Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients

Spondylo-meta-epiphyseal dysplasia (SMED) with short limbs and abnormal calcifications (SMED-SL) is a rare, autosomal recessive human growth disorder, characterized by disproportionate short stature, short limbs, short broad fingers, abnormal metaphyses and epiphyses, platyspondyly and premature calcifications. Recently, three missense mutations and one splice-site mutation in the DDR2 gene were identified as causative genetic defects for SMED-SL, but the underlying cellular and biochemical mechanisms were not explored. Here we report a novel DDR2 missense mutation, c.337G>A (p.E113K), that causes SMED-SL in two siblings in the United Arab Emirates. Another DDR2 missense mutation, c.2254C>T (p.R752C), matching one of the previously reported SMED-SL mutations, was found in a second affected family. DDR2 is a plasma membrane receptor tyrosine kinase that functions as a collagen receptor. We expressed DDR2 constructs with the identified point mutations in human cell lines and evaluated their localization and functional properties. We found that all SMED-SL missense mutants were defective in collagen-induced receptor activation and that the three previously reported mutants (p.T713I, p.I726R and p.R752C) were retained in the endoplasmic reticulum. The novel mutant (p.E113K), in contrast, trafficked normally, like wild-type DDR2, but failed to bind collagen. This finding is in agreement with our recent structural data identifying Glu113 as an important amino acid in the DDR2 ligand-binding site. Our data thus demonstrate that SMED-SL can result from at least two different loss-of-function mechanisms: namely defects in DDR2 targeting to the plasma membrane or the loss of its ligand-binding activity

Autophagic dysfunction in mucolipidosis type IV patients

Mutations in Mucolipin 1 (MCOLN1) have been linked to mucolipidosis type IV (MLIV), a lysosomal storage disease characterized by several neurological and ophthalmological abnormalities. It has been proposed that MCOLN1 might regulate transport of membrane components in the late endosomal–lysosomal pathway; however, the mechanisms by which defects of MCOLN1 function result in mental and psychomotor retardation remain largely unknown. In this study, we show constitutive activation of autophagy in fibroblasts obtained from MLIV patients. Accumulation of autophagosomes in MLIV cells was due to the increased de novo autophagosome formation and to delayed fusion of autophagosomes with late endosomes/lysosomes. Impairment of the autophagic pathway led to increased levels and aggregation of p62, suggesting that abnormal accumulation of ubiquitin proteins may contribute to the neurodegeneration observed in MLIV patients. In addition, we found that delivery of platelet-derived growth factor receptor to lysosomes is delayed in MCOLN1-deficient cells, suggesting that MCOLN1 is necessary for efficient fusion of both autophagosomes and late endosomes with lysosomes. Our data are in agreement with recent evidence showing that autophagic defects may be a common characteristic of many neurodegenerative disorders

Extrovert Followership and its Impact on Agreeable Leadership

This study recons the need for research on effective role of followership in mentoring a leader to set pattern or direction for leader. A reinvented concept of leader being a team man needs active participation from followers in changing business dynamics. The sample consisting of middle level management having leader (heads/ supervisors from education sector) above it has been taken and results are achieved using inferential statistics, so to verify the need of followers for result oriented leadership. The results depict that certain personality traits backed by “Big Five Model” are found to be important for followers to have an impact on leader’s decision making. As this study analyses the mutual characteristic of leader follower relation statistically while putting follower on the fore front, the originality of study is ensured. As for limitation, this study may show different results as per variant geographical and economical regions in which followers’ expectations may vary accordingly

Community Structure along Timberline Ecotone in Relation to Micro-topography and Disturbances in Western Himalaya

Four communities, formed as a result of locally varying site conditions, were identified and studied along the timberline ecotone in part of Kedarnath Wildlife Sanctuary (KWS). Communities on the vicinity of pilgrimage site and along gentler slopes were highly disturbed having sharp timberlines, while those located far and in the steep slopes were less affected, forming a little broader transition. The tree density ranged from 340 to 780 trees/ha, while the basal cover of communities varied greatly and ranged from 6.4 to 55.1 m2/ha. Birch dominated community had lowest basal area among all the communities, while mixed community had the highest. In all the respective communities, from subalpine zone, density and basal area was higher than that of timberline zone. The Importance Value Index (IVI), which used to determine the overall importance of each species in the community structure, of dominant species at timberline was more than 200 in all the communities, except in the mixed community. Influence of the anthropogenic disturbances was apparent on the regeneration performance of all the studied tree species. Rhododendron campanulatum was the dominant shrub species of the area and formed krummholz, while distribution of other species varies greatly with forest type. The shrub density decreased from high to low disturbance, while the herbaceous species density increased with prevalence of a few species favoring the high disturbance (grazing). The shrub and herb species richness was higher in the ecotone zone. Some uncommon species like Balanophora involucrata and Aralia cissifolia were also found at timberline. Three species of Ladys Slipper orchid were reported together from Betula utilis community at timberline ecotone

Guided Zoom: Zooming into Network Evidence to Refine Fine-Grained Model Decisions

In state-of-the-art deep single-label classification models, the top-k (k = 2,3,4,....) accuracy is usually significantly higher than the top-1 accuracy. This is more evident in fine-grained datasets, where differences between classes are quite subtle. Exploiting the information provided in the top k predicted classes boosts the final prediction of a model. We propose Guided Zoom, a novel way in which explainabitity could be used to improve model performance. We do so by making sure the model has "the right reasons" fora prediction. The reason/evidence upon which a deep neural network makes a prediction is defined to be the grounding, in the pixel space, for a specific class conditional probability in the model output. Guided Zoom examines how reasonable the evidence used to make each of the top-k predictions is. Test time evidence is deemed reasonable if it is coherent with evidence used to make similar correct decisions at training time. This leads to better informed predictions. We explore a variety of grounding techniques and study their complementarity for computing evidence. We show that Guided Zoom results in an improvement of a model's classification accuracy and achieves state-of-the-art classification performance on four fine-grained classification datasets

The overexpression of DNA repair genes in invasive ductal and lobular breast carcinomas: Insights on individual variations and precision medicine.

In the era of precision medicine, analyzing the transcriptomic profile of patients is essential to tailor the appropriate therapy. In this study, we explored transcriptional differences between two invasive breast cancer subtypes; infiltrating ductal carcinoma (IDC) and lobular carcinoma (LC) using RNA-Seq data deposited in the TCGA-BRCA project. We revealed 3854 differentially expressed genes between normal ductal tissues and IDC. In addition, IDC to LC comparison resulted in 663 differentially expressed genes. We then focused on DNA repair genes because of their known effects on patients' response to therapy and resistance. We here report that 36 DNA repair genes are overexpressed in a significant number of both IDC and LC patients' samples. Despite the upregulation in a significant number of samples, we observed a noticeable variation in the expression levels of the repair genes across patients of the same cancer subtype. The same trend is valid for the expression of miRNAs, where remarkable variations between patients' samples of the same cancer subtype are also observed. These individual variations could lie behind the differential response of patients to treatment. The future of cancer diagnostics and therapy will inevitably depend on high-throughput genomic and transcriptomic data analysis. However, we propose that performing analysis on individual patients rather than a big set of patients' samples will be necessary to ensure that the best treatment is determined, and therapy resistance is reduced