bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutational Profile and Potential Molecular Therapeutic Targets of Pheochromocytoma
Authors: Ma Xiaosen , Ling Chao , Zhao Meng , Wang Fen , Cui Yunying , Wen Jin , Ji Zhigang , Zhang Caili , Chen Shi , Tong Anli , Li Yuxiu
Published: July 2022

Purpose

Pheochromocytoma/paraganglioma (PCC/PGL; collectively known as PPGL) can be driven by germline and somatic mutations in susceptibility genes. We aimed to investigate the mutation profile and clinical features of pathogenic genes in highly genetically heterogeneous PPGL and to preliminary explore molecular therapeutic targets in PPGL.

Methods

We established a panel of 260 genes, including susceptibility genes of PPGL and other important tumorigenic genes to sequence 107 PPGL tissues.

Results

Overall, 608 genomic mutations were identified in 107 PPGL tissues. Almost 57% of PPGL tissue samples exhibited pathogenic mutations, and the most frequently mutated gene was SDHB (15/107, 14%). SDHB and HRAS were the most commonly mutated genes in germline-mutated PPGL (25/107, 23%) and nongermline-mutated PPGL (36/107, 34%), respectively. In addition, novel pathogenic mutations were detected in sporadic PPGL. PPGL with mutations in the hypoxia pathway had an earlier onset and higher norepinephrine level than those in the kinase pathway. Receptor tyrosine kinase (RTK; 22%, 24/107), mitogen-activated protein kinase (MAPK; 14%, 15/107), and tyrosine kinase (TK; 2%, 2/107) pathways were the most frequently mutated pathways in PPGL.

Conclusion

Our results provided the genetic mutation profile in PPGL tissues. Genetic mutations in PPGL were mainly concentrated in the RTK, TK, and MAPK pathways, suggesting potential molecular therapeutic targets for PPGL.
The Orexin receptors: Structural and anti-tumoral properties
Authors: Couvineau Alain , Nicole Pascal , Gratio Valérie , Voisin Thierry
Published: July 2022

At the end of the 20th century, two new neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) expressed in hypothalamus as a prepro-orexins precursor, were discovered. These two neuropeptides interacted with two G protein-coupled receptor isoforms named OX1R and OX2R. The orexins/OX receptors system play an important role in the central and peripheral nervous system where it controls wakefulness, addiction, reward seeking, stress, motivation, memory, energy homeostasis, food intake, blood pressure, hormone secretions, reproduction, gut motility and lipolysis. Orexins and their receptors are involved in pathologies including narcolepsy type I, neuro- and chronic inflammation, neurodegenerative diseases, metabolic syndrome, and cancers. Associated with these physiopathological roles, the extensive development of pharmacological molecules including OXR antagonists, has emerged in association with the determination of the structural properties of orexins and their receptors. Moreover, the identification of OX1R expression in digestive cancers encompassing colon, pancreas and liver cancers and its ability to trigger mitochondrial apoptosis in tumoral cells, indicate a new putative therapeutical action of orexins and paradoxically OXR antagonists. The present review focuses on structural and anti-tumoral aspects of orexins and their receptors.
Altered expression of Tim family molecules and an imbalanced ratio of Tim-3 to Tim-1 expression in patients with type 1 diabetes
Authors: Liu Yikai , Chen Zhiying , Xiao Yang , Chen Hongzhi , Zhou Zhiguang
Published: July 2022

Background

T-cell immunoglobulin and mucin domain (Tim) proteins are immunomodulatory molecules that play key roles in the regulation of T-cell activation. Published studies have reported that Tim molecules are involved in the pathogenesis of certain autoimmune diseases. Type 1 diabetes (T1D) is an autoimmune disease in which T cells mediate the destruction of islet β cells. However, the expression of Tim molecules in T1D remains unclear. In this study, we measured the expression of Tim family molecules as well as T-cell subset-specific transcription factors in T1D patients, and we explored the possible involvement of Tim molecules in the pathogenesis of T1D.

Methods

Ninety T1D patients, Thirty-six type 2 diabetes (T2D) patients and forty healthy controls (HCs) were recruited for this study. Peripheral blood mononuclear cells (PBMCs) were isolated, RNA was extracted from the PBMCs and reverse transcribed into cDNA, and gene expression patterns were analysed by RT–qPCR. The expression of Tim molecules in different T-cell subsets was analysed by flow cytometry.

Results

Compared with that in HCs, the mRNA expression of Tim-1 and RORC was increased in T1D patients (P=0.0355 and P=0.0423, respectively), while the expression of Tim-3 was decreased (P=0.0013). In addition, compared with HCs, the ratio of Tim-3 to Tim-1 expression in diabetic patients was decreased (P<0.0001 for T1D and P=0.0387 for T2D). The ratios of T-Bet to GATA3 expression and RORC to FOXP3 expression were higher in T1D patients than in HCs (P=0.0042 and P=0.0066, respectively). Furthermore, the T1D patients with defective islet function had more significant imbalances in the Tim-3/Tim-1 and RORC/FOXP3 ratios (P<0.0001, and P=0.001, respectively). Moreover, Both Tim-3 expression in CD4+ T cells and the Tim-3 to Tim-1 ratio were elevated in T1D in the remission phase compared to T1D.

Conclusion

Our study revealed altered expression of Tim molecules in T1D patients. The imbalanced ratios of Tim-3/Tim-1 expression were more pronounced in T1D patients with defective islet function. However, alterations in Tim molecule expression are mitigated in T1D in the remission phase. All these findings suggest that Tim family molecules may be involved in the pathogenesis of T1D.
Genetic sources and diversity of the paddy field carp in the Pearl River basin inferred from two mitochondrial loci
Authors: Zhong Zaixuan , Fan Jiajia , Su Huanhuan , Li Yaya , Ma Dongmei , Zhu Huaping
Published: July 2022

Paddy field carp (PF-carp) is an economically important fish cocultured with rice in traditional agricultural systems. Several distinctive strains of PF-carp have been formed through years of artificial and cross breeding. There is a concern about the status of germplasm resources among PF-carp, since little is known about the genetic sources, diversity, or differentiation. In this study we collected 17 PF-carp populations covering Daotian carp (DTL), Ru Yuan No. 1 (RY), Jinbian carp (JBL), Shaijiang carp (SJL), and Wu carp (WL) along the Pearl River basin to explore their genetic sources and diversity using concatenated sequences of the mitochondrial cytochrome b gene and the D-Loop region. According to the haplotype network analyses, 1, 9, and 57 haplotypes originated from Cyprinus carpio carpio, Cyprinus carpio haematopterus and Cyprinus carpio rubrofuscus, respectively, confirming that genetic introgression has occurred in Pearl River PF-carp populations and Cyprinus carpio carpio was the most common species for genetic origin. The results showed that RY exhibited the lowest level of nucleotide diversity (π = 0.0011) due to high-intensity breeding and was significantly differentiated from the other four strains. PF-carp strains in these remote traditional systems tended to experience artificial selection and a lack of farmer connection that gradually increased genetic differentiation among strains. Notably, three populations of JBL exhibited significant high-level differentiation, since they originated from mountainous areas hindering farmers from fry exchange. In contrast, no significant differentiation was uncovered in the WL populations, since this strain is the most popular cultured strain and has undergone artificial exchange of parents and fry in many cultured regions. This study helps us to understand the status of germplasm resources among PF-carp and to trace their genetic origin before being introduced for local cultivation.
Insights into phylogenetic divergence of Dalbergia (Leguminosae: Dalbergiae) from Mexico and Central America
Authors: Sotuyo Solange , Pedraza-Ortega Euler , Martínez-Salas Esteban , Linares José , Cabrera Lidia
Published: July 2022

The pantropical genus Dalbergia includes more than 250 species. Phylogenetic studies of the group are scarce and have only included two or three species distributed in Mexico. We obtained herbarium samples of Mexican, Central American, and South American species (sourced from MEXU). In addition, sequences of GenBank accessions were used to complement the study. Using internal transcribed spacer (ITS), the matK and rbcL sequences from 384 accessions comprising species from America, Asia, and Africa were sampled to evaluate phylogenetic relationships of Mexican species and infrageneric classifications based on morphological data. Phylogenetic analyses suggest that the genus Dalbergia is monophyletic and originated in South America. The species distributed in Mexico are not a monophyletic clade but are divided into four clades with affinities to South American and Asian species clades. There is no correlation between geography and large-scale phylogeny. The estimated ages of the Mexican and Central American clades ranged from 11.32 Ma (Dalbergia granadillo clade) to 1.88 Ma (Dalbergia ecastaphyllum clade). Multiple long-distance dispersal events should be used to explain the current genus distribution.
DNAM-1-chimeric receptor-engineered NK cells, combined with Nutlin-3a, more effectively fight neuroblastoma cells in vitro: a proof-of-concept study
Authors: Focaccetti Chiara , Benvenuto Monica , Pighi Chiara , Vitelli Alessandra , Napolitano Federico , Cotugno Nicola , Fruci Doriana , Palma Paolo , Rossi Paolo , Bei Roberto , Cifaldi Loredana
Published: July 2022

Adoptive transfer of engineered NK cells, one of clinical approaches to fight cancer, is gaining great interest in the last decade. However, the development of new strategies is needed to improve clinical efficacy and safety of NK cell-based immunotherapy. NK cell-mediated recognition and lysis of tumor cells are strictly dependent on the expression of ligands for NK cell-activating receptors NKG2D and DNAM-1 on tumor cells. Of note, the PVR/CD155 and Nectin-2/CD112 ligands for DNAM-1 are expressed primarily on solid tumor cells and poorly expressed in normal tissue cells. Here, we generated human NK cells expressing either the full length DNAM-1 receptor or three different DNAM-1-based chimeric receptor that provide the expression of DNAM-1 fused to a costimulatory molecule such as 2B4 and CD3ζ chain. Upon transfection into primary human NK cells isolated from healthy donors, we evaluated the surface expression of DNAM-1 and, as a functional readout, we assessed the extent of degranulation, cytotoxicity and the production of IFNγ and TNFα in response to human leukemic K562 cell line. In addition, we explored the effect of Nutlin-3a, a MDM2-targeting drug able of restoring p53 functions and known to have an immunomodulatory effect, on the degranulation of DNAM-1-engineered NK cells in response to human neuroblastoma (NB) LA-N-5 and SMS-KCNR cell lines. By comparing NK cells transfected with four different plasmid vectors and through blocking experiments, DNAM-1-CD3ζ-engineered NK cells showed the strongest response. Furthermore, both LA-N-5 and SMS-KCNR cells pretreated with Nutlin-3a were significantly more susceptible to DNAM-1-engineered NK cells than NK cells transfected with the empty vector. Our results provide a proof-of-concept suggesting that the combined use of DNAM-1-chimeric receptor-engineered NK cells and Nutlin-3a may represent a novel therapeutic approach for the treatment of solid tumors, such as NB, carrying dysfunctional p53.
Analysis of immunization time, amplitude, and adverse events of seven different vaccines against SARS-CoV-2 across four different countries
Authors: Romero-Ibarguengoitia Maria Elena , González-Cantú Arnulfo , Pozzi Chiara , Levi Riccardo , Mollura Maximiliano , Sarti Riccardo , Sanz-Sánchez Miguel Ángel , Rivera-Salinas Diego , Hernández-Ruíz Yodira Guadalupe , Armendariz-Vázquez Ana Gabriela , Del Rio-Parra Gerardo Francisco , Barco-Flores Irene Antonieta , González-Facio Rosalinda , Azzolini Elena , Barbieri Riccardo , de Azevedo Dias Alessandro Rodrigo , Henriques Guimarães Júnior Milton , Bastos-Borges Alessandra , Acciardi Cecilia , Paez-Bo Graciela , Teixeira Mauro Martins , Rescigno Maria
Published: July 2022

Background

Scarce information exists in relation to the comparison of seroconversion and adverse events following immunization (AEFI) with different SARS-CoV-2 vaccines. Our aim was to correlate the magnitude of the antibody response to vaccination with previous clinical conditions and AEFI.

Methods

A multicentric comparative study where SARS-CoV-2 spike 1-2 IgG antibodies IgG titers were measured at baseline, 21-28 days after the first and second dose (when applicable) of the following vaccines: BNT162b2 mRNA, mRNA-1273, Gam-COVID-Vac, Coronavac, ChAdOx1-S, Ad5-nCoV and Ad26.COV2. Mixed model and Poisson generalized linear models were performed.

Results

We recruited 1867 individuals [52 (SD 16.8) years old, 52% men]. All vaccines enhanced anti-S1 and anti-S2 IgG antibodies over time (p<0.01). The highest increase after the first and second dose was observed in mRNA-1273 (p<0.001). There was an effect of previous SARS-CoV-2 infection; and an interaction of age with previous SARS-CoV-2 infection, Gam-COVID-Vac and ChAdOx1-S (p<0.01). There was a negative correlation of Severe or Systemic AEFI (AEs) of naïve SARS-CoV-2 subjects with age and sex (p<0.001); a positive interaction between the delta of antibodies with Gam-COVID-Vac (p=0.002). Coronavac, Gam-COVID-Vac and ChAdOx1-S had less AEs compared to BNT162b (p<0.01). mRNA-1273 had the highest number of AEFIs. The delta of the antibodies showed an association with AEFIs in previously infected individuals (p<0.001).

Conclusions

The magnitude of seroconversion is predicted by age, vaccine type and SARS-CoV-2 exposure. AEs are correlated with age, sex, and vaccine type. The delta of the antibody response only correlates with AEs in patients previously exposed to SARS-CoV-2.

Registration number

ClinicalTrials.gov, identifier NCT05228912.
MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in rheumatoid arthritis
Authors: Wang Qiubo , Wang Yapeng , Liu Qingyang , Chu Ying , Mi Rui , Jiang Fengying , Zhao Jingjing , Hu Kelong , Luo Ran , Feng Yufeng , Lee Harrison , Zhou Dong , Mi Jingyi , Deng Ruoyu
Published: July 2022

Objective

MALT1 regulates immunity and inflammation in multiple ways, while its role in rheumatoid arthritis (RA) is obscure. This study aimed to investigate the relationship of MALT1 with disease features, treatment outcome, as well as its effect on Th1/2/17 cell differentiation and underlying molecule mechanism in RA.

Methods

Totally 147 RA patients were enrolled. Then their blood Th1, Th2, and Th17 cells were detected by flow cytometry. Besides, PBMC MALT1 expression was detected before treatment (baseline), at week (W) 6, W12, and W24. PBMC MALT1 in 30 osteoarthritis patients and 30 health controls were also detected. Then, blood CD4+ T cells were isolated from RA patients, followed by MALT1 overexpression or knockdown lentivirus transfection and Th1/2/17 polarization assay. In addition, IMD 0354 (NF-κB antagonist) and SP600125 (JNK antagonist) were also added to treat CD4+ T cells.

Results

MALT1 was increased in RA patients compared to osteoarthritis patients and healthy controls. Meanwhile, MALT1 positively related to CRP, ESR, DAS28 score, Th17 cells, negatively linked with Th2 cells, but did not link with other features or Th1 cells in RA patients. Notably, MALT1 decreased longitudinally during treatment, whose decrement correlated with RA treatment outcome (treatment response, low disease activity, or disease remission). In addition, MALT1 overexpression promoted Th17 differentiation, inhibited Th2 differentiation, less affected Th1 differentiation, activated NF-κB and JNK pathways in RA CD4+ T cells; while MALT1 knockdown exhibited the opposite effect. Besides, IMD 0354 and SP600125 addition attenuated MALT1’s effect on Th2 and Th17 differentiation.

Conclusion

MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in RA.
BSL2-compliant lethal mouse model of SARS-CoV-2 and variants of concern to evaluate therapeutics targeting the Spike protein
Authors: Manangeeswaran Mohanraj , Ireland Derek D. C. , Thacker Seth G. , Lee Ha-Na , Kelley-Baker Logan , Lewkowicz Aaron P. , Rothlauf Paul W. , Cornejo Pontelli Marjorie , Bloyet Louis-Marie , Eckhaus Michael A. , Mendoza Mirian I. , Whelan Sean , Verthelyi Daniela
Published: July 2022

Since first reported in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly acquiring mutations, particularly in the spike protein, that can modulate pathogenicity, transmission and antibody evasion leading to successive waves of COVID19 infections despite an unprecedented mass vaccination necessitating continuous adaptation of therapeutics. Small animal models can facilitate understanding host-pathogen interactions, target selection for therapeutic drugs, and vaccine development, but availability and cost of studies in BSL3 facilities hinder progress. To generate a BSL2-compatible in vivo system that specifically recapitulates spike protein mediated disease we used replication competent, GFP tagged, recombinant Vesicular Stomatitis Virus where the VSV glycoprotein was replaced by the SARS-CoV-2 spike protein (rVSV-SARS2-S). We show that infection requires hACE2 and challenge of neonatal but not adult, K18-hACE2 transgenic mice (hACE2tg) leads to productive infection of the lungs and brains. Although disease progression was faster in SARS-CoV-2 infected mice, infection with both viruses resulted in neuronal infection and encephalitis with increased expression of Interferon-stimulated Irf7, Bst2, Ifi294, as well as CxCL10, CCL5, CLC2, and LILRB4, and both models were uniformly lethal. Further, prophylactic treatment targeting the Spike protein (Receptor Binding Domain) with antibodies resulted in similar levels of protection from lethal infection against rVSV-SARS2-S and SARS-CoV-2 viruses. Strikingly, challenge of neonatal hACE2tg mice with SARS-CoV-2 Variants of Concern (SARS-CoV-2-α, -β, ϒ, or Δ) or the corresponding rVSV-SARS2-S viruses (rVSV-SARS2-Spike-α, rVSV-SARS2-Spike-β, rVSV-SARS2-Spike-ϒ or rVSV-SARS2-Spike-Δ) resulted in increased lethality, suggesting that the Spike protein plays a key role in determining the virulence of each variant. Thus, we propose that rVSV-SARS2-S virus can be used to understand the effect of changes to SARS-CoV-2 spike protein on infection and to evaluate existing or experimental therapeutics targeting spike protein of current or future VOC of SARS-CoV-2 under BSL-2 conditions.
Potential roles of non-lymphocytic cells in the pathogenesis of IgG4-related disease
Authors: Cai Shaozhe , Hu Ziwei , Chen Yu , Zhong Jixin , Dong Lingli
Published: July 2022

Studies have confirmed the involvement of a variety of lymphocyte subsets, including type 2 helper T lymphocytes (Th2) and IgG4+ B lymphocytes, in the pathogenesis of IgG4-related disease (IgG4-RD). Those lymphocytes contribute to the major pathogenetic features of IgG4-RD. However, they are not the only cellular components in the immunoinflammatory environment of this mysterious disease entity. Recent studies have suggested that various non-lymphocytic components, including macrophages and fibroblasts, may also play an important role in the pathogenetic process of IgG4-RD in terms of contributing to the chronic and complex progress of the disease. Therefore, the potential role of non-lymphocyte in the pathogenesis of IgG4-RD is worth discussing.
A Cross-Tissue Transcriptome-Wide Association Study Identifies Novel Susceptibility Genes for Juvenile Idiopathic Arthritis in Asia and Europe
Authors: Xu Jiawen , Ma Jun , Zeng Yi , Si Haibo , Wu Yuangang , Zhang Shaoyun , Shen Bin
Published: July 2022

Background

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children, and its pathogenesis is still unclear. Genome-wide association studies (GWASs) of JIA have identified hundreds of risk factors, but few of them implicated specific biological mechanisms.

Methods

A cross-tissue transcriptome-wide association study (TWAS) was performed with the functional summary-based imputation software (FUSION) tool based on GWAS summary datasets (898 JIA patients and 346,102 controls from BioBank Japan (BBJ)/FinnGen). The gene expression reference weights of skeletal muscle and the whole blood were obtained from the Genotype-Tissue Expression (GTExv8) project. JIA-related genes identified by TWAS findings genes were further compared with the differentially expressed genes (DEGs) identified by the mRNA expression profile of JIA from the Gene Expression Omnibus (GEO) database (accession number: GSE1402). Last, candidate genes were analyzed using functional enrichment and annotation analysis by Metascape to examine JIA-related gene sets.

Results

The TWAS identified 535 significant genes with P < 0.05 and contains 350 for Asian and 195 for European (including 10 genes both expressed in Asian and European), such as CDC16 (P = 1.72E-03) and PSMD5-AS1 (P = 3.65E-02). Eight overlapping genes were identified based on TWAS results and DEGs of JIA patients, such as SIRPB1 (PTWAS = 4.21E-03, PDEG = 1.50E-04) and FRAT2 (PTWAS = 2.82E-02, PDEG = 1.43E-02). Pathway enrichment analysis of TWAS identified 183 pathways such as cytokine signaling in the immune system and cell adhesion molecules. By integrating the results of DEGs pathway and process enrichment analyses, 19 terms were identified such as positive regulation of T-cell activation.

Conclusion

By conducting two populations TWAS, we identified a group of JIA-associated genes and pathways, which may provide novel clues to uncover the pathogenesis of JIA.
Progressive Host-Directed Strategies to Potentiate BCG Vaccination Against Tuberculosis
Authors: Negi Kriti , Bhaskar Ashima , Dwivedi Ved Prakash
Published: July 2022

The pursuit to improve the TB control program comprising one approved vaccine,M. bovisBacille Calmette-Guerin (BCG) has directed researchers to explore progressive approaches to halt the eternal TB pandemic.Mycobacterium tuberculosis(M.tb) was first identified as the causative agent of TB in 1882 by Dr. Robert Koch. However, TB has plagued living beings since ancient times and continues to endure as an eternal scourge ravaging even with existing chemoprophylaxis and preventive therapy. We have scientifically come a long way since then, but despite accessibility to the standard antimycobacterial antibiotics and prophylactic vaccine, almost one-fourth of humankind is infected latently withM.tb. Existing therapeutics fail to control TB, due to the upsurge of drug-resistant strains and increasing incidents of co-infections in immune-compromised individuals. Unresponsiveness to established antibiotics leaves patients with no therapeutic possibilities. Hence the search for an efficacious TB immunization strategy is a global health priority. Researchers are paving the course for efficient vaccination strategies with the radically advanced operation of core principles of protective immune responses againstM.tb. In this review; we have reassessed the progression of the TB vaccination program comprising BCG immunization in children and potential stratagems to reinforce BCG-induced protection in adults.
Knowledge mapping and research hotspots of immunotherapy in renal cell carcinoma: A text-mining study from 2002 to 2021
Authors: Liu Kun , Zhao Seling , Li Jian , Zheng Yikun , Wu Haiyang , Kong Jianqiu , Shen Zefeng
Published: July 2022

Background

Renal cell carcinoma (RCC) is one of the most lethal urological malignancies, and because early-stage RCC is asymptomatic, many patients present metastatic diseases at first diagnosis. With the development of immunotherapy, the treatment of RCC has entered a new stage and has made a series of progress. This study mainly outlines the knowledge map and detects the potential research hotspots by using bibliometric analysis.

Methods

Publications concerning RCC immunotherapy from 2002 to 2021 in the Web of Science Core Collection were collected. Visualization and statistical analysis were mainly performed by freeware tools VOSviewer, CiteSpace, R software, and Microsoft Office Excel 2019.

Results

A total of 3,432 papers were collected in this study, and the annual number of papers and citations showed a steady growth trend. The United States is the leading country with the most high-quality publications and is also the country with the most international cooperation. The University of Texas MD Anderson Cancer Center is the most productive organization. The Journal of Clinical Oncology is the highest co-cited journal, and Brian I. Rini is both the most prolific author and the author with the largest centrality. The current research hotspots may be focused on “immune checkpoint inhibitors (ICIs),” “PD-1,” and “mammalian target of rapamycin.”

Conclusion

Immunotherapy has a bright future in the field of RCC treatment, among which ICIs are one of the most important research hotspots. The main future research directions of ICI-based immunotherapy may focus on combination therapy, ICI monotherapy, and the development of new predictive biomarkers.
Chasing the offshore wind farm wind-wake-induced upwelling/downwelling dipole
Authors: Floeter Jens , Pohlmann Thomas , Harmer André , Möllmann Christian
Published: July 2022

The operational principle of offshore wind farms (OWF) is to extract kinetic energy from the atmosphere and convert it into electricity. Consequently, a region of reduced wind speed in the shadow zone of an OWF, the so-called wind-wake, is generated. As there is a horizontal wind speed deficit between the wind-wake and the undisturbed neighboring regions, the locally reduced surface stress results in an adjusted Ekman transport. Subsequently, the creation of a dipole pattern in sea surface elevation induces corresponding anomalies in the vertical water velocities. The dynamics of these OWF wind-wake induced upwelling/downwelling dipoles have been analyzed in earlier model studies, and strong impacts on stratified pelagic ecosystems have been predicted. Here we provide for the first time empirical evidence of the existence of such upwelling/downwelling dipoles. The data were obtained by towing a remotely operated vehicle (TRIAXUS ROTV) through leeward regions of operational OWFs in the summer stratified North Sea. The undulating TRIAXUS transects provided high-resolution CTD data which enabled the characterization of three different phases of the ephemeral life cycle of a wind-wake-induced upwelling/downwelling dipole: development, operation, and erosion. We identified two characteristic hydrographic signatures of OWF-induced dipoles: distinct changes in mixed layer depth and potential energy anomaly over a distance < 5 km and a diagonal excursion of the thermocline of ~10–14 m over a dipole dimension of ~10–12 km. Whether these anthropogenically induced abrupt changes are significantly different from the corridor of natural variability awaits further investigations.
Integration of ATAC-seq and RNA-seq identifies active G-protein coupled receptors functioning in molting process in muscle of Eriocheir sinensis
Authors: Sun Zhanpeng , Li Jingjing , Lv Li , Gou Yifei , Wang Bin , Hao Tong
Published: July 2022

Discontinuous muscle growth during molting is an important feature of Eriocheir sinensis. Molting is a physiological process completed by the cooperation of multiple organs. Signal transmission is critical for the accurate regulation of each step in molting. However, the knowledge of the signal transduction mechanism in the molting process of E. sinensis is presently very limited. In this work, the chromatin accessibility and gene expression of the muscle in E. sinensis in pre-molt (D) and post-molt (A) stages were sequenced by assay of transposase accessible chromatin sequencing (ATAC-seq) and RNA-seq, respectively. The differentially expressed genes (DEGs) in the muscle before and after molting were analyzed by combining ATAC-seq and RNA-seq, especially the G-protein coupled receptor (GPCR) genes in the process of signal transduction. The results showed that there were 616 common DEGs in ATAC-seq and RNA-seq in A vs. D stages, of which 538 were upregulated and 78 were downregulated. In the 19 DEGs included in the signaling transduction process, 13 were located in the GPCR signaling pathway and all were upregulated in A stages, which indicated that GPCRs play a leading role in muscle signal transmission during post-molt stage in molting. In these genes, the structure of the proteins encoded by 10 membrane-located genes with transmembrane activity was further analyzed. Six candidate GPCR genes were finally identified and further verified by real-time quantitative PCR (qRT-PCR). The GPCRs include metabotropic glutamate receptor 7, Mth-like 4, and Mth2 proteins. These results show the existence of GPCRs in the muscle of E. sinensis and, for the first time, found their dominant role in the signal transduction process during molting. It provides important clues for the study of muscle discontinuous growth and molting mechanism of E. sinensis.
Evaluating the effectiveness of three national marine protected areas in the Yangtze River Delta, China
Authors: Zeng Xu , Liang Jun , Zeng Jiangning , Chen Mingyang , Zeng Cong , Mazur Makenzie , Li Shenghui , Zhou Zengjie , Ding Wei , Ding Peng , Cao Ling
Published: July 2022

China’s coastal areas face serious environmental degradation as a consequence of large-scale economic development. To balance environmental sustainability with economic development, China is currently implementing a strategy of ‘eco-civilization’, with marine protected areas (MPAs) expected to be one approach to achieving sustainable marine ecosystems. Since the 1990s, China has established over 270 MPAs, but their effectiveness remains unknown, particularly in the Yangtze River Delta. This study modified pre-existing frameworks to evaluate the effectiveness of three national MPAs in the Yangtze River Delta. The modified framework includes conservation outcomes and their potential drivers. Drivers consist of – attributes species or ecosystems within the MPA, attributes of the MPA, institutional design principles, and participation. Five scenarios were proposed based on score combinations of the four drivers: proactive, well designed, well governed, interactive, and learning. All three MPAs achieved a satisfactory level of outcomes and most of the drivers for all three MPAs achieved a satisfactory level. Two of the MPAs were categorized into the learning scenario, and the third into the well-designed scenario, indicating that there is still room to improve institutional design principles and public participation. We suggest developing cost and benefit indicators to more deeply understand proportionality among stakeholders. In addition, the role of participation should be clarified and promoted. We recommend regular environmental performance monitoring and assessment to identify problems and optimize management.
Stability of a Tidal Marsh Under Very High Flow Velocities and Implications for Nature-Based Flood Defense
Authors: Schoutens Ken , Stoorvogel Marte , van den Berg Mario , van den Hoven Kim , Bouma Tjeerd J. , Aarninkhof Stefan , Herman Peter M. J. , van Loon-Steensma Jantsje M. , Meire Patrick , Schoelynck Jonas , Peeters Patrik , Temmerman Stijn
Published: July 2022

Nature-based strategies, such as wave attenuation by tidal marshes, are increasingly proposed as a complement to mitigate the risks of failure of engineered flood defense structures such as levees. However, recent analysis of historic coastal storms revealed smaller dike breach dimensions if there were natural, high tidal marshes in front of the dikes. Since tidal marshes naturally only experience weak flow velocities (~0-0.3 ms-1 during normal spring tides), we lack direct observations on the stability of tidal marsh sediments and vegetation under extreme flow velocities (order of several ms-1) as may occur when a dike behind a marsh breaches. As a first approximation, the stability of a tidal marsh sediment bed and winter-state vegetation under high flow velocities were tested in a flume. Marsh monoliths were excavated from Phragmites australis marshes in front of a dike along the Scheldt estuary (Dutch-Belgian border area) and installed in a 10 m long flume test section. Both sediment bed and vegetation responses were quantified over 6 experimental runs under high flow velocities up to 1.75 ms-1 and water depth up to 0.35 m for 2 hours. These tests showed that even after a cumulative 12 hours exposure to high flow velocities, erosion was limited to as little as a few millimeters. Manual removal of the aboveground vegetation did not enhance the erosion either. Present findings may be related to the strongly consolidated, clay- and silt-rich sediment and P. australis root system in this experiment. During the flow exposure, the P. australis stems were strongly bent by the water flow, but the majority of all shoots recovered rapidly when the flow had stopped. Although present results may not be blindly extrapolated to all other marsh types, they do provide a strong first indication that marshes can remain stable under high flow conditions, and confirm the potential of well-developed tidal marshes as a valuable extra natural barrier reducing flood discharges towards the hinterland, following a dike breach. These outcomes promote the consideration to implement tidal marshes as part of the overall flood defense and to rethink dike strengthening in the future.
A global atlas of potential thermal refugia for coral reefs generated by internal gravity waves
Authors: Bachman Scott D. , Kleypas Joan A. , Erdmann Mark , Setyawan Edy
Published: July 2022

Coral reefs are highly threatened by ocean warming and the majority are likely to be lost in less than three decades. A first step in maximizing reef conservation through this period is to identify where coral reefs are more likely to survive rising ocean temperatures, such as locations that experience lower temperatures than surrounding regions, high temperature variability, and high food supply. Such conditions are often the result of naturally occurring internal gravity waves (IGWs), oscillatory subsurface disturbances that can entrain cooler and/or nutrient-rich subsurface waters and cause high frequency temperature fluctuations. These features usually remain undetected because they occur subsurface and at spatial scales of O(1 km) and smaller. To shed light on where IGWs are likely to impact temperature conditions within coral reef regions, we present an analysis of data from the LLC4320, a massive high resolution (1/48˚; < 2.5 km) numerical global ocean simulation. The results highlight strong regional differences in the incidence of IGW-induced temperature variability. The analysis also reveals that thermal refugia are limited to depths where high temperature variability coincides with the actual reef depth and may not persist year-round. Assuming 10-m depth as the nominal reef depth, reef regions likely to benefit from IGW-induced cooling occur in SE Asia and the Coral Triangle, the Galápagos, along the Pacific shelf of Central America, and isolated locations worldwide. Such refugia are rare within the Atlantic reef sector. An interactive global atlas showing the results of this study has been made freely available online at https://ncar.github.io/coral-viz/.
Applications of social theories of learning in health professions education programs: A scoping review
Authors: Mukhalalati Banan , Elshami Sara , Eljaam Myriam , Hussain Farhat Naz , Bishawi Abdel Hakim
Published: July 2022

Introduction

In health professions education (HPE), acknowledging and understanding the theories behind the learning process is important in optimizing learning environments, enhancing efficiency, and harmonizing the education system. Hence, it is argued that learning theories should influence educational curricula, interventions planning, implementation, and evaluation in health professions education programs (HPEPs). However, learning theories are not regularly and consistently implemented in educational practices, partly due to a paucity of specific in-context examples to help educators consider the relevance of the theories to their teaching setting. This scoping review attempts to provide an overview of the use of social theories of learning (SToLs) in HPEPs.

Method

A scoping search strategy was designed to identify the relevant articles using two key concepts: SToLs, and HPEPs. Four databases (PubMed, ERIC, ProQuest, and Cochrane) were searched for primary research studies published in English from 2011 to 2020. No study design restrictions were applied. Data analysis involved a descriptive qualitative and quantitative summary according to the SToL identified, context of use, and included discipline.

Results

Nine studies met the inclusion criteria and were included in the analysis. Only two SToLs were identified in this review: Bandura's social learning theory (n = 5) and Lave and Wenger's communities of practice (CoP) theory (n = 4). A total of five studies used SToLs in nursing programs, one in medicine, one in pharmacy, and two used SToLs in multi-disciplinary programs. SToLs were predominantly used in teaching and learning (n = 7), with the remaining focusing on assessment (n = 1) and curriculum design (n = 1).

Conclusions

This review illustrated the successful and effective use of SToLs in different HPEPs, which can be used as a guide for educators and researchers on the application of SToLs in other HPEPs. However, the limited number of HPEPs that apply and report the use of SToLs suggests a potential disconnect between SToLs and educational practices. Therefore, this review supports earlier calls for collaborative reform initiatives to enhance the optimal use of SToLs in HPEPs. Future research should focus on the applicability and usefulness of other theories of learning in HPEPs and on measuring implementation outcomes.

Systematic Review Registration:https://www.researchregistry.com/browse-the-registry#registryofsystematicreviewsmetaanalyses/registryofsystematicreviewsmeta-analysesdetails/60070249970590001bd06f38/, identifier review registry1069.
Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors
Authors: Rosin Diane L. , Hall J. Perry , Zheng Shuqiu , Huang Liping , Campos-Bilderback Silvia , Sandoval Ruben , Bree Andrea , Beaumont Kevin , Miller Emily , Larsen Jennifer , Hariri Ghazal , Kaila Neelu , Encarnacion Iain M. , Gale Jeremy D. , van Elsas Andrea , Molitoris Bruce A. , Okusa Mark D.
Published: July 2022

Adenosine triphosphate (ATP) released from injured or dying cells is a potent pro-inflammatory “danger” signal. Alkaline phosphatase (AP), an endogenous enzyme that de-phosphorylates extracellular ATP, likely plays an anti-inflammatory role in immune responses. We hypothesized that ilofotase alfa, a human recombinant AP, protects kidneys from ischemia-reperfusion injury (IRI), a model of acute kidney injury (AKI), by metabolizing extracellular ATP to adenosine, which is known to activate adenosine receptors. Ilofotase alfa (iv) with or without ZM241,385 (sc), a selective adenosine A2A receptor (A2AR) antagonist, was administered 1 h before bilateral IRI in WT, A2AR KO (Adora2a–/–) or CD73–/– mice. In additional studies recombinant alkaline phosphatase was given after IRI. In an AKI-on-chronic kidney disease (CKD) ischemic rat model, ilofotase alfa was given after the three instances of IRI and rats were followed for 56 days. Ilofotase alfa in a dose dependent manner decreased IRI in WT mice, an effect prevented by ZM241,385 and partially prevented in Adora2a–/– mice. Enzymatically inactive ilofotase alfa was not protective. Ilofotase alfa rescued CD73–/– mice, which lack a 5′-ectonucleotidase that dephosphorylates AMP to adenosine; ZM241,385 inhibited that protection. In both rats and mice ilofotase alfa ameliorated IRI when administered after injury, thus providing relevance for therapeutic dosing of ilofotase alfa following established AKI. In an AKI-on-CKD ischemic rat model, ilofotase alfa given after the third instance of IRI reduced injury. These results suggest that ilofotase alfa promotes production of adenosine from liberated ATP in injured kidney tissue, thereby amplifying endogenous mechanisms that can reverse tissue injury, in part through A2AR-and non-A2AR-dependent signaling pathways.
Cytoplasmic strings between ICM and mTE are a positive predictor of clinical pregnancy and live birth outcomes: A time-lapse study
Authors: Ma Bing-Xin , Yang Liu , Tian Yu , Jin Lei , Huang Bo
Published: July 2022

Background

Elective single blastocyst transfer (eSBT) is considered to reduce the incidence of multiple pregnancy compared to double embryo transfer. Blastocyst selection is the key to achieving pregnancy. In the past, morphological assessment was the main criterion used to select blastocyst. Some important morphological parameters are considered to be clinically valuable, such as cytoplasmic strings traversing from the inner cell mass (ICM) and mural trophectoderm (mTE).

Methods

In this study, 1,267 elective frozen-thawed eSBT cycles cultured in a time-lapse culture system from January 2018 to May 2019 were included. Blastocysts were grouped into “present” and “absent” according to the appearance of cytoplasmic strings between ICM and mTE cells. The “present” group was further categorized according to the quantity of cytoplasmic strings between the ICM and mTE cells.

Results

A time-lapse analysis indicated that cytoplasmic strings between ICM and mTE were more visible among good quality blastocysts. Furthermore, blastocysts with cytoplasmic strings showed higher clinical pregnancy and live birth rates (P = 0.011 and 0.003), while no significant differences were observed in abortion rate and birth weight (P = 0.466 and 0.556).

Conclusions

In conclusion, although the results of previous studies about cytoplasmic strings have been controversial, the present time-lapse analysis provides evidence for the first time that cytoplasmic strings between ICM and mTE cells are a positive predictor of clinical pregnancy and live birth outcomes in elective frozen-thawed single blastocyst transfer cycles.
Comparative proteomic and clinicopathological analysis of breast adenoid cystic carcinoma and basal-like triple-negative breast cancer
Authors: Yao Qian , Hou Wei , Chen Junbing , Bai Yanhua , Long Mengping , Huang Xiaozheng , Zhao Chen , Zhou Lixin , Niu Dongfeng
Published: July 2022

Background

Adenoid cystic carcinoma (ACC) is a rare type of triple-negative breast cancer that has an indolent clinical behavior. Given the substantial overlapping morphological, immunohistochemical, and molecular features with other basal-like triple-negative breast cancer (BL-TNBC), accurate diagnosis of ACC is crucial for effective clinical treatment. The integrative analysis of the proteome and clinicopathological characteristics may help to distinguish these two neoplasms and provide a deep understanding on biological behaviors and potential target therapy of ACC.

Methods

We applied mass spectrometry-based quantitative proteomics to analyze the protein expression in paired tumor and adjacent normal breast tissue of five ACC and five BL-TNBC. Bioinformatic analyses and the clinicopathological characteristics, including histological features, immunohistochemistry, and FISH results, were also collected to get comprehensive information.

Results

A total of 307 differentially expressed proteins (DEPs) were identified between ACC and BL-TNBC. Clustering analysis of DEPs clearly separated ACC from BL-TNBC. GSEA found downregulation of the immune response of ACC compared with BL-TNBC, which is consistent with the negative PD-L1 expression of ACC. Vesicle-mediated transport was also inhibited, while ECM organization was enriched in ACC. The top upregulated proteins in DEPs were ITGB4, VCAN, and DPT. Moreover, in comparison with normal breast tissue, ACC showed elevated ribosome biogenesis and RNA splicing activity.

Conclusion

This study provides evidence that ACC presents a substantially different proteomic profile compared with BL-TNBC and promotes our understanding on the molecular mechanisms and biological processes of ACC, which might be useful for differential diagnosis and anticancer strategy.
Effect of aging on acute pancreatitis through gut microbiota
Authors: Jing Hui , Chang Qimeng , Xu Yayun , Wang Jianfa , Wu Xubo , Huang Jiating , Wang Lishun , Zhang Ziping
Published: July 2022

Background

Compared to younger people, older people have a higher risk and poorer prognosis of acute pancreatitis, but the effect of gut microbiota on acute pancreatitis is still unknown. We aim to investigate the effect of aging gut microbiota on acute pancreatitis and explore the potential mechanism of this phenomenon.

Methods

Eighteen fecal samples from healthy adult participants, including nine older and nine younger adults were collected. C57BL/6 mice were treated with antibiotics for fecal microbiota transplantation from older and younger participants. Acute pancreatitis was induced by cerulein and lipopolysaccharide in these mice. The effect of the aged gut microbiota was further tested via antibiotic treatment before or after acute pancreatitis induction.

Results

The gut microbiota of older and younger adults differed greatly. Aged gut microbiota exacerbated acute pancreatitis during both the early and recovery stages. At the same time, the mRNA expression of multiple antimicrobial peptides in the pancreas and ileum declined in the older group. Antibiotic treatment before acute pancreatitis could remove the effect of aging gut microbiota, but antibiotic treatment after acute pancreatitis could not.

Conclusion

Aging can affect acute pancreatitis through gut microbiota which characterizes the deletion of multiple types of non-dominant species. This change in gut microbiota may potentially regulate antimicrobial peptides in the early and recovery stages. The level of antimicrobial peptides has negative correlations with a more severe phenotype.
White matter integrity in delinquent emerging adults and non-delinquent controls, and its relationship with aggression, psychopathic traits, and cannabis use
Authors: Jansen Jochem M. , Zijlmans Josjan , Popma Arne , Marhe Reshmi
Published: July 2022

Background

Atypical white matter integrity may be one of the biological factors related to delinquency. In adults, decreased white matter integrity has been related to antisocial behavior, but findings from research in adolescent and young adult populations are either mixed or lacking. Here we investigated this association within a naturalistic sample of delinquent young adults (age 18–27).

Methods

In a sample of 95 young adult, delinquent men and 22 age and gender matched controls, we assessed white matter integrity through fractional anisotropy and mean diffusivity measures. We compared white matter integrity between the groups, and within the delinquent group assessed the association between white matter integrity and aggression, psychopathic traits, and cannabis use.

Results

We found no differences in fractional anisotropy or mean diffusivity between delinquent young adults and non-delinquent controls. Additionally, within the group of delinquent young adults, we found no associations between white matter integrity and aggression, psychopathic traits, or cannabis use.

Conclusion

Our null findings suggest that white matter integrity differences may be unrelated to antisocial behavior in emerging adults, and/or that white matter differences between delinquent populations and controls may only arise later in life.