Mitochondrial tRNALeu(UUR) mutation m.3302A > G presenting as childhood-onset severe myopathy: threshold determination through segregation study

Mitochondrial tRNALeu(UUR) mutation m.3302A > G is associated with respiratory chain complex I deficiency and has been described as a rare cause of mostly adult-onset slowly progressive myopathy. Five families with 11 patients have been described so far; 5 of them died young due to cardiorespiratory failure. Here, we report on a segregation study in a family with an index patient who already presented at the age of 18months with proximal muscular hypotonia, abnormal fatigability, and lactic acidosis. This early-onset myopathy was rapidly progressive. At 8years, the patient is wheel-chair bound, requires nocturnal assisted ventilation, and suffers from recurrent respiratory infections. Severe complex I deficiency and nearly homoplasmy for m.3302A > G were found in muscle. We collected blood, hair, buccal swabs and muscle biopsies from asymptomatic adults in this pedigree and determined heteroplasmy levels in these tissues as well as OXPHOS activities in muscle. All participating asymptomatic adults had normal OXPHOS activities. In contrast to earlier reports, we found surprisingly little variation of heteroplasmy levels in different tissues of the same individual. Up to 45% mutation load in muscle and up to 38% mutation load in other tissues were found in non-affected adults. The phenotypic spectrum of tRNALeu(UUR) m.3302A > G mutation seems to be wider than previously described. A threshold of more than 45% heteroplasmy in muscle seems to be necessary to alter complex I activity leading to clinical manifestation. The presented data may be helpful for prognostic considerations and counseling in affected familie

LIBRO BLANCO PARA UNA ESTRATEGIA DE ESPECIALIZACIÓN INTELIGENTE EN BOSQUES COMPLEJOS DEL SUDOE

29 páginasEl objetivo del proyecto COMFOR-SUDOE es potenciar los bosques con estructuras complejas (mixtos e irregulares) así como la plantación con varias especies, como una estrategia de adaptación que dé respuesta al cambio climático y a la disminución de la biodiversidad. Entendemos como “bosque complejo” aquellas estructuras irregulares o disetáneas y/o de composición pluriespecífica gestionadas bajo un principio de persistencia y de acuerdo con objetivos de multifuncionalidad (producción, protección y uso social) y estabilidad. El proyecto ha sido financiado por INTERREG-SUDOE en el marco del IV Programa y se lanzó para fomentar las sinergias y fortalecer una red que una transnacionalmente la investigación y la innovación en sectores específicos del Sudoeste Europeo (SUDOE). Se trata de promover un crecimiento inteligente y sostenible mediante la promoción de la investigación, el desarrollo, la innovación y la transferencia tecnológica. El proyecto se desarrolló para definir prioridades de innovación, investigación y especialización entorno a los bosques complejos, abarcando ámbitos como la biodiversidad y bioeconomía, la participación ciudadana y acciones transformadoras para incrementar los paisajes resilientes. El presente informe recoge los principales resultados del proyecto y las recomendaciones para incluir los bosques complejos como una prioridad estratégica de especialización inteligenteProyecto financiado por el programa INTERREG-SUDOE a través del Fonde Europeo de Desarrollo Regional (FEDER). Presupuesto 1.289.211,57 €N

The Mi-2 nucleosome-remodeling protein LET-418 is targeted via LIN-1/ETS to the promoter of lin-39/Hox during vulval development in C. elegans

The fate of the vulval cells in Caenorhabditis elegans is specified, at least in part, through a highly conserved RTK/Ras mediated signaling cascade that negatively regulates the activity of the ETS-like transcription factor LIN-1. The Hox gene lin-39 functions downstream of both, the LIN-3/RTK/Ras pathway and LIN-1 and plays a pivotal role in controlling vulva cell competence and induction. Here we show that LET-418, a C. elegans ortholog of the human NuRD component Mi-2, negatively modulates the activity of lin-39. LET-418 interacts in vivo with specific regions in the promoter of lin-39 and this interaction depends on LIN-1. Our data provide evidence for a model in which LIN-1 recruits LET-418/Mi-2 as co-repressor to the promoter of lin-39, thereby restricting its activity to the basal levels required in the vulva precursor cells (VPCs) for normal vulval development. Thus, our data suggest that the interaction between LIN-1 and LET-418/Mi-2 may link RTK/Ras signaling with chromatin remodeling and gene expression

Transcriptional control of Notch signaling by a HOX and a PBX/EXD protein during vulval development in C. elegans

The Notch signaling pathway controls growth, differentiation and patterning in divergent animal phyla; in humans, defective Notch signaling has been implicated in cancer, stroke and neurodegenerative disorders. Despite its developmental and medical significance, little is known about the factors that render cells to become competent for Notch signaling. Here we show that during vulval development in the nematode Caenorhabditis elegans the HOX protein LIN-39 and its EXD/PBX-like cofactor CEH-20 are required for LIN-12/Notch-mediated lateral signaling that specifies the 2° vulval cell fate. Inactivation of either lin-39 or ceh-20 resulted in the misspecification of 2° vulval cells and suppressed the multivulva phenotype of lin-12(n137) gain-of-function mutant animals. Furthermore, both LIN-39 and CEH-20 are required for the expression of basal levels of the genes encoding the LIN-12/Notch receptor and one of its ligands in the vulval precursor cells, LAG-2/Delta/Serrate, rendering them competent for the subsequent lin-12/Notch induction events. Our results suggest that the transcription factors LIN-39 and CEH-20, which function at the bottom of the RTK/Ras and Wnt pathways in vulval induction, serve as major integration sites in coordinating and transmitting signals to the LIN-12/Notch cascade to regulate vulval cell fates

Global Distribution of <i>Campylobacter jejuni</i> Penner Serotypes: A Systematic Review

<div><p>Penner serotyping has been the principal method for differentiating Campylobacter isolates since its inception. Campylobacter capsule polysaccharide (CPS), the principal serodeterminant on which Penner serotyping is based, is presently of interest as a vaccine component. To determine the required valency of an effective CPS-based vaccine, a comprehensive understanding of CPS distribution is needed. Because of the association between Penner serotype and CPS, we conducted a systematic review to estimate the frequency and distribution of Penner serotypes associated with cases of Campylobacteriosis. In total, more than 21,000 sporadic cases of <i>C. jejuni</i> cases were identified for inclusion. While regional variation exists, distribution estimates indicate that eight serotypes accounted for more than half of all sporadic diarrheal cases globally and three serotypes (HS4 complex, HS2, and HS1/44) were dominant inter-regionally as well as globally. Furthermore, a total of 17 different serotypes reached a representation of 2% or greater in at least one of the five regions sampled. While this review is an important first step in defining CPS distribution, these results make it clear that significant gaps remain in our knowledge. Eliminating these gaps will be critical to future vaccine development efforts.</p></div

HS Serotypes with Proportional Estimates of 2% or Greater by Economic Development Status.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067375#pone-0067375-t002" target="_blank">Tables 2</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067375#pone-0067375-t004" target="_blank">4</a>: HS serotypes with a proportional representation of 2% or greater, Globally (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067375#pone-0067375-t002" target="_blank">Table 2</a>), by Region (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067375#pone-0067375-t003" target="_blank">Table 3</a>), and by Economic Status (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067375#pone-0067375-t004" target="_blank">Table 4</a>). Proportional estimates (%) were computed using the DerSimonian & Laird random effects model and include the upper (uci) and lower (lci) 95% confidence intervals. Note: Isolates categorized as a cross-reactive pair HS serotype (e.g. HS1/44, HS5/31, HS6/7, HS8/17, and HS23/36) were originally reported as one of the two serotypes or as the paired serotype itself. Isolates categorized as HS4 complex (or HS4c) represent isolates reported as any combination of the following serotypes HS 4/13/16/43/50/63/64/65.</p

Comparison of HS Serotypes with Proportional Estimates by Region: Proportions that met or exceeded the 2% threshold are bolded and those that did not are indicated in italics.

<p>Comparison of HS Serotypes with Proportional Estimates by Region: Proportions that met or exceeded the 2% threshold are bolded and those that did not are indicated in italics.</p

Included Studies.

a<p>Country = Country from which sporadic diarrhea cases were identified;</p>b<p>Total = Total number of isolates analyzed;</p>c<p>Year = Year specimen collection initiated.</p>d<p>When the year in which specimen collection began was not specified, publication year used;</p>e<p>Duration = Length of specimen collection period in months;</p>f<p>Age in years, “Mixed” indicates specimens collected from both children and adults;</p>g<p>Catchment indicates the size of the collection area,</p>h<p>Point = a single collection point (e.g. single hospital or clinic);</p>i<p>Serotypes Tested = number of serotypes included in the panel of screening sera used in each study. A number of studies screened for <i>C. coli</i> serotypes in addition to those for <i>C. jejuni</i>. Therefore, the number of serotypes screened for may exceed the 35 <i>C. jejuni</i> serotypes enumerated in this review. Abbreviations: CAR = Central African Republic, UAE = United Arab Emirates, UK = United Kingdom, USA = United States of America; NS = Not Specified.</p

Global HS Serotypes with Proportional Estimates of 2% or Greater.

<p>Global HS Serotypes with Proportional Estimates of 2% or Greater.</p

Distribution of flagella secreted protein and integral membrane protein among <it>Campylobacter jejuni </it>isolated from Thailand

<p>Abstract</p> <p>Background</p> <p><it>Campylobacter jejuni</it>, a gram-negative bacterium, is a frequent cause of gastrointestinal food-borne illness in humans throughout the world. There are several reports that the virulence of <it>C. jejuni </it>might be modulated by non-flagellar proteins that are secreted through the filament. Recently, FspA (Flagella secreted proteins) have been described. Two alleles of <it>fspA </it>(<it>fspA1 </it>and <it>fspA2</it>) based on sequence analysis were previously reported and only the <it>fspA2 </it>allele was found in Thai isolates. The aim of this study is to analyze the deduced amino acid sequences <it>fspA </it>and the adjacent putative integral membrane protein from 103 Thai <it>C. jejuni </it>isolates.</p> <p>Results</p> <p>A total of 103 representative <it>C. jejuni </it>isolates were amplified by PCR for the <it>fspA </it>gene and the adjacent integral membrane protein gene. Two PCR product sizes were amplified using the same primers, an approximately 1600-bp PCR product from 19 strains that contained <it>fspA </it>and integral membrane protein genes and an approximately 800-bp PCR product from 84 strains that contained only the <it>fspA </it>gene. DNA sequencing was performed on the amplified products. The deduced amino acid sequences of both genes were analyzed separately using CLC Free Workbench 4 software. The analysis revealed three groups of FspA. Only FspA group 1 sequences (19/103) (corresponding to <it>fspA1</it>) consisting of 5 subgroups were associated with the adjacent gene encoding the integral membrane protein. FspA group 2 was the largest group (67/103) consisting of 9 subgroups. FspA group 2p (17/103) consisting of 7 subgroups was found to contain stop codons at a position before the terminal 142 position.</p> <p>Conclusions</p> <p>This study reveals greater heterogeneity of FspA (group 1, 2 and 2p) among Thai <it>C. jejuni </it>isolates than previously reported. Furthermore, the subgroups of FspA groups 1 were associated with groups of integral membrane protein. The significance of these different FspA variants to virulence requires further study.</p