Search results for: mutation.

Authors: M. M. Essa, S. Subash, M. Akbar, S. Al-Adawi, A. Al-Asmi, G. J. Guillemein

Abstract:

Objective: Transgenic (tg) mice which contain an amyloid precursor protein (APP) gene mutation, develop extracellular amyloid beta (Aβ) deposition in the brain, and severe memory and behavioural deficits with age. These mice serve as an important animal model for testing the efficacy of novel drug candidates for the treatment and management of symptoms of Alzheimer's disease (AD). Several reports have suggested that oxidative stress is the underlying cause of Aβ neurotoxicity in AD. Pomegranates contain very high levels of antioxidants and several medicinal properties that may be useful for improving the quality of life in AD patients. In this study, we investigated the effect of dietary supplementation of Omani pomegranate extract on the memory, anxiety and learning skills along with inflammation in an AD mouse model containing the double Swedish APP mutation (APPsw/Tg2576). Methods: The experimental groups of APP-transgenic mice from the age of 4 months were fed custom-mix diets (pellets) containing 4% pomegranate. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety-related behavior in Tg and wild-type mice at the age of 4-5 months and 18-19 months using the Morris water maze test, rota rod test, elevated plus maze test, and open field test. Further, inflammatory parameters also analysed. Results: APPsw/Tg2576 mice that were fed a standard chow diet without pomegranates showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial learning ability, position discrimination learning ability and motor coordination along with increased inflammation compared to the wild type mice on the same diet, at the age of 18-19 months In contrast, APPsw/Tg2576 mice that were fed a diet containing 4% pomegranates showed a significant improvements in memory, learning, locomotor function, and anxiety with reduced inflammatory markers compared to APPsw/Tg2576 mice fed the standard chow diet. Conclusion: Our results suggest that dietary supplementation with pomegranates may slow the progression of cognitive and behavioural impairments in AD. The exact mechanism is still unclear and further extensive research needed.

Keywords: Alzheimer's disease, pomegranates, oman, cognitive decline, memory loss, anxiety, inflammation

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Authors: Abishek Rajkumar

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Antibiotic resistance can occur naturally given the selective pressure placed on antibiotics. Within a large population of bacteria, there is a significant chance that some of those bacteria can develop resistance via mutations or genetic recombination. However, a growing public health concern has arisen over the fact that antibiotic resistance has increased significantly over the past few decades. This is because humans have been over-consuming and producing antibiotics, which has ultimately accelerated the antibiotic resistance seen in these bacteria. The product of all of this is an ongoing race between scientists and the bacteria as bacteria continue to develop resistance, which creates even more demand for an antibiotic that can still terminate the newly resistant strain of bacteria. This paper will focus on a myriad of aspects of antibiotic resistance in bacteria starting with how it occurs on a molecular level and then focusing on the antibiotic concentrations and how they affect the resistance and fitness seen in bacteria.

Keywords: antibiotic, molecular, mutation, resistance

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Authors: Mike Wei, Nebu Koshy, Koen van Besien, Giorgio Inghirami, Steven M. Horwitz

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T-cell prolymphocytic leukemia (T-PLL) is a rare hematologic disease characterized by a T-cell phenotype, rapid progression, and poor prognosis with median survival of less than a year. Alemtuzumab-based chemotherapy has increased the rate of complete remissions but these are often short-lived, and allogeneic transplant is considered the only curative therapy. In recent studies, JAK3 activating mutations have been identified in T-cell cancers, with T-PLL having the highest rate of JAK3 mutations (30 – 42%). As such, T-PLL is a model disease for evaluating the utility of JAK3 inhibitors. We present a case of a 64-year-old man with relapsed-refractory T-PLL. He was initially treated with alemtuzumab and obtained complete response and was consolidated with matched unrelated donor stem cell transplant. His disease stayed in remission for approximately 1.5 years before relapse, which was then treated with a clinical trial of romidepsin-lenalidomide (partial responses then progression at 6 months) and later alemtuzumab. Due to complications of myelosuppression and CMV reactivation, his treatment was interrupted leading to disease progression. The doubling time of lymphocyte count was approximately 20 days and over a span of 60 days the lymphocyte count rose from 8 x 109/L to 68 x 109/L. Exon sequencing showed a JAK3 mutation. The patient consented to and was treated with FDA-approved tofacitinib (initially 5 mg BID, increased to 10 mg BID after 15 days of treatment). An initial decrease in lymphocyte count was followed by progression. In vitro treatment of the patient’s cells showed modest effects of tofacitinib and ruxolitinib as single agents, in the range of doxorubicin, but synergy between the agents. After 40 days of treatment with tofacitinib and with a lymphocyte count of 150 x 109/L, ruxolitinib (5mg BID) was added. Over the 60 days since dual inhibition was started, the lymphocyte count has stabilized. The patient has remained completely asymptomatic during treatment with tofacitinib and ruxolitinib. Neutrophil count has remained normal. Platelet count and hemoglobin have however declined from ~50 x109/L to ~30 x109/L and from 11 g/dL to 8.1 g/dL respectively, since the introduction of ruxolitinib. The stabilization in lymphocyte count confirms the clinical activity of JAK inhibitors in T-PLL as suggested by the presence of JAK3 mutations and by in-vitro assays. It also suggests clinical synergy between ruxolitinib and tofacitinib in this setting. Prospective studies of JAK inhibitors in PLL patients with formal dose-finding studies are needed.

Keywords: tofacitinib, ruxolitinib, T-cell prolymphocytic leukemia, JAK3

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Authors: M. M. Essa, S. Subash, M. Akbar, S. Al-Adawi, A. Al-Asmi, G. J. Guillemein

Abstract:

Transgenic (tg) mice which contain an amyloid precursor protein (APP) gene mutation, develop extracellular amyloid beta (Aβ) deposition in the brain, and severe memory and behavioral deficits with age. These mice serve as an important animal model for testing the efficacy of novel drug candidates for the treatment and management of symptoms of Alzheimer's disease (AD). Several reports have suggested that oxidative stress is the underlying cause of Aβ neurotoxicity in AD. Date palm fruits contain very high levels of antioxidants and several medicinal properties that may be useful for improving the quality of life in AD patients. In this study, we investigated the effect of dietary supplementation of Omani date palm fruits on the memory, anxiety and learning skills along with inflammation in an AD mouse model containing the double Swedish APP mutation (APPsw/Tg2576). The experimental groups of APP-transgenic mice from the age of 4 months were fed custom-mix diets (pellets) containing 2% and 4% Date palm fruits. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety-related behavior in Tg and wild-type mice at the age of 4-5 months and 18-19 months using the Morris water maze test, rota rod test, elevated plus maze test, and open field test. Further, inflammatory parameters also analyzed. APPsw/Tg2576 mice that were fed a standard chow diet without dates showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial learning ability, position discrimination learning ability and motor coordination along with increased inflammation compared to the wild type mice on the same diet, at the age of 18-19 months In contrast, PPsw/Tg2576 mice that were fed a diet containing 2% and 4% dates showed a significant improvements in memory, learning, locomotor function, and anxiety with reduced inflammatory markers compared to APPsw/Tg2576 mice fed the standard chow diet. Our results suggest that dietary supplementation with dates may slow the progression of cognitive and behavioral impairments in AD. The exact mechanism is still unclear and further extensive research needed.

Keywords: Alzheimer's disease, date palm fruits, Oman, cognitive decline, memory loss, anxiety, inflammation

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Authors: Wissam Saliba, Mandy Nicholson

Abstract:

Secretory carcinoma (SC) is a rare type of salivary gland cancer. It was first realized as a distinct type of malignancy in 2010and wasinitially termed “mammary analogue secretory carcinoma” because of similarities with secretory breast cancer. The name was later changed to SC. Most SCs originate in parotid glands, and most harbour a rare gene mutation: ETV6-NTRK3. This mutation is rare in common cancers and common in rare cancers; it is present in most secretory carcinomas. Disease outcomes for SC are usually described as favourable as many cases of SC are lowgrade (LG), and cancer growth is slow. In early stages, localized therapy is usually indicated (surgery and/or radiation). Despitea favourable prognosis, a sub-set of casescan be much more aggressive.These cases tend to be of high-grade(HG).HG casesare associated with a poorer prognosis.Management of such cases can be challenging due to limited evidence for effective systemic therapy options. This case report describes the clinical management of a 46-year-oldmale patient with a unique case of SC. He was initially diagnosed with a low/intermediate grade carcinoma of the left parotid gland in 2009; he was treated with surgery and adjuvant radiation. Surgical pathology favoured primary salivary adenocarcinoma, and 2 lymph nodes were positive for malignancy. SC was not yet realized as a distinct type of cancerat the time of diagnosis, and the pathology reportvalidated this gap by stating that the specimen lacked features of the defined types of salivary carcinoma.Slow-growing pulmonary nodules were identified in 2017. In 2020, approximately 11 years after the initial diagnosis, the patient presented with malignant pleural effusion. Pathology from a pleural biopsy was consistent with metastatic poorly differentiated cancer of likely parotid origin, likely mammary analogue secretory carcinoma. The specimen was sent for Next Generation Sequencing (NGS); ETV6-NTRK3 gene fusion was confirmed, and systemic therapy was initiated.One cycle ofcarboplatin/paclitaxel was given in June 2020. He was switched to Larotrectinib (NTRK inhibitor (NTRKi)) later that month. Larotrectinib continued for approximately 9 months, with discontinuation in March 2021 due to disease progression. A second-generation NTRKi (Selitrectinib) was accessed and prescribedthrough a single patient study. Selitrectinib was well tolerated. The patient experienced a complete radiological response within~4 months. Disease progression occurred once again in October 2021. Progression was slow, and Selitrectinib continuedwhile the medical team performed a thorough search for additional treatment options. In January 2022, a liver lesion biopsy was performed, and NGS showed an NTRKG623R solvent-front resistance mutation. Various treatment pathways were considered. The patient pursuedanother investigational NTRKi through a clinical trial, and Selitrectinib was discontinued in July 2022. Excellent performance status was maintained throughout the entire course of treatment.It can be concluded that NTRK inhibitors provided satisfactory treatment efficacy and tolerance for this patient with high-grade transformation and NTRK gene fusion cancer. In the future, more clinical research is needed on systemic treatment options for high-grade transformations in NTRK gene fusion SCs.

Keywords: secretory carcinoma, high-grade transformations, NTRK gene fusion, NTRK inhibitor

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Authors: Salina Y. Saddick

Abstract:

Mild gestational hyperglycemia (MGH) is a very common complication of pregnancy that is characterized by intolerance to glucose. The association of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism to MGH has been previously reported. In this study, we evaluated the association between ACE polymorphism and the risk of MGH in a Saudi population. We conducted a case-control study in a population of 100 MGH patients and 100 control subjects. ACE gene polymorphism was analyzed by the novel approach of tetraprimer amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR). The frequency of ACE polymorphism was not associated with either alleles or genotypes in MGH patients. Glucose concentration was found to be significantly associated with the MGH group. Our study suggests that ACE genotypes were not associated with ACE polymorphism in a Saudi population.

Keywords: MGH, ACE, insertion polymorphism, deletion polymorphism

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Authors: Khaleel Saleh Al-Rababah

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Amyloid fibril forming regions, which are known as protein aggregates, in sequences of some protein families are associated with a number of diseases known as amyloidosis. Mutations play a role in forming fibrils by accelerating the fibril formation process. In this paper we want to extract diseases that caused by those mutations as a result of the impact of the mutations on structural and functional properties of the aggregated protein. We propose a text mining system, to automatically extract mutations, diseases and relations between mutations and diseases. We presented an algorithm based on finite state to cluster mutations found in the same sentence as a sentence could contain different mutation cause different diseases. Also, we presented a co reference algorithm that enables cross-link sentences.

Keywords: amyloid, amyloidosis, co reference, protein, text mining

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Authors: Hammoudi Abderazek

Abstract:

The present paper introduces a modified adaptive mixed differential evolution (MAMDE) to select the main geometry parameters of specific cylindrical spur gear. The developed algorithm used the self-adaptive mechanism in order to update the values of mutation and crossover factors. The feasibility rules are used in the selection phase to improve the search exploration of MAMDE. Moreover, the elitism is performed to keep the best individual found in each generation. For the constraints handling the normalization method is used to treat each constraint design equally. The finite element analysis is used to confirm the optimization results for the maximum bending resistance. The simulation results reached in this paper indicate clearly that the proposed algorithm is very competitive in precision gear design optimization.

Keywords: evolutionary algorithm, spur gear, tooth profile, meta-heuristics

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Authors: Yakup Ulusu, Numan Eczacıoğlu, İsa Gökçe, Helen Waller, Jeremy H. Lakey

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Besides having the appropriate amino acid sequence to perform the function of proteins, it is important to have correct conformation after this sequence to process. To consist of this conformation depends on the amino acid sequence at the primary structure, hydrophobic interaction, chaperones and enzymes in charge of folding etc. Misfolded proteins are not functional and tend to be aggregated. Cysteine originating disulfide cross-links make stable this conformation of functional proteins. When two of the cysteine amino acids come side by side, disulfide bond is established that forms a cystine bridge. Due to this feature cysteine plays an important role on the formation of three-dimensional structure of many proteins. There are two cysteine amino acids (C44, C69) in the Tol-A-III protein. Unlike protein disulfide bonds from within his own, any non-specific cystine bridge causes a change in the three dimensional structure of the protein. Proteins can be expressed in various host cells as directly or fusion (chimeric). As a result of overproduction of the recombinant proteins, aggregation of insoluble proteins in the host cell can occur by forming a crystal structure called inclusion body. In general fusion proteins are produced for provide affinity tags to make proteins more soluble and production of some toxic proteins via fusion protein expression system like pTolT. Proteins can be modified by using a site-directed mutagenesis. By this way, creation of non-specific disulfide crosslinks can be prevented at fusion protein expression system via the present cysteine replaced by another amino acid such as serine, glycine or etc. To do this, we need; a DNA molecule that contains the gene that encodes for the target protein, required primers for mutation to be designed according to site directed mutagenesis reaction. This study was aimed to be replaced cysteine encoding codon TGT with serine encoding codon AGT. For this sense and reverse primers designed (given below) and used site-directed mutagenesis reaction. Several new copy of the template plasmid DNA has been formed with above mentioned mutagenic primers via polymerase chain reaction (PCR). PCR product consists of both the master template DNA (wild type) and the new DNA sequences containing mutations. Dpn-l endonuclease restriction enzyme which is specific for methylated DNA and cuts them to the elimination of the master template DNA. E. coli cells obtained after transformation were incubated LB medium with antibiotic. After purification of plasmid DNA from E. coli, the presence of the mutation was determined by DNA sequence analysis. Developed this new plasmid is called PtolT-δ.

Keywords: site directed mutagenesis, Escherichia coli, pTolT, protein expression

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Authors: Sanjay Kumar Parjapati, Ajai Jain

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This paper presents optimization of makespan for ‘n’ jobs and ‘m’ machines flexible job shop scheduling problem with sequence dependent setup time using genetic algorithm (GA) approach. A restart scheme has also been applied to prevent the premature convergence. Two case studies are taken into consideration. Results are obtained by considering crossover probability (pc = 0.85) and mutation probability (pm = 0.15). Five simulation runs for each case study are taken and minimum value among them is taken as optimal makespan. Results indicate that optimal makespan can be achieved with more than one sequence of jobs in a production order.

Keywords: flexible job shop, genetic algorithm, makespan, sequence dependent setup times

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Authors: Alexandru-Ion Marinescu

Abstract:

There exist a plethora of methods in the scientific literature which tackle the well-established task of credit score evaluation. In its most abstract form, a credit scoring algorithm takes as input several credit applicant properties, such as age, marital status, employment status, loan duration, etc. and must output a binary response variable (i.e. “GOOD” or “BAD”) stating whether the client is susceptible to payment return delays. Data imbalance is a common occurrence among financial institution databases, with the majority being classified as “GOOD” clients (clients that respect the loan return calendar) alongside a small percentage of “BAD” clients. But it is the “BAD” clients we are interested in since accurately predicting their behavior is crucial in preventing unwanted loss for loan providers. We add to this whole context the constraint that the algorithm must yield an actual, tractable mathematical formula, which is friendlier towards financial analysts. To this end, we have turned to genetic algorithms and genetic programming, aiming to evolve actual mathematical expressions using specially tailored mutation and crossover operators. As far as data representation is concerned, we employ a very flexible mechanism – LINQ expression trees, readily available in the C# programming language, enabling us to construct executable pieces of code at runtime. As the title implies, they model trees, with intermediate nodes being operators (addition, subtraction, multiplication, division) or mathematical functions (sin, cos, abs, round, etc.) and leaf nodes storing either constants or variables. There is a one-to-one correspondence between the client properties and the formula variables. The mutation and crossover operators work on a flattened version of the tree, obtained via a pre-order traversal. A consequence of our chosen technique is that we can identify and discard client properties which do not take part in the final score evaluation, effectively acting as a dimensionality reduction scheme. We compare ourselves with state of the art approaches, such as support vector machines, Bayesian networks, and extreme learning machines, to name a few. The data sets we benchmark against amount to a total of 8, of which we mention the well-known Australian credit and German credit data sets, and the performance indicators are the following: percentage correctly classified, area under curve, partial Gini index, H-measure, Brier score and Kolmogorov-Smirnov statistic, respectively. Finally, we obtain encouraging results, which, although placing us in the lower half of the hierarchy, drive us to further refine the algorithm.

Keywords: expression trees, financial credit scoring, genetic algorithm, genetic programming, symbolic evolution

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Authors: Amit Chaudhary, B. S. Yadav, P. K. Maurya, A. M., S. Srivastava, S. Singh, A. Mani

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Cold shock protein A (CspA) is major cold inducible protein present in Escherichia coli. The protein is involved in stabilizing secondary structure of RNA by working as chaperone during cold temperature. Two RNA binding motifs play key role in the stabilizing activity. This study aimed to investigate implications of low temperature on structure and RNA binding activity of E. coli CspA. Molecular dynamics simulations were performed to compare the stability of the protein at 37°C and 10 °C. The protein was mutated at RNA binding motifs and docked with RNA to assess the stability of both complexes. Results suggest that CspA as well as CspA-RNA complex is more stable at low temperature. It was also confirmed that RNP1 and RNP2 play key role in RNA binding.

Keywords: CspA, homology modelling, mutation, molecular dynamics simulation

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Authors: Wafa’ Alma'Aitah, Khaled Almakadmeh

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this study presents an information retrieval system of using genetic algorithm to increase information retrieval efficiency. Using vector space model, information retrieval is based on the similarity measurement between query and documents. Documents with high similarity to query are judge more relevant to the query and should be retrieved first. Using genetic algorithms, each query is represented by a chromosome; these chromosomes are fed into genetic operator process: selection, crossover, and mutation until an optimized query chromosome is obtained for document retrieval. Results show that information retrieval with adaptive crossover probability and single point type crossover and roulette wheel as selection type give the highest recall. The proposed approach is verified using (242) proceedings abstracts collected from the Saudi Arabian national conference.

Keywords: genetic algorithm, information retrieval, optimal queries, crossover

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Authors: Wafa' Alsharafat, Suhila Farhan Abu-Owida

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Genetic algorithm (GA) is a powerful evolutionary searching technique that is used successfully to solve and optimize problems in different research areas. Genetic Algorithm (GA) considered as one of optimization methods used to solve Travel salesman Problem (TSP). The feasibility of GA in finding a TSP solution is dependent on GA operators; encoding method, population size, termination criteria, in general. In specific, crossover and its probability play a significant role in finding possible solutions for Symmetric TSP (STSP). In addition, the crossover should be determined and enhanced in term reaching optimal or at least near optimal. In this paper, we spot the light on using a modified crossover method called modified sequential constructive crossover and its impact on reaching optimal solution. To justify the relevance of a parameter value in solving the TSP, a set comparative analysis conducted on different crossover methods values.

Keywords: genetic algorithm, crossover, mutation, TSP

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Authors: H. Kishor, G. Prabhuling, D. S. Ambika, D. P. Prakash

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The chemical mutagens have become important tool to enhance agronomic traits of banana crop. It is being used to develop fusarium resistance lines in various susceptible banana cultivars. There are several mutagens like EMS and NaN3 available for banana crop improvement and each mutagen has its own important role as positive or negative effects on growth and development of banana plants. Explants from shoot tip culture were treated with various EMS (0.30, 0.60, 0.90 and 0.12%) and NaN3 (0.01, 0.02 and 0.03%) concentrations. The putative mutants obtained after in vitro rooting were subjected for artificial inoculation of Fusarium oxysporum f.sp. cubense. Screening putative mutants resistance to Panama disease was carried out by using syringe method of inoculation. It was observed that, EMS treated mutants were more susceptible compared to NaN3 treatment. Among the NaN3 doses 0.01% found to produce 3 resistant lines during preliminary screening under greenhouse conditions.

Keywords: Nanjangud rasabale, EMS, NaN3, putative mutants

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Authors: Mafalda Moreira, Diana Alba, Inês Paiva Ferreira, Rita Calejo, Ana Rita Soares, Leonilde Machado

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Intellectual disability (ID) is characterized by deficits in intellectualfunctioningassociatedwithalterations in the adaptive behaviour, whose onset is inthedevelopmentalperiod. Itaffects 3% of the population, ofwhich 10% have a geneticaetiology. One of those causes isAlwadeiSyndrome, with 3 cases describedworldwide. It results from a homozygous nonsense mutation in theRUSC2 gene andisassociatedwithintellectualdisabilityanddysmorphic facialfeatures. Theauthorsreportthe case of a 5-year-old-boy, born to a healthymotherafter a full-termuneventfulpregnancy, thatwasreferred to Neurodevelopmentalconsultationdue toglobal developmentaldelay. Familyhistoryrevealedlearningdifficulties in the paternal brotherhood. Milddismorphicfeatureswereevidentsuch as darkinfraorbitalregion, low-set ears, beakednose, retrognathism, high-archedpalateandjointhyperlaxity. WechslerIntelligenceScale for Children III fullscaleIQ quoted 61. Karyotypeandchromosomalmicroarrayanalysiswerenormal, as well as the fragile X molecular study. DNA sequencingwasthenperformedandallowedtheidentificationof amutation in the RUSC2 gene. Theetiologicaldiagnosisof ID remains unknown in up to 80% of cases, creatinguncertainty in children’sfamilies. Theadvances in DNA sequencingtechnologieshaveincreasedourknowledgeofthegeneticdiseasesinvolved, as theAlwadeisyndromewasonlydescribedsince 2016. Thegeneticdiagnosisof ID allowsfamilygeneticcounselingandenablesthedevelopmentof target therapeutic approaches.

Keywords: intellectual disability, genetic aetiology, alwadei syndrome, RUSC2

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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: Rasime Kalkan, Emine Ikbal Atli, Ali Arslantaş, Muhsin Özdemir, Sevilhan Artan

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Glioblastoma (WHO grade IV), is the malignant form of brain tumor, the genetic background of the GBM is highly variable. The tumor mass of a GBM is multilayered and every tumor layer shows distinct characteristics with a different cell population. The treatment planning of GBM should be focused on the tumor genetic characteristics. We screened primary glioblastoma multiforme (GBM) in a population-based study for MGMT and RARβ methylation and IDH1 mutation correlated them with clinical data and treatment. There was no correlation between MGMT-promoter methylation and overall survival. The overall survival time of the patients with methylated RARβ was statically (OS;p<0,05) significance between the patients who were treated with chemotherapy and radiotherapy. Here we showed the status of IDH1 gene associatied with younger age. We demonstrated that the together with MGMT gene the RARβ gene should be used as a potantial treatment decision marker for GBMs.

Keywords: RARβ, primary glioblastoma multiforme, methylation, MGMT

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Authors: Yu Pu, Chien-Ping Hsiao, Chien-Chang Huang, Chieh-Lun Cheng

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Free radicals can accelerate aging on human skin by causing lipid oxidation, protein denaturation, and even DNA mutation. Substances with the ability of anti-free radicals can be used as functional components in cosmetic products. Research are attracted to develop new anti-free radical components for cosmetic application. This study was aimed to evaluate the microbial metabolites on free radical scavenging ability. Two microorganisms, PU-01 and PU-02, were isolated from soil of hot spring environment and grew in LB agar at 50°C for 24 h. The suspension was collected by centrifugation at 4800 g for 3 min, The anti-free radical activity was determined by DPPH (1,1-diphenyl-2-picrylhydrazyl) scavenging assay. The result showed that the growth medium of PU-01 presented a higher DPPH scavenging effect than that of PU-02. This study presented potential anti-free radical components from microbial metabolites that might be applied in anti-aging cosmetics.

Keywords: anti-ageing, anti-free radical, biotechnology, microorganism

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Authors: Aydin Teymourifar, Gurkan Ozturk, Ozan Bahadir

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NSGA-II is one of the most well-known and most widely used evolutionary algorithms. In addition to its new versions, such as NSGA-III, there are several modified types of this algorithm in the literature. In this paper, a hybrid NSGA-II algorithm has been suggested for solving the multi-objective flexible job shop scheduling problem. For a better search, new neighborhood-based crossover and mutation operators are defined. To create new generations, the neighbors of the selected individuals by the tournament selection are constructed. Also, at the end of each iteration, before sorting, neighbors of a certain number of good solutions are derived, except for solutions protected by elitism. The neighbors are generated using a constraint-based neural network that uses various constructs. The non-dominated sorting and crowding distance operators are same as the classic NSGA-II. A comparison based on some multi-objective benchmarks from the literature shows the efficiency of the algorithm.

Keywords: flexible job shop scheduling problem, multi-objective optimization, NSGA-II algorithm, neighborhood structures

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Authors: Sirous Eydivandi

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Diacylglycerol-O-acyltransferase (DGAT1) gene encodes diacylglycerol transferase enzyme that plays an important role in glycerol lipid metabolism. DGAT1 is considered to be the key enzyme in controlling the synthesis of triglycerides in adipocytes. This enzyme catalyzes the final step of triglyceride synthesis (transform triacylglycerol (DAG) into triacylglycerol (TAG). A total of 20 DGAT1 gene sequences and corresponding amino acids belonging to 4 species include cattle, goats, sheep and yaks were analyzed, and the differentiation within and among the species was also studied. The length of the DGAT1 gene varies greatly, from 1527 to 1785 bp, due to deletion, insertion, and stop codon mutation resulting in elongation. Observed genetic diversity was higher among species than within species, and Goat had more polymorphisms than any other species. Novel amino acid variation sites were detected within several species which might be used to illustrate the functional variation. Differentiation of the DGAT1 gene was obvious among species, and the clustering result was consistent with the taxonomy in the National Center for Biotechnology Information.

Keywords: DGAT1gene, bioinformatic, ruminnants, biotechnology information

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Authors: Syed Talib Abbas Raza, Tahseen Ahmed Jilani, Saleem Abdullah

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This paper presents interval-valued intuitionistic fuzzy soft sets based TOPSIS method for group decision making. The interval-valued intuitionistic fuzzy soft set is a mutation of an interval-valued intuitionistic fuzzy set and soft set. In group decision making problems IVIFSS makes the process much more algebraically elegant. We have used weighted arithmetic averaging operator for aggregating the information and define a new Hybrid Score Function as metric tool for comparison between interval-valued intuitionistic fuzzy values. In an illustrative example we have applied the developed method to a criminological problem. We have developed a group decision making model for integrating the imprecise and hesitant evaluations of multiple law enforcement agencies working on target killing cases in the country.

Keywords: group decision making, interval-valued intuitionistic fuzzy soft set, TOPSIS, score function, criminology

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Authors: Biswabandhu Bankura, Srikanta Guria, Madhusudan Das

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Purpose: Thyroid peroxidase (TPO) is the key enzyme in the biosynthesis of thyroid hormones. We aimed to identify the spectrum of mutations in the TPO gene leading to hypothyroidism in the population of West Bengal to establish the genetic etiology of the disease. Methods: 200 hypothyroid patients (case) and their corresponding sex and age matched 200 normal individuals (control) were screened depending on their clinical manifestations. Genomic DNA was isolated from peripheral blood samples and TPO gene (Exon 7 to Exon 14) was amplified by PCR. The PCR products were subjected to sequencing to identify mutations. Results: Single nucleotide changes such as Glu 641 Lys, Asp 668 Asn, Thr 725 Pro, Asp 620 Asn, Ser 398 Thr, and Ala 373 Ser were found. Changes in the TPO were assayed in vitro to compare mutant and wild-type activities. Five mutants were enzymatically inactive in the guaiacol and iodide assays. This is a strong indication that the mutations are present at crucial positions of the TPO gene, resulting in inactivated TPO. Key Findings: The results of this study may help to develop a genetic screening protocol for goiter and hypothyroidism in the population of West Bengal.

Keywords: thyroid peroxidase, hypothyroidism, mutation, in vitro assay, transfection

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Authors: Biswabandhu Bankura, Srikanta Guria, Madhusudan Das

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Purpose: Thyroid peroxidase (TPO) is the key enzyme in the biosynthesis of thyroid hormones. We aimed to identify the spectrum of mutations in the TPO gene leading to hypothyroidism in the population of West Bengal to establish the genetic etiology of the disease. Methods: 200 hypothyroid patients (case) and their corresponding sex and age matched 200 normal individuals (control) were screened depending on their clinical manifestations. Genomic DNA was isolated from peripheral blood samples and TPO gene (Exon 7 to Exon 14) was amplified by PCR. The PCR products were subjected to sequencing to identify mutations. Results: Single nucleotide changes such as Glu 641 Lys, Asp 668 Asn, Thr 725 Pro, Asp 620 Asn, Ser 398 Thr, and Ala 373 Ser were found. Changes in the TPO were assayed in vitro to compare mutant and wild-type activities. Five mutants were enzymatically inactive in the guaiacol and iodide assays. This is a strong indication that the mutations are present at crucial positions of the TPO gene, resulting in inactivated TPO. Key Findings: The results of this study may help to develop a genetic screening protocol for goiter and hypothyroidism in the population of West Bengal.

Keywords: thyroid peroxidase, hypothyroidism, mutation, in vitro assay, transfection

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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: Abdelhadi Adel, Kadri Ouahab

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This paper proposes an improved approach based on MAS Architecture and Heuristic Algorithm for systematic maintenance to minimize makespan. We have implemented a problem-solving approach for optimizing the processing time, methods based on metaheuristics. The proposed approach is inspired by the behavior of the human body. This hybridization is between a multi-agent system and inspirations of the human body, especially genetics. The effectiveness of our approach has been demonstrated repeatedly in this paper. To solve such a complex problem, we proposed an approach which we have used advanced operators such as uniform crossover set and single point mutation. The proposed approach is applied to three preventive maintenance policies. These policies are intended to maximize the availability or to maintain a minimum level of reliability during the production chain. The results show that our algorithm outperforms existing algorithms. We assumed that the machines might be unavailable periodically during the production scheduling.

Keywords: multi-agent systems, emergence, genetic algorithm, makespan, systematic maintenance, scheduling, hybrid flow shop scheduling

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Authors: Abiodun Ladanu Ajala, Wuyi Oke

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Mathematical simulation and optimization models packaged within interactive computer programs provide a common way for planners and managers to predict the behaviour of any proposed water resources system design or management policy before it is implemented. Modeling presents a principal technique of predicting the behaviour of the proposed infrastructural designs or management policies. Models can be developed and used to help identify specific alternative plans that best meet those objectives. This study discusses various types of models, their development, architecture, data requirements, and applications in the field of engineering. It also outlines the advantages and limitations of each the optimization and simulation models presented. The techniques explored in this review include; dynamic programming, linear programming, fuzzy optimization, evolutionary algorithms and finally artificial intelligence techniques. Previous studies carried out using some of the techniques mentioned above were reviewed, and most of the results from different researches showed that indeed optimization and simulation provides viable alternatives and predictions which form a basis for decision making in building engineering structures and also in engineering planning and management.

Keywords: linear programming, mutation, optimization, simulation

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Authors: Malik SS, Masood N, Mubarik S, Khadim TM

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Introduction: Xeroderma pigmentosum group G (XPG) gene plays a crucial role in the correction of UV-induced DNA damage through nucleotide excision repair pathway. Single nucleotide polymorphisms in XPG gene have been reported to be associated with different cancers. Current case-control study was designed to evaluate the relationship between one of the most frequently found XPG (rs1047768 T>C) polymorphism and breast cancer risk. Methodology: A total of 200 individuals were screened for this polymorphism including 100 pathologically confirmed breast cancer cases and age-matched 100 controls. Genotyping was carried out using Tetra amplification-refractory mutation system (ARMS) PCR and results were confirmed by gel electrophoresis. Results: Conditional logistic regression analysis showed significant association between TC genotype (OR: 8.9, CI: 2.0 – 38.7) and increased breast cancer risk. Although homozygous CC genotype was more frequent in patients as compared to controls, but it was statistically non-significant (OR: 3.9, CI: 0.4 – 35.7). Conclusion: In conclusion, XPG (rs1047768 T>C) polymorphism may contribute towards increased risk of breast cancer but other polymorphisms may also be evaluated to elucidate their role in breast cancer.

Keywords: XPG, breast cancer, NER, ARMS-PCR

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Authors: Mei Chen, Yingping Hou, Michelle Hao, Soheil Aghamohammadzadeh, Esteban Terzo, Roger Clark, Vijay Modur

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Background: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genetic skin condition characterized by skin tearing and unremitting blistering upon minimal trauma. Repeated blistering, fibrosis, and scarring lead to aggressive squamous cell carcinoma later in life. RDEB is caused by mutations in the COL7A1 gene encoding collagen type VII (C7), the major component of anchoring fibrils mediating epidermis-dermis adherence. Nonsense mutations in the COL7A1 gene of a subset of RDEB patients leads to premature termination codons (PTC). Similarly, most Junctional Epidermolysis Bullosa (JEB) cases are caused by nonsense mutations in the LAMB3 gene encoding the β3 subunit of laminin 332. Currently, there is an unmet need for the treatment of RDEB and JEB. Zikani Therapeutics has discovered an array of macrocyclic compounds with ring structures similar to macrolide antibiotics that can facilitate readthrough activity of nonsense mutations in the COL7A1 and LAMB3 genes by acting as Ribosome Modulating Agents (RMAs). The medicinal chemistry synthetic advancements of these macrocyclic compounds have allowed targeting the human ribosome while preserving the structural elements responsible for the safety and pharmacokinetic profile of clinically used macrolide antibiotics. Methods: C7 expression was used as a measure of readthrough activity by immunoblot assays in two primary human fibroblasts from RDEB patients (R578X/R578X and R163X/R1683X-COL7A1). Similarly, immunoblot assays in C325X/c.629-12T > A-LAMB3 keratinocytes were used to measure readthrough activity for JEB. The relative readthrough activity of each compound was measured relative to Gentamicin. An imaging-based fibroblast migration assay was used as an assessment of C7 functionality in RDEB-fibroblasts over 16-20 hrs. The incubation period for the above experiments was 48 hrs for RDEB fibroblasts and 72 hours for JEB keratinocytes. Results: 9 RMAs demonstrated increased protein expression in both patient RDEB fibroblasts. The highest readthrough activity at tested concentrations without cytotoxicities increased protein expression up to 179% of Gentamicin (400 µg/ml), with favored readthrough activity in R163X/R1683X-COL7A1 fibroblasts. Concurrent with protein expression, fibroblast hypermotility phenotype observed in RDEB was rescued by reducing motility by ~35% to WT levels (the same level as 690 µM Gentamicin treated cells). Laminin β3 expression was also shown to be increased by 6 RMAs in keratinocytes to 33-83% of (400 µg/ml) Gentamicin. Conclusions: To date, 9 RMAs have been identified that enhance the expression of functional C7 in a mutation-dependent manner in two different RDEB patient fibroblast backgrounds (R578X/R578X and R163X/R1683X-COL7A1). A further 6 RMAs have been identified that enhance the readthrough of C325X-LAMB3 in JEB patient keratinocytes. Based on the clinical trial conducted by us with topical gentamycin in 2017, Zikani’s RMAs achieve clinically significant levels of read-through for the treatment of recessive dystrophic and Junctional Epidermolysis Bullosa.

Keywords: epidermolysis bullosa, nonsense mutation, readthrough, ribosome modulation

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Authors: Salma M. Wakil

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Advances in the field of genetics overwhelmed detecting large number of inherited disorders at the molecular level and directed to the development of innovative technologies. These innovations have led to gene sequencing, prenatal mutation detection, pre-implantation genetic diagnosis; population based carrier screening and genome wide analyses using microarrays. Microarrays are widely used in establishing clinical and diagnostic setup for genetic anomalies at a massive level, with the advent of cytoscan molecular karyotyping as a clinical utility card for detecting chromosomal aberrations with high coverage across the entire human genome. Unlike a regular karyotype that relies on the microscopic inspection of chromosomes, molecular karyotyping with cytoscan constructs virtual chromosomes based on the copy number analysis of DNA which improves its resolution by 100-fold. We have been investigating a large number of patients with Developmental Delay and Intellectual disability with this platform for establishing micro syndrome deletions and have detected number of novel CNV’s in the Arabian population with the clinical relevance.

Keywords: microarrays, molecular karyotyping, developmental delay, genetics

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