bluuebunny/crossref_metadata_2025 huggingface dataset:
‘Powers of Their Own Which Mere “Modernity” Cannot Kill’: The Doppelgänger and Temporal Modernist Terror in Dracula
Authors: May Whitney S.
Published: March 2021

Of the many haunting figures that Gothic fiction invokes, none so perfectly encapsulates the mode itself, in all its fantastic incursions of opposing forces and clashing sensibilities, as the doppelgänger. Indeed, this figure in Gothic literature helps to push the bounds of subjective tension so central to the genre. This article examines Bram Stoker's Dracula (1897) as an entry into the canon of doppelgänger fiction by complicating traditional readings of the central relationship between Count Dracula and Jonathan Harker. By revisiting the novel within the framework of a doppelgänger narrative, this article suggests that part of the real terror for Stoker's fin-de-siècle audience lies in the novel's timing. Located in the gap between the retreating Romantic and advancing high modern epochs, the novel dramatizes the apprehensions of a culture experiencing enormous technological and social upheaval. Specifically, it offers in its doubled pair a means to navigate those anxieties.
The role of informal learning in adults’ literacy proficiency
Authors: Sulkunen Sari , Nissinen Kari , Malin Antero
Published: March 2021

This study used the PIAAC dataset to compare the effects of informal literacy learning on adults’ literacy proficiency to those of formal and non-formal learning. The study participants were Nordic adults aged 35–65 years. The statistical method was regression analysis. The results indicate that informal literacy learning had the most significant effect on Nordic adults’ literacy proficiency. Non-formal adult education had a clearly smaller effect, and formal adult education seemed to have a negative effect when background factors were controlled for. Informal learning, particularly reading outside work, had a significant effect independent of adults’ backgrounds, indicating that it offers also less-educated and unemployed adults the opportunity to develop literacy proficiency.
Adrenergic Tone as an Intermediary in the Temperament Syndrome Associated With Flight Speed in Beef Cattle
Authors: Colditz Ian G.
Published: March 2021

The temperament of farm animals can influence their resilience to everyday variations within the managed production environment and has been under strong direct and indirect selection during the course of domestication. A prominent objective measure used for assessing temperament in beef cattle is the behavioral flight response to release from confinement in a crush or chute. This behavioral measure, termed flight speed (also known as escape velocity) is associated with physiological processes including body temperature, feeding behavior, growth rate, carcass composition, immune function, and health outcomes. This review examines the functional links between this suite of traits and adrenergic activity of the sympathetic nervous system and the adrenomedullary hormonal system. It is suggested that flight speed is the behavioral aspect of an underlying “flightiness” temperament syndrome, and that elevated adrenergic tone in animals with a high level of flightiness (i.e., flighty animals) tunes physiological activities toward a sustained “fight or flight” defense profile that reduces productivity and the capacity to flourish within the production environment. Nonetheless, despite a common influence of adrenergic tone on this suite of traits, variation in each trait is also influenced by other regulatory pathways and by the capacity of tissues to respond to a range of modulators in addition to adrenergic stimuli. It is suggested that tuning by adrenergic tone is an example of homeorhetic regulation that can help account for the persistent expression of behavioral and somatic traits associated with the flight speed temperament syndrome across the life of the animal. At a population level, temperament may modulate ecological fit within and across generations in the face of environmental variability and change. Associations of flight speed with the psychological affective state of the animal, and implications for welfare are also considered. The review will help advance understanding of the developmental biology and physiological regulation of temperament syndromes.
Rational Design and Synthesis of Naphthalene Diimide Linked Bis-Naphthalimides as DNA Interactive Agents
Authors: Malik M. Shaheer , Farooq Adil Syed , Moussa Ziad , Altass Hatem M. , Althagafi Ismail I. , Morad Moataz , Ansari Mohammad Azam , Sajid Jamal Qazi Mohammad , Obaid Rami J. , Al-Warthan Abdulrahman A. , Shaik Thokhir B. , Ahmed Saleh A.
Published: March 2021

A molecular modeling assisted rational design and synthesis of naphthalene diimide linked bis-naphthalimides as potential DNA interactive agents is described. Chemical templates incorporating naphthalene diimide as a linker in bis-naphthalimide motif were subjected to molecular docking analysis at specific intercalation and telomeric DNA G-quadruplex sites. Excellent results were obtained, which were better than the standards. A short and convenient synthetic route was employed to access these hybrids experimentally, followed by evaluation of their ability to cause thermal denaturation of DNA and cytotoxic properties along with ADME predictions. The obtained results provided useful insights and two potential molecules were identified for further development.
Clinical Safety and Efficacy of Ablation for Atrial Fibrillation Patients With a History of Stroke
Authors: Song Zi-liang , Wu Shao-hui , Zhang Dao-liang , Jiang Wei-feng , Qin Mu , Liu Xu
Published: March 2021

Objectives: To evaluate the clinical safety and efficacy of radiofrequency catheter ablation for atrial fibrillation patients with a history of stroke.

Methods and Results: A total of 116 symptomatic, drug-refractory AF patients with a history of stroke, and 1:2 matched patients without a history of stroke were enrolled. Of these, 28 cases occurred stroke within 3 months (Group 1), 88 cases with stroke history longer than 3 months (Group 2), and 232 cases without stroke (Group 3). PVI was performed in all patients, extended to ablation of linear lesions ablation. The periprocedural stroke rates and other procedure-related in-hospital complications did not differ significantly among the three groups. The maintenance rate of SR after the procedure showed no significant difference (p = 0.333), 52.7, 66.4, and 70.7% in Group 1, 2, and 3, respectively. Furthermore, the comparison between a history of stroke and those without it were also shown no significant difference (p = 0.351).

Conclusions: Radiofrequency ablation for AF patients occurred stroke, even within 3 months is safe and effective, without higher periprocedural complication rate and recurrence rate.
Neutrophil-Associated Inflammatory Changes in the Pre-Diabetic Pancreas of Early-Age NOD Mice
Authors: Garciafigueroa Yesica , Phillips Brett E. , Engman Carl , Trucco Massimo , Giannoukakis Nick
Published: March 2021

A growing body of evidence indicates that neutrophils are the first major leukocyte population accumulating inside the pancreas even before the onset of a lymphocytic-driven impairment of functional beta cells in type 1 diabetes mellitus (T1D). In humans, pancreata from T1D deceased donors exhibit significant neutrophil accumulation. We present a time course of previously unknown inflammatory changes that accompany neutrophil and neutrophil elastase accumulation in the pancreas of the non-obese diabetic (NOD) mouse strain as early as 2 weeks of age. We confirm earlier findings in NOD mice that neutrophils accumulate as early as 2 weeks of age. We also observe a concurrent increase in the expression of neutrophil elastase in this time period. We also detect components of neutrophil extracellular traps (NET) mainly in the exocrine tissue of the pancreas during this time as well as markers of vascular pathology as early as 2 weeks of age. Age- and sex-matched C57BL/6 mice do not exhibit these features inside the pancreas. When we treated NOD mice with inhibitors of myeloperoxidase and neutrophil elastase, two key effectors of activated neutrophil activity, alone or in combination, we were unable to prevent the progression to hyperglycemia in any manner different from untreated control mice. Our data confirm and add to the body of evidence demonstrating neutrophil accumulation inside the pancreas of mice genetically susceptible to T1D and also offer novel insights into additional pathologic mechanisms involving the pancreatic vasculature that have, until now, not been discovered inside the pancreata of these mice. However, inhibition of key neutrophil enzymes expressed in activated neutrophils could not prevent diabetes. These findings add to the body of data supporting a role for neutrophils in the establishment of early pathology inside the pancreas, independently of, and earlier from the time at onset of lymphocytic infiltration. However, they also suggest that inhibition of neutrophils alone, acting via myeloperoxidase and neutrophil elastase only, in the absence of other other effector cells, is insufficient to alter the natural course of autoimmune diabetes, at least in the NOD model of the disease.
The Impact of Down-Regulation on Obstetrics and Perinatal Outcomes in Singleton Pregnancies After In Vitro Fertilization
Authors: Jin Lei , Ai Jihui , Zheng Yu , Chen Biao , Wang Lan , Dong Xiyuan
Published: March 2021

Background

down-regulation has been widely used in IVF treatment; however, it lacks reports on the impact of down-regulation on obstetrics and perinatal outcomes. The purpose of this study was to compare the obstetrics and perinatal outcomes among different down-regulation conditions.

Methods

this is a retrospective cohort study on 3578 patients achieving cumulative singleton clinical pregnancy after their first oocytes retrieval cycle. Patients were grouped according to the serum estradiol after down-regulation (E2D) into three groups: <30, 30-55, >55 pg/ml. The obstetrics and perinatal outcomes, and live-birth rate per clinical pregnancy were main outcome measures. In the subgroup analysis, patients were further divided according to the mode of transfer. ANOVA, chi-square test, multivariate logistic regression, and multivariate general linear model were performed for statistical analysis.

Results

the patients with E2D <30, 30-55, >55 pg/ml had similar live-birth rates. The patients with E2D <30 pg/ml had a lower risk of hypertension disorders than those with E2D 30-55 pg/ml. No difference was found in the risks of placenta previa, placenta abruption, premature rupture of membrane, hemorrhage, gestational diabetes mellitus, or intrauterine growth restriction. The newborns in the group with E2D <30 pg/ml had a lower risk of PICU admission than those in the group with E2D >55 pg/ml. There was no difference in the risks of congenital anomalies or mortality among the three groups. No differences were found in the gestational week, percentages of preterm birth and very preterm birth, birth weight, percentages of low birth weight and very low birth weight, delivery mode, or sex of newborn. Subgroup analysis showed that E2D 30-55 pg/ml was associated with a higher risk of low birth weight in patients with one fresh transfer + frozen transfer(s).

Conclusion

Down-regulation has no effect on the live-birth rate per clinical pregnancy. Patients with E2D <30 pg/ml may have advantages regarding lower risks of both maternal hypertension and newborn PICU admission. E2D 30-55 pg/ml may be associated with low birth weight in patients with relatively low quality embryos.
IRX3 Overexpression Enhances Ucp1 Expression In Vivo
Authors: Zhang Zhiyin , Wu Qihan , He Yang , Lu Peng , Li Danjie , Yang Minglan , Gu Weiqiong , Liu Ruixin , Hong Jie , Wang Jiqiu
Published: March 2021

Objective

The Iroquois homeobox 3 (IRX3) gene was recently reported to be a functional downstream target of a common polymorphism in the FTO gene, which encodes an obesity-associated protein; however, the role of IRX3 in energy expenditure remains unclear. Studies have revealed that the overexpression of a dominant–negative form of IRX3 in the mouse hypothalamus and adipose tissue promoted energy expenditure by enhancing brown/browning activities. Meanwhile, we and others recently demonstrated that IRX3 knockdown impaired the browning program of primary preadipocytes in vitro. In this study, we aimed to further clarify the effects of overexpressing human IRX3 (hIRX3) on brown/beige adipose tissues in vivo.

Methods

Brown/beige adipocyte-specific hIRX3-overexpressing mice were generated and the browning program of white adipose tissues was induced by both chronic cold stimulation and CL316,243 injection. Body weight, fat mass, lean mass, and energy expenditure were measured, while morphological changes and the expression of thermogenesis-related genes in adipose tissue were analyzed. Moreover, the browning capacity of primary preadipocytes derived from hIRX3-overexpressing mice was assessed. RNA sequencing was also employed to investigate the effect of hIRX3 on the expression of thermogenesis-related genes.

Results

hIRX3 overexpression in embryonic brown/beige adipose tissues (Rosa26hIRX3;Ucp1-Cre) led to increased energy expenditure, decreased fat mass, and a lean body phenotype. After acute cold exposure or CL316,243 stimulation, brown/beige tissue hIRX3-overexpressing mice showed an increase in Ucp1 expression. Consistent with this, induced hIRX3 overexpression in adult mice (Rosa26hIRX3;Ucp1-CreERT2) also promoted a moderate increase in Ucp1 expression. Ex vitro experiments further revealed that hIRX3 overexpression induced by Ucp1-driven Cre recombinase activity upregulated brown/beige adipocytes Ucp1 expression and oxygen consumption rate (OCR). RNA sequencing analyses indicated that hIRX3 overexpression in brown adipocytes enhanced brown fat cell differentiation, glycolysis, and gluconeogenesis.

Conclusion

Consistent with the in vitro findings, brown/beige adipocyte-specific overexpression of hIRX3 promoted Ucp1 expression and thermogenesis, while reducing fat mass.
Case Report: Whole-Exome Sequencing With MLPA Revealed Variants in Two Genes in a Patient With Combined Manifestations of Spinal Muscular Atrophy and Duchenne Muscular Dystrophy
Authors: Xia Yu , Feng Yijie , Xu Lu , Chen Xiaoyang , Gao Feng , Mao Shanshan
Published: March 2021

Spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are two common kinds of neuromuscular disorders sharing various similarities in clinical manifestations. SMA is an autosomal recessive genetic disorder that results from biallelic mutations of the survival motor neuron 1 gene (SMN1; OMIM 600354) on the 5q13 chromosome. DMD is an X-linked disorder caused by defects in the DMD gene (OMIM 300377) on the X chromosome. Here, for the first time, we report a case from a Chinese family who present with clinical manifestations of both two diseases, including poor motor development and progressive muscle weakness. We identified a homozygous deletion in exons 7 and 8 of the SMN1 gene and a deletion in exon 50 of the DMD gene by whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA). This case expands our understanding of diagnosis for synchronous SMA and DMD and highlights the importance of various genetic testing methods, including WES, in differential diagnosis of neuromuscular diseases.
Evolution of Matrix Gla and Bone Gla Protein Genes in Jawed Vertebrates
Authors: Leurs Nicolas , Martinand-Mari Camille , Ventéo Stéphanie , Haitina Tatjana , Debiais-Thibaud Mélanie
Published: March 2021

Matrix Gla protein (Mgp) and bone Gla protein (Bgp) are vitamin-K dependent proteins that bind calcium in their γ-carboxylated versions in mammals. They are recognized as positive (Bgp) or negative (Mgp and Bgp) regulators of biomineralization in a number of tissues, including skeletal tissues of bony vertebrates. The Mgp/Bgp gene family is poorly known in cartilaginous fishes, which precludes the understanding of the evolution of the biomineralization toolkit at the emergence of jawed vertebrates. Here we took advantage of recently released genomic and transcriptomic data in cartilaginous fishes and described the genomic loci and gene expression patterns of the Mgp/Bgp gene family. We identified three genes, Mgp1, Mgp2, and Bgp, in cartilaginous fishes instead of the single previously reported Mgp gene. We describe their genomic loci, resulting in a dynamic evolutionary scenario for this gene family including several events of local (tandem) duplications, but also of translocation events, along jawed vertebrate evolution. We describe the expression patterns ofMgp1,Mgp2, andBgpin embryonic stages covering organogenesis in the small-spotted catsharkScyliorhinus caniculaand present a comparative analysis with Mgp/Bgp family members previously described in bony vertebrates, highlighting ancestral features such as early embryonic, soft tissues, and neuronal expressions, but also derived features of cartilaginous fishes such as expression in fin supporting fibers. Our results support an ancestral function of Mgp in skeletal mineralization and a later derived function of Bgp in skeletal development that may be related to the divergence of bony vertebrates.
The Integration Preference of Sleeping Beauty at Non-TA Site Is Related to the Transposon End Sequences
Authors: Zhou Yiting , Ma Guangwei , Yang Jiawen , Gao Zenghong , Guo Yabin
Published: March 2021

Recently, we proved that Sleeping Beauty (SB) transposon integrates into non-TA sites at a lower frequency. Here, we performed a further study on the non-TA integration of SB and showed that (1) SB can integrate into non-TA sites in HEK293T cells as well as in mouse cell lines; (2) Both the hyperactive transposase SB100X and the traditional SB11 catalyze integrations at non-TA sites; (3) The consensus sequence of the non-TA target sites only occurs at the opposite side of the sequenced junction between the transposon end and the genomic sequences, indicating that the integrations at non-TA sites are mainly aberrant integrations; and (4) The consensus sequence of the non-TA target sites is corresponding to the transposon end sequence. The consensus sequences changed following the changes of the transposon ends. This result indicated that the interaction between the SB transposon end and genomic DNA (gDNA) may be involved in the target site selection of the SB integrations at non-TA sites.
COVID-19 and Immigrants’ Increased Exclusion: The Politics of Immigrant Integration in Chile and Peru
Authors: Freier Luisa Feline , Vera Espinoza Marcia
Published: March 2021

The COVID-19 pandemic has put into sharp relief the need for socio-economic integration of migrants, regardless of their migratory condition. In South America, more than five million Venezuelan citizens have been forced to migrate across the region in the past five years. Alongside other intra-regional migrants and refugees, many find themselves in precarious legal and socio-economic conditions, as the surge in numbers has led to xenophobic backlashes in some of the main receiving countries, including Chile and Peru. In this paper, we explore in how far the COVID-19 crisis has offered stakeholders an opportunity to politically reframe migration and facilitate immigrant integration or, rather, further propelled xenophobic sentiments and the socio-economic and legal exclusion of immigrants.
Transcriptome and Differential Methylation Integration Analysis Identified Important Differential Methylation Annotation Genes and Functional Epigenetic Modules Related to Vitiligo
Authors: Pu Yihuan , Chen Xuenuo , Chen Yangmei , Zhang Lingzhao , Chen Jiayi , Zhang Yujie , Shao Xinyi , Chen Jin
Published: March 2021

Vitiligo is an pigmentation disorder caused by a variety of pathogenic factors; its main pathophysiological conditions include oxidative stress, immune activation, and genetic background. Additionally, DNA methylation is often associated with the pathogenesis of vitiligo; however, the underlying mechanism remains unknown. In the present study, we used the Human Methylation 850K BeadChip platform to detect DNA methylation changes in the vitiligo melanocytes. We then integrated the results with the transcriptome data of vitiligo melanocytes and lesions to analyse the correlation between differentially methylated levels and differentially expressed genes. The results showed that there was a significant negative correlation between methylation levels and differentially expressed genes. Subsequently, we enriched GO and KEGG based on methylated differentially expressed genes (MDEGs) using R package ClusterProfiler, and the results were closely related to the pathogenesis of vitiligo. In addition, we also constructed a PPI network of MDEGs and excavated three important functional epigenetic modules, involving a total of 12 (BCL2L1, CDK1, ECT2, HELLS, HSP90AA1, KIF23, MC1R, MLANA, PBK, PTGS2, SOX10, and TYRP1) genes. These genes affect melanocyte melanogenesis, cellular oxidative stress and other important biological processes. Our comprehensive analysis results support the significant contribution of the status of DNA methylation modification to vitiligo, which will help us to better understand the molecular mechanism of vitiligo and explore new therapeutic strategies.
Granulocyte Colony-Stimulating Factor Effectively Mobilizes TCR γδ and NK Cells Providing an Allograft Potentially Enhanced for the Graft-Versus-Leukemia Effect for Allogeneic Stem Cell Transplantation
Authors: Minculescu Lia , Sengelov Henrik , Marquart Hanne Vibeke , Ryder Lars Peter , Fischer-Nielsen Anne , Haastrup Eva
Published: March 2021

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potential cure for patients with hematological malignancies but substantial risks of recurrence of the malignant disease remain. TCR γδ and NK cells are perceived as potent innate effector cells in HSCT and have been associated with post-transplant protection from relapse in clinical studies. Immunocompetent cells from the donor are crucial for patient outcomes and peripheral blood stem cells (PBSC) are being increasingly applied as graft source. G-CSF is the preferential mobilizing agent in healthy donors for PBSC grafts, yet effects of G-CSF on TCR γδ and NK cells are scarcely uncovered and could influence the graft composition and potency of these cells. Therefore, we analyzed T and NK cell subsets and activation markers in peripheral blood samples of 49 donors before and after G-CSF mobilization and—for a subset of donors—also in the corresponding graft samples using multicolor flowcytometry with staining for CD3, CD4, CD8, TCRαβ, TCRγδ, Vδ1, Vδ2, HLA-DR, CD45RA, CD197, CD45RO, HLA-DR, CD16, CD56, and CD314. We found that TCR γδ cells were mobilized and harvested with an efficiency corresponding that of TCR αβ cells. For TCR γδ as well as for TCR αβ cells, G-CSF preferentially mobilized naïve and terminally differentiated effector (TEMRA) cells over memory cells. In the TCR γδ cell compartment, G-CSF preferentially mobilized cells of the nonVδ2 types and increased the fraction of HLA-DR positive TCR γδ cells. For NK cells, mobilization by G-CSF was increased compared to that of T cells, yet NK cells appeared to be less efficiently harvested than T cells. In the NK cell compartment, G-CSF-stimulation preserved the proportion of CD56dim NK effector cells which have been associated with relapse protection. The expression of the activating receptor NKG2D implied in anti-leukemic responses, was significantly increased in both CD56dim and CD56bright NK cells after G-CSF stimulation. These results indicate differentiated mobilization and altering properties of G-CSF which could improve the effects of donor TCR γδ and NK cells in the processes of graft-versus-leukemia for relapse prevention after HSCT.
NKG2D as a Cell Surface Marker on γδ-T Cells for Predicting Pregnancy Outcomes in Patients With Unexplained Repeated Implantation Failure
Authors: Huang Chunyu , Xiang Zheng , Zhang Yongnu , Li Yuye , Xu Jian , Zhang Hongzhan , Zeng Yong , Tu Wenwei
Published: March 2021

Maternal immune tolerance to semi-allogeneic fetus is essential for a successful implantation and pregnancy. Growing evidence indicated that low cytotoxic activity of γδ-T cells, which is mediated by activation and inhibitory receptors, is important for establishment of maternal immune tolerant microenvironment. However, the correlation between receptors on peripheral blood γδ-T cells, such as NKG2D, CD158a, and CD158b, and pregnancy outcome in patients with unexplained repeated implantation failure (uRIF) remains unclear. In this study, the association between the expression level of these receptors and pregnancy outcome in patients with uRIF was investigated. Thirty-eight women with uRIF were enrolled and divided into two groups: successful group and failed group, according to the pregnancy outcome on different gestational periods. The percentage of NKG2D+γδ-T cells in lymphocytes was significantly higher in uRIF patients who had failed clinical pregnancy in subsequent cycle, compared with those who had successful clinical pregnancy. However, there were no differences about the frequencies of CD158a+and CD158b+γδ-T cells between the successful and failed groups. The receiver operating characteristic curve exhibited that the optimal cut-off value of NKG2D+γδ-T cells was 3.24%, with 92.3% sensitivity and 66.7% specificity in predicting clinical pregnancy failure in uRIF patients. The patients with uRIF were further divided into two groups, group 1 (NKG2D+γδ-T cells <3.24%) and group 2 (NKG2D+γδ-T cells ≥3.24%), based on the cut-off value. The live birth rate of patients in the group 1 and group 2 were 61.5 and 28.0%, respectively. Kaplan-Meier survival curve further suggested that the frequency of NKG2D+γδ-T cells in lymphocytes negatively correlated with live birth rate in patients with uRIF. In conclusion, our study demonstrated that the frequency of peripheral blood NKG2D+γδ-T cells among lymphocytes is a potential predictor for pregnancy outcome in uRIF patients.
Immune Soluble Factors in the Cerebrospinal Fluid of Progressive Multiple Sclerosis Patients Segregate Into Two Groups
Authors: Donninelli Gloria , Studer Valeria , Brambilla Laura , Zecca Chiara , Peluso Daniele , Laroni Alice , Michelis Daniele , Mantegazza Renato , Confalonieri Paolo , Volpe Elisabetta
Published: March 2021

Primary-progressive (PP) and secondary-progressive (SP) multiple sclerosis (MS) are characterized by neurological deficits caused by a permanent neuronal damage, clinically quantified by the expanded disability status scale (EDSS). Neuronal tissue damage is also mediated by immune infiltrates producing soluble factors, such as cytokines and chemokines, which are released in the cerebrospinal fluid (CSF). The mechanisms regulating the production of a soluble factor are not completely defined. Using multiplex bead-based assays, we simultaneously measured 27 immune soluble factors in the CSF collected from 38 patients, 26 with PP-MS and 12 with SP-MS. Then, we performed a correlation matrix of all soluble factors expressed in the CSF. The CSF from patients with PP-MS and SP-MS had similar levels of cytokines and chemokines; however, the stratification of patients according to active or inactive magnetic resonance imaging (MRI) unveils some differences. Correlative studies between soluble factors in the CSF of patients with PP-MS and SP-MS revealed two clusters of immune mediators with pro-inflammatory functions, namely IFN-γ, MCP-1, MIP-1α, MIP-1β, IL-8, IP-10, and TNF-α (group 1), and anti-inflammatory functions, namely IL-9, IL-15, VEGF, and IL-1ra (group 2). However, most of the significant correlations between cytokines of group 1 and of group 2 were lost in patients with more severe disability (EDSS ≥ 4) compared to patients with mild to moderate disability (EDSS < 4). These results suggest a common regulation of cytokines and chemokines belonging to the same group and indicate that, in patients with more severe disability, the production of those factors is less coordinated, possibly due to advanced neurodegenerative mechanisms that interfere with the immune response.
Harnessing and Enhancing Macrophage Phagocytosis for Cancer Therapy
Authors: Chen Siqi , Lai Seigmund W. T. , Brown Christine E. , Feng Mingye
Published: March 2021

Cancer immunotherapy has revolutionized the paradigm for the clinical management of cancer. While FDA-approved cancer immunotherapies thus far mainly exploit the adaptive immunity for therapeutic efficacy, there is a growing appreciation for the importance of innate immunity in tumor cell surveillance and eradication. The past decade has witnessed macrophages being thrust into the spotlight as critical effectors of an innate anti-tumor response. Promising evidence from preclinical and clinical studies have established targeting macrophage phagocytosis as an effective therapeutic strategy, either alone or in combination with other therapeutic moieties. Here, we review the recent translational advances in harnessing macrophage phagocytosis as a pivotal therapeutic effort in cancer treatment. In addition, this review emphasizes phagocytosis checkpoint blockade and the use of nanoparticles as effective strategies to potentiate macrophages for phagocytosis. We also highlight chimeric antigen receptor macrophages as a next-generation therapeutic modality linking the closely intertwined innate and adaptive immunity to induce efficacious anti-tumor immune responses.
Regulation of Intestinal Stem Cell Stemness by the Aryl Hydrocarbon Receptor and Its Ligands
Authors: Wisniewski Paul J. , Nagarkatti Mitzi , Nagarkatti Prakash S.
Published: March 2021

Maintenance of intestinal homeostasis requires the integration of immunological and molecular processes together with environmental, diet, metabolic and microbial cues. Key to this homeostasis is the proper functioning of epithelial cells originating from intestinal stem cells (ISCs). While local factors and numerous molecular pathways govern the ISC niche, the conduit through which these processes work in concordance is the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, whose role in immunoregulation is critical at barrier surfaces. In this review, we discuss how AhR signaling is emerging as one of the critical regulators of molecular pathways involved in epithelial cell renewal. In addition, we examine the putative contribution of specific AhR ligands to ISC stemness and epithelial cell fate.
Natural Killer Cell Integrins and Their Functions in Tissue Residency
Authors: Shannon Michael J. , Mace Emily M.
Published: March 2021

Integrins are transmembrane receptors associated with adhesion and migration and are often highly differentially expressed receptors amongst natural killer cell subsets in microenvironments. Tissue resident natural killer cells are frequently defined by their differential integrin expression compared to other NK cell subsets, and integrins can further localize tissue resident NK cells to tissue microenvironments. As such, integrins play important roles in both the phenotypic and functional identity of NK cell subsets. Here we review the expression of integrin subtypes on NK cells and NK cell subsets with the goal of better understanding how integrin selection can dictate tissue residency and mediate function from the nanoscale to the tissue environment.
Deciphering the Prognostic Implications of the Components and Signatures in the Immune Microenvironment of Pancreatic Ductal Adenocarcinoma
Authors: Tang Rong , Liu Xiaomeng , Liang Chen , Hua Jie , Xu Jin , Wang Wei , Meng Qingcai , Liu Jiang , Zhang Bo , Yu Xianjun , Shi Si
Published: March 2021

Background: The treatment modalities for pancreatic ductal adenocarcinoma (PDAC) are limited and unsatisfactory. Although many novel drugs targeting the tumor microenvironment, such as immune checkpoint inhibitors, have shown promising efficacy for some tumors, few of them significantly prolong the survival of patients with PDAC due to insufficient knowledge on the tumor microenvironment.

Methods: A single-cell RNA sequencing (scRNA-seq) dataset and seven PDAC cohorts with complete clinical and bulk sequencing data were collected for bioinformatics analysis. The relative proportions of each cell type were estimated using the gene set variation analysis (GSVA) algorithm based on the signatures identified by scRNA-seq or previous literature.

Results: A meta-analysis of 883 PDAC patients showed that neutrophils are associated with worse overall survival (OS) for PDAC, while CD8+ T cells, CD4+ T cells, and B cells are related to prolonged OS for PDAC, with marginal statistical significance. Seventeen cell categories were identified by clustering analysis based on single-cell sequencing. Among them, CD8+ T cells and NKT cells were universally exhausted by expressing exhaustion-associated molecular markers. Interestingly, signatures of CD8+ T cells and NKT cells predicted prolonged OS for PDAC only in the presence of “targets” for pyroptosis and ferroptosis induction. Moreover, a specific state of T cells with overexpression of ribosome-related proteins was associated with a good prognosis. In addition, the hematopoietic stem cell (HSC)-like signature predicted prolonged OS in PDAC. Weighted gene co-expression network analysis identified 5 hub genes whose downregulation may mediate the observed survival benefits of the HSC-like signature. Moreover, trajectory analysis revealed that myeloid cells evolutionarily consisted of 7 states, and antigen-presenting molecules and complement-associated genes were lost along the pseudotime flow. Consensus clustering based on the differentially expressed genes between two states harboring the longest pseudotime span identified two PDAC groups with prognostic differences, and more infiltrated immune cells and activated immune signatures may account for the survival benefits.

Conclusion: This study systematically investigated the prognostic implications of the components of the PDAC tumor microenvironment by integrating single-cell sequencing and bulk sequencing, and future studies are expected to develop novel targeted agents for PDAC treatment.
Meiotic Spindle Formation Following Inhibition of First Polar Body Formation in the Zhikong Scallop (Chlamys farreri Jones et Preston)
Authors: Li Yongren , Zhang Baolu , Liang Shuang , Guo Yongjun
Published: March 2021

Fertilized Zhikong scallop (Chlamys farreri) eggs were treated with cytochalasin B (CB 0.5 mg/L) at 14–15 min postfertilization to inhibit first polar body formation. The eggs were then stained with fluorescein isothiocyanate (FITC) -anti-α-tubulin and propidium iodide (PI) to examine their microtubule patterns and chromosome, respectively. Fluorescent microscope observations of treated eggs sampled every 2–3 min during meiotic maturation revealed meiotic apparatus assembly and correlated chromosome segregation. In CB-treated groups, meiosis I proceeded normally and produced two groups of dyads, with 19 in each group. Both dyad groups were retained in the eggs as they entered meiosis II. Two, three, or four asters (centrosome with microtubules around it) in meiosis II rearranged the spindle in several patterns: bipolar [24.0 ± 4.1 μm (long axis) × 18.3 ± 4.1 μm (diameter: metaphase plate)], tripolar (18.6 ± 3.9 μm × 9.9 ± 1.3 μm), separated bipolar (18.3 ± 2.8 μm × 11.2 ± 1.8 μm), and other unclassified spindle patterns. Corresponding chromosome segregation, including bipolar (18.9%), tripolar (38.9%), double bipolar (16.5%), and unclassified (25.6%), was observed during meiosis II in CB-treated eggs. The data indicated that chromosome segregation patterns determined by spindle patterns were critically influenced by the number of centrosomes in meiosis II eggs following inhibition of polar body 1 (PB1) formation with CB.
Case Report: Premature Ventricular Beats-Induced Chronic Cough and Cough Syncope
Authors: Hu Yue , Hua Wen , Li Na , Huang Huaqiong
Published: March 2021

Background: Chronic cough is a common complaint that in rare cases can be caused by premature ventricular beats (PVCs).

Materials and Methods: In this report, we present the case of a healthy 44-year-old female who presented persistent cough and cough syncope that was attributed to PVCs.

Results: The cough disappeared after radiofrequency ablation, and no recurrence of arrhythmia or cough was observed.

Conclusion: PVCs should be considered a probable cause of chronic cough and cough syncope in differential diagnosis.
Impact of Rocky Desertification Control on Soil Bacterial Community in Karst Graben Basin, Southwestern China
Authors: Li Qiang , Song Ang , Yang Hui , Müller Werner E. G.
Published: March 2021

Microorganisms play critical roles in belowground ecosystems, and karst rocky desertification (KRD) control affects edaphic properties and vegetation coverage. However, the relationship between KRD control and soil bacterial communities remains unclear. 16S rRNA gene next-generation sequencing was used to investigate soil bacterial community structure, composition, diversity, and co-occurrence network from five ecological types in KRD control area. Moreover, soil physical-chemical properties and soil stoichiometry characteristics of carbon, nitrogen and phosphorus were analyzed. Soil N and P co-limitation decreased in the contribution of the promotion of KRD control on edaphic properties. Though soil bacterial communities appeared strongly associated with soil pH, soil calcium, soil phosphorus and plant richness, the key factor to determine their compositions was the latter via changed edaphic properties. The co-occurrence network analysis indicated that soil bacterial network complexity in natural ecosystem was higher than that in additional management ecosystem.Candidatus Udaeobacter,Chthoniobacterales, andPedosphaeraceaewere recognized as the key taxa maintaining karst soil ecosystems in KRD control area. Our results indicate that natural recovery is the suitable way for restoration and rehabilitation of degraded ecosystems, and thus contribute to the ongoing endeavor to appraise the interactions among soil-plant ecological networks.
The Redox Proteome of Thiol Proteins in the Rice Blast Fungus Magnaporthe oryzae
Authors: Zhang Xinrong , Zhang Zhenhua , Chen Xiao-Lin
Published: March 2021

Redox modification, a post-translational modification, has been demonstrated to be significant for many physiological pathways and biological processes in both eukaryotes and prokaryotes. However, little is known about the global profile of protein redox modification in fungi. To explore the roles of redox modification in the plant pathogenic fungi, a global thiol proteome survey was performed in the model fungal pathogen Magnaporthe oryzae. A total of 3713 redox modification sites from 1899 proteins were identified through a mix sample containing mycelia with or without oxidative stress, conidia, appressoria, and invasive hyphae of M. oryzae. The identified thiol-modified proteins were performed with protein domain, subcellular localization, functional classification, metabolic pathways, and protein–protein interaction network analyses, indicating that redox modification is associated with a wide range of biological and cellular functions. These results suggested that redox modification plays important roles in fungal growth, conidium formation, appressorium formation, as well as invasive growth. Interestingly, a large number of pathogenesis-related proteins were redox modification targets, suggesting the significant roles of redox modification in pathogenicity of M. oryzae. This work provides a global insight into the redox proteome of the pathogenic fungi, which built a groundwork and valuable resource for future studies of redox modification in fungi.
Multidimensional Face Representation in a Deep Convolutional Neural Network Reveals the Mechanism Underlying AI Racism
Authors: Tian Jinhua , Xie Hailun , Hu Siyuan , Liu Jia
Published: March 2021

The increasingly popular application of AI runs the risk of amplifying social bias, such as classifying non-white faces as animals. Recent research has largely attributed this bias to the training data implemented. However, the underlying mechanism is poorly understood; therefore, strategies to rectify the bias are unresolved. Here, we examined a typical deep convolutional neural network (DCNN), VGG-Face, which was trained with a face dataset consisting of more white faces than black and Asian faces. The transfer learning result showed significantly better performance in identifying white faces, similar to the well-known social bias in humans, the other-race effect (ORE). To test whether the effect resulted from the imbalance of face images, we retrained the VGG-Face with a dataset containing more Asian faces, and found a reverse ORE that the newly-trained VGG-Face preferred Asian faces over white faces in identification accuracy. Additionally, when the number of Asian faces and white faces were matched in the dataset, the DCNN did not show any bias. To further examine how imbalanced image input led to the ORE, we performed a representational similarity analysis on VGG-Face's activation. We found that when the dataset contained more white faces, the representation of white faces was more distinct, indexed by smaller in-group similarity and larger representational Euclidean distance. That is, white faces were scattered more sparsely in the representational face space of the VGG-Face than the other faces. Importantly, the distinctiveness of faces was positively correlated with identification accuracy, which explained the ORE observed in the VGG-Face. In summary, our study revealed the mechanism underlying the ORE in DCNNs, which provides a novel approach to studying AI ethics. In addition, the face multidimensional representation theory discovered in humans was also applicable to DCNNs, advocating for future studies to apply more cognitive theories to understand DCNNs' behavior.
Eye Movement Technique to Improve Executive Function in Patients With Stroke: A Randomized Controlled Trial
Authors: He Wen , Ji Yazheng , Wei Xiating , Wang Fan , Xu Feng , Lu Chengyi , Ma Qianqian , Wang Kai
Published: March 2021

Objective: To investigate the efficacy of eye movement technique for the treatment of executive dysfunction of patients with stroke.

Methods: This was a prospective, single-blinded, randomized, controlled, single-center clinical trial conducted from June 2018 to December 2019 in patients with stroke. The patients were randomized 1:1 to the routine (conventional management) and eye-move group (routine management plus eye movement technique: 5-min goal management training, 5-min computer-aided working memory, and 10 min of inhibitory control training and set conversion training). The intervention lasted 6 weeks, followed by a 4-week follow-up. The primary endpoint was the Behavioral Assessment of the Dysexecutive Syndrome (BADS) score. The secondary endpoints mainly included the Montreal Cognitive Assessment (MoCA), Wisconsin Card Sorting Test (WCST), and modified Barthel Index (MBI) scores.

Results: Sixty-four patients were enrolled (32/group). After the 6-week intervention, the BADS and WCST scores of the eye-move group were significantly improved than those of the routine group (all P < 0.05), but the effects were attenuated in certain subscores after follow-up (all P > 0.05). The MoCA and MBI scores of the eye-move group were significantly higher, and the reaction time was significantly lower than those of the routine group at 4 weeks after the intervention (all P < 0.05). After follow-up, the MBI scores of the eye-move group were still higher than that of the routine group (P < 0.001), but there were no differences for MoCA scores and reaction time (both P > 0.05).

Conclusion: The eye movement technique could improve the executive function of patients with stroke. These results have to be confirmed.

This was a prospective, single-blinded, randomized, controlled, single-center clinical trial (ChiCTR2000036393).

Clinical Trial Registration: [www.chictr.org.cn], identifier [ChiCTR2000036393].
Clinical and VNG Features in Anterior Canal BPPV—An Analysis of 13 Cases
Authors: Porwal Prateek , V. R. Ananthu , Pawar Vishal , Dorasala Srinivas , Bijlani Avinash , Nair Prem , Nayar Ravi
Published: March 2021

Objective: To define diagnostic VNG features in anterior canal BPPV during positional testing (Dix-Hallpike, supine head hanging, and McClure Pagnini tests).

Study Design: A retrospective study of patients diagnosed with anterior canal BPPV across four referral centers in New Delhi, Kochi, Bangalore, and Dubai.

Subjects and Methods: Clinical records of 13 patients with AC BPPV out of 1,350 cases, during a 3-years period, were reviewed and analyzed by four specialists.

Results: Four patients had positional down beating nystagmus with symptoms of vertigo during the bilateral DHP maneuver. Seven cases had positional down beating nystagmus only on one side of DHP. Typical down beating nystagmus was seen in 10 out of 13 cases during the straight head hanging maneuver. Down beating torsional nystagmus was seen in 6 out of 13 cases. Down beating with horizontal nystagmus was seen in three cases (in DHP and MCP mainly) while pure down beating nystagmus during SHH was only seen in four cases.

Conclusion: We conclude that anterior canal BPPV is a rare but definite entity. It may not be apparent on positional testing the first time, so repeated testing may be needed. The most consistent diagnostic maneuver is SHH though there were patients in which findings could only be elicited using DHP testing. We recommend a testing protocol that includes DHP testing on both sides and SHH. MCP testing may also evoke DBN with or without the torsional component. Reversal of nystagmus on reversal of testing position is unusual but can occur. The Yacovino maneuver is effective in resolving AC BPPV. We also propose a hypothesis that explains why DHP testing is sensitive to AC BPPV on either side, whereas MCP lateral position on one side is only sensitive to AC BPPV on one side. We have explained a possible role for the McClure Pagnini test in side determination and therapeutic implications.
A Case–Control Study of the Effects of Chimarrão (Ilex paraguariensis) and Coffee on Parkinson's Disease
Authors: Medeiros Márcio Schneider , Schumacher-Schuh Artur Francisco , Altmann Vivian , Rieder Carlos Roberto de Mello
Published: March 2021

Introduction: Coffee has been inversely associated with Parkinson's disease (PD) in many studies, and caffeine is the leading candidate to mediate this effect. Mate (Ilex paraguariensis, IP), a caffeinated beverage rich in antioxidants consumed in South America, was also inversely associated with PD in one study from Argentina. Other varieties of IP infusion, such as chimarrão, were never studied in PD. Chimarrão is a common caffeinated beverage consumed in Brazil made with the leaves and stems of IP.

Methods: A case–control study was conducted to evaluate the relationship between chimarrão ingestion and PD in southern Brazil. All subjects answered a questionnaire about the frequency of chimarrão and coffee intake. A multiple regression analysis adjusted for age and sex was performed to assess the association between PD and chimarrão consumption.

Results: We included 200 PD patients and 200 healthy controls. High consumption of chimarrão was inversely associated with PD (OR = 0.44, 95% CI = 0.24–0.81, P = 0.008). High consumption of coffee was also inversely associated with PD, as expected. Chimarrão remained associated when adjusted for coffee consumption, smoking history, and age (OR 0.46, 95% CI = 0.25–0.86, P = 0.014). These two exposures showed an additive effect.

Conclusion:Chimarrão consumption was inversely associated with PD, even after adjusting for coffee intake, suggesting a possible protective role. IP's effect can be mediated by caffeine and through its antioxidant components. Chimarrão has a lower concentration of caffeine compared with coffee and has numerous substances with antioxidative effects that may be important to PD protection. Further studies are needed to test this hypothesis.