Enteric Nervous System Progenitors Are Coordinately Controlled by the G Protein-Coupled Receptor EDNRB and the Receptor Tyrosine Kinase RET

AbstractThe enteric nervous system (ENS) in vertebrates is derived mainly from vagal neural crest cells that enter the foregut and colonize the entire wall of the gastrointestinal tract. Failure to completely colonize the gut results in the absence of enteric ganglia (Hirschsprung's disease). Two signaling systems mediated by RET and EDNRB have been identified as critical players in enteric neurogenesis. We demonstrate that interaction between these signaling pathways controls ENS development throughout the intestine. Activation of EDNRB specifically enhances the effect of RET signaling on the proliferation of uncommitted ENS progenitors. In addition, we reveal novel antagonistic roles of these pathways on the migration of ENS progenitors. Protein kinase A is a key component of the molecular mechanisms that integrate signaling by the two receptors. Our data provide strong evidence that the coordinate and balanced interaction between receptor tyrosine kinases and G protein-coupled receptors controls the development of the nervous system in mammals

Reconceptualizing critical cultural awareness for the context of FL literature education: The development of an assessment rubric for the secondary level

The construct of critical cultural awareness (CCA) is often regarded as an element pertaining to intercultural communicative competence (Byram, 1997, 2021). In this model, CCA is defined as the ability to “evaluate, critically, and on the basis of a systematic process of reasoning, values in one’s own culture and other cultures” (Byram, 2021, p. 90). Although the potential of literature to develop learners’ CCA is widely accepted by intercultural education scholars, Byram’s definition has some limitations as a theoretical basis for teaching students how to “evaluate and reason critically” about literary texts, as it does not take into account certain aspects of literary reading and critical interculturality that are essential in contemporary foreign language (FL) teaching and learning. This study aims to redefine CCA for the specific context of secondary literature education in a bottom-up manner, based on an analysis of student texts about migratory literature. To this end, 97 students learning Spanish as a FL in the upper forms of pre-university education (aged 15–19) at four schools in the Netherlands were asked to write an evaluation of two literary texts they read in class. Via qualitative analysis of these texts with Atlas.ti, three content categories – social justice, emotions and conflict – and two evaluative categories ­– cultural representation and transformation – were identified for CCA. The findings of this study have implications for other FL literature teaching settings, as a generic rubric for assessment of student texts was developed based on the criteria that emerged from the data

Activities of daily living in lower limb amputees with a bone-anchored prosthesis:a retrospective case series with 24 months’ follow-up

Background and purpose:Little is known about the activities of daily living (ADL) of patients with a bone-anchored prosthesis (BAP). We aimed to objectively measure ADL without and with BAP during standard care of follow-up. Our secondary aim was to measure mobility and walking ability. Patients and methods:Patients aged 18–99 years who underwent surgery for transfemoral or transtibial BAP between September 11, 2017, and February 11, 2021, were eligible for inclusion in this retrospective case series of patients with socket prosthesis. ADL was measured with a continuous recording activity monitor (hours [h]) before surgery, and at 6, 12, and 24 months with BAP. Mobility and walking ability were assessed by the Timed Up and Go test (TUG) (seconds [s]) and 6 Minute Walk Test (6MWT) (meters [m]), respectively. Results:48 of the 57 eligible patients provided informed consent and were included. Their age was 59 (1st quartile to 3rd quartile 51–63) years. Total daily activity before BAP was 1.6 h (0.82–2.1) and increased to 2.1 h (1.4–2.5) at 6, 2.0 h (1.5–2.7) at 12, and 2.7 h (2.0–3.3) at 24 months with BAP. Daily walking increased from 1.3 h (0.79–1.9) before BAP to 1.8 h (1.6–2.3) at 6, to 1.7 h (1.2–2.4) at 12, and 2.0 h (1.6–2.6) at 24 months. Median TUG decreased from 12 s (9.1–14) before BAP to 8.9 s (7.7–10) at 24 months. Mean 6MWT increased from 272 m (SD 92) before BAP to 348 m (SD 68) at 24 months.Conclusion:Objective measurements on ADL positively changed in patients with BAP. This effect was also seen in mobility and walking ability at 24 months.</p

Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial

Introduction: Recent cohort studies have identified the use of large tidal volumes as a major risk factor for development of lung injury in mechanically ventilated patients without acute lung injury (ALI). We compared the effect of conventional with lower tidal volumes on pulmonary inflammation and development of lung injury in critically ill patients without ALI at the onset of mechanical ventilation. Methods: We performed a randomized controlled nonblinded preventive trial comparing mechanical ventilation with tidal volumes of 10 ml versus 6 ml per kilogram of predicted body weight in critically ill patients without ALI at the onset of mechanical ventilation. The primary end point was cytokine levels in bronchoalveolar lavage fluid and plasma during mechanical ventilation. The secondary end point was the development of lung injury, as determined by consensus criteria for ALI, duration of mechanical ventilation, and mortality. Results: One hundred fifty patients (74 conventional versus 76 lower tidal volume) were enrolled and analyzed. No differences were observed in lavage fluid cytokine levels at baseline between the randomization groups. Plasma interleukin-6 (IL-6) levels decreased significantly more strongly in the lower-tidal-volume group ((from 51 (20 to 182) ng/ml to 11 (5 to 20) ng/ml versus 50 (21 to 122) ng/ml to 21 (20 to 77) ng/ml; P = 0.01)). The trial was stopped prematurely for safety reasons because the development of lung injury was higher in the conventional tidal-volume group as compared with the lower tidal-volume group (13.5% versus 2.6%; P = 0.01). Univariate analysis showed statistical relations between baseline lung-injury score, randomization group, level of positive end-expiratory pressure (PEEP), the number of transfused blood products, the presence of a risk factor for ALI, and baseline IL-6 lavage fluid levels and the development of lung injury. Multivariate analysis revealed the randomization group and the level of PEEP as independent predictors of the development of lung injury. Conclusions: Mechanical ventilation with conventional tidal volumes is associated with sustained cytokine production, as measured in plasma. Our data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury in patients without ALI at the onset of mechanical ventilation. (aut. ref.

Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors

We describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (IER3IP1) were found in patients from both families. IER3IP1 is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is characterized by increased apoptotic cell death as part of an uncontrolled unfolded protein response. Increased apoptosis has been shown to be a cause of microcephaly in animal models. An autopsy specimen from one patient showed increased apoptosis in the cerebral cortex and pancreas beta cells, implicating premature cell death as the pathogenetic mechanism. Both patient fibroblasts and control fibroblasts treated with siRNA specific for IER3IP1 showed an increased susceptibility to apoptotic cell death under stress conditions in comparison to controls. This directly implicates IER3IP1 in the regulation of cell survival. Identification of IER3IP1 mutations sheds light on the mechanisms of brain development and on the pathogenesis of infantile epilepsy and early-onset permanent diabetes.Facultad de Ciencias Médica

Pericentrosomal targeting of Rab6 secretory vesicles by Bicaudal-D-related protein 1 (BICDR-1) regulates neuritogenesis

Membrane and secretory trafficking are essential for proper neuronal development. However, the molecular mechanisms that organize secretory trafficking are poorly understood. Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. BICDR-1 expression is high during early neuronal development and strongly declines during neurite outgrowth. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation

Аналіз вибіркових даних при оцінюванні наукового потенціалу і характер статистичних властивостей вербальних моделей

OBJECTIVE: To determine sensitivity and specificity of a standardized recombinant cell-based indirect immunofluorescence assay (RC-IFA) for anti-Tr antibodies in comparison to a reference procedure. METHODS: Delta/Notch-like epidermal growth factor-related receptor (DNER) was expressed in HEK293 and used as a substrate for RC-IFA. HEK293 control cells expressing CDR2/Yo and CDR2L as well as mock-transfected HEK293 cells were used as controls. Serum samples from 38 patients with anti-Tr antibodies (33 with paraneoplastic cerebellar degeneration [PCD] and Hodgkin lymphoma), 66 patients with anti-Tr-negative PCD, 53 patients with Hodgkin lymphoma without neurologic symptoms, 40 patients with rheumatic diseases, and 42 healthy blood donors were tested for anti-DNER reactivity in the RC-IFA. In addition, RC-IFA results were compared to those from a commercial tissue-based IFA using monkey cerebellum. RESULTS: Using the RC-IFA, anti-DNER was detected in all anti-Tr-positive patients but in none of the controls (sensitivity 100%, 95% confidence interval [CI] 92.8%-100%; specificity 100%, 95% CI 98.7%-100%). In comparison, anti-Tr was not detected in 4 samples with low-titer autoantibodies using the commercial tissue-based assay. Preadsorption of sera with either recombinant full-length DNER or its extracellular domain selectively abolished anti-Tr reactivity. CONCLUSION: Anti-Tr antibodies bind to the extracellular domain of DNER and can be detected by RC-IFA using HEK293 cells expressing the recombinant receptor. The new method performs better than a frequently used commercial tissue-based indirect immunofluorescence assay (IFA) in samples with low-titer antibodies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that RC-IFA accurately detects anti-Tr as compared to conventional IFA