bluuebunny/crossref_metadata_2025 huggingface dataset:
Current representations about etiological factors in development of delayed puberty in children with inherited epidermolysis bullosa
Authors: Leonova M. A.
Published: May 2022

Inherited epidermolysis bullosa is distinguished by a wide range of clinical manifestations: from single blisters and erosions, mainly with acral localization, which insignifcantly affect the quality and life expectancy of patients with a mild course of the disease, to severe disabling forms with a high mortality rate from multifactorial malnutrition, septicemia in early age and high risk of developing squamous cell carcinoma of the skin in adult patients. According to research studies, in children suffering from chronic diseases, there is often a delay of puberty. To date, there are no reliable data on the incidence of delayed puberty in children with inherited epidermolysis bullosa, which is of interest for further research in order to more individualized approach to treatment and improve the quality of life of patients.
La gobernanza de los Grandes Lagos entre Canadá y Estados Unidos, ¿siempre de común acuerdo?
Authors: Lasserre Frédéric , Vega Cárdenas Yenny Esmeralda
Published: May 2022

Our objective is to analyze, from a geopolitical and legal point of view, the main challenges of water governance in the Great Lakes of North America. The analysis is based on an extended bibliographic search and a triangulation analysis of the corpus thus produced. The first part of the text identifies the concerns of riparian populations in recent years. The second presents the challenges of protecting the basin from climate change and political uncertainty. Overall, the text provides a better understanding of the construction of a transnational water governance model based on the community of interests, which seems to leave behind the old Harmon theory of absolute sovereignty. We will finally ask ourselves, if it will be necessary to attribute a new juridical status to this basin to protect these ecosystems from the challenges raised by climate change.
Lipid Ligands and Allergenic LTPs: Redefining the Paradigm of the Protein-Centered Vision in Allergy
Authors: Gonzalez-Klein Zulema , Pazos-Castro Diego , Hernandez-Ramirez Guadalupe , Garrido-Arandia Maria , Diaz-Perales Araceli , Tome-Amat Jaime
Published: May 2022

Lipid Transfer Proteins (LTPs) have been described as one of the most prevalent and cross-reactive allergen families in the general population. They are widely distributed among the plant kingdom, as well as in different plant organs ranging from pollen to fruits. Thus, they can initiate allergic reactions with very different outcomes, such as asthma and food allergy. Several mouse models have been developed to unravel the mechanisms that lead LTPs to promote such strong sensitization patterns. Interestingly, the union of certain ligands can strengthen the allergenic capacity of LTPs, suggesting that not only is the protein relevant in the sensitization process, but also the ligands that LTPs carry in their cavity. In fact, different LTPs with pro-allergenic capacity have been shown to transport similar ligands, thus positioning lipids in a central role during the first stages of the allergic response. Here, we offer the latest advances in the use of experimental animals to study the topic, remarking differences among them and providing future researchers a tool to choose the most suitable model to achieve their goals. Also, recent results derived from metabolomic studies in humans are included, highlighting how allergic diseases alter the lipidic metabolism toward a pathogenic state in the individual. Altogether, this review offers a comprehensive body of work that sums up the background evidence supporting the role of lipids as modulators of allergic diseases. Studying the role of lipids during allergic sensitization might broaden our understanding of the molecular events leading to tolerance breakdown in the epithelium, thus helping us to understand how allergy is initiated and established in the individuals.
Opportunities for the Progression of Farm Animal Welfare in China
Authors: Sinclair Michelle , Lee Hui Pin , Chen Maria , Li Xiaofei , Mi Jiandui , Chen Siyu , Marchant Jeremy N.
Published: May 2022

As the world's largest livestock producer, China has made some progress to improve farm animal welfare in recent years. Recognizing the importance of locally led initiatives, this study aimed to engage the knowledge and perspectives of Chinese leaders in order to identify opportunities to further improve farm animal welfare in China. A team of Chinese field researchers engaged 100 senior stakeholders in the agriculture sector (livestock business leaders, agriculture strategists and intellectuals, government representatives, licensed veterinarians, agriculture lawyers, and national animal welfare advocates). Participants completed a Chinese questionnaire hosted on a national platform. The raw data responses were then translated and subjected to qualitative and quantitative analyses from which themes were built and resulting recommendations were made. The findings of this study urge emphasis on the ties between improved animal welfare with food safety, product quality, and profit, and demonstrate the existence of animal welfare opportunities outside of the immediate introduction of specific animal protection legislation. The resulting applications are anticipated to be of strategic use to stakeholders interested in improving farm animal welfare in China.
Performance Evaluation of a Novel Ultrafast Molecular Diagnostic Device Integrated With Microfluidic Chips and Dual Temperature Modules
Authors: Lin Shan , Song Xiaojun , Zhu Kun , Shao Quanyu , Chen Yinhang , Cheng Wei , Lei Zhijing , Chen Yu , Luo Yun , Jin Dazhi
Published: May 2022

Ultrafast, portable, and inexpensive molecular diagnostic platforms are critical for clinical diagnosis and on-site detection. There are currently no available real-time polymerase chain reaction (PCR) devices able to meet the demands of point-of-care testing, as the heating and cooling processes cannot be avoided. In this study, the dual temperature modules were first designed to process microfluidic chips automatically circulating between them. Thus, a novel ultrafast molecular diagnostic real-time PCR device (approximately 18 and 23 min for DNA and RNA detection, respectively) with two channels (FAM and Cy5) for the detection of 12 targets was developed. The device contained three core functional components, including temperature control, optics, and motion, which were integrated into a portable compact box. The temperature modules accurately control temperature in rapid thermal cycles with less than ±0.1 °C, ±1 °C and ±0.5 °C for the temperature fluctuation, uniformity, and error of indication, respectively. The average coefficient of variation (CV) of the fluorescence intensity (FI) for all 12 wells was 2.3% for FAM and 2.7% for Cy5. There was a good linear relationship between the concentrations of fluorescent dye and the FIs of FAM and Cy5(R2 = 0.9990 and 0.9937), and the average CVs of the Ct values calculated by the embedded software were 1.4% for FAM and Cy5, respectively. The 100 double-blind mocked sputum and 249 clinical stool samples were analyzed by the ultrafast real-time PCR device in comparison with the DAAN Gene SARS-CoV-2 kit run on the ABI 7500 instrument and Xpert C. difficile/Epi, respectively. Among the 249 stool samples, the ultrafast real-time PCR device detected toxigenic C. difficile in 54 samples (54/249, 21.7%) with a specificity and positive predictive values of 99.0 and 96.3%, which were higher than the Xpert C. difficile/Epi values of 94.4 and 88.1% (p > 0.05). The ultrafast real-time PCR device detected 15 SARS-CoV-2 positive samples, which has a 100% concordance with that obtained by the DAAN Gene SARS-CoV-2 kit. This study demonstrated that the ultrafast real-time PCR device integrated with microfluidic chips and dual temperature modules is an ultrafast, reliable, easy-to-use, and cost-effective molecular diagnostic platform for clinical diagnosis and on-site testing, especially in resource-limited settings.
Strategies to Improve the Thermoelectric Figure of Merit in Thermoelectric Functional Materials
Authors: Sun Yan , Liu Yue , Li Ruichuan , Li Yanshuai , Bai Shizheng
Published: May 2022

In recent years, thermoelectric functional materials have been widely concerned in temperature difference power generation, electric refrigeration and integrated circui, and so on. In this paper, the design and research progress of thermoelectric materials around lifting ZT value in recent years are reviewed. Optimizing the carrier concentration to improve the Seebeck coefficient, the steady improvement of carrier mobility and the influence of energy band engineering on thermoelectric performance are discussed. In addition, the impact of lattice thermal conductivity on ZT value is also significant. We discuss the general law that the synergistic effect of different dimensions, scales, and crystal structures can reduce lattice thermal conductivity, and introduce the new application of electro-acoustic decoupling in thermoelectric materials. Finally, the research of thermoelectric materials is summarized and prospected in the hope of providing practical ideas for expanding the application and scale industrialization of thermoelectric devices.
Characteristics of the Intestinal Flora of TPOAb-Positive Women With Subclinical Hypothyroidism in the Second Trimester of Pregnancy: A Single-Center Prospective Cohort Study
Authors: Wu Min , Yang Yuxi , Fan Yali , Guo Shan , Li Tianhe , Gu Muqing , Zhang Tingting , Gao Huimin , Liu Ruixia , Yin Chenghong
Published: May 2022

Pregnant women are at high risk of developing subclinical hypothyroidism (SCH), and anti-thyroid peroxidase antibody (TPOAb) positivity can further inhibit thyroxine synthesis. Emerging evidence indicates that intestinal flora can modulate metabolic and immune homeostasis. The characteristics of intestinal flora of TPOAb-positive women with SCH in their second trimester of pregnancy have not been reported. This single-center prospective observational cohort study investigated gut microbial composition and metabolic function using sequencing of the 16S rRNA gene in fecal samples from 75 TPOAb-positive women with SCH and 90 TPOAb-negative women with SCH during their second trimester of pregnancy. Women were treated with no levothyroxine (LT4), low-dose LT4 (≤50ug/d), or high-dose LT4 (>50ug/d). Taxonomic analysis showed Firmicutes and Bacteroidetes were the dominant phyla, followed by Actinobacteria and Proteobacteria. Faecalibacterium, Bacteroides, Prevotella 9, Bifidobacterium, Subdoligranulum, Lachnospira, and Megamonas were the predominant genera. The intestinal flora of TPOAb-positive women with SCH who received no LT4 was characterized by bacterial amplicon sequence variants (ASVs)/operational taxonomic units (OTUs) enriched in the genus Subdoligranulum. The intestinal flora of TPOAb-positive women with SCH who received low-dose or high-dose LT4 were characterized by bacterial ASVs/OTUs depleted of the species Ruminococcus sp._or Bacteroides massiliensis, respectively. A total of 19 metabolic functions of intestinal flora, mainly involving lipid and amino acid metabolism, discriminated TPOAb-positive and TPOAb-negative women with SCH. Our study suggests that there are differences in the composition and metabolic function of intestinal flora of TPOAb-positive and TPOAb-negative women with SCH treated with different doses of LT4 in the second trimester of pregnancy. The findings provide insight into intestinal flora as novel targets for the treatment of TPOAb-positive women with SCH during pregnancy.
Human Guanylate-Binding Protein 1 Positively Regulates Japanese Encephalitis Virus Replication in an Interferon Gamma Primed Environment
Authors: Chhabra Simran , Sharma Kiran Bala , Kalia Manjula
Published: May 2022

RNA virus infection triggers interferon (IFN) receptor signaling, leading to the activation of hundreds of interferon-stimulated genes (ISGs). Guanylate-binding proteins (GBPs) belong to one such IFN inducible subfamily of guanosine triphosphatases (GTPases) that have been reported to exert broad anti-microbial activity and regulate host defenses against several intracellular pathogens. Here, we investigated the role of human GBP1 (hGBP1) in Japanese encephalitis virus (JEV) infection of HeLa cells in both an IFNγ unprimed and primed environment. We observed enhanced expression of GBP1 both at transcript and protein levels upon JEV infection, and GBP1 association with the virus replication membranes. Depletion of hGBP1 through siRNA had no effect on JEV replication or virus induced cell death in the IFNγ unprimed environment. IFNγ stimulation provided robust protection against JEV infection. Knockdown of GBP1 in the primed environment upregulated expression and phosphorylation of signal transducer and activator of transcription 1 (STAT1) and significantly reduced JEV replication. Depletion of GBP1 in an IFNγ primed environment also inhibited virus replication in human neuroblastoma SH-SH5Y cells. Our data suggests that in the presence of IFNγ, GBP1 displays a proviral role by inhibiting innate immune responses to JEV infection.
The Microbiome in Pancreatic Cancer-Implications for Diagnosis and Precision Bacteriophage Therapy for This Low Survival Disease
Authors: Kabwe Mwila , Dashper Stuart , Tucci Joseph
Published: May 2022

While the mortality rates for many cancers have decreased due to improved detection and treatments, that of pancreatic cancer remains stubbornly high. The microbiome is an important factor in the progression of many cancers. Greater understanding of the microbiome in pancreatic cancer patients, as well as its manipulation, may assist in diagnosis and treatment of this disease. In this report we reviewed studies that compared microbiome changes in pancreatic cancer patients and non-cancer patients. We then identified which bacterial genera were most increased in relative abundance across the oral, pancreatic, duodenal, and faecal tissue microbiomes. In light of these findings, we discuss the potential for utilising these bacteria as diagnostic biomarkers, as well as their potential control using precision targeting with bacteriophages, in instances where a causal oncogenic link is made.
Rapid Detection of Klebsiella pneumoniae Carrying Virulence Gene rmpA2 by Recombinase Polymerase Amplification Combined With Lateral Flow Strips
Authors: Li Na , Wang Lei , Wang Fang , Chen Huimin , Tao Shuan , Zhu Qing , Liu Liping , Liang Wei , Ma Fang
Published: May 2022

Highly virulent Klebsiella pneumoniae often causes invasive infections with high morbidity and mortality rates, posing an immense clinical challenge. Rapid and accurate detection of pathogenic bacteria is of great significance for treatment and preventive control. Conventional detection by polymerase chain reaction (PCR) is limited by a dependence on laboratory equipment and professional staff. Recombinase polymerase amplification (RPA) combined with a lateral flow strip (LFS) can rapidly amplify and visualize target genes in a short period of time. The aim of this study was to develop an RPA-LFS technique for detection of the K. pneumoniae virulence gene rmpA2. Primers were designed against conserved sequences specific to the virulence gene, and primer probe design was optimized by introducing base substitution to obtain a specific and sensitive primer-probe combination for clinical detection. We tested 65 actual samples collected from clinics to evaluate the performance of the newly established RPA-LFS system in comparison with conventional PCR methods and qPCR methods. The RPA-LFS assay was performed at for 25 min a constant temperature of 37°C, and results could be observed without instrumentation. The system could specifically identify highly virulent K. pneumoniae carrying the virulence gene rmpA2 with a minimum detection limit of 10−1 ng/μL and 10 copies/μL. For the 65 clinical samples tested, The RPA-LFS assay results were in complete agreement with the qPCR results and PCR results. The RPA-LFS assay provides a rapid, accurate, and simple method for identification of highly virulent K. pneumoniae carrying rmpA2.
Serpins in Tick Physiology and Tick-Host Interaction
Authors: Abbas Muhammad Nadeem , Chlastáková Adéla , Jmel Mohamed Amine , Iliaki-Giannakoudaki Evangelia , Chmelař Jindřich , Kotsyfakis Michail
Published: May 2022

Tick saliva has been extensively studied in the context of tick-host interactions because it is involved in host homeostasis modulation and microbial pathogen transmission to the host. Accumulated knowledge about the tick saliva composition at the molecular level has revealed that serine protease inhibitors play a key role in the tick-host interaction. Serpins are one highly expressed group of protease inhibitors in tick salivary glands, their expression can be induced during tick blood-feeding, and they have many biological functions at the tick-host interface. Indeed, tick serpins have an important role in inhibiting host hemostatic processes and in the modulation of the innate and adaptive immune responses of their vertebrate hosts. Tick serpins have also been studied as potential candidates for therapeutic use and vaccine development. In this review, we critically summarize the current state of knowledge about the biological role of tick serpins in shaping tick-host interactions with emphasis on the mechanisms by which they modulate host immunity. Their potential use in drug and vaccine development is also discussed.
Constructional Borrowing From English in Hong Kong Cantonese
Authors: Chan Brian Hok-Shing
Published: May 2022

Previous research on Cantonese-English contact in Hong Kong has focused on lexical phenomena, primarily lexical borrowing and intra-sentential, single-word code-switching (or code-mixing). Although code-switching may also involve longer English phrases, the English elements are mostly inserted into Cantonese-framed sentences in accordance with the Matrix Language Frame/MLF Model. In other words, the syntax of Cantonese appears to be largely intact despite words or phrases drawn from English. This paper underscores that in fact English syntax can be melded more intricately with lexis from both Cantonese and English, thus defying the MLF Model; however, recurrent cases are limited to three constructions so far, namely, thewhich-relative, the English PP-postmodifier, and an [NP COP P NP] sequence with an English preposition. A re-examination of these three constructions reveals that, rather than linguistic economy, they are semantically and pragmatically motivated to convey some specific meaning. Moreover, all these constructions are lexico-syntactic in the sense that they prototypically contain an English word, namely, the relativizerwhich, an English noun and an English preposition, respectively. Accordingly, these cases can also be treated as code-switching, though structural borrowing better captures the fact that some English syntactic structure is transferred. In line with Construction Grammar, these constructions are better understood as constructional borrowing in which each construction as a whole—composed of not only words from Cantonese and English but also a syntactic structure—conveys specific meaning. As for why such cases of structural or constructional borrowing are limited or partial, this paper suggests that it is more due to a soft constraint that separates English and Cantonese grammars—Hong Kong speakers still tend to convey a sense that they speak Cantonese among themselves—although they draw on linguistic resources from English. In this light, the Borrowability Hierarchy may be recast as a continuum of language separation and fluidity, which offers a more nuanced view to translanguaging.
Modulation of Regulatory T Cells Activity by Distinct CD80 and CD86 Interactions With CD28/CTLA-4 in Chagas Cardiomyopathy
Authors: Pinto Bruna F. , Medeiros Nayara I. , Teixeira-Carvalho Andrea , Fiuza Jacqueline A. , Eloi-Santos Silvana M. , Nunes Maria C. P. , Silva Silvana A. , Fontes-Cal Tereza C. M. , Belchior-Bezerra Mayara , Dutra Walderez O. , Correa-Oliveira Rodrigo , Gomes Juliana A. S.
Published: May 2022

Chagas cardiomyopathy is the symptomatic cardiac clinical form (CARD) of the chronic phase of Chagas disease caused byTrypanosoma cruziinfection. It was described as the most fibrosing cardiomyopathies, affecting approximately 30% of patients during the chronic phase. Other less frequent symptomatic clinical forms have also been described. However, most patients who progress to the chronic form develop the indeterminate clinical form (IND), may remain asymptomatic for life, or develop some cardiac damage. Some mechanisms involved in the etiology of the clinical forms of Chagas disease have been investigated. To characterize the contribution of CD80 and CD86 co-stimulatory molecules in the activation of different CD4+(Th1, Th2, Th17, and Treg) and CD8+T lymphocyte subsets, we used blocking antibodies for CD80 and CD86 receptors of peripheral blood mononuclear cells (PBMC) in cultures withT. cruziantigens from non-infected (NI), IND, and CARD individuals. We demonstrated a higher frequency of CD8+CD25+T lymphocytes and CD8+Treg cells after anti-CD80 antibody blockade only in the CARD group. In contrast, a lower frequency of CD4+Treg lymphocytes after anti-CD86 antibody blockade was found only in IND patients. A higher frequency of CD4+Treg CD28+lymphocytes, as well as an association between CD4+Treg lymphocytes and CD28+expression on CD4+Treg cells in the CARD group, but not in IND patients, and once again only after anti-CD80 antibody blockade, was observed. We proposed that Treg cells from IND patients could be activatedviaCD86-CTLA-4 interaction, leading to modulation of the immune response only in asymptomatic patients with Chagas disease, while CD80 may be involved in the proliferation control of T CD8+lymphocytes, as also in the modulation of regulatory cell activationviaCD28 receptor. For the first time, our data highlight the role of CD80 in modulation of Treg lymphocytes activation in patients with CARD, highlighting a key molecule in the development of Chagas cardiomyopathy.
Perioperative Myocardial Injury/Infarction After Non-cardiac Surgery in Elderly Patients
Authors: Gao Linggen , Chen Lei , He Jing , Wang Bin , Liu Chaoyang , Wang Rong , Fan Li , Cheng Rui
Published: May 2022

At present, we have entered an aging society. Many diseases suffered by the elderly, such as malignant tumors, cardiovascular diseases, fractures, surgical emergencies and so on, need surgical intervention. With the improvement of Geriatrics, surgical minimally invasive technology and anesthesia level, more and more elderly patients can safely undergo surgery. Elderly surgical patients are often complicated with a variety of chronic diseases, and the risk of postoperative myocardial injury/infarction (PMI) is high. PMI is considered to be the increase of cardiac troponin caused by perioperative ischemia, which mostly occurs during operation or within 30 days after operation, which can increase the risk of short-term and long-term death. Therefore, it is suggested to screen troponin in elderly patients during perioperative period, timely identify patients with postoperative myocardial injury and give appropriate treatment, so as to improve the prognosis. The pathophysiological mechanism of PMI is mainly due to the increase of myocardial oxygen consumption and / the decrease of myocardial oxygen supply. Preoperative and postoperative risk factors of myocardial injury can be induced by mismatch of preoperative and postoperative oxygen supply. The treatment strategy should first control the risk factors and use the drugs recommended in the guidelines for treatment. Application of cardiovascular drugs, such as antiplatelet β- Receptor blockers, statins and angiotensin converting enzyme inhibitors can effectively improve postoperative myocardial ischemia. However, the risk of perioperative bleeding should be fully considered before using antiplatelet and anticoagulant drugs. This review is intended to describe the epidemiology, diagnosis, pathophysiology, risk factors, prognosis and treatment of postoperative myocardial infarction /injury.
Early-Career Teachers Living on School Landscapes Shaped by Equity Policies and Practices: Helena’s and Kristin’s Stories
Authors: Ross Vicki Dea , Chaseley Tina , Mocanu R. Gabriela , Zhang Yuanyibo
Published: May 2022

Before moving beyond the beginning stages of becoming a teacher, one of every two teachers leaves the profession. Hence, for several decades, the recruitment, development, and retention of teachers has been a pernicious problem facing districts, schools, administrators, and school personnel. A productive line of narrative inquiry research has focused on teacher education and development. Additionally, narrative inquiries have focused on teacher retention and attrition. For example, several researchers have narratively inquired into the processes of transitioning out of the profession. In the present investigation, we asked an overarching question, what do beginning teachers need in order to tell stories of staying? And, relatedly, in schools working toward addressing questions of equity, what are the experiences of early-career teachers? And, what can be done to develop and sustain them in their professional commitments? Two novice teachers, Helena and Kristin, both of whom took initial positions in the same district, which had a commitment to promoting equity for children, were interviewed to gather perspectives on their early-career experiences. Both participants shared tension-filled stories from their beginning years as a teacher that created a sense of disequilibrium connected to their developing sense of self. The data analysis pointed to the value that the concept of the best-loved self may have in helping teachers construct their sense of identity. As in the case of Helena and Kristin, this sense of the best-loved self may develop early and can shift over time. For teacher educators, this aspect provides an opening for exploring philosophical commitments within preparations programs with teacher candidates. For teachers and administrators in schools who are intaking beginning teachers, understanding these nascent facets of best-loved teacher self may provide a window into these novice teachers’ motivations. And, these practices may prompt the reconnection to philosophical commitments and aspirations in the day-to-day tug at the fabric of teacher identity.
Assessing Measurement Quality of Multidimensional Classroom Incivility Scale in Higher Education
Authors: Asfiati Asfiati , Cahyadi Ani , Hendryadi Hendryadi , Hartinah Sitti
Published: May 2022

This study examined the reliability and validity of a measure of classroom incivility within an Indonesian context. Data were collected from 334 participants through two stages of online questionnaire distribution. The measurement quality was evaluated through seven stages of partial least squares confirmatory composite analysis (PLS-CCA). Our findings confirm the multidimensionality of classroom incivility (class disruption, disrespectful communication, integrity violation, and use of the cell phone). In addition, all sub-scales of classroom incivility were negatively related to civility and prosocial behavior, and no significant difference was found between male and female students. Higher education institutions in Indonesia can use this instrument as a supplementary tool to evaluate the level of classroom incivility. We also discuss its practical implications in educational settings in general and offer suggestions for future research on classroom incivility in non-Western countries.
INSC Is Down-Regulated in Colon Cancer and Correlated to Immune Infiltration
Authors: Yu Tao , Li Dan , Zeng Zhi , Xu Xu , Zhang Haiming , Wu Jie , Song Wei , Zhu Hua
Published: May 2022

Background: Previous studies have verified that Inscuteable Spindle Orientation Adaptor Protein (INSC) can regulate cell proliferation and differentiation in the developing nervous system. It also plays an important role in spindle orientation during mitosis and asymmetric division of fibroblasts and participates in the process of stratification of the squamous epithelium. The role and potential mechanism of INSC in the development of colonic adenocarcinoma (COAD) have not been fully understood. This study aimed at exploring the prognostic value of INSC in COAD and the correlation of its expression with immune infiltration.

Methods: The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) project, Gene Expression Profiling Interactive Analysis (GEPIA), and Gene Expression Omnibus (GEO) database were used to analyze the expression of INSC in COAD. The INSC protein expression level was analyzed by immunohistochemistry staining and the Human Protein Atlas (HPA) database. The diagnostic and prognostic values of INSC in COAD patients were analyzed using receiver operating characteristic (ROC) and Kaplan–Meier (KM) survival curves. In order to understand whether INSC is an independent prognostic factor, we used univariable and multivariate Cox analyses to analyze INSC expression and several clinical characteristics with survival. We use STRING analysis to find INSC-related proteins and related biological events analyzed by Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. At last, GEPIA and the Tumor Immune Estimation Resource (TIMER) were employed to explore the relationship between INSC and immune infiltrates and its marker gene set.

Results: INSC was lower expressed in COAD tissues than in normal colon tissues, which was correlated with tumor stage. Patients with lower expression of INSC had shorter overall survival (OS). Moreover, univariable Cox analysis demonstrated that high expression of INSC was an independent prognostic factor for COAD. ROC analysis showed INSC was an accurate marker for identifying tumors from normal colon tissue, and the AUC of the curve was 0.923. Significant GO term analysis by GSEA showed that genes correlated with INSC were found to be enriched in several immune-related pathways. Specifically, INSC expression showed significant negative correlations with infiltration levels of B cells, CD4+ T cells, macrophages, DCs, and their marker sets in COAD.

Conclusion: INSC was provided with prognostic value in COAD and related to immune invasion.
Prognostic Significance of Lineage Diversity in Bladder Cancer Revealed by Single-Cell Sequencing
Authors: Yu Lu , Hu Rixin , Peng Guoyu , Ding Qiuxia , Tao Tao , Wu Song
Published: May 2022

Bladder cancer is the most common malignant tumor of the urinary system. We investigated the clinical implications of cell lineages in bladder cancer by integrating single-cell and bulk transcriptome data. By investigating the single-cell transcriptional profiles of 12,424 cells from normal bladder, eleven cell types and five types of epithelial sub-population were identified. Based on the signature of cell types identified in single-cell profiles, deconvolution analysis was employed to estimate cell types and epithelial lineages in the bulk RNA sequencing bladder cancer cohort. Cancer subtypes with clinical implications were further identified based on the heterogeneity of the epithelial lineage across patients. This study suggests that the EMT-like subtype is robustly correlated with poor prognosis and the umbrella subtype is a positive factor for the patient survival. Our research has a high potential for accurate prognostic and therapeutic stratification of bladder cancer.
Signatures of mRNA Alternative Polyadenylation in Arabidopsis Leaf Development
Authors: Yu Zhibo , Hong Liwei , Li Qingshun Q.
Published: May 2022

Alternative polyadenylation (APA) of pre-mRNA is an important co-transcriptional mechanism that modulates gene expression, leading to transcriptomic and functional diversities. The role of APA in Arabidopsis leaf development, however, remains elusive. We applied a poly(A)-tag sequencing (PAT-seq) technique to characterize APA-mediated regulation events in cotyledon and in five stages of true leaf development. Over 60% APA was identified in genes expressed in leaves, consistent with the results in previous publications. However, a reduced APA level was detected in younger leaves, reaching 44% in the 18th true leaf. Importantly, we also found that >70% of the poly(A) site usages were altered in the second true leaf relative to the cotyledon. Compared with the cotyledon, more genes in the second true leaf tended to use the distal site of 3′UTR, but this was not found in pairwise comparison among other true leaves. In addition, a significant APA gene was found to be decreased in a pairwise comparison among true leaves, including differentially expressed genes. The APA genes identified herein were associated with specific biological processes, including metabolic and cellular processes and response to stimuli and hormones. These results provide a new insight into the regulation of Arabidopsis leaf development through APA.
NAP1L1 Functions as a Novel Prognostic Biomarker Associated With Macrophages and Promotes Tumor Progression by Influencing the Wnt/β-Catenin Pathway in Hepatocellular Carcinoma
Authors: Shen Bingbing , Zhu Wenjie , Liu Xinyuan , Jiang Jianxin
Published: May 2022

Hepatocellular carcinoma (HCC) is regarded as one of the universal cancers in the world. Therefore, our study is based on clinical, molecular mechanism and immunological perspectives to analyze how NAP1L1 affects the progression of HCC. To begin with, the gene expression datasets and clinical data of GSE14520, GSE76427, ICGC, and TCGA are originated from GEO, ICGC, and TCGA databases. Subsequently, DEG screening was performed on data using R studio, and we finally found that 2,145 overlapping DEGs were screened from four datasets at the end. Then, we used R studio to filter the survival-related genes of the GSE76427 and ICGC datasets, and we screened out 101 survival-related genes. Finally, 33 common genes were screened out from 2,145 overlapping DEGs and 101 survival-related genes. Then, NAP1L1 was screened from 33 common genes using the CytoHubba plug-in in Cytoscape software. Furthermore, ground on GEO, ICGC, and TCGA databases, the survival analysis, clinical feature analysis, univariate/multivariate regression analysis, and multiple GSEA were used to study NAP1L1. The Conclusion claimed that HCC patients with higher expression levels of NAP1L1 had a poorer prognosis than those with lower expression levels. Thus, we believe that NAP1L1 is an independent prognostic factor for HCC. In order to shed light on NAP1L1’s molecular mechanism promoting the progression of HCC closely, the GSEA tool was applied to complete the GSEA of the four datasets. Furthermore, the results confirmed that NAP1L1 could promote HCC progression by regulating the G2/M transition of the cell cycle and Wnt signaling pathway. Western blot and flow cytometry were also performed to understand those mechanisms in this study. The result of Western blot showed that NAP1L1 silencing led to downregulation of CDK1 and β-catenin proteins; the result of flow cytometry showed that cell numbers in the G2 phase were significantly increased when NAP1L1 was silenced. Thus, we claimed that NAP1L1 might promote HCC progression by activating the Wnt signaling pathway and promoting cell cycle G2/M transition. In addition, ground on GSE14520 and GSE76427 datasets, and ICGC and TCGA databases, the correlation between NAP1L1 and immune cells was analyzed in HCC patients. At the same time, the TISIDB online database and the TIMER online database were testified to the association between NAP1L1 and immune cells. Hence, the summary shows that NAP1L1 was connected with a certain amount of immune cells. We can speculate that NAP1L1 may influence macrophages to promote HCC progression through some potential mechanisms.
Plasticity of Innate Lymphoid Cells in Cancer
Authors: Heinrich Bernd , Korangy Firouzeh
Published: May 2022

Innate lymphoid cells (ILCs) are a heterogenous population of the innate immune system, enriched at mucosal surfaces and are pivotal regulators of immune homeostasis. ILCs are the innate counterpart of T cells. Like T cells, ILC subsets are highly plastic with their composition and function controlled by alterations in their microenvironment. This plasticity allows for the trans-differentiation between the subsets to rapidly respond to their immune environment. The tumor microenvironment (TME) is a heterogeneous milieu characterized by different cytokines and growth factors. Through interaction with the tumor microenvironment, ILCs can transdifferentiate into different subsets resulting in pro or anti-tumor immunity. Thus, studying ILC plasticity might result in new therapeutic approaches for cancer therapy. In this review, we summarize current findings of the functional and plastic heterogeneity of ILCs in homeostasis as well as disease settings with a specific focus on cancer. We specifically highlight tumor-driven plasticity and how ILC-induced inflammation can impact the tumor microenvironment and anti-tumor immunity.
Machine Learning-Assisted Screening of Herbal Medicine Extracts as Vaccine Adjuvants
Authors: Hioki Kou , Hayashi Tomoya , Natsume-Kitatani Yayoi , Kobiyama Kouji , Temizoz Burcu , Negishi Hideo , Kawakami Hitomi , Fuchino Hiroyuki , Kuroda Etsushi , Coban Cevayir , Kawahara Nobuo , Ishii Ken J.
Published: May 2022

Adjuvants are important vaccine components, composed of a variety of chemical and biological materials that enhance the vaccine antigen-specific immune responses by stimulating the innate immune cells in both direct and indirect manners to produce a variety cytokines, chemokines, and growth factors. It has been developed by empirical methods for decades and considered difficult to choose a single screening method for an ideal vaccine adjuvant, due to their diverse biochemical characteristics, complex mechanisms of, and species specificity for their adjuvanticity. We therefore established a robust adjuvant screening strategy by combining multiparametric analysis of adjuvanticity in vivo and immunological profiles in vitro (such as cytokines, chemokines, and growth factor secretion) of various library compounds derived from hot-water extracts of herbal medicines, together with their diverse distribution of nano-sized physical particle properties with a machine learning algorithm. By combining multiparametric analysis with a machine learning algorithm such as rCCA, sparse-PLS, and DIABLO, we identified that human G-CSF and mouse RANTES, produced upon adjuvant stimulation in vitro, are the most robust biological parameters that can predict the adjuvanticity of various library compounds. Notably, we revealed a certain nano-sized particle population that functioned as an independent negative parameter to adjuvanticity. Finally, we proved that the two-step strategy pairing the negative and positive parameters significantly improved the efficacy of screening and a screening strategy applying principal component analysis using the identified parameters. These novel parameters we identified for adjuvant screening by machine learning with multiple biological and physical parameters may provide new insights into the future development of effective and safe adjuvants for human use.
Anti-Mitochondrial Antibody Titers Decrease Over Time in Primary Biliary Cholangitis Patients With Ursodeoxycholic Acid Therapeutic Response: A Cohort Study Followed Up to 28 Years
Authors: Chang Ming-Ling , Chen Wei-Ting , Chan Tien-Ming , Lin Cheng-Yu , Chang Ming-Yu , Chen Shiang-Chi , Chien Rong-Nan
Published: May 2022

Background

How anti-mitochondrial antibody (AMA) and liver biochemistry levels change in primary biliary cholangitis (PBC) patients treated with ursodeoxycholic acid (UDCA) remains unclear.

Methods

A 28-year cohort of 157 PBC patients was conducted. Patients with alkaline phosphatase (Alk-p) levels >1.67 × upper limit of normal after 1 year of UDCA treatment were considered nonresponders.

Results

At baseline, of 157 (mean age: 54.41 years), 136 (86.6%) were female, 51 (32.5%) had cirrhosis, and 128 (81.5%) had detectable AMAs (immunoglobulin G). UDCA nonresponders (n=61) were younger and had higher Alk-p and total bilirubin levels and cirrhosis rates than UDCA responders (n=84). Alk-p levels and cirrhosis were negatively associated with UDCA response. Regardless of cirrhosis and UDCA response, most PBC patients had decreased Alk-p and γ-glutamyltransferase levels at last follow-up (up to 28.73 years) compared with baseline levels. Patients with baseline cirrhosis (2.78 ± 2.56 vs. 6.84 ± 9.00 mg/dL, p=0.024) and UDCA nonresponders (2.54 ± 2.19 vs. 4.51 ± 6.99 mg/dL, p=0.006) had increased total bilirubin levels while patients without cirrhosis (AST: 91.5 ± 84.5 vs. 58.9 ± 43.7 U/L, p<0.001; ALT: 107.3 ± 122.5 vs. 50.7 ± 36.8 U/L, p<0.001) and UDCA responders (AST: 83.8 ± 101.3 vs. 45.58 ± 38.42 U/L, p=0.014; ALT: 95.10 ± 144.6 vs. 39.12 ± 30.65 U/L, p=0.009) had decreased aminotransferase levels. Only UDCA responders had decreased AMA titers from 1 year after UDCA treatment (p=0.028) until the last follow-up (p<0.001).

Conclusions

UDCA responders exhibited decreased AMA titers 1 year after treatment. Regardless of UDCA response, PBC patients showed improved cholestatic features, but only UDCA responders and patients without baseline cirrhosis exhibited attenuated hepatobiliary damage following UDCA treatment.
Inferring Tissue-Specific, TLR4-Dependent Type 17 Immune Interactions in Experimental Trauma/Hemorrhagic Shock and Resuscitation Using Computational Modeling
Authors: Shah Ashti M. , Zamora Ruben , Korff Sebastian , Barclay Derek , Yin Jinling , El-Dehaibi Fayten , Billiar Timothy R. , Vodovotz Yoram
Published: May 2022

Trauma/hemorrhagic shock followed by resuscitation (T/HS-R) results in multi-system inflammation and organ dysfunction, in part driven by binding of damage-associated molecular pattern molecules to Toll-like Receptor 4 (TLR4). We carried out experimental T/HS-R (pseudo-fracture plus 2 h of shock followed by 0-22 h of resuscitation) in C57BL/6 (wild type [WT]) and TLR4-null (TLR4-/-) mice, and then defined the dynamics of 20 protein-level inflammatory mediators in the heart, gut, lung, liver, spleen, kidney, and systemic circulation. Cross-correlation and Principal Component Analysis (PCA) on data from the 7 tissues sampled suggested that TLR4-/- samples express multiple inflammatory mediators in a small subset of tissue compartments as compared to the WT samples, in which many inflammatory mediators were localized non-specifically to nearly all compartments. We and others have previously defined a central role for type 17 immune cells in human trauma. Accordingly, correlations between IL-17A and GM-CSF (indicative of pathogenic Th17 cells); between IL-17A and IL-10 (indicative of non-pathogenic Th17 cells); and IL-17A and TNF (indicative of memory/effector T cells) were assessed across all tissues studied. In both WT and TLR4-/- mice, positive correlations were observed between IL-17A and GM-CSF, IL-10, and TNF in the kidney and gut. In contrast, the variable and dynamic presence of both pathogenic and non-pathogenic Th17 cells was inferred in the systemic circulation of TLR4-/- mice over time, suggesting a role for TLR4 in efflux of these cells into peripheral tissues. Hypergraph analysis – used to define dynamic, cross compartment networks – in concert with PCA-suggested that IL-17A was present persistently in all tissues at all sampled time points except for its absence in the plasma at 0.5h in the WT group, supporting the hypothesis that T/HS-R induces efflux of Th17 cells from the circulation and into specific tissues. These analyses suggest a complex, context-specific role for TLR4 and type 17 immunity following T/HS-R.
Long-Term and Seasonal Variability of Wind and Wave Extremes in the Arctic Ocean
Authors: Cabral Isabela S. , Young Ian R. , Toffoli Alessandro
Published: May 2022

Over recent decades, the Arctic Ocean has experienced dramatic variations due to climate change. By retreating at a rate of 13% per decade, sea ice has opened up significant areas of ocean, enabling wind to blow over larger fetches and potentially enhancing wave climate. Considering the intense seasonality and the rapid changes to the Arctic Ocean, a non-stationary approach is applied to time-varying statistical properties to investigate historical trends of extreme values. The analysis is based on a 28-year wave hindcast (from 1991 to 2018) that was simulated using the WAVEWATCH III wave model forced by ERA5 winds. Despite a marginal increase in wind speed (up to about 5%), results demonstrate substantial seasonal differences and robust positive trends in extreme wave height, especially in the Beaufort and East Siberian seas, with increasing rates in areal average of the 100-year return period up to 60%. The reported variations in extreme wave height are directly associated with a more effective wind forcing in emerging open waters that drives waves to build up more energy, thus confirming the positive feedback of sea ice decline on wave climate.
Role of Winds in Interrupting the Formation of Coastal Hypoxia
Authors: Wang Kuo , Yao Juan , Wang Juying , Liu Hongbin , Yin Kedong
Published: May 2022

Enrichment of nutrients is believed to lead to coastal hypoxia which have become a seasonal phenomenon over large river estuarine areas such as the Mississippi River-Northern Gulf of Mexico and Changjiang-East China Sea. A similar nutrient enrichment process exists in the Pearl River. However, hypoxia occurs only as episodic events over a relatively small area. We hypothesize that frequent wind events play the interruptive mechanism in preventing the seasonal formation of bottom hypoxia. We used 29 years’ time series data of dissolved oxygen (DO) and winds in the Hong Kong coastal waters to test the hypothesis. Our results show that bottom DO at 3 stations in southern waters of Hong Kong occasionally drops below the hypoxic level (2 mg/L), lasting only for less than one month in summer. Episodic hypoxia events appear to occur more frequently in recent years, but bottom DO does not show a significantly decreasing trend. The wind speed of 6 m/s appears to be a threshold, above which a wind event could destroy water column stratification and interrupt the formation of low-oxygen (DO <3 mg/L) water mass. The wind events above the threshold occur 14.3 times in June, 14.2 times in July and 10.0 times in August during 1990-2018. This explains why episodic events of hypoxia hardly occur in June and July, and only occasionally in August. The frequency of such the above-threshold events appears to show a decreasing trend during 1990-2018, which coincides with an increasing occurrences of episodic hypoxia events in recent years.