Interrogation of individual intratumoral B lymphocytes from lung cancer patients for molecular target discovery.

Intratumoral B lymphocytes are an integral part of the lung tumor microenvironment. Interrogation of the antibodies they express may improve our understanding of the host response to cancer and could be useful in elucidating novel molecular targets. We used two strategies to explore the repertoire of intratumoral B cell antibodies. First, we cloned VH and VL genes from single intratumoral B lymphocytes isolated from one lung tumor, expressed the genes as recombinant mAbs, and used the mAbs to identify the cognate tumor antigens. The Igs derived from intratumoral B cells demonstrated class switching, with a mean VH mutation frequency of 4%. Although there was no evidence for clonal expansion, these data are consistent with antigen-driven somatic hypermutation. Individual recombinant antibodies were polyreactive, although one clone demonstrated preferential immunoreactivity with tropomyosin 4 (TPM4). We found that higher levels of TPM4 antibodies were more common in cancer patients, but measurement of TPM4 antibody levels was not a sensitive test for detecting cancer. Second, in an effort to focus our recombinant antibody expression efforts on those B cells that displayed evidence of clonal expansion driven by antigen stimulation, we performed deep sequencing of the Ig genes of B cells collected from seven different tumors. Deep sequencing demonstrated somatic hypermutation but no dominant clones. These strategies may be useful for the study of B cell antibody expression, although identification of a dominant clone and unique therapeutic targets may require extensive investigation.

ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide.

In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) - a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date - of schizophrenia and major depression - ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others(1), ENIGMA's genomic screens - now numbering over 30,000 MRI scans - have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants - and genetic variants in general - may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures - from tens of thousands of people - that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.

Por qué cae la productividad de los rodales forestales? : influencia de la dominancia de crecimiento del rodal y la eficiencia de crecimiento individual

Un patrón reconocido del desarrollo de los bosques (naturales o implantados) es la caída en su tasa de crecimiento luego de alcanzar un máximo. En el presente estudio se evaluó el efecto de los cambios en la estructura del rodal, caracterizados por la dominancia de crecimiento, sobre el crecimiento del rodal, la eficiencia de crecimiento del rodal y la eficiencia de crecimiento de árboles de distinto tamaño en parcelas raleadas y sin ralear de Pinus taeda. De acuerdo a la hipótesis planteada, la caída en el crecimiento del rodal estaría relacionada con la disminución en la eficiencia de crecimiento de los individuos de menor tamaño de un rodal debido al establecimiento de la dominancia de crecimiento. La dominancia de crecimiento en las parcelas sin ralear aumentó en forma continua con la edad, aunque siempre manteniendo valores bajos. En las parcelas raleadas los niveles de dominancia de crecimiento fueron aun menores y no se observó un patrón sistemático con la edad. Esta menor dominancia de crecimiento no resultó en una mayor eficiencia de crecimiento del rodal. Por otro lado, en las parcelas sin ralear los árboles de mayor tamaño siempre fueron más eficientes que los de menor tamaño, mientras que en las parcelas raleadas esto dependió del año. En contra de la hipótesis planteada, y al igual que la eficiencia de crecimiento de los árboles más chicos, la eficiencia de los árboles dominantes también disminuyó con la edad. De acuerdo a los bajos niveles de dominancia de crecimiento encontrados (en comparación a otros géneros) se concluye que ésta no es responsable de la caída de la eficiencia de crecimiento de los individuos más pequeños ni de la tasa de crecimiento del rodal en su conjunto. Asimismo, se propone que es la diferencia en eficiencia entre individuos la que conduce al desarrollo de la dominancia de crecimiento y no al revés.

On the application of variable frequency microwave technology for processing of individual surface mount components

Dual-section variable frequency microwave systems enable rapid, controllable heating of materials within an individual surface mount component in a chip-on=board assembly. The ability to process devices individually allows components with disparate processing requirements to be mounted on the same assembly. The temperature profile induced by the microwave system can be specifically tailored to the needs of the component, allowing optimisation and degree of cure whilst minimising thermomechanical stresses. This paper presents a review of dual-section microwave technology and its application to curing of thermosetting polymer materials in microelectronics applications. Curing processes using both conventional and microwave technologies are assessed and compared. Results indicate that dual-section microwave systems are able to cure individual surface mount packages in a significantly shorter time, at the expense of an increase in thermomechanical stresses and a greater variation in degree of cure.

Individual crisis episodes and cultural transition: finding the macrocosm in the microcosm

According to dialogical self theory (Hermans, 2001), individual identities reflect cultural and subcultural values, and appropriate voices and discourses from the social environment. Bronfenbrenner’s (1979) systemic theory of human development similarly postulates that individual and social development occur in a symbiotic and interdependent fashion. It would therefore be predicted that individual changes in identity reflect macrocosmic changes in cultural values and social structures. The current study investigated narratives of crisis transitions within adults aged 25-40, by way of interviews with 22 participants. An intensive qualitative analysis showed that the narratives of crisis could indeed be viewed as individual manifestations of contemporary cultural changes. National statistics and academic research have documented in the UK substantial cultural shifts over the last twenty years including the lessening popularity of marriage, the rise of freelance and portfolio careers and the growth of accepted alternative gender roles. In individual crises, changes made over the course of the episode were invariably in the same direction as these social changes; towards flexible work patterns, non-marital relationships and redefined gender identities. Before the crisis, participants described their identity as bound into an established discourse of conventionality, a traditional sense of masculinity or feminitity and a singular career role, while after the crisis alternative and fluid identities are explored, and identity is less defined by role and institution. These findings show that changes in the social macrocosm can be found in the individual microcosm, and therefore support dialogical self theory.

An individual-based model of the early life history of mackerel (Scomber scombrus) in the eastern North Atlantic, simulating transport, growth and mortality

The main purpose of this paper is to provide the core description of the modelling exercise within the Shelf Edge Advection Mortality And Recruitment (SEAMAR) programme. An individual-based model (IBM) was developed for the prediction of year-to-year survival of the early life-history stages of mackerel (Scomber scombrus) in the eastern North Atlantic. The IBM is one of two components of the model system. The first component is a circulation model to provide physical input data for the IBM. The circulation model is a geographical variant of the HAMburg Shelf Ocean Model (HAMSOM). The second component is the IBM, which is an i-space configuration model in which large numbers of individuals are followed as discrete entities to simulate the transport, growth and mortality of mackerel eggs, larvae and post-larvae. Larval and post-larval growth is modelled as a function of length, temperature and food distribution; mortality is modelled as a function of length and absolute growth rate. Each particle is considered as a super-individual representing 10 super(6) eggs at the outset of the simulation, and then declining according to the mortality function. Simulations were carried out for the years 1998-2000. Results showed concentrations of particles at Porcupine Bank and the adjacent Irish shelf, along the Celtic Sea shelf-edge, and in the southern Bay of Biscay. High survival was observed only at Porcupine and the adjacent shelf areas, and, more patchily, around the coastal margin of Biscay. The low survival along the shelf-edge of the Celtic Sea was due to the consistently low estimates of food availability in that area.

Simulation of mackerel (Scomber scombrus) recruitment with an individual-based model and comparison with field data

An individual-based model (IBM) for the simulation of year-to-year survival during the early life-history stages of the north-east Atlantic stock of mackerel (Scomber scombrus) was developed within the EU funded Shelf-Edge Advection, Mortality and Recruitment (SEAMAR) programme. The IBM included transport, growth and survival and was used to track the passive movement of mackerel eggs, larvae and post-larvae and determine their distribution and abundance after approximately 2 months of drift. One of the main outputs from the IBM, namely distributions and numbers of surviving post-larvae, are compared with field data as recruit (age-0/age-1 juveniles) distribution and abundance for the years 1998, 1999 and 2000. The juvenile distributions show more inter-annual and spatial variability than the modelled distributions of survivors; this may be due to the restriction of using the same initial egg distribution for all 3 yr of simulation. The IBM simulations indicate two main recruitment areas for the north-east Atlantic stock of mackerel, these being Porcupine Bank and the south-eastern Bay of Biscay. These areas correspond to areas of high juvenile catches, although the juveniles generally have a more widespread distribution than the model simulations. The best agreement between modelled data and field data for distribution (juveniles and model survivors) is for the year 1998. The juvenile catches in different representative nursery areas are totalled to give a field abundance index (FAI). This index is compared with a model survivor index (MSI) which is calculated from the total of survivors for the whole spawning season. The MSI compares favourably with the FAI for 1998 and 1999 but not for 2000; in this year, juvenile catches dropped sharply compared with the previous years but there was no equivalent drop in modelled survivors.

Mighty small: Observing and modeling individual microbes becomes big science

Progress in microbiology has always been driven by technological advances, ever since Antonie van Leeuwenhoek discovered bacteria by making an improved compound microscope. However, until very recently we have not been able to identify microbes and record their mostly invisible activities, such as nutrient consumption or toxin production on the level of the single cell, not even in the laboratory. This is now changing with the rapid rise of exciting new technologies for single-cell microbiology (1, 2), which enable microbiologists to do what plant and animal ecologists have been doing for a long time: observe who does what, when, where, and next to whom. Single cells taken from the environment can be identified and even their genomes sequenced. Ex situ, their size, elemental, and biochemical composition, as well as other characteristics can be measured with high-throughput and cells sorted accordingly. Even better, individual microbes can be observed in situ with a range of novel microscopic and spectroscopic methods, enabling localization, identification, or functional characterization of cells in a natural sample, combined with detecting uptake of labeled compounds. Alternatively, they can be placed into fabricated microfluidic environments, where they can be positioned, exposed to stimuli, monitored, and their interactions controlled “in microfluido.” By introducing genetically engineered reporter cells into a fabricated landscape or a microcosm taken from nature, their reproductive success or activity can be followed, or their sensing of their local environment recorded.

Quantifying ecosystem-level consequences of ocean acidification and warming by scaling up individual level responses of a predator snail and its trophic interactions

Understanding long‐term, ecosystem‐level impacts of climate change is challenging because experimental research frequently focuses on short‐term, individual‐level impacts in isolation. We address this shortcoming first through an interdisciplinary ensemble of novel experimental techniques to investigate the impacts of 14‐month exposure to ocean acidification and warming (OAW) on the physiology, activity, predatory behaviour and susceptibility to predation of an important marine gastropod (Nucella lapillus). We simultaneously estimated the potential impacts of these global drivers on N. lapillus population dynamics and dispersal parameters. We then used these data to parameterize a dynamic bioclimatic envelope model, to investigate the consequences of OAW on the distribution of the species in the wider NE Atlantic region by 2100. The model accounts also for changes in the distribution of resources, suitable habitat and environment simulated by finely resolved biogeochemical models, under three IPCC global emissions scenarios. The experiments showed that temperature had the greatest impact on individual‐level responses, while acidification had a similarly important role in the mediation of predatory behaviour and susceptibility to predators. Changes in Nucella predatory behaviour appeared to serve as a strategy to mitigate individual‐level impacts of acidification, but the development of this response may be limited in the presence of predators. The model projected significant large‐scale changes in the distribution of Nucella by the year 2100 that were exacerbated by rising greenhouse gas emissions. These changes were spatially heterogeneous, as the degree of impact of OAW on the combination of responses considered by the model varied depending on local‐environmental conditions and resource availability. Such changes in macro‐scale distributions cannot be predicted by investigating individual‐level impacts in isolation, or by considering climate stressors separately. Scaling up the results of experimental climate change research requires approaches that account for long‐term, multiscale responses to multiple stressors, in an ecosystem context.

Long-term individual foraging site fidelity – why some gannets don’t change their spots

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