bluuebunny/crossref_metadata_2025 huggingface dataset:
Rancang Bangun Sistem Informasi Rekam Medis Pada Klinik Menggunakan Metode Extreme Programing
Authors:   Sekolah Tinggi Teknologi Garut, Kurniadi Dede , Mulyani Asri
Published: May 2021

Klinik merupakan sebuah institusi pelayanan publik yang bergerak dalam bidang jasa kesehatan. Upaya meningkatkan pelayanan kesehatan terutama di klinik sangat dibutuhkan. Pengolahan dan penyimpanan rekam medis di beberapa klinik selama ini diolah dengan menggunakan cara manual yaitu di tulis di lembaran-lembaran kertas, seperti yang dilakukan klinik Denkesyah Kota Garut, oleh karena itu diperlukan suatu sistem yang dapat mempermudah staff/karyawan dalam melakukan pengolahan data rekam medis. Perancangan aplikasi web pada Klinik Denkesyah Kota Garut dilakukan dengan menggunakan metode Extreme programming (XP) dimana tahapannya meliputi planning, desain, coding dan testing. Sedangkan untuk pemodelan nya menggunakan UML terdiri dari use case, activity diagram dan tabel relasi. Sistem yang akan dibuat mengenai rekam medis Klinik Denkesyah Kota Garut, didalamnya terdapat form penunjang pengolahan data, seperti data Pasien (umum dan BPJS), data Dokter, data rawat jalan dan rawat inap dan lain sebagainya.
Pengaruh Kreasi Kertas Kokoru Terhadap Perkembangan Kreativitas Anak Di Taman Kanak-Kanak Nurul Yakin Ringan-Ringan Kabupaten Padang Pariaman
Authors: Amalia Mia , Pransiska Rismareni , Yulsofriend Yulsofriend
Published: May 2021

This study aims to determine the effect of kokoru paper on the development of children's creativity. This study uses a quantitative approach in the form of experimental quasy. Based on data analysis, the average test results of the experimental class were 80 while the control class was 73.75. Based on the t-test calculation, t count is greater than t table, indicating that there are significant differences between the two classes. So it can be concluded that the creation of kokoru paper affects the development of children's creativity in the Nurul Yakin Ringan-ringan Kabupaten Padang Pariaman District in the 2018/2019 school year.
Perrin numbers that are concatenations of two distinct repdigits
Authors: Batte Herbert , Chalebgwa Toboka , Ddamulira Mahadi
Published: May 2021

Let $ (P_n)_{n\ge 0}$ be the sequence of Perrin numbers defined by ternary relation $ P_0=3 $, $ P_1=0 $, $ P_2=2 $, and $ P_{n+3}=P_{n+1}+P_n $ for all $ n\ge 0 $. In this paper, we use Baker's theory for nonzero linear forms in logarithms of algebraic numbers and the reduction procedure involving the theory of continued fractions, to explicitly determine all Perrin numbers that are concatenations of two distinct repeated digit numbers.
Substrate Stiffness Regulates Cholesterol Efflux in Smooth Muscle Cells
Authors: Mao Xiuli , Tan Yiling , Wang Huali , Li Song , Zhou Yue
Published: May 2021

The infiltration and deposition of cholesterol in the arterial wall play an important role in the initiation and development of atherosclerosis. Smooth muscle cells (SMCs) are the major cell type in the intima. Upon exposure to cholesterol, SMCs may undergo a phenotype switching into foam cells. Meanwhile, the pathological processes of the blood vessel such as cholesterol deposition and calcification induce the changes in the substrate stiffness around SMCs. However, whether substrate stiffness affects the cholesterol accumulation in SMCs and the formation of foam cells is not well-understood. In this study, SMCs were cultured on the substrates with different stiffnesses ranging from 1 to 100 kPa and treated with cholesterol. We found that cholesterol accumulation in SMCs was higher on 1 and 100 kPa substrates than that on intermediate stiffness at 40 kPa; consistently, total cholesterol (TC) content on 1 and 100 kPa substrates was also higher. As a result, the accumulation of cholesterol increased the expression of macrophage marker CD68 and downregulated SMC contractile marker smooth muscle α-actin (ACTA2). Furthermore, the mRNA and protein expression level of cholesterol efflux gene ATP-binding cassette transporter A1 (ABCA1) was much higher on 40 kPa substrate. With the treatment of a liver X receptor (LXR) agonist GW3965, the expression of ABCA1 increased and cholesterol loading decreased, showing an additive effect with substrate stiffness. In contrast, inhibition of LXR decreased ABCA1 gene expression and increased cholesterol accumulation in SMCs. Consistently, when ABCA1 gene was knockdown, the cholesterol accumulation was increased in SMCs on all substrates with different stiffness. These results revealed that substrate stiffness played an important role on SMCs cholesterol accumulation by regulating the ABCA1 expression. Our findings on the effects of substrate stiffness on cholesterol efflux unravel a new mechanism of biophysical regulation of cholesterol metabolism and SMC phenotype, and provide a rational basis for the development of novel therapies.
Bioactive α-Pyrone Derivatives from the Endophytic Fungus Diaporthe sp. CB10100 as Inducible Nitric Oxide Synthase Inhibitors
Authors: Pu Hong , Liu Jianxin , Wang Yeji , Peng Yuhui , Zheng Wanying , Tang Yang , Hui Boping , Nie Chunmei , Huang Xueshuang , Duan Yanwen , Huang Yong
Published: May 2021

Inducible nitric oxide synthase (iNOS) produces NO from l-arginine and plays critical roles in inflammation and immune activation. Selective and potent iNOS inhibitors may be potentially used in many indications, such as rheumatoid arthritis, pain, and neurodegeration. In the current study, five new compounds, including a dibenzo-α- pyrone derivative ellagic acid B (5) and four α-pyrones diaporpyrone A–D (9–12), together with three known compounds (6–8), were isolated from the endophytic fungus Diaporthe sp. CB10100. The structures of these new natural products were unambiguously elucidated using NMR, HRESIMS or electronic circular dichroism calculations. Ellagic acid B (5) features a tetracyclic 6/6/6/6 ring system with a fused 2H-chromene, which is different from ellagic acid (4) with a fused 2H-chromen-2-one. Both 2-hydroxy-alternariol (6) and alternariol (7) reduced the expression of iNOS at protein levels in a dose-dependent manner, using a lipopolysaccharide (LPS)-induced RAW264.7 cell models. Also, they decreased the protein expression levels of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6 and monocyte chemotactic protein 1. Importantly, 6 and 7 significantly reduced the production of NO as low as 10 μM in LPS-induced RAW264.7 cells. Molecular docking of 6 and 7 to iNOS further suggests that both of them may interact with iNOS. Our study suggests that 6 and 7, as well as the alternariol scaffold may be further developed as potential iNOS inhibitors.
Mycobacterial Growth Inhibition Assay (MGIA) as a Host Directed Diagnostic Tool for the Evaluation of the Immune Response in Subjects Living With Type 2 Diabetes Mellitus
Authors: Bobadilla-del-Valle Miriam , Leal-Vega Francisco , Torres-Gonzalez Pedro , Ordaz-Vazquez Anabel , Garcia-Garcia Maria de Lourdes , Tovar-Vargas Ma. de los Angeles , Delgado-Sanchez Guadalupe , Guerra De Blas Paola Del Carmen , Wallis Robert S. , Ponce-De-León Alfredo , Sifuentes-Osornio José
Published: May 2021

The lack of efficient and cost-effective diagnostic tools contributes to poor control of tuberculosis in endemic countries. Moreover, host biological processes influence susceptibility, and infection resolution. It is well known that comorbidities such as type 2 diabetes mellitus (DM2) affect the host immune response, making individuals more susceptible to Mycobacterium tuberculosis infection. Currently, there are no laboratory tools that can identify those subjects who have a higher risk of developing the disease. In this study, we used a whole blood mycobacterial growth inhibition assay to assess the immune response capacity to inhibit mycobacterial growth between healthy subjects and those living with DM2 with optimal and poor glycemic control. We also measured cytokine levels in the culture supernatant by cytokine bead arrays. We included 89 patients with DM2: 54 patients with optimal control (mean age 56.2 ± 11.75 years) and 35 patients with poor control (mean age 52.05 ± 9.94 years). We also included 44 healthy subjects as controls (mean age 42.12 ± 11.75 years). We compared the Δlog UFC (a value that represents the difference between mycobacterial growth in the control tube versus the subject’s blood) between each group. Our results demonstrate that patients with DM2 had a lower capacity to inhibit M. tuberculosis growth (Δlog UFC DM2 subjects 0.9581 (-0.3897 to 2.495) vs Δlog UFC healthy subjects 0.7190 (-0.2678 to 2.098); p=0.013). Comparing subjects living with DM2 (optimal and poor glycemic control) vs healthy subjects, we found only significant differences between healthy subjects and patients poorly controlled (Δlog UFC optimal control group 0.876 (-0.3897 to 2.495); Δlog UFC poor control group 1.078 (0.068 to 2.33); Δlog UFC healthy subjects 0.7190 (-0.2678 to 2.098); p= 0.022). Therefore, glycemic control assessed by glycosylated hemoglobin values influences the capacity of the host to control the infection. Our results confirm that the whole blood mycobacterial growth inhibition assay has potential utility as an in vitro marker of M. tuberculosis immunological control in vivo in subjects living with DM2. This assay can be used to evaluate the immune response of each individual against M. tuberculosis, allowing clinicians to choose a more specific host-directed therapy.
Approaches to Understanding Mechanisms of Dentilisin Protease Complex Expression in Treponema denticola
Authors: Goetting-Minesky M. Paula , Godovikova Valentina , Fenno J. Christopher
Published: May 2021

The oral spirochete Treponema denticola is a keystone periodontal pathogen that, in association with members of a complex polymicrobial oral biofilm, contributes to tissue damage and alveolar bone loss in periodontal disease. Virulence-associated behaviors attributed to T. denticola include disruption of the host cell extracellular matrix, tissue penetration and disruption of host cell membranes accompanied by dysregulation of host immunoregulatory factors. T. denticola dentilisin is associated with several of these behaviors. Dentilisin is an outer membrane-associated complex of acylated subtilisin-family PrtP protease and two other lipoproteins, PrcB and PrcA, that are unique to oral spirochetes. Dentilisin is encoded in a single operon consisting of prcB-prcA-prtP. We employ multiple approaches to study mechanisms of dentilisin assembly and PrtP protease activity. To determine the role of each protein in the protease complex, we have made targeted mutations throughout the protease locus, including polar and nonpolar mutations in each gene (prcB, prcA, prtP) and deletions of specific PrtP domains, including single base mutagenesis of key PrtP residues. These will facilitate distinguishing between host cell responses to dentilisin protease activity and its acyl groups. The boundaries of the divergent promoter region and the relationship between dentilisin and the adjacent iron transport operon are being resolved by incremental deletions in the sequence immediately 5’ to the protease locus. Comparison of the predicted three-dimensional structure of PrtP to that of other subtilisin-like proteases shows a unique PrtP C-terminal domain of approximately 250 residues. A survey of global gene expression in the presence or absence of protease gene expression reveals potential links between dentilisin and iron uptake and homeostasis in T. denticola. Understanding the mechanisms of dentilisin transport, assembly and activity of this unique protease complex may lead to more effective prophylactic or therapeutic treatments for periodontal disease.
Development of a One-Step Multiplex PCR Assay for Differential Detection of Four species (Enterobacter cloacae, Enterobacter hormaechei, Enterobacter roggenkampii, and Enterobacter kobei) Belonging to Enterobacter cloacae Complex With Clinical Significance
Authors: Ji Yang , Wang Peihong , Xu Tingting , Zhou Yanzi , Chen Rongchang , Zhu Huaiqiu , Zhou Kai
Published: May 2021

Enterobacter cloacae complex (ECC) is composed of multiple species and the taxonomic status is consecutively updated. In last decades ECC is frequently associated with multidrug resistance and become an important nosocomial pathogen. Currently, rapid and accurate identification of ECC to the species level remains a technical challenge, thus impedes our understanding of the population at the species level. Here, we aimed to develop a simple, reliable, and economical method to distinguish four epidemiologically prevalent species of ECC with clinical significance, i.e., E. cloacae, E. hormaechei, E. roggenkampii, and E. kobei. A total of 977 ECC genomes were retrieved from the GenBank, and unique gene for each species was obtained by core-genome comparisons. Four pairs of species-specific primers were designed based on the unique genes. A total of 231 ECC clinical strains were typed both by hsp60 typing and by species-specific PCRs. The specificity and sensitivity of the four species-specific PCRs ranged between 96.56% and 100% and between 76.47% and 100%, respectively. The PCR for E. cloacae showed the highest specificity and sensitivity. A one-step multiplex PCR was subsequently established by combining the species-specific primers. Additional 53 hsp60-typed ECC and 20 non-ECC isolates belonging to six species obtained from samples of patients, sewage water and feces of feeding animals were tested by the multiplex PCR. The identification results of both techniques were concordant. The multiplex PCR established in this study provides an accurate, expeditious, and cost-effective way for routine diagnosis and molecular surveillance of ECC strains at species level.
Understanding Responses to Bullying From the Parent Perspective
Authors: Stives Kristen L. , May David C. , Mack Michayla , Bethel Cindy L.
Published: May 2021

Relatively little scholarly work addresses parental experiences with bullying in the United States. This lack of understanding about parental perceptions of bullying is a gap in both the scholarly research and the development of effective bullying prevention programming. This paper presents data from responses to a series of open-ended questions about perceptions of and experiences with bullying from 50 parents in a southeastern state. Parents self-reported their level of concern about bullying, their perceptions of why bullying occurs and the extent of bullying at their school, and their communication strategies with their children about bullying. Findings demonstrate that most parents 1) view bullying as problematic and are somewhat fearful of bullying affecting their child, 2) are confident their child is not telling them about all bullying situations they experience, and 3) are more than willing to approach school administrators when their children are victims of bullying. The findings suggest that parents remain concerned about bullying and its problematic nature, and efforts to encourage children to report bullying to adults are not entirely effective. Consequently, bullying prevention training will benefit from greater parental involvement with (and reinforcement of) bullying prevention strategies learned by children at school. Implications for policy and research are also discussed.
Primary Osteocyte Supernatants Metabolomic Profiling of Two Transgenic Mice With Connexin43 Dominant Negative Mutants
Authors: Chen Meng , Li Guobin , Zhang Lan , Ning Kaiting , Yang Baoqiang , Jiang Jean X. , Wang Dong-En , Xu Huiyun
Published: May 2021

Osteocytes could release some small molecules (≤ 1 kDa) through gap junctions and hemichannels to extracellular environment, such as prostaglandin E2 (PGE2), nitric oxide (NO) and adenosine triphosphate (ATP), which play key roles in transferring signals between bone cells and other tissue cells. Connexin (Cx) 43 is the most abundant connexin in osteocytes. To further discover molecules released by osteocytes through Cx43 channels and better understand the regulatory function of Cx43 channels in osteocytes, we performed non-targeted global metabolomics analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) on conditioned medium collected from osteocytes isolated from two transgenic mouse models with Cx43 dominant negative mutants driven by a 10 kb-DMP1 promoter: R76W (gap junctions are blocked, whereas hemichannels are promoted) and Δ130-136 (both gap junctions and hemichannels are blocked). The results revealed that several new categories of molecules, such as “fatty acyls” and “carboxylic acids and derivatives”, could be released through osteocytic Cx43 channels. In addition, alteration of Cx43 channel function affected the release of metabolites related to inflammatory reaction and oxidative stress. Pathway analysis further showed that citric acid cycle was the most differential metabolic pathway regulated by Cx43 channels. In sum, these results isolated new potential metabolites released by osteocytes through Cx43 channels, and offered a novel perspective to understand the regulatory mechanisms of osteocytes on themselves and other cells as well.
Proglucagon-Derived Peptides as Therapeutics
Authors: Lafferty Ryan A. , O’Harte Finbarr P. M. , Irwin Nigel , Gault Victor A. , Flatt Peter R.
Published: May 2021

Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced via tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.
Forest Soil Organic Carbon Stocks of Tessala Mount in North-West Algeria-Preliminary Estimates
Authors: Merabtene Mohammed Djemel , Faraoun Fatiha , Mlih Rawan , Djellouli Riad , Latreche Ali , Bol Roland
Published: May 2021

Mountainous forests in Algeria are severely affected by climate change. The degradation is exacerbated by overgrazing, deforestation, and poor land management linked to the harsh topographical conditions of the mountain agrosystem. These conditions have influenced the turnover of the soil organic matter and thus the SOC stocks storage. This study aims to investigate the average of organic carbon stored in forest soils of Tessala Mount in Algeria and to examine the influence of different plant formations alongside with geographical characteristics and soil physicochemical properties on the amount of carbon stored in the soil. We estimated the critical threshold, the saturation point, and the organic carbon deficit of soils. The correlation between geographical characteristics and soil physicochemical properties and soil organic carbon stocks was determined using principal component analysis and other statistical tools. The results of the study show that the organic carbon stock in soils of Tessala Mount area has an average value of 77.4 t ha−1. The maximum average of SOC stocks (121 t ha−1) of 0–30 cm depth was noted under dense matorral of green and kermes oak followed by sparse garrigue with a value of 112 t ha−1. The soil organic carbon stock in Tessala region was positively correlated with coarse silt, elevation, and northern exposure, but negatively with calcium carbonates contents. The current carbon contents of Tessala topsoil are 22 g C kg−1 which is very low and closer to the critical threshold (11 g C kg−1) whose estimate was based on their clay and silt content. The estimated maximum storage capacity is 160 g C kg−1. The preliminary estimate of the forest soils organic carbon stock of Tessala Mount under current natural conditions indicates an alarming situation with a low rate close to the critical threshold, thus exposing this area to further and stronger degradation.
Multiomics Analysis Reveals Molecular Abnormalities in Granulosa Cells of Women With Polycystic Ovary Syndrome
Authors: Zhao Rusong , Jiang Yonghui , Zhao Shigang , Zhao Han
Published: May 2021

Polycystic ovary syndrome (PCOS) is the most common complex endocrine and metabolic disease in women of reproductive age. It is characterized by anovulatory infertility, hormone disorders, and polycystic ovarian morphology. Regarding the importance of granulosa cells (GCs) in the pathogenesis of PCOS, few studies have investigated the etiology at a single “omics” level, such as with an mRNA expression array or methylation profiling assay, but this can provide only limited insights into the biological mechanisms. Here, genome-wide DNA methylation together with lncRNA-miRNA-mRNA profiles were simultaneously detected in GCs of PCOS cases and controls. A total of 3579 lncRNAs, 49 miRNAs, 669 mRNAs, and 890 differentially methylated regions (DMR)-associated genes were differentially expressed between PCOS cases and controls. Pathway analysis indicated that these differentially expressed genes were commonly associated with steroid biosynthesis and metabolism-related signaling, such as glycolysis/gluconeogenesis. In addition, we constructed ceRNA networks and identified some known ceRNA axes, such as lncRNAs-miR-628-5p-CYP11A1/HSD17B7. We also identified many new ceRNA axes, such as lncRNAs-miR-483-5p-GOT2. Interestingly, most ceRNA axes were also closely related to steroid biosynthesis and metabolic pathways. These findings suggest that it is important to systematically consider the role of reproductive and metabolic genes in the pathogenesis of PCOS.
Analysis of Porcine RIG-I Like Receptors Revealed the Positive Regulation of RIG-I and MDA5 by LGP2
Authors: Li Shuangjie , Yang Jie , Zhu Yuanyuan , Wang Hui , Ji Xingyu , Luo Jia , Shao Qi , Xu Yulin , Liu Xueliang , Zheng Wanglong , Meurens François , Chen Nanhua , Zhu Jianzhong
Published: May 2021

The RLRs play critical roles in sensing and fighting viral infections especially RNA virus infections. Despite the extensive studies on RLRs in humans and mice, there is a lack of systemic investigation of livestock animal RLRs. In this study, we characterized the porcine RLR members RIG-I, MDA5 and LGP2. Compared with their human counterparts, porcine RIG-I and MDA5 exhibited similar signaling activity to distinct dsRNA and viruses, via similar and cooperative recognitions. Porcine LGP2, without signaling activity, was found to positively regulate porcine RIG-I and MDA5 in transfected porcine alveolar macrophages (PAMs), gene knockout PAMs and PK-15 cells. Mechanistically, LGP2 interacts with RIG-I and MDA5 upon cell activation, and promotes the binding of dsRNA ligand by MDA5 as well as RIG-I. Accordingly, porcine LGP2 exerted broad antiviral functions. Intriguingly, we found that porcine LGP2 mutants with defects in ATPase and/or dsRNA binding present constitutive activity which are likely through RIG-I and MDA5. Our work provided significant insights into porcine innate immunity, species specificity and immune biology.
The Chromatin Accessibility Landscape of Peripheral Blood Mononuclear Cells in Patients With Systemic Lupus Erythematosus at Single-Cell Resolution
Authors: Yu Haiyan , Hong Xiaoping , Wu Hongwei , Zheng Fengping , Zeng Zhipeng , Dai Weier , Yin Lianghong , Liu Dongzhou , Tang Donge , Dai Yong
Published: May 2021

Objective

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, and various immune cells are involved in the initiation, progression, and regulation of SLE. Our goal was to reveal the chromatin accessibility landscape of peripheral blood mononuclear cells (PBMCs) in SLE patients at single-cell resolution and identify the transcription factors (TFs) that may drive abnormal immune responses.

Methods

The assay for transposase accessible chromatin in single-cell sequencing (scATAC-seq) method was applied to map the landscape of active regulatory DNA in immune cells from SLE patients at single-cell resolution, followed by clustering, peak annotation and motif analysis of PBMCs in SLE.

Results

Peripheral blood mononuclear cells were robustly clustered based on their types without using antibodies. We identified twenty patterns of TF activation that drive abnormal immune responses in SLE patients. Then, we observed ten genes that were highly associated with SLE pathogenesis by altering T cell activity. Finally, we found 12 key TFs regulating the above six genes (CD83, ELF4, ITPKB, RAB27A, RUNX3, and ZMIZ1) that may be related to SLE disease pathogenesis and were significantly enriched in SLE patients (p <0.05, FC >2). With qPCR experiments on CD83, ELF4, RUNX3, and ZMIZ1 in B cells, we observed a significant difference in the expression of genes (ELF4, RUNX3, and ZMIZ1), which were regulated by seven TFs (EWSR1-FLI1, MAF, MAFA, NFIB, NR2C2 (var. 2), TBX4, and TBX5). Meanwhile, the seven TFs showed highly accessible binding sites in SLE patients.

Conclusions

These results confirm the importance of using single-cell sequencing to uncover the real features of immune cells in SLE patients, reveal key TFs in SLE-PBMCs, and provide foundational insights relevant for epigenetic therapy.
TLR9- and CD40-Targeting Vaccination Promotes Human B Cell Maturation and IgG Induction via pDC-Dependent Mechanisms in Humanized Mice
Authors: Cheng Liang , Li Guangming , Pellegry Caroline Marnata , Yasui Fumihiko , Li Feng , Zurawski Sandra M. , Zurawski Gerard , Levy Yves , Ting Jenny P.-Y. , Su Lishan
Published: May 2021

Mice reconstituted with a human immune system (humanized mice) provide a robust model to study human immunology, vaccinology, and human infectious diseases. However, the development and function of B cells in humanized mice is impaired. B cells from humanized mice are immature and are impaired in IgM to IgG isotype switch in response to infection or vaccination. In the present study we report that Toll-like receptor 9 (TLR9) agonist CpG-B combined with CD40-targeting vaccination triggered human B cell immunoglobin class-switch from IgM+ to IgG+ B cells in humanized mice. Human B cells from mice vaccinated with CpG-B as adjuvant were more mature in phenotype and produced significant levels of both total IgG and antigen-specific IgG. We found that CpG-B treatment activated human pDCs (plasmacytoid dendritic cells) in vivo to induce interferon-alpha (IFN-α)expression in humanized mice. Pre-depletion of human pDC in vivo abrogated the adjuvant effect of CpG-B. Our results indicate that TLR9 and CD40-targeting vaccination triggers human B cell maturation and immunoglobulin class-switch in a pDC-dependent manner in humanized mice. The findings also shed light on induction of human IgG antibodies in humanized mouse models.
Pharmacological Approach for Neuroprotection After Cardiac Arrest—A Narrative Review of Current Therapies and Future Neuroprotective Cocktail
Authors: Choudhary Rishabh C. , Shoaib Muhammad , Sohnen Samantha , Rolston Daniel M. , Jafari Daniel , Miyara Santiago J. , Hayashida Kei , Molmenti Ernesto P. , Kim Junhwan , Becker Lance B.
Published: May 2021

Cardiac arrest (CA) results in global ischemia-reperfusion injury damaging tissues in the whole body. The landscape of therapeutic interventions in resuscitation medicine has evolved from focusing solely on achieving return of circulation to now exploring options to mitigate brain injury and preserve brain function after CA. CA pathology includes mitochondrial damage and endoplasmic reticulum stress response, increased generation of reactive oxygen species, neuroinflammation, and neuronal excitotoxic death. Current non-pharmacologic therapies, such as therapeutic hypothermia and extracorporeal cardiopulmonary resuscitation, have shown benefits in protecting against ischemic brain injury and improving neurological outcomes post-CA, yet their application is difficult to institute ubiquitously. The current preclinical pharmacopeia to address CA and the resulting brain injury utilizes drugs that often target singular pathways and have been difficult to translate from the bench to the clinic. Furthermore, the limited combination therapies that have been attempted have shown mixed effects in conferring neuroprotection and improving survival post-CA. The global scale of CA damage and its resultant brain injury necessitates the future of CA interventions to simultaneously target multiple pathways and alleviate the hemodynamic, mitochondrial, metabolic, oxidative, and inflammatory processes in the brain. This narrative review seeks to highlight the current field of post-CA neuroprotective pharmaceutical therapies, both singular and combination, and discuss the use of an extensive multi-drug cocktail therapy as a novel approach to treat CA-mediated dysregulation of multiple pathways, enhancing survival, and neuroprotection.
XBP1- IGFBP3 Signaling Pathway Promotes NSCLC Invasion and Metastasis
Authors: Luo Qingxi , Shi Wenwen , Dou Bo , Wang Jun , Peng Wei , Liu Xianyu , Zhao Deze , Tang Faqing , Wu Yingfang , Li Xizhe , Li Jiajia , Wen Siqi , Zhang Chunfang , Duan Chaojun
Published: May 2021

Lung cancer is the most frequently diagnosed cancer and the main cause of cancer death in the world. X-box binding protein 1 (XBP1), which is an important transcription factor involved in regulating the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, might act as a potent oncogenic protein in the processes of tumorigenesis, tumor proliferation and metastasis in various cancers. However, the clinical significance and pathological role of XBP1 in non-small cell lung cancer (NSCLC) remains unknown. In this study, we investigated the expression of XBP1s protein in the 104 NSCLC tumor tissues and matched adjacent normal lung tissues (ANLT) by Immunohistochemical (IHC), and we found overexpressed XBP1s protein was associated with NSCLC TNM stages, lymph node metastasis and poor prognosis. The further gain-and loss-of-function experiments indicated overexpression of XBP1s protein promoted cell invasion, migration and metastasis both in vitro and in vivo. Further study showed XBP1s protein could upregulate insulin-like growth factor binding protein-3 (IGFBP3) expression, and regulated NSCLC cells invasion and metastasis by regulating IGFBP3. Taken together, XBP1s protein is markedly overexpressed in NSCLC and serves as an oncogene that play a critical role in NSCLC tumorigenesis and development. Importantly, XBP1s protein might not only be a potential biomarker for metastasis and prognosis but also a potential therapeutic target in NSCLC.
Bone Marrow Soluble Mediator Signatures of Patients With Philadelphia Chromosome-Negative Myeloproliferative Neoplasms
Authors: Cominal Juçara Gastaldi , Cacemiro Maira da Costa , Berzoti-Coelho Maria Gabriela , Pereira Illy Enne Gomes , Frantz Fabiani Gai , Souto Elizabeth Xisto , Covas Dimas Tadeu , Figueiredo-Pontes Lorena Lobo de , Oliveira Maria Carolina , Malmegrim Kelen Cristina Ribeiro , Castro Fabíola Attié de
Published: May 2021

Background

Essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) are clonal hematological diseases classified as Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). MPN pathogenesis is associated with the presence of somatic driver mutations, bone marrow (BM) niche alterations, and tumor inflammatory status. The relevance of soluble mediators in the pathogenesis of MPN led us to analyze the levels of cytokines, chemokines, and growth factors related to inflammation, angiogenesis and hematopoiesis regulation in the BM niche of MPN patients.

Methods

Soluble mediator levels in BM plasma samples from 17 healthy subjects, 28 ET, 19 PV, and 16 PMF patients were determined using a multiplex assay. Soluble mediator signatures were created from categorical analyses of high mediator producers. Soluble mediator connections and the correlation between plasma levels and clinic-laboratory parameters were also analyzed.

Results

The soluble mediator signatures of the BM niche of PV patients revealed a highly inflammatory and pro-angiogenic milieu, with increased levels of chemokines (CCL2, CCL5, CXCL8, CXCL12, CXCL10), and growth factors (GM-CSF M-CSF, HGF, IFN-γ, IL-1β, IL-6Ra, IL-12, IL-17, IL-18, TNF-α, VEGF, and VEGF-R2). ET and PMF patients presented intermediate inflammatory and pro-angiogenic profiles. Deregulation of soluble mediators was associated with some clinic-laboratory parameters of MPN patients, including vascular events, treatment status, risk stratification of disease, hemoglobin concentration, hematocrit, and red blood cell count.

Conclusions

Each MPN subtype exhibits a distinct soluble mediator signature. Deregulated production of BM soluble mediators may contribute to MPN pathogenesis and BM niche modification, provides pro-tumor stimuli, and is a potential target for future therapies.
Tanshinone I Inhibits Oxidative Stress–Induced Cardiomyocyte Injury by Modulating Nrf2 Signaling
Authors: Wu Yu-Ting , Xie Ling-Peng , Hua Yue , Xu Hong-Lin , Chen Guang-Hong , Han Xin , Tan Zhang-Bin , Fan Hui-Jie , Chen Hong-Mei , Li Jun , Liu Bin , Zhou Ying-Chun
Published: May 2021

Cardiovascular disease, a disease caused by many pathogenic factors, is one of the most common causes of death worldwide, and oxidative stress plays a major role in its pathophysiology. Tanshinone I (Tan I), a natural compound with cardiovascular protective effects, is one of the main active compounds extracted from Salvia miltiorrhiza. Here, we investigated whether Tan I could attenuate oxidative stress and oxidative stress–induced cardiomyocyte apoptosis through Nrf2/MAPK signaling in vivo and in vitro. We found that Tan I treatment protected cardiomyocytes against oxidative stress and oxidative stress–induced apoptosis, based on the detection of relevant oxidation indexes such as reactive oxygen species, superoxide dismutase, malondialdehyde, and apoptosis, including cell viability and apoptosis-related protein expression. We further examined the mechanisms underlying these effects, determining that Tan I activated nuclear factor erythroid 2 (NFE2)–related factor 2 (Nrf2) transcription into the nucleus and dose-dependently promoted the expression of Nrf2, while inhibiting MAPK signaling activation, including P38 MAPK, SAPK/JNK, and ERK1/2. Nrf2 inhibitors in H9C2 cells and Nrf2 knockout mice demonstrated aggravated oxidative stress and oxidative stress–induced cardiomyocyte injury; Tan I treatment suppressed these effects in H9C2 cells; however, its protective effect was inhibited in Nrf2 knockout mice. Additionally, the analysis of surface plasmon resonance demonstrated that Tan I could directly target Nrf2 and act as a potential Nrf2 agonist. Collectively, these data strongly indicated that Tan I might inhibit oxidative stress and oxidative stress–induced cardiomyocyte injury through modulation of Nrf2 signaling, thus supporting the potential therapeutic application of Tan I for oxidative stress–induced CVDs.
Identification of Competing Endogenous RNA and Micro-RNA Profiles and Regulatory Networks in 4-Nonylphenol-induced Impairment of Sertoli Cells
Authors: Liu Wenjie , Wang Zhaokai , Hu Xiaopeng
Published: May 2021

The xenoestrogens nonylphenols (NPs), which are materials used in the plastic polymer industry, are considered endocrine disruptors in a wide range of organisms. Studies have shown that human health problems, such as infertility and reproductive toxicology, are linked with NPs. However, the mechanism by which NPs interfere with male reproduction is not fully elucidated. Here, we found that 4-NP can result in male reproductive impairment and reduce androgen receptor (AR) protein levels in rat sertoli cellsin vitroandin vivo. Moreover, we performed RNA sequencing to assess the differential expression of ceRNAs in rat primary sertoli cells treated with 4-NP. Bioinformatics methods, such as Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) database and ceRNA functional network analyses, were used to investigate the sequencing data and gain further understanding of the biological processes. Our analysis revealed a core set of mRNAs (Ar,Atf6andCbp), and circRNAs (circ673,circ1377,circ1789, andcircPTEN) that were selected and validated by RT-qPCR. In addition, the head-to-tail splicing ofcirc673,circ1377,circ1789, andcircPTENwas identified by Sanger sequencing. These findings provide the first insight into the ceRNA expression profiles of rat sertoli cells and reveal that ceRNAs participate in 4-NP-induced impairment of sertoli cell function, thereby indicating potential therapies for both reproductive toxicology and male infertility.
Chinese Herbal Medicine Xingnaojing Injection for Acute Ischemic Stroke: An Overview of Systematic Reviews and Meta-Analyses
Authors: Tian Zi-Yu , Feng Lu-Da , Xie Yao , Xu De-Hao , Zhang Chong-Yang , Kong Ling-Bo , An Rong-Rong , Ma Li-Fang , Robinson Nicola , Gao Ying , Liu Jian-Ping
Published: May 2021

Background: Xingnaojing injection (XNJ) is the only Chinese herbal injection approved for both intracerebral hemorrhage and ischemic stroke (IS) first-aid on ambulances in China; many systematic reviews (SRs) and meta-analyses (MAs) of XNJ on stroke have been published. The purpose of this research was to evaluate and summarize the current evidence on XNJ for IS.

Methods: A comprehensive search was conducted for SRs and MAs of XNJ on IS in seven databases up to January 1, 2021. Two authors independently identified SRs and MAs, extracted data, assessed the quality of the included SRs and MAs using the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2), and assessed quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE).

Results: A total of 10 SRs met the inclusion criteria. The quality of included SRs using AMSTAR 2 was critically low as the critical items were poorly reported. Only 10% of SRs reported 50% of the 16 items, while the remaining 90% SRs reported just less than half of the items on AMSTAR 2. For GRADE, 7 (35%) of outcomes had low-quality evidence, 10 (50%) with very low, and 3 (15%) with moderate quality evidence. Very low to low quality of evidence indicated XNJ plus conventional therapy (CT) alleviated the neurological deficits of acute IS. Moderate-quality evidence showed XNJ plus CT reduced mortality when compared to Danshen injection plus CT, and very low-quality evidence showed XNJ plus CT could not improve the degree of coma, while low-quality evidence indicated the opposite. Mild adverse events in the CT group were less than those in the XNJ plus CT group, and there were no serious adverse events, but there was no statistical difference between the two groups. The included 10 SRs indicated that XNJ was used for acute IS, but only four SRs (40%) reported the course of disease.

Conclusion: XNJ appears to be effective and safe for acute IS in improving the neurological deficits, but the evidence is not robust enough. However, whether administering XNJ immediately after or within 24 h of IS is best remains unknown due to the lack of data. Well-designed large-scale randomized controlled trials with measurable outcomes are required in future studies.
Protective Role of Mytilus edulis Hydrolysate in Lipopolysaccharide-Galactosamine Acute Liver Injury
Authors: Starikova Eleonora , Mammedova Jennet , Ozhiganova Arina , Lebedeva Aleksandra , Malashicheva Anna , Semenova Daria , Khokhlova Evgeniia , Mameli Eleonora , Caporali Andrea , Wills Jimi , Sokolov Alexey
Published: May 2021

Acute liver injury in its terminal phase trigger systemic inflammatory response syndrome with multiple organ failure. An uncontrolled inflammatory reaction is difficult to treat and contributes to high mortality. Therefore, to solve this problem a search for new therapeutic approaches remains urgent. This study aimed to explore the protective effects of M. edulis hydrolysate (N2-01) against Lipopolysaccharide-D-Galactosamine (LPS/D-GalN)-induced murine acute liver injure and the underlying mechanisms. N2-01 analysis, using Liquid Chromatography Mass Spectrometry (LCMS) metabolomic and proteomic platforms, confirmed composition, molecular-weight distribution, and high reproducibility between M. edulis hydrolysate manufactured batches. N2-01 efficiently protected mice against LPS/D-GalN-induced acute liver injury. The most prominent result (100% survival rate) was obtained by the constant subcutaneous administration of small doses of the drug. N2-01 decreased Vascular Cell Adhesion Molecule-1 (VCAM-1) expression from 4.648 ± 0.445 to 1.503 ± 0.091 Mean Fluorescence Intensity (MFI) and Interleukin-6 (IL-6) production in activated Human Umbilical Vein Endothelial Cells (HUVECs) from 7.473 ± 0.666 to 2.980 ± 0.130 ng/ml in vitro. The drug increased Nitric Oxide (NO) production by HUVECs from 27.203 ± 2.890 to 69.200 ± 4.716 MFI but significantly decreased inducible Nitric Oxide Synthase (iNOS) expression from 24.030 ± 2.776 to 15.300 ± 1.290 MFI and NO production by murine peritoneal lavage cells from 6.777 ± 0.373 µm to 2.175 ± 0.279 µm. The capability of the preparation to enhance the endothelium barrier function and to reduce vascular permeability was confirmed in Electrical Cell-substrate Impedance Sensor (ECIS) test in vitro and Miles assay in vivo. These results suggest N2-01 as a promising agent for treating a wide range of conditions associated with uncontrolled inflammation and endothelial dysfunction.
Reorganization of Substance Use Treatment and Harm Reduction Services During the COVID-19 Pandemic: A Global Survey
Authors: Radfar Seyed Ramin , De Jong Cornelis A. J. , Farhoudian Ali , Ebrahimi Mohsen , Rafei Parnian , Vahidi Mehrnoosh , Yunesian Masud , Kouimtsidis Christos , Arunogiri Shalini , Massah Omid , Deylamizadeh Abbas , Brady Kathleen T. , Busse Anja , Potenza Marc N. , Ekhtiari Hamed , Baldacchino Alexander Mario ,   ISAM-PPIG Global Survey Consortium
Published: May 2021

Background:The coronavirus disease 2019 (COVID-19) pandemic has impacted people with substance use disorders (SUDs) worldwide, and healthcare systems have reorganized their services in response to the pandemic.

Methods:One week after the announcement of the COVID-19 as a pandemic, in a global survey, 177 addiction medicine professionals described COVID-19-related health responses in their own 77 countries in terms of SUD treatment and harm reduction services. The health responses were categorized around (1) managerial measures and systems, (2) logistics, (3) service providers, and (4) vulnerable groups.

Results:Respondents from over 88% of countries reported that core medical and psychiatric care for SUDs had continued; however, only 56% of countries reported having had any business continuity plan, and 37.5% of countries reported shortages of methadone or buprenorphine supplies. Participants of 41% of countries reported partial discontinuation of harm-reduction services such as needle and syringe programs and condom distribution. Fifty-seven percent of overdose prevention interventions and 81% of outreach services were also negatively impacted.

Conclusions:Participants reported that SUD treatment and harm-reduction services had been significantly impacted globally early during the COVID-19 pandemic. Based on our findings, we highlight several issues and complications resulting from the pandemic concerning people with SUDs that should be tackled more efficiently during the future waves or similar pandemics. The issues and potential strategies comprise the following: (1) helping policymakers to generate business continuity plans, (2) maintaining the use of evidence-based interventions for people with SUDs, (3) being prepared for adequate medication supplies, (4) integrating harm reduction programs with other treatment modalities, and (5) having specific considerations for vulnerable groups such as immigrants and refugees.
Impact of Leaf Occlusions on Yield Assessment by Computer Vision in Commercial Vineyards
Authors: Íñiguez Rubén , Palacios Fernando , Barrio Ignacio , Hernández Inés , Gutiérrez Salvador , Tardaguila Javier
Published: May 2021

Yield assessment has been identified as critical topic for grape and wine industry. Computer vision has been applied for assessing yield, but the accuracy was greatly affected by fruit occlusion affected by leaves and other plant organs. The objective of this work was the consistent, continuous evaluation of the impact of leaf occlusions in different commercial vineyard plots at different defoliation stages. RGB (red, green and blue) images from five Tempranillo (Vitis vinifera L.) vineyards were manually acquired using a digital camera under field conditions at three different levels of defoliation: no defoliation, partial defoliation and full defoliation. Computer vision was used for the automatic detection of different canopy features, and for the calibration of regression equations for the prediction of yield computed per vine segment. Leaf occlusion rate (berry occlusion affected by leaves) was computed by machine vision in no defoliated vineyards. As occlusion rate increased, R2 between bunch pixels and yield was gradually reduced, ranging from 0.77 in low occlusion, to 0.63.
Bidimensional and Contrast-Enhanced Ultrasonography of the Spleen in Dogs Affected by Leishmaniosis
Authors: De Majo Massimo , Donato Giulia , Masucci Marisa , Mangano Cyndi , Persichetti Maria Flaminia , Liotta Luigi , Mazzullo Giuseppe , Visalli Rosanna , Quartuccio Marco , Iannelli Nicola Maria , Cristarella Santo , Pennisi Maria Grazia
Published: May 2021

Canine leishmaniosis (CanL) is responsible for splenic pathological changes. The main features detectable from ultrasound examination are splenomegaly and diffuse alterations of the echostructure. The study aimed to highlight whether these ultrasound changes are related to the severity of the disease or to a modification of splenic microvascularization that can be detected in vivo through contrast-enhanced ultrasonography (CEUS). Twenty-five adult dogs tested for CanL were enrolled in this prospective, controlled study and staged according to LeishVet guidelines. Bidimensional ultrasonography revealed that splenomegaly was seen in 50% of the affected dogs, and diffuse parenchymal changes were seen in more than 60% of dogs with splenomegaly, showing a positive correlation with severity of the disease; therefore, splenomegaly could be of prognostic significance. CEUS showed that a persistent heterogeneous distribution pattern appeared only in spleens with diffuse echostructure alterations. The evaluation of quantitative CEUS parameters regarding the volume and velocity of flow in three regions of interest did not show differences between affected and control dogs. Diffuse spleen microvascular modifications evidenced by CEUS were reported for the first time in dogs with CanL. In endemic areas, CanL could be included in the differential diagnoses list when detecting splenic alterations in dogs.