bluuebunny/crossref_metadata_2025 huggingface dataset:
The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease
Authors: Murphy Jiayuan , Le Tran Ngoc Van , Fedorova Julia , Yang Yi , Krause-Hauch Meredith , Davitt Kayla , Zoungrana Linda Ines , Fatmi Mohammad Kasim , Lesnefsky Edward J. , Li Ji , Ren Di
Published: February 2022

A progressive defect in the energy generation pathway is implicated in multiple aging-related diseases, including cardiovascular conditions and Alzheimer's Disease (AD). However, evidence of the pathogenesis of cardiac dysfunction in AD and the associations between the two organ diseases need further elucidation. This study aims to characterize cellular defects resulting in decreased cardiac function in AD-model. 5XFAD mice, a strain expressing five mutations in human APP and PS1 that shows robust Aβ production with visible plaques at 2 months and were used in this study as a model of AD. 5XFAD mice and wild-type (WT) counterparts were subjected to echocardiography at 2-, 4-, and 6-month, and 5XFAD had a significant reduction in cardiac fractional shortening and ejection fraction compared to WT. Additionally, 5XFAD mice had decreased observed electrical signals demonstrated as decreased R, P, T wave amplitudes. In isolated cardiomyocytes, 5XFAD mice showed decreased fraction shortening, rate of shortening, as well as the degree of transient calcium influx. To reveal the mechanism by which AD leads to cardiac systolic dysfunction, the immunoblotting analysis showed increased activation of AMP-activated protein kinase (AMPK) in 5XFAD left ventricular and brain tissue, indicating altered energy metabolism. Mito Stress Assays examining mitochondrial function revealed decreased basal and maximal oxygen consumption rate, as well as defective pyruvate dehydrogenase activity in the 5XFAD heart and brain. Cellular inflammation was provoked in the 5XFAD heart and brain marked by the increase of reactive oxygen species accumulation and upregulation of inflammatory mediator activities. Finally, AD pathological phenotype with increased deposition of Aβ and defective cognitive function was observed in 6-month 5XFAD mice. In addition, elevated fibrosis was observed in the 6-month 5XFAD heart. The results implicated that AD led to defective mitochondrial function, and increased inflammation which caused the decrease in contractility of the heart.
Effects of Plate Velocity Slowdown on Altering Continental Collision Patterns and Crustal-Lithospheric Deformation During the Collision Process
Authors: Liu Mengxue , Yang Dinghui , Huangfu Pengpeng
Published: February 2022

Continental collision zones are widely distributed across the earth’s surface with diverse types of tectonic processes. Even the same collision zone shows significant lateral tectonic variations along its strike. In this study, we systematically investigated how plate velocity slowdown after the closure of the ocean influences the continental collision evolution, as well as the effects of kinematic characteristics and continental rheology on varying the continental collision modes in a plate velocity slowdown model. From the comparison between the constant plate velocity system (CVS) and the plate velocity-dropping system (VDS), we can conclude the following: Plate velocity dropping promotes the extension inside the slab by decreasing the movement of the surface plate, whereas slab pull increases as subduction continues. The timing of the subducting slab break-off and the polarity alteration was initiated earlier in the plate velocity drop models than in the constant plate velocity models, and fast convergence may have triggered multiple episodes of slab break-off and caused strong deformation adjacent to the collision zone. Parametric tests of the initial subducting angle, plate convergence velocity, and continental crustal rheological strength in VDS indicated the following: (1) Three end members of the continental lithospheric mantle deformation modes were identified from the VDS; (2) models with a low subducting angle, fast continental convergence velocity, and medium-strength overriding crust were more likely to evolve into a polarity reversed mode, whereas steep-subducting-angle, slow-plate-velocity, weak-overriding-crust models tended toward a two-sided mode; (3) a strong overriding continent is more liable to develop a stable mode; and (4) overriding crustal rheological strength plays a significant role in controlling changes in continental collision modes.
Diagnostic Classification Models for Actionable Feedback in Education: Effects of Sample Size and Assessment Length
Authors: Maas Lientje , Brinkhuis Matthieu J. S. , Kester Liesbeth , Wijngaards-de Meij Leoniek
Published: February 2022

E-learning is increasingly used to support student learning in higher education. This results in huge amounts of item response data containing valuable information about students’ strengths and weaknesses that can be used to provide effective feedback to both students and teachers. However, in current practice, feedback in e-learning is often given in the form of a simple proportion of correctly solved items rather than diagnostic, actionable feedback. Diagnostic classification models (DCMs) provide opportunities to model the item response data from formative assessments in online learning environments and to obtain diagnostic information to improve teaching and learning. This simulation study explores the demands on the data structure (i.e., assessment length, respondent sample size) to apply log-linear DCMs to empirical data. Thereby we provide guidance to educational practitioners on how many items need to be administered to how many students in order to accurately assess skills at different levels of specificity using DCMs. In addition, effects of misspecification of the dimensionality of the assessed skills on model fit indices are explored. Results show that detecting these misspecifications statistically with DCMs can be problematic. Recommendations and implications for educational practice are discussed.
Mapping Motor Neuron Vulnerability in the Neuraxis of Male SOD1G93A Mice Reveals Widespread Loss of Androgen Receptor Occurring Early in Spinal Motor Neurons
Authors: McLeod Victoria M. , Chiam Mathew D. F. , Perera Nirma D. , Lau Chew L. , Boon Wah Chin , Turner Bradley J.
Published: February 2022

Sex steroid hormones have been implicated as disease modifiers in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Androgens, signalling via the androgen receptor (AR), predominate in males, and have widespread actions in the periphery and the central nervous system (CNS). AR translocates to the cell nucleus when activated upon binding androgens, whereby it regulates transcription of target genes via the classical genomic signalling pathway. We previously reported that AR protein is decreased in the lumbar spinal cord tissue of symptomatic male SOD1G93A mice. Here, we further explored the changes in AR within motor neurons (MN) of the CNS, assessing their nuclear AR content and propensity to degenerate by endstage disease in male SOD1G93A mice. We observed that almost all motor neuron populations had undergone significant loss in nuclear AR in SOD1G93A mice. Interestingly, loss of nuclear AR was evident in lumbar spinal MNs as early as the pre-symptomatic age of 60 days. Several MN populations with high AR content were identified which did not degenerate in SOD1G93A mice. These included the brainstem ambiguus and vagus nuclei, and the sexually dimorphic spinal MNs: cremaster, dorsolateral nucleus (DLN) and spinal nucleus of bulbocavernosus (SNB). In conclusion, we demonstrate that AR loss directly associates with MN vulnerability and disease progression in the SOD1G93A mouse model of ALS.
Vaginal Microbiota Changes in Patients With Premature Ovarian Insufficiency and Its Correlation With Ovarian Function
Authors: Wen Jingyi , Feng Yanzhi , Yan Wei , Yuan Suzhen , Zhang Jinjin , Luo Aiyue , Wang Shixuan
Published: February 2022

Objectives

To reveal the characteristics of vaginal microbiota in premature ovarian insufficiency (POI) patients and their relationship with ovarian function.

Materials and Methods

In this case-control study, the vaginal bacterial composition of 30 POI patients and 26 healthy women of comparable age was assessed by 16S rRNA gene sequencing targeting the V3-V4 hypervariable regions. The metabolic functions of vaginal microflora were preliminarily predicted through the PICRUSt2 analysis. Redundancy analysis and Spearman’s correlation analyzed the relationships between vaginal microbiota and ovarian function indicators.

Results

Actinobacteria, Atopobium, and Gardnerella were significantly increased in POI patients. Their increments were significantly negatively correlated with anti-müllerian hormone (AMH) and inhibin B, and positively correlated with follicle-stimulating hormone (FSH) and luteinizing hormone (LH). While Bifidobacterium was significantly decreased in POI patients. Its relative abundance was significantly positively correlated with AMH and negatively correlated with FSH and LH. Then, POI patients included in this study were divided into POI (25 < FSH ≤ 40) (n = 9) and premature ovarian failure (POF) (FSH > 40) (n = 21) subgroups according to serum FSH levels. Compared with the controls, Firmicutes and Lactobacillus were significantly decreased only in POF (FSH > 40) patients, while no difference was observed in POI (25 < FSH ≤ 40) patients. Lactobacillus was negatively correlated with FSH. Firmicutes was significantly reduced and Actinobacteria was significantly increased in POF (FSH > 40) patients compared with POI (25 < FSH ≤ 40) patients. The key bacterial taxa Gardnerella and Atopobium showed potency in predicting POI.

Conclusions

Here we demonstrated significant changes in the vaginal microbiota of POI patients, and these changes were significantly correlated with reduced ovarian reserve, endocrine disruption, and symptoms of perimenopausal syndrome. Differences in vaginal microbiota between POI (25 < FSH ≤ 40) and POF (FSH > 40) patients were also identified. These findings may provide new evidence for the relationship between vaginal microbiota and ovarian function.
Melatonin Accelerates Osteoporotic Bone Defect Repair by Promoting Osteogenesis–Angiogenesis Coupling
Authors: Zheng Sheng , Zhou Chunhao , Yang Han , Li Junhua , Feng Ziyu , Liao Liqing , Li Yikai
Published: February 2022

Previous studies have revealed that melatonin could play a role in anti-osteoporosis and promoting osteogenesis. However, the effects of melatonin treatment on osteoporotic bone defect and the mechanism underlying the effects of melatonin on angiogenesis are still unclear. Our study was aimed to investigate the potential effects of melatonin on angiogenesis and osteoporotic bone defect. Bone marrow mesenchymal stem cells (BMSCs) were isolated from the femur and tibia of rats. The BMSC osteogenic ability was assessed using alkaline phosphatase (ALP) staining, alizarin red S staining, qRT-PCR, western blot, and immunofluorescence. BMSC-mediated angiogenic potentials were determined using qRT-PCR, western blot, enzyme-linked immunosorbent assay, immunofluorescence, scratch wound assay, transwell migration assay, and tube formation assay. Ovariectomized (OVX) rats with tibia defect were used to establish an osteoporotic bone defect model and then treated with melatonin. The effects of melatonin treatment on osteoporotic bone defect in OVX rats were analyzed using micro-CT, histology, sequential fluorescent labeling, and biomechanical test. Our study showed that melatonin promoted both osteogenesis and angiogenesis in vitro. BMSCs treated with melatonin indicated higher expression levels of osteogenesis-related markers [ALP, osteocalcin (OCN), runt-related transcription factor 2, and osterix] and angiogenesis-related markers [vascular endothelial growth factor (VEGF), angiopoietin-2, and angiopoietin-4] compared to the untreated group. Significantly, melatonin was not able to facilitate human umbilical vein endothelial cell angiogenesis directly, but it possessed the ability to promote BMSC-mediated angiogenesis by upregulating the VEGF levels. In addition, we further found that melatonin treatment increased bone mineralization and formation around the tibia defect in OVX rats compared with the control group. Immunohistochemical staining indicated higher expression levels of osteogenesis-related marker (OCN) and angiogenesis-related markers (VEGF and CD31) in the melatonin-treated OVX rats. Then, it showed that melatonin treatment also increased the bone strength of tibia defect in OVX rats, with increased ultimate load and stiffness, as performed by three-point bending test. In conclusion, our study demonstrated that melatonin could promote BMSC-mediated angiogenesis and promote osteogenesis–angiogenesis coupling. We further found that melatonin could accelerate osteoporotic bone repair by promoting osteogenesis and angiogenesis in OVX rats. These findings may provide evidence for the potential application of melatonin in osteoporotic bone defect.
Edge Computing Application, Architecture, and Challenges in Ubiquitous Power Internet of Things
Authors: Liu Dongqi , Liang Haolan , Zeng Xiangjun , Zhang Qiong , Zhang Zidong , Li Minhong
Published: February 2022

The Ubiquitous Power Internet of Things (UPIoT) is a concrete manifestation of the Internet of things (IoT) in the power industry, which is a deep integration of the interconnected power network and communication network, realizing full perception of the system status and full business penetration in all links of power production, transmission, and consumption. The introduction of edge computing in UPIoT fully meets the requirements of rapid response, real-time perception, and to some extent, privacy protection. However, there is currently no comprehensive investigation on the application of edge computing technology in UPIoT. First, this paper introduces the development background and construction of UPIoT and its technical architecture. Then the challenges faced by UPIoT in the process of construction are analyzed. Furthermore, the paper elaborates on the functions and features of edge computing, proposes that the support of edge computing technology can solve the challenges of efficient, fast, and secure processing of massive edge data faced by the traditional cloud-based centralized big data processing technology of UPIoT, and analyzes the architecture of the edge computing-assisted UPIoT. For the three typical scenarios of UPIoT, namely power monitoring system, smart energy system and power metering system, the edge computing architecture of the three scenarios are analyzed, and the specific application methods and roles played by edge computing in the three scenarios are also elaborated. Finally, we discuss the challenges of edge computing in UPIoT, in terms of policy challenges, market challenges, and technical challenges, as well as outline the outlooks of the technical challenges.
Drivers of Ecological and Evolutionary Disruptions in the Seed Dispersal Process: Research Trends and Biases
Authors: Donoso Isabel , Fricke Evan C. , Hervías-Parejo Sandra , Rogers Haldre S. , Traveset Anna
Published: February 2022

As the sole opportunity for most plants to move, seed dispersal influences the biodiversity and functioning of plant communities. Global change drivers have the potential to disrupt seed dispersal processes, affecting plant communities and ecosystem functions. Even though much information is available on the effects of seed dispersal disruption (SDD), we still lack a comprehensive understanding of its main causes at a global scale, as well as the potential knowledge gaps derived from research biases. Here we present a systematic review of biotic and abiotic SDDs to ascertain the global change drivers addressed, dispersal modes impacted, plant processes affected, and spatial focus of existing research on this topic up-to-date. Although there are many modes of dispersal and global change drivers in temperate and tropical ecosystems worldwide, research efforts have predominantly addressed the effect of alien species for biotic seed dispersal in temperate systems and oceanic islands as well as how defaunation of bird or mammal dispersers has affected seed removal in the Neotropics. SDD studies were also biased toward forest ecosystems, with few in shrublands or grasslands. Finally, the effects of climate change, ecological consequences at the whole community level, and evolutionary changes were largely unrepresented in SDD studies. These trends are likely due to a combination of true geographic and ecological patterns in seed dispersal and global change and bias in research focus. We conclude that increased research investment in the less-studied systems and a better understanding of potential synergies and feedback between multiple global change drivers will be important to forecast the threats to plant biodiversity and those ecosystem functions derived from seed dispersal in the Anthropocene.
Decadal Patterns of Forest and Pollinator Recovery Following the Eradication of an Invasive Shrub
Authors: Ulyshen Michael D. , Horn Scott , Hanula James L.
Published: February 2022

Invasive non-native woody shrubs pose a major threat to forested ecosystems in many parts of the world and there is an urgent need for research on the restoration and recovery of these areas. We studied patterns of tree growth and regeneration 13 years after the experimental eradication (by chainsaw or mulching machine followed by herbicide treatments) ofLigustrum sinenseLour. (Chinese privet) from riparian forests in Georgia, United States. We also followed the recovery of bee and butterfly populations using sites with no history of privet invasion as a reference. By the end of the study, the basal area of restored plots was 24% greater, on average, than still-invaded control plots. Because tree growth rates did not differ among treatments, this increase is attributable to the 60% increase in the number of regenerating native stems (dominated byAcer negundoL.) following privet removal. The benefits of privet removal on pollinators were immediate and long-lasting with the richness and abundance of bees and butterflies being consistently higher in restored plots than in control plots. The diversity, abundance, and composition of bees in restored and reference (i.e., never invaded) plots were comparable by the end of the study. This was less true for butterflies, however, possibly due to the legacy effects of privet invasion on plant communities. Our results demonstrate the long-term benefits of removing privet on forest regeneration and pollinator communities. Indeed, without such efforts, it is probable that forest cover will gradually thin and ultimately disappear from privet-invaded areas as overstory trees die without replacement.
Development and Validation of a Novel Stemness-Index-Related Long Noncoding RNA Signature for Breast Cancer Based on Weighted Gene Co-Expression Network Analysis
Authors: Qian Da , Qian Cheng , Ye Buyun , Xu Ming , Wu Danping , Li Jialu , Li Dong , Yu Bin , Tao Yijing
Published: February 2022

Background: Breast cancer (BC) is a major leading cause of woman deaths worldwide. Increasing evidence has revealed that stemness features are related to the prognosis and progression of tumors. Nevertheless, the roles of stemness-index-related long noncoding RNAs (lncRNAs) in BC remain unclear.

Methods: Differentially expressed stemness-index-related lncRNAs between BC and normal samples in The Cancer Genome Atlas database were screened based on weighted gene co-expression network analysis and differential analysis. Univariate Cox and least absolute shrinkage and selection operator regression analyses were performed to identify prognostic lncRNAs and construct a stemness-index-related lncRNA signature. Time-dependent receiver operating characteristic curves were plotted to evaluate the predictive capability of the stemness-index-related lncRNA signature. Moreover, correlation analysis and functional enrichment analyses were conducted to investigate the stemness-index-related lncRNA signature-related biological function. Finally, a quantitative real-time polymerase chain reaction was used to detect the expression levels of lncRNAs.

Results: A total of 73 differentially expressed stemness-index-related lncRNAs were identified. Next, FAM83H-AS1, HID1-AS1, HOXB-AS1, RP11-1070N10.3, RP11-1100L3.8, and RP11-696F12.1 were used to construct a stemness-index-related lncRNA signature, and receiver operating characteristic curves indicated that stemness-index-related lncRNA signature could predict the prognosis of BC well. Moreover, functional enrichment analysis suggested that differentially expressed genes between the high-risk group and low-risk group were mainly involved in immune-related biological processes and pathways. Furthermore, functional enrichment analysis of lncRNA-related protein-coding genes revealed that FAM83H-AS1, HID1-AS1, HOXB-AS1, RP11-1070N10.3, RP11-1100L3.8, and RP11-696F12.1 were associated with neuroactive ligand–receptor interaction, AMPK signaling pathway, PPAR signaling pathway, and cGMP-PKG signaling pathway. Finally, quantitative real-time polymerase chain reaction revealed that FAM83H-AS1, HID1-AS1, RP11-1100L3.8, and RP11-696F12.1 might be used as the potential diagnostic biomarkers of BC.

Conclusion: The stemness-index-related lncRNA signature based on FAM83H-AS1, HID1-AS1, HOXB-AS1, RP11-1070N10.3, RP11-1100L3.8, and RP11-696F12.1 could be used as an independent predictor for the survival of BC, and FAM83H-AS1, HID1-AS1, RP11-1100L3.8, and RP11-696F12.1 might be used as the diagnostic markers of BC.
Integrative Analyses of Genes Associated With Otologic Disorders in Turner Syndrome
Authors: Xue Ruoyan , Tang Qi , Zhang Yongli , Xie Mengyao , Li Chen , Wang Shu , Yang Hua
Published: February 2022

Background:Loss or partial loss of one X chromosome induces Turner syndrome (TS) in females, causing major medical concerns, including otologic disorders. However, the underlying genetic pathophysiology of otologic disorders in TS is mostly unclear.

Methods:Ear-related genes of TS (TSEs) were identified by analyzing differentially expressed genes (DEGs) in two Gene Expression Omnibus (GEO)-derived expression profiles and ear-genes in the Comparative Toxicogenomic Database (CTD). Subsequently, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO) analyses; Gene Set Enrichment Analysis (GSEA); and Gene Set Variation Analysis (GSVA) were adopted to study biological functions. Moreover, hub genes within the TSEs were identified by assessing protein-protein interaction (PPI), gene-microRNA, and gene-transcription factor (TF) networks. Drug-Gene Interaction Database (DGIdb) analysis was performed to predict molecular drugs for TS. Furthermore, three machine-learning analysis outcomes were comprehensively compared to explore optimal biomarkers of otologic disorders in TS. Finally, immune cell infiltration was analyzed.

Results:The TSEs included 30 significantly upregulated genes and 14 significantly downregulated genes. Enrichment analyses suggested that TSEs play crucial roles in inflammatory responses, phospholipid and glycerolipid metabolism, transcriptional processes, and epigenetic processes, such as histone acetylation, and their importance for inner ear development. Subsequently, we described three hub genes in the PPI network and confirmed their involvement in Wnt/β-catenin signaling pathway and immune cell regulation and roles in maintaining normal auditory function. We also constructed gene-microRNA and gene-TF networks. A novel biomarker (SLC25A6) of the pathogenesis of otologic disorders in TS was identified by comprehensive comparisons of three machine-learning analyses with the best predictive performance. Potential therapeutic agents in TS were predicted using the DGIdb. Immune cell infiltration analysis showed that TSEs are related to immune-infiltrating cells.

Conclusion:Overall, our findings have deepened the understanding of the pathophysiology of otologic disorders in TS and made contributions to present a promising biomarker and treatment targets for in-depth research.
Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19
Authors: Maruthamuthu Stalinraja , Rajalingam Karan , Kaur Navchetan , Morvan Maelig G. , Soto Jair , Lee Nancy , Kong Denice , Hu Zicheng , Reyes Kevin , Ng Dianna , Butte Atul J. , Chiu Charles , Rajalingam Raja
Published: February 2022

Background:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-2019 (COVID-19) in some individuals, while the majority remain asymptomatic. Natural killer (NK) cells play an essential role in antiviral defense. NK cell maturation and function are regulated mainly by highly polymorphic killer cell immunoglobulin-like receptors (KIR) and cognate HLA class I ligands. Herein, we tested our hypothesis that the individualized KIR and HLA class I ligand combinations that control NK cell function determine the outcome of SARS-CoV-2 infection.

Methods:We characterized KIR and HLA genes in 200 patients hospitalized for COVID-19 and 195 healthy general population controls.

Results:The KIR3DL1+HLA-Bw4+[Odds ratio (OR) = 0.65,p= 0.03] and KIR3DL2+HLA-A3/11+(OR = 0.6,p= 0.02) combinations were encountered at significantly lower frequency in COVID-19 patients than in the controls. Notably, 40% of the patients lacked both of these KIR+HLA+combinations compared to 24.6% of the controls (OR = 2.04,p= 0.001). Additionally, activating receptors KIR2DS1+KIR2DS5+are more frequent in patients with severe COVID-19 than patients with mild disease (OR = 1.8,p= 0.05). Individuals carrying KIR2DS1+KIR2DS5+genes but missing either KIR3DL1+HLA-Bw4+combination (OR = 1.73,p= 0.04) or KIR3DL2+HLA-A3/11+combination (OR = 1.75,p= 0.02) or both KIR3DL1+HLA-Bw4+and KIR2DL2+HLA-A3/11+combinations (OR = 1.63,p= 0.03) were more frequent in the COVID-19 cohort compared to controls.

Conclusions:The absence of KIR3DL1+HLA-Bw4+and KIR3DL2+HLA-A3/11+combinations presumably yields inadequate NK cell maturation and reduces anti-SARS-CoV-2 defense, causing COVID-19. An increased frequency of KIR2DS1+KIR2DS5+in severe COVID-19 patients suggests vigorous NK cell response triggered via these activating receptors and subsequent production of exuberant inflammatory cytokines responsible for severe COVID-19. Our results demonstrate that specific KIR-HLA combinations that control NK cell maturation and function are underlying immunogenetic variables that determine the dual role of NK cells in mediating beneficial antiviral and detrimental pathologic action. These findings offer a framework for developing potential host genetic biomarkers to distinguish individuals prone to COVID-19.
LIMK2 Is a Novel Prognostic Biomarker and Correlates With Tumor Immune Cell Infiltration in Lung Squamous Cell Carcinoma
Authors: Su Yongcheng , Xu Beibei , Shen Qianwen , Lei Ziyu , Zhang Wenqing , Hu Tianhui
Published: February 2022

Previous research found that LIM domain kinase 2 (LIMK2) expression correlated with a poor prognosis in many cancers. However, its role in lung squamous cell carcinoma (LUSC) has not yet been clarified. Our study aimed to clarify the role of LIMK2 in LUSC prognosis prediction and explore the relationship between LIMK2 and immune infiltration in LUSC. In this study, we first analyzed the expression level and prognostic value of LIMK2 across cancers. Subsequently, we explored the association of LIMK2 expression with immune infiltrating cells and immune checkpoints. our study found that LIMK2 was highly expressed and positively associated with the overall survival of LUSC. Moreover, our study further indicated that LIMK2 expression was significantly negatively correlated with immune cell infiltration and immune checkpoints in LUSC. Finally, we confirmed upstream regulatory noncoding RNAs (ncRNAs) of LIMK2, and the PVT1 and DHRS4-AS1/miR-423-5p/LIMK2 regulatory axes were successfully constructed in LUSC. Put together, LIMK2 is a novel prognostic biomarker and correlates with tumor immune cell infiltration in LUSC, and the expression of LIMK2 is regulated by the PVT1 and DHRS4-AS1/miR-423-5p axes.
TRIM67 Suppresses TNFalpha-Triggered NF-kB Activation by Competitively Binding Beta-TrCP to IkBa
Authors: Fan Wenchun , Liu Xueyan , Zhang Jinyan , Qin Liuxing , Du Jian , Li Xiangmin , Qian Suhong , Chen Huanchun , Qian Ping
Published: February 2022

The transcription factor NF-κB plays an important role in modulation of inflammatory pathways, which are associated with inflammatory diseases, neurodegeneration, apoptosis, immune responses, and cancer. Increasing evidence indicates that TRIM proteins are crucial role in the regulation of NF-κB signaling pathways. In this study, we identified TRIM67 as a negative regulator of TNFα-triggered NF-κB activation. Ectopic expression of TRIM67 significantly represses TNFα-induced NF-κB activation and the expression of pro-inflammatory cytokines TNFα and IL-6. In contrast, Trim67 depletion promotes TNFα-induced expression of TNFα, IL-6, and Mcp-1 in primary mouse embryonic fibroblasts. Mechanistically, we found that TRIM67 competitively binding β-transducin repeat-containing protein (β-TrCP) to IκBα results inhibition of β-TrCP-mediated degradation of IκBα, which finally caused inhibition of TNFα-triggered NF-κB activation. In summary, our findings revealed that TRIM67 function as a novel negative regulator of NF-κB signaling pathway, implying TRIM67 might exert an important role in regulation of inflammation disease and pathogen infection caused inflammation.
Immunotherapy of COVID-19: Inside and Beyond IL-6 Signalling
Authors: Zizzo Gaetano , Tamburello Antonio , Castelnovo Laura , Laria Antonella , Mumoli Nicola , Faggioli Paola Maria , Stefani Ilario , Mazzone Antonino
Published: February 2022

Acting on the cytokine cascade is key to preventing disease progression and death in hospitalised patients with COVID-19. Among anti-cytokine therapies, interleukin (IL)-6 inhibitors have been the most used and studied since the beginning of the pandemic. Going through previous observational studies, subsequent randomised controlled trials, and meta-analyses, we focused on the baseline characteristics of the patients recruited, identifying the most favourable features in the light of positive or negative study outcomes; taking into account the biological significance and predictivity of IL-6 and other biomarkers according to specific thresholds, we ultimately attempted to delineate precise windows for therapeutic intervention. By stimulating scavenger macrophages and T-cell responsivity, IL-6 seems protective against viral replication during asymptomatic infection; still protective on early tissue damage by modulating the release of granzymes and lymphokines in mild-moderate disease; importantly pathogenic in severe disease by inducing the proinflammatory activation of immune and endothelial cells (through trans-signalling and trans-presentation); and again protective in critical disease by exerting homeostatic roles for tissue repair (through cis-signalling), while IL-1 still drives hyperinflammation. IL-6 inhibitors, particularly anti-IL-6R monoclonal antibodies (e.g., tocilizumab, sarilumab), are effective in severe disease, characterised by baseline IL-6 concentrations ranging from 35 to 90 ng/mL (reached in the circulation within 6 days of hospital admission), a ratio of partial pressure arterial oxygen (PaO2) and fraction of inspired oxygen (FiO2) between 100 and 200 mmHg, requirement of high-flow oxygen or non-invasive ventilation, C-reactive protein levels between 120 and 160 mg/L, ferritin levels between 800 and 1600 ng/mL, D-dimer levels between 750 and 3000 ng/mL, and lactate dehydrogenase levels between 350 and 500 U/L. Granulocyte-macrophage colony-stimulating factor inhibitors might have similar windows of opportunity but different age preferences compared to IL-6 inhibitors (over or under 70 years old, respectively). Janus kinase inhibitors (e.g., baricitinib) may also be effective in moderate disease, whereas IL-1 inhibitors (e.g., anakinra) may also be effective in critical disease. Correct use of biologics based on therapeutic windows is essential for successful outcomes and could inform future new trials with more appropriate recruiting criteria.
Advanced Pancreatic Cancer Patient Benefit From Personalized Neoantigen Nanovaccine Based Immunotherapy: A Case Report
Authors: Shao Jie , Liu Qin , Shen Jie , Qian Xiaoping , Yan Jing , Zhu Yahui , Qiu Xin , Lu Changchang , Cen Lanqi , Tian Manman , Du Juan , Liu Baorui
Published: February 2022

Personal neoantigen vaccines are considered to be effective methods for inducing, amplifying and diversifying antitumor T cell responses. We recently conducted a clinical study that combined neoantigen nanovaccine with anti-PD-1 antibody. Here, we reported a case with a clear beneficial outcome from this treatment. We established a process that includes comprehensive identification of individual mutations, computational prediction of new epitopes, and design and manufacture of unique nanovaccines for this patient. Nanovaccine started after a relapse in third-line treatment. We assessed the patient’s clinical outcome and circulating immune response. In this advanced pancreatic cancer patient, the OS associated with the vaccine treatment was 10.5 months. A peptide-specific T-cell response against 9 of the 12 vaccine peptides could be detected sequentially. Robust neoantigen-specific T cell responses were also detected by IFN-γ ELISPOT and intracellular cytokine staining. In conclusion, sustained functional neoantigen-specific T cell therapy combined with immune checkpoint targeting may be well suited to help control progressive metastatic pancreatic cancer.
Tumor Microenvironment in Acute Myeloid Leukemia: Adjusting Niches
Authors: Menter Thomas , Tzankov Alexandar
Published: February 2022

Acute myeloid leukemias (AML) comprise a wide array of different entities, which have in common a rapid expansion of myeloid blast cells leading to displacement of normal hematopoietic cells and also disruption of the microenvironment in the bone marrow niches. Based on an insight into the complex cellular interactions in the bone marrow niches in non-neoplastic conditions in general, this review delineates the complex relationship between leukemic cells and reactive cells of the tumor microenvironment (TME) in AML. A special focus is directed on niche cells and various T-cell subsets as these also provide a potential therapeutic rationale considering e.g. immunomodulation. The TME of AML on the one hand plays a vital role for sustaining and promoting leukemogenesis but - on the other hand - it also has adverse effects on abnormal blasts developing into overt leukemia hindering their proliferation and potentially removing such cells. Thus, leukemic cells need to and develop strategies in order to manipulate the TME. Interference with those strategies might be of particular therapeutic potential since mechanisms of resistance related to tumor cell plasticity do not apply to it.
Identification of Distinct Immune Cell Subsets Associated With Asymptomatic Infection, Disease Severity, and Viral Persistence in COVID-19 Patients
Authors: Wang Xiaorui , Bai Han , Ma Junpeng , Qin Hongyu , Zeng Qiqi , Hu Fang , Jiang Tingting , Mao Weikang , Zhao Yang , Chen Xiaobei , Qi Xin , Li Mengyang , Xu Jiao , Hao Jingcan , Wang Yankui , Ding Xi , Liu Yuanrui , Huang Tianlong , Fang Chao , Ge Changli , Li Dong , Hu Ke , Ren Xianwen , Zhang Baojun , Zhang Binghong , Shi Bingyin , Zhang Chengsheng
Published: February 2022

The cell-mediated protective and pathogenic immune responses to SARS-CoV-2 infection remain largely elusive. Here we identified 76 distinct cell subsets in the PBMC samples that were associated with various clinical presentations of COVID-19 using scRNA-seq technology coupled with a deep and comprehensive analysis of unique cell surface markers and differentially expressed genes. We revealed that (TRAV1-2+CD8+)MAIT cells and (NCAM1hiCD160+)NK cells significantly enriched in the asymptomatic subjects whereas (LAG3+CD160+CD8+)NKT cells increased in the symptomatic patients. We also observed that (CD68-CSF1R-IL1BhiCD14+)classical monocytes were positively correlated with the disease severity. Moreover, (CD33-HLA-DMA-CD14+)classical monocytes and (CLEC10A-S100A9lo)pDC were associated with the viral persistence. The GO and KEGG analyses identified enriched pathways related to immune responses, inflammation, and apoptosis. These findings may enhance our understanding of the immunopathogenesis of COVID-19 and help develop novel strategies against SARS-CoV-2 infection.
A Quantitative Approach to Unravel the Role of Host Genetics in IgG-FcγR Complex Formation After Vaccination
Authors: Lemke Melissa M. , Theisen Robert M. , Bozich Emily R. , McLean Milla R. , Lee Christina Y. , Lopez Ester , Rerks-Ngarm Supachai , Pitisuttithum Punnee , Nitayaphan Sorachai , Kratochvil Sven , Wines Bruce D. , Hogarth P. Mark , Kent Stephen J. , Chung Amy W. , Arnold Kelly B.
Published: February 2022

Fc-mediated immune functions have been correlated with protection in the RV144 HIV vaccine trial and are important for immunity to a range of pathogens. IgG antibodies (Abs) that form complexes with Fc receptors (FcRs) on innate immune cells can activate Fc-mediated immune functions. Genetic variation in both IgGs and FcRs have the capacity to alter IgG-FcR complex formation via changes in binding affinity and concentration. A growing challenge lies in unraveling the importance of multiple variations, especially in the context of vaccine trials that are conducted in homogenous genetic populations. Here we use an ordinary differential equation model to quantitatively assess how IgG1 allotypes and FcγR polymorphisms influence IgG-FcγRIIIa complex formation in vaccine-relevant settings. Using data from the RV144 HIV vaccine trial, we map the landscape of IgG-FcγRIIIa complex formation predicted post-vaccination for three different IgG1 allotypes and two different FcγRIIIa polymorphisms. Overall, the model illustrates how specific vaccine interventions could be applied to maximize IgG-FcγRIIIa complex formation in different genetic backgrounds. Individuals with the G1m1,17 and G1m1,3 allotypes were predicted to be more responsive to vaccine adjuvant strategies that increase antibody FcγRIIIa affinity (e.g. glycosylation modifications), compared to the G1m-1,3 allotype which was predicted to be more responsive to vaccine boosting regimens that increase IgG1 antibody titers (concentration). Finally, simulations in mixed-allotype populations suggest that the benefit of boosting IgG1 concentration versus IgG1 affinity may be dependent upon the presence of the G1m-1,3 allotype. Overall this work provides a quantitative tool for rationally improving Fc-mediated functions after vaccination that may be important for assessing vaccine trial results in the context of under-represented genetic populations.
The AiiDA-Spirit Plugin for Automated Spin-Dynamics Simulations and Multi-Scale Modeling Based on First-Principles Calculations
Authors: Rüßmann Philipp , Ribas Sobreviela Jordi , Sallermann Moritz , Hoffmann Markus , Rhiem Florian , Blügel Stefan
Published: February 2022

Landau-Lifshitz-Gilbert (LLG) spin-dynamics calculations based on the extended Heisenberg Hamiltonian is an important tool in computational materials science involving magnetic materials. LLG simulations allow to bridge the gap from expensive quantum mechanical calculations with small unit cells to large supercells where the collective behavior of millions of spins can be studied. In this work we present the AiiDA-Spirit plugin that connects the spin-dynamics code Spirit to the AiiDA framework. AiiDA provides a Python interface that facilitates performing high-throughput calculations while automatically augmenting the calculations with metadata describing the data provenance between calculations in a directed acyclic graph. The AiiDA-Spirit interface thus provides an easy way for high-throughput spin-dynamics calculations. The interface to the AiiDA infrastructure furthermore has the advantage that input parameters for the extended Heisenberg model can be extracted from high-throughput first-principles calculations including a proper treatment of the data provenance that ensures reproducibility of the calculation results in accordance to the FAIR principles. We describe the layout of the AiiDA-Spirit plugin and demonstrate its capabilities using selected examples for LLG spin-dynamics and Monte Carlo calculations. Furthermore, the integration with first-principles calculations through AiiDA is demonstrated at the example of γ–Fe, where the complex spin-spiral ground state is investigated.
Risk Factors for Fever After Esophageal Endoscopic Submucosal Dissection and Its Derived Technique
Authors: Liao Foqiang , Zhu Zhenhua , Lai Yongkang , Pan Xiaolin , Long Shunhua , Zhou Xiaojiang , Li Guohua , Zhu Yin , Chen Youxiang , Shu Xu
Published: February 2022

Background

Fever is one of the postoperative adverse events of endoscopic submucosal dissection and its derived technique, but the probability and risk factors of postoperative fever are still unclear. The aim of the current study was to investigate the incidence and risk factors of postoperative fever after esophageal lesion removal.

Methods

We conducted a retrospective study of 446 patients who underwent esophageal endoscopic submucosal dissection and its derived technique between January 2014 and January 2020. Cases included in this study were divided into fever and non-fever groups.

Results

Postoperative fever developed in 135 patients (30.3%). The median (range) highest fever temperature was 38 (37.8–38.4)°C, the median (range) duration of fever was 1 (1–2) day, and 127 (94.1%) patients developed fever within 24 h after operation. Through logistic regression analysis, factors associated with postoperative fever were age (OR: 1.740, 95% CI: 1.005–3.013, p = 0.048), lesion size (OR: 2.007, 95% CI: 1.198–3.362, p = 0.008), operation time (OR: 3.007, 95% CI: 1.756–5.147, p < 0.001) and nasogastric tube placement (OR: 1.881, 95% CI: 1.165–3.037, p = 0.010), while prophylactic antibiotics (OR: 0.181, 95% CI: 0.082–0.401, p < 0.001) were negatively associated with fever.

Conclusions

Age ≥52 years old, lesion size ≥19 mm, operation time ≥37 min, and nasogastric tube placement are risk factors for postoperative fever after esophageal endoscopic submucosal dissection and its derived technique, prophylactic antibiotic use after operation may help reduce fever rate. Attention should be paid to such patients to minimize the risk of postoperative fever.
Cardiovascular Risks and Risk Stratification in Inflammatory Joint Diseases: A Cross-Sectional Study
Authors: Yagensky Vasyl , Schirmer Michael
Published: February 2022

Background

It is well established that patients with inflammatory joint diseases (IJD) have an increased cardiovascular (CV) mortality and morbidity. According to the 2016 EULAR recommendations on CV risk management, rheumatologists should ensure appropriate management of CV risk in rheumatoid arthritis (RA) and other IJDs. The aim was to assess the CV risk and CV disease in Middle-European patients with IJD.

Methods

A retrospective chart review was performed for CV risk factors and CV disease in outpatients of a rheumatology outpatient clinic. CV risk was assessed according to the 2016 European Guidelines on CV disease prevention and also using 2 other approaches to compare the results with data from Norwegian and Spanish cohorts.

Results

Out of 432 patients, the prevalence of CV disease reached from 8.7% in spondyloarthritis (SpA) and 12.8% in psoriatic arthritis (PsA) to 18.7% in patients with RA. The number of CV risk factors did not differ between patients with RA, SpA, PsA, and non-inflammatory rheumatic disease (NIRD) (with 1.68 ± 0.13, 1.70 ± 0.13, 2.04 ± 0.16, and 1.78 ± 0.34, respectively). CV risk assessment could be performed in 82 patients after exclusion because of missing data and age. Stratification according to ESC guidelines showed low in 50%, moderate in 12.2%, high in 20.7%, and very high CV risk in 17.1% of patients aged between 40 and 65 years. CV risk in the Middle-European patients with IJD was higher than in the German general population (p = 0.004), and similar to the Norwegian patients with IJD, although patients with Middle-European PsA were at higher risk than the Norwegian patients (p = 0.045). Compared to the Spanish patients, Middle-European patients with IJD were more likely assigned to the high- to a very high-risk group (34.2 vs. 16.2%, p < 0.001), especially in RA disease (49.1 vs. 21%, respectively, p < 0.001).

Discussion

High prevalence of established CV disease together with high CV risk in patients with IJD urges for increased vigilance for CV risk factors followed by appropriate interaction by the treating physicians. The prospective use of an international CV risk assessment tool will allow not only estimation of the individual CV risk but also provide data for direct comparisons with the general population and other international cohorts.
Analysis of Globular Cells in Corneal Nerve Vortex
Authors: Hao Ran , Liu Ziyuan , Chou Yilin , Huang Chen , Jing Dalan , Wang Haikun , Gao Shuang , Li Xuemin
Published: February 2022

Purpose

Less was known about globular cells which were a type of dendritic cells (DCs) in cornea. We aimed to investigate the morphological and distribution characteristics of globular cells in corneal vortex and their clinical correlations with ocular surface.

Methods

Case records of patients who underwent in vivo confocal microscopy (IVCM) were evaluated retrospectively. The morphology and distribution features of globular cells in cornea nerve vortex and their co-existence status with Langerhans cells (LCs) were analyzed. Data of ocular surface symptoms and signs were collected and their correlations with globular cells distribution patterns and dendritic forms were performed. Dry eye patients without LCs were treated with preservative-free artificial tears, while patients with LCs were treated with artificial tears and fluoromethalone until the activated LCs disappeared.

Results

A total of 836 eyes from 451 individuals were included. Three distribution patterns of globular cells in vortex were investigated, type 1 scattered globular cells (57.66%), type 2 large amounts of globular cells (≥50 cells) gathering in vortex and along some fixed vortex direction horizontally (13.52%) and type 3 no globular cells (28.83%). Their location and cell count altered slightly in the follow-ups but would not disappear. LCs could co-exist with globular cells and could fade after treatment. The type 2 distribution pattern was associated with older age (p = 0.000) and higher upper eyelid Meiboscore (p = 0.006). Dendritic globular cells had higher Meiboscore than Non-dendritic forms.

Conclusions

Globular cells had characteristic distribution patterns and biological features different from LCs. They were associated with long-term irritation of the meibomian gland dysfunction.