Mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia

Resultados de investigaciónIn addition to its structural role in skeletogenesis, the extracellular matrix (ECM), particularly basement membrane proteins, facilitates communication with intracellular signaling pathways and cell to cell interactions to control differentiation, proliferation, migration and survival. Alterations in extracellular proteins cause a number of skeletal disorders and one attributed mechanism results from the deleterious effects of mutated proteins on ECM structure. Yet, the consequences of abnormal ECM on cellular communication remains less well understood. Herein, we describe an unclassified form of bent bone dysplasia caused by recessively inherited mutations in LAMA5, the gene encoding the alpha-5 laminin basement membrane protein. This finding uncovered a mechanism of disease driven by ECM-cell interactions between alpha-5-containing laminins, and integrin- mediated focal adhesion signaling, particularly in cartilage. Loss of LAMA5 altered b1 integrin signaling through the non-canonical kinase PYK2 and the skeletal enriched SRC kinase FYN. Loss of LAMA5 negatively impacted the actin cytoskeleton, vinculin localization, and WNT signaling, tying focal adhesion molecules to key skeletal signaling molecules. This newly described mechanism reveals that a LAMA5-b1 Integrin-PYK2-FYN focal adhesion complex regulatesskeletogenesis and, when dysregulated, produces a distinct skeletal disorder.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Free Energy Approach to the Formation of an Icosahedral Structure during the Freezing of Gold Nanoclusters

The freezing of metal nanoclusters such as gold, silver, and copper exhibits a novel structural evolution. The formation of the icosahedral (Ih) structure is dominant despite its energetic metastability. This important phenomenon, hitherto not understood, is studied by calculating free energies of gold nanoclusters. The structural transition barriers have been determined by using the umbrella sampling technique combined with molecular dynamics simulations. Our calculations show that the formation of Ih gold nanoclusters is attributed to the lower free energy barrier from the liquid to the Ih phases compared to the barrier from the liquid to the face-centered-cubic crystal phases

Emotion dysregulation mediates the relationship between nightmares and psychotic experiences: Results from a student population

Sleep-disruption is commonly associated with psychotic experiences. Whilst sparse, the literature to date highlights nightmares and related distress as prominent risk factors for psychosis in students. We aimed to further explore the relationship between specific nightmare symptoms and psychotic experiences in university students whilst examining the mediating role of emotion dysregulation. A sample (N=1273) of student respondents from UK universities completed measures of psychotic experiences, nightmare disorder symptomology, and emotion dysregulation. Psychotic experiences were significantly more prevalent in students reporting nightmares (n=757) relative to those who did not (n=516). Hierarchical linear regression analysis showed that psychotic experiences were significantly associated (Adjusted R2 = 32.4%) with perceived nightmare intensity, consequences and resulting awakenings, and with emotion regulation difficulties. Furthermore, multiple mediation analysis showed that the association between psychotic experiences and nightmare factors was mediated by emotion regulation difficulties. Adaptive regulation of dream content during rapid eye-movement sleep has previously been demonstrated to attenuate surges in affective arousal by controlling the intensity and variability of emotional content. Difficulties in emotion regulation may partially explain the experience of more intense and disruptive nightmares amongst individuals with psychotic experiences. Emotion regulation may represent an important control mechanism that safeguards dream content and sleep quality

Clinical Phenotypes and Comorbidity in European Sleep Apnoea Patients

Background Clinical presentation phenotypes of obstructive sleep apnoea (OSA) and their association with comorbidity as well as impact on adherence to continuous positive airway pressure (CPAP) treatment have not been established. Methods A prospective follow-up cohort of adult patients with OSA (apnoea-hypopnoea index (AHI) of 655/h) from 17 European countries and Israel (n = 6,555) was divided into four clinical presentation phenotypes based on daytime symptoms labelled as excessive daytime sleepiness ("EDS") and nocturnal sleep problems other than OSA (labelled as "insomnia"): 1) EDS (daytime+/nighttime-), 2) EDS/insomnia (daytime+/nighttime+), 3) non-EDS/noninsomnia (daytime-/nighttime-), 4) and insomnia (daytime-/nighttime+) phenotype. Results The EDS phenotype comprised 20.7%, the non-EDS/non-insomnia type 25.8%, the EDS/ insomnia type 23.7%, and the insomnia phenotype 29.8% of the entire cohort. Thus, clinical presentation phenotypes with insomnia symptoms were dominant with 53.5%, but only 5.6% had physician diagnosed insomnia. Cardiovascular comorbidity was less prevalent in the EDS and most common in the insomnia phenotype (48.9% vs. 56.8%, p<0.001) despite more severe OSA in the EDS group (AHI 35.0\ub125.5/h vs. 27.9\ub122.5/h, p<0.001, respectively). Psychiatric comorbidity was associated with insomnia like OSA phenotypes independent of age, gender and body mass index (HR 1.5 (1.188-1.905), p<0.001). The EDS phenotype tended to associate with higher CPAP usage (22.7 min/d, p = 0.069) when controlled for age, gender, BMI and sleep apnoea severity. Conclusions Phenotypes with insomnia symptoms comprised more than half of OSA patients and were more frequently linked with comorbidity than those with EDS, despite less severe OSA. CPAP usage was slightly higher in phenotypes with EDS