Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract

Developing efficacious vaccines against enteric diseases is a global challenge that requires a better understanding of cellular recruitment dynamics at the mucosal surfaces. The current paradigm of T cell homing to the gastrointestinal (GI) tract involves the induction of α4β7 and CCR9 by Peyer\u27s patch and mesenteric lymph node (MLN) dendritic cells (DCs) in a retinoic acid-dependent manner. This paradigm, however, cannot be reconciled with reports of GI T cell responses after intranasal (i.n.) delivery of antigens that do not directly target the GI lymphoid tissue. To explore alternative pathways of cellular migration, we have investigated the ability of DCs from mucosal and nonmucosal tissues to recruit lymphocytes to the GI tract. Unexpectedly, we found that lung DCs, like CD103+ MLN DCs, up-regulate the gut-homing integrin α4β7 in vitro and in vivo, and induce T cell migration to the GI tract in vivo. Consistent with a role for this pathway in generating mucosal immune responses, lung DC targeting by i.n. immunization induced protective immunity against enteric challenge with a highly pathogenic strain of Salmonella. The present report demonstrates novel functional evidence of mucosal cross talk mediated by DCs, which has the potential to inform the design of novel vaccines against mucosal pathogens

Interacção entre duas espécies exóticas de lagostins (pacifastacus leniusculus e procambarus clarkii): estudo experimental com recurso à PIT-telemetria

No rio Maçãs (bacia do Rio Douro), no Nordeste de Portugal, coexistem duas espécies de lagostins exóticos, o lagostim vermelho da Louisiana (Procambarus clarkii) e o lagostim sinal (Pacifastacus leniusculus). Para estudar o movimento e padrão de actividade de ambas as espécies foi desenvolvida uma experiência num espaço confinado (300 x 100 cm) e aplicada a técnica da PIT-telemetria (Passive Integrated Technology, UKID Systems, U.K.), com recurso a um MPD (Data-logger) e oito antenas circulares de detecção de transmissores (PIT-tags). Seleccionou-se um local de alimentação e alguns refúgios capazes de fornecer isolamento visual entre lagostins. Foram implantados PIT-tags, com identificação individual, em 5 machos e 5 fêmeas de cada espécie e monitorizado o seu comportamento de forma contínua (dia e noite) ao longo de 15 dias, durante o período estival de dois anos consecutivos. Obtiveram-se cerca de 30 000 dados, diferenciados em termos de frequência de dados repetidos (registos contínuos na mesma antena) e não repetidos por cada animal. A análise dos dados sugere um comportamento diferenciado entre espécies e sexos com dominância do lagostim vermelho relativamente ao lagostim sinal e dos machos sobre as fêmeas. As interacções entre espécies podem estar na origem do afastamento e menor actividade de P. leniusculus dos locais mais próximos da área de alimentação. Por outro lado, as fêmeas de ambas as espécies demonstraram ser menos activas do que os machos

Do borrão às aguadas: os engenheiros militares e a representação da Capitania de São Paulo

A análise do papel dos engenheiros militares perpassa as discussões sobre regiões específicas, mesmo quando eles, aparentemente, estão ausentes delas. Sua presença ou ausência sempre foi sinônimo de interesse e de projeto colonizador mais ou menos dirigido. Este ensaio tem como objeto de estudo a cartografia dos engenheiros militares atuantes na Capitania de São Paulo, território comumente visto como economicamente periférico e mais autônomo face aos desígnios da Coroa portuguesa. Com foco no corpus cartográfico de alguns profissionais que aqui atuaram, trata indiretamente da multifacetada atuação desses engenheiros, bem como do processo de feitura das cartas geográficas, corográficas e topográficas, do borrão às aguadas. Investigar a cartografia de alguns desses profissionais permite não apenas explorar a riqueza de suas biografias, como, também, acompanhar o processo de produção técnica dos mapas e os desígnios políticos envolvidos no devassamento e representação das terras descobertas no Novo Mundo.Analyzing the role of military engineers means venturing into discussions about specific regions, even those from which they are apparently absent. Their presence or absence has always been synonymous with interest and a more or less directed colonization project. This essay examines the maps produced by the military engineers working in the Captaincy of São Paulo, a territory often looked upon as one of little economic import and a rather autonomous area in light of the plans of the Portuguese Crown. By focusing on the cartographic corpus bequeathed by certain professionals serving in this region, we deal indirectly with the multifaceted role of these engineers as well as with the process of making geographic, chorographic and topographic charts - all the way from the sketch to watercolored maps. Perusing the charts constructed by some of these professionals enabled us not only to delve into the rich details of their biographies but also to observe the technical mapmaking process and to unravel the political designs behind the exploration and representation of the lands discovered in the New World

Acoustic Telemetry Unravels Movements and Habitat Use Patterns of Juvenile Meagre (A. regius) in the Tagus Estuary

The meagre is among the largest Sciaenidae in the world (max: 230 cm, 103 kg), with a wide distribution range encompassing the NE and CE Atlantic Ocean and the Mediterranean Sea. The life cycle in Atlantic waters includes migratory movements from feeding and overwintering areas at sea to spawning and nursery areas in estuaries and coastal waters. However, significant spawning aggregations are only observed in five locations, among which is the Tagus estuary (Portugal). The meagre fishery that takes place within the Tagus estuary is significant, accounting for approximately two-thirds of Portuguese meagre catches. Despite its economic relevance, the meagre movements in that region remain largely unknown. The existence of a target fishery inside the estuary alongside a lack of routine biological data collection targeting the species and incipient fisheries control in the area, highlight an urgency to adopt innovative methodologies to unravel meagre migrations and its use of critical areas. We present the first insights of movement patterns and habitat use in the Tagus estuary using acoustic biotelemetry data collected between 2019 and 2021. The acoustic receiver array obtained a total of 142.183 registers from a total of 34 individuals tagged. From the tagged specimens, 33% revisited the Tagus estuary in subsequent years at least once, during the spring and summer, and 49% remained in the Tagus at least until autumn. Further analysis was conducted with juveniles tracked over 3 years to identify critical nursery areas using dynamic Brownian bridge movement models (utilization distribution estimations). The effects of abiotic conditions on the meagre behaviour were assessed using in situ sensor data (e.g., temperature and salinity) and other environmental predictors (e.g., photoperiod and tide cycle) and an explanatory model was developed that helps to understand the use of the Tagus estuary by juveniles. The information collected will be discussed in light of possible applications to promote sustainable management of meagre fisheries in the Tagus estuary and adjacent coastal areas

The germline mutational landscape of BRCA1 and BRCA2 in Brazil

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.This work was supported in part by grants from Barretos Cancer Hospital (FINEP - CT-INFRA, 02/2010), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2013/24633-2 and 2103/23277-8), Fundação de Apoio à Pesquisa do Rio Grande do Norte (FAPERN), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Ministério da Saúde, the Breast Cancer Research Foundation (Avon grant #02-2013-044) and National Institute of Health/National Cancer Institute (grant #RC4 CA153828-01) for the Clinical Cancer Genomics Community Research Network. Support in part was provided by grants from Fundo de Incentivo a Pesquisa e Eventos (FIPE) from Hospital de Clínicas de Porto Alegre, by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, BioComputacional 3381/2013, Rede de Pesquisa em Genômica Populacional Humana), Secretaria da Saúde do Estado da Bahia (SESAB), Laboratório de Imunologia e Biologia Molecular (UFBA), INCT pra Controle do Câncer and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). RMR and PAP are recipients of CNPq Productivity Grants, and Bárbara Alemar received a grant from the same agencyinfo:eu-repo/semantics/publishedVersio

Multi-Parametric Analysis and Modeling of Relationships between Mitochondrial Morphology and Apoptosis

Mitochondria exist as a network of interconnected organelles undergoing constant fission and fusion. Current approaches to study mitochondrial morphology are limited by low data sampling coupled with manual identification and classification of complex morphological phenotypes. Here we propose an integrated mechanistic and data-driven modeling approach to analyze heterogeneous, quantified datasets and infer relations between mitochondrial morphology and apoptotic events. We initially performed high-content, multi-parametric measurements of mitochondrial morphological, apoptotic, and energetic states by high-resolution imaging of human breast carcinoma MCF-7 cells. Subsequently, decision tree-based analysis was used to automatically classify networked, fragmented, and swollen mitochondrial subpopulations, at the single-cell level and within cell populations. Our results revealed subtle but significant differences in morphology class distributions in response to various apoptotic stimuli. Furthermore, key mitochondrial functional parameters including mitochondrial membrane potential and Bax activation, were measured under matched conditions. Data-driven fuzzy logic modeling was used to explore the non-linear relationships between mitochondrial morphology and apoptotic signaling, combining morphological and functional data as a single model. Modeling results are in accordance with previous studies, where Bax regulates mitochondrial fragmentation, and mitochondrial morphology influences mitochondrial membrane potential. In summary, we established and validated a platform for mitochondrial morphological and functional analysis that can be readily extended with additional datasets. We further discuss the benefits of a flexible systematic approach for elucidating specific and general relationships between mitochondrial morphology and apoptosis

Impact of Vutrisiran on Quality of Life and Physical Function in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy

INTRODUCTION: Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study. METHODS: The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed. RESULTS: At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: –21.0; p = 1.84 × 10–10) and Norfolk QOL-DN domain scores, compared with external placebo. This benefit relative to external placebo was evident across all baseline polyneuropathy disability (PND) scores and most pronounced in patients with baseline PND scores I–II. Compared with external placebo, vutrisiran also demonstrated benefit in EuroQoL-Visual Analog Scale (EQ-VAS) score (LSMD in CFB: 13.7; nominal p = 2.21 × 10–7), 10-m walk test (LSMD in CFB: 0.239 m/s; p = 1.21 × 10–7), Rasch-built Overall Disability Score (LSMD in CFB: 8.4; p = 3.54 × 10–15), and modified body mass index (mBMI) (LSMD in CFB: 140.7; p = 4.16 × 10–15) at month 18. Overall, Norfolk QOL-DN, EQ-VAS, and mBMI improved from pretreatment baseline with vutrisiran, whereas all measures worsened from baseline in the external placebo group. At month 18, Karnofsky Performance Status was stable/improved from baseline in 58.2/13.1% with vutrisiran versus 34.7/8.1% with external placebo. CONCLUSION: Vutrisiran treatment provided significant clinical benefits in multiple measures of QOL and physical function in patients with ATTRv amyloidosis with polyneuropathy. Benefits were most pronounced in patients with earlier-stage disease, highlighting the importance of early diagnosis and treatment