Mutation analysis of the SLC4A11 gene in Indian families with congenital hereditary endothelial dystrophy 2 and a review of the literature

Purpose: Congenital hereditary endothelial dystrophy 2 (CHED2) is an autosomal recessive disorder caused by mutations in the solute carrier family 4, sodium borate transporter, member 11 (SLC4A11) gene. The purpose of this study was to identify the genetic cause of CHED2 in six Indian families and catalog all known mutations in the SLC4A11 gene. Methods: Peripheral blood samples were collected from individuals of the families with CHED2 and used in genomic DNA isolation. PCR primers were used to amplify the entire coding region including intron-exon junctions of SLC4A11. Amplicons were subsequently sequenced to identify the mutations. Results: DNA sequence analysis of the six families identified four novel (viz., p.Thr262Ile, p.Gly417Arg, p.Cys611Arg, and p.His724Asp) mutations and one known p.Arg869His homozygous mutation in the SLC4A11 gene. The mutation p.Gly417Arg was identified in two families. Conclusions: This study increases the mutation spectrum of the SLC4A11 gene. A review of the literature showed that the total number of mutations in the SLC4A11 gene described to date is 78. Most of the mutations are missense, followed by insertions-deletions. The present study will be helpful in genetic diagnosis of the families reported here.

The WNT Signaling Pathway Contributes to Dectin-1-Dependent Inhibition of Toll-Like Receptor-Induced Inflammatory Signature

Macrophages regulate cell fate decisions during microbial challenges by carefully titrating signaling events activated by innate receptors such as dectin-1 or Toll-like receptors (TLRs). Here, we demonstrate that dectin-1 activation robustly dampens TLR-induced proinflammatory signature in macrophages. Dectin-1 induced the stabilization of beta-catenin via spleen tyrosine kinase (Syk)-reactive oxygen species (ROS) signals, contributing to the expression of WNT5A. Subsequently, WNT5A-responsive protein inhibitors of activated STAT (PIAS-1) and suppressor of cytokine signaling 1 (SOCS-1) mediate the downregulation of IRAK-1, IRAK-4, and MyD88, resulting in decreased expression of interleukin 12 (IL-12), IL-1 beta, and tumor necrosis factor alpha (TNF-alpha). In vivo activation of dectin-1 with pathogenic fungi or ligand resulted in an increased bacterial burden of Mycobacteria, Klebsiella, Staphylococcus, or Escherichia, with a concomitant decrease in TLR-triggered proinflammatory cytokines. All together, our study establishes a new role for dectin-1-responsive inhibitory mechanisms employed by virulent fungi to limit the proinflammatory environment of the host.

Natural Variation In Recovery From A Short Period Of Anoxia Due To A cGMP-Dependent Protein Kinase in Drosophila melanogaster

[EN] Protein Kinase G (PKG) or cGMP-dependent protein kinases (PKG) have been shown to play an important role in resistance to abiotic stressors such as high temperatures or oxygen deprivation in Drosophila melanogaster. In Drosophila, the foraging gene encodes a PKG; natural variants for this gene exist, which differ in the level of expression of PKG: rovers (forR allele) which express high PKG levels, and sitters (forS allele) which express lower PKG levels. This project explores the differences in recovery from short periods of anoxia between natural variants (focusing on forS2, flies with a sitter gene in a rover background), as well as mutants with insertions in the foraging gene and RNAi recombinants that show a reduced PKG expression. The parameters measured were time to recovery and level of activity after anoxia. The results showed lower activity after anoxia in sitters than in rovers, reflecting a worse recovery from the anoxic coma in flies with lower PKG levels.

The Fisheries for Mangrove Cockles,Anadaraspp., from Mexico to Peru, With Descriptions of Their Habitats and Biology, the Fishermen’s Lives, and the Effects of Shrimp Farming

This paper provides the first description of the mangrove cockle, Anadara spp., fisheries throughout their Latin American range along the Pacific coast from Mexico to Peru. Two species, A. tuberculosa and A. grandis, are found over the entire range, while A. similis occurs from El Salvador to Peru. Anadara tuberculosa is by far the most abundant, while A. grandis has declined in abundance during recent decades. Anadara tuberculosa and A. similis occur in level mud sediments in mangrove swamps, comprised mostly of Rhizophora mangle, which line the main-lands and islands of lagoons, whereas A. grandis inhabits intertidal mud flats along the edges of the same mangrove swamps. All harvested cockles are sexually mature. Gametogenesis of the three species occurs year round, and juvenile cockles grow rap-idly. Cockle densities at sizes at least 16–42 mm long ranged from 7 to 24/m2 in Mexico. Macrofaunal associates of cockles include crustaceans, gastropods, and finfishes. The mangrove swamps are in nearly pristine condition in every country except Honduras, Ecuador, and Peru, where shrimp farms constructed in the 1980’s and 1990’s have destroyed some mangrove zones. In addition, Hurricane Mitch destroyed some Honduran mangrove swamps in 1998. About 15,000 fishermen, including men, women, and children, harvest the cockles. Ecuador has the largest tabulated number of fishermen, 5,055, while Peru has the fewest, 75. Colombia has a large number, perhaps exceeding that in Ecuador, but a detailed census of them has never been made. The fishermen are poor and live a meager existence; they do not earn sufficient money to purchase adequate food to allow their full health and growth potential. They travel almost daily from their villages to the harvesting areas in wooden canoes and fiberglass boats at low tide when they can walk into the mangrove swamps to harvest cockles for about 4 h. Harvest rates, which vary among countries owing to differences in cockle abundances, range from about 50 cockles/fisherman/day in El Salvador and Honduras to 500–1,000/ fisherman/day in Mexico. The fishermen return to their villages and sell the cockles to dealers, who sell them mainly whole to market outlets within their countries, but there is some exporting to adjacent countries. An important food in most countries, the cockles are eaten in seviche, raw on the half-shell, and cooked with rice. The cockles are under heavy harvesting pressure, except in Mexico, but stocks are not yet being depleted because they are harvested at sizes which have already spawned. Also some spawning stocks lie within dense mangrove stands which the fishermen cannot reach. Consumers fortunately desire the largest cockles, spurning the smallest. Cockles are important to the people, and efforts to reduce the harvests to prevent overfishing would lead to severe economic suffering in the fishing communities. Pro-grams to conserve and improve cockle habitats may be the most judicious actions to take. Preserving the mangrove swamps intact, increasing their sizes where possible, and controlling cockle predators would lead to an increase in cockle abundance and harvests. Fishes that prey on juvenile cockles might be seined along the edges of swamps before the tide rises and they swim into the swamps to feed. Transplanting mangrove seedlings to suitable areas might increase the size of those habitats. The numbers of fishermen may increase in the future, because most adults now have several children. If new fishermen are tempted to harvest small, immature cockles and stocks are not increased, minimum size rules for harvestable cockles could be implemented and enforced to ensure adequate spawning.

Strikingly different penetrance of LHON in two Chinese families with primary mutation G11778A is independent of mtDNA haplogroup background and secondary mutation G13708A

The penetrance of Leber's hereditary optic neuropathy (LHON) in families with primary mitochondrial DNA (mtDNA) mutations is very complex. Matrilineal and nuclear genetic background, as well as environmental factors, have been reported to be involved in d

Molecular characterization of six Chinese families with m.3460G > A and Leber hereditary optic neuropathy

The primary mutation m.3460G > A occurs with a very low frequency (similar to 1%) in Chinese patients with Leber hereditary optic neuropathy (LHON). Up to now, there is no comprehensive study of Chinese patients harboring this mutation. We characterized six unrelated probands with m.3460G > A in this study, which were identified from 1,626 patients with LHON or suspected with LHON. The overall penetrance of LHON (25.6% [10/39]) in four pedigrees with m.3460G > A was substantially lower than those families with m.11778G > A (33.3% [619/1859]) as reported in our previous study. Intriguingly, family Le688 with a heteroplasmic m.3460G > A presented a lower penetrance (12.5%) than the other three families with a homoplasmic mutation. There is an elevated gender bias (affected male to affected female = 4:1) in the four families with m.3460G > A compared to those LHON families with m.11778G > A (2.4:1). Complete mtDNA sequencing indicated that the six matrilines belonged to haplogroups B4d1, F2, A5b, M12a, D4b2b, and D4b2, respectively. We did not identify any potential secondary mutation(s) that will affect or be associated with the penetrance of LHON in the six probands by using an evolutionary analysis and protein secondary-structure prediction. Taken together, our results suggested that the m.3460G > A mutation occurred multiple times in Chinese LHON patients. The heteroplasmic status of mutation m.3460G > A might influence the penetrance of LHON in family Le688.

Using set operations to deal with the frame problem

This paper presents a simple approach to the so-called frame problem based on some ordinary set operations, which does not require non-monotonic reasoning. Following the notion of the situation calculus, we shall represent a state of the world as a set of fluents, where a fluent is simply a Boolean-valued property whose truth-value is dependent on the time. High-level causal laws are characterised in terms of relationships between actions and the involved world states. An effect completion axiom is imposed on each causal law, which guarantees that all the fluents that can be affected by the performance of the corresponding action are always totally governed. It is shown that, compared with other techniques, such a set operation based approach provides a simpler and more effective treatment to the frame problem.

Can density functional theory (DFT) be used as an aid to a deeper understanding of tandem mass spectrometric fragmentation pathways?

Prediction of tandem mass spectrometric (MS/MS) fragmentation for non-peptidic molecules based on structure is of immense interest to the mass spectrometrist. If a reliable approach to MS/MS prediction could be achieved its impact within the pharmaceutical industry could be immense. Many publications have stressed that the fragmentation of a molecular ion or protonated molecule is a complex process that depends on many parameters, making prediction difficult. Commercial prediction software relies on a collection of general heuristic rules of fragmentation, which involve cleaving every bond in the structure to produce a list of 'expected' masses which can be compared with the experimental data. These approaches do not take into account the thermodynamic or molecular orbital effects that impact on the molecule at the point of protonation which could influence the potential sites of bond cleavage based on the structural motif. A series of compounds have been studied by examining the experimentally derived high-resolution MS/MS data and comparing it with the in silico modelling of the neutral and protonated structures. The effect that protonation at specific sites can have on the bond lengths has also been determined. We have calculated the thermodynamically most stable protonated species and have observed how that information can help predict the cleavage site for that ion. The data have shown that this use of in silico techniques could be a possible way to predict MS/MS spectra. Copyright (C) 2009 John Wiley & Sons, Ltd.

Lack of MEF2A Δ7aa mutation in Irish families with early onset ischaemic heart disease, a family based study

Background: Ischaemic heart disease (IHD) is a complex disease due to the combination of environmental and genetic factors. Mutations in the MEF2A gene have recently been reported in patients with IHD. In particular, a 21 base pair deletion (Δ7aa) in the MEF2A gene was identified in a family with an autosomal dominant pattern of inheritance of IHD. We investigated this region of the MEF2A gene using an Irish family-based study, where affected individuals had early-onset IHD. Methods: A total of 1494 individuals from 580 families were included (800 discordant sib-pairs and 64 parent-child trios). The Δ7aa region of the MEF2A gene was investigated based on amplicon size. Results: The Δ7aa mutation was not detected in any individual. Variation in the number of CAG (glutamate) and CCG (proline) residues was detected in a nearby region. However, this was not found to be associated with IHD. Conclusion: The Δ7aa mutation was not detected in any individual within the study population and is unlikely to play a significant role in the development of IHD in Ireland. Using family-based tests of association the number of tri-nucleotide repeats in a nearby region of the MEF2A gene was not associated with IHD in our study group. © 2006 Horan et al; licensee BioMed Central Ltd.

'An aid to mental health': natural history, alienists and therapeutics in Victorian Scotland

In the nineteenth century natural history was widely regarded as a rational and ‘distracting’ pursuit that countered the ill-effects, physical and mental, of urban life. This familiar argument was not only made by members of naturalists’ societies but was also borrowed and adapted by alienists concerned with the moral treatment of the insane. This paper examines the work of five long-serving superintendents in Victorian Scotland and uncovers the connections made between an interest in natural history and the management of mental disease. In addition to recovering a significant influence on the conduct of several alienists the paper explores arguments made outside the asylum walls in favour of natural history as an aid to mental health. Investigating the promotion of natural history as a therapeutic recreation in Scotland and elsewhere reveals more fully the moral and cultural significance attached to natural history pursuits in the nineteenth century.

Relationships matter: The problems and prospects for social workers' relationships with young children in care

One of the key lessons learnt in the UK from the Laming Inquiry into the death of Victoria Climbié was the importance of social workers developing consistent and long-term relationships with young children in whose lives they are involved. This issue is now informing policy developments, including the proposed Social Work Practices which, based on a similar model to General Practitioner practices, aim to provide a lead professional to act as a parental figure and an advocate for every child in care. This paper begins by confirming the importance of developing relationships between social workers and young children, but questions the ability of the new policy developments to facilitate these. Drawing upon data from research involving interviews with social workers, the paper outlines the factors which hinder social workers' relationships with young children and argues that while the new proposals address some of the more surface structural and organizational factors, they do not address the deeper factors regarding attitudes, values and emotional competence which are crucial if social workers are to successfully build relationships with young children in care.

Identifying families with multiple problems: Perspectives of practitioners and managers in three nations

Whilst child welfare systems in the United Kingdom, Australia and the United States may share a number of common goals, they are not designed to identify families with multiple problems. Where system output measures have been utilised as proxy measures to detect such families they indicate the presence of families in the population served by child and family social work. In interviews with practitioners and managers working within contrasting welfare systems, we explore how families with multiple problems are identiifed, what repsonses they currently recieve and how their needs might be better met.

N1, P2 and T-complex of the auditory brain event-related potentials to tones with varying rise times in adults with and without dyslexia

Dyslexia is a learning difficulty affecting the acquisition of fluent reading and spelling skills due to poor phonological processing. Underlying deficits in processing sound rise time have also been found in children and adults with dyslexia. However, the neural basis for these deficits is unknown. In the present study event-related potentials were used to index neural processing and examine the effect of rise time manipulation on the obligatory N1. T-complex and P2 responses in English speaking adults with and without dyslexia. The Tb wave of the T-complex showed differences between groups, with the amplitudes for Tb becoming less negative with increased rise time for the participants with dyslexia only. Frontocentral N1 and P2 did not show group effects. Enhanced Tb amplitude that is modulated by rise time could indicate altered neural networks at the lateral surface of the superior temporal gyrus in adults with dyslexia. (C) 2011 Elsevier B.V. All rights reserved.

The effects of a volunteer mentoring programme on reading outcomes among eight- to nine-year-old children: A follow up randomized controlled trial

This article presents the findings of a randomized controlled trial evaluation of the effects of a revised version of the volunteer mentoring programme, Time to Read. Participating children received two 30-minute mentoring sessions per week from volunteer mentors who carried out paired reading activities with the children. The current trial involved 512 children aged eight to nine years from 50 primary schools. The programme was found to be effective in improving decoding skills (d=+.15), reading rate (d=+.22) and reading fluency (d=+.14) and there was some evidence of a positive effect in relation to the children’s aspirations for the future (d=+.11). However, no evidence was found of the programme having an effect on reading comprehension or reading confidence and enjoyment of reading. The article concludes by suggesting that mentoring programmes using non-specialist volunteers can be effective in improving foundational reading skills but would appear to be less effective in terms of improving higher-order skills such as comprehension. The article also suggests that such programmes are likely to be most effective if concentrating on core reading activities rather than attempting to address reading outcomes indirectly through improving children’s confidence or wider enjoyment of reading.

The UNCRC and social workers' relationships with young children

In the UK, The Munro Review of Child Protection (2010, 2011a, 2011b) has recently highlighted that among the failings in safeguarding children known to social services is the lack of meaningful relationships between social workers and children. In her final report, Munro (2011b) has made recommendations for a more child-centred system anchored on two themes – the child's journey and the United Nations Convention on the Rights of the Child (UNCRC). This article illustrates by way of practical examples how the UNCRC, together with the detailed advice and guidance contained in the UNCRC general comments numbers 5, 7 and 12, provides the best framework for developing effective social work relationships with, and safeguarding, young children.