Negative Clinical Evolution in COVID-19 Patients Is Frequently Accompanied With an Increased Proportion of Undifferentiated Th Cells and a Strong Underrepresentation of the Th1 Subset

The severity of SARS-CoV-2 infection has been related to uncontrolled inflammatory innate responses and impaired adaptive immune responses mostly due to exhausted T lymphocytes and lymphopenia. In this work we have characterized the nature of the lymphopenia and demonstrate a set of factors that hinder the effective control of virus infection and the activation and arming of effector cytotoxic T CD8 cells and showing signatures defining a high-risk population. We performed immune profiling of the T helper (Th) CD4+ and T CD8+ cell compartments in peripheral blood of 144 COVID-19 patients using multiparametric flow cytometry analysis. On the one hand, there was a consistent lymphopenia with an overrepresentation of non-functional T cells, with an increased percentage of naive Th cells (CD45RA+, CXCR3-, CCR4-, CCR6-, CCR10-) and persistently low frequency of markers associated with Th1, Th17, and Th1/Th17 memory-effector T cells compared to healthy donors. On the other hand, the most profound alteration affected the Th1 subset, which may explain the poor T cells responses and the persistent blood virus load. Finally, the decrease in Th1 cells may also explain the low frequency of CD4+ and CD8+ T cells that express the HLA-DR and CD38 activation markers observed in numerous patients who showed minimal or no lymphocyte activation response. We also identified the percentage of HLA-DR+CD4+ T cells, PD-1+CD+4/CD8+ T cells in blood, and the neutrophil/lymphocyte ratio as useful factors for predicting critical illness and fatal outcome in patients with confirmed COVID-1

Major Histocompatibility Complex Class I Chain-Related (MICA) STR Polymorphisms in COVID-19 Patients

The SARS-CoV-2 disease presents different phenotypes of severity. Comorbidities, age, and being overweight are well established risk factors for severe disease. However, innate immunity plays a key role in the early control of viral infections and may condition the gravity of COVID-19. Natural Killer (NK) cells are part of innate immunity and are important in the control of virus infection by killing infected cells and participating in the development of adaptive immunity. Therefore, we studied the short tandem repeat (STR) transmembrane polymorphisms of the major histocompatibility complex class I chain-related A (MICA), an NKG2D ligand that induces activation of NK cells, among other cells. We compared the alleles and genotypes of MICA in COVID-19 patients versus healthy controls and analyzed their relation to disease severity. Our results indicate that the MICA*A9 allele is related to infection as well as to symptomatic disease but not to severe disease. The MICA*A9 allele may be a risk factor for SARS-CoV-2 infection and symptomatic disease.Instituto de Salud Carlos III - FEDER funds (European Union) PI 16/00752 B-CTS-410-UGR-20Junta de Andalucia CTS-143 C-0013-201

Tumor Escape Phenotype in Bladder Cancer Is Associated with Loss of HLA Class I Expression, T-Cell Exclusion and Stromal Changes

Cancer eradication and clinical outcome of immunotherapy depend on tumor cell immunogenicity, including HLA class I (HLA-I) and PD-L1 expression on malignant cells, and on the characteristics of the tumor microenvironment, such as tumor immune infiltration and stromal reaction. Loss of tumor HLA-I is a common mechanism of immune escape from cytotoxic T lymphocytes and is linked to cancer progression and resistance to immunotherapy with the inhibitors of PD-L1/PD-1 signaling. Here we observed that HLA-I loss in bladder tumors is associated with T cell exclusion and tumor encapsulation with stromal elements rich in FAP-positive cells. In addition, PD-L1 upregulation in HLA-I negative tumors demonstrated a correlation with high tumor grade and worse overall- and cancer-specific survival of the patients. These changes define common immuno-morphological signatures compatible with cancer immune escape and acquired resistance to therapeutic interventions across different types of malignancy. They also may contribute to the search of new targets for cancer treatment, such as FAP-expressing cancer-associated fibroblasts, in refractory bladder tumors.ISCIII Research Institute co-financed by the European Union (FED-ER-Fondo Europeo de Desarrollo Regional) (RETIC RD 06/020, RD09/0076/00165PI14/01978, PI16/00752, Q2827015E, PI17/00197, PT17/0015/0041) and by the Junta de Andalucía in Spain (Groups CTS-143, CTS-695, CTS3952, CVI-4740).AbbottSpanish Research Institute IDI-URO, Madri

Characteristics of patients making serious inhaler errors with a dry powder inhaler and association with asthma-related events in a primary care setting

Acknowledgements The iHARP database was funded by unrestricted grants from Mundipharma International Ltd and Research in Real-Life Ltd; these analyses were funded by an unrestricted grant from Teva Pharmaceuticals. Mundipharma and Teva played no role in study conduct or analysis and did not modify or approve the manuscript. The authors wish to direct a special appreciation to all the participants of the iHARP group who contributed data to this study and to Mundipharma, sponsors of the iHARP group. In addition, we thank Julie von Ziegenweidt for assistance with data extraction and Anna Gilchrist and Valerie L. Ashton, PhD, for editorial assistance. Elizabeth V. Hillyer, DVM, provided editorial and writing support, funded by Research in Real-Life, Ltd.Peer reviewedPublisher PD

SHARDS: A global view of the star formation activity at z~0.84 and z~1.23

In this paper, we present a comprehensive analysis of star-forming galaxies (SFGs) at intermediate redshifts (z~1). We combine the ultra-deep optical spectro-photometric data from the Survey for High-z Absorption Red and Dead Sources (SHARDS) with deep UV-to-FIR observations in the GOODS-N field. Exploiting two of the 25 SHARDS medium-band filters, F687W17 and F823W17, we select [OII] emission line galaxies at z~0.84 and z~1.23 and characterize their physical properties. Their rest-frame equivalent widths (EW$_{\mathrm{rf}}$([OII])), line fluxes, luminosities, star formation rates (SFRs) and dust attenuation properties are investigated. The evolution of the EW$_{\mathrm{rf}}$([OII]) closely follows the SFR density evolution of the universe, with a trend of EW$_{\mathrm{rf}}$([OII])$\propto$(1+z)$^3$ up to redshift z~1, followed by a possible flattening. The SF properties of the galaxies selected on the basis of their [OII] emission are compared with complementary samples of SFGs selected by their MIR and FIR emission, and also with a general mass-selected sample of galaxies at the same redshifts. We demonstrate observationally that the UVJ diagram (or, similarly, a cut in the specific SFR) is only partially able to distinguish the quiescent galaxies from the SFGs. The SFR-M$_*$ relation is investigated for the different samples, yelding a logarithmic slope ~1, in good agreement with previous results. The dust attenuations derived from different SFR indicators (UV(1600), UV(2800), [OII], IR) are compared and show clear trends with respect to both the stellar mass and total SFR, with more massive and highly star-forming galaxies being affected by stronger dust attenuation.Comment: Replaced to match the accepted version (24 pages, 1 table, 17 figures). Published in ApJ, 812, 155 (2015): http://stacks.iop.org/0004-637X/812/15

Enzymatic oxidation of oleuropein and 3-hydroxytyrosol by laccase, peroxidase and tyrosinase.

The oxidation of oleuropein and 3‐hydroxytyrosol by oxidases laccase, tyrosinase, and peroxidase has been studied. The use of a spectrophotometric method and another spectrophotometric chronometric method has made it possible to determine the kinetic parameters Vmax and KM for each enzyme. The highest binding affinity was shown by laccase. The antioxidant capacities of these two molecules have been characterized, finding a very similar primary antioxidant capacity between them. Docking studies revealed the optimal binding position, which was the same for the two molecules and was a catalytically active position. Practical applications: One of the biggest environmental problems in the food industry comes from olive oil mill wastewater with a quantity of approximately 30 million tons per year worldwide. In addition, olive pomace, the solid residue obtained from the olive oil production, is rich in hydroxytyrosol and oleuropein and the action of enzymatic oxidases can give rise to products in their reactions that can lead to polymerization. This polymerization can have beneficial effects because it can increase the antioxidant capacity with potential application on new functional foods or as feed ingredients. Tyrosinase, peroxidase, and laccase are the enzymes degrading these important polyphenols. The application of a spectrophotometric method for laccase and a chronometric method, for tyrosinase and peroxidase, allowed us to obtain the kinetic information of their reactions on hydroxytyrosol and oleuropein. The kinetic information obtained could advance in the understanding of the mechanism of these important industrial enzymes

Kinetic characterization of the oxidation of catecolamines and related compounds by laccase

The pathways of melanization and sclerotization of the cuticle in insects are carried out by the action of laccases on dopamine and related compounds. In this work, the laccase action of Trametes versicolor (TvL) on catecholamines and related compounds has been kinetically characterized. Among them, dopamine, L-dopa, L-epinephrine, L-norepinephrine, DL-isoprenaline, L-isoprenaline, DL-α-methyldopa, L-α-methyldopa and L-dopa methylester. A chronometric method has been used, which is based on measuring the lag period necessary to consume a small amount of ascorbic acid, added to the reaction medium. The use of TvL has allowed docking studies of these molecules to be carried out at the active site of this enzyme. The hydrogen bridge interaction between the hydroxyl oxygen at C-4 with His-458, and with the acid group of Asp-206, would make it possible to transfer the electron to the T1 Cu-(II) copper centre of the enzyme. Furthermore, Phe-265 would facilitate the adaptation of the substrate to the enzyme through Π-Π interactions. To kinetically characterize these compounds, we need to take into consideration that, excluding L-dopa, L-α-methyldopa and DL-α-methyldopa, all compounds are in hydrochloride form. Because of this, first we need to kinetically characterize the inhibition by chloride and, after that, calculate the kinetic parameters K M and V max S. From the kinetic data obtained, it appears that the best substrate is dopamine. The presence of an isopropyl group bound to nitrogen (isoprenaline) makes it especially difficult to catalyse. The formation of the ester (L-dopa methyl ester) practically does not affect catalysis. The addition of a methyl group (α-methyl dopa) increases the rate but decreases the affinity for catalysis. L-Epinephrine and L-norepinephrine have an affinity similar to isoprenaline, but faster catalysis, probably due to the greater nucleophilic power of their phenolic hydroxyl

Expression of CD20 after viral reactivation renders HIV-reservoir cells susceptible to Rituximab

Rituximab; Viral reactivation; CD20Rituximab; Reactivació viral; CD20Rituximab; Reactivación viral; CD20The identification of exclusive markers to target HIV-reservoir cells will represent a significant advance in the search for therapies to cure HIV. Here, we identify the B lymphocyte antigen CD20 as a marker for HIV-infected cells in vitro and in vivo. The CD20 molecule is dimly expressed in a subpopulation of CD4-positive (CD4+) T lymphocytes from blood, with high levels of cell activation and heterogeneous memory phenotypes. In lymph node samples from infected patients, CD20 is present in productively HIV-infected cells, and ex vivo viral infection selectively upregulates the expression of CD20 during early infection. In samples from patients on antiretroviral therapy (ART) this subpopulation is significantly enriched in HIV transcripts, and the anti-CD20 monoclonal antibody Rituximab induces cell killing, which reduces the pool of HIV-expressing cells when combined with latency reversal agents. We provide a tool for targeting this active HIV-reservoir after viral reactivation in patients while on ART.This study was supported by the American National Institutes of Health (grant R21AI118411 to M.B.), the Spanish Secretariat of Science and Innovation and FEDER funds (grant SAF2015-67334-R [MINECO/FEDER]), the Spanish "Ministerio de Economia y Competitividad, Instituto de Salud Carlos III" (ISCIII, PI17/01470), GeSIDA and the Spanish AIDS network Red Tematica Cooperativa de Investigacion en SIDA (RD16/0025/0007). M.B. is supported by the Miguel Servet program funded by the Spanish Health Institute Carlos III (CP17/00179). M.G. is supported by the "Pla estrategic de recerca i innovacio en salut" (PERIS), from the Catalan Government

Signwalling: signals derived from arabiopsis cell wall activate specific resistance to pathogens

The cell wall is a dynamic structure that regulates both constitutive and inducible plant defence responses. Different molecules o DAMPs (damage-associated molecular patterns) can be released from plant cell walls upon pathogen infection or wounding and can trigger immune responses. To further characterize the function of cell wall on the regulation of these immune responses, we have performed a biased resistance screening of putative/well-characterized primary/secondary Arabidopsis thaliana cell wall mutants (cwm). In this screening we have identified more than 20 cwm mutants with altered susceptibility/resistance to at least one of the following pathogens: the necrotrophic fungi Plectosphaerella cucumerina, the vascular bacterium Ralstonia solanacearum, the biotrophic oomycete Hyaloperonospora arabidopsidis and the powdery mildew fungus Erisyphe cruciferarum. We found that cell wall extracts from some of these cwm plants contain novel DAMPs that activate immune responses and conferred enhanced resistance to particular pathogens when they were applied to wild-type plants. Using glycomic profiling we have performed an initial characterization of the active carbohydrate structures present in these cwm wall fractions, and we have determined the signalling pathways regulated by thesse fractions. . The data generated with this collection of wall mutants support the existence of specific correlations between cell wall structure/composition, resistance to particular type of pathogens and plant fitness. Remarkably, we have identified specific cwm mutations that uncoupled resistance to pathogens from plant trade-offs, further indicating the plasticity of wall structures in the regulation of plant immune responses

results from the prospective EPIC cohort study

Funding Information: This work was supported by Cancer Research UK (C33493/A29678), World Cancer Research Fund International (IIG_FULL_2020_033), and the Institut National du Cancer (INCa number 2021–138). The coordination of EPIC is financially supported by the IARC and the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the UK National Institute for Health and Care Research Imperial Biomedical Research Centre. The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM; France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF; Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC–Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund, Statistics Netherlands (Netherlands); Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (ICO; Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); and Cancer Research UK (14136 to EPIC–Norfolk; C8221/A29017 to EPIC–Oxford) and Medical Research Council (1000143 to EPIC–Norfolk; MR/M012190/1 to EPIC–Oxford; UK). Where authors are identified as personnel of the International Agency for Research on Cancer or WHO, they are responsible for the views expressed in this Article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer or WHO. Publisher Copyright: © 2023 World Health Organization UPDATE NOTICE Correction to Lancet Planet Health 2023; 7: e219–32. The Lancet Planetary Health. 2023;7(5):e357. Scopus ID: 85158098931Background: Food processing has been hypothesised to play a role in cancer development; however, data from large-scale epidemiological studies are scarce. This study investigated the association between dietary intake according to amount of food processing and risk of cancer at 25 anatomical sites using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Methods: This study used data from the prospective EPIC cohort study, which recruited participants between March 18, 1991, and July 2, 2001, from 23 centres in ten European countries. Participant eligibility within each cohort was based on geographical or administrative boundaries. Participants were excluded if they had a cancer diagnosis before recruitment, had missing information for the NOVA food processing classification, or were within the top and bottom 1% for ratio of energy intake to energy requirement. Validated dietary questionnaires were used to obtain information on food and drink consumption. Participants with cancer were identified using cancer registries or during follow-up from a combination of sources, including cancer and pathology centres, health insurance records, and active follow-up of participants. We performed a substitution analysis to assess the effect of replacing 10% of processed foods and ultra-processed foods with 10% of minimally processed foods on cancer risk at 25 anatomical sites using Cox proportional hazard models. Findings: 521 324 participants were recruited into EPIC, and 450 111 were included in this analysis (318 686 [70·8%] participants were female individuals and 131 425 [29·2%] were male individuals). In a multivariate model adjusted for sex, smoking, education, physical activity, height, and diabetes, a substitution of 10% of processed foods with an equal amount of minimally processed foods was associated with reduced risk of overall cancer (hazard ratio 0·96, 95% CI 0·95–0·97), head and neck cancers (0·80, 0·75–0·85), oesophageal squamous cell carcinoma (0·57, 0·51–0·64), colon cancer (0·88, 0·85–0·92), rectal cancer (0·90, 0·85–0·94), hepatocellular carcinoma (0·77, 0·68–0·87), and postmenopausal breast cancer (0·93, 0·90–0·97). The substitution of 10% of ultra-processed foods with 10% of minimally processed foods was associated with a reduced risk of head and neck cancers (0·80, 0·74–0·88), colon cancer (0·93, 0·89–0·97), and hepatocellular carcinoma (0·73, 0·62–0·86). Most of these associations remained significant when models were additionally adjusted for BMI, alcohol and dietary intake, and quality. Interpretation: This study suggests that the replacement of processed and ultra-processed foods and drinks with an equal amount of minimally processed foods might reduce the risk of various cancer types. Funding: Cancer Research UK, l'Institut National du Cancer, and World Cancer Research Fund International.publishersversionpublishersversionpublishe