The neocortical column

In the middle of the twentieth century, Rafael Lorente de Nó (1902?1990) introduced the fundamental concept of the ?elementary cortical unit of operation,? proposing that the cerebral cortex is formed of small cylinders containing vertical chains of neurons (Lorente de Nó, 1933, 1938). On the basis of this idea, the hypothesis was later developed of the columnar organization of the cerebral cortex, primarily following the physiological and anatomical studies of Vernon Mountcastle, David Hubel, Torsten Wiesel, János Szentágothai, Ted Jones, and Pasko Rakic (for a review of these early studies, see Mountcastle, 1998). The columnar organization hypothesis is currently the most widely adopted to explain the cortical processing of information, making its study of potential interest to any researcher interested in this tissue, both in a healthy and pathological state. However, it is frequently remarked that the nomenclature surrounding this hypothesis often generates problems, as the term ?Column? is used freely and promiscuously to refer to multiple, distinguishable entities, such as cellular or dendritic minicolumns or afferent macrocolumns, with respective diameters of menor que50 and 200?500 ?m. Another problem is the degree to which classical criteria may need to be modified (shared response properties, shared input, and common output) and if so, how. Moreover, similar problems arise when we consider the need to define area-specific and species-specific variations. Finally, and what is more an ultimate goal than a problem, it is still necessary to achieve a better fundamental understanding of what columns are and how they are used in cortical processes. Accordingly, it is now very important to translate recent technical advances and new findings in the neurosciences into practical applications for neuroscientists, clinicians, and for those interested in comparative anatomy and brain evolution.

República Federativa Evangélica: uma análise de gênero sobre a laicidade no Brasil a partir da atuação dos/as parlamentares evangélicos/as no Congresso Nacional no exercício da 54ª Legislatura São Bernardo do Campo

Essa pesquisa objetiva a análise da relação entre religião e política, em perspectiva de gênero considerando a atuação de parlamentares evangélicos/as na 54ª Legislatura (de 2011 a 2014) e a forma de intervenção desses atores no espaço político brasileiro quanto à promulgação de leis e ao desenvolvimento de políticas públicas que contemplem, dentre outras, a regulamentação do aborto, a criminalização da homofobia, a união estável entre pessoas do mesmo sexo e os desafios oriundos dessa posição para o Estado Brasileiro que se posiciona como laico. Ora, se laico remete à ideia de neutralidade estatal em matéria religiosa, legislar legitimado por determinados princípios fundamentados em doutrinas religiosas, pode sugerir a supressão da liberdade e da igualdade, o não reconhecimento da diversidade e da pluralidade e a ausência de limites entre os interesses públicos / coletivos e privados / particulares. Os procedimentos metodológicos para o desenvolvimento dessa pesquisa fundamentam-se na análise e interpretação bibliográfica visando estabelecer a relação entre religião e política, a conceituação, qualificação e tipificação do fenômeno da laicidade; levantamento documental; análise dos discursos de parlamentares evangélicos/as divulgados pela mídia, proferidos no plenário e adotados para embasar projetos de leis; pesquisa qualitativa com a realização de entrevistas e observações das posturas públicas adotadas pelos/as parlamentares integrantes da Frente Parlamentar Evangélica - FPE. Porquanto, os postulados das Ciências da Religião devidamente correlacionados com a interpretação do conjunto de dados obtidos no campo de pesquisa podem identificar o lugar do religioso na sociedade de forma interativa com as interfaces da laicidade visando aprofundar a compreensão sobre a democracia, sobre o lugar da religião nas sociedades contemporâneas e sobre os direitos difusos, coletivos e individuais das pessoas.

Antiviral agent blocks breathing of the common cold virus

A dynamic capsid is critical to the events that shape the viral life cycle; events such as cell attachment, cell entry, and nucleic acid release demand a highly mobile viral surface. Protein mass mapping of the common cold virus, human rhinovirus 14 (HRV14), revealed both viral structural dynamics and the inhibition of such dynamics with an antiviral agent, WIN 52084. Viral capsid digestion fragments resulting from proteolytic time-course experiments provided structural information in good agreement with the HRV14 three-dimensional crystal structure. As expected, initial digestion fragments included peptides from the capsid protein VP1. This observation was expected because VP1 is the most external viral protein. Initial digestion fragments also included peptides belonging to VP4, the most internal capsid protein. The mass spectral results together with x-ray crystallography data provide information consistent with a “breathing” model of the viral capsid. Whereas the crystal structure of HRV14 shows VP4 to be the most internal capsid protein, mass spectral results show VP4 fragments to be among the first digestion fragments observed. Taken together this information demonstrates that VP4 is transiently exposed to the viral surface via viral breathing. Comparative digests of HRV14 in the presence and absence of WIN 52084 revealed a dramatic inhibition of digestion. These results indicate that the binding of the antiviral agent not only causes local conformational changes in the drug binding pocket but actually stabilizes the entire viral capsid against enzymatic degradation. Viral capsid mass mapping provides a fast and sensitive method for probing viral structural dynamics as well as providing a means for investigating antiviral drug efficacy.

Protein kinase mutants of human ATR increase sensitivity to UV and ionizing radiation and abrogate cell cycle checkpoint control

In fission yeast, the rad3 gene product plays a critical role in sensing DNA structure defects and activating damage response pathways. A structural homologue of rad3 in humans (ATR) has been identified based on sequence similarity in the protein kinase domain. General information regarding ATR expression, protein kinase activity, and cellular localization is known, but its function in human cells remains undetermined. In the current study, the ATR protein was examined by gel filtration of protein extracts and was found to exist predominantly as part of a large protein complex. A kinase-inactivated form of the ATR gene was prepared by site-directed mutagenesis and was used in transfection experiments to probe the function of this complex. Introduction of this kinase-dead ATR into a normal fibroblast cell line, an ATM-deficient fibroblast line derived from a patient with ataxia–telangiectasia, or a p53 mutant cell line all resulted in significant losses in cell viability. Clones expressing the kinase-dead ATR displayed increased sensitivity to x-rays and UV and a loss of checkpoint control. We conclude that ATR functions as a critical part of a protein complex that mediates responses to ionizing and UV radiation in human cells. These responses include effects on cell viability and cell cycle checkpoint control.

Absence of cytokine receptor-dependent specificity in red blood cell differentiation in vivo

Erythropoietin (EPO) is required for red blood cell development, but whether EPO-specific signals directly instruct erythroid differentiation is unknown. We used a dominant system in which constitutively active variants of the EPO receptor were introduced into erythroid progenitors in mice. Chimeric receptors were constructed by replacing the cytoplasmic tail of constitutively active variants of the EPO receptor with tails of diverse cytokine receptors. Receptors linked to granulocyte or platelet production supported complete erythroid development in vitro and in vivo, as did the growth hormone receptor, a nonhematopoietic receptor. Therefore, EPOR-specific signals are not required for terminal differentiation of erythrocytes. Furthermore, we found that cellular context can influence cytokine receptor signaling.

Mahogany (mg) stimulates feeding and increases basal metabolic rate independent of its suppression of agouti

The mahogany (mg) locus originally was identified as a recessive suppressor of agouti, a locus encoding a skin peptide that modifies coat color by antagonizing the melanocyte-stimulating hormone receptor or MC1-R. Certain dominant alleles of agouti cause an obesity syndrome when ectopic expression of the peptide aberrantly antagonizes the MC4-R, a related melanocyte-stimulating hormone receptor expressed in hypothalamic circuitry and involved in the regulation of feeding behavior and metabolism. Recent work has demonstrated that mg, when homozygous, blocks not only the ability of agouti to induce a yellow coat color when expressed in the skin of the lethal yellow mouse (AY), but also the obesity resulting from ectopic expression of agouti in the brain. Detailed analysis of mg/mg AY/a animals, presented here, demonstrates that mg/mg blocks the obesity, hyperinsulinemia, and increased linear growth induced by ectopic expression of the agouti peptide. Remarkably, however, mg/mg did not reduce hyperphagia in the AY/a mouse. Furthermore, mg/mg induced hyperphagia and an increase in basal metabolic rate in the C57BL/6J mouse in the absence of AY. Consequently, although mahogany is broadly required for agouti peptide action, it also appears to be involved in the control of metabolic rate and feeding behavior independent of its suppression of agouti.

Moving from medical to health systems classifications of deaths : extending verbal autopsy to collect information on the circumstances of mortality

Funding A Health Systems Research Initiative Development Grant from the UK Department for International Development (DFID), Economic and Social Research Council (ESRC), Medical Research Council (MRC (and the Wellcome Trust (MR/N005597/1) funds the research presented in this paper. Support for the Agincourt HDSS including verbal autopsies was provided by The Wellcome Trust, UK (grants 058893/Z/99/A; 069683/Z/02/Z; 085477/Z/08/Z; 085477/B/08/Z), and the University of the Witwatersrand and Medical Research Council, South Africa.

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12

Funding: British Women’s Heart and Health Study is funded by the Department of Health grant no. 90049 and the British Heart Foundation grant no. PG/09/022. British Regional Heart Study is supported by the British Heart Foundation (grant RG/ 13/16/30528). CB (COPDBEAT) received funding from the Medical Research Council UK (grant no. G0601369), CB (COPDBEAT) and AJW (UKCOPD) were supported by the National Institute for Health Research (NIHR Leicester Biomedical Research Unit). MB (COPDBEAT) received funding from the NIHR (grant no. PDF-2013-06-052). Hertfordshire Cohort Study received support from the Medical Research Council, Arthritis Research UK, the International Osteoporosis Foundation and the British Heart Foundation; NIHR Biomedical Research Centre in Nutrition, University of Southampton; NIHR Musculoskeletal Biomedical Research Unit, University of Oxford. Generation Scotland: Scottish Family Health Study is funded by the Chief Scientist Office, Scottish Government Health Directorates, grant number CZD/16/6 and the Scottish Funding Council grant HR03006. EU COPD Gene Scan is funded by the European Union, grant no. QLG1-CT-2001-01012. English Longitudinal Study of Aging is funded by the Institute of Aging, NIH grant No. AG1764406S1. GoDARTs is funded by the Wellcome Trust grants 072960, 084726 and 104970. MDT has been supported by MRC fellowship G0902313. UK Biobank Lung Exome Variant Evaluation study was funded by a Medical Research Council strategic award to MDT, IPH, DPS and LVW (MC_PC_12010)

Why do health economists promote technology adoption rather than the search for efficiency? A proposal for a change in our approach to economic evaluation in health care

Acknowledgments Financial Support: HERU and HSRU receive a core grant from the Chief Scientist’s Office of the Scottish Government Health and Social Care Directorates, and the Centre for Clinical epidemiology & Evaluation is funded by Vancouver Coastal Health Authority. The model used for the illustrative case study in this paper was developed as part of a NHS Technology Assessment Review, funded by the National Institute for Health Research (NIHR) Health Technology Assessment Program (project number 09/146/01). The views and opinions expressed in this paper are those of the authors and do not necessarily reflect those of the Scottish Government, NHS, Vancouver Coastal Health, NIHR HTA Program or the Department of Health. The authors wish to thank Kathleen Boyd and members of the audience at the UK Health Economists Study Group, for comments received on an earlier version of this paper. We also wish to thank Cynthia Fraser (University of Aberdeen) for literature searches undertaken to inform the manuscript, and Mohsen Sadatsafavi (University of British Columbia) for comments on an earlier draft

Characterization of human telomerase complex

Telomerase, a ribonucleoprotein complex, adds hexameric repeats called “telomeres” to the growing ends of chromosomal DNA. Characterization of mammalian telomerase has been elusive because of its low level of expression. We describe a bioinformatics approach to enrich and characterize the human telomerase complex. Using local sequence homology search methods, we detected similarity of the Tetrahymena p80 subunit of telomerase with the autoantigen Ro60. Antibodies to Ro60 immunoprecipitated the telomerase activity. Ro60 and p80 proteins were cross-recognizable by antibodies to either protein. Telomerase activity and the RNA component of telomerase complex were localized to a doublet in a native gel from the Ro60 antibody-precipitated material. The enriched material showed specific binding to a TTA GGG probe in vitro in an RNA template-dependent manner. Polyclonal antibodies to the doublet also immunoprecipitated the telomerase activity. These results suggest an evolutionary conservation of the telomerase proteins.

Conservative management for postprostatectomy urinary incontinence

Peer reviewed