A fully human anti-IL-7Rα antibody promotes antitumor activity against T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer for which treatment options often result in incomplete therapeutic efficacy and long-term side-effects. Interleukin 7 (IL-7) and its receptor IL-7Rα promote T-ALL development and mutational activation of IL-7Rα associates with very high risk in relapsed disease. Using combinatorial phage-display libraries and antibody reformatting, we generated a fully human IgG1 monoclonal antibody (named B12) against both wild-type and mutant human IL-7Rα, predicted to form a stable complex with IL-7Rα at a different site from IL-7. B12 impairs IL-7/IL-7R-mediated signaling, sensitizes T-ALL cells to treatment with dexamethasone and can induce cell death per se. The antibody also promotes antibody-dependent natural killer-mediated leukemia cytotoxicity in vitro and delays T-cell leukemia development in vivo, reducing tumor burden and promoting mouse survival. B12 is rapidly internalized and traffics to the lysosome, rendering it an attractive vehicle for targeted intracellular delivery of cytotoxic cargo. Consequently, we engineered a B12-MMAE antibody-drug conjugate and provide proof-of-concept evidence that it has increased leukemia cell killing abilities as compared with the naked antibody. Our studies serve as a stepping stone for the development of novel targeted therapies in T-ALL and other diseases where IL-7Rα has a pathological role

JaVerT: JavaScript verification toolchain

The dynamic nature of JavaScript and its complex semantics make it a difficult target for logic-based verification. We introduce JaVerT, a semi-automatic JavaScript Verification Toolchain, based on separation logic and aimed at the specialist developer wanting rich, mechanically verified specifications of critical JavaScript code. To specify JavaScript programs, we design abstractions that capture its key heap structures (for example, prototype chains and function closures), allowing the developer to write clear and succinct specifications with minimal knowledge of the JavaScript internals. To verify JavaScript programs, we develop JaVerT, a verification pipeline consisting of: JS-2-JSIL, a well-tested compiler from JavaScript to JSIL, an intermediate goto language capturing the fundamental dynamic features of JavaScript; JSIL Verify, a semi-automatic verification tool based on a sound JSIL separation logic; and verified axiomatic specifications of the JavaScript internal functions. Using JaVerT, we verify functional correctness properties of: data-structure libraries (key-value map, priority queue) written in an object-oriented style; operations on data structures such as binary search trees (BSTs) and lists; examples illustrating function closures; and test cases from the official ECMAScript test suite. The verification times suggest that reasoning about larger, more complex code using JaVerT is feasible

Invasion of exotic earthworms into ecosystems inhabited by native earthworms

The most conspicuous biological invasions in terrestrial ecosystems have been by exotic plants, insects and vertebrates. Invasions by exotic earthworms, although not as well studied, may be increasing with global commerce in agriculture, waste management and bioremediation. A number of cases has documented where invasive earthworms have caused significant changes in soil profiles, nutrient and organic matter dynamics, other soil organisms or plant communities. Most of these cases are in areas that have been disturbed (e.g., agricultural systems) or were previously devoid of earthworms (e.g., north of Pleistocene glacial margins). It is not clear that such effects are common in ecosystems inhabited by native earthworms, especially where soils are undisturbed. We explore the idea that indigenous earthworm fauna and/or characteristics of their native habitats may resist invasion by exotic earthworms and thereby reduce the impact of exotic species on soil processes. We review data and case studies from temperate and tropical regions to test this idea. Specifically, we address the following questions: Is disturbance a prerequisite to invasion by exotic earthworms? What are the mechanisms by which exotic earthworms may succeed or fail to invade habitats occupied by native earthworms? Potential mechanisms could include (1) intensity of propagule pressure (how frequently and at what densities have exotic species been introduced and has there been adequate time for proliferation?); (2) degree of habitat matching (once introduced, are exotic species faced with unsuitable habitat conditions, unavailable resources, or unsuited feeding strategies?); and (3) degree of biotic resistance (after introduction into an otherwise suitable habitat, are exotic species exposed to biological barriers such as predation or parasitism, ‘‘unfamiliar’’ microflora, or competition by resident native species?). Once established, do exotic species coexist with native species, or are the natives eventually excluded? Do exotic species impact soil processes differently in the presence or absence of native species? We conclude that (1) exotic earthworms do invade ecosystems inhabited by indigenous earthworms, even in the absence of obvious disturbance; (2) competitive exclusion of native earthworms by exotic earthworms is not easily demonstrated and, in fact, co-existence of native and exotic species appears to be common, even if transient; and (3) resistance to exotic earthworm invasions, if it occurs, may be more a function of physical and chemical characteristics of a habitat than of biological interactions between native and exotic earthworms

Validação da estratégia de silenciamento gênico visando indução de resistência a Meloidogyne incognita e Heterodera glycines em soja GM.

Nematoides parasitas de plantas representam o maior estresse biótico da agricultura, causando perdas anuais maiores que US$ 100 bilhões. Baseado nas limitações dos métodos de atuais de controle, o desenvolvimento de novas estratégias deve ser uma prioridade. Recentemente, a estratégia de silenciamento gênico, por interferência mediada por RNA dupla fita, tem-se mostrado muito promissora para o controle de nematoides. Nesse trabalho foi inserida em embriões de soja, pela técnica de biobalística, uma construção de RNAi correspondente a uma fusão de regiões de dois genes que codificam para fatores de processamento de mRNA de Heterodera glycines e Meloidogyne incognita, visando a obtenção de eventos de soja GM resistentes à esses fitonematoides. Para averiguar o efeito do silenciamento, 6 eventos GM foram desafiados com M. incognita. Seis semanas após a inoculação, as raízes das plantas foram avaliadas quanto à indução de resistência. Quando comparados ao tratamento controle, os eventos transgênicos mostraram uma redução signiricativa entre 71% a 92% no número de ovos por grama de raiz. Os eventos transgênicos não foram estatisticamente diferentes quando comparados entre si, exceto o evento GmFSMiHg ? 4IT3. Trabalhos publicados até o momento demonstram silenciamento in planta de 12 genes-alvo de Meloidogyne spp. ou Heterodera spp., resultando em redução de nematoides estabelecidos, fêmeas em desenvolvimento e/ou número de ovos de 68-95% em relação ao controle. Os resultados aqui apresentados mostram claramente a capacidade da soja transgênica em reduzir o potencial reprodutivo de M. incognita por meio de silenciamento gênico. A completa redução de M. incognita continua a ser o objetivo final, mas a redução parcial, como observado no bioensaio, pode ter aplicações importantes no controle de NFGs

Prevalencia de diversos serovares de Leptospira interrogans en vacas no vacunadas en los estados de Puebla, Tabasco y Veracruz, México

The objective was to compare the prevalences of antibodies against different serovars of Leptospira interrogans among the states of Puebla, Tabasco and Veracruz, as well as among some of their municipalities, and to determine if the health status of the cows influences their fertility. Blood samples were taken from 423 cows (Bos taurus x Bos indicus and Bos indicus) from 24 ranches in 11 municipalities in the aforementioned states. The prevalences of the Hardjo and Inifap serovars were higher (P0.05). The number of serovars in the state of Veracruz was higher (P0.05); however, vaccination of cattle against Leptospira interrogans is recommended in order to decrease the risks associated with this bacterium in cattle and humans.El objetivo fue comparar las prevalencias de anticuerpos contra diferentes serovares de Leptospira interrogans entre los estados de Puebla, Tabasco y Veracruz, así como entre algunos de sus municipios, y determinar si el estatus sanitario de las vacas influye en su fertilidad. Se tomaron muestras de sangre de 423 vacas (Bos taurus x Bos indicus y Bos indicus) de 24 ranchos de 11 municipios de los estados mencionados. Las prevalencias de los serovares Hardjo e Inifap fueron mayores (P0.05). El número de serovares en el estado de Veracruz fue mayor (P0.05); sin embargo, se recomienda la vacunación del ganado contra Leptospira interrogans, con el fin de disminuir los riesgos asociados con esta bacteria en bovinos y humanos

IgG and IgG2 antibodies from cattle naturally infected with Anaplasma marginale recognize the recombinant vaccine candidate antigens VirB9, VirB10, and elongation factor-Tu.

Anaplasma marginale is an important vector-borne rickettsia of ruminants in tropical and subtropical regions of the world. Immunization with purified outer membranes of this organism induces protection against acute anaplasmosis. Previous studies, with proteomic and genomic approach identified 21 proteins within the outer membrane immunogen in addition to previously characterized major surface protein1a-5 (MSP1a-5). Among the newly described proteins were VirB9, VirB10, and elongation factor-Tu (EF-Tu). VirB9, VirB10 are considered part of the type IV secretion system (TFSS), which mediates secretion or cell-to-cell transfer of macromolecules, proteins, or DNA-protein complexes in Gram-negative bacteria. EF-Tu can be located in the bacterial surface, mediating bacterial attachment to host cells, or in the bacterial cytoplasm for protein synthesis. However, the roles of VirB9, VirB10, and TFSS in A. marginale have not been defined. VirB9, VirB10, and EF-Tu have not been explored as vaccine antigens. In this study, we demonstrate that sera of cattle infected with A. marginale, with homologous or heterologous isolates recognize recombinant VirB9, VirB10, and EF-Tu. IgG2 from naturally infected cattle also reacts with these proteins. Recognition of epitopes by total IgG and by IgG2 from infected cattle with A. marginale support the inclusion of these proteins in recombinant vaccines against this rickettsia

Hereditary breast cancer and ancestry in the Madeira archipelago: An exploratory study

Access to genetic testing and counselling in remote areas such as the Madeira archipelago, in the Northern Atlantic Ocean, may be complex. Different counselling methods, including telegenetics, should be explored. In this study, we characterise the Hereditary Breast/Ovarian Cancer (HBOC) families with Madeira ancestry enrolled in our programme. Of a total of 3, 566 index patients tested between January 2000 and June 2018, 68 had Madeira ancestry and 22 were diagnosed with a pathogenic germline variant (PV). As in the whole group, BRCA2 PV were more frequent in Madeira patients (68.4%: c.9382C>T (26.3%), c.658_659del (21%), c.156_157insAlu (10.5%), c.793+1G>A (5.3%) and c.298A>T (5.3%). However, the most frequently diagnosed PV in Madeira patients was the BRCA1 c.3331_3334del (31.6%). BRCA1/2 detection rates were 27.9% and 10.5% for Madeira and the whole group, respectively. This study is the first characterisation of HBOC patients with Madeira ancestry. A distinct pattern of BRCA1/2 variants was observed, and the geographic clustering of BRCA1 c.3331_3334del variant may support the possibility of a founder mutation previously described in Northern Portugal. The high detection rate observed reinforces the need to reduce gaps in access to genetic testing in Madeira and other remote areas. According to current guidelines, timely identification of HBOC patients can contribute to their ongoing care and treatment

Attenuation of particulate organic carbon flux in the Scotia Sea, Southern Ocean, is controlled by zooplankton fecal pellets

The Southern Ocean (SO) is an important CO2 reservoir, some of which enters via the production, sinking and remineralization of organic matter. Recent work suggests the fraction of production that sinks is inversely related to production in the SO, a suggestion we confirm from 20 stations in the Scotia Sea. The efficiency with which exported material is transferred to depth (transfer efficiency) is believed to be low in high latitude systems. However, our estimates of transfer efficiency are bimodal, with stations in the seasonal ice zone showing intense losses and others displaying increases in flux with depth. Zooplankton fecal pellets dominated organic carbon flux and at stations with transfer efficiency >100 % fecal pellets were brown, indicative of fresh phytodetritus. We suggest that active flux mediated by zooplankton vertical migration and the presence of sea ice regulate the transfer of organic carbon into the oceans interior in the Southern Ocean

Novel role for the innate immune receptor toll-like receptor 4 (TLR4) in the regulation of the wnt signaling pathway and photoreceptor apoptosis

Recent evidence has implicated innate immunity in regulating neuronal survival in the brain during stroke and other neurodegenerations. Photoreceptors are specialized light-detecting neurons in the retina that are essential for vision. In this study, we investigated the role of the innate immunity receptor TLR4 in photoreceptors. TLR4 activation by lipopolysaccharide (LPS) significantly reduced the survival of cultured mouse photoreceptors exposed to oxidative stress. With respect to mechanism, TLR4 suppressed Wnt signaling, decreased phosphorylation and activation of the Wnt receptor LRP6, and blocked the protective effect of the Wnt3a ligand. Paradoxically, TLR4 activation prior to oxidative injury protected photoreceptors, in a phenomenon known as preconditioning. Expression of TNFα and its receptors TNFR1 and TNFR2 decreased during preconditioning, and preconditioning was mimicked by TNFα antagonists, but was independent of Wnt signaling. Therefore, TLR4 is a novel regulator of photoreceptor survival that acts through the Wnt and TNFα pathways. © 2012 Yi et al