Search results for: mutations

Authors: Tareg Belali, Mosleh Abomughaid, Muhanad Alhujaily

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HNF4a is one of the steroid hormone receptor family of transcription factors with roles in the development of the liver and the regulation of several critical metabolic pathways, such as glycolysis, drug metabolism, and apolipoproteins and blood coagulation. The transcriptional potency of HNF4a is well known due to its involvement in diabetes and other metabolic diseases. However, recently HNF4a has been discovered to be closely associated with several haematological disorders, mainly because of genetic mutations, drugs, and hepatic disorders. We review HNF4a structure and function and its role in haematological disorders. We discuss possible good therapies that are based on targeting HNF4a.

Keywords: hepatocyte nuclear factor 4 alpha, HNF4a nuclear receptor, steroid hormone receptor family of transcription factors, hematological disorders

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Authors: Diaa Ahmed Mohamed Ahmedien

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Nowadays, it cannot be denied that the most important interactive arts trends have appeared as a result of significant scientific mutations in the modern sciences, and holographic art is not an exception, where it is considered as a one of the most important major contemporary interactive arts trends in visual arts. Holographic technique had been evoked through the modern physics application in late 1940s, for the improvement of the quality of electron microscope images by Denis Gabor, until it had arrived to Margaret Benyon’s art exhibitions, and then it passed through a lot of procedures to enhance its quality and artistic applications technically and visually more over 70 years in visual arts. As a modest extension to these great efforts, this research aimed to invoke extraordinary attempt to enroll sample of normal people in Egyptian community in holographic recording program to record their appreciated objects or antiques, therefore examine their abilities to interact with modern techniques in visual communication arts. So this research tried to answer to main three questions: 'can we use the analog holographic techniques to unleash new theoretical and practical knowledge in interactive arts for public in Egyptian community?', 'to what extent holographic art can be familiar with public and make them able to produce interactive artistic samples?', 'are there possibilities to build holographic interactive program for normal people which lead them to enhance their understanding to visual communication in public and, be aware of interactive arts trends?' This research was depending in its first part on experimental methods, where it conducted in Laser lab at Cairo University, using Nd: Yag Laser 532 nm, and holographic optical layout, with selected samples of Egyptian people that they have been asked to record their appreciated object, after they had already learned recording methods, and in its second part on a lot of discussion panel had conducted to discuss the result and how participants felt towards their holographic artistic products through survey, questionnaires, take notes and critiquing holographic artworks. Our practical experiments and final discussions have already lead us to say that this experimental research was able to make most of participants pass through paradigm shift in their visual and conceptual experiences towards more interaction with contemporary visual arts trends, as an attempt to emphasize to the role of mature relationship between the art, science and technology, to spread interactive arts out in our community through the latest scientific and artistic mutations around the world and the role of this relationship in our societies particularly with those who have never been enrolled in practical arts programs before.

Keywords: Egyptian community, holographic art, laser art, visual art

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Authors: Lakmini Wijesooriya, Vicki Chalker, Jessica Day, Priyantha Perera, N. P. Sunil-Chandra

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M. pneumoniae has been identified as an etiology for exacerbation of asthma (EQA), although viruses play a major role in EOA. M. pneumoniae infection is treated empirically with macrolides, and its antibiotic sensitivity is not detected routinely. Characterization of the organism by genotyping and determination of macrolide resistance is important epidemiologically as it guides the empiric antibiotic treatment. To date, there is no such characterization of M. pneumoniae performed in Sri Lanka. The present study describes the characterization of M. pneumoniae detected from a child with EOA following a screening of 100 children with EOA. Of the hundred children with EOA, M. pneumoniae was identified only in one child by Real-Time polymerase chain reaction (PCR) test for identifying the community-acquired respiratory distress syndrome (CARDS) toxin nucleotide sequences. The M. pneumoniae identified from this patient underwent detection of macrolide resistance via conventional PCR, amplifying and sequencing the region of the 23S rDNA gene that contains single nucleotide polymorphisms that confer resistance. Genotyping of the isolate was performed via nested Multilocus Sequence Typing (MLST) in which eight (8) housekeeping genes (ppa, pgm, gyrB, gmk, glyA, atpA, arcC, and adk) were amplified via nested PCR followed by gene sequencing and analysis. As per MLST analysis, the M. pneumoniae was identified as sequence type 14 (ST14), and no mutations that confer resistance were detected. Resistance to macrolides in M. pneumoniae is an increasing problem globally. Establishing surveillance systems is the key to informing local prescriptions. In the absence of local surveillance data, antibiotics are started empirically. If the relevant microbiological samples are not obtained before antibiotic therapy, as in most occasions in children, the course of antibiotic is completed without a microbiological diagnosis. This happens more frequently in therapy for M. pneumoniae which is treated with a macrolide in most patients. Hence, it is important to understand the macrolide sensitivity of M. pneumoniae in the setting. The M. pneumoniae detected in the present study was macrolide sensitive. Further studies are needed to examine a larger dataset in Sri Lanka to determine macrolide resistance levels to inform the use of macrolides in children with EOA. The MLST type varies in different geographical settings, and it also provides a clue to the existence of macrolide resistance. The present study enhances the database of the global distribution of different genotypes of M. pneumoniae as this is the first such characterization performed with the increased number of samples to determine macrolide resistance level in Sri Lanka. M. pneumoniae detected from a child with exacerbation of asthma in Sri Lanka was characterized as ST14 by MLST and no mutations that confer resistance were detected.

Keywords: mycoplasma pneumoniae, Sri Lanka, characterization, macrolide resistance

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Authors: Ananya Pal, Neelakshi Sarkar, Debraj Saha, Dipanwita Das, Subhashish Kamal Guha, Bibhuti Saha, Runu Chakravarty

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Presently, tenofovir disoproxil fumurate (TDF) is the most effective anti-viral agent for the treatment of hepatitis B virus (HBV) in individuals co-infected with HIV and HBV as TDF has activity to suppress both wild-type and lamivudine (3TC)-resistant HBV. However, suboptimal response to TDF was reported in HIV-HBV co-infected individuals with prior 3TC therapy from different countries recently. The incidence of 3TC-resistant HBV strains is quite high in HIV-HBV co-infected patients experiencing long-term anti-retroviral therapy (ART) in eastern India. In spite of this risk, most of the patients with long-term 3TC treatment are continued with the same anti-viral agent in this country. Only a few have received TDF in addition to 3TC in the ART regimen since TDF has been available in India for the treatment of HIV-infected patients in 2012. In this preliminary study, we investigated the virologic and biochemical parameters among HIV-HBV co-infected patients who are non-responders to 3TC treatment during the continuation of 3TC or TDF add-on to 3TC in their ART regimen. Fifteen HIV-HBV co-infected patients who experienced long-term 3TC (mean duration months 36.87 ± 24.08 months) were identified with high HBV viremia ( > 20,000 IU/ml) or harbouring 3TC-resistant HBV. These patients receiving ART from School of Tropical Medicine Kolkata, the main ART centre in eastern India were followed-up semi-annually for next three visits. Different virologic parameters including quantification of plasma HBV load by real-time PCR, detection of hepatitis B e antigen (HBeAg) by commercial ELISA and anti-viral resistant mutations by sequencing were studied. During three follow-up among study subjects, 86%, 47%, and 43% had 3TC-mono-therapy (mean treatment-duration 41.54±18.84, 49.67±11.67, 54.17±12.37 months respectively) whereas 14%, 53%, and 57% experienced TDF in addition to 3TC (mean treatment duration 4.5±2.12, 16.56±11.06, and 23±4.07 months respectively). Mean CD4 cell-count in patients receiving 3TC was tended to be lower during third follow-up as compared to the first and the second [520.67±380.30 (1st), 454.8±196.90 (2nd), and 397.5±189.24 (3rd) cells/mm3) and similar trend was seen in patients experiencing TDF in addition to 3TC [334.5±330.218 (1st), 476.5±194.25 (2nd), and 461.17±269.89 (3rd) cells/mm3]. Serum HBV load was increased during successive follow-up of patients with 3TC-mono-therapy. Initiation of TDF lowered serum HBV-load among 3TC-non-responders at the time of second visit ( < 2,000 IU/ml), interestingly during third follow-up, mean HBV viremia increased >1 log IU/ml (mean 3.56±2.84 log IU/ml). Persistence of 3TC-resistant double and triple mutations was also observed in both the treatment regimens. Mean serum alanine aminotransferase remained elevated in these patients during this follow-up study. Persistence of high HBV viraemia and 3TC-resistant mutation in HBV during the continuation of 3TC might lead to major public health threat in India. The inclusion of TDF in the ART regimen of 3TC non-responder HIV-HBV co-infected patients showed adverse treatment response in terms of virologic and biochemical parameters. Therefore, serious attention is necessary for proper management of long-term 3TC experienced HIV-HBV co-infected patients with high HBV viraemia or 3TC-resistant HBV mutants in India.

Keywords: HBV, HIV, TDF, 3TC-resistant

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Authors: Wing Kam Fung, Kexin Yu

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Child trafficking has been a serious problem in modern China. The Chinese government has established a national anti-trafficking DNA database to help reunite missing children with their families. The database collects DNA information from missing children's parents, trafficked and homeless children, then conducts paternity tests to find matched pairs. This paper considers the matching accuracy in such cases by looking into the exclusion probability in paternity testing. First, the situation of child trafficking in China is introduced. Next, derivations of the exclusion probability for both one-parent and two-parents cases are given, followed by extension to allow for 1 or 2 mutations. The accuracy of paternity testing of child trafficking cases is then assessed using the exclusion probabilities and available data. Finally, the number of loci that should be used to ensure a correct match is investigated.

Keywords: child trafficking, DNA database, exclusion probability, paternity testing

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Authors: Y. Z. Gad

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Disorders of Sex Development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical. The DSD are relatively prevalent in Egypt. In spite of that, the relative rarity of the individual disease types or their molecular pathologies frequently resulted in reporting on single or few cases. This augmented the challenging nature of phenotype-genotype correlation in this disease group and its utilization in the management of such medical emergency. Through critical assessment of the published DSD reports, the current review aims at analyzing the clinical characteristics of the various DSD forms in relation to the underlying molecular pathologies. A systematic literature search was done in Pubmed, using relevant keywords (Egypt versus DSD, genital ambiguity or ambiguous genitalia, the old terms of 'intersex, hermaphroditism and pseudohermaphroditism', and a list of the DSD entities and their related genes). The search yielded 24 reports of molecular data in Egyptian patients presenting with ambiguous genitalia. However, only 21 publications fulfilled the criteria of inclusion of detailed clinical descriptions and definitive molecular diagnoses of individual patients. Curation of the data yielded a total of 53 cases that were ascertained from 40 families. Fifty-one patients present with ambiguous genitalia only while 2 had multiple congenital anomalies. Parental consanguinity was noted in 60% of cases. Sex of rearing at initial presentation was female in 75% and 60% in 46,XY and 46,XX DSD cases, respectively. The external genital phenotype in 2/3 of the 46,XY DSD cases showed moderate undermasculinization [Quigley scores 3 & 4] and 1/3 had severe presentations [scores 5 & 6]. For 46,XX subjects, 1 had severe virilization of the external genitalia while 8 had moderate phenotype. Hormonal data were inconclusive or contradictory to final diagnosis in a forth of cases. Collectively, 31 families [31/40, 77.5%] with 46,XY DSD had molecular defects in the genes, 5 alpha reductase 2 (SRD5A2) [12/31], 17 beta-hydroxysteroid dehydrogenase 3 [8/31], androgen receptor [7/31], Steroidogenic factor 1 [2/31], luteinizing hormone receptor [1/31], and fibroblast growth factor receptor 1 [1/31]. In a multiethnic study, 9 families afflicted with 46,XX DSD due to 11 beta hydroxylase (CYP11B1) deficiency were documented. Two recurrent mutations, G34R and N160D, in SRD5A2 were present, respectively, in 42 and 17% of cases. Similarly, 4 recurrent mutations resulted in 89% of the CYP11B1 presentations. In conclusion, this analysis highlights the importance of autosomal recessive inheritance and inbreeding among DSD presentations, the importance of founder effect in at least 2 disorders, the difficulties in relating the genotype with the indeterminate genital phenotype, the under-reporting of some DSD subtypes, and the notion that the reported mutational profiles among Egyptian DSD cases are relatively different from those reported in other ethnic groups.

Keywords: disorders of sex development, genital ambiguity, mutation, molecular diagnosis, Egypt

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Authors: Kechikeche Nabil

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The MENA region has undergone many mutations throughout history. The most significant one was, yet, to happen during the colonial era, where the Arab Muslim ‘cosmic’ clock was recalibrated to match a more or less modern perception of time. As for modern civic and political experiences of life, they were left in a state of inertia. This article considers the problematic amalgam of traditional Islam, modernity and democratization in the Arab world, as well as the effects on the configuration of recent progressive endeavours. It is argued that the assimilation of democratic ethos - as a requisite for modernity - depends on the assimilation of power, progress and time, by what is referred to as the Umma. Drawing on postmodern and political literature, it is suggested that because of a conceptualization which draws mainly on traditional Islam, the Umma and the state in the Arab world remain in conflict while, at times, they appear to act collaboratively, either to embrace modernity or to obstruct democratization.

Keywords: Islam, democracy, Arab world, modernity

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Authors: Athini Ntloko

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Mycobacterium bovis and other species of Mycobacterium tuberculosis complex (MTBC) can result to a zoonotic infection known as Bovine tuberculosis (bTB). MTBC has members that may contaminate an extensive range of hosts, including wildlife. Diverse wild species are known to cause disease in domestic livestock and are acknowledged as TB reservoirs. It has been a main study worldwide to deliberate on bTB risk factors as a result and some studies focused on particular parts of risk factors such as wildlife and herd management. The significance of the study was to determine the incidence of Mycobacterium tuberculosis complex that is associated with soil, hayfeed and water. Questionnaires were administered to thirty (30) smallholding farm owners in the two villages (kwaMasele and Qungqwala) and three (3) three commercial farms (Fort Hare dairy farm, Middledrift dairy farm and Seven star dairy farm). Detection of M. tuberculosis complex was achieved by Polymerase Chain Reaction using primers for IS6110; whereas a genotypic drug resistance mutation was detected using Genotype MTBDRplus assays. Nine percent (9%) of respondents had more than 40 cows in their herd, while 60% reported between 10 and 20 cows in their herd. Relationship between farm size and vaccination for TB differed from forty one percent (41%) being the highest to the least five percent (5%). The highest number of respondents who knew about relationship between TB cases and cattle location was ninety one percent (91%). Approximately fifty one percent (51%) of respondents had knowledge about wild life access to the farms. Relationship between import of cattle and farm size ranged from nine percent (9%) to thirty five percent (35%). Cattle sickness in relation to farm size differed from forty three (43%) being the highest to the least three percent (3%); while thirty three percent (33%) of respondents had knowledge about health management. Respondents with knowledge about the occurrence of TB infections in farms were forty-eight percent (48%). The frequency of DNA isolation from samples ranged from the highest forty-five percent (45%) from water to the least twenty two percent (22%) from soil. Fort Hare dairy farm had the highest number of positive samples, forty four percent (44%) from water samples; whereas Middledrift dairy farm had the lowest positive from water, seventeen percent (17%). Twelve (22%) out of 55 isolates showed resistance to INH and RIF that is, multi-drug resistance (MDR) and nine percent (9%) were sensitive to either INH or RIF. The mutations at rpoB gene differed from 58% being the highest to the least (23%). Fifty seven percent (57%) of samples showed a S315T1 mutation while only 14% possessed a S531L in the katG gene. The highest inhA mutations were detected in T8A (80 %) and the least was observed in A16G (17%). The results of this study reveal that risk factors for bTB in cattle and dairy farm workers are a serious issue abound in the Eastern Cape of South Africa; with the possibility of widespread dissemination of multidrug resistant determinants in MTBC from the environment.

Keywords: hayfeed, isoniazid, multi-drug resistance, mycobacterium tuberculosis complex, polymerase chain reaction, rifampicin, soil, water

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Authors: Imad H. Hameed, Mohammad A. Jebor, Ammera J. Omer

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The aim of this research is to study the mitochonderial coding region by using the Sanger sequencing technique and establish the degree of variation characteristic of a fragment. FTA® Technology (FTA™ paper DNA extraction) utilized to extract DNA. Portion of coding region encompassing positions 11719 –12384 amplified in accordance with the Anderson reference sequence. PCR products purified by EZ-10 spin column then sequenced and Detected by using the ABI 3730xL DNA Analyzer. Five new polymorphic positions 11741, 11756, 11878, 11887 and 12133 are described may be suitable sources for identification purpose in future. The calculated value D= 0.95 and RMP=0.048 of the genetic diversity should be understood as high in the context of coding function of the analysed DNA fragment. The relatively high gene diversity and a relatively low random match probability were observed in Iraq population. The obtained data can be used to identify the variable nucleotide positions characterized by frequent occurrence which is most promising for various identifications.

Keywords: coding region, Iraq, mitochondrial DNA, polymorphic positions, sanger technique

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Authors: Efendi Zaenudin, Chien-Hung Huang, Ka-Lok Ng

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Essential genes play an important role in the survival of an organism. It has been shown that cancer-associated essential genes are genes necessary for cancer cell proliferation, where these genes are potential therapeutic targets. Also, it was demonstrated that mutations of the cancer-associated essential genes give rise to the resistance of immunotherapy for patients with tumors. In the present study, we focus on studying the biological effects of the essential genes from a network perspective. We hypothesize that one can analyze a biological molecular network by decomposing it into both three-node and four-node digraphs (subgraphs). These network subgraphs encode the regulatory interaction information among the network’s genetic elements. In this study, the frequency of occurrence of the subgraph-associated essential genes in a molecular network was quantified by using the statistical parameter, odds ratio. Biological effects of subgraph-associated essential genes are discussed. In summary, the subgraph approach provides a systematic method for analyzing molecular networks and it can capture useful biological information for biomedical research.

Keywords: biological molecular networks, essential genes, graph theory, network subgraphs

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Authors: D. R. Apoorva

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Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome is a rare oculocutaneous disorder of genetic origin. This disorder results from mutations in the membrane-bound transcription factor protease site, two genes that impair cholesterol homeostasis, and the ability to cope with endoplasmic reticulum stress. We report a rare case of IFAP syndrome with an atypical presentation, and it was interesting to note that the child had patchy non-scarring alopecia over the scalp along with unilateral madarosis. To our best knowledge, this unique presentation has not been described earlier. The child presented with photophobia and unilateral ptosis. The child also had short stature and intellectual disability. Skin histopathology was nonspecific and consisted of dilated hair follicles with keratin plugs extending above the skin surface. This rare oculocutaneous disorder requires proper documentation so that identification of its variants may be possible in the future. Early recognition of atypical presentations can help in preventing cardiovascular complications, which remain the major cause of death.

Keywords: alopecia, photophobia, ichthyosis follicularis, IFAP syndrome

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Authors: Negin Parsamanesh, Saman Ameri-Mahabadi, Ali Nikfar, Mojdeh Mansouri, Hossein Chiti, Gita Fatemi Abhari

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Duchenne muscular dystrophy (DMD) is a severe progressive X-linked neuromuscular illness that affects movement through mutations in dystrophin gene. The mutation leads to insufficient, lack of or dysfunction of dystrophin. The cause of DMD was determined in an Iranian family. Exome sequencing was carried out along with a complete physical examination of the family. In silico methods were applied to find the alteration in the protein structure. The homozygous variant in DMD gene (NM-004006.2) was defined as c.2732-2733delTT (p.Phe911CysfsX8) in exon 21. In addition, phylogenetic conservation study of the human dystrophin protein sequence revealed that phenylalanine 911 is one of the evolutionarily conserved amino acids. In conclusion, our study indicated a new deletion in the DMD gene in the affected family. This deletion with an X-linked inheritance pattern is new in Iran. These findings could facilitate genetic counseling for this family and other patients in the future.

Keywords: duchenne muscular dystrophy, whole exome sequencing, iran, metabolic syndrome

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Authors: A. T. Adetunji, F. B. Lewu, R. Mundembe

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Plants require nitrogen (N) to support desired production levels. Nitrogen is available to plants in the form of nitrate or ammonium, which are transported into the cell with the aid of various transport proteins. Ammonium transporters (AMTs) play a role in the uptake of ammonium, the form in which nitrogen is preferentially absorbed by plants. Solanum tuberosum AMT1 (StAMT1) was characterized using molecular biology and bioinformatics methods. Nucleotide database sequences were used to design AMT1-specific primers which were used to amplify the AMT1 internal regions. Nucleotide sequencing, alignment and phylogenetic analysis assigned StAMT1 to the AMT1 family. The deduced amino acid sequences showed that StAMT1 is 92%, 83% and 76% similar to Solanum lycopersicum LeAMT1.1, Lotus japonicus LjAMT1.1 and Solanum lycopersicum LeAMT1.2 respectively. StAMT1 fragments were shown to correspond to the 5th - 10th trans-membrane domains. Residue StAMT1 D15 is predicted to be essential for ammonium transport, while mutations of StAMT1 S76A may further enhance ammonium transport.

Keywords: ammonium transporter, bioinformatics, nitrogen, primers, Solanum tuberosum

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Authors: Joanna Marie A. Paulino-Morente, Vaneza Valentina L. Penolio, Grace Sabado

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Ovarian cancer is extremely hard to diagnose in its early stages, and those afflicted at the time of diagnosis are typically asymptomatic and in the late stages of the disease, with metastasis to other organs. Ovarian cancers often occur sporadically, with only 5% associated with hereditary mutations. Mutations in the BRCA1 and BRCA2 tumor suppressor genes have been found to be responsible for the majority of hereditary ovarian cancers. One type of ovarian tumor is Malignant Mixed Mullerian Tumor (MMMT), which is a very rare and aggressive type, accounting for only 1% of all ovarian cancers. Reported is a case of a 43-year-old G3P3 (3003), who came into our institution due to a 2-month history of difficulty of breathing. Family history reveals that her eldest and younger sisters both died of ovarian malignancy, with her younger sister having a histopathology report of endometrioid ovarian carcinoma, left ovary stage IIIb. She still has 2 asymptomatic sisters. Physical examination pointed to pleural effusion of right lung, and presence of bilateral ovarian new growth, which had a Sassone score of 13. Admitting Diagnosis was G3P3 (3003), Ovarian New Growth, bilateral, Malignant; Pleural effusion secondary to malignancy. BRCA was requested to establish a hereditary mutation; however, the patient had no funds. Once the patient was stabilized, TAHBSO with surgical staging was performed. Intraoperatively, the pelvic cavity was occupied by firm, irregularly shaped ovaries, with a colorectal metastasis. Microscopic sections from both ovaries and the colorectal metastasis had pleomorphic tumor cells lined by cuboidal to columnar epithelium exhibiting glandular complexity, displaying nuclear atypia and increased nuclear-cytoplasmic ratio, which are infiltrating the stroma, consistent with the features of Malignant Mixed Mullerian Tumor, since MMMT is composed histologically of malignant epithelial and sarcomatous elements. In conclusion, discussed is the clinic-pathological feature of a patient with primary ovarian Malignant Mixed Mullerian Tumor, a rare malignancy comprising only 1% of all ovarian neoplasms. Also, by understanding the hereditary ovarian cancer syndromes and its relation to this patient, it cannot be overemphasized that a comprehensive family history is really fundamental for early diagnosis. The familial association of the disease, given that the patient has two sisters who were diagnosed with an advanced stage of ovarian cancer and succumbed to the disease at a much earlier age than what is reported in the general population, points to a possible hereditary syndrome which occurs in only 5% of ovarian neoplasms. In a low-resource setting, being in a third world country, the following will be recommended for monitoring and/or screening women who are at high risk for developing ovarian cancer, such as the remaining sisters of the patient: 1) Physical examination focusing on the breast, abdomen, and rectal area every 6 months. 2) Transvaginal sonography every 6 months. 3) Mammography annually. 4) CA125 for postmenopausal women. 5) Genetic testing for BRCA1 and BRCA2 will be reserved for those who are financially capable.

Keywords: BRCA, hereditary breast-ovarian cancer syndrome, malignant mixed mullerian tumor, ovarian cancer

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Authors: Aishik Deb, Rituparna Sinha

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We have developed an algorithm to detect the abnormal segment/"structural variation in the genome across a number of samples. We have worked on simulated as well as real data from the BAM Files and have designed a segmentation algorithm where abnormal segments are detected. This algorithm aims to improve the accuracy and performance of the existing CNV-CH algorithm. The next-generation sequencing (NGS) approach is very fast and can generate large sequences in a reasonable time. So the huge volume of sequence information gives rise to the need for Big Data and parallel approaches of segmentation. Therefore, we have designed a map-reduce approach for the existing CNV-CH algorithm where a large amount of sequence data can be segmented and structural variations in the human genome can be detected. We have compared the efficiency of the traditional and map-reduce algorithms with respect to precision, sensitivity, and F-Score. The advantages of using our algorithm are that it is fast and has better accuracy. This algorithm can be applied to detect structural variations within a genome, which in turn can be used to detect various genetic disorders such as cancer, etc. The defects may be caused by new mutations or changes to the DNA and generally result in abnormally high or low base coverage and quantification values.

Keywords: cancer detection, convex hull segmentation, map reduce, next generation sequencing

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Authors: Masoud Alipanah, Sekineh Akbari, Gholamreza Dashab

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Myostatin genes or factor 8 affecting on growth and making differentiation works (GDF8) as a moderator in the development of skeletal muscle inhibitor. If mutations occurs in the coding region of myostatin, alter its inhibitory role and the muscle growth is increased. In this study, blood samples were collected randomly from 60 Kurdish sheep in northern Khorasan and DNA extraction was performed using a modified salt. A fragment 337 bp from exon 3 myostatin gene and-specific primers by using a polymerase chain reaction (PCR) were amplified. In order to detect different forms of an allele at this locus HaeΙΙΙ restriction enzymes and PCR-RFLP analysis were used. Band patterns clarification was performed using agarose gel electrophoresis. The frequency of genotypes mm, Mm, and MM, were respectively detected, 0, 0.15 and 0.85. The allele frequency for alleles m and M, were respectively, 0.07 and 0.93. The statistical analyses indicated that m allele was significantly associated with body weight. The results of this study suggest that the Myostatin gene possibly is a candidate gene that affects growth traits in Kurdish sheep.

Keywords: GDF8 gene, Kurdi Sheep of Northern Khorasan, polymorphism, weight traits

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Authors: Mohammed Hakim Jafferali, Balaje Vijayaraghavan, Ricardo A. Figueroa, Ellinor Crafoord, Veronica J. Larsson, Einar Hallberg, Santhosh Gudise

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The nuclear envelope which surrounds the chromatin of eukaryotic cells contains more than a hundred transmembrane proteins. Mutations in some genes encoding nuclear envelope proteins give rise to human diseases including neurological disorders. The function of many nuclear envelope proteins is not well established. This is partly because nuclear envelope proteins and their interactions are difficult to study due to the inherent resistance to extraction of nuclear envelope proteins. We have developed a novel method called MCLIP, to identify interacting partners of nuclear envelope proteins in live cells. Using MCLIP, we found three new binding partners of the inner nuclear membrane protein Samp1: the intermediate filament protein Lamin B1, the LINC complex protein Sun1 and the G-protein Ran. Furthermore, using in vitro studies, we show that Samp1 binds both Emerin and Ran directly. We have also studied the interaction between Samp1 and Ran in detail. The results show that the Samp1 binds stronger to RanGTP than RanGDP. Samp1 is the first transmembrane protein known to bind Ran and it is tempting to speculate that Samp1 may provide local binding sites for RanGTP at membranes.

Keywords: MCLIP, nuclear envelope, ran, Samp1

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Authors: Abdulaziz Alakeel, Abdulrahman Alomair, Mohammed Fouda

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Introduction: Methotrexate (MTX) is an antimetabolite used to treat multiple conditions, including neoplastic diseases, severe psoriasis, and rheumatoid arthritis. Skin cancer is the out-of-control growth of abnormal cells in the epidermis, the outermost skin layer, caused by unrepaired DNA damage that triggers mutations. These mutations lead the skin cells to multiply rapidly and form malignant tumors. The aim of this review is to evaluate the risk of skin cancer associated with the use of methotrexate and to suggest regulatory recommendations if required. Methodology: Signal Detection team at Saudi Food and Drug Authority (SFDA) performed a safety review using National Pharmacovigilance Center (NPC) database as well as the World Health Organization (WHO) VigiBase, alongside with literature screening to retrieve related information for assessing the causality between skin cancer and methotrexate. The search conducted in July 2020. Results: Four published articles support the association seen while searching in literature, a recent randomized control trial published in 2020 revealed a statistically significant increase in skin cancer among MTX users. Another study mentioned methotrexate increases the risk of non-melanoma skin cancer when used in combination with immunosuppressant and biologic agents. In addition, the incidence of melanoma for methotrexate users was 3-fold more than the general population in a cohort study of rheumatoid arthritis patients. The last article estimated the risk of cutaneous malignant melanoma (CMM) in a cohort study shows a statistically significant risk increase for CMM was observed in MTX exposed patients. The WHO database (VigiBase) searched for individual case safety reports (ICSRs) reported for “Skin Cancer” and 'Methotrexate' use, which yielded 121 ICSRs. The initial review revealed that 106 cases are insufficiently documented for proper medical assessment. However, the remaining fifteen cases have extensively evaluated by applying the WHO criteria of causality assessment. As a result, 30 percent of the cases showed that MTX could possibly cause skin cancer; five cases provide unlikely association and five un-assessable cases due to lack of information. The Saudi NPC database searched to retrieve any reported cases for the combined terms methotrexate/skin cancer; however, no local cases reported up to date. The data mining of the observed and the expected reporting rate for drug/adverse drug reaction pair is estimated using information component (IC), a tool developed by the WHO Uppsala Monitoring Centre to measure the reporting ratio. Positive IC reflects higher statistical association, while negative values translated as a less statistical association, considering the null value equal to zero. Results showed that a combination of 'Methotrexate' and 'Skin cancer' observed more than expected when compared to other medications in the WHO database (IC value is 1.2). Conclusion: The weighted cumulative pieces of evidence identified from global cases, data mining, and published literature are sufficient to support a causal association between the risk of skin cancer and methotrexate. Therefore, health care professionals should be aware of this possible risk and may consider monitoring any signs or symptoms of skin cancer in patients treated with methotrexate.

Keywords: methotrexate, skin cancer, signal detection, pharmacovigilance

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Authors: Emanuela Chiarella, Annamaria Aloisio, Nisticò Clelia, Maria Mesuraca

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ZNF521 is a stem cell-associated transcription co-factor, that plays a crucial role in the homeostatic regulation of the stem cell compartment in the hematopoietic, osteo-adipogenic, and neural system. In normal hematopoiesis, primary human CD34+ hematopoietic stem cells display typically a high expression of ZNF521, while its mRNA levels rapidly decrease when these progenitors progress towards erythroid, granulocytic, or B-lymphoid differentiation. However, most acute myeloid leukemias (AMLs) and leukemia-initiating cells keep high ZNF521 expression. In particular, AMLs are often characterized by chromosomal translocations involving the Mixed Lineage Leukemia (MLL) gene, which MLL gene includes a variety of fusion oncogenes arisen from genes normally required during hematopoietic development; once they are fused, they promote epigenetic and transcription factor dysregulation. The chromosomal translocation t(9;11)(p21-22;q23), fusing the MLL gene with AF9 gene, results in a monocytic immune phenotype with an aggressive course, frequent relapses, and a short survival time. To better understand the dysfunctional transcriptional networks related to genetic aberrations, AML gene expression profile datasets were queried for ZNF521 expression and its correlations with specific gene rearrangements and mutations. The results showed that ZNF521 mRNA levels are associated with specific genetic aberrations: the highest expression levels were observed in AMLs involving t(11q23) MLL rearrangements in two distinct datasets (MILE and den Boer); elevated ZNF521 mRNA expression levels were also revealed in AMLs with t(7;12) or with internal rearrangements of chromosome 16. On the contrary, relatively low ZNF521 expression levels seemed to be associated with the t(8;21) translocation, that in turn is correlated with the AML1-ETO fusion gene or the t(15;17) translocation and in AMLs with FLT3-ITD, NPM1, or CEBPα double mutations. Invitro, we found that the enforced co-expression of ZNF521 in cord blood-derived CD34+ cells induced a significant proliferative advantage, improving MLL-AF9 effects on the induction of proliferation and the expansion of leukemic progenitor cells. Transcriptome profiling of CD34+ cells transduced with either MLL-AF9, ZNF521, or a combination of the two transgenes highlighted specific sets of up- or down-regulated genes that are involved in the leukemic phenotype, including those encoding transcription factors, epigenetic modulators, and cell cycle regulators as well as those engaged in the transport or uptake of nutrients. These data enhance the functional cooperation between ZNF521 and MA9, resulting in the development, maintenance, and clonal expansion of leukemic cells. Finally, silencing of ZNF521 in MLL-AF9-transformed primary CD34+ cells inhibited their proliferation and led to their extinction, as well as ZNF521 silencing in the MLL-AF9+ THP-1 cell line resulted in an impairment of their growth and clonogenicity. Taken together, our data highlight ZNF521 role in the control of self-renewal and in the immature compartment of malignant hematopoiesis, which, by altering the gene expression landscape, contributes to the development and/or maintenance of AML acting in concert with the MLL-AF9 fusion oncogene.

Keywords: AML, human zinc finger protein 521 (hZNF521), mixed lineage leukemia gene (MLL) AF9 (MLLT3 or LTG9), cord blood-derived hematopoietic stem cells (CB-CD34+)

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Authors: Dana Gabriková, Martin Mistrík, Jarmila Bernasovská, Iveta Tóthová, Jana Kisková

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The Roma (Gypsies) is a transnational minority with a high degree of consanguineous marriages. Similar to other genetically isolated founder populations, the Roma harbor a number of unique or rare genetic disorders. This paper discusses about a rare form of Charcot-Marie-Tooth disease – type 4G (CMT4G), also called Hereditary Motor and Sensory Neuropathy type Russe, an autosomal recessive disease caused by mutation private to Roma characterized by abnormally increased density of non-myelinated axons. CMT4G was originally found in Bulgarian Roma and in 2009 two putative causative mutations in the HK1 gene were identified. Since then, several cases were reported in Roma families mainly from Bulgaria and Spain. Here we present a Slovak Roma family in which CMT4G was diagnosed on the basis of clinical examination and genetic testing. This case is a further proof of the role of the HK1 gene in pathogenesis of the disease. It confirms that mutation in the HK1 gene is a common cause of autosomal recessive CMT disease in Roma and should be considered as a common part of a diagnostic procedure.

Keywords: gypsies, HK1, HSMN-Russe, rare disease

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Authors: Ahreum Choi, Otgontuya Tsogbadrakh, Kwang-Hwan Jung

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Microbial rhodopsins are well-known seven-transmembrane proteins that have been extensively studied. These retinal-binding proteins have divided into two types. The type I is microbial rhodopsin, and type II (visual pigment) is expressed mostly in mammalian eyes. For type I rhodopsin, there are two main functions that are ion pumping activity and sensory transduction. Anabaena sensory rhodopsin (ASR) is one of the microbial rhodopsin with main function as photo-sensory transduction. Although ASR is expressed fairly well in Escherichia coli, the expression level is relatively less compare to Proteorhodopsin. In this study, full length of ASR was used to test for the expression influence by codon usage in E. coli. Eight amino acids of codon at N-terminal part of ASR were changed randomly with designed primers, which allow 8,192 nucleotide different cases. The codon changes were screened for the preferable codons of each residue, which have given higher expression yield. Among those 57 selected mutations, there are 24 color-enhanced E. coli colonies that contain ASR proteins, and it showed better expression level than the wild type ASR codon usage. This strongly suggests that high codon usage of only partial N-terminal of protein can increase the expression level of whole protein.

Keywords: 7-transmembrane, all-trans retinal, rhodopsin, codon-usage, protein expression

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Authors: Gagandeep Singh Digra, Pawan Kumar, Mandeep Kaur Sidhu

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INTRODUCTION: Chronic Progressive External Ophthalmoplegia (CPEO), also known as Progressive External Ophthalmoplegia (PEO), is a type of eye disorder characterized by a loss of the muscle functions involved in eye and eyelid movement. CPEO can be caused by mutations in mitochondrial DNA. It typically manifests in young adults with bilateral and progressive ptosis as the most common presentation but can also present with difficulty swallowing (dysphagia) and general weakness of the skeletal muscles (myopathy), particularly in the neck, arms, or legs. CASE PRESENTATION: This is a case discussion of 3 cousins who presented to our clinic. A 23-year-old male with past surgical history (PSH) of ptosis repair 2 years ago presented with a chief complaint of nasal intonation for 1.5 years associated with difficulty swallowing. The patient also complained of nasal regurgitation of liquids. He denied any headaches, fever, seizures, weakness of arms or legs, urinary complaints or changes in bowel habits. Physical Examination was positive for facial muscle weakness, including an inability to lift eyebrows (Frontalis), inability to close eyes tightly (Orbicularis Oculi), corneal reflex absent bilaterally, difficulty clenching jaw (Masseter muscle), difficulty smiling (Zygomaticus major), inability to elevate upper lip (Zygomaticus minor). Another cousin of the first patient, a 25-year-old male with no past medical history, presented with complaints of nasal intonation for 2 years associated with difficulty swallowing. He denied a history of nasal regurgitation, headaches, fever, seizures, weakness, urinary complaints or changes in bowel habits. Physical Examination showed facial muscle weakness of the Frontalis muscle, Orbicularis Oculi muscle, Masseter Muscle, Zygomaticus Major, Zygomaticus Minor and absent corneal reflexes. A 28-year-old male, a cousin of the first two patients, presented with chief complaints of ptosis and nasal intonation for the last 8 years. He also complained of difficulty swallowing and nasal regurgitation of liquids. His physical examination showed facial muscle weakness, including frontalis muscle (inability to lift eyebrows), Orbicularis Oculi (inability to close eyes tightly), absent corneal reflexes bilaterally, Zygomaticus Major (difficulty smiling), and Zygomaticus Minor (inability to elevate upper lip). MRI brain and visual field of all the patients were normal. Differential diagnoses, including Grave’s disease, Myasthenia Gravis and Glioma, were ruled out. Due to financial reasons, muscle biopsy could not be pursued. Pedigree analysis revealed only males were affected, likely due to maternal inheritance, so the clinical diagnosis of CPEO was made. The patients underwent symptomatic management, including ptosis surgical correction for the third patient. CONCLUSION: Chronic Progressive External Ophthalmoplegia (CPEO), a rare case entity, occurs in young adults as a manifestation of mitochondrial myopathy. There are three modes of transmission- maternal transmission associated with mitochondrial point mutations, autosomal recessive, and autosomal dominant. CPEO can sometimes be difficult to diagnose, especially in asymmetric presentation. Therefore, it is crucial to keep it in differential diagnosis to avoid delay in diagnosis.

Keywords: neurology, chronic, progressive, ophthalmoplegia

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Authors: Y. Ruchi, A. Prerna, S. Deepshikha

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Amyotrophic lateral sclerosis (ALS), also known as “Lou Gehrig’s disease”. It is a neurodegenerative disease associated with degeneration of motor neurons in the cerebral cortex, brain stem, and spinal cord characterized by distal muscle weakness, atrophy, normal sensation, pyramidal signs and progressive muscular paralysis reflecting. ALS2 is a juvenile autosomal recessive disorder, slowly progressive, that maps to chromosome 2q33 and is associated with mutations in the alsin gene, a putative GTPase regulator. In this paper we have done homology modeling of alsin2 protein using multiple templates (3KCI_A, 4LIM_A, 402W_A, 4D9S_A, and 4DNV_A) designed using the Prime program in Schrödinger software. Further modeled structure is used to identify effective binding sites on the basis of structural and physical properties using sitemap program in Schrödinger software, structural and function analysis is done by using Prosite and ExPASy server that gives insight into conserved domains and motifs that can be used for protein classification. This paper summarizes the structural, functional and binding site property of alsin2 protein. These binding sites can be potential drug target sites and can be used for docking studies.

Keywords: ALS, binding site, homology modeling, neuronal degeneration

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Authors: G. V. Novikov, V. S. Sivozhelezov, S. S. Kolesnikov, K. V. Shaitan

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The study reports about the influence of binding of orthosteric ligands as well as point mutations on the conformational dynamics of β-2-adrenoreceptor. Using molecular dynamics simulation we found that there was a little fraction of active states of the receptor in its apo (ligand free) ensemble corresponded to its constitutive activity. Analysis of MD trajectories indicated that such spontaneous activation of the receptor is accompanied by the motion in intracellular part of its alpha-helices. Thus receptor’s constitutive activity directly results from its conformational dynamics. On the other hand the binding of a full agonist resulted in a significant shift of the initial equilibrium towards its active state. Finally, the binding of the inverse agonist stabilized the receptor in its inactive state. It is likely that the binding of inverse agonists might be a universal way of constitutive activity inhibition in vivo. Our results indicate that ligand binding redistribute pre-existing conformational degrees of freedom (in accordance to the Monod-Wyman-Changeux-Model) of the receptor rather than cause induced fit in it. Therefore, the ensemble of biologically relevant receptor conformations is encoded in its spatial structure, and individual conformations from that ensemble might be used by the cell in conformity with the physiological behaviour.

Keywords: seven-transmembrane receptors, constitutive activity, activation, x-ray crystallography, principal component analysis, molecular dynamics simulation

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Authors: Hanjun Zhao

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Limited efficacy of current antivirals and antiviral-resistant mutations impair anti-influenza treatment. Here, we evaluated the in vitro and in vivo antiviral effect of three defective interfering genes (DIG-3) of influenza virus. Virus replication was significantly reduced in 293T and A549 cells transfected with DIG-3. Mice transfected with DIG-3 encoded by jetPEI-vector, as prophylaxis and therapeutics against A(H7N7) virus respectively, had significantly better survivals (80% and 50%) than control mice (0%). We further developed a dual-functional peptide TAT-P1, which delivers DIG-3 with high transfection efficiency and concomitantly exerts antiviral activity by preventing endosomal acidification. TAT-P1/DIG-3 was more effective than jetPEI/DIG-3 in treating A(H7N7) or A(H1N1)pdm09-infected mice and showed potent prophylactic protection on A(H7N7) or A(H1N1)pdm09-infected mice. The addition of P1 peptide, preventing endosomal acidification, could enhance the protection of TAT-P1/DIG-3 on A(H1N1)pdm09-infected mice. Dual-functional TAT-P1 with DIG-3 can effectively protect or treat mice infected by avian and seasonal influenza virus infection.

Keywords: antiviral peptide, dual-functional peptide, defective interfering genes, influenza virus

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Authors: H. Merhni, A. Sbiti, I. Ratbi, A. Sefiani

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The proximal spinal muscular atrophy (SMA) is a group of neuromuscular disorders characterized by progressive muscle weakness due to the degeneration and loss of anterior motor neurons of the spinal cord. Depending on the age of onset of symptoms and their evolution, four types of SMA, varying in severity, result in a mutations of the SMN gene (survival of Motor neuron). We have analyzed the DNA of 295 patients referred to our genetic counseling; since January 1996 until October 2014; for suspected SMA. The homozygous deletion of exon 7 of the SMN gene was found in 133 patients; of which, 40.6% were born to consanguineous parents. In countries like Morocco, where the frequency of heterozygotes for SMA is high, genetic testing should be offered as first-line and, after careful clinical assessment, especially in newborns and infants with congenital hypotonia unexplained and prognosis compromise. The molecular diagnosis of SMA allows a quick and certainly diagnosis, provide adequate genetic counseling for families at risk and suggest, for couples who want prenatal diagnosis. The analysis of the SMN gene is a perfect example of genetic testing with an excellent cost/benefit ratio that can be of great interest in public health, especially in low-income countries. We emphasize in this work for the benefit of the generalization of molecular diagnosis of SMA by the technique of PCR-enzymatic digestion in other centers in Morocco.

Keywords: Exon7, PCR-digestion, SMA, SMN gene

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Authors: Purva Mishra, Rajesh Potlia, Kuljeet Singh Sandhu

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The role of glycyl residues in the protein structure has lingered within the research community for the last several decades. Glycyl residue is the only amino acid that is achiral due to the lack of a side chain and can, therefore, exhibit Ramachandran conformations that are disallowed for L-amino acids. The structural and functional significance of glycyl residues with L-disallowed conformation, however, remains obscure. Through statistical analysis of various datasets, we found that the glycyls with L-disallowed conformations are over-represented at disease-associated sites and tend to be evolutionarily conserved. The mutations of L-disallowed glycyls tend to destabilize the native conformation, reduce protein solubility, and promote inter-molecular aggregations. We uncovered a structural motif referred to as “β-crescent” formed around the L-disallowed glycyl, which prevents β-sheet aggregation by disrupting the alternating pattern of β-pleats. The L-disallowed conformation of glycyls also holds predictive power to infer the pathogenic missense variants. Altogether, our observations highlight that the L-disallowed conformation of glycyls is selected to facilitate native folding and prevent inter-molecular aggregations. The findings may also have implications for designing more stable proteins and prioritizing the genetic lesions implicated in diseases.

Keywords: Ramachandran plot, β-sheet, protein stability, protein aggregation

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Authors: Pritika Ramharack, Mahmoud E. S. Soliman

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The re-emerging Zika virus is an arthropod-borne virus that has been described to have explosive potential as a worldwide pandemic. The initial transmission of the virus was through a mosquito vector, however, evolving modes of transmission has allowed the spread of the disease over continents. The virus already been linked to irreversible chronic central nervous system (CNS) conditions. The concerns of the scientific and clinical community are the consequences of Zika viral mutations, thus suggesting the urgent need for viral inhibitors. There have been large strides in vaccine development against the virus but there are still no FDA-approved drugs available. Rapid rational drug design and discovery research is fundamental in the production of potent inhibitors against the virus that will not just mask the virus, but destroy it completely. In silico drug design allows for this prompt screening of potential leads, thus decreasing the consumption of precious time and resources. This study demonstrates an optimized and proven screening technique in the discovery of two potential small molecule inhibitors of Zika virus Methyltransferase and RNA-dependent RNA polymerase. This in silico “per-residue energy decomposition pharmacophore” virtual screening approach will be critical in aiding scientists in the discovery of not only effective inhibitors of Zika viral targets, but also a wide range of anti-viral agents.

Keywords: NS5 protein inhibitors, per-residue decomposition, pharmacophore model, virtual screening, Zika virus

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Authors: Christina Roman, Deepak Koirala, Joseph A. Piccirilli

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Phage displaying synthetic Fab libraries have been used to obtain Fabs that bind to specific RNA targets with high affinity and specificity. These Fabs have been demonstrated to facilitate RNA crystallization. However, the antibody framework used in the construction of these phage display libraries contains numerous bulky, flexible, and charged residues, which facilitate solubility and hinder aggregation. These residues can interfere with crystallization due to the entropic cost associated with burying them within crystal contacts. To systematically reduce the surface entropy of the Fabs and improve their crystallization properties, a protein engineering strategy termed surface entropy reduction (SER) is being applied to the Fab framework. In this approach, high entropy residues are mutated to smaller ones such as alanine or serine. Focusing initially on Fab BL3-6, which binds an RNA AAACA pentaloop with 20nM affinity, the SER P server (http://services.mbi.ucla.edu/SER/) was used and analysis was performed on existing RNA-Fab BL3-6 co-crystal structures. From this analysis twelve surface entropy reduced mutants were designed. These SER mutants were expressed and are now being measured for their crystallization and diffraction performance with various RNA targets. So far, one mutant has generated 3.02 angstrom diffraction with the yjdF riboswitch RNA. Ultimately, the most productive mutations will be combined into a new Fab framework to be used in a optimized phage displayed Fab library.

Keywords: antibody fragment, crystallography, RNA, surface entropy reduction

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Authors: Giang Tran Thi Huong, Hieu Dong Van, Tung Dao Duy, Saadanov Iskender, Isakeev Mairambek, Tsutomu Omatsu, Yukie Katayama, Tetsuya Mizutani, Yuki Ozeki, Yohei Takeda, Haruko Ogawa, Kunitoshi Imai

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Newcastle disease virus (NDV) is a contagious viral disease of the poultry industry and other birds throughout the world. At present, very little is known about molecular epidemiological data regarding the causes of ND outbreak in commercial poultry farms in Kyrgyzstan. In the current study, the NDV isolated from the one out of three samples from the unvaccinated flock was confirmed as NDV. Phylogenetic analysis indicated that this NDV strain is clustered in the Class II subgenotype VIId, and closely related to the Chinese NDV isolate. Phylogenetic analyses revealed that the isolated NDV strain has an origin different from the 4 NDV strains previously identified in Kyrgyzstan. According to the mean death time (MDT: 61.1 h) and a multibasic amino acid (aa) sequence at the F0 proteolytic cleavage site (¹¹²R-R-Q-K-R-F¹¹⁷), the NDV isolate was determined as mesogenic strain. Several mutations in the neutralizing epitopes (notably, ³⁴⁷E→K) and the global head were observed in the hemagglutinin-neuraminidase (HN) protein of the current isolate. The present study represents the molecular characterization of the coding gene region of NDV in Kyrgyzstan. Additionally, further study will be investigated on the antigenic characterization using monoclonal antibody.

Keywords: Kyrgyzstan, Newcastle disease, genotype, genome characterization

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