bluuebunny/crossref_metadata_2025 huggingface dataset:
Bienes privados, males comunes. Un análisis crítico desde la teoría feminista
Authors: Palomo Cermeño Eva , Ávila Bravo-Villasante María
Published: July 2022

La cuestión de los comunes ha adquirido especial relevancia en la actualidad. En este artículo se analizan las dificultades a la hora de abordar la multitud de significados del término y la diversidad de acercamientos al mismo. Esta revisión conceptual pretende señalar las tensiones existentes entre distintas perspectivas, así como acotar nuestro campo de estudio, para proponer un cambio de foco que visibilice el sesgo androcéntrico de los discursos ético-políticos de la modernidad. Por último, se destaca la importancia del cuidado como eje de todo proyecto común que tenga en cuenta la vulnerabilidad humana.
Thomas Hobbes y la distinción entre propiedad estatal, individual y común
Authors: León Pérez Miguel
Published: July 2022

La filosofía jurídica de Hobbes tiene la particularidad, dentro del paradigma liberal, de que al tratar el derecho de propiedad individual como un derecho condicional derivado del derecho absoluto de propiedad que tiene el Estado, reconoce explícitamente la propiedad común, la estatal y la individual como tres realidades jurídicas diferentes. Al establecer el lugar que ocupan las referencias puntuales de Hobbes a la propiedad común dentro de su filosofía jurídica, es posible convertir el pensamiento de este autor clásico en una herramienta teórica muy útil para pensar las posibilidades y los límites de una estrategia política que apueste por la propiedad común contra la propiedad estatal.
Latour, Deleuze y Harman hacia una nueva concepción de la teoría del actor red
Authors: León Eduardo Alberto
Published: July 2022

Este artículo tiene como objetivo, en primer lugar, describir algunas de las principales características de la teoría del actor red de Latour. En segundo lugar, muestra de qué manera la práctica de escribir la naturaleza podría considerarse como un precursor de la teoría del actor red. En tercer lugar, se esboza algunos conceptos deleuzianos y de Harman, que podrían ser útiles para futuras teorías del actor red. Y finalmente, este trabajo sostiene que hacer una teoría del actor red implica una serie de cambios fundamentales en la práctica de los estudios literarios y culturales, así como como en la práctica de las humanidades y las ciencias sociales en general.
Desacuerdos estratégicos y dinámicas de conflicto antagónicas
Authors: Bordonaba-Plou David
Published: July 2022

El objetivo de este artículo es doble. Primero, analizar los desacuerdos estratégicos, es decir, aquellas situaciones en las que una de las partes usa una expresión que le permite reestructurar el debate y, de este modo, obtener alguna ventaja estratégica para hacer avanzar su agenda política. El trabajo examina este tipo de desacuerdos en un contexto específico: los debates parlamentarios del Congreso de los Diputados de España pertenecientes a la VIII Legislatura (2004-2008). Segundo, mostrar que los desacuerdos estratégicos constituyen dinámicas de conflicto antagónicas, es decir, situaciones en las que se niega a una o a ambas partes un tratamiento moralmente aceptable de sus puntos de vista. De este modo, los desacuerdos estratégicos impiden que se puedan desarrollar las dinámicas necesarias para gestionar el conflicto de manera cooperativa.
« Je renonce de bon cœur au contentement d’estre à moy » : les marges du livre comme tremplin chez Marin Le Roy de Gomberville
Authors: Bernard Mathilde
Published: July 2022

Marin Le Roy de Gomberville, académicien et auteur du roman à succès Polexandre, se sert de marges du livre, préfaces et dédicaces aux grands de ce monde, pour construire une stratégie de carrière, dans les belles-lettres. Derrière le calcul à l’œuvre, revient, lancinante et marginale, l’expression d’un désir, celui d’écrire l’histoire. Là serait la faille de Gomberville, car il est parfois difficile d’être homme de science et homme de pouvoir.
Linguistic Mediation as a Means to Develop Soft Skills and Intercultural/Interlinguistic Communication in Higher Education
Authors: Álvarez Miguel Fernández
Published: July 2022

This chapter focuses on the new conceptualization of linguistic mediation as presented in the Common European Framework of Reference (CFER) Companion Volume and its role in the development of soft skills as the foundation for intercultural and interlinguistic communication. By the time of graduation, the 21st century student must have acquired a set of skills that were not required in the past, and educators have the responsibility to integrate these skills into their instructional practices. Therefore, these concepts are key elements in today's society characterized by globalization and connection with stakeholders in different environments.
Examining Vedic Yajna's Effects on the AQI of India in the Second Wave of the COVID-19 Pandemic
Authors: Rastogi Rohit , Chaturvedi Devendra K. , Rastogi Mukund K. , Chauhan Saransh , Aggarwal Vaibhav , Agrawal Utkarsh , Singh Richa
Published: July 2022

This paper depicts Vedic science importance in reducing AQI level and betterment of life with use of Indian Vedic ritual Yajna and Havan. The dataset collected here supports the facts and scientifically proves the proposed analysis. The Central Pollution Control Board (CPCB) and the author's team have collected data through installed sensors in different areas. The presented analysis includes experiments in constrained environments as well as open environments. The sensors have been installed to give their output regarding concentration levels of PM2.5, PM10, SO2, NO2 and CO2 in air at every 30 minutes and a dataset of the last four months has been collected. On the basis of pollutants in the environment before and after the Yajna activity, the analysis was done and the graphical depictions verify that the pollution level decreased after the Havan. Yajna activity is an alternative tool to solve the problem of air pollution on an individual as well as community level. The ingredients and material used in Havan as samagri are easily available and are in reach of common man.
Study on Corrosion Tendency Evaluation of Microstructure in Welding Heat Affected Zone of Austenitic Stainless Steel
Authors: Jin Dong , Zhao Bo , Tong Liang Huai , Dai Qiang , Rong Yan , Zhang Guang Hui
Published: July 2022

In this paper, the simulated welding structure in different area of heat affected zone (HAZ) of S30408 austenitic stainless steel are prepared, and the corrosion resistance properties are evaluated by electrochemistry method and micro-morphology analysis. The result shows that the corrosion resistance of different areas of the HAZ presents different performance, and the corrosion resistance of the area with the highest heating temperature of 1000-1100 °C is slightly lower than that of other areas.The micro-morphology shows that the pitting of the simulated structure in the HAZ have a certain orientation. The rapid cooling process at high temperature is conducive to the uniform distribution of alloying elements, and it can increase the pitting corrosion resistance of the raw material.
Numerical Simulation of Direct Tensile Test of Reinforced Concrete Using Abaqus Software
Authors: Sadeq Hajar , Nasser Abdelkader , El-Miad Abdelhamid Kerkour , Lahlou Mohammed
Published: July 2022

Concrete is characterized by its resistance to compressive forces; however, this material has a low resistance to tensile forces. Due to its resistance to tensile forces, we add steel reinforcements in order to increase the mechanical properties of concrete. In this work we simulated a direct traction test using the Abaqus software. The tensile test characterizes the elasticity of a material and measures its resistance to tensile forces, the tests were carried out on cylindrical specimens complying with the standards. We modeled this test because of the difficulty of carrying out the experiments due to the appearance of stress concentrations during tightening the specimen with the two fasteners of the traction machine. The aim of this simulation is to compare the resistance to the tensile strengths applied on a concrete test piece and a second reinforced concrete test piece. The study revealed that the reinforced concrete structure is more resistant than the concrete structure alone, and that concrete deformations are more significant than reinforced concrete deformations. Thus, the stresses generated in the concrete structure exceed those of the reinforced concrete.
Strain Effects on the Band Structures of Monolayer GaN from the Density Functional Theory
Authors: Hidayati Sri , Sholihun Sholihun
Published: July 2022

We perform the density functional theory calculations (DFT) to study the effect of biaxial strain on the band structures of monolayer GaN. We apply compressive and tensile strains up to 10%. There is no change of bandgap for the applied tensile strains below 8%. The compressive strains have a constant bandgap which is slightly smaller than that of the zero strain. We find that the applied tensile strain above 8% affects its electronic structure and decreases its bandgap energy by about 0.05 eV while the compressive strain above 4% decreases its bandgap about 0.22 eV.
Photocatalytic Degradation of Allura Red (AR) with TiO2 Immobilized on Solution Blow Spinning (SBS) - Spun TIPP/PVP Membranes
Authors: Dalman Danielle , Caquilala Kennex , Paquibot Kathleen , Tan Noel Peter
Published: July 2022

Titanium dioxide (TiO2) nanoparticles were immobilized on the surface of 14% TIPP/PVP membranes by (1) dip coating the membrane in the powdered nanoparticles and (2) dip coating the membranes in PAN/DMF solution containing the nanoparticles. The composite membranes were then used for the photocatalytic degradation of Allura Red (AR) dye. The effect of the presence of PAN/DMF, the initial dye concentration, and irradiation time was investigated. The extent of photocatalytic degradation was observed by measuring the absorbance of the solution using a UV-Vis spectrophotometer. The presence of PAN/DMF allowed more TiO2 nanoparticles to adhere to the surface of the membrane. The membrane with PAN/DMF/TiO2 has greater degradation efficiency across all concentrations used than the membrane without PAN/DMF. In the same membrane, the degradation efficiency increased as the initial dye concentration increased from 0.0008 mg/g AR to 0.004 mg/g AR. However, a further increase to 0.008 mg/g decreased the degradation efficiency. On the other hand, the membrane without PAN/DMF decreased its degradation efficiency as the concentration increased. The degradation efficiency increases with irradiation time but reaches equilibrium after 120 minutes. The experimental data for the membrane with PAN/DMF/TiO2 followed the Langmuir-Hinshelwood (L-H) rate form with a rate constant of 0.0253 min-1. The membrane can be reused up to 10 times at 0.0008 mg/g dye concentrations but with reduced degradation efficiency values on the extent of membrane photocatalyst reusability.
Phenotype of Chronic Obstructive Pulmonary Disease Based on Computed Tomography–Defined Underlying Pathology
Authors: Kim Won-Dong
Published: July 2022

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous disease. Not all patients with COPD respond to available drugs. Identifying respondents to therapy is critical to delivering the most appropriate treatment and avoiding unnecessary medication. Recognition of individual patients’ dominant characteristics by phenotype is a useful tool to better understand their disease and tailor treatment accordingly. To look for a suitable phenotype, it is important to understand what makes COPD complex and heterogeneous. The pathology of COPD includes small airway disease and/or emphysema. Thus, COPD is not a single disease entity. In addition, there are two types (panlobular and centrilobular) of emphysema in COPD. The coexistence of different pathological subtypes could be the reason for the complexity and heterogeneity of COPD. Thus, it is necessary to look for the phenotype based on the difference in the underlying pathology. Review of the literature has shown that clinical manifestation and therapeutic response to pharmacological therapy are different depending on the presence of computed tomography–defined airway wall thickening in COPD patients. Defining the phenotype of COPD based on the underlying pathology is encouraging as most clinical manifestations can be distinguished by the presence of increased airway wall thickness. Pharmacological therapy has shown significant effect on COPD with airway wall thickening. However, it has limited use in COPD without an airway disease. The phenotype of COPD based on the underlying pathology can be a useful tool to better understand the disease and adjust treatment accordingly.
Long-Term Outcome of Chronic Obstructive Pulmonary Disease: A Review
Authors: Jo Yong Suk
Published: July 2022

Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammation characterized by fixed airflow limitation and chronic respiratory symptoms, such as cough, sputum, and dyspnea. COPD is a progressive disease characterized by a decline in lung function. During the natural course of the disease, acute deterioration of symptoms leading to hospital visits can occur and influence further disease progression and subsequent exacerbation. Moreover, COPD is not only restricted to pulmonary manifestations but can present with other systemic diseases as comorbidities or systemic manifestations, including lung cancer, cardiovascular disease, pulmonary hypertension, sarcopenia, and metabolic abnormalities. These pulmonary and extrapulmonary conditions lead to the aggravation of dyspnea, physical inactivity, decreased exercise capacity, functional decline, reduced quality of life, and increased mortality. In addition, pneumonia, which is attributed to both COPD itself and an adverse effect of treatment (especially the use of inhaled and/or systemic steroids), can occur and lead to further deterioration in the prognosis of COPD. This review summarizes the long-term outcomes of patients with COPD. In addition, recent studies on the prediction of adverse outcomes are summarized in the last part of the review.
Pharmacologically Inferred Glycolysis and Glutaminolysis Requirement of B Cells in Lupus-Prone Mice
Authors: Choi Seung-Chul , Li Wei , Zhang Xiaojuan , Kanda Nathalie , Zeumer-Spataro Leilani , Teng Xiangyu , Morel Laurence
Published: July 2022

Several studies have shown an enhanced metabolism in the CD4+ T cells of lupus patients and lupus-prone mice. Little is known about the metabolism of B cells in lupus. In this study, we compared the metabolism of B cells between lupus-prone B6.Sle1.Sle2.Sle3 triple-congenic mice and C57BL/6 controls at steady state relative to autoantibody production, as well as during T cell–dependent (TD) and T cell–independent (TI) immunizations. Starting before the onset of autoimmunity, B cells from triple-congenic mice showed an elevated glycolysis and mitochondrial respiration, which were normalized in vivo by inhibiting glycolysis with a 2-deoxy-d-glucose (2DG) treatment. 2DG greatly reduced the production of TI-Ag–specific Abs, but showed minimal effect with TD-Ags. In contrast, the inhibition of glutaminolysis with 6-diazo-5-oxo-l-norleucine had a greater effect on TD than TI-Ag–specific Abs in both strains. Analysis of the TI and TD responses in purified B cells in vitro suggests, however, that the glutaminolysis requirement is not B cell-intrinsic. Thus, B cells have a greater requirement for glycolysis in TI than TD responses, as inferred from pharmacological interventions. B cells from lupus-prone and control mice have different intrinsic metabolic requirements or different responses toward 2DG and 6-diazo-5-oxo-l-norleucine, which mirrors our previous results obtained with follicular Th cells. Overall, these results predict that targeting glucose metabolism may provide an effective therapeutic approach for systemic autoimmunity by eliminating both autoreactive follicular Th and B cells, although it may also impair TI responses.
Realization of the T Lineage Program Involves GATA-3 Induction of Bcl11b and Repression of Cdkn2b Expression
Authors: Thompson Patrycja K , Chen Edward L Y , de Pooter Renée F , Frelin Catherine , Vogel Walter K , Lee Christina R , Venables Thomas , Shah Divya K , Iscove Norman N , Leid Mark , Anderson Michele K , Zúñiga-Pflücker Juan Carlos
Published: July 2022

The zinc-finger transcription factor GATA-3 plays a crucial role during early T cell development and also dictates later T cell differentiation outcomes. However, its role and collaboration with the Notch signaling pathway in the induction of T lineage specification and commitment have not been fully elucidated. We show that GATA-3 deficiency in mouse hematopoietic progenitors results in an early block in T cell development despite the presence of Notch signals, with a failure to upregulate Bcl11b expression, leading to a diversion along a myeloid, but not a B cell, lineage fate. GATA-3 deficiency in the presence of Notch signaling results in the apoptosis of early T lineage cells, as seen with inhibition of CDK4/6 (cyclin-dependent kinases 4 and 6) function, and dysregulated cyclin-dependent kinase inhibitor 2b (Cdkn2b) expression. We also show that GATA-3 induces Bcl11b, and together with Bcl11b represses Cdkn2b expression; however, loss of Cdkn2b failed to rescue the developmental block of GATA-3–deficient T cell progenitor. Our findings provide a signaling and transcriptional network by which the T lineage program in response to Notch signals is realized.
Efficient Identification of Tembusu Virus CTL Epitopes in Inbred HBW/B4 Ducks Using a Novel MHC Class I–Restricted Epitope Screening Scheme
Authors: Zhang Lin , Li Zhuolin , Tang Ziche , Han Lingxia , Wei Xiaohui , Xie Xiaoli , Ren Shuaimeng , Meng Kai , Liu Yueyue , Xu Minli , Qi Lihong , Chen Hongyan , Wu Jiaqiang , Zhang Nianzhi
Published: July 2022

The identification of MHC class I–restricted CTL epitopes in certain species, particularly nonmammals, remains a challenge. In this study, we developed a four-step identification scheme and confirmed its efficiency by identifying the Anpl-UAA*76–restricted CTL epitopes of Tembusu virus (TMUV) in inbred haplotype ducks HBW/B4. First, the peptide binding motif of Anpl-UAA*76 was determined by random peptide library in de novo liquid chromatography–tandem mass spectrometry, a novel nonbiased, data-independent acquisition method that we previously established. Second, a total of 38 TMUV peptides matching the motif were screened from the viral proteome, among which 11 peptides were conserved across the different TMUV strains. Third, the conserved TMUV peptides were refolded in vitro with Anpl-UAA*76 and Anpl–β2-microglobulin to verify the results from the previous two steps. To clarify the structural basis of the obtained motif, we resolved the crystal structure of Anpl-UAA*76 with the TMUV NS3 peptide LRKRQLTVL and found that Asp34 is critical for the preferential binding of the B pocket to bind the second residue to arginine as an anchor residue. Fourth, the immunogenicity of the conserved TMUV peptides was tested in vivo using specific pathogen-free HBW/B4 ducks immunized with the attenuated TMUV vaccine. All 11 conserved TMUV epitopes could bind stably to Anpl-UAA*76 in vitro and stimulate the secretion of IFN-γ and lymphocyte proliferation, and three conserved and one nonconserved peptides were selected to evaluate the CTL responses in vivo by flow cytometry and their tetramers. We believe that this new scheme could improve the identification of MHC class I–restricted CTL epitopes, and our data provide a foundation for further study on duck anti-TMUV CTL immunity.
Profibrotic Role of Inducible Heat Shock Protein 90α Isoform in Systemic Sclerosis
Authors: RuizdelRio Jorge , Muñoz Pedro , Carreira Patricia , Maestro David , Pablos Jose L , Palanca Ana , Merino Jesus , Serrano-Mollar Anna , Merino Ramon , Tamayo Esther , Lopez-Hoyos Marcos , Diaz-Gonzalez Federico , Martinez-Taboada Victor , Villar Ana V
Published: July 2022

Systemic sclerosis (SSc) is an autoimmune disease that affects skin and multiple internal organs. TGF-β, a central trigger of cutaneous fibrosis, activates fibroblasts with the involvement of the stress-inducible chaperone heat shock protein 90 isoform α (Hsp90α). Available evidence supports overexpression and secretion of Hsp90α as a feature in profibrotic pathological conditions. The aim of this work is to investigate the expression and function of Hsp90α in experimental models of skin fibrosis such as human fibroblasts, C57BL/6 mice, and in human SSc. For this purpose, we generated a new experimental model based on doxorubicin administration with improved characteristics with respect to the bleomycin model. We visualized disease progression in vivo by fluorescence imaging. In this work, we obtained Hsp90α mRNA overexpression in human skin fibroblasts, in bleomycin- and doxorubicin-induced mouse fibrotic skin, and in lungs of bleomycin- and doxorubicin-treated mice. Hsp90α-deficient mice showed significantly decreased skin thickness compared with wild-type mice in both animal models. In SSc patients, serum Hsp90α levels were increased in patients with lung involvement and in patients with the diffuse form of SSc (dSSc) compared with patients with the limited form of SSc. The serum Hsp90α levels of patients dSSc were correlated with the Rodnan score and the forced vital capacity variable. These results provide new supportive evidence of the contribution of the Hsp90α isoform in the development of skin fibrosis. In SSc, these results indicated that higher serum levels were associated with dSSc and lung fibrosis.
A Dual Role for Cysteinyl Leukotriene Receptors in the Pathogenesis of Corneal Infection
Authors: Carion Thomas W , Wang Yuxin , Stambersky Ashten , Ebrahim Abdul Shukkur , Berger Elizabeth A
Published: July 2022

Cysteinyl leukotrienes (CysLTs) have been defined as central mediators of inflammation. Despite our extensive understanding of these bioactive lipid mediators in the pathogenesis of diseases such as asthma, allergic rhinitis, and even neurological disorders, information regarding the eye is markedly lacking. As a result, this study examined the expression profiles of two major CysLT receptors, CysLT1 and CysLT2, in the cornea using experimental mouse models of Pseudomonas aeruginosa–induced keratitis with contrasting outcomes: susceptible C57BL/6 (B6) and resistant BALB/c. Postinfection, disparate levels of CysLT receptors were accompanied by distinct expression profiles for select proinflammatory and anti-inflammatory cell surface markers detected on macrophages and polymorphonuclear neutrophils between the two strains. Further, inhibition of either CysLT receptor converted the disease response of both strains, where corneal perforation was prevented in B6 mice, and BALB/c mice fared significantly worse. In addition, receptor antagonist studies revealed changes in inflammatory cell infiltrate phenotypes and an influence on downstream CysLT receptor signaling pathways. Although the B6 mouse model highlights the established proinflammatory activities related to CysLT receptor activation, results generated from BALB/c mice indicate a protective mechanism that may be essential to disease resolution. Further, basal expression levels of CysLT1 and CysLT2 were significantly higher in uninfected corneas of both mouse strains as opposed to during infection, suggestive of a novel role in homeostatic maintenance within the eye. In light of these findings, therapeutic targeting of CysLT receptors extends beyond inhibition of proinflammatory activities and may impact inflammation resolution, as well as corneal surface homeostasis.
Extracellular pH Controls Chemotaxis of Neutrophil Granulocytes by Regulating Leukotriene B4 Production and Cdc42 Signaling
Authors: Oster Leonie , Schröder Julia , Rugi Micol , Schimmelpfennig Sandra , Sargin Sarah , Schwab Albrecht , Najder Karolina
Published: July 2022

Neutrophil granulocytes are the first and robust responders to the chemotactic molecules released from an inflamed acidic tissue. The aim of this study was to elucidate the role of microenvironmental pH in neutrophil chemotaxis. To this end, we used neutrophils from male C57BL/6J mice and combined live cell imaging chemotaxis assays with measurements of the intracellular pH (pHi) in varied extracellular pH (pHe). Observational studies were complemented by biochemical analyses of leukotriene B4 (LTB4) production and activation of the Cdc42 Rho GTPase. Our data show that pHi of neutrophils dose-dependently adapts to a given pH of the extracellular milieu. Neutrophil chemotaxis toward C5a has an optimum at pHi ∼7.1, and its pHi dependency is almost parallel to that of LTB4 production. Consequently, a shallow pHe gradient, resembling that encountered by neutrophils during extravasation from a blood vessel (pH ∼7.4) into the interstitium (pH ∼7.2), favors chemotaxis of stimulated neutrophils. Lowering pHe below pH 6.8, predominantly affects neutrophil chemotaxis, although the velocity is largely maintained. Inhibition of the Na+/H+ exchanger 1 (NHE1) with cariporide drastically attenuates neutrophil chemotaxis at the optimal pHi irrespective of the high LTB4 production. Neutrophil migration and chemotaxis are almost completely abrogated by inhibiting LTB4 production or blocking its receptor (BLT1). The abundance of the active GTP-bound form of Cdc42 is strongly reduced by NHE1 inhibition or pHe 6.5. In conclusion, we propose that the pH dependence of neutrophil chemotaxis toward C5a is caused by a pHi-dependent production of LTB4 and activation of Cdc42. Moreover, it requires the activity of NHE1.
Poor-Quality Vβ Recombination Signal Sequences and the DNA Damage Response ATM Kinase Collaborate to Establish TCRβ Gene Repertoire and Allelic Exclusion
Authors: Wu Glendon S , Culberson Erica J , Allyn Brittney M , Bassing Craig H
Published: July 2022

The monoallelic expression (allelic exclusion) of diverse lymphocyte Ag receptor genes enables specific immune responses. Allelic exclusion is achieved by asynchronous initiation of V(D)J recombination between alleles and protein encoded by successful rearrangement on the first allele signaling permanent inhibition of V rearrangement on the other allele. The ATM kinase that guides DNA repair and transiently suppresses V(D)J recombination also helps impose allelic exclusion through undetermined mechanisms. At the TCRβ locus, one Vβ gene segment (V31) rearranges only by inversion, whereas all other Vβ segments rearrange by deletion except for rare cases in which they rearrange through inversion following V31 rearrangement. The poor-quality recombination signal sequences (RSSs) of V31 and V2 help establish TCRβ gene repertoire and allelic exclusion by stochastically limiting initiation of Vβ rearrangements before TCRβ protein-signaled permanent silencing of Vβ recombination. We show in this study in mice that ATM functions with these RSSs and the weak V1 RSS to shape TCRβ gene repertoire by restricting their Vβ segments from initiating recombination and hindering aberrant nonfunctional Vβ recombination products, especially during inversional V31 rearrangements. We find that ATM collaborates with the V1 and V2 RSSs to help enforce allelic exclusion by facilitating competition between alleles for initiation and functional completion of rearrangements of these Vβ segments. Our data demonstrate that the fundamental genetic DNA elements that underlie inefficient Vβ recombination cooperate with ATM-mediated rapid DNA damage responses to help establish diversity and allelic exclusion of TCRβ genes.
Mouse Liver B Cells Phagocytose Streptococcus pneumoniae and Initiate Immune Responses against Their Antigens
Authors: Nakashima Masahiro , Kinoshita Manabu , Nakashima Hiroyuki , Kato Azusa , Mori Kazuma , Koiwai Kazuki , Shinomiya Nariyoshi , Seki Shuhji
Published: July 2022

Recent studies have revealed that mammalian B cells ingest particulate Ags, such as bacteria, although little is known about the effect of this function on acquired immunity. We investigated the role of bacterium-phagocytosing B cells in acquired host immune responses. Cultured mouse liver B cells substantially phagocytosed serum-opsonized Streptococcus pneumoniae and produced IgM. On adoptive transfer of liver B cells that phagocytose S. pneumoniae labeled with pHrodo Red succinimidyl ester, recipient mice showed elevated plasma levels of IgG specific for bacterial Ags. In particular, the levels of IgG2a and IgG2b specific for pneumococcal surface protein A, as well as IgG3 for pneumococcal polysaccharide, were markedly increased compared with total IgG specific for each Ag. When phagocytic liver B cells were cultured with spleen CD4+ T cells obtained from mice primed with heat-killed S. pneumoniae 7 d before, they induced IL-2 production and proliferation of the CD4+ T cells, along with Th1 cytokine production. However, they induced neither the CD4+ T cell production of IL-21, a suggested marker promoting B cell proliferation and differentiation, nor the expression of genes important for somatic hypermutation or isotype switching; such responses were particularly evident when splenic B cells merely capturing S. pneumoniae without processing them were cultured with spleen CD4+ T cells. These findings suggest that phagocytic liver B cells may be involved in acquired immune responses by presenting derivative peptides to CD4+ T cells without their own somatic hypermutation or isotype switching.
Essential Roles of the Transcription Factor NR4A1 in Regulatory T Cell Differentiation under the Influence of Immunosuppressants
Authors: Sekiya Takashi , Kasahara Hidenori , Takemura Ryo , Fujita Shinya , Kato Jun , Doki Noriko , Katayama Yuta , Ozawa Yukiyasu , Takada Satoru , Eto Tetsuya , Fukuda Takahiro , Ichinohe Tatsuo , Takanashi Minoko , Onizuka Makoto , Atsuta Yoshiko , Okamoto Shinichiro , Yoshimura Akihiko , Takaki Satoshi , Mori Takehiko
Published: July 2022

Calcineurin inhibitors (CNIs), used as immunosuppressants, have revolutionized transplantation medicine with their strong suppressive activity on alloreactive T lymphocytes; however, they may also cause various adverse effects, including an increased risk for infection and nephrotoxicity. Regulatory T (Treg) cells can complement the deleterious side effects of CNIs with their effective Ag-specific suppressive activities. However, several studies have shown that CNIs suppress Treg cell differentiation. Therefore, an understanding of the mechanisms by which CNIs suppress Treg cell differentiation, as well as an approach for promoting the differentiation of Treg cells in the presence of CNIs, has significant clinical value. In this article, we report that the nuclear orphan receptor Nr4a1 plays a pivotal role in Treg cell differentiation in the presence of CNIs. Unlike that of its family members, Nr4a2 and Nr4a3, the expression of Nr4a1 was not suppressed by CNI treatment, thereby mediating Treg cell differentiation in the presence of CNIs. In a mouse allogeneic graft-versus-host disease model, Nr4a1 mediated tolerance by promoting Treg cell differentiation in mice administered cyclosporine A, prolonging the survival of recipients. Furthermore, activation of Nr4a1 via its agonist partially restored Treg cell differentiation, which was suppressed by cyclosporine A treatment. Finally, we found that the rs2701129 single-nucleotide polymorphism, which was shown to downregulate NR4A1 expression, showed a trend toward a higher incidence of chronic graft-versus-host disease in patients undergoing hematopoietic stem cell transplantation. Therefore, our study will be of clinical significance because we demonstrated the role of Nr4a1 in Treg cell differentiation in the presence of CNIs.
Apo-Form Selective Inhibition of IDO for Tumor Immunotherapy
Authors: Liu Wen , Zou Yi , Li Kaiming , Zhong Haiqing , Yu Longbo , Ge Shushan , Lai Yisheng , Dong Xianchi , Xu Qiang , Guo Wenjie
Published: July 2022

The pharmacological inhibition of IDO1 is considered an effective therapeutic approach for cancer treatment. However, the inadequate response of existing holo-IDO1 inhibitors and unclear biomarkers available in clinical practice limit the possibility of developing efficacious IDO1 inhibitors. In the current study, we aimed to elucidate the activity and mechanism of a potent 1H-pyrrole-2-carboxylic acid derivative (B37) targeting apo-IDO1 and to determine its role in tumor therapy. By competing with heme for binding to apo-IDO1, B37 potently inhibited IDO1 activity, with an IC50 of 22 pM assessed using a HeLa cell–based assay. The x-ray cocrystal structure of the inhibitor–enzyme complex showed that the B37–human IDO1 complex has strong hydrophobic interactions, which enhances its binding affinity, determined using isothermal titration calorimetry. Stronger noncovalent interactions, including π stacking and hydrogen bonds formed between B37 and apo-human IDO1, underlay the enthalpy-driven force for B37 for binding to the enzyme. These binding properties endowed B37 with potent antitumor efficacy, which was confirmed in a mouse colon cancer CT26 syngeneic model in BALB/c mice and in an azoxymethane/dextran sulfate sodium–induced colon carcinogenesis model in C57BL/6 mice by activating the host immune system. Moreover, the combination of B37 and anti-PD1 Ab synergistically inhibited tumor growth. These results suggested that B37 may serve as a unique candidate for apo-IDO1 inhibition-mediated tumor immunotherapy.
STAP-2 Is a Novel Positive Regulator of TCR-Proximal Signals
Authors: Saitoh Kodai , Kashiwakura Jun-ichi , Kagohashi Kota , Sasaki Yuto , Kawahara Shoya , Sekine Yuichi , Kitai Yuichi , Muromoto Ryuta , Ichii Michiko , Nakatsukasa Hiroko , Yoshimura Akihiko , Oritani Kenji , Matsuda Tadashi
Published: July 2022

TCR ligation with an Ag presented on MHC molecules promotes T cell activation, leading to the selection, differentiation, and proliferation of T cells and cytokine production. These immunological events are optimally arranged to provide appropriate responses against a variety of pathogens. We here propose signal-transducing adaptor protein-2 (STAP-2) as a new positive regulator of TCR signaling. STAP-2–deficient T cells showed reduced, whereas STAP-2–overexpressing T cells showed enhanced, TCR-mediated signaling and downstream IL-2 production. For the mechanisms, STAP-2 associated with TCR-proximal CD3ζ immunoreceptor tyrosine activation motifs and phosphorylated LCK, resulting in enhancement of their binding after TCR stimulation. In parallel, STAP-2 expression is required for full activation of downstream TCR signaling. Importantly, STAP-2–deficient mice exhibited slight phenotypes of CD4+ T-cell–mediated inflammatory diseases, such as experimental autoimmune encephalomyelitis, whereas STAP-2–overexpressing transgenic mice showed severe phenotypes of these diseases. Together, STAP-2 is an adaptor protein to enhance TCR signaling; therefore, manipulating STAP-2 will have an ability to improve the treatment of patients with autoimmune diseases as well as the chimeric Ag receptor T cell therapy.
Viral Delivery of IL-7 Is a Potent Immunotherapy Stimulating Innate and Adaptive Immunity and Confers Survival in Sepsis Models
Authors: Lélu Karine , Dubois Clarisse , Evlachev Alexei , Crausaz Morgane , Baldazza Marie , Kehrer Nadine , Brandely Renée , Schlesinger Yasmin , Silvestre Nathalie , Marchand Jean-Baptiste , Bastien Bérangère , Leung-Theung-Long Stéphane , Unsinger Jacqueline , Martin Perrine , Inchauspé Geneviève
Published: July 2022

Persistence of an immunosuppressive state plays a role in septic patient morbidity and late mortality. Both innate and adaptive pathways are impaired, pointing toward the need for immune interventions targeting both arms of the immune system. We developed a virotherapy using the nonpropagative modified vaccinia virus Ankara (MVA), which harbors the intrinsic capacity to stimulate innate immunity, to deliver IL-7, a potent activator of adaptive immunity. The rMVA–human IL-7 (hIL-7)–Fc encoding the hIL-7 fused to the human IgG2-Fc was engineered and shown to express a dimeric, glycosylated, and biologically active cytokine. Following a single i.v. injection in naive mice, the MVA–hIL-7–Fc increased the number of total and activated B, T, and NK cells but also myeloid subpopulations (Ly6Chigh, Ly6Cint, and Ly6Cneg cells) in both lung and spleen. It triggered differentiation of T cells in central memory, effector memory, and acute effector phenotypes and enhanced polyfunctionality of T cells, notably the number of IFN-γ–producing cells. The MVA vector contributed significantly to immune cell activation, particularly of NK cells. The MVA–hIL-7–Fc conferred a significant survival advantage in the cecal ligation and puncture (CLP) and Candida albicans sepsis models. It significantly increased cell numbers and activation in both spleen and lung of CLP mice. Comparatively, in naive and CLP mice, the rhIL-7–Fc soluble counterpart overall induced less vigorous, shorter lasting, and narrower immune activities than did the MVA–hIL-7–Fc and favored TNF-α–producing cells. The MVA–hIL-7–Fc represents a novel class of immunotherapeutic with clinical potential for treatment of septic patients.
The Pre-Existing Human Antibody Repertoire to Computationally Optimized Influenza H1 Hemagglutinin Vaccines
Authors: Nagashima Kaito , Dzimianski John V , Han Julianna , Abbadi Nada , Gingerich Aaron D , Royer Fredejah , O’Rourke Sara , Sautto Giuseppe A , Ross Ted M , Ward Andrew B , DuBois Rebecca M , Mousa Jarrod J
Published: July 2022

Computationally optimized broadly reactive Ag (COBRA) hemagglutinin (HA) immunogens have previously been generated for several influenza subtypes to improve vaccine-elicited Ab breadth. As nearly all individuals have pre-existing immunity to influenza viruses, influenza-specific memory B cells will likely be recalled upon COBRA HA vaccination. We determined the epitope specificity and repertoire characteristics of pre-existing human B cells to H1 COBRA HA Ags. Cross-reactivity between wild-type HA and H1 COBRA HA proteins P1, X6, and Y2 were observed for isolated mAbs. The mAbs bound five distinct epitopes on the pandemic A/California/04/2009 HA head and stem domains, and most mAbs had hemagglutination inhibition and neutralizing activity against 2009 pandemic H1 strains. Two head-directed mAbs, CA09-26 and CA09-45, had hemagglutination inhibition and neutralizing activity against a prepandemic H1 strain. One mAb, P1-05, targeted the stem region of H1 HA, but did not compete with a known stem-targeting H1 mAb. We determined that mAb P1-05 recognizes a recently discovered HA epitope, the anchor epitope, and we identified similar mAbs using B cell repertoire sequencing. In addition, the trimerization domain distance from HA was critical to recognition of this epitope by mAb P1-05, suggesting the importance of protein design for vaccine formulations. Overall, these data indicate that seasonally vaccinated individuals possess a population of functional H1 COBRA HA–reactive B cells that target head, central stalk, and anchor epitopes, and they demonstrate the importance of structure-based assessment of subunit protein vaccine candidates to ensure accessibility of optimal protein epitopes.
Cell-Penetrating Peptide TAT-HuR-HNS3 Suppresses Proinflammatory Gene Expression via Competitively Blocking Interaction of HuR with Its Partners
Authors: Wang Ke , Tong Haibin , Gao Yitian , Xia Lan , Jin Xin , Li Xiaoxue , Zeng Xianlu , Boldogh Istvan , Ke Yueshuang , Ba Xueqing
Published: July 2022

Proinflammatory cytokines/chemokines are commonly regulated by RNA-binding proteins at posttranscriptional levels. Human Ag R (HuR)/embryonic lethal abnormal vision-like 1 (ELAVL1) is one of the well-characterized RNA-binding proteins that increases the stability of short-lived mRNAs, which encode proinflammatory mediators. HuR employs its nucleocytoplasmic shuttling sequence (HNS) domain, interacting with poly(ADP-ribose) polymerase 1 (PARP1), which accounts for the enhanced poly-ADP-ribosylation and cytoplasmic shuttling of HuR. Also by using its HNS domain, HuR undergoes dimerization/oligomerization, underlying the increased binding of HuR with proinflammatory cytokine/chemokine mRNAs and the disassociation of the miRNA-induced silencing complex from the targets. Therefore, competitively blocking the interactions of HuR with its partners may suppress proinflammatory mediator production. In this study, peptides derived from the sequence of the HuR-HNS domain were synthesized, and their effects on interfering HuR interacting with PARP1 and HuR itself were analyzed. Moreover, cell-penetrating TAT-HuR-HNS3 was delivered into human and mouse cells or administered into mouse lungs with or without exposure of TNF-α or LPS. mRNA levels of proinflammatory mediators as well as neutrophil infiltration were evaluated. We showed that TAT-HuR-HNS3 interrupts HuR–PARP1 interaction and therefore results in a lowered poly-ADP-ribosylation level and decreased cytoplasmic distribution of HuR. TAT-HuR-HNS3 also blocks HuR dimerization and promotes Argonaute 2–based miRNA-induced silencing complex binding to the targets. Moreover, TAT-HuR-HNS3 lowers mRNA stability of proinﬂammatory mediators in TNF-α–treated epithelial cells and macrophages, and it decreases TNF-α–induced inflammatory responses in lungs of experimental animals. Thus, TAT-HuR-HNS3 is a promising lead peptide for the development of inhibitors to treat inﬂammation-related diseases.
Dicer and PKR as Novel Regulators of Embryonic Stem Cell Fate and Antiviral Innate Immunity
Authors: Guo Yan-Lin , Gurung Chandan , Fendereski Mona , Huang Faqing
Published: July 2022

Embryonic stem cells (ESCs) represent a unique cell population in the blastocyst stage embryo. They have been intensively studied as a promising cell source for regenerative medicine. Recent studies have revealed that both human and mouse ESCs are deficient in expressing IFNs and have attenuated inflammatory responses. Apparently, the ability to express IFNs and respond to certain inflammatory cytokines is not “innate” to ESCs but rather is developmentally acquired by somatic cells during differentiation. Accumulating evidence supports a hypothesis that the attenuated innate immune response may serve as a protective mechanism allowing ESCs to avoid immunological cytotoxicity. This review describes our current understanding of the molecular basis that shapes the immune properties of ESCs. We highlight the recent findings on Dicer and dsRNA-activated protein kinase R as novel regulators of ESC fate and antiviral immunity and discuss how ESCs use alternative mechanisms to accommodate their stem cell properties.
The Legend of Delta: Finding a New TCR Gene
Authors: Dent Alexander L
Published: July 2022

This Pillars of Immunology article is a commentary on “A new T-cell receptor gene located within the alpha locus and expressed early in T-cell differentiation,” a pivotal article written by Y.-H. Chien, M. Iwashima, K. B. Kaplan, J. F. Elliott, and M. M. Davis, and published in Nature, in 1987. https://www.nature.com/articles/327677a0.
Efficacy of ketamine, propofol, and dexmedetomidine for anesthesia in electroconvulsive therapy in treatment-resistant major depressive disorder patients
Authors: Modir Hesameddin , Mahmoodiyeh Behnam , Shayganfard Mehran , Abdus Ayda , Almasi-Hashiani Amir
Published: July 2022

Electroconvulsive therapy (ECT) is one of the therapeutic opportunities for patients with psychological disorders when they may decline to take medication. We sought to systematically compare the anesthetic efficacy of ketamine, propofol, and dexmedetomidine for electroconvulsive therapy in treatment-resistant major depressive disorder patients. This double-blind trial enrolled treatment-resistant major depressive disorder patients (n = 85) who had been hospitalized for ECT in the Amir Kabir Hospital’s psychiatric ward (Arak, Iran). The ketamine, propofol, and dexmedetomidine groups received a dose of 0.2 μg/kg ketamine, 1.5 mg/kg propofol, and 0.8 mg/kg dexmedetomidine, respectively. In all intervention groups, 10 mL of interventional drugs was injected intravenously for 10 minutes, and in the placebo group, 10 mL of normal saline was given over the same period. The dexmedetomidine group’s blood pressure was revealed comparatively lower at all times. Dexmedetomidine-treated patients showed their marked satisfaction, while those treated with propofol had shorter recovery time, shorter seizure duration, and shorter time to achieve an Aldrete score of 9–10 and increased relaxation, and next dexmedetomidine produced deeper relaxation. Propofol could shorten recovery time and seizure duration, and enhance relaxation, while dexmedetomidine was associated with higher patient satisfaction. Considering that any anesthetic which does not shorten seizure duration may serve efficiently for ECT and that ketamine-treated patients had more prolonged seizure duration, the preferred drug can hence be considered from various angles, thereby offering anesthetic agents with highly favorable efficacy in treatment-resistant major depressive disorder patients needing ECT. The drug choice thus depends on physical conditions, underlying diseases, and psychiatrist consultation.
Alterations of hand muscle strength in children due to schoolbag carriage
Authors: Mukherjee Ruchira , Dutta Koumi , Sen Devashish , Sahu Subhashis , Mukhopadhyay Aparna
Published: July 2022

BACKGROUND:

Heavy schoolbag carriage induces pain and fatigue in children. It can alter the handgrip strength (HGS) in children – an important parameter given that most activities in school curriculum require hand dexterity. The purpose of this study is to explore if and how schoolbag carriage influence HGS in children.

MATERIALS AND METHODS:

Twenty-five healthy male participants (10–15 years) walked without schoolbag (0% load of bodyweight) or with schoolbags (weighing 4%, 8%, 12%, or 16% of their bodyweight) for 20 min on plane surface at preferred pace. The number of steps taken during walk was measured using pedometer. HGS was measured before and after each walk using dynamometer. The heart rate during walk was measured using Polar HR monitor. Pain occurrence in the entire body was mapped.

RESULTS:

HGS averaged for both hand decreased from 17.8 (±6.72) kg to 17.3 (±6.28) kg after 20-min walk (P = 0.033, paired sample t-test). The adopted speed and heart rate was higher when carrying a schoolbag but it portrayed no significant association with HGS. Occurrence of shoulder pain significantly associated with increasing in HGS of right hand after walking (Phi coefficient = 0.21[P = 0.030]). If shoulder pain was perceived during walk, there was a 2.5 times higher likelihood that the participants' HGS for right hand increased (odd's ratio = 2.515, 95% confidence interval = 1.086–5.825).

CONCLUSION:

Schoolbag carriage reduces HGS in children. Therefore, performing upper body conditioning exercises may help ameliorate the ill effects of heavy backpack carriage.