Exit of Plasmodium Sporozoites from Oocysts Is an Active Process That Involves the Circumsporozoite Protein

Plasmodium sporozoites develop within oocysts residing in the mosquito midgut. Mature sporozoites exit the oocysts, enter the hemolymph, and invade the salivary glands. The circumsporozoite (CS) protein is the major surface protein of salivary gland and oocyst sporozoites. It is also found on the oocyst plasma membrane and on the inner surface of the oocyst capsule. CS protein contains a conserved motif of positively charged amino acids: region II-plus, which has been implicated in the initial stages of sporozoite invasion of hepatocytes. We investigated the function of region II-plus by generating mutant parasites in which the region had been substituted with alanines. Mutant parasites produced normal numbers of sporozoites in the oocysts, but the sporozoites were unable to exit the oocysts. In in vitro as well, there was a profound delay, upon trypsin treatment, in the release of mutant sporozoites from oocysts. We conclude that the exit of sporozoites from oocysts is an active process that involves the region II-plus of CS protein. In addition, the mutant sporozoites were not infective to young rats. These findings provide a new target for developing reagents that interfere with the transmission of malaria

Obstetric training: competence and care in birth assistance

Esta tese consiste em uma análise da formação em obstetrícia durante a graduação em medicina, baseada em pesquisa etnográfica realizada em duas escolas conceituadas. Objetivou-se estudar o modo como se articulam a competência técnica e científica e o cuidado ou relação com a paciente no ensino teórico e prático da assistência ao parto. As técnicas utilizadas na coleta de dados foram: observação participante, entrevistas semi-estruturadas e, de modo complementar, a análise de livros-texto e protocolos assistenciais. O trabalho abrangeu uma caracterização das propostas curriculares e um exame da experiência dos alunos quanto ao ensino teórico e prático, incluindo sua supervisão nas diversas atividades assistenciais. Ênfase maior recai sobre o desenvolvimento de conhecimentos científicos na formação. Mesmo no internato ênfase é colocada na aprendizagem da construção e encenação de narrativas clínicas, privilegiando-se a transmissão oral do conhecimento e a memória em relação ao registro escrito e à consulta ao prontuário das pacientes. Pautado em parte por assim chamadas concepções \"clássicas\", que sustentam uma visão patológica da fisiologia do parto, o exercício da prática envolve condutas que têm sido questionadas a partir das evidencias científicas ou até abandonadas em outros contextos As decisões acerca das condutas ou tratamentos adotados não são compartilhadas com as mulheres atendidas que frequentemente não são consultadas ou sequer informadas à respeito. Por vezes juízos de valor também influenciam o julgamento clínico e a tomada de decisões médicas. Há poucos parâmetros para avaliar as atitudes dos alunos em sua interação com as pacientes. Nos serviços em que há maior interação entre alunos e pacientes, a supervisão é menor. Existem acordos informais entre os assistentes na divisão de plantões que se contrapõe aos organogramas formais dos serviços obstétricos vinculados as Faculdades de medicina pesquisadas. Esses acordos subordinam os objetivos institucionais da boa formação e assistência em obstetrícia aos interesses individuais e coletivos dos profissionais obstetras responsáveis pela supervisão do ensino. Componente do currículo oculto, esses acordos servem de modelo para outros envolvendo residentes e/ou alunos. Ao longo da formação dos estudantes de medicina, as interações entre os sujeitos em relação no exercício do ato médico contribuem de diversas maneiras para desqualificar a prática médica da obstetrícia como técnica moral-dependente.This thesis consists of an analysis of obstetric training during medical school. It is based on ethnographic research undertaken at two acknowledged medical schools. The objective was to study how technical and scientific competence and care, that is, the relationship with the patient, are articulated in theoretical and practical training of birth assistance. The techniques employed in fieldwork were: participant observation, semi-structured interviews and, in a complementary form, the analysis of textbooks and assistance protocols. A characterization of the curriculum offered by the schools and an examination of students experience with respect to learning the theory and practice of obstetrics, including the supervision of the various activities involving obstetric assistance are discussed. Description and analysis of the scission between the development of technical and scientific competence in the educational process was undertaken. The implications of this scission for training in the practice of medicine as a moral dependent technique are discussed. Great emphasis is placed on the development of scientific knowledge during training. Even in the clinical years, emphasis is placed on learning to construct clinical narratives, placing priority on memory and the oral transmission of knowledge rather than written registration and consultation of patiente\'s charts. Learning and training is based in part on so-called \"classical\" concepts, which sustain a pathological approach to birthing. In training, this approach involves norms of conduct that have been questioned by scientific evidence and that have even been abandoned in other contexts. Obstetrical decisions involving conduct and training are not taken in conjunction with the women receiving assistance who frequently are not even consulted or informed of these decisions. Sometimes prejudices influence medical judgment and decision-making. There are few parameters to evaluate student attitudes in their interaction with patients. In the work stations where students interact more with patients there is less supervision. Informal arrangements between assistants with respect to rounds conflict with the formal schedules of the obstetric services associated to the medical schools where research was undertaken. These arrangements subordinate the institutional objectives of good medical practice and assistance to the individual and collective interests of the obstetricians responsible for supervising training. These arrangements are a component of the hidden curriculum and serve as a model for other arrangements involving residents and/or students. Throughout the obstetric training of medical students, interactions between the subjects involved in the medical act contribute in several ways to disqualify the medical practice of obstetrics as a morally-dependent technique

Collective fluorescence and decoherence of a few nearly identical quantum dots

We study the collective interaction of excitons in closely spaced artificial molecules and arrays of nearly identical quantum dots with the electromagnetic modes. We discuss how collective fluorescence builds up in the presence of a small mismatch of the transition energy. We show that a superradiant state of a single exciton in a molecule of two dots with realistic energy mismatch undergoes a two-rate decay. We analyze also the stability of subdecoherent states for non-identical systems.Comment: 7 pages, 5 figure

Obstetric training: competence and care in birth assistance

Esta tese consiste em uma análise da formação em obstetrícia durante a graduação em medicina, baseada em pesquisa etnográfica realizada em duas escolas conceituadas. Objetivou-se estudar o modo como se articulam a competência técnica e científica e o cuidado ou relação com a paciente no ensino teórico e prático da assistência ao parto. As técnicas utilizadas na coleta de dados foram: observação participante, entrevistas semi-estruturadas e, de modo complementar, a análise de livros-texto e protocolos assistenciais. O trabalho abrangeu uma caracterização das propostas curriculares e um exame da experiência dos alunos quanto ao ensino teórico e prático, incluindo sua supervisão nas diversas atividades assistenciais. Ênfase maior recai sobre o desenvolvimento de conhecimentos científicos na formação. Mesmo no internato ênfase é colocada na aprendizagem da construção e encenação de narrativas clínicas, privilegiando-se a transmissão oral do conhecimento e a memória em relação ao registro escrito e à consulta ao prontuário das pacientes. Pautado em parte por assim chamadas concepções \"clássicas\", que sustentam uma visão patológica da fisiologia do parto, o exercício da prática envolve condutas que têm sido questionadas a partir das evidencias científicas ou até abandonadas em outros contextos As decisões acerca das condutas ou tratamentos adotados não são compartilhadas com as mulheres atendidas que frequentemente não são consultadas ou sequer informadas à respeito. Por vezes juízos de valor também influenciam o julgamento clínico e a tomada de decisões médicas. Há poucos parâmetros para avaliar as atitudes dos alunos em sua interação com as pacientes. Nos serviços em que há maior interação entre alunos e pacientes, a supervisão é menor. Existem acordos informais entre os assistentes na divisão de plantões que se contrapõe aos organogramas formais dos serviços obstétricos vinculados as Faculdades de medicina pesquisadas. Esses acordos subordinam os objetivos institucionais da boa formação e assistência em obstetrícia aos interesses individuais e coletivos dos profissionais obstetras responsáveis pela supervisão do ensino. Componente do currículo oculto, esses acordos servem de modelo para outros envolvendo residentes e/ou alunos. Ao longo da formação dos estudantes de medicina, as interações entre os sujeitos em relação no exercício do ato médico contribuem de diversas maneiras para desqualificar a prática médica da obstetrícia como técnica moral-dependente.This thesis consists of an analysis of obstetric training during medical school. It is based on ethnographic research undertaken at two acknowledged medical schools. The objective was to study how technical and scientific competence and care, that is, the relationship with the patient, are articulated in theoretical and practical training of birth assistance. The techniques employed in fieldwork were: participant observation, semi-structured interviews and, in a complementary form, the analysis of textbooks and assistance protocols. A characterization of the curriculum offered by the schools and an examination of students experience with respect to learning the theory and practice of obstetrics, including the supervision of the various activities involving obstetric assistance are discussed. Description and analysis of the scission between the development of technical and scientific competence in the educational process was undertaken. The implications of this scission for training in the practice of medicine as a moral dependent technique are discussed. Great emphasis is placed on the development of scientific knowledge during training. Even in the clinical years, emphasis is placed on learning to construct clinical narratives, placing priority on memory and the oral transmission of knowledge rather than written registration and consultation of patiente\'s charts. Learning and training is based in part on so-called \"classical\" concepts, which sustain a pathological approach to birthing. In training, this approach involves norms of conduct that have been questioned by scientific evidence and that have even been abandoned in other contexts. Obstetrical decisions involving conduct and training are not taken in conjunction with the women receiving assistance who frequently are not even consulted or informed of these decisions. Sometimes prejudices influence medical judgment and decision-making. There are few parameters to evaluate student attitudes in their interaction with patients. In the work stations where students interact more with patients there is less supervision. Informal arrangements between assistants with respect to rounds conflict with the formal schedules of the obstetric services associated to the medical schools where research was undertaken. These arrangements subordinate the institutional objectives of good medical practice and assistance to the individual and collective interests of the obstetricians responsible for supervising training. These arrangements are a component of the hidden curriculum and serve as a model for other arrangements involving residents and/or students. Throughout the obstetric training of medical students, interactions between the subjects involved in the medical act contribute in several ways to disqualify the medical practice of obstetrics as a morally-dependent technique

RAGs and Regulation of Autoantibodies

Autoreactive antibodies are etiologic agents in a number of autoimmune diseases. Like all other antibodies these antibodies are produced in developing B cells by V(D)J recombination in the bone marrow. Three mechanisms regulate autoreactive B cells: deletion, receptor editing, and anergy. Here we review the prevalence of autoantibodies in the initial antibody repertoire, their regulation by receptor editing, and the role of the recombinase proteins (RAG l and RAG2) in this process

Crystal Structure of the Cysteine-Rich Domain of Mannose Receptor Complexed with a Sulfated Carbohydrate Ligand

The macrophage and epithelial cell mannose receptor (MR) binds carbohydrates on foreign and host molecules. Two portions of MR recognize carbohydrates: tandemly arranged C-type lectin domains facilitate carbohydrate-dependent macrophage uptake of infectious organisms, and the NH2-terminal cysteine-rich domain (Cys-MR) binds to sulfated glycoproteins including pituitary hormones. To elucidate the mechanism of sulfated carbohydrate recognition, we determined crystal structures of Cys-MR alone and complexed with 4-sulfated-N-acetylgalactosamine at 1.7 and 2.2 Å resolution, respectively. Cys-MR folds into an approximately three-fold symmetric β-trefoil shape resembling fibroblast growth factor. The sulfate portions of 4-sulfated-N-acetylgalactosamine and an unidentified ligand found in the native crystals bind in a neutral pocket in the third lobe. We use the structures to rationalize the carbohydrate binding specificities of Cys-MR and compare the recognition properties of Cys-MR with other β-trefoil proteins

TRYPANOSOMA-CRUZI TRANS-SIALIDASE and NEURAMINIDASE ACTIVITIES CAN BE MEDIATED BY the SAME ENZYMES

Trans-sialidase and neuraminidase activities have been detected on the surface membrane of trypomastigotes of Trypanosoma cruzi, and both have been implicated in the parasite's invasion of host cells. We show here that these enzymes are structurally related. They are recognized by two independently derived monoclonal antibodies, are anchored to the membrane by glycosylphosphatidylinositol, copurify by ion exchange, molecular sieving, and hydrophobic chromatography, have maximal activities between pH 6.5 and 7.5, and are inactivated by heating at 56-degrees-C. Furthermore, the neuraminidase and trans-sialidase reactions are coupled. An increase of the concentration of acceptors of the transfer reaction decreases the amount of free sialic acid released through the neuraminidase reaction. We conclude that a single enzyme can catalyze the transfer or the hydrolysis of macromolecular-bound sialic acid. the predominant direction of the reaction will depend on the availability of appropriate oligosaccharide acceptors of sialic acid.NYU MED CTR,DEPT PATHOL,NEW YORK,NY 10016NYU MED CTR,KAPLAN CANC CTR,NEW YORK,NY 10016Web of Scienc

Human immunodeficiency virus neutralizing antibodies and methods of use thereof [APPLICATION]

The invention provides broadly neutralizing antibodies directed to epitopes of Human Immunodeficiency Virus, or HIV. The invention further provides compositions containing HIV antibodies used for prophylaxis, and methods for diagnosis and treatment of HIV infection

Thwarting endogenous stress: BRCA protects against aldehyde toxicity

Homologous recombination (HR) and the Fanconi Anemia (FA) pathways constitute essential repair pathways for DNA damage, which includes DNA double-stranded breaks (DSB) and inter-strand cross-links (ICL), respectively. Germline mutations affecting a single copy of the HR factors BRCA1 and BRCA2 predispose individuals to cancers of the breast, ovary, prostate, and pancreas. Cells deficient for BRCA proteins display high levels of genome instability due to defective repair of endogenous DSBs and are also exquisitely sensitive to DNA-damaging agents. In addition to their roles in repair of DSBs and ICLs, HR and FA proteins have a genetically separable function in the protection of stalled DNA replication forks from nuclease-mediated degradation (Schlacher et al, ). Although it has been hypothesized that loss of functional HR and ICL repair is the primary cause of cancer in BRCA- and FA-deficient patients (Prakash et al, ), the contribution of replication fork instability associated with the degradation of nascent DNA remains unclear. Two recent papers explain how endogenous toxins render cells vulnerable to genomic instability, which explains how the BRCA/FA pathway suppresses tumorigenesis (Tacconi et al, ; Tan et al, )

Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice

We have examined the regulatory role of the individual components of the immunoglobulin antigen receptor in B-cell development by transgenic complementation of Rag-1 deficient (Rag-1⁻) mice. Complementation with a membrane µ heavy chain (µHC) gene allows progression of developmentally arrested Rag-1⁻ pro-B-cells to the small pre-B cell stage, whereas the introduction of independently integrated µHC and κ light chain (κLC) transgenes promotes the appearance of peripheral lymphocytes which, however, remain unresponsive to external stimuli. Complete reconstitution of the B-cell lineage and the emergence of functionally nature Rag-1⁻ peripheral B cells is achieved by the introduction of cointegrated heavy and light chain transgenes encoding an anti-H-2^k antibody. This experimental system demonstrates the competence of the µHC and κLC to direct and regulate the sequential stages of B-cell differentiation, defines the time at which negative selection of self-reactive B cells occurs, and shows that elimination of these cells occurs equally well in the absence of Rag-1 as in its presence. These data also support the hypothesis that Rag-1 directly participates in the V(D)J recombination process