bluuebunny/crossref_metadata_2025 huggingface dataset:
PPA1 Promotes Breast Cancer Proliferation and Metastasis Through PI3K/AKT/GSK3β Signaling Pathway
Authors: Guo Chunlei , Li Shuang , Liang Ang , Cui Mengchao , Lou Yunwei , Wang Hui
Published: September 2021

Breast cancer is the most common malignancy among women. Inorganic pyrophosphatase 1 (PPA1) is a multifunctional protein involved in the development of several tumors. However, the role of PPA1 in breast cancer progression remains unclear. In this study, we found that PPA1 was highly expressed in breast cancer compared to its levels in normal breast tissue and that it was correlated with breast cancer clinicopathological characteristics, as well as poor survival in breast cancer patients. Silencing PPA1 restrained breast cancer proliferation and metastasis by regulating Slug-mediated epithelial-mesenchymal transition (EMT). Opposite results were observed following PPA1 overexpression. In addition, investigation of the underlying mechanism demonstrated that PPA1 ablation led to decrease phosphatidylinositol 3 kinase (PI3K) phosphorylation levels and attenuate phosphorylated AKT and glycogen synthase kinase-3 β (GSK3β), while ectopic PPA1 expression had the opposite effects. Moreover, PI3K inhibitors suppress the signaling pathways mediating the effects of PPA1 on breast cancer, resulting in tumor growth and metastasis suppression in vitro and in vivo. In summary, our results verify that PPA1 can act as an activator of PI3K/AKT/GSK3β/Slug-mediated breast cancer progression and that it is a potential therapeutic target for the inhibition of tumor progression.
Impact of Inosine on Chronic Unpredictable Mild Stress-Induced Depressive and Anxiety-Like Behaviors With the Alteration of Gut Microbiota
Authors: Liu Xueer , Teng Teng , Li Xuemei , Fan Li , Xiang Yajie , Jiang Yuanliang , Du Kang , Zhang Yuqing , Zhou Xinyu , Xie Peng
Published: September 2021

Current antidepressants do not confer a clear advantage in children and adolescents with major depressive disorder (MDD). Accumulating evidence highlights the potential antidepressant-like effects of inosine on adult MDD, and gut microbiomes are significantly associated with MDD via the microbiota-gut-brain axis. However, few studies have investigated possible associations between inosine and gut microbiota in adolescents with MDD. The current study investigated the potential antidepressant effects of inosine in adolescent male C57BL/6 mice. After 4 weeks of chronic unpredictable mild stress (CUMS) stimulation, the mice were assessed by body weight, the sucrose preference test (SPT), open field test, and the elevated plus maze (EPM). The microbiota compositions of feces were determined by 16S rRNA gene sequencing. Inosine significantly improved CUMS-induced depressive and anxiety-like behaviors in adolescent mice including SPT and EPM results. Fecal microbial composition differed in the CON+saline, CUMS+saline, and CUMS+inosine groups, which were characterized by 126 discriminative amplicon sequence variants belonging to Bacteroidetes and Firmicute at the phylum level and Muribaculaceae and Lachnospiraceae at the family level. Muribaculaceae was positively associated with depressive and anxiety-like behaviors. KEGG functional analysis suggested that inosine might affect gut microbiota through carbohydrate metabolism and lipid metabolism pathways. The results of the study indicated that inosine improved depressive and anxiety-like behaviors in adolescent mice, in conjunction with the alteration of fecal microbial composition. Our findings may provide a novel perspective on the antidepressant effects of inosine in children and adolescents.
A Rapid and Sensitive Detection Method for Pseudomonas aeruginosa Using Visualized Recombinase Polymerase Amplification and Lateral Flow Strip Technology
Authors: Yang Haitao , Wang Yan , Yang Qiankun , Fan Hui , Wang Lei , Zhang Tianmeng , Li Zhixing , Liu Gang , Zhao Panpan , Wu Huahua , Dong Jingquan , Liang Wei
Published: September 2021

Pseudomonas aeruginosa is a common opportunistic pathogen that causes acute nosocomial necrotizing pneumonia and is the predominant source of chronic lung infections in patients with the genetic disorder cystic fibrosis. Early diagnosis in infected patients and monitoring P. aeruginosa contamination is therefore of great importance in controlling disease spread and development with timely drugs intervention treatment and cut off infection source. Traditional culture-biochemical methods are time consuming and highly dependent on technicians and expensive instruments. To address these challenges, the present study aimed to develop a rapid, sensitive, and specific, on-site detection method for P. aeruginosa based on recombinase polymerase amplification (RPA) combined with lateral flow strip (LFS) technology. The experimental process included screening and modification of primer and probe sets targeting the unique virulence gene elastase B (lasB); specificity detection in 29 strains of P. aeruginosa and 23 closely-related pathogenic bacteria; sensitivity measurements with gradient-diluted P. aeruginosa genomic DNA and probit regression analysis; and clinical application evaluation using 574 patients samples and calculating coincidence rate and kappa index value in comparison with the culture-biochemical method. The P. aeruginosa RPA-LFS assay could complete the amplification process at 37°C constant temperature within 30 min and results could be visualized by the naked eye within 10 min on LFS. The assay displayed high sensitivity with a limit of detection of 3.05 CFU/reaction. It also demonstrated high specificity by showing no cross reaction with other pathogenic bacteria, and rapidness by being completed in less than an hour. Furthermore, when used with clinical samples, the assay had a coincidence rate of 98.26% with the culture-biochemical method and a kappa index value of 0.9433. These data indicate that the RPA-LFS assay represents a major improvement for P. aeruginosa detection, especially in resource-limited areas.
Case Report: The Cox-Maze IV Procedure in the Mirror: The Use of Three-Dimensional Printing for Pre-operative Planning in a Patient With Situs Inversus Dextrocardia
Authors: Song Long , Fan Chengming , Zhang Hao , Liu Hongduan , Iroegbu Chukwuemeka Daniel , Luo Cheng , Liu Liming
Published: September 2021

The safety and efficacy of the Cox-Maze IV procedure (CMP-IV) for situs inversus dextrocardia patients with atrial fibrillation is yet to be determined. Herein, we present the case of a 39-year-old male patient admitted to our cardiac center following progressive exertional dyspnea. The patient was diagnosed with situs inversus dextrocardia, severe mitral regurgitation, and paroxysmal atrial fibrillation. A three-dimensional (3D) heart model printing device embedded with designated ablation lines was used for pre-operative planning. Mitral valvuloplasty, CMP-IV, and tricuspid annuloplasty were performed. The patient had an uneventful recovery and was in sinus rhythm during a 12-month follow-up period using a 24-h Holter monitoring device. The case herein is one of the first to report on adopting the CMP-IV procedure for situs inversus dextrocardia patients with complex valvuloplasty operation. In addition, the 3D printing technique enabled us to practice the Cox-maze IV procedure, given the patient's unique cardiac anatomy.
Epicardial Transplantation of Autologous Cardiac Micrografts During Coronary Artery Bypass Surgery
Authors: Nummi Annu , Mulari Severi , Stewart Juhani A. , Kivistö Sari , Teittinen Kari , Nieminen Tuomo , Lampinen Milla , Pätilä Tommi , Sintonen Harri , Juvonen Tatu , Kupari Markku , Suojaranta Raili , Kankuri Esko , Harjula Ari , Vento Antti ,   the AADC consortium
Published: September 2021

Background: Cardio-regenerative cell therapies offer additional biologic support to coronary artery bypass surgery (CABG) and are aimed at functionally repairing the myocardium that suffers from or is damaged by ischemia. This non-randomized open-label study assessed the safety and feasibility of epicardial transplantation of atrial appendage micrografts (AAMs) in patients undergoing CABG surgery.

Methods: Twelve consecutive patients destined for CABG surgery were included in the study. Six patients received AAMs during their operation and six patients were CABG-operated without AAMs transplantation. Data from 30 elective CABG patients was collected for a center- and time-matched control group. The AAMs were processed during the operation from a biopsy collected from the right atrial appendage. They were delivered epicardially onto the infarct scar site identified in preoperative late gadolinium enhancement cardiac magnetic resonance imaging (CMRI). The primary outcome measures at the 6-month follow-up were (i) patient safety in terms of hemodynamic and cardiac function over time and (ii) feasibility of therapy administration in a clinical setting. Secondary outcome measures were left ventricular wall thickness, change in myocardial scar tissue volume, changes in left ventricular ejection fraction, plasma concentrations of N-terminal pro-B-type natriuretic peptide levels, NYHA class, number of days in hospital and changes in the quality of life.

Results: Epicardial transplantation of AAMs was safe and feasible to be performed during CABG surgery. CMRI demonstrated an increase in viable cardiac tissue at the infarct site in patients receiving AAMs treatment.

Conclusions and Relevance: Transplantation of AAMs shows good clinical applicability as performed during cardiac surgery, shows initial therapeutic effect on the myocardium and has the potential to serve as a delivery platform for cardiac gene therapies.

Trial Registration:ClinicalTrials.gov, identifier: NCT02672163.
LncRNA PVT1 Knockdown Ameliorates Myocardial Ischemia Reperfusion Damage via Suppressing Gasdermin D-Mediated Pyroptosis in Cardiomyocytes
Authors: Li Cuizhi , Song Huafeng , Chen Chunlin , Chen Shaoxian , Zhang Qiyu , Liu Dehui , Li Jinglong , Dong Haojian , Wu Yueheng , Liu Youbin
Published: September 2021

Objective: Myocardial ischemia reperfusion (I/R) damage is a life-threatening vascular emergency after myocardial infarction. Here, we observed the cardioprotective effect of long non-coding RNA (lncRNA) PVT1 knockdown against myocardial I/R damage.

Methods: This study constructed a myocardial I/R-induced mouse model and a hypoxia/reoxygenation (H/R)-treated H9C2 cells. PVT1 expression was examined via RT-qPCR. After silencing PVT1 via shRNA against PVT1, H&E, and Masson staining was performed to observe myocardial I/R damage. Indicators of myocardial injury including cTnI, LDH, BNP, and CK-MB were examined by ELISA. Inflammatory factors (TNF-α, IL-1β, and IL-6), Gasdermin D (GSDMD), and Caspase1 were detected via RT-qPCR, western blot, immunohistochemistry, or immunofluorescence. Furthermore, CCK-8 and flow cytometry were presented for detecting cell viability and apoptosis.

Results: LncRNA PVT1 was markedly up-regulated in myocardial I/R tissue specimens as well as H/R-induced H9C2 cells. Silencing PVT1 significantly lowered serum levels of cTnI, LDH, BNP, and CK-MB in myocardial I/R mice. H&E and Masson staining showed that silencing PVT1 alleviated myocardial I/R injury. PVT1 knockdown significantly lowered the production and release of inflammatory factors as well as inhibited the expression of GSDMD-N and Caspase1 in myocardial I/R tissue specimens as well as H/R-induced H9C2 cells. Moreover, silencing PVT1 facilitated cell viability and induced apoptosis of H/R-treated H9C2 cells.

Conclusion: Our findings demonstrated that silencing PVT1 could alleviate myocardial I/R damage through suppressing GSDMD-mediated pyroptosis in vivo and in vitro. Thus, PVT1 knockdown may offer an alternative therapeutic strategy against myocardial I/R damage.
The Elements and Color of Lacustrine Record Revealed Lake Environmental Changes in Semiarid Northern China: A Case Study From Chagan Nur Lake of Southern Mongolian Plateau
Authors: Wang Zhong , Li Guoqiang , Wang Xiaoyan , Gou Siyi , Deng Yanqing , Tao Shuxian , Zhang Yunian , Yang He , Zhao Wenwei , Jin Ming
Published: September 2021

The lakes at the southern Mongolian Plateau are sensitive to the variation of EASM changes during the Holocene, and hence the lacustrine records of these lakes provide prospects for understanding how lake environmental changes respond to EASM variation at different timescales. The interpretation of proxy indexes of lacustrine sediments is complex due to the various climatic or/and environmental factors influencing the processes during deposition and after deposition. In this study, the elements and colors of an 11.7-m lacustrine record from Chagan Nur at the southern Mongolian Plateau of northern China were analyzed to constrain the lake environmental changes during the Holocene. The results show that stable elements of Al, Si, K, Ti, Fe, and Rb are more related to surface erosion or/and vegetation coverage, and the variation of Sr is related to the lake-level change in Chagan Nur. The element and color of the lacustrine records show that a small and shallow lake environment occurred at Chagan Nur during 11.7–10.5 ka, the lake level had increased during 10.5–7 ka, and then the lake shrank with strength surface erosion during 7–6.2 ka and from 2 ka to the present. The lake level and surface erosion changes of Chagan Nur have shown a direct response to EASM precipitation changes as reconstructed from the pollen record from the Chagan Nur Lake and other records from northern China.
An Assessment of Recently Released High-Degree Global Geopotential Models Based on Heterogeneous Geodetic and Ocean Data
Authors: Wu Yihao , He Xiufeng , Luo Zhicai , Shi Hongkai
Published: September 2021

The development of the global geopotential model (GGM) broadens its applications in ocean science, which emphasizes the importance for model assessment. We assess the recently released high-degree GGMs over the South China Sea through heterogeneous geodetic observations and synthetic/ocean reanalysis data. The comparisons with a high resolution (∼3 km) airborne gravimetric survey over the Paracel Islands show that XGM2019e_2159 has relatively high quality, where the standard deviation (SD) of the misfits against the airborne gravity data is ∼3.1 mGal. However, the comparisons with local airborne/shipborne gravity data hardly discriminate the qualities of other GGMs that have or truncated to the same expansion degree. Whereas, the comparisons with the synthetic/ocean reanalysis data demonstrate that the qualities of the values derived from different GGMs are not identical, and the ones derived from XGM2019e_2159 have better performances. The SD of the misfits between the mean dynamic topography (MDT) derived from XGM2019e_2159 and the ocean data is 2.5 cm; and this value changes to 7.1 cm/s (6.8 cm/s) when the associated zonal (meridian) geostrophic velocities are assessed. In contrast, the values derived from the other GGMs show deteriorated qualities compared to those derived from XGM2019e_2159. In particular, the contents computed from the widely used EGM2008 have relatively poor qualities, which is reduced by 3.9 cm when the MDT is assessed, and by 4.0 cm/s (5.5 cm/s) when the zonal (meridian) velocities are assessed, compared to the results derived from XGM2019e_2159. The results suggest that the choice of a GGM in oceanographic study is crucial, especially over coastal zones. Moreover, the synthetic/ocean data sets may be served as additional data sources for global/regional gravity field assessment, which are useful in regions that lack of high-quality geodetic data.
The First Step to Learning Place Value: A Role for Physical Models?
Authors: Yuan Lei , Prather Richard , Mix Kelly , Smith Linda
Published: September 2021

Very few questions have cast such an enduring effect in cognitive science as the question of “symbol-grounding”: Do human-invented symbol systems have to be grounded to physical objects to gain meanings? This question has strongly influenced research and practice in education involving the use of physical models and manipulatives. However, the evidence on the effectiveness of physical models is mixed. We suggest that rethinking physical models in terms of analogies, rather than groundings, offers useful insights. Three experiments with 4- to 6-year-old children showed that they can learn about how written multi-digit numbers are named and how they are used to represent relative magnitudes based on exposure to either a few pairs of written multi-digit numbers and their corresponding names, or exposure to multi-digit number names and their corresponding physical models made up by simple shapes (e.g., big-medium-small discs); but they failed to learn with traditional mathematical manipulatives (i.e., base-10 blocks, abacus) that provide a more complete grounding of the base-10 principles. These findings have implications for place value instruction in schools and for the determination of principles to guide the use of physical models.
Management of Patients With Glucocorticoid-Related Diseases and COVID-19
Authors: Chifu Irina , Detomas Mario , Dischinger Ulrich , Kimpel Otilia , Megerle Felix , Hahner Stefanie , Fassnacht Martin , Altieri Barbara
Published: September 2021

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health crisis affecting millions of people worldwide. SARS-CoV-2 enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2) after being cleaved by the transmembrane protease serine 2 (TMPRSS2). In addition to the lung, gastrointestinal tract and kidney, ACE2 is also extensively expressed in endocrine tissues, including the pituitary and adrenal glands. Although glucocorticoids could play a central role as immunosuppressants during the cytokine storm, they can have both stimulating and inhibitory effects on immune response, depending on the timing of their administration and their circulating levels. Patients with adrenal insufficiency (AI) or Cushing’s syndrome (CS) are therefore vulnerable groups in relation to COVID-19. Additionally, patients with adrenocortical carcinoma (ACC) could also be more vulnerable to COVID-19 due to the immunosuppressive state caused by the cancer itself, by secreted glucocorticoids, and by anticancer treatments. This review comprehensively summarizes the current literature on susceptibility to and outcome of COVID-19 in AI, CS and ACC patients and emphasizes potential pathophysiological mechanisms of susceptibility to COVID-19 as well as the management of these patients in case of SARS-CoV-2. Finally, by performing an in silico analysis, we describe the mRNA expression of ACE2, TMPRSS2 and the genes encoding their co-receptors CTSB, CTSL and FURIN in normal adrenal and adrenocortical tumors (both adenomas and carcinomas).
Decrease in Serum Urate Level Is Associated With Loss of Visceral Fat in Male Gout Patients
Authors: Ran Zijing , Xue Xiaomei , Han Lin , Terkeltaub Robert , Merriman Tony R. , Zhao Ting , He Yuwei , Wang Can , Li Xinde , Liu Zhen , Cui Lingling , Li Hailong , Ji Aichang , Hu Shuhui , Lu Jie , Li Changgui
Published: September 2021

Objective

To clarify the relationship between serum urate (SU) decrease and visceral fat area (VFA) reduction in patients with gout.

Methods

We retrospectively analyzed 237 male gout patients who had two sets of body composition and metabolic measurements within 6 months. Subjects included had all been treated with urate-lowering therapy (ULT) (febuxostat 20–80 mg/day or benzbromarone 25–50 mg/day, validated by the medical record). All patients were from the specialty gout clinic of The Affiliated Hospital of Qingdao University. The multiple linear regression model evaluated the relationship between change in SU [ΔSU, (baseline SU) – (final visit SU)] and change in VFA [ΔVFA, (baseline VFA) – (final visit VFA)].

Results

ULT resulted in a mean (standard deviation) decrease in SU level (464.22 ± 110.21 μmol/L at baseline, 360.93 ± 91.66 μmol/L at the final visit, p <0.001) accompanied by a decrease in median (interquartile range) VFA [97.30 (81.15–118.55) at baseline, 90.90 (75.85–110.05) at the final visit, p < 0.001]. By multiple regression model, ΔSU was identified to be a significant determinant variable of decrease in VFA (beta, 0.302; p = 0.001).

Conclusions

The decrease in SU level is positively associated with reduced VFA. This finding provides a rationale for clinical trials to affirm whether ULT promotes loss of visceral fat in patients with gout.
Vegetation Response to Holocene Climate Change in the Qinling Mountains in the Temperate–Subtropical Transition Zone of Central–East China
Authors: Zhang Yao , Cui Qiaoyu , Huang Youliang , Wu Duo , Zhou Aifeng
Published: September 2021

Global warming is having a profound influence on vegetation and biodiversity patterns, especially in alpine areas and high latitudes. The Qinling Mountain range is located in the transition zone between the temperate and subtropical ecosystems of central–east China and thus the vegetation of the area is diverse. Understanding the long-term interactions between plant diversity and climate change can potentially provide a reference for future landscape management and biodiversity conservation strategies in the Qinling Mountains region. Here, we use a pollen record from the Holocene sediments of Daye Lake, on Mount Taibai in the Qingling Mountains, to study regional vegetation changes based on biomes reconstruction and diversity analysis. Temperature and precipitation records from sites close to Daye Lake are used to provide environmental background to help determine the vegetation response to climate change. The results indicate that climate change was the main factor influencing vegetation and palynological diversity in the Qinling Mountains during the Holocene. The cold and dry climate at the beginning of the early Holocene (11,700–10,700 cal yr BP) resulted in a low abundance and uneven distribution of regional vegetation types, with the dominance of coniferous forest. During the early Holocene (10,700–7,000 cal yr BP), temperate deciduous broadleaf forest expanded, palynological diversity and evenness increased, indicating that the warm and humid climate promoted vegetation growth. In the middle Holocene (7,000–3,000 cal yr BP), the climate became slightly drier but a relatively warm environment supported the continued increase in palynological diversity. After ∼3,000 cal yr BP, palynological diversity and the evenness index commenced a decreasing trend, in agreement with the decreased temperature and precipitation in the Qinling Mountains. It’s noteworthy that human activity at this time had a potential influence on the vegetation. During the past few centuries, however, palynological diversity has increased along with the global temperature, and therefore it is possible that in the short-term ongoing climatic warming will promote vegetation development and palynological diversity in the area without human interference.
Comparative Immunogenomics of Canine Natural Killer Cells as Immunotherapy Target
Authors: Gingrich Alicia A. , Reiter Taylor E. , Judge Sean J. , York Daniel , Yanagisawa Mio , Razmara Aryana , Sturgill Ian , Basmaci Ugur Nur , Brady Rachel V. , Stoffel Kevin , Murphy William J. , Rebhun Robert B. , Brown C. Titus , Canter Robert J.
Published: September 2021

Natural killer (NK) cells are key effectors of the innate immune system, but major differences between human and murine NK cells have impeded translation. Outbred dogs offer an important link for studies of NK biology and immunotherapy. We analyzed gene expression of putative NK populations from healthy dogs and dogs with naturally-occurring cancers examining differential gene expression across multiple conditions, including steady-state,in vitroactivation with cytokines and co-culture, andin vivoactivation with inhaled IL-15 in dogs receiving IL-15 immunotherapy. We also compared dog, mouse and human CD3-NKp46+ NK cells using a novel orthologous transcriptome. Distinct transcriptional profiles between NK populations exist between conditions andin vitroversusin vivotreatments. In cross-species analysis, canine NK cells were globally more similar to human NK cells than mice. These data define canine NK cell gene expression under multiple conditions and across species, filling an important gap in translational NK studies.
Do Engineered Nanomaterials Affect Immune Responses by Interacting With Gut Microbiota?
Authors: Tang Mingxing , Li Shuo , Wei Lan , Hou Zhaohua , Qu Jing , Li Liang
Published: September 2021

Engineered nanomaterials (ENMs) have been widely exploited in several industrial domains as well as our daily life, raising concern over their potential adverse effects. While in general ENMs do not seem to have detrimental effects on immunity or induce severe inflammation, their indirect effects on immunity are less known. In particular, since the gut microbiota has been tightly associated with human health and immunity, it is possible that ingested ENMs could affect intestinal immunity indirectly by modulating the microbial community composition and functions. In this perspective, we provide a few pieces of evidence and discuss a possible link connecting ENM exposure, gut microbiota and host immune response. Some experimental works suggest that excessive exposure to ENMs could reshape the gut microbiota, thereby modulating the epithelium integrity and the inflammatory state in the intestine. Within such microenvironment, numerous microbiota-derived components, including but not limited to SCFAs and LPS, may serve as important effectors responsible of the ENM effect on intestinal immunity. Therefore, the gut microbiota is implicated as a crucial regulator of the intestinal immunity upon ENM exposure. This calls for including gut microbiota analysis within future work to assess ENM biocompatibility and immunosafety. This also calls for refinement of future studies that should be designed more elaborately and realistically to mimic the human exposure situation.
The Antimicrobial Peptide Human β-Defensin-3 Accelerates Wound Healing by Promoting Angiogenesis, Cell Migration, and Proliferation Through the FGFR/JAK2/STAT3 Signaling Pathway
Authors: Takahashi Miho , Umehara Yoshie , Yue Hainan , Trujillo-Paez Juan Valentin , Peng Ge , Nguyen Hai Le Thanh , Ikutama Risa , Okumura Ko , Ogawa Hideoki , Ikeda Shigaku , Niyonsaba François
Published: September 2021

In addition to its antimicrobial activity, the skin-derived antimicrobial peptide human β-defensin-3 (hBD-3) promotes keratinocyte proliferation and migration to initiate the wound healing process; however, its effects on fibroblasts, which are the major cell type responsible for wound healing, remain unclear. We investigated the role of hBD-3 in cell migration, proliferation and production of angiogenic growth factors in human fibroblasts and evaluated the in vivo effect of hBD-3 on promoting wound healing and angiogenesis. Following hBD-3 treatment, the mouse wounds healed faster and showed accumulation of neutrophils and macrophages in the early phase of wound healing and reduction of these phagocytes 4 days later. hBD-3-treated wounds also displayed an increased number of fibroblasts and newly formed vessels compared to those of the control mice. Furthermore, the expression of various angiogenic growth factors was increased in the hBD-3-treated wounds. Additionally, in vitro studies demonstrated that hBD-3 enhanced the secretion of angiogenic growth factors such as fibroblast growth factor, platelet-derived growth factor and vascular endothelial growth factor and induced the migration and proliferation of human fibroblasts. The hBD-3-mediated activation of fibroblasts involves the fibroblast growth factor receptor 1 (FGFR1)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathways, as evidenced by the inhibitory effects of pathway-specific inhibitors. We indeed confirmed that hBD-3 enhanced the phosphorylation of FGFR1, JAK2 and STAT3. Collectively, the current study provides novel evidence that hBD-3 might be a potential candidate for the treatment of wounds through its ability to promote wound healing, angiogenesis and fibroblast activation.
Lactobacillus rhamnosus GR-1 Prevents Escherichia coli-Induced Apoptosis Through PINK1/Parkin-Mediated Mitophagy in Bovine Mastitis
Authors: Li Yanan , Zhu Yaohong , Chu Bingxin , Liu Ning , Chen Shiyan , Wang Jiufeng
Published: September 2021

Escherichia coli is one of the most important pathogens that cause clinical mastitis in dairy cattle worldwide and lead to severe economic losses. Antibiotics are often used to treat this inflammatory disease; however, antimicrobial resistance and environmental pollution cannot be ignored. Probiotic is the best alternative; however, its mechanisms of action to prevent mastitis remain unclear. Moreover, the role of probiotics in regulating mitophagy, a selective autophagy that maintains mitochondrial quality, needs to be explored. E. coli infection induced NOD-like receptor family member pyrin domain-containing protein 3 (NLRP3) inflammasome assembly, Caspase-1 activation, and apoptosis in MAC-T cells. Infection also resulted in mitochondrial damage and subsequent increase in reactive oxygen species (ROS) production. Moreover, inhibition of ROS release by scavenger N-acetyl-L-cysteine (NAC) abrogated the importance of ROS in NLRP3 assembly and apoptosis in MAC-T cells. Pretreatment with Lactobacillus rhamnosus GR-1 (LGR-1), a probiotic, alleviated E. coli-induced NLRP3 inflammasome activation and apoptosis via ROS inhibition. Besides, E. coli infection inhibited mitophagy while LGR-1 pretreatment augmented PINK1/Parkin–mediated mitophagy activation, which further blocked ROS generation. To explore the effect of LGR-1 in vivo, a mouse mastitis model was established. The results showed that LGR-1 pretreatment had preventive and protective effects on E. coli induced mastitis, and could reduce cytokines levels such as IL-1β and TNF-α. In accordance with the results in vitro, E. coli can inhibit mitophagy and activate NLRP3 inflammasome and apoptosis, while LGR-1 can weaken the effect of E. coli. Taken together, our data indicated that LGR-1 pretreatment induced PINK1/Parkin-mediated mitophagy that eliminated damaged mitochondria and reduced ROS production and NLRP3 inflammasome activation, which subsequently decreased E. coli-induced apoptosis. To conclude, our study suggests that therapeutic strategies aiming at the upregulation of mitophagy under E. coli-induced mastitis may preserve mitochondrial function and provide theoretical support for the application of probiotics in bovine mastitis.
Leukocyte Immunoglobulin-Like Receptors in Regulating the Immune Response in Infectious Diseases: A Window of Opportunity to Pathogen Persistence and a Sound Target in Therapeutics
Authors: Abdallah Florence , Coindre Sixtine , Gardet Margaux , Meurisse Florian , Naji Abderrahim , Suganuma Narufumi , Abi-Rached Laurent , Lambotte Olivier , Favier Benoit
Published: September 2021

Immunoregulatory receptors are essential for orchestrating an immune response as well as appropriate inflammation in infectious and non-communicable diseases. Among them, leukocyte immunoglobulin-like receptors (LILRs) consist of activating and inhibitory receptors that play an important role in regulating immune responses modulating the course of disease progression. On the one hand, inhibitory LILRs constitute a safe-guard system that mitigates the inflammatory response, allowing a prompt return to immune homeostasis. On the other hand, because of their unique capacity to attenuate immune responses, pathogens use inhibitory LILRs to evade immune recognition, thus facilitating their persistence within the host. Conversely, the engagement of activating LILRs triggers immune responses and the production of inflammatory mediators to fight microbes. However, their heightened activation could lead to an exacerbated immune response and persistent inflammation with major consequences on disease outcome and autoimmune disorders. Here, we review the genetic organisation, structure and ligands of LILRs as well as their role in regulating the immune response and inflammation. We also discuss the LILR-based strategies that pathogens use to evade immune responses. A better understanding of the contribution of LILRs to host–pathogen interactions is essential to define appropriate treatments to counteract the severity and/or persistence of pathogens in acute and chronic infectious diseases lacking efficient treatments.
Rapid Characterization of Complex Killer Cell Immunoglobulin-Like Receptor (KIR) Regions Using Cas9 Enrichment and Nanopore Sequencing
Authors: Bruijnesteijn Jesse , van der Wiel Marit , de Groot Natasja G. , Bontrop Ronald E.
Published: September 2021

Long-read sequencing approaches have considerably improved the quality and contiguity of genome assemblies. Such platforms bear the potential to resolve even extremely complex regions, such as multigenic immune families and repetitive stretches of DNA. Deep sequencing coverage, however, is required to overcome low nucleotide accuracy, especially in regions with high homopolymer density, copy number variation, and sequence similarity, such as the MHC and KIR gene clusters of the immune system. Therefore, we have adapted a targeted enrichment protocol in combination with long-read sequencing to efficiently annotate complex KIR gene regions. Using Cas9 endonuclease activity, segments of the KIR gene cluster were enriched and sequenced on an Oxford Nanopore Technologies platform. This provided sufficient coverage to accurately resolve and phase highly complex KIR haplotypes. Our strategy eliminates PCR-induced amplification errors, facilitates rapid characterization of large and complex multigenic regions, including its epigenetic footprint, and is applicable in multiple species, even in the absence of a reference genome.
The History, Present and Future of Allergen Standardization in the United States and Europe
Authors: Zimmer Julia , Bridgewater Jennifer , Ferreira Fatima , van Ree Ronald , Rabin Ronald L. , Vieths Stefan
Published: September 2021

The topic of standardization in relation to allergen products has been discussed by allergists, regulators, and manufacturers for a long time. In contrast to synthetic medicinal products, the natural origin of allergen products makes the necessary comparability difficult to achieve. This holds true for both aspects of standardization: Batch-to-batch consistency (or product-specific standardization) and comparability among products from different manufacturers (or cross-product comparability). In this review, we focus on how the United States and the European Union have tackled the topic of allergen product standardization in the past, covering the early joint standardization efforts in the 1970s and 1980s as well as the different paths taken by the two players thereafter until today. So far, these two paths have been based on rather classical immunological methods, including the corresponding benefits like simple feasability. New technologies such as mass spectrometry present an opportunity to redefine the field of allergen standardization in the future.
Long-Range Control of Class Switch Recombination by Transcriptional Regulatory Elements
Authors: Dauba Audrey , Khamlichi Ahmed Amine
Published: September 2021

Immunoglobulin class switch recombination (CSR) plays a crucial role in adaptive immune responses through a change of the effector functions of antibodies and is triggered by T-cell-dependent as well as T-cell-independent antigens. Signals generated following encounter with each type of antigen direct CSR to different isotypes. At the genomic level, CSR occurs between highly repetitive switch sequences located upstream of the constant gene exons of the immunoglobulin heavy chain locus. Transcription of switch sequences is mandatory for CSR and is induced in a stimulation-dependent manner. Switch transcription takes place within dynamic chromatin domains and is regulated by long-range regulatory elements which promote alignment of partner switch regions in CSR centers. Here, we review recent work and models that account for the function of long-range transcriptional regulatory elements and the chromatin-based mechanisms involved in the control of CSR.
Study on the Residual Stress Relieving Mechanism of C/C Composite-Nb Brazed Joint by Employing a Structurally Optimized Graphene Reinforced Cu Foam Interlayer
Authors: Li Hongliang , Wang Zeyu , Butt Hassaan Ahmad , Ye Maocheng , Chen Hao , Zhao Tianmo , Li Manni , Ma Qiang , Lei Yucheng
Published: September 2021

Cu foam has previously been investigated and verified to be an excellent interlayer candidate for relieving high residual stress within C/C composite-Nb brazed joints. However, the optimized geometric structure of Cu foam for brazing has never been properly investigated since it was always employed as a reactant for acquiring homogeneous distribution of the interfacial structures in the brazed joints. In this work, graphene reinforced Cu foam composite (G-Cuf) interlayers were used for brazing C/C composite and Nb. Through the protection effect of graphene on the Cu foam substrate, the impact of porosity and thickness of a structurally intact Cu foam on the joint structure and properties were investigated by finite elemental analysis as well as through experimental studies. By introducing a G-Cuf interlayer with an optimized porosity of 90% and thickness of 0.15 mm, the shear strength of the C/C composite-Nb brazed joint reached 45 MPa, which is 3.5 times higher than that of the joint brazed directly without an interlayer. The strain energy of the brazed joint assisted by G-Cuf interlayer reduced from as high as 10.98 × 10–6 J to 6.90 × 10–6 J, suggesting that the residual stress was effectively mitigated.
Hospital Admission to a Window-Side Bed Does Not Prevent Delirium: A Retrospective Cohort Study of Older Medical Inpatients in General Wards
Authors: Aomura Daiki , Yamada Yosuke , Harada Makoto , Hashimoto Koji , Kamijo Yuji
Published: September 2021

Background:Delirium in older inpatients is a serious problem. The presence of a window in the intensive care unit has been reported to improve delirium. However, no study has investigated whether window-side bed placement is also effective for delirium prevention in a general ward.

Objectives:This study aims to clarify the association between admission to a window-side bed and delirium development in older patients in a general ward.

Design:This research is designed as a retrospective cohort study of older patients admitted to the internal medicine departments of Shinshu University Hospital, Japan.

Participants:The inclusion criteria were the following: (1) admitted to hospital internal medicine departments between April 2009 and December 2018, (2) older than 75 years, (3) admitted to a multi-patient room in a general ward, and (4) unplanned admission. The number of eligible patients was 1,556.

Exposure:This study is a comparison of 495 patients assigned to a window-side bed (window group) with 1,061 patients assigned to a non-window-side bed (non-window group). When patients were transferred to the other type bed after admission, observation was censored.

Main Measures:The main outcome of interest was “delirium with event” (e.g., the use of medication or physical restraint for delirium) within 14 days after admission as surveyed by medical chart review in a blinded manner.

Key Results:The patients had a median age of 80 years and 38.1% were female. The main outcome was recorded in 36 patients in the window group (10.7 per thousand person-days) and 84 in the non-window group (11.7 per thousand person-days). Log-rank testing showed no significant difference between the groups (p= 0.78). Multivariate analysis with Cox regression modeling also revealed no significant association for the window group with main outcome development (adjusted hazard ratio 0.90, 95% confidence interval of 0.61–1.34).

Conclusions:Admission to a window-side bed did not prevent delirium development in older patients admitted to a general ward.
Isolation of Ciprofloxacin and Ceftazidime-Resistant Enterobacterales From Vegetables and River Water Is Strongly Associated With the Season and the Sample Type
Authors: Díaz-Gavidia Constanza , Barría Carla , Rivas Lina , García Patricia , Alvarez Francisca P. , González-Rocha Gerardo , Opazo-Capurro Andrés , Araos Rafael , Munita José M. , Cortes Sandra , Olivares-Pacheco Jorge , Adell Aiko D. , Moreno-Switt Andrea I.
Published: September 2021

The dissemination of antibiotic-resistant bacteria (ARB) from water used for crop irrigation to vegetables is poorly studied. During a year, five farmer markets in a city in Central Chile were visited, and 478 vegetable samples (parsleys, corianders, celeries, lettuces, chards, and beets) were collected. Simultaneously, 32 water samples were collected from two rivers which are used to irrigate the vegetables produced in the area. Resistant Enterobacterales were isolated and identified. Colistin resistance gene mcr-1 and extended spectrum β-lactamases (ESBL) were molecularly detected. The association of environmental factors was evaluated, with the outcomes being the presence of Enterobacterales resistant to four antibiotic families and the presence of multidrug resistance (MDR) phenotypes. Parsley, coriander, and celery showed the highest prevalence of resistant Enterobacterales (41.9% for ciprofloxacin and 18.5% for ceftazidime). A total of 155 isolates were obtained, including Escherichia coli (n=109), Citrobacter sp. (n=20), Enterobacter cloacae complex (n=8), Klebsiella pneumoniae (n=8), and Klebsiella aerogenes (n=1). Resistance to ampicillin (63.2%) and ciprofloxacin (74.2%) was most frequently found; 34.5% of the isolates showed resistance to third-generation cephalosporins, and the MDR phenotype represented 51.6% of the isolates. In two E. coli isolates (1.29%), the gene mcr-1 was found and ESBL genes were found in 23/62 isolates (37%), with blaCTX-M being the most frequently found in 20 isolates (32%). Resistant Enterobacterales isolated during the rainy season were less likely to be MDR as compared to the dry season. Understanding environmental associations represent the first step toward an improved understanding of the public health impact of ARB in vegetables and water.
Current Status of Chikungunya in India
Authors:   The Translational Research Consortia (TRC) for Chikungunya Virus in India
Published: September 2021

Chikungunya fever (CHIKF) is an arbovirus disease caused by chikungunya virus (CHIKV), an alphavirus of Togaviridae family. Transmission follows a human-mosquito-human cycle starting with a mosquito bite. Subsequently, symptoms develop after 2–6 days of incubation, including high fever and severe arthralgia. The disease is self-limiting and usually resolve within 2 weeks. However, chronic disease can last up to several years with persistent polyarthralgia. Overlapping symptoms and common vector with dengue and malaria present many challenges for diagnosis and treatment of this disease. CHIKF was reported in India in 1963 for the first time. After a period of quiescence lasting up to 32 years, CHIKV re-emerged in India in 2005. Currently, every part of the country has become endemic for the disease with outbreaks resulting in huge economic and productivity losses. Several mutations have been identified in circulating strains of the virus resulting in better adaptations or increased fitness in the vector(s), effective transmission, and disease severity. CHIKV evolution has been a significant driver of epidemics in India, hence, the need to focus on proper surveillance, and implementation of prevention and control measure in the country. Presently, there are no licensed vaccines or antivirals available; however, India has initiated several efforts in this direction including traditional medicines. In this review, we present the current status of CHIKF in India.
Identification, Isolation, and Characterization of Medipeptins, Antimicrobial Peptides From Pseudomonas mediterranea EDOX
Authors: Zhou Lu , de Jong Anne , Yi Yunhai , Kuipers Oscar P.
Published: September 2021

The plant microbiome is a vastly underutilized resource for identifying new genes and bioactive compounds. Here, we used Pseudomonas sp. EDOX, isolated from the leaf endosphere of a tomato plant grown on a small farm in the Netherlands. To get more insight into its biosynthetic potential, the genome of Pseudomonas sp. EDOX was sequenced and subjected to bioinformatic analyses. The genome sequencing analysis identified strain EDOX as a member of the Pseudomonas mediterranea. In silico analysis for secondary metabolites identified a total of five non-ribosomally synthesized peptides synthetase (NRPS) gene clusters, related to the biosynthesis of syringomycin, syringopeptin, anikasin, crochelin A, and fragin. Subsequently, we purified and characterized several cyclic lipopeptides (CLPs) produced by NRPS, including some of the already known ones, which have biological activity against several plant and human pathogens. Most notably, mass spectrometric analysis led to the discovery of two yet unknown CLPs, designated medipeptins, consisting of a 22 amino acid peptide moiety with varying degrees of activity against Gram-positive and Gram-negative pathogens. Furthermore, we investigated the mode of action of medipeptin A. The results show that medipeptin A acts as a bactericidal antibiotic against Gram-positive pathogens, but as a bacteriostatic antibiotic against Gram-negative pathogens. Medipeptin A exerts its potent antimicrobial activity against Gram-positive bacteria via binding to both lipoteichoic acid (LTA) and lipid II as well as by forming pores in membranes. Collectively, our study provides important insights into the biosynthesis and mode of action of these novel medipeptins from P. mediterranea EDOX.
Exploring Phenolic Compounds as Quorum Sensing Inhibitors in Foodborne Bacteria
Authors: Santos Catarina Angeli , Lima Emília Maria França , Franco Bernadette Dora Gombossy de Melo , Pinto Uelinton Manoel
Published: September 2021

The emergence of multidrug-resistant bacteria stimulates the search for new substitutes to traditional antimicrobial agents, especially molecules with antivirulence properties, such as those that interfere with quorum sensing (QS). This study aimed to evaluate the potential of phenolic compounds for QS inhibition in a QS biosensor strain (Chromobacterium violaceum) and three foodborne bacterial species (Aeromonas hydrophila, Salmonella enterica serovar Montevideo, and Serratia marcescens). Initially, an in silico molecular docking study was performed to select the compounds with the greatest potential for QS inhibition, using structural variants of the CviR QS regulator of C. violaceum as target. Curcumin, capsaicin, resveratrol, gallic acid, and phloridizin presented good affinity to at least four CviR structural variants. These phenolic compounds were tested for antimicrobial activity, inhibition of biofilm formation, and anti-QS activity. The antimicrobial activity when combined with kanamycin was also assessed. Curcumin, capsaicin, and resveratrol inhibited up to 50% of violacein production by C. violaceum. Biofilm formation was inhibited by resveratrol up to 80% in A. hydrophila, by capsaicin and curcumin up to 40% in S. Montevideo and by resveratrol and capsaicin up to 60% in S. marcescens. Curcumin completely inhibited swarming motility in S. marcescens. Additionally, curcumin and resveratrol increased the sensitivity of the tested bacteria to kanamycin. These results indicate that curcumin and resveratrol at concentrations as low as 6μM are potential quorum sensing inhibitors besides having antimicrobial properties at higher concentrations, encouraging applications in the food and pharmaceutical industries.