The hologenome of Daphnia magna reveals possible DNA methylation and microbiome-mediated evolution of the host genome.

Properties that make organisms ideal laboratory models in developmental and medical research are often the ones that also make them less representative of wild relatives. The waterflea Daphnia magna is an exception, by both sharing many properties with established laboratory models and being a keystone species, a sentinel species for assessing water quality, an indicator of environmental change and an established ecotoxicology model. Yet, Daphnia's full potential has not been fully exploited because of the challenges associated with assembling and annotating its gene-rich genome. Here, we present the first hologenome of Daphnia magna, consisting of a chromosomal-level assembly of the D. magna genome and the draft assembly of its metagenome. By sequencing and mapping transcriptomes from exposures to environmental conditions and from developmental morphological landmarks, we expand the previously annotates gene set for this species. We also provide evidence for the potential role of gene-body DNA-methylation as a mutagen mediating genome evolution. For the first time, our study shows that the gut microbes provide resistance to commonly used antibiotics and virulence factors, potentially mediating Daphnia's environmental-driven rapid evolution. Key findings in this study improve our understanding of the contribution of DNA methylation and gut microbiota to genome evolution in response to rapidly changing environments.

Predigested Mixture of Arachidonic and Docosahexaenoic Acids for Better Bio-Accessibility.

A predigested product from arachidonic acid oil (ARA) and docosahexaenoic acid (DHA) oil in a 2:1 (w/w) ratio has been developed and evaluated in an in vitro digestion model. To produce this predigested lipid mixture, first, the two oils were enzymatically hydrolyzed up to 90% of free fatty acids (FFAs) were achieved. Then, these two fatty acid (FA) mixtures were mixed in a 2:1 ARA-to-DHA ratio (w/w) and enzymatically esterified with glycerol to produce a mixture of FFAs, mono-, di-, and triacylglycerides. Different glycerol ratios and temperatures were evaluated. The best results were attained at 10 °C and a glycerol-to-FA molar ratio of 3:1. The bio-accessibility of this predigested mixture was studied in an in vitro digestion model. A total of 90% of the digestion product was found in the micellar phase, which contained 30% monoacylglycerides, more than 50% FFAs, and a very small amount of triacylglycerols (3% w/w). All these data indicate an excellent bio-accessibility of this predigested mixture.

Quality of life, fatigue, sleep quality, and mental health in systemic lupus erythematosus patients with a high cardiovascular risk profile.

Systemic lupus erythematosus (SLE) patients report worse health-related quality of life (HRQL), fatigue, anxiety, depression, and sleep quality, when compared to the general population and other chronic diseases. Furthermore, cardiometabolic diseases are highly prevalent in SLE and are also associated with these parameters. Thus, it is plausible to suggest that SLE patients with a high cardiovascular risk may report worse results for these parameters. The aim of the study is to describe HRQL, fatigue, anxiety and depression symptoms, and sleep quality in a sample of SLE patients with a high cardiovascular risk profile (i.e., BMI between 25 and 40 kg/m2 and/or dyslipidemia, hypertension, or diabetes). This was a cross-sectional study where patients were assessed for (i) demographic, anthropometric, and disease-related parameters, (ii) HRQL, (iii) fatigue, (iv) anxiety and depression symptoms, and (v) sleep quality. One-hundred patients completed the study; however, only 87 patients were assessed for sleep quality data. Patients averaged 41.7 ± 9 years, and most patients were classified as overweight/obese (87%). SF-36 scores for physical and mental components summary were 51.3 ± 9.6 and 54.2 ± 15.6, respectively, with "bodily pain" and "role emotional" presenting the lower scores. The total SLEQOL score was 105.1 ± 42.0, with lower scores reported for "self-image" and "mood." Fatigue score was 30.8 ± 8.9, and 78% and 93% reported severe symptoms of anxiety and depression, respectively. The average sleep effectiveness was 82.9 ± 6.6%. Sleep latency, total time in bed (TTiB), and total sleep time (TST) were 8.4 ± 8.9, 495.8 ± 79.7, and 409.7 ± 69.9 min, respectively. Patients reported an average of 17.8 ± 6.2 WE, with 4.5 ± 1.5 min duration and a WASO of 77.7 ± 36.6 min. Despite similar HRQL, fatigue, and sleep quality parameters to those reported by other SLE populations, SLE patients with a high cardiovascular risk had a higher prevalence of depression and anxiety. Understanding SLE patients' quality of life and psychological symptoms is of utmost importance to improve disease management. The findings of this study highlight the need for more intensive and global care regarding mental health when considering a high cardiovascular risk in SLE.

N-Edited Guanine Isosteres.

Guanine is one out of five endogenous nucleobases and of key interest in drug discovery and chemical biology. Hitherto, the synthesis of guanine derivatives involves lengthy multistep sequential synthesis of low overall diversity, resulting in the quest for innovation. Using a "single-atom skeletal editing" approach, we designed 2-aminoimidazo[2,1-f][1,2,4]triazin-4(3H)-one as a guanine isostere, conserving the biologically important HBA-HBD-HBD (HBA = hydrogen bond acceptor; HBD = hydrogen bond donor) substructure. We realized our design by a simple one-pot two-step method combining the Groebke-Blackburn-Bienaymé reaction (GBB-3CR) and a deprotection reaction to assemble the innovative guanine isosteres in moderate to good yields. Our innovative, diverse, short, and reliable multicomponent reaction synthesis will add to the toolbox of guanine isostere syntheses.

A randomized controlled trial of an intervention promoting physical activity and healthy eating recommendations in systemic lupus erythematosus: the protocol study "Living Well with Lupus".

There is a paucity of studies assessing multidisciplinary interventions focused on tackling physical inactivity/sedentary behavior and poor dietary habits in SLE. The Living well with Lupus (LWWL) is a randomized controlled trial to investigate whether a six-month lifestyle change intervention will improve cardiometabolic risk factors (primary outcome) among systemic lupus erythematosus (SLE) patients with low disease activity (SLEDAI score ≤ 4) and with high cardiovascular risk. As secondary goals, we will evaluate: (1) the intervention's safety, efficacy, and feasibility in promoting lifestyle changes, and (2) the effects of the intervention on secondary outcomes (i.e., clinical parameters, functional capacity, fatigue, psychological aspects, sleep quality and health-related quality of life). Patients will be randomly allocated to either a control (i.e., standard care) or a lifestyle intervention group using a simple randomization (1:1 ratio, blocks of 20). Mixed Model analyses will be conducted for comparing groups following an intention-to-treat approach. A per protocol analysis will also be conducted. This study has the potential to generate new, clinically relevant data able to refine the multidisciplinary management of SLE patients. Protocol version number: NCT04431167 (first version).

bsAS, an antisense long non-coding RNA, essential for correct wing development through regulation of blistered/DSRF isoform usage.

Natural Antisense Transcripts (NATs) are long non-coding RNAs (lncRNAs) that overlap coding genes in the opposite strand. NATs roles have been related to gene regulation through different mechanisms, including post-transcriptional RNA processing. With the aim to identify NATs with potential regulatory function during fly development, we generated RNA-Seq data in Drosophila developing tissues and found bsAS, one of the most highly expressed lncRNAs in the fly wing. bsAS is antisense to bs/DSRF, a gene involved in wing development and neural processes. bsAS plays a crucial role in the tissue specific regulation of the expression of the bs/DSRF isoforms. This regulation is essential for the correct determination of cell fate during Drosophila development, as bsAS knockouts show highly aberrant phenotypes. Regulation of bs isoform usage by bsAS is mediated by specific physical interactions between the promoters of these two genes, which suggests a regulatory mechanism involving the collision of RNA polymerases transcribing in opposite directions. Evolutionary analysis suggests that bsAS NAT emerged simultaneously to the long-short isoform structure of bs, preceding the emergence of wings in insects.

Genomic and functional conservation of lncRNAs: lessons from flies.

Over the last decade, the increasing interest in long non-coding RNAs (lncRNAs) has led to the discovery of these transcripts in multiple organisms. LncRNAs tend to be specifically, and often lowly, expressed in certain tissues, cell types and biological contexts. Although lncRNAs participate in the regulation of a wide variety of biological processes, including development and disease, most of their functions and mechanisms of action remain unknown. Poor conservation of the DNA sequences encoding for these transcripts makes the identification of lncRNAs orthologues among different species very challenging, especially between evolutionarily distant species such as flies and humans or mice. However, the functions of lncRNAs are unexpectedly preserved among different species supporting the idea that conservation occurs beyond DNA sequences and reinforcing the potential of characterising lncRNAs in animal models. In this review, we describe the features and roles of lncRNAs in the fruit fly Drosophila melanogaster, focusing on genomic and functional comparisons with human and mouse lncRNAs. We also discuss the current state of advances and limitations in the study of lncRNA conservation and future perspectives.

Disseminated and recurrent infundibulofolliculitis in children in Mexico.

Disseminated and recurrent infundibulofolliculitis is an uncommon non-infectious skin eruption characterized by recurrent, sometimes pruritic, follicular papules commonly seen on the trunk and proximal extremities. We describe the clinical, dermoscopic, and histopathologic characteristics of disseminated and recurrent infundibulofolliculitis in three young pediatric patients from the tropical regions of Mexico, Guerrero, and Chiapas.

Cabut/dTIEG associates with the transcription factor Yorkie for growth control.

The Drosophila transcription factor Cabut/dTIEG (Cbt) is a growth regulator, whose expression is modulated by different stimuli. Here, we determine Cbt association with chromatin and identify Yorkie (Yki), the transcriptional co-activator of the Hippo (Hpo) pathway as its partner. Cbt and Yki co-localize on common gene promoters, and the expression of target genes varies according to changes in Cbt levels. Down-regulation of Cbt suppresses the overgrowth phenotypes caused by mutations in expanded (ex) and yki overexpression, whereas its up-regulation promotes cell proliferation. Our results imply that Cbt is a novel partner of Yki that is required as a transcriptional co-activator in growth control.

Brk regulates wing disc growth in part via repression of Myc expression.

The molecular mechanisms regulating tissue size represent an unsolved puzzle in developmental biology. One signalling pathway controlling growth of the Drosophila wing is Dpp. Dpp promotes growth by repression of the transcription factor Brk. The transcriptional targets of Brk that control cell growth and proliferation, however, are not yet fully elucidated. We report here a genome-wide ChIP-Seq of endogenous Brk from wing imaginal discs. We identify the growth regulator Myc as a target of Brk and show that repression of Myc and of the miRNA bantam explains a significant fraction of the growth inhibition caused by Brk. This work sheds light on the effector mechanisms by which Dpp signalling controls tissue growth.

Food consumption, physical activity and aerobic capacity in systemic lupus erythematosus patients with high cardiovascular risk.

Systemic Lupus Erythematosus (SLE) is a chronic, autoimmune and multisystemic rheumatic disease. Patients with SLE have decreased functional and aerobic capacity, as well as increased prevalence of Cardiovascular Diseases (CVD), which are the primary causes of morbimortality in this condition. Dietary intake and physical activity are well-known modifiable cardiovascular risk factors. The aim of this study is to describe food consumption, sedentary behavior, physical activity level, and functional and aerobic capacity in a sample of SLE patients with high cardiovascular risk. This was a cross-sectional study in which patients were assessed for (i) Demographic, anthropometric, and disease-related parameters; (ii) Food consumption; (iii) Physical activity level and sedentary behavior; (iv) Functional and aerobic capacity. Patients averaged 41.7 ± 9 years, and most were classified as overweight/obese (87%). Average macronutrient intake was within recommendations; however, fiber (16 ± 9g) and calcium (391 ± 217 mg) intakes were below, and sodium intake (2.9 ± 1.3 mg) was above recommendations. Besides, food consumption assessed by the Nova system showed a predominance of unprocessed foods (43.8 ± 14.0%TEI), although ultraprocessed food intake (20.0 ± 13.9%TEI) was slightly higher than that seen in the Brazilian population. Patients also exhibited high sedentary behavior (8.2 ± 2.2h) and only eighteen participants reached the minimum recommended amount of moderate-to-vigorous physical activity. Overall, patients had a low functional and aerobic capacity compared to the general population. Data from this study may help design dedicated clinical trials aiming to investigate the effects of lifestyle intervention to mitigate CVD in SLE.

Effects of a lifestyle intervention on cardiovascular risk factors in systemic lupus erythematosus patients: The study "Living well with lupus".

OBJECTIVE: The aim of the present study was to investigate the effects of a lifestyle intervention on cardiometabolic risk factors in patients with systemic lupus erythematosus with a high cardiovascular risk profile. METHODS: This trial was conducted in Sao Paulo, Brazil between August 2020 and March 2023. The patients were randomly assigned to lifestyle intervention or control. The intervention was a 6-month multifaced program focused on behavioral changes through personalized recommendations for increasing physical activity (structured and non-structured) and improving eating aspects. Cardiometabolic risk score (primary outcome), anthropometry and visceral fat, aerobic capacity, blood pressure, inflammatory and oxidative stress markers, and blood flow and endothelial function were assessed before and after the intervention. RESULTS: A total of 80 patients were randomized. Twelve and 6 patients dropped out due to personal reasons in the intervention and control groups, respectively. Average adherence rate for the intervention was 56.9%. Intention-to-treat analysis showed no significant difference between groups in the cardiometabolic risk score (intervention group - Pre: 1.7 ± 3.6; Post: -1.6 ± 4.0; control group - Pre: -1.9 ± 3.6; Post: -2.0 ± 3.8; estimated mean difference between groups at post: -0.4; 95% confidence intervals: -2.7; 1.9; p = 0.96). This finding was confirmed by exploratory, per-protocol analysis. No significant differences were observed between adherents vs. non-adherent participants. Secondary outcomes did not change between groups. CONCLUSION: This 6-month, individualized, lifestyle intervention did not improve cardiovascular risk factors in SLE patients with a high cardiovascular risk profile. TRIAL REGISTRATION: clinicaltrials.gov (NCT04431167).

A retrospective study of Taenia spp. in Cuban patients: what does molecular analysis tell us?

Taeniosis is a neglected disease, particularly in developing countries, and is caused by infection with the adult tapeworm of either Taenia solium, Taenia saginata, and Taenia asiatica. Of these, T. solium is of primary concern due to the potential for cysticercosis should T. solium eggs be ingested. In Cuba, all cases of taeniosis are assumed to be caused by T. saginata, although some cases of cysticercosis have been documented. It is therefore important to gain further insights regarding the species causing taeniosis in Cuba, especially as diagnostic records indicate an increasing incidence, with the highest number of cases reported in 2020. In this study, we analysed 37 Taenia-positive faecal samples (or proglottids isolated from faecal samples) from the period 2001 until 2020 from all regions of the country. Genomic DNA was extracted from the samples, which had been stored in 10% formalin, using the QIAamp Tissue Kit. Species identification was carried out by duplex real-time PCR targeting the mitochondrial DNA. All cases were found to be T. saginata, and sequence analysis of three isolates confirmed the identification of this species. Our data do not provide any evidence that T. solium currently occurs in Cuba. However, given the relatively low number of samples analysed here, that the parasite may be imported with visitors or travellers who have been in endemic countries, and that taeniosis has relatively mild symptoms and thus infected patients may not seek medical attention, we recommend species determination for all taeniosis cases reported in Cuba.

Zebrafish as a model to study inflammation: A tool for drug discovery.

This study aims to demonstrate the applicability and importance of zebrafish (Danio rerio) model to study acute and chronic inflammatory responses induced by different stimuli: carrageenan phlogogen (nonimmune); acute infection by bacteria (immune); foreign body reaction (chronic inflammation by round glass coverslip implantation); reaction induced by xenotransplantation. In addition to the advantages of presenting low breeding cost, high prolificity, transparent embryos, high number of individuals belonging to the same spawning and high genetic similarity that favor translational responses to vertebrate organisms like humans, zebrafish proved to be an excellent tool, allowing the evaluation of edema formation, accumulation of inflammatory cells in the exudate, mediators, signaling pathways, gene expression and production of specific proteins. Our studies demonstrated the versatility of fish models to investigate the inflammatory response and its pathophysiology, essential for the successful development of studies to discover innovative pharmacological strategies.

Gene expression following induction of regeneration in Drosophila wing imaginal discs. Expression profile of regenerating wing discs.

BACKGROUND: Regeneration is the ability of an organism to rebuild a body part that has been damaged or amputated, and can be studied at the molecular level using model organisms. Drosophila imaginal discs, which are the larval primordia of adult cuticular structures, are capable of undergoing regenerative growth after transplantation and in vivo culture into the adult abdomen. RESULTS: Using expression profile analyses, we studied the regenerative behaviour of wing discs at 0, 24 and 72 hours after fragmentation and implantation into adult females. Based on expression level, we generated a catalogue of genes with putative role in wing disc regeneration, identifying four classes: 1) genes with differential expression within the first 24 hours; 2) genes with differential expression between 24 and 72 hours; 3) genes that changed significantly in expression levels between the two time periods; 4) genes with a sustained increase or decrease in their expression levels throughout regeneration. Among these genes, we identified members of the JNK and Notch signalling pathways and chromatin regulators. Through computational analysis, we recognized putative binding sites for transcription factors downstream of these pathways that are conserved in multiple Drosophilids, indicating a potential relationship between members of the different gene classes. Experimental data from genetic mutants provide evidence of a requirement of selected genes in wing disc regeneration. CONCLUSIONS: We have been able to distinguish various classes of genes involved in early and late steps of the regeneration process. Our data suggests the integration of signalling pathways in the promoters of regulated genes.

[Trends in psychiatric admissions in adults over 65 years old]. / Tendencias en las hospitalizaciones psiquiátricas de personas mayores de 65 años.

BACKGROUND: The aim of this study was to analyse the trend in the percentages of elderly patients admitted to hospital for psychiatric reasons. An additional aim was to analyse the characteristics of the elderly population admitted to a psychiatric hospitalisation unit. MATERIAL AN METHODS: An analysis was made of the trends in the percentages of discharges in elderly population at the national level and in the Mental Health Hospitalisation Unit (MHHU) of the Regional University Hospital of Malaga for a period of at least 18years using segmented regression. For the study of the characteristics of the elderly population, all patients (N=5,925) and consecutive episodes of admission (N=15,418) were compared between 1999 and 2017 in the MHHU. RESULTS: At the national level, there was an increase in hospital discharges in elderly patients with a significant mean annual percent change of 2.0%. In the study unit, the elderly population were more frequently female, involuntarily admitted, and had a longer hospital stay. They had been diagnosed more frequently with organic and depressive mental disorders, and less frequently with schizophrenia, substance use, and personality disorders. CONCLUSIONS: There was a growing trend in the percentage of elderly psychiatric patients admitted to hospitals during the study period. These results point to the increase in elderly psychiatric admissions and thus the need to adapt psychiatric units to the characteristics of this population.

IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms.

INTRODUCTION: The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. METHODS: SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. RESULTS: The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. CONCLUSIONS: These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells.

Cbt modulates Foxo activation by positively regulating insulin signaling in Drosophila embryos.

In late Drosophila embryos, the epidermis exhibits a dorsal hole as a consequence of germ band retraction. It is sealed during dorsal closure (DC), a morphogenetic process in which the two lateral epidermal layers converge towards the dorsal midline and fuse. We previously demonstrated the involvement of the Cbt transcription factor in Drosophila DC. However its molecular role in the process remained obscure. In this study, we used genomic approaches to identify genes regulated by Cbt as well as its direct targets during late embryogenesis. Our results reveal a complex transcriptional circuit downstream of Cbt and evidence that it is functionally related with the Insulin/insulin-like growth factor signaling pathway. In this context, Cbt may act as a positive regulator of the pathway, leading to the repression of Foxo activity. Our results also suggest that the DC defects observed in cbt embryos could be partially due to Foxo overactivation and that a regulatory feedback loop between Foxo and Cbt may be operating in the DC context.

Proyecto Ágora: un cambio de mirada hacia lo dialógico en salud mental / Ágora project: a change of view towards dialogical aspects in mental health

Este artículo muestra el desarrollo del Proyecto Ágora desde sus inicios, una Investigación Acción Participativa (IAP) que persigue la construcción social de conocimiento en torno a la presencia de procesos dialógicos en los contextos sociosanitarios de atención a la salud mental en la Comunidad de Madrid. Se ha contado con una muestra de 91 personas pertenecientes al ámbito de la salud mental, ya sean personas atendidas, familiares o profesionales. Para observar la realidad de estudio, se han tomado como base los principios que enuncian el enfoque de Diálogo Abierto y la Teoría Colaborativa. Los resultados muestran que aún pesa la herencia de una visión moderna de la ciencia, traducida en un modelo biomédico que reduce en gran medida la problemática de la persona a su enfermedad, con gran énfasis en el diagnóstico y tratamientos indicados. A partir del análisis de este fenómeno y sus consecuencias, se pretende impulsar una investigación-acción que sirva para conocer más a fondo esta problemática y aportar ideas respecto a cómo incorporar aspectos colaborativos y dialógicos eficaces y demandados por los participantes en la intervención psiquiátrica y psicosocial. (AU)

This paper presents the Ágora Project's development since its origins. The Ágora Project is a participatory action research (PAR). This approach focuses on social construction of environmental knowledge based on dialogical processes applied in social care and mental health services contexts in the Community of Madrid. The study included 91 subjects from mental health services, including service users, families, and professionals. Open Dialogue and Collaboration Theory were applied in this research. Results show that there is still a strong presence of modern science vision, through the biomedical model of health, which reduces users' problem to their medical issues, emphasizing diagnostics and treatments. The participatory action research is driven to enhance the understanding of the current problems and arise new ideas to implement effective collaboration and the dialogic elements required by participants involved in psychiatric, psychological, and social care. (AU)