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1.
Benjamin Pelletier Audrey Perrin Noémie Assoun Camille Plaquet Nathalie Oreal Laetitia Gaulme Adeline Bouzereau Jean-Louis Labernardière Mélanie Ligouis Vincent Dioszeghy Sophie Wavrin Katie Matthews Fabrice Porcheray Hugh A. Sampson Pierre-Louis Hervé 《Allergy》2021,76(4):1213-1222
Background
The prevalence of tree nut allergy has increased worldwide, and cashew has become one of the most common food allergens. More critically, cashew allergy is frequently associated with severe anaphylaxis. Despite the high medical need, no approved treatment is available and strict avoidance and preparedness for prompt treatment of allergic reactions are considered dual standard of care. In the meantime, Phase III study results suggest investigational epicutaneous immunotherapy (EPIT) may be a relevant and safe treatment for peanut allergy and may improve the quality of life for many peanut allergic children.Objective
We aimed to evaluate the capacity of EPIT to provide protection against cashew-induced anaphylaxis in a relevant mouse model.Methods
The efficacy of EPIT was evaluated by applying patches containing cashew allergens to cashew-sensitized mice. As negative control, sham mice received patches containing excipient. Following treatment, mice were challenged orally to cashew and anaphylactic symptoms, as well as plasmatic levels of mast-cell proteases (mMCP)-1/7, were quantified.Results
Of 16 weeks of EPIT significantly protects against anaphylaxis by promoting a faster recovery of challenged mice. This protection was characterized by a significant reduction of temperature drop and clinical symptoms, 60 minutes after challenge. This was associated with a decrease in mast-cell reactivity as attested by the reduction of mMCP-1/7 in plasma, suggesting that EPIT specifically decrease IgE-mediated anaphylaxis.Conclusion
We demonstrate that EPIT markedly reduced IgE-mediated allergic reactions in a mouse model of cashew allergy, which suggests that EPIT may be a relevant approach to treating cashew allergy.2.
Stefan Kabasser Christine Hafner Sharon Chinthrajah Sayantani B. Sindher Divya Kumar Laurie E. Kost Andrew J. Long Kari C. Nadeau Heimo Breiteneder Merima Bublin 《Allergy》2021,76(5):1463-1472
Background
Oral food challenges have demonstrated that diagnosis of almond allergy based on extract-sIgE tests displays low specificity. Molecular allergy diagnosis is expected to improve accuracy, but its value in diagnosing almond allergy remains unknown. The aim of this study was to identify relevant almond allergens and examine their ability to improve almond allergy diagnosis.Methods
IgE-reactive proteins were purified from almond kernels. IgE binding to almond extract and the allergens was analyzed by quantitative ELISA using sera from 18 subjects with a proven almond allergy. The control group consisted of sera from 18 subjects allergic to peanut and/or tree nuts but tolerant to almond.Results
Three IgE-binding proteins were identified: legumin (Pru du 6), alpha-hairpinin (Pru du 8), and mandelonitrile lyase (Pru du 10). Positive IgE (≥0.35 kU/L) to almond extract showed 94% sensitivity but only 33% specificity. IgE to Pru du 6 maintained high sensitivity (83%) and provided superior specificity (78%). Sera from almond-allergic subjects had significantly higher IgE levels to almond extract (P < .0001) and Pru du 6 (P < .0001) than sera from tolerant donors. Sensitization to Pru du 6 was highly specific for almond allergy, while frequencies of sensitization to legumins from peanut, walnut, hazelnut, and cashew were similar in both groups. IgE to Pru du 8 and Pru du 10 was less sensitive (41% and 67%), but showed specificities of 100% and 61%.Conclusion
The use of almond allergens markedly increases the diagnostic specificity compared to the extract. Pru du 6 is a potential new molecular marker for almond allergy.3.
Arnaud Bourdin Alberto A. Papi Jonathan Corren J. Christian Virchow Megan S. Rice Yamo Deniz Michel Djandji Paul Rowe Ian D. Pavord 《Allergy》2021,76(1):269-280
Background
Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13, key drivers of type 2 inflammation. In phase 2b (NCT01854047) and phase 3 LIBERTY ASTHMA QUEST (NCT02414854), add-on dupilumab 200/300 mg every 2 weeks (q2w) reduced severe exacerbations, improved prebronchodilator (pre-BD) forced expiratory volume in 1 second (FEV1) and quality of life measures, and it was generally well tolerated in patients with uncontrolled, persistent (phase 2b), or moderate-to-severe (phase 3) asthma.Methods
In patients on high-dose inhaled corticosteroids (ICS) with type 2-high asthma (subgroups including baseline blood eosinophils ≥150/300 cells/µL and/or fractional exhaled nitric oxide [FeNO] ≥25 ppb), annualized severe exacerbation rates over the treatment period, changes from baseline in pre-BD FEV1 and asthma control (5-item asthma control questionnaire [ACQ-5]) were analyzed.Results
In high-dose ICS type 2-high subgroups, dupilumab 200/300 mg q2w vs placebo in the phase 2b (24 weeks) and phase 3 (52 weeks) studies significantly reduced severe exacerbations by 55%-69%/57%-60% (all P<.05) and 53%-69%/48%-66% (all P < .001), respectively, except in patients with ≥ 300 eosinophils/µL in phase 2b study (24%/50% (P = .52/0.15). Across subgroups, pre-BD FEV1 improved by 0.18-0.22 L/0.19-0.24 L (all P < .05) and 0.23-0.36 L/0.15-0.25 L (all P < .01) and ACQ-5 scores were reduced by 0.46-0.55/0.47-0.85 (all P < .05) and 0.38-0.50/0.24-0.30 (all P < .05), respectively, except dupilumab 200 mg q2w in phase 2b in patients with FeNO ≥ 25 ppb (0.41; P = .09). Dupilumab was also effective in patients taking medium-dose ICS.Conclusion
Dupilumab significantly reduced severe exacerbations and improved lung function and asthma control in patients with type 2-high asthma on high-dose ICS at baseline.4.
Deniz Eyice Karabacak Semra Demir Osman Ozan Yeğit Ali Can Kadriye Terzioğlu Derya Ünal Müge Olgaç Raif Coşkun Bahauddin Çolakoğlu Suna Büyüköztürk Aslı Gelincik 《Allergy》2021,76(8):2535-2543
Background
Hereditary angioedema (HAE) attacks can be provoked with psychological factors. The aim of this study was to assess the effects of anxiety, depression and stress related to COVID-19 pandemic on disease activity of HAE patients during the quarantine period (QP) and the return to normal period (RTNP).Methods
This study was conducted between March 2020 and September 2020 in four allergy centres. Demographic, clinical features and mental health status were evaluated in QP (from March to the beginning of June) and RTNP (from June to the beginning of September) applied by the government. The 10-point visual analogue scale (VAS10) was used to define the severity of HAE attacks. Depression, Anxiety and Stress Scales-21 (DASS-21) and Fear of COVID-19 (FC-19) scale were performed to assess mental health status.Results
139 HAE patients were included in the study. In QP, median attack numbers and median VAS10 scores were 5 (min-max: 0–45) and 6 (min-max: 0–10), respectively. HAE attack numbers, DASS-21 stress, anxiety, depression and total DASS-21 scores, and FC-19 scores were higher in QP than RTNP (p = 0.001, p < 0.001, p = 0.001, p < 0.001, p < 0.001, p < 0.001, respectively). However, there was no difference in attack severity scores between the two periods (p > 0.05).Conclusions
This study revealed that the restriction measures during COVID-19 outbreak cause an increase in the number of HAE attacks in relation to anxiety, depression, stress and fear of COVID-19 pandemic. Therefore, it is important to provide psychological support to HAE patients during the pandemic.5.
Tuomas Jartti Unna Liimatainen Paraskevi Xepapadaki Tero Vahlberg Claus Bachert Susetta Finotto Marek L Kowalski Anna Sobanska Heikki Lukkarinen Maria Pasioti Tytti Vuorinen Nan Zhang Theodor Zimmermann Nikolaos G Papadopoulos 《Allergy》2021,76(1):247-254
Background
Investigation of preschool asthma is important since not all children outgrow their illness during this age. Data are scarce on the role of rhinovirus (RV) infections in this patient group.Objectives
To investigate the role of RV infections in preschool asthma: (i) susceptibility factors, (ii) clinical course, and (iii) medium-term outcome.Methods
A total of 130 asthmatic children aged 4-6 years from the multinational PreDicta cohort were prospectively followed for a 12-month period. Allergy tests and a standard health questionnaire were carried out at study entry. Respiratory virus presence in nasopharyngeal washes was studied at illness visits and at 3 scheduled visits.Results
At study entry, mean age of the children was 5.3 years. Of 571 visits, 54% were positive for any virus and 39% for RV. Patient characteristics were only assessed with RV infection due to low number of other viruses. The use of supplementary vitamin D was inversely associated with RV infection (P < .05). RV infection was associated with more severe course of acute illness in terms of more severe nighttime coughing, more sleep disturbances, and more days with runny nose (all P < .05). RV infection was also associated with more severe disease course during the 12-month follow-up in terms of more nights with awakenings and more days of exercise-related symptoms (both P < .05).Conclusions
Vitamin D supplementation may have an anti-rhinovirus effect. Both short- and medium-term outcomes suggest RV infection to be an important clinical marker of instable preschool asthma.6.
Gunter Johannes Sturm Sereina Annik Herzog Werner Aberer Teresa Alfaya Arias Darío Antolín-Amérigo Patrizia Bonadonna Elisa Boni Andrzej Bożek Marta Chełmińska Barbara Ernst Nina Frelih Radoslaw Gawlik Asli Gelincik Thomas Hawranek Wolfram Hoetzenecker Aránzazu Jiménez Blanco Karolina Kita Reşat Kendirlinan Mitja Košnik Karin Laipold Roland Lang Francesco Marchi Marina Mauro Marita Nittner-Marszalska Iwona Poziomkowska-Gęsicka Valerio Pravettoni Donatella Preziosi Oliviero Quercia Norbert Reider Marta Rosiek-Biegus Berta Ruiz-Leon Christoph Schrautzer Pilar Serrano Aytül Sin Betül Ayşe Sin Johanna Stoevesandt Axel Trautmann Martina Vachová Lisa Arzt-Gradwohl 《Allergy》2021,76(7):2166-2176
Background
There is controversy whether taking β-blockers or ACE inhibitors (ACEI) is a risk factor for more severe systemic insect sting reactions (SSR) and whether it increases the number or severity of adverse events (AE) during venom immunotherapy (VIT).Methods
In this open, prospective, observational, multicenter trial, we recruited patients with a history of a SSR and indication for VIT. The primary objective of this study was to evaluate whether patients taking β-blockers or ACEI show more systemic AE during VIT compared to patients without such treatment.Results
In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. Of all patients included, 388 (27.2%) took antihypertensive (AHT) drugs (10.4% took β-blockers, 11.9% ACEI, 5.0% β-blockers and ACEI). Only 5.6% of patients under AHT treatment experienced systemic AE during VIT as compared with 7.4% of patients without these drugs (OR: 0.74, 95% CI: 0.43–1.22, p = 0.25). The severity of the initial sting reaction was not affected by the intake of β-blockers or ACEI (OR: 1.14, 95% CI: 0.89–1.46, p = 0.29). In total, 210 (17.7%) patients were re-stung during VIT and 191 (91.0%) tolerated the sting without systemic symptoms. Of the 19 patients with VIT treatment failure, 4 took β-blockers, none an ACEI.Conclusions
This trial provides robust evidence that taking β-blockers or ACEI does neither increase the frequency of systemic AE during VIT nor aggravate SSR. Moreover, results suggest that these drugs do not impair effectiveness of VIT. (Funded by Medical University of Graz, Austria; Clinicaltrials.gov number, NCT04269629).7.
Jia Song Ming Zeng Hai Wang Chuan Qin Hong-Yan Hou Zi-Yong Sun San-Peng Xu Guo-Ping Wang Cui-Lian Guo Yi-Ke Deng Zhi-Chao Wang Jin Ma Li Pan Bo Liao Zhi-Hui Du Qi-Miao Feng Yang Liu Jun-Gang Xie Zheng Liu 《Allergy》2021,76(2):483-496
Background
The impacts of chronic airway diseases on coronavirus disease 2019 (COVID-19) are far from understood.Objective
To explore the influence of asthma and chronic obstructive pulmonary disease (COPD) comorbidity on disease expression and outcomes, and the potential underlying mechanisms in COVID-19 patients.Methods
A total of 961 hospitalized COVID-19 patients with a definite clinical outcome (death or discharge) were retrospectively enrolled. Demographic and clinical information were extracted from the medical records. Lung tissue sections from patients suffering from lung cancer were used for immunohistochemistry study of angiotensin-converting enzyme II (ACE2) expression. BEAS-2B cell line was stimulated with various cytokines.Results
In this cohort, 21 subjects (2.2%) had COPD and 22 (2.3%) had asthma. After adjusting for confounding factors, COPD patients had higher risk of developing severe illness (OR: 23.433; 95% CI 1.525-360.135; P < .01) and acute respiratory distress syndrome (OR: 19.762; 95% CI 1.461-267.369; P = .025) than asthmatics. COPD patients, particularly those with severe COVID-19, had lower counts of CD4+ T and CD8+ T cells and B cells and higher levels of TNF-α, IL-2 receptor, IL-10, IL-8, and IL-6 than asthmatics. COPD patients had increased, whereas asthmatics had decreased ACE2 protein expression in lower airways, compared with that in control subjects without asthma and COPD. IL-4 and IL-13 downregulated, but TNF-α, IL-12, and IL-17A upregulated ACE2 expression in BEAS-2B cells.Conclusion
Patients with asthma and COPD likely have different risk of severe COVID-19, which may be associated with different ACE2 expression.8.
Objective
This study examined how patterns of repetitive (≥5 instances) nonsuicidal self-injury (NSSI) associate with measures of resilience and life events retrospectively reported to have occurred within the last year, 1 to <5 years ago, and 5 to <10 years ago.Method
Life events reported by 557 young adults (mean [SD] age 25.3 [0.68]; 59.2% women) were classified as positive, negative, or profoundly negative based on their relationship to participants' mental health and well-being. We subsequently examined how these categories, together with resilience, were cross-sectionally associated with reporting no NSSI, and the (full/partial) cessation/continuation of repetitive NSSI from adolescence to young adulthood.Results
Repetitive NSSI in adolescence was associated with (profoundly) negative life events. Relative to cessation, NSSI continuation was significantly associated with more kinds of negative life events (odds ratio [OR] = 1.79) and fewer kinds of positive life events 1 to <5 years ago (OR = 0.65) and tended to be associated with lower resilience (b = −0.63, p = 0.056). Neither life events nor resilience significantly differentiated individuals reporting full or partial cessation.Conclusion
Resilience appears important for the cessation of repetitive NSSI, but contextual factors must still be considered. Assessing positive life events in future studies holds promise.9.
10.
João M. Santos Matilde Barata Sara Rathenau Inês Amaro Alexandre Vaz Daniel Sousa Margarida Severino Mafalda Taveira 《Journal of clinical psychology》2023,79(4):1166-1177
Objective
Psychotherapy studies have revealed that therapist characteristics are responsible for 5% to 9% of outcome variance. The therapist-facilitative interpersonal skills (FIS) have been shown to predict both alliance and outcomes, indicating that higher FIS therapists are more effective than lower FIS therapists. The current study focused on the development and validation of the FIS-client version (FIS-C) instrument, aimed at collecting the clients' perspectives on relevant therapist characteristics.Method
The clinical outcomes in routine evaluation—outcome measures, the session rating scale, and the FIS questionnaire—client version were filled out by psychotherapy clients. Exploratory, confirmatory factor, and test–retest analysis were conducted.Results
Results indicate robust psychometric characteristics, in terms of validity (factorial, convergent, discriminant, and nomological), reliability, and sensitivity.Conclusion
The validation of the FIS-C represents an important contribution to clinical research and practice, namely to the field of client feedback and therapist expertise.11.
Erin McKay Hannah Kirk Rachael Martin Kim Cornish 《Journal of clinical psychology》2023,79(4):1113-1129
Background
Many interventions have been developed to address the social difficulties commonly experienced by adolescents with attention-deficit/hyperactivity disorder (ADHD), yet they are largely ineffective.Objective
This study examined social impairment among adolescents with and without ADHD, determining whether gender, social anxiety, age, and ADHD symptom type (inattention and hyperactivity/impulsivity) and severity are associated with social impairment.Method
Parents and primary caregivers of adolescents (aged 13–17) with (n = 76) and without ADHD (n = 36) completed the Strengths and Weaknesses of ADHD and Normal Behavior, Social Responsiveness Scale 2nd Edition, and Spence Children's Anxiety Scale.Results
Adolescents with ADHD scored significantly higher than TD adolescents across social impairment domains. ADHD symptoms were associated with severity of impairment in all domains excluding Social Motivation. Hyperactivity/impulsivity and social anxiety predicted social impairment, whereas gender did not.Conclusion
Adolescents with ADHD are more likely to experience social impairment than TD adolescents, and interventions targeting symptom reduction and social anxiety may improve these social impairments.12.
Amene Tesfaye Alba Rodríguez-Nogales Sara Benedé Tahía D. Fernández Juan L. Paris Maria J. Rodriguez Isabel M. Jiménez-Sánchez Gador Bogas Cristobalina Mayorga María J. Torres María I. Montañez 《Allergy》2021,76(10):3183-3193
Background
Amoxicillin (AX) is nowadays the β-lactam that more frequently induces immediate allergic reactions. Nevertheless, diagnosis of AX allergy is occasionally challenging due to risky in vivo tests and non-optimal sensitivity of in vitro tests. AX requires protein haptenation to form multivalent conjugates with increased size to be immunogenic. Knowing adduct structural features for promoting effector cell activation would help to improve in vitro tests. We aimed to identify the optimal structural requirement in specific cellular degranulation to AX using well-precised nanoarchitectures of different lengths.Method
We constructed eight Bidendron Antigens (BiAns) based on polyethylene glycol (PEG) linkers of different lengths (600–12,000 Da), end-coupled with polyamidoamine dendrons that were terminally multi-functionalized with amoxicilloyl (AXO). In vitro IgE recognition was studied by competitive radioallergosorbent test (RAST) and antibody–nanoarchitecture complexes by transmission electron microscopy (TEM). Their allergenic activity was evaluated using bone marrow-derived mast cells (MCs) passively sensitized with mouse monoclonal IgE against AX and humanized RBL-2H3 cells sensitized with polyclonal antibodies from sera of AX-allergic patients.Results
All BiAns were recognized by AX-sIgE. Dose-dependent activation responses were observed in both cellular assays, only with longer structures, containing spacers in the range of PEG 6000–12,000 Da. Consistently, greater proportion of immunocomplexes and number of antibodies per complex for longer BiAns were visualized by TEM.Conclusions
BiAns are valuable platforms to study the mechanism of effector cell activation. These nanomolecular tools have demonstrated the importance of the adduct size to promote effector cell activation in AX allergy, which will impact for improving in vitro diagnostics.13.
Bernhard Kratzer Doris Trapin Paul Ettel Ulrike Körmöczi Arno Rottal Friedrich Tuppy Melanie Feichter Pia Gattinger Kristina Borochova Yulia Dorofeeva Inna Tulaeva Milena Weber Katharina Grabmeier-Pfistershammer Peter A. Tauber Marika Gerdov Bernhard Mühl Thomas Perkmann Ingrid Fae Sabine Wenda Harald Führer Rainer Henning Rudolf Valenta Winfried F. Pickl 《Allergy》2021,76(3):751-765
Background
SARS-CoV-2 has triggered a pandemic that is now claiming many lives. Several studies have investigated cellular immune responses in COVID-19-infected patients during disease but little is known regarding a possible protracted impact of COVID-19 on the adaptive and innate immune system in COVID-19 convalescent patients.Methods
We used multiparametric flow cytometry to analyze whole peripheral blood samples and determined SARS-CoV-2-specific antibody levels against the S-protein, its RBD-subunit, and viral nucleocapsid in a cohort of COVID-19 convalescent patients who had mild disease ~10 weeks after infection (n = 109) and healthy control subjects (n = 98). Furthermore, we correlated immunological changes with clinical and demographic parameters.Results
Even ten weeks after disease COVID-19 convalescent patients had fewer neutrophils, while their cytotoxic CD8+ T cells were activated, reflected as higher HLA-DR and CD38 expression. Multiparametric regression analyses showed that in COVID-19-infected patients both CD3+CD4+ and CD3+CD8+ effector memory cells were higher, while CD25+Foxp3+ T regulatory cells were lower. In addition, both transitional B cell and plasmablast levels were significantly elevated in COVID-19-infected patients. Fever (duration, level) correlated with numbers of central memory CD4+ T cells and anti-S and anti-RBD, but not anti-NC antibody levels. Moreover, a “young immunological age” as determined by numbers of CD3+CD45RA+CD62L+CD31+ recent thymic emigrants was associated with a loss of sense of taste and/or smell.Conclusion
Acute SARS-CoV-2 infection leaves protracted beneficial (ie, activation of T cells) and potentially harmful (ie, reduction of neutrophils) imprints in the cellular immune system in addition to induction of specific antibody responses.14.
Jin-jin Zhang Yi-yuan Cao Ge Tan Xiang Dong Bin-chen Wang Jun Lin You-qin Yan Guang-hui Liu Mübeccel Akdis Cezmi A. Akdis Ya-dong Gao 《Allergy》2021,76(2):533-550
Background
The coronavirus disease 2019 (COVID-19) has become a global pandemic, with 10%-20% of severe cases and over 508 000 deaths worldwide.Objective
This study aims to address the risk factors associated with the severity of COVID-19 patients and the mortality of severe patients.Methods
289 hospitalized laboratory-confirmed COVID-19 patients were included in this study. Electronic medical records, including patient demographics, clinical manifestation, comorbidities, laboratory tests results, and radiological materials, were collected and analyzed. According to the severity and outcomes of the patients, they were divided into three groups: nonsurvived (n = 49), survived severe (n = 78), and nonsevere (n = 162) groups. Clinical, laboratory, and radiological data were compared among these groups. Principal component analysis (PCA) was applied to reduce the dimensionality and visualize the patients on a low-dimensional space. Correlations between clinical, radiological, and laboratory parameters were investigated. Univariate and multivariate logistic regression methods were used to determine the risk factors associated with mortality in severe patients. Longitudinal changes of laboratory findings of survived severe cases and nonsurvived cases during hospital stay were also collected.Results
Of the 289 patients, the median age was 57 years (range, 22-88) and 155 (53.4%) patients were male. As of the final follow-up date of this study, 240 (83.0%) patients were discharged from the hospital and 49 (17.0%) patients died. Elder age, underlying comorbidities, and increased laboratory variables, such as leukocyte count, neutrophil count, neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), procalcitonin (PCT), D-dimer, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood urea nitrogen (BUN) on admission, were found in survived severe cases compared to nonsevere cases. According to the multivariate logistic regression analysis, elder age, a higher number of affected lobes, elevated CRP levels on admission, increased prevalence of chest tightness/dyspnea, and smoking history were independent risk factors for death of severe patients. A trajectory in PCA was observed from "nonsevere" toward "nonsurvived" via "severe and survived" patients. Strong correlations between the age of patients, the affected lobe numbers, and laboratory variables were identified. Dynamic changes of laboratory findings of survived severe cases and nonsurvived cases during hospital stay showed that continuing increase of leukocytes and neutrophil count, sustained lymphopenia and eosinopenia, progressing decrease in platelet count, as well as high levels of NLR, CRP, PCT, AST, BUN, and serum creatinine were associated with in-hospital death.Conclusions
Survived severe and nonsurvived COVID-19 patients had distinct clinical and laboratory characteristics, which were separated by principle component analysis. Elder age, increased number of affected lobes, higher levels of serum CRP, chest tightness/dyspnea, and smoking history were risk factors for mortality of severe COVID-19 patients. Longitudinal changes of laboratory findings may be helpful in predicting disease progression and clinical outcome of severe patients.15.
Musa Khaitov Alexandra Nikonova Igor Shilovskiy Ksenia Kozhikhova Ilya Kofiadi Lyudmila Vishnyakova Alexander Nikolskii Pia Gattinger Valeria Kovchina Ekaterina Barvinskaia Kirill Yumashev Valeriy Smirnov Artem Maerle Ivan Kozlov Artem Shatilov Anastasiia Timofeeva Sergey Andreev Olesya Koloskova Nadezhda Kuznetsova Daria Vasina Maria Nikiforova Sergei Rybalkin Ilya Sergeev Dmitriy Trofimov Alexander Martynov Igor Berzin Vladimir Gushchin Aleksey Kovalchuk Sergei Borisevich Rudolf Valenta Rakhim Khaitov Veronica Skvortsova 《Allergy》2021,76(9):2840-2854
Background
First vaccines for prevention of Coronavirus disease 2019 (COVID-19) are becoming available but there is a huge and unmet need for specific forms of treatment. In this study we aimed to evaluate the anti-SARS-CoV-2 effect of siRNA both in vitro and in vivo.Methods
To identify the most effective molecule out of a panel of 15 in silico designed siRNAs, an in vitro screening system based on vectors expressing SARS-CoV-2 genes fused with the firefly luciferase reporter gene and SARS-CoV-2-infected cells was used. The most potent siRNA, siR-7, was modified by Locked nucleic acids (LNAs) to obtain siR-7-EM with increased stability and was formulated with the peptide dendrimer KK-46 for enhancing cellular uptake to allow topical application by inhalation of the final formulation – siR-7-EM/KK-46. Using the Syrian Hamster model for SARS-CoV-2 infection the antiviral capacity of siR-7-EM/KK-46 complex was evaluated.Results
We identified the siRNA, siR-7, targeting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) as the most efficient siRNA inhibiting viral replication in vitro. Moreover, we showed that LNA-modification and complexation with the designed peptide dendrimer enhanced the antiviral capacity of siR-7 in vitro. We demonstrated significant reduction of virus titer and lung inflammation in animals exposed to inhalation of siR-7-EM/KK-46 in vivo.Conclusions
Thus, we developed a therapeutic strategy for COVID-19 based on inhalation of a modified siRNA-peptide dendrimer formulation. The developed medication is intended for inhalation treatment of COVID-19 patients.16.
Qing Lei Yang Li Hong-yan Hou Feng Wang Zhu-qing Ouyang Yandi Zhang Dan-yun Lai Jo-Lewis Banga Ndzouboukou Zhao-wei Xu Bo Zhang Hong Chen Jun-biao Xue Xiao-song Lin Yun-xiao Zheng Zong-jie Yao Xue-ning Wang Cai-zheng Yu He-wei Jiang Hai-nan Zhang Huan Qi Shu-juan Guo Sheng-hai Huang Zi-yong Sun Sheng-ce Tao Xiong-lin Fan 《Allergy》2021,76(2):551-561
Background
The missing asymptomatic COVID-19 infections have been overlooked because of the imperfect sensitivity of the nucleic acid testing (NAT). Globally understanding the humoral immunity in asymptomatic carriers will provide scientific knowledge for developing serological tests, improving early identification, and implementing more rational control strategies against the pandemic.Measure
Utilizing both NAT and commercial kits for serum IgM and IgG antibodies, we extensively screened 11 766 epidemiologically suspected individuals on enrollment and 63 asymptomatic individuals were detected and recruited. Sixty-three healthy individuals and 51 mild patients without any preexisting conditions were set as controls. Serum IgM and IgG profiles were further probed using a SARS-CoV-2 proteome microarray, and neutralizing antibody was detected by a pseudotyped virus neutralization assay system. The dynamics of antibodies were analyzed with exposure time or symptoms onset.Results
A combination test of NAT and serological testing for IgM antibody discovered 55.5% of the total of 63 asymptomatic infections, which significantly raises the detection sensitivity when compared with the NAT alone (19%). Serum proteome microarray analysis demonstrated that asymptomatics mainly produced IgM and IgG antibodies against S1 and N proteins out of 20 proteins of SARS-CoV-2. Different from strong and persistent N-specific antibodies, S1-specific IgM responses, which evolved in asymptomatic individuals as early as the seventh day after exposure, peaked on days from 17 days to 25 days, and then disappeared in two months, might be used as an early diagnostic biomarker. 11.8% (6/51) mild patients and 38.1% (24/63) asymptomatic individuals did not produce neutralizing antibody. In particular, neutralizing antibody in asymptomatics gradually vanished in two months.Conclusion
Our findings might have important implications for the definition of asymptomatic COVID-19 infections, diagnosis, serological survey, public health, and immunization strategies.17.
Bethany A. Stahl Robert Peuß Brittnee McDole Alexander Kenzior James B. Jaggard Karin Gaudenz Jaya Krishnan Suzanne E. McGaugh Erik R. Duboue Alex C. Keene Nicolas Rohner 《Developmental dynamics》2019,248(8):679-687
Background
Astyanax mexicanus is a well-established fish model system for evolutionary and developmental biology research. These fish exist as surface forms that inhabit rivers and 30 different populations of cavefish. Despite important progress in the deployment of new technologies, deep mechanistic insights into the genetic basis of evolution, development, and behavior have been limited by a lack of transgenic lines commonly used in genetic model systems.Results
Here, we expand the toolkit of transgenesis by characterizing two novel stable transgenic lines that were generated using the highly efficient Tol2 system, commonly used to generate transgenic zebrafish. A stable transgenic line consisting of the zebrafish ubiquitin promoter expresses enhanced green fluorescent protein ubiquitously throughout development in a surface population of Astyanax. To define specific cell-types, a Cntnap2-mCherry construct labels lateral line mechanosensory neurons in zebrafish. Strikingly, both constructs appear to label the predicted cell types, suggesting many genetic tools and defined promoter regions in zebrafish are directly transferrable to cavefish.Conclusion
The lines provide proof-of-principle for the application of Tol2 transgenic technology in A. mexicanus. Expansion on these initial transgenic lines will provide a platform to address broadly important problems in the quest to bridge the genotype-phenotype gap.18.
Background
The Minnesota Multiphasic Personality Inventory-3 (MMPI-3) is a commonly used psychological test that includes several scales relevant to measuring manic and depressive symptoms of bipolar spectrum disorders.Aims
The goal of the present study was to evaluate the construct validity of MMPI-3 scale scores with respect to self-report measures of bipolar psychopathology.Materials & Methods
Using a sample of 644 university students in New Zealand, we calculated correlations between scores on the MMPI-3 and the Hypomanic Personality Scale-Short Form (HPS-SF) total and factor scores and the Altman Self-Report Mania Scale (ASRM) total and item scores.Results
For associations against the HPS-SF, almost all of the hypotheses were supported, whereas for the ASRM scale, several were not. We also estimated a series of regression models predicting HPS-SF and ASRM scores from meaningfully associated MMPI-3 scores. Hypomanic Activation (RC9), Activation (ACT), and Self-Importance (SFI) scores emerged as the most consistent and substantial predictors of criteria, with SFI scores being more specifically associated with total scores and criteria related to Social Vitality. Several internalizing and thought dysfunction MMPI-3 scales were also meaningfully associated with scores on the HPS-SF and ASRM.Discussion & Conclusion
Implications and limitations, such as the use of a university student convenience sample, are discussed.19.
Emily R. Czajkowski Marilyn Cisneros Bianca S. Garcia Jim Shen Richard M. Cripps 《Developmental dynamics》2021,250(1):99-110
Background
To identify novel myofibrillar components of the Drosophila flight muscles, we carried out a proteomic analysis of chemically demembranated flight muscle myofibrils, and characterized the knockdown phenotype of a novel gene identified in the screen, CG1674.Results
The CG1674 protein has some similarity to vertebrate synaptopodin 2-like, and when expressed as a FLAG-tagged fusion protein, it was localized during development to the Z-disc and cytoplasm. Knockdown of CG1674 expression affected the function of multiple muscle types, and defective flight in adults was accompanied by large actin-rich structures in the flight muscles that resembled overgrown Z-discs. Localization of CG1674 to the Z-disc depended predominantly upon presence of the Z-disc component alpha-actinin, but also depended upon other Z-disc components, including Mask, Zasp52, and Sals. We also observed re-localization of FLAG-CG1674 to the nucleus in Alpha-actinin and sals knockdown animals.Conclusions
These studies identify and characterize a previously unreported myofibrillar component of Drosophila muscle that is necessary for proper myofibril assembly during development.20.
Lorella Paparo Rita Nocerino Elena Ciaglia Carmen Di Scala Carmen De Caro Roberto Russo Giovanna Trinchese Rosita Aitoro Antonio Amoroso Cristina Bruno Margherita Di Costanzo Annalisa Passariello Francesco Messina Annalisa Agangi Marcello Napolitano Luana Voto Giusy Della Gatta Laura Pisapia Francesco Montella Maria Pina Mollica Antonio Calignano Annibale Puca Roberto Berni Canani 《Allergy》2021,76(5):1398-1415