bluuebunny/crossref_metadata_2025 huggingface dataset:
El proceso contable y su normativa
Authors: Carrasco Ruano Yolanda Tatiana , Falconí Tello María Auxiliadora , Chávez Haro Mauricio , Naranjo Lozada Silvia Guadalupe
Published: December 2021

La evolución de la tecnología y la ciencia a través del tiempo es inegable, y las leyes y normativas no se quedan fuera de ella. La normativa evoluciona con el accionar de la gente, constantemente cambia y se adapta al medio para evitar quedar en deshuso y seguirle el paso a las nuevas formas de negocios, cada vez más influenciados por una economía global, donde el mayor bien es el conocimiento. Objetivos: el presente trabajo pretende identificar la normativa contable vigente dentro del proceso contable. Metodología: aplica el método cuantitativo, diseño bibliográfico, tipo documental, de corte transversal, analítico explicativo. Aporte: establecer una base documental de la normativa contable actual.
El abordaje de la memoria traumática desde un enfoque educativo
Authors: González Meyer Tristán
Published: December 2021

Trabajar los lugares de memoria traumática presenta unas dificultades añadidas a la hora de patrimonializar sus recursos turísticos.
EFFECT OF COVID-19 ON EXERCISE HEALTH BELIEF, EMOTIONAL INTELLIGENCE AND STRESS LEVELS IN EMERGENCY UNIT NURSES
Authors: DURMUŞ Mustafa , ALKAN Halil , ÇİFTCİ Necmettin
Published: December 2021

This study was conducted to examine the effect of Covid-19 on exercise health belief, emotional intelligence and stress levels in emergency unit nurses. Research was carried out on 1-30.01.2021 with 210 nurses who is working in emergency units located in five hospitals in Eastern Anatolia region of Turkey. A significant relationship was found between the nurses' status of contracting Covid-19 and exercise belief, emotional intelligence, and perceived stress levels. While it was found that the exercise health belief and stress levels of nurses who had Covid-19 were higher than those who did not have Covid-19, it was found that the emotional intelligence levels of nurses who had Covid-19 were lower than those who did not.
Acute Chest Syndrome in Children with Sickle Cell Disease: Current Perspectives on Pathogenesis and Treatment
Authors: Uwaezuoke Samuel N.
Published: December 2021

Acute chest syndrome (ACS) is the most prominent cause of mortality in children with sickle cell disease. Its cause was initially not clearly understood, but there are now established concepts regarding its aetiopathogenesis. This narrative review discusses the current perspectives on sickle cell disease pathogenesis and treatment. The PubMed database was searched for articles that met the review objective. The major causative factors are pulmonary infections, pulmonary infarction, and pulmonary fat embolism from bone marrow necrosis. These factors initiate events that result in ACS, in which a vicious cycle of infarction, inflammation, and lung collapse occurs, leading to ventilation-perfusion mismatch and hypoxaemia. ACS is best managed in hospital settings because intensive care of the patient may be required. Despite its complex management, the primary treatment modalities are supportive care, transfusion therapy, and pharmacotherapy. Although the efficacy of several modalities in attenuating or preventing ACS are well established, the outcomes from instituting others are not convincing. More research is, therefore, needed to strengthen the evidence for their therapeutic efficacy.
Reed Sternberg-Like Cells in an Aggressive Lymphoma: Report of a Rare Case and Review of Literature
Authors: Ahuja Sana , Bharati Vandana , Gupta Arvind , JoshI Prashant Pranesh , Kant Ravi , Singh Ashok
Published: December 2021

Peripheral T-cell lymphomas are aggressive lymphomas with a rapidly progressive clinical course and sinister prognosis even with the best available treatment modalities. Epstein–Barr virus-positive peripheral T-cell lymphoma is an unusual variant of the disease; it is extremely rare and associated with a fulminant course spanning weeks to months. Treatment protocols are different for this entity because of its rarity.
‘richesse in fassone and in fairness’: Marriage, Manhood and Sartorial Splendour for Sixteenth-century Scottish Kings
Authors: Dean Lucinda H. S.
Published: December 2021

Marriage was a prominent ‘life-stage’ ritual linked to achievement of the hegemonic manly state in the early modern period: it was associated with self-control and was seen as a stabilising force against the ‘follies of youth’. James IV (1488–1513), James V (1513–1542) and James VI (1567–1625) came to the throne as minors and their weddings provided particularly potent opportunities for shaping their identity both at home and abroad. Clothing was a crucial element of the social dialogue performed by both men and women in late medieval and early modern Europe. Dress, of the royal person and of others, was a mode of display in which all three monarchs invested heavily at the moment of their weddings. By offering a comparative analysis of the investment in sartorial splendour and the use of dress and personal adornment through a gendered lens, this article demonstrates how clothing and adornments were used to make statements about both manhood and royal status by three sixteenth-century Stewart kings attempting to secure their place in the homosocial hierarchy.
Status, Magic and Belief: Exploring Identity through Dress Accessories and Other Amulets in Medieval Scotland: A Perthshire Case-study
Authors: Hall Mark A.
Published: December 2021

This paper explores belief and identity as expressed through the material culture of dress. It focuses on supernatural engagements through material culture linked to human and animal bodies and offers a view of the means by which everyday ritual, habit and devotion were embodied and facilitated through dress and other amulets, including contextually re-purposed coins. The evidence is primarily archaeological and derives from medieval Perthshire, a place with wide connections, and so the discussion is presented in the context of Scottish and European practices. The key themes are status, magic and belief, all three of which speak to identity. The practices they elucidate are explored primarily through jewellery and dress fittings, pilgrimage souvenirs, coins and other amulets.
Activation of lymphocytes in vitro for immunotherapy of patients with melanoma
Authors: Abakushina E. V. , Gel’m Yu. V. , Lyssuk E. Yu.
Published: December 2021

This article describes a method for activating lymphocytes isolated from the peripheral blood of melanoma patients and cultured in a medium supplemented with IL‑2 and IL‑15. It was shown that in these terms, lymphocytes have an increased proliferative and activation potential. The combination of cytokines has a positive effect on cytotoxicity, viability and the expression of activation markers (CD38, CD69, CD25, HLA-DR and NKG2D) on NK- and T-lymphocyte, and may be recommended for the culture of lymphocytes in melanoma patients for the purpose of adoptive immunotherapy.
Re-understanding speech understanding: Closing the cohort loop
Authors: Marslen-Wilson William
Published: December 2021

Human listeners understand spoken language literally as they hear it, reflecting a perceptually seamless process of real-time comprehension of what the speaker is saying. This remarkable experience of immediacy is rooted in the exceptional earliness with which information carried by successive words is integrated into the interpretation of the current utterance. But despite 50 years of research, there has been no accepted mechanistic neurobiological account of the brain systems that support this process. Only recently have scientific tools emerged that allow us to probe the real-time activity of these brain systems, telling us where and when such activity can be detected and what their neurocomputational content might be. The resulting research enables us, first, to reject the historically dominant account of early speech interpretation as a linguistically stratified computational hierarchy, centered around the notion of a phoneme, and based on sequential transitions between successive representational states.
Long Noncoding RNA HCG18 Promotes Malignant Phenotypes of Breast Cancer Cells via the HCG18/miR-103a-3p/UBE2O/mTORC1/HIF-1α–Positive Feedback Loop
Authors: Liu Xu , Qiao Kun , Zhu Kaiyuan , Li Xianglan , Zhao Chunbo , Li Jiaqi , Feng Dawei , Fang Yu , Wang Peng , Qian Cheng , Qiao Wenbo
Published: December 2021

In recent years, an increasing number of studies have reported that long noncoding RNAs (lncRNAs) play crucial roles in breast cancer (BC) progression and metastasis. Another study group of our research center reported that lncRNA HCG18 was one of the 30 upregulated lncRNAs in BC tissues compared with normal tissues in The Cancer Genome Atlas database. However, the exact biological roles of HCG18 in BC remain unclear. In this study, we demonstrated that HCG18 is significantly upregulated in BC tissues and cells and that BC patients with high HCG18 expression tend to have poor prognosis. In vitro assays indicated that HCG18 promotes BC cell proliferation and invasion and endows BC cells with cancer stemness properties. In vivo assays revealed that reducing HCG18 expression in the BC cell line MDA-MB-231 markedly decreased tumor growth and lung metastasis in xenograft mouse models. In terms of mechanism, we found that HCG18 positively regulated the expression of BC-related ubiquitin-conjugating enzyme E2O (UBE2O) by sponging miR-103a-3p, and our previous research verified that UBE2O could promote the malignant phenotypes of BC cells through the UBE2O/AMPKα2/mTORC1 axis. Furthermore, as a downstream target of the HCG18/miR-103a-3p/UBE2O/mTORC1 axis, hypoxia-inducible factor 1α transcriptionally promoted HCG18 expression and then formed a positive feedback loop in BC. Taken together, these results confirm that HCG18 plays an oncogenic role in BC and might serve as a prognostic biomarker and a potential therapeutic target for BC treatment.
Gut Microbiota and SCFAs Play Key Roles in QingFei Yin Recipe Anti-Streptococcal Pneumonia Effects
Authors: Sun Xiaozhou , Wang Dandan , Wei Lina , Ding Lizhong , Guo Yinan , Wang Zhongtian , Kong Yibu , Yang Jingjing , Sun Liwei , Sun Liping
Published: December 2021

Emerging evidence has revealed the presence in animals of a bidirectional regulatory “lung-gut axis” that provides resistance to respiratory infections. Clues to the existence of this system stem from observations that respiratory infections are often accompanied by gastrointestinal symptoms, whereby intestinal microbiota appear to play pivotal roles in combating pathogenic infections. Importantly, short-chain fatty acids (SCFAs) produced by the gut microbiota appear to serve as the biological link between host immune defenses and gut flora. Streptococcus pneumoniae (S.pn), the main cause of lower respiratory tract infections, is involved in more than 1.189 million deaths per year. QingFei Yin (QFY) is known for its excellent therapeutic efficacy in combating bacterial lung infections. In this study, effects of S.pn infection on gut homeostasis were assessed using 16S RNA-based microbiota community profiling analysis. In addition, potential mechanisms underlying QFY recipe beneficial therapeutic effects against bacterial pneumonia were explored using S.pn-infected gut microbiota-depleted mice. Results of data analysis indicated that QFY treatment alleviated lung infection-associated pathogenic processes, while also promoting repair of disordered gut flora and counteracting S.pn infection-associated decreases in levels of SCFAs, particularly of acetate and butyrate. Mechanistically, QFY treatment suppressed inflammatory lung injury through inhibition of the host NF-κB-NLRP3 pathway. These results inspired us to identify precise QFY targets and mechanisms underlying QFY anti-inflammatory effects. In addition, we conducted an in-depth evaluation of QFY as a potential treatment for bacterial pneumonia.
Reconstructing 1200 years of Hydroclimate Variability in the Southern Margins of the Arabian Desert: Insights From a Paleo-Lake in Southern Yemen
Authors: Parth Shah , Russell James , Waldmann Nicolas
Published: December 2021

The climate of the Arabian Desert is not well documented during the past two millennia due to the scarcity of continuous and well-dated terrestrial archives in the region. Reliable interpretation from the climatic records from this region are pivotal for identifying periodicities of inter-annual to multi-decadal variability and trends driven by shifts in position of the Intertropical Convergence Zone (ITCZ) and the strength of the monsoons. A high-resolution multiproxy approach is presented for a ∼3.3 m composite core, GBW, from a karst lake located in Ghayl ba Wazir, southern Yemen. Sedimentary proxies, including particle size distribution, coupled with magnetic susceptibility (MS) and geochemistry (XRF), provide a comprehensive picture of sediment depositional changes that may be linked to climate and environmental variability over the southern Arabian Desert. The chronology of the GBW core is provided by five radiocarbon (14C) dates from terrestrial macrofossils (wood and twigs) extracted from sediment samples and indicates the core extends to ∼900 CE. Our data indicates generally wetter conditions from 930 to 1400 CE corresponding to the “Medieval climate anomaly (MCA)” followed by arid phases during 1,410–1700 CE coinciding with the “Little Ice Age (LIA)”. Evidence for a drier LIA include high authigenic calcium precipitation [Ca/(Al + Fe + Ti)], decreased TOC/TIC values, and gypsum precipitation, whereas the wetter MCA is characterized by higher detrital element ratios (Ti/Al, K/Al, Rb/Sr), and increased TOC/TIC and deposition of finer sediments (EM1). Furthermore, end-member mixing analyses (EMMA) derived from the grain-size distribution (EM2 and EM3) corroborates the deposition of coarser silt sediment through wind erosion and production of carbonate sand during the LIA concurrently with low lake levels under generally dry conditions. Aridity during the LIA is consistent with evidence and theory for weakened boreal summer monsoons during intervals of northern hemisphere cooling.
Observed Quantile Features of Summertime Temperature Trends over China: Non-Negligible Role of Temperature Variability
Authors: Li Xing , Li Xiao , Ma Hedi , Hua Wenjian , Sun Shanlei , Wang Di , Gao Chujie
Published: December 2021

Changes in temperature variability can have more serious social and ecological impacts than changes in the mean state of temperature, especially when they are concurrent with global warming. The present study examines the summertime temperatures’ trends over China from the quantile perspective. Through fully investigating the quantile trends (QTs) of the maximum (Tmax) and minimum temperature (Tmin) using the homogenized observation data and quantile regression analysis, we identify evident region-specific quantile features of summertime temperature trends. In most of northern China, the QTs in Tmax and Tmin for all percentiles generally show strong uniform warmings, which are dominated by a warm shift in mean state temperatures. In contrast, the QTs of Tmax in the Yangtze River Basin show distinguishable inter-quantile features, i.e., an increasing tendency of QTs from cooling trends in the lower percentile to warming trends in the higher percentile. Further investigations show that such robust growing QTs of Tmax across quantiles are dominated by the temperature variance. Our results highlight that more attention should be paid to the region-specific dominance of temperature variability in trends and the related causes.
Adaptive IES Load Forecasting Method Based on the Octopus Model
Authors: Zhang Na , Pan Xiao , Wang Yihe , Zhang Mingli , Cheng Mengzeng , Shang Wenying
Published: December 2021

Improving the accuracy and speed of integrated energy system load forecasting is a great significance for improving the real-time scheduling and optimized operation of the integrated energy system. In order to achieve rapid and accurate forecasting of the integrated energy system, this paper proposes an adaptive integrate energy system (IES) load forecasting method based on the octopus model. This method uses long short-term memory (LSTM), support vector machines (SVMs), restricted Boltzmann machines (RBMs), and Elman neural network as the octopus model quadrupeds. Through taking over differences in different data and training principles and utilizing the advantages of the octopus quadruped model, a special octopus-head and XGBoost algorithm were adopted to set the weight of the octopus’ quadruped and prevent local minimum points in the model. We train the octopus model through RMSProp adaptive learning algorithm, constrain the learning rate, get the best parameters, and improve the model’s adaptability to different types of data. In addition, for the incomplete comprehensive energy load data, the generative confrontation network is used to fill it. The simulation results show that compared with other prediction methods, the effectiveness and feasibility of the method proposed in this paper are verified.
High Resolution 3-D Simulations of Venting in 18650 Lithium-Ion Cells
Authors: Li Weisi , León Quiroga Vanessa , Crompton K. R. , Ostanek Jason K.
Published: December 2021

High temperature gases released through the safety vent of a lithium-ion cell during a thermal runaway event contain flammable components that, if ignited, can increase the risk of thermal runaway propagation to other cells in a multi-cell pack configuration. Computational fluid dynamics (CFD) simulations of flow through detailed geometric models of four vent-activated commercial 18650 lithium-ion cell caps were conducted using two turbulence modeling approaches: Reynolds-averaged Navier-Stokes (RANS) and scale-resolving simulations (SRS). The RANS method was compared with independent experiments of discharge coefficient through the cap across a range of pressure ratios and then used to investigate the ensemble-averaged flow field for the four caps. At high pressure ratios, choked flow occurs either at the current collector plate when flow through the current collector plate is more restrictive or the positive terminal vent holes when flow through the current collector plate is less restrictive. Turbulent mixing occurred within the vent cap assembly, in the jets emerging from the vent holes, and in recirculating zones directly above the vent cap assembly. The global maximum turbulent viscosity ratio (μT/μ) of the MTI, LG MJ1, K2, and LG M36 caps at pressure ratio ofP1/P2= 7 were 4,575, 3,360, 3,855, and 2,993, respectively. SRS and RANS simulations showed that both velocity magnitude and fluctuating velocity magnitude were lower for vent holes which are obstructed by the burst disk. SRS showed high levels of fluctuating velocity in the jets, up to 48.5% of the global maximum velocity. The present CFD models and the resulting insights provide the groundwork for future studies to investigate how jet structure and turbulence levels influence combustion and heat transfer in propagating thermal runaway scenarios.
Linkage Disequilibrium and Effective Population Size of Buffalo Populations of Iran, Turkey, Pakistan, and Egypt Using a Medium Density SNP Array
Authors: Rahimmadar Shirin , Ghaffari Mokhtar , Mokhber Mahdi , Williams John L.
Published: December 2021

Linkage disequilibrium (LD) across the genome provides information to identify the genes and variations related to quantitative traits in genome-wide association studies (GWAS) and for the implementation of genomic selection (GS). LD can also be used to evaluate genetic diversity and population structure and reveal genomic regions affected by selection. LD structure and Ne were assessed in a set of 83 water buffaloes, comprising Azeri (AZI), Khuzestani (KHU), and Mazandarani (MAZ) breeds from Iran, Kundi (KUN) and Nili-Ravi (NIL) from Pakistan, Anatolian (ANA) buffalo from Turkey, and buffalo from Egypt (EGY). The values of corrected r2 (defined as the correlation between two loci) of adjacent SNPs for three pooled Iranian breeds (IRI), ANA, EGY, and two pooled Pakistani breeds (PAK) populations were 0.24, 0.28, 0.27, and 0.22, respectively. The corrected r2 between SNPs decreased with increasing physical distance from 100 Kb to 1 Mb. The LD values for IRI, ANA, EGY, and PAK populations were 0.16, 0.23, 0.24, and 0.21 for less than 100Kb, respectively, which reduced rapidly to 0.018, 0.042, 0.059, and 0.024, for a distance of 1 Mb. In all the populations, the decay rate was low for distances greater than 2Mb, up to the longest studied distance (15 Mb). The r2 values for adjacent SNPs in unrelated samples indicated that the Affymetrix Axiom 90 K SNP genomic array was suitable for GWAS and GS in these populations. The persistency of LD phase (PLDP) between populations was assessed, and results showed that PLPD values between the populations were more than 0.9 for distances of less than 100 Kb. The Ne in the recent generations has declined to the extent that breeding plans are urgently required to ensure that these buffalo populations are not at risk of being lost. We found that results are affected by sample size, which could be partially corrected for; however, additional data should be obtained to be confident of the results.
Protumorigenic Role of Elevated Levels of DNA Polymerase Epsilon Predicts an Immune-Suppressive Microenvironment in Clear Cell Renal Cell Carcinoma
Authors: Wu Xiaohui , Tang Haijia , Xu Wen-Hao , Tang Haidan , Wei Shiyin , Anwaier Aihetaimujiang , Huang Haineng , Qu Yuan-Yuan , Zhang Hailiang , Zhao Shuai , Li Hui , Liu Wangrui , Chen Hongjing , Ding Chen , Ye Dingwei
Published: December 2021

Increasing evidence indicates that DNA polymerase epsilon (POLE), which mediates DNA damage repair, is significantly associated with tumor prognosis. This study aimed to analyze POLE expression in tumor samples and its prognostic value for patients with clear cell renal cell carcinoma (ccRCC). We found significantly elevated POLE expression in ccRCC tissues compared with normal tissues of multiple independent cohorts. The POLE expression levels of 523 patients with ccRCC (The Cancer Genome Atlas RNA-seq data) and 179 patients with ccRCC with immunohistochemical data (Fudan University Shanghai Cancer Center) were analyzed to investigate the prognostic implications of POLE expression. Cox regression analyses were implemented to explore the effect of POLE expression on the prognosis of pan-cancer. These findings revealed that elevated POLE expression levels significantly correlated with shorter overall survival (p < 0.001, n = 701) of patients with ccRCC. These data indicate that POLE expression may serve as a prognostic biomarker for cancers. Although POLE mutations were not significantly associated with survival benefits conferred upon patients with ccRCC, a CD4+ T cell-regulated immune microenvironment was significantly activated. Moreover, we found that POLE expression in cancers significantly correlated with an immunosuppressive tumor microenvironment, higher intratumoral heterogeneity, and expression of immune checkpoint genes PDCD1, CTLA4, and CD86, possibly mediated via the JAK/STAT and Notch signaling pathways. In conclusion, the present study is the first to our knowledge to indicate that elevated POLE expression is significantly associated with poor survival and an immune-suppressive tumor microenvironment in ccRCC. These findings suggest that POLE can serve as a biomarker for guiding molecular diagnosis and facilitating the development of novel individual therapeutic strategies for patients with advanced ccRCC.
A PD-L1 Negative Advanced Gastric Cancer Patient With a Long Response to PD-1 Blockade After Failure of Systematic Treatment: A Case Report
Authors: Zhang Fangyuan , Zhang Jieying , Zhao Lei , Zhai Menglan , Zhang Tao , Yu Dandan
Published: December 2021

Background

It was widely accepted that programmed death-ligand 1 (PD-L1) positive, tumor mutational burden-high (TMB-H) or microsatellite instability-high (MSI-H) tumor are prone to have better treatment response to immune checkpoint blockade. The value of immune checkpoint blockade in PD-L1 negative gastric cancer patients has been questioned due to lower objective response rate (ORR).

Case Presentation

We report an unusual case of a PD-L1 negative, proficient mismatch repair (pMMR)/microsatellite stability (MSS), tumor mutational burden-low (TMB-L) gastric cancer patient who achieved good response to immune checkpoint blockade after failure of systematic treatment. Multiple lymph nodes and bone metastases are the main characteristics of this patient. The patient survived for more than 30 months after diagnosis.

Conclusions

This case suggested that PD-L1 negative gastric cancer patient may also benefit from immune checkpoint blockade. In gastric cancer, patients with lymph node metastasis may be potential beneficiaries.
Citrullinated Histone H3 Mediates Sepsis-Induced Lung Injury Through Activating Caspase-1 Dependent Inflammasome Pathway
Authors: Tian Yuzi , Li Patrick , Wu Zhenyu , Deng Qiufang , Pan Baihong , Stringer Kathleen A. , Alam Hasan B. , Standiford Theodore J. , Li Yongqing
Published: December 2021

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection that often results in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). An emerging mechanism of sepsis-induced ARDS involves neutrophils/macrophages undergoing cell death, releasing nuclear histones to cause tissue damage that exacerbates pulmonary injury. While published studies focus on unmodified histones, little is known about the role of citrullinated histone H3 (CitH3) in the pathogenesis of sepsis and ALI. In this study, we found that levels of CitH3 were elevated in the patients with sepsis-induced ARDS and correlated to PaO2/FiO2 in septic patients. Systematic administration of CitH3 peptide in mice provoked Caspase-1 activation in the lung tissue and caused ALI. Neutralization of CitH3 with monoclonal antibody improved survival and attenuated ALI in a mouse sepsis model. Furthermore, we demonstrated that CitH3 induces ALI through activating Caspase-1 dependent inflammasome in bone marrow derived macrophages and bone marrow derived dendritic cells. Our study suggests that CitH3 is an important mediator of inflammation and mortality during sepsis-induced ALI.
Donor T-Cell Repertoire Profiling in Recipient Lymphoid and Parenchyma Organs Reveals GVHD Pathogenesis at Clonal Levels After Bone Marrow Transplantation in Mice
Authors: Wu Yongxia , Fu Jianing , Wang Haizhen , Yu Xue-Zhong
Published: December 2021

The diversity and composition of T-cell receptor (TCR) repertoire, which is the result of V, (D), and J gene recombination in TCR gene locus, has been found to be implicated in T-cell responses in autoimmunity, cancer, and organ transplantation. The correlation of T-cell repertoire with the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation remains largely undefined. Here, by utilizing high-throughput sequencing of the genes encoding TCRβ-chain, we comprehensively analyzed the profile of T-cell repertoire in recipient lymphoid and GVHD target organs after bone marrow transplantation (BMT) in mice. In lymphoid organs, TCR diversity was narrowed, accompanied with reduced numbers of unique clones while increased accumulation of dominant clones in allogeneic T cells compared to syngeneic T cells. In an individual allogeneic recipient, donor-derived TCR clones were highly overlapped among tissue sites, and the degree of overlapping was increasing from day 7 to 14 after allogeneic BMT. The top clones in peripheral blood, gut, liver, and lungs were highly mutually shared in an allogenic recipient, indicating that blood has the potential to predict dominant clones in these GVHD target organs. T cells in GVHD target organs from allogeneic recipients had fewer overlapped clones with pre-transplant donor T cells compared to those from syngeneic recipients. Importantly, the top 10 clones in allogeneic recipients were not detectable in pre-transplant donor T cells, indicating clonal expansion of rare rearrangements. Interestingly, even starting from the same pool of donor repertoires, T cells had very few overlapped clones between each allogeneic recipient who developed completely different dominant clones. We were only able to trace a single clone shared by three replicate allogeneic recipients within the top 500 clones. Although dominant clones were different among allogeneic recipients, V26 genes were consistently used more frequently by TCR clones in allogeneic than syngeneic recipients. This is the first study to extensively examine the feature of T-cell repertoire in multiple lymphoid and parenchyma organs, which establishes the association between T-cell activation and GVHD pathogenesis at the level of TCR clones. Immune repertoire sequencing-based methods may represent a novel personalized strategy to guide diagnosis and therapy in GVHD.
Correlation Between Immune-Related Adverse Events and Prognosis in Hepatocellular Carcinoma Patients Treated With Immune Checkpoint Inhibitors
Authors: Xu Shuo , Lai Ruixue , Zhao Qian , Zhao Pandong , Zhao Ruili , Guo Zhanjun
Published: December 2021

Background

Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) were associated with clinical benefit in cancer patients of melanoma, a lung cancer. In the present study, we investigated the correlation between irAE and ICI efficacy in hepatocellular carcinoma (HCC) patients.

Methods

We divided the HCC patients who received the anti-PD-1 antibody into two groups as irAE group and non-irAE group according to the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03. The treatment efficacy of ICIs was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

Result

Of the 65 HCC patients who received the anti-PD-1 antibody (monotherapy or combined with targeted medicine), median PFS in the irAE group was superior to that in the non-irAE group (302 days vs. 148 days, p = 0.004). Median OS in the irAE group was also better than that in the non-irAE group (374 days vs. 279 days, p = 0.038). Although the statistical difference for DCR in the irAE group and non-irAE group was not reached, the DCR of the irAE displayed a trend better than that of the non-irAE group (41.20% vs. 20.80%, p = 0.118). Multivariate analysis also demonstrated that the non-irAE group (HR = 6.410, 95% CI: 1.404 to 29.275) was associated independently with the poor prognosis.

Conclusions

Development of irAEs was associated with clinical benefit for HCC patients who were treated with immune checkpoint inhibitors; irAE, particularly low-grade irAE, was a predictable marker for better ICI treatment efficiency in HCC patients.
Integrated Analyses Identify Key Molecules and Reveal the Potential Mechanism of miR-182-5p/FOXO1 Axis in Alcoholic Liver Disease
Authors: Zuo Zhihua , Li Yiqin , Zeng Chuyi , Xi Yuge , Tao Hualin , Guo Yongcan
Published: December 2021

Background: Alcoholic liver disease (ALD) is one of the most common chronic liver diseases worldwide. However, the potential molecular mechanism in ALD development remains unclear. The objective of this work was to identify key molecules and demonstrate the underlying regulatory mechanisms.

Methods: RNA-seq datasets were obtained from Gene Expression Omnibus (GEO), and key molecules in ALD development were identified with bioinformatics analysis. Alcoholic liver disease mouse and cell models were constructed using Lieber-DeCarli diets and alcohol medium, respectively. Quantitative real-time PCR and Western blotting were conducted to confirm the differential expression level. Dual-luciferase reporter assays were performed to explore the targeting regulatory relationship. Overexpression and knockdown experiments were applied to reveal the potential molecular mechanism in ALD development.

Results: Between ALD patients and healthy controls, a total of 416 genes and 21 microRNAs (miRNAs) with significantly differential expression were screened. A comprehensive miRNA-mRNA network was established; within this network, the miR-182-5p/FOXO1 axis was considered a significant pathway in ALD lipid metabolism. Mouse and cell experiments validated that miR-182-5p was substantially higher in ALD than in normal livers, whereas the expression of FOXO1 was dramatically decreased by alcohol consumption (P < 0.05). Next, dual-luciferase reporter assays demonstrated that miR-182-5p directly targets the binding site of the FOXO1 3′UTR and inhibits its mRNA and protein expression. In addition, miR-182-5p was found to promote hepatic lipid accumulation via targeting the FOXO1 signaling pathway, and inhibition of the miR-182-5p/FOXO1 axis improved hepatic triglyceride (TG) deposition in ALD by regulating downstream genes involved in lipid metabolism.

Conclusion: In summary, key molecules were identified in ALD development and a comprehensive miRNA–mRNA network was established. Meanwhile, our results suggested that miR-182-5p significantly increases lipid accumulation in ALD by targeting FOXO1, thereby providing novel scientific insights and potential therapeutic targets for ALD.
Standardization of SYBR Green-Based Real-Time PCR Through the Evaluation of Different Thresholds for Different Skin Layers: An Accuracy Study and Track of the Transmission Potential of Multibacillary and Paucibacillary Leprosy Patients
Authors: Sevilha-Santos Lais , Cerqueira Selma Regina Penha Silva , Gomes Ciro Martins
Published: December 2021

The development of new molecular techniques is essential for the early diagnosis of leprosy. Studies in the field have failed to elucidate the performance of these tests in clinical practice. We aimed to design a new primer pair for the repetitive element (RLEP) target of Mycobacterium leprae and to test the accuracy of SYBR green-based real-time PCR through the evaluation of different thresholds for different skin layers. We also aimed to track the transmission potential of multibacillary and paucibacillary leprosy patients. The in vitro validation of our reaction resulted in a quantification limit of 0.03 bacilli. We then conducted a cross-sectional/cohort-based study of diagnostic accuracy. Patients were included, and skin samples were divided into four layers: epidermis, superior dermis, inferior dermis, and hypodermis. We also quantified M. leprae in nasal swabs of the included patients and compared the results to the number of household contacts also diagnosed with leprosy. One hundred patients with a clinical presentation compatible with leprosy were allocated to the leprosy or control group. Although the parasite load was greater in the superior and inferior dermis, M. leprae DNA was found in all skin layers. The best sensitivity was observed for the superior dermis using the presence of any quantifiable bacillus DNA as the threshold [sensitivity=59.26% (95% CI=45.97–71.32)]. In the epidermis, setting 1 quantifiable bacillus as the threshold resulted in 100% specificity (95% CI=92.29–100). The number of bacilli found in nasal swabs was not significantly related to the number of household contacts also diagnosed with leprosy. Paucibacillary patients tested positive only for bacillus fragments in nasal swabs but not for the entire bacilli. We can conclude that superficial biopsies might result in sensitivity loss, although different skin sample types will have little influence on the final accuracy. In contrast, threshold changes greatly influence these properties. Paucibacillary patients may not be a relevant source of disease transmission.
Microorganisms in Whole Botanical Fermented Foods Survive Processing and Simulated Digestion to Affect Gut Microbiota Composition
Authors: Chan Miin , Liu Di , Wu Yingying , Yang Fan , Howell Kate
Published: December 2021

Botanical fermented foods have been shown to improve human health, based on the activity of potentially beneficial lactic acid bacteria (LAB) and yeasts and their metabolic outputs. However, few studies have explored the effects of prolonged storage and functional spices on microbial viability of whole fermented foods from fermentation to digestion. Even fewer have assessed their impact on the gut microbiota. Our study investigated the effects of production processes on LAB and yeast microbial viability and gut microbiota composition. We achieved this by using physicochemical assessments and an in vitro gastrointestinal and a porcine gut microbiota model. In low-salt sauerkraut, we assessed the effects of salt concentration, starter cultures, and prolonged storage, and in tibicos, prolonged storage and the addition of spices cayenne, ginger, and turmeric. In both food matrices, LAB counts significantly increased (p<0.05), reaching a peak of 7–8 log cfu/g, declining to 6–6.5 log cfu/g by day 96. Yeast viability remained at 5–6 log cfu/g in tibicos. Ginger tibicos had significantly increased LAB and yeast viability during fermentation and storage (p<0.05). For maximum microbial consumption, tibicos should be consumed within 28days, and sauerkraut, 7weeks. Simulated upper GI digestion of both products resulted in high microbial survival rates of 70–80%. The 82% microbial survival rate of cayenne tibicos was significantly higher than other treatments (p<0.05). 16S rRNA sequencing of simulated porcine colonic microbiota showed that both spontaneously fermented sauerkraut and tibicos increase the relative abundance of Megasphaera 85-fold. These findings will inform researchers, producers, and consumers about the factors that affect the microbial content of fermented foods, and their potential effects on the gut.
A Comprehensive View on the Host Factors and Viral Proteins Associated With Porcine Epidemic Diarrhea Virus Infection
Authors: Hu Yi , Xie Xiaohong , Yang Lingchen , Wang Aibing
Published: December 2021

Porcine epidemic diarrhea virus (PEDV), a coronavirus pathogen of the pig intestinal tract, can cause fatal watery diarrhea in piglets, thereby causing huge economic losses to swine industries around the world. The pathogenesis of PEDV has intensively been studied; however, the viral proteins of PEDV and the host factors in target cells, as well as their interactions, which are the foundation of the molecular mechanisms of viral infection, remain to be summarized and updated. PEDV has multiple important structural and functional proteins, which play various roles in the process of virus infection. Among them, the S and N proteins play vital roles in biological processes related to PEDV survival via interacting with the host cell proteins. Meanwhile, a number of host factors including receptors are required for the infection of PEDV via interacting with the viral proteins, thereby affecting the reproduction of PEDV and contributing to its life cycle. In this review, we provide an updated understanding of viral proteins and host factors, as well as their interactions in terms of PEDV infection. Additionally, the effects of cellular factors, events, and signaling pathways on PEDV infection are also discussed. Thus, these comprehensive and profound insights should facilitate for the further investigations, control, and prevention of PEDV infection.
Identification of a Five-Gene Signature Derived From MYCN Amplification and Establishment of a Nomogram for Predicting the Prognosis of Neuroblastoma
Authors: Xia Yuren , Li Xin , Tian Xiangdong , Zhao Qiang
Published: December 2021

Background:Neuroblastoma (NB), the most common solid tumor in children, exhibits vastly different genomic abnormalities and clinical behaviors. While significant progress has been made on the research of relations between clinical manifestations and genetic abnormalities, it remains a major challenge to predict the prognosis of patients to facilitate personalized treatments.

Materials and Methods:Six data sets of gene expression and related clinical data were downloaded from the Gene Expression Omnibus (GEO) database, ArrayExpress database, and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. According to the presence or absence of MYCN amplification, patients were divided into two groups. Differentially expressed genes (DEGs) were identified between the two groups. Enrichment analyses of these DEGs were performed to dig further into the molecular mechanism of NB. Stepwise Cox regression analyses were used to establish a five-gene prognostic signature whose predictive performance was further evaluated by external validation. Multivariate Cox regression analyses were used to explore independent prognostic factors for NB. The relevance of immunity was evaluated by using algorithms, and a nomogram was constructed.

Results:A five-gene signature comprising CPLX3, GDPD5, SPAG6, NXPH1, and AHI1 was established. The five-gene signature had good performance in predicting survival and was demonstrated to be superior to International Neuroblastoma Staging System (INSS) staging and the MYCN amplification status. Finally, a nomogram based on the five-gene signature was established, and its clinical efficacy was demonstrated.

Conclusion:Collectively, our study developed a novel five-gene signature and successfully built a prognostic nomogram that accurately predicted survival in NB. The findings presented here could help to stratify patients into subgroups and determine the optimal individualized therapy.
Ikaros Proteins in Tumor: Current Perspectives and New Developments
Authors: Xia Ruolan , Cheng Yuan , Han Xuejiao , Wei Yuquan , Wei Xiawei
Published: December 2021

Ikaros is a zinc finger transcription factor (TF) of the Krüppel family member, which significantly regulates normal lymphopoiesis and tumorigenesis. Ikaros can directly initiate or suppress tumor suppressors or oncogenes, consequently regulating the survival and proliferation of cancer cells. Over recent decades, a series of studies have been devoted to exploring and clarifying the relationship between Ikaros and associated tumors. Therapeutic strategies targeting Ikaros have shown promising therapeutic effects in both pre-clinical and clinical trials. Nevertheless, the increasingly prominent problem of drug resistance targeted to Ikaros and its analog is gradually appearing in our field of vision. This article reviews the role of Ikaros in tumorigenesis, the mechanism of drug resistance, the progress of targeting Ikaros in both pre-clinical and clinical trials, and the potential use of associated therapy in cancer therapy.
Baseline Neuroimaging Predicts Decline to Dementia From Amnestic Mild Cognitive Impairment
Authors: Gullett Joseph M. , Albizu Alejandro , Fang Ruogu , Loewenstein David A. , Duara Ranjan , Rosselli Monica , Armstrong Melissa J. , Rundek Tatjana , Hausman Hanna K. , Dekosky Steven T. , Woods Adam J. , Cohen Ronald A.
Published: December 2021

Background and Objectives: Prediction of decline to dementia using objective biomarkers in high-risk patients with amnestic mild cognitive impairment (aMCI) has immense utility. Our objective was to use multimodal MRI to (1) determine whether accurate and precise prediction of dementia conversion could be achieved using baseline data alone, and (2) generate a map of the brain regions implicated in longitudinal decline to dementia.

Methods: Participants meeting criteria for aMCI at baseline (N = 55) were classified at follow-up as remaining stable/improved in their diagnosis (N = 41) or declined to dementia (N = 14). Baseline T1 structural MRI and resting-state fMRI (rsfMRI) were combined and a semi-supervised support vector machine (SVM) which separated stable participants from those who decline at follow-up with maximal margin. Cross-validated model performance metrics and MRI feature weights were calculated to include the strength of each brain voxel in its ability to distinguish the two groups.

Results: Total model accuracy for predicting diagnostic change at follow-up was 92.7% using baseline T1 imaging alone, 83.5% using rsfMRI alone, and 94.5% when combining T1 and rsfMRI modalities. Feature weights that survived the p < 0.01 threshold for separation of the two groups revealed the strongest margin in the combined structural and functional regions underlying the medial temporal lobes in the limbic system.

Discussion: An MRI-driven SVM model demonstrates accurate and precise prediction of later dementia conversion in aMCI patients. The multi-modal regions driving this prediction were the strongest in the medial temporal regions of the limbic system, consistent with literature on the progression of Alzheimer’s disease.
Combining Protein Expression and Molecular Data Improves Mutation Characterization of Dystrophinopathies
Authors: Gaina Gisela , Vossen Rolf H. A. M. , Manole Emilia , Plesca Doina Anca , Ionica Elena
Published: December 2021

Duchenne and Becker muscular dystrophy are X-linked recessive inherited disorders characterized by progressive weakness due to skeletal muscle degeneration. Different mutations in the DMD gene, which encodes for dystrophin protein, are responsible for these disorders. The aim of our study was to investigate the relationship between type, size, and location of the mutation that occurs in the DMD gene and their effect on dystrophin protein expression in a cohort of 40 male dystrophinopathy patients and nine females, possible carriers. We evaluated the expression of dystrophin by immunofluorescence and immunoblotting. The mutational spectrum of the DMD gene was established by MLPA for large copy number variants, followed by HRM analysis for point mutations and sequencing of samples with an abnormal melting profile. MLPA revealed 30 deletions (75%) and three duplications (7.5%). HRM analysis accounted for seven-point mutations (17.5%). We also report four novel small mutations (c. 8507G>T, c.3021delG, c.9563_9563+1insAGCATGTTTATGATACAGCA, c.7661-60T>A) in DMD gene. Our work shows that the DNA translational open reading frame and the location of the mutation both influence the expression of dystrophin and disease severity phenotype. The proposed algorithm used in this study demonstrates its accuracy for the characterization of dystrophinopathy patients.
Validation of the Chinese Version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease
Authors: Xu Tian , Cao Lanxiao , Long Wenying , Zhao Guohua
Published: December 2021

Background: Impulse control and related disorders (ICRDs) have gained recognition as a severe complication of Parkinson's disease (PD) and are connected to poor quality of life and devastating financial and social problems. This study aimed to evaluate the usefulness of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) and estimate the risk factors for ICRDs in Chinese patients with PD.

Methods: 207 PD patients were assessed using the QUIP and evaluated for PD motor and nonmotor symptoms. ICRDs were diagnosed via interviews of patients or their caregivers, and the clinical characteristics of patients with and without ICRDs were compared.

Results: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the C-QUIP were 95.0, 83.4, 38.0, 99.4, and 84.5%. The prevalence of each disorder among participants diagnosed via interview was pathological gambling (0.5%), hypersexuality (1.9%), compulsive shopping (1.0%), binge eating (3.9%), hobbyism (1.9%), punding (0.5%), walkabout (0.5%), and dopamine dysregulation syndrome (2.9%). PD patients with ICRDs had longer PD duration, higher Hoehn and Yahr stage, Non-Motor Symptoms Scale (NMSS), and Hamilton-Depression Rating Scale (HAMD). Also, they received a larger total daily levodopa equivalent dose (LED), levodopa dosage, and dopamine agonist only LED (DA-LED) than did PD patients without ICRDs.

Conclusions: Given its psychometric properties, the C-QUIP is a valid and rapid screening instrument for assessing of ICRDs in PD patients. Higher Hoehn and Yahr staging, NMSS and HAMD scores, a larger mean LED and levodopa dosage are risk factors for ICRDs.