bluuebunny/crossref_metadata_2025 huggingface dataset:
ACTIVIDADES EXTRAESCOLARES EN MATEMÁTICAS PARA MEJORAR EL CÁLCULO MENTAL EN NIÑOS DE 7 AÑOS
Authors:   Universidad Técnica de Ambato, Álvarez Viera Patricia Elizabeth
Published: December 2020

Las actividades extraescolares en matemáticas surgen como una necesidad de ayudar a niños que no alcanzan las competencias, a mejorar su desempeño en esta área. El objetivo del estudio fue realizar varias actividades extraescolares con el fin de mejorar el cálculo mental en niños de 7 años. Se seleccionaron 14 niños, 9 niñas y 5 niños de 7 años. La intervención se efectuó en la Fundación Caminos del Sol durante 10 semanas, por dos horas por semana, durante los meses de mayo a julio de 2018. Se efectuaron actividades de repaso de tablas de sumas y restas, resolución de problemas de sumas, restas, combinación de sumas y restas y en cálculo mental. Los resultados determinaron que la intervención educativa mejoró el cálculo mental en los niños en un 80% más en el Postest con relación al Pretest. En conclusión, las actividades extraescolares en matemáticas ayudaron al desempeño de los niños en el cálculo mental
A High-promising Inquiry-based Lab Experience in Electronics Using Remote Labs for Higher Education Students
Authors:   Department of Military Science, Hellenic Army Academy, Vari, Greece, Gargalakos Michail , Sotiriou Sofoklis ,   Department of R&D, Greek-German Education, Pallini, Greece
Published: December 2020

Technology enhanced learning applications are used more and more in terms of curriculum in primary and secondary education as it has been shown that they have a positive impact to the learning outcome of youngsters. However, for tertiary education this is not the case, since more traditional methods of teaching are still dominant. Despite this fact, there are cases in which e-tools have been proven to be valuable for tertiary education, especially when the shortage of personnel and adequately equipped laboratories can become a serious obstacle for the teaching process. The recent pandemic has proven that technology can offer a unique channel for keep delivering lessons, seminars, and organizing meetings. Innovative interfaces can offer access to remote labs and offer the opportunity to deliver laboratory classes. The impact of the implementation of such e-tools has been carefully investigated using a large number of tertiary students (n > 100) and useful conclusions have been drawn, highlighting that the educational value of technology enhanced learning tools is generally underestimated in the field of tertiary education, especially, nowadays, that the pandemic has highlighted the added value of remote laboratories in the teaching process.
The Effect of PhET Simulation-based Instruction on 6th Grade Students’ Achievement Regarding the Concept of Greenhouse Gas
Authors:   Department of Science Education, Faculty of Education, Aksaray University, Aksaray, Turkey, Özcan Hasan , Çetin Gülcan ,   Department of Biology Education, Faculty of Necatibey Education, Balıkesir University, Balıkesir, Turkey, Koştur H. İlker ,   Department of Primary Education, Faculty of Education, Başkent University, Ankara, Turkey
Published: December 2020

This study investigated the effectiveness of simulation-based instruction on students’ greenhouse effect achievement. The simulations were chosen from the Physics Education Technology Project (PhET) website. The research was a pretest-posttest with a control group design quasi-experimental study. The sample of the study consisted of 45 6th grade students taking a science course in a secondary school from a city located in the Central Anatolia Region of Turkey in the 2017–2018 academic year. Participants were assigned randomly to control and experimental groups. There were 23 participants in the experimental group and 22 participants in the control group. While the control group was instructed with the constructive instructional methods, the experimental group was instructed by PhET simulation-based instruction over 1 week. Data were collected by the Greenhouse Effect Achievement Test. Independent samples t-test and paired samples t-test were used to analyze the data. The study results revealed that the PhET simulation-based instruction created a statistically significant difference between the control group and the experimental group in the students’ greenhouse effect in favor of the experimental group (p = 0.03).
High NESTIN Expression Marks the Endosteal Capillary Network in Human Bone Marrow
Authors: Panvini Francesca M. , Pacini Simone , Montali Marina , Barachini Serena , Mazzoni Stefano , Morganti Riccardo , Ciancia Eugenio M. , Carnicelli Vittoria , Petrini Mario
Published: December 2020

Hematopoiesis is hosted, supported and regulated by a special bone marrow (BM) microenvironment known as “niche.” BM niches have been classified based on micro-anatomic distance from the bone surface into “endosteal” and “central” niches. Whilst different blood vessels have been found in both BM niches in mice, our knowledge of the human BM architecture is much more limited. Here, we have used a combination of markers including NESTIN, CD146, and αSMA labeling different blood vessels in benign human BM. Applying immunohistochemical/immunofluorescence techniques on BM trephines and performing image analysis on almost 300 microphotographs, we detected high NESTIN expression in BM endothelial cells (BMECs) of small arteries (A) and endosteal arterioles (EA), and also in very small vessels we named NESTIN+capillary-like tubes (NCLTs), not surrounded by sub-endothelial perivascular cells that occasionally reported low levels of NESTIN expression. Statistically, NCLTs were detected within 40 μm from bone trabecula, frequently found in direct contact to the bone line and spatially correlated with hematopoietic stem/progenitor cells. Our results support the expression of NESTIN in human BMECs of EA and A in accordance with the updated classification of murine BM micro-vessels. NCLTs for their peculiar characteristics and micro-anatomical localization have been here proposed as transitional vessels possibly involved in regulating human hematopoiesis.
Long Non-coding RNA X-Inactive Specific Transcript Mediates Cell Proliferation and Intrusion by Modulating the miR-497/Bcl-w Axis in Extranodal Natural Killer/T-cell Lymphoma
Authors: Liu Qinhua , Ran Ruonan , Wu Zhengsheng , Li Xiaodan , Zeng Qingshu , Xia Ruixiang , Wang Yalei
Published: December 2020

The present study was directed toward laying new findings for Extranodal natural killer/T-cell lymphoma (ENKL)-oriented therapy with a focus on long non-coding RNA (lncRNA)–microRNAs (miRNAs)–mRNA interaction. The expression and function of XIST (X-inactive specific transcript) were analyzed both in vivo and in vitro. The online database of lncRNA-miRNA interaction was used to screen the target of XIST, and miR-497 was selected. Next, the predicted binding between XIST and miR-497, and the dynamic effect of XIST and miR-497 on downstream Bcl-w was evaluated. We found that XIST dramatically increased in the blood of ENKL patients and cell lines. XIST knockdown suppressed the cell proliferation and migration in vivo and in vitro. Herein, we confirmed the negative interaction between XIST and miR-497. Moreover, XIST knockdown reduced the protein levels of Bcl-w, a downstream target of miR-497. XIST sponges miR-497 to promote Bcl-w expression, and finally modulating ENKL cell proliferation and migration. To be interested, inhibition of Bcl-w by ABT737 can overcome the high expression of XIST, and suppressed the ENKL proliferation and migration by inducing apoptosis. This study provided a novel experimental basis for ENKL-oriented therapy with a focus on the lncRNA–miRNA–mRNA interaction.
A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway
Authors: Wang Yulu , Gao Shichao , Zheng Victor , Chen Ling , Ma Min , Shen Shichen , Qu Jun , Zhang Hanting , Gurney Mark E. , O’Donnell James M. , Xu Ying
Published: December 2020

A global, quantitative proteomics/systems-biology analysis of the selective pharmacological inhibition of phosphodiesterase-4D (PDE4D) revealed the differential regulation of pathways associated with neuroplasticity in memory-associated brain regions. Subtype selective inhibitors of PDE4D bind in an allosteric site that differs between mice and humans in a single amino acid (tyrosine vs. phenylalanine, respectively). Therefore to study selective inhibition of PDE4D by BPN14770, a subtype selective allosteric inhibitor of PDE4D, we utilized a line of mice in which the PDE4D gene had been humanized by mutating the critical tyrosine to phenylalanine. Relatively low doses of BPN14770 were effective at reversing scopolamine-induced memory and cognitive deficits in humanized PDE4D mice. Inhibition of PDE4D alters the expression of protein kinase A (PKA), Sirt1, Akt, and Bcl-2/Bax which are components of signaling pathways for regulating endocrine response, stress resistance, neuronal autophagy, and apoptosis. Treatment with a series of antagonists, such as H89, sirtinol, and MK-2206, reversed the effect of BPN14770 as shown by behavioral tests and immunoblot analysis. These findings suggest that inhibition of PDE4D enhances signaling through the cAMP-PKA-SIRT1-Akt -Bcl-2/Bax pathway and thereby may provide therapeutic benefit in neurocognitive disorders.
The Developmental Phenotype of the Great Toe in Fibrodysplasia Ossificans Progressiva
Authors: Towler O. Will , Kaplan Frederick S. , Shore Eileen M.
Published: December 2020

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder in which extensive heterotopic ossification (HO) begins to form during early childhood and progresses throughout life. Although HO does not occur during embryonic development, children who carry the ACVR1R206H mutation that causes most cases of FOP characteristically exhibit malformation of their great toes at birth, indicating that the mutation acts during embryonic development to alter skeletal formation. Despite the high prevalence of the great toe malformation in the FOP population, it has received relatively little attention due to its clinically benign nature. In this study, we examined radiographs from a cohort of 41 FOP patients ranging from 2 months to 48 years of age to provide a detailed analysis of the developmental features, progression, and variability of the great toe malformation of FOP, which include absent skeletal structures, malformed epiphyses, ectopic ossification centers, malformed first metatarsals and phalangeal fusion.
Molecular Basis for CCRL2 Regulation of Leukocyte Migration
Authors: Schioppa Tiziana , Sozio Francesca , Barbazza Ilaria , Scutera Sara , Bosisio Daniela , Sozzani Silvano , Del Prete Annalisa
Published: December 2020

CCRL2 is a seven-transmembrane domain receptor that belongs to the chemokine receptor family. At difference from other members of this family, CCRL2 does not promote chemotaxis and shares structural features with atypical chemokine receptors (ACKRs). However, CCRL2 also differs from ACKRs since it does not bind chemokines and is devoid of scavenging functions. The only commonly recognized CCRL2 ligand is chemerin, a non-chemokine chemotactic protein. CCRL2 is expressed both by leukocytes and non-hematopoietic cells. The genetic ablation of CCRL2 has been instrumental to elucidate the role of this receptor as positive or negative regulator of inflammation. CCRL2 modulates leukocyte migration by two main mechanisms. First, when CCRL2 is expressed by barrier cells, such endothelial, and epithelial cells, it acts as a presenting molecule, contributing to the formation of a non-soluble chemotactic gradient for leukocytes expressing CMKLR1, the functional chemerin receptor. This mechanism was shown to be crucial in the induction of NK cell-dependent immune surveillance in lung cancer progression and metastasis. Second, by forming heterocomplexes with other chemokine receptors. For instance, CCRL2/CXCR2 heterodimers were shown to regulate the activation of β2-integrins in mouse neutrophils. This mini-review summarizes the current understanding of CCRL2 biology, based on experimental evidence obtained by the genetic deletion of this receptor in in vivo experimental models. Further studies are required to highlight the complex functional role of CCRL2 in different organs and pathological conditions.
Controlled Growth of CdS Nanostep Structured Arrays to Improve Photoelectrochemical Performance
Authors: Jiang Jiangang , Wang He , An Hongchang , Du Guangyuan
Published: December 2020

CdS nanostep-structured arrays were grown on F-doped tin oxide-coated glasses using a two-step hydrothermal method. The CdS arrays consisted of a straight rod acting as backbone and a nanostep-structured morphology on the surface. The morphology of the samples can be tuned by varying the reaction parameters. The phase purity, morphology, and structure of the CdS nanostep-structured arrays were characterized by X-ray diffraction and field emission scanning electron microscopy. The light and photoelectrochemical properties of the samples were estimated by a UV-Vis absorption spectrum and photoelectrochemical cells. The experimental results confirmed that the special nanostep structure is crucial for the remarkable enhancement of the photoelectrochemical performance. Compared with CdS rod arrays, the CdS nanostep-structured arrays showed increased absorption ability and dramatically improved photocurrent and energy conversion efficiency. This work may provide a new approach for improving the properties of photoelectrodes in the future.
The Effects of Gene Duplication Modes on the Evolution of Regulatory Divergence in Wild and Cultivated Soybean
Authors: Zhao Na , Ding Xiaoyang , Lian Taotao , Wang Meng , Tong Yan , Liang Di , An Qi , Sun Siwen , Jackson Scott A. , Liu Bao , Xu Chunming
Published: December 2020

Regulatory changes include divergence in bothcis-elements andtrans-factors, which play roles in organismal evolution. Whole genome duplications (WGD) followed by diploidization are a recurrent feature in the evolutionary history of angiosperms. Prior studies have shown that duplicated genes have different evolutionary fates due to variable selection constraints and results in genomic compositions with hallmarks of paleopolyploidy. The recent sequential WGDs and post-WGD evolution in the common ancestor of cultivated soybean (Glycine max) and wild soybean (Glycine soja), together with other models of gene duplication, have resulted in a highly duplicated genome. In this study, we investigated the transcriptional changes inG. sojaandG. max. We identified a sizable proportion of interspecific differentially expressed genes (DEGs) and found parental expression level dominance ofG. maxin their F1 hybrids. By classifying genes into different regulatory divergence types, we found thetrans-regulatory changes played a predominant role in transcriptional divergence between wild and cultivated soybean. The same gene ontology (GO) and protein family (Pfam) terms were found to be over-represented in DEGs and genes ofcis-only between JY47 and GS, suggesting the substantial contribution ofcis-regulatory divergences to the evolution of wild and cultivated soybeans. By further dissecting genes into five different duplication modes, we found genes in different duplication modes tend to accumulate different types of regulatory differences. A relatively higher proportion ofcis-only regulatory divergences was detected in singleton, dispersed, proximal, and tandem duplicates than WGD duplicates and genome-wide level, which is in line with the prediction of gene balance hypothesis for the differential fates of duplicated genes post-WGD. The numbers ofcis-only andtrans-only regulated genes were similar for singletons, whereas there were more genes oftrans-only thancis-only in the rest duplication types, especially in WGD in which there were two times moretrans-only genes than that incis-only type. Tandem duplicates showed the highest proportion oftrans-only genes probably due to some special features of this class. In summary, our results demonstrate that genes in different duplication modes have different fates in transcriptional evolution underpinned bycis- ortrans-regulatory divergences in soybean and likely in other paleopolyploid higher organisms.
Structural and Functional Characteristics of miRNAs in Five Strategic Millet Species and Their Utility in Drought Tolerance
Authors: Chakraborty Animikha , Viswanath Aswini , Malipatil Renuka , Rathore Abhishek , Thirunavukkarasu Nepolean
Published: December 2020

Millets are the strategic food crops in arid and drought-prone ecologies. Millets, by virtue of nature, are very well-adapted to drought conditions and able to produce sustainable yield. Millets have important nutrients that can help prevent micro-nutrient malnutrition. As a result of the adverse effect of climate change and widespread malnutrition, millets have attained a strategic position to sustain food and nutritional security. Although millets can adapt well to the drought ecologies where other cereals fail completely, the yield level is very low under stress. There is a tremendous opportunity to increase the genetic potential of millet crops in dry lands when the genetics of the drought-tolerance mechanism is fully explained. MicroRNAs (miRNAs) are the class of small RNAs that control trait expression. They are part of the gene regulation but little studied in millets. In the present study, novel miRNAs and gene targets were identified from the genomic resources of pearl millet, sorghum, foxtail millet, finger millet, and proso millet through in silico approaches. A total of 1,002 miRNAs from 280 families regulating 23,158 targets were identified using different filtration criteria in five millet species. The unique as well as conserved structural features and functional characteristics of miRNA across millets were explained. About 84 miRNAs were conserved across millets in different species combinations, which explained the evolutionary relationship of the millets. Further, 215 miRNAs controlling 155 unique major drought-responsive genes, transcription factors, and protein families revealed the genetics of drought tolerance that are accumulated in the millet genomes. The miRNAs regulating the drought stress through specific targets or multiple targets showed through a network analysis. The identified genes regulated by miRNA genes could be useful in developing functional markers and used for yield improvement under drought in millets as well as in other crops.
Corticosterone Enhances the AMPK-Mediated Immunosuppressive Phenotype of Testicular Macrophages During Uropathogenic Escherichia coli Induced Orchitis
Authors: Zhang Zhengguo , Jiang Ziming , Zhang Yiming , Zhang Yu , Yan Yan , Bhushan Sudhanshu , Meinhardt Andreas , Qin Zhihai , Wang Ming
Published: December 2020

Testicular macrophages (TM) play a central role in maintaining testicular immune privilege and protecting spermatogenesis. Recent studies showed that their immunosuppressive properties are maintained by corticosterone in the testicular interstitial fluid, but the underlying molecular mechanisms are unknown. In this study, we treated mouse bone marrow-derived macrophages (BMDM) with corticosterone (50 ng/ml) and uncovered AMP-activated protein kinase (AMPK) activation as a critical event in M2 polarization at the phenotypic, metabolic, and cytokine production level. Primary TM exhibited remarkably similar metabolic and phenotypic features to corticosterone-treated BMDM, which were partially reversed by AMPK-inhibition. In a murine model of uropathogenic E. coli-elicited orchitis, intraperitoneal injection with corticosterone (0.1mg/day) increased the percentage of M2 TM in vivo, in a partially AMPK-dependent manner. This study integrates the influence of corticosterone on M2 macrophage metabolic pathways, phenotype, and function, and highlights a promising new avenue for the development of innovative therapeutics for orchitis patients.
Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success
Authors: Silvis Max J. M. , Kaffka genaamd Dengler Selma E. , Odille Clémence A. , Mishra Mudit , van der Kaaij Niels P. , Doevendans Pieter A. , Sluijter Joost P. G. , de Kleijn Dominique P. V. , de Jager Saskia C. A. , Bosch Lena , van Hout Gerardus P. J.
Published: December 2020

In the setting of myocardial infarction (MI), ischemia reperfusion injury (IRI) occurs due to occlusion (ischemia) and subsequent re-establishment of blood flow (reperfusion) of a coronary artery. A similar phenomenon is observed in heart transplantation (HTx) when, after cold storage, the donor heart is connected to the recipient’s circulation. Although reperfusion is essential for the survival of cardiomyocytes, it paradoxically leads to additional myocardial damage in experimental MI and HTx models. Damage (or danger)-associated molecular patterns (DAMPs) are endogenous molecules released after cellular damage or stress such as myocardial IRI. DAMPs activate pattern recognition receptors (PRRs), and set in motion a complex signaling cascade resulting in the release of cytokines and a profound inflammatory reaction. This inflammatory response is thought to function as a double-edged sword. Although it enables removal of cell debris and promotes wound healing, DAMP mediated signalling can also exacerbate the inflammatory state in a disproportional matter, thereby leading to additional tissue damage. Upon MI, this leads to expansion of the infarcted area and deterioration of cardiac function in preclinical models. Eventually this culminates in adverse myocardial remodeling; a process that leads to increased myocardial fibrosis, gradual further loss of cardiomyocytes, left ventricular dilation and heart failure. Upon HTx, DAMPs aggravate ischemic damage, which results in more pronounced reperfusion injury that impacts cardiac function and increases the occurrence of primary graft dysfunction and graft rejection via cytokine release, cardiac edema, enhanced myocardial/endothelial damage and allograft fibrosis. Therapies targeting DAMPs or PRRs have predominantly been investigated in experimental models and are potentially cardioprotective. To date, however, none of these interventions have reached the clinical arena. In this review we summarize the current evidence of involvement of DAMPs and PRRs in the inflammatory response after MI and HTx. Furthermore, we will discuss various current therapeutic approaches targeting this complex interplay and provide possible reasons why clinical translation still fails.
Immovable Object Meets Unstoppable Force? Dialogue Between Resident and Peripheral Myeloid Cells in the Inflamed Brain
Authors: Spiteri Alanna G. , Wishart Claire L. , King Nicholas J. C.
Published: December 2020

Inflammation of the brain parenchyma is characteristic of neurodegenerative, autoimmune, and neuroinflammatory diseases. During this process, microglia, which populate the embryonic brain and become a permanent sentinel myeloid population, are inexorably joined by peripherally derived monocytes, recruited by the central nervous system. These cells can quickly adopt a morphology and immunophenotype similar to microglia. Both microglia and monocytes have been implicated in inducing, enhancing, and/or maintaining immune-mediated pathology and thus disease progression in a number of neuropathologies. For many years, experimental and analytical systems have failed to differentiate resident microglia from peripherally derived myeloid cells accurately. This has impeded our understanding of their precise functions in, and contributions to, these diseases, and hampered the development of novel treatments that could target specific cell subsets. Over the past decade, microglia have been investigated more intensively in the context of neuroimmunological research, fostering the development of more precise experimental systems. In light of our rapidly growing understanding of these cells, we discuss the differential origins of microglia and peripherally derived myeloid cells in the inflamed brain, with an analysis of the problems resolving these cell types phenotypically and morphologically, and highlight recent developments enabling more precise identification.
CD8+ T Cells Directed Against a Peptide Epitope Derived From Peptidoglycan-Associated Lipoprotein of Legionella pneumophila Confer Disease Protection
Authors: Kim Sun Jin , Sin Jeong-Im , Kim Min Ja
Published: December 2020

Legionella pneumophila, an intracellular bacterium, may cause life-threatening pneumonia in immunocompromised individuals. Mononuclear cells and antibodies have been reported to be associated with the host defense response againstL. pneumophila.This study is to determine whetherLegionellapeptidoglycan-associated lipoprotein (PAL)-specific CD8+T cells are directly associated with protection againstL. pneumophila, with a focus on potential epitopes. Synthetic peptides derived from PAL ofL. pneumophilawere obtained and tested through invitroandin vivocytotoxic T lymphocyte (CTL) assays for immunogenicity. PAL DNA vaccines or a peptide epitope with or without CpG-oligodeoxynucleotides (ODN) was evaluated for protection againstL. pneumophilainfection in animal models. When mice were immunized with DNA vaccines expressing the PAL ofL. pneumophila, they were significantly protected against a lethal challenge withL. pneumophilathrough induction of antigen-specific CD8+CTLs. Of the 13 PAL peptides tested, PAL92-100(EYLKTHPGA) was the most immunogenic and induced the strongest CTL responses. When mice were immunized with the PAL92-100peptide plus CpG-ODN, they were protected against the lethal challenge, while control mice died within 3–6 days after the challenge. Consistent with lung tissue histological data, bacterial counts in the lungs of immunized mice were significantly lower than those in control mice. Also, the amino acid sequence of PAL92-100peptides is conserved among variousLegionellaspecies. To our knowledge, this study is the first to demonstrate that PAL92-100-specific CD8+T cells play a central role in the host defense response againstL. pneumophila.
Pregnancy Outcomes in Patients With Adult-Onset Still's Disease: A Cohort Study From China
Authors: Wang Zhihong , Chi Huihui , Feng Tienan , Du Qinwen , Zeng Ting , Teng Jialin , Liu Honglei , Cheng Xiaobing , Ye Junna , Shi Hui , Sun Yue , Hu Qiongyi , Jia Jinchao , Liu Tingting , Wan Liyan , Wu Xinyao , Zhou Zhuochao , Yang Chengde , Su Yutong
Published: December 2020

Objective: Adult-onset Still's disease (AOSD) is an autoinflammatory disease with a higher prevalence rate in young females. The purpose of this study is to investigate whether AOSD has an adverse impact on pregnancy outcomes, or conversely exacerbated by pregnancy.

Methods: The outcomes of 191 pregnancies were evaluated in 86 female patients with AOSD. The generalized linear mixed model and propensity score matching method were conducted to evaluate the influence of AOSD on pregnancy outcomes. A dependent sample sign test was applied to assess the impact of pregnancy on the relapse of AOSD.

Results: The results showed that the post-AOSD group had a lower proportion of normal delivery (25.0 vs. 52.4%, p = 0.036) and a higher proportion of spontaneous abortion (STA) (18.8 vs. 0.6%, p = 0.002) compared with the pre-AOSD group. Moreover, pregnancy after being diagnosed with AOSD was a significant high risk factor of STA (adjusted OR = 4.577, 95% CI: 4.166–845.119; p = 0.003). Disease flare upon conception was observed in one of 16 post-AOSD pregnancies (p = 1.000). There were 11 patients with new-onset AOSD during gestation or postpartum, among which five (45.4%) evolved into the polycyclic course.

Conclusions: AOSD patients might suffer from a higher risk of STA, however, pregnancy might not be related with the exacerbation of diagnosed AOSD. New-onset AOSD during gestation or postpartum tend to evolve into the polycyclic course.
Fast-Track Ultrasound Clinic for the Diagnosis of Giant Cell Arteritis Changes the Prognosis of the Disease but Not the Risk of Future Relapse
Authors: Monti Sara , Bartoletti Alice , Bellis Elisa , Delvino Paolo , Montecucco Carlomaurizio
Published: December 2020

Background: Color Duplex sonography (CDS) of temporal arteries and large vessels (LV) is a recently validated diagnostic methodology for Giant Cell Arteritis (GCA). CDS combined with a fast-track approach (FTA) has improved the early diagnosis of the disease.

Objectives: To assess FTA effects on the prevention of permanent visual loss (PVL), relapse and late complications of GCA compared to conventional practice. To assess the impact of COVID-19 pandemic on outcomes of GCA patients assessed with FTA.

Methods: GCA patients diagnosed up to June 2020 at the Rheumatology Department, University of Pavia, were included. FTA was implemented since October 2016. FTA consists in the referral within 1 working day of a suspected GCA case to an expert rheumatologist who performs clinical evaluation and CDS.

Results: One hundred sixty patients were recruited [female 120 (75%), mean age 72.4 ± 8.2 years]. Sixty-three (39.4%) evaluated with FTA, 97 (60.6%) with conventional approach. FTA patients were older (75.1 ± 7.6 vs. 70.6 ± 8.2 years old; p < 0.001). Median follow-up duration was shorter in the FTA group compared to the conventional one (0.9 vs. 5.0 years; p < 0.001). There was no difference between the two cohorts regarding major vessel district involvement (LV-GCA 17.5% vs. 22.7%; p = 0.4). PVL occurred in 8 (12.7%) FTA patients and 26 (26.8%) conventional ones (p = 0.03). The relative risk of blindness in the conventional group was 2.11 (95% C.I. 1.02–4.36; P = 0.04) as compared to FTA. Median symptom latency of patients experiencing PVL was higher in the conventional group (23 days IQR 12–96 vs. 7 days IQR 4–10, p = 0.02). During COVID-19 there was a significant increase in the occurrence of PVL (40%) including bilateral blindness despite a regularly operating FTA clinic. Cumulative incidence of relapses and time to first relapse did not change after FTA introduction (P = 0.2). No difference in late complications (stenosis/aneurysms) was detected.

Conclusions: FTA including CDS evaluation contributed to a substantial reduction of PVL in GCA by shortening the time to diagnosis and treatment initiation. Relapse rate did not change upon FTA introduction, highlighting the need for better disease activity monitoring and treatment strategies optimization based on risk stratification that would predict the occurrence of relapse during glucocorticoid de-escalation.
Butyrate Mitigates Weanling Piglets From Lipopolysaccharide-Induced Colitis by Regulating Microbiota and Energy Metabolism of the Gut–Liver Axis
Authors: Han Yunsheng , Zhao Qingyu , Tang Chaohua , Li Ying , Zhang Kai , Li Fadi , Zhang Junmin
Published: December 2020

Inflammatory bowel disorder is accompanied by the destruction of immunity homeostasis, gut microbiota perturbation, and chronic inflammatory liver diseases. Butyrate is known as a primary energy source for colonocytes and functional substances for mitigating pathological features of colitis. However, it is still unclear whether butyrate alleviates colitis progression by regulation of microbiota and metabolism in the gut–liver axis. In the present study, we aimed to determine the role of microbiota and metabolism of the gut–liver axis in ameliorating lipopolysaccharide (LPS)-induced colitis in piglets using protected butyrate administration. Eighteen crossbred male piglets were weaned at 30 days old and were randomly allocated to three treatments, with CON (basal diet), LPS (basal diet + LPS), and BT-LPS (basal diet + 3.0 g/kg protected butyrate + LPS). On days 19 and 21, piglets in the LPS and BT-LPS groups were intraperitoneally challenged with LPS at 100 μg/kg body weight. Butyrate administration significantly decreased LPS-induced rise in the clinical score of piglets and colonic histological scores and reduced the susceptibility to LPS-induced severe inflammatory response by decreasing proinflammatory (IL-1β, IL-6, IL-8, and TNF-α) cytokines. Butyrate supplementation accelerated the prevalence of Faecalibacterium and Lactobacillus by enhancing the tricarboxylic acid (TCA) cycle of colonocytes. Dietary supplementation with protected butyrate significantly targeted increased concentrations of butyric acid in the colon and portal venous circulation, and enhanced the TCA cycle in the gut–liver axis by mobilizing amino acid and vitamin B group as a coenzyme. Meanwhile, during this progress, LPS increased fatty acid synthesis that was reversed by butyrate treatment, which was reflected by decreased acylcarnitines. Butyrate-reshaped colonic microbial community and metabolism in the gut–liver axis contributed to morphology integrity and immunity homeostasis by promoting anti-inflammatory (IL-10 and TGF-β) cytokines and suppressing inflammatory mediator hypoxia-inducible factor 1α and its downstream response elements cyclooxygenase 2 and inducible nitric oxide synthase. These results identified the pivotal role of colonic microbiota and metabolism in the gut–liver axis for alleviating inflammatory progression and possible therapeutic targets.
Phosphatase and Tensin Homolog Mutation in Immune Cell Infiltration and Clinicopathological Features of Low-Grade Gliomas
Authors: Feng Peng , Li Zhenqing , Li Yuchen , Zhang Yuelin
Published: December 2020

The mutation of phosphatase and tensin homolog (PTEN) genes frequently occur in low-grade gliomas (LGGs) and are deeply associated with a poor prognosis and survival rate. In order to identify the crucial signaling pathways and genes associated with the PTEN mutation, we performed bioinformatics analysis on the RNA sequencing results, which were obtained from The Cancer Genome Atlas database. A total of 352 genes were identified as differentially expressed genes (DEGs). The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the DEGs were significantly enriched in categories associated with cell division and multiple metabolic progressions. The histological stage was significantly associated with PTEN expression levels. In addition, the PTEN mutation was associated with an abundance of B cells, neutrophils, macrophages, dendritic cells, and CD8+ T cells during tumor infiltration. The results showed that patients with LGGs harboring the PTEN mutation had a poor prognosis and more serious immune cell infiltration occurred depending on the mRNA expression level. These results demonstrated that multiple genes and signaling pathways play a key role in LGG from low grade to high grade, and are associated with PTEN mutations. In this study, we outlined an approach to assess the influence of PTEN mutations on prognosis, overall survival, and messenger RNA (mRNA) expression. Our results provided alternative strategies for the personalized treatment of patients with LGGs harboring the PTEN mutation.
Delayed Comparison and Apriori Algorithm (DCAA): A Tool for Discovering Protein–Protein Interactions From Time-Series Phosphoproteomic Data
Authors: Ding Lianhong , Xie Shaoshuai , Zhang Shucui , Shen Hangyu , Zhong Huaqiang , Li Daoyuan , Shi Peng , Chi Lianli , Zhang Qunye
Published: December 2020

Analysis of high-throughput omics data is one of the most important approaches for obtaining information regarding interactions between proteins/genes. Time-series omics data are a series of omics data points indexed in time order and normally contain more abundant information about the interactions between biological macromolecules than static omics data. In addition, phosphorylation is a key posttranslational modification (PTM) that is indicative of possible protein function changes in cellular processes. Analysis of time-series phosphoproteomic data should provide more meaningful information about protein interactions. However, although many algorithms, databases, and websites have been developed to analyze omics data, the tools dedicated to discovering molecular interactions from time-series omics data, especially from time-series phosphoproteomic data, are still scarce. Moreover, most reported tools ignore the lag between functional alterations and the corresponding changes in protein synthesis/PTM and are highly dependent on previous knowledge, resulting in high false-positive rates and difficulties in finding newly discovered protein–protein interactions (PPIs). Therefore, in the present study, we developed a new method to discover protein–protein interactions with the delayed comparison and Apriori algorithm (DCAA) to address the aforementioned problems. DCAA is based on the idea that there is a lag between functional alterations and the corresponding changes in protein synthesis/PTM. The Apriori algorithm was used to mine association rules from the relationships between items in a dataset and find PPIs based on time-series phosphoproteomic data. The advantage of DCAA is that it does not rely on previous knowledge and the PPI database. The analysis of actual time-series phosphoproteomic data showed that more than 68% of the protein interactions/regulatory relationships predicted by DCAA were accurate. As an analytical tool for PPIs that does not rely on a priori knowledge, DCAA should be useful to predict PPIs from time-series omics data, and this approach is not limited to phosphoproteomic data.
The Chemical Basis of Intracerebral Hemorrhage and Cell Toxicity With Contributions From Eryptosis and Ferroptosis
Authors: Derry Paul J. , Vo Anh Tran Tram , Gnanansekaran Aswini , Mitra Joy , Liopo Anton V. , Hegde Muralidhar L. , Tsai Ah-Lim , Tour James M. , Kent Thomas A.
Published: December 2020

Intracerebral hemorrhage (ICH) is a particularly devastating event both because of the direct injury from space-occupying blood to the sequelae of the brain exposed to free blood components from which it is normally protected. Not surprisingly, the usual metabolic and energy pathways are overwhelmed in this situation. In this review article, we detail the complexity of red blood cell degradation, the contribution of eryptosis leading to hemoglobin breakdown into its constituents, the participants in that process, and the points at which injury can be propagated such as elaboration of toxic radicals through the metabolism of the breakdown products. Two prominent products of this breakdown sequence, hemin, and iron, induce a variety of pathologies including free radical damage and DNA breakage, which appear to include events independent from typical oxidative DNA injury. As a result of this confluence of damaging elements, multiple pathways of injury, cell death, and survival are likely engaged including ferroptosis (which may be the same as oxytosis but viewed from a different perspective) and senescence, suggesting that targeting any single cause will likely not be a sufficient strategy to maximally improve outcome. Combination therapies in addition to safe methods to reduce blood burden should be pursued.
Multivariate Brain Functional Connectivity Through Regularized Estimators
Authors: Salvador Raymond , Verdolini Norma , Garcia-Ruiz Beatriz , Jiménez Esther , Sarró Salvador , Vilella Elisabet , Vieta Eduard , Canales-Rodríguez Erick Jorge , Pomarol-Clotet Edith , Voineskos Aristotle N.
Published: December 2020

Functional connectivity analyses are typically based on matrices containing bivariate measures of covariability, such as correlations. Although this has been a fruitful approach, it may not be the optimal strategy to fully explore the complex associations underlying brain activity. Here, we propose extending connectivity to multivariate functions relating to the temporal dynamics of a region with the rest of the brain. The main technical challenges of such an approach are multidimensionality and its associated risk of overfitting or even the non-uniqueness of model solutions. To minimize these risks, and as an alternative to the more common dimensionality reduction methods, we propose using two regularized multivariate connectivity models. On the one hand, simple linear functions of all brain nodes were fitted with ridge regression. On the other hand, a more flexible approach to avoid linearity and additivity assumptions was implemented through random forest regression. Similarities and differences between both methods and with simple averages of bivariate correlations (i.e., weighted global brain connectivity) were evaluated on a resting state sample of N = 173 healthy subjects. Results revealed distinct connectivity patterns from the two proposed methods, which were especially relevant in the age-related analyses where both ridge and random forest regressions showed significant patterns of age-related disconnection, almost completely absent from the much less sensitive global brain connectivity maps. On the other hand, the greater flexibility provided by the random forest algorithm allowed detecting sex-specific differences. The generic framework of multivariate connectivity implemented here may be easily extended to other types of regularized models.
Biomechanical Forces Regulate Gene Transcription During Stretch-Mediated Growth of Mammalian Neurons
Authors: Loverde Joseph R. , Tolentino Rosa E. , Soteropoulos Patricia , Pfister Bryan J.
Published: December 2020

At birth, there are 100 billion neurons in the human brain, with functional neural circuits extending through the spine to the epidermis of the feet and toes. Following birth, limbs and vertebrae continue to grow by several orders of magnitude, forcing established axons to grow by up to 200 cm in length without motile growth cones. The leading regulatory paradigm suggests that biomechanical expansion of mitotic tissue exerts tensile force on integrated nervous tissue, which synchronizes ongoing growth of spanning axons. Here, we identify unique transcriptional changes in embryonic rat DRG and cortical neurons while the corresponding axons undergo physiological levels of controlled mechanical stretchin vitro. Using bioreactors containing cultured neurons, we recapitulated the peak biomechanical increase in embryonic rat crown-rump-length. Biologically paired sham and “stretch-grown” DRG neurons spanned 4.6- and 17.2-mm in length following static or stretch-induced growth conditions, respectively, which was associated with 456 significant changes in gene transcription identified by genome-wide cDNA microarrays. Eight significant genes found in DRG were cross-validated in stretch-grown cortical neurons by qRT-PCR, which included upregulation ofGpat3, Crem, Hmox1, Hpse, Mt1a, Nefm,Sprr1b, and downregulation ofNrep.The results herein establish a link between biomechanics and gene transcription in mammalian neurons, which elucidates the mechanism underlying long-term growth of axons, and provides a basis for new research in therapeutic axon regeneration.
Prognostic Value of Local Treatment in Prostate Cancer Patients With Different Metastatic Sites: A Population Based Retrospective Study
Authors: Jin Shengming , Wei Jiaming , Wang Junjie , Wang Beihe , Wu Junlong , Gan Hualei , Dai Bo , Qin Xiaojian , Lin Guowen , Wei Yu , Yang Chen , Shen Yijun , Zhu Yiping , Zhu Yao , Ye Dingwei
Published: December 2020

Purpose

Our study aims to examine the impact of definitive local therapy in prostate cancer patients with different metastatic sites.

Methods

Totally, 5,849 patients diagnosed with metastatic prostate carcinoma from 2010 to 2014 were selected from Surveillance, Epidemiology, and End Results (SEER). Log-rank analyses, multivariable regression analysis, and Kaplan–Meier methods were used to assess prognostic impact of local treatment in patients with different metastatic sites. Survival curves and forest plots were also plotted to describe the prognostic value of definitive local therapy.

Results

In our study, 159 patients received radical prostatectomy, and 62 received brachytherapy, while 5,628 did not receive local definitive local therapy. Survival analysis revealed that patients who received definitive local therapy had a better 5-year overall survival (OS) (P = 0.011) and cancer-specific survival (CSS) (P = 0.012). Multivariate regression analyses demonstrated that type of treatment was an independent prognostic indicator for OS (P = 0.011) and CSS (P = 0.012), along with age at diagnosis, chemotherapy, PSA level, and Gleason score. According to subgroup analysis, patients with bone metastasis or distant lymph node (LN) metastasis were significantly more likely to benefit from definitive local therapy. In addition, forest plots demonstrated that RP group had significant favorable OS and CSS in subgroups of younger age at diagnosis, T2–3 stage, N0–1 stage, Gleason score =7 or ≥8, bone metastasis, and distant LN metastasis.

Conclusions

Our study suggested that local therapy improved survival in prostate cancer patients with bone or distant LN metastasis. Furthermore, patients who were at T2–3 stage or Gleason score ≥7 also significantly benefit from definitive local therapy.
A Hematological-Related Prognostic Scoring System for Patients With Newly Diagnosed Glioblastoma
Authors: Zhao Chao , Li Long-Qing , Yang Feng-Dong , Wei Ruo-Lun , Wang Min-Kai , Song Di-Xiang , Guo Xiao-Yue , Du Wei , Wei Xin-Ting
Published: December 2020

Background

Glioblastoma is the most common primary malignant brain tumor. Recent studies have shown that hematological biomarkers have become a powerful tool for predicting the prognosis of patients with cancer. However, most studies have only investigated the prognostic value of unilateral hematological markers. Therefore, we aimed to establish a comprehensive prognostic scoring system containing hematological markers to improve the prognostic prediction in patients with glioblastoma.

Patients and Methods

A total of 326 patients with glioblastoma were randomly divided into a training set and external validation set to develop and validate a hematological-related prognostic scoring system (HRPSS). The least absolute shrinkage and selection operator Cox proportional hazards regression analysis was used to determine the optimal covariates that constructed the scoring system. Furthermore, a quantitative survival-predicting nomogram was constructed based on the hematological risk score (HRS) derived from the HRPSS. The results of the nomogram were validated using bootstrap resampling and the external validation set. Finally, we further explored the relationship between the HRS and clinical prognostic factors.

Results

The optimal cutoff value for the HRS was 0.839. The patients were successfully classified into different prognostic groups based on their HRSs (P < 0.001). The areas under the curve (AUCs) of the HRS were 0.67, 0.73, and 0.78 at 0.5, 1, and 2 years, respectively. Additionally, the 0.5-, 1-y, and 2-y AUCs of the HRS were 0.51, 0.70, and 0.79, respectively, which validated the robust prognostic performance of the HRS in the external validation set. Based on both univariate and multivariate analyses, the HRS possessed a strong ability to predict overall survival in both the training set and validation set. The nomogram based on the HRS displayed good discrimination with a C-index of 0.81 and good calibration. In the validation cohort, a high C-index value of 0.82 could still be achieved. In all the data, the HRS showed specific correlations with age, first presenting symptoms, isocitrate dehydrogenase mutation status and tumor location, and successfully stratified them into different risk subgroups.

Conclusions

The HRPSS is a powerful tool for accurate prognostic prediction in patients with newly diagnosed glioblastoma.