Search results for: multiple rare variants

Authors: Kuniyoshi Abe

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Bi-conjugate gradient (Bi-CG) is a well-known method for solving linear equations Ax = b, for x, where A is a given n-by-n matrix, and b is a given n-vector. Typically, the dimension of the linear equation is high and the matrix is sparse. A number of hybrid Bi-CG methods such as conjugate gradient squared (CGS), Bi-CG stabilized (Bi-CGSTAB), BiCGStab2, and BiCGstab(l) have been developed to improve the convergence of Bi-CG. Bi-CGSTAB has been most often used for efficiently solving the linear equation, but we have seen the convergence behavior with a long stagnation phase. In such cases, it is important to have Bi-CG coefficients that are as accurate as possible, and the stabilization strategy, which stabilizes the computation of the Bi-CG coefficients, has been proposed. It may avoid stagnation and lead to faster computation. Motivated by a large number of processors in present petascale high-performance computing hardware, the scalability of Krylov subspace methods on parallel computers has recently become increasingly prominent. The main bottleneck for efficient parallelization is the inner products which require a global reduction. The resulting global synchronization phases cause communication overhead on parallel computers. The parallel variants of Krylov subspace methods reducing the number of global communication phases and hiding the communication latency have been proposed. However, the numerical stability, specifically, the convergence speed of the parallel variants of Bi-CGSTAB may become worse than that of the standard Bi-CGSTAB. In this paper, therefore, we compare the convergence speed between the standard Bi-CGSTAB and the parallel variants by numerical experiments and show that the convergence speed of the standard Bi-CGSTAB is faster than the parallel variants. Moreover, we propose the stabilization strategy for the parallel variants.

Keywords: bi-conjugate gradient stabilized method, convergence speed, Krylov subspace methods, linear equations, parallel variant

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Authors: Vijay Kumar Kutala, Addepalli Pavani, M. Amresh Rao, Naushad Sm

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In this study, we evaluated the impact of CYP2C9*2 and CYP2C9*3 variants on binding and hydroxylation of warfarin. In silico data revealed that warfarin forms two hydrogen bonds with protein backbone i.e. I205 and S209, one hydrogen bond with protein side chain i.e. T301 and stacking interaction with F100 in CYP2C9*1. In CYP2C9*2 and CYP2C9*3 variants, two hydrogen bonds with protein backbone are disrupted. In double variant, all the hydrogen bonds are disrupted. The distances between C7 of S-warfarin and Fe-O in CYP2C9*1, CYP2C9*2, CYP2C9*3 and CYP2C9*2/*3 were 5.81A°, 7.02A°, 7.43° and 10.07°, respectively. The glide scores (Kcal/mol) were -7.698, -7.380, -6.821 and -6.986, respectively. Increase in warfarin/7-hydroxy warfarin ratio was observed with increase in variant alleles. To conclude, CYP2C9*2 and CYP2C9*3 variants result in disruption of hydrogen bonding interactions with warfarin and longer distance between C7 and Fe-O thus impairing warfarin 7-hydroxylation due to lower binding affinity of warfarin.

Keywords: warfarin, CYP2C9 polymorphism, personalized medicine, in Silico

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Authors: Mariia A. Parfenenko, Ilya S. Dantsev, Sergei V. Bochenkov, Natalia V. Vinogradova, Olga S. Groznova, Victoria Yu. Voinova

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Introduction: Autism is the most common neurodevelopmental disorder. Autism is characterized by difficulties in social interaction and adherence to stereotypic behavioral patterns and frequently co-occurs with epilepsy, intellectual disabilities, connective tissue disorders, and other conditions. CHD8 codes for chromodomain-helicase-DNA-binding protein 8 - a chromatin remodeler that regulates cellular proliferation and neurodevelopment in embryogenesis. CHD8 is one of the genes most frequently involved in autism. Patients and methods: 2 unrelated male patients, P3 and P12, aged 3 and 12 years old, underwent whole genome sequencing, which determined that they both had different likely pathogenic variants, both previously undescribed in literature. Sanger sequencing later determined that P12 inherited the variant from his affected mother. Results: P3 and P12 presented with autism, a developmental delay, ataxia, sleep disorders, overgrowth, and macrocephaly, as well as other clinical features typically present in patients with causative variants in CHD8. The mother of P12 also has autistic traits, as well as ataxia, hypotonia, sleep disorders, and other symptoms. However, P3 and P12 also have different cardiac abnormalities. P3 had signs of a repolarization disorder: a flattened T wave in the III and aVF derivations and a negative T wave in the V1-V2 derivations. He also had structural valve anomalies with associated regurgitation, local contractility impairment of the left ventricular, and diastolic dysfunction of the right ventricle. Meanwhile, P12 had Wolff-Parkinson-White syndrome and underwent radiofrequency ablation at the age of 2 years. At the time of observation, P12 had mild sinus arrhythmia and an incomplete right bundle branch block, as well as arterial hypertension. Discussion: Cardiac abnormalities were not previously reported in patients with causative variants in CHD8. The underlying mechanism for the formation of those abnormalities is currently unknown. However, the two hypotheses are either a disordered interaction with CHD7 – another chromodomain remodeler known to be directly involved in the cardiophenotype of CHARGE syndrome – a rare condition characterized by coloboma, heart defects and growth abnormalities, or the disrupted functioning of CHD8 as an A-Kinase Anchoring Protein, which are known to modulate cardiac function. Conclusion: We observed 2 unrelated autistic males with likely pathogenic variants in CHD8 that presented with typical symptoms of CHD8-related neurodevelopmental disorder, as well as cardiac abnormalities. Cardiac abnormalities have, until now, been considered uncharacteristic for patients with causative variants in CHD8. Further accumulation of data, including experimental evidence of the involvement of CHD8 in heart formation, will elucidate the mechanism underlying the cardiophenotype of those patients. Acknowledgements: Molecular genetic testing of the patients was made possible by the Charity Fund for medical and social genetic aid projects «Life Genome.»

Keywords: autism spectrum disorders, chromodomain-helicase-DNA-binding protein 8, neurodevelopmental disorder, cardio phenotype

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Authors: Hamsa T. Tayeb, Mohammad A. Arafah, Dana M. Bakheet, Duaa M. Khalaf, Agnieszka Tarnoska, Nduna Dzimiri

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Background: CYP2D6 is a member of the cytochrome P450 mixed-function oxidase system. The enzyme is responsible for the metabolism and elimination of approximately 25% of clinically used drugs, especially in breast cancer and psychiatric therapy. Different phenotypes have been described displaying alleles that lead to a complete loss of enzyme activity, reduced function (poor metabolizers – PM), hyperfunctionality (ultrarapid metabolizers–UM) and therefore drug intoxication or loss of drug effect. The prevalence of these variants may vary among different ethnic groups. Furthermore, the xTAG system has been developed to categorized all patients into different groups based on their CYP2D6 substrate metabolization. Aim of the study: To determine the prevalence of the different CYP2D6 variants in our population, and to evaluate their clinical relevance in personalized medicine. Methodology: We used the Luminex xMAP genotyping system to sequence 305 Saudi individuals visiting the Blood Bank of our Institution and determine which polymorphisms of CYP2D6 gene are prevalent in our region. Results: xTAG genotyping showed that 36.72% (112 out of 305 individuals) carried the CYP2D6_*2. Out of the 112 individuals with the *2 SNP, 6.23% had multiple copies of *2 SNP (19 individuals out of 305 individuals), resulting in an UM phenotype. About 33.44% carried the CYP2D6_*41, which leads to decreased activity of the CYP2D6 enzyme. 19.67% had the wild-type alleles and thus had normal enzyme function. Furthermore, 15.74% carried the CYP2D6_*4, which is the most common nonfunctional form of the CYP2D6 enzyme worldwide. 6.56% carried the CYP2D6_*17, resulting in decreased enzyme activity. Approximately 5.73% carried the CYP2D6_*10, consequently decreasing the enzyme activity, resulting in a PM phenotype. 2.30% carried the CYP2D6_*29, leading to decreased metabolic activity of the enzyme, and 2.30% carried the CYP2D6_*35, resulting in an UM phenotype, 1.64% had a whole-gene deletion CYP2D6_*5, thus resulting in the loss of CYP2D6 enzyme production, 0.66% carried the CYP2D6_*6 variant. One individual carried the CYP2D6_*3(B), producing an inactive form of the enzyme, which leads to decrease of enzyme activity, resulting in a PM phenotype. Finally, one individual carried the CYP2D6_*9, which decreases the enzyme activity. Conclusions: Our study demonstrates that different CYP2D6 variants are highly prevalent in ethnic Saudi Arabs. This finding sets a basis for informed genotyping for these variants in personalized medicine. The study also suggests that xTAG is an appropriate procedure for genotyping the CYP2D6 variants in personalized medicine.

Keywords: CYP2D6, hormonal breast cancer, pharmacogenetics, polymorphism, psychiatric treatment, Saudi population

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Authors: Lamis Naddaf, Yuval Tabach

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We identified missense genetic variants with the potential to enhance resistance against cancer. Such a field has not been widely explored as researchers tend to investigate the mutations that cause diseases, in response to the suffering of patients, rather than those mutations that protect from them. In conjunction with the genomic revolution and the advances in genetic engineering and synthetic biology, identifying the protective variants will increase the power of genotype-phenotype predictions and have significant implications for improved risk estimation, diagnostics, prognosis, and even personalized therapy and drug discovery. To approach our goal, we systematically investigated the sites of the coding genomes and selected the alleles that showed a correlation with the species’ cancer resistance. Interestingly, we found several amino acids that are more generally preferred (like the Proline) or avoided (like the Cysteine) by the resistant species. Furthermore, Cancer resistance in mammals and reptiles is significantly predicted by the number of the predicted protecting variants (PVs) a species has. Moreover, PVs-enriched-genes are enriched in pathways relevant to tumor suppression. For example, they are enriched in the Hedgehog signaling and silencing pathways, which its improper activation is associated with the most common form of cancer malignancy. We also showed that the PVs are mostly more abundant in healthy people compared to cancer patients within different human races.

Keywords: cancer resistance, protecting variant, naked mole rat, comparative genomics

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Authors: Rakesh Dogra, Arun Kumar, Arvind Kumar Sharma

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This paper reports the thermoluminescence as well as optical properties of rare earth doped lithium fluoride (LiF) nanophosphor, synthesized via chemical route. The rare earth impurities (Yb and Sm) have been observed to increase the deep trap center capacity, which, in turn, enhance the radiation resistance of the LiF. This suggests the viability of these materials to be used as high dose thermoluminescent detectors at high temperature. Further, optical absorption measurements revealed the formation of radiation induced stable color centers in LiF at room temperature, which are independent of the rare earth dopant.

Keywords: lithium flouride, thermoluminescence, UV-VIS spectroscopy, Gamma radiations

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Authors: D. Tohlob, E. Abo Hashem, N. Ghareeb, M. Ghanem, R. Elfarahaty, S. A. Roberts, P. Pemberton, L. Mohiyiddeen, W. G. Newman

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Gonadotropin stimulation is used in females undergoing assisted reproductive treatment for ovulation induction, but ovarian response is variable and unpredictable in these women. More effective protocols and individualization of treatment are needed to increase the success rate of IVF/ICSI cycles. We genotyped seven variants reported in previous studies to be associated with ovarian response (number of ova retrieved and total gonadotropin dose) in women undergoing IVF treatment including FSHR variants Asn 680 Ser (c.2039 A > G), Thr 307 Ala (c. 919 > A), -29 G > A, HRG c.610 C > T gene, BMP15 -9 C > G, AMH Ile 49 Ser (c.146 G > T), and AMHR -489A˃G in 118 Egyptian females attending Mansoura Integrated Fertility Center in Egypt, these females were undergoing their first cycle of controlled ovarian hyper stimulation for IVF/ICSI treatment. They were analyzed by TaqMan allelic discrimination assay in Manchester Center of Genomic Medicine. We found no evidence of any significant difference (p value < 0.05) in the number of eggs retrieved or the gonadotropin dose used between individuals in all genotypes except for HRG c.610 C > T gene polymorphism where regression analysis gives a p value of 0.04 with a fewer eggs number in TT genotyped females. These results indicate that these variants do not provide sufficient clinically relevant data to individualize the treatment protocols.

Keywords: controlled ovarian hyperstimulation, gene variants, ovarian response, assisted reproduction

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Authors: Radomir Perzina, Jaroslav Ramik

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The Analytic Hierarchy Process is frequently used approach for solving decision making problems. There exists wide range of software programs utilizing that approach. Their main disadvantage is that they are relatively expensive and missing intermediate calculations. This work introduces a Microsoft Excel add-in called DAME – Decision Analysis Module for Excel. Comparing to other computer programs DAME is free, can work with scenarios or multiple decision makers and displays intermediate calculations. Users can structure their decision models into three levels – scenarios/users, criteria and variants. Items on all levels can be evaluated either by weights or pair-wise comparisons. There are provided three different methods for the evaluation of the weights of criteria, the variants as well as the scenarios – Saaty’s Method, Geometric Mean Method and Fuller’s Triangle Method. Multiplicative and additive syntheses are supported. The proposed software package is demonstrated on couple of illustrating examples of real life decision problems.

Keywords: analytic hierarchy process, multi-criteria decision making, pair-wise comparisons, Microsoft Excel, scenarios

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Authors: B. Kahouadji, L. Guerbous, L. Lamiri, A. Mendoud

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Recently, nanomaterials are developed in the form of nano-films, nano-crystals and nano-pores. Lanthanide phosphates as a material find extensive application as laser, ceramic, sensor, phosphor, and also in optoelectronics, medical and biological labels, solar cells and light sources. Among the different kinds of rare-earth orthophosphates, yttrium orthophosphate has been shown to be an efficient host lattice for rare earth activator ions, which have become a research focus because of their important role in the field of light display systems, lasers, and optoelectronic devices. It is in this context that the 4fn- « 4fn-1 5d transitions of rare earth in insulating materials, lying in the UV and VUV, are the aim of large number of studies .Though there has been a few reports on Eu3+, Nd3+, Pr3+,Er3+, Ce3+, Tm3+ doped YPO4. The 4fn- « 4fn-1 5d transitions of the rare earth dependent to the host-matrix, several matrices ions were used to study these transitions, in this work we are suggesting to study on a very specific class of inorganic material that are orthophosphate doped with rare earth ions. This study focused on the effect of Ce3+ concentration on the structural and optical properties of Ce3+ doped YPO4 yttrium orthophosphate with powder form prepared by the Sol Gel method.

Keywords: YPO4, Ce3+, 4fn- <->4fn-1 5d transitions, scintillator

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Authors: Badis Kahouadji, Lakhdar Guerbous, Lyes Lamiri

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For many years, the luminescent materials were investigated principally in the infrared and visible areas, because the ultraviolet (UV) and especially in vacuum Ultraviolet (VUV) are technically more difficult to explore, especially absence of applications requiring of materials suitable to short wavelengths.Recent necessary, related to the development of certain technologies, encouraged research in these spectra domains. It is in this context that the 4Fn-4Fn-1 5d transitions of rare earth in insulating materials, lying in the UV and VUV, are the aim of large number of studies. These studies relate in particular to search for new scintillator materials used for spectroscopy and X-ray, ɤ, as well as medical imaging. The 4Fn- 4Fn-15d transitions of the rare earth dependent to the host-matrix, several matrices ions were used to study these transitions, in this work we are suggeting to study on a very specific class of inorganic scintillators that are orthophosphate doped with rare earth ions, this study focused on the Pr3+ concentration on the structural and optical properties of Pr3+ doped YPO4 (yttriumorthophosphate) with powder form prepared by the Sol Gel method.

Keywords: rare earth, scintillator, YPO4:Pr3+ nanophosphors, sol gel, 4Fn-4Fn-15d transitions

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Authors: N. C. van der Merwe, J. Oosthuizen, M. F. Makhetha, J. Adams, B. K. Dajee, S-R. Schneider

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Women representing high-risk breast cancer families, who tested negative for pathogenic mutations in BRCA1 and BRCA2, are four times more likely to develop breast cancer compared to women in the general population. Sequencing of genes involved in genomic stability and DNA repair led to the identification of novel contributors to familial breast cancer risk. These include BLM and PALB2. Bloom's syndrome is a rare homozygous autosomal recessive chromosomal instability disorder with a high incidence of various types of neoplasia and is associated with breast cancer when in a heterozygous state. PALB2, on the other hand, binds to BRCA2 and together, they partake actively in DNA damage repair. Archived DNA samples of 66 BRCA1/2 negative high-risk breast cancer patients were retrospectively selected based on the presence of an extensive family history of the disease ( > 3 affecteds per family). All coding regions and splice-site boundaries of both genes were screened using High-Resolution Melting Analysis. Samples exhibiting variation were bi-directionally automated Sanger sequenced. The clinical significance of each variant was assessed using various in silico and splice site prediction algorithms. Comprehensive screening identified a total of 11 BLM and 26 PALB2 variants. The variants detected ranged from global to rare and included three novel mutations. Three BLM and two PALB2 likely pathogenic mutations were identified that could account for the disease in these extensive breast cancer families in the absence of BRCA mutations (BLM c.11T > A, p.V4D; BLM c.2603C > T, p.P868L; BLM c.3961G > A, p.V1321I; PALB2 c.421C > T, p.Gln141Ter; PALB2 c.508A > T, p.Arg170Ter). Conclusion: The study confirmed the contribution of pathogenic mutations in BLM and PALB2 to the familial breast cancer burden in South Africa. It explained the presence of the disease in 7.5% of the BRCA1/2 negative families with an extensive family history of breast cancer. Segregation analysis will be performed to confirm the clinical impact of these mutations for each of these families. These results justify the inclusion of both these genes in a comprehensive breast and ovarian next generation sequencing cancer panel and should be screened simultaneously with BRCA1 and BRCA2 as it might explain a significant percentage of familial breast and ovarian cancer in South Africa.

Keywords: Bloom Syndrome, familial breast cancer, PALB2, South Africa

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Authors: Agnieszka H. Ludwig-Slomczynska, Michal T. Seweryn, Przemyslaw Kapusta, Ewelina Pitera, Katarzyna Cyganek, Urszula Mantaj, Lucja Dobrucka, Ewa Wender-Ozegowska, Maciej T. Malecki, Pawel Wolkow

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Obesity results from an imbalance between energy intake and its expenditure. Genome-Wide Association Study (GWAS) analyses have led to discovery of only about 100 variants influencing body mass index (BMI), which explain only a small portion of genetic variability. Analysis of gene epistasis gives a chance to discover another part. Since it was shown that interaction and communication between nuclear and mitochondrial genome are indispensable for normal cell function, we have looked for epistatic interactions between the two genomes to find their correlation with BMI. Methods: The analysis was performed on 366 T1DM patients using Illumina Infinium OmniExpressExome-8 chip and followed by imputation on Michigan Imputation Server. Only genes which influence mitochondrial functioning (listed in Human MitoCarta 2.0) were included in the analysis – variants of nuclear origin (MAF > 5%) in 1140 genes and 42 mitochondrial variants (MAF > 1%). Gene expression analysis was performed on GTex data. Association analysis between genetic variants and BMI was performed with the use of Linear Mixed Models as implemented in the package 'GENESIS' in R. Analysis of association between mRNA expression and BMI was performed with the use of linear models and standard significance tests in R. Results: Among variants involved in epistasis between mitochondria and nucleus we have identified one in mitochondrial transcription factor, TFB2M (rs6701836). It interacted with mitochondrial variants localized to MT-RNR1 (p=0.0004, MAF=15%), MT-ND2 (p=0.07, MAF=5%) and MT-ND4 (p=0.01, MAF=1.1%). Analysis of the interaction between nuclear variant rs6701836 (nuc) and rs3021088 localized to MT-ND2 mitochondrial gene (mito) has shown that the combination of the two led to BMI decrease (p=0.024). Each of the variants on its own does not correlate with higher BMI [p(nuc)=0.856, p(mito)=0.116)]. Although rs6701836 is intronic, it influences gene expression in the thyroid (p=0.000037). rs3021088 is a missense variant that leads to alanine to threonine substitution in the MT-ND2 gene which belongs to complex I of the electron transport chain. The analysis of the influence of genetic variants on gene expression has confirmed the trend explained above – the interaction of the two genes leads to BMI decrease (p=0.0308). Each of the mRNAs on its own is associated with higher BMI (p(mito)=0.0244 and p(nuc)=0.0269). Conclusıons: Our results show that nuclear-mitochondrial epistasis can influence BMI in T1DM patients. The correlation between transcription factor expression and mitochondrial genetic variants will be subject to further analysis.

Keywords: body mass index, epistasis, mitochondria, type 1 diabetes

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Authors: Arati Inamdar, Siddharth Bhattacharyya, Kester Haye

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Collision tumors are rare entities characterized by neoplasms of two different cell populations with distinct separating boundaries. Such tumors could be benign, malignant, or a combination of both. The exact mechanism of origin for collision tumors is predicted to be tumor heterogeneity or concurrent occurrence of neoplasm in the same organ. We present two cases of plasmacytoma presenting as a collision tumor, one with a tumor of hematological origin and another with a non-hematological origin, namely Chronic Lymphocytic Leukemia and Adenocarcinoma of the colon, respectively. The immunohistochemical stains and flowcytometry analysis performed on the specimens aided incorrect diagnosis. Interestingly, neoplastic cells of plasmacytoma in the first case demonstrated strong cytokeratin along with weak Epithelial Specific Antigen/ Epithelial cell adhesion molecule Monoclonal Antibody (MOC31) positivity, indicating that the tumor may influence the microenvironment of the tumor in the vicinity. Furthermore, the next-generation sequencing studies performed on the specimen with plasmacytoma and chronic lymphocytic lymphoma demonstrated BReast CAncer gene (BRCA2) and Tumor Necrosis Factor Alpha Induced Protein 3 (TNFAIP3) as a disease associated variants suggestive of risk for multiple tumors including collision tumors. Our reports highlight the unique collision tumors involving plasmacytoma, which have never been reported previously, as well as provide necessary insights about the underline genetic aberrations and tumor heterogeneity through sequencing studies and allow clonality assessment for subsequent tumors.

Keywords: BRCA2, collision tumor, chronic lymphocytic leukemia, plasmacytoma

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Authors: F. Brunke, L. Waalkes, C. Siemers

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Due to reduced stiffness, research on second generation titanium alloys for implant applications, like the metastable β-titanium alloy Ti-15Mo, become more and more important in the recent years. The machinability of these alloys is generally poor leading to problems during implant production and comparably large production costs. Therefore, in the present study, Ti 15Mo was alloyed with 0.8 wt.-% of the rare earth metals lanthanum (Ti-15Mo+0.8La) and neodymium (Ti-15Mo+0.8Nd) to improve its machinability. Their microstructure consisted of a titanium matrix and micrometer-size particles of the rare earth metals and two of their oxides. The particles stabilized the micro structure as grain growth was minimized. As especially the ductility might be affected by the precipitates, the behavior of Ti-15Mo+0.8La and Ti-15Mo+0.8Nd was investigated during static and dynamic deformation at elevated temperature to develop a processing route. The resulting mechanical properties (static strength and ductility) were similar in all investigated alloys.

Keywords: Ti 15Mo, titanium alloys, rare earth metals, free machining alloy

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Authors: Ahmed Tarek, Ahmed Alveed

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In the theory of computing, there are a wide variety of direct and indirect proof techniques. However, mathematical induction (MI) stands out to be one of the most powerful proof techniques for proving hypotheses, theorems, and new results. There are variations of mathematical induction-based proof techniques, which are broadly classified into three categories, such as structural induction (SI), weak induction (WI), and strong induction (SI). In this expository paper, several different variants of the mathematical induction techniques are explored, and the specific scenarios are discussed where a specific induction technique stands out to be more advantageous as compared to other induction strategies. Also, the essential difference among the variants of mathematical induction are explored. The points of separation among mathematical induction, recursion, and logical deduction are precisely analyzed, and the relationship among variations of recurrence relations, and mathematical induction are being explored. In this context, the application of recurrence relations, and mathematical inductions are considered together in a single framework for codewords over a given alphabet.

Keywords: alphabet, codeword, deduction, mathematical, induction, recurrence relation, strong induction, structural induction, weak induction

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Authors: Julianto Agung Saputro, Jogiyanto Hartono

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Multiple valuation is widely used by investors and practitioners but its accuracy is questionable. Multiple valuation inaccuracies are due to the unreliability of information used in valuation, inaccuracies comparison group selection, and use of individual multiple values. This study investigated the accuracy of valuation to examine factors that can increase the accuracy of the valuation of multiple ratios, that are discretionary accruals, the comparison group, and the composite of multiple valuation. These results indicate that multiple value adjustment method with discretionary accruals provides better accuracy, the industry comparator group method combined with the size and growth of companies also provide better accuracy. Composite of individual multiple valuation gives the best accuracy. If all of these factors combined, the accuracy of valuation of multiple ratios will give the best results.

Keywords: multiple, valuation, composite, accuracy

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Authors: M. Ridwanul Hassan, Samuel George

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Aims: Steroid injections are commonly used as a diagnostic tool or an alternative to surgical management of carpal tunnel syndrome (CTS) and are generally safe. Ischaemia is a rare complication with very few cases reported in the literature. Methods: We report a case of a 50-year-old female that presented with a necrotic wound to her left palm one month after a steroid injection into the carpal tunnel. She had a 2-year history of CTS in her left hand that was treated with six previous steroid injections in primary care during this period. The wound evolved from a blister to a necrotic ulcer which led to a painful, hollow defect in the centre of her palm. She did not report any history of trauma, nor did she have any co-morbidities. Clinical photographs were taken. Results: On examination, she had a 0.5 cmx1 cm defect in the palm of her left hand down to aponeurosis. There was purulent discharge in the wound with surrounding erythema but no spreading cellulitis. She had full function of her fingers but was very tender on movements and at rest. She was admitted for intravenous antibiotics and underwent a debridement, washout, and carpal tunnel release the next day. The defect was packed to heal by secondary intention and has now fully healed one month following her operation. Conclusions: This is an extremely rare complication of steroid injections to the carpal tunnel and may have been avoided by earlier referral for surgery rather than treatment using multiple steroid injections.

Keywords: hand surgery, complication, rare, carpal tunnel syndrome

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Authors: Sara A. Al-Jaberi, Salma Ben-Salem, Meriam Messedi, Fatma Ayadi, Lihadh Al-Gazali, Bassam R. Ali

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Background: The chemokine receptor components play crucial roles in the immune system and some of them serve as co-receptors for the HIV virus. Several studies have documented those variants in chemokine receptors are correlated with susceptibility and resistance to infection with HIV virus. For example, mutations in the chemokine receptor 5 gene (CCR5) resulting in loss-of-function (such as the homozygous CCR5Δ32) confer high degree of resistance to HIV infection. Heterozygotes for these variants exhibit slow progression to AIDS. The prevalence of CCR5 polymorphisms varies among ethnic and geographical groups. For example, the CCR5 Δ32 variant is present in 10–15% of north Europeans but is rarely encountered among Africans. This study aims to identify the prevalence of some CCR5 variants in two geographically distant Arab populations (namely Emiratis and Tunisians). Methodology: The prevalence of CCR5 gene variants including CCR5Δ32, FS299, C101X, A29S and C178R has been determined using PCR and direct DNA sequencing. A total of 403 unrelated healthy individuals (253 Emiratis and 150 Tunisians) were genotyped for the CCR5Δ32 variant using PCR amplification and gel electrophoresis. In addition, 200 Emiratis have been screened for other SNPs using Sanger DNA sequencing. Results: Among Emiratis, the allele frequency of the CCR5Δ32 variant has been found to be 0.002. In addition, two variants L55Q and A159 were found at a frequency of 0.002.Moreover, the prevalence of the CCR5Δ32 variant in Tunisians was estimated to be 0.013 which is relatively higher than its frequency in Emiratis but lower than Europeans. Conclusion: We conclude that the allele frequency of the most critical CCR5 polymorphism (Δ32) is extremely low among Emiratis compared to other Arabs and North Europeans. In addition, very low allele frequencies of other CCR5 polymorphisms have been detected among Emiratis.

Keywords: chemokine receptors, CCR5Δ32, CCR5 polymorphisms, Emiratis, Arab populations

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Authors: Nam-Kuk Kim, Jin Kim, Soomin Park, Changhee Lee, Mijin Chu, Seong-Hun Lee

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In this study, we conducted whole genome re-sequencing of 10 cultivars originated from five countries including Korea, China, India, Pakistan and Ethiopia with Sesamum indicum (Zhongzho No. 13) genome as a reference. Almost 80% of the whole genome sequences of the reference genome could be covered by sequenced reads. Numerous SNP and InDel were detected by bioinformatic analysis. Among these variants, 266,051 SNPs were identified as unique to countries. Pakistan and Ethiopia had high densities of SNPs compared to other countries. Three main clusters (cluster 1: Korea, cluster 2: Pakistan and India, cluster 3: Ethiopia and China) were recovered by neighbor-joining analysis using all variants. Interestingly, some variants were detected in DGAT1 (diacylglycerol O-acyltransferase 1) and FADS (fatty acid desaturase) genes, which are known to be related with fatty acid synthesis and metabolism. These results can provide useful information to understand the regional characteristics and develop DNA markers for origin discrimination of sesame.

Keywords: Sesamum indicum, NGS, SNP, DNA marker

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Authors: Raghvendra Singh Yadav, Ivo Kuřitka, Jaromir Havlica, Zuzana Kozakova, Jiri Masilko, Lukas Kalina, Miroslava Hajdúchová, Vojtěch Enev, Jaromir Wasserbauer

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In this work, we investigated the structural and magnetic properties of CoFe2O4:Nd3+/Dy3+/Pr3+/Gd3+ nanoparticles synthesized by starch-assisted sol-gel combustion method. X-ray diffraction pattern confirmed the formation of cubic spinel structure of rare-earth ions (Nd3+, Dy3+, Pr3+, Gd3+) doped CoFe2O4 spinel ferrite nanoparticles. Raman and Fourier Transform Infrared spectroscopy study also confirmed cubic spinel structure of rare-earth ions (Nd3+, Dy3+, Pr3+, Gd3+) substituted CoFe2O4 nanoparticles. The field emission scanning electron microscopy study revealed the effect of annealing temperature on size of rare-earth ions (Nd3+, Dy3+, Pr3+, Gd3+) substituted CoFe2O4 nanoparticles and particles were in the range of 10-100 nm. The magnetic properties of rare-earth ions (Nd3+, Dy3+, Pr3+, Gd3+) substituted CoFe2O4 nanoparticles were investigated by using vibrating sample magnetometer. The variation in saturation magnetization, coercivity and remanent magnetization with annealing temperature/ particle size of rare-earth ions (Nd3+, Dy3+, Pr3+, Gd3+) substituted CoFe2O4 nanoparticles was observed. Acknowledgment: This work was supported by the Ministry of Education, Youth and Sports of the Czech Republic – Program NPU I (LO1504).

Keywords: starch, sol-gel combustion method, rare-earth ions, spinel ferrite nanoparticles, magnetic properties

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Authors: Raffaele A. Calogero

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RNAseq represents an attractive methodology for the detection of functional genomic variants. RNAseq results obtained from polyA+ RNA selection protocol (POLYA) and from exonic regions capturing protocol (ACCESS) indicate that ACCESS detects 10% more coding SNV/INDELs with respect to POLYA. ACCESS requires less reads for coding SNV detection with respect to POLYA. However, if the analysis aims at identifying SNV/INDELs also in the 5’ and 3’ UTRs, POLYA is definitively the preferred method. No particular advantage comes from ACCESS or POLYA in the detection of fusion transcripts.

Keywords: fusion transcripts, INDEL, RNA-seq, WES, SNV

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Authors: H. Sakamoto, S. Kurosawa, M. Suzuki, S. Oguri

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In Arabidopsis, several genes encoding proteins with ankyrin repeats and trans-membrane domains (AtANKTM) have been identified as mediators of biotic and abiotic stress responses. It has been known that the expression of an AtANKTM gene, At2g24600, is induced in response to abiotic stress and that there are four splicing variants derived from this locus. In this study, by RT-PCR and sequencing analysis, an unknown splicing variant of the At2g24600 transcript was identified. Based on differences in the predicted amino acid sequences, the five splicing variants are divided into three groups. The three predicted proteins are highly homologous, yet have different numbers of ankyrin repeats and trans-membrane domains. It is generally considered that ankyrin repeats mediate protein-protein interaction and that the number of trans-membrane domains affects membrane topology of proteins. The protein variants derived from the At2g24600 locus may have different molecular functions each other.

Keywords: alternative splicing, ankyrin repeats, trans-membrane domains, arabidopsis

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Authors: Josselyn Mata Calidonio, Arianna I. Maddox, Kimberly Hamad-Schifferli

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Rapid diagnostics are critical infectious disease tools that are designed to detect a known biomarker using antibodies specific to that biomarker. However, a way to detect unknown viruses has not yet been achieved in a paper test format. We describe here a route to make an adaptable paper immunoassay that can detect an unknown biomarker, demonstrating it on SARS-CoV-2 variants. The immunoassay repurposes cross-reactive antibodies raised against the alpha variant. Gold nanoparticles of two different colors conjugated to two different antibodies create a colorimetric signal, and machine learning of the resulting colorimetric pattern is used to train the assay to discriminate between variants of alpha and Omicron BA.5. By using principal component analysis, the colorimetric test patterns can pick up and discriminate an unknown that it has not encountered before, Omicron BA.1. The test has an accuracy of 100% and a potential calculated discriminatory power of 900. We show that it can be used adaptively and that it can be used to pick up emerging variants without the need to raise new antibodies.

Keywords: adaptive immunoassay, detecting unknown viruses, gold nanoparticles, paper immunoassay, repurposing antibodies

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Authors: Rohit Kothari, Muneer Mohamed, Vivekanandh K., Sunmeet Sandhu, Preema Sinha, Anuj Bhatnagar

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Introduction: Hyper-IgE syndrome is a rare primary immunodeficiency syndrome characterised by triad of severe atopic dermatitis, recurrent pulmonary infections, and recurrent staphylococcal skin infections. The diagnosis requires a high degree of suspicion, typical clinical features, and not mere rise in serum-IgE levels, which may be seen in multiple conditions. Genetic studies are not always possible in a resource poor setting. This study highlights various presentations of Hyper-IgE syndrome in skin of color children. Case-series: Our study had six children of Hyper-IgE syndrome aged twomonths to tenyears. All had onset in first ten months of life except one with a late-onset at two years. All had recurrent eczematoid rash, which responded poorly to conventional treatment, secondary infection, multiple episodes of hospitalisation for pulmonary infection, and raised serum IgE levels. One case had occasional vesicles, bullae, and crusted plaques over both the extremities. Genetic study was possible in only one of them who was found to have pathogenic homozygous deletions of exon-15 to 18 in DOCK8 gene following which he underwent bone marrow transplant (BMT), however, succumbed to lower respiratory tract infection two months after BMT and rest of them received multiple courses of antibiotics, oral/ topical steroids, and cyclosporine intermittently with variable response. Discussion: Our study highlights various characteristics, presentation, and management of this rare syndrome in children. Knowledge of these manifestations in skin of color will facilitate early identification and contribute to optimal care of the patients as representative data on the same is limited in literature.

Keywords: absolute eosinophil count, atopic dermatitis, eczematous rash, hyper-immunoglobulin E syndrome, pulmonary infection, serum IgE, skin of color

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Authors: U. Arjun, K. Brinda, M. Padmanabhan, R. Nath

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Polycrystalline samples of rare-earth oxy-carbonates Ln2O2CO3 (Ln = Nd, Sm, and Dy) are synthesized, and their structural and magnetic properties are investigated. All of them crystallize in a hexagonal structure with space group P6_3/mmc. They form a double layered structure with frustrated triangular arrangement of rare-earth magnetic ions. An antiferromagnetic transition is observed at TN ≈ 1.25 K, 0.61 K, and 1.21 K for Nd2O2CO3, Sm2O2CO3, and Dy2O2CO3, respectively. From the analysis of magnetic susceptibility, the value of the Curie-Weiss temperature θ_CW is obtained to be ≈ 21.7 K, 18 K, and 10.6 K for Nd2O2CO3, Sm2O2CO3, and Dy2O2CO3, respectively. The magnetic frustration parameter f ( = |θ_CW|/T_N) is calculated to be ≈ 17.4, 31, and 8.8 for Nd2O2CO3, Sm2O2CO3, and Dy2O2CO3, respectively which indicates that Sm2O2CO3 is strongly frustrated compared to its Nd and Dy analogues.

Keywords: chemical synthesis, exchange and superexchange, heat capacity, magnetically ordered materials

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Authors: Steven Robinson, Adriana Dager, Param Patel

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Wandering spleen is a rare variant where there is abnormal development of the ligamentous peritoneal attachments of the spleen which normally anchor it in the left upper quadrant of the abdomen. Ligamentous abnormalities can be congenital, or acquired through pregnancy, injury, or iatrogenic causes. Absence or laxity of these ligaments allows migration of the spleen into ectopic portions of the abdomen, which is also associated with an elongated vascular pedicle. Incidence of wandering spleen is reported at less than 0.25% with a female to male ratio of approximately 6:1. The most common complication of a wandering spleen is torsion around its vascular pedicle which can lead to thrombosis and infarction. Torsion of a wandering spleen is a rare but important cause of an acute abdomen. Imaging, and specifically CT or ultrasound, is crucial in the diagnosis. We present a case of a torsed wandering spleen which was treated with splenectomy.

Keywords: Wandering Spleen, Torsion, Splenic Torsion, Spleen

Procedia PDF Downloads 57

Authors: Camilla Trevor, Matthew K. Higgins, Andrea Gonzalez-Munoz, Mark Carrington

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Trypanosomiasis is a devastating disease affecting both humans and livestock in sub-Saharan Africa. The diseases are caused by infection with African trypanosomes, protozoa transmitted by tsetse flies. Treatment currently relies on the use of chemotherapeutics with ghastly side effects. Here, we describe the development of effective antibody-drug conjugates that target the T. brucei transferrin receptor. The receptor is essential for trypanosome growth in a mammalian host but there are approximately 12 variants of the transferrin receptor in the genome. Two of the most divergent variants were used to generate recombinant monoclonal immunoglobulin G using phage display and we identified cross-reactive antibodies that bind both variants using phage ELISA, fluorescence resonance energy transfer assays and surface plasmon resonance. Fluorescent antibodies were used to demonstrate uptake into trypanosomes in culture. Toxin-conjugated antibodies were effective at killing trypanosomes at sub-nanomolar concentrations. The approach of using antibody-drug conjugates has proven highly effective.

Keywords: antibody-drug conjugates, phage display, transferrin receptor, trypanosomes

Procedia PDF Downloads 139

Authors: S. Mohamed, D. Gonzalez, C. Sayada, P. Halfon

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Drug resistance mutations are routinely detected using standard Sanger sequencing, which does not detect minor variants with a frequency below 20%. The impact of detecting minor variants generated by ultra-deep sequencing (UDS) on HIV drug-resistance (DR) interpretations has not yet been studied. Fifty HIV-1 patients who experienced virological failure were included in this retrospective study. The HIV-1 UDS protocol allowed the detection and quantification of HIV-1 protease and reverse transcriptase variants related to genotypes A, B, C, E, F, and G. DeepChek®-HIV simplified DR interpretation software was used to compare Sanger sequencing and UDS. The total time required for the UDS protocol was found to be approximately three times longer than Sanger sequencing with equivalent reagent costs. UDS detected all of the mutations found by population sequencing and identified additional resistance variants in all patients. An analysis of DR revealed a total of 643 and 224 clinically relevant mutations by UDS and Sanger sequencing, respectively. Three resistance mutations with > 20% prevalence were detected solely by UDS: A98S (23%), E138A (21%) and V179I (25%). A significant difference in the DR interpretations for 19 antiretroviral drugs was observed between the UDS and Sanger sequencing methods. Y181C and T215Y were the most frequent mutations associated with interpretation differences. A combination of UDS and DeepChek® software for the interpretation of DR results would help clinicians provide suitable treatments. A cut-off of 1% allowed a better characterisation of the viral population by identifying additional resistance mutations and improving the DR interpretation.

Keywords: HIV-1, ultra-deep sequencing, Sanger sequencing, drug resistance

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Authors: E. L. Albuquerque, U. L. Fulco, G. S. Ourique

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The focus of this work is on the numerical investigation of the charge transport properties of the de novo-designed alpha3 polypeptide, as well as in its variants, all of them probed by gene engineering. The theoretical framework makes use of a tight-binding model Hamiltonian, together with ab-initio calculations within quantum chemistry simulation. The alpha3 polypeptide is a 21-residue with three repeats of the seven-residue amino acid sequence Leu-Glu-Thr-Leu-Ala-Lys-Ala, forming an alpha–helical bundle structure. Its variants are obtained by Ala→Gln substitution at the e (5th) and g (7th) position, respectively, of the alpha3 polypeptide amino acid sequence. Using transmission electron microscopy and atomic force microscopy, it was observed that the alpha3 polypeptide and one of its variant do have the ability to form fibrous assemblies, while the other does not. Our main aim is to investigate whether or not the biased alpha3 polypeptide and its variants can be also identified by quantum charge transport measurements through current-voltage (IxV) curves as a pattern to characterize their fibrous assemblies. It was observed that each peptide has a characteristic current pattern, which may be distinguished by charge transport measurements, suggesting that it might be a useful tool for the development of biosensors.

Keywords: charge transport properties, electronic transmittance, current-voltage characteristics, biological sensor

Procedia PDF Downloads 654

Authors: Saeb Ahmadi, Mohsen Vafaie Sefti, Mohammad Mahdi Shadman, Ebrahim Tangestani

Abstract:

Carbon nanotube has shown great potential for the removal of various inorganic and organic components due to properties such as large surface area and high adsorption capacity. Central composite design is widely used method for determining optimal conditions. Also due to the economic reasons and wide application, the rare earth elements are important components. The analyses of cerium (Ce(III)) adsorption as one of the Rare Earth Elements (REEs) adsorption on Multiwall Carbon Nanotubes (MWCNTs) have been studied. The optimization process was performed using Response Surface Methodology (RSM). The optimum amount conditions were pH of 4.5, initial Ce (III) concentration of 90 mg/l and MWCNTs dosage of 80 mg. Under this condition, the optimum adsorption percentage of Ce (III) was obtained about 96%. Next, at the obtained optimum conditions the kinetic and isotherm studied and result showed the pseudo-second order and Langmuir isotherm are more fitted with experimental data than other models.

Keywords: cerium, rare earth element, MWCNTs, adsorption, optimization

Procedia PDF Downloads 147