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Home > Mapping Genes Causing Congenital Syndromic and Non-Syndromic Skin Disorders in Consanguineous Families

Mapping Genes Causing Congenital Syndromic and Non-Syndromic Skin Disorders in Consanguineous Families

Thesis Info

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Author

Farooq Ahmad

Program

PhD

Institute

Quaid-I-Azam University

City

Islamabad

Province

Islamabad.

Country

Pakistan

Thesis Completing Year

2018

Thesis Completion Status

Completed

Subject

Biochemistry

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/12696/1/Farooq%20Ahmad_Biochem%20Molecular%20Bio_2018_QAU_PRR.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676726611500

Similar


The research work, presented in the dissertation, described characterization of eighteen families segregating various types of isolated and syndromic skin disorders. Four of the families showed clinical features of congenital ichthyosis, two junctional epidermolysis bullosa, four hair loss disorders, two isolated spoon shaped nail/koilonychias, two hypohidrotic ectodermal dysplasia (HED), one each with ectodermal dysplasia syndactyly syndrome, hypotrichosis, palmoplantar keratoderma and nail dysplasia, hypotrichosis-anonychia-post-axial polydactyly and hair-nailteeth-skin type ectodermal dysplasia. Clinical investigation of affected members in each family was carried out with the help of medical officers/dermatologists working at local government and private hospitals. Based on the clinical spectrum developed in each family, genetic characterization was performed by typing microsatellite and SNP markers. Further, disease causing variants were searched using exome and /or Sanger sequencing. In one case effect of the mutation was validated through exon trapping. Bioinformatics tools and protein modeling studies were performed where possible. In addition to associating skin phenotypes with three novel genes, seven novels and six known mutations were identified in families segregating other skin-related clinical features. Two novel missense mutations p.Asp34Glu and p.Gly439Ser were identified in the PNPLA1 and ST14 gene, respectively causing two different types of ichthyosis. In a related phenotype called junctional epidermolysis bullosa, observed in two other families, sequence analysis revealed a novel non-sense (p.Ser3298*) and a previously reported missense variant (p.Arg1303Gln) in the LAMA3 and COL17A1 gene, respectively. Four other novel variants including p.Gln230*, p.Trp485*, p.Gln417* and p.Leu81Pro were detected in the genes LIPH, CDH3, EDAR and PVRL4, respectively. The mutations in the LIPH and CDH3 produced hair loss disorders, in the EDAR results in hypohidrotic ectodermal dysplasia (HED) and in the PVRL4 results in ectodermal dysplasia cutaneous syndactyly syndrome. Previously reported sequence variants including a missense (p.Pro498Leu) in the DSP gene causing hypotrichosis-palmoplantar keratoderma-nail dysplasia, a missense (p.Asp63Val) in the LPAR6 gene causing hypotrichosis, a missense (p.Gly382Ser) in the EDAR gene causing HED, and a non-sense (p.Arg110*) in the LIPH and a missense (p.Met1Ileu) in the RSPO4 producing hypotrichosis-nail dysplasia (anonychia) -post-axial polydactyly were identified as well.
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جیہڑا حسن ازل مہتاباں وچ

جیہڑا حسن ازل مہتاباں وچ
اوہو چمکے نور آفتاباں وچ
جیہڑی ہووے بھل چک بھل جانا
اساں لکھیا خط شتاباں وچ
جہیڑا وڑیا عشق قبیلے نوں
اوہ آگیا سدا بے تاباں وچ
سانوں مان نہ مال و دولت دا
روٹی اوہو جیہڑی رکاباں وچ
جس کان پنجاب دا ناں بنیا
پانی لبھدا نہیں چناباں وچ
نہیں شوق عمل دی داد کوئی
علم رہ گیا صرف کتاباں وچ

توں یار میرے دی پچھنا ایں
جیویں سوہنا پھل گلاباں وچ
کدی عشق دے قیدی نہیں چھٹ دے
اینویں گزری عمر عذاباں وچ
اینویں دکھاں درداں ماریا اے
جگر جیوں کر سیخ کباباں وچ
کسے دکھی دل دی کر خدمت
رب لبھدا نہیں محراباں وچ
ہو عقل حیران کھلوندی اے
کیا لذت عشق دے باباں وچ
جیہڑے مال خزانے ونڈ دے سن
اوہ صفتاں کدوں نواباں وچ
جہدی خاطر جگ جہان بنیا
پڑھاں لکھ سلام جناباں وچ
کدی پچھ حنیف نوں جا کے تے
کی لبھیا عشق نصاباں وچ

Awareness and Utilisation of Primary Healthcare to Reduce Emergency Department Overcrowding in Saudi Arabia

Background Patients seeking emergency department (ED) care for non-acute conditions are a major contributor to ED overcrowding, which results in longer wait times. Method This was a cross-sectional study, conducted using an online survey among the Saudi population to assess their awareness about primary healthcare clinics (PHCCs) and urgent care clinics (UCCs), their role, and their scope of practice. Results A total of 565 participants were included in this study. Most of the respondents (81.1%) reported lengthy waiting times in the ED. Moreover, most (81.6%) stated that they had never visited a family doctor, yet they (92.6%) favoured having one for follow-up care. Close to half of the participants (50.3%) reported attending PHCCs without an appointment, and the majority of them (69.2%) said that PHCCs were overcrowded. Finally, most participants (92.4%) had not heard aboutUCCs. Conclusion ED overcrowding and prolonged waiting times remain a public concern. PHCCs and UCCs are underutilised, and this is attributed to the lack of awareness about their scope and their services.  

Boosting Based Multiclass Ensembles and Their Applications in Machine Learning

Boosting is a generic statistical process for generating accurate classifier ensembles from only a moderately accurate learning algorithm. AdaBoost (Adaptive Boosting) is a machine learning algorithm that iteratively fits a number of classifiers on the training data and forms a linear combination of these classifiers to form a final ensemble. This dissertation presents our three major contributions to boosting based ensemble learning literature which includes two multi-class ensemble learning algorithms, a novel way to incorporate domain knowledge into a variety of boosting algorithms and an application of boosting in a connectionist framework to learn a feed-forward artificial neural network. To learn a multi-class classifier a new multi-class boosting algorithm, called M-Boost, has been proposed that introduces novel classifier selection and classifier combining rules. M-Boost uses a simple partitioning algorithm (i.e., decision stumps) as base classifier to handle a multi-class problem without breaking it into multiple binary problems. It uses a global optimality measures for selecting a weak classifier as compared to standard AdaBoost variants that use a localized greedy approach. It also uses a confidence based reweighing strategy for training examples as opposed to standard exponential multiplicative factor. Finally, M-Boost outputs a probability distribution over classes rather than a binary classification decision. The algorithm has been tested for eleven datasets from UCI repository and has consistently performed much better for 9 out of 11 datasets in terms of classification accuracy. Another multi-class ensemble learning algorithm, CBC: Cascaded Boosted Classifiers, is also presented that creates a multiclass ensemble by learning a cascade of boosted classifiers. It does not require explicit encoding of the given multiclass problem, rather it learns a multi-split decision tree and implicitly learns the encoding as well. In our recursive approach, an optimal partition of all classes is selected from the set of all possible partitions and training examples are relabeled. The reduced multiclass learning problem is then learned by using a multiclass learner. This procedure is recursively applied for each partition in order to learn a complete cascade. For experiments we have chosen M-Boost as the multi-class ensemble learning algorithm. The proposed algorithm was tested for network intrusion detection dataset (NIDD) adopted from the KDD Cup 99 (KDDâ˘A ´ Z99) prepared and managed by MIT Lincoln Labs as part of the 1998 DARPA Intrusion Detection Evaluation Program. To incorporate domain knowledge into boosting an entirely new strategy for incorporating prior into any boosting algorithm has also been devised. The idea behind incorporating prior into boosting in our approach is to modify the weight distribution over training examples using the prior during each iteration. This modification affects the selection of base classifier included in the ensemble and hence incorporate prior in boosting. Experimental results show that the proposed method improves the convergence rate, improves accuracy and compensate for lack of training data. A novel weight adaptation method in a connectionist framework that uses AdaBoost to minimize an exponential cost function instead of the mean square error minimization is also presented in this dissertation. This change was introduced to achieve better classification accuracy as the exponential loss function minimized by AdaBoost is more suitable for learning a classifier. Our main contribution in this regard is the introduction of a new representation of decision stumps that when used as base learner in AdaBoost becomes equivalent to a perceptron. This boosting based method for learning a perceptron is called BOOSTRON. The BOOSTRON algorithm has also been extended and generalized to learn a multi-layered perceptron. This generalization uses an iterative strategy along with the BOOSTRON algorithm to learn weights of hidden layer neurons and output neurons by reducing these problems into problems of learning a single layer perceptron.