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Support for this work was provided by the Strategic Funding UID/Multi/04423/2013 through national funds provided by the Foundation for Science and Technology (FCT) and the European Regional Development Fund (ERDF), in the framework of the programme PT2020 and funding was provided by the project NASCEM PTDC/BTA-BTA/31422/2017 (POCI-01-0145-FEDER-031422), financed by the FCT, COMPETE2020 and PORTUGAL2020. J.A. and A.C. also acknowledge the FCT for PhD and Postdoctoral scholarships SFRH/BD/99003/2013 and SFRH/BPD/103683/2014, respectively.

Biofouling, which occurs when certain marine species attach and accumulate in artificial submerged structures, represents a serious economic and environmental issue worldwide. The discovery of new non-toxic and eco-friendly antifouling systems to control or prevent biofouling is, therefore, a practical and urgent need. In this work, the antifouling activity of a series of 24 xanthones, with chemical similarities to natural products, was exploited. Nine (1, 2, 4, 6, 8, 16, 19, 21, and 23) of the tested xanthones presented highly significant anti-settlement responses at 50 μM against the settlement of mussel Mytilus galloprovincialis larvae and low toxicity to this macrofouling species. Xanthones 21 and 23 emerged as the most effective larval settlement inhibitors (EC50 = 7.28 and 3.57 µM, respectively). Additionally, xanthone 23 exhibited a therapeutic ratio (LC50/EC50) > 15, as required by the US Navy program attesting its suitability as natural antifouling agents. From the nine tested xanthones, none of the compounds were found to significantly inhibit the growth of the marine biofilm-forming bacterial strains tested. Xanthones 4, 6, 8, 16, 19, 21, and 23 were found to be non-toxic to the marine non-target species Artemia salina (<10% mortality at 50 μM). Insights on the antifouling mode of action of the hit xanthones 21 and 23 suggest that these two compounds affected similar molecular targets and cellular processes in mussel larvae, including that related to mussel adhesion capacity. This work exposes for the first time the relevance of C-1 aminated xanthones with a 3,4-dioxygenated pattern of substitution as new non-toxic products to prevent marine biofouling.

A 56‐year‐old man presented with right‐sided pleuritic chest pain and intermittent cough for 4 months, with a background history of well‐controlled asthma and allergic rhinitis. Chest radiographs revealed right‐sided pleural effusion, the fluid chemistry showed an exudate effusion with negative cytology and abundant eosinophils. Thoracoscopic pleural biopsy showed moderate lymphoplasmacytic chronic inflammation. Immunohistochemistry showed IgG4 staining up to 90 plasma cells/hpf (> 10% diagnostic), and the IgG4: IgG ratio was 40% (> 40% diagnostic), confirming the diagnosis of IgG4‐related disease (IgG4‐RD). Elevated serum IgG4 level (300 mg/dL; normal range: 3–201 mg/dL), further supported the diagnosis. While eosinophilic pleural effusion (EPE) accounts for 5%–16% of all exudative pleural effusions, IgG4‐related pleural disease is an extremely rare cause of EPE. Pleural disease is uncommon in IgG4‐RD and pleural effusion is even less frequent. Also, IgG4‐RD is an extremely rare cause of eosinophilic pleural effusion. To our knowledge, this is the first report of IgG4‐related eosinophilic pleural effusion from India.

manifests as diverse clinical pathologies in cattle that significantly impacts cow health and productivity worldwide. Current diagnostic methods rely on active infection to detect antibodies and bacterial DNA, however, these methods could be improved for subclinical infections. This is of particular importance in long-term surveillance programs in countries that have decided to eradicate , such as New Zealand. This study investigated small extracellular vesicles (sEV) from serum samples of infected dairy cows to identify protein cargo that may be used as potential diagnostic markers during subclinical infection to complement current testing methods. Small EV were isolated from serum of dairy cows positive for infection ( = 45) and their protein cargo compared with those from serum sEV from non-infected dairy cows ( = 49). Proteins were identified using liquid chromatography-ion mobility-tandem mass spectrometry in pooled samples ( = 10/group), resulting in 695 non-redundant top proteins identified across all samples. Differential protein abundance analysis indicated 90 proteins significantly ( -value < 0.05) different in sEV of infected animals compared with controls. Proteins associated with inflammation and the complement system as well as proteins involved in the oxidative stress pathway, were in greater abundance in sEV from positive animals compared with negative animals. Several histone proteins and antimicrobial peptides exhibited lower abundance in sEV from positive compared with negative cows. Although this study has not identified a protein candidate specific enough for use as a single diagnostic marker, our results indicate a shift towards a diseased state in infected dairy cows and provide valuable insight into sEV biology during infection.

The study evaluates the Indian summer monsoon prediction skill of the Atmospheric General Circulation Model (AGCM) and the impact of sea surface temperature (SST) boundary forcing on the model performance. The National Center for Environmental Prediction's (NCEP's) T170/L42 AGCM model configured with a horizontal resolution of 75 × 75 km, with 42 vertical levels is used for the study. The SST-rainfall relationship is examined in the coupled Climate Forecast System version 2 (CFSv2) model, as CFSv2-predicted SST is used as input for the T170 model. The NCEP Global Forecast System-T170 (GFS-T170) simulations are carried out with boundary forcing of observed SST, CFSv2-predicted SST and the bias-corrected CFSv2 SST. An ensemble of seasonal runs was made using the initial conditions of May to September, and integrated up to September 30th. The significance of discontinuity in the initial conditions due to climate forecast system reanalysis (CFSR) is assessed based on the two-period approach of climatology for the two time scales of 1985–1998 and 1998–2009. CFSv2 predicted climatological summer monsoon rainfall with a significant dry bias over the three convection zones; Western Ghats, Central India and North-east India, and cold bias over the Indian ocean basin and central equatorial Pacific, with strong cold bias over a narrow region of equatorial Pacific. The model could capture 64% (16 out of 25) of the year’s rainfall anomaly signal. The skill of the model is improved in the recent period (1999–2009). The model could simulate the negative Nino 3 and excess rainfall and the La Nina event realistically for the year 1988. The model shows a large difference in Nino indices for the years 1987 and 1998, which led to the unrealistic rainfall simulation. The model has a low skill for indicating the relationship between the Indian Ocean Dipole (IOD) and Indian summer monsoon rainfall (ISMR). The CFSv2 model could not capture the strong positive correlation of the IOD and strong negative correlation of Nino 3 with the ISMR for the period 1999–2009 realistically, suggesting improvement of SST simulation in the CFSv2 model. The T170 model forced with observed SST shows wet bias in peninsular India and dry bias over North-east India, whereas that of CFSv2-predicted SST simulated a wet bias in peninsular India and widespread dry bias in North and Central India. When the model was forced with bias-corrected CFSv2 SST, the dry bias improved in North and Central India, and the intensity of wet bias increased in peninsular India. The model could capture 56, 48 and 64% of the year’s rainfall anomaly signal (positive or negative) correctly in the same sign for being forced with observed SST, CFSv2-predicted SST, and bias-corrected CFSv2 SST, respectively.

Background The clinical description of superior vena cava syndrome has been widely studied; however, there is limited information on bronchoscopic findings in clinical practice. Case presentation A 57-year-old man presented with facial and neck swelling and pedal edema of 6 months duration. Computed tomography showed mediastinal lesions in the right paratracheal stations with thrombosis of the right internal jugular vein and superior vena cava (SVC). Without establishing a diagnosis, he was started on oral steroids elsewhere and his symptoms progressed. He did not receive anticoagulation therapy. Bronchoscopy showed edematous supraglottic and glottic regions with hyperemia of the airway mucosa. Endobronchial Ultrasonography revealed a mediastinal mass of heterogeneous echotexture in the lower right paratracheal region, with mediastinal collateral blood vessels. He underwent EBUS-guided aspiration cytology and intranodal forceps biopsy, which confirmed the diagnosis of non-Hodgkin’s. Conclusion In cases with an unconfirmed diagnosis of lymphoma, it is prudent to refrain from administering glucocorticoids, as these medications can exhibit lympholytic properties and may hinder the diagnostic process. Due to extensive collateral formation in superior vena cava syndrome, utilizing Doppler during endobronchial ultrasound transbronchial needle aspiration (EBUS TBNA) can identify numerous mediastinal collateral vessels, thus minimizing the risk of bleeding.

Introduction: The purpose of this retrospective study was to investigate the possible short-term benefit of a single intra-articular corticosteroid injection in those patients treated with physiotherapy when compared to a group of patients undergoing physiotherapy only (PT only). Methods: A retrospective chart review was conducted to identify eligible patients treated over a 4-year period. All female patients between 40 years and 60 years with a confirmed clinical diagnosis of idiopathic adhesive capsulitis who completed a prescribed physiotherapy program were considered eligible. Sixty-three patients fulfilled the inclusion criteria, but 22 were excluded because of missing data in the medical record. The remaining 41 patients comprise the study cohort; an experienced musculoskeletal physiotherapist assessed these patients both at initial presentation and at 12 weeks. Twenty patients with a mean age of 55.1 years underwent PT only and 21 patients with a mean age of 52.4 years received a single intra-articular dose of 40 mg methylprednisolone followed by physiotherapy. Outcome measures included the visual analogue scale (VAS) and measurement of range of motion. Results: At final assessment (12 weeks), significant between-group differences were identified for the ‘PT only’ group for flexion (p = 0.01) and abduction (p = 0.008). When comparing the mean change from the initial assessment, a significant between-group difference was observed for abduction (p = 0.03). Conclusions: The results of this study suggest that the intra-articular injection of a single dose of cortisone has no significant short-term benefit in female patients with idiopathic adhesive capsulitis managed with physiotherapy.

BackgroundGangliosides are glycosphingolipids that are involved in cellular functions, including signal transduction, cell proliferation, differentiation, adhesion, and angiogenesis.1 We confirmed marked overexpression of GD3 in tumors associated with Tuberous Sclerosis complex (TSC) and proposed to evaluate the use of T cells expressing a second-generation chimeric antigen receptor (GD3CAR T-cells) for patient treatment. To evaluate the potency of GD3CAR T-cells targeting solid tumor cells, we performed in vitro assays using Tsc2 knockout, GD3 overexpressing tumor cells isolated from mice heterozygous for Tsc2. HEK293 cells transfected or not with an expression plasmid encoding the enzyme SIAT8, responsible for converting GM3 to GD3, were used as controls. Cell were subjected to cytotoxicity assays using live cell imaging, and single cell cytokine secretome analysis among CD4 or CD8 CAR T-cells.MethodsGD3CAR construct generated includes an anti-GD3 antibody single-chain antibody fragment and intracellular sequence of CD28 and CD3 zeta chain.2 Mouse T cells were transduced, and transduction was established by flow cytometry. GD3 expressing Tsc2-/- tumor cells or HEK cells were co cultured with untranduced or GD3CAR T-cells and cytotoxicity was measured using the Incucyte S3 system. Cytokine secretion patterns of CD4 and CD8 subpopulations of CAR T-cells were measured after coculture in a single cell polyfunctional strength mouse Isocode Chip (IsoPlexis). Secretory profiles of single cells were analyzed by IsoSpeak Software. IFNγ secretion was quantified by ELISA as a functional readout of T cell activity.ResultsTransduction efficiencies observed were upward of 70% live GD3 CAR T-cells with 96% transduction efficiency of CD4 T cells and 90% of CD8 T cells. The cytotoxicity assay in the Incucyte live-cell imaging system indicated 4-fold increased apoptosis (p=0.038) when target cells were co-cultured with GD3CAR T-cells. Both CD8 and CD4 T cells were efficiently transduced to express the GD3CAR. In single - cell cytokine analysis, both T cell subsets showed enhanced polyfunctionality with increased polyfunctional strength index (PSI) by 9 and 10-fold in the GD3CAR T-cells in the CD4 and CD8 populations, respectively. This was mainly attributed to effector, chemo-attractive and stimulatory cytokines IFNγ production was increased significantly in response to target cells expressing GD3ConclusionsBoth CD4 and CD8 GD3CAR T-cells express polyfunctional cytokine profiles in response to GD3 expressing tumor cells, and CAR T- cells were selectively cytotoxic to relevant tumor cells. The data suggests that GD3CAR T-cells may reduce tumor growth observed in patients with TSCAcknowledgementsThis study is supported by a Department of Defense grant W81XWH-17-TSCRP-CTRA- TS170066 to CLP.ReferencesYu RK, Tsai YT, Ariga T, Yanagisawa M. Structures, biosynthesis, and functions of gangliosides-an overview. J Oleo Sci 2011;60(10):537–544.Lo AS, Ma Q, Liu DL, Junghans RP. Anti-GD3 chimeric sFv-CD28/T-cell receptor zeta designer T cells for treatment of metastatic melanoma and other neuroectodermal tumors. Clin Cancer Res 2010;16(10):2769–2780.

Background The use of deer velvet antler (DVA) as a potent traditional medicine ingredient goes back for over 2000 years in Asia. Increasingly, though, DVA is being included as a high protein functional food ingredient in convenient, ready to consume products in Korea and China. As such, it is a potential source of endogenous bioactive peptides and of ‘cryptides’, i.e. bioactive peptides enzymatically released by endogenous proteases, by processing and/or by gastrointestinal digestion. Fermentation is an example of a processing step known to release bioactive peptides from food proteins. In this study, we aimed to identify in silico bioactive peptides and cryptides in DVA, before and after fermentation, and subsequently to validate the major predicted bioactivity by in vitro analysis. Methods Peptides that were either free or located within proteins were identified in the DVA samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by database searching. Bioactive peptides and cryptides were identified in silico by sequence matching against a database of known bioactive peptides. Angiotensin-converting enzyme (ACE) inhibitory activity was measured by a colorimetric method. Results Three free bioactive peptides (LVVYPW, LVVYPWTQ and VVYPWTQ) were solely found in fermented DVA, the latter two of which are known ACE inhibitors. However matches to multiple ACE inhibitor cryptides were obtained within protein and peptide sequences of both unfermented and fermented DVA. In vitro analysis showed that the ACE inhibitory activity of DVA was more pronounced in the fermented sample, but both unfermented and fermented DVA had similar activity following release of cryptides by simulated gastrointestinal digestion. Conclusions DVA contains multiple ACE inhibitory peptide sequences that may be released by fermentation or following oral consumption, and which may provide a health benefit through positive effects on the cardiovascular system. The study illustrates the power of in silico combined with in vitro methods for analysis of the effects of processing on bioactive peptides in complex functional ingredients like DVA.

Background:Oral Anticoagulant is a therapy indicated for thromboembolic disorders, which requires close observation of the international normalized ratio and patient education for better therapeutic outcomes. Management of Oral Anticoagulation Therapy (OAT) in cardiovascular disease is one greater concern because of numerous drug-related problems and non-compliance towards medications due to poor knowledge. As a result, the pharmacist offers patient counseling to improve knowledge. Therefore, the objective of this study is to compare the knowledge score of the patients about anticoagulation therapy and its impact on international normalized ratio levels in patients undergoing oral anticoagulation therapy.Materials and Methods:A randomized controlled study among 102 patients in the Cardiology department. Patient information leaflet and patient counseling on oral anticoagulation therapy were given as Interventions. Knowledge level was assessed from the baseline and followed in the first and third months.Results:A total of 102 patients actively participated in the study. Considering the area of knowledge, no more significant difference was seen in either group (U=1018, p-value=0.058) during the pre-test. Following the intervention, a notable disparity was observed in the Intervention group (U=528.00, p=0.0001). The mean INR is significantly different between the control and intervention groups in the therapeutic range (t=-5.80, p=0.0001*) and the supratherapeutic range (t=-3.42, p=0.002*).Conclusion:A collaborative educational approach with a pharmacist helps to improve the patient’s knowledge of anticoagulation control. Establishing a pharmacist-managed anticoagulation service for the benefit of patients so that a clinical pharmacist can manage anticoagulation effectively and provide the best treatment.