Recognition of nonhybridizing base pairs during nucleotide excision repair of DNA

Nondistorting C4' backbone adducts serve as molecular tools to analyze the strategy by which a limited number of human nucleotide excision repair (NER) factors recognize an infinite variety of DNA lesions. We have constructed composite DNA substrates containing a noncomplementary site adjacent to a nondistorting C4' adduct to show that the loss of hydrogen bonding contacts between partner strands is an essential signal for the recruitment of NER enzymes. This specific conformational requirement for excision is mediated by the affinity of xeroderma pigmentosum group A (XPA) protein for nonhybridizing sites in duplex DNA. XPA recognizes defective Watson-Crick base pair conformations even in the absence of DNA adducts or other covalent modifications, apparently through detection of hydrophobic base components that are abnormally exposed to the double helical surface. This recognition function of XPA is enhanced by replication protein A (RPA) such that, in combination, XPA and RPA constitute a potent molecular sensor of denatured base pairs. Our results indicate that the XPA-RPA complex may promote damage recognition by monitoring Watson-Crick base pair integrity, thereby recruiting the human NER system preferentially to sites where hybridization between complementary strands is weakened or entirely disrupted.     

Radiation-induced cataract in astronauts and cosmonauts

BACKGROUND: Opacification of the ocular lens is an important effect of exposure to ionizing radiation. Astronauts and cosmonauts are exposed to relatively high doses of all types of radiation in space, including high-energy particle radiation. A study was initiated to examine the lenses of the eyes of astronauts/cosmonauts to detect signs of radiation-induced cataracts. The aim of this study was to take a first step towards gaining improved, quantitative insight into the risk of radiation-induced cataract associated with long space missions. METHODS: The lenses of 21 former astronauts and cosmonauts were examined, using an upgraded Topcon SL-45 B Scheimpflug camera system. The degrees of opacification in this group of astronauts and cosmonauts were compared with the measurements in a reference group. This reference group was established by examining a cohort of 395 persons using the same Scheimpflug system. RESULTS: Initial results indicated that opacity values in most of the astronauts and cosmonauts were slightly to strongly increased in regions IV (posterior cortex) and V (posterior capsule), compared with the average opacity values for the respective age-group of the reference cohort. CONCLUSION: The aim of this study - to conduct first examinations of astronauts' and cosmonauts' ocular lenses with regard to signs of radiation-induced cataract - was successfully achieved in a total of 21 astronauts and cosmonauts using a Scheimpflug camera system. It is planned to examine a larger group of astronauts and cosmonauts in the future.     

Long-term therapy of viramin D-resistant richets with 25-hydroxycholecalciferol.

The long-term effects of the vitamin D metabolite, 25-hydroxycholecalciferol (25-HCC), were evaluated in 2 children with hypophosphatemic vitamin D-resistant rickets. Serial total balance studies demonstrated an apparent lack of correlation between the effects of the vitamin on intestinal absorption of calcium and phosphorus and both the onset of healing in 1 of the 2 patients treated with 5,000 to 7,500 u of the metabolite and the absence of demonstrable radiologic improvement in another patient in whom the final dosage was 20,000 u. per day. At first, the metabolite induced a positive calcium balance in both patients resulting largely from a reduction in intestinal calcium excretion. Despite a continued positive calcium balance, 1 of the 2 patients did not demonstrate further healing, while in the other patient healing was noted even when total calcium balance was negative. Serum phosphate levels did not return to normal in either patient, nor was phosphate excretion altered by 25-HCC. Serum alkaline phosphatase remained elevated in both. Serum immunoassayable parathyroid hormone levels were consistently normal to high-normal in the 2 patients throughout more than 24 months of observation. No instances of hypercalcemia and only occasional hypercalciuric episodes were noted.     

Efficacy of Human Adipose Tissue-Derived Stem Cells on Neonatal Bilirubin Encephalopathy in Rats

Kernicterus is a neurological syndrome associated with indirect bilirubin accumulation and damages to the basal ganglia, cerebellum and brain stem nuclei particularly the cochlear nucleus. To mimic haemolysis in a rat model such that it was similar to what is observed in a preterm human, we injected phenylhydrazine in 7-day-old rats to induce haemolysis and then infused sulfisoxazole into the same rats at day 9 to block bilirubin binding sites in the albumin. We have investigated the effectiveness of human adiposity-derived stem cells as a therapeutic paradigm for perinatal neuronal repair in a kernicterus animal model. The level of total bilirubin, indirect bilirubin, brain bilirubin and brain iron was significantly increased in the modelling group. There was a significant decreased in all severity levels of the auditory brainstem response test in the two modelling group. Akinesia, bradykinesia and slip were significantly declined in the experience group. Apoptosis in basal ganglia and cerebellum were significantly decreased in the stem cell-treated group in comparison to the vehicle group. All severity levels of the auditory brainstem response tests were significantly decreased in 2-month-old rats. Transplantation results in the substantial alleviation of walking impairment, apoptosis and auditory dysfunction. This study provides important information for the development of therapeutic strategies using human adiposity-derived stem cells in prenatal brain damage to reduce potential sensori motor deficit.     

Disrupted rich club network in behavioral variant frontotemporal dementia and early‐onset Alzheimer's disease

In network analysis, the so‐called “rich club” describes the core areas of the brain that are more densely interconnected among themselves than expected by chance, and has been identified as a fundamental aspect of the human brain connectome. This is the first in‐depth diffusion imaging study to investigate the rich club along with other organizational changes in the brain's anatomical network in behavioral frontotemporal dementia (bvFTD), and a matched cohort with early‐onset Alzheimer's disease (EOAD). Our study sheds light on how bvFTD and EOAD affect connectivity of white matter fiber pathways in the brain, revealing differences and commonalities in the connectome among the dementias. To analyze the breakdown in connectivity, we studied three groups: 20 bvFTD, 23 EOAD, and 37 healthy elderly controls. All participants were scanned with diffusion‐weighted magnetic resonance imaging (MRI), and based on whole‐brain probabilistic tractography and cortical parcellations, we analyzed the rich club of the brain's connectivity network. This revealed distinct patterns of disruption in both forms of dementia. In the connectome, we detected less disruption overall in EOAD than in bvFTD [false discovery rate (FDR) critical P_perm = 5.7 × 10^?3, 10,000 permutations], with more involvement of richly interconnected areas of the brain (chi‐squared P = 1.4 × 10^?4)—predominantly posterior cognitive alterations. In bvFTD, we found a greater spread of disruption including the rich club (FDR critical P_perm = 6 × 10^?4), but especially more peripheral alterations (chi‐squared P = 6.5 × 10^?3), particularly in medial frontal areas of the brain, in line with the known behavioral socioemotional deficits seen in these patients. Hum Brain Mapp 37:868–883, 2016. © 2015 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc .     

Computational models of MRI characteristics of focal cortical dysplasia improve lesion detection

In many patients, focal cortical dysplasia (FCD) is characterized by minor structural changes that may go unrecognized by standard radiological analysis. We previously demonstrated that visual analysis of a composite map based on three simple models of MRI features of FCD increased the sensitivity of FCD lesion detection, compared to visual analysis of conventional MRI. Here we report on the use of improved methods for characterizing FCD which improve contrast in the composite maps: a Laplacian-based metric for measuring cortical thickness, a convolutional kernel to model blurring of the GM-WM interface, and an operator to measure hyperintense T1 signal. To validate these methods, we processed the MRIs of 14 FCD patients with our original set of image processing operators and an improved set of image processing operators. Comparison of the composite maps associated with the two sets of operators revealed that contrast between lesional tissue and nonlesional cortex was significantly increased in the composite maps associated with the set of improved operators. Increasing this contrast is an important step toward the goal of automated FCD lesion detection.