Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis.     

An earlier origin for the Acheulian

The Acheulian is one of the first defined prehistoric techno-complexes and is characterized by shaped bifacial stone tools. It probably originated in Africa, spreading to Europe and Asia perhaps as early as ～1?million years (Myr) ago. The origin of the Acheulian is thought to have closely coincided with major changes in human brain evolution, allowing for further technological developments. Nonetheless, the emergence of the Acheulian remains unclear because well-dated sites older than 1.4?Myr ago are scarce. Here we report on the lithic assemblage and geological context for the Kokiselei 4 archaeological site from the Nachukui formation (West Turkana, Kenya) that bears characteristic early Acheulian tools and pushes the first appearance datum for this stone-age technology back to 1.76?Myr ago. Moreover, co-occurrence of Oldowan and Acheulian artefacts at the Kokiselei site complex indicates that the two technologies are not mutually exclusive time-successive components of an evolving cultural lineage, and suggests that the Acheulian was either imported from another location yet to be identified or originated from Oldowan hominins at this vicinity. In either case, the Acheulian did not accompany the first human dispersal from Africa despite being available at the time. This may indicate that multiple groups of hominins distinguished by separate stone-tool-making behaviours and dispersal strategies coexisted in Africa at 1.76?Myr ago.     

Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function

Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.     

A genetically humanized mouse model for hepatitis C virus infection

Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro, we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo.     

System Dynamics and Learning Scenarios for Process Improvement and Regional Resilience: A Study in The Footwear Industry of Southern Brazil

Systemic Practice and Action Research - By means of integrated and systemic resilience strategies, it is possible to reduce vulnerability and risk, and at the same time increase the capacity to...     

Mining patterns of the aspen leaf miner, Phyllocnistis populiella, on its host plant, Populus tremuloides

Feeding behavior of aspen leaf miner ( Phyllocnistis populiella ) larvae on quaking aspen ( Populus tremuloides ) leaves was examined, by using image-analysis software, to determine the pattern and distance of the larvae’s mining trails and measure the surface area of infested leaves and consumed leaf tissue. Mining pathways between hatching and pupation sites were serpentine and generally followed predictable, sequential changes in orientation. This pattern was most obvious in smaller leaves, those with a surface area of about 700 mm 2 or less. In leaves larger than 700 mm 2 , plasticity in mining behavior increased. The serpentine pattern was initiated but became truncated when larvae reached full growth without having to consume all available leaf material. The final phase of the behavioral program was still executed, however, and larvae entered pupation at the usual leaf-edge location. We hypothesize that the serpentine pattern is genetically controlled and that it has been selected for because it promotes efficient consumption of a fixed food supply and ensures a favorable location for pupation, especially when reproductive females oviposit on small leaves. Se examinó el comportamiento alimenticio de la larva del minero de hoja de álamo ( Phyllocnistis populiella ) en las hojas del álamo temblante ( Populus tremuloides ) utilizando software de análisis de imágenes para determinar el patrón y la longitud del rastro de las larvas y medir la superficie de las hojas infestadas y del tejido de hoja consumido. Los rastros del minero entre los sitios de eclosión y los de pupación fueron serpentinos, y en general sus cambios de orientación fueron predecibles y secuenciales. Esto fue más obvio en las hojas pequeñas, aquellas con una superficie de menos de 700 mm 2 . En las hojas con una superficie mayor de 700 mm 2 aumentó la plasticidad en el comportamiento minero. El patrón serpentino apareció al inicio pero se truncó cuando las larvas alcanzaron su pleno desarrollo sin tener que consumir todo el material herbáceo disponible. Sin embargo, la última fase del patrón conductual aún se llevó a cabo, y comenzaron la pupación en el borde de la hoja como de costumbre. Planteamos la hipótesis de que el patrón serpentino tiene origen genético y que ha sido seleccionado a favor porque facilita el consumo eficiente de un suministro fijo de alimento y garantiza un lugar favorable para la pupación, especialmente cuando las hembras reproductoras ovipositan en hojas pequeñas.