Multi-system neurological disease is common in patients with OPA1 mutations

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal ‘dominant optic atrophy plus’ variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44–6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08–4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment

Single allele loss-of-function mutations select and sculpt conditional cooperative networks in breast cancer

The most common events in breast cancer (BC) involve chromosome arm losses and gains. Here we describe identification of 1089 gene-centric common insertion sites (gCIS) from transposon-based screens in 8 mouse models of BC. Some gCIS are driver-specific, others driver non-specific, and still others associated with tumor histology. Processes affected by driver-specific and histology-specific mutations include well-known cancer pathways. Driver non-specific gCIS target the Mediator complex, Ca++ signaling, Cyclin D turnover, RNA-metabolism among other processes. Most gCIS show single allele disruption and many map to genomic regions showing high-frequency hemizygous loss in human BC. Two gCIS, Nf1 and Trps1, show synthetic haploinsufficient tumor suppressor activity. Many gCIS act on the same pathway responsible for tumor initiation, thereby selecting and sculpting just enough and just right signaling. These data highlight ~1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC

História de vida de Laetacara aff. araguaiae Ottoni & Costa, 2009 (Perciformes, Cichlidae) em dois riachos no Noroeste do Estado de São Paulo, Brasil

Foi investigada a estrutura em tamanho, densidade, alimentação, fecundidade e presença de ectoparasitos em duas populações de Laetacara aff. araguaiae no Noroeste do Estado de São Paulo, em dois riachos, sendo um estruturalmente mais heterogêneo (HET) e outro relativamente mais simplificado (SIM). Foram realizadas seis amostragens em cada riacho, sendo três no período chuvoso (outubro, dezembro/2007, fevereiro/2008) e três no seco (abril, julho e setembro/2008), durante 15 minutos de coletas em cada riacho, utilizando-se uma peneira com malha de 3 mm. Foram coletados 118 indivíduos no riacho HET (49 no período chuvoso e 69 no seco) e 146 no riacho SIM (82 no chuvoso e 64 no seco). Os peixes coletados no riacho HET foram maiores do que aqueles coletados no riacho SIM, independente do período considerado. A densidade populacional foi similar entre os dois riachos, com aumento que coincidiu com o pico do período seco. Fragmentos de insetos aquáticos representaram os itens mais importantes da dieta, com variação espaço-temporal pouco relevante. A fecundidade foi significativamente maior no riacho HET, variando de 977 a 1.602 ovócitos, em contraste com as fêmeas do riacho SIM, que apresentaram de 338 a 814 ovócitos. Os ectoparasitos (Digenea) estiveram presentes somente em indivíduos do riacho SIM e encontravam-se aderidos às nadadeiras (dorsal e anal), com maior prevalência no mês de outubro. A alimentação e densidade foram similares nas duas populações de Laetacara aff. araguaiae, ao contrário da estrutura em tamanho e fecundidade. As diferenças nestes parâmetros demográficos não ocorrem ao acaso e são possivelmente reflexo das elevadas taxas de parasitismo no riacho mais simplificado que determinam menor alocação de recursos para crescimento e reprodução nesta população de peixes.The structure in size, density, feeding, fecundity, and presence of ectoparasites in two populations of Laetacara aff. araguaiae was investigated in two streams, in Northwestern São Paulo State, one structurally more heterogeneous (HET) and other relatively more simplified (SIM). Six samples were taken in each stream, three in the wet period (October, December/2007, February/2008) and three in the dry period (April, July, September/2008), which were performed during 15 minutes of sampling in each stream, using a 3 mm-mesh sieve. A total of 118 individuals in HET stream (49 in the wet season and 69 in dry) and 146 in SIM stream were captured (82 in wet and 64 in dry). Fish collected in HET stream were larger than those collected in the SIM, both in wet and dry periods. The density was similar between two streams, with an increase agreeing with the peak of the dry period. Fragments of aquatic insects were the most important items of diet, which showed little spatial and temporal variation. Fecundity was significantly higher in HET, ranging from 977 to 1,602 oocytes, in contrast with females of the SIM, which had 338 to 814 oocytes. The ectoparasites (Digenea) were present only in specimens of the SIM, and were attached to the fins (dorsal and anal) with higher prevalence in October. Feeding and density were similar in the two populations of Laetacara aff. araguaiae, contrasting with the structure in size and fecundity. The differences in these demographic parameters do not occur randomly and are possibly reflecting the high rates of parasitism in the more simplified stretch that determines lower resources allocation to growth and reproduction of fishes in this population.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Estadual Paulista Instituto de Biociências, Letras e Ciências Exatas Departamento de Zoologia e BotânicaUniversidade Estadual Paulista Instituto de Biociências, Letras e Ciências Exatas Departamento de Zoologia e Botânic

Cold War : a Transnational Approach to a Global Heritage

Although within living memory, many countries now consider their surviving Cold War architecture as part of their heritage. It can even be a priority for heritage managers given that significant buildings are often suitable for reuse while extensive ‘brownfield’ sites such as airfields can be used for large-scale redevelopment. In a number of countries whose work we refer to here (notably the United Kingdom and elsewhere in Europe), agencies responsible for managing their country’s heritage have approached this priority by creating national inventories of sites and buildings with a view to taking informed decisions on their future. This paper presents the argument that the wider international context of the Cold War provides a more appropriate (or additional, higher-level) framework for such decision making. Such a ‘transnational’ approach would allow the comparison of similar (e.g. European) sites not merely within national borders but across the full extent of their western NATO1 deployment in Europe and North America. Taking this approach would also allow comparison with related sites in countries that formed part of the eastern-bloc Warsaw Pact.2 After outlining some examples of how national agencies have approached their Cold War heritage, this paper presents the four stages of this transnational approach making provision for an improved understanding and management of Cold War heritage sites wherever they occur. With a specific focus on the direct comparison between England and Russia, and also referring to sites surviving elsewhere within the former NATO and Warsaw Pact regions, as well as the United States, we argue that this four-stage approach: provides new understandings of a complex archaeological and architectural record; gives fresh perspectives on significance; and (importantly in a time of geopolitical instability) does so in a spirit of cooperation and friendship

Identification of nine new susceptibility loci for endometrial cancer

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study

A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer

Murine tissues harbor signature γδ T cell compartments with profound yet differential impacts on carcinogenesis. Conversely, human tissue-resident γδ cells are less well defined. In the present study, we show that human lung tissues harbor a resident Vδ1 γδ T cell population. Moreover, we demonstrate that Vδ1 T cells with resident memory and effector memory phenotypes were enriched in lung tumors compared with nontumor lung tissues. Intratumoral Vδ1 T cells possessed stem-like features and were skewed toward cytolysis and helper T cell type 1 function, akin to intratumoral natural killer and CD8+ T cells considered beneficial to the patient. Indeed, ongoing remission post-surgery was significantly associated with the numbers of CD45RA−CD27− effector memory Vδ1 T cells in tumors and, most strikingly, with the numbers of CD103+ tissue-resident Vδ1 T cells in nonmalignant lung tissues. Our findings offer basic insights into human body surface immunology that collectively support integrating Vδ1 T cell biology into immunotherapeutic strategies for nonsmall cell lung cancer