Transformation of organic matter in a Barents Sea sediment profile: coupled geochemical and microbiological processes.

Process-based, mechanistic investigations of organic matter transformation and diagenesis directly beneath the sediment-water interface (SWI) in Arctic continental shelves are vital as these regions are at greatest risk of future change. This is in part due to disruptions in benthic-pelagic coupling associated with ocean current change and sea ice retreat. Here, we focus on a high-resolution, multi-disciplinary set of measurements that illustrate how microbial processes involved in the degradation of organic matter are directly coupled with inorganic and organic geochemical sediment properties (measured and modelled) as well as the extent/depth of bioturbation. We find direct links between aerobic processes, reactive organic carbon and highest abundances of bacteria and archaea in the uppermost layer (0-4.5 cm depth) followed by dominance of microbes involved in nitrate/nitrite and iron/manganese reduction across the oxic-anoxic redox boundary (approx. 4.5-10.5 cm depth). Sulfate reducers dominate in the deeper (approx. 10.5-33 cm) anoxic sediments which is consistent with the modelled reactive transport framework. Importantly, organic matter reactivity as tracked by organic geochemical parameters (n-alkanes, n-alkanoic acids, n-alkanols and sterols) changes most dramatically at and directly below the SWI together with sedimentology and biological activity but remained relatively unchanged across deeper changes in sedimentology. This article is part of the theme issue 'The changing Arctic Ocean: consequences for biological communities, biogeochemical processes and ecosystem functioning'.

A Deformed Exponential Statistical Manifold.

Consider µ a probability measure and P µ the set of µ -equivalent strictly positive probability densities. To endow P µ with a structure of a C ∞ -Banach manifold we use the φ -connection by an open arc, where φ is a deformed exponential function which assumes zero until a certain point and from then on is strictly increasing. This deformed exponential function has as particular cases the q-deformed exponential and κ -exponential functions. Moreover, we find the tangent space of P µ at a point p, and as a consequence the tangent bundle of P µ . We define a divergence using the q-exponential function and we prove that this divergence is related to the q-divergence already known from the literature. We also show that q-exponential and κ -exponential functions can be used to generalize of Rényi divergence.

Mixture and Exponential Arcs on Generalized Statistical Manifold.

In this paper, we investigate the mixture arc on generalized statistical manifolds. We ensure that the generalization of the mixture arc is well defined and we are able to provide a generalization of the open exponential arc and its properties. We consider the model of a φ -family of distributions to describe our general statistical model.

Factors Associated with Nipple Lesions in Puerperae.

This retrospective cross-sectional study aimed to evaluate the factors associated with nipple lesion development in puerperae. Analyses were performed using the Poisson regression with robust variance. The level of significance was set at 5% (p < 0.05). We evaluated 1270 puerperae, among whom 193 (15.4%) presented with nipple lesions. The condition was more prevalent among the mothers who did not receive information about breastfeeding [PR, 1.69; 95% confidence interval (CI), 1.19-2.42], those who underwent cesarean delivery (PR, 1.48; 95% CI, 1.02-2.16), those who used a pacifier (prevalence ratios (PR), 2.04; 95% CI, 1.05-3.95), those who used baby formula only (PR, 1.61; 95% CI, 4.82-5.36) and those who used baby formula combined with breastfeeding (PR, 1.61; 95% CI, 1.06-2.45). A lower incidence of nipple lesions was observed among those who did not receive information on hand expression of breast milk (PR, 0.65; 95% CI, 0.46-0.93) and those who did not breastfeed in the first hour of life (PR, 0.61; 95% CI, 0.38-0.97).

Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni.

The treatment of schistosomiasis, a disease caused by blood flukes parasites of the Schistosoma genus, depends on the intensive use of a single drug, praziquantel, which increases the likelihood of the development of drug-resistant parasite strains and renders the search for new drugs a strategic priority. Currently, inhibitors of human epigenetic enzymes are actively investigated as novel anti-cancer drugs and have the potential to be used as new anti-parasitic agents. Here, we report that Schistosoma mansoni histone deacetylase 8 (smHDAC8), the most expressed class I HDAC isotype in this organism, is a functional acetyl-L-lysine deacetylase that plays an important role in parasite infectivity. The crystal structure of smHDAC8 shows that this enzyme adopts a canonical α/ß HDAC fold, with specific solvent exposed loops corresponding to insertions in the schistosome HDAC8 sequence. Importantly, structures of smHDAC8 in complex with generic HDAC inhibitors revealed specific structural changes in the smHDAC8 active site that cannot be accommodated by human HDACs. Using a structure-based approach, we identified several small-molecule inhibitors that build on these specificities. These molecules exhibit an inhibitory effect on smHDAC8 but show reduced affinity for human HDACs. Crucially, we show that a newly identified smHDAC8 inhibitor has the capacity to induce apoptosis and mortality in schistosomes. Taken together, our biological and structural findings define the framework for the rational design of small-molecule inhibitors specifically interfering with schistosome epigenetic mechanisms, and further support an anti-parasitic epigenome targeting strategy to treat neglected diseases caused by eukaryotic pathogens.

The genome of the blood fluke Schistosoma mansoni.

Schistosoma mansoni is responsible for the neglected tropical disease schistosomiasis that affects 210 million people in 76 countries. Here we present analysis of the 363 megabase nuclear genome of the blood fluke. It encodes at least 11,809 genes, with an unusual intron size distribution, and new families of micro-exon genes that undergo frequent alternative splicing. As the first sequenced flatworm, and a representative of the Lophotrochozoa, it offers insights into early events in the evolution of the animals, including the development of a body pattern with bilateral symmetry, and the development of tissues into organs. Our analysis has been informed by the need to find new drug targets. The deficits in lipid metabolism that make schistosomes dependent on the host are revealed, and the identification of membrane receptors, ion channels and more than 300 proteases provide new insights into the biology of the life cycle and new targets. Bioinformatics approaches have identified metabolic chokepoints, and a chemogenomic screen has pinpointed schistosome proteins for which existing drugs may be active. The information generated provides an invaluable resource for the research community to develop much needed new control tools for the treatment and eradication of this important and neglected disease.

Effects of Early Weaning on Performance and Carcass Quality of Nellore Young Bulls.

This study compared early weaning (EW; 150 days) with conventional weaning (CW; 240 days) in Nellore young bulls, evaluating performance, carcass characteristics, and meat quality. A total of 74 non-castrated male calves were divided into two weaning strategies: EW (n = 37) and CW (n = 37). During the growth phase, which lasted 454 ± 14 d for EW calves and 359 ± 16 d for CW calves, animals received a protein-energy supplement at a ratio of 5 g per kg of body weight while grazing Brachiaria brizantha cv. Marandu. The animals were managed for an 87d finishing phase in three collective feedlot pens, with a 3-week adaptation protocol, starting with corn silage to a concentrate ratio of 55:45 and reaching a ratio of 30:70 in the final diet. Body weight, average daily gain (ADG), dry matter intake (DMI), feed efficiency (FE), carcass characteristics, and meat quality were evaluated. The EW group was approximately 44 kg lighter than the CW at the time of conventional weaning (p < 0.001). However, this weight difference did not influence ADG, DMI, and FE in the finishing phase. No significant differences were observed in carcass characteristics such as yield percentage, loin area, subcutaneous fat thickness, and meat quality, except for the weight of primal cuts, which was greater in the CW group (p < 0.001). Thus, although calves weaned early are lighter throughout subsequent production phases than those weaned conventionally, performance, efficiency, carcass yield, and meat quality are not affected.

Schistosoma mansoni coactivator associated arginine methyltransferase 1 (SmCARM1) effect on parasite reproduction.

Introduction: The human blood fluke parasite Schistosoma mansoni relies on diverse mechanisms to adapt to its diverse environments and hosts. Epigenetic mechanisms play a central role in gene expression regulation, culminating in such adaptations. Protein arginine methyltransferases (PRMTs) promote posttranslational modifications, modulating the function of histones and non-histone targets. The coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) is one of the S. mansoni proteins with the PRMT core domain. Methods: We carried out in silico analyses to verify the expression of SmPRMTs in public datasets from different infection stages, single-sex versus mixed-worms, and cell types. The SmCARM1 function was evaluated by RNA interference. Gene expression levels were assessed, and phenotypic alterations were analyzed in vitro, in vivo, and ex vivo. Results: The scRNAseq data showed that SmPRMTs expression is not enriched in any cell cluster in adult worms or schistosomula, except for Smcarm1 expression which is enriched in clusters of ambiguous cells and Smprmt1 in NDF+ neurons and stem/germinal cells from schistosomula. Smprmt1 is also enriched in S1 and late female germ cells from adult worms. After dsRNA exposure in vitro, we observed a Smcarm1 knockdown in schistosomula and adult worms, 83 and 69%, respectively. Smcarm1-knockdown resulted in reduced oviposition and no significant changes in the schistosomula or adult worm phenotypes. In vivo analysis after murine infection with Smcarm1 knocked-down schistosomula, showed no significant change in the number of worms recovered from mice, however, a significant reduction in the number of eggs recovered was detected. The ex vivo worms presented a significant decrease in the ovary area with a lower degree of cell differentiation, vitelline glands cell disorganization, and a decrease in the testicular lobe area. The worm tegument presented a lower number of tubercles, and the ventral sucker of the parasites presented a damaged tegument and points of detachment from the parasite body. Discussion: This work brings the first functional characterization of SmCARM1 shedding light on its roles in S. mansoni biology and its potential as a drug target. Additional studies are necessary to investigate whether the reported effects of Smcarm1 knockdown are a consequence of the SmCARM1-mediated methylation of histone tails involved in DNA packaging or other non-histone proteins.

Corrigendum: Schistosoma mansoni coactivator associated arginine methyltransferase 1 (SmCARM1) effect on parasite reproduction.

[This corrects the article DOI: 10.3389/fmicb.2023.1079855.].

Microbial diversity and anaerobic hydrocarbon degradation potential in an oil-contaminated mangrove sediment.

BACKGROUND: Mangrove forests are coastal wetlands that provide vital ecosystem services and serve as barriers against natural disasters like tsunamis, hurricanes and tropical storms. Mangroves harbour a large diversity of organisms, including microorganisms with important roles in nutrient cycling and availability. Due to tidal influence, mangroves are sites where crude oil from spills farther away can accumulate. The relationship between mangrove bacterial diversity and oil degradation in mangrove sediments remains poorly understood. RESULTS: Mangrove sediment was sampled from 0-5, 15-20 and 35-40 cm depth intervals from the Suruí River mangrove (Rio de Janeiro, Brazil), which has a history of oil contamination. DGGE fingerprinting for bamA, dsr and 16S rRNA encoding fragment genes, and qPCR analysis using dsr and 16S rRNA gene fragment revealed differences with sediment depth. CONCLUSIONS: Analysis of bacterial 16S rRNA gene diversity revealed changes with depth. DGGE for bamA and dsr genes shows that the anaerobic hydrocarbon-degrading community profile also changed between 5 and 15 cm depth, and is similar in the two deeper sediments, indicating that below 15 cm the anaerobic hydrocarbon-degrading community appears to be well established and homogeneous in this mangrove sediment. qPCR analysis revealed differences with sediment depth, with general bacterial abundance in the top layer (0-5 cm) being greater than in both deeper sediment layers (15-20 and 35-40 cm), which were similar to each other.

Eukaryotic protein kinases (ePKs) of the helminth parasite Schistosoma mansoni.

BACKGROUND: Schistosomiasis remains an important parasitic disease and a major economic problem in many countries. The Schistosoma mansoni genome and predicted proteome sequences were recently published providing the opportunity to identify new drug candidates. Eukaryotic protein kinases (ePKs) play a central role in mediating signal transduction through complex networks and are considered druggable targets from the medical and chemical viewpoints. Our work aimed at analyzing the S. mansoni predicted proteome in order to identify and classify all ePKs of this parasite through combined computational approaches. Functional annotation was performed mainly to yield insights into the parasite signaling processes relevant to its complex lifestyle and to select some ePKs as potential drug targets. RESULTS: We have identified 252 ePKs, which corresponds to 1.9% of the S. mansoni predicted proteome, through sequence similarity searches using HMMs (Hidden Markov Models). Amino acid sequences corresponding to the conserved catalytic domain of ePKs were aligned by MAFFT and further used in distance-based phylogenetic analysis as implemented in PHYLIP. Our analysis also included the ePK homologs from six other eukaryotes. The results show that S. mansoni has proteins in all ePK groups. Most of them are clearly clustered with known ePKs in other eukaryotes according to the phylogenetic analysis. None of the ePKs are exclusively found in S. mansoni or belong to an expanded family in this parasite. Only 16 S. mansoni ePKs were experimentally studied, 12 proteins are predicted to be catalytically inactive and approximately 2% of the parasite ePKs remain unclassified. Some proteins were mentioned as good target for drug development since they have a predicted essential function for the parasite. CONCLUSIONS: Our approach has improved the functional annotation of 40% of S. mansoni ePKs through combined similarity and phylogenetic-based approaches. As we continue this work, we will highlight the biochemical and physiological adaptations of S. mansoni in response to diverse environments during the parasite development, vector interaction, and host infection.

Primary health care quality assessment according to the level of satisfaction of elderly users. / Avaliação da qualidade da atenção primária à saúde segundo o nível de satisfação dos idosos.

OBJECTIVE: To evaluate the quality of Primary Health Care according to the level of satisfaction of elderly users. METHOD: An exploratory-descriptive study, with a quantitative approach, performed with 381 elderly users of Primary Health Care. For data collection, the Service Quality scale (SERVQUAL) was adapted to the context of the Primary Health Units (UBS) of Family Health Strategy (ESF) and a questionnaire with 44 questions was elaborated. Data was treated using SSPS® and analyzed using descriptive and inferential statistical techniques. RESULTS: the SERVQUAL subscales "expectations" and "perceptions" exhibited excellent reliability and internal consistency, with Cronbach's Alpha 0.948 and 0.932, respectively. The evaluated dimensions presented negative Gaps results: tangible aspects -0.65, reliability -1.19, responsiveness -0.56, guarantee -0.91, and empathy -0.52. CONCLUSION: negative Gaps in all dimensions show gaps in the quality of services and demonstrates the low satisfaction of the elderly users of UBS/ESF/APS.

Utilização de Cateter Central de Inserção Periférica para Realização de Transplante de Células-Tronco Hematopoiéticas / Use of Peripherally Inserted Central Catheter to Perform Hematopoietic Stem Cell Transplantation / Uso de Catéter Central de Inserción Periférica para Realizar Trasplante de Células Madre Hematopoyéticas

Introdução: O acesso venoso seguro é indispensável aos pacientes no transplante de células-tronco hematopoiéticas (TCTH), e o enfermeiro participa de todo o seu processo de decisão e manutenção. Objetivo: Sistematizar a experiência de enfermeiros na utilização do cateter central de inserção periférica (CCIP) para a realização de TCTH em um centro de transplante de medula óssea de uma instituição pública, referência nacional em oncologia. Método: Estudo descritivo elaborado a partir da sistematização criada por Oscar Jara Holliday. Resultados: A experiência de utilização do CCIP, para a realização de TCTH, no centro de transplante estudado, teve início em 2017. Durante a implementação da nova rotina, surgiram obstáculos relacionados à resistência da equipe, aceitação dos pacientes, disponibilidade de material adequado e profissionais habilitados. Pensando na assistência terapêutica endovenosa de qualidade e segura para o paciente, registrou-se a marca de 130 CCIP implantados nos últimos seis anos (2017-2022), o que representou 32% do total de cateteres utilizados no último ano para realização de transplantes autólogos, alogênicos aparentados, alogênicos não aparentados e haploidênticos. Outro dado referente ao sucesso desse procedimento nesse centro mostra que 80% dos CCIP foram retirados por motivo de alta e os outros 20% por trombose (2%); obstrução (8%); óbito (5%); e febre (5%). Conclusão: Observa-se que, apesar das dificuldades enfrentadas, a implementação e a utilização de CCIP para infusão de células-tronco hematopoiéticas têm apresentado bons resultados e contribuem para a prática de obtenção de acesso vascular seguro no TCTH

Introduction: Safe venous access is essential for patients undergoing hematopoietic stem cell transplantation (HSCT) and the nurse participates in the entire decision-making process and maintenance. Objective: To systematize the experience of nurses in using the peripherally inserted central catheter (PICC) to perform HSCT in a bone marrow transplant center of a public institution that is a national oncology reference. Method: Descriptive study based in Jara Holliday's systematization. Results: The experience of using PICC to perform HSCT at the transplant center investigated began in 2017. During the implementation of the new routine, obstacles related to the team's resistance, patient acceptance, availability of adequate material and qualified professionals were detected. Regarding quality and safe intravenous therapeutic assistance for the patient, 130 PICC have been implanted in the last six years (2017-2022), accounting for 32% of the total number of catheters used to perform autologous, related allogeneic, unrelated allogeneic and haploidentical transplants in the last year. 80% of PICC was removed due to hospital discharge and 20% due to thrombosis (2%), obstruction (8%), death (5%) and fever (5%) confirming the success of this procedure in the center investigated. Conclusion: Despite the difficulties, the implementation and use of PICC for the infusion of hematopoietic stem cells has shown good results and contributed to obtaining safe vascular access in HSCT

Introducción: El acceso venoso seguro es fundamental para los pacientes sometidos a trasplante de células madre hematopoyéticas (TCMH) y el personal de enfermería participa en todo el proceso de toma de decisiones y mantenimiento de este acceso. Objetivo: Sistematizar la experiencia de enfermeros en el uso del catéter central de inserción periférica (PICC) para realizar trasplante de células madre hematopoyéticas en un centro de trasplante de médula ósea de una institución pública de referencia nacional en oncología. Método: Estudio descriptivo elaborado a partir de la sistematización realizada por Oscar Jara Holliday. Resultados: La experiencia de utilizar el PICC para realizar el TCMH en el centro de trasplante estudiado se inició en 2017. Durante la implementación de la nueva rutina surgieron obstáculos relacionados con la resistencia del equipo, aceptación del paciente, disponibilidad de material adecuado y profesionales calificados. Pensando en una asistencia terapéutica intravenosa de calidad y segura para el paciente, nos lanzamos y elevamos la marca de 130 PICC implantados en los últimos seis años (2017-2022), lo que representó en el último año el 32% del total de catéteres utilizados para realizar trasplantes autólogos, alogénicos relacionados, alogénicos no relacionados y haploidénticos. Otro dato referente al éxito de este procedimiento en nuestro centro muestra que el 80% de los PICC se retiraron por alta y el otro 20% por trombosis (2%); obstrucción (8%); muerte (5%) y fiebre (5%). Conclusión: Al final de este informe, observamos que, a pesar de las dificultades enfrentadas, la implementación y el uso de PICC para la infusión de células madre hematopoyéticas mostró buenos resultados y contribuyó para la práctica de obtener un acceso vascular seguro en el TCMH

How to access and exploit natural resources sustainably: petroleum biotechnology.

As we transition from fossil fuel reliance to a new energy future, innovative microbial biotechnologies may offer new routes to maximize recovery from conventional and unconventional energy assets; as well as contributing to reduced emission pathways and new technologies for carbon capture and utilization. Here we discuss the role of microbiology in petroleum biotechnologies in relation to addressing UN Sustainable Development Goal 12 (ensure sustainable consumption and production patterns), with a focus on microbially-mediated energy recovery from unconventionals (heavy oil to methane), shale gas and fracking, bioelectrochemical systems for the production of electricity from fossil fuel resources, and innovations in synthetic biology. Furthermore, using wastes to support a more sustainable approach to fossil fuel extraction processes is considered as we undertake the move towards a more circular global economy.

Steel wastes as versatile materials for treatment of biorefractory wastewaters.

Recent research on novel cost-effective adsorbent materials suggests potential use of industrial wastes for effluent treatment, with the added benefit of reuse of the wastes. Waste steel materials, including blast oxygen furnace sludge (BOFS), blast furnace sludge (BFS), and blast furnace dust (BFD), were investigated as low-cost adsorbents for removal of an oil emulsion and RR195 dye. The residues were characterized by X-ray diffraction, Brunauer-Emmett-Teller area, volume and distribution of pore diameters, Mössbauer spectroscopy, X-ray fluorescence, granulometry, scanning electron microscopy/energy dispersive spectroscopy, and pHpzc. Adsorption kinetics data were obtained by UV-vis spectrophotometry at the maximum absorption wavelength of the dye solution and crude oil emulsion. The use of waste as an adsorbent was more efficient for treatment of the oil emulsion than the dye solution. BOFS had higher total organic carbon (TOC) removal efficiency than the other waste materials. For the RR195 dye, good color removal was observed for all adsorbents, >90 % within 24 h. TOC removal was poor, <10 % for BFD and BFS and a maximum of 37 % for BOFS. For the oil emulsion, 97 % TOC removal was obtained by adsorption onto BOFS and 87 % onto BFS.

Avaliação da qualidade da atenção primária à saúde segundo o nível de satisfação dos idosos / Evaluación de la calidad de la atención primaria de la salud según el nivel de satisfacción de los ancianos / Primary health care quality assessment according to the level of satisfaction of elderly users

Resumo OBJETIVO Avaliar a qualidade da Atenção Primária à Saúde segundo o nível de satisfação dos usuários idosos. MÉTODO Estudo exploratório, descritivo, com abordagem quantitativa, realizado com 381 idosos usuários dos serviços da Atenção Primária à Saúde. Para a coleta de dados, o Service Quality (SERVQUAL) foi adaptado ao contexto das Unidades Básicas de Saúde (UBS) da Estratégia Saúde da Família (ESF) e foi elaborado um questionário com 44 questões. Os dados foram tratados utilizando o SSPS® e analisados por meio de técnicas estatísticas descritivas e inferenciais. RESULTADOS O SERVQUAL exibiu excelente confiabilidade e consistência interna das subescalas expectativas e percepções, com Alpha Cronbach 0,948 e 0,932, respectivamente. As dimensões avaliadas apresentaram Gaps negativos: aspectos tangíveis -0,65; confiabilidade -1,19; capacidade de resposta -0,56; garantia -0,91 e empatia -0.52. CONCLUSÃO Os Gaps negativos, em todas as dimensões, evidenciam lacunas na qualidade dos serviços e demonstram a baixa satisfação dos idosos usuários das UBS/ESF/APS.

Resumen OBJETIVO Evaluar la calidad de la Atención Primaria a la Salud según el nivel de satisfacción de los usuarios ancianos. MÉTODO Estudio exploratorio, descriptivo, con abordaje cuantitativo, realizado con 381 ancianos usuarios de los servicios de Atención Primaria Salud. Para la recolección de los datos, el Service Quality (SERVQUAL) fue adaptado al contexto de las Unidades Básicas de Salud (UBS) Estrategia Salud de la Familia (ESF) y elaboró ​​un cuestionario con 44 preguntas. Los datos fueron tratados utilizando SSPS® y analizados a través de las técnicas estadísticas descriptivas e inferenciales. RESULTADOS El SERVQUAL exhibió excelente confiabilidad y consistencia interna de las sub-escalas expectativas y percepciones con Alpha de Cronbach 0,948 y 0,932, respectivamente. Las dimensiones evaluadas presentaron Gaps negativos: aspectos tangibles -0,65, confiabilidad -1,19, capacidad de respuesta -0,56, garantía -0,91 y empatía -0.52. CONCLUSIÓN Los Gaps negativos evidencian lagunas en la calidad de los servicios y demuestran la satisfacción baja de los ancianos usuarios de las UBS/ESF/APS.

Abstract OBJECTIVE To evaluate the quality of Primary Health Care according to the level of satisfaction of elderly users. METHOD An exploratory-descriptive study, with a quantitative approach, performed with 381 elderly users of Primary Health Care. For data collection, the Service Quality scale (SERVQUAL) was adapted to the context of the Primary Health Units (UBS) of Family Health Strategy (ESF) and a questionnaire with 44 questions was elaborated. Data was treated using SSPS® and analyzed using descriptive and inferential statistical techniques. RESULTS the SERVQUAL subscales "expectations" and "perceptions" exhibited excellent reliability and internal consistency, with Cronbach's Alpha 0.948 and 0.932, respectively. The evaluated dimensions presented negative Gaps results: tangible aspects -0.65, reliability -1.19, responsiveness -0.56, guarantee -0.91, and empathy -0.52. CONCLUSION negative Gaps in all dimensions show gaps in the quality of services and demonstrates the low satisfaction of the elderly users of UBS/ESF/APS.

Regulation of Schistosoma mansoni development and reproduction by the mitogen-activated protein kinase signaling pathway.

BACKGROUND: Protein kinases are proven targets for drug development with an increasing number of eukaryotic Protein Kinase (ePK) inhibitors now approved as drugs. Mitogen-activated protein kinase (MAPK) family members connect cell-surface receptors to regulatory targets within cells and influence a number of tissue-specific biological activities such as cell proliferation, differentiation and survival. However, the contributions of members of the MAPK pathway to schistosome development and survival are unclear. METHODOLOGY/PRINCIPAL FINDINGS: We employed RNA interference (RNAi) to elucidate the functional roles of five S. mansoni genes (SmCaMK2, SmJNK, SmERK1, SmERK2 and SmRas) involved in MAPK signaling pathway. Mice were injected with post-infective larvae (schistosomula) subsequent to RNAi and the development of adult worms observed. The data demonstrate that SmJNK participates in parasite maturation and survival of the parasites, whereas SmERK are involved in egg production as infected mice had significantly lower egg burdens with female worms presenting underdeveloped ovaries. Furthermore, it was shown that the c-fos transcription factor was overexpressed in parasites submitted to RNAi of SmERK1, SmJNK and SmCaMK2 indicating its putative involvement in gene regulation in this parasite's MAPK signaling cascade. CONCLUSIONS: We conclude that MAPKs proteins play important roles in the parasite in vivo survival, being essential for normal development and successful survival and reproduction of the schistosome parasite. Moreover SmERK and SmJNK are potential targets for drug development.

Targeting schistosome histone modifying enzymes for drug development.

The histone modifying enzymes (HME) represent particularly promising targets for the development of alternatives to praziquantel, the only currently available drug to combat schistosomiasis. The inhibition of these enzymes frequently arrests the cell cycle or induces apoptosis in cancer cells, but not in normal cells and numerous HME inhibitors are under investigation as potential anticancer agents. The recent resolution of the genome sequences of Schistosoma mansoni and Schistosoma japonicum has allowed us to identify all the schistosome genes encoding histone acetyltransferases, deacetylases, methyltransferases and demethylases. We have chosen a strategy using phylogenetic screening with inhibitors of HME classes, screening of individual HME targets by both high-throughput and reasoned (in silico docking using resolved crystal structures) approaches in a project funded by the European Community, named SEtTReND (Schistosome Epigenetics: Targets, Regulation, New Drugs). The initial focus is on the class I histone deacetylase (HDAC) 8 since the comparison of the catalytic site of the schistosome and human enzymes shows crucial differences, rendering possible the development of inhibitors specific for SmHDAC8. However, phenotypic screening shows that inhibitors of all HME classes tested were able to induce apoptosis and death in parasites in vitro, indicating that other enzymes may prove to be viable targets.

Functional Diversity of the Schistosoma mansoni Tyrosine Kinases.

Schistosoma mansoni, one of the causative agents of schistosomiasis, has a complex life cycle infecting over 200 million people worldwide. Such a successful and prolific parasite life cycle has been shown to be dependent on the adaptive interaction between the parasite and hosts. Tyrosine kinases (TKs) play a key role in signaling pathways as demonstrated by a large body of experimental work in eukaryotes. Furthermore, comparative genomics have allowed the identification of TK homologs and provided insights into the functional role of TKs in several biological systems. Finally, TK structural biology has provided a rational basis for obtaining selective inhibitors directed to the treatment of human diseases. This paper covers the important aspects of the phospho-tyrosine signaling network in S. mansoni, Caenorhabditis elegans, and humans, the main process of functional diversification of TKs, that is, protein-domain shuffling, and also discusses TKs as targets for the development of new anti-schistosome drugs.