bluuebunny/crossref_metadata_2025 huggingface dataset:
Peroxidative damage of mitochondrial respiration is substrate-dependent
Authors: Endlicher R , Křiváková P , Rauchová H , Nůsková H , Červinková Z , Drahota Z
Published: February 2021

The concentration-dependence of tert-butyl hydroperoxide (BHP)
inhibitory effect on oxygen consumption in isolated rat liver
mitochondria was measured in the presence of various
respiratory substrates. Strong inhibitory effect at low
concentrations of BHP (15-30 µM) was found for oxoglutarate
and palmitoyl carnitine oxidation. Pyruvate and glutamate
oxidation was inhibited at higher concentrations of BHP (100-200
µM). Succinate oxidation was not affected even at 3.3 mM BHP.
Determination of mitochondrial membrane potential has shown
that in the presence of NADH-dependent substrates the
membrane potential was dissipated by BHP but was completely
restored after addition of succinate. Our data thus indicate that
beside peroxidative damage of complex I also various
mitochondrial NADH-dependent dehydrogenases are inhibited,
but to a different extent and with different kinetics. Our data also
show that succinate could be an important nutritional substrate
protecting hepatocytes during peroxidative damage.
Effect of alpha1-adrenergic antagonist prazosin on behavioral alterations induced by MK-801 in a spatial memory task in Long-Evans rats
Authors: Stuchlík A , Petrásek T , Valeš K
Published: February 2021

Animal models of neuropsychiatric disorders are current topics in
behavioral neuroscience. Application of non-competitive
antagonists of NMDA receptors (such as MK-801) was proposed
as a model of schizophrenia, as it leads to specific behavioral
alterations, which are partly analogous to human psychotic
symptoms. This study examined an animal model of
schizophrenia induced by a systemic application of MK-801 (0.15
and 0.20 mg/kg) into rats tested in the active allothetic place
avoidance (AAPA) task. Previous studies suggested that MK-801
may interact in vivo with other neurotransmitter systems,
including noradrenergic system. Our experiments therefore
evaluated the hypothesis that both locomotor stimulation and
deficit in avoidance behavior in AAPA task induced by this drug
would be reversible by application of alpha1-adrenergic
antagonist prazosin (1 and 2 mg/kg). The results showed that
both doses of prazosin partially reversed hyperlocomotion
induced by higher doses of MK-801 and an avoidance deficit
measured as number of entrances into the shock sector.
Interestingly, no effect of prazosin on the MK-801-induced
decrease of maximum time between two entrances (another
measure of cognitive performance) was observed. These results
support previous data showing that prazosin can compensate for
the hyperlocomotion induced by MK-801 and newly show that
this partial reduction sustains even in the forced locomotor
conditions, which are involved in the AAPA task. The study also
shows that certain parameters of avoidance efficiency may be
closely related to locomotor activity, whereas other measures of
cognition may more selectively reflect cognitive changes.
ANÁLISE DAS CERTIFICAÇÕES AMBIENTAIS DE EDIFICAÇÕES
Authors: Sugahara Estefani Suana , Freitas Márcia Regina de , Cruz Victor Afonso Lopes da
Published: February 2021

Com os impactos ambientais agravando-se a uma velocidade avançada e visto que a ação do setor da construção civil é indispensável na busca pelo desenvolvimento sustentável, as edificações destinadas a qualquer propósito devem adotar medidas de sustentabilidade desde a fase inicial do projeto. Desta forma, os países têm criado seus próprios sistemas de certificação ambiental de edifícios. Visto isto, justifica-se a importância deste estudo com enfoque nas certificações ambientais, tanto para conhecimento no meio técnico-científico, quanto para toda a cadeia do setor. Assim, este trabalho objetiva analisar e comparar os principais instrumentos de certificação ambiental aplicáveis ao mercado construtivo brasileiro, reunindo informações que apoiem a tomada de decisão dos gestores na escolha do sistema mais adequado, aplicável às edificações habitacionais brasileiras. A metodologia adotada foi de pesquisa bibliográfica e pesquisa comparativa descritiva simplificada para os quatro tipos de certificação ambiental analisadas. Observou-se que, de uma forma geral, os sistemas avaliados possuem critérios, características e objetivos distintos uns dos outros. Foram apresentadas, portanto, as principais características, assim como também foram indicadas as principais diferenças entre os métodos avaliados, fornecendo referências importantes para auxiliar a tomada de decisão de gestores de empreendimentos do setor quanto ao método mais aplicável em cada caso.
The Meaning Extraction Method: An Approach to Evaluate Content Patterns From Large-Scale Language Data
Authors: Markowitz David M.
Published: February 2021

Qualitative content analyses often rely on a top-down approach to understand themes in a collection of texts. A codebook prescribes how humans should judge if a text fits a theme based on rules and judgment criteria. Qualitative approaches are challenging because they require many resources (e.g., coders, training, rounds of coding), can be affected by researcher or coder bias, may miss meaningful patterns that deviate from the codebook, and often use a subsample of the data. A complementary, bottom-up approach—the Meaning Extraction Method—has been popular in social psychology but rarely applied to communication research. This paper outlines the value of the Meaning Extraction Method, concluding with a guide to conduct analyses of content and themes from massive and complete datasets, quantitatively. The Meaning Extraction Method is performed on a public and published archive of pet adoption profiles to demonstrate the approach. Considerations for communication research are offered.
Potential Target miR-455 Delaying Arterial Stenosis Progression Through PTEN
Authors: Lin Ruoran , Lv Junyuan , Wang Lei , Li Xuan , Zhang Jing , Sun Weifeng , Hu Xiaoyun , Xin Shijie
Published: February 2021

Background: Vascular smooth muscle cells (VSMC) underwent phenotypic switching upon stimulation signals, and this is the prerequisite for their proliferation and migration. Previous work revealed that miR-455 may be involved in vascular stenosis. Thus, this study aimed to explore potential targets and mechanisms underlying the dynamics of miR-455 in vascular stenosis.

Methods: miR-455 and PTEN expression levels were studied in normal and stenosis tissue, as well as in VSMC in proliferation model. Manipulating miR-455 expression levels was achieved by transfection of either miR-455 mimic or inhibitor, and its effect on cell proliferation was studied by CCK-8 assay. Its effect on gene expression was studied by RT-qPCR and western blot. The expression regulation mechanism was studied by luciferase reporter system. Finally, the effect of miR-455 on regulating vascular stenosis was studied using a rat balloon-injured carotid artery stenosis model.

Results: High expression levels of miR-455 were detected in both stenosis arterial tissues and VSMC proliferation models. In contrast, the expression levels of PTEN were downregulated in these systems. miR-455 transfected VSMC showed higher levels of proliferation and decreased levels of PTEN. Potential binding sites between miR-455 and PTEN 3′UTR were predicted and confirmed. NF-kB p65 was found to bind directly on miR-455 promoter region and regulate its transcription. The progression of arterial stenosis could be delayed by introducing miR-455 antagomir.

Conclusions: The p65/miR-455/PTEN signaling pathway plays a crucial role in regulating VSMC proliferation and vascular stenosis. This indicated that miR-455 is a novel target that would help improve treatment outcomes in patients suffering from vascular stenosis.
The Impact of Complex Volcanic Plumbing on the Nature of Seismicity in the Developing Magmatic Natron Rift, Tanzania
Authors: Reiss Miriam Christina , Muirhead James D. , Laizer Amani S. , Link Frederik , Kazimoto Emmanuel O. , Ebinger Cynthia J. , Rümpker Georg
Published: February 2021

Constraining the architecture of complex 3D volcanic plumbing systems within active rifts, and their impact on rift processes, is critical for examining the interplay between faulting, magmatism and magmatic fluids in developing rift segments. The Natron basin of the East African Rift System provides an ideal location to study these processes, owing to its recent magmatic-tectonic activity and ongoing active carbonatite volcanism at Oldoinyo Lengai. Here, we report seismicity and fault plane solutions from a 10 month-long temporary seismic network spanning Oldoinyo Lengai, Naibor Soito volcanic field and Gelai volcano. We locate 6,827 earthquakes with ML−0.85 to 3.6, which are related to previous and ongoing magmatic and volcanic activity in the region, as well as regional tectonic extension. We observe seismicity down to ∼17 km depth north and south of Oldoinyo Lengai and shallow seismicity (3–10 km) beneath Gelai, including two swarms. The deepest seismicity (∼down to 20 km) occurs above a previously imaged magma body below Naibor Soito. These seismicity patterns reveal a detailed image of a complex volcanic plumbing system, supporting potential lateral and vertical connections between shallow- and deep-seated magmas, where fluid and melt transport to the surface is facilitated by intrusion of dikes and sills. Focal mechanisms vary spatially. T-axis trends reveal dominantly WNW-ESE extension near Gelai, while strike-slip mechanisms and a radial trend in P-axes are observed in the vicinity of Oldoinyo Lengai. These data support local variations in the state of stress, resulting from a combination of volcanic edifice loading and magma-driven stress changes imposed on a regional extensional stress field. Our results indicate that the southern Natron basin is a segmented rift system, in which fluids preferentially percolate vertically and laterally in a region where strain transfers from a border fault to a developing magmatic rift segment.
Friction and Wear Properties of CrAl-Based Coatings for Nuclear Fuel Cladding
Authors: Ma Biao , Luo Bin , Wang Zhuozheng , Meng Chuiyi , He Xiujie
Published: February 2021

Friction and wear performance is one of the key mechanical properties of accident tolerant fuel cladding coatings. In this study, reciprocating sliding wear tests had performed on two types of CrAl and CrAlN coatings with two different Al content ratios and Zr-4. The coefficient of friction, wear depth, and abrasion loss were measured and compared. The results indicated that the CrAl-based coatings improve the wear behavior significantly and nitrogen has an obvious improvement on the wear resistance of the coating. The friction and wear performance was also studied in a water environment. The results show that the presence of water degrade the wear performance of Zr-4 and CrAl coatings but ameliorates the friction and wear performance of CrAlN coatings. The feasibility of depositing ATF coating on conventional Zr-4 substrates to mitigate the influence of grid-to-rod fretting was demonstrated.
The Subgenual Organ Complex in Stick Insects: Functional Morphology and Mechanical Coupling of a Complex Mechanosensory Organ
Authors: Strauß Johannes , Moritz Leif , Rühr Peter T.
Published: February 2021

Leg chordotonal organs in insects show different adaptations to detect body movements, substrate vibrations, or airborne sound. In the proximal tibia of stick insects occur two chordotonal organs: the subgenual organ, a highly sensitive vibration receptor organ, and the distal organ, of which the function is yet unknown. The distal organ consists of a linear set of scolopidial sensilla extending in the tibia in distal direction toward the tarsus. Similar organs occur in the elaborate hearing organs in crickets and bushcrickets, where the auditory sensilla are closely associated with thin tympanal membranes and auditory trachea in the leg. Here, we document the position and attachment points for the distal organ in three species of stick insects without auditory adaptations (Ramulus artemis,Sipyloidea sipylus, andCarausius morosus). The distal organ is located in the dorsal hemolymph channel and attaches at the proximal end to the dorsal and posterior leg cuticle by tissue strands. The central part of the distal organ is placed closer to the dorsal cuticle and is suspended by fine tissue strands. The anterior part is clearly separated from the tracheae, while the distal part of the organ is placed over the anterior trachea. The distal organ is not connected to a tendon or muscle, which would indicate a proprioceptive function. The sensilla in the distal organ have dendrites oriented in distal direction in the leg. This morphology does not reveal obvious auditory adaptations as in tympanal organs, while the position in the hemolymph channel and the direction of dendrites indicate responses to forces in longitudinal direction of the leg, likely vibrational stimuli transmitted in the leg’s hemolymph. The evolutionary convergence of complex chordotonal organs with linear sensilla sets between tympanal hearing organs and atympanate organs in stick insects is emphasized by the different functional morphologies and sensory specializations.
Sex-Specific Associations of MIR137 Polymorphisms With Schizophrenia in a Han Chinese Cohort
Authors: Yin Jingwen , Luo Xudong , Peng Qian , Xiong Susu , Lv Dong , Dai Zhun , Fu Jiawu , Wang Ying , Wei Yaxue , Liang Chunmei , Xu Xusan , Zhang Dandan , Wang Lulu , Zhu Dongjian , Wen Xia , Ye Xiaoqing , Lin Zhixiong , Lin Juda , Li You , Wang Jiafeng , Ma Guoda , Li Keshen , Wang Yajun
Published: February 2021

Objective: To investigate the effects of microRNA-137 (MIR137) polymorphisms (rs1198588 and rs2660304) on the risk of schizophrenia in a Han Chinese population.

Methods: Schizophrenia was diagnosed according to the DSM-5. Clinical symptoms and cognitive functions were assessed with the Positive and Negative Symptom Scale (PANSS) and Brief Assessment of Cognition in Schizophrenia (BACS), respectively. The polymorphisms were genotyped by improved multiplex ligation detection reaction (iMLDR) technology in 1,116 patients with schizophrenia and 1,039 healthy controls.

Results: Significant associations were found between schizophrenia and MIR137 in the distributions of genotypes (p = 0.037 for rs1198588; p = 0.037 for rs2660304, FDR corrected) and alleles (p = 0.043 for rs1198588; p = 0.043 for rs2660304, FDR corrected) of two SNPs. When the population was stratified by sex, we found female-specific associations between MIR137 and schizophrenia in terms of genotype and allele distributions of rs1198588 (χ2 = 4.41, p = 0.036 and χ2 = 4.86, p = 0.029, respectively, FDR corrected) and rs2660304 (χ2 = 4.74, p=0.036 and χ2 = 4.80, p = 0.029, respectively, FDR corrected). Analysis of the MIR137 haplotype rs1198588-rs2660304 showed a significant association with schizophrenia in haplotype T-T [χ2 = 4.60, p = 0.032, OR = 1.32, 95% CI (1.02–1.70)]. Then, significant female-specific associations were found with the haplotypes T-T and G-A [χ2 = 4.92, p = 0.027, OR = 1.62, 95% CI (1.05–2.50); χ2 = 4.42, p = 0.035, OR = 0.62, 95% CI (0.39–0.97), respectively]. When the TT genotype of rs1198588 was compared to the GT+GG genotype, a clinical characteristics analysis also showed a female-specific association in category instances (t = 2.76, p = 0.042, FDR corrected).

Conclusion: The polymorphisms within the MIR137 gene are associated with susceptibility to schizophrenia, and a female-specific association of MIR137 with schizophrenia was reported in a Han Chinese population.
Expression Profile Analysis Identifies a Novel Seven Immune-Related Gene Signature to Improve Prognosis Prediction of Glioblastoma
Authors: Hu Li , Han Zhibin , Cheng Xingbo , Wang Sida , Feng Yumeng , Lin Zhiguo
Published: February 2021

Glioblastoma multiform (GBM) is a malignant central nervous system cancer with dismal prognosis despite conventional therapies. Scientists have great interest in using immunotherapy for treating GBM because it has shown remarkable potential in many solid tumors, including melanoma, non-small cell lung cancer, and renal cell carcinoma. The gene expression patterns, clinical data of GBM individuals from the Cancer Genome Atlas database (TCGA), and immune-related genes (IRGs) from ImmPort were used to identify differentially expressed IRGs through the Wilcoxon rank-sum test. The association between each IRG and overall survival (OS) of patients was investigated by the univariate Cox regression analysis. LASSO Cox regression assessment was conducted to explore the prognostic potential of the IRGs of GBM and construct a risk score formula. A Kaplan–Meier curve was created to estimate the prognostic role of IRGs. The efficiency of the model was examined according to the area under the receiver operating characteristic (ROC) curve. The TCGA internal dataset and two GEO external datasets were used for model verification. We evaluated IRG expression in GBM and generated a risk model to estimate the prognosis of GBM individuals with seven optimal prognostic expressed IRGs. A landscape of 22 types of tumor-infiltrating immune cells (TIICs) in glioblastoma was identified, and we investigated the link between the seven IRGs and the immune checkpoints. Furthermore, there was a correlation between the IRGs and the infiltration level in GBM. Our data suggested that the seven IRGs identified in this study are not only significant prognostic predictors in GBM patients but can also be utilized to investigate the developmental mechanisms of GBM and in the design of personalized treatments for them.
Long-Term Liver Expression of an Apolipoprotein A-I Mimetic Peptide Attenuates Interferon-Alpha-Induced Inflammation and Promotes Antiviral Activity
Authors: Fernandez-Sendin Myriam , Di Trani Claudia Augusta , Bella Angela , Vasquez Marcos , Ardaiz Nuria , Gomar Celia , Arrizabalaga Leire , Ciordia Sergio , Corrales Fernando J. , Aranda Fernando , Berraondo Pedro
Published: February 2021

Apolipoprotein A-I mimetic peptides are amphipathic alpha-helix peptides that display similar functions to apolipoprotein A-I. Preclinical and clinical studies have demonstrated the safety and efficacy of apolipoprotein A-I mimetic peptides in multiple indications associated with inflammatory processes. In this study, we evaluated the effect of the long-term expression of L37pA in the liver by an adeno-associated virus (AAV-L37pA) on the expression of an adeno-associated virus encoding interferon-alpha (AAV-IFNα). Long-term IFNα expression in the liver leads to lethal hematological toxicity one month after AAV administration. Concomitant administration of AAV-L37pA prevented the lethal toxicity since the IFNα expression was reduced one month after AAV administration. To identify the mechanism of action of L37pA, a genomic and proteomic analysis was performed 15 days after AAV administration when a similar level of IFNα and interferon-stimulated genes were observed in mice treated with AAV-IFNα alone and in mice treated with AAV-IFNα and AAV-L37pA. The coexpression of the apolipoprotein A-I mimetic peptide L37pA with IFNα modulated the gene expression program of IFNα, inducing a significant reduction in inflammatory pathways affecting pathogen-associated molecular patterns receptor, dendritic cells, NK cells and Th1 immune response. The proteomic analysis confirmed the impact of the L37pA activity on several inflammatory pathways and indicated an activation of LXR/RXR and PPPARα/γ nuclear receptors. Thus, long-term expression of L37pA induces an anti-inflammatory effect in the liver that allows silencing of IFNα expression mediated by an adeno-associated virus.
Role of HCA2 in Regulating Intestinal Homeostasis and Suppressing Colon Carcinogenesis
Authors: Li Zhuoyue , McCafferty Kayleen J. , Judd Robert L.
Published: February 2021

Hydroxycarboxylic acid receptor 2 (HCA2) is vital for sensing intermediates of metabolism, including β-hydroxybutyrate and butyrate. It also regulates profound anti-inflammatory effects in various tissues, indicating that HCA2 may serve as an essential therapeutic target for mediating inflammation-associated diseases. Butyrate and niacin, endogenous and exogenous ligands of HCA2, have been reported to play an essential role in maintaining intestinal homeostasis. HCA2, predominantly expressed in diverse immune cells, is also present in intestinal epithelial cells (IECs), where it regulates the intricate communication network between diet, microbiota, and immune cells. This review summarizes the physiological role of HCA2 in intestinal homeostasis and its pathological role in intestinal inflammation and cancer.
Treg and Oligoclonal Expansion of Terminal Effector CD8+ T Cell as Key Players in Multiple Myeloma
Authors: Joshua Douglas E. , Vuckovic Slavica , Favaloro James , Lau Ka Hei Aleks , Yang Shihong , Bryant Christian E. , Gibson John , Ho Phoebe Joy
Published: February 2021

The classical paradigm of host-tumor interaction, i.e. elimination, equilibrium, and escape (EEE), is reflected in the clinical behavior of myeloma which progresses from the premalignant condition, Monoclonal Gammopathy of Unknown Significance (MGUS). Despite the role of other immune cells, CD4+ regulatory T cells (Treg) and cytotoxic CD8+ T cells have emerged as the dominant effectors of host control of the myeloma clone. Progression from MGUS to myeloma is associated with alterations in Tregs and terminal effector CD8+ T cells (TTE). These changes involve CD39 and CD69 expression, affecting the adenosine pathway and residency in the bone marrow (BM) microenvironment, together with oligoclonal expansion within CD8+ TTE cells. In this mini-review article, in the context of earlier data, we summarize our recent understanding of Treg involvement in the adenosine pathway, the significance of oligoclonal expansion within CD8+ TTE cells and BM-residency of CD8+ TTE cells in MGUS and newly diagnosed multiple myeloma patients.
The Role of Siglec-G on Immune Cells in Sepsis
Authors: Royster William , Wang Ping , Aziz Monowar
Published: February 2021

Sepsis is a life-threatening clinical syndrome that results from an overwhelming immune response to infection. During sepsis, immune cells are activated by sensing pathogen-associated molecular patterns and damage-associated molecular patterns (DAMPs) through pattern recognizing receptors (PRRs). Regulation of the immune response is essential to preventing or managing sepsis. Sialic acid-binding immunoglobulin-type lectin-G (Siglec-G), a CD33 group of Siglec expressed in B-1a cells and other hematopoietic cells, plays an important immunoregulatory role. B-1a cells, a subtype of B lymphocytes, spontaneously produce natural IgM which confers protection against infection. B-1a cells also produce IL-10, GM-CSF, and IL-35 to control inflammation. Sialic acids are present on cell membranes, receptors, and glycoproteins. Siglec-G binds to the sialic acid residues on the B cell receptor (BCR) and controls BCR-mediated signal transduction, thereby maintaining homeostasis of Ca++ influx and NFATc1 expression. Siglec-G inhibits NF-κB activation in B-1a cells and regulates B-1a cell proliferation. In myeloid cells, Siglec-G inhibits DAMP-mediated inflammation by forming a ternary complex with DAMP and CD24. Thus, preserving Siglec-G’s function could be a novel therapeutic approach in sepsis. Here, we review the immunoregulatory functions of Siglec-G in B-1a cells and myeloid cells in sepsis. A clear understanding of Siglec-G is important to developing novel therapeutics in treating sepsis.
Immunopathogenesis of Craniotomy Infection and Niche-Specific Immune Responses to Biofilm
Authors: de Morais Sharon DB , Kak Gunjan , Menousek Joseph P. , Kielian Tammy
Published: February 2021

Bacterial infections in the central nervous system (CNS) can be life threatening and often impair neurological function. Biofilm infection is a complication following craniotomy, a neurosurgical procedure that involves the removal and replacement of a skull fragment (bone flap) to access the brain for surgical intervention. The incidence of infection following craniotomy ranges from 1% to 3% with approximately half caused by Staphylococcus aureus (S. aureus). These infections present a significant therapeutic challenge due to the antibiotic tolerance of biofilm and unique immune properties of the CNS. Previous studies have revealed a critical role for innate immune responses during S. aureus craniotomy infection. Experiments using knockout mouse models have highlighted the importance of the pattern recognition receptor Toll-like receptor 2 (TLR2) and its adaptor protein MyD88 for preventing S. aureus outgrowth during craniotomy biofilm infection. However, neither molecule affected bacterial burden in a mouse model of S. aureus brain abscess highlighting the distinctions between immune regulation of biofilm vs. planktonic infection in the CNS. Furthermore, the immune responses elicited during S. aureus craniotomy infection are distinct from biofilm infection in the periphery, emphasizing the critical role for niche-specific factors in dictating S. aureus biofilm-leukocyte crosstalk. In this review, we discuss the current knowledge concerning innate immunity to S. aureus craniotomy biofilm infection, compare this to S. aureus biofilm infection in the periphery, and discuss the importance of anatomical location in dictating how biofilm influences inflammatory responses and its impact on bacterial clearance.
Cartilage Oligomeric Matrix Protein Induced Arthritis—A New Model for Rheumatoid Arthritis in the C57BL/6 Mouse
Authors: Zhao Yunjuan , Urbonaviciute Vilma , Xu Bingze , Cai Weiwei , Sener Zeynep , Ge Changrong , Holmdahl Rikard
Published: February 2021

The most commonly used strains in experimental research, including genetically modified strains, are C57BL/6 mice. However, so far, no reliable model for rheumatoid arthritis is available, mainly due to the restriction by the MHC class II haplotype H-2b. Collagen-induced arthritis (CIA) is the most widely used animal model of rheumatoid arthritis, but C57BL/6 strain is resistant to CIA because there is no collagen II peptide associated with H-2b. To establish a rheumatoid arthritis model in C57BL/6 mice, we immunized C57BL/6NJ (B6N) mice with human cartilage oligomeric matrix protein (COMP), which induced severe arthritis with high incidence, accompanied by a strong auto-antibody response. Native COMP was required, as denatured COMP lost its ability to induce arthritis in B6N mice. An immunodominant COMP peptide was identified as the key T cell epitope, with a perfect fit into the Abclass II peptide binding pocket. A critical amino acid in this peptide was found to be phenylalanine at position 95. Recombinant COMP mutated at position 95 (COMP_F95S) lost its ability to induce arthritis or a strong immune response in the B6N mice. In conclusion, A new model for RA has been established using C57BL/6 mice through immunization with COMP, which is dependent on a COMP specific peptide binding Ab, thus in similarity with CIA in Aqexpressing strains.
Regulatory Cell Therapy in Organ Transplantation: Achievements and Open Questions
Authors: Fortunato Marta , Morali Konstantina , Passeri Laura , Gregori Silvia
Published: February 2021

The effective development of innovative surgical applications and immunosuppressive agents have improved remarkable advancements in solid organ transplantation. Despite these improvements led to prevent acute rejection and to promote short-term graft survival, the toxicity of long-term immunosuppression regiments has been associated to organ failure or chronic graft rejection. The graft acceptance is determined by the balance between the regulatory and the alloreactive arm of the immune system. Hence, enhance regulatory cells leading to immune tolerance would be the solution to improve long-term allograft survival which, by reducing the overall immunosuppression, will provide transplanted patients with a better quality of life. Regulatory T cells (Tregs), and regulatory myeloid cells (MRCs), including regulatory macrophages and tolerogenic dendritic cells, are promising cell populations for restoring tolerance. Thus, in the last decade efforts have been dedicated to apply regulatory cell-based therapy to improve the successful rate of organ transplantation and to promote allogeneic tolerance. More recently, this approach has been translated into clinical application. The aim of this review is to summarize and discuss results on regulatory cell-based strategies, focusing on Tregs and MRCs, in terms of safety, feasibility, and efficacy in clinical studies of organ transplantation.
Ferromagnetism With High Curie Temperature of Cu Doped LiMgN New Dilute Magnetic Semiconductors
Authors: Deng Junquan , Yang Wuqing , Hu Aiyuan , Yu Peng , Cui Yuting , Ding Shoubing , Wu Zhimin
Published: February 2021

New diluted magnetic semiconductors represented by Li(Zn,Mn)As with decoupled charge and spin doping have received much attention due to their potential applications for spintronics. However, their low Curie temperature seriously restricts the wide application of these spintronic devices. In this work, the electronic structures, ferromagnetic properties, formation energy, and Curie temperature of Cu doped LiMgN and the corresponding Li deficient system are calculated by using the first principles method based on density functional theory, combined with Heisenberg model in the Mean-Field Approximation. We find that the Cu doped systems have high temperature ferromagnetism, and the highest Curie temperature is up to 573K, much higher than the room temperature. Li(Mg0.875Cu0.125)N is a half metallic ferromagnet and its net magnetic moments are 2.0 μв. When Li is deficient, the half metallic ferromagnetism becomes stronger, the magnetic moments increase to 3.0 μв. The bonding and differential charge density indicate that the half metallic ferromagnetism can be mainly attributed to the strong hybridization between N 2p and doped Cu 3d orbitals. The results show that Cu doped LiMgN is a kind of ideal new dilute magnetic semiconductor that will benefit potential spintronics applications.
Effect of Spironolactone on COVID-19 in Patients With Underlying Liver Cirrhosis: A Nationwide Case-Control Study in South Korea
Authors: Jeon Dongsub , Son Minkook , Choi Jonggi
Published: February 2021

Purpose: On the basis that spironolactone is involved in ACE2 expression and TMPRSS2 activity, previous studies have suggested that spironolactone may influence the infectivity of COVID-19. Research has suggested that cell entry of SARS-CoV-2, the virus that induces COVID-19, is associated with the ACE2 receptor and TMPRSS2. The purpose of this study was to investigate whether spironolactone has a protective effect against COVID-19 and the development of associated complications in patients with liver cirrhosis.

Methods: We conducted a nationwide case-control study on liver cirrhosis patients with or without COVID-19 from the population-based data acquired from the National Health Insurance Systems of Republic of Korea. After 1:5 case-control matching, multivariable adjusted conditional logistic regression analysis was performed.

Results: Among the patients with liver cirrhosis, the case group with COVID-19 was found to be significantly less exposed to spironolactone compared with the control group without COVID-19. The adjusted odds ratio (OR) and 95% confidence interval (CI) between the two groups was 0.20 (0.07–0.54). In addition, regardless of cumulative dose of spironolactone, exposure to spironolactone was associated with lower COVID-19 infection. In terms of the development of complications due to COVID-19, spironolactone did not show any significant association between the patients with and without complications (P = 0.43). The adjusted OR and 95% CI between the two groups was 1.714 (0.246–11.938).

Conclusion: We conclude that spironolactone may reduce susceptibility to COVID-19 but does not affect the development of its associated complications; however, further studies are needed to confirm the exact association between spironolactone and COVID-19 infection.
Comparative Study on Different Skin Pruritus Mouse Models
Authors: Donglang Guan , Tongtong Liu , Dan Chen , Chan Zhu , Changming Wang , Guang Yu , Yan Yang , Zongxiang Tang
Published: February 2021

The animal model is an important tool to study the mechanism of disease formation. Different animal models of pruritus have been adopted based on the purpose of researchers in the study of the itching mechanism. Although the symptoms of various models are quite different, scratching behavior is a key indicator. Therefore, it is necessary to find an animal model that can quickly induce animal scratching and maintain the stability of scratching behavior. In this study, we compared animal models of pruritus induced by four substances and found that the scratching behavior of mice induced by urushiol not only reached the plateau stage quickly but also showed more stability in the plateau phase than that induced by 2,4-dinitrofluorobenzene, oxazolone, and imiquimod. Meanwhile, in the animal model induced by urushiol, the changes of epidermal thickening and inflammatory cell aggregation were also more obvious. In addition, pruritus induced by urushiol is prevalent all over the world, especially in the United States and Europe, involving outdoor groups such as firefighters, forest loggers, and farmers. Therefore, we believe that the urushiol-induced animal model is an ideal choice for the study of the itch formation mechanism and the development of antipruritic drugs.
Therapeutic Insights in Chronic Kidney Disease Progression
Authors: Shabaka Amir , Cases-Corona Clara , Fernandez-Juarez Gema
Published: February 2021

Chronic kidney disease (CKD) has been recognized as a leading public health problem worldwide. Through its effect on cardiovascular risk and end-stage kidney disease, CKD directly affects the global burden of morbidity and mortality. Classical optimal management of CKD includes blood pressure control, treatment of albuminuria with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, avoidance of potential nephrotoxins and obesity, drug dosing adjustments, and cardiovascular risk reduction. Diabetes might account for more than half of CKD burden, and obesity is the most important prompted factor for this disease. New antihyperglycemic drugs, such as sodium-glucose-cotransporter 2 inhibitors have shown to slow the decline of GFR, bringing additional benefit in weight reduction, cardiovascular, and other kidney outcomes. On the other hand, a new generation of non-steroidal mineralocorticoid receptor antagonist has recently been developed to obtain a selective receptor inhibition reducing side effects like hyperkalemia and thereby making the drugs suitable for administration to CKD patients. Moreover, two new potassium-lowering therapies have shown to improve tolerance, allowing for higher dosage of renin-angiotensin system inhibitors and therefore enhancing their nephroprotective effect. Regardless of its cause, CKD is characterized by reduced renal regeneration capacity, microvascular damage, oxidative stress and inflammation, resulting in fibrosis and progressive, and irreversible nephron loss. Therefore, a holistic approach should be taken targeting the diverse processes and biological contexts that are associated with CKD progression. To date, therapeutic interventions when tubulointerstitial fibrosis is already established have proved to be insufficient, thus research effort should focus on unraveling early disease mechanisms. An array of novel therapeutic approaches targeting epigenetic regulators are now undergoing phase II or phase III trials and might provide a simultaneous regulatory activity that coordinately regulate different aspects of CKD progression.
Gut Microbiota Comparison Between Intestinal Contents and Mucosa in Mice With Repeated Stress-Related Diarrhea Provides Novel Insight
Authors: Zhang Chen-Yang , Peng Xin-Xin , Shao Hao-Qing , Li Xiao-Ya , Wu Yi , Tan Zhou-Jin
Published: February 2021

Repeated stress-related diarrhea is a kind of functional bowel disorders (FBDs) that are mainly stemming from dysregulation of the microbiota–gut–brain axis mediated by a complex interplay of 5-hydroxytryptophan (5-HT). Intestinal content and intestinal mucosa microbiota belong to two different community systems, and the role of the two microbiota community systems in repeated stress-related diarrhea remains largely unknown. In order to ascertain the difference in composition and the potential function between intestinal content and intestinal mucosa microbiota response on repeated stress-related diarrhea, we collected intestinal contents and mucosa of mice with repeated stress-related diarrhea for 16S rRNA PacBio SMRT gene full-length sequencing, and with the digital modeling method of bacterial species abundance, the correlations among the two microbiota community systems and serum 5-HT concentration were analyzed. We found that the microbiotal composition differences both in intestinal contents and mucosa were consistent throughout all the phylogenetic ranks, with an increasing level of resolution. Compared with intestinal content microbiota, the diversity and composition of microbiota colonized in intestinal mucosa are more sensitive to repeated stress-related diarrhea. The PICRUSt2 of metagenomic function analysis found that repeated stress-related diarrhea is more likely to perturb the intestinal mucosa microbiota metagenomic functions involved in the neural response. We further found that the mucosal microbiota-based relative abundance model was more predictive on serum 5-HT concentration with the methods of machine-learning model established and multivariate dimensionality reduction (R2 = 0.876). These findings suggest that the intestinal mucosa microbiota might serve as a novel potential prediction model for the serum 5-HT concentration involvement in the repeated stress-related diarrhea, in addition to focusing on its mechanism in the gastrointestinal dysfunction.
BamA and BamD Are Essential for the Secretion of Trimeric Autotransporter Adhesins
Authors: Rooke Jessica L. , Icke Christopher , Wells Timothy J. , Rossiter Amanda E. , Browning Douglas F. , Morris Faye C. , Leo Jack C. , Schütz Monika S. , Autenrieth Ingo B. , Cunningham Adam F. , Linke Dirk , Henderson Ian R.
Published: February 2021

The BAM complex in Escherichia coli is composed of five proteins, BamA-E. BamA and BamD are essential for cell viability and are required for the assembly of β-barrel outer membrane proteins. Consequently, BamA and BamD are indispensable for secretion via the classical autotransporter pathway (Type 5a secretion). In contrast, BamB, BamC, and BamE are not required for the biogenesis of classical autotransporters. Recently, we demonstrated that TamA, a homologue of BamA, and its partner protein TamB, were required for efficient secretion of proteins via the classical autotransporter pathway. The trimeric autotransporters are a subset of the Type 5-secreted proteins. Unlike the classical autotransporters, they are composed of three identical polypeptide chains which must be assembled together to allow secretion of their cognate passenger domains. In contrast to the classical autotransporters, the role of the Bam and Tam complex components in the biogenesis of the trimeric autotransporters has not been investigated fully. Here, using the Salmonella enterica trimeric autotransporter SadA and the structurally similar YadA protein of Yersinia spp., we identify the importance of BamA and BamD in the biogenesis of the trimeric autotransporters and reveal that BamB, BamC, BamE, TamA and TamB are not required for secretion of functional passenger domain on the cell surface.

Importance

The secretion of trimeric autotransporters (TAA’s) has yet to be fully understood. Here we show that efficient secretion of TAAs requires the BamA and D proteins, but does not require BamB, C or E. In contrast to classical autotransporter secretion, neither trimeric autotransporter tested required TamA or B proteins to be functionally secreted.
Using ESN-Smartphone Application to Maximize AIS Reperfusion Therapy in Alexandria Stroke Network: A Stroke Chain of Survival Organizational Model
Authors: Mansour Ossama Yassin , Ramadan Ismail , Elfatatry Amer , Hamdi Mohamed , Abudu Ashraf , Hassan Tamer , Eldeeb Hany , Marouf Hazem , Mogahed Mohamed , Farouk Mohamed , Abas Mohamed , Hamed Mervat , Afify Mohamed , Abdallah Tamer , Zaidat Osama
Published: February 2021

Background: In developing countries like Egypt, the clinical workflow of stroke management is poorly established due to the lack of awareness of the stroke patients concerning their need of therapeutic intervention and the poor identification of facilities equipped to treat stroke. Hence, establishing a stroke system of care in developing countries that can efficiently and rapidly triage patients to the appropriate reperfusion therapy center is imperative to improving stroke management and outcomes.

Aims: To evaluate a pilot experience in stroke hospital identification and expediting decision-making in AIS treatment through the Alexandria stroke network and Egyptian Stroke Network (ESN)-app.

Methods: Between 2017 and 2019, seven hospitals registered themselves on the AS-Network as pilot hospitals. The ESN-application was used to detect stroke type, tele-connect stroke teams and hospitals, track triage of patients to equipped facility in real time, and streamline stroke workflow. The quality of and time required for stroke management were compared between 84 patients with acute ischemic stroke (AIS) whose treatment involved the ESN-app and 276 patients whose treatment did not.

Results: During this pilot study, 360 AIS cases received reperfusion therapy, 84 of which were indicated by the ESN-app. The use of the application was associated with the significant drop in time metrics for the reperfusion AIS-patients (door-in-door-out time; 56 ± 34 min vs. 96 ± 45 min, door-to-groin puncture time; 50 ± 7 min vs. 120 ± 25 min, door-to-needle time; 55 ± 12 min vs. 78 ± 16 min with p < 0.0001). Its use was also associated with higher rates of excellent outcomes at the 90-day follow-up (without ESN-app vs. with ESN-app, 67.9 vs. 47.1%, p = 0.001) but no difference in 90-day mortality or symptomatic intracerebral hemorrhage (without ESN-app vs. with ESN-app, 9.5 vs. 11.2% and 4.8 vs. 5.1%, p > 0.05).

Conclusion: Our pilot experience demonstrated that the use of the ESN-app expedited the stroke treatment workflow and facilitated tele-connection between registered stroke facilities. Additionally, its use might be associated with achieving higher rates of excellent outcomes at 90 days, where a larger scale study is needed for more confirmation.
Examining Criteria for Defining Persistent Post-concussion Symptoms in Children and Adolescents
Authors: Iverson Grant L. , Karr Justin E. , Maxwell Bruce , Zafonte Ross , Berkner Paul D. , Cook Nathan E.
Published: February 2021

Researchers operationalize persistent post-concussion symptoms in children and adolescents using varied definitions. Many pre-existing conditions, personal characteristics, and current health issues can affect symptom endorsement rates in the absence of, or in combination with, a recent concussion, and the use of varied definitions can lead to differences in conclusions about persistent symptoms and recovery across studies. This study examined how endorsement rates varied by 14 different operational definitions of persistent post-concussion symptoms for uninjured boys and girls with and without pre-existing or current health problems. This cross-sectional study included a large sample (age range: 11–18) of girls (n = 21,923) and boys (n = 26,556) without a recent concussion who completed the Post-Concussion Symptom Scale at preseason baseline. Endorsements rates varied substantially by definition, health history, and current health issues. The most lenient definition (i.e., a single mild symptom) was endorsed by most participants (54.5% of boys/65.3% of girls). A large portion of participants with pre-existing mental health problems (42.7% of boys/51.5% of girls), current moderate psychological distress (70.9% of boys/72.4% of girls), and insufficient sleep prior to testing (33.4% of boys/47.6% of girls) endorsed symptoms consistent with mild ICD-10 postconcussional syndrome; whereas participants with no current or prior health problems rarely met this definition (1.6% of boys/1.6% of girls). The results illustrate the tremendous variability in the case definitions of persistent symptoms and the importance of harmonizing definitions across future studies.
RETRACTED: lncRNA-XLOC_012370 Promotes the Development of Pancreatic Cancer and Inactivates the NF-κB Pathway Through miR-140-5p
Authors: Nie Han-Xiao , Zhang Ling , He Tao , Wang Li , Wan Bai-Shun , Wang Xiao-Qian , Han Feng
Published: February 2021

Pancreatic cancer is a high incidence, high degree of malignancy, and high mortality in the digestive system tumor. The incidence of pancreatic cancer in China has increased nearly six folds in the past 20 years, ranking fifth in the mortality rate of malignant tumors, so it is particularly important to actively explore clinical indicators with better diagnostic significance for pancreatic cancer. LncRNA performs an essential regulatory function in the occurrence, development, and metastasis of many kinds of tumors, playing both a carcinogenic role and a tumor suppressor gene. Here, we demonstrated the function and mechanism of LncRNA-XLOC_012370 in the development of pancreatic cancer. In our research, the abnormal upregulation of XLOC_012370 was observed in pancreatic cancer patients’ tumor tissues. XLOC_012370 was related to tumor stage, lymph node metastasis, and overall survival. Silencing of XLOC_012370 prevented the proliferation, migration, and invasion via the NF-κB signal pathway. Further, miR-140-5p was identified as the target and downstream of XLOC_012370 and involved in pancreatic cancer progression. In vivo, knockdown of XLOC_012370 inhibited tumor growth via the NF-κB signal pathway. In conclusion, lncRNA-XLOC_012370 is closely related to some malignant clinicopathological features and prognosis of pancreatic cancer. Thus the miR-140-5p/NF-κB signal pathway might represent a promising treatment strategy to combat pancreatic cancer.
Application of Advanced Mass Spectrometry-Based Proteomics to Study Hypoxia Driven Cancer Progression
Authors: Vinaiphat Arada , Low Jee Keem , Yeoh Kheng Wei , Chng Wee Joo , Sze Siu Kwan
Published: February 2021

Cancer is one of the largest contributors to the burden of chronic disease in the world and is the second leading cause of death globally. It is associated with episodes of low-oxygen stress (hypoxia or ischemia/reperfusion) that promotes cancer progression and therapeutic resistance. Efforts have been made in the past using traditional proteomic approaches to decipher oxygen deprivation stress-related mechanisms of the disease initiation and progression and to identify key proteins as a therapeutic target for the treatment and prevention. Despite the potential benefits of proteomic in translational research for the discovery of new drugs, the therapeutic outcome with this approach has not met expectations in clinical trials. This is mainly due to the disease complexity which possess a multifaceted molecular pathology. Therefore, novel strategies to identify and characterize clinically important sets of modulators and molecular events for multi-target drug discovery are needed. Here, we review important past and current studies on proteomics in cancer with an emphasis on recent pioneered labeling approaches in mass spectrometry (MS)-based systematic quantitative analysis to improve clinical success. We also discuss the results of the selected innovative publications that integrate advanced proteomic technologies (e.g. MALDI-MSI, pSILAC/SILAC/iTRAQ/TMT-LC-MS/MS, MRM-MS) for comprehensive analysis of proteome dynamics in different biosystems, including cell type, cell species, and subcellular proteome (i.e. secretome and chromatome). Finally, we discuss the future direction and challenges in the application of these technological advancements in mass spectrometry within the context of cancer and hypoxia.