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Large-scale application of desalination technology can result in impacts to the marine biota, such as phytoplankton and zooplankton, basal components of marine trophic webs. In this context, our perspective aimed to summarize the impacts of effluent discharges from desalination plants on phytoplankton and zooplankton in order to identify the main gaps and challenges in this theme, propose solutions, and provide recommendations for future work. We identified two main approaches to assess the desalination impacts: laboratory experiments and field studies. Most of these studies were conducted in areas impacted by effluent discharges using the BACI (before, after, and control-impact) approach. They primarily aimed to set out the impacts of hypersaline brine on the surrounding environment and, to a lesser extent, the high-temperature effluents and contaminants from desalination plants. Moreover, phytoplankton was more sensitive to effluent discharges than zooplankton. The main changes observed were a decrease in primary productivity, a loss in diversity, and a change in the community structure of planktonic populations due to the dominance of saline-tolerant groups, which highlights the importance improving treatment or dilution of effluent discharges to minimize the impacts over whole neritic trophic webs, which depend on phytoplankton. From the impacts related to effluent discharges analyzed herein, RO technology was related to most cases of negative impact related to salinity modifications. However, coagulants were related to negative effects in all study cases. Future work should focus on escalate the impacts of such effluents on other trophic levels that could be directly or indirectly impacted as well as on how to improve the quality of effluent discharges. Also, we highlight the importance of further baseline and long-term monitoring studies to investigate desalination-induced changes and community resilience to these impacts, as well as studies to provide alternatives to the use of toxic chemicals in the pre-treatment phases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Obesogenic environments such as Westernized diets, overnutrition, and exposure to glycation during gestation and lactation can alter peripheral neuroendocrine factors in offspring, predisposing for metabolic diseases in adulthood. Thus, we hypothesized that exposure to obesogenic environments during the perinatal period reprograms offspring energy balance mechanisms. Four rat obesogenic models were studied: maternal diet-induced obesity (DIO); early-life obesity induced by postnatal overfeeding; maternal glycation; and postnatal overfeeding combined with maternal glycation. Metabolic parameters, energy expenditure, and storage pathways in visceral adipose tissue (VAT) and the liver were analyzed. Maternal DIO increased VAT lipogenic [NPY receptor-1 (NPY1R), NPY receptor-2 (NPY2R), and ghrelin receptor], but also lipolytic/catabolic mechanisms [dopamine-1 receptor (D1R) and p-AMP-activated protein kinase (AMPK)] in male offspring, while reducing NPY1R in females. Postnatally overfed male animals only exhibited higher NPY2R levels in VAT, while females also presented NPY1R and NPY2R downregulation. Maternal glycation reduces VAT expandability by decreasing NPY2R in overfed animals. Regarding the liver, D1R was decreased in all obesogenic models, while overfeeding induced fat accumulation in both sexes and glycation the inflammatory infiltration. The VAT response to maternal DIO and overfeeding showed a sexual dysmorphism, and exposure to glycotoxins led to a thin-outside-fat-inside phenotype in overfeeding conditions and impaired energy balance, increasing the metabolic risk in adulthood.

Background: Early and delayed behavioral changes are well recognized after anesthesia. Intravenous anesthesia may prevent emergence delirium. However, it has not been evaluated as a preventive strategy for delayed postoperative behavior changes., Aims: We aimed to determine whether intravenous anesthesia is effective at reducing postoperative behavior changes in children undergoing ambulatory endoscopic procedures when compared to inhalation anesthesia., Methods: This randomized, double-blinded controlled trial was approved by the local IRB. Children aged 1-12 years who underwent ambulatory endoscopic procedures were recruited. Preoperative anxiety was evaluated through the modified Yale Preoperative Anxiety Scale. All children underwent face mask inhalation induction with sevoflurane. After a peripheral line was placed, each child was allocated to sevoflurane or propofol maintenance. Emergence delirium was evaluated through the Pediatric Anesthesia Emergence Delirium scale. The child was discharged home, and behavioral changes were assessed through the Posthospitalization Behavior Questionnaire for Ambulatory Surgery on Days 1, 7, and 14., Results: Overall, 175 children were enrolled. On Day 1 after the procedure, 57 children presented at least one negative behavior. On Days 7 and 14, 49 and 44 children presented at least one negative behavior, respectively. The median number of negative behaviors was similar between the groups. Post hoc analyses showed a moderate correlation between emergence delirium and negative postoperative behavior on Day 7 (r = .34; p = <.001) and an increase of 3.31 (95% CI 1.90; 4.36 p < .001) points in the mean summed score of new negative behaviors for individuals with emergence delirium., Conclusion: The incidence of postoperative behavior changes in children undergoing ambulatory endoscopic procedures was similar when comparing intravenous with inhalation anesthesia. Children who experience emergence delirium might show a greater incidence of negative postoperative behavior changes., (© 2022 John Wiley & Sons Ltd.)

Background: Endoscopic ultrasound guided gastrojejunostomy (EUS-GJ) with lumen apposing metal stents has recently emerged as a viable option, as an alternative to surgical gastrojejunostomy and endoscopic enteral stenting, for managing gastric outlet obstruction (GOO). We aim to perform a retrospective analysis of the efficacy, safety and outcomes of EUS-GJ performed at three tertiary institutions in the United Kingdom., Methods: Consecutive patients who underwent EUS-GJ between August 2018 and March 2021 were identified from a prospectively maintained database. Data were obtained from interrogation of electronic health records., Results: Twenty five patients (15 males) with a median age of 63 years old (range 29-80) were included for analysis. 88% (22/25) of patients had GOO due to underlying malignant disease. All patients were deemed surgically inoperable or at high surgical risk. Both technical and clinical success were achieved in 92% (23/25) of patients. There was an improvement in the mean Gastric Outlet Obstruction Scoring System scores following a technically successful EUS-GJ (2.52 vs 0.68, p < 0.01). Adverse events occurred in 2/25 patients (8%), both due to stent maldeployment necessitating endoscopic closure of the gastric defect with clips. Long-term follow-up data were available for 21 of 23 patients and the re-intervention rate was 4.8% (1/21) over a median follow-up period of 162 (range 5-474) days., Conclusion: EUS-GJ in carefully selected patients is an effective and safe procedure when performed by experienced endoscopists., (© 2022. Crown.)

Brain insulin resistance has been pointed to as a possible link between diabetes and neuropsychiatric disorders; therefore, therapeutic approaches using anti-diabetic drugs to improve insulin levels or signaling could prevent type 1 (T1D) and type 2 diabetes mellitus (T2D)-induced brain dysfunction. The present study aimed to determine whether metformin exerts beneficial effects on metabolic and neurobehavioral outcomes in the streptozotocin (STZ)-induced T1D model and western diet (WD)-induced obesity model in male Swiss mice. T1D was induced by intraperitoneal injection of STZ (50 mg/kg, for five consecutive days). The animals were then treated daily with saline or metformin (200 mg/kg/day, oral gavage), and a battery of tests recapitulating different neurobehavioral anomalies related to anxiogenic/depressive-like phenotype was conducted after 18 days. WD-induced obesity was modeled in mice by high-fat and high-fructose diet (HFFD) feeding for 15 days. In the sequence, control and diet-induced obesity mice were treated daily with saline or metformin (200 mg/kg/day), and a battery of behavioral tests was performed after 17 days. STZ injection and WD feeding induced metabolic and neurobehavioral impairments in mice. Remarkably, metformin improved the metabolic and neurobehavioral parameters in WD-induced obesity mice. Moreover, metformin ameliorated STZ-induced neurobehavioral deficits while it failed to improve the associated metabolic impairments. The beneficial effects of metformin in STZ-induced neurobehavioral impairments were not mediated by improving peripheral insulin signaling. Our results suggest that conventional diabetes treatment could be repurposed to simultaneously improve neurobehavioral symptoms and diabetes., (© 2022 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Background: Earlier detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes, as it is mostly detected at advanced stages which are associated with poor survival. Developing non-invasive blood tests for early detection would be an important breakthrough., Methods: The primary objective of the work presented here is to use a dataset that is prospectively collected, to quantify a set of cancer-associated proteins and construct multi-marker models with the capacity to predict PDAC years before diagnosis. The data used is part of a nested case-control study within the UK Collaborative Trial of Ovarian Cancer Screening and is comprised of 218 samples, collected from a total of 143 post-menopausal women who were diagnosed with pancreatic cancer within 70 months after sample collection, and 249 matched non-cancer controls. We develop a stacked ensemble modelling technique to achieve robustness in predictions and, therefore, improve performance in newly collected datasets., Results: Here we show that with ensemble learning we can predict PDAC status with an AUC of 0.91 (95% CI 0.75-1.0), sensitivity of 92% (95% CI 0.54-1.0) at 90% specificity, up to 1 year prior to diagnosis, and at an AUC of 0.85 (95% CI 0.74-0.93) up to 2 years prior to diagnosis (sensitivity of 61%, 95% CI 0.17-0.83, at 90% specificity)., Conclusions: The ensemble modelling strategy explored here outperforms considerably biomarker combinations cited in the literature. Further developments in the selection of classifiers balancing performance and heterogeneity should further enhance the predictive capacity of the method., (© 2023. The Author(s).)

Background: Cardiovascular disease is the leading cause of death worldwide. Existing studies on the association between temperatures and cardiovascular deaths have been limited in geographic zones and have generally considered associations with total cardiovascular deaths rather than cause-specific cardiovascular deaths., Methods: We used unified data collection protocols within the Multi-Country Multi-City Collaborative Network to assemble a database of daily counts of specific cardiovascular causes of death from 567 cities in 27 countries across 5 continents in overlapping periods ranging from 1979 to 2019. City-specific daily ambient temperatures were obtained from weather stations and climate reanalysis models. To investigate cardiovascular mortality associations with extreme hot and cold temperatures, we fit case-crossover models in each city and then used a mixed-effects meta-analytic framework to pool individual city estimates. Extreme temperature percentiles were compared with the minimum mortality temperature in each location. Excess deaths were calculated for a range of extreme temperature days., Results: The analyses included deaths from any cardiovascular cause (32 154  935), ischemic heart disease (11 745 880), stroke (9 351 312), heart failure (3 673 723), and arrhythmia (670 859). At extreme temperature percentiles, heat (99th percentile) and cold (1st percentile) were associated with higher risk of dying from any cardiovascular cause, ischemic heart disease, stroke, and heart failure as compared to the minimum mortality temperature, which is the temperature associated with least mortality. Across a range of extreme temperatures, hot days (above 97.5th percentile) and cold days (below 2.5th percentile) accounted for 2.2 (95% empirical CI [eCI], 2.1-2.3) and 9.1 (95% eCI, 8.9-9.2) excess deaths for every 1000 cardiovascular deaths, respectively. Heart failure was associated with the highest excess deaths proportion from extreme hot and cold days with 2.6 (95% eCI, 2.4-2.8) and 12.8 (95% eCI, 12.2-13.1) for every 1000 heart failure deaths, respectively., Conclusions: Across a large, multinational sample, exposure to extreme hot and cold temperatures was associated with a greater risk of mortality from multiple common cardiovascular conditions. The intersections between extreme temperatures and cardiovascular health need to be thoroughly characterized in the present day-and especially under a changing climate.

Brain aging involves regional alterations of specific cellular subpopulations in the human hippocampus: a network hub for memory consolidation. The present study investigates whether age, sex, education years, and the concentration of neuropathological and inflammatory proteins influence neuronal-type marker expression in the elderly hippocampus. We analyzed the digital images (1 µm/pixel) of postmortem hippocampal sections from 19 non-demented individuals (from 78 to 99 years). This material was obtained from the "Aging Dementia and TBI Study" open database. Brain samples were processed through in situ hybridization (ISH) for the immunodetection of VGLUT1 (glutamatergic transporter) and GAT1 (GABAergic transporter) and mRNAs and Luminex protein quantifications. After image acquisition, we delineated the dentate gyrus, CA 3/2, and CA1 hippocampal subdivisions. Then, we estimated the area fraction in which the ISH markers were expressed. Increased VGLUT1 was observed in multiple hippocampal subfields at late ages. This glutamatergic marker is positively correlated with beta-amyloid and tau proteins and negatively correlated with interleukin-7 levels. Additionally, education years are positively correlated with GAT1 in the hippocampus of elderly women. This GABAergic marker expression is associated with interferon-gamma and brain-derived neurotrophic factor levels. These associations can help to explain how hippocampal sub-regions and neurotransmitter systems undergo distinct physiological changes during normal aging.

Parkinson's disease (PD) is a movement disorder characterized by the progressive degeneration of dopaminergic neurons resulting in dopamine deficiency in the striatum . Given the estimated escalation in the number of people with PD in the coming decades, interventions aimed at minimizing morbidity and improving quality of life are crucial. Mitochondrial dysfunction and oxidative stress are intrinsic factors related to PD pathogenesis. Accumulating evidence suggests that patients with PD might benefit from various forms of exercise in diverse ways, from general health improvements to disease-specific effects and, potentially, disease-modifying effects. However, the signaling and mechanism connecting skeletal muscle-increased activity and brain remodeling are poorly elucidated. In this review, we describe skeletal muscle-brain crosstalk in PD, with a special focus on mitochondrial effects, proposing mitochondrial dysfunction as a linker in the muscle-brain axis in this neurodegenerative disease and as a promising therapeutic target. Moreover, we outline how exercise secretome can improve mitochondrial health and impact the nervous system to slow down PD progression. Understanding the regulation of the mitochondrial function by exercise in PD may be beneficial in defining interventions to delay the onset of this neurodegenerative disease.

Baccharis dracunculifolia DC (Lamiaceae) (Asteraceae) is found in South America, mainly in Argentina, Brazil, Bolivia, Paraguay and Uruguay. Folk medicine is used as a sedative, hypotensive, bronchodilator, cardiovascular disorders, anti-flu, and also in skin wounds. Considered the main source of green propolis, which increases the pharmacological interest in this species. It is also known as a "benefactor" plant facilitating the development of other plant species around it, being indicated for the recovery of degraded areas. This species has been studied for decades in order to isolate and identify the active principles present in the aerial parts (leaves and flowers) and roots. The present study consists of a review of the scientific literature addressing the ethnobotanical, ethnomedicinal, phytochemical, pharmacological and potential cytotoxic effects of the B. dracunculifolia species. In this survey, we sought to investigate issues related to the botanical and geographic description of the species, the ethnobotanical uses, as well as the phytochemical studies of the essential oil, extracts and green propolis obtained from the aerial parts and roots of B. dracunculifolia . Using high precision analytical tools, numerous compounds have already been isolated and identified from leaves and flowers such as the flavonoids: naringenin, acacetin, dihydrokaempferol, isosakuranetin and kaempferide; phenolic acids: p -coumaric, dihydrocoumaric, ferulic (E)-cinnamic, hydroxycinnamic, gallic, caffeic, and several caffeoylquinic acids derivatives; phenolic acids prenylated: artepillin C, baccharin, drupanin; the glycosides dracuculifosides and the pentacyclic triterpenoids: Baccharis oxide and friedelanol. The predominant class in the essential oil of leaves and flowers are terpenoids comprising oxygenated monoterpenes and sesquiterpenes, highlighting the compounds nerolidol, spathulenol, germacrene D and bicyclogermacrene. These compounds give the species high antimicrobial, antioxidant, antitumor, analgesic, immunomodulatory and antiparasitic potential, making this species a promising herbal medicine. In vitro toxicity assays with B. dracunculifolia extract showed low or no cytotoxicity. However, in vivo analyses with high doses of the aqueous extract resulted in genotoxic effects, which leads us to conclude that the toxicity of this plant is dose-dependent., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gazim, Valle, Carvalho dos Santos, Rahal, Silva, Lopes, Ruiz, Faria, Piau Junior and Gonçalves.)

Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed at a late stage and are locally advanced or with concurrent metastases. The aggressive phenotype and relative chemo- and radiotherapeutic resistance of PDAC is thought to be mediated largely by its prominent stroma, which is supported by an extracellular matrix (ECM). Therefore, we investigated the impact of tissue-matched human ECM in driving PDAC and the role of the ECM in promoting chemotherapy resistance. Decellularized human pancreata and livers were recellularized with PANC-1 and MIA PaCa-2 (PDAC cell lines), as well as PK-1 cells (liver-derived metastatic PDAC cell line). PANC-1 cells migrated into the pancreatic scaffolds, MIA PaCa-2 cells were able to migrate into both scaffolds, whereas PK-1 cells were able to migrate into the liver scaffolds only. These differences were supported by significant deregulations in gene and protein expression between the pancreas scaffolds, liver scaffolds, and 2D culture. Moreover, these cell lines were significantly more resistant to gemcitabine and doxorubicin chemotherapy treatments in the 3D models compared to 2D cultures, even after confirmed uptake by confocal microscopy. These results suggest that tissue-specific ECM provides the preserved native cues for primary and metastatic PDAC cells necessary for a more reliable in vitro cell culture.

Background: Although emerging data evidences that EUS-guided needle-based confocal laser endomicroscopy (nCLE) accurately diagnoses pancreatic cystic lesions (PCLs), there are a lack of interobserver agreement (IOA) studies utilizing reference histopathological diagnosis and for specific PCL subtypes. Hence, we sought to assess the IOA, intra-observer reliability (IOR), and diagnostic performance of EUS-nCLE using a large cohort of patients with histopathological diagnosis amongst a broad panel of international observers., Methods: EUS-nCLE videos (n = 76) of subjects with PCLs [intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystadenoma (SCA), pseudocyst, and cystic-neuroendocrine tumors/solid pseudopapillary neoplasm (cystic-NET/SPN)], simulating clinical prevalence rates were obtained from 3 prospective studies. An international panel of 13 endosonographers with nCLE experience, blinded to all PCL data, evaluated the video library twice with a two-week washout for PCL differentiation (mucinous vs. non-mucinous) and subtype diagnosis., Results: The IOA (κ = 0.82, 95% CI 0.77-0.87) and IOR (κ = 0.82, 95% CI 0.78-0.85) were "almost perfect" to differentiate mucinous vs. non-mucinous PCLs. For PCL subtype, IOA was highest for SCA (almost perfect; κ = 0.85), followed by IPMN (substantial, κ = 0.72), and cystic-NET/SPN (substantial, κ = 0.73). The IOA was moderate for MCN (κ = 0.47), and pseudocyst (κ = 0.57). Compared to histopathology, observers differentiated mucinous vs. non-mucinous PCLs with high accuracy (94.8%, 95% CI 93.3-96.1). For detecting specific PCLs subtypes, EUS-nCLE was highly accurate in diagnosing non-mucinous cysts (SCA: 98%; cystic-NET/SPN: 96%; pseudocyst: 96%) and slightly less accurate for mucinous lesions (IPMN: 86%; MCN: 84%)., Conclusion: Diagnosis of PCLs by EUS-nCLE guided virtual biopsy is very accurate and reliable for the most prevalent pancreatic cysts in clinical practice., Competing Interests: Declaration of competing interest Krishna SG is PI of an investigator-initiated study. The study in part is funded by a grant to The Ohio State University Wexner Medical Center from Mauna Kea Technologies, Paris, France. Pereira SP was supported by the NIHR Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust and UCL., (Copyright © 2022 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Although penile cancer (PC) is uncommon in developed countries, it is widespread in developing countries. The state of Maranhão (Northeast, Brazil) has the highest global incidence recorded for PC, and, despite its socioeconomic vulnerability, it has been attributed to human papillomavirus (HPV) infection. This study aimed to determine the histopathological features, the prevalence of HPV infection, and the immunohistochemical profile of PC in Maranhão., Methods: A retrospective cohort of 200 PC cases were evaluated. HPV detection was performed using nested-PCR followed by direct sequencing for genotyping. Immunohistochemistry (IHC) was performed using monoclonal antibodies anti-p16 INK4a , p53, and ki-67., Results: Our data revealed a delay of 17 months in diagnosis, a high rate of penile amputation (96.5%), and HPV infection (80.5%) in patients from Maranhão (Molecular detection). We demonstrated the high rate of HPV in PC also by histopathological and IHC analysis. Most patients presented koilocytosis (75.5%), which was associated with those reporting more than 10 different sexual partners during their lifetime (p = 0.001). IHC revealed frequent p16 INK4a overexpression (26.0%) associated with basaloid (p < 0.001) and high-grade tumors (p = 0.008). Interestingly, p16 appears not to be a better prognostic factor in our disease-free survival analysis, as previously reported. We also demonstrated high ki-67 and p53 expression in a subset of cases, which was related to worse prognostic factors such as high-grade tumors, angiolymphatic and perineural invasion, and lymph node metastasis. We found a significant impact of high ki-67 (p = 0.002, log-rank) and p53 (p = 0.032, log-rank) expression on decreasing patients' survival, as well as grade, pT, stage, pattern, and depth of invasion (p < 0.05, log-rank)., Conclusions: Our data reaffirmed the high incidence of HPV infection in PC cases from Maranhão and offer new insights into potential factors that may contribute to the high PC incidence in the region. We highlighted the possible association of HPV with worse clinical prognosis factors, differently from what was observed in other regions. Furthermore, our IHC analysis reinforces p16, ki-67, and p53 expression as important diagnosis and/or prognosis biomarkers, potentially used in the clinical setting in emerging countries such as Brazil., (© 2022. The Author(s).)

Parkinson's disease (PD) is identified by the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), and is correlated to aggregates of proteins such as α-synuclein, Lewy's bodies. Although the PD etiology remains poorly understood, evidence suggests a main role of oxidative stress on this process. Lippia grata Schauer, known as "alecrim-do-mato", "alecrim-de-vaqueiro", "alecrim-da-chapada", is a native bush from tropical areas mainly distributed throughout the Central and South America. This plant species is commonly used in traditional medicine for relief of pain and inflammation conditions, and that has proven antioxidant effects. We evaluated the effects of essential oil of the L. grata after its complexed with β-cyclodextrin (LIP) on PD animal model induced by reserpine (RES). Behavioral assessments were performed across the treatment. Upon completion the treatment, the animals were euthanized, afterwards their brains were isolated and processed for immunohistochemical and oxidative stress analysis. The LIP treatment delayed the onset of the behavior of catalepsy, decreased the number of oral movements and prevented the memory impairment on the novel object recognition task. In addition, the treatment with LIP protected against dopaminergic depletion in the SNpc and dorsal striatum (STRd), and decreased the α-syn immunoreactivity in the SNpc and hippocampus (HIP). Moreover, there was reduction of the oxidative stability index. These findings demonstrated that the LIP treatment has neuroprotective effect in a progressive parkinsonism model, suggesting that LIP could be an important source for novel treatment approaches in PD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We report an unusual case of cerebral venous thrombosis (CVT temporally associated with an otherwise asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. While coronavirus disease 2019 (COVID-19) has been associated with thrombotic events at different sites, most published cases report on symptomatic SARS-CoV-2 infection. We are confident this was an otherwise asymptomatic infection as the patient reported no symptoms and molecular and serological testing was consistent with infection more than 3weeks in the past. We believe this is an important report as it adds to the existing literature on thrombotic events in patients with COVID. It may even inform discussion of COVID vaccines and CVT since our patient, as those reported in association with vaccines, also had thrombocytopenia on admission., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of PBJ-Associação Porto Biomedical/Porto Biomedical Society. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is a health concern affecting 24% of the population worldwide. Although the pathophysiologic mechanisms underlying disease are not fully clarified, mitochondrial dysfunction and oxidative stress are key players in disease progression. Consequently, efforts to develop more efficient pharmacologic strategies targeting mitochondria for NAFLD prevention/treatment are underway. The conjugation of caffeic acid anti-oxidant moiety with an alkyl linker and a triphenylphosphonium cation (TPP + ), guided by structure-activity relationships, led to the development of a mitochondria-targeted anti-oxidant (AntiOxCIN 4 ) with remarkable anti-oxidant properties. Recently, we described that AntiOxCIN 4 improved mitochondrial function, upregulated anti-oxidant defense systems, and cellular quality control mechanisms (mitophagy/autophagy) via activation of the Nrf2/Keap1 pathway, preventing fatty acid-induced cell damage. Despite the data obtained, AntiOxCIN 4 effects on cellular and mitochondrial energy metabolism in vivo were not studied. In the present work, we proposed that AntiOxCIN 4 (2.5 mg/day/animal) may prevent non-alcoholic fatty liver (NAFL) phenotype development in a C57BL/6J mice fed with 30% high-fat, 30% high-sucrose diet for 16 weeks. HepG2 cells treated with AntiOxCIN 4 (100 μM, 48 h) before the exposure to supraphysiologic free fatty acids (FFAs) (250 μM, 24 h) were used for complementary studies. AntiOxCIN 4 decreased body (by 43%), liver weight (by 39%), and plasma hepatocyte damage markers in WD-fed mice. Hepatic-related parameters associated with a reduction of fat liver accumulation (by 600%) and the remodeling of fatty acyl chain composition compared with the WD-fed group were improved. Data from human HepG2 cells confirmed that a reduction of lipid droplets size and number can be a result from AntiOxCIN 4 -induced stimulation of fatty acid oxidation and mitochondrial OXPHOS remodeling. In WD-fed mice, AntiOxCIN 4 also induced a hepatic metabolism remodeling by upregulating mitochondrial OXPHOS, anti-oxidant defense system and phospholipid membrane composition, which is mediated by the PGC-1α-SIRT3 axis. AntiOxCIN 4 prevented lipid accumulation-driven autophagic flux impairment, by increasing lysosomal proteolytic capacity. AntiOxCIN 4 improved NAFL phenotype of WD-fed mice, via three main mechanisms: a) increase mitochondrial function (fatty acid oxidation); b) stimulation anti-oxidant defense system (enzymatic and non-enzymatic) and; c) prevent the impairment in autophagy. Together, the findings support the potential use of AntiOxCIN 4 in the prevention/treatment of NAFLD., Competing Interests: Declaration of competing interest Paulo J. Oliveira and Fernanda Borges are cofounders of the CNC-UP spin-off company MitoTAG (Coimbra, Portugal). This spin-off had no involvement in the data collection, analysis and interpretation, manuscript writing, and the decision to submit the manuscript for publication., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Insulin resistance can be assessed by the Triglyceride-Glucose Index (TyG), a simple, low-cost, and easy-to-apply method., Objective: To assess the predictive capacity of the TyG index about cardiovascular risk and identify its cutoff point in a population at cardiometabolic risk., Methods: Cross-sectional study with 264 individuals at cardiometabolic risk (54.9% women, age: 43.1 ± 16.3 years). Demographic, anthropometric, clinical-laboratory, and lifestyle data were collected. The TyG index was determined using the formula Ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg (dL)/2]. The ten-year cardiovascular risk was assessed by the Framingham risk score (FRS). The receiver operating characteristic curve (ROC) was used to define the cutoff point for the TyG index, and the associations were tested by Poisson regression., Results: ROC curve analysis indicated an area under the curve of 0.678 (95% CI = 0.618-0.734; p < 0.001), with a cutoff of 9.04 (sensitivity = 62.5%, specificity = 66.7%, positive predictive value = 29.4% and negative predictive value = 88.9%). Elevated TyG values ​​(≥9.04) were positively associated with cardiometabolic risk factors (total cholesterol, LDL, VLDL, uric acid, alanine aminotransferase, aspartate aminotransferase, waist-hip ratio, systolic blood pressure, HOMA-IR, smoking, metabolic syndrome, diabetes, and hepatic steatosis). After adjustment for confounding factors, individuals with high TyG showed an increase of 69% (RP = 1.69; 95%CI = 1.03-2.78) in the prevalence of intermediate/high risk by FRS, compared to those with low TyG., Conclusion: The TyG index showed a good predictive capacity for cardiovascular risk in ten years assessed by the FRS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Purpose: The registration of Laparoscopic Ultrasound (LUS) to CT can enhance the safety of laparoscopic liver surgery by providing the surgeon with awareness on the relative positioning between critical vessels and a tumour. In an effort to provide a translatable solution for this poorly constrained problem, Content-based Image Retrieval (CBIR) based on vessel information has been suggested as a method for obtaining a global coarse registration without using tracking information. However, the performance of these frameworks is limited by the use of non-generalisable handcrafted vessel features., Methods: We propose the use of a Deep Hashing (DH) network to directly convert vessel images from both LUS and CT into fixed size hash codes. During training, these codes are learnt from a patient-specific CT scan by supplying the network with triplets of vessel images which include both a registered and a mis-registered pair. Once hash codes have been learnt, they can be used to perform registration with CBIR methods., Results: We test a CBIR pipeline on 11 sequences of untracked LUS distributed across 5 clinical cases. Compared to a handcrafted feature approach, our model improves the registration success rate significantly from 48% to 61%, considering a 20 mm error as the threshold for a successful coarse registration., Conclusions: We present the first DH framework for interventional multi-modal registration tasks. The presented approach is easily generalisable to other registration problems, does not require annotated data for training, and may promote the translation of these techniques., (© 2022. Crown.)

Epilepsy is a chronic neurological disorder characterized by an abnormal, spontaneous, and synchronized neuronal hyperactivity. Therapeutic approaches for controlling epileptic seizures are associated with pharmacoresistance and side effects burden. Previous studies reported that different natural products may have neuroprotector effects. Sakuranetin (SAK) is a flavanone with antiparasitic, anti-inflammatory, antimutagenic, antiallergic, and antioxidant activity. In the present work, the effect of SAK on seizures in a model of status epilepticus induced by bicuculline (BIC) in mice was evaluated. Male Swiss mice received an intracerebroventricular injection (i.c.v.) of SAK (1, 10, or 20 mg/kg-SAK1, SAK10, or SAK20). Firstly, animals were evaluated in the open field (OF; 20 min), afterwards in the elevated plus maze (EPM) test (5 min). Next, 30 min prior the administration of BIC (1 mg/kg), mice received an injection of SAK (1 or 10 mg/kg, i.c.v.) and were observed in the OF (20 min) for seizures assessment. After behavioral procedures, immunohistochemical analysis of c-Fos was performed. Our main results showed that the lowest doses of SAK (1 and 10 mg/kg) increased the total distance traveled in the OF, moreover protected against seizures and death on the BIC-induced seizures model. Furthermore, SAK treatment reduced neuronal activity on the dentate gyrus of the BIC-treated animals. Taken together, our results suggest an anticonvulsant effect of SAK, which could be used for the development of anticonvulsants based on natural products from herbal source., (© 2022 Société Française de Pharmacologie et de Thérapeutique.)

Cholangiocarcinoma (CCA) is a malignant tumour arising from the biliary system. In Europe, this tumour frequently presents as a sporadic cancer in patients without defined risk factors and is usually diagnosed at advanced stages with a consequent poor prognosis. Therefore, the identification of biomarkers represents an utmost need for patients with CCA. Numerous studies proposed a wide spectrum of biomarkers at tissue and molecular levels. With the present paper, a multidisciplinary group of experts within the European Network for the Study of Cholangiocarcinoma discusses the clinical role of tissue biomarkers and provides a selection based on their current relevance and potential applications in the framework of CCA. Recent advances are proposed by dividing biomarkers based on their potential role in diagnosis, prognosis and therapy response. Limitations of current biomarkers are also identified, together with specific promising areas (ie, artificial intelligence, patient-derived organoids, targeted therapy) where research should be focused to develop future biomarkers., Competing Interests: Competing interests: Dr Angela Lamarca reports travel and educational support from Ipsen, Pfizer, Bayer, AAA, Sirtex, Novartis, Mylan and Delcath; Speaker honoraria from Merck, Pfizer, Ipsen, Incyte, AAA, QED, Servier, Astra Zeneca and EISAI; Advisory and consultancy honoraria from EISAI, Nutricia Ipsen, QED, Roche, Servier, Boston Scientific and Albireo Pharma; Member of the Knowledge Network and NETConnect Initiatives funded by Ipsen.Alejandro Forner: Lecture fees from Bayer, Gilead, Roche, Boston Scientific and MSD; consultancy fees from Bayer, AstraZeneca, Roche, Boston Scientific, SIRTEX, Exact Science and Guerbert.Chiara Braconi (or family members) received honoraria from Incyte, Merck-Serono, EliLilly, Pfizer, Roche.Jakob N Kather has provided consulting services for Owkin, France and Panakeia, UK and has received honoraria by MSD, Eisai and Falk Pharma., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Lentinus crinitus (Basidiomycota: Polyporales) is a saprophytic fungus with biotechnological importance described more than 20 years ago. However, there are few studies on the long-term preservation of this basidiomycete. Cryopreservation is a long-term storage technique that reduces the metabolic activity of microorganisms, but its success depends on the adjustment of the freezing process, the cryoprotectants, and the protective substrates for each species. This study aimed to assess the mycelial viability and genetic stability of L. crinitus strains cryopreserved at -86 °C for two years by the wheat grain technique using different cryoprotectants and freezing methods. Three strains of L. crinitus (U9-1, U13-5, and U15-12) were subjected to different concentrations and types of cryoprotectants (dimethyl sulfoxide, glycerol, glucose, and sucrose), freezing methods such as immediate freezing from 25 to -86 °C and progressing freezing from 25 to -86 °C in a freezing container with isopropyl alcohol to control the rate of cell freezing at -1 °C min -1 , protective substrate (wheat grain and 2% malt extract agar), and cryopreservation period (1, 6, 12, and 24 months). After thawing, samples were evaluated for mycelial viability, time to mycelial recovery, mycelial stability, and genetic stability of the fungus. All techniques achieved effective cryopreservation at -86 °C, mainly with the wheat grain technique. All cryoprotectants (3.5% glycerol, 1.5% dimethyl sulfoxide, 25% sucrose, and 5% glucose), freezing methods (immediate and gradual), and protective substrate (wheat grain and malt extract agar) were effective for cryopreservation of the three L.crinitus strains in an ultra-low temperature freezer for two years. Mycelial viability, mycelial stability, and genetic stability of the fungus were not affected after two-year cryopreservation, evidencing the robustness of the long-term cryopreservation technique and the fungus., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cardiovascular disease (CVD) is the biggest killer worldwide, composing a major economic burden for health care systems. Obesity and diabetes are dual epidemics on the rise and major risk factors predisposing for CVD. Increased obesity- and diabetes-related incidence is now observed among children, adolescents, and young adults. Gestational diabetes mellitus (GDM) is the most common metabolic pregnancy disorder, and its prevalence is rapidly increasing. During pregnancies complicated by GDM, the offspring are exposed to a compromised intrauterine environment characterized by hyperglycemic periods. Unfavorable in utero conditions at critical periods of fetal cardiac development can produce developmental adaptations that remodel the cardiovascular system in a way that can contribute to adult-onset of heart disease due to the programming during fetal life. Epidemiological studies have reported increased cardiovascular complications among GDM-descendants, highlighting the urgent need to investigate and understand the mechanisms modulated during fetal development of in utero GDM-exposed offspring that predispose an individual to increased CVD during life. In this manuscript, we overview previous studies in this area and gather evidence linking GDM and CVD development in the offspring, providing new insights on novel mechanisms contributing to offspring CVD programming by GDM, from the role of maternal-fetal interactions to their impact on fetal cardiovascular development, how the perpetuation of cardiac programming is maintained in postnatal life, and advance the intergenerational implications contributing to increased CVD premature origin. Understanding the perpetuation of CVD can be the first step to manage and reverse this leading cause of morbidity and mortality. This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology Cardiovascular Diseases > Molecular and Cellular Physiology Metabolic Diseases > Genetics/Genomics/Epigenetics., (© 2022 Wiley Periodicals LLC.)

Ultrasound imaging is a commonly used technology for visualising patient anatomy in real-time during diagnostic and therapeutic procedures. High operator dependency and low reproducibility make ultrasound imaging and interpretation challenging with a steep learning curve. Automatic image classification using deep learning has the potential to overcome some of these challenges by supporting ultrasound training in novices, as well as aiding ultrasound image interpretation in patient with complex pathology for more experienced practitioners. However, the use of deep learning methods requires a large amount of data in order to provide accurate results. Labelling large ultrasound datasets is a challenging task because labels are retrospectively assigned to 2D images without the 3D spatial context available in vivo or that would be inferred while visually tracking structures between frames during the procedure. In this work, we propose a multi-modal convolutional neural network (CNN) architecture that labels endoscopic ultrasound (EUS) images from raw verbal comments provided by a clinician during the procedure. We use a CNN composed of two branches, one for voice data and another for image data, which are joined to predict image labels from the spoken names of anatomical landmarks. The network was trained using recorded verbal comments from expert operators. Our results show a prediction accuracy of 76% at image level on a dataset with 5 different labels. We conclude that the addition of spoken commentaries can increase the performance of ultrasound image classification, and eliminate the burden of manually labelling large EUS datasets necessary for deep learning applications.

This study aimed to describe the transmission of T. gondii in naturally infected goats in the semiarid region of northeastern Brazil, through evaluating the serological status of these animals from one to 12 months of age. Seven goat farms were selected. During the first visit, an epidemiological questionnaire was applied. Blood samples were collected from pregnant goats and from their female offspring every month, to monitor them for anti-T. gondii antibodies, using the indirect fluorescence antibody test (IFAT). Out of 66 pregnant goats evaluated, 47% (31/66) (95% CI: 34.6% - 59.7%) were positive and out of 93 female offspring, 61.3% (57/93) (95% CI: 52.4% - 69.2%) were positive, in at least one month during the evaluation period. Among the positive female offspring, 43.3% (27/57) (95% CI: 39.7% - 56.9%) presented environmental infection and 56.7% (30/57) (95% CI: 43.4% - 66.3 %) probably had only colostral antibodies or vertical transmission. It was observed that 92,6% (25/27) from environmental infections occurred until reproductive age (six months) (p<0.0001). It was also noted that there is a correlation between the titration of mothers and offspring, until four months of age (p<0.0001). Large fluctuations in the presence of antibodies were observed among the animals over the months monitored. It can be concluded that the prevalence of anti-T. gondii antibodies within the herds was greater than what has been expressed in specific prevalence studies and that most goat become infected up to the six months of life in the studied area., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: The intrinsic sensitivity limitations of basic parasitological methods, along with the particular biological characteristics of parasites, make these methods ineffective to differentiate morphologically indistinguishable species. Molecular detection and characterization techniques could be used to overcome these problems. The purpose of this work was to standardize molecular polymerase chain reaction (PCR) techniques, described in the literature, for the detection and molecular characterization of intestinal protozoa and other pathogens in humans., Methods: DNA was extracted from human or animal feces, previously washed or cultured in Boeck Drbohlav's Modified Medium. DNA extraction was performed with Machery-Nagel extraction kits. The standardization of the PCR, nested-PCR or RFLP techniques was carried out according to the literature. For each molecular technique performed, the sensitivity of the test was determined based on the minimun quantity required of DNA (sensitivity A) and the minimum quantity of life forms that the test detected (sensitivity B)., Results: Sensitivity A was 10 fg for G. duodenalis , 12.5 pg for Entamoeba histolytica or Entamoeba dispar , 50 fg for Cryptosporidium spp., 225 pg for Cyclospora spp. and 800 fg or 8 fg for Blastocystis spp. after performing a 1780 bp PCR or 310 bp nested PCR, respectively. The sensitivity B was 100 cysts for G. duodenalis, 500 cysts for E. histolytica or E. dispar , 1000 oocysts for Cyclospora spp. and 3600 or four vegetatives forms for PCR or nested PCR of Blastocystis spp., respectively., Conclusions: The molecular detection of protozoa and chromist was achieved and the molecular characterization allowed the genotyping of some of the parasites such as Giardia duodenalis , Cryptosporidium spp., and Blastocystis spp. This study summarizes the molecular techniques for epidemiological studies in humans and animals, and helps in the investigation of their transmission sources in countries where intestinal parasites are a public health problem., Competing Interests: Competing interests: The authors declare that they have no competing interests.

The persistence of virally infected cells as reservoirs despite effective antiretroviral therapy is a major barrier to an HIV/SIV cure. These reservoirs are predominately contained within cells present in the B cell follicles (BCFs) of secondary lymphoid tissues, a site that is characteristically difficult for most cytolytic antiviral effector cells to penetrate. Here, we identified a population of NK cells in macaque lymph nodes that expressed BCF-homing receptor CXCR5 and accumulated within BCFs during chronic SHIV infection. These CXCR5+ follicular NK cells exhibited an activated phenotype coupled with heightened effector functions and a unique transcriptome characterized by elevated expression of cytolytic mediators (e.g., perforin and granzymes, LAMP-1). CXCR5+ NK cells exhibited high expression of FcγRIIa and FcγRIIIa, suggesting a potential for elevated antibody-dependent effector functionality. Consistently, accumulation of CXCR5+ NK cells showed a strong inverse association with plasma viral load and the frequency of germinal center follicular Th cells that comprise a significant fraction of the viral reservoir. Moreover, CXCR5+ NK cells showed increased expression of transcripts associated with IL-12 and IL-15 signaling compared with the CXCR5- subset. Indeed, in vitro treatment with IL-12 and IL-15 enhanced the proliferation of CXCR5+ granzyme B+ NK cells. Our findings suggest that follicular homing NK cells might be important in immune control of chronic SHIV infection, and this may have important implications for HIV cure strategies.

The traumatic event produces intolerable excitations to the psychic apparatus that searches to relief them through the production of symptoms. When established, patients with post-traumatic stress disorders (PTSD) and complex post-traumatic stress disorder (CPTSD) may experience flashbacks, somatizations, negative emotions about themselves, and difficulty in social contact. This work seeks to understand how the psychodynamic functioning of women victims of interpersonal and urban violence, diagnosed with these disorders, is organized, identifying traumatic experiences, ways of interpersonal relationships, conflicts and psychic structures and use of defense mechanisms, and for peculiarities that may differentiate these disorders. The qualitative transversal method was used through the content analysis of clinical interviews based on the Operationalized Psychodynamic Diagnosis (OPD-2). The sample of this study consisted of five women with PTSD and five with CPTSD. The following categories were created: reasons for seeking care, symptoms and desire for treatment, traumatic developmental events, and characteristics of the psychic functioning. Early trauma generates psychic organizations with greater disintegration. A new traumatic event destabilizes the psychic organization and intensifies symptoms. Relationships were marked by dependence and isolation. Participants with CPTSD presented tendency to disintegration related to the object relation regulation and the psychic conflict was of Individuation versus Dependence, with more primitive flaws in object representations, existential need for the other and direct discharge of impulses. Participants with PTSD had moderate to low level of object relation integration and the conflict was need to be care of versus self-sufficiency, with self-representations being fragile and with reduced capacity to manage impulses. Thus, it could be observed that OPD-2 is capable of assessing in a broad and deep way patients with traumatic disorders, in addition to identifying essential peculiarities to guide health professionals towards treatment in the search for better quality of life for patients., (© 2022. The Author(s).)

Farmers focus on reducing the cost of production and aim to increase profit. The objective of this study was to quantify the reduction of pesticides applied to soybean (Glycine max (L.) Merrill) and maize (Zea mays L.) crops in several stages of the production cycle using a site-specific spraying application based on real-time sensors in the Brazilian Cerrado region. The sprayers were equipped with a precision spraying control system based on a real-time sensor. The spraying operations were performed not only for herbicide, but also for fungicide and insecticides applications. The maps recorded the percentage of the spray boom when the application was turned on (on/off spray system) with nozzle-to-nozzle control. The precision spraying system based on real-time sensors reduced the volume of pesticides (including herbicides, insecticides, and fungicides) applied to soybean and maize crops. There was a more significant reduction in the volume of pesticides applied post-emergence of the crops in the initial stages of soybean and maize when the crops had less leaf area or less foliage coverage between the rows. The cost reduction achieved using this technology was 2.3 times lower than the cost associated with pesticide application over the entire area using a conventional sprayer. Under the experimental conditions, there were no differences in the average crop yield, compared to the historical productivity of soybean and maize crops by applying this technology because the recommended doses were not affected and the site of application was limited to points where the presence of plants was present was detected., (© 2022. The Author(s).)

Despite advances in antiretroviral therapy, chronic immune activation continues to be observed among individuals with well-controlled HIV viral loads, and is associated with non-AIDS defining morbidities among people living with HIV. Alcohol use disorder impacts a significant proportion of individuals living with HIV, and alcohol exposure is known to damage the intestinal epithelium which may increase translocation of pathogens and their molecular products, driving systemic immune activation and dysregulation. The aim of this study was to determine if adults living with HIV with well-controlled viral loads, who also suffer from alcohol use disorder with and without hepatitis C virus co-infection (n=23), exhibit evidence of advanced systemic immune activation, intestinal damage, and microbial translocation, as compared to adults living with HIV who are not exposed to chronic alcohol or other substances of abuse (n=29). The impact of a 1-month intervention to treat alcohol-use disorder was also examined. Alcohol-use disorder was associated with evidence of advanced innate immune activation, alterations in monocyte phenotype including increased expression of Toll-like receptor 4, increased burden of stimulatory ligands for Toll-like receptor 4, and alterations in plasma cytokine signature, most notably elevations in soluble CD40 ligand and transforming growth factor beta. Alcohol-associated immune activation was more pronounced among individuals with hepatitis C virus co-infection. Although the 1-month intervention to treat alcohol use disorder did not result in significant reductions in the interrogated indicators of immune activation, our findings suggest that chronic alcohol exposure is a major modifiable risk factor for chronic immune activation and dysregulation among people-living with HIV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer TW declared a shared affiliation with the authors RPS and SR to the handling editor at the time of review., (Copyright © 2022 Underwood, Park, Uebelhoer, Gu, Kunkel, Korthuis, Cook, Sekaly, Ribeiro and Lancioni.)

Lentinus crinitus basidiocarps are an alternative to antimicrobials, but the stipe (24% basidiocarp) is discarded even with potential antimicrobial activity. This study evaluated the antimicrobial activity of L. crinitus basidiocarp pileus and stipe extracts against foodborne pathogens and food spoilage microorganisms. Basidiocarps of L. crinitus were grown in sugarcane bagasse and rice husks and the pileus and stipe methanolic extract was analyzed by broth microdilution method for antimicrobial activity against eight bacteria and eight fungi. The minimum bactericidal concentration values for pileus and stipe ranged from 0.40 to 0.50 mg mL - 1 , for streptomycin from 0.10 to 0.50 mg mL - 1 , and for ampicillin from 0.40 to 1.20 mg mL - 1 . The minimum fungicidal concentration values for pileus and stipe ranged from 0.06 to 0.60 mg mL - 1 , for bifonazole from 0.20 to 0.25 mg mL - 1 , and for ketoconazole from 0.30 to 3.50 mg mL - 1 . Extracts had bacteriostatic, bactericidal, fungistatic and fungicidal activity against all microorganisms, but with greater efficiency and specificity for some microorganisms. Both pileus and stipe are promising and sustainable alternatives for use in food, agricultural, and pharmaceutical industries., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Type I IFNs (TI-IFNs) drive immune effector functions during acute viral infections and regulate cell cycling and systemic metabolism. That said, chronic TI-IFN signaling in the context of HIV infection treated with antiretroviral therapy (ART) also facilitates viral persistence, in part by promoting immunosuppressive responses and CD8+ T cell exhaustion. To determine whether inhibition of IFN-α might provide benefit in the setting of chronic, ART-treated SIV infection of rhesus macaques, we administered an anti-IFN-α antibody followed by an analytical treatment interruption (ATI). IFN-α blockade was well-tolerated and associated with lower expression of TI-IFN-inducible genes (including those that are antiviral) and reduced tissue viral DNA (vDNA). The reduction in vDNA was further accompanied by higher innate proinflammatory plasma cytokines, expression of monocyte activation genes, IL-12-induced effector CD8+ T cell genes, increased heme/metabolic activity, and lower plasma TGF-β levels. Upon ATI, SIV-infected, ART-suppressed nonhuman primates treated with anti-IFN-α displayed lower levels of weight loss and improved erythroid function relative to untreated controls. Overall, these data demonstrated that IFN-α blockade during ART-treated SIV infection was safe and associated with the induction of immune/erythroid pathways that reduced viral persistence during ART while mitigating the weight loss and anemia that typically ensue after ART interruption.

Iron bioaccumulation in basidiomycetes is an alternative to recover ferrous sulphate from titanium dioxide pigment production and to produce an iron-enriched mycelial biomass. This study aimed to evaluate iron bioaccumulation capacity in vegetative mycelium of edible and medicinal fungi grown in malt extract liquid medium with different ferrous sulphate contents. Five basidiomycetes were grown in malt extract liquid medium with different iron contents from 0.116 to 100 mg L -1 iron. The iron content of dried mycelial biomass bioaccumulated with iron was determined by flame atomic absorption spectrophotometry. All fungi grew on the iron culture media and the mycelial biomass growth ranged from 3.24 ± 0.65a mg mL -1 to 12.46 ± 0.29 mg mL -1 . Iron addition to culture media increased the iron content in the mycelial biomass from 4000-13,000-fold compared with control. Pleurotus ostreatus (2181 ± 218 mg kg -1 ) presented the greatest iron content in the mycelial biomass, followed by Schizophyllum commune (1769 ± 131 mg kg -1 ), Agaricus subrufescens (1272 ± 8.84 mg kg -1 ), and Ganoderma lucidum (840 ± 75 mg kg -1 ). P. ostreatus , followed by S. commune , and G. lucidum at 90 and 100 mg L -1 iron in the culture medium are the best choices to produce iron-enriched mycelial biomass. This extensive study of several edible and medicinal basidiomycetes grown in different iron contents was effective in recovering ferrous sulphate byproduct and transferring it to mycelium to produce a new nutraceutical food of iron-enriched mycelial biomass.

Patients with cancers have been severely affected by the COVID-19 pandemic. This is highlighted by the adverse outcomes in cancer patients with COVID-19 as well as by the impact of the COVID-19 pandemic on cancer care. Patients with cancer constitute a heterogeneous population that exhibits distinct mechanisms of immune dysfunction, associated with distinct systemic features of hot (T-cell-inflamed/infiltrated) and cold (Non-T-cell-inflamed and/or infiltrated) tumors. The former show hyper immune activated cells and a highly inflammatory environment while, contrastingly, the latter show the profile of a senescent and/or quiescent immune system. Thus, the evolution of SARS-CoV-2 infection in different types of cancers can show distinct trajectories which could lead to a variety of clinical and pathophysiological outcomes. The altered immunological environment including cytokines that characterizes hot and cold tumors will lead to different mechanisms of immune dysfunction, which will result in downstream effects on the course of SARS-CoV-2 infection. This review will focus on defining the known contributions of soluble pro- and anti-inflammatory mediators on immune function including altered T-cells and B-cells responses and as well on how these factors modulate the expression of SARS-CoV-2 receptor ACE2, TMPRSS2 expression, and lymph node fibrosis in cancer patients. We will propose immune mechanisms that underlie the distinct courses of SARS-CoV-2 infection in cancer patients and impact on the success of immune based therapies that have significantly improved cancer outcomes. Better understanding of the immune mechanisms prevalent in cancer patients that are associated to the outcomes of SARS-CoV-2 infection will help to identify the high-risk cancer patients and develop immune-based approaches to prevent significant adverse outcomes by targeting these pathways., (Copyright © 2021. Published by Elsevier Inc.)

Epilepsy is a chronic neuropathology characterized by an abnormal hyperactivity of neurons that generate recurrent, spontaneous, paradoxical and synchronized nerve impulses, leading or not to seizures. This neurological disorder affects around 70 million individuals worldwide. Pharmacoresistance is observed in about 30% of the patients and long-term use of antiepileptics may induce serious side effects. Thus, there is an interest in the study of the therapeutic potential of bioactive substances isolated from natural products in the treatment of epilepsy. Arthropod venoms contain neurotoxins that have high affinity for molecular structures in the neural tissue such as receptors, transporters and ion channels both in glial and neuronal membranes. This study evaluated the potential neuroprotective effect of melittin (MEL), an active compound of bee venom, in the bicuculline-induced seizure model (BIC) in rats. Male Wistar rats (3 months, 250-300 g) were submitted to surgery for the implantation of a unilateral cannula in the lateral ventricle. After the recovery period, rats received a microinjection of saline solution or MEL (0.1 mg per animal). Firstly, rats were evaluated in the open field (20 min) and in the elevated plus maze (5 min) tests after received microinjection of saline or MEL. After, 30 min later animals received BIC (100 mg/ml) or saline, and their behaviors were analyzed for 20 min in the open field according to a seizure scale. At the end, rats were euthanized, brains collected and processed to glial fibrillary acidic protein (GFAP) immunohistochemistry evaluation. No changes were observed in MEL-treated rats in the open field and elevated plus maze. However, 90% of MEL-treated animals were protected against seizures induced by BIC. There was an increase in the latency for the onset of seizures, accompanied by a reduction of GFAP-immunoreactivity cells in the dentate gyrus and CA1. Thus, our study suggests that MEL has an anticonvulsant potential, and further studies are needed to elucidate the mechanisms involved in this action., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The aim of this study was to determine the seroprevalence of anti-Toxoplasma gondii antibodies and factors associated with infection in goats, and to isolate protozoan strains in tissue samples from seropositive goats that were destined for human consumption in the state of Paraíba, northeastern Brazil. Serum samples from 229 slaughtered goats were tested using the indirect fluorescence antibody test (IFAT), with a cutoff point of 1:64. Epidemiological questionnaires were applied to the producers, to acquire information about the sanitary management used in their herds. Tissue samples from the animals were collected during slaughter, in order to perform bioassays in mice. The seroprevalence found was 21.39% (49/229), with antibody titers ranging from 1:64 to 1:32,768. The municipalities of origin, Patos (OR: 3.047; CI: 1.384-6.706) and Sousa (OR: 3.355; CI: 1.536-7.327), were considered to be factors associated with infection by T. gondii. Thirty-eight bioassays were performed in mice, using tissues from seropositive goats, with an isolation rate of 50% (19/38). There was no correlation between isolation rate and antibody titers. Only one mouse died, at 30 days post-infection, which demonstrated that the strains isolated had low virulence towards mice. It was concluded that there is high seroprevalence in goats in northeastern Brazil, as well as a high percentage of viable tissue cysts in slaughtered animals destined for human consumption. These results demonstrate that there is an imminent one health problem relating to toxoplasmosis, especially in the most populous municipalities in the study (Patos and Sousa), which were identified as factors associated with T. gondii infection in goats., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Microglia have been increasingly implicated in neurodegenerative diseases (NDs), and specific disease associated microglia (DAM) profiles have been defined for several of these NDs. Yet, the microglial profile in Machado-Joseph disease (MJD) remains unexplored. Here, we characterized the profile of microglia in the CMVMJD135 mouse model of MJD. This characterization was performed using primary microglial cultures and microglial cells obtained from disease-relevant brain regions of neonatal and adult CMVMJD135 mice, respectively. Machine learning models were implemented to identify potential clusters of microglia based on their morphological features, and an RNA-sequencing analysis was performed to identify molecular perturbations and potential therapeutic targets. Our findings reveal morphological alterations that point to an increased activation state of microglia in CMVMJD135 mice and a disease-specific transcriptional profile of MJD microglia, encompassing a total of 101 differentially expressed genes, with enrichment in molecular pathways related to oxidative stress, immune response, cell proliferation, cell death, and lipid metabolism. Overall, these results allowed us to define the cellular and molecular profile of MJD-associated microglia and to identify genes and pathways that might represent potential therapeutic targets for this disorder.

Over the last few decades, several emerging or reemerging viral diseases with no readily available vaccines have ravaged the world. A platform to fastly generate vaccines inducing potent and durable neutralizing antibody and T cell responses is sorely needed. Bioinformatically identified epitope-based vaccines can focus on immunodominant T cell epitopes and induce more potent immune responses than a whole antigen vaccine and may be deployed more rapidly and less costly than whole-gene vaccines. Increasing evidence has shown the importance of the CD4+ T cell response in protection against HIV and other viral infections. The previously described DNA vaccine HIVBr18 encodes 18 conserved, promiscuous epitopes binding to multiple HLA-DR-binding HIV epitopes amply recognized by HIV-1-infected patients. HIVBr18 elicited broad, polyfunctional, and durable CD4 + and CD8+ T cell responses in BALB/c and mice transgenic to HLA class II alleles, showing cross-species promiscuity. To fully delineate the promiscuity of the HLA class II vaccine epitopes, we assessed their binding to 34 human class II (HLA-DR, DQ, and -DP) molecules, and immunized nonhuman primates. Results ascertained redundant 100% coverage of the human population for multiple peptides. We then immunized Rhesus macaques with HIVBr18 under in vivo electroporation. The immunization induced strong, predominantly polyfunctional CD4+ T cell responses in all animals to 13 out of the 18 epitopes; T cells from each animal recognized 7-11 epitopes. Our results provide a preliminary proof of concept that immunization with a vaccine encoding epitopes with high and redundant coverage of the human population can elicit potent T cell responses to multiple epitopes, across species and MHC barriers. This approach may facilitate the rapid deployment of immunogens eliciting cellular immunity against emerging infectious diseases, such as COVID-19., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Evaluating the influence of vitamin D concentrations together with preoperative metabolic phenotypes on remission of chronic noncommunicable diseases (CNCDs) after 6 months of Roux-en-Y gastric bypass (RYGB). Cross-sectional analytical study comprising 30 adult individuals who were assessed preoperatively (T0) and 6 months (T1) after undergoing RYGB. Participants were distributed preoperatively into metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO) individuals according to HOMA-IR classification and to the adequacy and inadequacy of vitamin D concentrations in the form of 25(OH)D. All participants were assessed for anthropometric characteristics, biochemical variables, and presence of CNCDs. The statistical program used was the SPSS version 21. In face of vitamin D adequacy and regardless of the metabolic phenotype classification in the preoperative period, the means found for HOMA-IR allowed us to define them as metabolically healthy 6 months after RYGB. Only those with vitamin D inadequacy with the MUHO phenotype showed better results regarding the reduction of glucose that accompanied the shift in serum 25(OH)D concentrations from deficient to insufficient. It is possible that preoperative vitamin D adequacy, even in the presence of an unhealthy phenotype, may contribute to the reduction of dyslipidemia and improvement in cholesterol. It is suggested that preoperative vitamin D adequacy in both phenotypes may have a protective effect on metabolic health.

Introduction: Given that chronic inflammatory pain is highly prevalent worldwide, it is important to study new techniques to treat or relieve this type of pain. The present study evaluated the effect of transcranial direct current stimulation (tDCS) in rats submitted to a chronic inflammatory model by nociceptive response, biomarker levels (brain-derived neurotrophic factor [BDNF] and interleukin [IL]-6 and IL-10), and by histological parameters., Methods: Sixty-day-old male Wistar rats were used in this study and randomized by weight into 6 major groups: total control, control + sham-tDCS, control + active tDCS, total CFA, CFA + sham-tDCS, and CFA + active tDCS. After inflammatory pain was established, the animals were submitted to the treatment protocol for 8 consecutive days, according to the experimental group. The nociceptive tests (von Frey and hot plate) were assessed, and euthanasia by decapitation occurred at day 8 after the end of tDCS treatment, and the blood serum and central nervous structures were collected for BDNF and IL measurements. All experiments and procedures were approved by the Institutional Committee for Animal Care and Use (UFPel #4538)., Results: The tDCS treatment showed a complete reversal of the mechanical allodynia induced by the pain model 24 h and 8 days after the last tDCS session, and there was partial reversal of the thermal hyperalgesia at all time points. Serum BDNF levels were decreased in CFA + sham-tDCS and CFA + tDCS groups compared to the control + tDCS group. The control group submitted to tDCS exhibited an increase in serum IL-6 levels in relation to the other groups. In addition, there was a significant decrease in IL-10 striatum levels in control + tDCS, CFA, and CFA + sham-tDCS groups in relation to the control group, with a partial tDCS effect on the CFA pain model. Local histology demonstrated tDCS effects in decreasing lymphocytic infiltration and neovascularization and tissue regeneration in animals exposed to CFA., Conclusion: tDCS was able to reverse the mechanical allodynia and decrease thermal hyperalgesia and local inflammation in a chronic inflammatory pain model, with a modest effect on striatum IL-10 levels. As such, we suggest that analgesic tDCS mechanisms may be related to tissue repair by modulating the local inflammatory process., (© 2022 S. Karger AG, Basel.)

Background: Screening for pancreatic ductal adenocarcinoma (PDAC) in populations at high risk is recommended. Individuals with new-onset type 2 diabetes mellitus (NOD) are the largest high-risk group for PDAC. To facilitate screening, we sought biomarkers capable of stratifying NOD subjects into those with type 2 diabetes mellitus (T2DM) and those with the less prevalent PDAC-related diabetes (PDAC-DM), a form of type 3c DM commonly misdiagnosed as T2DM., Methods: Using mass spectrometry- and immunoassay-based methodologies in a multi-stage analysis of independent sample sets (n=443 samples), blood levels of 264 proteins were considered using Ingenuity Pathway Analysis, literature review and targeted training and validation., Findings: Of 30 candidate biomarkers evaluated in up to four independent patient sets, 12 showed statistically significant differences in levels between PDAC-DM and T2DM. The combination of adiponectin and interleukin-1 receptor antagonist (IL-1Ra) showed strong diagnostic potential, (AUC of 0.91; 95% CI: 0.84-0.99) for the distinction of T3cDM from T2DM., Interpretation: Adiponectin and IL-1Ra warrant further consideration for use in screening for PDAC in individuals newly-diagnosed with T2DM., Funding: North West Cancer Research, UK, Cancer Research UK, Pancreatic Cancer Action, UK., Competing Interests: Declaration of Competing Interest LO, EC, WG, CH and PG are named as inventors on GB patent GB1806002.0; PCT/GB2019/050998, submitted by the University of Liverpool, that covers the measurement of adiponectin and IL-1Ra as a biomarker for early detection of pancreatic cancer. UM holds patent number EP EP10178345.4 for breast cancer diagnosis, and has stock ownership awarded by the University College London (UCL) in Abcodia., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Viral diseases are the cause of many global epidemics, leading to deaths, affecting the quality of life of populations, and impairing public health. The limitations in the treatment of viral diseases and the constant resistance to conventional antiviral treatments encourage researchers to discover new compounds. In this perspective, this literature review presents isolated molecules and extracts of natural products capable of inhibiting the activity of the nonstructural protein that acts as the RNA-dependent RNA polymerase. The literature review presented natural compounds with the potential to be tested as alternative medicines or used in the development of synthetic drugs to prevent the replication of RNA viruses, such as COVID-19, hepatitis C, and dengue viruses, among others. Natural products are known to exhibit remarkable activities in mitigation of different viral diseases, in addition, they help to decrease the aggravation of infections. Consequently, reducing hospitalization time and deaths., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Pancreatic cancer is one of the deadliest cancers partly due to late diagnosis, poor drug delivery to the target site, and acquired resistance to therapy. Therefore, more effective therapies are urgently needed to improve the outcome of patients. In this work, we have tested self-assembling genetically engineered polymeric nanoparticles formed by elastin-like recombinamers (ELRs), carrying a small peptide inhibitor of the protein kinase Akt, in both PANC-1 and patient-derived pancreatic cancer cells (PDX models). Nanoparticle cell uptake was measured by flow cytometry, and subcellular localization was determined by confocal microscopy, which showed a lysosomal localization of these nanoparticles. Furthermore, metabolic activity and cell viability were significantly reduced after incubation with nanoparticles carrying the Akt inhibitor in a time- and dose-dependent fashion. Self-assembling 73 ± 3.2 nm size nanoparticles inhibited phosphorylation and consequent activation of Akt protein, blocked the NF-κB signaling pathway, and triggered caspase 3-mediated apoptosis. Furthermore, in vivo assays showed that ELR-based nanoparticles were suitable devices for drug delivery purposes with long circulating time and minimum toxicity. Hence, the use of these smart nanoparticles could lead to the development of more effective treatment options for pancreatic cancer based on the inhibition of Akt.

Objective: This study analysed the association between caesarean section and early childhood caries (ECC), estimating the effects using regression and causal inference models., Methods: This was a historical cohort study of 697 mother-child dyads, conducted in São Luís, Brazil. The caesarean section was the exposure, and the severity of ECC (dmft) was the outcome. Covariates household income, maternal schooling, maternal hypertension, maternal obesity and birth weight were adjusted for in the models. The effects were estimated by Poisson regression (Means Ratio-MR) and causal inference using a marginal structural model (MSM) (MR and Average Treatment Effect-ATE coefficients), weighted by the inverse probability (IPW) of exposure., Results: Caesarean section was protective against caries in the bivariate (MR 0.81; CI 0.70-0.94; P = 0.005) and multivariate (MR 0.78; CI 0.67-0.91; P = 0.002) models. In MSM analyses, the caesarean section had no effect on ECC (ATE = -0.35; P = 0.107), controlling for IPW of exposure., Conclusion: The apparent association between caesarean section and ECC severity seems spurious, as it did not persist after employing a superior approach to estimating causality., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Current pharmacological approaches to treat Parkinson's disease have low long-term efficacy and important adverse side effects. The development of new pharmacological therapies has focused on novel plant-derived phytochemicals. The alcoholic monoterpene myrtenol has been isolated from several plant species, and has anxiolytic, analgesic, anti-inflammatory and antioxidant actions. Our study evaluated the neuroprotective potential of myrtenol complexed with β-cyclodextrin (MYR) on a progressive parkinsonism model induced by reserpine (RES) in mice. The complexation with cyclodextrins enhances the pharmacological action of monoterpenes. Male Swiss mice were treated daily with MYR (5 mg/kg, p.o.) and with RES (0.1 mg/kg, s.c.) every other day during 28 days. Behavioural evaluations were conducted across treatment. At the end of the treatment, immunohistochemistry for tyrosine hydroxylase (TH) and oxidative stress parameters were evaluated. Chronic MYR-treatment protected against olfactory sensibility loss, restored short-term memory and decreased RES-induced motor impairments. Moreover, this treatment prevented dopaminergic depletion and reduced the oxidative status index in the dorsal striatum. Therefore, MYR ameliorated motor and non-motor impairments in the progressive animal model of parkinsonism, possibly by an antioxidant action. Additional research is needed to investigate the mechanisms involved in this neuroprotective effect., (© 2021 John Wiley & Sons Australia, Ltd.)

Toxoplasma gondii is a zoonotic parasite capable of infecting almost all warm-blooded animals. Currently, studies assessing the viability of cysts present in sheep meat are still scarce, especially in the northeastern region of Brazil. Therefore, the aim of this study was to evaluate the seroprevalence of anti-Toxoplasma gondii antibodies, isolate the parasite from tissue samples, and determine factors associated with infection of sheep intended for human consumption in the state of Paraíba, northeastern Brazil. Serum samples from 205 sheep slaughtered in Paraíba were tested using the indirect fluorescence antibody test (IFAT ≥ 64) for the presence of anti-T. gondii antibodies. Among the animals sampled, 30.7% (63/205) were seropositive, with antibody titers ranging from 1:64 to 1:16384. Sixty-one bioassays were performed in mice, and an isolation rate of 47.5% (29/61) was obtained. The infection was lethal to at least one infected mouse in 24.1% (7/29) of the bioassays. The mean length of survival of infected mice was 36.4 days. Females (OR = 3.183; CI = [1.452-6.976]), extensive breeding system (OR = 2.612; CI = [1.120-6.094]), and purebred animals (OR = 2.157; CI = [1.009-4.612]) were considered to be factors associated with infection. These results revealed that the prevalence of anti-T. gondii antibodies and the percentage of viable cysts recovered from sheep destined for human consumption in Paraíba, northeastern Brazil, were high., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pancreatic cancer has the worst survival rate among all cancers. Almost 70% of patients in the UK were diagnosed at Stage IV., Aim: This study aimed to investigate the symptoms associated with the diagnoses of pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine neoplasms (PNEN), and comparatively characterise the symptomatology between the two tumour types to inform earlier diagnosis., Design and Setting: A nested case-control study in primary care was conducted using data from the QResearch ® database. Patients aged ≥25 years and diagnosed with PDAC or PNEN during 2000 to 2019 were included as cases. Up to 10 controls from the same general practice were matched with each case by age, sex, and calendar year using incidence density sampling., Method: Conditional logistic regression was used to investigate the association between the 42 shortlisted symptoms and the diagnoses of PDAC and (or) PNEN in different timeframes relative to the index date, adjusting for patients' sociodemographic characteristics, lifestyle, and relevant comorbidities., Results: A total of 23 640 patients were identified as diagnosed with PDAC and 596 with PNEN. Of the symptoms identified, 23 were significantly associated with PDAC, and nine symptoms with PNEN. The two alarm symptoms for both tumours were jaundice and gastrointestinal bleeding. The two newly identified symptoms for PDAC were thirst and dark urine. The risk of unintentional weight loss may be longer than 2 years before the diagnosis of PNEN., Conclusion: PDAC and PNEN have overlapping symptom profiles. The QCancer ® (pancreas) risk prediction model could be updated by including the newly identified symptoms and comorbidities, which could help GPs identify high-risk patients for timely investigation in primary care., (© The Authors.)