens in generalized aggressive periodontitis. These types of bacterial findings closely resemble those found for chronic periodontitis, representing a mixed polymicrobial infection without a clear association with any specific microorganism. In aggressive periodontitis, the role of novel and not-yet-cultivable bacteria has not yet been elucidated. There are geographic and ethnic differences in the carriage of periodontitis-associated microorganisms, and they need to be taken into account when comparing study reports on periodontal microbiology in different study populations. In the present review, we provide an overview on the colonization of potential periodontal pathogens in childhood and adolescence, and on specific microorganisms that have been suspected for their role in the initiation and progression of aggressive forms of periodontal disease.
Diffusion tensor imaging can identify amyotrophic lateral sclerosis-associated patterns of brain alterations at the group level. Recently, a neuropathological staging system for amyotrophic lateral sclerosis has shown that amyotrophic lateral sclerosis may disseminate in a sequential regional pattern during four disease stages. The objective of the present study was to apply a new methodological diffusion tensor imaging-based approach to automatically analyse in vivo the fibre tracts that are prone to be involved at each neuropathological stage of amyotrophic lateral sclerosis. Two data samples, consisting of 130 diffusion tensor imaging data sets acquired at 1.5 T from 78 patients with amyotrophic lateral sclerosis and 52 control subjects; and 55 diffusion-tensor imaging data sets at 3.0 T from 33 patients with amyotrophic lateral sclerosis and 22 control subjects, were analysed by a tract of interest-based fibre tracking approach to analyse five tracts that become involved during the course of amyotrophic lateral sclerosis: the corticospinal tract (stage 1); the corticorubral and the corticopontine tracts (stage 2); the corticostriatal pathway (stage 3); the proximal portion of the perforant path (stage 4); and two reference pathways. The statistical analyses of tracts of interest showed differences between patients with amyotrophic lateral sclerosis and control subjects for all tracts. The significance level of the comparisons at the group level was lower, the higher the disease stage with corresponding involved fibre tracts. Both the clinical phenotype as assessed by the amyotrophic lateral sclerosis functional rating scale-revised and disease duration correlated significantly with the resulting staging scheme. In summary, the tract of interest-based technique allowed for individual analysis of predefined tract structures, thus making it possible to image in vivo the disease stages in amyotrophic lateral sclerosis. This approach can be used not only for individual clinical work-up purposes, but enlarges the spectrum of potential non-invasive surrogate markers as a neuroimaging-based read-out for amyotrophic lateral sclerosis studies within a clinical context.
The lidA Cohort Study (German Cohort Study on Work, Age, Health and Work Participation) was set up to investigate and follow the effects of work and work context on the physical and psychological health of the ageing workforce in Germany and subsequently on work participation. Cohort participants are initially employed people subject to social security contributions and born in either 1959 (n = 2909) or 1965 (n = 3676). They were personally interviewed in their homes in 2011 and will be visited every 3 years. Data collection comprises socio-demographic data, work and private exposures, work ability, work and work participation attitudes, health, health-related behaviour, personality and attitudinal indicators. Employment biographies are assessed using register data. Subjective health reports and physical strength measures are complemented by health insurance claims data, where permission was given. A conceptual framework has been developed for the lidA Cohort Study within which three confirmatory sub-models assess the interdependencies of work and health considering age, gender and socioeconomic status. The first set of the data will be available to the scientific community by 2015. Access will be given by the Research Data Centre of the German Federal Employment Agency at the Institute for Employment Research (http://fdz.iab.de/en.aspx).
Intrinsic functional connectivity magnetic resonance imaging (iFCMRI) provides an encouraging approach for mapping large-scale intrinsic connectivity networks (ICNs) in the "resting" brain. Structural connections as measured by diffusion tensor imaging (DTI) are a major constraint on the identified ICNs. This study aimed at the combined investigation of ten well-defined ICNs in healthy elderly subjects at single subject level as well as at the group level, together with the underlying structural connectivity. IFCMRI and DTI data were acquired in twelve subjects (68 ± 7 years) at a 3T scanner and were studied using the tensor imaging and fiber tracking software package. The seed-based iFCMRI analysis approach was comprehensively performed with DTI analysis, following standardized procedures including an 8-step processing of iFCMRI data. Our findings demonstrated robust ICNs at the single subject level and conclusive brain maps at the group level in the healthy elderly sample, supported by the complementary fiber tractography. The findings demonstrated here provide a methodological framework for future comparisons of pathological (e.g., neurodegenerative) conditions with healthy controls on the basis of multiparametric functional connectivity mapping.
The key feature of heparin-induced thrombocytopenia (HIT) is the production of antibodies (Ab) against the platelet factor 4 (PF4)/heparin complex. These Ab are directed against neoepitopes of the PF4 tetramer, which are induced by the complex formation with heparin. To study this humoral immune response in greater detail, either in a murine immunization model or in human blood samples, reliable and specific immune assays to detect specifically Ab against the PF4/heparin complexes, but not PF4 alone are required.
The interaction between lipid bilayers in water has been intensively studied over the last decades. Osmotic stress was applied to evaluate the forces between two approaching lipid bilayers in aqueous solution. The force-distance relation between lipid mono- or bilayers deposited on mica sheets using a surface force apparatus (SFA) was also measured. Lipid stabilised foam films offer another possibility to study the interactions between lipid monolayers. These films can be prepared comparatively easy with very good reproducibility. Foam films consist usually of two adsorbed surfactant monolayers separated by a layer of the aqueous solution from which the film is created. Their thickness can be conveniently measured using microinterferometric techniques. Studies with foam films deliver valuable information on the interactions between lipid membranes and especially their stability and permeability. Presenting inverse black lipid membrane (BLM) foam films supply information about the properties of the lipid self-organisation in bilayers. The present paper summarises results on microscopic lipid stabilised foam films by measuring their thickness and contact angle. Most of the presented results concern foam films prepared from dispersions of the zwitterionic lipid 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC) and some of its mixtures with the anionic lipid - 1,2-dimyristoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DMPG). The strength of the long range and short range forces between the lipid layers is discussed. The van der Waals attractive force is calculated. The electrostatic repulsive force is estimated from experiments at different electrolyte concentrations (NaCl, CaCl2) or by modification of the electrostatic double layer surface potential by incorporating charged lipids in the lipid monolayers. The short range interactions are studied and modified by using small carbohydrates (fructose and sucrose), ethanol (EtOH) or dimethylsulfoxide (DMSO). Some results are compared with the structure of lipid monolayers deposited at the liquid/air interface (monolayers spread in Langmuir trough), which are one of most studied biomembrane model system. The comparison between the film thickness and the free energy of film formation is used to estimate the contribution of the different components of the disjoining pressure to the total interaction in the film and their dependence on the composition of the film forming solution.
Small vessel cerebrovascular disease (SVCD) is one of the most frequent vessel disorders in the aged brain. Among the spectrum of neurological disturbances related to SVCD, oculomotor dysfunction is a not well understood symptom- in particular, it remains unclear whether vascular lesion load in specific brain regions affects oculomotor function independent of cognitive decline in SVCD patients or whether the effect of higher brain function deficits prevails. In this study, we examined a cohort of 25 SVCD patients and 19 healthy controls using video-oculographic eye movement recording in a laboratory environment, computer-based MRI assessment of white matter lesion load (WMLL), assessment of extrapyramidal motor deficits, and psychometric testing. In comparison to controls, the mean WMLL of patients was significantly larger than in controls. With respect to eye movement control, patients performed significantly worse than controls in almost all aspects of oculomotion. Likewise, patients showed a significantly worse performance in all but one of the neuropsychological tests. Oculomotor deficits in SVCD correlated with the patients' cognitive dysfunctioning while there was only weak evidence for a direct effect of WMLL on eye movement control. In conclusion, oculomotor impairment in SVCD seems to be mainly contingent upon cognitive deterioration in SVCD while WMLL might have only a minor specific effect upon oculomotor pathways.
To evaluate the contribution of individual synaptic constituents, all available in vivo imaging studies on schizophrenic patients were subjected to a retrospective analysis. For the pool of drug-naïve, drug-free, and acutely medicated patients, major findings were increases in neostriatal dopamine (DA) synthesis and release and decreases in neostriatal DA transporters and D1 receptors, neostriatal, thalamic, frontal, and parietal D2 receptors, mesencephalic/pontine and temporal 5-HT1A receptors, frontal and temporal HT2A and ?-amino butyric acid (GABA)A receptors. Based on the findings on drug-naïve and drug-free patients, it may be hypothesized that schizophrenia initially is characterized by an impaired mechanism of D2 autoreceptor and heteroreceptor sensitization leading to sensitization instead of desensitization in response to increased levels of neostriatal DA. Neuroleptic medication blocks neostriatal D2 autoreceptor and heteroreceptors, reducing neostriatal DA and disinhibiting DA action mediated by D2 heteroreceptor binding sites. Ultimately, this may result in a restitution of GABA function, leading to a recovery of inhibitory input to the target regions of the descending corticothalamostriatal efferents. Furthermore, a blockade of inhibitory and excitatory neocortical 5-HT function may be inferred, which is likely to reduce (excitatory) DAergic input to the mesolimbic target regions of corticothalamostriatal projections.
We identified a suitable biomatrix that improved axon regeneration and functional outcome after partial (moderate) and complete (severe) chronic spinal cord injury (SCI) in rat. Five weeks after dorsal thoracic hemisection injury the lesion scar was resected via aspiration and the resulting cavity was filled with different biopolymers such as Matrigel™, alginate-hydrogel and polyethylene glycol 600 (PEG) all of which have not previously been used as sole graft-materials in chronic SCI. Immunohistological staining revealed marked differences between these compounds regarding axon regeneration, invasion/elongation of astrocytes, fibroblasts, endothelial and Schwann cells, revascularization, and collagen deposition. According to axon regeneration-supporting effects, the biopolymers could be ranked in the order PEG>alginate-hydrogel>Matrigel™. Even after complete chronic transection, the PEG-bridge allowed long-distance axon regeneration through the grafted area and for, at least, 1cm beyond the lesion/graft border. As revealed by electron microscopy, bundles of regenerating axons within the matrix area received myelin ensheathment from Schwann cells. The beneficial effects of PEG-implantation into the resection-cavity were accompanied by long-lasting significant locomotor improvement over a period of 8months. Following complete spinal re-transection at the rostral border of the PEG-graft the locomotor recovery was aborted, suggesting a functional role of regenerated axons in the initial locomotor improvement. In conclusion, scar resection and subsequent implantation of PEG into the generated cavity leads to tissue recovery, axon regeneration, myelination and functional improvement that have not been achieved before in severe chronic SCI.
In the last century, research in the field of spinal cord trauma has brought insightful knowledge which has led to a detailed understanding of mechanisms that are involved in injury- and recovery-related processes. The quest for a cure for the yet generally incurable condition as well as the exponential rise in gained information has brought about the development of numerous treatment approaches while at the same time the abundance of data has become quite unmanageable. Owing to an enormous amount of preclinical therapeutic approaches, this report highlights important trends rather than specific treatment strategies. We focus on current advances in the treatment of spinal cord injury and want to further draw attention to arising problems in spinal cord injury (SCI) research and discuss possible solutions.
Gene function curation via Gene Ontology (GO) annotation is a common task among Model Organism Database groups. Owing to its manual nature, this task is considered one of the bottlenecks in literature curation. There have been many previous attempts at automatic identification of GO terms and supporting information from full text. However, few systems have delivered an accuracy that is comparable with humans. One recognized challenge in developing such systems is the lack of marked sentence-level evidence text that provides the basis for making GO annotations. We aim to create a corpus that includes the GO evidence text along with the three core elements of GO annotations: (i) a gene or gene product, (ii) a GO term and (iii) a GO evidence code. To ensure our results are consistent with real-life GO data, we recruited eight professional GO curators and asked them to follow their routine GO annotation protocols. Our annotators marked up more than 5000 text passages in 200 articles for 1356 distinct GO terms. For evidence sentence selection, the inter-annotator agreement (IAA) results are 9.3% (strict) and 42.7% (relaxed) in F1-measures. For GO term selection, the IAAs are 47% (strict) and 62.9% (hierarchical). Our corpus analysis further shows that abstracts contain ? 10% of relevant evidence sentences and 30% distinct GO terms, while the Results/Experiment section has nearly 60% relevant sentences and >70% GO terms. Further, of those evidence sentences found in abstracts, less than one-third contain enough experimental detail to fulfill the three core criteria of a GO annotation. This result demonstrates the need of using full-text articles for text mining GO annotations. Through its use at the BioCreative IV GO (BC4GO) task, we expect our corpus to become a valuable resource for the BioNLP research community. Database URL: http://www.biocreative.org/resources/corpora/bc-iv-go-task-corpus/.
Aggressive behavior and violence in patients, residents or clients are growing challenges in nursing. Aggressive behavior can have both, physical and psychological consequences for nurses and can lead to a reduced performance at work, demotivation, sickness absence and the premature exit from the nursing profession. To develop purposive strategies and to deal with aggressive behavior and health promotion programs, it is crucial to know more about the prevalence of aggressive behavior from patients and the effect on the work ability of nurses in different types of institutions.
WormBase (http://www.wormbase.org/) is a highly curated resource dedicated to supporting research using the model organism Caenorhabditis elegans. With an electronic history predating the World Wide Web, WormBase contains information ranging from the sequence and phenotype of individual alleles to genome-wide studies generated using next-generation sequencing technologies. In recent years, we have expanded the contents to include data on additional nematodes of agricultural and medical significance, bringing the knowledge of C. elegans to bear on these systems and providing support for underserved research communities. Manual curation of the primary literature remains a central focus of the WormBase project, providing users with reliable, up-to-date and highly cross-linked information. In this update, we describe efforts to organize the original atomized and highly contextualized curated data into integrated syntheses of discrete biological topics. Next, we discuss our experiences coping with the vast increase in available genome sequences made possible through next-generation sequencing platforms. Finally, we describe some of the features and tools of the new WormBase Web site that help users better find and explore data of interest.
Ca2+ homeostasis and signalling rely on physical contacts between Ca2+ sensors in the endoplasmic reticulum (ER) and Ca2+ channels in the plasma membrane (PM). STIM1 and STIM2 Ca2+ sensors oligomerize upon Ca2+ depletion in the ER lumen, contact phosphoinositides at the PM via their cytosolic lysine (K)-rich domains, and activate Ca2+ channels. Differential sensitivities of STIM1 and STIM2 towards ER luminal Ca2+ have been studied but responses towards elevated cytosolic Ca2+ concentration and the mechanism of lipid binding remain unclear. We found that tetramerization of the STIM1 K-rich domain is necessary and sufficient for binding to PI(4,5)P2-containing PM-like liposomes consistent with an oligomerization-driven STIM1 activation. In contrast, dimerization of STIM2 K-rich domain was sufficient for lipid binding. Further, the K-rich domain of STIM2, but not of STIM1, forms an amphipathic ?-helix. These distinct features of the STIM2 K-rich domain cause an increased affinity for PI(4,5)P2, consistent with the lower activation threshold of STIM2 and a function as regulator of basal Ca2+ levels. Concomitant with higher affinity for PM lipids, binding of Calmodulin inhibited the interaction of the STIM2 K-rich domain with liposomes in a Ca2+ and PI(4,5)P2 concentration-dependent manner. Therefore, we suggest that elevated cytosolic Ca2+ concentration down-regulates STIM2-mediated ER-PM contacts via Calmodulin binding.
The effect of clinical L-3,4-dihydroxyphenylalanine (L-DOPA) doses on the binding of [121I]N-?-fluoropropyl-2?-carbomethoxy-3?-(4-iodophenyl)nortropane (121[I]FP-CIT) to the rat dopamine transporter (DAT) was investigated using small animal single-photon emission computed tomography.
The popularity of robotic surgery highlights the need for strategies to integrate this technique into surgical education. We present 5 year data for robotic cholecystectomy (RC) as a model for training residents.
Previous studies have shown weak associations between human dilated cardiomyopathy (DCM) and certain human leucocyte antigen (HLA) class II polymorphisms. Using a sequence-specific primer-PCR (SSP-PCR) technology, we compared the allelic distribution in the HLA-DQ and -DR locus in a cohort of German DCM patients (n=165) and DCM-free controls (n=79). With the exception of HLA-DQB1 0309, we found no significant differences between the two groups, even without adjustment for multiple testing. The HLA-DQB1 0309 allele, however, was detected more frequently in DCM patients as compared to controls (28.5% versus 10.1%, p=0.0010), leading to an odds ratio of 3.5 (95% confidence interval=1.5-9.1). The frequency of this allele was significantly higher in DCM patients without lymphocytic infiltrates in endomyocardial biopsies as compared to patients classified histologically as inflammatory DCM (33.1% versus 14.6%, p=0.028). There was no significant difference in the allelic HLA-DQB1 0309 distribution between DCM patients with and without viral genomes detected in the heart (24.2% versus 29.5%, p=0.668). In summary, the frequency of the HLA-DQB1 0309 allele is overrepresented in DCM patients, suggesting that carriers of this HLA class II variant are associated with an increased risk for developing DCM. Although Bonferroni adjustment was applied, controlled studies in larger samples of DCM patients and in different ethnic populations are warranted to confirm this observation and reveal the pathophysiological mechanisms behind this association.
Diffusion tensor imaging (DTI) techniques provide information on the microstructural processes of the cerebral white matter (WM) in vivo. The present applications are designed to investigate differences of WM involvement patterns in different brain diseases, especially neurodegenerative disorders, by use of different DTI analyses in comparison with matched controls. DTI data analysis is performed in a variate fashion, i.e. voxelwise comparison of regional diffusion direction-based metrics such as fractional anisotropy (FA), together with fiber tracking (FT) accompanied by tractwise fractional anisotropy statistics (TFAS) at the group level in order to identify differences in FA along WM structures, aiming at the definition of regional patterns of WM alterations at the group level. Transformation into a stereotaxic standard space is a prerequisite for group studies and requires thorough data processing to preserve directional inter-dependencies. The present applications show optimized technical approaches for this preservation of quantitative and directional information during spatial normalization in data analyses at the group level. On this basis, FT techniques can be applied to group averaged data in order to quantify metrics information as defined by FT. Additionally, application of DTI methods, i.e. differences in FA-maps after stereotaxic alignment, in a longitudinal analysis at an individual subject basis reveal information about the progression of neurological disorders. Further quality improvement of DTI based results can be obtained during preprocessing by application of a controlled elimination of gradient directions with high noise levels. In summary, DTI is used to define a distinct WM pathoanatomy of different brain diseases by the combination of whole brain-based and tract-based DTI analysis.
Previous cross-sectional findings from the European Nurses Early Exit Study (NEXT) show that nurses who were dissatisfied with their work schedule tended to consider leaving the nursing profession. Mediating factors in this decision process may be caused by self-perceived poor work ability and/or health. The aim of this paper is to investigate changes in work ability and general health among nurses in relation to requested, forced and denied change of shift schedule.
Complete transection of the spinal cord leaves a gap of several mm which fills with fibrous scar tissue. Several approaches in rodent models have used tubes, foams, matrices or tissue implants to bridge this gap. Here, we describe a mechanical microconnector system (mMS) to re-adjust the retracted spinal cord stumps. The mMS is a multi-channel system of polymethylmethacrylate (PMMA), designed to fit into the spinal cord tissue gap after transection, with an outlet tubing system to apply negative pressure to the mMS thus sucking the spinal cord stumps into the honeycomb-structured holes. The stumps adhere to the microstructure of the mMS walls and remain in the mMS after removal of the vacuum. We show that the mMS preserves tissue integrity and allows axonal regrowth at 2, 5 and 19 weeks post lesion with no adverse tissue effects like in-bleeding or cyst formation. Preliminary assessment of locomotor function in the open field suggested beneficial effects of the mMS. Additional inner micro-channels enable local substance delivery into the lesion center via an attached osmotic minipump. We suggest that the mMS is a suitable device to adapt and stabilize the injured spinal cord after surgical resection of scar tissue (e.g., for chronic patients) or traumatic injuries with large tissue and bone damages.
Late-onset myasthenia gravis (LOMG) has become the largest MG subgroup, but the underlying pathogenetic mechanisms remain mysterious. Among the few etiological clues are the almost unique serologic parallels between LOMG and thymoma-associated MG (TAMG), notably autoantibodies against acetylcholine receptors, titin, ryanodine receptor, type I interferons or IL-12. This is why we checked LOMG patients for two further peculiar features of TAMG - its associations with the CTLA4(high/gain-of-function) +49A/A genotype and with increased thymic export of naïve T cells into the blood, possibly after defective negative selection in AIRE-deficient thymomas. We analyzed genomic DNA from 116 Caucasian LOMG patients for CTLA4 alleles by PCR/restriction fragment length polymorphism, and blood mononuclear cells for recent thymic emigrants by quantitative PCR for T cell receptor excision circles. In sharp contrast with TAMG, we now find that: i) CTLA4(low) +49G(+) genotypes were more frequent (p = 0.0029) among the 69 LOMG patients with age at onset ?60 years compared with 172 healthy controls; ii) thymic export of naïve T cells from the non-neoplastic thymuses of 36 LOMG patients was lower (p = 0.0058) at diagnosis than in 77 age-matched controls. These new findings are important because they suggest distinct initiating mechanisms in TAMG and LOMG and hint at aberrant immuno-regulation in the periphery in LOMG. We therefore propose alternate defects in central thymic or peripheral tolerance induction in TAMG and LOMG converging on similar final outcomes. In addition, our data support a 60-year-threshold for onset of true LOMG and an LOMG/early-onset MG overlapping group of patients between 40 and 60.
In addition to the skeleto-motor deficits, patients with Parkinsons disease (PD) frequently present with oculomotor dysfunctions such as impaired smooth pursuit and saccadic abnormalities. There is increasing evidence for an impaired cortical function to be responsible for oculomotor deficits that are associated with lack of inhibitory control; however, these pathomechanisms still remain poorly understood. By means of "task-free" resting-state functional magnetic resonance imaging (rs-fMRI), functional connectivity changes in PD within the default mode network (DMN) have been reported. The aim of this study was to investigate whether altered functional connectivity within the DMN was correlated with oculomotor parameter changes in PD. Twelve PD patients and 13 matched healthy controls underwent rs-fMRI at 1.5 T and videooculography (VOG) using Eye-Link-System. Rs-fMRI seed-based region-to-region connectivity analysis was performed, including medial prefrontal cortex (mPFC), medial temporal lobe (MTL), posterior cingulate cortex (PCC), and hippocampal formation (HF); while VOG examination comprised ocular reactive saccades, smooth pursuit, and executive tests. Rs-fMRI analysis demonstrated a decreased region-to-region functional connectivity between mPFC and PCC as well as increased connectivity between bilateral HF in PD compared with controls. In VOG, patients and controls differed in terms of executive tests outcome, smooth pursuit eye movement, and visually guided reactive saccades but not in peak eye velocity. A significant relationship was observed between saccadic accuracy and functional connectivity strengths between MTL and PCC. These results suggest that PD-associated changes of DMN connectivity are correlated with PD-associated saccadic hypometria, in particular in the vertical direction.
Cellular therapies represent a novel treatment approach for spinal cord injury (SCI), with many different cellular substrates showing promise in preclinical animal models of SCI. Considerable interest therefore exists to translate such cellular interventions into human clinical trials. Balanced against the urgency for clinical translation is the desire to establish the robustness of a cellular therapys efficacy in preclinical studies, thereby optimizing its chances of succeeding in human trials. Uncertainty exists, however, on the extent to which a therapy needs to demonstrate efficacy in the preclinical setting in order to justify the initiation of a lengthy, expensive, and potentially risky clinical trial. The purpose of this initiative was to seek perspectives on the level of evidence required in experimental studies of cellular therapies before proceeding with clinical trials of SCI. We conducted a survey of 27 SCI researchers actively involved in either preclinical and/or clinical research of cellular interventions for SCI, and then held a focus group meeting to facilitate more in-depth discussion around a number of translational issues. These included: the use of animal models, the use of injury models and mechanisms, the window for demonstrating efficacy, independent replication, defining "relevant, meaningful efficacy" in preclinical studies, and the expectation of therapeutic benefits for cellular interventions. Here we present the key findings from both the survey and focus group meeting in order to summarize and underscore the areas of consensus and disagreement amongst the sampled researchers. It is anticipated that the knowledge generated from this initiative will help to incite future scientific discussions and expert guidelines towards translation of a cell therapy for persons with SCI.
When applying the recommended standard doses of recombinant human thyrotropin (rhTSH) in the diagnostic/therapeutic management of patients with differentiated thyroid cancer (DTC), the resulting peak TSH levels vary extensively. Previous studies applying multivariate statistics identified patient-inherent variables influencing the rhTSH/peak TSH relation. However, those results were inconclusive and partly conflicting. Notably, no independent role of renal function was substantiated, despite the fact that the kidneys are known to play a prominent role in TSH clearance from blood. Therefore, the studys aim was to investigate the impact of renal function on the peak TSH concentration after the standard administration of rhTSH used in the management of thyroid cancer. The second objective was to calculate a ranking regarding the effect sizes of the selected variables on the peak TSH.
We report a newly developed analysis algorithm for optical coherence tomography (OCT) that makes a retinal single-layer analysis with calculation of the average thickness of retinal layers possible. The aim of the study was to examine specific patterns of retinal layer pathology as a potential marker of neurodegeneration in Parkinsons disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Spectral domain OCT with a semiautomatic algorithm to calculate the average thickness of single retinal layers was applied to foveal scans of 65 PD, 16 PSP, and 12 MSA patients as well as 41 matched controls. Demographic and clinical data were collected for correlation analysis. Only PSP and MSA showed a significant reduction of retinal layers in comparison to controls. In PD, there were no significant findings in single retinal layer measurement. Most remarkably, the thickening of the outer nuclear layer in PSP and the outer plexiform layer in MSA was highly specific for these disease entities and allowed differentiating PSP from MSA with high sensitivity and specificity. With this analysis algorithm of OCT data, disease-specific retinal layer changes could be observed. Despite a general tendency to whole retinal and single retinal layer thinning that may reflect neurodegeneration in all Parkinsonian syndromes, the specific findings in MSA and PSP may serve as a highly sensitive and specific differential diagnostic tool and as a progression marker in these disease entities. Upcoming studies with a longitudinal setting will have to prove this assumption.
Filopodia explore the environment, sensing soluble and mechanical cues during directional motility and tissue morphogenesis. How filopodia are initiated and spatially restricted to specific sites on the plasma membrane is still unclear. Here, we show that the membrane deforming and curvature sensing IRSp53 (Insulin Receptor Substrate of 53?kDa) protein slows down actin filament barbed end growth. This inhibition is relieved by CDC42 and counteracted by VASP, which also binds to IRSp53. The VASP:IRSp53 interaction is regulated by activated CDC42 and promotes high-density clustering of VASP, which is required for processive actin filament elongation. The interaction also mediates VASP recruitment to liposomes. In cells, IRSp53 and VASP accumulate at discrete foci at the leading edge, where filopodia are initiated. Genetic removal of IRSp53 impairs the formation of VASP foci, filopodia and chemotactic motility, while IRSp53 null mice display defective wound healing. Thus, IRSp53 dampens barbed end growth. CDC42 activation inhibits this activity and promotes IRSp53-dependent recruitment and clustering of VASP to drive actin assembly. These events result in spatial restriction of VASP filament elongation for initiation of filopodia during cell migration, invasion, and tissue repair.
The reproductive ability of female tephritids can be limited and prevented by denying access to host plants and restricting the dietary precursors of vitellogenesis. The mechanisms underlying the delayed egg production in each case are initiated by different physiological processes that are anticipated to have dissimilar effects on lifespan and reproductive ability later in life. The egg laying abilities of laboratory reared females of the Mediterranean fruit fly (Ceratitis capitata Wiedmann) and melon fly (Bactrocera cucurbitae Coquillett) from Hawaii are delayed or suppressed by limiting access to host fruits and dietary protein. In each case, this is expected to prevent the loss of lifespan associated with reproduction until protein or hosts are introduced. Two trends are observed in each species: Firstly, access to protein at eclosion leads to a greater probability of survival and higher reproductive ability than if it is delayed, and secondly, that delayed host access reduces lifetime reproductive ability without improving life expectancy. When host access and protein availability are delayed, the rate of reproductive senescence is reduced in the medfly, whereas the rate of reproductive senescence is generally increased in the melon fly. Overall, delaying reproduction lowers the fitness of females by constraining their fecundity for the remainder of the lifespan without extending the lifespan.
Intercellular signalling via growth factors plays an important role in controlling cell differentiation and cell movements during the development of multicellular animals. Fibroblast Growth Factor (FGF) signalling induces changes in cellular behaviour allowing cells in the embryo to move, to survive, to divide or to differentiate. Several examples argue that FGF signalling is used in multi-step morphogenetic processes to achieve and maintain a transitional state of the cells required for the control of cell fate. In the genetic model Drosophila melanogaster, FGF signalling via the receptor tyrosine kinases Heartless (Htl) and Breathless (Btl) is particularly well studied. These FGF receptors affect gene expression, cell shape and cell-cell interactions during mesoderm layer formation, caudal visceral muscle (CVM) formation, tracheal morphogenesis and glia differentiation. Here, we will address the current knowledge of the biological functions of FGF signalling in the fly on the tissue, at a cellular and molecular level.
Body fat distribution changes are associated with multiple alterations in metabolism. Therefore, the assessment of body fat compartments by MRI in animal models is a promising approach to obesity research. Standard T1-weighted (T1w) whole body MRI was used here to quantify different effects in the subcutaneous and visceral fat compartments in rats under treatment with an anorexiant.
Wheat and maize genes were hypothesized to be clustered into islands but the hypothesis was not statistically tested. The hypothesis is statistically tested here in four grass species differing in genome size, Brachypodium distachyon, Oryza sativa, Sorghum bicolor, and Aegilops tauschii. Density functions obtained under a model where gene locations follow a homogeneous Poisson process and thus are not clustered are compared with a model-free situation quantified through a non-parametric density estimate. A simple homogeneous Poisson model for gene locations is not rejected for the small O. sativa and B. distachyon genomes, indicating that genes are distributed largely uniformly in those species, but is rejected for the larger S. bicolor and Ae. tauschii genomes, providing evidence for clustering of genes into islands. It is proposed to call the gene islands "gene insulae" to distinguish them from other types of gene clustering that have been proposed. An average S. bicolor and Ae. tauschii insula is estimated to contain 3.7 and 3.9 genes with an average intergenic distance within an insula of 2.1 and 16.5 kb, respectively. Inter-insular distances are greater than 8 and 81 kb and average 15.1 and 205 kb, in S. bicolor and Ae. tauschii, respectively. A greater gene density observed in the distal regions of the Ae. tauschii chromosomes is shown to be primarily caused by shortening of inter-insular distances. The comparison of the four grass genomes suggests that gene locations are largely a function of a homogeneous Poisson process in small genomes. Nonrandom insertions of LTR retroelements during genome expansion creates gene insulae, which become less dense and further apart with the increase in genome size. High concordance in relative lengths of orthologous intergenic distances among the investigated genomes including the maize genome suggests functional constraints on gene distribution in the grass genomes.
Fast in-vivo high resolution diffusion tensor imaging (DTI) of the mouse brain has recently been shown to enable cohort studies by the combination of appropriate pulse sequences and cryogenically cooled resonators (CCR). The objective of this study was to apply this DTI approach at the group level to ?-amyloid precursor protein (APP) transgenic mice.
amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that leads to death within a few years after diagnosis. Malnutrition and weight loss are frequent and are indexes of poor prognosis. Total body fat and fat distribution have not been studied in ALS patients.
In addition to wind and photovoltaic power, concentrating solar thermal power (CSP) will make a major contribution to electricity provision from renewable energies. Drawing on almost 30 years of operational experience in the multi-megawatt range, CSP is now a proven technology with a reliable cost and performance record. In conjunction with thermal energy storage, electricity can be provided according to demand. To date, solar thermal power plants with a total capacity of 1.3 GW are in operation worldwide, with an additional 2.3 GW under construction and 31.7 GW in advanced planning stage. Depending on the concentration factors, temperatures up to 1000°C can be reached to produce saturated or superheated steam for steam turbine cycles or compressed hot gas for gas turbine cycles. The heat rejected from these thermodynamic cycles can be used for sea water desalination, process heat and centralized provision of chilled water. While electricity generation from CSP plants is still more expensive than from wind turbines or photovoltaic panels, its independence from fluctuations and daily variation of wind speed and solar radiation provides it with a higher value. To become competitive with mid-load electricity from conventional power plants within the next 10-15 years, mass production of components, increased plant size and planning/operating experience will be accompanied by technological innovations. On 30 October 2009, a number of major industrial companies joined forces to establish the so-called DESERTEC Industry Initiative, which aims at providing by 2050 15 per cent of European electricity from renewable energy sources in North Africa, while at the same time securing energy, water, income and employment for this region. Solar thermal power plants are in the heart of this concept.
The expression of HDAC2 is reported as reduced in chronic obstructive pulmonary disease (COPD). We assessed HDAC2 expression within the airways of smokers and subjects with COPD and effects of inhaled corticosteroids (ICS), using immuno-histology to contrast with previous molecular methodology. Endobronchial biopsies (ebb) from current smokers with COPD (COPD-CS; n?=?15), ex-smokers with COPD (COPD-ES; n?=?17), smokers with normal lung function (NS; n?=?16) and normal controls (NC; n?=?9) were immunostained for HDAC2. A double-blinded, randomized, placebo-controlled 6 months intervention study assessed effects of ICS on HDAC2 in 34 COPD subjects. There was no difference in epithelial HDAC2 staining in all groups. There was a significant reduction in total cell numbers in the lamina propria (LP) in COPD-CS and NS (p<0.05). LP cellularity correlated inversely with smoking history in COPD-CS (R?=?-0.8, p<0.003). HDAC2 expression increased markedly in NS (p<0.001); in contrast COPD-CS was associated with suppressed signal (p<0.03), while normal in COPD-ES. ICS did not affect HDAC2 cell staining. Our findings suggest that airway HDAC2 expression is increased in the LP by smoking itself, but is reduced in COPD. Ex-smokers have normalised HDAC2 cell expression, but ICS had no effect. The paper emphasise the pit-falls of relying on molecular data alone to define airway changes. Clinical Trial Registration Information:
In many databases, biocuration primarily involves literature curation, which usually involves retrieving relevant articles, extracting information that will translate into annotations and identifying new incoming literature. As the volume of biological literature increases, the use of text mining to assist in biocuration becomes increasingly relevant. A number of groups have developed tools for text mining from a computer science/linguistics perspective, and there are many initiatives to curate some aspect of biology from the literature. Some biocuration efforts already make use of a text mining tool, but there have not been many broad-based systematic efforts to study which aspects of a text mining tool contribute to its usefulness for a curation task. Here, we report on an effort to bring together text mining tool developers and database biocurators to test the utility and usability of tools. Six text mining systems presenting diverse biocuration tasks participated in a formal evaluation, and appropriate biocurators were recruited for testing. The performance results from this evaluation indicate that some of the systems were able to improve efficiency of curation by speeding up the curation task significantly (?1.7- to 2.5-fold) over manual curation. In addition, some of the systems were able to improve annotation accuracy when compared with the performance on the manually curated set. In terms of inter-annotator agreement, the factors that contributed to significant differences for some of the systems included the expertise of the biocurator on the given curation task, the inherent difficulty of the curation and attention to annotation guidelines. After the task, annotators were asked to complete a survey to help identify strengths and weaknesses of the various systems. The analysis of this survey highlights how important task completion is to the biocurators overall experience of a system, regardless of the systems high score on design, learnability and usability. In addition, strategies to refine the annotation guidelines and systems documentation, to adapt the tools to the needs and query types the end user might have and to evaluate performance in terms of efficiency, user interface, result export and traditional evaluation metrics have been analyzed during this task. This analysis will help to plan for a more intense study in BioCreative IV.
In diffusion tensor imaging (DTI), an improvement in the signal-to-noise ratio (SNR) of the fractional anisotropy (FA) maps can be obtained when the number of recorded gradient directions (GD) is increased. Vice versa, elimination of motion-corrupted or noisy GD leads to a more accurate characterization of the diffusion tensor. We previously suggest a slice-wise method for artifact detection in FA maps. This current study applies this approach to a cohort of 18 premanifest Huntingtons disease (pHD) subjects and 23 controls. By 2-D voxelwise statistical comparison of original FA-maps and FA-maps with a reduced number of GD, the effect of eliminating GD that were affected by motion was demonstrated.We present an evaluation metric that allows to test if the computed FA-maps (with a reduced number of GD) still reflect a "true" FA-map, as defined by simulations in the control sample. Furthermore, we investigated if omitting data volumes affected by motion in the pHD cohort could lead to an increased SNR in the resulting FA-maps.A high agreement between original FA maps (with all GD) and corrected FA maps (i.e. without GD corrupted by motion) were observed even for numbers of eliminated GD up to 13. Even in one data set in which 46 GD had to be eliminated, the results showed a moderate agreement.
Disturbances of dopaminergic neurotransmission may be caused by changes in concentrations of synaptic dopamine (DA) and/or availabilities of pre- and post-synaptic transporter and receptor binding sites. We present a series of experiments which focus on the regulatory mechanisms of the dopamin(DA)ergic synapse in the rat striatum. In these studies, DA transporter (DAT) and/or D(2) receptor binding were assessed with either small animal single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after pharmacological challenge with haloperidol, L-DOPA and methylphenidate, and after nigrostriatal 6-hydroxydopamine lesion. Investigations of DAT binding were performed with [(123)I]N-?-fluoropropyl-2?-carbomethoxy-3?-(4-iodophenyl)nortropane ([(123)I]FP-CIT). D(2) receptor bindingd was assessed with either [(123)I](S)-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide ([(123)I]IBZM) or [(18)F]1[3-(4fluorobenzoyl)propyl]-4-(2-keto-3-methyl-1-benzimidazolinyl)piperidine ([(18)F]FMB). Findings demonstrate that in vivo investigations of transporter and/or receptor binding are feasible with small animal SPECT and PET. Therefore, tracers that are radiolabeled with isotopes of comparatively long half-lives such as (123)I may be employed. Our approach to quantify DAT and/or D(2) receptor binding at baseline and after pharmacological interventions inducing DAT blockade, D(2) receptor blockade, and increases or decreases of endogenous DA concentrations holds promise for the in vivo assessment of synaptic function. This pertains to animal models of diseases associated with pre- or postsynaptic DAergic deficiencies such as Parkinsons disease, Huntingtons disease, attention-deficit/hyperactivity disorder, schizophrenia or drug abuse.
Since its release in 2000, WormBase (http://www.wormbase.org) has grown from a small resource focusing on a single species and serving a dedicated research community, to one now spanning 15 species essential to the broader biomedical and agricultural research fields. To enhance the rate of curation, we have automated the identification of key data in the scientific literature and use similar methodology for data extraction. To ease access to the data, we are collaborating with journals to link entities in research publications to their report pages at WormBase. To facilitate discovery, we have added new views of the data, integrated large-scale datasets and expanded descriptions of models for human disease. Finally, we have introduced a dramatic overhaul of the WormBase website for public beta testing. Designed to balance complexity and usability, the new site is species-agnostic, highly customizable, and interactive. Casual users and developers alike will be able to leverage the public RESTful application programming interface (API) to generate custom data mining solutions and extensions to the site. We report on the growth of our database and on our work in keeping pace with the growing demand for data, efforts to anticipate the requirements of users and new collaborations with the larger science community.
The chemokine stromal cell-derived factor 1 (SDF-1/CXCL12), is not only the most ancient, but also one of the most potent chemotactic factors. Orchestrating the migration of cells as well as promoting axon outgrowth in the presence of myelin inhibitors, SDF-1 is fundamental to central nervous system development, homeostasis and traumatic injury. SDF-1 attracts endogenous stem/precursor cells and immune cells to the injury site and, upon local infusion, enhances axonal sprouting following spinal cord injury. Together these features make SDF-1 a very exciting molecule for spinal cord repair.
Stem cell therapy is a potential treatment for spinal cord injury and different stem cell types have been grafted into animal models and humans suffering from spinal trauma. Due to inconsistent results, it is still an important and clinically relevant question which stem cell type will prove to be therapeutically effective. Thus far, stem cells of human sources grafted into spinal cord mostly included barely defined heterogeneous mesenchymal stem cell populations derived from bone marrow or umbilical cord blood. Here, we have transplanted a well-defined unrestricted somatic stem cell isolated from human umbilical cord blood into an acute traumatic spinal cord injury of adult immune suppressed rat. Grafting of unrestricted somatic stem cells into the vicinity of a dorsal hemisection injury at thoracic level eight resulted in hepatocyte growth factor-directed migration and accumulation within the lesion area, reduction in lesion size and augmented tissue sparing, enhanced axon regrowth and significant functional locomotor improvement as revealed by three behavioural tasks (open field Basso-Beattie-Bresnahan locomotor score, horizontal ladder walking test and CatWalk gait analysis). To accomplish the beneficial effects, neither neural differentiation nor long-lasting persistence of the grafted human stem cells appears to be required. The secretion of neurite outgrowth-promoting factors in vitro further suggests a paracrine function of unrestricted somatic stem cells in spinal cord injury. Given the highly supportive functional characteristics in spinal cord injury, production in virtually unlimited quantities at GMP grade and lack of ethical concerns, unrestricted somatic stem cells appear to be a highly suitable human stem cell source for clinical application in central nervous system injuries.
Genotype-specific effects of parvovirus B19 (B19V) infections on left ventricular function in patients with dilated cardiomyopathy (DCM) have not been investigated so far. In this prospective clinical study, the prevalences of B19V genotypes in endomyocardial biopsies from patients presenting with inflammatory heart disease and DCM were determined. A total of 139 consecutive patients were included in the study; among them 53 patients were diagnosed as DCM. Among the total study cohort, B19V DNA was detected in 65 study participants (46.8%). Genotyping of the B19V genomes in the total cohort identified genotype 1 in 38 samples (27.3%), genotype 2 in 25 samples (18.0%), and genotype 3 in only two patients (1.4%). During an average follow-up period of 8 months left ventricular ejection fraction (LVEF) improved significantly both in B19V-positive (7.1?±?13.8%, n?=?17, P?=?0.038) as well as B19V-negative patients with DCM (9.5?±?13.9%, n?=?20, P?=?0.017). However, mean LVEF improved only in patients with genotype 1 (11.0?±?14.4%, n?=?7), whereas it even decreased in patients with genotype 2 (-6.2?±?6.3%, n?=?5, P?=?0.033). These data from a small sample of patients diagnosed as DCM suggested that myocardial function during short-time follow-up differed between genetic variants of B19V. Patients with genotype 1 were on average younger than genotype 2 and appeared to be more prone to a beneficial course of left ventricular function than patients with genotype 2. Future studies with larger sample sizes and longer follow-up periods will be required to confirm this observation.
Reproductive data of individual insects are extremely hard to collect under natural conditions, thus the study of research questions related to oviposition has not advanced. Patterns of oviposition are often inferred only indirectly, through monitoring of host infestation, whereas the influence of age structure and several other factors on oviposition remains unknown. Using a new approach, in this article, we live-trapped wild Ceratitis capitata (Wiedemann) (Diptera: Tephritidae) females on the Greek island of Chios during two field seasons. For their remaining lifetime, these females were placed individually in small cages and their daily oviposition was monitored. Reproduction rates between cohorts from different collection dates were then compared. The results showed that in the different captive cohorts the average remaining lifetime and reproduction were highly variable within and between seasons. Multivariate regression analysis showed that the month of capture had a significant effect on captive life span, average daily reproduction, and patterns of egg laying. The effect of year was significant on reproduction, but not on captive life span. These differences between sampling periods probably reflect differences in the availability of hosts and other factors that vary during the season and affect age structure and reproduction. Using a non-parametric generalized additive model, we found a statistically significant correlation between the captive life span and the average daily reproduction. These findings and the experimental approach have several important implications.
Agricultural NH(3) emissions affect air quality and influence the nitrogen cycle. In the subject study, NH(3) emissions from a broiler farm and the resulting atmospheric concentrations in the immediate vicinity during three growing cycles have been quantified. Additionally, vegetation along a transect in an adjacent woodland was analysed. The emissions were as high as 10 kg NH(3)?h(-1) and the atmospheric concentrations ranged between 33 and 124 ?g NH(3)?m(-3) per week in the immediate vicinity. Measurements of the atmospheric concentrations over 7 weeks showed a substantial decline of mean concentrations (based on a 3-week average) from ?13 to <3 ?g NH(3)?m(-3), at 45- and 415-m distance from the farm. Vegetation surveys showed that nitrophilous species flourished when they grew closest to the farm (their occurrence sank proportionately with distance). A clearly visible damage of pine trees was observed within 200 m of the farm; this illustrated the significant impact of NH(3) emissions from agricultural sources on the sensitive ecosystem.
Traumatic spinal cord injury (SCI) results in the formation of a fibrous scar acting as a growth barrier for regenerating axons at the lesion site. We have previously shown (Klapka et al., 2005) that transient suppression of the inhibitory lesion scar in rat spinal cord leads to long distance axon regeneration, retrograde rescue of axotomized cortical motoneurons, and improvement of locomotor function. Here we applied a systemic approach to investigate for the first time specific and dynamic alterations in the cortical gene expression profile following both thoracic SCI and regeneration-promoting anti-scarring treatment (AST). In order to monitor cortical gene expression we carried out microarray analyses using total RNA isolated from layer V/VI of rat sensorimotor cortex at 1-60?days post-operation (dpo). We demonstrate that cortical neurons respond to injury by massive changes in gene expression, starting as early as 1 dpo. AST, in turn, results in profound modifications of the lesion-induced expression profile. The treatment attenuates SCI-triggered transcriptional changes of genes related to inhibition of axon growth and impairment of cell survival, while upregulating the expression of genes associated with axon outgrowth, cell protection, and neural development. Thus, AST not only modifies the local environment impeding spinal cord regeneration by reduction of fibrous scarring in the injured spinal cord, but, in addition, strikingly changes the intrinsic capacity of cortical pyramidal neurons toward enhanced cell maintenance and axonal regeneration.
Fibroblast growth factor (FGF)-dependent epithelial-mesenchymal transitions and cell migration contribute to the establishment of germ layers in vertebrates and other animals, but a comprehensive demonstration of the cellular activities that FGF controls to mediate these events has not been provided for any system. The establishment of the Drosophila mesoderm layer from an epithelial primordium involves a transition to a mesenchymal state and the dispersal of cells away from the site of internalisation in a FGF-dependent fashion. We show here that FGF plays multiple roles at successive stages of mesoderm morphogenesis in Drosophila. It is first required for the mesoderm primordium to lose its epithelial polarity. An intimate, FGF-dependent contact is established and maintained between the germ layers through mesoderm cell protrusions. These protrusions extend deep into the underlying ectoderm epithelium and are associated with high levels of E-cadherin at the germ layer interface. Finally, FGF directs distinct hitherto unrecognised and partially redundant protrusive behaviours during later mesoderm spreading. Cells first move radially towards the ectoderm, and then switch to a dorsally directed movement across its surface. We show that both movements are important for layer formation and present evidence suggesting that they are controlled by genetically distinct mechanisms.
Journal articles and databases are two major modes of communication in the biological sciences, and thus integrating these critical resources is of urgent importance to increase the pace of discovery. Projects focused on bridging the gap between journals and databases have been on the rise over the last five years and have resulted in the development of automated tools that can recognize entities within a document and link those entities to a relevant database. Unfortunately, automated tools cannot resolve ambiguities that arise from one term being used to signify entities that are quite distinct from one another. Instead, resolving these ambiguities requires some manual oversight. Finding the right balance between the speed and portability of automation and the accuracy and flexibility of manual effort is a crucial goal to making text markup a successful venture.
Alexithymia is a personality construct predominately associated with an impaired ability to identify and communicate emotions. Functional imaging studies showed that an altered function of the anterior cingulate cortex (ACC) may be relevant in alexithymia. In this study we investigated if the altered functional anatomy is related to structural changes (A) in the whole brain and (B) specifically in the ACC by applying a region-of-interest analysis.
In vivo molecular imaging of pre- and postsynaptic nigrostriatal neuronal degeneration and sympathetic cardiac innervation with SPECT is used to distinguish idiopathic Parkinson disease (PD) from atypical parkinsonian disorder (APD). However, the diagnostic accuracy of these imaging approaches as stand-alone procedures is often unsatisfying. The aim of this study was therefore to evaluate to which extent diagnostic accuracy can be increased by their combined use together with a multidimensional statistical algorithm.
We examined experimentally the relationship between the period of unhealthy life and longevity in the medfly by using the first sign of supine behavior (upside down; immobile) in medflies as an indication of their poor health and by altering cohort longevity through dietary manipulations. Our main findings included the following: i) for longer lived medflies it was more likely to observe the supine behavior while shorter lived flies would more likely die before exhibiting the supine behavior. ii) males have similar total life expectancy as females but a longer healthy life expectancy; iii) the total number of healthy days, spent in the pre-supine period, and the amount of healthy life span as a fraction of the total lifespan varied with both sex and diet; iv) despite the large difference in longevity between both male and female medflies when reared on sugar-only diets versus on full diets, the differences in the fraction of their lifespans in the disabled state were relatively modest (64 vs 61% in females and 77 vs 72% in males). This finding that there is no significant change in the proportion of the life course in the unhealthy state is consistent with the dynamic equilibrium model of healthy aging.
Movement artifacts and other sources of noise are a matter of concern particularly in the neuroimaging research of movement disorders such as Huntingtons disease (HD). Using diffusion weighted imaging (DWI) and fractional anisotropy (FA) as a compound marker of white matter integrity, we investigated the effect of movement on HD specific changes in magnetic resonance imaging (MRI) data and how post hoc compensation for it affects the MRI results. To this end, we studied by 3T MRI: 18 early affected, 22 premanifest gene-positive subjects, 23 healthy controls (50 slices of 2.3 mm thickness per volume, 64 diffusion-weighted directions (b = 1000 s/mm2), 8 minimal diffusion-weighting (b = 100 s/mm2)); and by 1.5 T imaging: 29 premanifest HD, 30 controls (40 axial slices of 2.3 mm thickness per volume, 61 diffusion-weighted directions (b = 1000 s/mm2), minimal diffusion-weighting (b = 100 s/mm2)). An outlier based method was developed to identify movement and other sources of noise by comparing the index DWI direction against a weighted average computed from all other directions of the same subject. No significant differences were observed when separately comparing each group of patients with and without removal of DWI volumes that contained artifacts. In line with previous DWI-based studies, decreased FA in the corpus callosum and increased FA around the basal ganglia were observed when premanifest mutation carriers and early affected patients were compared with healthy controls. These findings demonstrate the robustness of the FA value in the presence of movement and thus encourage multi-center imaging studies in HD.
Autoclaved oats were inoculated with a strain of Fusarium sporotrichioides or Fusarium poae. Moisture content of oats after inoculation was at 38%, incubation took place in standing culture at 28 °C. The A-type trichothecenes, 4,15-diacetoxyscirpenol (4,15-DAS), 15-monoacetoxyscirpenol (15-MAS), and scirpentriol (SCIRP) were analyzed by GC/MS. For each strain, three culture flasks were harvested at 2-3 day intervals starting immediately after inoculation. Total incubation time was 42 days (F. poae) and 56 days (F. sporotrichioides). Following peak accumulation, 4,15-DAS decreased below the detection limit for both strains, 15-MAS decreased below this limit for the isolate of F. sporotrichioides, for the isolate of F. poae it decreased to a level markedly below the peak value. SCIRP, after having peaked, decreased to some extent for the strain F. sporotrichioides, with a significant (P = 0.0029) negative linear regression of toxin content against culture age during this period. The content of 15-MAS, and in part also of 4,15-DAS, decreased along with an increase of SCIRP. This sequential accumulation pattern suggests the successive induction of esterases deacetylating 4,15-DAS and 15-MAS, as well as of enzymes involved in the metabolization of the parent alcohol, SCIRP. The results may explain, at least in part, the somewhat higher incidence in naturally contaminated compounds reported in the literature for SCIRP compared to 4,15-DAS and 15-MAS.
Unrestricted somatic stem cells (USSCs) represent an intrinsically multipotent CD45-negative fetal population from human cord blood. They show differentiation into neuronal cells of a dopaminergic phenotype, which express neuronal markers such as synaptophysin, neuronal-specific nuclear protein, and neurofilament and release the neurotransmitter dopamine accompanied by expression of dopaminergic key factors tyrosine hydroxylase and Nurr1 (NR4A2). MicroRNA expression analysis highlighted their importance in neural development but their specific functions remain poorly understood. Here, downregulation of a set of 18 microRNAs during neuronal lineage differentiation of unrestricted somatic stem cells, including members of the miR-17-92 family and additional microRNAs such as miR-130a, -138, -218, and -335 as well as their target genes, is described. In silico target gene predictions for this microRNA group uncovered a large set of proteins involved in neuronal differentiation and having a strong impact on differentiation-related pathways such as axon guidance and TGF?, WNT, and MAPK signaling. Experimental target validations confirmed approximately 35% of predictions tested and revealed a group of proteins with specific impact on neuronal differentiation and function including neurobeachin, neurogenic differentiation 1, cysteine-rich motor neuron protein 1, neuropentraxin 1, and others. These proteins are combined targets for several subgroups from the set of 18 downregulated microRNAs. This finding was further supported by the observed upregulation of a significant amount of predicted and validated target genes based on Illumina Beadstudio microarray data. Confirming the functional relationship of a limited panel of microRNAs and predicted target proteins reveals a clear network-like impact of the group of 18 downregulated microRNAs on proteins involved in neuronal development and function.
Spindle pole bodies (SPBs), like nuclear pore complexes, are embedded in the nuclear envelope (NE) at sites of fusion of the inner and outer nuclear membranes. A network of interacting proteins is required to insert a cytoplasmic SPB precursor into the NE. A central player of this network is Nbp1 that interacts with the conserved integral membrane protein Ndc1. Here, we establish that Nbp1 is a monotopic membrane protein that is essential for SPB insertion at the inner face of the NE. In vitro and in vivo studies identified an N-terminal amphipathic ?-helix of Nbp1 as a membrane-binding element, with crucial functions in SPB duplication. The karyopherin Kap123 binds to a nuclear localization sequence next to this amphipathic ?-helix and prevents unspecific tethering of Nbp1 to membranes. After transport into the nucleus, Nbp1 binds to the inner nuclear membrane. These data define the targeting pathway of a SPB component and suggest that the amphipathic ?-helix of Nbp1 is important for SPB insertion into the NE from within the nucleus.
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What is Visualize?
JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.
How does it work?
We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.
Video X seems to be unrelated to Abstract Y...
In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.