A zebrafish model of Ifih1-driven Aicardi-Goutières syndrome reproduces the interferon signature and the exacerbated inflammation of patients.

Type I interferonopathies are a heterogenic group of rare diseases associated with an increase in type I interferon (IFN). The main challenge for the study of Type I interferonopathies is the lack of a well-founded animal model to better characterize the phenotype as well as to perform fast and large drug screenings to offer the best treatment options. In this study, we report the development of a transgenic zebrafish model of Type I interferonopathy overexpressing ifih1 carrying the mutation p.Arg742His (Tg(ifih1_mut)), corresponding to the human mutation p.Arg779His. RNA sequence analysis from Tg(ifih1_mut) larvae revealed a systemic inflammation and IFN signature upon a suboptimal poly I:C induction compared with wild-type larvae, confirming the phenotype observed in patients suffering from Type I interferonopathies. More interestingly, the phenotype was manifested in the zebrafish inflammation and Type I IFN reporters nfkb:eGFP and isg15:eGFP, respectively, making this zebrafish model suitable for future high-throughput chemical screening (HTS). Using the unique advantages of the zebrafish model for gene editing, we have generated Tg(ifih1_mut) knocked down for mavs and ikbke, which completely abrogated the Poly I:C induction and activation of the GFP of the reporters. Finally, we used an FDA-approved drug, Baricitinib (Jak1/Jak2 inhibitor), which was able to reduce the inflammation and the ISG expression. Our results demonstrate the potential of this model to further understand AGS pathological mechanisms and to identify novel therapeutic drugs by HTS.

(R,S)-Equol 7-ß-D-glucuronide, but not other circulating isoflavone metabolites, modulates migration and tubulogenesis in human aortic endothelial cells targeting the VEGF pathway.

Current knowledge indicates that the consumption of isoflavone-rich foodstuffs can have a beneficial impact on cardiovascular health. To what extent these isoflavones act as the main actors of that benefit is less clear. Genistein (GEN), daidzein (DAZ), and the DAZ-derived microbial metabolite equol (Eq) exhibit antiangiogenic effects in vitro, but their low bloodstream concentrations make it difficult to rationalize the in vivo effects. Their derived phase-II metabolites (glucuronides and sulfates) are major metabolites found in plasma, but their role as antiangiogenic molecules remains unexplored. We aimed here to first assess the anti-angiogenic activities of the main circulating isoflavone metabolites (glucuronides and sulfates) and compare them with their corresponding free forms at physiological concentrations (0.1-10 µM). The effects of the conjugated vs. free forms on tubulogenesis, cell migration, and VEGF-induced signalling were investigated in primary human aortic endothelial cells (HAECs). While (R,S)-equol 7-ß-D-glucuronide (Eq 7-glur) exerted dose-dependent inhibition of tubulogenesis and endothelial migration comparable to that exerted by the free forms (GEN, DAZ, and Eq), the rest of the phase-II conjugates exhibited no significant effects. The underlying molecular mechanisms were independent of the bFGF but related to the modulation of the VEGF pathway. Besides, the observed dissimilar cellular metabolism (conjugation/deconjugation) places the phase-II metabolites as precursors of the free forms; however, the question of whether this metabolism impacts their biological activity requires additional studies. These new insights suggest that isoflavones and their circulating metabolites, including Eq 7-glur, may be involved in cardiovascular health (e.g., targeting angiogenesis).

Heterotopic bone formation with extramedullary haematopoiesis in a thyroid nodule.

The presence of mature bone and bone marrow in the thyroid gland is an exceedingly rare occurrence. Extramedullary haematopoiesis (EMH) and heterotopic bone formation (HBF) should be suspected when cytology of thyroid nodules reveals evidence of megakaryocytes or bone marrow fat, respectively. The cause of these abnormalities has not been fully elucidated, but the role of bone morphogenic factors (BMPs) in their pathogenesis has been suggested. Both EMH and HBF can be seen in both benign and malignant primary thyroid conditions, and although they have not been definitively associated with significant pathology, it is recommended that extension studies be considered in the event of these findings to rule out concomitant haematological conditions.

ZAKα/P38 kinase signaling pathway regulates hematopoiesis by activating the NLRP1 inflammasome.

Chronic inflammatory diseases are associated with hematopoietic lineage bias, including neutrophilia and anemia. We have recently identified that the canonical inflammasome mediates the cleavage of the master erythroid transcription factor GATA1 in hematopoietic stem and progenitor cells (HSPCs). We report here that genetic inhibition of Nlrp1 resulted in reduced number of neutrophils and increased erythrocyte counts in zebrafish larvae. We also found that the NLRP1 inflammasome in human cells was inhibited by LRRFIP1 and FLII, independently of DPP9, and both inhibitors regulated hematopoiesis. Mechanistically, erythroid differentiation resulted in ribosomal stress-induced activation of the ZAKα/P38 kinase axis which, in turn, phosphorylated and promoted the assembly of NLRP1 in both zebrafish and human. Finally, inhibition of Zaka with the FDA/EMA-approved drug Nilotinib alleviated neutrophilia in a zebrafish model of neutrophilic inflammation and promoted erythroid differentiation and GATA1 accumulation in K562 cells. In conclusion, our results reveal that the NLRP1 inflammasome regulates hematopoiesis and pave the way to develop novel therapeutic strategies for the treatment of hematopoietic alterations associated with chronic inflammatory and rare diseases.

Telomerase RNA-based aptamers restore defective myelopoiesis in congenital neutropenic syndromes.

Telomerase RNA (TERC) has a noncanonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus facilitating myeloid gene expression. The CR4/CR5 domain of TERC is known to play this role, since a mutation of this domain found in dyskeratosis congenita (DC) patients decreases its affinity for RNA Pol II, impairing its myelopoietic activity as a result. In this study, we report that two aptamers, short single-stranded oligonucleotides, based on the CR4/CR5 domain were able to increase myelopoiesis without affecting erythropoiesis in zebrafish. Mechanistically, the aptamers functioned as full terc; that is, they increased the expression of master myeloid genes, independently of endogenous terc, by interacting with RNA Pol II and with the terc-binding sequences of the regulatory regions of such genes, enforcing their transcription. Importantly, aptamers harboring the CR4/CR5 mutation that was found in DC patients failed to perform all these functions. The therapeutic potential of the aptamers for treating neutropenia was demonstrated in several preclinical models. The findings of this study have identified two potential therapeutic agents for DC and other neutropenic patients.

Implementing medical abortion through telemedicine in Colombia: a qualitative study.

The non-governmental organisation Profamilia developed and implemented medical abortion through telemedicine in response to the Covid-19 pandemic. This service is now integrated as an alternative to in-person care and available to abortion-seekers across Colombia. Previous research has emphasised bottlenecks in abortion provision, but less is known about implementation processes and experiences. We assessed the feasibility and acceptability of telemedicine for medical abortion from the perspectives of key informants involved in the implementation in Colombia. We conducted 15 in-depth interviews with healthcare professionals, coordinators and support staff implementing telemedicine for medical abortion in the early phase of implementation, between March and October 2021. We analysed the data using the framework method and applied the normalisation process theory in our analysis and interpretation of findings. Our findings show that strong leadership, organisational efforts on pre-implementation training, monitoring and evaluation, and collaboration between diversely skilled and experienced providers are essential for successful implementation. Participants were generally positive towards the use of telemedicine for medical abortion; concerns related to effectiveness, safety and safeguarding existed mainly among providers with less clinical experience. We identified contextual barriers, such as social opposition, regulatory barriers, providers' unavailability, and poor phone and internet connections in rural areas, which impacted the feasibility of the intervention negatively. In conclusion, to ensure stakeholders' buy-in and for the service to reach all abortion seekers in need, future implementation endeavours must address concerns about safety and effectiveness, and tackle identified contexual barriers.Plain Language SummaryIn telemedicine for medical abortion, all or some components of abortion care, such as initial consultations, home delivery of abortion medication, and post-abortion follow up are provided with the use of telecommunications. Telemedicine for medical abortion has been shown to be a safe and effective form of service delivery.In this study, we interviewed 15 healthcare providers and staff involved in the implementation of a telemedicine service for medical abortion in Colombia to determine whether they deemed the service to be acceptable and feasible. We found that collaboration between providers of different backgrounds and levels of experience, appropriate training and strong leadership were key factors for successfully implementing the service. However, some healthcare providers, especially those with less clinical experience, were concerned that telemedicine for medical abortion may not be safe and may risk the health and well-being of abortion-seekers. Further, social opposition to abortion, unclear regulation and limited access to technology were identified as barriers that need to be addressed to ensure the service reaches all abortion-seekers in need.In conclusion, despite contextual barriers and some provider's concerns about medical safety, telemedicine for medical abortion was viewed as a positive and feasible form of service delivery in Colombia.

Sex differences in stress responses among underrepresented minority adolescents at risk for substance use disorder.

Adolescence is a period of dramatic physiological changes preparing individuals to face future challenges. Prolonged exposure to stressors during childhood can result in dysregulated stress systems which alter normative physiological progression, leading to exacerbated risk for developing psychiatric disorders. Parental substance use disorder (SUD) is considered a significant childhood stressor which increases risk for the offspring to develop SUD. Thus, it is important to understand stress reactivity among adolescents with parental SUD. We used the Trier Social Stress Task (TSST), which includes a public speech presentation, as an acute stressor. Changes in heart-rate (HR) were measured while disadvantaged minority adolescents with and without a family history (FH+/FH-) of SUD performed the TSST. We investigated sex-specific stress response patterns during the TSST. HR peaked during the speech presentation and was overall higher in females than males. Changes in HR measures between baseline and speech showed an interaction between biological sex and FH group. Specifically, FH- females and FH+ males had significantly larger positive HR changes than FH- males. These results suggest that male and female adolescents with parental SUD have atypical, but divergent changes in stress reactivity that could explain their increased risk for developing SUD via different sexually dimorphic mechanisms.

NAMPT and PARylation Are Involved in the Pathogenesis of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease of very high prevalence, especially in childhood, with no specific treatment or cure. As its pathogenesis is complex, multifactorial and not fully understood, further research is needed to increase knowledge and develop new targeted therapies. We have recently demonstrated the critical role of NAD+ and poly (ADP-ribose) (PAR) metabolism in oxidative stress and skin inflammation. Specifically, we found that hyperactivation of PARP1 in response to DNA damage induced by reactive oxygen species, and fueled by NAMPT-derived NAD+, mediated inflammation through parthanatos cell death in zebrafish and human organotypic 3D skin models of psoriasis. Furthermore, the aberrant induction of NAMPT and PARP activity was observed in the lesional skin of psoriasis patients, supporting the role of these signaling pathways in psoriasis and pointing to NAMPT and PARP1 as potential novel therapeutic targets in treating skin inflammatory disorders. In the present work, we report, for the first time, altered NAD+ and PAR metabolism in the skin of AD patients and a strong correlation between NAMPT and PARP1 expression and the lesional status of AD. Furthermore, using a human 3D organotypic skin model of AD, we demonstrate that the pharmacological inhibition of NAMPT and PARP reduces pathology-associated biomarkers. These results help to understand the complexity of AD and reveal new potential treatments for AD patients.

Evolution of LPS recognition and signaling: The bony fish perspective.

Fish are the most diverse and successful group of vertebrate animals, with about 30,000 species. The study of fish immunity is of great importance for understanding the evolution of vertebrate immunity, as they are the first animals to show both innate and adaptive immune responses. Although fish immunity is similar to that of mammals, there are obvious differences, such as their dependence of ambient temperature, their poor antibody response, and lack of antibody switching and lymph nodes. In addition, several important differences have also been found between the innate immune responses of fish and mammals. Among these, we will discuss in this review the high resistance of fish to the toxic effects of lipopolysaccharide (LPS) which can be explained by the absence of a Toll-like receptor 4 (Tlr4) ortholog in most fish species or by the inability of the Tlr4/Md2 (Myeloid differentiation 2) complex to recognize LPS, together with the presence of a negative regulator of the LPS signaling complex formed by the TLR-like molecule Rp105 (Radioprotective 105) and Md1. Taken together, these data support the idea that, although TLR4 and RP105 arose from a common ancestor to fish and tetrapods, the TLR4/MD2 receptor complex for LPS recognition arose after their divergence about 450 million years ago.

Dual Role of DUOX1-Derived Reactive Oxygen Species in Melanoma.

Melanoma is the most serious type of skin cancer. Inflammation and oxidative stress play an essential role in the development of several types of cancer, including melanoma. Although oxidative stress promotes tumor growth, once cells escape from the primary tumor, they are subjected to a more hostile environment, with higher levels of oxidative stress typically killing most cancer cells. As Dual Oxidase 1 (DUOX1) is a major producer of reactive oxygen species (ROS) in epithelia, we used allotransplantation and autochthonous melanoma models in zebrafish together with in silico analysis of the occurrence and relevance of DUOX1 expression of the skin cutaneous melanoma (SKCM) cohort of The Cancer Genome Atlas (TCGA) to address the role of this enzyme in the aggressiveness of melanoma cells in vivo. It was found that high transcript levels of the gene encoding DUOX1 were associated with the poor prognosis of patients in the early-stage melanoma of TCGA cohort. However, DUOX1 transcript levels were not found to be associated to the prognosis of late-stage SKCM patients. In addition, the transcript level of DUOX1 in metastatic SKCM was lower than in primary SKCM. Using zebrafish primary melanoma and allotransplantation models, we interrogated the role of DUOX1 in vivo. Our results confirmed a dual role of DUOX1, which restrains melanoma proliferation but promotes metastasis. As this effect is only observed in immunocompromised individuals, the immune system appears to be able to counteract this elevated metastatic potential of DUOX1-deficient melanomas.

Nocardiosis pulmonar y del sistema nervioso central: el alcoholismo como factor de inmunocompromiso / Pulmonary and central nervous system nocardiosis: Alcoholism as an immunocompromising factor

La nocardiosis es una enfermedad de distribución mundial; de forma habitual se encuentra en zonas tropicales y afecta principalmente a pacientes inmunocomprometidos, sin embargo, también existen casos reportados de infección en personas inmunocompetentes. Esta infección es causada por actinomicetos del género Nocardia spp. que son bacterias Gram positivas, saprófitos ambientales. Aunque la exposición a Nocardia spp. es casi universal, solo una pequeña fracción de las personas expuestas desarrollan la enfermedad. Se presenta el caso de un hombre de 47 años, sin dato de inmunosupresión, procedente de un área rural de Boyacá, que consultó por un cuadro clínico de cefalea intensa e intermitente, con parestesias y, finalmente, alteración del estado de conciencia. Se practicó una resonancia magnética cerebral, en la que se evidenció una lesión que ocupaba espacio de localización córtico-subcortical en la región fronto-témporo-parietal izquierda, con efecto compresivo y desplazamiento de las cavidades del sistema ventricular. Se sospechó, inicialmente, una lesión neoplásica o un absceso cerebral. El paciente fue sometido a una resección quirúrgica, y el cultivo de la lesión documentó Nocardia africana/nova; en estudios posteriores, se evidenció un posible foco pulmonar primario. Como único factor de riesgo en el paciente, se documentó alcoholismo. Completó seis semanas de tratamiento antibiótico intrahospitalario con evolución clínica y radiológica, y egresó con plan de un año de terapia antibiótica ambulatoria. Aunque la enfermedad por Nocardia spp. afecta principalmente a pacientes inmunocomprometidos, la "evidencia" clínica demuestra que este microorganismo también puede ser una amenaza para individuos sin los factores de riesgo tradicionales para inmunosupresión.

Nocardiosis is a disease with worldwide distribution. It is usually found in tropical areas and mainly affects immunocompromised patients, however, there are also cases where its infection has been reported in immunocompetent patients. This pathology is caused by bacteria known as Nocardia spp., which are gram-positive microorganisms and environmental saprophytes, and although exposure to Nocardia spp. is almost universal, only a small fraction of exposed people develops the disease. We present the case of a 47-year-old man, with no evidence of immunosuppression, from a rural area of Boyacá, who was admitted due to intense and intermittent headache accompanied by paresthesia and, finally, a decrease in consciousness. A brain magnetic resonance was performed and evidenced a fronto-temporo- occipital space-occupying lesion in the cortico-subcortical region with a compressive effect and displacement of the ventricular system cavities. It was suspected at first a neoplastic lesion or a brain abscess. The lesion was surgically resected, and its culture showed Nocardia africana/nova. In later studies a possible primary pulmonary focus was evidenced. Alcoholism was the only risk factor documented. The patient completed 6 weeks of hospital antibiotic treatment with favorable clinical and radiological evolution and was discharged with a 1-year plan of outpatient antibiotic therapy. Although Nocardia spp. mainly affects immunocompromised patients, evidence shows that this microorganism can also be a threat to individuals without traditional immunosuppression risk factors.

Connectivity based Real-Time fMRI Neurofeedback Training in Youth with a History of Major Depressive Disorder.

BACKGROUND: Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) has proven to be a powerful technique to help subjects to gauge and enhance emotional control. Traditionally, rtfMRI-nf has focused on emotional regulation through self-regulation of amygdala. Recently, rtfMRI studies have observed that regulation of a target brain region is accompanied by connectivity changes beyond the target region. Therefore, the aim of present study is to investigate the use of connectivity between amygdala and prefrontal regions as the target of neurofeedback training in healthy individuals and subjects with a life-time history of major depressive disorder (MDD) performing an emotion regulation task. METHOD: Ten remitted MDD subjects and twelve healthy controls (HC) performed an emotion regulation task in 4 runs of rtfMRI-nf training followed by one transfer run without neurofeedback conducted in a single session. The functional connectivity between amygdala and prefrontal cortex was presented as a feedback bar concurrent with the emotion regulation task. Participants' emotional state was measured by the Positive and Negative Affect Schedule (PANAS) prior to and following the rtfMRI-nf. Psychological assessments were used to determine subjects' history of depression. RESULTS: Participants with a history of MDD showed a trend of decreasing functional connectivity across the four rtfMRI-nf runs, and there was a marginally significant interaction between the MDD history and number of training runs. The HC group showed a significant increase of frontal cortex activation between the second and third neurofeedback runs. Comparing PANAS scores before and after connectivity-based rtfMRI-nf, we observed a significant decrease in negative PANAS score in the whole group overall, and a significant decrease in positive PANAS score in the MDD group alone.

Zebrafish models of COVID-19.

Although COVID-19 has only recently appeared, research studies have already developed and implemented many animal models for deciphering the secrets of the disease and provided insights into the biology of SARS-CoV-2. However, there are several major factors that complicate the study of this virus in model organisms, such as the poor infectivity of clinical isolates of SARS-CoV-2 in some model species, and the absence of persistent infection, immunopathology, severe acute respiratory distress syndrome, and, in general, all the systemic complications which characterize COVID-19 clinically. Another important limitation is that SARS-CoV-2 mainly causes severe COVID-19 in older people with comorbidities, which represents a serious problem when attempting to use young and immunologically naïve laboratory animals in COVID-19 testing. We review here the main animal models developed so far to study COVID-19 and the unique advantages of the zebrafish model that may help to contribute to understand this disease, in particular to the identification and repurposing of drugs to treat COVID-19, to reveal the mechanism of action and side-effects of Spike-based vaccines, and to decipher the high susceptibility of aged people to COVID-19.

Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats: A short report.

Remdesivir is a leading therapy in patients with moderate to severe coronavirus 2 (SARS-CoV-2) infection; the majority of whom are older individuals. Remdesivir is a nucleoside analog that incorporates into nascent viral RNA, inhibiting RNA-directed RNA polymerases, including that of SARS-CoV-2. Less is known about remdesivir's effects on mitochondria, particularly in older adults where mitochondria are known to be dysfunctional. Furthermore, its effect on age-induced mitochondrial mutations and copy number has not been previously studied. We hypothesized that remdesivir adversely affects mtDNA copy number and deletion mutation frequency in aged rodents. To test this hypothesis, 30-month-old male F333BNF1 rats were treated with remdesivir for three months. To determine if remdesivir adversely affects mtDNA, we measured copy number and mtDNA deletion frequency in rat hearts, kidneys, and skeletal muscles using digital PCR. We found no effects from three months of remdesivir treatment on mtDNA copy number or deletion mutation frequency in 33-month-old rats. These data support the notion that remdesivir does not compromise mtDNA quality or quantity at old age in mammals. Future work should focus on examining additional tissues such as brain and liver, and extend testing to human clinical samples.

Morphological and anatomical characterization of yellow diploid potato flower for effective breeding program.

The diploid yellow potato (Solanum tuberosum L. Phureja Group) is an important plant genetic resource. In this study, we report for the first time the characterization of anther development and pollen formation in the cultivar Criolla Colombia. The description of morphological and histological characters of buds and flowers at different developmental stages permitted to identify ten main stages, from the differentiation of the male cells of the sporangium, meiosis, microspores formation and maturation, to the release of mature pollen. In addition, the results provide a graphic guide of the development of the anther, through the sequential and orderly formation of the epidermis, the endothecium, the middle layer and the nutritive layer or tapetum. This microanatomical information will be useful for work focused on androgenesis and identification of gene regulation in floral biology and gamete formation. Therefore, this study determined that to efficiently obtain haploids, flower buds between 5 and 8.9 mm long (stage 6 to 8) should be used, in which tetrads and microspores are in the early uninucleate and binucleate stage.

Differential proinflammatory activities of Spike proteins of SARS-CoV-2 variants of concern.

The coronavirus disease 2019 (COVID-19) pandemic turned the whole world upside down in a short time. One of the main challenges faced has been to understand COVID-19-associated life-threatening hyperinflammation, the so-called cytokine storm syndrome (CSS). We report here the proinflammatory role of Spike (S) proteins from different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern in zebrafish. We found that wild-type/Wuhan variant S1 (S1WT) promoted neutrophil and macrophage recruitment, local and systemic hyperinflammation, emergency myelopoiesis, and hemorrhages. In addition, S1γ was more proinflammatory S1δ was less proinflammatory than S1WT, and, notably, S1ß promoted delayed and long-lasting inflammation. Pharmacological inhibition of the canonical inflammasome alleviated S1-induced inflammation and emergency myelopoiesis. In contrast, genetic inhibition of angiotensin-converting enzyme 2 strengthened the proinflammatory activity of S1, and angiotensin (1-7) fully rescued S1-induced hyperinflammation and hemorrhages. These results shed light into the mechanisms orchestrating the COVID-19-associated CSS and the host immune response to different SARS-CoV-2 S protein variants.

Cultural and ethnobotanical legacy of native potatoes in Colombia.

BACKGROUND: Native potatoes are Andean tubers of great historical, social, food, genetic and nutritional importance, and they contribute significantly to food security by supplementing the household diet and also providing alternative income. Even when their cultivation and consumption imply great benefits, their use and local preservation depend to a large extent on the recognition of their ethnobotanical and cultural importance. In this context, this study consolidates an important ethnobotanical research bases for native potatoes in Colombia. METHODS: The study collected data through semi-structured interviews and dialogues (130) in the municipality of Chiscas, department of Boyacá, central-eastern Colombia. The questionnaire was focused on native potatoes and sought to investigate the knowledge related to cultivation, diversity, patterns and forms of preparation for use and consumption. Likewise, knowledge heritability mechanisms were investigated and ethnobotanical indices of relative importance, use and culture were estimated. RESULTS: Documentation of ethnobotanical knowledge included aspects such as seed care and availability, cultural management of the crop, patterns of use and consumption, as well as ways of preparing the tubers. In total, 23 vernacular names of native potato and 360 reports of use (commercial, domestic or ritual-magical) were recorded for the 15 main genotypes. Quantitative estimates included the importance index: (a) cultural, for which values ranged between 0.059 and 0.812; (b) relative, with records between 0.04 and 0.43; and (c) use, which ranged between 0.06 and 0.63. The ethnobotanical importance index (d) for native potatoes was 57.26, which corresponds to a "very high" ethnobotanical value. This allowed us to identify that Criollas were the most recognized and used potatoes within the community. In addition, it was shown that vertical transmission is the main way in which traditional knowledge about native potatoes is inherited. Finally, an artificial intelligence tool was preliminarily implemented to identify the polarity generated in the interviewees by the questions. CONCLUSION: The results of this research provide valuable information on the ethnobotany of native potatoes in Colombia. The genotypes used by the community of the municipality of Chiscas were recognized for their high gastronomic and nutritional potential, as well as for their great ethnobotanical and cultural importance. These data can be considered as a valuable tool to support any action aimed at the conservation and revaluation of these tubers.

Peroxisome proliferator-activated receptors alpha and beta mediate the anti-inflammatory effects of the cyclopentenone prostaglandin 15-deoxy-Δ12,14-PGJ2 in fish granulocytes.

Prostaglandins (PGs) are highly reactive small lipophilic molecules derived from polyunsaturated fatty acids of the cell membrane and play a key role in the resolution of inflammation processes. 15-deoxy-Δ12,14-PGJ2 (15dPGJ2) is a cyclopentenone PG (CyPG) of the J series with anti-inflammatory, anti-proliferative and pro-apoptotic effects. This CyPG can signal through: (i) the PGD2 receptor (DP2) and peroxisome proliferator-activated receptor γ (PPARγ) or (ii) by covalent binding to protein nucleophiles, such as, thiols groups of cysteine, lysine or histidine via a Michael addition reaction, modifying its structure and function. In this work we show that acidophilic granulocytes (AGs) of gilthead seabream (Sparus aurata L.), the functional equivalent to mammalian neutrophils, constitutively expressed ppara, pparb and pparg genes, the latter showing the highest expression and up-regulation when stimulated by bacterial DNA. In addition, we tested the ability of 15dPGJ2, and its biotinylated analog, as well as several PPARγ ligands, to modulate reactive oxygen species (ROS) and/or cytokines production during a Toll like receptor (TLR)-mediated granulocyte response. Thus, 15dPGJ2 was able to significantly decrease bacterial DNA-induced ROS production and transcript levels of pparg, interleukin-1ß (il1b) and prostaglandin-endoperoxide synthase 2 (ptgs2). In contrast, its biotinylated analog was less potent and a higher dose was required to elicit the same effects on ROS production and cytokine expression. In addition, different PPARγ agonists were able to mimic the effects of 15dPGJ2. Conversely, the PPARγ antagonist T007097 abolished the effect of 15dPGJ2 on DNA bacterial-induced ROS production. Surprisingly, transactivation assays revealed that both 15dPGJ2 and its biotinylated analog signaled via Pparα and Pparß, but not by Pparγ. These results were further confirmed by HPLC/MS analysis, where Pparß was identified as an interactor of biotin-15dPGJ2 in naïve and DNA-stimulated leukocytes. Taken together, our data show that 15dPGJ2 acts both through Ppar activation and covalent binding to proteins in fish granulocytes and identify for the first time in vertebrates a role for Pparα and Pparß in the resolution of inflammation mediated by 15dPGJ2.

Zebrafish Models to Study the Crosstalk between Inflammation and NADPH Oxidase-Derived Oxidative Stress in Melanoma.

Melanoma is the deadliest form of skin cancer, and its incidence continues to increase. In the early stages of melanoma, when the malignant cells have not spread to lymph nodes, they can be removed by simple surgery and there is usually low recurrence. Melanoma has a high mortality rate due to its ability to metastasize; once melanoma has spread, it becomes a major health complication. For these reasons, it is important to study how healthy melanocytes transform into melanoma cells, how they interact with the immune system, which mechanisms they use to escape immunosurveillance, and, finally, how they spread and colonize other tissues, metastasizing. Inflammation and oxidative stress play important roles in the development of several types of cancer, including melanoma, but it is not yet clear under which conditions they are beneficial or detrimental. Models capable of studying the relevance of inflammation and oxidative stress in the early steps of melanocyte transformation are urgently needed, as they are expected to help recognize premetastatic lesions in patients by improving both early detection and the development of new therapies.

Changes in appetite during quarantine and their association with pre-COVID-19 mental and physical health.

BACKGROUND: The COVID-19 Pandemic resulted in high levels of fear, anxiety, and stress. People with pre-existing physical and mental health conditions may have been more affected by the sudden changes in daily habits during the initial months of global quarantine imposed during the COVID-19 pandemic. METHODS: We designed the Quarantine, Anxiety, and Diet (QUAD) Survey to investigate the effect of pre-existing health conditions on the relationship of COVID-19 stress and food behavior. The anonymous survey was distributed online and only adults were eligible to participate. RESULTS: The results showed that responders with pre-existing health conditions differed from healthy participants in eating behavior during this time of stress. Compared to those classified as healthy, fewer people with pre-existing physical illness showed an increase in appetite with stress during the COVID-19 pandemic. Responders with pre-existing psychiatric illness were more likely to show increases or decreases in appetite with stress compared to healthy responders. Furthermore, higher BMI was associated with higher rate of increased appetite, whereas low BMI showed a higher rate of decreased appetite, both compared to normal BMI. CONCLUSION: The QUAD Survey demonstrated that individuals with pre-COVID-19 psychiatric conditions are at a higher risk of maladaptive food behavior under stress. Since pre-existing psychiatric illnesses and acute stressors are known risk factors for eating disorders, special attention should be placed on those at risk to mediate the psychological and physical effects of stress and anxiety.