Mutation causing self-aggregation in human γC-crystallin leading to congenital cataract

Purpose: Many forms of congenital hereditary cataract are associated with mutations in the crystallin genes. The authors focus attention on congenital lamellar cataract, which is associated with the R168W mutation in γC-crystallin, and congenital zonular pulverulent cataract, which is associated with a 5-bp insertion in the γC-crystallin gene. Methods: To understand the molecular phenotypes-i.e., the functional defects that have occurred in the mutant γC-crystallin molecule in two cases described-the authors cloned, expressed, isolated, and compared the solution state structural features of these mutants with those of normal (wild-type) γC-crystallin. Structural models of the wild-type and mutant have been generated using comparative modeling. Circular dichroism and fluorescence spectroscopic methods were used to determine the conformation of the proteins, and temperature dependent self-aggregation was used to observe the quaternary structural features. The structural stability of the proteins was monitored with the use of chemical and thermal denaturation. Results: The authors found that the 5-bp insertion led to a loss of secondary and tertiary structures of the molecule and to an enhanced tendency of self-aggregation into light-scattering particles, offering a possible factor in lens opacification. The R168W mutant, on the other hand, was remarkably similar to the wild-type molecule in its conformation and structural stability, but it differed in its ability to aggregate and scatter light. Conclusions: These results support the idea that unfolding or structural destabilization is not always necessary for crystallin-associated cataractogenesis

A new Indian species of Rhinophis Hemprich, 1820 closely related to R. sanguineus Beddome, 1863 (Serpentes: Uropeltidae)

A new species of the uropeltid (shieldtail snake) genus Rhinophis is described based on a type series of seven specimens from the Wayanad region of the Western Ghats of peninsular India. The holotype was collected before 1880 but had been misidentified as the phenotypically similar and parapatric (possibly partly sympatric) R. sanguineus. Rhinophis karinthandani sp. nov. is diagnosed by a combination of 15 dorsal scale rows at midbody, 4–8 pairs of subcaudal scales, colour pattern (uniformly dark above, whitish below with extensive dark mottling), and by its distinct mitochondrial DNA sequences (e.g. >7.6% uncorrected p-distance for nd4). Phylogenetic analysis of mitochondrial DNA sequence data indicates that the new species is most closely related to R. sanguineus among currently recognised species, with this pair most closely related to the partly sympatric R. melanoleucus. The new species description brings the number of currently recognised species in the genus to 24, six of which are endemic to India and 18 endemic to Sri Lanka. A new key to the identification of Indian species of Rhinophis is provided

Mutation Causing Self-Aggregation in Human ␥C-Crystallin Leading to Congenital Cataract

PURPOSE. Many forms of congenital hereditary cataract are associated with mutations in the crystallin genes. The authors focus attention on congenital lamellar cataract, which is associated with the R168W mutation in ␥C-crystallin, and congenital zonular pulverulent cataract, which is associated with a 5-bp insertion in the ␥C-crystallin gene. METHODS. To understand the molecular phenotypes-i.e., the functional defects that have occurred in the mutant ␥C-crystallin molecule in two cases described-the authors cloned, expressed, isolated, and compared the solution state structural features of these mutants with those of normal (wild-type) ␥C-crystallin. Structural models of the wild-type and mutant have been generated using comparative modeling. Circular dichroism and fluorescence spectroscopic methods were used to determine the conformation of the proteins, and temperature dependent self-aggregation was used to observe the quaternary structural features. The structural stability of the proteins was monitored with the use of chemical and thermal denaturation. RESULTS. The authors found that the 5-bp insertion led to a loss of secondary and tertiary structures of the molecule and to an enhanced tendency of self-aggregation into light-scattering particles, offering a possible factor in lens opacification. The R168W mutant, on the other hand, was remarkably similar to the wild-type molecule in its conformation and structural stability, but it differed in its ability to aggregate and scatter light. CONCLUSIONS. These results support the idea that unfolding or structural destabilization is not always necessary for crystallinassociated cataractogenesis. (Invest Ophthalmol Vis Sci. 2006; 47:5212-5217

Social Defeat: Impact on Fear Extinction and Amygdala-Prefrontal Cortical Theta Synchrony in 5-HTT Deficient Mice

Emotions, such as fear and anxiety, can be modulated by both environmental and genetic factors. One genetic factor is for example the genetically encoded variation of the serotonin transporter (5-HTT) expression. In this context, the 5-HTT plays a key role in the regulation of central 5-HT neurotransmission, which is critically involved in the physiological regulation of emotions including fear and anxiety. However, a systematic study which examines the combined influence of environmental and genetic factors on fear-related behavior and the underlying neurophysiological basis is missing. Therefore, in this study we used the 5-HTT-deficient mouse model for studying emotional dysregulation to evaluate consequences of genotype specific disruption of 5-HTT function and repeated social defeat for fear-related behaviors and corresponding neurophysiological activities in the lateral amygdala (LA) and infralimbic region of the medial prefrontal cortex (mPFC) in male 5-HTT wild-type (+/+), homo- (−/−) and heterozygous (+/−) mice. Naive males and experienced losers (generated in a resident-intruder paradigm) of all three genotypes, unilaterally equipped with recording electrodes in LA and mPFC, underwent a Pavlovian fear conditioning. Fear memory and extinction of conditioned fear was examined while recording neuronal activity simultaneously with fear-related behavior. Compared to naive 5-HTT+/+ and +/− mice, 5-HTT−/− mice showed impaired recall of extinction. In addition, 5-HTT−/− and +/− experienced losers showed delayed extinction learning and impaired recall of extinction. Impaired behavioral responses were accompanied by increased theta synchronization between the LA and mPFC during extinction learning in 5-HTT-/− and +/− losers. Furthermore, impaired extinction recall was accompanied with increased theta synchronization in 5-HTT−/− naive and in 5-HTT−/− and +/− loser mice. In conclusion, extinction learning and memory of conditioned fear can be modulated by both the 5-HTT gene activity and social experiences in adulthood, accompanied by corresponding alterations of the theta activity in the amygdala-prefrontal cortex network

Myelination- and immune-mediated MR-based brain network correlates

Background Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by inflammatory and neurodegenerative processes. Despite demyelination being a hallmark of the disease, how it relates to neurodegeneration has still not been completely unraveled, and research is still ongoing into how these processes can be tracked non-invasively. Magnetic resonance imaging (MRI) derived brain network characteristics, which closely mirror disease processes and relate to functional impairment, recently became important variables for characterizing immune-mediated neurodegeneration; however, their histopathological basis remains unclear. Methods In order to determine the MRI-derived correlates of myelin dynamics and to test if brain network characteristics derived from diffusion tensor imaging reflect microstructural tissue reorganization, we took advantage of the cuprizone model of general demyelination in mice and performed longitudinal histological and imaging analyses with behavioral tests. By introducing cuprizone into the diet, we induced targeted and consistent demyelination of oligodendrocytes, over a period of 5 weeks. Subsequent myelin synthesis was enabled by reintroduction of normal food. Results Using specific immune-histological markers, we demonstrated that 2 weeks of cuprizone diet induced a 52% reduction of myelin content in the corpus callosum (CC) and a 35% reduction in the neocortex. An extended cuprizone diet increased myelin loss in the CC, while remyelination commenced in the neocortex. These histologically determined dynamics were reflected by MRI measurements from diffusion tensor imaging. Demyelination was associated with decreased fractional anisotropy (FA) values and increased modularity and clustering at the network level. MRI-derived modularization of the brain network and FA reduction in key anatomical regions, including the hippocampus, thalamus, and analyzed cortical areas, were closely related to impaired memory function and anxiety-like behavior. Conclusion Network-specific remyelination, shown by histology and MRI metrics, determined amelioration of functional performance and neuropsychiatric symptoms. Taken together, we illustrate the histological basis for the MRI-driven network responses to demyelination, where increased modularity leads to evolving damage and abnormal behavior in MS. Quantitative information about in vivo myelination processes is mirrored by diffusion-based imaging of microstructural integrity and network characteristics

NOX4-derived ROS are neuroprotective by balancing intracellular calcium stores

Hyperexcitability is associated with neuronal dysfunction, cellular death, and consequently neurodegeneration. Redox disbalance can contribute to hyperexcitation and increased reactive oxygen species (ROS) levels are observed in various neurological diseases. NOX4 is an NADPH oxidase known to produce ROS and might have a regulating function during oxidative stress. We, therefore, aimed to determine the role of NOX4 on neuronal firing, hyperexcitability, and hyperexcitability-induced changes in neural network function. Using a multidimensional approach of an in vivo model of hyperexcitability, proteomic analysis, and cellular function analysis of ROS, mitochondrial integrity, and calcium levels, we demonstrate that NOX4 is neuroprotective by regulating ROS and calcium homeostasis and thereby preventing hyperexcitability and consequently neuronal death. These results implicate NOX4 as a potential redox regulator that is beneficial in hyperexcitability and thereby might have an important role in neurodegeneration.</p

Neoplastic transformation of breast epithelial cells by genotoxic stress

<p>Abstract</p> <p>Background</p> <p>Exposure to genotoxic stresses such as radiation and tobacco smoke can cause increased cancer incidence rate as reflected in an in depth meta-analysis of data for women and breast cancer incidence. Published reports have indicated that exposures to low dose radiation and tobacco smoke are factors that contribute to the development of breast cancer. However, there is a scarcity of information on the combinatorial effects of low dose radiation and tobacco smoke on formation and progression of breast cancer. The combination of these two genotoxic insults can induce significant damage to the genetic material of the cells resulting in neoplastic transformation.</p> <p>Methods</p> <p>To study the effects of low dose ionizing radiation and tobacco smoke on breast cells, MCF 10A cells were treated either with radiation (Rad - 0.1 Gray) or cigarette smoke condensate (Csc - 10 microgram/ml of medium) or a combination of Rad + Csc. Following treatments, cells were analyzed for cell cycle distribution patterns and the ability to extrude the Hoechst 33342 dye. In addition, <it>in vitro </it>invasion and migration as well as mammosphere formation assays were performed. Finally, differential gene expression profiles were generated from the individual and combination treatment.</p> <p>Results</p> <p>Exposure of MCF 10A cells to the combination of radiation plus cigarette smoke condensate generated a neoplastic phenotype. The transformed phenotype promoted increased mammosphere numbers, altered cell cycle phases with a doubling of the population in S phase, and increased invasion and motility. Also, exclusion of Hoechst 33342 dye, a surrogate marker for increased ABC transporters, was observed, which indicates a possible increase in drug resistance. In addition, changes in gene expression include the up regulation of genes encoding proteins involved in metabolic pathways and inflammation.</p> <p>Conclusions</p> <p>The results indicate that when normal breast cells are exposed to low dose radiation in combination with cigarette smoke condensate a phenotype is generated that exhibits traits indicative of neoplastic transformation. More importantly, this is the first study to provide a new insight into a possible etiology for breast cancer formation in individuals exposed to low dose radiation and tobacco smoke.</p

Mutation Causing Self-Aggregation in Human \gamma C-Crystallin Leading to Congenital Cataract

PURPOSE. Many forms of congenital hereditary cataract are associated with mutations in the crystallin genes. The authors focus attention on congenital lamellar cataract, which is associated with the R168W mutation in \gamma C-crystallin, and congenital zonular pulverulent cataract, which is associated with a 5-bp insertion in the \gamma C-crystallin gene. METHODS. To understand the molecular phenotypes-i.e., the functional defects that have occurred in the mutant \gamma C-crystallin molecule in two cases described-the authors cloned, expressed, isolated, and compared the solution state structural features of these mutants with those of normal (wild-type) \gamma C-crystallin. Structural models of the wild-type and mutant have been generated using comparative modeling. Circular dichroism and fluorescence spectroscopic methods were used to determine the conformation of the proteins, and temperature dependent self-aggregation was used to observe the quaternary structural features. The structural stability of the proteins was monitored with the use of chemical and thermal denaturation. RESULTS. The authors found that the 5-bp insertion led to a loss of secondary and tertiary structures of the molecule and to an enhanced tendency of self- aggregation into light-scattering particles, offering a possible factor in lens opacification. The R168W mutant, on the other hand, was remarkably similar to the wild-type molecule in its conformation and structural stability, but it differed in its ability to aggregate and scatter light. CONCLUSIONS. These results support the idea that unfolding or structural destabilization is not always necessary for crystallin-associated cataractogenesis

A new Indian species of Rhinophis Hemprich, 1820 closely related to R. sanguineus Beddome, 1863 (Serpentes: Uropeltidae)

Sampaio, Filipa L., Narayanan, Surya, Cyriac, Vivek Philip, Venu, Govindappa, Gower, David J. (2020): A new Indian species of Rhinophis Hemprich, 1820 closely related to R. sanguineus Beddome, 1863 (Serpentes: Uropeltidae). Zootaxa 4881 (1): 1-24, DOI: https://doi.org/10.11646/zootaxa.4881.1.