Molecular genetics of Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS) is a multiple malformation disorder characterized by peculiar facial features, growth and mental retardation, and a variety of other abnormalities affecting multiple organ systems. The molecular pathology underlying the disease phenotypes is not known. In the past, 3q26.3 was considered as a candidate region. However, no patient-specific mutations in the giant gene, NAALADL2, truncated by the 3q26.3 breakpoint were found. Thus, in this study, we tried to find the disease gene in loci other than 3q26.3 mainly by FISH mapping in patients with t(5; 13), t(14; 21) de novo balanced translocation. Of all the three regions (5p13,13g12,14q32) we studied, the novel gene that crosses the 5p translocation breakpoint was found to be the most likely candidate gene for CdIS. Subsequent finer FISH mapping using fosmid clones as probes confirmed the novel gene was truncated by the translocation breakpoint in intron 1. Standard point mutational screening of the newly found gene detected patient-specific mutations. The gene was named, NIPBL, which is the major determinant for this rare syndrome (Tonkin et al., 2004). Analysis of the NIPBL gene in further patients with CdIS revealed a wide variety of pathogenic mutations. More than half of the mutations resulted in premature termination. Loss of function causing haploinsufficiency is supported by patients with heterozygous deletion involving the whole NIPBL gene. No genotype-phenotype correlation was observed. The exact functions of delangin are not known. Tissue in situ studies of NIPBL, using riboprobes in early human embryos, showed expression in developing brain, limbs, muscle, bone, renal tubules and lung bronchioles. In our preliminary data, the expression of NIPBL is mainly in the active proliferating tissue in early mammalian development. However, the tissue expression pattern in later mammalian development is not known. The predicted protein sequence of the NIPBL product, delangin, is 2804 amino acids for the long isoform and 2697 amino acids for the short isoform. In the carboxy-terminal region there is a clustering of HEAT repeats and these motifs (also called adherin) are highly conserved in the carboxy-terminal region of delangin homologues, Nipped-B of Drosophila, Scc2 of Saccharomyces cerevisiae and Mis4 of Schizosaccharomyces pombe, which are required for mitotic sister chromatid cohesion. Delangin is also related to Rad9 of Coprinus cinereus, which is required for DNA repair and meiotic chromosome paring. The Scc2 and Mis4 yeast, and Drosophila Nipped-B adherin homologues of human delangin are required for the Cohesin protein complex that mediates sister chromatid cohesin to associate with chromosomes. The major role in yeast and Xenopus Scc2 is to interact with Scc4 to help in loading the cohesin ring onto chromatin in the early S phase during cell replication. We also identified the sequence of the human Scc4 homologue, which we call human Mau-2. Tissue in situ hybridization data using a probe to dectect human Mau-2 showed a similar expression pattern to NIPBL in human embryos. However, no hMau-2 mutations were detected in CdLS patients in our mutation screen. In Drosophila, Nipped-B was also found to participate in remote activation of the cut and Ultrabithorax genes. Reducing the Nipped-B dosage reduces activation of the wild-type cut gene by the remote wing margin enhancer and causes the wing margin defect in Drosophila. Furthermore, Mau-2, the C. elegans homologue of yeast Scc4, which interacts with Scc2 to help in the establishment of the cohesion loading onto the chromatin, was found to guide axonal migrations in the CNS. However, the exact functions of both NIPBL and hMau-2 need to be further elucidated.EThOS - Electronic Theses Online ServiceKaohsiung Medical Centre, Chang-Gung Memorial HospitalGBUnited Kingdo

Novel Mutation in Boy With Cartilage-hair Hypoplasia

BackgroundCartilage-hair hypoplasia (MIM 250250) is an autosomal recessive disease with diverse clinical manifestations. The clinical phenotypes include variable degrees of bone and hair dysplasia, deficient cellular and/or humoral immunity, and a predisposition to malignancy.MethodsWe performed genetic studies of a patient with disproportionate short stature and brittle scalp hair. Genetic studies were also carried out in the patient's parents.ResultsA novel maternal mutation that consisted of a duplication of 14 nucleotides at position −13 of the RNA component of the RNA component of mitochondrial RNA processing endoribonuclease gene (RMRP; g. −26 to −13 dupTACTACTCTGTGAA, promoter region) and a paternal mutation base substitution of C to T at nucleotide + 230 (designated as + 1 in the transcription initiation site) in the coding sequence of RMRP were detected in this patient.ConclusionA novel maternal RMRP mutation was found in a Chinese boy with typical cartilage-hair hypoplasia

Quantum correlation generation capability of experimental processes

Einstein-Podolsky-Rosen (EPR) steering and Bell nonlocality illustrate two different kinds of correlations predicted by quantum mechanics. They not only motivate the exploration of the foundation of quantum mechanics, but also serve as important resources for quantum-information processing in the presence of untrusted measurement apparatuses. Herein, we introduce a method for characterizing the creation of EPR steering and Bell nonlocality for dynamical processes in experiments. We show that the capability of an experimental process to create quantum correlations can be quantified and identified simply by preparing separable states as test inputs of the process and then performing local measurements on single qubits of the corresponding outputs. This finding enables the construction of objective benchmarks for the two-qubit controlled operations used to perform universal quantum computation. We demonstrate this utility by examining the experimental capability of creating quantum correlations with the controlled-phase operations on the IBM Quantum Experience and Amazon Braket Rigetti superconducting quantum computers. The results show that our method provides a useful diagnostic tool for evaluating the primitive operations of nonclassical correlation creation in noisy intermediate scale quantum devices.Comment: 5 figures, 3 appendice

Developing Customized Dental Miniscrew Surgical Template from Thermoplastic Polymer Material Using Image Superimposition, CAD System, and 3D Printing

[[abstract]]This study integrates cone-beam computed tomography (CBCT)/laser scan image superposition, computer-aided design (CAD), and 3D printing (3DP) to develop a technology for producing customized dental (orthodontic) miniscrew surgical templates using polymer material. Maxillary bone solid models with the bone and teeth reconstructed using CBCT images and teeth and mucosa outer profile acquired using laser scanning were superimposed to allow miniscrew visual insertion planning and permit surgical template fabrication. The customized surgical template CAD model was fabricated offset based on the teeth/mucosa/bracket contour profiles in the superimposition model and exported to duplicate the plastic template using the 3DP technique and polymer material. An anterior retraction and intrusion clinical test for the maxillary canines/incisors showed that two miniscrews were placed safely and did not produce inflammation or other discomfort symptoms one week after surgery. The fitness between the mucosa and template indicated that the average gap sizes were found smaller than 0.5 mm and confirmed that the surgical template presented good holding power and well-fitting adaption. This study addressed integrating CBCT and laser scan image superposition; CAD and 3DP techniques can be applied to fabricate an accurate customized surgical template for dental orthodontic miniscrews.[[notice]]補正完

Determinants and Dynamic Changes of Generic Quality of Life in Human Bladder Cancer Patients

We measured and determined the factors associated with long-term generic quality-of-life (QOL) changes in human bladder cancer patients. We utilized the World Health Organization QOL-Brief questionnaire to assess consecutive patients’ QOL at outpatient clinics of our hospital. A mixed-effects model was constructed to investigate the determinants of QOL changes according to each domain and individual item after controlling for demographic and clinical factors, as well as the effect of radical cystectomy. We also applied a kernel smoothing method to describe the long-term dynamic changes after the first definite treatment. In total, 1185 repeated measurements were collected from 343 bladder cancer patients. The mixed-effects models demonstrated that marital status, monthly income, and comorbidity with heart disease and diabetes were significant determinants among all the study participants. Regardless of the urinary diversion type, radical cystectomy contributed to lower scores for all four domains, mainly from 4–5 years after cystectomy, which declined significantly in patients who were older than 60 years. As for non-muscle-invasive bladder cancer (NMIBC) patients with preserved bladders, tumor recurrence was a major predictor for lower scores for sexual activity in the social domain. In summary, generic QOL can be independently influenced by many factors, not only cystectomy and tumor recurrence, which should be discussed with patients before treatment

Mediating effects of shoulder-arm exercise on the postoperative severity of symptoms and quality of life of women with breast cancer

Background: The postoperative severity of symptoms among women with breast cancer affects their quality of life (QoL). Although it is recommended that performing shoulder-arm exercise 30 min/day can alleviate symptoms and improve the QoL, there is little research on the mediating effects of performing shoulder-arm exercise 30 min/day on the postoperative severity of symptoms and QoL among patients with breast cancer. Methods: A cross-sectional study was conducted 2 ~ 4 months after surgery on women diagnosed with breast cancer but with no distant metastasis and who had undergone breast cancer surgery for the first time. A structured questionnaire was employed which included a severity of symptoms scale, performing shoulder-arm exercise for 30 min/day, a QoL scale, demographic characteristics, and medical status. Results: In total, 117 women with breast cancer completed the survey. The severity of symptoms and performing shoulder-arm exercise 30 min/day separately affected the QoL (B = -0.447, standard error (SE) = 0.050, p \u3c 0.001; B = 15.666, SE = 4.542, p = 0.001, respectively). In model 3, performing shoulder-arm exercise for 30 min/day played a partial mediating role in the relationship of the severity of symptoms and QoL (R 2 = 0.51, F = 5.41, p \u3c 0.001). Conclusions: During 2 ~ 4 months after surgery, regular shoulder-arm exercise for 30 min/day could decrease the effect of the severity of symptoms on the QoL among women with breast cancer. Clinical healthcare providers may inform and educate patients as to the benefits of regular shoulder-arm exercise for 30 min/day

Comorbidity as a mediator of depression in adults with congenital heart disease: A population-based cohort study

BACKGROUND: The population of adults with congenital heart disease (CHD) has increased dramatically with a high prevalence of acquired cardiac and non-cardiac comorbidities. However, the relationship among congenital heart disease, physical comorbidities, and psychological health in this population is not well studied. AIMS: The purpose of this study was to investigate (a) the association between adult congenital heart disease and the occurrence of depression and (b) whether physical comorbidities mediated the association between congenital heart disease and the occurrence of depression. METHODS: This retrospective cohort study was followed from 1 January 2010-31 December 2013, based on the data from the National Health Insurance Research Database 2010 in Taiwan. We used mediation analysis in survival data to assess the mediated effect. The hazard ratios were adjusted by age, sex, area of residence, and estimated propensity scores. RESULTS: We recruited 2122 adult congenital heart disease patients and 8488 matched controls. Nearly half of patients diagnosed with simple congenital heart disease, 39.0% had complex congenital heart disease, and 11.2% had unclassified congenital heart disease. Adult congenital heart disease patients had a significantly higher risk of depression than matched controls (adjusted hazard ratio = 1.43 and 1.48, for all and complex congenital heart disease, respectively, p<0.05). Coronary artery disease and chronic obstructive pulmonary disease were the significant comorbidities mediating the relationship between adult congenital heart disease and depression, the proportions mediated by coronary artery disease or chronic obstructive pulmonary disease were 35.5% and 12.9%, respectively. CONCLUSIONS: Helping patients to prevent psychological and physical acquired disease is imperative. Coronary artery disease is a potent mediator between congenital heart disease and depression, especially for patients with complex congenital heart disease.status: publishe

Proteomic Profiling of Outer Membrane Vesicles Released by Escherichia coli LPS Mutants Defective in Heptose Biosynthesis

Escherichia coli releases outer membrane vesicles (OMVs) into the extracellular environment. OMVs, which contain the outer membrane protein, lipopolysaccharides (LPS), and genetic material, play an important role in immune response modulation. An isobaric tag for relative and absolute quantitation (iTRAQ) analysis was used to investigate OMV constituent proteins and their functions in burn trauma. OMV sizes ranged from 50 to 200 nm. Proteomics and Gene Ontology analysis revealed that &Delta;rfaC and &Delta;rfaG were likely involved in the upregulation of the structural constituent of ribosomes for the outer membrane and of proteins involved in protein binding and OMV synthesis. &Delta;rfaL was likely implicated in the downregulation of the structural constituent of the ribosome, translation, and cytosolic large ribosomal subunit. Kyoto Encyclopedia of Genes and Genomes analysis indicated that &Delta;rfaC and &Delta;rfaG downregulated ACP, ACEF, and ADHE genes; &Delta;rfaL upregulated ACP, ACEF, and ADHE genes. Heat map analysis demonstrated upregulation of galF, clpX, accA, fabB, and grpE and downregulation of pspA, ydiY, rpsT, and rpmB. These results suggest that RfaC, RfaG, and RfaL proteins were involved in outer membrane and LPS synthesis. Therefore, direct contact between wounds and LPS may lead to apoptosis, reduction in local cell proliferation, and delayed wound healing