Cryoelectron tomography reveals periodic material at the inner side of subpellicular microtubules in apicomplexan parasites

Microtubules are dynamic cytoskeletal structures important for cell division, polarity, and motility and are therefore major targets for anticancer and antiparasite drugs. In the invasive forms of apicomplexan parasites, which are highly polarized and often motile cells, exceptionally stable subpellicular microtubules determine the shape of the parasite, and serve as tracks for vesicle transport. We used cryoelectron tomography to image cytoplasmic structures in three dimensions within intact, rapidly frozen Plasmodium sporozoites. This approach revealed microtubule walls that are extended at the luminal side by an additional 3 nm compared to microtubules of mammalian cells. Fourier analysis revealed an 8-nm longitudinal periodicity of the luminal constituent, suggesting the presence of a molecule interacting with tubulin dimers. In silico generation and analysis of microtubule models confirmed this unexpected topology. Microtubules from extracted sporozoites and Toxoplasma gondii tachyzoites showed a similar density distribution, suggesting that the putative protein is conserved among Apicomplexa and serves to stabilize microtubules

Clinical and Genetic Evaluation of Patients with KATP Channel Mutations from the German Registry for Congenital Hyperinsulinism

Congenital hyperinsulinism (CHI) causes hypoglycemia due to irregular insulin secretion. In infants, a rapid diagnosis and appropriate management to avoid severe hypoglycemia is mandatory. CHI is a heterogeneous condition at the clinical and genetic level, and disease-causing genes have been identified in about half of the patients. The majority of mutations have been identified in the ABCC8 and KCNJ11 genes encoding subunits of the KATP channel responsible for two distinct histological forms. The diffuse form is caused by autosomal recessive or dominant inherited mutations, whereas the focal form is caused by a paternally transmitted recessive mutation and a second somatic event. We report on an unselected cohort of 136 unrelated patients from the German CHI registry. Mutations in either the ABCC8 or KCNJ11 gene were identified in 61 of these patients (45%). In total, 64 different mutations including 38 novel ones were detected in this cohort. We observed biparental (recessive) inheritance in 34% of mutation-positive patients, dominant inheritance in 11% and paternal transmission of a mutation associated with a focal CHI type in 38%. In addition, we observed inheritance patterns that do not exactly follow the classical recessive or dominant mode, further adding to the genetic complexity of this disease

Investigating photo-catalytic activity of metal-ceramic composites in eosin degradation using complex iron compounds

Iron-containing metal-ceramic composites based on silicon nitrides, titanium, and sialon were investigated in terms of their phase composition, as well as identification and evaluation of acid-base surface centers. It is shown that the base Lewis centers and the acid centers of Brensted are prevalent on the surface of the materials. The photocatalytic activity of composites was examined in the process of eosin degradation in presence of Н[2]О[2] and EDTA. The composites based on nitrides of silicon and titanium demonstrate the highest activity under ferric complex system conditions

Idomeneo Rey de Creta

De cada obra s'ha digitalitzat un programa sencer. De la resta s'han digitalitzat les parts que són diferents.Direcció artística Empresa Juan Mestres CalvetDirector Hans MeissnerÒpera de Wolfgang Amadeus Mozar

Rapid functional plasticity in the primary somatomotor cortex and perceptual changes after nerve block

Abstract The mature human primary somatosensory cortex displays a striking plastic capacity to reorganize itself in response to changes in sensory input. Following the elimination of afferent return, produced by either amputation, deafferentation by dorsal rhizotomy, or nerve block, there is a well-known but little-understood 'invasion' of the deafferented region of the brain by the cortical representation zones of still-intact portions of the brain adjacent to it. We report here that within an hour of abolishing sensation from the radial and medial three-quarters of the hand by pharmacological blockade of the radial and median nerves, magnetic source imaging showed that the cortical representation of the little finger and the skin beneath the lower lip, whose intact cortical representation zones are adjacent to the deafferented region, had moved closer together, presumably because of their expansion across the deafferented area. A paired-pulse transcranial magnetic stimulation procedure revealed a motor cortex disinhibition for two muscles supplied by the unaffected ulnar nerve. In addition, two notable perceptual changes were observed: increased two-point discrimination ability near the lip and mislocalization of touch of the intact ulnar portion of the fourth finger to the neighbouring third finger whose nerve supply was blocked. We suggest that disinhibition within the somatosensory system as a functional correlate for the known enlargement of cortical representation zones might account for not only the 'invasion' phenomenon, but also for the observed behavioural correlates of the nerve block

Las Bodas de Figaro

De cada obra s'ha digitalitzat un programa sencer. De la resta s'han digitalitzat les parts que són diferents.Direcció artística Empresa Juan Mestres CalvetDirector Hans MeissnerÒpera de Wolfgang Amadeus Mozar

Use of Placebos and Nonspecific and Complementary Treatments by German Physicians - Rationale and Development of a Questionnaire for a Nationwide Survey

Background: We are performing a nationwide survey in a random sample ofGerman general practitioners (GPs), orthopedists, and internists on theuse of placebos and nonspecific as well as complementary treatments andtheir association with basic professional attitudes. In this article weexplain the theoretical considerations behind the study approach and thedevelopment of the questionnaire. Methods: Based on a systematic reviewof published surveys, own surveys on the topic, and on theoreticalconsiderations we developed a preliminary version of a 4-pagequestionnaire that was tested for feasibility in a convenience sample of80 participants of a general medical education event. We also performedcognitive interviews with 8 physicians to investigate whether thequestions were understood adequately. Results: The questions on typicalplacebos and complementary treatments were well understood and easy toanswer for participants. Discussions about the phrasing of questions onnonspecific treatments during interview reflected the vagueness of thisconcept; but this did not seem to create major problems when answeringthe related questions. The original questions regarding basicprofessional attitudes partly were not understood in the mannerintended. The relevant questions were modified but the interviewssuggest that these issues are difficult to grasp in a quantitativesurvey. Conclusion: Our testing procedures suggest that ourquestionnaire is well-suited to investigate our questions with somelimitations regarding the issue of basic professional attitudes

Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons

International audienceAggregation of the multifunctional RNA-binding protein TDP-43 defines large subgroups of amyotrophic lateral sclerosis and frontotemporal dementia and correlates with neurodegeneration in both diseases. In disease, characteristic C-terminal fragments of ~25 kDa ("TDP-25") accumulate in cytoplasmic inclusions. Here, we analyze gain-of-function mechanisms of TDP-25 combining cryo-electron tomography, proteomics, and functional assays. In neurons, cytoplasmic TDP-25 inclusions are amorphous, and photobleaching experiments reveal gel-like biophysical properties that are less dynamic than nuclear TDP-43. Compared with full-length TDP-43, the TDP-25 interactome is depleted of low-complexity domain proteins. TDP-25 inclusions are enriched in 26S proteasomes adopting exclusively substrate-processing conformations, suggesting that inclusions sequester proteasomes, which are largely stalled and no longer undergo the cyclic conformational changes required for proteolytic activity. Reporter assays confirm that TDP-25 impairs proteostasis, and this inhibitory function is enhanced by ALScausing TDP-43 mutations. These findings support a pathophysiological relevance of proteasome dysfunction in ALS/FTD

Las bodas de Figaro

De cada obra s'ha digitalitzat un programa sencer. De la resta s'han digitalitzat les parts que són diferents.Direcció artística Empresa Juan Mestres CalvetDirector Franz KonwitschnyÒpera de Wolfgang Amadeus Mozar