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Objective: Since the approval of pembrolizumab for advanced or recurrent PD-L1 positive (CPS > 1%) cervical cancer, the clinical characteristics associated with response have remained undefined. We sought to characterize the clinicopathologic features of patients with advanced cervical cancer at our institution who derived durable clinical benefit from treatment with pembrolizumab. Methods: We conducted a retrospective cohort study of 14 patients with recurrent or metastatic cervical cancer who received pembrolizumab monotherapy from August 2017 to November 2019 and were followed until November 1, 2020. Reviewed clinical data included age, histology, tumor molecular profiling results, stage at diagnosis, treatment history, baseline pattern of metastatic disease at initiation of anti-PD-1 therapy, and outcomes. Treatment response was evaluated by computed tomography using RECIST v1.1 criteria. Results: The objective response rate was 21% (n = 3), including two partial responses and one complete response. Two patients (14%) had stable disease of six months or greater, for an observed durable clinical benefit rate of 36%. When stratified by those who derived clinical benefit, metastatic spread to lung and/or lymph node only at baseline was associated with improved response to pembrolizumab (n = 7, p = 0.02) and associated with significantly improved PFS and OS. Tumor mutational burden was higher in those with durable clinical benefit compared to non-responders (median 12.7 vs. 3.5 mutations/megabase, p = 0.03). Conclusions: Our findings highlight clinical features that may select for a population most likely to benefit from pembrolizumab monotherapy and underscores the need for identification of additional biomarkers of response.

Objective: We sought to describe the clinicopathologic features and outcomes of patients undergoing quaternary, quinary, or senary cytoreductive surgery for ovarian cancer. Methods: We retrospectively identified patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who underwent quaternary or beyond cytoreduction at our institution between 1/1/1989 and 12/31/2020. Kaplan-Meier curves were used to estimate survival and compared using the log-rank test. Cox-proportional hazards regression was used to detect variables associated with survival. Results: Twenty patients underwent 24 quaternary (n = 20), quinary (n = 3), or senary (n = 1) cytoreductive surgeries. Most patients had high-grade (89.5%) and serous (75.0%) tumors. At the time of quaternary cytoreduction, 44.7% of patients had single-site disease and 85.0% achieved a complete gross resection. After quaternary cytoreduction, 34.8% of patients developed a surgical complication, most of which were grade 1 or 2. Postoperatively, 80.0% of patients received additional medical treatment and 20.0% underwent observation alone. On univariate analysis, factors associated with progression-free survival included prolonged treatment-free interval (TFI), platinum sensitivity, and complete gross resection. Factors associated with disease-specific survival included platinum sensitivity and complete gross resection. Quinary and senary surgeries were associated with similar safety profiles, with no surgical complications reported. After quinary surgery, progression-free survival ranged from 5.0 to 216.0 months. Conclusions: In carefully selected patients, quaternary cytoreduction may be associated with acceptable morbidity and a relatively robust disease-specific survival. Patients who present to surgery with a prolonged TFI and achieve a complete gross resection likely derive the greatest benefit from quaternary surgery.

As a recently explored agricultural practice, the controlled elicitation of plants offers high potential in multiple crop needs as growth promotion, activation of defenses and the production of specific metabolites. Extracellular DNA has been identified as a plant immune system elicitor but some aspects of the plant response have not been explored. In the present work, five DNA treatments were applied in tomato plants and the response of catalase, superoxide dismutase, phenylalanine ammonia lyase activities, hydrogen peroxide, total phenolics and flavonoid contents in leaves were spectrophotometrically measured. Treatments differed by the source and concentration of DNA and plant phenological stage of application. Furthermore, mathematical modeling and principal component analysis were performed to explore the behavior of each variable and their interaction. The most effective treatment was the self-DNA application in young plants based on the intensity and duration of immune system activation. The information given by the measured variables correlated positively with the phenylpropanoid pathway markers and negatively with catalase and superoxide dismutase activities. Results reported here propose an easy way to evaluate plant immune response activation by DNA and any other elicitor and provide useful information for future development of controlled elicitation strategies in crop production.

The Jurkat E6.1 clone has been extensively used as a powerful tool for the genetic and biochemical dissection of the TCR signaling pathway. More recently, these cells have been exploited in imaging studies to identify key players in immunological synapse (IS) assembly in superantigen-specific conjugates and to track the dynamics of signaling molecules on glass surfaces coated with activating anti-CD3 antibodies. By comparison, Jurkat cells have been used only scantily for imaging on supported lipid bilayers (SLBs) incorporating laterally mobile TCR and integrin ligands, which allow to study synaptic rearrangements of surface molecules and the fine architecture of the mature IS, likely due to limitations in the assembly of immune synapses with well-defined architecture. Here we have explored whether upregulating the low levels of endogenous LFA-1 expression on Jurkat E6.1 cells through transduction with CD11a- and CD18-encoding lentiviruses can improve IS architecture. We show that, while forced LFA-1 expression did not affect TCR recruitment to the IS, E6.1 LFA-1high cells assembled better structured synapses, with a tighter distribution of signaling-competent TCRs at the center of the IS. LFA-1 upregulation enhanced protein phosphotyrosine signaling on SLBs but not at the IS formed in conjugates with SEE-pulsed APCs, and led to the constitutive formation of an intracellular phosphotyrosine pool co-localizing with endosomal CD3ζ. This was paralleled by an increase in the levels of p-ZAP-70 and p-Erk both under basal conditions and following activation, and in enhanced Ca2+ mobilization from intracellular stores. The enhancement in early signaling E6.1 LFA-1high cells did not affect expression of the early activation marker CD69 but led to an increase in IL-2 expression. Our results highlight a new role for LFA-1 in the core architecture of the IS that can be exploited to study the spatiotemporal redistribution of surface receptors on SLBs, thereby extending the potential of E6.1 cells and their derivatives for fine-scale imaging studies.

Abstract Background In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the health care system into integrated care with organizational health literacy. Main body As an example for chronic disease care, MASK (Mobile Airways Sentinel NetworK), a new project of the ARIA (Allergic Rhinitis and its Impact on Asthma) initiative, and POLLAR (Impact of Air POLLution on Asthma and Rhinitis, EIT Health), in collaboration with professional and patient organizations in the field of allergy and airway diseases, are proposing real-life ICPs centred around the patient with rhinitis, and using mHealth to monitor environmental exposure. Three aspects of care pathways are being developed: (i) Patient participation, health literacy and self-care through technology-assisted “patient activation”, (ii) Implementation of care pathways by pharmacists and (iii) Next-generation guidelines assessing the recommendations of GRADE guidelines in rhinitis and asthma using real-world evidence (RWE) obtained through mobile technology. The EU and global political agendas are of great importance in supporting the digital transformation of health and care, and MASK has been recognized by DG Santé as a Good Practice in the field of digitally-enabled, integrated, person-centred care. Conclusion In 20 years, ARIA has considerably evolved from the first multimorbidity guideline in respiratory diseases to the digital transformation of health and care with a strong political involvement.

Objective The association between inflammation and dysregulated bone remodeling is apparent in rheumatoid arthritis and is recapitulated in the human tumor necrosis factor transgenic (hTNFtg) mouse model. We investigated whether extracellular binding immunoglobulin protein (BiP) would protect the hTNFtg mouse from both inflammatory arthritis as well as extensive systemic bone loss and whether BiP had direct antiosteoclast properties in vitro. Methods hTNFtg mice received a single intraperitoneal administration of BiP at onset of arthritis. Clinical disease parameters were measured weekly. Bone analysis was performed by microcomputed tomography and histomorphometry. Mouse bone marrow macrophage and human peripheral blood monocyte precursors were used to study the direct effect of BiP on osteoclast differentiation and function in vitro. Monocyte and osteoclast signaling was analyzed by Western blotting, flow cytometry, and imaging flow cytometry. Results BiP‐treated mice showed reduced inflammation and cartilage destruction, and histomorphometric analysis revealed a decrease in osteoclast number with protection from systemic bone loss. Abrogation of osteoclast function was also observed in an ex vivo murine calvarial model. BiP inhibited differentiation of osteoclast precursors and prevented bone resorption by mature osteoclasts in vitro. BiP also induced downregulation of CD115/c‐Fms and Receptor Activator of NF‐κB (RANK) messenger RNA and protein, causing reduced phosphorylation of the p38 mitogen–activated protein kinases, extracellular signal–regulated kinases 1/2 and p38, with suppression of essential osteoclast transcription factors, c‐Fos and NFATc1. BiP directly inhibited TNF‐α– or Receptor Activator of NF–κB Ligand (RANKL)–induced NF‐κB nuclear translocation in THP‐1 monocytic cells and preosteoclasts by the canonical and noncanonical pathways. Conclusion BiP combines an anti‐inflammatory function with antiosteoclast activity, which establishes it as a potential novel therapeutic for inflammatory disorders associated with bone loss.

Short-chain fatty acids (SCFAs) have immunomodulatory effects, but the underlying mechanisms are still unclear. Here the authors show that a SCFA, pentanoate, suppresses autoimmune inflammation in mouse models of colitis and multiple sclerosis via epigenetic modulation of immune cell metabolic and functional pathways.

Drum-drying results in pregelatinized starch with relatively low starch fragmentation and a great ability to absorb water and swell at room temperature. However, the effect of the degree of cold particle swelling and the thickening potential of drum-dried starch on its suitability as oil replacer in low-fat oil-in-water emulsions has received little attention. In this work, the potential of three pregelatinized drum-dried starches with almost identical molecular structure (as measured by size exclusion chromatography) and Water Binding Capacity (WBC), but different swelling behavior, was investigated to replace up to 60% oil in a mayonnaise-like emulsion system. The microstructure, stability, and rheology of the oil-in-water emulsions were noticeably affected by the substitution of oil with a pregelatinized drum-dried starch paste. Specifically, reduced-fat emulsions presented smaller droplet-size, a higher consistency index and increased emulsion stability, especially against freeze-thaw cycles, compared to the control full-fat mayonnaise. Importantly, the differences in cold swelling behavior (rather than simply assessing WBC) greatly influenced the consistency index and stability of low-fat emulsions, and results showed that drum-dried starch particles with high swelling potential perform better as oil replacers.

Objective: To report characteristics of patients with low-grade endometrioid endometrial carcinoma (EC) who develop brain metastases. Methods: We retrospectively identified all patients treated at our institution for FIGO grades 1/2 EC from 1/2000–12/2016, who developed brain metastases. Electronic medical records were reviewed, data abstracted. Overall survival (OS) was determined from time of brain metastases to death or last follow-up. Appropriate statistical tests were used. Results: Of 3052 patients, 23 (9, grade 1; 14, grade 2) developed brain metastases (incidence = 0.75%). Presentation at initial diagnosis: median age = 61.3 years (range, 41–81); median BMI = 29.8 kg/m2 (range, 20.3–42.6 kg/m2); distribution by stage: I, 15/23 (65%); II, 2/23 (8.7%); III, 3/23 (13.0%); IV, 3 (13.0%). None showed clinical evidence of brain metastases at presentation. Median time to diagnosis of brain metastases = 29.7 months (range, 6–145); median age = 64.6 years (range, 47.5–86.5). Brain metastases were the first, isolated site of recurrence in 2/23 (9%). All presented with neurological symptoms. Six (26%) had solitary brain lesions. Seventeen (74%) received treatment; 6 (28%), supportive care only. Median OS for patients receiving any treatment = 5.8 months (95% CI, 1.6–10.0), versus 2.4 months (95% CI, 1.5–3.3; p = .04) for best supportive care. Conclusion: Brain metastases in low-grade EC is rare, prognosis generally poor. Compared to supportive care only, any treatment results in more favorable outcomes. Keywords: Brain metastases, Endometrial carcinoma, Low-grade endometrial carcinoma

Recent advances in numerical modeling, satellite data, and coastal processes, together with the rapid evolution of CMEMS products and the increasing pressures on coastal zones, suggest the timeliness of extending such products toward the coast. The CEASELESS EU H2020 project combines Sentinel and in-situ data with high-resolution models to predict coastal hydrodynamics at a variety of scales, according to stakeholder requirements. These predictions explicitly introduce land discharges into coastal oceanography, addressing local conditioning, assimilation memory and anisotropic error metrics taking into account the limited size of coastal domains. This article presents and discusses the advances achieved by CEASELESS in exploring the performance of coastal models, considering model resolution and domain scales, and assessing error generation and propagation. The project has also evaluated how underlying model uncertainties can be treated to comply with stakeholder requirements for a variety of applications, from storm-induced risks to aquaculture, from renewable energy to water quality. This has led to the refinement of a set of demonstrative applications, supported by a software environment able to provide met-ocean data on demand. The article ends with some remarks on the scientific, technical and application limits for CMEMS-based coastal products and how these products may be used to drive the extension of CMEMS toward the coast, promoting a wider uptake of CMEMS-based predictions.

Over several decades, UCSD has developed and continually updated a time-dependent iterative three-dimensional (3-D) reconstruction technique to provide global heliospheric parameters—density, velocity, and component magnetic fields. For expediency, this has used a kinematic model as a kernel to provide a fit to either interplanetary scintillation (IPS) or Thomson-scattering observations. This technique has been used in near real time over this period, employing Institute for Space-Earth Environmental Research, Japan, IPS data to predict the propagation of these parameters throughout the inner heliosphere. We have extended the 3-D reconstruction analysis to include other IPS Stations around the Globe in a Worldwide Interplanetary Scintillation Stations Network. In addition, we also plan to resurrect the Solar Mass Ejection Imager Thomson-scattering analysis as a basis for 3-D analysis to be used by the latest NASA Small Explorer heliospheric imagers of the Polarimeter to Unify the Corona and Heliosphere mission, the All Sky Heliospheric Imager, and other modern wide-field imagers. Better data require improved heliospheric modeling that incorporates non-radial transport of heliospheric flows, and shock processes. Looking ahead to this, we have constructed an interface between the 3-D reconstruction tomography and 3-D MHD models and currently include the ENLIL model as a kernel in the reconstructions to provide this fit. In short, we are now poized to provide all of these innovations in a next step: to include them for planned ground-based and spacecraft instruments, all to be combined into a truly global 3-D heliospheric system which utilizes these aspects in their data and modeling.

Background: Limited data are available on the management of pregnant women with severe or critical forms of COVID-19, such as the optimal timing of provider-initiated delivery, and post-partum care, including antithrombotic prophylaxis. We present the clinical course, pre- and post-partum management, and outcomes of two pregnant women critically ill with COVID-19. Cases: Both women had confirmed SARS-CoV-2 pneumonia with rapid clinical decompensation that required admission to the intensive care unit, intubation, and delivery by emergency cesarean section at 32 and 29 weeks. Both patients clinically improved in the first two postoperative days, but this was followed by clinical, laboratory and radiological deterioration on the third postoperative day; however, they both improved again after full anticoagulation. This pattern suggests the possible formation of pulmonary microthrombi in the early puerperium. We discuss the challenges faced by the multiprofessional team in the management of these patients. Conclusions: There are few resources to guide health professionals caring for pregnant women with critical COVID-19. These two cases contribute to the rapidly evolving knowledge on the management and outcomes of pregnant women with COVID-19.

Background: In Behçet's disease (BD), an auto-inflammatory vasculitis, an unbalanced gut microbiota can contribute to pro-inflammatory reactions. In separate studies, distinct pro- and anti-inflammatory bacteria associated with BD have been identified.Methods: To establish disease-associated determinants, we performed gut microbiome profiling in BD patients from the Netherlands (n = 19) and Italy (n = 13), matched healthy controls (HC) from the Netherlands (n = 17) and Italy (n = 15) and oral microbiome profiling in Dutch BD patients (n = 18) and HC (n = 15) by 16S rRNA gene sequencing. In addition, we used fecal IgA-SEQ analysis to identify specific IgA coated bacterial taxa in Dutch BD patients (n = 13) and HC (n = 8).Results: In BD stool samples alpha-diversity was conserved, whereas beta-diversity analysis showed no clustering based on disease, but a significant segregation by country of origin. Yet, a significant decrease of unclassified Barnesiellaceae and Lachnospira genera was associated with BD patients compared to HC. Subdivided by country, the Italian cohort displays a significant decrease of unclassified Barnesiellaceae and Lachnospira genera, in the Dutch cohort this decrease is only a trend. Increased IgA-coating of Bifidobacterium spp., Dorea spp. and Ruminococcus bromii species was found in stool from BD patients. Moreover, oral Dutch BD microbiome displayed increased abundance of Spirochaetaceae and Dethiosulfovibrionaceae families.Conclusions: BD patients show decreased fecal abundance of Barnesiellaceae and Lachnospira and increased oral abundance of Spirochaetaceae and Dethiosulfovibrionaceae. In addition, increased fecal IgA coating of Bifidobacterium, Ruminococcus bromii and Dorea may reflect retention of anti-inflammatory species and neutralization of pathosymbionts in BD, respectively. Additional studies are warranted to relate intestinal microbes with the significance of ethnicity, diet, medication and response with distinct pro- and inflammatory pathways in BD patients.

This study evaluated simultaneously the raw vinasse degradation, an effluent from the sugar-alcohol industry, the laccase production by Pleurotus sajor-caju and its purification using aqueous two-phase systems (ATPS). To improve laccase production, different concentrations of inducers (ethanol and CuSO4) were added. The higher laccase production promoted an increase of 4-fold using 0.4 mM of CuSO4 as inducer, with maximum enzymatic activity of 539.3 U/L on the 3rd day of fermentation. The final treated vinasse had a decolorization of 92% and turbidity removal of 99% using CuSO4. Moreover, the produced laccase was then purified by ATPS in a single purification step, reaching 2.9-fold and recovered ≈ 99,9 %, in the top phase (PEG-rich phase) using 12 wt% of PEG 1500 + 20 wt% of citrate buffer + enzyme broth + water, at 25 °C. Thus, an integrated process of vinasse degradation, laccase production and purification with potential industrial application was proposed. Keywords: Biomass, biological treatment, decolorization, inducers, laccase purification

Abstract A strong mesoscale convective system affected northeastern Italy on August 8, 2008. Notable damage and two casualties resulted, mainly due to the strong wind gusts. The event is analysed using observations, including surface data from a meso‐network of meteorological stations, radar reflectivity and velocity data from a C‐band Doppler radar, polar satellite images, lightning measurements from a lightning detection network and the ambient thermodynamic conditions derived from local radiosoundings. The role of the cold front is investigated; in particular, the associated strong wind descending from the Alps, which interacted with the preexisting convection in the plain, is analysed to understand the way it affected the storm development. A simple density current model is applied to describe the flow characteristics and to identify the mechanisms that could support the development of such a high wind speed. Lastly, observed wind speeds are compared with the theoretical estimates from the proposed model. The results show that different factors contribute to the very strong wind gusts registered by surface stations. The main contributor to the windstorm is a density current (a) driven by the cold front, (b) maintained by the interaction between the cold air impinging on the Friuli Venezia Giulia plain from the north and the strong regional density gradient and (c) eventually enhanced by the storm cold pool. This study highlights the complex evolution of severe storms in a region on the lee side of the Alpine chain, and emphasizes the role of the orography in the enhancement of storm.

Abstract The study was carried out to assess meteorological drought on the basis of the standardized precipitation index (SPI) and standardized precipitation evapotranspiration index (SPEI) evaluated in future climate scenarios. Yazd province, located in an arid region in the centre of Iran, was chosen for analysis. The study area has just one synoptic station with a long‐term record (56 years). The impact of climate change on future drought was examined by using the CanESM2 of the CMIP5 model under three scenarios, that is, representative concentration pathways RCP2.6, RCP4.5 and RCP8.5. Given that a drought is defined by several dependent variables, the evaluation of this phenomenon should be based on a multivariate analysis. For this purpose, two main characteristics of drought (severity and duration) were extracted by run theory in a past (1961–2016) and future (2017–2100) period based on the SPI and SPEI, and studied using copula theory. Three functions, that is, Frank, Gaussian and Gumbel copula, were selected to fit with drought severity and duration. The results of the bivariate analysis using copula showed that, according to both indicators, the study area will experience droughts with greater severity and duration in future as compared with the historical period, and the drought represented by the SPEI is more severe than that associated with the SPI. Also, drought simulated using the RCP8.5 scenario was more severe than when using the other two scenarios. Finally, droughts with a longer return period will become more frequent in future.

Group 2 innate lymphoid cells (ILC2s) are a recently recognized subset of innate lymphocytes with crucial role in mucosal immunity and tissue homeostasis. Over the past decade, substantial advances in our understanding of ILC2 biology have established them as an essential element in innate and adaptive immunity. However, their relatively low abundance and laborious purification from mucosal tissues make their study difficult. Moreover, due to a lack of an ILC2-specific Cre mouse-line, adoptive transfer of ILC2s into ILC-deficient hosts is inevitable. Herein we describe an in-depth protocol for the induction, isolation, and expansion of murine ILC2s. By combining an in vivo gene delivery approach to boost ILC2 numbers and a cell culture strategy to expand isolated cells, large quantities of highly pure ILC2s can be obtained. The isolated cells maintain their phenotype and can be used for subsequent cell transfer or in vitro studies. In comparison to previous protocols, this approach is cost-effective and efficient with potential yield of more than 20 million ILC2s isolated per mouse.• Group 2 innate lymphoid cells (ILC2s) are extensively studied in mouse models and humans in recent years.• Low abundance of ILC2s and current lack of specific ILC2 knockout mice makes in vivo research challenging.• This method allows high and pure ILC2 numbers for in vitro or adoptive in vivo transfer experiments.

While type 2 immunity has traditionally been associated with the control of parasitic infections and allergic reactions, increasing evidence suggests that type 2 immunity exerts regulatory functions on inflammatory diseases such as arthritis, and also on bone homeostasis. This review summarizes the current evidence of the regulatory role of type 2 immunity in arthritis and bone. Key type 2 cytokines, like interleukin (IL)-4 and IL-13, but also others such as IL-5, IL-9, IL-25, and IL-33, exert regulatory properties on arthritis, dampening inflammation and inducing resolution of joint swelling. Furthermore, these cytokines share anti-osteoclastogenic properties and thereby reduce bone resorption and protect bone. Cellular effectors of this action are both T cells (i.e., Th2 and Th9 cells), but also non-T cells, like type 2 innate lymphoid cells (ILC2). Key regulatory actions mediated by type 2 cytokines and immune cells on both inflammation as well as bone homeostasis are discussed.

Obesity—in which free fatty acid (FFA) levels are chronically elevated—is a known risk factor for different rheumatic diseases, and obese patients are more likely to develop osteoarthritis (OA) also in non-weight-bearing joints. These findings suggest that FFA may also play a role in inflammation-related joint damage and bone loss in rheumatoid arthritis (RA) and OA. Therefore, the objective of this study was to analyze if and how FFA influence cells of bone metabolism in rheumatic diseases. When stimulated with FFA, osteoblasts from RA and OA patients secreted higher amounts of the proinflammatory cytokine interleukin (IL)-6 and the chemokines IL-8, growth-related oncogene α, and monocyte chemotactic protein 1. Receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin, and osteoblast differentiation markers were not influenced by FFA. Mineralization activity of osteoblasts correlated inversely with the level of FFA-induced IL-6 secretion. Expression of the Wnt signaling molecules, axin-2 and β-catenin, was not changed by palmitic acid (PA) or linoleic acid (LA), suggesting no involvement of the Wnt signaling pathway in FFA signaling for osteoblasts. On the other hand, Toll-like receptor 4 blockade significantly reduced PA-induced IL-8 secretion by osteoblasts, while blocking Toll-like receptor 2 had no effect. In osteoclasts, IL-8 secretion was enhanced by PA and LA particularly at the earliest time point of differentiation. Differences were observed between the responses of RA and OA osteoclasts. FFA might therefore represent a new molecular factor by which adipose tissue contributes to subchondral bone damage in RA and OA. In this context, their mechanisms of action appear to be dependent on inflammation and innate immune system rather than Wnt-RANKL pathways.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CD66a) is a receptor for Candida albicans. It is crucial for the immune response of intestinal epithelial cells to this opportunistic pathogen. Moreover, CEACAM1 is of importance for the mucosal colonization by different bacterial pathogens. We therefore studied the influence of the human CEACAM1 receptor in human CEACAM1-transgenic mice on the C. albicans colonization and infection utilizing a colonization/dissemination and a systemic infection mouse model. Our results showed no alterations in the host response between the transgenic mice and the wild-type littermates to the C. albicans infections. Both mouse strains showed comparable C. albicans colonization and mycobiota, similar fungal burdens in various organs, and a similar survival in the systemic infection model. Interestingly, some of the mice treated with anti-bacterial antibiotics (to prepare them for C. albicans colonization via oral infection) also showed a strong reduction in endogenous fungi instead of the normally observed increase in fungal numbers. This was independent of the expression of human CEACAM1. In the systemic infection model, the human CEACAM1 expression was differentially regulated in the kidneys and livers of Candida-infected transgenic mice. Notably, in the kidneys, a total loss of the largest human CEACAM1 isoform was observed. However, the overwhelming immune response induced in the systemic infection model likely covered any CEACAM1-specific effects in the transgenic animals. In vitro studies using bone marrow-derived neutrophils from both mouse strains also revealed no differences in their reaction to C. albicans. In conclusion, in contrast to bacterial pathogens interacting with CEACAM1 on different mucosal surfaces, the human CEACAM1-transgenic mice did not reveal a role of human CEACAM1 in the in vivo candidiasis models used here. Further studies and different approaches will be needed to reveal a putative role of CEACAM1 in the host response to C. albicans.

Summary: Group 2 innate lymphoid cells (ILC2s) were detected in the peripheral blood and the joints of rheumatoid arthritis (RA) patients, serum-induced arthritis (SIA), and collagen-induced arthritis (CIA) using flow cytometry. Circulating ILC2s were significantly increased in RA patients compared with healthy controls and inversely correlated with disease activity. Induction of arthritis in mice led to a fast increase in ILC2 number. To elucidate the role of ILC2 in arthritis, loss- and gain-of-function mouse models for ILC2 were subjected to arthritis. Reduction of ILC2 numbers in RORαcre/GATA3fl/fl and Tie2cre/RORαfl/fl mice significantly exacerbated arthritis. Increasing ILC2 numbers in mice by IL-25/IL-33 mini-circles or IL-2/IL-2 antibody complex and the adoptive transfer of wild-type (WT) ILC2s significantly attenuated arthritis by affecting the initiation phase. In addition, adoptive transfer of IL-4/13-competent WT but not IL-4/13−/− ILC2s and decreased cytokine secretion by macrophages. These data show that ILC2s have immune-regulatory functions in arthritis. : The role of ILC2s in the initiation phase of inflammatory arthritis has remained unclear. Omata et al. demonstrate that the ILC2-derived IL-4/13 decrease pro-inflammatory cytokine secretion by macrophages, thereby attenuating arthritis. Keywords: innate lymphoid cells, rheumatoid arthritis, immunoregulation

Objetivou-se verificar as espécies de leveduras da mucosa cérvico-vaginal de cadelas e a virulência “in vitro” dos isolados por ensaios de produção de protease e fosfolipase. Utilizou-se 40 fêmeas caninas, divididas em não ovariectomizadas e cadelas gestantes. As coletas ocorreram por lavado cérvico-vaginal, com tampão salina estéril, seguindo-se isolamento em meio Ágar Infuso Cérebro e Coração, sucedido de provas bioquímicas para identificação das leveduras. A avaliação da produção de protease e de fosfolipase foi realizada “in vitro”, com meios específicos. Das 40 cadelas, em 82,5% obteve-se o crescimento fúngico. Foram obtidos 60 isolados, sendo 21 (35,0%) identificados como Candida spp, 19 (31.66%) Malassezia spp, 13 (21,66%) Rhodotorula spp e 7 (11,66%) Trichosporon spp. Das 60 cepas testadas para produção de protease 36,66% foram negativas, 33,33% positivas e 30,0% forte positivas. Para produção de fosfolipase, 45,0% foram negativas, 38,33% forte positivas e 16,66% positivas. A maioria dos isolados apresentou algum grau de virulência se considerarmos a capacidade de produção destas enzimas. O isolamento de cepas que são possíveis agentes de distúrbios reprodutivos, a determinação das espécies e a avaliação dos fatores de virulência representam talvez a solução de inúmeros distúrbios ainda pouco explicados e controlados na medicina veterinária.

Short-chain fatty acids (SCFA) are a main class of metabolites derived from fermentation of dietary fibre in the intestine. Here, the authors show that dietary administration of SCFA is associated with inhibition of osteoclast differentiation, increased bone mass, and reduced pathological bone loss in mice.

A Bayesian hierarchical framework with a Gaussian copula and a generalized extreme value (GEV) marginal distribution is proposed for the description of spatial dependencies in data. This spatial copula model was applied to extreme summer temperatures over the Extremadura Region, in the southwest of Spain, during the period 1980–2015, and compared with the spatial noncopula model. The Bayesian hierarchical model was implemented with a Monte Carlo Markov Chain (MCMC) method that allows the distribution of the model’s parameters to be estimated. The results show the GEV distribution’s shape parameter to take constant negative values, the location parameter to be altitude dependent, and the scale parameter values to be concentrated around the same value throughout the region. Further, the spatial copula model chosen presents lower deviance information criterion (DIC) values when spatial distributions are assumed for the GEV distribution’s location and scale parameters than when the scale parameter is taken to be constant over the region.

Short-chain fatty acids are gut-bacteria-derived metabolites that execute important regulatory functions on adaptive immune responses, yet their influence on inflammation driven by innate immunity remains understudied. Here, we show that propionate treatment in drinking water or upon local application into the joint reduced experimental arthritis and lowered inflammatory tissue priming mediated by synovial fibroblasts. On a cellular level, incubation of synovial fibroblasts with propionate or a physiological mixture of short-chain fatty acids interfered with production of inflammatory mediators and migration and induced immune-regulatory fibroblast senescence. Our study suggests that propionate mediates its alleviating effect on arthritis by direct abrogation of local arthritogenic fibroblast function.

Infections with different helminth species have been observed to ameliorate a variety of chronic inflammatory diseases. Herein, we show that the natural murine helminth species, Heligmosomoides polygyrus bakeri (Hp) is capable of attenuating disease severity in two different inflammatory arthritis models. Furthermore, we show that excretory–secretory (ES) products from Hp directly suppress osteoclast differentiation in vitro. Taken together, these results demonstrate that helminth infections can dampen autoimmune diseases and highlight a previously unrecognized and important role for ES products, by directly impacting on bone destruction.

Abstract Exposure of human monocytes to lipopolysaccharide (LPS) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called endotoxin tolerance. In this study, we investigated the LPS-induced global glycoprotein expression changes of tolerant human monocytes and THP-1 cells to identify markers and glycoprotein targets capable to modulate the immunosuppressive state. Using hydrazide chemistry and LC-MS/MS analysis, we analyzed glycoprotein expression changes during a 48 h LPS time course. The cellular snapshots at different time points identified 1491 glycoproteins expressed by monocytes and THP-1 cells. Label-free quantitative analysis revealed transient or long-lasting LPS-induced expression changes of secreted or membrane-anchored glycoproteins derived from intracellular membrane coated organelles or from the plasma membrane. Monocytes and THP-1 cells demonstrated marked differences in glycoproteins differentially expressed in the tolerant state. Among the shared differentially expressed glycoproteins G protein-coupled receptor 84 (GPR84) was identified as being capable of modulating pro-inflammatory TNFα mRNA expression in the tolerant cell state when activated with its ligand Decanoic acid.

The Shc family adaptor p66Shc acts as a negative regulator of proliferative and survival signals triggered by the B-cell receptor and, by enhancing the production of reactive oxygen species, promotes oxidative stress-dependent apoptosis. Additionally, p66Shc controls the expression and function of chemokine receptors that regulate lymphocyte traffic. Chronic lymphocytic leukemia cells have a p66Shc expression defect which contributes to their extended survival and correlates with poor prognosis. We analyzed the impact of p66Shc ablation on disease severity and progression in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia. We showed that Eμ-TCL1/p66Shc−/− mice developed an aggressive disease that had an earlier onset, occurred at a higher incidence and led to earlier death compared to that in Eμ-TCL1 mice. Eμ-TCL1/p66Shc−/− mice displayed substantial leukemic cell accumulation in both nodal and extranodal sites. The target organ selectivity correlated with upregulation of chemokine receptors whose ligands are expressed therein. This also applied to chronic lymphocytic leukemia cells, where chemokine receptor expression and extent of organ infiltration were found to correlate inversely with these cells’ level of p66Shc expression. p66Shc expression declined with disease progression in Eμ-TCL1 mice and could be restored by treatment with the Bruton tyrosine kinase inhibitor ibrutinib. Our results highlight p66Shc deficiency as an important factor in the progression and severity of chronic lymphocytic leukemia and underscore p66Shc expression as a relevant therapeutic target.

Redescription of the advertisement call of Brachycephalus tridactylus (Anura: Brachycephalidae). Miniaturized frogs of the genus Brachycephalus have restricted geographical distributions throughout the Atlantic Forest. Ecological data for most species are scarce and advertisement calls have been described for only 12 of the 36 known species, including B. tridactylus. The considerable duration of note length of the advertisement call of B. tridactylus has been mentioned in comparative studies of vocalizations in Brachycephalus. The single original recording of B. tridactylus, together with recordings made in March 2016 at the type locality, were analyzed to document any variation and redescribe the advertisement call of the species. In the recent recordings of B. tridactylus, the average length of the call is 50.8 s and the call is composed of 10–13 notes emitted at a note rate of 3.7–8.3 notes per min. The notes are isolated and composed of 1–3 pulses, with the note duration varying from 0.002–0.021 s. These values are not consistent with the original description of the call of B. tridactylus. The note duration is 89% shorter and the original description does not include notes with 1–3 pulses. The notes of B. tridactylus have few pulses, whereas those of B. ephippium have several. The advertisement call of B. tridactylus differs from that of B. albolineatus and B. mirissimus by having only isolated notes.

El principal objetivo de este trabajo es analizar el conocimiento ecológico de niños tseltales en relación con los sistemas de producción agrícola, los productos que los componen y su clasificación fría o caliente. A través de un taller, entrevistas a informantes clave e investigación de campo se estudió el conocimiento de los niños con respecto a los diversos sistemas productivos, plantas y animales silvestres asociados a ellos y sus características frías o calientes. Los resultados muestran que la participación activa de los infantes en los sistemas productivos y de obtención de alimentos es la mejor manera de transmisión del conocimiento ecológico tradicional. Los niños tseltales poseen un amplio conocimiento sobre su medioambiente, los sistemas productivos y su tradición alimentaria. La conservación del CET y de los sistemas alimentarios tradicionales puede preservar el medioambiente y garantizar la seguridad y autosuficiencia alimentaria.

Long-term monitoring of species assemblages provides a unique opportunity to test hypotheses regarding environmentally induced directional trajectories of freshwater species assemblages. We used 57 years of lockchamber fish rotenone and boat electrofishing survey data (1957-2014) collected by the Ohio River Valley Water Sanitation Commission (ORSANCO) to test for directional trajectories in taxonomy, trophic classifications, and life history strategies of freshwater fish assemblages in the Ohio River Basin. We found significant changes in taxonomic and trophic composition of freshwater fishes in the Ohio River Basin. Annual species richness varied from 31 to 90 species and generally increased with year. Temporal trajectories were present for taxonomic and trophic assemblages. Assemblage structure based on taxonomy was correlated with land use change (decrease in agriculture and increase in forest). Taxonomic assemblage structure was also correlated with altered hydrology variables of increased minimum discharge, decreased fall rate, and increased rise rate. Trophic composition of fish catch correlated with land use change (decrease in agriculture and increase in forest) and altered hydrology. Altered hydrology of increased minimum discharge, increased fall discharge, decreased base flows, and increased number of high pulse events was correlated with increased counts of herbivore-detritivores and decreased counts of piscivores and planktivores. We did not find directional changes in life history composition. We hypothesized a shift occurred from benthic to phytoplankton production throughout the basin that may have decreased secondary production of benthic invertebrates. This may also be responsible for lower trophic position of invertivore and piscivore fishes observed in other studies.

[This corrects the article DOI: 10.1371/journal.pone.0211848.].

Benefits and harms of different components of human diet have been known for hundreds of years. Alcohol is one the highest consumed, abused, and addictive substances worldwide. Consequences of alcohol abuse are increased risks for diseases of the cardiovascular system, liver, and nervous system, as well as reduced immune system function. Paradoxically, alcohol has also been a consistent protective factor against the development of autoimmune diseases such as type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis (RA). Here, we focused on summarizing current findings on the effects of alcohol, as well as of its metabolites, acetaldehyde and acetate, on the immune system and RA. Heavy or moderate alcohol consumption can affect intestinal barrier integrity, as well as the microbiome, possibly contributing to RA. Additionally, systemic increase in acetate negatively affects humoral immune response, diminishing TFH cell as well as professional antigen-presenting cell (APC) function. Hence, alcohol consumption has profound effects on the efficacy of vaccinations, but also elicits protection against autoimmune diseases. The mechanism of alcohol’s negative effects on the immune system is multivariate. Future studies addressing alcohol and its metabolite acetate’s effect on individual components of the immune system remains crucial for our understanding and development of novel therapeutic pathways.

The interaction and crosstalk of Toll-like receptors (TLRs) is an established pathway in which the innate immune system recognises and fights pathogens. In a single nucleotide polymorphisms (SNP) analysis of an Indian cohort, we found evidence for both TLR4-399T and TRL8-1A conveying increased susceptibility towards tuberculosis (TB) in an interdependent manner, even though there is no established TLR4 ligand present in Mycobacterium tuberculosis (Mtb), which is the causative pathogen of TB. Docking studies revealed that TLR4 and TLR8 can build a heterodimer, allowing interaction with TLR8 ligands. The conformational change of TLR4-399T might impair this interaction. With immunoprecipitation and mass spectrometry, we precipitated TLR4 with TLR8-targeted antibodies, indicating heterodimerisation. Confocal microscopy confirmed a high co-localisation frequency of TLR4 and TLR8 that further increased upon TLR8 stimulation. The heterodimerisation of TLR4 and TLR8 led to an induction of IL12p40, NF-κB, and IRF3. TLR4-399T in interaction with TLR8 induced an increased NF-κB response as compared to TLR4-399C, which was potentially caused by an alteration of subsequent immunological pathways involving type I IFNs. In summary, we present evidence that the heterodimerisation of TLR4 and TLR8 at the endosome is involved in Mtb recognition via TLR8 ligands, such as microbial RNA, which induces a Th1 response. These findings may lead to novel targets for therapeutic interventions and vaccine development regarding TB.

This study provides fundamental insight and offers a promising catalytic hydrothermal method to harness cranberry pomace as a potential bioenergy and/or hydrochar source. The physical and chemical properties of Canadian cranberry pomace, supplied by Fruit d’Or Inc., were examined and the optimum operational conditions, in terms of biocrude yield, were obtained by the I-optimal matrix of Design Expert 11. Afterward, cranberry pomace hydrochar (CPH) and zeolite were separately introduced to the hydrothermal liquefaction (HTL) process to investigate the benefits and disadvantages associated with their catalytic activity. CPH was found to be a better host than zeolite to accommodate cellulosic sugars and showed great catalytic performance in producing hydrocarbons. However, high amounts of corrosive amino and aliphatic acids hinder the practical application of CPH as a catalyst. Alternatively, zeolite, as a commercial high surface area catalyst, had a higher activity for deoxygenation of compounds containing carbonyl, carboxyl, and hydroxyl groups than CPH and resulted in higher selectivity of phenols. Due to the low hydrothermal structural stability, coke formation, and narrow pore size distribution, further activations and modifications are needed to improve the catalytic behavior of zeolite. Our results suggest that a composite composed of CPH and zeolite can resolve the abovementioned limitations and help with the development and commercialization of advanced biofuels from cranberry pomace.

El objetivo del trabajo fue evaluar el efecto de un alimento fermentado con pollinaza en las características sensoriales, calidad sanitaria y composición nutricional de la leche de vaca. Los tratamientos (T) evaluados fueron: T1, alimento fermentado con pollinaza (AFBP) y T2 (control), alimento sin fermentar con grano (ASFBG). Se utilizaron 10 vacas, las cuales se aleatorizaron en un diseño rectángulo Latino cross over de forma que los tratamientos se probaron en todas las vacas en dos periodos de tiempo, con lapso de 30 d para cada periodo. Se realizaron análisis de composición nutricional y de calidad sanitaria de la leche cruda. Antes del análisis sensorial la leche se pasteurizó para este análisis se utilizaron las pruebas discriminativas triangular y dúo-trío, y una prueba de análisis descriptivo cuantitativo. La calidad sanitaria de la leche en ambos tratamientos estuvo dentro de los rangos permitidos por las Normas Ociales Mexicanas. No se encontró diferencia signicativa (p > 0.05) entre los tratamientos estudiados en composición nutricional y características sensoriales. Solo se observó diferencia signicativa (p < 0.05) en la prueba discriminativa tipo triangular en el segundo periodo de muestreo. Se concluye que el AFBP puede utilizarse en la suplementación de vacas de doble propósito sin causar efectos negativos en la leche.

Introducción. La infección por el virus del dengue es una de las arbovirosis más importantes en el país y es un grave problema de salud pública. Objetivo. Determinar las características clínicas y los resultados de los exámenes de laboratorio de los pacientes que consultaron por dengue en la Clínica Universitaria Rafael Uribe Uribe de Cali, y analizar la tendencia del número de casos por semanas epidemiológicas durante el 2013. Materiales y métodos. Se hizo un estudio observacional retrospectivo de los pacientes que ingresaron con sospecha de dengue a la Clínica Rafael Uribe Uribe de Cali durante el 2013. Los pacientes con diagnóstico confirmado de infección por dengue se clasificaron de acuerdo con las definiciones de la Organización Mundial de la Salud y, posteriormente, se describieron los parámetros clínicos que presentaban. Resultados. Se notificaron 1.173 casos sospechosos, de los cuales 287 (24,5 %) fueron confirmados por serología; 152 (53,0 %) eran mujeres y 135 (47,0 %), hombres; 40,1 % no presentaba signos de alarma, 34,8 % sí y 25,1 % tuvo manifestaciones graves. Los síntomas más frecuentes fueron la fiebre (287; 100 %), las mialgias (223; 78,0 %), y la cefalea (183; 64,0 %). Las manifestaciones hemorrágicas se presentaron en 100 (34,8 %) de los pacientes. Cuatro pacientes (1,4 %) presentaron manifestaciones neurológicas. Se reportaron tres muertes (0,7 %), dos de las cuales se asociaron a la drepanocitosis. Conclusiones. La forma grave de la infección y la mortalidad que causó durante el periodo de estudio fueron más frecuentes en la población pediátrica. Se sugiere la implementación de estrategias que garanticen la atención específica de los pacientes con enfermedades concomitantes, como la drepanocitosis.

We present an algorithm for converting proofs from the OpenTheory interchange format, which can be translated to and from any of the HOL family of proof languages (HOL4, HOL Light, ProofPower, and Isabelle), into the ZFC-based Metamath language. This task is divided into two steps: the translation of an OpenTheory proof into a Metamath HOL formalization, hol.mm, followed by the embedding of the HOL formalization into the main ZFC foundations of the main Metamath library, set.mm. This process provides a means to link the simplicity of the Metamath foundations to the intense automation efforts which have borne fruit in HOL Light, allowing the production of complete Metamath proofs of theorems in HOL Light, while also proving that HOL Light is consistent, relative to Metamath's ZFC axiomatization.

Through the analysis of archival material, mainly cartographic, this article explores the processes of territorial delimitation between the province of Yucatan and El Petén, as well as of the region then occupied by the British (present-day Belize). The elaboration of reports and maps for the establishment of limits and borders between provinces, and later between nation states, reflects the policies of those states regarding the establishment of their territories. In this context it studies the impact that the indigenous uprising known as the War of the Castes had on the process of establishing limits and borders.

Chronic inflammatory diseases are often initiated and guided by the release of proinflammatory mediators. Rheumatoid arthritis (RA) is caused by an imbalance between the pro- and anti-inflammatory mediators in the joints, thereby favoring chronic inflammation and joint damage. Here, we investigate if short-term high-fiber dietary intervention shifts this towards anti-inflammatory mediators. Healthy controls (n = 10) and RA patients (n = 29) under routine care received daily high-fiber bars for 15 or 30 days, respectively. Stool and sera were analyzed for pro- and anti-inflammatory mediators. A high-fiber dietary intervention resulted in increased anti-inflammatory short-chain fatty acids (SCFA), decreased proarthritic cytokine concentrations, along with a durable shift in the Firmicutes-to-Bacteroidetes ratio. Together, these results further strengthen high-fiber dietary interventions as a practical approach complementing existing pharmacological therapies.

The objective was to modify functional properties of breadfruit flours using twin-screw extrusion and test the physicochemical properties of the extruded flours. Extruded breadfruit flours were produced with twin-screw extrusion using different last barrel temperature (80 °C or 120 °C) and feed moisture content (17% or 30%). These conditions resulted in four extruded flours with different mechanical (specific mechanical energy, SME) and thermal (melt temperature) energies. At temperatures below the gelatinization of the native starch (

The pasting profile of starchy tissues is conventionally measured by recording the apparent viscosity (η) in heating/cooling cycles. However, conventional rheometers show critical limitations when the starch is embedded in compact protein-rich cotyledon matrices, as occurs in pulses. In this work, the pasting profile of 13 red kidney beans (Phaseolus vulgaris) from the same cultivar but different growing locations was investigated using a heating/cooling cycle at higher temperature (130 °C) and pressurized conditions, using both water and brine as cooking solvents. It was hypothesized that the continuous measure of η at these conditions of flours from the dry seed would correlate with the texture, as determined by the mini-Kramer cell, of the beans after the entire process of soaking and canning. Furthermore, mechanistic answers were obtained by investigating their composition (starch, protein, and ash content) and physical properties (water holding capacity, seed ratio and weight). Interestingly, as opposed to the pasting profile at 95 °C, pasting indicators at 130 °C, including trough and final viscosity, strongly correlated with starch and protein content, seed coat ratio and, remarkably, with the firmness of the beans after canning when brine was incorporated. These results clearly show that small beans with a high protein content would bring about a more compact matrix that restricts starch from swelling and results in canned beans with a hard texture, which can be predicted by a lower pasting profile of the whole bean flour.

Aerial Thermal Infrared (TIR) imagery has demonstrated tremendous potential to monitor active forest fires and acquire detailed information about fire behavior. However, aerial video is usually unstable and requires inter-frame registration before further processing. Measurement of image misalignment is an essential operation for video stabilization. Misalignment can usually be estimated through image similarity, although image similarity metrics are also sensitive to other factors such as changes in the scene and lighting conditions. Therefore, this article presents a thorough analysis of image similarity measurement techniques useful for inter-frame registration in wildfire thermal video. Image similarity metrics most commonly and successfully employed in other fields were surveyed, adapted, benchmarked and compared. We investigated their response to different camera movement components as well as recording frequency and natural variations in fire, background and ambient conditions. The study was conducted in real video from six fire experimental scenarios, ranging from laboratory tests to large-scale controlled burns. Both Global and Local Sensitivity Analyses (GSA and LSA, respectively) were performed using state-of-the-art techniques. Based on the obtained results, two different similarity metrics are proposed to satisfy two different needs. A normalized version of Mutual Information is recommended as cost function during registration, whereas 2D correlation performed the best as quality control metric after registration. These results provide a sound basis for image alignment measurement and open the door to further developments in image registration, motion estimation and video stabilization for aerial monitoring of active wildland fires.