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Let X be a set and H a collection of functions from X to { 0 , 1 } . We say that H shatters a finite set C ⊂ X if the restriction of H yields every possible function from C to { 0 , 1 } . The VC-dimension of H is the largest number d such that there exists a set of size d shattered by H , and no set of size d + 1 is shattered by H . Vapnik and Chervonenkis introduced this idea in the early 70s in the context of learning theory, and this idea has also had a significant impact on other areas of mathematics. In this paper we study the VC-dimension of a class of functions H defined on F q d , the d-dimensional vector space over the finite field with q elements. Define H t d = { h y (x) : y ∈ F q d } , where for x ∈ F q d , h y (x) = 1 if ‖ x - y ‖ = t , and 0 otherwise, where here, and throughout, ‖ x ‖ = x 1 2 + x 2 2 + ⋯ + x d 2 . Here t ∈ F q , t ≠ 0 . Define H t d (E) the same way with respect to E ⊂ F q d . The learning task here is to find a sphere of radius t centered at some point y ∈ E unknown to the learner. The learning process consists of taking random samples of elements of E of sufficiently large size. We are going to prove that when d = 2 , and | E | ⩾ C q 15 / 8 , the VC-dimension of H t 2 (E) is equal to 3. This leads to an intricate configuration problem which is interesting in its own right and requires a new approach. [ABSTRACT FROM AUTHOR]

Summary: We present here the complete mtDNA genome (mitogenome) of Heterorhabditis bacteriophora , an important biological control agent of soil-dwelling insect pests in agriculture and horticulture. This is the first description of a mitogenome for a member of the family Heterorhabditidae. The genome contains the typical chromadorean complement of 12 protein-coding genes, 22 tRNA genes and two rRNA genes. All genes are transcribed in the same direction and have a nucleotide composition high in A and T. For the entire genome, the nucleotide contents are 47.02% (T), 28.81% (A), 16.10% (G), 8.08% (C) and 75.83% (AT). Heterorhabditis bacteriophora has a unique, idiosyncratic gene arrangement. It differs from that of Caenorhabditis elegans in having a block of seven genes: trnQ-trnF-cytb-trnL1-cox3-trnT-nad4 translocated to a position between nad3 and nad5 , as well as having a change in the position of the four tRNA block gene cluster, trnC-trnM-trnD-trnG , where trnC and trnM have switched places and trnD and trnG have translocated between nad4 and nad5 genes. The H. bacteriophora mitogenome is 18 128 bp long, and thus is ca 4 kb larger than the mitogenomes of most chromadoreans. This relatively large genome is due to the presence of five non-coding regions (NCR): NCR1 (114 bp), NCR2 (159 bp), NCR3 (498 bp), NCR4 (1917 bp) and NCR5 (2154 bp), which make up 26.7% of the genome. The NCR5 had the highest A + T content of 83.47% indicating that this region is the likely AT-rich control region. The complete 498 bp NCR3 sequence is duplicated in NCR4 and in NCR5 (the putative AT-rich control region). Such an organisation has not been reported previously in nematode mtDNA. [ABSTRACT FROM AUTHOR]

• Functional properties of excitatory inputs onto cortical neurons are more diverse. • Cortical neurons can receive imbalanced synaptic excitation and inhibition. • Current theoretical models are consistent with these findings. • New evidence suggests cortical circuits support operational flexibility. Establishing the fundamental principles that underlie the integration of excitatory and inhibitory presynaptic input populations is crucial to understanding how individual cortical neurons transform signals from peripheral receptors. Here we review recent studies using novel tools to examine the functional properties of excitatory synaptic inputs and the tuning of excitation and inhibition onto individual neurons. New evidence challenges existing synaptic connectivity rules and suggests a more complex functional synaptic architecture that supports a broad range of operations, enabling single neurons to encode multiple sensory features and flexibly shape their computations in the face of diverse sensory input. [ABSTRACT FROM AUTHOR]

Our ability to make accurate and specific genetic diagnoses in individuals with severe developmental disorders has been transformed by data derived from genomic sequencing technologies. These data reveal both the patterns and rates of different mutational mechanisms and identify regions of the human genome with fewer mutations than would be expected. In outbred populations, the most common identifiable cause of severe developmental disorders is de novo mutation affecting the coding region in one of approximately 500 different genes, almost universally showing constraint. Simply combining the location of a de novo genomic event with its predicted consequence on the gene product gives significant diagnostic power. Our knowledge of the diversity of phenotypic consequences associated with comparable diagnostic genotypes at each locus is improving. Computationally useful phenotype data will improve diagnostic interpretation of ultrarare genetic variants and, in the long run, indicate which specific embryonic processes have been perturbed. [ABSTRACT FROM AUTHOR]

Historians have long contended that Emory Upton (1839-81) was a "militaristic zealot" whose anti-democratic ideas caused generations of U.S. Army officers to sink into "Uptonian pessimism," a belief that democracies were unable to manifest a coherent military policy. This essay argues otherwise. First, it contends that Upton was not a militarist and that he intended his reforms to protect democracy, not undermine it. Second, it argues that the U.S. Army officer corps in the late nineteenth and early twentieth centuries was not mired in pessimism, Uptonian or otherwise. [ABSTRACT FROM AUTHOR]

This phenomenological study explored the decision-making experience of parents whose children joined Special Olympics programs. The experiences of 16 families with children 10-22 years old were gathered through interviews, artifacts, and field notes. Three themes emerged from the thematic analysis (a) thoughtful instruction, (b) finding the fit, and (c) security of acceptance. Parents sought instructors who were interested in building relationships with their children and creating anxiety-free instructional environments for them. A good program fit occurred when instructors had expectations for motor skill development and increased independence. Parents also preferred environments that encouraged meaningful peer interactions. The findings were interpreted within the context of self-determination theory. [ABSTRACT FROM AUTHOR]

The investigation explored 12 adults' past experiences of physical awkwardness. Hermeneutic phenomenology, a descriptive and interpretative methodology, uncovered feelings and meanings associated with childhood reminiscences of physical awkwardness, from 18 semi-structured interviews. Findings focus upon four themes, namely: "failing and falling," "hurt and humiliation," "worrying and wondering," and seeking ways of "avoiding awkwardness" in the future. A heightened awareness of the subjective lived experience of those who are awkward in physical activity and sport situations would alert teachers, coaches, and others of the potential emotional and social consequences associated with it and the need to address the problem of physical awkwardness, in particular, during early growth, maturation, skill development, and learning. [ABSTRACT FROM AUTHOR]

Focuses on the attacks of critic Emory Upton on the role of citizen soldier in the United States military. Information on the academic historians who criticized Upton's evaluation of citizen soldiers; Value of Upton's emphasis on discipline and training; His involvement in military reform efforts; Discussion on the books he has written.

The sodium leak channel nonselective protein (NALCN) is a regulator of the pacemaker neurons that are responsible for rhythmic behavior (including respiration), maintaining the resting membrane potential, and are required for action potential production. NALCN-null mice show early death associated with disrupted respiratory rhythms, characterized by frequent and profound apneas. We report 3 children (2 siblings) with compound heterozygous mutations in NALCN associated with developmental impairment, hypotonia, and central sleep-disordered breathing causing apneas. Supplemental oxygen normalized the respiratory rhythm. NALCN mutations have been previously reported to cause severe hypotonia, speech impairment, and cognitive delay as well as infantile neuroaxonal dystrophy and facial dysmorphism. Nonsynonymous changes in the 2 affected extracellular loops may be responsible for the deleterious effect on the stability of the respiratory rhythm. Although oxygen is known to be a stabilizer of respiratory rhythm in central apnea in children, its role in NALCN dysfunction requires further investigation. [ABSTRACT FROM AUTHOR]

This study presents the use of relaxed molecular clock methods to infer the dates of divergence between Panagrolaimus species. Autocorrelated relaxed tree methods, combined with well characterised fossil calibration dates, yield estimates of nematode divergence dates in accordance with the palaeontological age of fossil ascarid eggs and with the previously estimated date of 18 Ma (range 11.6 to 29.9 Ma) for the divergence of the Caenorhabditis lineage. Our data indicate that Panagrolaimus davidi from Antarctica separated ca 21.98 Ma from its currently known, most closely related strain. Thus, P. davidi may have existed in Antarctica prior to the Last Glacial Maximum, although this seems unlikely as it shares physiological and life history traits with closely related nematodes from temperate climates. These traits may have facilitated colonisation of Antarctica by P. davidi after the quaternary glaciation, analogous to the colonisation of Surtsey Island, Iceland, by P. superbus after its volcanic formation. This study demonstrates that autocorrelated relaxed tree methods combined with well characterised fossil calibration dates may be used as a method to estimate the divergence dates within nematodes in order to gain insight into their evolutionary history. [ABSTRACT FROM AUTHOR]

Reviewed: Winfield Scott Hancock: Gettysburg Hero. Jamieson, Perry D.

Reviewed: George Gordon Meade and the War in the East. Rafuse, Ethan S.

An acid-active exo/endo-chitinase; comprising a GH18 catalytic domain and substrate insertion domain; originating from the thermophilic filamentous fungus Rasamsonia emersonii, was expressed in Pichia pastoris. In silico analysis including phylogenetic analysis, and recombinant production, purification, biochemical characterisation, and industrial application testing, was carried out. The expressed protein was identified by SDS-PAGE as a smear from 56.3 to 125.1 kDa, which sharpens into bands at 46.0 kDa, 48.4 kDa and a smear above 60 kDa when treated with PNGase F. The acid-active chitinase was primarily a chitobiosidase but displayed some endo-chitinase and acetyl-glucosamidase activity. The enzyme was optimally active at 50 °C, and markedly low pH of 2.8. As far as the authors are aware, this is the lowest pH optima reported for any fungal chitinase. The acid-active chitinase likely plays a role in chitin degradation for cell uptake in its native environment, perhaps in conjunction with a chitin deacetylase. Comparative studies with other R. emersonii chitinases indicate that they may play a synergistic role in this. The acid-active chitinase displayed some efficacy against non-treated substrates; fungal chitin and chitin from shrimp. Thus, it may be suited to industrial chitin hydrolysis reactions for extraction of glucosamine and chitobiose at low pH. [ABSTRACT FROM AUTHOR]

The Canadian archivist Jennifer Douglas has highlighted six layers of archival creation which she argues shape the ways in which a writer’s archive is formed, appraised, enhanced, arranged and interpreted over time. This article applies Douglas’s notion of the six layers of creation to the George Orwell archive, which is held at University College London, by showing the ways in which the archive has been shaped and interpreted over time by various contributors; it discusses not only the value of these contributions, but also how typical such contributions are. The article also discusses the challenge that collections like the Orwell archive pose to our understanding of the concept of the fonds. In agreement with Geoffrey Yeo’s recent writings on the subject, this article concludes that a collection such as the Orwell archive, which has been supplemented with additional material over time, is best understood as a collection of items that reflects the contributions of a number of different creators and custodians, something that is distinct from its main creator’s ‘conceptual’ fonds, which is dispersed across a number of collections. [ABSTRACT FROM PUBLISHER]

Background: Hypoglycaemia is a common and potentially life threatening consequence of insulin and sulphonylurea treated Diabetes. Some severe hypoglycaemic events result in emergency ambulance attendance. Many of these patients are treated at home and do not require immediate transportation to an Emergency Department. However only 27-37 % of patients then follow up their care with a diabetes specialist. Consequently repeat severe hypoglycaemic events occur.Methods: The intervention was implemented for 8 months, using a prospective cohort design with a historic control, in one Scottish Health Board in 2012. Data was collected using postal survey questionnaires to patients and ambulance clinicians, telephone survey follow-up questions to patients. Scottish Ambulance Service electronic records were linked with the SCI-Diabetes database of patient records to enable objective measurement of follow-up behaviour.Results: Ambulance clinicians' (n = 92) awareness of the intervention was high and both the prompt card and telephone call components of the intervention were delivered to most eligible patients. The intervention was perceived as highly acceptable to patients (n = 37), and very useful by both patients and ambulance clinicians. However, comparison of patient follow-up behaviours using linked-data (n = 205), suggest that the intervention was unsuccessful in improving rates of patients' following up their care.Conclusions: This study shows that the intervention is implementable, highly acceptable to patients, and considered very useful by both patients and ambulance clinicians. However, preliminary evidence of effectiveness is not encouraging. The study's novel use of linking existing clinical data for outcome measurement exposed challenges in the feasibility of using this data for intervention development and evaluation. Future research should examine challenges to the successful testing and effectiveness of the intervention. Revisions are likely to be required, both to study design and the optimisation of the intervention's content and components. [ABSTRACT FROM AUTHOR]

The distribution of potential clinically relevant antibiotic resistance (AR) genes across soil, water, animal, plant and human microbiomes is not well understood. We aimed to investigate if there were differences in the distribution and relative abundances of resistance genes across a variety of ecological niches. All sequence reads (human, animal, water, soil, plant and insect metagenomes) from the MG-RAST database were downloaded and assembled into a local sequence database. We show that there are many reservoirs of the basic form of resistance genes e.g. blaTEM, but the human and mammalian gut microbiomes contain the widest diversity of clinically relevant resistance genes using metagenomic analysis. The human microbiomes contained a high relative abundance of resistance genes, while the relative abundances varied greatly in the marine and soilmetagenomes, when datasetswith greater than onemillion geneswere compared. While these results reflect a bias in the distribution of AR genes across the metagenomes, we note this interpretation with caution. Metagenomics analysis includes limits in terms of detection and identification of AR genes in complex and diverse microbiome population. Therefore, if we do not detect the AR gene is it in fact not there or just below the limits of our techniques? [ABSTRACT FROM AUTHOR]

Background: Prions are transmissible, propagating alternative states of proteins, and are usually made from the fibrillar, beta-sheet-rich assemblies termed amyloid. Prions in the budding yeast Saccharomyces cerevisiae propagate heritable phenotypes, uncover hidden genetic variation, function in large-scale gene regulation, and can act like diseases. Almost all these amyloid prions have asparagine/glutamine-rich (N/Q-rich) domains. Other proteins, that we term here 'prionogenic amyloid formers' (PAFs), have been shown to form amyloid in vivo, and to have N/Qrich domains that can propagate heritable states in yeast cells. Also, there are >200 other S.cerevisiae proteins with prion-like N/Q-rich sequence composition. Furthermore, human proteins with such N/Q-rich composition have been linked to the pathomechanisms of neurodegenerative amyloid diseases. Results: Here, we exploit the increasing abundance of complete fungal genomes to examine the ancestry of prions/PAFs and other N/Q-rich proteins across the fungal kingdom. We find distinct evolutionary behavior for Q-rich and N-rich prions/PAFs; those of ancient ancestry (outside the budding yeasts, Saccharomycetes) are Q-rich, whereas N-rich cases arose early in Saccharomycetes evolution. This emergence of N-rich prion/PAFs is linked to a large-scale emergence of N-rich proteins during Saccharomycetes evolution, with Saccharomycetes showing a distinctive trend for population sizes of prion-like proteins that sets them apart from all the other fungi. Conversely, some clades, e.g. Eurotiales, have much fewer N/Q-rich proteins, and in some cases likely lose them en masse, perhaps due to greater amyloid intolerance, although they contain relatively more non-N/Q-rich predicted prions. We find that recent mutational tendencies arising during Saccharomycetes evolution (i.e., increased numbers of N residues and a tendency to form more poly-N tracts), contributed to the expansion/development of the prion phenomenon. Variation in these mutational tendencies in Saccharomycetes is correlated with the population sizes of prion-like proteins, thus implying that selection pressures on N/Q-rich protein sequences against amyloidogenesis are not generally maintained in budding yeasts. Conclusions: These results help to delineate further the limits and origins of N/Q-rich prions, and provide insight as a case study of the evolution of compositionally-defined protein domains. [ABSTRACT FROM AUTHOR]

Gamma-ray bursts (GRBs) categorically produce broad-band afterglow emission, but in some cases, emission in the optical band is dimmer than expected based on the contemporaneously observed X-ray flux. This phenomenon, aptly dubbed 'optical darkness', has been studied extensively in long GRBs (associated with the explosive deaths of massive stars), with possible explanations ranging from host environment extinction to high redshift to possibly unique emission mechanisms. However, investigations into optical darkness in short GRBs (associated with the mergers of compact object binaries) have thus far been limited. This work implements a procedure for determining the darkness of GRBs based on spectral indices calculated using temporally matched Swift– X-ray Telescope data and optical follow-up observations; presents a complete and up-to-date catalogue of known short GRBs that exhibit optical darkness; and outlines some of the possible explanations for optically dark short GRBs. In the process of this analysis, we developed versatile and scalable data processing code that facilitates reproducibility and reuse of our pipeline. These analysis tools and resulting complete sample of dark short GRBs enable a systematic statistical study of the phenomenon and its origins, and reveal that optical darkness is indeed quite rare in short GRBs, and highly dependent on observing response time and observational effects. [ABSTRACT FROM AUTHOR]

Microphthalmia, anophthalmia and coloboma (MAC) are distinct phenotypes that represent a continuum of structural developmental eye defects. In severe bilateral cases (anophthalmia or severe microphthalmia) the genetic cause is now identifiable in approximately 80 percent of cases, with de novo heterozygous loss-of-function mutations in SOX2 or OTX2 being the most common. The genetic cause of other forms of MAC, in particular isolated coloboma, remains unknown in the majority of cases. This review will focus on MAC phenotypes that are associated with mutation of the genes SOX2, OTX2, PAX6, STRA6, ALDH1A3, RARB, VSX2, RAX, FOXE3, BMP4, BMP7, GDF3, GDF6, ABCB6, ATOH7, C12orf57, TENM3 (ODZ3), and VAX1. Recently reported mutation of the SALL2 and YAP1 genes are discussed in brief. Clinical and genetic features were reviewed in a total of 283 unrelated MAC cases or families that were mutation-positive from these 20 genes. Both the relative frequency of mutations in MAC cohort screens and the level of confidence in the assignment of disease-causing status were evaluated for each gene. [ABSTRACT FROM AUTHOR]

Many hospitals struggle to implement the full sepsis care bundle, but research suggests that many patients with sepsis are transported to hospital by ambulance. In 2011, the Scottish Ambulance Service introduced a pre-hospital sepsis screening tool (PSST) to expedite sepsis identification and care delivery. However, ambulance clinicians have reported varying degrees of interest and enthusiasm from hospital staff during handover. Therefore, an online survey was set up to investigate medical and nursing staff perceptions and experiences of the introduction of a PSST. This article discusses the results, which show that participants perceive the PSST reduces time to treatment, improves continuity of care, benefits patients and is accurately applied by ambulance clinicians, but which also highlight problems with communication. The delivery of in-hospital and pre-hospital sepsis care is challenging, but simple measures such as improving and standardising communication and alert systems between ambulance services and receiving hospitals could improve the clinical effects of a PSST. [ABSTRACT FROM AUTHOR]

Background Outbreaks of equine influenza ( EI) in endemic populations cause disruption and economic loss. Objectives To identify (i) factors involved in the spread of EI (ii) virus strains responsible for outbreaks (iii) single radial haemolysis ( SRH) antibody levels correlating with protection against current virus strains (iv) evidence of vaccination breakdown. Methods RT- PCR, virus isolation and SRH were carried out on nasopharyngeal swabs and blood samples collected from horses, ponies and donkeys on affected premises. Data relating to 629 samples from 135 equidae were analysed. Results and conclusions Outbreaks were sporadic, self limiting and associated with the movement of horses. Vaccination status and age influenced clinical signs of disease while housing and fomites contributed to virus spread. Subclinical infection as defined as a horse which tested positive by one or more of the following; RT- PCR, virus isolation and seroconversion in the absence of clinical signs, was identified in 9% of animals. Of the horses with up to date vaccination records 32% developed clinical signs. Vaccine breakdown occurred among horses vaccinated with all four commercially available vaccines. Analysis of HA1 sequence data generated for 26 viruses indicated that they all belonged to clade 2 of the Florida sublineage. Higher SRH antibody levels were required for both clinical and virological protection than reported in studies where vaccine strains were antigenically and genetically similar to those circulating in the field. The results of this study therefore support the OIE recommendations that vaccines be updated to include representatives of both clades of the Florida sublineage. [ABSTRACT FROM AUTHOR]

The article presents a comparative study of molecular evolution of signalling pathway members across olfactory, gustatory and photosensory modalities. The study revealed large gene duplication events conserved within each phylum within each signalling pathway. The study concludes 'sessile' mechanism of sensory pathway evolution which on one side is facilitated by gene duplication and relaxed selection whereas on other side it is anchored by high levels of selective constraint.

Purpose: The incorporation of three-dimensional (3D) planning for the treatment of bone metastases has been embraced in many North American practices with assumed superior tumor targeting, sparing of normal structures, and improvement in patient outcomes. The goal of our project was to evaluate the dosimetric and clinical impact of 3D vs. two-dimensional (2D) planning for patients who require simple palliative radiotherapy techniques (≤2 beams) for bone metastases. Methods: Patients undergoing palliative radiation therapy for bone metastases were eligible. The study oncologists first documented the intended treatment target, defined the treatment target/field using digital radiographs (2D), followed by using full 3D planning computerized tomography volumetric datasets. Treatment plans were compared dosimetrically, and patient-reported outcomes (pain, fatigue, anorexia, and nausea) were compared against a historical cohort treated with 2D plans. Results: Eighty-five patients were enrolled in the study group. Review of the 3D datasets led to changes in the target area of interest in 44/85 (52 %) of cases, of which 21/85 (25 %) were clinically significant. 3D plans resulted in superior target coverage and normal tissue sparing. There was no significant difference in patient-reported outcomes however. Conclusion: 3D radiotherapy planning resulted in superior treatment plans but we were unable to demonstrate a significant benefit in clinical outcomes. Prospective study designs are needed to describe the contemporary expectation of palliative radiotherapy for bone metastases in the modern era of 3D planning. [ABSTRACT FROM AUTHOR]

W. B. Yeats and Louis MacNeice had much in common. Each had been ‘brought up in an Irish middle-class Protestant family’; each was profoundly affected by family roots in Connaught; both expressed violent and inconsistent responses to Irish political and religious conflicts; both lived mostly in England while preserving their very different Irish identities and accents. Like so many Irish writers adapting to a cosmopolitan world, Yeats and MacNeice found it expedient to conceal or distort certain awkward elements of their background. Being Irish in England was bad enough, without having to overcome liberal repugnance for the arrogance of Yeats’s ‘Anglo-Ireland’ or the bigotry of MacNeice’s ‘Black North’. However eloquently they disowned such stereotypes, neither writer could erase the imprint of a Protestant Irish upbringing. This article explores coded passages in their writings which reveal, when fully contextualized, the importance of Orangeism in their own families (Yeats’s Sligo relatives, MacNeice’s father). Each writer, when alluding to Orangeism, used a surrogate to avoid admitting a family connection (Yeats’s stable-boy in Sligo, MacNeice’s gardener in Carrickfergus). Drawing on unfamiliar biographical and institutional sources, the article indicates what each writer had to hide, and why he wished to hide it. Concealed Orange influences in certain poems by each writer are discussed. For Yeats, Orange ballads provided raw material for his celebration of violence and conflict in later life. For MacNeice, Orangeism took on a more benign aspect as he grew older and became reconciled with the mild puritanism of his once terrifying clergyman-father. [ABSTRACT FROM PUBLISHER]

Do most academic historians of twentieth-century Ireland conform to a 'constitutional narrative', driven by a moral imperative to subvert republican interpretations? Has their shared political agenda led to widespread distortion, suppression, 'elision' and falsification of the evidential record? Is it high time to root out 'the insidious influence of Irish public histories presented as objective historical evidence'? In the view of John M. Regan, the answer in all cases is an emphatic 'yes'. This riposte to his recent article in History examines the credibility of Regan's critique, with particular attention to his claim that the late Peter Hart was guilty of 'academic fraud' in his controversial analysis of republican sectarianism and 'ethnic cleansing' in the Irish revolution. When closely examined, Regan's analysis seems perverse and untenable, implicitly relying on a reductionist conspiracy theory which ignores the rich variety and sound scholarship displayed by several generations of historians of modern Ireland. [ABSTRACT FROM AUTHOR]

Horizontal gene transfer ( HGT) is frequently observed in prokaryotes and until recently was assumed to be of limited importance to eukaryotes. However, there is an increasing body of evidence to suggest that HGT is an important mechanism in eukaryotic genome evolution, particularly in unicellular organisms. The transfer of individual genes, gene clusters or entire chromosomes can have significant impacts on niche specification, disease emergence or shift in metabolic capabilities. In terms of genomic sequencing, the fungal kingdom is one of the most densely sampled eukaryotic lineages and is at the forefront of eukaryote comparative genomics and enables us to use fungi to study eukaryotic evolutionary mechanisms including HGT. This review describes the bioinformatics-based methodologies commonly used to locate HGT in fungal genomes and investigates the possible mechanisms involved in transferring genetic material laterally into fungal species. I will highlight a number of fungal HGT events and discuss the impact they have played on fungal evolution and discuss the implications HGT may have on the fungal tree of life. [ABSTRACT FROM AUTHOR]

The relationship between biological network architectures and evolution is unclear. Within the phylum nematoda olfaction represents a critical survival tool. For nematodes, olfaction contributes to multiple processes including the finding of food, hosts, and reproductive partners, making developmental decisions, and evading predators. Here we examine a dynamic nematode odor genetic network to investigate how divergence, diversity, and contribution are shaped by network topology. Our findings describe connectivity frameworks and characteristics that correlate with molecular evolution and contribution across the olfactory network. Our data helps guide the development of a robust evolutionary description of the nematode odor network that may eventually aid in the prediction of interactive and functional qualities of novel nodes. [ABSTRACT FROM AUTHOR]

The yeast prion [PSI+] has been implicated in the generation of novel phenotypes by a mechanism involving a reduction in translation fidelity causing readthrough of naturally occurring stop codons. Some [PSI+] associated phenotypes may also be generated due to readthrough of inactivating stop codon mutations (ISCMs). Using next generation sequencing we have sequenced the genomes of two Saccharomyces cerevisiae strains that are commonly used for the study of the yeast [PSI+] prion. We have identified approximately 26,000 and 6,500 single nucleotide polymorphisms (SNPs) in strains 74-D694 and G600 respectively, compared to reference strain S288C. In addition to SNPs that produce non-synonymous amino acid changes we have also identified a number of SNPs that cause potential ISCMs in these strains, one of which we show is associated with a [PSI+]-dependent stress resistance phenotype in strain G600. We identified twenty-two potential ISCMs in strain 74-D694, present in genes involved in a variety of cellular processes including nitrogen metabolism, signal transduction and oxidative stress response. The presence of ISCMs in a subset of these genes provides possible explanations for previously identified [PSI+]-associated phenotypes in this strain. A comparison of ISCMs in strains G600 and 74-D694 with S. cerevisiae strains sequenced as part of the Saccharomyces Genome Resequencing Project (SGRP) shows much variation in the generation of strain-specific ISCMs and suggests this process is possible under complex genetic control. Additionally we have identified a major difference in the abilities of strains G600 and 74-D694 to grow at elevated temperatures. However, this difference appears unrelated to novel SNPs identified in strain 74-D694 present in proteins involved in the heat shock response, but may be attributed to other SNP differences in genes previously identified as playing a role in high temperature growth. [ABSTRACT FROM AUTHOR]

Background: Candida species are the most common cause of opportunistic fungal infection worldwide. Recent sequencing efforts have provided a wealth of Candida genomic data. We have developed the Candida Gene Order Browser (CGOB), an online tool that aids comparative syntenic analyses of Candida species. CGOB incorporates all available Candida clade genome sequences including two Candida albicans isolates (SC5314 and WO-1) and 8 closely related species (Candida dubliniensis, Candida tropicalis, Candida parapsilosis, Lodderomyces elongisporus, Debaryomyces hansenii, Pichia stipitis, Candida guilliermondii and Candida lusitaniae). Saccharomyces cerevisiae is also included as a reference genome. Results: CGOB assignments of homology were manually curated based on sequence similarity and synteny. In total CGOB includes 65617 genes arranged into 13625 homology columns. We have also generated improved Candida gene sets by merging/removing partial genes in each genome. Interrogation of CGOB revealed that the majority of tandemly duplicated genes are under strong purifying selection in all Candida species. We identified clusters of adjacent genes involved in the same metabolic pathways (such as catabolism of biotin, galactose and N-acetyl glucosamine) and we showed that some clusters are species or lineage-specific. We also identified one example of intron gain in C. albicans. Conclusions: Our analysis provides an important resource that is now available for the Candida community. CGOB is available at http://cgob.ucd.ie. [ABSTRACT FROM AUTHOR]

Phenazines are secondary metabolites with broad-spectrum antibiotic activity against bacteria, fungi, and eukaryotes. In pseudomonad species, a conserved seven-gene phenazine operon ( phzABCDEFG) is required for the conversion of chorismic acid to the broad-spectrum antibiotic phenazine-1-carboxylate. Previous analyses of genes involved in phenazine production from nonpseudomonad species uncovered a high degree of sequence similarity to pseudomonad homologues. The analyses undertaken in this study wished to eluciadate the evolutionary history of genes involved in the production of phenazines. Furthermore, I wanted to determine if the phenazine operon has been transferred through horizontal gene transfer. Analyses of GC content, codon usage patterns, frequency of 3:1 dinucleotides, sequence similarities, and phylogenetic reconstructions were undertaken to map the evolutionary history of phenazine genes from multiple bacterial species. Patchy phyletic distribution, high sequence similarities, and phylogenetic evidence infer that pseudomonad, Streptomyces cinnamonensis, Pantoea agglomerans, Burkholderia cepacia, Pectobacterium atrosepticum, Brevibacterium linens, and Mycobacterium abscessus species all contain a phenazine operon which has most likely been transferred among these species through horizontal gene transfer. The acquisition of an antibiotic-associated operon is significant, as it may increase the relative fitness of the recipient species. [ABSTRACT FROM AUTHOR]

Background: To date very few incidences of interdomain gene transfer into fungi have been identified. Here, we used the emerging genome sequences of Candida albicans WO-1, Candida tropicalis, Candida parapsilosis, Clavispora lusitaniae, Pichia guilliermondii, and Lodderomyces elongisporus to identify recent interdomain HGT events. We refer to these as CTG species because they translate the CTG codon as serine rather than leucine, and share a recent common ancestor. Results: Phylogenetic and syntenic information infer that two C. parapsilosis genes originate from bacterial sources. One encodes a putative proline racemase (PR). Phylogenetic analysis also infers that there were independent transfers of bacterial PR enzymes into members of the Pezizomycotina, and protists. The second HGT gene in C. parapsilosis belongs to the phenazine F (PhzF) superfamily. Most CTG species also contain a fungal PhzF homolog. Our phylogeny suggests that the CTG homolog originated from an ancient HGT event, from a member of the proteobacteria. An analysis of synteny suggests that C. parapsilosis has lost the endogenous fungal form of PhzF, and subsequently reacquired it from a proteobacterial source. There is evidence that Schizosaccharomyces pombe and Basidiomycotina also obtained a PhzF homolog through HGT. Conclusion: Our search revealed two instances of well-supported HGT from bacteria into the CTG clade, both specific to C. parapsilosis. Therefore, while recent interkingdom gene transfer has taken place in the CTG lineage, its occurrence is rare. However, our analysis will not detect ancient gene transfers, and we may have underestimated the global extent of HGT into CTG species. [ABSTRACT FROM AUTHOR]

Functional maps arise in developing visual cortex as response selectivities become organized into columnar patterns of population activity. Recent studies of developing orientation and direction maps indicate that both are sensitive to visual experience, but not to the same degree or duration. Direction maps have a greater dependence on early vision, while orientation maps remain sensitive to experience for a longer period of cortical maturation. There is also a darker side to experience: abnormal vision through closed lids produces severe impairments in neuronal selectivity, rendering these maps nearly undetectable. Thus, the rules that govern their formation and the construction of the underlying neural circuits are modulated—for better or worse—by early vision. Direction maps, and possibly maps of other properties that are dependent upon precise conjunctions of spatial and temporal signals, are most susceptible to the potential benefits and maladaptive consequences of early sensory experience. [Copyright &y& Elsevier]

We report on three unrelated mentally disabled patients, each carrying a de novo balanced translocation that truncates the autism susceptibility candidate 2 ( AUTS2) gene at 7q11.2. One of our patients shows relatively mild mental retardation; the other two display more profound disorders. One patient is also physically disabled, exhibiting urogenital and limb malformations in addition to severe mental retardation. The function of AUTS2 is presently unknown, but it has been shown to be disrupted in monozygotic twins with autism and mental retardation, both carrying a translocation t(7;20)(q11.2;p11.2) (de la Barra et al. in Rev Chil Pediatr 57:549–554, ; Sultana et al. in Genomics 80:129–134, ). Given the overlap of this autism/mental retardation (MR) phenotype and the MR-associated disorders in our patients, together with the fact that mapping of the additional autosomal breakpoints involved did not disclose obvious candidate disease genes, we ascertain with this study that AUTS2 mutations are clearly linked to autosomal dominant mental retardation. [ABSTRACT FROM AUTHOR]

Abstract: An accurate and repeatable tibial measurement system will aid in the definition of tibial geometry and improving tibial prosthesis design. Unlike in the femur, there is no standardized method for constructing a tibial coordinate frame. Most tibial measurements are given relative to femoral axes or the coordinate frame of the CT/MRI scanner or radiograph machine. The objective of this study was to establish an independent tibial coordinate frame. Data consisted of CT scans from 34 subjects. The tibial anatomical axis was chosen as the axial axis. The anteroposterior (AP) axis was selected to be parallel to the lateral surface of the tibial shaft and orthogonal to the anatomical axis and from this the mediolateral axis could be derived. The selected AP axis was compared with the surgical tibial AP axis by measuring their variability relative to a common axis, the posterior tibial condylar line (PTCL). The mean angle between the selected AP axis and the perpendicular to the PTCL was measured as −4.07°, standard deviation of 4.28°. The mean angle between the surgical AP axis and the perpendicular to the PTCL was measured as −18.56°, standard deviation of 4.66°. There was no significant difference in the variance of the two sets of measurements (p =0.63). Variability of the selected AP axis was even smaller (standard deviation of 2.74°) when measured independently from the PTCL reference axis, by aligning virtual resection profiles. Anatomically, the selected AP axis was almost perpendicular to the posterior tibial condylar axis. This coordinate system can aid in gathering consistent and repeatable anthropometric data that can be used to improve tibial implant design and could also, in combination with CT/MR imaged-based computer assisted surgery, be used as a guideline for tibial component positioning in TKR. [Copyright &y& Elsevier]

Abstract: This study defines, in the context of unicompartmental tibial replacement, the medial and lateral resection surfaces of 34 tibiae at a depth of 5 mm below the articular surface. Using statistical techniques, three optimal theoretical size and shape unicompartmental tibial designs, (i) implants of consistent shape in varying size (ii) implants symmetric about their ML axis; (iii) implants of varying size and shape, were constructed to best fit the population. Two currently available commercial implants, the Preservation Uni System (DePuy Orthopaedics Inc., Warsaw, IN) and the LCS Uni System (DePuy Orthopaedics Inc., Warsaw, IN), which were similar to types (i) and (ii) respectively, of the theoretical designs, were also included in the analysis. All implants, commercial and theoretical, were compared with one another to determine which implant designs gave the best cortical bone coverage on both the medial and lateral compartments. Of the commercial implants, the type (i) design fitted best, with an average of 67% of the implant edge lying on cortical bone, compared with 57% for the type (ii) implants. Of the theoretical implants, 72%, 67% and 76% of the implant edge lay on cortical bone for types (i), (ii) and (iii) designs, respectively, indicating that there is room for improvement in current implant designs to achieve better coverage in both the medial and lateral compartments combined. [Copyright &y& Elsevier]

Anophthalmia and microphthalmia describe, respectively, the absence of an eye and the presence of a small eye within the orbit. The combined birth prevalence of these conditions is up to 30 per 100,000 population, with microphthalmia reported in up to 11% of blind children. High-resolution cranial imaging, post-mortem examination and genetic studies suggest that these conditions represent a phenotypic continuum. Both anophthalmia and microphthalmia may occur in isolation or as part of a syndrome, as in one-third of cases. Anophthalmia/microphthalmia have complex aetiology with chromosomal, monogenic and environmental causes identified. Chromosomal duplications, deletions and translocations are implicated. Of monogenic causes only SOX2 has been identified as a major causative gene. Other linked genes include PAX6, OTX2, CHX10 and RAX. SOX2 and PAX6 mutations may act through causing lens induction failure. FOXE3 mutations, associated with lens agenesis, have been observed in a few microphthalmic patients. OTX2, CHX10 and RAX have retinal expression and may result in anophthalmia/microphthalmia through failure of retinal differentiation. Environmental factors also play a contributory role. The strongest evidence appears to be with gestational-acquired infections, but may also include maternal vitamin A deficiency, exposure to X-rays, solvent misuse and thalidomide exposure. Diagnosis can be made pre- and post-natally using a combination of clinical features, imaging (ultrasonography and CT/MR scanning) and genetic analysis. Genetic counselling can be challenging due to the extensive range of genes responsible and wide variation in phenotypic expression. Appropriate counselling is indicated if the mode of inheritance can be identified. Differential diagnoses include cryptophthalmos, cyclopia and synophthalmia, and congenital cystic eye. Patients are often managed within multidisciplinary teams consisting of ophthalmologists, paediatricians and/or clinical geneticists, especially for syndromic cases. Treatment is directed towards maximising existing vision and improving cosmesis through simultaneous stimulation of both soft tissue and bony orbital growth. Mild to moderate microphthalmia is managed conservatively with conformers. Severe microphthalmia and anophthalmia rely upon additional remodelling strategies of endo-orbital volume replacement (with implants, expanders and dermis-fat grafts) and soft tissue reconstruction. The potential for visual development in microphthalmic patients is dependent upon retinal development and other ocular characteristics. [ABSTRACT FROM AUTHOR]

Large-scale changes in luminance are known to exert a significant suppressive or masking effect on visual perception, but the neural substrate for this effect remains unclear. In this report, we describe the results of experiments using in vivo intracellular recording to explore the impact of luminance transients on the responses of orientation-selective neurons in layer 2/3 of tree shrew primary visual cortex. By measuring changes in excitatory and inhibitory conductances, we find that instantaneous changes in luminance evoke strong cortical inhibition. When combined with visual stimuli that would otherwise yield strong excitatory responses, luminance transients produce significant reductions in excitation as well as increases in inhibition. As a result, luminance transients significantly delay the emergence of orientation tuned cortical responses, and virtually eliminate ongoing responses to effective stimuli. We conclude that cortical inhibition is a critical factor in luminance-evoked cortical suppression and the likely substrate for luminance-induced visual masking phenomenon. [ABSTRACT FROM AUTHOR]

In animal olfactory systems, odorant molecules are detected by olfactory receptors (ORs). ORs are part of the G-protein-coupled receptor (GPCR) superfamily. Heterotrimeric guanine nucleotide binding G-proteins (G-proteins) relay signals from GPCRs to intracellular effectors. G-proteins are comprised of three peptides. The G-protein α subunit confers functional specificity to G-proteins. Vertebrate and insect Gα-subunit genes are divided into four subfamilies based on functional and sequence attributes. The nematode Caenorhabditis elegans contains 21 Gα genes, 14 of which are exclusively expressed in sensory neurons. Most individual mammalian cells express multiple distinct GPCR gene products, however, individual mammalian and insect olfactory neurons express only one functional odorant OR. By contrast C. elegans expresses multiple ORs and multiple Gα subunits within each olfactory neuron. Here we show that, in addition to having at least one member of each of the four mammalian Gα gene classes, C. elegans and other nematodes also possess two lineage-specific Gα gene expansions, homologues of which are not found in any other organisms examined. We hypothesize that these novel nematode-specific Gα genes increase the functional complexity of individual chemosensory neurons, enabling them to integrate odor signals from the multiple distinct ORs expressed on their membranes. This neuronal gene expansion most likely occurred in nematodes to enable them to compensate for the small number of chemosensory cells and the limited emphasis on cephalization during nematode evolution. [ABSTRACT FROM AUTHOR]

Development of the selective response properties that define columns in sensory cortex is thought to begin early in cortical maturation, without the need for experience. We investigated the development of direction selectivity in ferret visual cortex using optical imaging and electrophysiological techniques and found an exception to this view. Unlike orientation selectivity and ocular dominance, direction selectivity was not detected at eye opening. Direction selectivity emerged several days later and strengthened to adult levels over the following 2 weeks. Visual experience was essential for this process, as shown by the absence of direction selectivity in dark-reared ferrets. The impairment persisted in dark-reared ferrets that were given experience after this period, despite the recovery of response amplitude, preference and bandwidth for stimulus orientation, spatial and temporal frequency, and contrast. Visual experience in early postnatal life plays a necessary and unique role in the development of cortical direction selectivity. [ABSTRACT FROM AUTHOR]

Background: To date, most fungal phylogenies have been derived from single gene comparisons, or from concatenated alignments of a small number of genes. The increase in fungal genome sequencing presents an opportunity to reconstruct evolutionary events using entire genomes. As a tool for future comparative, phylogenomic and phylogenetic studies, we used both supertrees and concatenated alignments to infer relationships between 42 species of fungi for which complete genome sequences are available. Results: A dataset of 345,829 genes was extracted from 42 publicly available fungal genomes. Supertree methods were employed to derive phylogenies from 4,805 single gene families. We found that the average consensus supertree method may suffer from long-branch attraction artifacts, while matrix representation with parsimony (MRP) appears to be immune from these. A genome phylogeny was also reconstructed from a concatenated alignment of 153 universally distributed orthologs. Our MRP supertree and concatenated phylogeny are highly congruent. Within the Ascomycota, the sub-phyla Pezizomycotina and Saccharomycotina were resolved. Both phylogenies infer that the Leotiomycetes are the closest sister group to the Sordariomycetes. There is some ambiguity regarding the placement of Stagonospora nodurum, the sole member of the class Dothideomycetes present in the dataset. Within the Saccharomycotina, a monophyletic clade containing organisms that translate CTG as serine instead of leucine is evident. There is also strong support for two groups within the CTG clade, one containing the fully sexual species Candida lusitaniae, Candida guilliermondii and Debaryomyces hansenii, and the second group containing Candida albicans, Candida dubliniensis, Candida tropicalis, Candida parapsilosis and Lodderomyces elongisporus. The second major clade within the Saccharomycotina contains species whose genomes have undergone a whole genome duplication (WGD), and their close relatives. We could not confidently resolve whether Candida glabrata or Saccharomyces castellii lies at the base of the WGD clade. Conclusion: We have constructed robust phylogenies for fungi based on whole genome analysis. Overall, our phylogenies provide strong support for the classification of phyla, sub-phyla, classes and orders. We have resolved the relationship of the classes Leotiomyctes and Sordariomycetes, and have identified two classes within the CTG clade of the Saccharomycotina that may correlate with sexual status. [ABSTRACT FROM AUTHOR]

Background: Guanylyl cyclases (GCs) are responsible for the production of the secondary messenger cyclic guanosine monophosphate, which plays important roles in a variety of physiological responses such as vision, olfaction, muscle contraction, homeostatic regulation, cardiovascular and nervous function. There are two types of GCs in animals, soluble (sGCs) which are found ubiquitously in cell cytoplasm, and receptor (rGC) forms which span cell membranes. The complete genomes of several vertebrate and invertebrate species are now available. These data provide a platform to investigate the evolution of GCs across a diverse range of animal phyla. Results: In this analysis we located GC genes from a broad spectrum of vertebrate and invertebrate animals and reconstructed molecular phylogenies for both sGC and rGC proteins. The most notable features of the resulting phylogenies are the number of lineage specific rGC and sGC expansions that have occurred during metazoan evolution. Among these expansions is a large nematode specific rGC clade comprising 21 genes in C. elegans alone; a vertebrate specific expansion in the natriuretic receptors GC-A and GC-B; a vertebrate specific expansion in the guanylyl GC-C receptors, an echinoderm specific expansion in the sperm rGC genes and a nematode specific sGC clade. Our phylogenetic reconstruction also shows the existence of a basal group of nitric oxide (NO) insensitive insect and nematode sGCs which are regulated by O2. This suggests that the primordial eukaryotes probably utilized sGC as an O2 sensor, with the ligand specificity of sGC later switching to NO which provides a very effective local cell-to-cell signalling system. Phylogenetic analysis of the sGC and bacterial heme nitric oxide/oxygen binding protein domain supports the hypothesis that this domain originated from a cyanobacterial source. Conclusion: The most salient feature of our phylogenies is the number of lineage specific expansions, which have occurred within the GC gene family during metazoan evolution. Our phylogenetic analyses reveal that the rGC and sGC multi-domain proteins evolved early in eumetazoan evolution. Subsequent gene duplications, tissue specific expression patterns and lineage specific expansions resulted in the evolution of new networks of interaction and new biological functions associated with the maintenance of organismal complexity and homeostasis. [ABSTRACT FROM AUTHOR]

Meningococcal meningitidis is a life-threatening disease. In Europe and the United States the majority of cases are caused by virulent meningococcal strains belonging to serogroup B. Presently there is no effective vaccine against serogroup B strains, as traditional vaccine antigens such as polysaccharide capsules are unusable as they lead to autoimmunity. The year 2000 saw the publication of the complete genome of Neisseria meningitidis MC58, a virulent serogroup B bacterium. Working in conjunction with the sequencing project, researchers endeavored to locate highly conserved membrane-associated proteins that elicit an immune response. It is hoped that these proteins will provide a basis for novel vaccines against serogroup B strains. A number of potential vaccine antigens have been located and are presently in phase I clinical trials. Recently many reports pertaining to the evidence of positive Darwinian selection in membrane proteins of pathogens have been reported. This study utilized in silico methods to test for evidence of historical positive Darwinian selection in seven such vaccine candidates. We found that two of these proteins show signatures of adaptive evolution, while the remaining proteins show evidence of strong purifying selection. This has significant implications for the design of a vaccine against serogroup B strains, as it has been shown that vaccines that target epitopes that are under strong purifying selection are better than those that target variable epitopes. [ABSTRACT FROM AUTHOR]

In developed countries, malformations of the eye are among the most common causes of serious visual impairment in newborns. The identification of pathogenic mutations in autosomal and X-linked transcription factors has advanced our understanding of the critical stages in human eye development and has begun to explain some unusual inheritance characteristics of these disorders. The functional characterisation of these genes in model organisms has prompted reinvestigation of affected individuals to identify previously unrecognized but consistent extra-ocular malformations. This dialogue between clinical genetics and basic developmental biology provides a paradigm to enhance our understanding of many critical developmental processes in human embryogenesis. [Copyright &y& Elsevier]

Autosomal trisomy is a common cause of human miscarriage, malformations and learning disability. Primary gene-dosage effects have been confirmed by recent transcriptome analyses. The importance (or existence) of trans-acting effects on disomic genes remains, surprisingly, controversial. In this article, I propose a model of the main genetic mechanisms that are responsible for producing the transcriptional derangement associated with trisomy. This has implications for future study design. [Copyright &y& Elsevier]

Omp85 is a highly conserved outer membrane protein found in all gram-negative bacteria. It is essential for bacterial cell viability and plays an integral function in the positioning and folding of other outer membrane proteins into the bacterial outer membrane. We have employed a maximum likelihood and a maximum parsimony approach to detect evidence of positive Darwinian selection in Omp85 homologues from 10 d-proteobacteria and have identified 14 amino acid sites that show evidence of being under the influence of adaptive evolution. Interestingly all sites bar one are concentrated within surface loops of the protein that most likely interact with host immune response or the surrounding environment. Alternatively amino acids within membrane-spanning regions of the protein are found to be under purifying selection most likely as a result of structural constraints. [ABSTRACT FROM AUTHOR]

Here we review the results of anatomical and physiological studies in tree shrew visual cortex which focus on the contribution of vertical and horizontal inputs to receptive field center and surround properties of layer 2/3 neurons. A fundamental feature of both sets of connections is the arrangement of axon arbors in a fashion that respects both the orientation preference and retinotopic displacement of the target site. As a result, layer 2/3 neurons receive convergent input from populations of layer 4 and other layer 2/3 neurons whose receptive fields are displaced along an axis in visual space that corresponds to their preferred orientation. Although, horizontal connections extend for greater distances across the cortical surface than vertical connections, the majority of these inputs link neurons with overlapping receptive fields, emphasizing that both feed-forward and recurrent circuits are likely to play a constructive role in generating properties (such as orientation selectivity) that define the receptive field center. Both within and beyond the dimensions of the receptive field center, the distribution of horizontal connections accords remarkably well with the magnitude and axial tuning of length summation effects. Taken together, these results suggest a continuum of functional properties that transcends the traditional designation of receptive field center and surround. By extension, we suggest that the perceptual effects of stimulus context may arise from stimulus interactions within the receptive field center as well as between center and surround. [Copyright &y& Elsevier]

Objective. To assess and model the influence of collagen fibre imbalance within the annulus fibrosus on the initiation and progression of adolescent idiopathic scoliosis deformity.Background. A number of aetiological factors have been proposed for idiopathic scoliosis, including a contribution from the intervertebral disc. The specific influence of the annulus fibrosus has yet to be effectively modelled.Methods. A mathematical model was used to determine the contribution of collagen fibre orientation and directional imbalance within the annulus fibrosus to vertebral rotation and overall deformity of thoracic spine. Rotations, due to collagen fibre imbalance, and translations, due to rapid growth, were applied to a simplified model of the thoracic spine, using a three-dimensional transformation matrix approach.Results. The ratio of clockwise to anti-clockwise fibres in the intervertebral disc (from unity to 0.80) influenced the induced rotation. The three-dimensional model illustrates the initiation and progression of the scoliotic deformity during adolescent growth, being most obvious at larger growth rates.Conclusions. Imbalance in the ratio of clockwise and anti-clockwise collagen fibres within the annulus fibrosus has been demonstrated to have the potential to contribute to the progression of scoliosis. For a given fibre ratio, the rate of growth does not influence the induced rotation, but directly influences the severity of the resulting deformity.RelevanceThe model defines the potential contribution of collagen fibre imbalance to adolescent idiopathic scoliosis, supporting the clinical observation that greatest progression of deformity occurs during phases of rapid adolescent growth. However, the underlying mechanism is within the annulus fibrosus, assisting in the search for the responsible genes. [Copyright &y& Elsevier]

DNA methylation is a focus of epigenetic research in the immune system. This overview begins with a synopsis of the players and processes involved in DNA methylation, demethylation, methyl-CpG-recognition, histone modification, and chromatin remodeling. The role of these mechanisms in immune responses, with a focus on T lymphocytes, is then reviewed. There is evidence for epigenetic regulation of several key immune processes including thymocyte development, antigen presentation, differentiation, cytokine expression, effector function, and memory. DNA methylation contributes, along with other epigenetic mechanisms, to the establishment of transcriptional thresholds that vary between genes and T cell types. The immune system is a fertile field for studies of epigenetic regulation of cell fate and function. [Copyright &y& Elsevier]

Mycobacterium tuberculosis is a high GC Gram-positive member of the actinobacteria. The mycobacterial cell wall is composed of a complex assortment of lipids and is the interface between the bacterium and its environment. The biosynthesis of fatty acids plays an essential role in the formation of cell wall components, in particular mycolic acids, which have been targeted by many of the drugs used to treat M. tuberculosis infection. M. tuberculosis has ≈250 genes involved in fatty acid metabolism, a much higher proportion than in any other organism. In silico methods have been used to compare the genome of M. tuberculosis CDC1551 to a database of 58 complete bacterial genomes. The resulting alignments were scanned for genes specifically involved in fatty acid biosynthetic pathway I. Phylogenetic analysis of these alignments was used to investigate horizontal gene transfer, gene duplication, and adaptive evolution. It was found that of the eight gene families examined, five of the phylogenies reconstructed suggest that the actinobacteria have a closer relationship with the αproteobacteria than expected. This is either due to either an ancient transfer of genes or deep paralogy and subsequent retention of the genes in unrelated lineages. Additionally, adaptive evolution and gene duplication have been an influence in the evolution of the pathway. This study provides a key insight into how M. tuberculosis has developed its unique fatty acid synthetic abilities. [ABSTRACT FROM AUTHOR]