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  • 1
    Article
    Article
    Anopheles metabolic proteins in malaria transmission, prevention and control: a review
    2020
    ISSN: 1756-3305 
    Details
    Language: English
    In: Parasites & vectors, 2020-09-10, Vol.13 (1), p.465-465
    Description: The increasing resistance to currently available insecticides in the malaria vector, Anopheles mosquitoes, hampers their use as an effective vector control strategy for the prevention of malaria transmission. Therefore, there is need for new insecticides and/or alternative vector control strategies, the development of which relies on the identification of possible targets in Anopheles. Some known and promising targets for the prevention or control of malaria transmission exist among Anopheles metabolic proteins. This review aims to elucidate the current and potential contribution of Anopheles metabolic proteins to malaria transmission and control. Highlighted are the roles of metabolic proteins as insecticide targets, in blood digestion and immune response as well as their contribution to insecticide resistance and Plasmodium parasite development. Furthermore, strategies by which these metabolic proteins can be utilized for vector control are described. Inhibitors of Anopheles metabolic proteins that are designed based on target specificity can yield insecticides with no significant toxicity to non-target species. These metabolic modulators combined with each other or with synergists, sterilants, and transmission-blocking agents in a single product, can yield potent malaria intervention strategies. These combinations can provide multiple means of controlling the vector. Also, they can help to slow down the development of insecticide resistance. Moreover, some metabolic proteins can be modulated for mosquito population replacement or suppression strategies, which will significantly help to curb malaria transmission.
    Subject(s): Acetylcholinesterase ; Animals ; Anopheles - drug effects ; Anopheles - genetics ; Anopheles - metabolism ; Anopheles - parasitology ; Humans ; Immune response ; Insect Proteins - genetics ; Insect Proteins - metabolism ; Insecticide ; Insecticide Resistance ; Insecticides - pharmacology ; Malaria - parasitology ; Malaria - prevention & control ; Malaria - transmission ; Mosquito Control ; Mosquito Vectors - drug effects ; Mosquito Vectors - genetics ; Mosquito Vectors - metabolism ; Mosquito Vectors - parasitology ; Plasmodium ; Plasmodium - physiology ; Review ; Vector control
    ISSN: 1756-3305
    E-ISSN: 1756-3305
    DOI: 10.1186/s13071-020-04342-5
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    URL: https://www.ncbi.nlm.nih.gov/pubmed/32912275$$D View this record in MEDLINE/PubMed
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  • 2
    Article
    Article
    Essential gene prediction in Drosophila melanogaster using machine learning approaches based on sequence and functional features
    2020
    ISSN: 2001-0370 
    Details
    Language: English
    In: Computational and structural biotechnology journal, 2020, Vol.18, p.612-621
    Description: [Display omitted] Genes are termed to be essential if their loss of function compromises viability or results in profound loss of fitness. On the genome scale, these genes can be determined experimentally employing RNAi or knockout screens, but this is very resource intensive. Computational methods for essential gene prediction can overcome this drawback, particularly when intrinsic (e.g. from the protein sequence) as well as extrinsic features (e.g. from transcription profiles) are considered. In this work, we employed machine learning to predict essential genes in Drosophila melanogaster. A total of 27,340 features were generated based on a large variety of different aspects comprising nucleotide and protein sequences, gene networks, protein-protein interactions, evolutionary conservation and functional annotations. Employing cross-validation, we obtained an excellent prediction performance. The best model achieved in D. melanogaster a ROC-AUC of 0.90, a PR-AUC of 0.30 and a F1 score of 0.34. Our approach considerably outperformed a benchmark method in which only features derived from the protein sequences were used (P 〈 0.001). Investigating which features contributed to this success, we found all categories of features, most prominently network topological, functional and sequence-based features. To evaluate our approach we performed the same workflow for essential gene prediction in human and achieved an ROC-AUC = 0.97, PR-AUC = 0.73, and F1 = 0.64. In summary, this study shows that using our well-elaborated assembly of features covering a broad range of intrinsic and extrinsic gene and protein features enabled intelligent systems to predict well the essentiality of genes in an organism.
    Subject(s): Drosophila ; Essential genes ; Essentiality prediction ; Homo sapiens ; Lethal ; Machine-learning
    ISSN: 2001-0370
    E-ISSN: 2001-0370
    DOI: 10.1016/j.csbj.2020.02.022
    Source: PubMed Central
    URL: https://www.ncbi.nlm.nih.gov/pubmed/32257045$$D View this record in MEDLINE/PubMed
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  • 3
    Article
    Article
    SOPH syndrome in three affected individuals showing similarities with progeroid cutis laxa conditions in early infancy
    2019
    ISSN: 1434-5161 
    Details
    Language: English
    In: Journal of human genetics, 2019-07-01, Vol.64 (7), p.609-616
    Description: Individuals affected with autosomal recessive cutis laxa type 2B and 3 usually show translucent skin with visible veins and abnormal elastic fibers, intrauterine and/or postnatal growth restriction and a typical triangular facial gestalt. Here we describe three unrelated individuals in whom such a cutis laxa syndrome was suspected, especially after electron microscopy revealed immature and less dense dermal elastic fibers in one of them. However, one of these children also displayed optic atrophy and two hypogammaglobulinemia. All had elevated liver enzymes and acute liver failure during febrile episodes leading to early demise in two of them. The only surviving patient had been treated with immunoglobulins. Through exome sequencing we identified mutations in NBAS, coding for a protein involved in Golgi-to-ER transport. NBAS deficiency causes several rare conditions ranging from isolated recurrent acute liver failure to a multisystem disorder mainly characterized by short stature, optic nerve atrophy and Pelger-Huet anomaly (SOPH). Since we subsequently verified PelgerHuet anomaly in two of the patients the diagnosis SOPH syndrome was unequivocally proven. Our data show that SOPH syndrome can be regarded as a differential diagnosis for the progeroid forms of cutis laxa in early infancy and that possibly treatment of the hypogammaglobulinemia can be of high relevance for the prognosis.
    Subject(s): Agammaglobulinemia - blood ; Agammaglobulinemia - physiopathology ; Atrophy ; Cutis Laxa - diagnosis ; Cutis Laxa - genetics ; Cutis Laxa - pathology ; Diagnosis, Differential ; Differential diagnosis ; Elastic Tissue - ultrastructure ; Electron microscopy ; Enzymes ; Fibers ; Genetics ; Genetics & Heredity ; Golgi apparatus ; Growth Disorders - diagnosis ; Growth Disorders - genetics ; Growth Disorders - pathology ; Humans ; Hypogammaglobulinemia ; Immunoglobulins ; Infant ; Life Sciences & Biomedicine ; Liver ; Liver - enzymology ; Liver - pathology ; Liver diseases ; Male ; Mutation ; Neoplasm Proteins - genetics ; Neuroblastoma ; Optic atrophy ; Optic nerve ; Optic Nerve Diseases - diagnosis ; Optic Nerve Diseases - genetics ; Optic Nerve Diseases - pathology ; Pediatrics ; Pelger-Huet Anomaly - diagnosis ; Pelger-Huet Anomaly - genetics ; Pelger-Huet Anomaly - pathology ; Progeria - diagnosis ; Progeria - genetics ; Protein transport ; Proteins ; Science & Technology ; Skin ; Skin - pathology ; Syndrome ; Whole Exome Sequencing ; Young Adult
    ISSN: 1434-5161
    E-ISSN: 1435-232X
    DOI: 10.1038/s10038-019-0602-8
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Alma/SFX Local Collection
    URL: https://www.ncbi.nlm.nih.gov/pubmed/31015584$$D View this record in MEDLINE/PubMed
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  • 4
    Article
    Article
    Predicting host dependency factors of pathogens in Drosophila melanogaster using machine learning
    2021
    ISSN: 2001-0370 
    Details
    Language: English
    In: Computational and structural biotechnology journal, 2021, Vol.19, p.4581-4592
    Description: [Display omitted] Pathogens causing infections, and particularly when invading the host cells, require the host cell machinery for efficient regeneration and proliferation during infection. For their life cycle, host proteins are needed and these Host Dependency Factors (HDF) may serve as therapeutic targets. Several attempts have approached screening for HDF producing large lists of potential HDF with, however, only marginal overlap. To get consistency into the data of these experimental studies, we developed a machine learning pipeline. As a case study, we used publicly available lists of experimentally derived HDF from twelve different screening studies based on gene perturbation in Drosophila melanogaster cells or in vivo upon bacterial or protozoan infection. A total of 50,334 gene features were generated from diverse categories including their functional annotations, topology attributes in protein interaction networks, nucleotide and protein sequence features, homology properties and subcellular localization. Cross-validation revealed an excellent prediction performance. All feature categories contributed to the model. Predicted and experimentally derived HDF showed a good consistency when investigating their common cellular processes and function. Cellular processes and molecular function of these genes were highly enriched in membrane trafficking, particularly in the trans-Golgi network, cell cycle and the Rab GTPase binding family. Using our machine learning approach, we show that HDF in organisms can be predicted with high accuracy evidencing their common investigated characteristics. We elucidated cellular processes which are utilized by invading pathogens during infection. Finally, we provide a list of 208 novel HDF proposed for future experimental studies.
    Subject(s): Bacteria ; Drosophila ; Host factors ; Infection ; Knockout screen ; Machine learning
    ISSN: 2001-0370
    E-ISSN: 2001-0370
    DOI: 10.1016/j.csbj.2021.08.010
    Source: PubMed Central
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  • 5
    Article
    Article
    Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations
    2007
    ISSN: 0022-2593  ISSN: 1468-6244 
    Details
    Language: English
    In: Journal of medical genetics, 2007-02, Vol.44 (2), p.131-135
    Description: Background: Noonan syndrome, cardio-facio-cutaneous syndrome (CFC) and Costello syndrome constitute a group of developmental disorders with an overlapping pattern of congenital anomalies. Each of these conditions can be caused by germline mutations in key components of the highly conserved Ras-MAPK pathway, possibly reflecting a similar pathogenesis underlying the three disorders. Germline mutations in KRAS have recently been identified in a small number of patients with Noonan syndrome and CFC. Methods and results: 260 patients were screened for KRAS mutations by direct sequencing. Overall, we detected KRAS mutations in 12 patients, including three known and eight novel sequence alterations. All mutations are predicted to cause single amino acid substitutions. Remarkably, our cohort of individuals with KRAS mutations showed a high clinical variability, ranging from Noonan syndrome to CFC, and also included two patients who met the clinical criteria of Costello syndrome. Conclusion: Our findings reinforce the picture of a clustered distribution of disease associated KRAS germline alterations. We further defined the phenotypic spectrum associated with KRAS missense mutations and provided the first evidence of clinical differences in patients with KRAS mutations compared with Noonan syndrome affected individuals with heterozygous PTPN11 mutations and CFC patients carrying a BRAF, MEK1 or MEK1 alteration, respectively. We speculate that the observed phenotypic variability may be related, at least in part, to specific genotypes and possibly reflects the central role of K-Ras in a number of different signalling pathways.
    Subject(s): Abnormalities, Multiple - genetics ; Biological and medical sciences ; cardio-facio-cutaneous syndrome ; CFC ; Diagnosis ; Europe ; Female ; Fundamental and applied biological sciences. Psychology ; GAP ; Gene mutations ; Genes, ras ; Genetic aspects ; Genetic Variation ; Genetics of eukaryotes. Biological and molecular evolution ; Germ-Line Mutation ; GTPase activating protein ; Health aspects ; Humans ; Intracellular Signaling Peptides and Proteins - genetics ; Male ; Medical genetics ; Medical sciences ; Molecular and cellular biology ; Noonan syndrome ; Noonan Syndrome - genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 ; Protein Tyrosine Phosphatases - genetics ; Research ; Short Report
    ISSN: 0022-2593
    ISSN: 1468-6244
    E-ISSN: 1468-6244
    DOI: 10.1136/jmg.2006.046300
    Source: Hellenic Academic Libraries Link
    Source: BMJ Journals - NESLi2
    Source: PubMed Central
    URL: http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18497378$$DView record in Pascal Francis
    URL: https://www.ncbi.nlm.nih.gov/pubmed/17056636$$D View this record in MEDLINE/PubMed
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  • 6
    Article
    Article
    PITX1 Is a Regulator of TERT Expression in Prostate Cancer with Prognostic Power
    2022
    ISSN: 2072-6694 
    Details
    Language: English
    In: Cancers, 2022-03-01, Vol.14 (5), p.1267
    Description: The current risk stratification in prostate cancer (PCa) is frequently insufficient to adequately predict disease development and outcome. One hallmark of cancer is telomere maintenance. For telomere maintenance, PCa cells exclusively employ telomerase, making it essential for this cancer entity. However, TERT, the catalytic protein component of the reverse transcriptase telomerase, itself does not suit as a prognostic marker for prostate cancer as it is rather low expressed. We investigated if, instead of , transcription factors regulating may suit as prognostic markers. To identify transcription factors regulating , we developed and applied a new gene regulatory modeling strategy to a comprehensive transcriptome dataset of 445 primary PCa. Six transcription factors were predicted as regulators, and most prominently, the developmental morphogenic factor PITX1. PITX1 expression positively correlated with telomere staining intensity in PCa tumor samples. Functional assays and chromatin immune-precipitation showed that PITX1 activates expression in PCa cells. Clinically, we observed that PITX1 is an excellent prognostic marker, as concluded from an analysis of more than 15,000 PCa samples. PITX1 expression in tumor samples associated with (i) increased Ki67 expression indicating increased tumor growth, (ii) a worse prognosis, and (iii) correlated with telomere length.
    Subject(s): Androgens ; Biomarkers ; Brachytherapy ; Cancer therapies ; Cell division ; Chromatin ; DNA methylation ; Gene expression ; Genomes ; Invasiveness ; Linear programming ; Metastases ; Metastasis ; mixed integer linear programming ; modularity ; Mutation ; Optimization ; PITX1 ; Prostate cancer ; Prostatectomy ; regulatory networks ; RNA-directed DNA polymerase ; Semantics ; Surveillance ; Telomerase ; Telomeres ; Transcription factors ; Transcriptomes ; Tumors
    ISSN: 2072-6694
    E-ISSN: 2072-6694
    DOI: 10.3390/cancers14051267
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: Alma/SFX Local Collection
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    URL: https://www.ncbi.nlm.nih.gov/pubmed/35267575$$D View this record in MEDLINE/PubMed
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  • 7
    Article
    Article
    Novel N-terminal truncating CLCN1 mutation in severe becker disease
    2014
    ISSN: 0148-639X 
    Details
    Language: English
    In: Muscle & nerve, 2014-11, Vol.50 (5), p.866-867
    Description: Byline: Franziska Hoche, Kay Seidel, Eduardo Barbosa-Sicard, Tonio Heidegger, Jun-Suk Kang, Rainer Koenig, Matthias Kieslich
    Subject(s): Adolescent ; Chloride Channels - genetics ; Humans ; Male ; Mutation - genetics ; Myotonia Congenita - genetics
    ISSN: 0148-639X
    E-ISSN: 1097-4598
    DOI: 10.1002/mus.24312
    Source: Hellenic Academic Libraries Link
    URL: https://www.ncbi.nlm.nih.gov/pubmed/24920213$$D View this record in MEDLINE/PubMed
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  • 8
    Article
    Article
    Deletions in the 3′ Part of the NFIX Gene Including a Recurrent Alu-Mediated Deletion of Exon 6 and 7 Account for Previously Unexplained Cases of Marshall-Smith Syndrome
    2014
    ISSN: 1059-7794 
    Details
    Language: English
    In: Human mutation, 2014-09, Vol.35 (9), p.1092-1100
    Description: Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner
    Subject(s): Abnormalities, Multiple - diagnosis ; Abnormalities, Multiple - genetics ; Adolescent ; Adult ; Alu Elements ; Bone Diseases, Developmental - diagnosis ; Bone Diseases, Developmental - genetics ; Child ; Child, Preschool ; Chromosome Breakpoints ; Craniofacial Abnormalities - diagnosis ; Craniofacial Abnormalities - genetics ; DNA Mutational Analysis ; Exons ; Facies ; Female ; Gene Expression ; Genetic Loci ; Humans ; Infant ; intellectual disability ; Male ; Marshall-Smith syndrome ; Mutation ; NFI Transcription Factors - genetics ; NFIX ; nonsense-mediated decay ; nuclear factor 1/X ; Phenotype ; RNA, Messenger - genetics ; Septo-Optic Dysplasia - diagnosis ; Septo-Optic Dysplasia - genetics ; Sequence Deletion ; Young Adult
    ISSN: 1059-7794
    E-ISSN: 1098-1004
    DOI: 10.1002/humu.22603
    Source: Hellenic Academic Libraries Link
    URL: https://www.ncbi.nlm.nih.gov/pubmed/24924640$$D View this record in MEDLINE/PubMed
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  • 9
    Article
    Article
    Osteopathia Striata With Cranial Sclerosis Owing to WTX Gene Defect
    2010
    ISSN: 0884-0431 
    Details
    Language: English
    In: Journal of bone and mineral research, 2010-01, Vol.25 (1), p.82-90
    Description: Osteopathia striata with cranial sclerosis (OSCS) is an X‐linked dominant condition marked by linear striations mainly affecting the metaphyseal region of the long bones and pelvis in combination with cranial sclerosis. Recently, the disease‐causing gene was identified as the WTX gene (FAM123B), an inhibitor of WNT signaling. A correlation was suggested between the position of the mutation and male lethality. We performed genotype and phenotype studies using 18 patients from eight families with possible WTX gene defects and expanded the clinical spectrum of the affected females. All investigated families diagnosed with OSCS had WTX gene defects. One family had a WTX gene deletion; three of four point mutations were novel. The earlier reported WTX c.1072C〉T was detected in four sporadic patients and appears to be a hotspot for mutations. Based on the nature of the mutation present in a surviving male patient, our data do not support the hypothesis raised by Jenkins et al. (2009) regarding a genotype‐phenotype correlation for male lethality. The finding of a gene involved in WNT signaling as the cause of this sclerosing bone phenotype is not unexpected, but further functional studies are needed to explain the specific features. The WTX gene is mutated in different types of cancer, and it remains to be explained why osteopathia striata patients appear not to have an increased risk of cancer. Copyright © 2010 American Society for Bone and Mineral Research
    Subject(s): Adaptor Proteins, Signal Transducing ; Adolescent ; Adult ; Aged ; Alternative Splicing - genetics ; Bone Diseases, Developmental - complications ; Bone Diseases, Developmental - diagnostic imaging ; Bone Diseases, Developmental - genetics ; Child ; Child, Preschool ; Female ; GENOTYPE ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; OSTEOPATHIA STRIATA WITH CRANIAL SCLEROSIS ; Pedigree ; PHENOTYPE ; Polymerase Chain Reaction ; Pregnancy ; Radiography ; Sclerosis ; Skull - diagnostic imaging ; Skull - pathology ; Tumor Suppressor Proteins - chemistry ; Tumor Suppressor Proteins - genetics ; WTX
    ISSN: 0884-0431
    E-ISSN: 1523-4681
    DOI: 10.1359/jbmr.090707
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    URL: https://www.ncbi.nlm.nih.gov/pubmed/20209645$$D View this record in MEDLINE/PubMed
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  • 10
    Article
    Article
    Description of a novel c.374 G〉A mutation in becker disease
    2013
    ISSN: 0148-639X 
    Details
    Language: English
    In: Muscle & nerve, 2013-04, Vol.47 (4), p.616-617
    Subject(s): Child ; Chloride Channels - genetics ; Female ; Humans ; Mutation, Missense ; Myotonia Congenita - genetics
    ISSN: 0148-639X
    E-ISSN: 1097-4598
    DOI: 10.1002/mus.23698
    Source: Hellenic Academic Libraries Link
    URL: https://www.ncbi.nlm.nih.gov/pubmed/23456831$$D View this record in MEDLINE/PubMed
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