bluuebunny/crossref_metadata_2025 huggingface dataset:
Perspective on Dentoalveolar Manifestations Resulting From PHOSPHO1 Loss-of-Function: A Form of Pseudohypophosphatasia?
Authors: Mohamed Fatma F. , Chavez Michael B. , Amadeu de Oliveira Flavia , Narisawa Sonoko , Farquharson Colin , Millán José Luis , Foster Brian L.
Published: February 2022

Mineralization of the skeleton occurs by several physicochemical and biochemical processes and mechanisms that facilitate the deposition of hydroxyapatite (HA) in specific areas of the extracellular matrix (ECM). Two key phosphatases, phosphatase, orphan 1 (PHOSPHO1) and tissue-non-specific alkaline phosphatase (TNAP), play complementary roles in the mineralization process. The actions of PHOSPHO1 on phosphocholine and phosphoethanolamine in matrix vesicles (MVs) produce inorganic phosphate (Pi) for the initiation of HA mineral formation within MVs. TNAP hydrolyzes adenosine triphosphate (ATP) and the mineralization inhibitor, inorganic pyrophosphate (PPi), to generate Pi that is incorporated into MVs. Genetic mutations in the ALPL gene-encoding TNAP lead to hypophosphatasia (HPP), characterized by low circulating TNAP levels (ALP), rickets in children and/or osteomalacia in adults, and a spectrum of dentoalveolar defects, the most prevalent being lack of acellular cementum leading to premature tooth loss. Given that the skeletal manifestations of genetic ablation of the Phospho1 gene in mice resemble many of the manifestations of HPP, we propose that Phospho1 gene mutations may underlie some cases of “pseudo-HPP” where ALP may be normal to subnormal, but ALPL mutation(s) have not been identified. The goal of this perspective article is to compare and contrast the loss-of-function effects of TNAP and PHOSPHO1 on the dentoalveolar complex to predict the likely dental phenotype in humans that may result from PHOSPHO1 mutations. Potential cases of pseudo-HPP associated with PHOSPHO1 mutations may resist diagnosis, and the dental manifestations could be a key criterion for consideration.
Assessment of GRACE/GRACE Follow-On Terrestrial Water Storage Estimates Using an Improved Forward Modeling Method: A Case Study in Africa
Authors: Zhou Hao , Dai Min , Wang Penghui , Wei Min , Tang Lu , Xu Siyou , Luo Zhicai
Published: February 2022

Leakage errors derived from spatial filters are the major limitation for estimating terrestrial water storage via the Gravity Recovery and Climate Experiment (GRACE) mission and the recently launched GRACE Follow-On mission. Here we develop an improved forward modeling method and assess its performance of reducing leakage errors over Africa. In noise-free condition, the forward modeling method shows its outperformance in restoring signals, and the improved forward modeling method can further reduce the leakage errors along the coastline of Africa. In noise-contaminated condition, the simulated environment is set as real as possible to GRACE mission and GRACE Follow-On mission. The results based on the simulated GRACE and GRACE Follow-On solutions demonstrate the capacity of improved forward modeling method in reducing leakage errors. In the case of simulated GRACE data, the average improvements of 24 basins over Africa are respectively 37% for annual amplitudes and 36% for trends. When compared with these simulated GRACE data, the improvements via simulated GRACE Follow-On solutions are minor over large and medium size river basins, but they are significant over small size river basins. In the case of simulated GRACE Follow-On solutions, the average improvements over Africa are 39% for annual amplitudes and 41% for trends. Eventually, the improved forward modeling method is used to process GRACE spherical harmonic datasets from the Center for Space Research (CSR). The results present better agreement with those derived from the newly released mascon solutions from Jet Propulsion Laboratory (JPL) and CSR, when compared with those derived from CSR Tellus grids with scale factors. The better consistency between these model-independent approaches indicates the good performance of our improved forward modeling method and the further necessity of careful evaluation of model-dependent approaches when using different prior hydrological models. Overall, experiments based on noise-free observations, noise-contaminated observations, and GRACE datasets indicate that improved forward modeling method is capable of restoring temporal signals.
Geochemical Characteristics and Genesis of Cambrian Shale Gas in the Southern Margin of Hannan Ancient Uplift
Authors: Guo Tianxu , Chen Xianglin , Ge Mingna , Wang Chao , Bao Shujing , Shi Dishi
Published: February 2022

The geological characteristics of shale and the gas composition and carbon isotopic variation from the shale are very important indicators for the shale gas study. This article analyzed the geological characteristics of Cambrian Niutitang shale and focused on the gas composition and carbon isotopic characteristics of the shale gas from the Cambrian Niutitang Formation. We can see that the total organic carbon content ranges from 0.41 to 4.29%, with an average of 1.65%, which is mainly type I and Ⅱ1. The thermal maturity of sample ranges from 1.98 to 2.53%, with an average of 2.30%, which is in the postmature stage of thermal evolution. The Cambrian Niutitang Formation shale gas in the southern margin of the Hannan ancient uplift is the high-quality hydrocarbon gas methane that takes an absolute majority with a content ranging from 89.60 to 99.19% with an average of 96.46%. The wetness of the gas from the study area ranges from 0.06 to 0.42%, with only 0.25% on an average, which is defined as typical dry gas. The distribution of carbon isotope values has partial “reverse” characteristics that are δ13C1 > δ13C2 and δ13C2 < δ13C3. The natural gas of Niutitang Formation in the study area belongs to thermogenic gas. At the same time, it is found that some data points are beyond the range of thermogenic gas, which is mainly due to the low-humidity and heavy carbon isotope value of methane caused by the high maturity of source rock. In the study area, the Niutitang Formation natural gas carbon isotope values are located in Zone III with the characteristics of mixed reversal gas in the δ13C1-δ13C2 part.
Case Report: Phenotype-Gene Correlation in a Case of Novel Tandem 4q Microduplication With Short Stature, Speech Delay and Microcephaly
Authors: Umlai Umm-Kulthum Ismail , Haris Basma , Hussain Khalid , Jithesh Puthen Veettil
Published: February 2022

We describe a sporadic case of a pure, tandem, interstitial chromosome 4q duplication, arr[hg19] 4q28.1q32.3 (127,008,069-165,250,477) x3 in a boy born at 36 weeks of gestation. He presented with microcephaly (head circumference <1st percentile), short stature (height <2nd percentile) and poor weight gain (weight <3rd percentile). Hypospadias and horseshoe shaped kidneys were also revealed following a urinary tract ultrasound. Biochemical analysis revealed normal growth hormone and thyroid hormone levels. While gross and fine motor skill development was in line with his age, speech delay was observed. This patient adds to a group of more than 30 cases of pure 4q tandem duplication with common and differing phenotypic presentations. Using a retrospective analysis of previous case studies alongside the current case and bioinformatics analysis of the duplicated region, we deduced the most likely dosage sensitive genes for some of the major phenotypes in the patient. The positive predictive value (PPV) was calculated for each gene and phenotype and was derived by comparing the previously reported patients who have gene duplications and an associated phenotype versus those who had the gene duplications but were unaffected. Thus, the growth retardation phenotype may be associated with NAA15 duplication, speech delay with GRIA2 and microcephaly with PLK4 duplication. Functional studies will help in confirming the observations and elucidating the mechanisms. However, our study highlights the importance of analysing case reports with pure duplications in defining phenotype-gene relationships and in improving our knowledge of the function of precise chromosomal regions.
The Evolution of Oxytocin and Vasotocin Receptor Genes in Jawed Vertebrates: A Clear Case for Gene Duplications Through Ancestral Whole-Genome Duplications
Authors: Ocampo Daza Daniel , Bergqvist Christina A. , Larhammar Dan
Published: February 2022

The neuronal and neuroendocrine peptides oxytocin (OT) and vasotocin (VT), including vasopressins, have six cognate receptors encoded by six receptor subtype genes in jawed vertebrates. The peptides elicit a broad range of responses that are specifically mediated by the receptor subtypes including neuronal functions regulating behavior and hormonal actions on reproduction and water/electrolyte balance. Previously, we have demonstrated that these six receptor subtype genes, which we designated VTR1A, VTR1B, OTR, VTR2A, VTR2B and VTR2C, arose from a syntenic ancestral gene pair, one VTR1/OTR ancestor and one VTR2 ancestor, through the early vertebrate whole-genome duplications (WGD) called 1R and 2R. This was supported by both phylogenetic and chromosomal conserved synteny data. More recently, other studies have focused on confounding factors, such as the OTR/VTR orthologs in cyclostomes, to question this scenario for the origin of the OTR/VTR gene family; proposing instead less parsimonious interpretations involving only one WGD followed by complex series of chromosomal or segmental duplications. Here, we have updated the phylogeny of the OTR/VTR gene family, including a larger number of vertebrate species, and revisited seven representative neighboring gene families from our previous conserved synteny analyses, adding chromosomal information from newer high-coverage genome assemblies from species that occupy key phylogenetic positions: the polypteriform fish reedfish (Erpetoichthys calabaricus), the cartilaginous fish thorny skate (Amblyraja radiata) and a more recent high-quality assembly of the Western clawed frog (Xenopus tropicalis) genome. Our analyses once again add strong support for four-fold symmetry, i.e., chromosome quadruplication in the same time window as the WGD events early in vertebrate evolution, prior to the jawed vertebrate radiation. Thus, the evolution of the OTR/VTR gene family can be most parsimoniously explained by two WGD events giving rise to the six ancestral genes, followed by differential gene losses of VTR2 genes in different lineages. We also argue for more coherence and clarity in the nomenclature of OT/VT receptors, based on the most parsimonious scenario.
Proteomic Analysis of the Alterations in Follicular Fluid Proteins During Oocyte Maturation in Humans
Authors: Wang Chong , Fei Xiaoyang , Zhang Hongyan , Zhou Wenjing , Cheng Zhaojun , Feng Ying
Published: February 2022

Many components in ovarian follicles (follicular fluid, cumulus cells, granular cells, etc.) dynamically change during folliculogenesis and play a positive or negative role in oocyte maturation. Infertile women who underwent intracytoplasmic sperm injection (ICSI) treatment in the reproductive medicine centre of Hangzhou Women’s Hospital between October 2018 and October 2021 were included. The ovarian follicular fluid and cumulus cells of diminished ovarian response (DOR) patients and control subjects with medical records of clinical data were collected. In total, 31 differentially expressed proteins, including 10 upregulated proteins (>1.50-fold, P<0.05) and 21 downregulated proteins (<0.67-fold, P<0.05), were identified in mature vs. immature oocytes by iTRAQ labelling coupled with 2D LC-MS/MS. GO analysis revealed that ‘cell population proliferation’ was the most diverse enrichment trend between up/downregulated proteins, while phagosome process and the PI3K-Akt signaling pathway were the two most significant pathways revealed by KEGG enrichment classification. Human prostatic acid phosphatase (PAP, ACPP) and CD5 antigen-like (CD5L) were two proteins verified by ELISA to be differentially expressed between MII and Gv oocytes (P<0.0001 and P<0.0001, respectively). Further measurement found significantly lower level of ACPP in follicular fluids and cumulus cells of DOR patients (P=0.028 and P=0.004, respectively), as an indicator of oocyte quality. Otherwise, CD5L level is upregulated in follicular fluid of DOR patients (P<0.0001). Our study provided experimental data to establish the objective indicator of oocyte maturation in the microenvironment of ovarian follicles, and also provided new insight into the measurement of oocyte quality.
Controlled Lithium Deposition
Authors: Zhang Simeng , Yang Gaojing , Li Xiaoyun , Li Yejing , Wang Zhaoxiang , Chen Liquan
Published: February 2022

Lithium metal is a promising anode material for its low redox potential and high theoretical specific capacity. However, the commercial application of the lithium metal anode is hindered with safety concerns arising from the uncontrolled growth of the lithium dendrites and significant volume variation during the lithium plating and stripping processes. Modification to the current collector is effective in tailoring the morphology of the deposited lithium and improving the cycling performance of the lithium metal batteries This review summarizes at first the global research advances in the structural design and the selection of the current collectors and their textures. It then presents some of our efforts in realizing controlled lithium deposition by designing current collectors in three aspects, lithium deposition induced by the micro-to-nano structures, lithiophilic alloys and iron carbides. Finally, conclusions and prospects are made for the further research of the current collectors.
Evaluation of a Genetics Education Program for Health Interpreters: A Pilot Study
Authors: Vidgen Miranda E. , Fowles Lindsay F. , Istiko Satrio Nindyo , Evans Erin , Cutler Katrina , Sullivan Kate , Bean Jessica , Healy Louise , Hondow Gary , McInerney-Leo Aideen M. , Pratt Gregory , Robins Deborah , Best Stephanie , Finlay Keri , Ramarao-Milne Priya , Waddell Nicola
Published: February 2022

Health Interpreters enable effective communication between health practitioners and patients with limited knowledge of the predominant language. This study developed and evaluated a training session introducing Health Interpreters to genetics. The online training was delivered multiple times as a single 2-h session comprising lectures and activities. Participants completed questionnaires (pre-, post-, and 6-months follow-up) to assess the impact of training on knowledge, attitude, self-efficacy, and self-reported practice behaviour. Questionnaires were analysed using descriptive statistics, Fisher’s Exact, or independent t-test. In total, 118 interpreters participated in the training sessions. Respondent knowledge improved, with gains maintained at 6-months (p < 0.01). There were no changes in self-efficacy, and attitudes. Training did not change self-reported practice behaviour, but there was notable pre-existing variability in participants’ methods of managing unknown genetic words. Most respondents agreed that training was useful (93%) and relevant (79%) to their work. More respondents reported learning more from the case study activity (86%) than the group activity (58%). Health Interpreters found the training acceptable and demonstrated sustained improvement in knowledge of genetic concepts. Increased delivery of this training and associated research is needed to assess findings in a larger cohort and to measure the impact on patients.
Identification of Potential Blind-Side Hypermelanosis-Related lncRNA–miRNA–mRNA Regulatory Network in a Flatfish Species, Chinese Tongue Sole (Cynoglossus semilaevis)
Authors: Li Yangzhen , Hu Yuanri , Cheng Peng , Chen Songlin
Published: February 2022

Blind-side hypermelanosis has emerged as a major concern in commercial rearing environments of the flatfish aquaculture industry. To date, the underlying molecular mechanisms are not well understood. To fill this gap, in this study, whole transcriptomic sequencing and analyses were performed using normal skins and hypermelanic skins of the blind side of Chinese tongue sole (Cynoglossus semilaevis). Differentially expressed long non-coding RNAs (DElncRNAs), miRNAs (DEmiRNAs), and differentially expressed genes as well as their competing endogenous RNA (ceRNA) networks were identified. A total of 34 DElncRNAs, 226 DEmiRNAs, and 610 DEGs were identified. Finally, lncRNA–miRNA–mRNA regulatory networks (involving 29 DElncRNAs, 106 DEmiRNAs, and 162 DEGs) associated with blind-side hypermelanosis were constructed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of 162 DEGs in ceRNA networks identified DEGs (e.g., oca2, mc1r, and ihhb) in pigmentation-related biological processes and DEGs (e.g., ca4, glul, and fut9) in nitrogen metabolism, glycosphingolipid biosynthesis, and folate biosynthesis pathways, as well as their corresponding DElncRNAs and DEmiRNAs to potentially play key regulatory roles in blind-side hypermelanosis. In conclusion, this is the first study on the ceRNA regulatory network associated with blind-side hypermelanosis in flatfish. These new findings expand the spectrum of non-coding regulatory mechanisms underpinning blind-side hypermelanosis, which facilitates the further exploration of molecular regulatory mechanisms of malpigmentation in flatfish.
Genome-Wide SNP Analysis of Hybrid Clariid Fish Reflects the Existence of Polygenic Sex-Determination in the Lineage
Authors: Nguyen Dung Ho My , Ponjarat Jatupong , Laopichienpong Nararat , Panthum Thitipong , Singchat Worapong , Ahmad Syed Farhan , Kraichak Ekaphan , Muangmai Narongrit , Duengkae Prateep , Peyachoknagul Surin , Na-Nakorn Uthairat , Srikulnath Kornsorn
Published: February 2022

The African catfish (Clarias gariepinus) may exhibit the co-existence of XX/XY and ZZ/ZW sex-determination systems (SDSs). However, the SDS of African catfish might be influenced by a polygenic sex-determination (PSD) system, comprising multiple independently segregating sex “switch” loci to determine sex within a species. Here, we aimed to detect the existence of PSD using hybrid. The hybrid produced by crossing male African catfish with female bighead catfish (C. macrocephalus, XX/XY) is a good animal model to study SDSs. Determining the SDS of hybrid catfish can help in understanding the interactions between these two complex SDS systems. Using the genotyping-by-sequencing “DART-seq” approach, we detected seven moderately male-linked loci and seventeen female-linked loci across all the examined hybrid specimens. Most of these loci were not sex-linked in the parental species, suggesting that the hybrid exhibits a combination of different alleles. Annotation of the identified sex-linked loci revealed the presence of one female-linked locus homologous with the B4GALNT1 gene, which is involved in the spermatogenesis pathway and hatchability. However, this locus was not sex-linked in the parental species, and the African catfish might also exhibit PSD.
Identification and Expression Analysis of WRKY Gene Family in Response to Abiotic Stress in Dendrobium catenatum
Authors: Zhang Tingting , Xu Ying , Ding Yadan , Yu Wengang , Wang Jian , Lai Hanggui , Zhou Yang
Published: February 2022

Dendrobium catenatum has become a rare and endangered medicinal plant due to habitat loss in China. As one of the most important and largest transcription factors, WRKY plays a critical role in response to abiotic stresses in plants. However, little is known regarding the functions of the WRKY family in D. catenatum. In this study, a total of 62 WRKY genes were identified from the D. catenatum genome. Phylogenetic analysis revealed that DcWRKY proteins could be divided into three groups, a division supported by the conserved motif compositions and intron/exon structures. DcWRKY gene expression and specific responses under drought, heat, cold and salt stresses were analyzed through RNA-seq data and RT-qPCR assay. The results showed that these genes had tissue-specificity and displayed different expression patterns in response to abiotic stresses. The expression levels of DcWRKY22, DcWRKY36 and DcWRKY45 were up-regulated by drought stress. Meanwhile, DcWRKY22 was highly induced by heat in roots, and DcWRKY45 was significantly induced by cold stress in leaves. Furthermore, DcWRKY27 in roots and DcWRKY58 in leaves were extremely induced under salt treatment. Finally, we found that all the five genes may function in ABA- and SA-dependent manners. This study identified candidate WRKY genes with possible roles in abiotic stress and these findings not only contribute to our understanding of WRKY family genes, but also provide valuable information for stress resistance development in D. catenatum.
Identification and Structure Analysis of KCS Family Genes Suggest Their Reponding to Regulate Fiber Development in Long-Staple Cotton Under Salt-Alkaline Stress
Authors: Rui Cun , Chen Xiugui , Xu Nan , Wang Jing , Zhang Hong , Li Shengmei , Huang Hui , Fan Yapeng , Zhang Yuexin , Lu Xuke , Wang Delong , Gao Wenwei , Ye Wuwei
Published: February 2022

Plant 3-ketoacyl-CoA synthase (KCS) gene family catalyzed a β ketoacyl-CoA synthase, which was the rate-limiting enzyme for the synthesis of very long chain fatty acids (VLCFAs). Gossypium barbadense was well-known not only for high-quality fiber, which was perceived as a cultivated species of Gossypium. In this study, a total of 131 KCS genes were identified in four cotton species, there were 38, 44, 26, 23 KCS genes in the G. barbadense, the G. hirsutum, the G. arboreum and G. raimondii, respectively. The gene structure and expression pattern were analyzed. GBKCS genes were divided into six subgroups, the chromosome distribution of members of the family were mapped. The prediction of cis-acting elements of the GBKCS gene promoters suggested that the GBKCS genes may be involved in hormone signaling, defense and the stress response. Collinearity analysis on the KCS genes of the four cotton species were formulated. Tandem duplication played an indispensable role in the evolution of the KCS gene family. Specific expression analysis of 20 GBKCS genes indicated that GBKCS gene were widely expressed in the first 25 days of fiber development. Among them, GBKCS3, GBKCS8, GBKCS20, GBKCS34 were expressed at a high level in the initial long-term level of the G. barbadense fiber. This study established a foundation to further understanding of the evolution of KCS genes and analyze the function of GBKCS genes.
Toll-Like Receptor-Induced Immune Responses During Early Childhood and Their Associations With Clinical Outcomes Following Acute Illness Among Infants in Sub-Saharan Africa
Authors: Uebelhoer Luke S. , Gwela Agnes , Thiel Bonnie , Nalukwago Sophie , Mukisa John , Lwanga Christopher , Getonto Justine , Nyatichi Emily , Dena Grace , Makazi Alexander , Mwaringa Shalton , Mupere Ezekiel , Berkley James A. , Lancioni Christina L.
Published: February 2022

Severely ill children in low- and middle-income countries (LMICs) experience high rates of mortality from a broad range of infectious diseases, with the risk of infection-related death compounded by co-existing undernutrition. How undernutrition and acute illness impact immune responses in young children in LMICs remains understudied, and it is unclear what aspects of immunity are compromised in this highly vulnerable population. To address this knowledge gap, we profiled longitudinal whole blood cytokine responses to Toll-like receptor (TLR) ligands among severely ill children (n=63; 2-23 months old) with varied nutritional backgrounds, enrolled in the CHAIN Network cohort from Kampala, Uganda, and Kilifi, Kenya, and compared these responses to similar-aged well children in local communities (n=41). Cytokine responses to ligands for TLR-4 and TLR-7/8, as well as Staphylococcus enterotoxin B (SEB), demonstrated transient impairment in T cell function among acutely ill children, whereas innate cytokine responses were exaggerated during both acute illness and following clinical recovery. Nutritional status was associated with the magnitude of cytokine responses in all stimulated conditions. Among children who died following hospital discharge or required hospital re-admission, exaggerated production of interleukin-7 (IL-7) to all stimulation conditions, as well as leukopenia with reduced lymphocyte and monocyte counts, were observed. Overall, our findings demonstrate exaggerated innate immune responses to pathogen-associated molecules among acutely ill young children that persist during recovery. Heightened innate immune responses to TLR ligands may contribute to chronic systemic inflammation and dysregulated responses to subsequent infectious challenges. Further delineating mechanisms of innate immune dysregulation in this population should be prioritized to identify novel interventions that promote immune homeostasis and improve outcomes.
Non-Structural Protein 3 of Duck Tembusu Virus Induces Autophagy via the ERK and PI3K–AKT–mTOR Signaling Pathways
Authors: Zhao Jun , Zhang Tingting , Chen Guomin , Geng Ningwei , Guo Zhiyun , Cao Shengliang , Yang Yudong , Liu Kuihao , Wang Siqi , Zhao Yiran , Meng Fanliang , Liu Sidang , Jiang Meijie , Li Ning
Published: February 2022

Despite autophagy’s pivotal role in the replication of viruses such as duck Tembusu virus (DTMUV), which has caused massive economic losses to the poultry industry in the world, the specific relationships between DTMUV and cellular autophagy remain largely unknown. In response, we investigated the interactions between autophagy and DTMUV, the effects of the structural and non-structural proteins of DTMUV on autophagy, and the autophagy-related signaling pathways induced by DTMUV. Among the results, DTMUV increased the autophagy flux in duck embryo fibroblasts (DEF) and BHK-21 cells, while autophagy facilitated viral replication. After we pharmacologically induced autophagy with rapamycin (RAPA), the replication of DTMUV increased by 15.23-fold compared with the control group of DEF cells. To identify which DTMUV protein primarily induced autophagy, all three structural proteins and seven non-structural proteins of DTMUV were transfected into cells, and the results showed that non-structural protein 3 (NS3) induced significant autophagy in DEF cells. By means of Western blot, immunofluorescence, and transmission electron microscopy, we confirmed that NS3 protein could significantly induce autophagy and autophagy flux. Furthermore, we showed that NS3 induced autophagy in DEF cells through extracellular signal-regulated kinase 2 (ERK2) and phosphatidylinositol-3-kinase (PI3K)/AKT and the mammalian target of rapamycin (mTOR) signaling pathways using specific inhibitors and RNA interference assays. Finally, autophagy induced by NS3 promoted DTMUV replication. These results provide novel insight into the relationship between DTMUV and autophagy, broadening the current understanding of the molecular pathogenesis of DTMUV.
A Spontaneous Model of Experimental Autoimmune Encephalomyelitis Provides Evidence of MOG-Specific B Cell Recruitment and Clonal Expansion
Authors: Salvador Florent , Deramoudt Laure , Leprêtre Frédéric , Figeac Martin , Guerrier Thomas , Boucher Julie , Bas Mathilde , Journiac Nathalie , Peters Anneli , Mars Lennart T. , Zéphir Hélène
Published: February 2022

The key role of B cells in the pathophysiology of multiple sclerosis (MS) is supported by the presence of oligoclonal bands in the cerebrospinal fluid, by the association of meningeal ectopic B cell follicles with demyelination, axonal loss and reduction of astrocytes, as well as by the high efficacy of B lymphocyte depletion in controlling inflammatory parameters of MS. Here, we use a spontaneous model of experimental autoimmune encephalomyelitis (EAE) to study the clonality of the B cell response targeting myelin oligodendrocyte glycoprotein (MOG). In particular, 94% of SJL/j mice expressing an I-As: MOG92-106 specific transgenic T cell receptor (TCR1640) spontaneously develop a chronic paralytic EAE between the age of 60-500 days. The immune response is triggered by the microbiota in the gut-associated lymphoid tissue, while there is evidence that the maturation of the autoimmune demyelinating response might occur in the cervical lymph nodes owing to local brain drainage. Using MOG-protein-tetramers we tracked the autoantigen-specific B cells and localized their enrichment to the cervical lymph nodes and among the brain immune infiltrate. MOG-specific IgG1 antibodies were detected in the serum of diseased TCR1640 mice and proved pathogenic upon adoptive transfer into disease-prone recipients. The ontogeny of the MOG-specific humoral response preceded disease onset coherent with their contribution to EAE initiation. This humoral response was, however, not sufficient for disease induction as MOG-antibodies could be detected at the age of 69 days in a model with an average age of onset of 197 days. To assess the MOG-specific B cell repertoire we FACS-sorted MOG-tetramer binding cells and clonally expand them in vitro to sequence the paratopes of the IgG heavy chain and kappa light chains. Despite the fragility of clonally expanding MOG-tetramer binding effector B cells, our results indicate the selection of a common CDR-3 clonotype among the Igk light chains derived from both disease-free and diseased TCR1640 mice. Our study demonstrates the pre-clinical mobilization of the MOG-specific B cell response within the brain-draining cervical lymph nodes, and reiterates that MOG antibodies are a poor biomarker of disease onset and progression.
Development and Characterization of New Monoclonal Antibodies Against Porcine Interleukin-17A and Interferon-Gamma
Authors: Manirarora Jean N. , Walker Kristen E. , Patil Veerupaxagouda , Renukaradhya Gourapura J. , LaBresh Joanna , Sullivan Yvonne , Francis Ore , Lunney Joan K.
Published: February 2022

Current research efforts require a broad range of immune reagents, but those available for pigs are limited. The goal of this study was to generate priority immune reagents for pigs and pipeline them for marketing. Our efforts were aimed at the expression of soluble swine cytokines and the production of panels of monoclonal antibodies (mAbs) to these proteins. Swine interleukin-17A (IL-17A) and Interferon-gamma (IFNγ) recombinant proteins were produced using yeast expression and used for monoclonal antibody (mAb) production resulting in panels of mAbs. We screened each mAb for cross-species reactivity with orthologs of IL-17A or IFNγ and checked each mAb for inhibition by other related mAbs, to assign mAb antigenic determinants. For porcine IL-17A, the characterization of a panel of 10 mAbs identified eight different antigenic determinants; interestingly, most of the mAbs cross-reacted with the dolphin recombinant ortholog. Likewise, the characterization of a panel of nine anti-PoIFNγ mAbs identified four different determinants; most of the mAbs cross-reacted with dolphin, bovine, and caprine recombinant orthologs. There was a unique reaction of one anti-PoIFNγ mAb that cross-reacted with the zebrafish recombinant ortholog. The αIL-17A mAbs were used to develop a quantitative sandwich ELISA detecting the yeast expressed protein as well as native IL-17A in stimulated peripheral blood mononuclear cell (PBMC) supernatants. Our analyses showed that phorbol myristate acetate/ionomycin stimulation of PBMC induced significant expression of IL-17A by CD3+ T cells as detected by several of our mAbs. These new mAbs expand opportunities for immunology research in swine.
Gnawing Between Cells and Cells in the Immune System: Friend or Foe? A Review of Trogocytosis
Authors: Zhao Siyu , Zhang Lichao , Xiang Suoyu , Hu Yunyi , Wu Zhongdao , Shen Jia
Published: February 2022

Trogocytosis occurs when one cell contacts and quickly nibbles another cell and is characterized by contact between living cells and rapid transfer of membrane fragments with functional integrity. Many immune cells are involved in this process, such as T cells, B cells, NK cells, APCs. The transferred membrane molecules including MHC molecules, costimulatory molecules, receptors, antigens, etc. An increasing number of studies have shown that trogocytosis plays an important role in the immune system and the occurrence of relevant diseases. Thus, whether trogocytosis is a friend or foe of the immune system is puzzling, and the precise mechanism underlying it has not yet been fully elucidated. Here, we provide an integrated view of the acquired findings on the connections between trogocytosis and the immune system.
Protein O-GlcNAcylation Regulates Innate Immune Cell Function
Authors: Dong Hong , Liu Zihao , Wen Haitao
Published: February 2022

Metabolite-mediated protein posttranslational modifications (PTM) represent highly evolutionarily conserved mechanisms by which metabolic networks participate in fine-tuning diverse cellular biological activities. Modification of proteins with the metabolite UDP-N-acetylglucosamine (UDP-GlcNAc), known as protein O-GlcNAcylation, is one well-defined form of PTM that is catalyzed by a single pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Previous studies have discovered critical roles of protein O-GlcNAcylation in many fundamental biological activities via modifying numerous nuclear and cytoplasmic proteins. A common mechanism by which O-GlcNAc affects protein function is through the cross-regulation between protein O-GlcNAcylation and phosphorylation. This is of particular importance to innate immune cell functions due to the essential role of protein phosphorylation in regulating many aspects of innate immune signaling. Indeed, as an integral component of cellular metabolic network, profound alteration in protein O-GlcNAcylation has been documented following the activation of innate immune cells. Accumulating evidence suggests that O-GlcNAcylation of proteins involved in the NF-κB pathway and other inflammation-associated signaling pathways plays an essential role in regulating the functionality of innate immune cells. Here, we summarize recent studies focusing on the role of protein O-GlcNAcylation in regulating the NF-κB pathway, other innate immune signaling responses and its disease relevance.
Robust and Functional Immune Memory Up to 9 Months After SARS-CoV-2 Infection: A Southeast Asian Longitudinal Cohort
Authors: Vo Hoa Thi My , Maestri Alvino , Auerswald Heidi , Sorn Sopheak , Lay Sokchea , Seng Heng , Sann Sotheary , Ya Nisa , Pean Polidy , Dussart Philippe , Schwartz Olivier , Ly Sovann , Bruel Timothée , Ly Sowath , Duong Veasna , Karlsson Erik A. , Cantaert Tineke
Published: February 2022

The duration of humoral and cellular immune memory following SARS-CoV-2 infection in populations in least developed countries remains understudied but is key to overcome the current SARS-CoV-2 pandemic. Sixty-four Cambodian individuals with laboratory-confirmed infection with asymptomatic or mild/moderate clinical presentation were evaluated for Spike (S)-binding and neutralizing antibodies and antibody effector functions during acute phase of infection and at 6-9 months follow-up. Antigen-specific B cells, CD4+ and CD8+ T cells were characterized, and T cells were interrogated for functionality at late convalescence. Anti-S antibody titers decreased over time, but effector functions mediated by S-specific antibodies remained stable. S- and nucleocapsid (N)-specific B cells could be detected in late convalescence in the activated memory B cell compartment and are mostly IgG+. CD4+ and CD8+ T cell immune memory was maintained to S and membrane (M) protein. Asymptomatic infection resulted in decreased antibody-dependent cellular cytotoxicity (ADCC) and frequency of SARS-CoV-2-specific CD4+ T cells at late convalescence. Whereas anti-S antibodies correlated with S-specific B cells, there was no correlation between T cell response and humoral immune memory. Hence, all aspects of a protective immune response are maintained up to nine months after SARS-CoV-2 infection and in the absence of re-infection.
Strategies Towards Antigen-Specific Treatments for Membranous Nephropathy
Authors: Köllner Sarah M. S. , Seifert Larissa , Zahner Gunther , Tomas Nicola M.
Published: February 2022

Membranous nephropathy (MN) is a rare but potentially severe autoimmune disease and a major cause of nephrotic syndrome in adults. Traditional treatments for patients with MN include steroids with alkylating agents such as cyclophosphamide or calcineurin inhibitors such as cyclosporine, which have an undesirable side effect profile. Newer therapies like rituximab, although superior to cyclosporine in maintaining disease remission, do not only affect pathogenic B or plasma cells, but also inhibit the production of protective antibodies and therefore the ability to fend off foreign organisms and to respond to vaccination. These are undesired effects of general B or plasma cell-targeted treatments. The discovery of several autoantigens in patients with MN offers the great opportunity for more specific treatment approaches. Indeed, such treatments were recently developed for other autoimmune diseases and tested in different preclinical models, and some are about to jump to clinical practice. As such treatments have enormous potential to enhance specificity, efficacy and compatibility also for MN, we will discuss two promising strategies in this perspective: The elimination of pathogenic antibodies through endogenous degradation systems and the depletion of pathogenic B cells through chimeric autoantibody receptor T cells.
Innate Lymphoid Cells in the Central Nervous System
Authors: Wang Shuaiwei , van de Pavert Serge A.
Published: February 2022

Immune cells are present within the central nervous system and play important roles in neurological inflammation and disease. As relatively new described immune cell population, Innate Lymphoid Cells are now increasingly recognized within the central nervous system and associated diseases. Innate Lymphoid Cells are generally regarded as tissue resident and early responders, while conversely within the central nervous system at steady-state their presence is limited. This review describes the current understandings on Innate Lymphoid Cells in the central nervous system at steady-state and its borders plus their involvement in major neurological diseases like ischemic stroke, Alzheimer’s disease and Multiple Sclerosis.
New Discovery of Myeloid-Derived Suppressor Cell’s Tale on Viral Infection and COVID-19
Authors: Park Soo-Jeung , Nam Da-eun , Seong Hae Chang , Hahn Young S.
Published: February 2022

Myeloid-derived suppressor cells (MDSCs) are generated under biological stress such as cancer, inflammatory tissue damage, and viral infection. In recent years, with occurrence of global infectious diseases, new discovery on MDSCs functions has been significantly expanded during viral infection and COVID-19. For a successful viral infection, pathogens viruses develop immune evasion strategies to avoid immune recognition. Numerous viruses induce the differentiation and expansion of MDSCs in order to suppress host immune responses including natural killer cells, antigen presenting cells, and T-cells. Moreover, MDSCs play an important role in regulation of immunopathogenesis by balancing viral infection and tissue damage. In this review article, we describe the overview of immunomodulation and genetic regulation of MDSCs during viral infection in the animal model and human studies. In addition, we include up-to-date review of role of MDSCs in SARS-CoV-2 infection and COVID-19. Finally, we discuss potential therapeutics targeting MDSCs.
New Opportunities and Untapped Scientific Potential in the Abyssal Ocean
Authors: Marlow Jeffrey J. , Anderson Rika E. , Reysenbach Anna-Louise , Seewald Jeffrey S. , Shank Timothy M. , Teske Andreas P. , Wanless V. Dorsey , Soule S. Adam
Published: February 2022

The abyssal ocean covers more than half of the Earth’s surface, yet remains understudied and underappreciated. In this Perspectives article, we mark the occasion of the Deep Submergence Vehicle Alvin’s increased depth range (from 4500 to 6500 m) to highlight the scientific potential of the abyssal seafloor. From a geologic perspective, ultra-slow spreading mid-ocean ridges, Petit Spot volcanism, transform faults, and subduction zones put the full life cycle of oceanic crust on display in the abyss, revealing constructive and destructive forces over wide ranges in time and space. Geochemically, the abyssal pressure regime influences the solubility of constituents such as silica and carbonate, and extremely high-temperature fluid-rock reactions in the shallow subsurface lead to distinctive and potentially unique geochemical profiles. Microbial residents range from low-abundance, low-energy communities on the abyssal plains to fast growing thermophiles at hydrothermal vents. Given its spatial extent and position as an intermediate zone between coastal and deep hadal settings, the abyss represents a lynchpin in global-scale processes such as nutrient and energy flux, population structure, and biogeographic diversity. Taken together, the abyssal ocean contributes critical ecosystem services while facing acute and diffuse anthropogenic threats from deep-sea mining, pollution, and climate change.
Metabolic Dysfunctions of Intestinal Fatty Acids and Tryptophan Reveal Immuno-Inflammatory Response Activation in IgA Nephropathy
Authors: Wu Hongwei , Tang Donge , Yun Manhua , Liu Haiping , Huang Shaoxing , Yun Chen , Hocher Berthold , Zhang Xinzhou , Liu Fanna , Yin Lianghong , Dai Yong
Published: February 2022

Background

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis. Although an important link between intestinal metabolites and immune activity is widely established, the metabolic profile of IgAN is still poorly understood, which severely limits the mechanistic studies and therapy of IgAN.

Methods

The diversity of intestinal flora and relative abundance of metabolites in IgAN patients and healthy subjects were measured by 16s ribosomal RNA gene sequencing combined with liquid chromatography tandem-mass spectrometry. The levels of serum Gd-IgA1, IL-6, IL-10, IL-22, and TNF-a were tested by ELISA. We employed the tryptophan-targeted UHPLC-MRM-MS approach to assess the content of tryptophan metabolites quantitatively.

Results

Intestinal fatty acid levels, mainly unsaturated fatty acids, were observed to be dramatically decreased in IgAN patients. Disorders in linoleic acid and arachidonic acid metabolism, metabolic imbalances of anti-/pro- inflammatory fatty acid metabolites, and intestinal AhR signaling deficiency might reflect the damage of the intestinal mucosal barrier in IgAN patients. In addition, we found that high levels of Gd-IgA1, IL-22, and TNF-α were associated with the activity of the tryptophan-kynurenine metabolic pathway, as well as lower levels of 3-indolepropionic acid. 3-indolepropionic acid, kynurenine, and indoleacrylic acid had synergistic effects on regulating immuno-inflammatory responses in IgAN patients.

Conclusions

The metabolic characteristic of fatty acids and tryptophan in the intestinal system is disturbed in IgAN patients, leading to active immune-inflammatory reactions.
Effects of Exercise on Patients Important Outcomes in Older People With Sarcopenia: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials
Authors: Shen Yanjiao , Liu Dan , Li Sheyu , He Yazhou , Tan Fucha , Sun Xuelian , Li Daiping , Xia Xin , Hao Qiukui
Published: February 2022

Background

Many clinical practice guidelines strongly recommend exercise as an intervention for patients with sarcopenia. However, the significance of exercise on patient-important outcomes in older adults with sarcopenia is inconsistent when considering available minimal important differences. To synthesize current systematic review and meta-analyses evidence on the efficacy of exercise on patient-important outcomes in the treatment of sarcopenia in older adults.

Methods

We searched MEDLINE, EMBASE, Cochrane Library (Cochrane database of systematic review, CDSR) via OvidSP and Web of science until April 2021 and reference lists. Two independent investigators performed abstracted and title screening, assessed the full text and quality of evidence. This umbrella review included systematic reviews and meta-analyses of randomized controlled trials (RCTs). Eligible reviews aim to evaluate the effect of exercise on patient-important sarcopenic outcomes (muscle or physical function, mortality, and quality of life) in treating sarcopenia in older people. We used the minimally important differences (MIDs) of these outcomes to assess if the effects of exercise matter to patients.

Results

This umbrella review provided a broad overview of the existing evidence and evaluated the systematic reviews' methodological quality and evidence for all these associations. In older patients with sarcopenia, moderate- to high-quality evidence showed that exercise intervention probably increases walking speed and improved physical performance (measured by TUG test); exercise may increase the muscle strength (grip strength, keen extension strength); but the effect size for grip strength probably too small to achieve patients important changes. Evidence for older people with sarcopenic obesity is limited, and we found the consistent effect of exercise interventions on grip strength and usual walking speed.

Conclusion

Exercise has a positive and important effect on physical performance for older adults with sarcopenia, which supports leaving the current recommendations unchanged. New systematic reviews to summarize the effect of exercise on the quality of life are warranted to fill the current evidence gap.
Prediction of Moderate to Severe Obstructive Sleep Apnea Using Neck Computed Tomography With Computational Fluid Dynamics Study
Authors: Chung Wei-Sheng , Chung Sunny
Published: February 2022

Background

Moderate to severe obstructive sleep apnea (OSA) is associated with cardiovascular disease. Polysomnography is time intensive and difficult to access for diagnosis of OSA. Neck computed tomography (CT) provides upper airway delineation but not diagnostic criteria for moderate to severe OSA. We explored neck CT with computational fluid dynamics (CFD) study for airway pressure and airflow velocity to predict moderate to severe OSA.

Methods

Enrolled from February 1, 2020, to June 30, 2021, patients with OSA with overnight oxygen desaturation (sPO2 <90%) received awake neck CT with a CFD study of their airway pressure and airflow velocity. CTL12 and CTL34 were defined as airflow velocity <3 and ≥3 m/s, respectively, and airway pressure <10 and ≥10 pa, respectively, in the narrowest upper airway.

Results

Sixty-two patients (42 male and 20 female; mean age: 50.4 ± 14.6 years) were included; 12 and 50 patients had mild OSA and moderate to severe OSA, respectively. The minimum sPO2 in the supine position was 80.7 ± 9.1%. The total time of sPO2 <90% at overnight oximetry was 29.3 ± 51.1 min. Most (85.5%) neck CT examinations with CFD study presented CTL34. Patients with CTL34 had a lower minimum sPO2 in the supine position (78.4 vs. 88.1%, P = 0.004) and longer duration of sPO2 <90% at overnight oximetry (33.9 vs. 1.9 min, P = 0.001) than those with CTL12. The values of the area under the receiver operating characteristic curves of airway pressure and of airflow velocity at the narrowest upper airway were 0.788 and 0.733, respectively.

Conclusion

Neck CT with CFD study of airway pressure and airflow velocity may provide a quick prediction of moderate to severe OSA.