bluuebunny/crossref_metadata_2025 huggingface dataset:
Population Genetic Analysis and Sub-Structuring of Theileria annulata in Sudan
Authors: Salih Diaeldin A. , Ali Awadia M. , Njahira Moses , Taha Khalid M. , Mohammed Mohammed S. , Mwacharo Joram M. , Mbole-Kariuki Ndila , El Hussein Abdelrhim M. , Bishop Richard , Skilton Robert
Published: November 2021

Theileria annulata, which causes tropical theileriosis, is a major impediment to improving cattle production in Sudan. Tropical theileriosis disease is prevalent in the north and central regions of Sudan. Outbreaks of the disease have been observed outside the known endemic areas, in east and west regions of the country, due to changes in tick vector distribution and animal movement. A live schizont attenuated vaccination based on tissue culture technology has been developed to control the disease. The parasite in the field as well as the vaccine strain need to be genotyped before the vaccinations are practiced, in order to be able to monitor any breakthrough or breakdown, if any, after the deployment of the vaccine in the field. Nine microsatellite markers were used to genotype 246 field samples positive forT. annulataDNA and the vaccine strain. North and central populations have a higher multiplicity of infection than east and west populations. The examination of principal components showed two sub-structures with a mix of all four populations in both clusters and the vaccine strain used being aligned with left-lower cluster. Only the north population was in linkage equilibrium, while the other populations were in linkage disequilibrium, and linkage equilibrium was found when all samples were regarded as single population. The genetic identity of the vaccine and field samples was 0.62 with the north population and 0.39 with west population. Overall, genetic investigations of fourT. annulatapopulations in Sudan revealed substantial intermixing, with only two groups exhibiting regional origin independence. In the four geographically distant regions analyzed, there was a high level of genetic variation within each population. The findings show that the live schizont attenuated vaccine, Atbara strain may be acceptable for use in all Sudanese regions where tropical theileriosis occurs.
Novel LAT Pathogenic Variants in a POI Family and Its Role in the Ovary
Authors: Chu Kun , He Yi , Li Ziyuan , Jiang Zhongxin , Wang Liang , Ji Yixuan , Wang Xiang , Pang Wenjuan , Sun Ningxia , Yang Fu , Li Wen
Published: November 2021

Premature ovarian insufficiency (POI) affects about 1% of women under 40 years and leads most often to definitive infertility with adverse health outcomes. Genetic factor has been reported to play an important role in POI. However, the genetic etiology remains unknown in the majority of the POI patients. Whole-exome sequencing and variant analysis were carried out in a POI pedigree. In vitro studies of the wild-type and mutant proteins were conducted in primary granulosa cells (GCs) and granulosa cell line. The result showed that the patients carried compound heterozygous nonsynonymous mutations (c.245C > T and c.181C > G) in LAT gene, which were identified to be transmitted from their parents. The two variants were assessed to affect residues that were conserved across different species examined, and were predicted to be deleterious by software predictions. Protein structure predicting result indicated that the two variants could alter their interactions with surrounding residues, which may change the internal structure of the LAT protein. Moreover, LAT protein expression in GCs was demonstrated for the first time, and further functional assays suggested that this mutation could reduce LAT expression and influence GC survival, which may contribute to the etiology of POI. In summary, we detect novel LAT pathogenic variants in a POI pedigree and report for the first time that LAT is present and functional in the GCs of the ovary. Our findings not only shed new light on the role of LAT in GCs, but also broaden the spectrum of genetic causes of POI.
Transcriptome Analysis Reveals Higher Levels of Mobile Element-Associated Abnormal Gene Transcripts in Temporal Lobe Epilepsy Patients
Authors: Hu Kai , Liang Ping
Published: November 2021

Mesial temporal lobe epilepsy (MTLE) is the most common form of epilepsy, and temporal lobe epilepsy patients with hippocampal sclerosis (TLE-HS) show worse drug treatment effects and prognosis. TLE has been shown to have a genetic component, but its genetic research has been mostly limited to coding sequences of genes with known association to epilepsy. Representing a major component of the genome, mobile elements (MEs) are believed to contribute to the genetic etiology of epilepsy despite limited research. We analyzed publicly available human RNA-seq-based transcriptome data to determine the role of mobile elements in epilepsy by performing de novo transcriptome assembly, followed by identification of spliced gene transcripts containing mobile element (ME) sequences (ME-transcripts), to compare their frequency across different sample groups. Significantly higher levels of ME-transcripts in hippocampal tissues of epileptic patients, particularly in TLE-HS, were observed. Among ME classes, short interspersed nuclear elements (SINEs) were shown to be the most frequent contributor to ME-transcripts, followed by long interspersed nuclear elements (LINEs) and DNA transposons. These ME sequences almost in all cases represent older MEs normally located in the intron sequences. For protein coding genes, ME sequences were mostly found in the 3′-UTR regions, with a significant portion also in the coding sequences (CDSs), leading to reading frame disruption. Genes associated with ME-transcripts showed enrichment for the mRNA splicing process and an apparent bias in epileptic transcriptomes toward neural- and epilepsy-associated genes. The findings of this study suggest that abnormal splicing involving MEs, leading to loss of functions in critical genes, plays a role in epilepsy, particularly in TLE-HS, thus providing a novel insight into the molecular mechanisms underlying epileptogenesis.
Discovery and Validation of a Recessively Inherited Major-Effect QTL Conferring Resistance to Maize Lethal Necrosis (MLN) Disease
Authors: Murithi Ann , Olsen Michael S. , Kwemoi Daniel B. , Veronica Ogugo , Ertiro Berhanu Tadesse , L. M. Suresh , Beyene Yoseph , Das Biswanath , Prasanna Boddupalli M. , Gowda Manje
Published: November 2021

Maize lethal necrosis (MLN) is a viral disease with a devastating effect on maize production. Developing and deploying improved varieties with resistance to the disease is important to effectively control MLN; however, little is known about the causal genes and molecular mechanism(s) underlying MLN resistance. Screening thousands of maize inbred lines revealed KS23-5 and KS23-6 as two of the most promising donors of MLN resistance alleles. KS23-5 and KS23-6 lines were earlier developed at the University of Hawaii, United States, on the basis of a source population constituted using germplasm from Kasetsart University, Thailand. Both linkage mapping and association mapping approaches were used to discover and validate genomic regions associated with MLN resistance. Selective genotyping of resistant and susceptible individuals within large F2 populations coupled with genome-wide association study identified a major-effect QTL (qMLN06_157) on chromosome 6 for MLN disease severity score and area under the disease progress curve values in all three F2 populations involving one of the KS23 lines as a parent. The major-effect QTL (qMLN06_157) is recessively inherited and explained 55%–70% of the phenotypic variation with an approximately 6 Mb confidence interval. Linkage mapping in three F3 populations and three F2 populations involving KS23-5 or KS23-6 as one of the parents confirmed the presence of this major-effect QTL on chromosome 6, demonstrating the efficacy of the KS23 allele at qMLN06.157 in varying populations. This QTL could not be identified in population that was not derived using KS23 lines. Validation of this QTL in six F2 populations with 20 SNPs closely linked with qMLN06.157 was further confirmed its consistent expression across populations and its recessive nature of inheritance. On the basis of the consistent and effective resistance afforded by the KS23 allele at qMLN06.157, the QTL can be used in both marker-assisted forward breeding and marker-assisted backcrossing schemes to improve MLN resistance of breeding populations and key lines for eastern Africa.
Data-Driven Analysis of COVID-19 Reveals Persistent Immune Abnormalities in Convalescent Severe Individuals
Authors: Lim Jackwee , Puan Kia Joo , Wang Liang Wei , Teng Karen Wei Weng , Loh Chiew Yee , Tan Kim Peng , Carissimo Guillaume , Chan Yi-Hao , Poh Chek Meng , Lee Cheryl Yi-Pin , Fong Siew-Wai , Yeo Nicholas Kim-Wah , Chee Rhonda Sin-Ling , Amrun Siti Naqiah , Chang Zi Wei , Tay Matthew Zirui , Torres-Ruesta Anthony , Leo Fernandez Norman , How Wilson , Andiappan Anand Kumar , Lee Wendy , Duan Kaibo , Tan Seow-Yen , Yan Gabriel , Kalimuddin Shirin , Lye David Chien , Leo Yee-Sin , Ong Sean W. X. , Young Barnaby E. , Renia Laurent , Ng Lisa F. P. , Lee Bernett , Rötzschke Olaf
Published: November 2021

Severe SARS-CoV-2 infection can trigger uncontrolled innate and adaptive immune responses, which are commonly associated with lymphopenia and increased neutrophil counts. However, whether the immune abnormalities observed in mild to severely infected patients persist into convalescence remains unclear. Herein, comparisons were drawn between the immune responses of COVID-19 infected and convalescent adults. Strikingly, survivors of severe COVID-19 had decreased proportions of NKT and Vδ2 T cells, and increased proportions of low-density neutrophils, IgA+/CD86+/CD123+ non-classical monocytes and hyperactivated HLADR+CD38+ CD8+ T cells, and elevated levels of pro-inflammatory cytokines such as hepatocyte growth factor and vascular endothelial growth factor A, long after virus clearance. Our study suggests potential immune correlates of “long COVID-19”, and defines key cells and cytokines that delineate true and quasi-convalescent states.
Analysis of Serological Biomarkers of SARS-CoV-2 Infection in Convalescent Samples From Severe, Moderate and Mild COVID-19 Cases
Authors: Castillo-Olivares Javier , Wells David A. , Ferrari Matteo , Chan Andrew C. Y. , Smith Peter , Nadesalingam Angalee , Paloniemi Minna , Carnell George W. , Ohlendorf Luis , Cantoni Diego , Mayora-Neto Martin , Palmer Phil , Tonks Paul , Temperton Nigel J. , Peterhoff David , Neckermann Patrick , Wagner Ralf , Doffinger Rainer , Kempster Sarah , Otter Ashley D. , Semper Amanda , Brooks Tim , Albecka Anna , James Leo C. , Page Mark , Schwaeble Wilhelm , Baxendale Helen , Heeney Jonathan L.
Published: November 2021

Precision monitoring of antibody responses during the COVID-19 pandemic is increasingly important during large scale vaccine rollout and rise in prevalence of Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2) variants of concern (VOC). Equally important is defining Correlates of Protection (CoP) for SARS-CoV-2 infection and COVID-19 disease. Data from epidemiological studies and vaccine trials identified virus neutralising antibodies (Nab) and SARS-CoV-2 antigen-specific (notably RBD and S) binding antibodies as candidate CoP. In this study, we used the World Health Organisation (WHO) international standard to benchmark neutralising antibody responses and a large panel of binding antibody assays to compare convalescent sera obtained from: a) COVID-19 patients; b) SARS-CoV-2 seropositive healthcare workers (HCW) and c) seronegative HCW. The ultimate aim of this study is to identify biomarkers of humoral immunity that could be used to differentiate severe from mild or asymptomatic SARS-CoV-2 infections. Some of these biomarkers could be used to define CoP in further serological studies using samples from vaccination breakthrough and/or re-infection cases. Whenever suitable, the antibody levels of the samples studied were expressed in International Units (IU) for virus neutralisation assays or in Binding Antibody Units (BAU) for ELISA tests. In this work we used commercial and non-commercial antibody binding assays; a lateral flow test for detection of SARS-CoV-2-specific IgG/IgM; a high throughput multiplexed particle flow cytometry assay for SARS-CoV-2 Spike (S), Nucleocapsid (N) and Receptor Binding Domain (RBD) proteins); a multiplex antigen semi-automated immuno-blotting assay measuring IgM, IgA and IgG; a pseudotyped microneutralisation test (pMN) and an electroporation-dependent neutralisation assay (EDNA). Our results indicate that overall, severe COVID-19 patients showed statistically significantly higher levels of SARS-CoV-2-specific neutralising antibodies (average 1029 IU/ml) than those observed in seropositive HCW with mild or asymptomatic infections (379 IU/ml) and that clinical severity scoring, based on WHO guidelines was tightly correlated with neutralisation and RBD/S antibodies. In addition, there was a positive correlation between severity, N-antibody assays and intracellular virus neutralisation.
Pro- and Anti- Effects of Immunoglobulin A- Producing B Cell in Tumors and Its Triggers
Authors: Zhong Ziwen , Nan Ke , Weng Meilin , Yue Ying , Zhou Wenchang , Wang Zhiqiang , Chu Yiwei , Liu Ronghua , Miao Changhong
Published: November 2021

B cells are well known as key mediators of humoral immune responsesviathe production of antibodies. Immunoglobulin A (IgA) is the most abundantly produced antibody isotype and provides the first line of immune protection at mucosal surfaces. However, IgA has long been a divisive molecule with respect to tumor progression. IgA exerts anti- or pro-tumor effect in different tumor types. In this review, we summarize emerging evidence regarding the production and effects of IgA and IgA+cells in the tumor microenvironment (TME). Moreover, we discuss that the TME cytokines, host diet, microbiome, and metabolites play a pivotal role in controlling the class-switch recombination (CSR) of IgA. The analysis of intratumoral Ig repertoires and determination of metabolites that influence CSR may help establish novel therapeutic targets for the treatment of cancers.
The Chicken Embryo Model: A Novel and Relevant Model for Immune-Based Studies
Authors: Garcia Paul , Wang Yan , Viallet Jean , Macek Jilkova Zuzana
Published: November 2021

Dysregulation of the immune system is associated with many pathologies, including cardiovascular diseases, diabetes, and cancer. To date, the most commonly used models in biomedical research are rodents, and despite the various advantages they offer, their use also raises numerous drawbacks. Recently, anotherin vivomodel, the chicken embryo and its chorioallantoic membrane, has re-emerged for various applications. This model has many benefits compared to other classical models, as it is cost-effective, time-efficient, and easier to use. In this review, we explain how the chicken embryo can be used as a model for immune-based studies, as it gradually develops an embryonic immune system, yet which is functionally similar to humans’. We mainly aim to describe the avian immune system, highlighting the differences and similarities with the human immune system, including the repertoire of lymphoid tissues, immune cells, and other key features. We also describe the generalin ovoimmune ontogeny. In conclusion, we expect that this review will help future studies better tailor their use of the chicken embryo model for testing specific experimental hypotheses or performing preclinical testing.
Distribution of a Newly Recorded Gastropod Species, Mainwaringia leithii (Gastropoda, Littorinidae), in Young, Rehabilitated Mangroves in China
Authors: Chen Shunyang , Xing Bingpeng , Yu Weiwei , Chen Bin , Liao Jianji , An Wenshuo , Chen Guangcheng
Published: November 2021

The species within the genusMainwaringiain Littorininae have been recognized as being strongly associated with mangroves; however, their abundance and distribution patterns in mangroves have rarely been reported. In this study, we reportedMainwaringia leithiispecimens collected from young, rehabilitated mangroves in Xiamen city as a newly recordedMainwaringiaspecies in China, based on their DNA barcoding and morphological taxonomy characteristics. The recruitment pattern of this species and its relationships with mangrove species in the early stage of mangrove rehabilitation were also investigated. The snails were mainly collected from the backsides of leaves and from some leaf nodes. Continuous sampling showed the rapid recruitment ofM. leithiifollowing mangrove rehabilitation, with a density up to 278 ind m–2in a 2.5-year-old mangrove site; however, declining densities were observed and snails were only occasionally collected at mangrove sites 4 years after rehabilitation.Aegiceras corniculatummangroves in shrub form could support a snail abundance higher than that supported byKandelia obovatamangroves of the same age. The present study suggests thatM. leithiicould be common in mangrove forests and that intensive changes in its assemblage occurs in the early stage of mangrove rehabilitation. Moreover, the recruitment ofM. leithiifollowing mangrove rehabilitation is related to the planting of different mangrove species. The spatio-temporal patterns ofM. leithiidistribution are likely owing to the variability in habitat characteristics related to mangrove species and stand age. Future studies should give more attention to the ecology of this species in mangrove forests.
Modulation of Internal Tides by Turbulent Mixing in the South China Sea
Authors: Li Bingtian , Du Libin , Peng Shiqiu , Yuan Yibo , Meng Xiangqian , Lv Xianqing
Published: November 2021

Modulations of internal tides (ITs) including the baroclinic tidal energy budget, the incoherency, and the nonlinear interactions among different tidal components by turbulent mixing in the South China Sea (SCS) are investigated through numerical simulations. The baroclinic tidal energy budget can hardly be affected by the structure of mixing. Meanwhile, change in the mixing intensity in a reasonable range also cannot obviously modulate the baroclinic tidal energy budget in the SCS. Compared to the baroclinic energy budget, the distributions of conversion and dissipation are more sensitive to the change of mixing. Turbulent mixing also modulates the incoherency of ITs by changing the horizontal density in the ocean. The horizontal variation of density adds incoherence to ITs largely by affecting the internal tidal amplitudes. Furthermore, nonlinear interactions among different components of ITs are generally modulated by the mixing intensity, whereas the variation of the mixing structure can hardly influence the nonlinear interactions. Therefore, the diapycnal diffusivity can set to be horizontally and vertically homogeneous in most of the internal tidal simulations, except for those in which the incoherency of ITs needs to be simulated. However, excessive strong mixing will destroy the stratification. Thus, the optimum range for IT simulations in the SCS is from O (10–5) to O (10–3) m2s–1.
MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells Function
Authors: Yan Wei , Shen Yingchun , Huang Jinny , Lu Ling , Zhang Qian
Published: November 2021

Acute liver injury (ALI) raises high mortality rates due to a rapid pathological process. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has already been reported to show strong hepatoprotective effects in many different liver diseases. In this study, we unveiled the role of MCC950 in carbon tetrachloride (CCl4)-induced ALI and its underlying molecular mechanisms on days 1, 2, and 3. MCC950 could significantly inhibit liver injury, evidenced by decreased serum alamine aminotransferase (ALT) and aspartate aminotransferase (AST) levels on days 1 and 2, increased Albumin (ALB) level on day 3, and decreased histological score during the whole period. Moreover, lower M1 macrophage related to pro-inflammatory genes expression was observed in MCC950-treated ALI mice on day 1, while MCC950 pretreatment also polarized macrophage to M2 phenotype indicating anti-inflammatory response on days 2 and 3. Additionally, MDSC was significantly increased in blood, liver, and spleen in ALI mice at different time courses. Specifically, upregulated myeloid-derived suppressor cell (MDSC) proportions were found in blood and spleen on days 1 and 2, but showed decreased trend on day 3. However, liver MDSC numbers were increased on days 2 and 3, but no significance on day 1. In conclusion, MCC950 pretreatment alleviates CCl4-induced ALI through enhanced M2 macrophage and MDSC function at different time points of ALI. Further understanding of MCC950 in ALI may be a new potential therapeutic strategy.
Structural and Functional Alterations of Gut Microbiota in Males With Hyperuricemia and High Levels of Liver Enzymes
Authors: Sheng Shifeng , Chen Jingfeng , Zhang Yuheng , Qin Qian , Li Weikang , Yan Su , Wang Youxiang , Li Tiantian , Gao Xinxin , Tang Lin , Li Ang , Ding Suying
Published: November 2021

Objective: To investigate the correlation between the structure and function alterations of gut microbiota and biochemical indicators in males with hyperuricemia (HUA) and high levels of liver enzymes, in order to provide new evidences and therapeutic targets for the clinical diagnosis and treatment of HUA.

Methods: A total of 69 patients with HUA (HUA group) and 118 healthy controls were enrolled in this study. Their age, height, waist circumference, weight, and pressure were measured. The clinical parameters such as fasting plasma glucose (FBG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum uric acid (SUA), serum creatinine (Scr), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), white blood cell (WBC), platelet (PLT), and absolute value of neutrophils (NEUT) were examined. We used whole-genome shotgun sequencing technology and HUMAnN2 MetaCyc pathway database to detect the composition and pathways of the gut microbiota. The main statistical methods were student's t test, chi-square tests, and Wilcoxon rank sum test. The correlations among bacterial diversity, microbial pathways, and biochemical indicators were evaluated by the R function “cor.test” with spearman method.

Results: The gut bacterial diversity in HUA group reduced significantly and the community of the microbiota was of significant difference between the two groups. The pathways that can produce 5-aminoimidazole ribonucleotide (PWY-6122, PWY-6277, and PWY-6121), aromatic amino acids, and chorismate (COMPLETE-ARO-PWY, ARO-PWY, and PWY-6163) were enriched in the HUA group; while the pathways that can produce short-chain fatty acids (SCFAs, such as CENTFERM-PWY and PWY-6590) and the gut microbiotas that can produce SCFAs (Roseburia hominis, Odoribacter splanchnicus, Ruminococcus callidus, Lachnospiraceae bacterium 3_1_46FAA, Bacteroides uniformis, Butyricimonas synergistica) and equol (Adlercreutzia equolifaciens) were enriched in healthy controls.

Conclusion: The structure and function of the gut microbiota in males with HUA and high levels of liver enzymes have altered apparently. In-depth study of related mechanisms may provide new ideas for the treatment of HUA.
Description of the First Four Species of the Genus Pseudogymnoascus From Antarctica
Authors: Villanueva Pablo , Vásquez Ghislaine , Gil-Durán Carlos , Oliva Vicente , Díaz Anaí , Henríquez Marlene , Álvarez Eduardo , Laich Federico , Chávez Renato , Vaca Inmaculada
Published: November 2021

The genus Pseudogymnoascus represents a diverse group of fungi widely distributed in different cold regions on Earth. Our current knowledge of the species of Pseudogymnoascus is still very limited. Currently, there are only 15 accepted species of Pseudogymnoascus that have been isolated from different environments in the Northern Hemisphere. In contrast, species of Pseudogymnoascus from the Southern Hemisphere have not yet been described. In this work, we characterized four fungal strains obtained from Antarctic marine sponges. Based on multilocus phylogenetic analyses and morphological characterizations we determined that these strains are new species, for which the names Pseudogymnoascus antarcticus sp. nov., Pseudogymnoascus australis sp. nov., Pseudogymnoascus griseus sp. nov., and Pseudogymnoascus lanuginosus sp. nov. are proposed. Phylogenetic analyses indicate that the new species form distinct lineages separated from other species of Pseudogymnoascus with strong support. The new species do not form sexual structures and differ from the currently known species mainly in the shape and size of their conidia, the presence of chains of arthroconidia, and the appearance of their colonies. This is the first report of new species of Pseudogymnoascus not only from Antarctica but also from the Southern Hemisphere.
Characterization of a Novel Hypotrich Ciliate From Heavy Metal-Contaminated Industrial Outlet in Onsan, Ulsan, South Korea
Authors: Kumar Santosh , Bharti Daizy , Shazib Shahed Uddin Ahmed , Shin Mann Kyoon
Published: November 2021

Very few studies exist on the description of protozoan ciliates from industrially contaminated sites. In this study, we report a description of a novel hypotrich ciliate isolated from water samples collected from an industrially contaminated outlet in Onsan, Ulsan, South Korea. The oxytrichid ciliate, Histriculus tolerans n. sp., was investigated using live observation and protargol impregnation. The morphology, morphogenesis, and molecular phylogeny inferred from small-subunit (SSU) rRNA gene sequences were studied. The new species is mainly characterized by a cell size of about 70 × 40 μm in vivo, two elongate ellipsoidal macronuclear nodules and one or two micronuclei, adoral zone of about 51% of body length with 32 membranelles on average, about 34 cirri in the right and 24 cirri in the left marginal row, 18 frontoventral transverse cirri, six dorsal kineties including two dorsomarginal rows, and dorsal kinety 1 with 26 bristles. Morphogenesis is similar to that of the type species, i.e., Histriculus histrio, except that oral primordium does not contribute to anlage II of the proter. Phylogenetic analyses, based on small-subunit rRNA gene sequences, consistently place the new species within the family Oxytrichidae, clustering with H. histrio.
Spermidine Is Critical for Growth, Development, Environmental Adaptation, and Virulence in Fusarium graminearum
Authors: Tang Guangfei , Xia Haoxue , Liang Jingting , Ma Zhonghua , Liu Wende
Published: November 2021

Putrescine, spermidine, and spermine are the most common natural polyamines. Polyamines are ubiquitous organic cations of low molecular weight and have been well characterized for the cell function and development processes of organisms. However, the physiological functions of polyamines remain largely obscure in plant pathogenic fungi. Fusarium graminearum causes Fusarium head blight (FHB) and leads to devastating yield losses and quality reduction by producing various kinds of mycotoxins. Herein, we genetically analyzed the gene function of the polyamine biosynthesis pathway and evaluated the role of the endogenous polyamines in the growth, development, and virulence of F. graminearum. Our results found that deletion of spermidine biosynthesis gene FgSPE3 caused serious growth defects, reduced asexual and sexual reproduction, and increased sensitivity to various stresses. More importantly, ΔFgspe3 exhibited significantly decreased mycotoxin deoxynivalenol (DON) production and weak virulence in host plants. Additionally, the growth and virulence defects of ΔFgspe3 could be rescued by exogenous application of 5 mM spermidine. Furthermore, RNA-seq displayed that FgSpe3 participated in many essential biological pathways including DNA, RNA, and ribosome synthetic process. To our knowledge, these results indicate that spermidine is essential for growth, development, DON production, and virulence in Fusarium species, which provides a potential target to control FHB.
SUMO-specific Isopeptidases Tuning Cardiac SUMOylation in Health and Disease
Authors: Hotz Paul W. , Müller Stefan , Mendler Luca
Published: November 2021

SUMOylation is a transient posttranslational modification with small-ubiquitin like modifiers (SUMO1, SUMO2 and SUMO3) covalently attached to their target-proteins via a multi-step enzymatic cascade. SUMOylation modifies protein-protein interactions, enzymatic-activity or chromatin binding in a multitude of key cellular processes, acting as a highly dynamic molecular switch. To guarantee the rapid kinetics, SUMO target-proteins are kept in a tightly controlled equilibrium of SUMOylation and deSUMOylation. DeSUMOylation is maintained by the SUMO-specific proteases, predominantly of the SENP family. SENP1 and SENP2 represent family members tuning SUMOylation status of all three SUMO isoforms, while SENP3 and SENP5 are dedicated to detach mainly SUMO2/3 from its substrates. SENP6 and SENP7 cleave polySUMO2/3 chains thereby countering the SUMO-targeted-Ubiquitin-Ligase (StUbL) pathway. Several biochemical studies pinpoint towards the SENPs as critical enzymes to control balanced SUMOylation/deSUMOylation in cardiovascular health and disease. This study aims to review the current knowledge about the SUMO-specific proteases in the heart and provides an integrated view of cardiac functions of the deSUMOylating enzymes under physiological and pathological conditions.
Two Novel Ceramide-Like Molecules and miR-5100 Levels as Biomarkers Improve Prediction of Prostate Cancer in Gray-Zone PSA
Authors: Mello-Grand Maurizia , Bruno Antonino , Sacchetto Lidia , Cristoni Simone , Gregnanin Ilaria , Dematteis Alessandro , Zitella Andrea , Gontero Paolo , Peraldo-Neia Caterina , Ricotta Riccardo , Noonan Douglas M. , Albini Adriana , Chiorino Giovanna
Published: November 2021

Reliable liquid biopsy-based tools able to accurately discriminate prostate cancer (PCa) from benign prostatic hyperplasia (BPH), when PSA is within the “gray zone” (PSA 4–10), are still urgent. We analyzed plasma samples from a cohort of 102 consecutively recruited patients with PSA levels between 4 and 16 ng/ml, using the SANIST-Cloud Ion Mobility Metabolomic Mass Spectrometry platform, combined with the analysis of a panel of circulating microRNAs (miR). By coupling CIMS ion mobility technology with SANIST, we were able to reveal three new structures among the most differentially expressed metabolites in PCa vs. BPH. In particular, two were classified as polyunsaturated ceramide ester-like and one as polysaturated glycerol ester-like. Penalized logistic regression was applied to build a model to predict PCa, using six circulating miR, seven circulating metabolites, and demographic/clinical variables, as covariates. Four circulating metabolites, miR-5100, and age were selected by the model, and the corresponding prediction score gave an AUC of 0.76 (C.I. = 0.66–0.85). At a specified cut-off, no high-risk tumor was misclassified, and 22 out of 53 BPH were correctly identified, reducing by 40% the false positives of PSA. We developed and applied a novel, minimally invasive, liquid biopsy-based powerful tool to characterize novel metabolites and identified new potential non-invasive biomarkers to better predict PCa, when PSA is uninformative as a tool for precision medicine in genitourinary cancers.
Advanced Pathogenetic Concepts in T-Cell Prolymphocytic Leukemia and Their Translational Impact
Authors: Braun Till , Dechow Annika , Friedrich Gregor , Seifert Michael , Stachelscheid Johanna , Herling Marco
Published: November 2021

T-cell prolymphocytic leukemia (T-PLL) is the most common mature T-cell leukemia. It is a typically aggressively growing and chemotherapy-resistant malignancy with a poor prognosis. T-PLL cells resemble activated, post-thymic T-lymphocytes with memory-type effector functions. Constitutive transcriptional activation of genes of the T-cell leukemia 1 (TCL1) family based on genomic inversions/translocations is recognized as a key event in T-PLL’s pathogenesis. TCL1’s multiple effector pathways include the enhancement of T-cell receptor (TCR) signals. New molecular dependencies around responses to DNA damage, including repair and apoptosis regulation, as well as alterations of cytokine and non-TCR activation signaling were identified as perturbed hallmark pathways within the past years. We currently witness these vulnerabilities to be interrogated in first pre-clinical concepts and initial clinical testing in relapsed/refractory T-PLL patients. We summarize here the current knowledge on the molecular understanding of T-PLL’s pathobiology and critically assess the true translational progress around this to help appraisal by caregivers and patients. Overall, the contemporary concepts on T-PLL’s pathobiology are condensed in a comprehensive mechanistic disease model and promising interventional strategies derived from it are highlighted.
An Integrated Analysis Reveals Geniposide Extracted From Gardenia jasminoides J.Ellis Regulates Calcium Signaling Pathway Essential for Influenza A Virus Replication
Authors: Zhou Lirun , Bao Lei , Wang Yaxin , Chen Mengping , Zhang Yingying , Geng Zihan , Zhao Ronghua , Sun Jing , Bao Yanyan , Shi Yujing , Yao Rongmei , Guo Shanshan , Cui Xiaolan
Published: November 2021

Geniposide, an iridoid glycoside purified from the fruit of Gardenia jasminoides J.Ellis, has been reported to possess pleiotropic activity against different diseases. In particular, geniposide possesses a variety of biological activities and exerts good therapeutic effects in the treatment of several strains of the influenza virus. However, the molecular mechanism for the therapeutic effect has not been well defined. This study aimed to investigate the mechanism of geniposide on influenza A virus (IAV). The potential targets and signaling pathways of geniposide in the IAV infection were predicted using network pharmacology analysis. According to the result of network pharmacology analysis, we validated the calcium signaling pathway induced by IAV and investigated the effect of geniposide extracted from Gardenia jasminoides J.Ellis on this pathway. The primary Gene Ontology (GO) biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways KEGG enrichment analysis indicated that geniposide has a multi-target and multi-pathway inhibitory effect against influenza, and one of the mechanisms involves calcium signaling pathway. In the current study, geniposide treatment greatly decreased the levels of RNA polymerase in HEK-293T cells infected with IAV. Knocking down CAMKII in IAV-infected HEK-293T cells enhanced virus RNA (vRNA) production. Geniposide treatment increased CAMKII expression after IAV infection. Meanwhile, the CREB and c-Fos expressions were inhibited by geniposide after IAV infection. The experimental validation data showed that the geniposide was able to alleviate extracellular Ca2+ influx, dramatically decreased neuraminidase activity, and suppressed IAV replication in vitro via regulating the calcium signaling pathway. These anti-IAV effects might be related to the disrupted interplay between IAV RNA polymerase and CAMKII and the regulation of the downstream calcium signaling pathway essential for IAV replication. Taken together, the findings reveal a new facet of the mechanism by which geniposide fights IAV in a way that depends on CAMKII replication.
Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells
Authors: Okoloko Oghenemega , Vanderwall Elizabeth R. , Rich Lucille M. , White Maria P. , Reeves Stephen R. , Harrington Whitney E. , Barrow Kaitlyn A. , Debley Jason S.
Published: November 2021

Rationale: SARS-CoV-2 gains entrance to airway epithelial cells (AECs) through binding of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) on the cell surface. However, ACE2 also converts angiotensin II into angiotensin-(1-7) and counterbalances the renin-angiotensin-aldosterone system, with resultant protective effects in the cardiovascular system. Some data suggest that two common antihypertension medications (angiotensin II receptor antagonists, ARBs; and angiotensin-converting-enzyme inhibitors, ACEIs) may increase ACE2 expression in heart and kidney cells, fueling debate about how these widely used medications may modulate SARS-CoV-2 infectivity and risk of COVID-19.

Aim: Determine whether exposure of bronchial AECs to the ARB losartan or the ACEI captopril modulate expression of ACE2 by AECs, SARS CoV2 replication, or expression of proinflammatory cytokines and type I and III interferon (IFN) responses.

Methods: Primary bronchial AECs from children and adults (n = 19; Ages 8–75 yrs) were differentiated ex vivo at an air-liquid interface to generate organotypic cultures. Cultures were treated with captopril (1 μM) or losartan (2 μM) with culture media changes starting 72 h before infection with SARS-CoV-2. In a biosafety level 3 (BSL-3) facility, cultures were infected with SARS-CoV-2 isolate USA-WA1/2020 at a multiplicity of infection (MOI) of 0.5. At 96 h following infection, RNA and protein were isolated. SARS-CoV-2 replication in cultures was assessed with quantitative PCR (qPCR). ACE2, IL-6, IL-1B, IFNB1, and IFNL2 expression were assessed by qPCR.

Results: Neither captopril nor losartan treatment significantly changed ACE2, IL-6, IL-1B, IFNB1, or IFNL2 expression by AECs as compared to SARS-CoV-2 infected AEC cultures without captopril or losartan treatment. At 96 h following infection, SARS-CoV-2 copy number/ng RNA was not significantly different between untreated AEC cultures, cultures treated with captopril, or cultures treated with losartan.

Conclusion: These findings suggest that at the level of the airway epithelium neither the ACEI captopril or ARB losartan significantly modify expression of the SARS-CoV-2 entry factor ACE2, nor does either medication increase replication SARS-CoV-2 replication. This ex vivo data is reassuring and is consistent with evolving clinical data suggesting ACEIs and ARBs do not increase the risk for poor prognosis with COVID-19 and may actually reduce the risk of COVID-19 disease.
Flush Flow Behaviour Affected by the Morphology of Intravascular Endoscope: A Numerical Simulation and Experimental Study
Authors: Li Yujie , Zhang Mingzi , Tupin Simon , Mitsuzuka Kohei , Nakayama Toshio , Anzai Hitomi , Ohta Makoto
Published: November 2021

Background: Whilst intravascular endoscopy can be used to identify lesions and assess the deployment of endovascular devices, it requires temporary blockage of the local blood flow during observation, posing a serious risk of ischaemia.

Objective: To aid the design of a novel flow-blockage-free intravascular endoscope, we explored changes in the haemodynamic behaviour of the flush flow with respect to the flow injection speed and the system design.

Methods: We first constructed the computational models for three candidate endoscope designs (i.e., Model A, B, and C). Using each of the three endoscopes, flow patterns in the target vessels (straight, bent, and twisted) under three different sets of boundary conditions (i.e., injection speed of the flush flow and the background blood flowrate) were then resolved through use of computational fluid dynamics and in vitro flow experiments. The design of endoscope and its optimal operating condition were evaluated in terms of the volume fraction within the vascular segment of interest, as well as the percentage of high-volume-fraction area (PHVFA) corresponding to three cross-sectional planes distal to the microcatheter tip.

Results: With a mild narrowing at the endoscope neck, Model B exhibited the highest PHVFA, irrespective of location of the cross-sectional plane, compared with Models A and C which, respectively, had no narrowing and a moderate narrowing. The greatest difference in the PHVFA between the three models was observed on the cross-sectional plane 2 mm distal to the tip of the microcatheter (Model B: 33% vs. Model A: 18%). The background blood flowrate was found to have a strong impact on the resulting volume fraction of the flush flow close to the vascular wall, with the greatest difference being 44% (Model A).

Conclusion: We found that the haemodynamic performance of endoscope Model B outperformed that of Models A and C, as it generated a flush flow that occupied the largest volume within the vascular segment of interest, suggesting that the endoscope design with a diameter narrowing of 30% at the endoscope neck might yield images of a better quality.
Mechanisms of Hypercapnia-Induced Endoplasmic Reticulum Dysfunction
Authors: Kryvenko Vitalii , Vadász István
Published: November 2021

Protein transcription, translation, and folding occur continuously in every living cell and are essential for physiological functions. About one-third of all proteins of the cellular proteome interacts with the endoplasmic reticulum (ER). The ER is a large, dynamic cellular organelle that orchestrates synthesis, folding, and structural maturation of proteins, regulation of lipid metabolism and additionally functions as a calcium store. Recent evidence suggests that both acute and chronic hypercapnia (elevated levels of CO2) impair ER function by different mechanisms, leading to adaptive and maladaptive regulation of protein folding and maturation. In order to cope with ER stress, cells activate unfolded protein response (UPR) pathways. Initially, during the adaptive phase of ER stress, the UPR mainly functions to restore ER protein-folding homeostasis by decreasing protein synthesis and translation and by activation of ER-associated degradation (ERAD) and autophagy. However, if the initial UPR attempts for alleviating ER stress fail, a maladaptive response is triggered. In this review, we discuss the distinct mechanisms by which elevated CO2 levels affect these molecular pathways in the setting of acute and chronic pulmonary diseases associated with hypercapnia.
Lin11-Isl1-Mec3 Domain Proteins as Mechanotransducers in Endothelial and Vascular Smooth Muscle Cells
Authors: Sporkova Alexandra , Ghosh Subhajit , Al-Hasani Jaafar , Hecker Markus
Published: November 2021

Arterial hypertension is the leading risk factor for cardiovascular morbidity and mortality worldwide. However, little is known about the cellular mechanisms underlying it. In small arteries and arterioles, a chronic increase in blood pressure raises wall tension and hence stretches, namely, the medial vascular smooth muscle cells (VSMC) but also endothelial cell (EC) to cell contacts. Initially compensated by an increase in vascular tone, the continuous biomechanical strain causes a prominent change in gene expression in both cell types, frequently driving an arterial inward remodeling process that ultimately results in a reduction in lumen diameter, stiffening of the vessel wall, and fixation of blood pressure, namely, diastolic blood pressure, at the elevated level. Sensing and propagation of this supraphysiological stretch into the nucleus of VSMC and EC therefore seems to be a crucial step in the initiation and advancement of hypertension-induced arterial remodeling. Focal adhesions (FA) represent an important interface between the extracellular matrix and Lin11-Isl1-Mec3 (LIM) domain-containing proteins, which can translocate from the FA into the nucleus where they affect gene expression. The varying biomechanical cues to which vascular cells are exposed can thus be rapidly and specifically propagated to the nucleus. Zyxin was the first protein described with such mechanotransducing properties. It comprises 3 C-terminal LIM domains, a leucine-rich nuclear export signal, and N-terminal features that support its association with the actin cytoskeleton. In the cytoplasm, zyxin promotes actin assembly and organization as well as cell motility. In EC, zyxin acts as a transcription factor, whereas in VSMC, it has a less direct effect on mechanosensitive gene expression. In terms of homology and structural features, lipoma preferred partner is the nearest relative of zyxin among the LIM domain proteins. It is almost exclusively expressed by smooth muscle cells in the adult, resides like zyxin at FA but seems to affect mechanosensitive gene expression indirectly, possibly via altering cortical actin dynamics. Here, we highlight what is currently known about the role of these LIM domain proteins in mechanosensing and transduction in vascular cells.
Metabolome and Transcriptome Reveal Novel Formation Mechanism of Early Mature Trait in Kiwifruit (Actinidia eriantha)
Authors: Liao Guanglian , Liu Qing , Xu Xiaobiao , He Yanqun , Li Yiqi , Wang Hailing , Ye Bin , Huang Chunhui , Zhong Min , Jia Dongfeng
Published: November 2021

Kiwifruit (Actinidia eriantha) is a peculiar berry resource in China, and the maturation period is generally late. Fortunately, we found an early mature A. eriantha germplasm. In order to explore the formation mechanism of its early mature trait, we determined the main carbohydrate and endogenous hormone content of the fruit, and used off-target metabolomics and transcriptomics to identify key regulatory metabolites and genes. We found that early mature germplasm had faster starch conversion rate and higher sucrose, glucose, and fructose content when harvested, while with lower auxin (IAA), abscisic acid (ABA), and zeatin (ZR) content. Through the non-targeted metabolome, 19 and 20 metabolites closely related to fruit maturity and early maturity were identified, respectively. At the same time, weighted correlation network analysis (WGCNA) showed that these metabolites were regulated by 73 and 99 genes, respectively, especially genes related to sugar metabolism were mostly. Based on above, the formation of early mature trait of A. eriantha was mainly due to the sucrose decomposition rate was reduced and the soluble solid content (SSC) accumulated at low levels of endogenous hormones, so as to reach the harvest standard earlier than the late mature germplasm. Finally, ten single nucleotide polymorphism (SNP) loci were developed which can be used for the identification of early mature trait of A. eriantha.