Functional divergence in the role of N-linked glycosylation in smoothened signaling

The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice

Modeling community integration in workers with delayed recovery from mild traumatic brain injury

Background: Delayed recovery in persons after mild traumatic brain injury (mTBI) is poorly understood. Community integration (CI) is endorsed by persons with neurological disorders as an important outcome. We aimed to describe CI and its associated factors in insured Ontario workers with delayed recovery following mTBI. Methods: A cross-sectional study of insured workers in the chronic phase following mTBI was performed at a rehabilitation hospital in Ontario, Canada. Sociodemographic, occupational, injury-related, clinical, and claim-related data were collected from self-reports, medical assessments, and insurers’ referral files. Community Integration Questionnaire (CIQ) scores were compared using analysis of variance or Spearman’s correlation tests. Stepwise multivariable linear regression models were used to evaluate the associations with CI. Results: Ninety-four workers with mTBI (45.2 ± 9.9 years old, 61.2 % male) at 197 days post-injury (interquartile range, 139–416 days) were included. The CIQ total and subscale scores were similar to those reported in more severe TBI samples. The CIQ scores were moderately to strongly correlated with various sociodemographic, claim-related, and clinical variables. In the multivariable regression analysis, several covariates accounted for 36.4 % of the CIQ variance in the final fully adjusted model. Discussion: This study evaluated CI in workers with mTBI, and analyzed its associated variables. Analysis revealed insomnia, head or neck pain, being married or in a relationship, time since injury, and a diagnosis of possible/probable malingering were independently associated with limited CI. Conclusions: Workers with delayed recovery from mTBI experience difficulty with CI. Insomnia is a particularly relevant covariate, explaining the greater part of its variance. To enhance participation, care should focus on clinical and non-clinical covariates

A deletion and a duplication in distal 22q11.2 deletion syndrome region. Clinical implications and review

<p>Abstract</p> <p>Background</p> <p>Individuals affected with DiGeorge and Velocardiofacial syndromes present with both phenotypic diversity and variable expressivity. The most frequent clinical features include conotruncal congenital heart defects, velopharyngeal insufficiency, hypocalcemia and a characteristic craniofacial dysmorphism. The etiology in most patients is a 3 Mb recurrent deletion in region 22q11.2. However, cases of infrequent deletions and duplications with different sizes and locations have also been reported, generally with a milder, slightly different phenotype for duplications but with no clear genotype-phenotype correlation to date.</p> <p>Methods</p> <p>We present a 7 month-old male patient with surgically corrected ASD and multiple VSDs, and dysmorphic facial features not clearly suggestive of 22q11.2 deletion syndrome, and a newborn male infant with cleft lip and palate and upslanting palpebral fissures. Karyotype, FISH, MLPA, microsatellite markers segregation studies and SNP genotyping by array-CGH were performed in both patients and parents.</p> <p>Results</p> <p>Karyotype and FISH with probe N25 were normal for both patients. MLPA analysis detected a partial <it>de novo </it>1.1 Mb deletion in one patient and a novel partial familial 0.4 Mb duplication in the other. Both of these alterations were located at a distal position within the commonly deleted region in 22q11.2. These rearrangements were confirmed and accurately characterized by microsatellite marker segregation studies and SNP array genotyping.</p> <p>Conclusion</p> <p>The phenotypic diversity found for deletions and duplications supports a lack of genotype-phenotype correlation in the vicinity of the LCRC-LCRD interval of the 22q11.2 chromosomal region, whereas the high presence of duplications in normal individuals supports their role as polymorphisms. We suggest that any hypothetical correlation between the clinical phenotype and the size and location of these alterations may be masked by other genetic and/or epigenetic modifying factors.</p

Direction of Association Between Depressive Symptoms and Lifestyle Behaviors in Patients with Coronary Heart Disease: the Heart and Soul Study

BACKGROUND: Emerging evidence indicates that the association between depression and subsequent cardiovascular events is largely mediated by health behaviors. However, it is unclear whether depression is the cause or the consequence of poor health behaviors. PURPOSE: To examine prospective, bidirectional relationships of depressive symptoms with behavioral and lifestyle factors among patients with coronary heart disease. METHODS: Depressive symptoms and lifestyle behaviors (physical activity, medication adherence, body mass index, waist-to-hip ratio, sleep quality, and smoking status) were assessed at baseline and 5 years later among a prospective cohort of 667 patients with stable coronary heart disease. RESULTS: Greater depressive symptoms at baseline predicted poorer lifestyle behaviors 5 years later (less physical activity, lower medication adherence, higher body mass index, higher waist-to-hip ratio, worse sleep quality, and smoking). After adjustment for demographics, cardiac disease severity, comorbidity, and baseline lifestyle behaviors, depressive symptom severity remained predictive of subsequent worsening of physical activity (beta = −0.08; 95% CI= −0.16, −0.01; p = 0.03), medication adherence (beta = −0.16; 95% CI= −0.24, −0.08; p < 0.001), and sleep quality (beta = −0.19; 95% CI = −0.27, −0.11; p < 0.001). Baseline lifestyle behaviors also predicted 5-year change in depressive symptoms, although the associations were attenuated after adjustment for baseline depressive symptoms and covariates. CONCLUSIONS: Among patients with coronary heart disease, depressive symptoms were linked to a range of lifestyle risk factors and predicted further declines in physical activity, medication adherence, and sleep quality

Data Fusion for Food Authentication: Fresh/Frozen–Thawed Discrimination in West African Goatfish (Pseudupeneus prayensis) Fillets

The substitution of fresh fish with frozen–thawed fish is a typical fraud that not only damages consumers from an economical point of view, but also causes safety issues. Furthermore, fish authentication is important for correct product labeling, as promoted by recent regulatory actions. In this paper, we present the results of the authentication of fresh west African goatfish (Pseudupeneus prayensis) fillets using different analytical technologies, namely a portable visible/nearinfrared spectrometer, a compact digital camera, and a texture analyzer. First, the classification performance of the abovementioned analytical technologies is evaluated and compared. Then, it is shown how the fusion of different technologies can be effectively used to improve the classification accuracy. Particularly, spectra and color features extracted from digital images returned a classification accuracy of 100 and 98.5 %, respectively, when considered separately. However, the classification accuracy fell to 80 % when considering measurements taken with a 24-h delay. Data fusion, instead, allowed a classification accuracy of 100 % also after 24 h. Hence, the combination of a spectrometer and a digital camera is very promising for cost-effective on-line/atline applications, as both sensors are rapid, non-invasive, and do not require sample preparation. Furthermore, since more than 200 samples were collected over a prolonged period of time (1 year), the classification models encompassed some sources of variability (seasonality effects and size) that are not usually accounted for in similar studies