bluuebunny/crossref_metadata_2025 huggingface dataset:
Tinjauan Kebutuhan Tenaga Kerja Petugas Rekam Medis Berdasarkan Metode Workload Indicator of Staffing Needs (WISN) di Klinik Rawat Inap Ramdani Husada
Authors: Wulandari Irma , Indahsari Fitri
Published: February 2021

The medical record is one of the most important parts of a health service which must be supported by an adequate number of human resources, so it is necessary to calculate the exact workforce requirements. Medical record activities at Ramdani Husada Inpatient Clinic are not done by officers with medical record education qualifications but are carried out by officers with qualifications of high school education, midwifery diploma, and midwifery diploma. The research objective was to describe the need for medical record personnel based on the WISN (Workload Indicator of Staffing Need) method at the Ramdani Husada Inpatient Clinic. The research design used descriptive quantitative with a cross-sectional approach. The population and sample of the study were all officers who carried out medical record activities as many as 3 people including the clinic manager, head of administration, and administrative staff. The results showed that the available work time was 1,953 hours/year or equivalent to 117,180 minutes/year, the workload standard was not in accordance with the number of available officers, the allowance standard was 1.70 workers. So that the need for medical record officers based on the WISN method is 9 workers. Based on the research results, there is a gap between theory and practice, where the Ramdani Husada Inpatient Clinic does not use the WISN method or other methods for planning its workforce. It is suggested that the Ramdani Husada Inpatient Clinic do deeper planning related to the workforce, especially for medical record officers to increase work productivity and reduce the risk of fatigue in officers.
PENINGKATAN PEMBELAJARAN MELALUI BLOGSPOT BAGI GURU SEKOLAH MENENGAH PERTAMA NEGERI 6 KISARAN
Authors: Syafnur Afdhal , Nofitri Rika
Published: February 2021

Abstract: The development of information and communication technology as well as the development of times is very fast, so it does not rule out the possibility of influence on human life, especially in everyday life using technology. Blog is one of the media that can help in delivering information quickly and up to date. The use of an easy blog can help in the teaching and learning process so that it can be easier to share knowledge outside of school hours through media blogs.    Keywords: information, learning, blog. Abstrak: Semakin berkembangnya teknologi informasi dan komunikasi serta dengan perkembangan zaman yang sangat cepat, sehingga tidak menutup kemungkinan adanya pengaruh pada kehidupan manusia terutama pada kehidupan keseharian dengan menggunakan teknologi. Blog merupakan salah satu media yang dapat membantu dalam penyampaian informasi yang cepat dan up to date. Penggunaan blog yang mudah dapat membantu dalam proses belajar mengajar sehingga dapat lebih mudah berbagi pengetahuan di luar jam belajar sekolah melalui media blog. Kata kunci: informasi,pembelajaran,blog
PENINGKATAN PEMANFATAN PERAN TEKNOLOGI INFORMASI BAGI PESERTA DIDIK LKP BINTANG MULIA BATUBARA
Authors: Aulia Romy , Mardalius Mardalius , Dristyan Febri
Published: February 2021

Abstract: Community Service Activities in the form of internet utilization training at LKP Bintang Mulia Batubara aim to increase students' knowledge of internet technology and the benefits of the internet and encourage students to be able to independently manage networks and the internet. The target audience in this community service is LKP Bintang Mulia Batubara students. The training method used is a form of training in the classroom using the lecture method, discussion and question and answer. The lecture method used is intended to provide a theoretical explanation of internet and network material. The discussion method is used to explore students' understanding of the material given in lectures. The practice method is used to show directly how to make a network cable. The benefits obtained from this training activity are that students are able to make wired network connections and know the benefits of the internet.Keywords: Internet, Benefits, Training, NetworksAbstrak : Kegiatan Pengabdian Pada Masyarakat berupa pelatihan pemanfaatan internet di LKP Bintang Mulia Batubara bertujuan untuk meningkatkan pengetahuan peserta didik terhadap teknologi internet dan manfaat dari internet serta mendorong peserta didik agar mampu dengan mandiri mengelola jaringan dan internet. Khalayak sasaran dalam pengabdian masyrakat ini adalah peserta didik LKP Bintang Mulia Batubara. Metode pelatihan yang digunakan adalah bentuk pelatihan di dalam kelas dengan menggunakan metode ceramah, diskusi dan tanya jawab. Metode ceramah yang digunakan dimaksudkan untuk memberikan penjelasan secara teori terhadap materi internet dan jaringan. Metode diskusi digunakan untuk menggali pemahaman peserta didik terhadap materi yang diberikan secara ceramah. Metode praktek digunakan untuk menunjukan langsung cara membuat kabel jaringan. Manfaat yang diperoleh dari kegiatan pelatihan ini adalah peserta didik mampu membuat koneksi jaringan dengan kabel serta mengetahui manfaat dari internet.Kata kunci : Internet, Manfaat, Pelatihan, Jaringan
A Case Report on the Management of Intractable Chyle Leakage after Left Neck Level V Lymph Node Biopsy
Authors: Ryu Somi , Lee Byeong Min , Won Seongjun , Park Jung Je
Published: February 2021

Chyle leakage from the neck, which usually occurs after iatrogenic injury of the thoracic or lymphatic duct, is an uncommon complication of head and neck surgeries, which include neck dissection or thyroidectomy. A small amount of chyle leakage can be treated with conservative approaches, such as nutritional limitation, somatostatin analogues, and wound compression. However, massive or uncontrolled chyle leakage requires surgical exploration of the wound and thoracic duct ligation via the chest or transabdominal thoracic duct embolization can be applied. Here, we report a case of intractable massive chyle leakage in a 78-year-old male after a left neck level V lymph node biopsy, which was not controlled after conservative management and explorative surgery. Various treatment approaches were attempted and successful management of chyle leakage was ultimately achieved by thoracic duct embolization.
Analisis Pembelajaran Berbasis WhatsApp Grup Terhadap Prestasi dan Kesulitan Belajar Siswa Sekolah Dasar
Authors: Nuryanti Nuryanti
Published: February 2021

This study aims to analyze WhatsApp group-based learning on the achievement and learning difficulties of elementary school students. The method used in this research is descriptive qualitative with a case study approach. The population of this research is elementary schools in Glagaharum Porong District, Sidoarjo Regency. Through purposive sampling technique from several informants. Informants consist of teachers, parents of students, and students. Data collection in this study was carried out by: (1) interviews; (2) observation; and (3) documentation. The data collected through interviews, observation and documentation were then analyzed using inductive descriptive techniques. Data analysis was performed by data reduction, data display and data levers. The results of the research of the three respondents agreed with WhatsApp-based learning as much as 28.5% and disagreed 71.48%.. It’s  WA-based learning an application there are obstacles experienced by teachers, parents and students, including the lack of facilities, and students bored the learning process.
Prevalence of Genetically Complex Leishmania Strains With Hybrid and Mito-Nuclear Discordance
Authors: Kato Hirotomo , Cáceres Abraham G. , Gomez Eduardo A. , Tabbabi Ahmed , Mizushima Daiki , Yamamoto Daisuke S. , Hashiguchi Yoshihisa
Published: February 2021

Approximately 20 Leishmania species are known to cause cutaneous, mucocutaneous, and visceral disorders in humans. Identification of the causative species in infected individuals is important for appropriate treatment and a favorable prognosis because infecting species are known to be the major determinant of clinical manifestations and may affect treatments for leishmaniasis. Although Leishmania species have been conventionally identified by multilocus enzyme electrophoresis, genetic analysis targeting kinetoplast and nuclear DNA (kDNA and nDNA, respectively) is now widely used for this purpose. Recently, we conducted countrywide epidemiological studies of leishmaniasis in Ecuador and Peru to reveal prevalent species using PCR-RFLP targeting nDNA, and identified unknown hybrid parasites in these countries together with species reported previously. Furthermore, comparative analyses of kDNA and nDNA revealed the distribution of parasites with mismatches between these genes, representing the first report of mito-nuclear discordance in protozoa. The prevalence of an unexpectedly high rate (~10%) of genetically complex strains including hybrid strains, in conjunction with the observation of mito-nuclear discordance, suggests that genetic exchange may occur more frequently than previously thought in natural Leishmania populations. Hybrid Leishmania strains resulting from genetic exchanges are suggested to cause more severe clinical symptoms when compared with parental strains, and to have increased transmissibility by vectors of the parental parasite species. Therefore, it is important to clarify how such genetic exchange influences disease progression and transmissibility by sand flies in nature. In addition, our aim was to identify where and how the genetic exchange resulting in the formation of hybrid and mito-nuclear discordance occurs.
Type 2 Diabetes and Myocardial Infarction: Recent Clinical Evidence and Perspective
Authors: Cui Jing , Liu Yanfei , Li Yiwen , Xu Fengqin , Liu Yue
Published: February 2021

Type 2 diabetes mellitus (T2DM) and its complications are seriously affecting public health worldwide. Myocardial infarction (MI) is the primary cause of death in patients with T2DM. T2DM patients without a history of coronary artery disease (CAD) have the same risk of major coronary events as those with CAD; T2DM patients with a history of MI have >40% risk of recurrence of MI. Thus, CAD in patients with T2DM needs to be treated actively to reduce the risk of MI. The cardiology community focused on the role of T2DM in the development of CAD and on the related issues of T2DM and MI with respect to comorbidities, prognosis, drug therapy, and heredity. In this mini review, the latest progress of clinical evidence-based research between T2DM and MI in recent years was reviewed, and the possible research directions in this field were considered and prospected.
Resveratrol and Its Analogs as Functional Foods in Periodontal Disease Management
Authors: Lim Yi Rong Ivan , Preshaw Philip M. , Lin Haishu , Tan Kai Soo
Published: February 2021

Periodontitis is a common chronic inflammatory disease driven by the interaction between a dysbiotic oral microbiome and the dysregulated host immune-inflammatory response. Naturally derived nutraceuticals, such as resveratrol and its analogs, are potential adjunctive therapies in periodontal treatment due to their antimicrobial and anti-inflammatory properties. Furthermore, different analogs of resveratrol and the choice of solvents used may lead to varying effects on therapeutic properties. This review presents the current findings and gaps in our understanding on the potential utility of resveratrol and its analogs in periodontal treatment.
Monitoring and Assessment for the Susceptibility of Landslide Changes After the 2017 Ms 7.0 Jiuzhaigou Earthquake Using the Remote Sensing Technology
Authors: Guo Xinyi , Fu Bihong , Du Jie , Shi Pilong , Li Jingxia , Li Zhao , Du Jiaxin , Chen Qingyu , Fu Han
Published: February 2021

Monitoring the change of post-seismic landslides could provide valuable information for geological disaster treatment. The 2017 Jiuzhaigou Ms 7.0 earthquake has triggered a large number of landslides in the Jiuzhaigou United Nations Educational, Scientific and Cultural Organization (UNESCO) Natural Heritage site, which provides a unique opportunity for monitoring the spatio-temporal characteristics and exploring the impact factors of post-seismic landslides change. In this study, the spatio-temporal characteristics of landslides and their post-seismic changes are analyzed using multi-source, multi-temporal, and multi-scale remote sensing data combining with the field study. The Support Vector Machine classification, visual interpretation, field investigation, and Geographic Information System technology are employed to extract landslides and analyze their spatial distribution patterns. Moreover, the Certainty Factor method is used to explore the susceptibility of landslides and to find key impact factors. Our results show that the net increase area of landslide is 1.2 km2 until September 27th, 2019, which are induced by the expansion of coseismic landslide, the post-seismic landslide, and the expansion of vegetation degradation. Moreover, the area expansion of the coseismic and post-seismic landslides is mainly related to the increase of debris flow induced by the post-seismic torrential rainfalls. The highest net increase rate of post-seismic landslide change does not distribute on the regions with the highest density of coseismic landslides. The susceptibility of post-seismic landslide change is greatly influenced by slope, altitude, aspect, peak ground acceleration fault, and strata. It is higher in the coseismic landslide area with low susceptibility. This study also suggests that the potential landslides will most likely occur in the unstable slope region affected by the additional driving force. Therefore, great attention should be paid to identify and prevent the potential landslides on unstable slopes in addition to treatments of the sliding slopes. This study provides a good example for the monitoring and assessment of post-seismic landslides in mountainous regions with a steep slope and deep valley.
Key Information Processes for Thinking Critically in Data-Rich Environments
Authors: Leighton Jacqueline P. , Cui Ying , Cutumisu Maria
Published: February 2021

The objective of the present paper is to propose arefined conceptionof critical thinking in data-rich environments. The rationale for refining critical thinking stems from the need to identify specific information processes that direct the suspension of prior beliefs and activate broader interpretations of data. Established definitions of critical thinking, many of them originating in philosophy, do not include such processes. A refinement of critical thinking in the digital age is developed by integrating two of the most relevant areas of research for this purpose: First, thetripartite modelof critical thinking is used to outline proactive and reactive information processes in data-rich environments. Second, a new assessment framework is used to illustrate how educational interventions and assessments can be used to incorporate processes outlined in the tripartite model, thus providing a defensible conceptual foundation for inferences about higher-level thinking in data-rich environments. Third, recommendations are provided for how a performance-based teaching and assessment module of critical thinking can be designed.
Microplastics in Marine and Estuarine Species From the Coast of Portugal
Authors: Pequeno João , Antunes Joana , Dhimmer Viren , Bessa Filipa , Sobral Paula
Published: February 2021

Microplastics (MP) have been confirmed as emerging pollutants in the marine environment due to their ubiquity, bioavailability, persistence and potential toxicity. This study contributes with valuable data regarding the abundance and characteristics of the MP found in five species collected from Portugal. The mussel Mytilus galloprovincialis (n = 140) was collected from the Tagus estuary and Porto Covo coastal area, the peppery furrow shell Scrobicularia plana (n = 140) and the polychaete Marphysa sanguinea (n = 30) both from the Sado estuary, and Trachurus trachurus (n = 82) and Scomber colias (n = 82) fished off Figueira da Foz and Sesimbra. Soft tissues of all individuals were digested using a KOH (10%) solution, which allowed the extraction of MP. All studied species presented MP. In a total of 502 MP observed from all samples, 80% were fibers and 20% were fragments, with a size range of 73 μm–4,680 μm and blue was the most common color recorded (46%). The frequency of occurrence of MP was higher in T. trachurus (70%) and lowest in M. sanguinea (17%). MP abundance ranged from 0.30 ± 0.63 MP. ind−1 in S. plana, to 2.46 ± 4.12 MP. ind−1 in S. colias. No significant correlation was found between the individual biometric parameters and total MP, fibers and fragments ingested by each species. The FTIR analysis revealed that polyester and polyethylene were the most common polymers present. These results can be used as a reference for future studies regarding the use of indicator species for monitoring MP pollution in the coast of Portugal.
Incubation Behavior Differences in Urban and Rural House Wrens, Troglodytes aedon
Authors: Heppner Jennifer J. , Ouyang Jenny Q.
Published: February 2021

As global land surfaces are being converted to urban areas at an alarming rate, understanding how individuals respond to urbanization is a key focus for behavioral ecology. As a critical component of avian parental care, incubating adults face a tradeoff between maintaining an optimal thermal environment for the developing embryos while meeting their own energetic demands. Urban habitats are biotically and abiotically different from their rural counterparts,i.e., in food availability, predator compositions, and the thermal environment. Therefore, urban birds may face different incubation challenges than their natural counterparts. We measured incubation behavior of rural and urban house wrens,Troglodytes aedon, with temperature loggers throughout the 12-day period. We found that urban females had more incubation bouts of shorter duration and spent less total time incubating per day than rural females. Results could provide evidence of behavioral shifts of wrens in cities, which have implications for the evolution of parental care. Our findings contribute to our understanding of the behavioral traits needed for city life and possible environmental pressures driving urban adaptations.
CoExp: A Web Tool for the Exploitation of Co-expression Networks
Authors: García-Ruiz Sonia , Gil-Martínez Ana L. , Cisterna Alejandro , Jurado-Ruiz Federico , Reynolds Regina H. ,   NABEC (North America Brain Expression Consortium), Cookson Mark R. , Hardy John , Ryten Mina , Botía Juan A.
Published: February 2021

Gene co-expression networks are a powerful type of analysis to construct gene groupings based on transcriptomic profiling. Co-expression networks make it possible to discover modules of genes whose mRNA levels are highly correlated across samples. Subsequent annotation of modules often reveals biological functions and/or evidence of cellular specificity for cell types implicated in the tissue being studied. There are multiple ways to perform such analyses with weighted gene co-expression network analysis (WGCNA) amongst one of the most widely used R packages. While managing a few network models can be done manually, it is often more advantageous to study a wider set of models derived from multiple independently generated transcriptomic data sets (e.g., multiple networks built from many transcriptomic sources). However, there is no software tool available that allows this to be easily achieved. Furthermore, the visual nature of co-expression networks in combination with the coding skills required to explore networks, makes the construction of a web-based platform for their management highly desirable. Here, we present the CoExp Web application, a user-friendly online tool that allows the exploitation of the full collection of 109 co-expression networks provided by the CoExpNets suite of R packages. We describe the usage of CoExp, including its contents and the functionality available through the family of CoExpNets packages. All the tools presented, including the web front- and back-ends are available for the research community so any research group can build its own suite of networks and make them accessible through their own CoExp Web application. Therefore, this paper is of interest to both researchers wishing to annotate their genes of interest across different brain network models and specialists interested in the creation of GCNs looking for a tool to appropriately manage, use, publish, and share their networks in a consistent and productive manner.
Genome-Wide Identification and Characterization of bHLH Transcription Factors Related to Anthocyanin Biosynthesis in Red Walnut (Juglans regia L.)
Authors: Zhao Wei , Liu Yonghui , Li Lin , Meng Haijun , Yang Ying , Dong Zhaobin , Wang Lei , Wu Guoliang
Published: February 2021

Basic helix-loop-helix (bHLH) proteins are transcription factors (TFs) that have been shown to regulate anthocyanin biosynthesis in many plant species. However, the bHLH gene family in walnut (Juglans regia L.) has not yet been reported. In this study, 102 bHLH genes were identified in the walnut genome and were classified into 15 subfamilies according to sequence similarity and phylogenetic relationships. The gene structure, conserved domains, and chromosome location of the genes were analyzed by bioinformatic methods. Gene duplication analyses revealed that 42 JrbHLHs were involved in the expansion of the walnut bHLH gene family. We also characterized cis-regulatory elements of these genes and performed Gene Ontology enrichment analysis of gene functions, and examined protein-protein interactions. Four candidate genes (JrEGL1a, JrEGL1b, JrbHLHA1, and JrbHLHA2) were found to have high homology to genes encoding bHLH TFs involved in anthocyanin biosynthesis in other plants. RNA sequencing revealed tissue- and developmental stage-specific expression profiles and distinct expression patterns of JrbHLHs according to phenotype (red vs. green leaves) and developmental stage in red walnut hybrid progeny, which were confirmed by quantitative real-time PCR analysis. All four of the candidate JrbHLH proteins localized to the nucleus, consistent with a TF function. These results provide a basis for the functional characterization of bHLH genes and investigations on the molecular mechanisms of anthocyanin biosynthesis in red walnut.
Poorly Expressed Alleles of Several Human Immunoglobulin Heavy Chain Variable Genes are Common in the Human Population
Authors: Ohlin Mats
Published: February 2021

Extensive diversity has been identified in the human heavy chain immunoglobulin locus, including allelic variation, gene duplication, and insertion/deletion events. Several genes have been suggested to be deleted in many haplotypes. Such findings have commonly been based on inference of the germline repertoire from data sets covering antibody heavy chain encoding transcripts. The inference process operates under conditions that may limit identification of genes transcribed at low levels. The presence of rare transcripts that would indicate the existence of poorly expressed alleles in haplotypes that otherwise appear to have deleted these genes has been assessed in the present study. Alleles IGHV1-2*05, IGHV1-3*02, IGHV4-4*01, and IGHV7-4-1*01 were all identified as being expressed from multiple haplotypes, but only at low levels, haplotypes that by inference often appeared not to express these genes at all. These genes are thus not as commonly deleted as previously thought. An assessment of the 5’ untranslated region (up to and including the TATA-box), the signal peptide-encoding part of the gene, and the 3’-heptamer suggests that the alleles have no or minimal sequence difference in these regions in comparison to highly expressed alleles. This suggest that they may be able to participate in immunoglobulin gene rearrangement, transcription and translation. However, all four poorly expressed alleles harbor unusual sequence variants within their coding region that may compromise the functionality of the encoded products, thereby limiting their incorporation into the immunoglobulin repertoire. Transcripts based on IGHV7-4-1*01 that had undergone somatic hypermutation and class switch had mutated the codon that encoded the unusual residue in framework region 3 (cysteine 92; located far from the antigen binding site). This finding further supports the poor compatibility of this unusual residue in a fully functional protein product. Indications of a linkage disequilibrium were identified as IGHV1-2*05 and IGHV4-4*01 co-localized to the same haplotypes. Furthermore, transcripts of two of the poorly expressed alleles (IGHV1-3*02 and IGHV4-4*01) mostly do not encode in-frame, functional products, suggesting that these alleles might be essentially non-functional. It is proposed that the functionality status of immunoglobulin genes should also include assessment of their ability to encode functional protein products.
Super-Treg: Toward a New Era of Adoptive Treg Therapy Enabled by Genetic Modifications
Authors: Amini Leila , Greig Jenny , Schmueck-Henneresse Michael , Volk Hans-Dieter , Bézie Séverine , Reinke Petra , Guillonneau Carole , Wagner Dimitrios L. , Anegon Ignacio
Published: February 2021

Regulatory Tcells (Treg) are essential components of peripheral immune homeostasis. Adoptive Treg cell therapy has shown efficacy in a variety of immune-mediated diseases in preclinical studies and is now moving from phase I/IIa to larger phase II studies aiming to demonstrate efficacy. However, hurdles such asin vivostability and efficacy remain to be addressed. Nevertheless, preclinical models have shown that Treg function and specificity can be increased by pharmacological substances or gene modifications, and even that conventional T cells can be converted to Treg potentially providing new sources of Treg and facilitating Treg cell therapy. The exponential growth in genetic engineering techniques and their application to T cells coupled to a large body of knowledge on Treg open numerous opportunities to generate Treg with “superpowers”. This review summarizes the genetic engineering techniques available and their applications for the next-generation of Super-Treg with increased function, stability, redirected specificity and survival.
Cytotoxic CD8+ T Cells Expressing CXCR5 Are Detectable in HIV-1 Elite Controllers After Prolonged In Vitro Peptide Stimulation
Authors: Adams Philipp , Iserentant Gilles , Servais Jean-Yves , Vandekerckhove Linos , Vanham Guido , Seguin-Devaux Carole ,   the PhenoCure Study Group
Published: February 2021

Antiretroviral therapy (ART) is not curative as HIV-1 persists in long-lived viral reservoirs. Consequently, patients are dependent on life-long drug adherence with possible side effects. To overcome these limitations strategies of a functional cure aim at ART free viral remission. In this study, we sought to identify detailed subsets of anti-viral CD8+ T cell immunity linked to natural long-term control of HIV-1 infection. Here, we analyzed HIV controllers and ART suppressed progressors for in vitro viral suppressive capacity (VSC) at baseline and after peptide stimulation. Functional properties and phenotypes of CD8+ T cells were assessed by IFN-γ ELISPOT and 18 color flow cytometry. HIV controllers showed significantly increased suppression at baseline as well as after peptide stimulation. IFN-γ secretion and the proliferation marker Ki67 positively correlated with VSC. Moreover, the detailed phenotype of three distinct multifunctional memory CD8+ T cell subsets were specific traits of HIV controllers of which two correlated convincingly with VSC. Our results underline the importance of multifunctional CD8+ T cell responses during natural control. Especially the role of CXCR5 expressing cytotoxic subsets emphasizes potential surveillance in sites of reservoir persistence and demand further study.
Recent Advances in Costimulatory Blockade to Induce Immune Tolerance in Liver Transplantation
Authors: Ding Mingjie , He Yuting , Zhang Shuijun , Guo Wenzhi
Published: February 2021

Liver transplantation is an effective therapy for end-stage liver disease. However, most postoperative patients must take immunosuppressive drugs to prevent organ rejection. Interestingly, some transplant recipients have normal liver function and do not experience organ rejection after the withdrawal of immunosuppressive agents. This phenomenon, called immune tolerance, is the ultimate goal in clinical transplantation. Costimulatory molecules play important roles in T cell-mediated immune responses and the maintenance of T cell tolerance. Blocking costimulatory pathways can alter T cell responses and prolong graft survival. Better understanding of the roles of costimulatory molecules has facilitated the use of costimulatory blockade to effectively induce immune tolerance in animal transplantation models. In this article, we review the state of the art in costimulatory pathway blockade for the induction of immune tolerance in transplantation and its potential application prospects for liver transplantation.
Proteasome-Generated cis-Spliced Peptides and Their Potential Role in CD8+ T Cell Tolerance
Authors: Mansurkhodzhaev Artem , Barbosa Camila R. R. , Mishto Michele , Liepe Juliane
Published: February 2021

The human immune system relies on the capability of CD8+ T cells to patrol body cells, spot infected cells and eliminate them. This cytotoxic response is supposed to be limited to infected cells to avoid killing of healthy cells. To enable this, CD8+ T cells have T Cell Receptors (TCRs) which should discriminate between self and non-self through the recognition of antigenic peptides bound to Human Leukocyte Antigen class I (HLA-I) complexes—i.e., HLA-I immunopeptidomes—of patrolled cells. The majority of these antigenic peptides are produced by proteasomes through either peptide hydrolysis or peptide splicing. Proteasome-generated cis-spliced peptides derive from a given antigen, are immunogenic and frequently presented by HLA-I complexes. Theoretically, they also have a very large sequence variability, which might impinge upon our model of self/non-self discrimination and central and peripheral CD8+ T cell tolerance. Indeed, a large variety of cis-spliced epitopes might enlarge the pool of viral-human zwitter epitopes, i.e., peptides that may be generated with the exact same sequence from both self (human) and non-self (viral) antigens. Antigenic viral-human zwitter peptides may be recognized by CD8+ thymocytes and T cells, induce clonal deletion or other tolerance processes, thereby restraining CD8+ T cell response against viruses. To test this hypothesis, we computed in silico the theoretical frequency of zwitter non-spliced and cis-spliced epitope candidates derived from human proteome (self) and from the proteomes of a large pool of viruses (non-self). We considered their binding affinity to the representative HLA-A*02:01 complex, self-antigen expression in Medullary Thymic Epithelial cells (mTECs) and the relative frequency of non-spliced and cis-spliced peptides in HLA-I immunopeptidomes. Based on the present knowledge of proteasome-catalyzed peptide splicing and neglecting CD8+ TCR degeneracy, our study suggests that, despite their frequency, the portion of the cis-spliced peptides we investigated could only marginally impinge upon the variety of functional CD8+ cytotoxic T cells (CTLs) involved in anti-viral response.
Natural Killer Cells: Friend or Foe in Metabolic Diseases?
Authors: Li Yi , Wang Fangjie , Imani Saber , Tao Ling , Deng Youcai , Cai Yue
Published: February 2021

The worldwide epidemic of metabolic diseases, especially obesity and other diseases caused by it, has shown a dramatic increase in incidence. A great deal of attention has been focused on the underlying mechanisms of these pathological processes and potential strategies to solve these problems. Chronic inflammation initiated by abdominal adipose tissues and immune cell activation in obesity is the major cause of the consequent development of complications. In addition to adipocytes, macrophages and monocytes, natural killer (NK) cells have been verified to be vital components involved in shaping the inflammatory microenvironment, thereby leading to various obesity-related metabolic diseases. Here, we provide an overview of the roles of NK cells and the interactions of these cells with other immune and nonimmune cells in the pathological processes of metabolic diseases. Finally, we also discuss potential therapeutic strategies targeting NK cells to treat metabolic diseases.
Molecular Characterization and Immunological Evaluation of Truncated Babesia microti Rhoptry Neck Protein 2 as a Vaccine Candidate
Authors: Cai Yu chun , Yang Chun li , Hu Wei , Song Peng , Xu Bin , Lu Yan , Ai Lin , Chu Yan hong , Chen Mu xin , Chen Jia xu , Chen Shao hong
Published: February 2021

Babesia microtiis a protozoan that infects red blood cells. Babesiosis is becoming a new global threat impacting human health. Rhoptry neck proteins (RONs) are proteins located at the neck of the rhoptry and studies indicate that these proteins play an important role in the process of red blood cell invasion. In the present study, we report on the bioinformatic analysis, cloning, and recombinant gene expression of two truncated rhoptry neck proteins 2 (BmRON2), as well as their potential for incorporation in a candidate vaccine for babesiosis. Western blot and immunofluorescence antibody (IFA) assays were performed to detect the presence of specific antibodies against BmRON2 in infected mice and the localization of N-BmRON2 inB. microtiparasites.In vitroexperiments were carried out to investigate the role of BmRON2 proteins during theB. microtiinvasion process andin vivoexperiments to investigate immunoprotection. Homologous sequence alignment and molecular phylogenetic analysis indicated that BmRON2 showed similarities with RON2 proteins of otherBabesiaspecies. We expressed the truncated N-terminal (33–336 aa, designated rN-BmRON2) and C-terminal (915–1171 aa, designated rC-BmRON2) fragments of the BmRON2 protein, with molecular weights of 70 and 29 kDa, respectively. Western blot assays showed that the native BmRON2 protein is approximately 170 kDa, and that rN-BmRON2 was recognized by serum of mice experimentally infected withB. microti.Immunofluorescence analysis indicated that the BmRON2 protein was located at the apical end of merozoites, at the opposite end of the nucleus.In vitrored blood cell invasion inhibition studies withB. microtirBmRON2 proteins showed that relative invasion rate of rN-BmRON2 and rC-BmRON2 group is 45 and 56%, respectively. Analysis of the host immune response after immunization andB. microtiinfection showed that both rN-BmRON2 and rC-BmRON2 enhanced the immune response, but that rN-BmRON2 conferred better protection than rC–BmRON2. In conclusion, our results indicate that truncated rhoptry neck protein 2, especially its N-terminal fragment (rN-BmRON2), plays an important role in the invasion of host red blood cells, confers immune protection, and shows good potential as a candidate vaccine against babesiosis.
Comprehensive Integration of Genome-Wide Association and Gene Expression Studies Reveals Novel Gene Signatures and Potential Therapeutic Targets for Helicobacter pylori-Induced Gastric Disease
Authors: Badr Mohamed Tarek , Omar Mohamed , Häcker Georg
Published: February 2021

Helicobacter pylori is a gram-negative bacterium that colonizes the human gastric mucosa and can lead to gastric inflammation, ulcers, and stomach cancer. Due to the increase in H. pylori antimicrobial resistance new methods to identify the molecular mechanisms of H. pylori-induced pathology are urgently needed. Here we utilized a computational biology approach, harnessing genome-wide association and gene expression studies to identify genes and pathways determining disease development. We mined gene expression data related to H. pylori-infection and its complications from publicly available databases to identify four human datasets as discovery datasets and used two different multi-cohort analysis pipelines to define a H. pylori-induced gene signature. An initial Helicobacter-signature was curated using the MetaIntegrator pipeline and validated in cell line model datasets. With this approach we identified cell line models that best match gene regulation in human pathology. A second analysis pipeline through NetworkAnalyst was used to refine our initial signature. This approach defined a 55-gene signature that is stably deregulated in disease conditions. The 55-gene signature was validated in datasets from human gastric adenocarcinomas and could separate tumor from normal tissue. As only a small number of H. pylori patients develop cancer, this gene-signature must interact with other host and environmental factors to initiate tumorigenesis. We tested for possible interactions between our curated gene signature and host genomic background mutations and polymorphisms by integrating genome-wide association studies (GWAS) and known oncogenes. We analyzed public databases to identify genes harboring single nucleotide polymorphisms (SNPs) associated with gastric pathologies and driver genes in gastric cancers. Using this approach, we identified 37 genes from GWA studies and 61 oncogenes, which were used with our 55-gene signature to map gene-gene interaction networks. In conclusion, our analysis defines a unique gene signature driven by H. pylori-infection at early phases and that remains relevant through different stages of pathology up to gastric cancer, a stage where H. pylori itself is rarely detectable. Furthermore, this signature elucidates many factors of host gene and pathway regulation in infection and can be used as a target for drug repurposing and testing of infection models suitability to investigate human infection.
The Role of Regulatory Myeloid Cell Therapy in Renal Allograft Rejection
Authors: Zhuang Jingming , Hou Jiangang
Published: February 2021

Kidney transplantation is a primary therapy for end-stage renal disease (ESRD) all the time. But it does not mean that we have fully unraveling the mystery of kidney transplantation and confer every patient favorable prognosis. Immune rejection has always been a stumbling block when we try to increase the success rate of kidney transplantation and improve long-term outcomes. Even if the immune rejection is effectively controlled in acute phase, there is a high possibility that the immune response mediated by chronically activated antibodies will trigger chronic rejection and ultimately lead to graft failure. At present, immunosuppressive agent prepared chemically is mainly used to prevent acute or chronic rejection, but it failed to increase the long-term survival rate of allografts or reduce the incidence of chronic rejection after acute rejection, and is accompanied by many adverse reactions. Therefore, many studies have begun to use immune cells to regulate the immune response in order to control allograft rejection. This article will focus on the latest study and prospects of more popular regulatory myeloid cells in the direction of renal transplantation immunotherapy and introduce their respective progress from experimental research to clinical research.
NLRP3 Deficiency Protects Against Intermittent Hypoxia-Induced Neuroinflammation and Mitochondrial ROS by Promoting the PINK1-Parkin Pathway of Mitophagy in a Murine Model of Sleep Apnea
Authors: Wu Xu , Gong Linjing , Xie Liang , Gu Wenyu , Wang Xinyuan , Liu Zilong , Li Shanqun
Published: February 2021

Obstructive sleep apnea (OSA) associated neurocognitive impairment is mainly caused by chronic intermittent hypoxia (CIH)-triggered neuroinflammation and oxidative stress. Previous study has demonstrated that mitochondrial reactive oxygen species (mtROS) was pivotal for hypoxia-related tissue injury. As a cytosolic multiprotein complex that participates in various inflammatory and neurodegenerative diseases, NLRP3 inflammasome could be activated by mtROS and thereby affected by the mitochondria-selective autophagy. However, the role of NLRP3 and possible mitophagy mechanism in CIH-elicited neuroinflammation remain to be elucidated. Compared with wild‐type mice, NLRP3 deficiency protected them from CIH-induced neuronal damage, as indicated by the restoration of fear-conditioning test results and amelioration of neuron apoptosis. In addition, NLRP3 knockout mice displayed the mitigated microglia activation that elicited by CIH, concomitantly with elimination of damaged mitochondria and reduction of oxidative stress levels (malondialdehyde and superoxide dismutase). Elevated LC3 and beclin1 expressions were remarkably observed in CIH group. In vitro experiments, intermittent hypoxia (IH) significantly facilitated mitophagy induction and NLRP3 inflammasome activation in microglial (BV2) cells. Moreover, IH enhanced the accumulation of damaged mitochondria, increased mitochondrial depolarization and augmented mtROS release. Consistently, NLRP3 deletion elicited a protective phenotype against IH through enhancement of Parkin-mediated mitophagy. Furthermore, Parkin deletion or pretreated with 3MA (autophagy inhibitor) exacerbated these detrimental actions of IH, which was accompanied with NLRP3 inflammasome activation. These results revealed NLRP3 deficiency acted as a protective promotor through enhancing Parkin-depended mitophagy in CIH-induced neuroinflammation. Thus, NLRP3 gene knockout or pharmacological blockage could be as a potential therapeutic strategy for OSA-associated neurocognitive impairment.
HLA-Restriction of Human Treg Cells Is Not Required for Therapeutic Efficacy of Low-Dose IL-2 in Humanized Mice
Authors: Tyagi Rajeev K. , Jacobse Justin , Li Jing , Allaman Margret M. , Otipoby Kevin L. , Sampson Erik R. , Wilson Keith T. , Goettel Jeremy A.
Published: February 2021

Regulatory T (Treg) cells are essential to maintain immune homeostasis in the intestine and Tregcell dysfunction is associated with several inflammatory and autoimmune disorders including inflammatory bowel disease (IBD). Efforts using low-dose (LD) interleukin-2 (IL-2) to expand autologous Tregcells show therapeutic efficacy for several inflammatory conditions. Whether LD IL-2 is an effective strategy for treating patients with IBD is unknown. Recently, we demonstrated that LD IL-2 was protective against experimental colitis in immune humanized mice in which human CD4+T cells were restricted to human leukocyte antigen (HLA). Whether HLA restriction is required for human Tregcells to ameliorate colitis following LD IL-2 therapy has not been demonstrated. Here, we show that treatment with LD IL-2 reduced 2,4,6-trinitrobenzensulfonic acid (TNBS) colitis severity in NOD.PrkdcscidIl2rg-/-(NSG) mice reconstituted with human CD34+hematopoietic stem cells. These data demonstrate the utility of standard immune humanized NSG mice as a pre-clinical model system to evaluate therapeutics targeting human Tregcells to treat IBD.
Spontaneously Resolved Atopic Dermatitis Shows Melanocyte and Immune Cell Activation Distinct From Healthy Control Skin
Authors: Rindler Katharina , Krausgruber Thomas , Thaler Felix M. , Alkon Natalia , Bangert Christine , Kurz Harald , Fortelny Nikolaus , Rojahn Thomas B. , Jonak Constanze , Griss Johannes , Bock Christoph , Brunner Patrick M.
Published: February 2021

Atopic dermatitis (AD) typically starts in infancy or early childhood, showing spontaneous remission in a subset of patients, while others develop lifelong disease. Despite an increased understanding of AD, factors guiding its natural course are only insufficiently elucidated. We thus performed suction blistering in skin of adult patients with stable, spontaneous remission from previous moderate-to-severe AD during childhood. Samples were compared to healthy controls without personal or familial history of atopy, and to chronic, active AD lesions. Skin cells and tissue fluid obtained were used for single-cell RNA sequencing and proteomic multiplex assays, respectively. We found overall cell composition and proteomic profiles of spontaneously healed AD to be comparable to healthy control skin, without upregulation of typical AD activity markers (e.g., IL13, S100As, and KRT16). Among all cell types in spontaneously healed AD, melanocytes harbored the largest numbers of differentially expressed genes in comparison to healthy controls, with upregulation of potentially anti-inflammatory markers such as PLA2G7. Conventional T-cells also showed increases in regulatory markers, and a general skewing toward a more Th1-like phenotype. By contrast, gene expression of regulatory T-cells and keratinocytes was essentially indistinguishable from healthy skin. Melanocytes and conventional T-cells might thus contribute a specific regulatory milieu in spontaneously healed AD skin.
Specialized Pro-Resolving Mediators as Potential Regulators of Inflammatory Macrophage Responses in COVID-19
Authors: Balta Maria G. , Papathanasiou Evangelos , Christopoulos Panagiotis F.
Published: February 2021

The recent outbreak of SARS-CoV2 has emerged as one of the biggest pandemics of our century, with outrageous health, social and economic consequences globally. Macrophages may lay in the center of COVID-19 pathogenesis and lethality and treatment of the macrophage-induced cytokine storm has emerged as essential. Specialized pro-resolving mediators (SPMs) hold strong therapeutic potentials in the management of COVID-19 as they can regulate macrophage infiltration and cytokine production but also promote a pro-resolving macrophage phenotype. In this review, we discuss the homeostatic functions of SPMs acting directly on macrophages on various levels, towards the resolution of inflammation. Moreover, we address the molecular events that link the lipid mediators with COVID-19 severity and discuss the clinical potentials of SPMs in COVID-19 immunotherapeutics.
Regulation of Enteric Infection and Immunity by Dietary Proanthocyanidins
Authors: Andersen-Civil Audrey I. S. , Arora Pankaj , Williams Andrew R.
Published: February 2021

The role of dietary components in immune function has acquired considerable attention in recent years. An important focus area is to unravel the role of bioactive dietary compounds in relation to enteric disease and their impact on gut mucosal immunity. Proanthocyanidins (PAC) are among the most common and most consumed dietary polyphenols, and are characterised by their variable molecular structures and diverse bioactivities. In particular, their anti-oxidative effects and ability to modulate gut microbiota have been widely described. However, there is limited evidence on the mechanism of action of PAC on the immune system, nor is it clearly established how PAC may influence susceptibility to enteric infections. Establishing the sites of action of PAC and their metabolites within the gut environment is fundamental to determine the applicability of PAC against enteric pathogens. Some mechanistic studies have shown that PAC have direct modulatory effects on immune cell signalling, isolated pathogens, and gut mucosal barrier integrity. Boosting the recruitment of immune cells and suppressing the amount of pro-inflammatory cytokines are modulating factors regulated by PAC, and can either be beneficial or detrimental in the course of re-establishing gut homeostasis. Herein, we review how PAC may alter distinct immune responses towards enteric bacterial, viral and parasitic infections, and how the modulation of gut microbiota may act as a mediating factor. Furthermore, we discuss how future studies could help unravel the role of PAC in preventing and/or alleviating intestinal inflammation and dysbiosis caused by enteric disease.