Regulation of ABCC6 trafficking and stability by a conserved C-terminal PDZ-like sequence

Mutations in the ABCC6 ABC-transporter are causative of pseudoxanthoma elasticum (PXE). The loss of functional ABCC6 protein in the basolateral membrane of the kidney and liver is putatively associated with altered secretion of a circulatory factor. As a result, systemic changes in elastic tissues are caused by progressive mineralization and degradation of elastic fibers. Premature arteriosclerosis, loss of skin and vascular tone, and a progressive loss of vision result from this ectopic mineralization. However, the identity of the circulatory factor and the specific role of ABCC6 in disease pathophysiology are not known. Though recessive loss-of-function alleles are associated with alterations in ABCC6 expression and function, the molecular pathologies associated with the majority of PXE-causing mutations are also not known. Sequence analysis of orthologous ABCC6 proteins indicates the C-terminal sequences are highly conserved and share high similarity to the PDZ sequences found in other ABCC subfamily members. Genetic testing of PXE patients suggests that at least one disease-causing mutation is located in a PDZ-like sequence at the extreme C-terminus of the ABCC6 protein. To evaluate the role of this C-terminal sequence in the biosynthesis and trafficking of ABCC6, a series of mutations were utilized to probe changes in ABCC6 biosynthesis, membrane stability and turnover. Removal of this PDZ-like sequence resulted in decreased steady-state ABCC6 levels, decreased cell surface expression and stability, and mislocalization of the ABCC6 protein in polarized cells. These data suggest that the conserved, PDZ-like sequence promotes the proper biosynthesis and trafficking of the ABCC6 protein. © 2014 Xue et al

Climate change and freshwater zooplankton: what does it boil down to?

Recently, major advances in the climate–zooplankton interface have been made some of which appeared to receive much attention in a broader audience of ecologists as well. In contrast to the marine realm, however, we still lack a more holistic summary of recent knowledge in freshwater. We discuss climate change-related variation in physical and biological attributes of lakes and running waters, high-order ecological functions, and subsequent alteration in zooplankton abundance, phenology, distribution, body size, community structure, life history parameters, and behavior by focusing on community level responses. The adequacy of large-scale climatic indices in ecology has received considerable support and provided a framework for the interpretation of community and species level responses in freshwater zooplankton. Modeling perspectives deserve particular consideration, since this promising stream of ecology is of particular applicability in climate change research owing to the inherently predictive nature of this field. In the future, ecologists should expand their research on species beyond daphnids, should address questions as to how different intrinsic and extrinsic drivers interact, should move beyond correlative approaches toward more mechanistic explanations, and last but not least, should facilitate transfer of biological data both across space and time

Age at Menarche, Schooling, and Sexual Debut in Northern Malawi

Background: Age at sexual debut is a key behavioural indicator used in HIV behavioural surveillance. Early age at menarche may precipitate early sex through perceived readiness for sex, or through school drop-out, but this is rarely studied. We investigated trends and circumstances of sexual debut in relation to schooling and age at menarche.Methods and Findings: A cross-sectional sexual behaviour survey was conducted on all individuals age 15-59 within a demographic surveillance site in Karonga District, Malawi. Time trends were assessed using birth cohorts. Survival analysis was used to estimate the median age at menarche, sexual debut and first marriage. The 25(th) centile was used to define "early" sex, and analyses of risk factors for early sex were restricted to those who had reached that age, and were done using logistic regression. Of the 8232 women and 7338 men resident in the area, 88% and 78%, respectively, were seen, and, 94% and 92% of these were interviewed. The median reported age at first sex was 17.5 for women and 18.8 for men. For women, ages at menarche, sexual debut and first marriage did not differ by birth cohort. For men, age at sexual debut and first marriage decreased slightly in later birth cohorts. For both men and women increased schooling was associated with later sexual debut and a longer delay between sexual debut and first marriage, but the associations were stronger for women. Earlier age at menarche was strongly associated with earlier sexual debut and marriage and lower schooling levels. In women early sexual debut (= 16 (OR 0.04, 95%CI 0.02-0.05) compared to those with menarche at = 16. The association between age at menarche and schooling was partly explained by age at sexual debut. The association between age at menarche and early sex was not altered by adjusting for schooling.Conclusions: Women with early menarche start sex and marry early, leading to school drop-out. It is important to find ways to support those who reach menarche early to access the same opportunities as other young women

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

ICAR: endoscopic skull‐base surgery

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Poaceae pollen grain size as a tool to distinguish past grasslands in South America: a new methodological approach

Despite the dominance of grasslands during the last glacial period, especially in South America, the highly uniform morphology of Poaceae pollen grains has so far allowed only very few palynological studies based on Poaceae pollen. In our study we compare two methods of distinguishing between South American grassland ecosystems based on quantitative morphology of Poaceae pollen grains. We investigated data sets from Paramo in southern Ecuador, Campos de Altitude and Campos in south-eastern and southern Brazil as well as data sets from the Pampa in Argentina by measuring the pollen grain length, grain width, pore diameter and annulus width. Firstly we investigated the potential influence of chemical treatment of pollen grains on pollen grain size as well as the measurement setting for defining the boundary conditions for using Poaceae pollen grains in a palaeoecological investigation. Finally the measured pollen grain parameters were analyzed by comparison of average grain length using statistical tests. This approach reveals highly significant differences in average grain size between all grassland ecosystems. Assuming that a certain grain size range can be assigned to a certain Poaceae taxon, conclusions about differences and similarities in taxa composition can be derived. We used two methods of multivariate data analysis. One uses the pollen grain parameters directly for a Principle Component Analysis (PCA). The other is an already established method in grassland ecology which defines parameter based pollen grain types to investigate similarities between grassland ecosystems. Both approaches confirm the results of the grain length analysis. In this work we demonstrate that the method we developed has the potential to provide acquisition of so far inaccessible information on spatial and temporal patterns and dynamics of South American grasslands

Lifespan and population dynamics of the endemic South American shrimpArtemesia longinaris (Crustacea: Penaeidae) in southeastern Brazil

ABSTRACT The present study investigated the growth, longevity and reproductive dynamics ofArtemesia longinaris in the southeastern coast of Brazil over a two-year period. Monthly collections were conducted in Ubatuba and Caraguatatuba using a shrimp fishing boat equipped with "double-rig" nets. Each region was divided into 7 sampling stations up to 35 m deep. Size frequency distributions, growth, longevity, sex ratio, and abundance of individuals in each demographic class, were compared. The relationship between abiotic factors and abundance of each demographic class was assessed using a Canonical Correlation Analysis. A total of 64,641 individuals were collected (6,928 measured) with an estimated longevity of 1.30 (Ubatuba) and 1.14 (Caraguatatuba) years for females and 1.03 years for males in both regions. There was a statistically significant bias in sex ratio toward females (Chi-squared test, p < 0.05) in both regions. The Canonical Correlation Analysis resulted in a canonical correlation coefficient of 0.31 (p = 0.00002). Salinity and temperature showed high correlation mainly with the presence of reproductive females. In general, this demographic class was most common in conditions of low temperature and high salinity. These findings, as well as other studies carried out in colder regions with the same species, are consistent with classical latitudinal paradigm