bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.
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.
Dentinal Defects Induced by Offset and Alternating Contact Endodontic Rotary Files
Authors: Abass Abeer A. , Fadhil Haidar T. , Albaaj Firas S. O. 
Published: July 2022

Objective:
Dentinal defects during root canal preparation could lead to treatment failure and tooth extraction. Many rotary files are manufactured with asymmetric cross sections or alternating cutting edges to minimize contact with the canal wall. Decreasing contacts may generate low stresses and, hence, fewer dental defects during root canal instrumentation. This study aimed to evaluate the incidence of dentinal defects induced by ProTaper Next, Wave One Gold (Dentsply Maillefer, Ballaigues, Switzerland), and iRace (FKG Dentaire SA, La Chaux-de-Fonds, Switzerland) in comparison to the symmetric file HyFlex CM (Coltene-Whaledent, Allstetten, Switzerland).

Materials and Methods:
Sixty extracted single-rooted premolars with round canals were selected for this study. All teeth were decoronated and divided into four experimental groups according to the tested file systems. In each group, 15 canals were prepared with the crown down technique using a speed and torque recommended by manufacturers. The root samples were then sectioned horizontally at 3, 6, and 9 mm from the apex and examined under a stereomicroscope to evaluate the presence or absence of dentinal defects. Data were statistically analyzed with SPSS software using a chi-square test.

Results:
Dentinal defects were observed at all canal levels following all methods of instrumentation. ProTaper Next showed the lowest values of dentinal defects, whereas Hyflex CM displayed the highest values.

Conclusion:
Files with few contacts with the canal wall decreased the number of dentinal defects compared to the HyFlex CM file, with a nonsignificant difference being observed.
Comparison of Fracture Resistance of the Endodontically Treated Roots with Two Sealer Types
Authors: Hajihassani Neda , Heidari Soolmaz , Ghanati Mohammad , Mohammadi Navid 
Published: July 2022

Introduction:
This study aimed to compare the fracture resistance using a bioceramic sealer and an epoxy resin-based sealer.

Materials and Methods:
One hundred maxillary central incisors were randomly assigned to three experimental groups: AH Plus sealer using the single-cone technique, AH Plus sealer using the lateral compaction technique, SureSeal Root sealer, and two positive and negative control groups. Then the fracture resistance of the prepared tooth roots was determined. The data were analyzed with one-way ANOVA and Tukey Post Hoc tests.

Results:
There were statistically significant differences between the five study groups (P < 0.001). There was no significant difference between the negative control and Sureseal groups (P = 0.183). There were significant differences between the SureSeal and AH Plus groups (P < 0.05).

Conclusion:
SureSeal Root sealer significantly increased the fracture resistance of the teeth compared to AH Plus sealer.
Analysis of Therapy by Means of Gallium Aluminum Arsenide Laser During Orthodontic Tooth Movement
Authors: Giudice Antonino Lo , Palazzo Giuseppe , Campagna Paola , Fichera Grazia , Isola Gaetano 
Published: July 2022

Indroduction:
Preliminary evidence have shown that low intensity laser therapy is able to increase the rate of tooth movement. The aim of this study was to analyze the effects of gallium aluminum arsenide (GaAlAs) laser therapy in the enhancement of speed of orthodontic tooth movement (OTM) in a clinical protocol.

Materials and Methods:
Thirty-six upper canines were analyzed on 18 enrolled patients. On all experimental canine, an orthodontic force of 40 g/side was applied by a nickel-titanium closed coil spring. Using a split mouth randomized design, the test side was treated using a diode laser operating at a wavelength of 780 nm in continuous wave mode with flattop handpiece (20 mW output power, dose of 5 J/cm2, and exposure time of 10 seconds) (test side) at baseline and at 7, 14, and 28 days and every 14 days until the space closure. On the control side, selected teeth were only tractionated. The primary outcome was the overall time needed to complete leveling and closing space, measured on study cast. The secondary outcome was the evaluation of pain levels related to tooth traction, evaluated using a visual analogue scale (VAS).

Results:
The test side showed a significant reduced overall time needed for tooth space closure (at 7 and 14 days) and less VAS score (P < 0.001) compared to control side. Conclusion: This study shows that the use of low-level laser therapy by means of GaAlAs laser was effective for accelerating tooth movement and reducing pain levels related to OTM.
Platelet Count Estimation on Peripheral Smear
Authors: Tiwari Arnav , Pal Shweta , Singh Neha , Anthony Michael Leonard , Chowdhury Nilotpal , Rao Shalinee 
Published: July 2022

Context:
Automated cell counters have revolutionised laboratory medicine and are being used worldwide. They give accurate results, can run large number of samples and generate accurate results within a short span of time. Quality check procedures in this equipment ensure accuracy of results. However, for platelet counts, the pathologist is still dependent on confirming the results by manual methods, especially in situations of low platelet count and flagging by the electronic counter. Different laboratories use different methods for manual estimation of platelet counts.

Aims:
This study was done to compare the platelet counts assessed on peripheral smear examination by different multiplication factors, and to identify the multiplication factor which derives the most accurate platelet count.

Settings and Design:
This was an observational study.

Methods:
Peripheral smears prepared from 100 ethylenediaminetetraacetic acid-anticoagulated blood samples were manually examined under oil immersion field (OIF) for platelets. Platelet count was further calculated by multiplying the number of platelets per OIF using multiplication factors of 10,000, 15,000 and 20,000. This was compared with platelet (PLT)/red blood cell (RBC) method and automated platelet counts. Accuracy of various manual methods was evaluated by calculating the per cent difference of the methods with automated analyser counts.

Statistical Analysis Used:
Descriptive statistics was used for statistical analysis.

Results:
Manual platelet count estimation on peripheral smear employing multiplication factor of 15,000 was found to have comparable accuracy to analyser counts, followed by the PLT/RBC ratio method.

Conclusions:
This study confirms that for manual estimation of platelet counts on peripheral smear, a standard multiplication factor of 15,000 on OIF gives the most accurate result, which is closest to counts obtained by automated analysers.