Risk of anti-TNF therapy on pregnancy, breastfeeding, live vaccines and related information in patients with inflammatory bowel disease: Real-world data from a nationwide study.

BACKGROUND: Anti-TNF are usually maintained during pregnancy in patients with inflammatory bowel disease (IBD) but safety is still a concern for them. AIMS: To provide data on management of anti-TNF agents during pregnancy, safety of live vaccines (BCG-MMR-rotavirus) and breastfeeding in newborns and dedicated information delivered to IBD women. METHODS: We performed an observational study in 25 centers from 2016 to 2018. We administered questionnaires to women with IBD receiving anti-TNF during pregnancy with newborn follow-up ≥ one year. RESULTS: Of 153 patients, 52 % maintained anti-TNF during the third trimester. Anti-TNF was shortly resumed in 79 % (58/73) after delivery. The rate of breastfeeding was 44 % (68/153) without any complication; 38 % of the mothers denied to breastfeed based on physician's advice. 26 % (34/129) of the newborns received live vaccines before 6 months-old (BCG:30 %; MMR:63 %; Rotavirus:8 %) and only 3 complications occurred (local BCGitis=1, fever=2). Information concerning anti-TNF during pregnancy/post-partum was delivered to 92 % of the patients, mainly by a gastroenterologist (97 %) who discussed with the obstetrician or the paediatrician in only 48 % and 25 %. CONCLUSION: In IBD patients, maintaining anti-TNF during pregnancy and breastfeeding is safe. Accidental live vaccines before 6 months did not lead to significant adverse events. The communication about these questions remains to improve.

Synchronic distribution of the dinoflagellate Protoceratium reticulatum and yessotoxins in a high stratified fjord system: Tidal or light modulation?

Protoceratium reticulatum is the main yessotoxin-producer along the Chilean coast. Thus far, the yessotoxin levels recorded in this region have not posed a serious threat to human health. However, a bloom of P. reticulatum during the austral summer of 2022 caused the first ban of shellfish collection, due to the high toxin levels. A bloom of P. reticulatum during the austral summer of 2020 allowed an evaluation of the fine-scale distribution of the dinoflagellate during a tidal cycle. High-resolution measurements of biophysical properties were carried out in mid-summer (February 18-19) at a fixed sampling station in Puyuhuapi Fjord, Chilean Patagonia, as part of an intensive 24-h biophysical experiment to monitor the circadian distributions of P. reticulatum vegetative cells and yessotoxins. High P. reticulatum cell densities (>20 × 103 cells L-1) were found in association with a warmer (14.5-15 °C) and estuarine (23.5-24.5 g kg-1) sub-surface water layer (6-8 m). P. reticulatum cell numbers and yessotoxins followed a synchronic distribution pattern consistent with the excursions of the pycnocline. Nevertheless, the surface aggregation of the cells was modulated by the light cycle, suggesting daily vertical migration. The yessotoxin content per P. reticulatum cell ranged from 9.4 to 52.2 pg. This study demonstrates both the value of fine-scale resolution measurements of biophysical properties in a highly stratified system and the potential ecosystem impact of P. reticulatum strains producing high levels of yessotoxins.

Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer.

Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. SIGNIFICANCE: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.

Pediatric emergency department-based asthma education tools and parent/child asthma knowledge.

Asthma exacerbations are a leading cause of pediatric hospitalizations despite multiple efforts to educate patients and families on disease course and medication management. Asthma education in the pediatric emergency department (ED) is challenging, and although the use of written action plans has been associated with reduction in hospitalizations and ED visits, written tools may not be useful for individuals with low health literacy. Moreover, asthmatic children should participate in their asthma education. In this prospective randomized study of 53 families presenting to a pediatric ED with a child experiencing an asthma exacerbation, education on asthma was presented via an interactive mobile-based video-game versus a standard-of-care asthma education video (SAV). Median age was 10 years; 64% were males. Many patients had moderate-to-severe asthma, with 57% experiencing ≥ 2 asthma-related ED visits in the last year, 58% requiring hospitalization and 32% reporting a critical care admission. In this cohort, the mobile-based video-game was found to be a feasible, acceptable educational tool; 86% of parents and 96% of children liked the game, while 96% of parents and 76% of children preferred playing the game over watching a SAV. Despite a history of persistent asthma, only 34% of children used an inhaled corticosteroid while 70% required rescue inhaler use in the prior week. Basic asthma knowledge was sub-optimal with only 60% of parents and 43% of children correctly recognizing symptoms that should prompt immediate medical care. This reflects a major gap in asthma knowledge that coexists with parental misconceptions regarding optimal asthma management.

Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial-Efficacy and Biomarker Discovery.

PURPOSE: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. PATIENTS AND METHODS: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy "graduates" if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. RESULTS: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. CONCLUSIONS: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

Protein signaling and drug target activation signatures to guide therapy prioritization: Therapeutic resistance and sensitivity in the I-SPY 2 Trial.

Molecular subtyping of breast cancer is based mostly on HR/HER2 and gene expression-based immune, DNA repair deficiency, and luminal signatures. We extend this description via functional protein pathway activation mapping using pre-treatment, quantitative expression data from 139 proteins/phosphoproteins from 736 patients across 8 treatment arms of the I-SPY 2 Trial (ClinicalTrials.gov: NCT01042379). We identify predictive fit-for-purpose, mechanism-of-action-based signatures and individual predictive protein biomarker candidates by evaluating associations with pathologic complete response. Elevated levels of cyclin D1, estrogen receptor alpha, and androgen receptor S650 associate with non-response and are biomarkers for global resistance. We uncover protein/phosphoprotein-based signatures that can be utilized both for molecularly rationalized therapeutic selection and for response prediction. We introduce a dichotomous HER2 activation response predictive signature for stratifying triple-negative breast cancer patients to either HER2 or immune checkpoint therapy response as a model for how protein activation signatures provide a different lens to view the molecular landscape of breast cancer and synergize with transcriptomic-defined signatures.

Contribution of the satellitome to the exceptionally large genome of dinoflagellates: The case of the harmful alga Alexandrium minutum.

Dinoflagellates are known to possess an exceptionally large genome organized in permanently condensed chromosomes. Focusing on the contribution of satellite DNA (satDNA) to the whole DNA content of genomes and its potential role in the architecture of the chromosomes, we present the characterization of the satellitome of Alexandriun minutum strain VGO577. To achieve this, we analyzed Illumina reads using graph-based clustering and performed complementary bioinformatic analyses. In this way, we discovered 180 satDNAs occupying 17.38 % of the genome. The 12 most abundant satDNAs represent the half of the satellitome but no satDNA is overrepresented, with the most abundant contributing ∼1.56 % of the genome. The largest repeat unit is 517 bp long but more than the half of the satDNAs (101) have repeat units shorter than 20 bp. We used FISH to map a selected set of 26 satDNAs. Although some satDNAs generate discrete hybridization signals at specific chromosomal locations (hybridization sites, HS), our cytological analysis showed that most satDNAs are dispersed throughout the genome, probably forming short arrays. Two satDNAs co-localize with the 45S rDNA. With the exception of telomeric DNA, no other satDNA yields HS on all chromosomes. In addition, we analyzed nine satDNAs yielding HS in VGO577 in four other A. minutum strains. Polymorphism at the intraspecific level was found for the presence/absence and/or abundance of some satDNAs, suggesting the amplification/deletion of these satDNAs following geographic separation or during culture maintenance of the strains. We also discuss how these results contribute to the understanding of chromosome architecture and evolution of dinoflagellate genomes.

Decreased Pyruvate but Not Fatty Acid Driven Mitochondrial Respiration in Skeletal Muscle of Growth Restricted Fetal Sheep.

Fetuses with intrauterine growth restriction (FGR) have impaired oxidative and energy metabolism, with persistent consequences on their postnatal development. In this study, we test the hypothesis that FGR skeletal muscle has lower mitochondrial respiration rate and alters the transcriptomic profiles associated with energy metabolism in an ovine model. At late gestation, mitochondrial oxygen consumption rates (OCRs) and transcriptome profiles were evaluated in the skeletal muscle collected from FGR and control fetuses. The ex vivo mitochondrial OCRs were reduced (p < 0.01) in permeabilized FGR soleus muscle compared to the control muscle but only with pyruvate as the metabolic substrate. Mitochondrial OCRs were similar between the FGR and control groups for palmitoyl-carnitine (fatty acid-driven) or pyruvate plus palmitoyl-carnitine metabolic substrates. A total of 2284 genes were differentially expressed in the semitendinosus muscle from growth restricted fetuses (false discovery rate (FDR) ≤ 0.05). A pathway analysis showed that the upregulated genes (FGR compared to control) were overrepresented for autophagy, HIF-1, AMPK, and FOXO signaling pathways (all with an FDR < 0.05). In addition, the expression of genes modulating pyruvate's entry into the TCA cycle was downregulated, whereas the genes encoding key fatty acid oxidation enzymes were upregulated in the FGR muscle. These findings show that FGR skeletal muscle had attenuated mitochondrial pyruvate oxidation, possibly associated with the inability of pyruvate to enter into the TCA cycle, and that fatty acid oxidation might compensate for the attenuated energy metabolism. The current study provided phenotypic and molecular evidence for adaptive deficiencies in FGR skeletal muscle.

Intelligent Care Management for Diabetic Foot Ulcers: A Scoping Review of Computer Vision and Machine Learning Techniques and Applications.

Ten percent of adults in the United States have a diagnosis of diabetes and up to a third of these individuals will develop a diabetic foot ulcer (DFU) in their lifetime. Of those who develop a DFU, a fifth will ultimately require amputation with a mortality rate of up to 70% within five years. The human suffering, economic burden, and disproportionate impact of diabetes on communities of color has led to increasing interest in the use of computer vision (CV) and machine learning (ML) techniques to aid the detection, characterization, monitoring, and even prediction of DFUs. Remote monitoring and automated classification are expected to revolutionize wound care by allowing patients to self-monitor their wound pathology, assist in the remote triaging of patients by clinicians, and allow for more immediate interventions when necessary. This scoping review provides an overview of applicable CV and ML techniques. This includes automated CV methods developed for remote assessment of wound photographs, as well as predictive ML algorithms that leverage heterogeneous data streams. We discuss the benefits of such applications and the role they may play in diabetic foot care moving forward. We highlight both the need for, and possibilities of, computational sensing systems to improve diabetic foot care and bring greater knowledge to patients in need.

Elevated Norepinephrine Stimulates Adipocyte Hyperplasia in Ovine Fetuses With Placental Insufficiency and IUGR.

Prevailing hypoxemia and hypoglycemia in near-term fetuses with placental insufficiency-induced intrauterine growth restriction (IUGR) chronically increases norepinephrine concentrations, which lower adrenergic sensitivity and lipid mobilization postnatally, indicating a predisposition for adiposity. To determine adrenergic-induced responses, we examined the perirenal adipose tissue transcriptome from IUGR fetuses with or without hypercatecholaminemia. IUGR was induced in sheep with maternal hyperthermia, and hypercatecholaminemia in IUGR was prevented with bilateral adrenal demedullation. Adipose tissue was collected from sham-operated control (CON) and IUGR fetuses and adrenal-demedullated control (CAD) and IUGR (IAD) fetuses. Norepinephrine concentrations were lower in IAD fetuses than in IUGR fetuses despite both being hypoxemic and hypoglycemic. In IUGR fetuses, perirenal adipose tissue mass relative to body mass was greater compared with the CON, adrenal-demedullated control, and IAD groups. Transcriptomic analysis identified 581 differentially expressed genes (DEGs) in CON vs IUGR adipose tissue and 193 DEGs in IUGR vs IAD adipose tissue. Integrated functional analysis of these 2 comparisons showed enrichment for proliferator-activated receptor signaling and metabolic pathways and identified adrenergic responsive genes. Within the adrenergic-regulated DEGs, we identified transcripts that regulate adipocyte proliferation and differentiation: adipogenesis regulatory factor, C/CCAAT/enhancer binding protein α, and sterol carrier protein 2. DEGs associated with the metabolic pathway included pyruvate dehydrogenase kinase 4, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4, IGF-binding proteins (IGFBP-5 and IGFBP-7). Sex-specific expression differences were also found for adipogenesis regulatory factor, pyruvate dehydrogenase kinase 4, IGFBP5, and IGFBP7. These findings indicate that sustained adrenergic stimulation during IUGR leads to adipocyte hyperplasia with alterations in metabolism, proliferation, and preadipocyte differentiation pathways.

Small and patchy is enough: An example about how toxic HAB events can spread through low resting cyst loads.

The frequency of harmful algal blooms (HABs) has increased over the last two decades, a phenomenon enhanced by global climate change. However, the effects of climate change will not be distributed equally, and Chile has emerged as one important, vulnerable area. The Chilean Patagonian region (41‒56°S) hosts two marine ecoregions that support robust blue economies via wild fisheries, aquaculture, and tourism. However, the harmful algal bloom-forming dinoflagellate Alexandrium catenella, a causative agent of paralytic shellfish poisoning outbreaks, threatens the viability of blue industries in this region and others worldwide. Despite the proliferation of A. catenella blooms over the last few decades, the role of sedimentary resting cysts in the recurrence of harmful algal blooms and the species' northward expansion across Chilean Patagonia is not well understood. As a resting cyst-producing species, the sediment-cyst dynamics of A. catenella likely contribute to the geographical expansion and bloom recurrence of this species. For this purpose, we analyzed a decade of A. catenella surface sediment cyst records across the two ecoregions of the Chilean Patagonian System that were further stratified into five subregions based on water temperature, salinity, dissolved oxygen, and nutrient characteristics. We also analyzed spatio-temporal cyst dynamics in a pre-, during-, and post-bloom scenario of the Chiloense ecoregion (more northern) of the Magellanic province. Our results indicated highly variable A. catenella resting cyst abundances, with a maximum of 221 cysts cm-3 recorded in 2002 after an intense bloom. Generalized linear mixed models and linear mixed models found that sampling season, subregion, and Total Organic Matter (%) explained resting cyst presence and density. The results also demonstrated the presence of A. catenella cysts in northern subregions, evidencing the northward geographical expansion observed during the last few decades. The risks of A. catenella bloom recurrence from small, patchy resting cyst distributions across broad geographical areas and under changing environmental conditions are discussed.

Decoding clinical and molecular pathways of liver dysfunction in Psoriatic Arthritis: Impact of cumulative methotrexate doses.

BACKGROUND: The occurrence of liver abnormalities in Psoriatic Arthritis (PsA) has gained significant recognition. Identifying key factors at the clinical and molecular level can help to detect high-risk patients for non-alcoholic fatty liver disease in PsA. OBJECTIVES: to investigate the influence of PsA and cumulative doses of methotrexate on liver function through comprehensive in vivo and in vitro investigations. METHODS: A cross-sectional study involving 387 subjects was conducted, 200 patients with PsA, 87 NAFLD-non-PsA patients, and 100 healthy donors (HDs), age and sex-matched. Additionally, a retrospective longitudinal study was carried out, including 83 PsA patients since initiation with methotrexate. Detailed clinical, and laboratory parameters along with liver disease risk were analyzed. In vitro, experiments with hepatocyte cell line (HEPG2) were conducted. RESULTS: PsA patients present increased liver disease risk associated with the presence of cardiometabolic comorbidities, inflammatory markers, onychopathy, and psoriasis. The treatment with PsA serum on hepatocytes encompassed inflammatory, fibrotic, cell stress, and apoptotic processes. At the molecular level, methotrexate impacts liver biology, although the cumulative doses did not affect those alterations, causing any potential damage to liver function at the clinical level. Finally, anti-PDE-4 or anti-JAK decreased the inflammatory profile induced by PsA serum on hepatocytes. CONCLUSION: 1)This study identifies the complex link between liver disease risk, comorbidities, and disease-specific features in PsA patients. 2)Methotrexate dose in PsA patients had no significant effect on liver parameters, confirmed by hepatocyte in vitro studies. 3)Anti-PDE-4 and anti-JAK therapies show promise in reducing PsA serum-induced hepatocyte activation, potentially aiding liver complication management.

The COVID-19 Pandemic and the Surgical Workload of the UPR-affiliated Hospitals.

OBJECTIVE: To evaluate how the COVID-19 pandemic (declared in March 2020) affected our surgical workload. METHODS: Using the University of Puerto Rico Department of Surgery database, we evaluated the number of surgical cases and their characteristics for the years 2019 through 2021. The variables examined included age, sex, American Society of Anesthesiology classification, type of surgery (elective/emergency), whether the patient had been admitted or was an outpatient, and outcome. RESULTS: The total number of surgical cases decreased 30%, falling from 5,040 in 2019 to 3,564 in 2020, but then increasing about 10% to 3,935 in 2021. The number of elective surgery cases dropped 33%, going from 4,383 in 2019 to 2,924 in 2020. The number of emergency surgeries had a minor decrease of 16%, diminishing from 650 to 546 between 2019 and 2020, inclusive. Patients undergoing elective surgery during 2020 were found to be older, were more frequently men, and required inpatient admission more often. Three significant periods were identified and correlated to the number of surgical cases, the first being the COVID-19 lockdown (March 2020) and the second and third being the increases in infections caused by the Delta and Omicron variants of the virus (July 2021 and December 2021, respectively). CONCLUSION: The COVID-19 pandemic resulted in a significant decrease in the number of surgical cases. Two years after the pandemic, we have not recovered and continue to have fewer surgical cases than we did in 2019.

Mujer y urología: ¿cuál es la situación en España? / Women in urology: What is their current situation in Spain?

Objetivo Analizar la situación actual de las mujeres en la especialidad de Urología en España. Material y métodos Estudio descriptivo a partir de los resultados de una encuesta electrónica remitida entre febrero y abril de 2020 a través de la base de datos del grupo de Residentes y Jóvenes Urólogos (RAEU) de la Asociación Española de Urología (AEU). Se analizaron las características demográficas de la encuesta y los resultados de la misma. Resultados Se obtuvieron 257 respuestas, correspondientes a 210 mujeres (81,71%) y 47 hombres (18,29%) procedentes de 111 hospitales en total. Se obtuvieron diferencias estadísticamente significativas (p<0,001), con una mayor proporción de hombres en todas las categorías, excepto en el grupo de adjuntas y adjuntos jóvenes (29-39años; p=0,789) y en el de residentes mujeres frente a residentes hombres (p=0,814). En los hospitales con unidades subespecializadas se encontró un mayor número de hombres en todas, excepto en la unidad de suelo pélvico, en la que no se observó una diferencia estadísticamente significativa (p=0,06). Respecto a cargos de responsabilidad, en solo 7 de 111 hospitales había jefas de servicio. Conclusiones La presencia de las mujeres en la especialidad de Urología es cada vez mayor, debido mayoritariamente a las generaciones más jóvenes. Sin embargo, el acceso de estas mujeres a puestos de relevancia es anecdótica (AU)

Objective To analyze the current state of women in urology in Spain. Material and methods Descriptive study based on the results of an online survey sent between February and April 2020 through the database of the Residents and Young Urologists group (RAEU) of the Spanish Association of Urology (AEU). Demographic characteristics of the survey and its results were analyzed. Results In total, 257 responses were obtained from 210 women (81.71%) and 47 men (18.29%) belonging to 111 hospitals. Statistically significant differences were observed (P<.001) with a higher proportion of men in all categories except for the group of young female and male attendings (29-39 years, P=.789), and the group of female residents against male residents (P=.814). The number of men was higher in hospitals with subspecialty units except for the Pelvic Floor Unit, where no statistically significant difference was observed (P=.06). Regarding positions of responsibility, only 7 out of 111 hospitals had female department chiefs. Conclusions Women's representation in urology is increasing, mainly due to the younger generations. However, the access of these women to relevant positions is anecdotal (AU)

A New Ultrafine Luminescent La2O3:Eu3+ Aerogel.

This paper reports on the synthesis and characterization of La2O3:Eu3+ luminescent aerogels fabricated by the sol-gel method and the supercritical drying technique. The % mol concentration of the Eu3+ ion was varied to study the effects on the luminescent properties of the aerogels. XRD and TEM analysis showed that the La2O3:Eu3+ aerogels exhibited a semi-crystalline behavior regardless of whether the concentration of europium was increased. SEM micrographs revealed a porous structure in the aerogels, which were composed of quasi-spherical nanoparticles that were interconnected and formed coral-shaped agglomerates. Photoluminescence spectroscopy characterization showed that the aerogels had an infrared emission located at λ = 793 nm, and the maximum photoluminescence emission intensity was observed for the aerogel with 50% Eu3+. The results demonstrate that, without heat treatment, it is possible to manufacture luminescent aerogels of rare-earth oxides that can be used in opto-electronic devices.

Blood Transcriptomic Analyses Reveal Functional Pathways Associated with Thermotolerance in Pregnant Ewes Exposed to Environmental Heat Stress.

Environmental heat stress triggers a series of compensatory mechanisms in sheep that are dependent on their genetic regulation of thermotolerance. Our objective was to identify genes and regulatory pathways associated with thermotolerance in ewes exposed to heat stress. We performed next-generation RNA sequencing on blood collected from 16 pregnant ewes, which were grouped as tolerant and non-tolerant to heat stress according to a physiological indicator. Additional samples were collected to measure complete blood count. A total of 358 differentially expressed genes were identified after applying selection criteria. Gene expression analysis detected 46 GO terms and 52 KEGG functional pathways. The top-three signaling pathways were p53, RIG-I-like receptor and FoxO, which suggested gene participation in biological processes such as apoptosis, cell signaling and immune response to external stressors. Network analysis revealed ATM, ISG15, IRF7, MDM4, DHX58 and TGFßR1 as over-expressed genes with high regulatory potential. A co-expression network involving the immune-related genes ISG15, IRF7 and DXH58 was detected in lymphocytes and monocytes, which was consistent with hematological findings. In conclusion, transcriptomic analysis revealed a non-viral immune mechanism involving apoptosis, which is induced by external stressors and appears to play an important role in the molecular regulation of heat stress tolerance in ewes.

Toxic Algal Bloom Recurrence in the Era of Global Change: Lessons from the Chilean Patagonian Fjords.

Toxic and harmful algal blooms (HABs) are a global problem affecting human health, marine ecosystems, and coastal economies, the latter through their impact on aquaculture, fisheries, and tourism. As our knowledge and the techniques to study HABs advance, so do international monitoring efforts, which have led to a large increase in the total number of reported cases. However, in addition to increased detections, environmental factors associated with global change, mainly high nutrient levels and warming temperatures, are responsible for the increased occurrence, persistence, and geographical expansion of HABs. The Chilean Patagonian fjords provide an "open-air laboratory" for the study of climate change, including its impact on the blooms of several toxic microalgal species, which, in recent years, have undergone increases in their geographical range as well as their virulence and recurrence (the species Alexandrium catenella, Pseudochattonella verruculosa, and Heterosigma akashiwo, and others of the genera Dinophysis and Pseudo-nitzschia). Here, we review the evolution of HABs in the Chilean Patagonian fjords, with a focus on the established connections between key features of HABs (expansion, recurrence, and persistence) and their interaction with current and predicted global climate-change-related factors. We conclude that large-scale climatic anomalies such as the lack of rain and heat waves, events intensified by climate change, promote the massive proliferation of these species by creating ideal conditions for their growth and persistence, as they affect water-column stratification, nutrient inputs, and reproductive rates.

Clinical features and immune mechanisms directly linked to the altered liver function in patients with rheumatoid arthritis.

BACKGROUND: The aim of this study was to explore the impact of arthritis on liver function using different approaches in vivo and in vitro. METHODS: A cross-sectional study was performed on 330 non-obese/non-T2DM subjects: 180 RA patients, 50 NAFLD non-RA patients, and 100 healthy donors (HDs). A longitudinal study was conducted on 50 RA patients treated with methotrexate for six months. Clinical and laboratory parameters and markers of liver disease were collected. Mechanistic studies were carried out in both the CIA mouse model and hepatocytes treated with anti-citrullinated protein antibodies (ACPAs). RESULTS: RA patients have an increased risk of suffering from liver disease independent of obesity or T2DM. This risk was associated with factors such as insulin resistance, autoantibodies, inflammation, and component C3. Methotrexate treatment for six months was associated with liver abnormalities in those newly-diagnosed patients having CV risk factors. ACPAs induced a defective hepatocyte function, promoting IR and inflammation. The induction of arthritis in mice caused the infiltration of immune cells in the liver and increased inflammatory, apoptotic, and fibrotic processes. CONCLUSION: RA patients may experience mild to moderate liver inflammation due to the infiltration of T, B cells, and macrophages, and the action of ACPAs. This is independent of obesity or diabetes and linked to systemic inflammation, and disease activity levels. The negative effects of methotrexate on liver function could be restricted to the concomitant presence of cardiovascular risk factors.

Sexual dimorphic gene expression profile of perirenal adipose tissue in ovine fetuses with growth restriction.

Worldwide, fetal growth restriction (FGR) affects 7%-10% of pregnancies, or roughly 20.5 million infants, each year. FGR increases not only neonatal mortality and morbidity but also the risk of obesity in later life. Currently, the molecular mechanisms by which FGR "programs" an obese phenotype are not well understood. Studies demonstrate that FGR females are more prone to obesity compared to males; however, the molecular mechanisms that lead to the sexually dimorphic programming of FGR are not known. Thus, we hypothesized that FGR leads to the sexually dimorphic programming of preadipocytes and reduces their ability to differentiate into mature adipocytes. To test the hypothesis, we utilized a maternal hyperthermia-induced placental insufficiency to restrict fetal growth in sheep. We collected perirenal adipose tissue from near-term (∼140 days gestation) male and female FGR and normal-weight fetal lambs (N = 4 to 5 in each group), examined the preadipocytes' differentiation potential, and identified differential mRNA transcript expression in perirenal adipose tissue. Male FGR fetuses have a lower cellular density (nuclei number/unit area) compared to control male fetuses. However, no difference was observed in female FGR fetuses compared to control female fetuses. In addition, the ability of preadipocytes to differentiate into mature adipocytes with fat accumulation was impaired in male FGR fetuses, but this was not observed in female FGR fetuses. Finally, we examined the genes and pathways involved in the sexually dimorphic programming of obesity by FGR. On enrichment of differentially expressed genes in males compared to females, the Thermogenesis KEGG Pathway was downregulated, and the Metabolic and Steroid Biosynthesis KEGG pathways were upregulated. On enrichment of differentially expressed genes in male FGR compared to male control, the Steroid Biosynthesis KEGG Pathway was downregulated, and the PPAR Signaling KEGG pathway was upregulated. No pathways were altered in females in response to growth restriction in perirenal adipose tissue. Thus, the present study demonstrates a sexually dimorphic program in response to growth restriction in sheep fetal perirenal adipose tissue.