We have recorded multiple attenuated total reflection spectra of liquid H20 and D20, using the Spectra-Tech CIRCLE cell, and calculated from them the infrared optical and dielectric constants and molar conductivities from 9000 to 1250 cm"1 for H20 and from 8500 to 700 cm"1 for D20. Our results agree well with the literature for H20, while our results for D20 are the most extensive reported to date. We have calculated the dipole moment derivatives with respect to stretching and bending internal coordinates from the areas under the bands in our molar conductivity spectra. For lack of information, we have used the assumptions of the simple bond-moment model, a diagonal force field, and neglect of stretch-bend interaction.We found µ/dr for the stretching vibrations to be 3.02 D/Á ±1% and 3.04 D/Á ±0.5% for H20 and D20, respectively, and µ/ for the bending vibration to be 0.73 D ±3% for HzO and 0.63 D ±5% for D20. The two values for the stretching vibrations are indistinguishable, but this is not true for the bend. The disagreement for the bending vibration is probably due, at least in part, to our simulation of the absorption by three distinct bands of mixed Gauss-Lorentzian character, in order to try to separate the bending mode from the background absorption. It is probable that no such separation exists precisely. The bond moments for H20 and D20 agree with those calculated by the same approximations from literature data for HDO to about the extent allowed by the approximations. The intensities for liquid H20 are compared with those for water in the gas phase, in Ba(C103)2-H20, in ice I, and in lithium ^-alumínate. The intensity of the bending mode, v2(H20), is essentially independent of the strength of the hydrogen bonds. That of the OH stretching modes increases with hydrogen bond strength in Ba(C103)2-H20, liquid water, ice I, and lithium ß-aluminate being 20, 17.5, 25, and 40, respectively, times more intense than in the gas. Explanations for this are briefly summarized.

Digital clubbing, recognized by Hippocrates in the fifth century BC, is the outward hallmark of pulmonary hypertrophic osteoarthropathy, a clinical constellation that develops secondary to various acquired diseases, especially intrathoracic neoplasm. The pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood, but a clinically indistinguishable primary (idiopathic) form of hypertrophic osteoarthropathy (PHO) is recognized. This familial disorder can cause diagnostic confusion, as well as significant disability. By autozygosity methods, we mapped PHO to chromosome 4q33-q34 and identified mutations in HPGD, encoding 15-hydroxyprostaglandin dehydrogenase, the main enzyme of prostaglandin degradation. Homozygous individuals develop PHO secondary to chronically elevated prostaglandin E(2) levels. Heterozygous relatives also show milder biochemical and clinical manifestations. These findings not only suggest therapies for PHO, but also imply that clubbing secondary to other pathologies may be prostaglandin mediated. Testing for HPGD mutations and biochemical testing for HPGD deficiency in patients with unexplained clubbing might help to obviate extensive searches for occult pathology.

Healthy dental enamel is the hardest and most highly mineralized human tissue. Though acellular, nonvital, and without capacity for turnover or repair, it can nevertheless last a lifetime. Amelogenesis imperfecta (AI) is a collective term for failure of normal enamel development, covering diverse clinical phenotypes that typically show Mendelian inheritance patterns. One subset, known as hypomaturation AI, is characterised by near-normal volumes of organic enamel matrix but with weak, creamy-brown opaque enamel that fails prematurely after tooth eruption. Mutations in genes critical to enamel matrix formation have been documented, but current understanding of other key events in enamel biomineralization is limited. We investigated autosomal-recessive hypomaturation AI in a consanguineous Pakistani family. A whole-genome SNP autozygosity screen identified a locus on chromosome 15q21.3. Sequencing candidate genes revealed a point mutation in the poorly characterized WDR72 gene. Screening of WDR72 in a panel of nine additional hypomaturation AI families revealed the same mutation in a second, apparently unrelated, Pakistani family and two further nonsense mutations in Omani families. Immunohistochemistry confirmed intracellular localization in maturation-stage ameloblasts. WDR72 function is unknown, but as a putative β propeller is expected to be a scaffold for protein-protein interactions. The nearest homolog, WDR7, is involved in vesicle mobilization and Ca2+-dependent exocytosis at synapses. Vesicle trafficking is important in maturation-stage ameloblasts with respect to secretion into immature enamel and removal of cleaved enamel matrix proteins via endocytosis. This raises the intriguing possibility that WDR72 is critical to ameloblast vesicle turnover during enamel maturation.

The critical importance of cytoskeletal function for correct neuronal migration during development of the cerebral cortex has been underscored by the identities of germline mutations underlying a number of human neurodevelopmental disorders. The proteins affected include TUBA1A, a major alpha-tubulin isoform, and microtubule-associated components such as doublecortin, and LIS1. Mutations in these genes are associated with the anatomical abnormality lissencephaly, which is believed to reflect failure of neuronal migration. An important recent observation has been the dependence of cortical neuronal migration upon acetylation of alpha-tubulin at lysine 40 by the histone acetyltransferase Elongator complex. Here, we describe a recognizable autosomal recessive syndrome, characterized by generalized polymicrogyria in association with optic nerve hypoplasia (PMGOH). By autozygosity mapping, we show that the molecular basis for this condition is mutation of the TUBA8 gene, encoding a variant alpha-tubulin of unknown function that is not susceptible to the lysine 40 acetylation that regulates microtubule function during cortical neuron migration. Together with the unique expression pattern of TUBA8 within the developing cerebral cortex, these observations suggest a role for this atypical microtubule component in regulating mammalian brain development.

This study aimed to explore the hopes and fears of young adults with cystic fibrosis (CF). Fifteen young adults with CF, aged 18-29, were interviewed about their hopes and fears using a grounded theory approach. Five themes were identified during the analysis: perceptions of living with unpredictable health and fear of death and dying; hopes for normality; hopes for a normal relationship and/or marriage; hopes for having children; and hopes for a normal work life. Participants feared the unpredictable nature of CF and the suffering that they believed they would have to endure due to ill health before premature death. Despite their fears, participants hoped to live a "normal" life by achieving their hopes of having long-lasting relationships, having children and pursuing a career. The findings highlight the need to help alleviate the fears of young adults with CF and to enable them to plan to achieve their hopes, hence giving them a sense of control over their condition.

Abstract:The current study presents the use of Raman spectroscopy combined with support vector machine (SVM) for the classification of dengue suspected human blood sera. Raman spectra for 84 clinically dengue suspected patients acquired from Holy Family Hospital, Rawalpindi, Pakistan, have been used in this study.The spectral differences between dengue positive and normal sera have been exploited by using effective machine learning techniques. In this regard, SVM models built on the basis of three different kernel functions including Gaussian radial basis function (RBF), polynomial function and linear functionhave been employed to classify the human blood sera based on features obtained from Raman Spectra.The classification model have been evaluated with the 10-fold cross validation method. In the present study, the best performance has been achieved for the polynomial kernel of order 1. A diagnostic accuracy of about 85% with the precision of 90%, sensitivity of 73% and specificity of 93% has been achieved under these conditions. Langenburg, and M. D. Klein, "Raman spectroscopy for neoplastic tissue differentiation: a pilot study," J. Pediatr. Surg. 39(6), 953-956 (2004). 12. K. Kong, C. Kendall, N. Stone, and I. Notingher, "Raman spectroscopy for medical diagnostics--From in-vitro biofluid assays to in-vivo cancer detection," Adv. Drug Deliv. Rev. 89, 121-134 (2015). 13. P. Crow, J. S. Uff, J. A. Farmer, M. P. Wright, and N. Stone, "The use of Raman spectroscopy to identify and characterize transitional cell carcinoma in vitro," BJU Int. 93(9), 1232-1236 (2004). 14. A. Sikirzhytskaya, V. Sikirzhytski, and I. K. Lednev, "Raman spectroscopy coupled with advanced statistics for differentiating menstrual and peripheral blood," J. Biophotonics 7(1-2), 59-67 (2014 L. Martin, "Vibrational biospectroscopy coupled with multivariate analysis extracts potentially diagnostic features in blood plasma/serum of ovarian cancer patients," J. Biophotonics 7(3-4), 200-209 (2014). 18.

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BackgroundThe genetic aetiology of neurodevelopmental defects is extremely diverse, and the lack of distinctive phenotypic features means that genetic criteria are often required for accurate diagnostic classification. We aimed to identify the causative genetic lesions in two families in which eight affected individuals displayed variable learning disability, spasticity and abnormal gait.MethodsAutosomal recessive inheritance was suggested by consanguinity in one family and by sibling recurrences with normal parents in the second. Autozygosity mapping and exome sequencing, respectively, were used to identify the causative gene.ResultsIn both families, biallelic loss-of-function mutations in HACE1 were identified. HACE1 is an E3 ubiquitin ligase that regulates the activity of cellular GTPases, including Rac1 and members of the Rab family. In the consanguineous family, a homozygous mutation p.R219* predicted a truncated protein entirely lacking its catalytic domain. In the other family, compound heterozygosity for nonsense mutation p.R748* and a 20-nt insertion interrupting the catalytic homologous to the E6-AP carboxyl terminus (HECT) domain was present; western blot analysis of patient cells revealed an absence of detectable HACE1 protein.ConclusionHACE1 mutations underlie a new autosomal recessive neurodevelopmental disorder. Previous studies have implicated HACE1 as a tumour suppressor gene; however, since cancer predisposition was not observed either in homozygous or heterozygous mutation carriers, this concept may require re-evaluation.