The Era of Antimicrobial Peptides: Use of Hepcidins to Prevent or Treat Bacterial Infections and Iron Disorders

The current treatments applied in aquaculture to limit disease dissemination are mostly based on the use of antibiotics, either as prophylactic or therapeutic agents, with vaccines being available for a limited number of fish species and pathogens. Antimicrobial peptides are considered as promising novel substances to be used in aquaculture, due to their antimicrobial and immunomodulatory activities. Hepcidin, the major iron metabolism regulator, is found as a single gene in most mammals, but in certain fish species, including the European sea bass (Dicentrarchus labrax), two different hepcidin types are found, with specialized roles: the single type 1 hepcidin is involved in iron homeostasis trough the regulation of ferroportin, the only known iron exporter; and the various type 2 hepcidins present antimicrobial activity against a number of different pathogens. In this study, we tested the administration of sea bass derived hepcidins in models of infection and iron overload. Administration with hamp2 substantially reduced fish mortalities and bacterial loads, presenting itself as a viable alternative to the use of antibiotics. On the other hand, hamp1 seems to attenuate the effects of iron overload. Further studies are necessary to test the potential protective effects of hamp2 against other pathogens, as well as to understand how hamp2 stimulate the inflammatory responses, leading to an increased fish survival upon infection.This work was funded by the structured program of R&D&I ATLANTIDA - Platform for the monitoring of the North Atlantic Ocean and tools for the sustainable exploitation of the marine resources (NORTE-01-0145-FEDER-000040), supported by the North Portugal Regional Operational Programme (NORTE2020), through the European Regional Development Fund (ERDF). CB is supported by a Ph.D. fellowship (SFRH/BD/ 114899/2016) financed by FCT - Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia e Ensino Superior

LOCUS (LOng Covid–Understanding Symptoms, events and use of services in Portugal): A three-component study protocol

Approximately 10% of patients experience symptoms of Post COVID-19 Condition (PCC) after a SARS-CoV-2 infection. Akin acute COVID-19, PCC may impact a multitude of organs and systems, such as the cardiovascular, respiratory, musculoskeletal, and neurological systems. The frequency and associated risk factors of PCC are still unclear among both community and hospital settings in individuals with a history of COVID-19. The LOCUS study was designed to clarify the PCC's burden and associated risk factors. LOCUS is a multi-component study that encompasses three complementary building blocks. The "Cardiovascular and respiratory events following COVID-19" component is set to estimate the incidence of cardiovascular and respiratory events after COVID-19 in eight Portuguese hospitals via electronic health records consultation. The "Physical and mental symptoms following COVID-19" component aims to address the community prevalence of self-reported PCC symptoms through a questionnaire-based approach. Finally, the "Treating and living with Post COVID-19 Condition" component will employ semi-structured interviews and focus groups to characterise reported experiences of using or working in healthcare and community services for the treatment of PCC symptoms. This multi-component study represents an innovative approach to exploring the health consequences of PCC. Its results are expected to provide a key contribution to the optimisation of healthcare services design.info:eu-repo/semantics/publishedVersio

Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer

Kinase suppressor of Ras 1 (KSR1) has been implicated in tumorigenesis in multiple cancers, including skin, pancreatic and lung carcinomas. However, our recent study revealed a role of KSR1 as a tumour suppressor in breast cancer, the expression of which is potentially correlated with chemotherapy response. Here, we aimed to further elucidate the KSR1-regulated signalling in response to genotoxic agents in breast cancer. Stable isotope labelling by amino acids in cell culture (SILAC) coupled to high-resolution mass spectrometry (MS) was implemented to globally characterise cellular protein levels induced by KSR1 in the presence of doxorubicin or etoposide. The acquired proteomic signature was compared and GO-STRING analysis was subsequently performed to illustrate the activated functional signalling networks. Furthermore, the clinical associations of KSR1 with identified targets and their relevance in chemotherapy response were examined in breast cancer patients. We reveal a comprehensive repertoire of thousands of proteins identified in each dataset and compare the unique proteomic profiles as well as functional connections modulated by KSR1 after doxorubicin (Doxo-KSR1) or etoposide (Etop-KSR1) stimulus. From the up-regulated top hits, several proteins, including STAT1, ISG15 and TAP1 are also found to be positively associated with KSR1 expression in patient samples. Moreover, high KSR1 expression, as well as high abundance of these proteins, is correlated with better survival in breast cancer patients who underwent chemotherapy. In aggregate, our data exemplify a broad functional network conferred by KSR1 with genotoxic agents and highlight its implication in predicting chemotherapy response in breast cancer

Anthropogenic disturbance in tropical forests can double biodiversity loss from deforestation

Concerted political attention has focused on reducing deforestation1,2,3, and this remains the cornerstone of most biodiversity conservation strategies4,5,6. However, maintaining forest cover may not reduce anthropogenic forest disturbances, which are rarely considered in conservation programmes6. These disturbances occur both within forests, including selective logging and wildfires7,8, and at the landscape level, through edge, area and isolation effects9. Until now, the combined effect of anthropogenic disturbance on the conservation value of remnant primary forests has remained unknown, making it impossible to assess the relative importance of forest disturbance and forest loss. Here we address these knowledge gaps using a large data set of plants, birds and dung beetles (1,538, 460 and 156 species, respectively) sampled in 36 catchments in the Brazilian state of Pará. Catchments retaining more than 69–80% forest cover lost more conservation value from disturbance than from forest loss. For example, a 20% loss of primary forest, the maximum level of deforestation allowed on Amazonian properties under Brazil’s Forest Code5, resulted in a 39–54% loss of conservation value: 96–171% more than expected without considering disturbance effects. We extrapolated the disturbance-mediated loss of conservation value throughout Pará, which covers 25% of the Brazilian Amazon. Although disturbed forests retained considerable conservation value compared with deforested areas, the toll of disturbance outside Pará’s strictly protected areas is equivalent to the loss of 92,000–139,000 km2 of primary forest. Even this lowest estimate is greater than the area deforested across the entire Brazilian Amazon between 2006 and 2015 (ref. 10). Species distribution models showed that both landscape and within-forest disturbances contributed to biodiversity loss, with the greatest negative effects on species of high conservation and functional value. These results demonstrate an urgent need for policy interventions that go beyond the maintenance of forest cover to safeguard the hyper-diversity of tropical forest ecosystems

Human and murine clonal CD8+ T cell expansions arise during tuberculosis because of TCR selection

The immune system can recognize virtually any antigen, yet T cell responses against several pathogens, including Mycobacterium tuberculosis, are restricted to a limited number of immunodominant epitopes. The host factors that affect immunodominance are incompletely understood. Whether immunodominant epitopes elicit protective CD8+ T cell responses or instead act as decoys to subvert immunity and allow pathogens to establish chronic infection is unknown. Here we show that anatomically distinct human granulomas contain clonally expanded CD8+ T cells with overlapping T cell receptor (TCR) repertoires. Similarly, the murine CD8+ T cell response against M. tuberculosis is dominated by TB10.44-11-specific T cells with extreme TCRß bias. Using a retro genic model of TB10.44-11-specific CD8+ Tcells, we show that TCR dominance can arise because of competition between clonotypes driven by differences in affinity. Finally, we demonstrate that TB10.4-specific CD8+ T cells mediate protection against tuberculosis, which requires interferon-? production and TAP1-dependent antigen presentation in vivo. Our study of how immunodominance, biased TCR repertoires, and protection are inter-related, provides a new way to measure the quality of T cell immunity, which if applied to vaccine evaluation, could enhance our understanding of how to elicit protective T cell immunity.This work was supported by the Portuguese Foundation for Science and Technology individual fellowship (CNA) www.fct.pt, a National Institutes of Health Grant R01 AI106725 (SMB) www.nih.gov, and a Center for AIDS Research Grant P30 AI 060354 (SMB) www.nih.gov. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Metabolomics-Based Discovery of Diagnostic Biomarkers for Onchocerciasis

Onchocerciasis, caused by the filarial parasite Onchocerca volvulus, afflicts millions of people, causing such debilitating symptoms as blindness and acute dermatitis. There are no accurate, sensitive means of diagnosing O. volvulus infection. Clinical diagnostics are desperately needed in order to achieve the goals of controlling and eliminating onchocerciasis and neglected tropical diseases in general. In this study, a metabolomics approach is introduced for the discovery of small molecule biomarkers that can be used to diagnose O. volvulus infection. Blood samples from O. volvulus infected and uninfected individuals from different geographic regions were compared using liquid chromatography separation and mass spectrometry identification. Thousands of chromatographic mass features were statistically compared to discover 14 mass features that were significantly different between infected and uninfected individuals. Multivariate statistical analysis and machine learning algorithms demonstrated how these biomarkers could be used to differentiate between infected and uninfected individuals and indicate that the diagnostic may even be sensitive enough to assess the viability of worms. This study suggests a future potential of these biomarkers for use in a field-based onchocerciasis diagnostic and how such an approach could be expanded for the development of diagnostics for other neglected tropical diseases