bluuebunny/crossref_metadata_2025 huggingface dataset:
Surto concentrado de choque tóxico estreptocócico
Authors: Souto Bernardino Geraldo Alves , Rigueti Marcelo , Pellini Alessandra Cristina Guedes , Lima Gisele Dias de Freitas , Oliveira Maria Emília Braite de
Published: May 2014

Introdução: Síndrome do Choque Tóxico (SCT) é um processo autoinflamatório imunomediado, pouco frequente, mas  clinicamente muito grave. Instala-se abruptamente e,  comumente, leva a pessoa à morte em poucas horas. Um dos seus determinantes é a infecção por Streptococcus pyogenes. Não há relatos de epidemias desse agravo, mas surtos eventuais acontecem e estão aumentando de frequência. Este artigo relata uma experiência relacionada a um surto de SCT estreptocócico, vivenciada pelo Serviço Municipal de Vigilância Epidemiológica de São Carlos, SP, juntamente com o Centro de Vigilância Epidemiológica do Estado de São Paulo. Relato de caso: Diante da morte de duas pessoas residentes no mesmo domicílio, ocorridas no mesmo dia em condições inusitadas e idênticas, estratégias epidemiológicas descritivas permitiram a aplicação imediata de medidas de controle e assistência. Dez dias depois houve a confirmação de que se tratava de SCT estreptocócico. Agravos emergentes e reemergentes têm exigido dos Serviços de Vigilância em Saúde um estado de alerta e agilidade no trato com problemas inusitados e agudos. A ferramenta disponível mais eficiente é, ainda, a epidemiologia descritiva, devido ao seu potencial para identificar os meios de controle de agravos antes mesmo do respectivo diagnóstico. Conclusão: Surto de SCT estreptocócico é um problema reemergente, vêm aumentando de frequência, ocorre abruptamente e apresenta elevada letalidade. É necessário, pois, especial atenção dos Serviços de Vigilância em Saúde a essa possibilidade diante da circulação de infecções por Staphylococcus ou Streptococcus ou quando ocorrerem óbitos concentrados a partir de eventos de rápida evolução clínica em pessoas previamente sadias.
Hanseníase: avaliação em contatos intradomiciliares
Authors: Temoteo Rayrla Cristina De Abreu , Souza Marilena Maria de , Farias Maria do Carmo Andrade Duarte de , Abreu Luiz Carlos de , Martins Netto Eduardo
Published: May 2014

Introdução: Os contatos intradomiciliares de hanseníase são meios para a manutenção da endemia. Objetivo: Identificar os motivos por que os contatos intradomiciliares não procuraram a Unidade de Saúde da Família (USF) para realização do exame dermatoneurológico, no município de Cajazeiras (PB). Métodos: Pesquisa exploratório-descritiva, com abordagem qualitativa, realizada em três USF do referido município. Os dados foram coletados em entrevista, mediante aplicação de roteiro estruturado, durante visitas domiciliares a 31 contatos de casos de hanseníase; os dados foram tratados por meio da análise de conteúdo de Bardin. Resultados: O principal motivo para a não realização do exame dermatoneurológico foi ausência de sinais e sintomas de hanseníase, e sentimentos como: medo do exame, desconfiança no serviço, dentre outros. Conclusão: Os contatos intradomiciliares não procuraram a USF para realização do exame dermatoneurológico por falta de informações prestadas pelos profissionais de saúde que os atendem na Estratégia em Saúde da Família.
Perfil epidemiológico da infecção nosocomial do trato urinário em hospital universitário de Campina Grande (PB)
Authors: Baracuhy Ygor Paiva Schiel , Gondin Cátia Sueli De Sousa Eufrazino , Barros Andréa Amorim Pereira , Baracuhy Haysa Paiva , Baracuhy Verena Schiel
Published: May 2014

Introdução: A infecção do trato urinário (ITU) é a infecção hospitalar mais frequente. Objetivo: Este estudo tem como objetivo categorizar e identificar aspectos relacionados à infecção nosocomial do trato urinário (ITUN) no Hospital Universitário Alcides Carneiro (HUAC), em Campina Grande (PB), traçando um perfil dos pacientes com este diagnóstico durante internação de janeiro a julho de 2012 em enfermarias clínicas do hospital (clínica geral, cardiologia, endocrinologia, infectologia e pneumologia). Métodos: Foram analisados prontuários referentes a 436 internamentos. A pesquisa de base quantitativa e qualitativa se caracterizou por um estudo descritivo. As variáveis examinadas incluíram idade, sexo, enfermaria, tempo de internação, sondagem vesical de demora (SVD) e sua duração, exames diagnósticos, evolução para ITUN, drogas utilizadas como terapia empírica inicial, agentes isolados em uroculturas e susceptibilidade antimicrobiana dos patógenos isolados. Resultados: Foi identificada a evolução para ITUN em 12,61% das internações, predominando entre pacientes idosos e naqueles com SVD, além da supremacia da Escherichia coli entre os patógenos isolados e sua taxa de resistência às fluoroquinolonas de 50%. Conclusão: As cepas de E. coli isoladas mostraram sensibilidade às cefalosporinas de 2ª e 3ª gerações, amicacina e meropenem. As cepas isoladas de Klebsiella pneumoniae, segundo patógeno mais frequente, foram sensíveis apenas à cefoxitina e ao meropenem. As fluoroquinolonas foram, em nossa pesquisa, as mais prescritas como terapia empírica, o que pode justificar as elevadas taxas de resistência encontradas, tornando, então, seu uso impróprio para tratamento empírico de novos casos.
Integrative aspects of the relationship between stress and heart rate variability
Authors: Lorenzo Suelen Moraes de , Valenti Vitor Engrácia , Abreu Luiz Carlos de , Ferreira Celso , Monteiro Carlos Bandeira de Mello
Published: May 2014

The literature indicates stress as a response of the organism to a stimulation that requires enormous efforts to adapt to the changes in the environment and the body. When an individual is subjected to stress, the autonomic nervous system is triggered, the sympathetic pathway is activated, and the parasympathetic system is suppressed, which exerts several effects on the cardiovascular system and affects heart rate variability. This research aimed to conduct a literature review to find and analyze the studies that address clearly the implications of stress on heart rate variability. The methodology employed was an active search in the databases SciELO, PubMed and Lilacs. The results were five articles, most of which suggest a relationship between stress and heart rate variability. We observed that the majority of the studies indicated a strong association between stress and cardiac autonomic activity. The stress is present in the daily activities of the population, especially in labor. The subject is vast, however, were observed in the references the effects of stress on the body making it vulnerable to diseases. Thus, this information may contribute to the aid of preventive strategies against stress and diseases of the cardiovascular system.
Auroral electrojet indices in the Northern and Southern Hemispheres: A statistical comparison
Authors: Weygand J. M. , Zesta E. , Troshichev O.
Published: May 2014

The auroral electrojet (AE) index is traditionally derived from about 12 ground magnetometer observatories located around the average northern auroral oval location. The AE index calculation has only been performed with Northern Hemisphere data, because similar coverage in the Southern Hemisphere does not exist. In this study, eight southern auroral ground magnetometers and their near conjugate Northern Hemisphere counterparts are used to calculate conjugate AE indices for 274 days covering all four seasons from 2005 to 2010. The correlation coefficient between the northern and southern AE indices for many of the intervals is 0.65 indicating strong asymmetries between the two hemispheres. We compare our conjugate AE indices with the standard AE index and find a number of asymmetries because of station coverage gaps in the southern and northern arrays. The mean difference between the southern and northern AE indices is largest during northern summer season, and the smallest mean difference occurs in the spring. The mean differences between the southern and conjugate northern AE indices are about 31 nT with the largest differences occurring in the midnight magnetic local time (MLT) sector. We suggest that these differences may be a function of seasonal, MLT, and ionospheric effects. We also find a difference in the southern and northern AE related to UT and believe that this pertains to the distribution of the magnetometers. The fact that a difference between the southern and northern AE indices exists indicates the importance of examining geomagnetic activity in both hemispheres when considering magnetospheric phenomena.
Comparison of Martian surface ionizing radiation measurements from MSL‐RAD with Badhwar‐O'Neill 2011/HZETRN model calculations
Authors: Kim Myung‐Hee Y. , Cucinotta Francis A. , Nounu Hatem N. , Zeitlin Cary , Hassler Donald M. , Rafkin Scot C. R. , Wimmer‐Schweingruber Robert F. , Ehresmann Bent , Brinza David E. , Böttcher Stephan , Böhm Eckart , Burmeister Soenke , Guo Jingnan , Köhler Jan , Martin Cesar , Reitz Guenther , Posner Arik , Gómez‐Elvira Javier , Harri Ari‐Matti ,   the MSL Science Team
Published: May 2014

Dose rate measurements from Mars Science Laboratory‐radiation assessment detector (MSL‐RAD) for 300 sols on Mars are compared to simulation results using the Badhwar‐O'Neill 2011 galactic cosmic ray (GCR) environment model and the high‐charge and energy transport (HZETRN) code. For the nuclear interactions of primary GCR through Mars atmosphere and Curiosity rover, the quantum multiple scattering theory of nuclear fragmentation is used. Daily atmospheric pressure is measured at Gale Crater by the MSL Rover Environmental Monitoring Station. Particles impinging on top of the Martian atmosphere reach RAD after traversing varying depths of atmosphere that depend on the slant angles, and the model accounts for shielding of the RAD “E” detector (used for dosimetry) by the rest of the instrument. Simulation of average dose rate is in good agreement with RAD measurements for the first 200 sols and reproduces the observed variation of surface dose rate with changing heliospheric conditions and atmospheric pressure. Model results agree less well between sols 200 and 300 due to subtleties in the changing heliospheric conditions. It also suggests that the average contributions of albedo particles (charge number Z < 3) from Martian regolith comprise about 10% and 42% of the average daily point dose and dose equivalent, respectively. Neutron contributions to tissue‐averaged effective doses will be reduced compared to point dose equivalent estimates because a large portion of the neutron point dose is due to low‐energy neutrons with energies <1 MeV, which do not penetrate efficiently to deep‐seated tissues. However the exposures from neutrons to humans on Mars should become an important consideration in radiobiology research and risk assessment.
A new bathymetric compilation for the South Orkney Islands region, Antarctic Peninsula (49°–39°W to 64°–59°S): Insights into the glacial development of the continental shelf
Authors: Dickens William A. , Graham Alastair G. C. , Smith James A. , Dowdeswell Julian A. , Larter Robert D. , Hillenbrand Claus‐Dieter , Trathan Phil N. , Erik Arndt Jan , Kuhn Gerhard
Published: May 2014

We present a new, high resolution (300 m) bathymetric grid of the continental shelf surrounding the South Orkney Islands, northeast of the Antarctic Peninsula. The new grid, derived from a compilation of marine echo‐sounding data, improves previous regional bathymetric representations and helps to visualize the morphology of the shelf in unrivalled detail. The compilation forms important baseline information for a range of scientific applications and end users including oceanographers, glacial modelers, biologists, and geologists. In particular, due to the limited understanding of glacial history in this region, the bathymetry provides the first detailed insights into past glacial regimes. The continental shelf is dominated by seven glacially eroded troughs, marking the pathways of glacial outlets that once drained a former ice cap centered on the South Orkney Islands. During previous glacial periods, grounded ice extended to the shelf edge north of the islands. A large, ∼250 km long sediment depocenter, interpreted as a maximum former ice limit of one or more Cenozoic glaciations, suggests that ice was only grounded to the ∼300–350 m contour in the south. Hypsometric analyses support this interpretation, indicating that a significant proportion of the shelf has been unaffected by glacial erosion. Using these observations, we propose a preliminary ice cap reconstruction for maximum glaciation of the South Orkney plateau, suggesting an ice coverage of about ∼19,000 km2. The timing of maximum ice extent, number of past advances and pattern of subsequent deglaciation(s) remain uncertain and will require further targeted marine geological and geophysical investigations to resolve.
Relative water and gas permeability for gas production from hydrate‐bearing sediments
Authors: Mahabadi Nariman , Jang Jaewon
Published: May 2014

Relative water and gas permeability equations are important for estimating gas and water production from hydrate‐bearing sediments. However, experimental or numerical study to determine fitting parameters of those equations is not available in the literature. In this study, a pore‐network model is developed to simulate gas expansion and calculate relative water and gas permeability. Based on the simulation results, fitting parameters for modified Stone equation are suggested for a distributed hydrate system where initial hydrate saturations range from Sh = 0.1 to 0.6. The suggested fitting parameter for relative water permeability is nw ≈ 2.4 regardless of initial hydrate saturation while the suggested fitting parameter for relative gas permeability is increased from ng = 1.8 for Sh = 0.1 to ng = 3.5 for Sh = 0.6. Results are relevant to other systems that experience gas exsolution such as pockmark formation due to sea level change, CO2 gas formation during geological CO2 sequestration, and gas bubble accumulation near the downstream of dams.
Intense duskside lower band chorus waves observed by Van Allen Probes: Generation and potential acceleration effect on radiation belt electrons
Authors: Su Zhenpeng , Zhu Hui , Xiao Fuliang , Zheng Huinan , Wang Yuming , He Zhaoguo , Shen Chao , Shen Chenglong , Wang C. B. , Liu Rui , Zhang Min , Wang Shui , Kletzing C. A. , Kurth W. S. , Hospodarsky G. B. , Spence H. E. , Reeves G. D. , Funsten H. O. , Blake J. B. , Baker D. N. , Wygant J. R.
Published: May 2014

Local acceleration driven by whistler mode chorus waves largely accounts for the enhancement of radiation belt relativistic electron fluxes, whose favored region is usually considered to be the plasmatrough with magnetic local time approximately from midnight through dawn to noon. On 2 October 2013, the Van Allen Probes recorded a rarely reported event of intense duskside lower band chorus waves (with power spectral density up to 10−3nT2/Hz) in the low‐latitude region outside of L=5. Such chorus waves are found to be generated by the substorm‐injected anisotropic suprathermal electrons and have a potentially strong acceleration effect on the radiation belt energetic electrons. This event study demonstrates the possibility of broader spatial regions with effective electron acceleration by chorus waves than previously expected. For such intense duskside chorus waves, the occurrence probability, the preferential excitation conditions, the time duration, and the accurate contribution to the long‐term evolution of radiation belt electron fluxes may need further investigations in future.
The Midlatitude Summer Night Anomaly as observed by CHAMP and GRACE: Interpreted as tidal features
Authors: Xiong Chao , Lühr Hermann
Published: May 2014

This paper presents a description of the Midlatitude Summer Night Anomaly (MSNA) in terms of solar tidal signatures, based on in situ observations from CHAMP (CHAllenging Minisatellite Payload) and GRACE (Gravity Recovery and Climate Experiment) during the solar minimum years 2008 and 2009. Our analysis is focusing on 40° to 60° magnetic latitude ranges in both hemispheres, where the reversed diurnal variations of the electron density are strongest. The results revealed that in the Southern Hemisphere the longitudinally symmetric tide D0 is particularly strong during December solstice. The well‐known Weddell Sea Anomaly is caused by a simultaneous constructive interference of three components D0, DW2, and SPW1. During June solstice the eastward propagating tide DE1 is the strongest in the Northern Hemisphere, which causes a wave‐2 longitudinal pattern. The two crests of the wave‐2 pattern at nighttime correspond well with the MSNA feature in the Northern Hemisphere. The MSNA feature over the USA continent is particularly strong, which can be explained by the combined contributions of the components DE1, D0, and DW2. The diurnally varying difference in electron density between the USA East and West Coast can also be explained by the phase propagation of the DE1. A similar effect has also been observed in the Asian region. The peak electron densities of the tidal component D0 appear around 0700 LT and 2000 LT in the Southern and Northern Hemispheres, respectively. The time shift suggests that the two hemispheres move in antiphase up and down. The planetary wave SPW1 exhibits an electron density crest near longitude sectors where the dip equator reaches far into the summer hemisphere.
Improving mesoscale modeling using satellite‐derived land surface parameters in the Pearl River Delta region, China
Authors: Li Mengmeng , Song Yu , Huang Xin , Li Jianfeng , Mao Yi , Zhu Tong , Cai Xuhui , Liu Bing
Published: May 2014

Land surface parameters play an important role in mesoscale modeling by regulating the regional heat flux and hydrological cycle. Recently, significant urbanization and afforestation occurred in the Pearl River Delta (PRD) region, China, which exert an important effect on local meteorology and thermal circulation. But previous studies failed to capture the complex changes of the surface characteristics in the PRD and thus were difficult to accurately describe the land‐atmosphere coupling. In this study, high‐resolution Moderate Resolution Imaging Spectroradiometer observations are used to specify the land cover type, green vegetation fraction, and leaf area index in the Weather Research and Forecasting model. Comparisons with ground‐based observations during eight episodes, as well as satellite measurements, all indicate an improved model performance when the satellite‐derived land surface parameters are assimilated. Moreover, the remote sensing data accurately reflect the surface inhomogeneity and successfully represent the intensity and spatiotemporal characteristics of the urban heat island (UHI) effect. The UHI effect in turn modifies the local thermal circulation by enhancing the urban‐rural horizontal advection and initiating the urban heat island circulation, as well as interacting with the sea/land breeze over the PRD. This work not only improves the understanding of local meteorological simulation and forecasting but also sets the stage for further research on the feedback between air quality and meteorological responses due to land cover changes.
Brain Imaging: Localisation of Brain Functions
Authors: Abdullaev Yalchin
Published: May 2014

Neuroimaging provides a method to locate areas of the brain active when organisms perceive or respond to sensory events or carry out a wide variety of tasks. The methods have made it possible to examine where in the brain cognitive and emotional systems are located, thus providing new approaches to understanding normal and pathological human information processing. Positron emission tomography accomplishes this by detecting concentrations of radioactive oxygen, glucose, or neurotransmitter molecules in the brain. High‐density multichannel electrical activity recorded from the scalp electroencephalogram supplements important information about the time course of these neurophysiological events. Functional magnetic resonance imaging allows to measure the blood oxygenation level in the brain during carrying out a wide variety of tasks. Recent methodological advances are moving beyond the localisation of task‐related activations to functional connectivity of remote brain areas and detection of patterns of remote brain areas in a variety of states and tasks.

Key Concepts:

Neuroimaging provides methods to locate areas of the human brain that are active during certain tasks or behaviours.

PET and functional MRI allow to map functional anatomy of the human brain noninvasively in healthy volunteers.

Mapping electrical activity of the human brain can supply important additional information about the time course of these local brain activations in various tasks or behaviours.

Later approaches to functional mapping of the human brain function by fMRI have focussed on the connectivity of remote brain areas.

Newest approaches to the functional mapping of the human brain focus on multiple pattern recognition algorithms to try to characterise each task or behavioural act by a pattern or set of multiple remote brain areas active at the moment.
Lymphocytes
Authors: Hwang Shen‐An , Actor Jeffrey K
Published: May 2014

Lymphocytes are white blood cells that are derived from a common lymphoid progenitor in the bone marrow. They function as specific mediators involved in inducible immune responses against infectious agents. The classically defined adaptive B and T lymphocytes use defined surface molecules, antigen receptors, to detect antigens. The activation of lymphocytes requires multiple signals, including binding of the antigen‐specific receptor to the antigen, costimulation and/or exposure to environmental molecules. Activation results in an expansion of clonally reactive cells, which become effector cells (plasma cells and activated T cells) that function to eliminate pathogens, or which become memory cells to facilitate later secondary responses. A secondary group of lymphocytes, the innate lymphocytes (natural killer (NK) cells, γδ T cells, invariant NK T cells and B‐1 cells) also play a role in immune function. Specifically, they represent a pool of cells that respond quickly to a limited repertoire of antigens at sites of infection.

Key Concepts:

Cells of the lymphoid lineage are derived from the common lymphoid progenitors that differentiate from multipotent haematopoietic stem cells in the bone marrow.

The role of lymphocytes is to facilitate recognition of foreign antigens (immune stimulators) and to mount responses for their neutralization and/or elimination.

The developmental stages of B and T cells correspond to gene rearrangement events, leading to the different specificity of B cell and T cell receptors. B cells mature in the bone marrow, whereas T cells undergo education and maturation in the thymus.

B lymphocytes utilise an immunoglobulin receptor to recognise conformational antigens. Upon activation, they mature into plasma cells to secrete specific antibodies with directed target specificity.

T lymphocytes recognised processed antigen presented via major histocompatibility molecules. Multiple phenotypic subsets exist, allowing for differential regulation of cellular immune function.

T‐helper cells express CD4 molecules, and assist in both cellular and humoral functions. Specific helper activity is directed via secretion of pleiotropic cytokines.

Cytotoxic T cells express CD8 molecules, and target viral infected or tumour targets for destruction.

All T lymphocytes bear the CD3 molecule to assist in signalling once antigen is encountered.

The primary response of lymphocytes leads to the generation of ‘daughter clones’, which become effectors, a small fraction of which become memory cells. This generates a persistent population that can rapidly expand and respond with higher magnitude upon secondary encounter with an antigen.

The innate lymphocytes (natural killer cells, γδ T cells, invariant natural killer T cells and B‐1 cells) represent a special reservoir of cells that are able to respond quickly to a limited subset of antigens at sites of infection.
Nitrogenase Complex
Authors: Wiig Jared A , Rebelein Johannes G , Hu Yilin
Published: May 2014

Nitrogenases are a family of metalloenzymes that catalyse a key step in the global nitrogen cycle: theadenosine triphosphate (ATP)‐dependent reduction of dinitrogen (N2) to ammonia (NH3). The molybdenum (Mo)‐nitrogenase is the best characterised member of this enzyme family. It is a two‐component system comprising an iron (Fe) protein and a molybdenum‐iron (MoFe) protein, each containing FeS cluster(s) which are responsible for the electron flow during the process of substrate reduction. This article provides an overview of the current knowledge on the structure, assembly and catalysis of Mo‐nitrogenase, as well as a brief discussion of alternative substrates of nitrogenase and other members in this enzyme family.

Key Concepts:

The nitrogenase complex consists of two Fe protein dimers and one MoFe protein tetramer; each component harbours metallocluster(s) that mediate electron flow to the active centre within the complex.

The active centre of Mo‐nitrogenase, designated the FeMoco or the M‐cluster, is a [MoFe7S9C‐homocitrate] cluster.

Electrons are transferred from the [Fe4S4] cluster in the Fe protein to the P‐cluster and then the M‐cluster in the MoFe protein, where substrate reduction occurs.

Nitrogenase catalyses the ATP‐dependent reduction of dinitrogen (N2) to ammonia (NH3) under ambient temperature and pressure.

Nitrogenase has been found to catalyse the reduction of alternative substrates, such as H+, N3−, CN−, C2H2and CO.
Carrel, Alexis
Authors: Cruse Julius M , Lewis Robert E
Published: May 2014

Alexis Carrel (1873–1944) was a French surgeon who successfully joined blood vessels by end‐to‐end anastomosis with triangulation sutures, thereby permitting the rapid re‐establishment of blood circulation to a transplanted organ. The successful transplantation of organs was realised only after the discovery, many years later, of powerful immunosuppressant drugs. Carrel's other scientific contributions included the invention, with Charles Lindberg, of a perfusion pump to facilitate organ transplantation, wound antisepsis and the culture of organs and cells. He was awarded the Nobel Prize for Medicine for his successful procedures of vascular suturing and anastomosis techniques.
Jerne, Niels Kaj
Authors: Cruse Julius M , Lewis Robert E
Published: May 2014

Niels Kaj Jerne (1911–1994) was a Danish immunologist who proposed a selection theory of antibody formation, the functional network of antibodies and lymphocytes and distinction of self from nonself by T lymphocytes. Jerne achieved scientific acclaim for his theories to explain immune system interactions. He postulated that the immune system contains specific antibody populations for interaction with antigens. He advanced the concept that the development of self‐tolerance takes place in the thymus and developed a ‘network theory’ postulating T‐ and B‐cell interactions. His network theory proposed that antibody active sites are attracted to specific antigens (idiotypes) as well as to antibodies reactive with the same site. He postulated that under physiological conditions, antibodies are in equilibrium or balance which is interrupted on exposure to antigen, leading to activation of an immune response. After working at the Danish National Serum Institute in Copenhagen, he joined the Biological Standards and Immunology Division of the World Health Organization in Geneva. He next served as Chair of Microbiology at the University of Pittsburg, PA but returned to Europe to serve as Professor at the University of Frankfurt and Director of the Paul Ehrlich Institute. Later, he was appointed Director of the Basel Institute for Immunology (1969–1980). He shared the 1984 Nobel Prize in Physiology or Medicine with Köhler and Milstein in recognition of his natural selection theory and related immunological hypotheses.
Milstein, César
Authors: Cruse Julius M , Lewis Robert E
Published: May 2014

César Milstein (1927–2002), an Argentinian molecular biologist, and Georges Köhler, a German immunologist, perfected the technique of monoclonal antibody production from hybridomas, for which they shared the Nobel Prize in Medicine. This discovery proved the validity of the clonal selection theory of antibody formation. On receiving the PhD in Biochemistry in Buenos Aries, he completed a second doctorate at Cambridge. On joining the staff of the Medical Research Council of Molecular Biology, Milstein
et al.
established the complete sequence of an immunoglobulin light chain. They discovered only one type of messenger
ribonucleic acid (RNA)
for both constant and variable light chain domains. Milstein reasoned that the constant domain genes must come together in antibody‐synthesising cells. Milstein and Köhler fused antibody‐forming spleen cells with mutant myeloma cells to form hybridomas to study the genetic basis of antibody diversity. The mutant myeloma cells conferred immortality on the fused cell line, whereas the spleen cells conferred antibody specificity. Thus, the hybrid cell or hybridoma cell line exhibited long‐term survival in culture, producing an unlimited quantity of monoclonal antibodies.
Beyond Consent: Respect for Community in Genetic Research
Authors: Jones Derek J , Bush Paula L , Macaulay Ann C
Published: May 2014

Paralleling the broadening of scientific thought occasioned by the human genome project, calls have been sounded to expand research ethics to include a principle of ‘respect for community’ in genetic research. The principle is responsive to a history of genetic research that has harmed some groups. The principle recognises that communities hold dignitary interests, values and rights. For such reasons, it has gained recognition in national and international health research ethics norms. To help translate respect for community into research practice, we identify selected ethics elements and research approaches, including: collaborative community research; jointly defining research priorities and questions; informed consent; joint interpretation and dissemination of results; community ethics deliberations and fair benefit sharing. Implementing such elements presents challenges that merit interdisciplinary study, pluralistic debate and analysis. With such work, we project a future with fuller recognition of respect for community as an ethical principle and duty in human research ethics.

Key Concepts:

Evolving research ethics requires protection of communities, in addition to protection of individuals – this also applies to genetic research.

Protection of communities supports the ethical concept of respect for communities.

National and international research ethics guidelines support these concepts.

Respect for communities can be achieved through researchers using collaborative research with communities.

Collaborative research uses principles and practice from both participatory research and community‐engaged research.

Collaborative research maximises benefits and minimises harms for communities and groups within the communities.

Collaborative research impacts researchers, communities, institutional and community ethics boards and those publishing the results.
Inferring the Process of Human–Chimpanzee Speciation
Authors: Mailund Thomas , Munch Kasper , Schierup Mikkel Heide
Published: May 2014

Although the fossil record around the times of the key speciation events that splits humans from orangutans, gorillas and chimpanzees is sparse, genetic comparisons of the extant apes enable us to analyse the process of speciation that lead to modern humans.
Deoxyribonucleic acid (DNA)
sequencing technology has improved greatly over the last decade and the complete genomes of all great apes have now been mapped. Analysis of this rich data has enabled the inference of key parameters of their speciation events. Though inference of the speciation events has so far focussed on simple models it is an active area of research to develop better models and understand the processes involved in the speciation and divergence of the great apes. Of the speciations along the human lineage, the split between ourselves and our closest living relatives, the chimpanzees and bonobos, naturally receives special attention.

Key Concepts:

Population genetics modelling of speciation events informs us of the timing and mode of ancient speciations from present day genomic data.

A strong source of information about speciation is found in the changing gene trees along a genomic alignment.

By studying great ape genomes we learn about the speciations along the human lineage, where the human–chimpanzee speciation is of special interest.

It is still an open question if this speciation was a clean (allopatric) split or if occurred in the presence of gene flow or was followed by admixture events.

If the speciation happened in the presence of gene flow it might have left signals of which genes first became incompatible and drove the speciation.
Molecular Genetics of Obsessive‐Compulsive Disorder
Authors: Taylor Steven
Published: May 2014

Genetic association studies of obsessive‐compulsive disorder (OCD) have yielded inconsistent findings because those studies have tended to have small sample sizes and low statistical power, thereby making it difficult to reliably detect small genetic effects. Meta‐analysis combines individual studies thereby increasing the power to detect small effects. Meta‐analysis suggests that OCD is associated with serotonin‐related polymorphisms (
5‐HTTLPR
and
HTR2A
) and, in males only, polymorphisms involving catecholamine modulation (
COMT
and
MAOA
). There is also suggestive evidence that many other polymorphisms are associated with OCD. Effects of individual polymorphisms are small, suggesting that OCD is shaped by multiple genes that each make small, incremental contributions to the risk of developing the disorder. Twin studies show that there are genetic similarities and differences across OCD subtypes (early versus late onset) and across major types of OCD symptoms (e.g. washing, checking, and ordering). Genetic association studies of specific subtypes and symptoms may advance our understanding of OCD.

Key Concepts:

Genetic association studies, typically with small sample sizes, tend to fail to reliably identify OCD‐related polymorphisms, because genetic effects tend to be small.

Meta‐analysis, combining numerous genetic studies, indicates that numerous genes play a small, incremental role in the risk of developing OCD.

The genes most robustly associated with OCD are serotonin‐related and, in males, are those broadly involved in catecholamine modulation.

There is suggestive evidence that other genes are involved.

Haplotypes associated with glutamate regulation may also be associated with OCD.

Twin studies can facilitate molecular genetic research by shedding light on aetiologic differences among OCD symptoms and subtypes.

Twin research shows that some genetic factors are common to all OCD symptoms, whereas others are symptom‐specific.

Genetic association studies of specific subtypes and symptoms may advance our understanding of OCD.
Animal Research Ethics: Is Directive 2010/63/EUSpeciesist?
Authors: De Miguel Beriain Iñigo , Jorqui Azofra María
Published: May 2014

Animal rights defenders criticise the Directive 2010/63/EU for at least three objections: experimentation with higher species is not as necessary as the authors seem to assume; even if we accept that it is necessary from a scientific point of view, it would be morally unacceptable; even while it may be necessary from a scientific point of view and morally acceptable, there are no relevant reasons for using apes in experimentation instead of those human beings whose moral status could hardly be considered superior to apes. This article seeks to demonstrate that those objections are not acceptable. Hence, it especially focuses on the third one, assessing that the preference for animals as objects of research is not speciesist discrimination. It is stated that this preference is simply the consequence that is given by the need to ensure the application of the moral criterion highlighted: the maximisation of happiness.

Key Concepts:

Speciesism involves the assignment of different values, rights or special consideration to individuals solely on the basis of their species membership.

Directive 2010/63/UE has been considered speciesist as far as it settles an unfair discrimination between animals and marginal human beings.

This critique is built on the basis of the argument from marginal cases.

This argument tries to demonstrate that it is unfair to treat human beings and animals in a different way as far as at least some of them share the same moral value.

Marginal human beings are those who are not moral agents due to a lack of a morally relevant quality, such as rationality.

The argument from marginal cases does not work in the case of research with animals as far as our preferences are not based on a species prejudice.

The use of animals instead of marginal human beings can be justified on the basis of a utilitarian argument.
Xylem Function and Evolution
Authors: Brodribb Tim J
Published: May 2014

Water transporting xylem tissues are among the most obvious and attractive features of land plants. The stems, roots, branches and leaf veins in all vascular plants are largely composed of xylem tissues, and remarkably, most of these xylem cells are dead. The water transport network in plants is closely linked to the capacity for photosynthesis and growth due to the shared pathway for water vapour and photosynthetic carbon dioxide between the leaf and atmosphere. Adaptations in the anatomy and architecture of xylem conduits and leaf vein density enable angiosperms to achieve the highest water transport capacity among land plants. Evolutionary pressure to improve water transport efficiency is counter‐balanced by the need to maintain the integrity of the water column inside the plant, which operates under high tension.

Key Concepts:

Land plants trade water for carbon.

Using the cohesive nature of water, plants transport huge volumes of water without metabolic cost.

Water is transported under tension, leading to cavitation as soil dries.

Water transport and photosynthesis are linked by the common stomatal pathway for water and CO
2
.

High rates of photosynthesis require high xylem hydraulic conductivity.

Xylem physiology is highly adaptive both in transport efficiency and safety.

Angiosperm xylem vessels provide the best compromise of safety and efficiency.

Water transport in leaves is limited by the density of veins.

Radiation of angiosperms saw a sharp rise in vein density in leaves.

Leaf vein density is highly plastic, enabling optimisation of carbon investment.
Clinical and Phenotypic Relevance of
cis
‐Acting Regulatory Polymorphisms
Authors: Liebert Anke , Jones Bryony L , Swallow Dallas M
Published: May 2014

Genetic variants that regulate the expression level of a transcript are known as expression quantitative trait loci (eQTLs) or regulatory single nucleotide polymorphisms.
Cis
‐variants are those that only act on a target gene (or genes) on the same chromosomal homologue. They cause additive differences in gene expression that are tightly associated with the three genotypes of the regulatory eQTL, and cause allelic expression imbalance in heterozygous samples. Unlike
trans
‐variants, which can act on many genes located at a distance,
cis
‐acting variants are less likely to have all‐or‐none effects if inactivated, and these may be tissue specific and thus less severe. Such
cis
‐variants are found occasionally in Mendelian disease and now increasingly implicated in polygenic disorders. The interactions of these regulatory variations with other genetic and also environmental factors are likely to account for some of the complexity of multifactorial diseases.

Key Concepts:

Regulatory polymorphisms, otherwise known as eQTLs (expression quantitative trait loci), are DNA sequence variations that alter the level of expression of particular transcripts.

Cis
‐eQTLs are
cis
‐acting polymorphisms that cause variation in the expression of a nearby gene or genes on the same chromosomal homologue.

In heterozygous individuals there is a difference in the level of expression from each of the pair of genes transcribed from the two chromosomal homologues.

This difference in expression in heterozygous individuals can be observed as allelic expression imbalance (AEI) if there are also allelic sequence differences in the transcript.

Such AEI is distinguishable from imprinting in that unlike the case of imprinting the higher expressing transcript can come from either the mother or the father.

Cis
‐acting polymorphisms can affect expression in a tissue‐specific and developmentally specific manner.

They are strong candidates for positive selection and evolutionary adaptation but such variants might be maladaptive in different environments.

Cis
‐acting regulatory sequence changes have been identified as a class of rare mutations in Mendelian disorders, and more common variants are increasingly implicated as causal polymorphisms involved in multifactorial diseases.
Genetic Susceptibility to Triple‐Negative Breast Cancers
Authors: Wong‐Brown Michelle W , Scott Rodney J
Published: May 2014

Triple‐negative breast cancer (TNBC) is a histological classification of breast cancer, where there is no expression of either the oestrogen or the progesterone receptor and no amplification of the HER2 receptor. TNBC is an important breast cancer subtype as it is aggressive in nature and has a poorer disease prognosis, mainly due to a paucity of targeted therapies. Studies in recent years have tried to elucidate the genetic aetiology of TNBC to better understand the disease and to predict response to treatments based on their genetic profile. TNBC has been shown to be very similar to
BRCA1
mutation‐associated breast tumours, where it is estimated that approximately 20% of TNBC patients harbour germline
BRCA
(especially
BRCA1
) mutations. The contribution of germline mutations in other breast cancer susceptibility genes to TNBC still remains to be determined. Several common and novel breast cancer susceptibility loci have also been specifically linked to TNBC. These findings support the argument that genetic testing should be offered to patients based on the triple‐negative phenotype of their breast tumours.

Key Concepts:

TNBC is an important area of study due to the aggressive nature of this tumour subtype and the difficulties in disease treatment.

Women with TNBC have a poorer prognosis due to lack of endocrine therapies.

TNBC has histopathological characteristics similar to
BRCA1
‐ and
BRCA
2‐associated tumours, and could have similar molecular aetiology.

Germline mutations in
BRCA1
and
BRCA2
have been associated with up to 20% of TNBC cohorts unselected for family history of the disease.

The contribution of germline mutations in other breast cancer susceptibility genes to TNBC remains to be determined.

Several known breast cancer susceptibility loci have been shown to be specifically associated with TNBC.

Patients with TNBC could benefit from genetic screening of both
BRCA
genes based solely on the phenotype of their breast tumour.
Role of Chromosomal Reorganisations in the Human–Chimpanzee Speciation
Authors: Farré Marta , Ruiz‐Herrera Aurora
Published: May 2014

The elucidation of how recombination is shaping the genomic architecture of organisms and, more in particular, how this affects the speciation process has been a long‐standing question in evolutionary biology. Large‐scale genomic changes such as inversions, translocations, fusions and fissions contribute to the reshuffling of genomes, providing new chromosomal forms on which natural selection can work. Despite large efforts employed in the last decade, few empirical data are available on the mechanisms by which genome reshuffling contribute to the formation of new species. Here, the authors discuss on the models of chromosomal evolution and the contribution of chromosomal reorganisations in mammalian chromosome evolution, and more specifically, during the human–chimpanzee speciation event.

Key Concepts:

The evolutionary process by which new biological species arise (speciation) is a complex process that requires the understanding of many mechanisms such as reproductive isolation, patterns of species diversity, together with the genetic basis underlying the process.

Understanding the mechanisms by which reproductive isolation (breakdown of gene flow between two populations) is achieved, is fundamental for speciation.

Genetic speciation makes references to the group of genes that are involved in maintaining reproductive isolation between species.

Chromosomal reorganisations may contribute to speciation due to the underdominant fitness effects associated with meiotic abnormalities when occurring in heterozygotes.

Chromosome rearrangements, such as inversions, can suppress recombination thus contributing to a reduction of gene flow across genomic regions and the accumulation of genetic incompatibilities.
Slice Culture Method for Studying Migration of Neuronal Progenitor Cells Derived from Human Embryonic Stem Cells (hESC)
Authors: Filipovic Radmila , Kumar Saranya Santosh , Bahr Ben A. , Loturco Joseph
Published: May 2014

In this unit we describe an overlay brain slice culture assay for studying migration of transgenic neurospheres derived from human embryonic stem cells (hESC). Neuronal progenitor cells were generated from hESC by derivation of embryoid bodies and rosettes. Rosettes were transfected using the PiggyBac transposon system with either control plasmids (GFP) or plasmid encoding a gene important for migration of neuronal progenitor cells, Doublecortin (DCX). Transfected cells were subsequently grown in low‐adhesion plates to generate transgenic human neurospheres (t‐hNS). Organotypic slice cultures were prepared from postnatal rat forebrain and maintained using the interface method, before transfected t‐hNS were overlaid below the cortex of each hemisphere. After 1 to 5 days, forebrain slices were fixed and processed for immunofluorescence. The distance at which cells migrated from the center of neurospheres to the host forebrain tissue was measured using Image J software. This protocol provides details for using the slice culture method for studying migration and integration of human neuronal cells into the host brain tissue. Curr. Protoc. Stem Cell Biol. 29:1H.7.1‐1H.7.14. © 2014 by John Wiley & Sons, Inc.
Generation of GFP Reporter Human Induced Pluripotent Stem Cells Using AAVS1 Safe Harbor Transcription Activator‐Like Effector Nuclease
Authors: Luo Yongquan , Rao Mahendra , Zou Jizhong
Published: May 2014

Generation of a fluorescent GFP reporter line in human induced pluripotent stem cells (hiPSCs) provides enormous potentials in both basic stem cell research and regenerative medicine. A protocol for efficiently generating such an engineered reporter line by gene targeting is highly desired. Transcription activator‐like effector nucleases (TALENs) are a new class of artificial restriction enzymes that have been shown to significantly promote homologous recombination by >1000‐fold. The AAVS1 (adeno‐associated virus integration site 1) locus is a “safe harbor” and has an open chromatin structure that allows insertion and stable expression of transgene. Here, we describe a step‐by‐step protocol from determination of TALENs activity, hiPSC culture, and delivery of a donor into AAVS1 targeting site, to validation of targeted integration by PCR and Southern blot analysis using hiPSC line, and a pair of open‐source AAVS1 TALENs. Curr. Protoc. Stem Cell Biol. 29:5A.7.1‐5A.7.18. © 2014 by John Wiley & Sons, Inc.