bluuebunny/crossref_metadata_2025 huggingface dataset:
Three polymethoxyflavones from the peel of Citrus reticulata “Chachi” inhibits oxidized low-density lipoprotein-induced macrophage-derived foam cell formation
Authors: Liang Pu-Lin , Liang Qian-Wen , He Pei-Wen , Chen Xue-Lian , Xu Ya , Tu Hai-Sheng , Zhang Liang , Qiu Xiao-Hui , Zhang Jing , Huang Zhi-Hai , Xu Wen
Published: July 2022

Foam cell formation is the hallmark of the development and progression of atherosclerosis. The aim of this study was to investigate the regulatory effects of three polymethoxyflavones (PMFs), namely, tangeretin (TAN), 5,6,7,3′,4′,5′-hexamethoxyflavone (HxMF), and 3,5,6,7,8,3′,4′-heptamethoxyflavone (HpMF) on macrophage-derived foam cell formation and to further explore the molecular mechanisms. The RAW264.7 macrophage-derived foam cell model was successfully induced by oxidized low-density lipoprotein (ox-LDL) (80 μg/ml). It showed that TAN, HxMF, and HpMF alleviated ox-LDL-induced NO release while also inhibiting the expression of IL-1β, IL-6, and TNF-α in RAW264.7 cells. Uptake of excess ox-LDL was inhibited by TAN, HxMF, and HpMF, resulting in the reduction of its foam cell formation. Moreover, TAN, HxMF, and HpMF promoted HDL-mediated cholesterol efflux. Western blot experiment showed that TAN, HxMF, and HpMF inhibited the expression of scavenger receptor class A type I (SRA1) and cluster of differentiation 36 (CD36), while upregulating peroxisome proliferator-activated receptor γ (PPARγ), liver X receptor α (LXRα), phospholipid ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor class B type I (SRB1) expression. Together, our findings suggested that PMFs inhibited foam cell formation might inhibit lipid uptake via downregulating SRA1/CD36 expression and promote cholesterol efflux from foam cells via upregulating PPARγ/LXRα/ABCG1/SRB1 expression. This antiatherosclerotic activity is expected to provide new insights into the development of healthcare uses for PMFs.
Cryoballoon ablation for atrial fibrillation: Effects on neuromodulation
Authors: Del Monte Alvise , Pannone Luigi , Bisignani Antonio , Osório Thiago G. , Iacopino Saverio , Chierchia Gian-Battista , de Asmundis Carlo
Published: July 2022

Pulmonary vein isolation (PVI) represents the mainstay of atrial fibrillation (AF) ablation, and PVI with cryoballoon catheter (CB) ablation (CB-A) has proven to be as effective and safe as radiofrequency ablation (RF-A). Although AF is initiated by triggers arising from the pulmonary veins (PV) and non-PV foci, the intrinsic cardiac nervous system (ICNS) plays a significant role in the induction and maintenance of AF. The ICNS is an epicardial neural system composed of ganglionated plexi (GPs) and a complex network of interconnecting neurons. In the left atrium, the major GPs are located in proximity to the PV-left atrial junction. Vagal reactions have been described as markers of autonomic modulation during PVI with both RF-A and CB-A. The occurrence of neuromodulation during PVI with CB-A may be explained by both the anatomical relationship between the GPs and the PVs and the characteristics of the CB. Due to the CB/PV size mismatch, the CB creates a wide ablation area that extends from the PV ostium toward the antrum, possibly including the GPs. Although targeted GPs ablation, as a supplemental strategy to PVI, has been associated with a better AF outcome in patients undergoing RF-A, the additional clinical benefit of neuromodulation during PVI with CB-A remains a matter of debate. In this review, we provide an overview of the anatomy of the ICNS, the relationship between the ICNS and AF pathophysiology, and the current evidence on the clinical relevance of neuromodulation during PVI with CB-A.
Juxtaposing generic skills development in collaborative knowledge work competences and related pedagogical practices in higher education
Authors: Muukkonen Hanni , Lakkala Minna , Ilomäki Liisa , Toom Auli
Published: July 2022

This study employs the term knowledge work competence to address generic aspects of higher education graduates’ expected learning outcomes. Twenty-eight higher education courses were investigated: 1069 students responded to the Collaborative Knowledge Practices (CKP) questionnaire to rate their self-evaluated competence development. From the same courses, 56 teachers provided descriptions of the course pedagogical practices. First, students’ self-reported generic collaboration competence gains were analyzed statistically for differences between courses. Second, qualitative categorization of the pedagogical practices based on rich description of pedagogical designs and teachers’ reflective responses was carried out. This offered a categorization with elaborated descriptions and a clustering to three types of enacted pedagogical practices. Finally, the study juxtaposed these previous two results to investigate how the pedagogical features were related to students’ self-evaluations on collaboration competence gains. The findings highlighted one cluster of pedagogical practices, collaborative knowledge creation with systematic support for epistemic and group work, as most beneficial for student competence gains. In it, professional ways of working were explicitly modeled and practiced, teacher support for knowledge creation during contact teaching was available, and time was reserved for reflection with students. Such pedagogical practices are important to ensure graduates’ fluent transition to complex knowledge work.
Interest of Bone Histomorphometry in Bone Pathophysiology Investigation: Foundation, Present, and Future
Authors: Chavassieux Pascale , Chapurlat Roland
Published: July 2022

Despite the development of non-invasive methods, bone histomorphometry remains the only method to analyze bone at the tissue and cell levels. Quantitative analysis of transiliac bone sections requires strict methodologic conditions but since its foundation more 60 years ago, this methodology has progressed. Our purpose was to review the evolution of bone histomorphometry over the years and its contribution to the knowledge of bone tissue metabolism under normal and pathological conditions and the understanding of the action mechanisms of therapeutic drugs in humans. The two main applications of bone histomorphometry are the diagnosis of bone diseases and research. It is warranted for the diagnosis of mineralization defects as in osteomalacia, of other causes of osteoporosis as bone mastocytosis, or the classification of renal osteodystrophy. Bone biopsies are required in clinical trials to evaluate the safety and mechanism of action of new therapeutic agents and were applied to anti-osteoporotic agents such as bisphosphonates and denosumab, an anti-RANKL, which induces a marked reduction of the bone turnover with a consequent elongation of the mineralization period. In contrast, an increased bone turnover with an extension of the formation site is observed with teriparatide. Romosozumab, an anti-sclerostin, has a dual effect with an early increased formation and reduced resorption. Bone histomorphometric studies allow us to understand the mechanism of coupling between formation and resorption and to evaluate the respective role of bone modeling and remodeling. The adaptation of new image analysis techniques will help bone biopsy analysis in the future.
Kisspeptin treatment improves fetal-placental development and blocks placental oxidative damage caused by maternal hypothyroidism in an experimental rat model
Authors: Santos Bianca Reis , dos Anjos Cordeiro Jeane Martinha , Santos Luciano Cardoso , Barbosa Erikles Macedo , Mendonça Letícia Dias , Santos Emilly Oliveira , de Macedo Isabella Oliveira , de Lavor Mário Sergio Lima , Szawka Raphael Escorsim , Serakides Rogeria , Silva Juneo Freitas
Published: July 2022

Maternal hypothyroidism is associated with fetal growth restriction, placental dysfunction, and reduced kisspeptin/Kiss1R at the maternal-fetal interface. Kisspeptin affects trophoblastic migration and has antioxidant and immunomodulatory activities. This study aimed to evaluate the therapeutic potential of kisspeptin in the fetal-placental dysfunction of hypothyroid Wistar rats. Hypothyroidism was induced by daily administration of propylthiouracil. Kisspeptin-10 (Kp-10) treatment was performed every other day or daily beginning on day 8 of gestation. Feto-placental development, placental histomorphometry, and expression levels of growth factors (VEGF, PLGF, IGF1, IGF2, and GLUT1), hormonal (Dio2) and inflammatory mediators (TNFα, IL10, and IL6), markers of hypoxia (HIF1α) and oxidative damage (8-OHdG), antioxidant enzymes (SOD1, Cat, and GPx1), and endoplasmic reticulum stress mediators (ATF4, GRP78, and CHOP) were evaluated on day 18 of gestation. Daily treatment with Kp-10 increased free T3 and T4 levels and improved fetal weight. Both treatments reestablished the glycogen cell population in the junctional zone. Daily treatment with Kp-10 increased the gene expression levels of Plgf, Igf1, and Glut1 in the placenta of hypothyroid animals, in addition to blocking the increase in 8-OHdG and increasing protein and/or mRNA expression levels of SOD1, Cat, and GPx1. Daily treatment with Kp-10 did not alter the higher protein expression levels of VEGF, HIF1α, IL10, GRP78, and CHOP caused by hypothyroidism in the junctional zone compared to control, nor the lower expression of Dio2 caused by hypothyroidism. However, in the labyrinth zone, this treatment restored the expression of VEGF and IL10 and reduced the GRP78 and CHOP immunostaining. These findings demonstrate that daily treatment with Kp-10 improves fetal development and placental morphology in hypothyroid rats, blocks placental oxidative damage, and increases the expression of growth factors and antioxidant enzymes in the placenta.
The association between a body shape index and elevated urinary albumin–creatinine ratio in Chinese community adults
Authors: Zhang Yue , Gao Wenxing , Li Binqi , Liu Yang , Chen Kang , Wang Anping , Tang Xulei , Yan Li , Luo Zuojie , Qin Guijun , Chen Lulu , Wan Qin , Gao Zhengnan , Wang Weiqing , Ning Guang , Mu Yiming
Published: July 2022

Background

Obesity, especially visceral obesity, seems to be one of the most decisive risk factors for chronic kidney disease. A Body Shape Index (ABSI) is an emerging body size measurement marker of visceral obesity. This study aimed to explore whether ABSI is associated with albuminuria in Chinese community adults.

Methods

This cross-sectional study enrolled 40,726 participants aged 40 or older from seven provinces across China through a cluster random sampling method. ABSI was calculated by body mass index, waist circumference, and height. Increased albuminuria was defined as urinary albumin–creatinine ratio (UACR) ≥ 30 mg/g, indicating kidney injury. For ABSI, we divided it by quartile cutoff points and tried to determine the association between ABSI levels and UACR by multiple regression analysis. DAG (Directed Acyclic Graph) was plotted using literature and expert consensus to identify potential confounding factors.

Results

The average age of subjects with elevated UACR was 61.43 ± 10.07, and 26% were men. The average age of subjects with normal UACR was 57.70 ± 9.02, and 30.5% were men. Multiple logistic regression analysis was conducted and demonstrated that the ABSI quartiles were related to elevated UACR positively (OR [95% CI] Q2 vs. Q1: 1.094 [1.004, 1.197]; OR [95% CI] Q3 vs. Q1: 1.126 [1.030, 1.231]; OR [95% CI] Q4 vs. Q1: 1.183 [1.080, 1.295], p for trend < 0.001) after adjustments for confounding factors. The stratified analysis further showed that with the mounting for ABSI levels, elevated UACR more easily occurred in the people characterized by the elderly, men, and hypertension.

Conclusions

In Chinese community adults, people with higher ABSI levels can be deemed as high-risk individuals with UACR elevation, and it will be beneficial for them to lose weight and significantly reduce visceral fat.
Negative regulation of receptor tyrosine kinases by ubiquitination: Key roles of the Cbl family of E3 ubiquitin ligases
Authors: Tang Rong , Langdon Wallace Y. , Zhang Jian
Published: July 2022

Receptor tyrosine kinases (RTKs) serve as transmembrane receptors that participate in a broad spectrum of cellular processes including cellular growth, motility, differentiation, proliferation, and metabolism. Hence, elucidating the regulatory mechanisms of RTKs involved in an assortment of diseases such as cancers attracts increasing interest from researchers. Members of the Cbl family ubiquitin ligases (c-Cbl, Cbl-b and Cbl-c in mammals) have emerged as negative regulators of activated RTKs. Upon activation of RTKs by growth factors, Cbl binds to RTKs via its tyrosine kinase binding (TKB) domain and targets them for ubiquitination, thus facilitating their degradation and negative regulation of RTK signaling. RTKs such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGF), fibroblast growth factor receptor (FGFR) and hepatocyte growth factor receptor (HGFR) undergo ubiquitination upon interaction with Cbl family members. In this review, we summarize the current knowledge related to the negative regulation of RTKs by Cbl family proteins.
Two thousand years of Landscape—Human interactions at a coastal peninsula in Norway revealed through pollen analysis, shoreline reconstruction, and radiocarbon dates from archaeological sites
Authors: Hjelle Kari Loe , Overland Anette , Gran Magnar Mojaren , Romundset Anders , Ystgaard Ingrid
Published: July 2022

Human impact on long-term vegetation and biodiversity changes is often discussed on a general level, connecting palynological data to archaeological time periods. In the present paper we present environmental change during the last 2,400 years on a coastal peninsula in Norway using pollen data from three sites: one lake and two bogs, in addition to 621 radiocarbon dates and in-context pollen samples from archaeological sites. Locally, a close relationship between palynological richness reflecting high landscape, habitat and floristic diversity, and the summed probability distribution of radiocarbon dates was found. During the settlement period 400 BCE–550 CE, concordant with maximum number of dates from archaeological contexts, a mosaic landscape containing infields and outfields developed. Cereals were cultivated and animals were grazing in heathlands that could provide both summer grazing and winter fodder. Additionally, seashores and wetlands were used for grazing. Settlement recession from 350 CE and abandonment following the 536 CE climate event, resulted in vegetation successions toward reforestation, abandonment of arable fields, and marshes turning into ombrotrophic peat. At the same time the distance to the sea, and to species rich shoreline meadows, continued to increase due to continuous postglacial land uplift in a flat landscape. A new increase in the summed probability distribution 900–1250 CE, is reflected in expansion of outfield pastures, heathlands in particular, a management that continued up into modern time. The local development is supported by the results on a regional scale, indicating overall climatic and social causes for observed vegetation changes. Both palynological richness and pollen-based landcover reconstructions indicate reforestation and less habitat diversity in the sixth century. On a regional scale, reforestation in the fifteenth century following the late medieval crises, is more pronounced than on the local scale, although both reflect exploitation of outfield resources.
Mass spectrometry imaging identifies altered hepatic lipid signatures during experimental Leishmania donovani infection
Authors: Tans Roel , Dey Shoumit , Dey Nidhi Sharma , Cao Jian-Hua , Paul Prasanjit S. , Calder Grant , O’Toole Peter , Kaye Paul M. , Heeren Ron M. A.
Published: July 2022

Introduction

Spatial analysis of lipids in inflammatory microenvironments is key to understand the pathogenesis of infectious disease. Granulomatous inflammation is a hallmark of leishmaniasis and changes in host and parasite lipid metabolism have been observed at the bulk tissue level in various infection models. Here, mass spectrometry imaging (MSI) is applied to spatially map hepatic lipid composition following infection with Leishmania donovani, an experimental mouse model of visceral leishmaniasis.

Methods

Livers from naïve and L. donovani-infected C57BL/6 mice were harvested at 14- and 20-days post-infection (n=5 per time point). 12 µm transverse sections were cut and covered with norhamane, prior to lipid analysis using MALDI-MSI. MALDI-MSI was performed in negative mode on a Rapiflex (Bruker Daltonics) at 5 and 50 µm spatial resolution and data-dependent analysis (DDA) on an Orbitrap-Elite (Thermo-Scientific) at 50 µm spatial resolution for structural identification analysis of lipids.

Results

Aberrant lipid abundances were observed in a heterogeneous distribution across infected mouse livers compared to naïve mouse liver. Distinctive localized correlated lipid masses were found in granulomas and surrounding parenchymal tissue. Structural identification revealed 40 different lipids common to naïve and d14/d20 infected mouse livers, whereas 15 identified lipids were only detected in infected mouse livers. For pathology-guided MSI imaging, we deduced lipids from manually annotated granulomatous and parenchyma regions of interests (ROIs), identifying 34 lipids that showed significantly different intensities between parenchyma and granulomas across all infected livers.

Discussion

Our results identify specific lipids that spatially correlate to the major histopathological feature of Leishmania donovani infection in the liver, viz. hepatic granulomas. In addition, we identified a three-fold increase in the number of unique phosphatidylglycerols (PGs) in infected liver tissue and provide direct evidence that arachidonic acid-containing phospholipids are localized with hepatic granulomas. These phospholipids may serve as important precursors for downstream oxylipin generation with consequences for the regulation of the inflammatory cascade. This study provides the first description of the use of MSI to define spatial-temporal lipid changes at local sites of infection induced by Leishmania donovani in mice.
B cell intrinsic and extrinsic factors impacting memory recall responses to SRBC challenge
Authors: Valeri Viviana , Sochon Akhésa , Ye Chaoliang , Mao Xinru , Lecoeuche Damiana , Fillatreau Simon , Weill Jean-Claude , Reynaud Claude-Agnès , Hao Yi
Published: July 2022

MBCs (MBCs) generated in T-dependent immune responses can persist for a lifetime and rapidly react upon secondary antigen exposure to differentiate into plasma cells (PCs) and/or to improve the affinity of their BCR through new rounds of hypermutation in germinal centers (GCs). The fate of a MBC in secondary immune reactions appears to depend upon multiple parameters, whose understanding is mandatory for the design of efficient vaccine strategies. We followed the behavior of MBCs in recall responses to SRBCs using an inducible AID fate mapping mouse model in which B cells engaged in a germinal center (GC) response are irreversibly labeled upon simultaneous tamoxifen ingestion and immunization. We used different schemes of mouse immunization and tamoxifen feeding in adoptive-transfer experiments of total splenic B cells into congenic mice that have been pre-immunized or not, to assess the contribution of the different effector subsets in a physiological competitive context. We were able to show that naive B cells can differentiate into GC B cells with kinetics similar to MBCs in the presence of previously activated T follicular helper (TFH) cells and a primed microenvironment. We also showed that MBCs are recruited into secondary GCs, together with naive B cells. In contrast, PC differentiation, which dominated secondary MBC responses, was not dependent upon a previous TFH activation. We observed that the presence of persisting germinal centers and circulating antibody levels are key factors determining the germinal center versus plasma cell fate in a recall response. Notably, disruption of persistent germinal center structures by a lymphotoxin beta-receptor fusion protein or a longer timing between the prime and the boost, which correlated with reduced antigen-specific immunoglobulin levels in serum, were two conditions with an opposite impact, respectively inhibiting or promoting a GC fate for MBCs. Altogether, these studies highlight the complexity of recall responses, whose outcome varies according to immunization contexts.
Role of hepatic stellate cells in liver ischemia-reperfusion injury
Authors: Peng Yuming , Yin Qiang , Yuan Miaoxian , Chen Lijian , Shen Xinyi , Xie Weixin , Liu Jinqiao
Published: July 2022

Liver ischemia-reperfusion injury (IRI) is a major complication of liver trauma, resection, and transplantation. IRI may lead to liver dysfunction and failure, but effective approach to address it is still lacking. To better understand the cellular and molecular mechanisms of liver IRI, functional roles of numerous cell types, including hepatocytes, Kupffer cells, neutrophils, and sinusoidal endothelial cells, have been intensively studied. In contrast, hepatic stellate cells (HSCs), which are well recognized by their essential functions in facilitating liver protection and repair, have gained less attention in their role in IRI. This review provides a comprehensive summary of the effects of HSCs on the injury stage of liver IRI and their associated molecular mechanisms. In addition, we discuss the regulation of liver repair and regeneration after IRI by HSCs. Finally, we highlight unanswered questions and future avenues of research regarding contributions of HSCs to IRI in the liver.
nCD64 index as a novel inflammatory indicator for the early prediction of prognosis in infectious and non-infectious inflammatory diseases: An observational study of febrile patients
Authors: Liu Qianqian , Gao Yan , Yang Tao , Zhou Zhe , Lin Ke , Zhang Wei , Li Ting , Lu Yi , Shao Lingyun , Zhang Wenhong
Published: July 2022

Background

Generally, febrile patients admitted to the Department of Infectious Diseases, Fudan University Affiliated Huashan Hospital, China may eventually be diagnosed as infectious (ID) or non-infectious inflammatory diseases (NIID). Furthermore, mortality from sepsis remains incredibly high. Thus, early diagnosis and prognosis evaluation of sepsis is necessary. Here, we investigated neutrophil (n)CD64 index profile in a cohort of febrile patients and explored its diagnostic and prognostic value in ID and NIID.

Methods

This observational cohort study enrolled 348 febrile patients from the Emergency Department and Department of Infectious Diseases. nCD64 index were detected using flow cytometry, and dynamically measured at different timepoints during follow-up. Procalcitonin (PCT), C-reactive protein (CRP), and ferritin levels were measured routinely. Finally, the diagnostic and prognostic value of nCD64 index were evaluated by receiver operating characteristic (ROC) analysis and Kaplan-Meier curve analysis.

Results

Of included 348 febrile patients, 238, 81, and 29 were categorized into ID, NIID, and lymphoma groups, respectively. In ID patients, both SOFA score and infection site had impact on nCD64 index expression. In NIID patients, adult-onset Still’s disease patients had the highest nCD64 index value, however, nCD64 index couldn’t distinguish between ID and NIID. Regardless of the site of infection, nCD64 index was significantly higher in bacterial and viral infections than in fungal infections, but it could not discriminate between bacterial and viral infections. In bloodstream infections, gram-negative (G-) bacterial infections showed an obvious increase in nCD64 index compared to that of gram-positive (G+) bacterial infections. nCD64 index has the potential to be a biomarker for distinguishing between DNA and RNA virus infections. The routine measurement of nCD64 index can facilitate septic shock diagnosis and predict 28-day hospital mortality in patients with sepsis. Serial monitoring of nCD64 index in patients with sepsis is helpful for evaluating prognosis and treatment efficacy. Notably, nCD64 index is more sensitive to predict disease progression and monitor glucocorticoid treatment in patients with NIID.

Conclusions

nCD64 index can be used to predict 28-day hospital mortality in patients with sepsis and to evaluate the prognosis. Serial determinations of nCD64 index can be used to predict and monitor disease progression in patients with NIID.
Alveolar macrophages in early stage COPD show functional deviations with properties of impaired immune activation
Authors: Baßler Kevin , Fujii Wataru , Kapellos Theodore S. , Dudkin Erika , Reusch Nico , Horne Ari , Reiz Benedikt , Luecken Malte D. , Osei-Sarpong Collins , Warnat-Herresthal Stefanie , Bonaguro Lorenzo , Schulte-Schrepping Jonas , Wagner Allon , Günther Patrick , Pizarro Carmen , Schreiber Tina , Knoll Rainer , Holsten Lisa , Kröger Charlotte , De Domenico Elena , Becker Matthias , Händler Kristian , Wohnhaas Christian T. , Baumgartner Florian , Köhler Meike , Theis Heidi , Kraut Michael , Wadsworth Marc H. , Hughes Travis K. , Ferreira Humberto J. , Hinkley Emily , Kaltheuner Ines H. , Geyer Matthias , Thiele Christoph , Shalek Alex K. , Feißt Andreas , Thomas Daniel , Dickten Henning , Beyer Marc , Baum Patrick , Yosef Nir , Aschenbrenner Anna C. , Ulas Thomas , Hasenauer Jan , Theis Fabian J. , Skowasch Dirk , Schultze Joachim L.
Published: July 2022

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD. Modeling cell-to-cell communication, signaling pathway usage, and transcription factor binding predicts TGF-β1 to be a major upstream regulator of transcriptional changes in alveolar macrophages of COPD patients. Functionally, macrophages in COPD showed reduced antigen presentation capacity, accumulation of cholesteryl ester, reduced cellular chemotaxis, and mitochondrial dysfunction, reminiscent of impaired immune activation.
Mucosal immunization with an adenoviral vector vaccine confers superior protection against RSV compared to natural immunity
Authors: Maier Clara , Fuchs Jana , Irrgang Pascal , Wißing Michael Hermann , Beyerlein Jasmin , Tenbusch Matthias , Lapuente Dennis
Published: July 2022

Respiratory syncytial virus (RSV) infections are the leading cause of severe respiratory illness in early infancy. Although the majority of children and adults mount immune responses against RSV, recurrent infections are frequent throughout life. Humoral and cellular responses contribute to an effective immunity but also their localization at respiratory mucosae is increasingly recognized as an important factor. In the present study, we evaluate a mucosal vaccine based on an adenoviral vector encoding for the RSV fusion protein (Ad-F), and we investigate two genetic adjuvant candidates that encode for Interleukin (IL)-1β and IFN-β promoter stimulator I (IPS-1), respectively. While vaccination with Ad-F alone was immunogenic, the inclusion of Ad-IL-1β increased F-specific mucosal immunoglobulin A (IgA) and tissue-resident memory T cells (TRM). Consequently, immunization with Ad-F led to some control of virus replication upon RSV infection, but Ad-F+Ad-IL-1β was the most effective vaccine strategy in limiting viral load and weight loss. Subsequently, we compared the Ad-F+Ad-IL-1β-induced immunity with that provoked by a primary RSV infection. Systemic F-specific antibody responses were higher in immunized than in previously infected mice. However, the primary infection provoked glycoprotein G-specific antibodies as well eventually leading to similar neutralization titers in both groups. In contrast, mucosal antibody levels were low after infection, whereas mucosal immunization raised robust F-specific responses including IgA. Similarly, vaccination generated F-specific TRM more efficiently compared to a primary RSV infection. Although the primary infection resulted in matrix protein 2 (M2)-specific T cells as well, they did not reach levels of F-specific immunity in the vaccinated group. Moreover, the infection-induced T cell response was less biased towards TRM compared to vaccine-induced immunity. Finally, our vaccine candidate provided superior protection against RSV infection compared to a primary infection as indicated by reduced weight loss, virus replication, and tissue damage. In conclusion, our mucosal vaccine candidate Ad-F+Ad-IL-1β elicits stronger mucosal immune responses and a more effective protection against RSV infection than natural immunity generated by a previous infection. Harnessing mucosal immune responses by next-generation vaccines is therefore a promising option to establish effective RSV immunity and thereby tackle a major cause of infant hospitalization.
Neutrophils in malaria: A double-edged sword role
Authors: Babatunde Kehinde Adebayo , Adenuga Oluwadamilola Fatimat
Published: July 2022

Neutrophils are the most abundant leukocytes in human peripheral blood. They form the first line of defense against invading foreign pathogens and might play a crucial role in malaria. According to World Health Organization (WHO), malaria is a globally significant disease caused by protozoan parasites from the Plasmodium genus, and it’s responsible for 627,000 deaths in 2020. Neutrophils participate in the defense response against the malaria parasite via phagocytosis and reactive oxygen species (ROS) production. Neutrophils might also be involved in the pathogenesis of malaria by the release of toxic granules and the release of neutrophil extracellular traps (NETs). Intriguingly, malaria parasites inhibit the anti-microbial function of neutrophils, thus making malaria patients more susceptible to secondary opportunistic Salmonella infections. In this review, we will provide a summary of the role of neutrophils during malaria infection, some contradicting mouse model neutrophil data and neutrophil-related mechanisms involved in malaria patients’ susceptibility to bacterial infection.
Lactobacillus spp. act in synergy to attenuate splenomegaly and lymphadenopathy in lupus-prone MRL/lpr mice
Authors: Cabana-Puig Xavier , Mu Qinghui , Lu Ran , Swartwout Brianna , Abdelhamid Leila , Zhu Jing , Prakash Meeta , Cecere Thomas E. , Wang Zhuang , Callaway Sabrina , Sun Sha , Reilly Christopher M. , Ahmed S. Ansar , Luo Xin M.
Published: July 2022

Commensal bacteria and the immune system have a close and strong relationship that maintains a balance to control inflammation. Alterations of the microbiota, known as dysbiosis, can direct reactivity to self-antigens not only in the intestinal mucosa but also at the systemic level. Our laboratory previously reported gut dysbiosis, particularly lower abundance of bacteria in the familyLactobacillaceae, in lupus-prone MRL/lprmice, a model of systemic autoimmunity. Restoring the microbiota with a mix of 5 differentLactobacillusspecies (spp.),L. reuteri, L. oris, L. johnsonii, L. gasseriandL. rhamnosus, attenuated lupus-liked clinical signs, including splenomegaly and lymphadenopathy. However, our understanding of the mechanism was limited. In this study, we first investigated the effects of individual species. Surprisingly, none of the species individually recapitulated the benefits of the mix. Instead,Lactobacillusspp. acted synergistically to attenuate splenomegaly and renal lymphadenopathy through secreted factors and a CX3CR1-dependent mechanism. Interestingly, oral administration of MRS broth exerted the same benefits likely through increasing the relative abundance of endogenousLactobacillusspp. Mechanistically, we found increased percentages of FOXP3-negative type 1 regulatory T cells with administration of the mix in both spleen and mesenteric lymph nodes. In addition, oral gavage ofLactobacillusspp. decreased the percentage of central memory T cells while increasing that of effector memory T cells in the lymphoid organs. Furthermore, a decreased percentage of double negative T cells was observed in the spleen with the mix. These results suggest thatLactobacillusspp. might act on T cells to attenuate splenomegaly and lymphadenopathy. Together, this study advances our understanding of howLactobacillusspp. attenuate lupus in MRL/lprmice. The synergistic action of these bacteria suggests that multiple probiotic bacteria in combination may dampen systemic autoimmunity and benefit lupus patients.
A Systematic Review and Meta-Analysis of 19 Randomized Controlled Trials of Iguratimod Combined With Other Therapies for Sjogren’s Syndrome
Authors: Zeng Liuting , He Qi , Yang Kailin , Hao Wensa , Yu Ganpeng , Chen Hua
Published: July 2022

Objective

To explore the efficacy and safety of Iguratimod intervention in Primary Sjogren’s syndrome (pSS).

Methods

Many databases were searched to collect the RCTs. Three independent reviewers extracted data and assessed the quality of the studies based on the Cochrane Handbook. The statistical analysis was done by RevMan 5.3 and STATA. The quality of evidence was evaluated by GRADE tool.

Results

Twenty-nine RCTs with 2258 participants were included in this review. The meta-analysis shows that: iguratimod experiment group can reduce the ESSPRI score (WMD -1.93 [-2.33, -1.52], P<0.00001), ESSDAI score (WMD -1.39 [-1.81, -0.98], P<0.00001), Schirmer’s test (WMD 1.77 [0.85, 2.70], P=0.0002), RF (WMD -5.78 [-7.59, -3.97], P<0.00001), and decrease the ESR level (WMD -7.05 [-9.84, -4.26], P<0.00001). Meanwhile, the summary result showed the addiction of Iguratimod may not increase the adverse events. The adverse events were mainly gastrointestinal discomfort, abnormal liver function, and rash and itching. The quality of evidence of adverse events was moderate. Referring to minimal clinically important difference (MCID), the improvement of ESSPRI is clinically significant, and the improvement of ESSDAI for patients older than 60 years old may be clinically significant.

Conclusion

Based on current evidence, iguratimod can effectively reduce ESSPRI score, ESSDAI score, Schirmer’s test score and decrease systemic inflammatory response (such as ESR level and RF level) without increasing the probability of adverse events. The recommended course of treatment is at least 12 weeks.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?, identifier CRD42020220770.
Identification of CD8+ T-cell epitope from multiple myeloma-specific antigen AKAP4
Authors: Ma Ning , Liu Huihui , Zhang Yang , Liu Wei , Liang Zeyin , Wang Qian , Sun Yuhua , Wang Lihong , Li Yuan , Ren Hanyun , Dong Yujun
Published: July 2022

Multiple myeloma (MM) is a malignant plasma cell disorder affecting mainly the elderly population. Revolutionary progress in immunotherapy has been made recently, including monoclonal antibodies and chimeric antigen receptor T cell (CAR-T) therapies; however, the high relapse rate remains problematic. Therefore, combination therapies against different targets would be a reasonable strategy. In this study, we present a new X-chromosome encoded testis-cancer antigen (CTA) AKAP4 as a potential target for MM. AKAP4 is expressed in MM cell lines and MM primary malignant plasma cells. HLA-A*0201-restricted cytotoxic T lymphocytes (CTLs) induced by dendritic cells (DCs) transduced with an adenovirus vector encoding the full-length AKAP4 gene were demonstrated to lyse AKAP4+ myeloma cells. Seven of the 12 candidate epitopes predicated by the BIMAS and SYFPEITH algorithms were able to bind HLA-A*0201 in the T2 binding assay, of which only two peptides were able to induce CTL cytotoxicity in the co-culture of peptide-loaded human mature dendritic cells and the autologous peripheral blood mononuclear cells (PBMCs) from the same HLA-A*0201 donor. The AKAP4 630–638 VLMLIQKLL was identified as the strongest CTL epitope by the human IFN-γ ELISPOT assay. Finally, the VLMLIQKLL-specific CTLs can lyse the HLA-A*0201+AKAP4+ myeloma cell line U266 in vitro, and inhibit tumor growth in the mice bearing U266 tumors in vivo. These results suggest that the VLMLIQKLL epitope could be used to develop cancer vaccine or T-cell receptor transgenic T cells (TCR-T) to kill myeloma cells.
ELISA based assays to measure adenosine deaminases concentration in serum and saliva for the diagnosis of ADA2 deficiency and cancer
Authors: Luo Wenwen , Dong Liang , Chen Fenghong , Lei Wenbin , He Liya , Zhou Qing , Lamy Thierry , Zavialov Andrey V.
Published: July 2022

Adenosine deaminases (ADAs) are enzymes of purine metabolism converting adenosine to inosine. There are two types of ADAs in humans ADA1 and ADA2. While both ADA1 and ADA2 share the same substrate, they differ in expression, cellular localization, and catalytic properties. The genetic deficiency of ADA1 results in severe combined immunodeficiency (SCID), while lack in ADA2 (DADA2) results in multiple phenotypes ranging from systemic inflammation to vascular pathology. Clinical studies have shown that the levels of ADAs in biological fluids are altered in pathophysiological conditions, suggesting that ADA activity could be a convenient marker for the diagnosis of immune diseases and cancer. Here, we describe sensitive and straightforward ELISA assays to measure ADA1 and ADA2 concentrations in biological fluids. Analysis of the serum and saliva samples from the healthy controls and DADA2 patients revealed that ADA2 enzyme concentration is significantly lower in patients than in healthy controls. In contrast, the concentration of ADA2 increases in the serum of patients with large granular leukocyte leukemia (LGLL) and patients’ saliva with head and neck cancer. Thus, this simple, non-invasive method allows for distinguishing healthy controls from the affected patient. It can be implemented in screening and diagnosis of DADA2 and follow up the treatment of LGLL and several types of head and neck cancer.
Involvement of B cells in the development of systemic sclerosis
Authors: Yoshizaki Ayumi , Fukasawa Takemichi , Ebata Satoshi , Yoshizaki-Ogawa Asako , Sato Shinichi
Published: July 2022

Systemic sclerosis (SSc) is a rare intractable systemic disease that causes fibrosis and vasculopathy against a background of autoimmune abnormalities. Although the etiology is not yet fully understood, the type of autoantibodies detected in SSc is closely associated with disease severity and prognosis, supporting that those autoimmune abnormalities play an important role in the pathogenesis of SSc. Although the direct pathogenicity of autoantibodies found in SSc is unknown, many previous studies have shown that B cells are involved in the development of SSc through a variety of functions. Furthermore, a number of clinical studies have been conducted in which B-cell depletion therapy has been tried for SSc, and many of these studies have found B-cell depletion therapy to be effective for SSc. However, the involvement of B cells in pathogenesis is complex, as they not only promote inflammation but also play an inhibitory role. This article outlines the role of B cells in the development of SSc, including the latest research.
Transcriptional dynamics and epigenetic regulation of E and ID protein encoding genes during human T cell development
Authors: Roels Juliette , Van Hulle Jolien , Lavaert Marieke , Kuchmiy Anna , Strubbe Steven , Putteman Tom , Vandekerckhove Bart , Leclercq Georges , Van Nieuwerburgh Filip , Boehme Lena , Taghon Tom
Published: July 2022

T cells are generated from hematopoietic stem cells through a highly organized developmental process, in which stage-specific molecular events drive maturation towards αβ and γδ T cells. Although many of the mechanisms that control αβ- and γδ-lineage differentiation are shared between human and mouse, important differences have also been observed. Here, we studied the regulatory dynamics of the E and ID protein encoding genes during pediatric human T cell development by evaluating changes in chromatin accessibility, histone modifications and bulk and single cell gene expression. We profiled patterns of ID/E protein activity and identified up- and downstream regulators and targets, respectively. In addition, we compared transcription of E and ID protein encoding genes in human versus mouse to predict both shared and unique activities in these species, and in prenatal versus pediatric human T cell differentiation to identify regulatory changes during development. This analysis showed a putative involvement of TCF3/E2A in the development of γδ T cells. In contrast, in αβ T cell precursors a pivotal pre-TCR-driven population with high ID gene expression and low predicted E protein activity was identified. Finally, in prenatal but not postnatal thymocytes, high HEB/TCF12 levels were found to counteract high ID levels to sustain thymic development. In summary, we uncovered novel insights in the regulation of E and ID proteins on a cross-species and cross-developmental level.
The anti-obesity effects of a water-soluble glucan from Grifola frondosa via the modulation of chronic inflammation
Authors: Jiang Xue , Hao Jie , Zhu Yanfeng , Liu Zijian , Li Lanzhou , Zhou Yulin , Li Yu , Teng Lirong , Wang Di
Published: July 2022

Polysaccharides from Grifola frondosa (G. frondosa) have anti-obesity and anti-inflammatory activities. In this study, the major type, molecular weight, homogeneity and structure of a polysaccharide purified from G. frondosa (denoted GFPA) were determined. In high-fat diet (HFD)-treated mice, 8 weeks of GFPA administration efficiently decreased body weight and blood glucose concentration and counteracted hyperlipidemia. GFPA efficiently decreased adipocyte size and ameliorated inflammatory infiltration in the three types of white adipose tissue and alleviated steatosis, fat accumulation and inflammatory infiltration in the livers of HFD-fed mice. GFPA also decreased the concentrations of aspartate aminotransferase, alanine aminotransferase and pro-inflammatory factors in the sera and livers of HFD-treated mice. Furthermore, GFPA was found to regulate lipid metabolism via the inhibition of ceramide levels in HFD-treated mice. GFPA exhibited strong anti-obesity effects via the modulation of chronic inflammation through Toll-like receptor 4/nuclear factor kappa-B signaling, which supports the use of GFPA for the treatment of obesity.
The efficiency of convalescent plasma in COVID-19 patients: A systematic review and meta-analysis of randomized controlled clinical trials
Authors: Qian Zhenbei , Zhang Zhijin , Ma Haomiao , Shao Shuai , Kang Hanyujie , Tong Zhaohui
Published: July 2022

The objective of this study was to assess whether convalescent plasma therapy could offer survival advantages for patients with novel coronavirus disease 2019 (COVID-19). An electronic search of Pubmed, Web of Science, Embase, Cochrane library and MedRxiv was performed from January 1st, 2020 to April 1st, 2022. We included studies containing patients with COVID-19 and treated with CCP. Data were independently extracted by two reviewers and synthesized with a random-effect analysis model. The primary outcome was 28-d mortality. Secondary outcomes included length of hospital stay, ventilation-free days, 14-d mortality, improvements of symptoms, progression of diseases and requirements of mechanical ventilation. Safety outcomes included the incidence of all adverse events (AEs) and serious adverse events (SAEs). The Cochrane risk-of-bias assessment tool 2.0 was used to assess the potential risk of bias in eligible studies. The heterogeneity of results was assessed by I^2 test and Q statistic test. The possibility of publication bias was assessed by conducting Begg and Egger test. GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used for quality of evidence. This study had been registered on PROSPERO, CRD42021273608. 32 RCTs comprising 21478 patients with Covid-19 were included. Compared to the control group, COVID-19 patients receiving CCP were not associated with significantly reduced 28-d mortality (CCP 20.0% vs control 20.8%; risk ratio 0.94; 95% CI 0.87-1.02; p = 0.16; I² = 8%). For all secondary outcomes, there were no significant differences between CCP group and control group. The incidence of AEs (26.9% vs 19.4%,; risk ratio 1.14; 95% CI 0.99-01.31; p = 0.06; I² = 38%) and SAEs (16.3% vs 13.5%; risk ratio 1.03; 95% CI 0.87-1.20; p = 0.76; I² = 42%) tended to be higher in the CCP group compared to the control group, while the differences did not reach statistical significance. In all, CCP therapy was not related to significantly improved 28-d mortality or symptoms recovery, and should not be viewed as a routine treatment for COVID-19 patients.

Trial registration number

CRD42021273608. Registration on February 28, 2022

Systematic review registration

https://www.crd.york.ac.uk/prospero/, Identifier CRD42022313265.
Oviposition selection in spotted lanternfly: impact of habitat and substrate on egg mass size and hatchability
Authors: Liu Houping
Published: July 2022

Oviposition strategies adopted by insects (e.g., habitat selection, substrate preference, egg size, clutch size, structure, arrangement, parental care) are critical to the survival and development of their eggs. The impact of habitat and oviposition substrate on spotted lanternfly egg mass size and hatchability was studied in Pennsylvania through laboratory observations and field monitoring in 2019 and 2021. Eggs were arranged in single layers of 1–13 columns (1–18 eggs/column) on surfaces of various types of oviposition substrates, with the longest column(s) in the middle of the egg mass. Egg mass size was positively correlated with column number, with a mean of 26.6–35.1 (0–105) eggs/egg mass for different samples. Significant differences in egg mass size were observed between study sites, with larger egg masses found at Wertz (44.8), Sam Lewis (40.6), Pinnacle (39.1), Marsh Creek (37.9), Susquehannock (34.5), and Memorial Lake (33.3) and smaller egg masses at Nolde Forest (25.0), Gordon (24.4), and Antietam (21.0). Significant differences were also detected between types of oviposition substrates with smaller egg masses found on American hornbeam (22.7). In general, more (31.6%–48.0%) eggs hatched in the field compared with the laboratory (10.0%). Egg hatch success was positively correlated with egg mass size, with the highest rates recorded on American beech, American hophornbeam, black birch, black cherry, black locust, hackberry, Norway maple, red maple, and sweet cherry at Wertz, Marsh Creek, Memorial Lake, and Pinnacle. Potential (positive or negative) impacts of tree-of-heaven density, initial infestation, treatment history, and incubation conditions are discussed.