bluuebunny/crossref_metadata_2025_split huggingface dataset:
Germline-Encoded Positional Cysteine Polymorphisms Enhance Diversity in Antibody Ultralong CDR H3 Regions
Authors: Jenkins Gabrielle Warner , Safonova Yana , Smider Vaughn V 
Published: January 2023

Abstract
Ab “ultralong” third H chain complementarity-determining regions (CDR H3) appear unique to bovine Abs and may enable binding to difficult epitopes that shorter CDR H3 regions cannot easily access. Diversity is concentrated in the “knob” domain of the CDR H3, which is encoded by the DH gene segment and sits atop a β-ribbon “stalk” that protrudes far from the Ab surface. Knob region cysteine content is quite diverse in terms of total number of cysteines, sequence position, and disulfide bond pattern formation. We investigated the role of germline cysteines in production of a diverse CDR H3 structural repertoire. The relationship between DH polymorphisms and deletions relative to germline at the nucleotide level, as well as diversity in cysteine and disulfide bond content at the structural level, was ascertained. Structural diversity is formed through (1) DH polymorphisms with altered cysteine positions, (2) DH deletions, and (3) new cysteines that arise through somatic hypermutation that form new, unique disulfide bonds to alter the knob structure. Thus, a combination of mechanisms at both the germline and somatic immunogenetic levels results in diversity in knob region cysteine content, contributing to remarkable complexity in knob region disulfide patterns, loops, and Ag binding surface.
CD96 Blockade Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis via Suppression of IL-17A Production by Dermal γδ T Cells
Authors: Oh-oka Kyoko , Abe Fumie , Shibuya Akira , Shibuya Kazuko 
Published: January 2023

Abstract
Psoriasis is a chronic inflammatory skin disease. IL-23 plays a critical role in its pathogenesis by inducing production of IL-17A from pathological Th17 cells and IL-17A–producing γδ T cells. However, the mechanisms regulating the IL-23/IL-17 axis in psoriasis are incompletely understood. In this study, we show that, in comparison with wild-type mice, those deficient in the CD96 immunoreceptor had lower production of IL-17A in their dermal γδ T cells and milder psoriasis-like dermatitis after topical application of imiquimod (IMQ). Moreover, transfer of CD96-deficient dermal γδ T cells into the skin of Rag1-deficient mice resulted in them developing milder IMQ-induced dermatitis compared with Rag1-deficient mice transferred with wild-type dermal γδ T cells. In γδ T cells in vitro, CD96 provides a costimulatory signal for the production of IL-23–induced IL-17A. In mice given an anti-CD96 neutralizing Ab, IL-17A production from dermal γδ T cells decreased and IMQ-induced dermatitis was milder compared with mice given a control Ab. These results suggest that CD96 is a potential molecular target for the treatment of psoriasis.
Transcriptional Profiling of Phagocytic Leukocytes and Microglia Reveals a Critical Role for Reactive Oxygen Species in Biofilm Containment during Staphylococcus aureus Craniotomy Infection
Authors: Menousek Joseph , Horn Christopher M , Heim Cortney E , Van Roy Zachary , Korshoj Lee E , Kielian Tammy 
Published: January 2023

Abstract
Craniotomies are performed to treat a variety of intracranial pathology. Surgical site infection remains a complication of craniotomy despite the use of prophylactic antibiotics and universal sterile precautions. Infections occur in 1–3% of procedures, with approximately half caused by Staphylococcus aureus that forms a biofilm on the bone flap and is recalcitrant to systemic antibiotic therapy. We used an S. aureus-dsRed construct to compare the phagocytic capacity of leukocytes and microglia in vitro and in vivo using a mouse model of craniotomy infection. In addition, single-cell RNA sequencing (scRNA-seq) was applied to determine whether a transcriptional signature could be identified for phagocytic versus nonphagocytic cells in vivo. S. aureus was phagocytosed to equivalent extents in microglia, macrophages, neutrophils, and granulocytic myeloid-derived suppressor cells in vitro; however, microglial uptake of S. aureus was limited in vivo, whereas the other leukocyte populations exhibited phagocytic activity. scRNA-seq comparing the transcriptional signatures of phagocytic (S. aureus-dsRed+) versus nonphagocytic (S. aureus-dsRed−) leukocytes identified classical pathways enriched in phagocytic cells (i.e., reactive oxygen species [ROS]/reactive nitrogen species, lysosome, iron uptake, and transport), whereas nonphagocytic populations had increased ribosomal, IFN, and hypoxia signatures. scRNA-seq also revealed a robust ROS profile, which led to the exploration of craniotomy infection in NADPH oxidase 2 knockout mice. S. aureus burden, leukocyte recruitment, and intracellular bacterial load were significantly increased in NADPH oxidase 2 KO compared with wild-type animals. Collectively, these results highlight the importance of ROS generation in phagocytes for S. aureus biofilm containment, but not clearance, during craniotomy infection.
Memory B Cells and Memory T Cells Induced by SARS-CoV-2 Booster Vaccination or Infection Show Different Dynamics and Responsiveness to the Omicron Variant
Authors: Mise-Omata Setsuko , Ikeda Mari , Takeshita Masaru , Uwamino Yoshifumi , Wakui Masatoshi , Arai Tomoko , Yoshifuji Ayumi , Murano Kensaku , Siomi Haruhiko , Nakagawara Kensuke , Ohyagi Masaki , Ando Makoto , Hasegawa Naoki , Saya Hideyuki , Murata Mitsuru , Fukunaga Koichi , Namkoong Ho , Lu Xiuyuan , Yamasaki Sho , Yoshimura Akihiko 
Published: January 2023

Abstract
Although the immunological memory produced by BNT162b2 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well studied and established, further information using different racial cohorts is necessary to understand the overall immunological response to vaccination. We evaluated memory B and T cell responses to the severe acute respiratory syndrome coronavirus 2 spike protein before and after the third booster using a Japanese cohort. Although the Ab titer against the spike receptor-binding domain (RBD) decreased significantly 8 mo after the second vaccination, the number of memory B cells continued to increase, whereas the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the Ab titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, whereas memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR6− circulating follicular Th1 was positively correlated with RBD-specific Ab-secreting B cells. For the response to variant RBDs, although 60–80% of memory B cells could bind to the omicron RBD, their avidity was low, whereas memory T cells show an equal response to the omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate Ab production and T cell responses after omicron strain infection, which prevents severe illness and death due to coronavirus disease 2019.
Theilovirus 3C Protease Cleaves the C-Terminal Domain of the Innate Immune RNA Sensor, Melanoma Differentiation–Associated Gene 5, and Impairs Double-Stranded RNA–Mediated IFN Response
Authors: Miyamoto Masahiko , Himeda Toshiki , Ishihara Kazuki , Okuwa Takako , Kobayashi Daiki , Nameta Masaaki , Karasawa Yu , Chunhaphinyokul Benyapa , Yoshida Yutaka , Tanaka Nobuyuki , Higuchi Masaya , Komuro Akihiko 
Published: January 2023

Abstract
Melanoma differentiation–associated gene 5 (MDA5), a member of the retinoic acid–inducible gene I (RIG-I)–like receptors (RLRs), has pivotal roles in innate immune responses against many positive-stranded RNA viruses, including picornavirus and coronavirus. Upon engagement with dsRNA derived from viral infection, MDA5 initiates coordinated signal transduction leading to type I IFN induction to restrict viral replication. In this study, we describe a targeted cleavage events of MDA5 by the 3C protease from Theilovirus. Upon ectopic expression of theilovirus 3C protease from Saffold virus or Theiler’s murine encephalomyelitis virus but not encephalomyocarditis virus, fragments of cleaved MDA5 were observed in a dose-dependent manner. When enzymatically inactive Theilovirus 3C protease was expressed, MDA5 cleavage was completely abrogated. Mass spectrometric analysis identified two cleavage sites at the C terminus of MDA5, cleaving off one of the RNA-binding domains. The same cleavage pattern was observed during Theilovirus infection. The cleavage of MDA5 by Theilovirus protease impaired ATP hydrolysis, RNA binding, and filament assembly on RNA, resulting in dysfunction of MDA5 as an innate immune RNA sensor for IFN induction. Furthermore, the cleavage-resistant MDA5 mutant against the 3C protease showed an enhanced IFN response during Saffold virus infection, indicating that Theilovirus has a strategy to circumvent the antiviral immune response by cleaving MDA5 using 3C protease. In summary, these data suggest MDA5 cleavage by 3C protease as a novel immune evasive strategy of Theilovirus.
Cutting Edge: High-Dose Live Attenuated Influenza Vaccines Elicit Pulmonary Tissue-Resident Memory CD8+ T Cells in the Face of Pre-Existing Humoral Immunity
Authors: Zheng Ming Z M , Fritzlar Svenja , Wang Zhongfang , Tan Tiong Kit , Kedzierska Katherine , Townsend Alain , Reading Patrick C , Wakim Linda M 
Published: January 2023

Abstract
In this study, we investigated how pre-existing Ab immunity to influenza virus established from prior immunizations affects the development of CD8+ T cell responses evoked after vaccination with a live attenuated vaccine. Using a mouse model and a panel of live attenuated influenza virus vaccine candidates (cold adapted and single cycle), we show that pre-existing influenza-specific Abs directed against the vaccine backbone attenuate the size and quality of the vaccine-induced CD8+ T cell response. Importantly, we show that increasing the vaccine dose can overcome this impediment, resulting in improved vaccine-induced circulating and tissue-resident memory CD8+ T cell responses, which were protective against heterologous influenza challenge. Thus, the reduced size and quality of the T cell response elicited by a live attenuated influenza virus vaccine imparted by the influenza-specific Ab landscape of the vaccinee can be overcome by increasing vaccine dose.
Arginase 1 Expression by Macrophages Promotes Cryptococcus neoformans Proliferation and Invasion into Brain Microvascular Endothelial Cells
Authors: Hansakon Adithap , Ngamphiw Chumpol , Tongsima Sissades , Angkasekwinai Pornpimon 
Published: January 2023

Abstract
Cryptococcal meningoencephalitis caused by Cryptococcus neoformans infection is the most common cause of death in HIV/AIDS patients. Macrophages are pivotal for the regulation of immune responses to cryptococcal infection by either playing protective function or facilitating fungal dissemination. However, the mechanisms underlying macrophage responses to C. neoformans remain unclear. To analyze the transcriptomic changes and identify the pathogenic factors of macrophages, we performed a comparative transcriptomic analysis of alveolar macrophage responses during C. neoformans infection. Alveolar macrophages isolated from C. neoformans–infected mice showed dynamic gene expression patterns, with expression change from a protective M1 (classically activated)–like to a pathogenic M2 (alternatively activated)–like phenotype. Arg1, the gene encoding the enzyme arginase 1, was found as the most upregulated gene in alveolar macrophages during the chronic infection phase. The in vitro inhibition of arginase activity resulted in a reduction of cryptococcal phagocytosis, intracellular growth, and proliferation, coupled with an altered macrophage response from pathogenic M2 to a protective M1 phenotype. In an in vitro model of the blood–brain barrier, macrophage-derived arginase was found to be required for C. neoformans invasion of brain microvascular endothelium. Further analysis of the degree of virulence indicated a positive correlation between arginase 1 expression in macrophages and cryptococcal brain dissemination in vivo. Thus, our data suggest that a dynamic macrophage activation that involves arginase expression may contribute to the cryptococcal disease by promoting cryptococcal growth, proliferation, and the invasion to the brain endothelium.
B Cell and T Cell Dissimilarities in BAFF-Deficient versus BR3-Deficient C57BL/6 Mice
Authors: Stohl William , Yu Ning , Wu Ying 
Published: January 2023

Abstract
BAFF is a potent B cell survival and differentiation factor with three receptors, TACI, BCMA, and BR3. B cells are greatly reduced in BAFF-deficient mice, and among mice deficient in a single BAFF receptor, B cell reduction is characteristic only of BR3-deficient mice. Nevertheless, there may be important differences between BR3-deficient mice, in which interactions between BAFF and only BR3 are abrogated, and BAFF-deficient mice, in which interactions between BAFF and all its receptors are abrogated. We demonstrate that: 1) the numbers of CD19+ cells in C57BL/6 (B6).Baff−/− and B6.Br3−/− mice diverge as the mice age; 2) the distribution of B cell subsets significantly differ between B6.Baff−/− and B6.Br3−/− mice regardless of age or sex; 3) the relationships of CD3+ and CD4+ cells to B cells vastly differ between B6.Baff−/− and B6.Br3−/− mice as a function of age and sex; 4) the numbers and percentages of CD4+Foxp3+ and CD4+CD25+Foxp3+ are greater in B6.Baff−/− mice than in B6.Br3−/− mice; and 5) for any given number of CD19+ cells or CD4+ cells, percentages of Foxp3+ cells and CD4+CD25+Foxp3+ cells are lower in B6.Br3−/− mice than in B6.Baff−/− mice, with proliferation of these cells being greater, and survival being lesser, in B6.Br3−/− mice than in B6.Baff−/− mice. Collectively, these observations raise the possibility that interactions between TACI and/or BCMA and BAFF modulate expression of B cell subsets and Foxp3+ cells and may help explain prior enigmatic observations of autoimmunity and autoimmune disease in mice despite the absence of functional engagement of BR3 by BAFF.
The Interplay of Transcription and Genome Topology Programs T Cell Development and Differentiation
Authors: Zhao Xin , Zhu Shaoqi , Peng Weiqun , Xue Hai-Hui 
Published: January 2023

Abstract
T cells are essential for mounting defense against various pathogens and malignantly transformed cells. Thymic development and peripheral T cell differentiation are highly orchestrated biological processes that require precise gene regulation. Higher-order genome organization on multiple scales, in the form of chromatin loops, topologically associating domains and compartments, provides pivotal control of T cell gene expression. CTCF and the cohesin machinery are ubiquitously expressed architectural proteins responsible for establishing chromatin structures. Recent studies indicate that transcription factors, such as T lineage–defining Tcf1 and TCR-induced Batf, may have intrinsic ability and/or engage CTCF to shape chromatin architecture. In this article, we summarize current knowledge on the dynamic changes in genome topology that underlie normal or leukemic T cell development, CD4+ helper T cell differentiation, and CD8+ cytotoxic T cell functions. The knowledge lays a solid foundation for elucidating the causative link of spatial chromatin configuration to transcriptional and functional output in T cells.
Emerging Roles of Growth Differentiation Factor 15 in Immunoregulation and Pathogenesis
Authors: Reyes Jojo , Yap George S 
Published: January 2023

Abstract
Growth differentiation factor 15 (GDF-15) is a cytokine that is widely used as a biomarker for the severity of diverse disease states. It also has been shown to play a protective role after tissue injury and to promote a negative energy balance during obesity and diabetes. In addition to its metabolic effects, GDF-15 also regulates the host’s immune responses to infectious and noninfectious diseases. GDF-15 can suppress a type 1 and, in contrast, promote a type 2 inflammatory response. In this brief review, we discuss how GDF-15 affects the effector function and recruitment of immune cells, the pathways that induce its expression, and the diverse mechanisms by which it is regulated during inflammation and infection. We further highlight outstanding questions that should be the focus of future investigations in this emerging field.
Topoisomerases in Immune Cell Development and Function
Authors: Muralidhara Prerana , Kumar Amit , Chaurasia Mukesh Kumar , Bansal Kushagra 
Published: January 2023

Abstract
DNA topoisomerases (TOPs) are complex enzymatic machines with extraordinary capacity to maintain DNA topology during torsion-intensive steps of replication and transcription. Recently, TOPs have gained significant attention for their tissue-specific function, and the vital role of TOPs in immune homeostasis and dysfunction is beginning to emerge. TOPs have been implicated in various immunological disorders such as autoimmunity, B cell immunodeficiencies, and sepsis, underscoring their importance in immune regulation. However, much remains unknown about immunological underpinnings of TOPs, and a deeper understanding of the role of TOPs in the immune system will be critical for yielding significant insights into the etiology of immunological disorders. In this review, we first discuss the recent literature highlighting the contribution of TOPs in the development of immune cells, and we further provide an overview of their importance in immune cell responses.
Frequency of JAK2V617F and CALR somatic mutations in Egyptian patients with thrombocytosis
Authors: Hamed Gehan Mostafa , Abdelmaksoud Mariam Fathy , Abdulrahman Doha Osama , El Sakhawy Yasmin Nabil 
Published: January 2023

Background
Thrombocytosis has a multitude of potential etiologies: spurious, reactive, and clonal. Clonal thrombocytosis carries a greater risk of thrombosis than reactive causes. Therefore, careful distinction between the causes of thrombocytosis is important and challenging as it carries implications for evaluation, prognosis, and treatment strategies.

Aim of the work
To determine the frequency of JAK2V617F and calreticulin (CALR) somatic mutations in patients with thrombocytsis and their relation with clinical and hematological phenotype.

Patients and methods
A total of 50 BCR-ABL-negative patients with persistent thrombocytosis were tested for both JAK2V617F mutation by real-time polymerase-chain reaction (RT-PCR) and CALR exon-9 mutation by high-resolution melting PCR.

Results
JAK2V615F mutation was detected in 17 (34%), whereas CALR exon-9 mutation was detected in 10 (20%) out of the 50 studied patients with thrombocytosis. One patient with essential thrombocythemia was heterozygous for both mutations. The incidence of JAK2V615F mutation was significantly higher in males (P=0.007), with higher mean age (P=0.001), higher incidence of thrombosis (0.034), and leukocytosis (0.035) compared with CALR and dual-negative mutations. Meanwhile, anemia (P=0.001), platelets (P=0.009), and lactate dehydrogenase (P=0.009) were significantly higher in CALR-mutated patients.

Conclusion
Both JAK2 and CALR somatic mutations were detected in 52% of patients with thrombocytosis. CALR-mutated cases show clinical and hematological phenotype different from JAKV617F-positive ones and might be considered as a distinct disease entity with more indolent course.
Study of pattern & distribution of adverse drug reactions in acute coronary syndrome patients in a tertiary care hospital
Authors: Mahadevappa Manjappa , Meher Chinmay , Pushpa N.B. , Kulkarni Prashanth , Poornima K.S. , Desai Nagaraj 
Published: January 2023

Background & objectives:
With the availability of a wide range of drugs to treat patients with acute coronary syndrome (ACS), adverse drug reactions (ADRs) have become inevitable in clinical practice. Thorough knowledge of such reactions is essential for the treating physician for optimal treatment and better outcomes. There are many scales to define, measure and assess the ADRs, but there is a dearth of data available on such drug reactions among ACS patients. Hence, this study attempted to analyze the pattern, causality, severity, predictability and preventability of ADRs in ACS patients. All the ADRs reported during the study period were analyzed for causality by the World Health Organization–Uppsala Monitoring Centre (WHO-UMC), Naranjo’s and Karch and Lasagna scales; severity by modified Hartwig and Siegel scale; predictability by Rawlins and Thompson criterion and preventability by Schumock and Thornton scale.

Methods:
A single-centre, record-based analysis for the occurrence of ADRs was done among ACS patients admitted to the department of Cardiology between January and October 2017. Demographic data, comorbid conditions, reported ADRs and ADR assessment details were noted from the hospital case records and ADR monitoring centre (AMC) records. The data were analyzed and presented in a descriptive manner using percentages, mean and standard deviation. The Pearson’s chi-squared test was used to ascertain the significance of the association between different groups.

Results:
Out of 324 patients under evaluation, 67 had developed one or more ADRs. There were 30 different types of ADRs reported, headache being the most common. Among the drugs, heparin was the most common factor, causing 27 per cent of ADRs. Definite causality of a suspected drug causing ADRs was seen in 11.9 (n=8), nine (n=6) and 7.5 (n=5) per cent cases as per WHO-UMC, Naranjo (Naranjo algorithm) and Karch and Lasagna scales, respectively. In the severity of ADRs, the most severe reactions according to the modified Hartwig-Siegel scale (level 4a in our study) were seen in 17.5 (n=12) per cent of patients, and the rest were either level 2 or 3 reactions. Nearly 92.5 (n=62) per cent of reactions were predictable according to the Rawlins and Thompson criterion. Application of the modified Schumock-Thornton scale showed that 22.4 per cent of ACS patients had preventable reactions, and the rest were not preventable.

Interpretation & conclusions:
The study results suggest that ADRs are relatively common among ACS patients. Most of these can be identified and assessed for causality, severity, predictability and preventability using various available scales. Diligent pharmacovigilance for identifying and assessing ADRs may help manage and mitigate morbidity associated with these in high-risk ACS patients.