bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Design and Interpretation of Terrestrial Ecosystem Studies Using 15N Tracers: Practical and Statistical Considerations
Authors: Schleppi Patrick , Wessel Wim W.
Published: May 2021

The stable isotope 15N is an extremely useful tool for studying the nitrogen (N) cycle of terrestrial ecosystems. The affordability of isotope-ratio mass spectrometry has increased in the last decades and routine measurements of δ15N with an accuracy better than 1‰ are now easily achieved. Except perhaps for wood, which has a very high C/N ratio, isotope analysis of samples is, thus, no longer the main challenge in measuring the partitioning of 15N used as tracer in ecosystem studies. The central aim of such experiments is to quantitatively determine the fate of N after it enters an ecosystem, mainly as fertilizer, as atmospheric deposition or as plant litter. By measuring how much of this incoming N goes into different ecosystem pools, inferences can be made about the entire N cycle. Sample collection and preparation can be tedious work. Optimizing sampling schemes is thus an important aspect in the application of 15N in ecosystem research and can be helpful for obtaining a high precision of the results with the available manpower and budget. In this contribution, we combine statistical and practical considerations and give recommendations for the design of labeling experiments and also for assessments of natural 15N abundance. In particular, we discuss soil, vegetation and water sampling. We additionally address the most common questions arising during the calculation of tracer partitioning, and we provide some examples of the interpretation of experimental results.
Effects of Typhoon Mangkhut on a Monsoon Evergreen Broad-Leaved Forest Community in Dinghushan Nature Reserve, Lower Subtropical China
Authors: Li Yuelin , Mwangi Brian , Zhou Shun , Liu Shizhong , Zhang Qianmei , Liu Juxiu , Chu Guowei , Tang Xuli , Zhang Deqiang , Wei Shimin , Lie Zhiyang , Wu Ting , Wang Chen , Yang Guangfei , Meng Ze
Published: May 2021

Sensitivity to climate change is one of the key features of the Dinghushan National Nature Reserve that is located in the lower subtropical China. Having faced typhoon Mangkhut in 2018, there emerged a need to study the effects that the typhoon had on the evergreen broad-leaved forest community in Dinghushan. The forest composition data for 2015, 2018, and 2020 was used in this study. The aim was to establish a scientific basis for the restoration of natural forests that have the ability to withstand strong weather phenomena such as typhoons and the hypothesis stated that typhoon Mangkhut had a long-term detrimental effect on the forest community in Dinghushan forest. The results showed that trees that have a DBH of less than 5 cm and a height of less than 2 m were more prone to damage during a severe weather events. In 2015, there was a total of 5,682 trees per hectare while in 2018 there was a total of 5,022 trees per hectare showing a decline in the number of trees per hectare of 660 due to the typhoon. Number of trees in each DBH class, height class, total above ground dry weight and average tree height was also lower in 2018 as compared to 2015 and 2020. The species abundance was also adversely affected with a loss of 672 species per hectare in 2018 compared to 2015. In 2020, about 83% of all trees had a DBH of less than 5 cm and an average height of 3.8 m making up a large proportion of trees that could be damaged if another storm occurred of similar or greater magnitude as the one that hit the region in 2018. Of interest was the forests remarkable ability to bounce back as there is an increase in biomass when 2018 is compared to 2020. The results support the hypothesis of the study. It is therefore of utmost importance that strategies be put in place to protect this ecosystem and others of a similar nature, by employing the use of natural forests that have great resilience against typhoons.
Omics-Based Identification of Shared and Gender Disparity Routes in Hras12V-Induced Hepatocarcinogenesis: An Important Role for Dlk1-Dio3 Genomic Imprinting Region
Authors: Zhang Jing , Li Huiling , Dong Jianyi , Zhang Nan , Liu Yang , Luo Xiaoqin , Chen Jun , Wang Jingyu , Wang Aiguo
Published: May 2021

The phenomenon of gender disparity is very profound in hepatocellular carcinoma (HCC). Although previous research has revealed important roles of microRNA (miRNA) in HCC, there are no studies investigating the role of miRNAs in gender disparity observed hepatocarcinogenesis. In the present study, we investigated the global miRNAomics changes related to Ras-induced male-prevalent hepatocarcinogenesis in a Hras12V-transgenic mouse model (Ras-Tg) by next-generation sequencing (NGS). We identified shared by also unique changes in miRNA expression profiles in gender-dependent hepatocarcinogenesis. Two hundred sixty-four differentially expressed miRNAs (DEMIRs) with q value ≤0.05 and fold change ≥2 were identified. A vertical comparison revealed that the lower numbers of DEMIRs in the hepatic tumor (T) compared with the peri-tumor precancerous tissue (P) of Ras-Tg and normal liver tissue of wild-type C57BL/6J mice (W) in males indicated that males are more susceptible to develop HCC. The expression pattern analysis revealed 43 common HCC-related miRNAs and 4 Ras-positive-related miRNAs between males and females. By integrating the mRNA transcriptomic data and using 3-node FFL analysis, a group of significant components commonly contributing to HCC between sexes were filtered out. A horizontal comparison showed that the majority of DEMIRs are located in the Dlk1-Dio3 genomic imprinting region (GIR) and that they are closely related to not only hepatic tumorigenesis but also to gender disparity in hepatocarcinogenesis. This is achieved by regulating multiple metabolic pathways, including retinol, bile acid, and steroid hormones. In conclusion, the identification of shared and gender-dependent DEMIRs in hepatocarcinogenesis provides valuable insights into the mechanisms that contribute to male-biased Ras-induced hepatic carcinogenesis.
Genome-Wide Analysis of the G2-Like Transcription Factor Genes and Their Expression in Different Senescence Stages of Tobacco (Nicotiana tabacum L.)
Authors: Qin Mingyue , Zhang Binghui , Gu Gang , Yuan Jiazheng , Yang Xuanshong , Yang Jiahan , Xie Xiaofang
Published: May 2021

The Golden2-like (GLK) transcription factors play important roles in regulating chloroplast growth, development, and senescence in plants. In this study, a total of 89 NtGLK genes (NtGLK1–NtGLK89) were identified in the tobacco genome and were classified into 10 subfamilies with variable numbers of exons and similar structural organizations based on the gene structure and protein motif analyses. Twelve segmental duplication pairs of NtGLK genes were identified in the genome. These NtGLK genes contain two conserved helix regions related to the HLH structure, and the sequences of the first helix region are less conserved than that of the second helix motif. Cis-regulatory elements of the NtGLK promoters were widely involved in light responsiveness, hormone treatment, and physiological stress. Moreover, a total of 206 GLK genes from tomato, tobacco, maize, rice, and Arabidopsis were retrieved and clustered into eight subgroups. Our gene expression analysis indicated that NtGLK genes showed differential expression patterns in tobacco leaves at five senescence stages. The expression levels of six NtGLK genes in group C were reduced, coinciding precisely with the increment of the degree of senescence, which might be associated with the function of leaf senescence of tobacco. Our results have revealed valuable information for further functional characterization of the GLK gene family in tobacco.
Comparative Analysis of MicroRNA Expression Profiles Between Skeletal Muscle- and Adipose-Derived Exosomes in Pig
Authors: Li Weite , Wen Shulei , Wu Jiahan , Zeng Bin , Chen Ting , Luo Junyi , Shu Gang , Wang Song-bo , Zhang Yongliang , Xi Qianyun
Published: May 2021

Skeletal muscle and adipose tissues are both involved in regulation of metabolism. In the skeletal muscle-adipose tissue crosstalk, exosomes may play an important role but the main components of exosomes are not clear. In this study, we found skeletal muscle-derived exosomes can inhibit adipogenesis of porcine preadipocytes. We identified microRNA expression profiles of muscle exosomes and adipose exosomes by high-throughput sequencing. There were 104 (both novel and known microRNAs) microRNAs differentially expressed (DE miRNAs) between M-EXO (muscle-derived exosomes) and A-EXO (adipose–derived exosomes) groups. A total of 2,137 target genes of DE miRNAs for M-EXO and 2,004 target genes of DE miRNAs for A-EXO were detected. Bioinformatic analyses revealed that some DE miRNAs of M-EXO (especially miR-221-5p) were mainly enriched in lipid-related metabolism processes. The findings may serve as a fundamental resource for understanding the detailed functions of exosomes between the skeletal muscle-adipose crosstalk and the potential relationship between skeletal muscle atrophy and obesity.
Identification of Genetic Loci and Candidate Genes Related to Grain Zinc and Iron Concentration Using a Zinc-Enriched Wheat ‘Zinc-Shakti’
Authors: Rathan Nagenahalli Dharmegowda , Sehgal Deepmala , Thiyagarajan Karthikeyan , Singh Ravi , Singh Anju-Mahendru , Govindan Velu
Published: May 2021

The development of nutritionally enhanced wheat (Triticum aestivum L.) with higher levels of grain iron (Fe) and zinc (Zn) offers a sustainable solution to micronutrient deficiency among resource-poor wheat consumers. One hundred and ninety recombinant inbred lines (RILs) from ‘Kachu’ × ‘Zinc-Shakti’ cross were phenotyped for grain Fe and Zn concentrations and phenological and agronomically important traits at Ciudad Obregon, Mexico in the 2017–2018, 2018–2019, and 2019–2020 growing seasons and Diversity Arrays Technology (DArT) molecular marker data were used to determine genomic regions controlling grain micronutrients and agronomic traits. We identified seven new pleiotropic quantitative trait loci (QTL) for grain Zn and Fe on chromosomes 1B, 1D, 2B, 6A, and 7D. The stable pleiotropic QTL identified have expanded the diversity of QTL that could be used in breeding for wheat biofortification. Nine RILs with the best combination of pleiotropic QTL for Zn and Fe have been identified to be used in future crossing programs and to be screened in elite yield trials before releasing as biofortified varieties. In silico analysis revealed several candidate genes underlying QTL, including those belonging to the families of the transporters and kinases known to transport small peptides and minerals (thus assisting mineral uptake) and catalyzing phosphorylation processes, respectively.
Extensive Variation in Drought-Induced Gene Expression Changes Between Loblolly Pine Genotypes
Authors: Li Jingjia , West Jason B. , Hart Alexander , Wegrzyn Jill L. , Smith Matthew A. , Domec Jean-Christophe , Loopstra Carol A. , Casola Claudio
Published: May 2021

Drought response is coordinated through expression changes in a large suite of genes. Interspecific variation in this response is common and associated with drought-tolerant and -sensitive genotypes. The extent to which different genetic networks orchestrate the adjustments to water deficit in tolerant and sensitive genotypes has not been fully elucidated, particularly in non-model or woody plants. Differential expression analysis via RNA-seq was evaluated in root tissue exposed to simulated drought conditions in two loblolly pine (Pinus taeda L.) clones with contrasting tolerance to drought. Loblolly pine is the prevalent conifer in southeastern U.S. and a major commercial forestry species worldwide. Significant changes in gene expression levels were found in more than 4,000 transcripts [drought-related transcripts (DRTs)]. Genotype by environment (GxE) interactions were prevalent, suggesting that different cohorts of genes are influenced by drought conditions in the tolerant vs. sensitive genotypes. Functional annotation categories and metabolic pathways associated with DRTs showed higher levels of overlap between clones, with the notable exception of GO categories in upregulated DRTs. Conversely, both differentially expressed transcription factors (TFs) and TF families were largely different between clones. Our results indicate that the response of a drought-tolerant loblolly pine genotype vs. a sensitive genotype to water limitation is remarkably different on a gene-by-gene level, although it involves similar genetic networks. Upregulated transcripts under drought conditions represent the most diverging component between genotypes, which might depend on the activation and repression of substantially different groups of TFs.
Hypoxia-Induced miR-148a Downregulation Contributes to Poor Survival in Colorectal Cancer
Authors: Nersisyan Stepan , Galatenko Alexei , Chekova Milena , Tonevitsky Alexander
Published: May 2021

Hypoxia is an extensively investigated condition due to its contribution to various pathophysiological processes including cancer progression and metastasis formation. MicroRNAs (miRNAs) are well-known post-transcriptional gene expression regulators. However, their contribution to molecular response to hypoxia is highly dependent on cell/tissue types and causes of hypoxia. One of the most important examples is colorectal cancer, where no consensus on hypoxia-regulated miRNAs has been reached so far. In this work, we applied integrated mRNA and small RNA sequencing, followed by bioinformatics analysis, to study the landscape of hypoxia-induced miRNA and mRNA expression alterations in human colorectal cancer cell lines (HT-29 and Caco-2). A hypoxic microenvironment was chemically modeled using two different treatments: cobalt(II) chloride and oxyquinoline. Only one miRNA, hsa-miR-210-3p, was upregulated in all experimental conditions, while there were nine differentially expressed miRNAs under both treatments within the same cell line. Further bioinformatics analysis revealed a complex hypoxia-induced regulatory network: hypoxic downregulation of hsa-miR-148a-3p led to the upregulation of its two target genes, ITGA5 and PRNP, which was shown to be a factor contributing to tumor progression and poor survival in colorectal cancer patients.
Transcriptome Profiling Analysis of the Testis After Eyestalk Ablation for Selection of the Candidate Genes Involved in the Male Sexual Development in Macrobrachium nipponense
Authors: Jin Shubo , Fu Yin , Hu Yuning , Fu Hongtuo , Jiang Sufei , Xiong Yiwei , Qiao Hui , Zhang Wenyi , Gong Yongsheng , Wu Yan
Published: May 2021

The eyestalk of crustacean species secretes many hormones, affecting the process of reproduction, molting, metabolism of glucose, and other functions in crustaceans. In this study, important metabolic pathways and candidate genes involved in the male sexual development were identified through performing the transcriptome profiling analysis of the testis after the ablation of eyestalk from Macrobrachium nipponense. The histological observations revealed that the testis development became vigorous after eyestalk ablation, indicating that the hormones secreted by the eyestalk have negative effects on the testis development in M. nipponense. Transcriptome profiling analysis revealed that 1,039, 1,226, and 3,682 differentially expressed genes (DEGs) were identified between normal prawns (CG) vs single-side eyestalk ablation prawns (SS), SS vs double-side eyestalk ablation prawns (DS), and CG vs DS, respectively, indicating that the ablation of double-side eyestalk has more significant regulatory roles on male sexual development than that of single-side ablation, which was consistent with the histological observations. Lysosome, Apoptosis, Glycolysis/Gluconeogenesis, and Insulin signaling pathway were the main enriched metabolic pathways in all of these three comparisons, and the important genes from these metabolic pathways were also selected. The qPCR verifications of 10 DEGs from these metabolic pathways were the same as those of RNA-seq. The qPCR, in situ hybridization, and RNA interference analysis of Mn-NFkBα revealed that NFkBα has a positive regulatory effect on testis development. This study provided new insights on male sexual development in M. nipponense, promoting the studies on male sexual development in other crustaceans as well.
Herpes Simplex Virus 1 Infection of Neuronal and Non-Neuronal Cells Elicits Specific Innate Immune Responses and Immune Evasion Mechanisms
Authors: Verzosa Amanda L. , McGeever Lea A. , Bhark Shun-Je , Delgado Tracie , Salazar Nicole , Sanchez Erica L.
Published: May 2021

Alphaherpesviruses (α-HV) are a large family of double-stranded DNA viruses which cause many human and animal diseases. There are three human α-HVs: Herpes Simplex Viruses (HSV-1 and HSV-2) and Varicella Zoster Virus (VZV). All α-HV have evolved multiple strategies to suppress or exploit host cell innate immune signaling pathways to aid in their infections. All α-HVs initially infect epithelial cells (primary site of infection), and later spread to infect innervating sensory neurons. As with all herpesviruses, α-HVs have both a lytic (productive) and latent (dormant) stage of infection. During the lytic stage, the virus rapidly replicates in epithelial cells before it is cleared by the immune system. In contrast, latent infection in host neurons is a life-long infection. Upon infection of mucosal epithelial cells, herpesviruses immediately employ a variety of cellular mechanisms to evade host detection during active replication. Next, infectious viral progeny bud from infected cells and fuse to neuronal axonal terminals. Here, the nucleocapsid is transportedviasensory neuron axons to the ganglion cell body, where latency is established until viral reactivation. This review will primarily focus on how HSV-1 induces various innate immune responses, including host cell recognition of viral constituents by pattern-recognition receptors (PRRs), induction of IFN-mediated immune responses involving toll-like receptor (TLR) signaling pathways, and cyclic GMP‐AMP synthase stimulator of interferon genes (cGAS-STING). This review focuses on these pathways along with other mechanisms including autophagy and the complement system. We will summarize and discuss recent evidence which has revealed how HSV-1 is able to manipulate and evade host antiviral innate immune responses both in neuronal (sensory neurons of the trigeminal ganglia) and non-neuronal (epithelial) cells. Understanding the innate immune response mechanisms triggered by HSV-1 infection, and the mechanisms of innate immune evasion, will impact the development of future therapeutic treatments.
Disruption of Tfh:B Cell Interactions Prevents Antibody-Mediated Rejection in a Kidney Transplant Model in Rats: Impact of Calcineurin Inhibitor Dose
Authors: Steines Louisa , Poth Helen , Schuster Antonia , Amann Kerstin , Banas Bernhard , Bergler Tobias
Published: May 2021

We aimed to investigate the mechanisms of humoral immune activation in ABMR using a MHC-mismatched rat kidney transplant model. We applied low dose cyclosporine A (loCNI) to allow donor-specific antibody (DSA) formation and rejection and high dose cyclosporine A (hiCNI) for non-rejection. DSA and leukocyte subsets were measured by flow cytometry. Germinal centers (GC), T follicular helper cells (Tfh), plasma cells and interleukin-21 (IL-21) expression were analyzed by immunofluorescence microscopy. Expression of important costimulatory molecules and cytokines was measured by qRT-PCR. Allograft rejection was evaluated by a nephropathologist. We found that DSA formation correlated with GC frequency and expansion, and that GC size was linked to the number of activated Tfh. In hiCNI, GC and activated Tfh were virtually absent, resulting in fewer plasma cells and no DSA or ABMR. Expression of B cell activating T cell cytokine IL-21 was substantially inhibited in hiCNI, but not in loCNI. In addition, hiCNI showed lower expression of ICOS ligand and IL-6, which stimulate Tfh differentiation and maintenance. Overall, Tfh:B cell crosstalk was controlled only by hiCNI treatment, preventing the development of DSA and ABMR. Additional strategies targeting Tfh:B cell interactions are needed for preventing alloantibody formation and ABMR.
Host-Parasite Interaction of Atlantic salmon (Salmo salar) and the Ectoparasite Neoparamoeba perurans in Amoebic Gill Disease
Authors: Botwright Natasha A. , Mohamed Amin R. , Slinger Joel , Lima Paula C. , Wynne James W.
Published: May 2021

Marine farmed Atlantic salmon (Salmo salar) are susceptible to recurrent amoebic gill disease (AGD) caused by the ectoparasite Neoparamoeba perurans over the growout production cycle. The parasite elicits a highly localized response within the gill epithelium resulting in multifocal mucoid patches at the site of parasite attachment. This host-parasite response drives a complex immune reaction, which remains poorly understood. To generate a model for host-parasite interaction during pathogenesis of AGD in Atlantic salmon the local (gill) and systemic transcriptomic response in the host, and the parasite during AGD pathogenesis was explored. A dual RNA-seq approach together with differential gene expression and system-wide statistical analyses of gene and transcription factor networks was employed. A multi-tissue transcriptomic data set was generated from the gill (including both lesioned and non-lesioned tissue), head kidney and spleen tissues naïve and AGD-affected Atlantic salmon sourced from an in vivo AGD challenge trial. Differential gene expression of the salmon host indicates local and systemic upregulation of defense and immune responses. Two transcription factors, znfOZF-like and znf70-like, and their associated gene networks significantly altered with disease state. The majority of genes in these networks are candidates for mediators of the immune response, cellular proliferation and invasion. These include Aurora kinase B-like, rho guanine nucleotide exchange factor 25-like and protein NDNF-like inhibited. Analysis of the N. perurans transcriptome during AGD pathology compared to in vitro cultured N. perurans trophozoites, as a proxy for wild type trophozoites, identified multiple gene candidates for virulence and indicates a potential master regulatory gene system analogous to the two-component PhoP/Q system. Candidate genes identified are associated with invasion of host tissue, evasion of host defense mechanisms and formation of the mucoid lesion. We generated a novel model for host-parasite interaction during AGD pathogenesis through integration of host and parasite functional profiles. Collectively, this dual transcriptomic study provides novel molecular insights into the pathology of AGD and provides alternative theories for future research in a step towards improved management of AGD.
A Component-Resolved Therapeutic Vaccine for Cockroach Allergy Made of Per a 9 and Transforming Growth Factor-β Homologue, an Immunosuppressive Protein of Brugia malayi
Authors: Prangtaworn Pannathee , Mahasongkram Kodchakorn , Saeung Atiporn , Chaisri Urai , Seesuay Watee , Reamtong Onrapak , Tungtrongchitr Anchalee , Chaicumpa Wanpen , Sookrung Nitat
Published: May 2021

Allergen-specific-immunotherapy (ASIT) can cause long-term resolution of allergic diseases, reduces drug use and chances of new allergen sensitization. Nevertheless, therapeutic vaccine and data on ASIT efficacy for cockroach (CR) allergy are relatively scarce. In this study, efficacy and mechanism of a novel intranasal vaccine consisting of liposome (L)-entrapped mixture of American CR (Periplaneta americana) major allergen (Per a 9) and immunosuppressive protein ofBrugia malayinematode named transforming growth factor-beta homologue (TGH) in treatment of CR allergy were investigated along with two other vaccines (L-Per a 9 alone and L-TGH alone). All three vaccines could reduce pathogenic type 2 response and lung immunopathology in the vaccines-treated CR-allergic mice, but by different mechanisms. L-Per a 9 caused a deviation of the pathogenic type 2 to type 1 response (IFN-γ-upregulation), whereas the L-(TGH + Per a 9) and L-TGH generated regulatory immune responses including up-expression of immunosuppressive cytokine genes and increment of serum adenosine and lung indoleamine-2,3-dioxygenase-1 which are signatures of regulatory T cells (Tregs) and tolerogenic dendritic cells, respectively. The L-(TGH + Per a 9) should be further evaluated towards clinical application, as this vaccine has a propensity to induce broadly effective therapeutic effects for inhalant allergies.
FasL Is Required for Osseous Healing in Extraction Sockets in Mice
Authors: Apaza Alccayhuaman Karol Alí , Heimel Patrick , Lee Jung-Seok , Tangl Stefan , Strauss Franz J. , Stähli Alexandra , Matalová Eva , Gruber Reinhard
Published: May 2021

Fas ligand (FasL) is a member of the tumor necrosis factor (TNF) superfamily involved in the activation of apoptosis. Assuming that apoptosis is initiated after tooth extraction it is reasonable to suggest that FasL may play a pivotal role in the healing of extraction sockets. Herein, we tested the hypothesis of whether the lack of FasL impairs the healing of extraction sockets. To this end, we extracted upper right incisors of FasL knockout (KO) mice and their wildtype (WT) littermates. After a healing period of two weeks, bone volume over total volume (BV/TV)viaµCT and descriptive histological analyses were performed. µCT revealed that BV/TV in the coronal region of the socket amounted to 39.4% in WT and 21.8% in KO, with a significant difference between the groups (p=0.002). Likewise, in the middle region of the socket, BV/TV amounted to 50.3% in WT and 40.8% in KO (p<0.001). In the apical part, however, no difference was noticed. Consistently, WT mice displayed a significantly higher median trabecular thickness and a lower trabecular separation when compared to the KO group at the coronal and central region of the socket. There was the overall tendency that in both, female and male mice, FasL affects bone regeneration. Taken together, these findings suggest that FasL deficiency may reduce bone regeneration during the healing process of extraction sockets.
Glioma-Derived Extracellular Vesicles – Far More Than Local Mediators
Authors: Tankov Stoyan , Walker Paul R.
Published: May 2021

Extracellular vesicle (EV) secretion is a ubiquitous cellular process with both physiologic and pathologic consequences. EVs are small lipid bilayer vesicles that encompass both microvesicles and exosomes and which are secreted by virtually all cells including cancer cells. In this review, we will focus on the roles of EVs in mediating the crosstalk between glioblastoma (GBM) cells and innate and adaptive immune cells and the potential impact on glioma progression. Glioma-derived EVs contain many bioactive cargoes that can broaden and amplify glioma cell mediated immunosuppressive functions and thereby contribute to shaping the tumor microenvironment. We will discuss evidence demonstrating that the low oxygen (hypoxia) in the GBM microenvironment, in addition to cell-intrinsic effects, can affect intercellular communication through EV release, raising the possibility that properties of the tumor core can more widely impact the tumor microenvironment. Recent advances in glioma-derived EV research have shown their importance not only as message carriers, but also as mediators of immune escape, with the capacity to reprogram tumor infiltrating immune cells. Exploring EV function in cancer-immune crosstalk is therefore becoming an important research area, opening up opportunities to develop EV monitoring for mechanistic studies as well as novel diagnostic glioma biomarker applications. However, robust and reproducible EV analysis is not always routinely established, whether in research or in clinical settings. Taking into account the current state of the art in EV studies, we will discuss the challenges and opportunities for extending the many exciting findings in basic research to a better interpretation of glioma and its response to current and future immunotherapies.
Contribution of Gut Microbiota to Immunological Changes in Alzheimer’s Disease
Authors: van Olst Lynn , Roks Sigrid J.M. , Kamermans Alwin , Verhaar Barbara J. H. , van der Geest Anne M. , Muller Majon , van der Flier Wiesje M. , de Vries Helga E.
Published: May 2021

Emerging evidence suggests that both central and peripheral immunological processes play an important role in the pathogenesis of Alzheimer’s disease (AD), but regulatory mechanisms remain unknown. The gut microbiota and its key metabolites are known to affect neuroinflammation by modulating the activity of peripheral and brain-resident immune cells, yet an overview on how the gut microbiota contribute to immunological alterations in AD is lacking. In this review, we discuss current literature on microbiota composition in AD patients and relevant animal models. Next, we highlight how microbiota and their metabolites may contribute to peripheral and central immunological changes in AD. Finally, we offer a future perspective on the translation of these findings into clinical practice by targeting gut microbiota to modulate inflammation in AD. Since we find that gut microbiota alterations in AD can induce peripheral and central immunological changes via the release of microbial metabolites, we propose that modulating their composition may alter ongoing inflammation and could therefore be a promising future strategy to fight progression of AD.
Compositional and Functional Microbiome Variation Between Tubes of an Intertidal Polychaete and Surrounding Marine Sediment
Authors: Fuirst Matthew , Ward Christopher S. , Schwaner Caroline , Diana Zoie , Schultz Thomas F. , Rittschof Daniel
Published: May 2021

The decorator worm Diopatra cuprea, a tube-forming marine polychaete common to intertidal and shallow subtidal waters, modifies habitats it occupies through microreef construction and algal gardening. While several studies have demonstrated that decorator worm tubes are hotspots of biogeochemical activity (i.e., nitrogen and sulfur cycling), it is still largely unclear whether the tube microbiome differs compositionally from the surrounding sediment and what distinct functional processes tube microbiomes may have. To address these unknowns, this study analyzed the bacterial communities of D. cuprea tubes and surrounding sediments using high-throughput 16S rRNA gene amplicon sequencing. Tubes and sediments were sampled at three sites along an anthropogenic stress gradient within the Newport River Estuary to also assess geographic variation of tube microbiomes and the possible influence of human disturbance. We found a clear distinction in the microbial community composition and diversity between tubes and surrounding sediment. Tube microbiomes were significantly enriched for the phyla Bacteriodetes, Actinobacteria, Verrucomicrobia, Deferribacteres, Latescibacteria, and Lentisphaerae. Chloroplast sequences of macroalgae and grass species were consistently abundant in tubes and nearly absent in surrounding sediment. Functional annotation of prokaryotic taxa (FAPROTAX)-based functional predictions suggested that tube microbiomes have higher potentials for aerobic chemoheterotrophy, sulfur compound respiration, nitrate reduction, methylotrophy, and hydrocarbon degradation than surrounding sediments. Tube microbiomes vary across sites, though dissimilarity is comparatively low compared to tube-to-sediment differences. Contrary to our hypothesis, the tubes at the most highly impacted site had the highest microbial diversity [i.e., amplicon sequence variant (ASV) richness and Shannon’s diversity], yet tubes from the medium impacted site actually had the lowest microbial diversity. Our findings show that D. cuprea tubes support a microbiome that is significantly distinct in composition and function from the surrounding sediment. Diopatra cuprea tubes appear to create unique microhabitats that facilitate numerous microbially-mediated biogeochemical processes in the marine benthic environment.
Spatial and Structural Factors Shape Seagrass-Associated Bacterial Communities in Singapore and Peninsular Malaysia
Authors: Rabbani Golam , Yan Bertrand Chengxiang , Lee Nicole Li Ying , Ooi Jillian Lean Sim , Lee Jen Nie , Huang Danwei , Wainwright Benjamin J.
Published: May 2021

Plant-microbe relationships play critical roles in the functioning and health of terrestrial plants, but little is known about this relationship in marine angiosperms such as seagrasses. Here, we investigated the microbial communities associated with the seagrass Enhalus acoroides throughout Singapore and Peninsular Malaysia. At each sampling location we collected 10 individual and unconnected plants. Each plant was subsequently broken down into leaves, roots, and rhizomes. In addition to living plant parts a sediment sample was taken in close proximity to each. Using high throughput 16S rRNA gene amplicon sequencing we characterised the bacterial communities associated with each plant part and the associated sediment sample. Results indicate geographic structuring of bacterial communities, with a significant pattern of distance decay suggesting dispersal limitation is a contributing factor to the differences we see in bacterial community structure. Bacterial communities can be further differentiated by the function of the collected sample (leaf, root, and rhizome), and we identified a number of microbial indicator species that are associated with each plant part. Further analysis revealed the presence of several microbial taxa that have previously been identified as indicators of “unhealthy” or “stressed” seagrass meadows. This study addresses a current scientific gap related to the characterisation of seagrass microbiomes, and provides a foundation on which future studies can build, particularly those in the Southeast Asian seagrass biodiversity hotspot.
Marine Genetic Resources in Areas Beyond National Jurisdiction: Promoting Marine Scientific Research and Enabling Equitable Benefit Sharing
Authors: Rogers Alex D. , Baco Amy , Escobar-Briones Elva , Currie Duncan , Gjerde Kristina , Gobin Judith , Jaspars Marcel , Levin Lisa , Linse Katrin , Rabone Muriel , Ramirez-Llodra Eva , Sellanes Javier , Shank Timothy M. , Sink Kerry , Snelgrove Paul V. R. , Taylor Michelle L. , Wagner Daniel , Harden-Davies Harriet
Published: May 2021

Growing human activity in areas beyond national jurisdiction (ABNJ) is driving increasing impacts on the biodiversity of this vast area of the ocean. As a result, the United Nations General Assembly committed to convening a series of intergovernmental conferences (IGCs) to develop an international legally-binding instrument (ILBI) for the conservation and sustainable use of marine biological diversity of ABNJ [the biodiversity beyond national jurisdiction (BBNJ) agreement] under the United Nations Convention on the Law of the Sea. The BBNJ agreement includes consideration of marine genetic resources (MGR) in ABNJ, including how to share benefits and promote marine scientific research whilst building capacity of developing states in science and technology. Three IGCs have been completed to date with the fourth delayed by the Covid pandemic. This delay has allowed a series of informal dialogues to take place between state parties, which have highlighted a number of areas related to MGR and benefit sharing that require technical guidance from ocean experts. These include: guiding principles on the access and use of MGR from ABNJ; the sharing of knowledge arising from research on MGR in ABNJ; and capacity building and technology transfer for developing states. In this paper, we explain what MGR are, the methods required to collect, study and archive them, including data arising from scientific investigation. We also explore the practical requirements of access by developing countries to scientific cruises, including the sharing of data, as well as participation in research and development on shore whilst promoting rather than hindering marine scientific research. We outline existing infrastructure and shared resources that facilitate access, research, development, and benefit sharing of MGR from ABNJ; and discuss existing gaps. We examine international capacity development and technology transfer schemes that might facilitate or complement non-monetary benefit sharing activities. We end the paper by highlighting what the ILBI can achieve in terms of access, utilization, and benefit sharing of MGR and how we might future-proof the BBNJ Agreement with respect to developments in science and technology.
Risk Stratification Score to Predict Readmission of Patients With Acute Decompensated Cirrhosis Within 90 Days
Authors: Xu Xiaomei , Tan Juntao , Wang Haolin , Zhao Wenlong , Qin Bo
Published: May 2021

Background and Aims: Patients with acute decompensated (AD) cirrhosis are frequently readmitted to the hospital. An accurate predictive model for identifying high-risk patients may facilitate the development of effective interventions to reduce readmission rates.

Methods: This cohort study of patients with AD cirrhosis was conducted at six tertiary hospitals in China between September 2012 and December 2016 (with 705 patients in the derivation cohort) and between January 2017 and April 2020 (with 251 patients in the temporal validation cohort). Least absolute shrinkage and selection operator Cox regression was used to identify the prognostic factors and construct a nomogram. The discriminative ability, calibration, and clinical net benefit were evaluated based on the C-index, area under the curve, calibration curve, and decision curve analysis. Kaplan–Meier curves were constructed for stratified risk groups, and log-rank tests were used to determine significant differences between the curves.

Results: Among 956 patients, readmission rates were 24.58, 42.99, and 51.78%, at 30, 60, and 90 days, respectively. Bacterial infection was the main reason for index hospitalization and readmission. Independent factors in the nomogram included gastrointestinal bleeding [hazard rate (HR): 2.787; 95% confidence interval (CI): 2.221–3.499], serum sodium (HR: 0.955; 95% CI: 0.933–0.978), total bilirubin (HR: 1.004; 95% CI: 1.003–1.005), and international normalized ratio (HR: 1.398; 95% CI: 1.126–1.734). For the convenience of clinicians, we provided a web-based calculator tool (https://cqykdx1111.shinyapps.io/dynnomapp/). The nomogram exhibited good discrimination ability, both in the derivation and validation cohorts. The predicted and observed readmission probabilities were calibrated with reliable agreement. The nomogram demonstrated superior net benefits over other score models. The high-risk group (nomogram score >56.8) was significantly likely to have higher rates of readmission than the low-risk group (nomogram score ≤ 56.8; p < 0.0001).

Conclusions: The nomogram is useful for assessing the probability of short-term readmission in patients with AD cirrhosis and to guide clinicians to develop individualized treatments based on risk stratification.
Dental Education in the Time of COVID-19 Pandemic: Challenges and Recommendations
Authors: Hassan Mohamed G. , Amer Hala
Published: May 2021

Moving within the second wave of the coronavirus (COVID-19) pandemic, dental education delivery has been profoundly affected by this crisis, so has the structure, evaluation, and future of dental education. Both pre-clinical and clinical dental education have experienced challenges ranging from fully online educational content to limited dental training for senior dental students. This crisis appears to be a tipping point that produced confusion in dental teaching especially clinical sciences. Although medical institutions immediately started to adapt to the unexpected COVID-19 crisis, dental and oral health educational services are profoundly impaired due to the dental team's propinquity to the patient and the aerosols generated during routine dental therapeutic procedures. Dental students unlike other medical students are considered to be at the highest risk due to the nature of their clinical training that includes working in the oral cavity of patients using aerosol-generating equipment. Some dental schools have taken the leadership and documented their modifications during this pandemic; however, there is a serious need for further investigation and wide range screening of the situation in the dental schools during the COVID-19 crisis. The aim of this mini-review is to present these challenges and how academic dental institutions have implemented strategies to overcome them.
The Application of Mesenchymal Stem Cells in the Treatment of Liver Diseases: Mechanism, Efficacy, and Safety Issues
Authors: Yang Ya , Zhao Yalei , Zhang Lingjian , Zhang Fen , Li Lanjuan
Published: May 2021

Mesenchymal stem cell (MSC) transplantation is a novel treatment for liver diseases due to the roles of MSCs in regeneration, fibrosis inhibition and immune regulation. However, the mechanisms are still not completely understood. Despite the significant efficacy of MSC therapy in animal models and preliminary clinical trials, issues remain. The efficacy and safety of MSC-based therapy in the treatment of liver diseases remains a challenging issue that requires more investigation. This article reviews recent studies on the mechanisms of MSCs in liver diseases and the associated challenges and suggests potential future applications.
Evaluation of Consistency of Treatment Response Across Regions—the LEADER Trial in Relation to the ICH E17 Guideline
Authors: Nielsen Henrik K. , DeChiaro Stephanie , Goldman Bryan
Published: May 2021

The US Food and Drug Administration in 2008 required new type 2 diabetes (T2D) medications to be subject to cardiovascular outcomes safety requirements. Accordingly, the global LEADER trial investigated cardiovascular outcomes of T2D treatment with liraglutide, a glucagon-like peptide-1 receptor agonist. LEADER (NCT01179048) was a multiregional clinical trial (MRCT) conducted from 2010 to 2016, thus completed before publication of the International Council for Harmonization (ICH) E17 guideline on MRCTs in 2017. Novo Nordisk pre-specified analysis of regional cardiovascular outcomes of LEADER participants. This paper assesses the pre-specified regional outcomes based on the ICH E17 guidelines on consistency evaluation. Regional LEADER participant numbers were broadly aligned with ICH E17 guidance and equally balanced across Europe, Asia, North America, and rest of the world. Overall primary major adverse cardiovascular events (MACE) composite outcome for the trial: hazard ratio (HR) (95% CI) 0.87 (0.78; 0.97); regional results varied, ranging from HR (95% CI) 0.62 (0.37; 1.04) (Asia) to 1.01 (0.84; 1.22) (North America). However, pre-specified Cox proportional-hazard regression analyses did not show clear evidence of interaction between regions and primary outcome (p = 0.20). Furthermore, post hoc analysis of the US population in the North American region found that adjusting for extrinsic or intrinsic factors did not account for this difference [HR (95% CI) 1.03 (0.84; 1.25)]. LEADER data evaluation demonstrated general consistency in cardiovascular safety across regions, except for US participants. Discrepancies in the North American region may relate to drug exposure or chance, but, as these were post hoc findings, the overall primary result is valid, aligned with ICH E17 guidelines.
Early Changes and Indicators Characterizing Lung Aging in Neonatal Chronic Lung Disease
Authors: Sucre Jennifer , Haist Lena , Bolton Charlotte E. , Hilgendorff Anne
Published: May 2021

Infants suffering from neonatal chronic lung disease, i.e., bronchopulmonary dysplasia, are facing long-term consequences determined by individual genetic background, presence of infections, and postnatal treatment strategies such as mechanical ventilation and oxygen toxicity. The adverse effects provoked by these measures include inflammatory processes, oxidative stress, altered growth factor signaling, and remodeling of the extracellular matrix. Both, acute and long-term consequences are determined by the capacity of the immature lung to respond to the challenges outlined above. The subsequent impairment of lung growth translates into an altered trajectory of lung function later in life. Here, knowledge about second and third hit events provoked through environmental insults are of specific importance when advocating lifestyle recommendations to this patient population. A profound exchange between the different health care professionals involved is urgently needed and needs to consider disease origin while future monitoring and treatment strategies are developed.
Core Values of Family Physicians and General Practitioners in the African Context
Authors: Lawson Henry J. O. , Nortey David N. N.
Published: May 2021

Introduction: Family Medicine is a growing specialty in the medical world. While it is expected that the specialty should have its own unique and established core values and tasks, the breath of the practice in several countries of the world has made this a daunting task. Core values and Tasks have far reaching effects on professions. They guide development of curricula, methods of instruction, standards of performance and even the culture of the profession. We aimed to explore the core value system of Family Physicians and General Practitioners practicing in Africa.

Methods: Using the Delphi technique, a purposive selection of African Family Medicine practitioners in academia, public service, private practice and clinical training across Central, East, North, South and West Africa was conducted. Participants were asked to select five core values from an alphabetically collated global list of 29 core values in an online survey. The five most selected core values were collated and sent out in the second round to the participants to rank in order of importance.

Results: Practitioners from nine African countries in three out of the five United Nations subregions of Africa completed the study. The first round of the study saw participation of a team of nineteen experts who selected the following five core values—Comprehensive care, Continuity of Care, Collaborative Care, Patient centered care, and Life-long learning.

Discussion/Conclusion: The core values selected were not very different from global literature. These core values should guide the development of curricula, standardization of training methods and creation of benchmarks for standards of practice for the specialty in Africa.