bluuebunny/crossref_metadata_2025 huggingface dataset:
Large Choroidal Melanocytoma Simulating Choroidal Melanoma: A Difficult Differential Diagnosis and an Inevitable Enucleation
Authors: Abdellaoui Taoufik , Belfaiza Soukaina , Malek Yassine , Essaoudi Mohamed-amine , Elasri Fouad , Reda Karim , Oubaaz Abdelbarre
Published: November 2020

Purpose. To describe a case of choroidal melanocytoma mimicking a melanoma. Methods. Retrospective case report. Patient. A 48-year-old Moroccan woman presented with progressive, painless decreased vision in her left eye for 2 months. Results. Her visual acuity was light perception in the left eye and 20/20 in the right one. Fundus examination and fluorescein angiography of the left eye showed a total retinal detachment with a large superior brownish mass. The clinical examination, B-scan ultrasonography, and magnetic resonance imaging all suggested a malignant melanoma. Consequently, the eye was enucleated. The histopathology later revealed a benign melanocytoma of the choroid. Discussion. Melanocytoma is a rare benign pigmented tumor. It is classically described as a tumor of the optic nerve head, but there are some exceptional case reports of uveal tract locations (iris, ciliary body, and choroid). In such cases, it can be difficult to clinically differentiate a melanocytoma from a malignant melanoma.
Path Planning for Excavator Arm: Fuzzy Logic Control Approach
Authors: Vu Nga Thi-Thuy , Tran Nam Phuong
Published: November 2020

This paper proposes an algorithm to design the path for automated excavator arm. The path designing is divided into two phases. Firstly, the fuzzy logic technique is used to determine the change of the path to adapt with the variation of the material after each digging period. Secondly, the B-spline algorithm is used to build the optimal trajectory. By this, the excavator can maximize the dug weight although the shape of the material is variation. The effectiveness of the algorithm is verified through computer simulation and real-time experiment. The simulation and experimental results show that the generated optimal path keeps the dug weight around the expected value regardless of the change of the environment.
Exploiting GWmZd Model by Exploring Knowledge-Based Grey-Holistic Technique for Sustainable Vendor Evaluation
Authors: Bu Zhiqiong , Prabhu M. , Ahmed Ramyar Rzgar , Sahu Anoop Kumar
Published: November 2020

It is investigated that the thoughts of sustainability gained the momentum among researchers in the present era. The industrial empirical research survey proved that green operations, waste minimization strategies, and zero defect planning are three potential pillars in mapping the sustainability of supplier/vendor units. The authors built and proposed a grey knowledge-based green-waste minimizing and zero defect (GWmZd) sustainability appraisement hierarchical structural evaluation model/framework to production companies for assessing the sustainability ratio of their candidate suppliers/partners. Due to the uncertainty associated with the measures and metrics of the proposed model, the incomplete information is procured from a cluster of professionals’ vs GWmZd measures and metrics in the terms of the grey (except fuzzy) set. It is sensed by the prior literature survey that a few grey knowledge-based sustainability model are framed, but they were constrained to the individual first level layer without weight evaluation cum noncomparative analysis-based modern technique, and it is respected as a major research gap and challenge. To compensate the major research gap, the authors elected AHP and enabled AHP (analytic hierarchy process) to materialize and aggregate the assigned rating of each expert for evaluating weights of 2nd level metrics (overcoming the drawback of combined/group ratings). Later, the authors structured and proposed a new mathematical equation, assisted authors to evaluate the global weight of the first layer-three pillars-measures of the proposed model. Eventually, the authors constructed and fruitfully implemented a grey-holistic technique (merger of grey-MOORA-FMF fused with the dominance theory) on the model to compute sustainability index and score of suppliers. A production company is investigated to exhibit the application of the research work practically. The sustainability of supplier A1 is found the best than the residue of suppliers. The research forum can be explored by production companies to opt the feasible supplier under the proposed model. The conducted research has a value across the global production companies. The research forum can be explored by managers of production companies for benchmarking the performance of global suppliers under GWmZd and future advancing models along with grey-holistic technique fused with the dominance theory.
Mitochondrial-Protective Effects of R-Phenibut after Experimental Traumatic Brain Injury
Authors: Kupats Einars , Stelfa Gundega , Zvejniece Baiba , Grinberga Solveiga , Vavers Edijs , Makrecka-Kuka Marina , Svalbe Baiba , Zvejniece Liga , Dambrova Maija
Published: November 2020

Altered neuronal Ca2+ homeostasis and mitochondrial dysfunction play a central role in the pathogenesis of traumatic brain injury (TBI). R-Phenibut ((3R)-phenyl-4-aminobutyric acid) is an antagonist of the α2δ subunit of voltage-dependent calcium channels (VDCC) and an agonist of gamma-aminobutyric acid B (GABA-B) receptors. The aim of this study was to evaluate the potential therapeutic effects of R-phenibut following the lateral fluid percussion injury (latFPI) model of TBI in mice and the impact of R- and S-phenibut on mitochondrial functionality in vitro. By determining the bioavailability of R-phenibut in the mouse brain tissue and plasma, we found that R-phenibut (50 mg/kg) reached the brain tissue 15 min after intraperitoneal (i.p.) and peroral (p.o.) injections. The maximal concentration of R-phenibut in the brain tissues was 0.6 μg/g and 0.2 μg/g tissue after i.p. and p.o. administration, respectively. Male Swiss-Webster mice received i.p. injections of R-phenibut at doses of 10 or 50 mg/kg 2 h after TBI and then once daily for 7 days. R-Phenibut treatment at the dose of 50 mg/kg significantly ameliorated functional deficits after TBI on postinjury days 1, 4, and 7. Seven days after TBI, the number of Nissl-stained dark neurons (N-DNs) and interleukin-1beta (IL-1β) expression in the cerebral neocortex in the area of cortical impact were reduced. Moreover, the addition of R- and S-phenibut at a concentration of 0.5 μg/ml inhibited calcium-induced mitochondrial swelling in the brain homogenate and prevented anoxia-reoxygenation-induced increases in mitochondrial H2O2 production and the H2O2/O ratio. Taken together, these results suggest that R-phenibut could serve as a neuroprotective agent and promising drug candidate for treating TBI.
Quinovic Acid Impedes Cholesterol Dyshomeostasis, Oxidative Stress, and Neurodegeneration in an Amyloid-β-Induced Mouse Model
Authors: Saeed Kamran , Shah Shahid Ali , Ullah Rahat , Alam Sayed Ibrar , Park Jun Sung , Saleem Samreen , Jo Myeung Hoon , Kim Min Woo , Hahm Jong Ryeal , Kim Myeong Ok
Published: November 2020

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder typified by several neuropathological features including amyloid-beta (Aβ) plaque and neurofibrillary tangles (NFTs). Cholesterol retention and oxidative stress (OS) are the major contributors of elevated β- and γ-secretase activities, leading to excessive Aβ deposition, signifying the importance of altered cholesterol homeostasis and OS in the progression of Aβ-mediated neurodegeneration and cognitive deficit. However, the effect of Aβ on cholesterol metabolism is lesser-known. In this study, we evaluated the effect of quinovic acid (QA; 50 mg/kg body weight, i.p.) against the intracerebroventricular (i.c.v.) injection of Aβ (1-42)-induced cholesterol dyshomeostasis, oxidative stress, and neurodegeneration in the cortex and hippocampal brain regions of wild-type male C57BL/6J mice. Our results indicated that Aβ (1-42)-treated mice have increased Aβ oligomer formation along with increased β-secretase expression. The enhanced amyloidogenic pathway in Aβ (1-42)-treated mice intensified brain cholesterol accumulation due to increased expressions of p53 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) enzyme. Importantly, we further confirmed the p53-mediated HMGCR axis activation by using pifithrin-α (PFT) in SH-SY5Y cells. Furthermore, the augmented brain cholesterol levels were also associated with increased OS. However, the QA administration to Aβ (1-42)-injected mice significantly ameliorated the Aβ burden, p53 expression, and cholesterol accumulation by deterring the oxidative stress through upregulating the Nrf2/HO-1 pathway. Moreover, the QA downregulated gliosis, neuroinflammatory mediators (p-NF-κB and IL-1β), and the expression of mitochondrial apoptotic markers (Bax, cleaved caspase-3, and cytochrome c). QA treatment also reversed the deregulated synaptic markers (PSD-95 and synaptophysin) and improved spatial learning and memory behaviors in the Aβ-treated mouse brains. These results suggest that Aβ (1-42) induces its acute detrimental effects on cognitive functions probably by increasing brain cholesterol levels through a possible activation of the p53/HMGCR axis. However, QA treatment reduces the cholesterol-induced oxidative stress, neuroinflammation, and neurodegeneration, leading to the restoration of cognitive deficit after Aβ (1-42) i.c.v. injection in mice.
MicroRNA‐148b Inhibits the Malignant Biological Behavior of Melanoma by Reducing Sirtuin 7 Expression Levels
Authors: Sun Rui , Guo Meiliang , Fan Xiaojing , Meng Qinqin , Yuan Dingfen , Yang Xinrong , Yan Kexiang , Deng Hui
Published: November 2020

There is growing evidence that microRNA‐148b (miR‐148b) can inhibit the growth of malignant cells while sirtuin 7 (SIRT7) may perform its carcinogenic effect by deacetylating H3K18. This study investigated the mechanism of miR‐148b/SIRT7 on how it affects the malignant biological behavior of melanoma. It was established that the expression of miR‐148b was downregulated in melanoma while that of SIRT7 was upregulated but negatively regulated by miR‐148b through binding to the 3 ′UTR of SIRT7. Ectopic expression of miR‐148b reduced the proliferation, migration, and invasion of melanoma cells, but SIRT7 reversed these functions of miR‐148b. Moreover, tumor growth and metastasis experiments showed that miR‐148b could significantly suppress proliferation and metastasis of melanoma in vivo. Overall, miR‐148b inhibits the malignant biological behavior of melanoma by reducing the expression level of SIRT7. The development of miR‐148b as a novel potential therapeutic approach for melanoma may be possible in the future.
Challenges in using authentic assessment in 21st century ESL classrooms
Authors: Aziz Muhammad Noor Abdul , Mohd Yusoff Nurahimah , Mohd Yaakob Mohd Faiz
Published: November 2020

This paper seeks to explore the challenges faced by excellent teachers in preparing for authentic assessment in their English as a Second Language (ESL) classrooms. This qualitative case study involving six excellent teachers was based on purposive sampling. Data sources in this study used classroom observation and a series of semi-structured interviews with the excellent teachers. Thematic analysis was used to identify emerging themes from the codes gathered from the interviews and observations. Data showed that excellent teachers faced multiple challenges prior to preparing for authentic assessment. They have also been using variations of authentic assessment to help children in their learning besides accurate documentation and extensive reading from around the globe to equip themselves with the current knowledge. Since there is no clear guideline for teachers who practice authentic assessment in their classes, this study provided some insights on the preparations and the use of authentic assessment as part of their teaching and learning process.
Agricultural Knowledge, Local Environment, and the Experts: Silkworm Production in Nineteenth-Century Bursa
Authors: Akçakaya Zeynep
Published: November 2020

This article is a case study of silkworm production in Bursa in the nineteenth century. This case was chosen mainly to discuss the relationship between scientific agricultural knowledge and peasants’ knowledge. The article argues that neither type of knowledge was static and that hybrid knowledge was the product of the interaction between scientific and peasants’ knowledge. Furthermore, it analyses how scientific knowledge turned from a cure for pebrine, a disease of silkworms, into a means of standardisation and control of the peasants’ production by the government and the Ottoman Public Debt Administration so that they could increase their revenue from sericulture. In this framework, the article also discusses how peasants’ knowledge changed partly by embracing scientific knowledge and partly by resisting it.
AN INVENTORY OF THE BUTTERFLIES OF MANIPUR, INDIA (INSECTA: LEPIDOPTERA)
Authors: IRUNGBAM JATISHWOR SINGH , MEITEI LAISHRAM RICKY , HUIDROM HARMENN , SOIBAM BALESHWOR SINGH , NGANGOM AOMAO , NGANGOM BENDANG , MEITEI RONALD , FRIC ZDENEK FALTYNEK
Published: November 2020

The butterfly fauna of Manipur is poorly known, and a few sporadic studies were carried out decades ago. In this study, butterflies were photographed and/or collected in 80 localities including revisiting of 12 historical localities in the hills and valleys from Manipur state, India. Butterflies were regularly sampled between 2010 and 2019. In the present checklist, we have included both previously published and recently recorded species: 798 species belong to six families; Papilionidae (52 sp.), Pieridae (39 sp.), Riodinidae (17 sp.), Lycaenidae (225 sp.), Nymphalidae (270 sp.), and Hesperiidae (195 sp.). Eight species were rediscovered during the study; Byasa latreillei kabrua, Papilio machaon suroia, Lamproptera meges indistincta, Bhutanitis lidderdalii lidderdalii, Lethe kangjupkula, Una usta usta, Arhopala hellenore hellenore and Celaenorrhinus munda maculicornis. Thirty–two species were new records to Manipur; Papilio agestor agestor, Lamproptera curius curius, Appias albina darada, Artogeia erutae montana, Miletus mallus, Flos fulgida fulgida, Cigaritis nipalicus, Rapala rectivitta, Heliophorus kohimensis, H. tamu, Jamides caeruleus, Tarucus venosus, Everes huegelii dipora, Talicada nyseus nyseus, Lestranicus transpectus, Euploea radamanthus radamanthus, Lethe distans, L. dura gammiei, L. latiaris latiaris, L. sura, Neope pulaha, N. yama yama, Zipaetis scylax, Algia fasciata fasciata, Athyma opaline, Pantoporia paraka paraka, Kallima knyvettii, Celaenorrhinus asmara, Hyarotis adrastus praba, Erionota torus, Baoris penicillata chapmani, and Potanthus mingo ajax of which, Miletus mallus was a new record for India. Ninety species are legally protected in schedules (I, II & IV) of Indian (Wildlife) Protection Act, 1972.
Two genera Campyloneurus Szépligeti and Iphiaulax Foerster in China, with the descriptions of fourteen new species (Hymenoptera, Braconidae, Braconinae)
Authors: LI YANG , ACHTERBERG CORNELIS VAN , CHEN XUE-XIN
Published: November 2020

The species of the genus Campyloneurus Szépligeti and Iphiaulax Foerster (Hymenoptera, Braconidae, Braconinae) from China are revised and 32 species are recognized, including 14 new species (Campyloneurus brachyurus sp. nov., C. lasiofacialis sp. nov., C. longitergum sp. nov., C. longitudinalis sp. nov., C. micromacularis sp. nov., C. nigriventris sp. nov., C. promiscuus sp. nov., C. pachypus sp. nov., C. quadraticeps sp. nov., C. robusticella sp. nov., C. rugifacialis sp. nov., C. stigmosus sp. nov., C. tergipunctatus sp. nov. and Iphiaulax longinervis sp. nov.), which are described and fully illustrated. Campyloneurus kirbyi (Cameron, 1905) is reported from China for the first time. A key to taxonomically similar genera, Campyloneurus, Craspedolcus Enderlein, Cyanopterus Haliday, Iphiaulax and Maculibracon Li, van Achterberg & Chen), and a key to the Chinese species of the genera Campyloneurus and Iphiaulax are provided.
The association between albuminuria and thyroid antibodies in newly diagnosed type 2 diabetes mellitus patients with Hashimoto’s thyroiditis and euthyroidism
Authors: Zhu Wei , Dong Xuejie , Pan Qingrong , Hu Yanjin , Wang Guang
Published: November 2020

Background

Microalbuminuria is a prognostic marker of diabetes kidney disease. It is generally diagnosed as the ratio of urinary albumin to creatinine (UACR) of 30-300 mg/g. Hashimoto’s thyroiditis is a common disease in the endocrinology and the thyroid antibodies may associated with kidney disease. We investigated the UACR in the newly diagnosed T2DM with Hashimoto’s thyroiditis and tried to detect the relationship between the UACR and thyroid antibodies.

Methods

One hundred twenty newly diagnosed T2DM patients with Hashimoto’s thyroiditis and euthyroidism and 50 sex and age-matched T2DM with non-Hashimoto’s and other thyroid disease were recruited. T2DM patients were divided into 2 groups by the titer of TPOAb: (1). TPOAb (+) group: T2DM with positive TPOAb (n = 105); (2). TPOAb (−) group: T2DM with negative TPOAb (n = 65).

Results

T2DM with positive TPOAb group had higher UACR than T2DM with negative TPOAb group (21.55 ± 7.28 vs 15.13 ± 5.69 mg/g, P < 0.01). UACR were positively related to BMI (r = 0.255, P < 0.05), FPG (r = 0.285, P < 0.05), HbA1c (r = 0.260, P < 0.05) and TPOAb (r = 0.349, P < 0.05). HbA1c (β = 0.793, P < 0.05), BMI (β = 0.342, P < 0.05) and lnTPOAb (β = 1.207, P < 0.05) were independently associated with UACR.

Conclusions

In the newly diagnosed T2DM patients, Hashimoto’s thyroiditis with TPOAb positive had higher UACR levels. TPOAb titer, BMI and HbA1c were independent associated with UACR in these patients.
Molecular detection and genetic characterization of infectious laryngotracheitis virus in poultry in Myanmar
Authors: Yang Zhiyuan , Murata Shiro , Fujisawa Sotaro , Takehara Masaki , Katakura Ken , Hmoon Myint Myint , Win Shwe Yee , Bawm Saw , Konnai Satoru , Ohashi Kazuhiko
Published: November 2020

Background

Avian infectious laryngotracheitis (ILT) is a highly contagious viral disease that causes severe economic losses to the poultry industry worldwide. In Southeast Asian countries, including Myanmar, poultry farming is a major industry. Although it is known that infectious respiratory pathogens, including infectious laryngotracheitis virus (ILTV), are a major threat to poultry farms, there are no data currently available on the epidemiology of ILTV in Myanmar. Therefore, in this study, we conducted a molecular detection of ILTV in 20 poultry farms in Myanmar.

Results

Of the 57 tested oropharyngeal swabs, 10 were positive for ILTV by polymerase chain reaction of a 647 bp region of the thymidine kinase (TK) gene, giving a prevalence of ILTV of 17.5% (10/57). Further sequencing analysis of infected cell protein 4 (ICP4) gene and glycoprotein B, G, and J (gB, gG, and gJ) genes indicated that these isolates were field strains. Phylogenetic analysis revealed that the Myanmar strains clustered together in a single branch and were closely related to other reference strains isolated from Asian countries.

Conclusions

This study demonstrated the presence of ILTV in poultry farms in Myanmar. The genetic characterization analysis performed provides the fundamental data for epidemiological studies that monitor circulating strains of ILTV in Myanmar.
Identification of contributing genes of Huntington’s disease by machine learning
Authors: Cheng Jack , Liu Hsin-Ping , Lin Wei-Yong , Tsai Fuu-Jen
Published: November 2020

Background

Huntington’s disease (HD) is an inherited disorder caused by the polyglutamine (poly-Q) mutations of the HTT gene results in neurodegeneration characterized by chorea, loss of coordination, cognitive decline. However, HD pathogenesis is still elusive. Despite the availability of a wide range of biological data, a comprehensive understanding of HD’s mechanism from machine learning is so far unrealized, majorly due to the lack of needed data density.

Methods

To harness the knowledge of the HD pathogenesis from the expression profiles of postmortem prefrontal cortex samples of 157 HD and 157 controls, we used gene profiling ranking as the criteria to reduce the dimension to the order of magnitude of the sample size, followed by machine learning using the decision tree, rule induction, random forest, and generalized linear model.

Results

These four Machine learning models identified 66 potential HD-contributing genes, with the cross-validated accuracy of 90.79 ± 4.57%, 89.49 ± 5.20%, 90.45 ± 4.24%, and 97.46 ± 3.26%, respectively. The identified genes enriched the gene ontology of transcriptional regulation, inflammatory response, neuron projection, and the cytoskeleton. Moreover, three genes in the cognitive, sensory, and perceptual systems were also identified.

Conclusions

The mutant HTT may interfere with both the expression and transport of these identified genes to promote the HD pathogenesis.
RNA sequencing analysis reveals increased expression of interferon signaling genes and dysregulation of bone metabolism affecting pathways in the whole blood of patients with osteogenesis imperfecta
Authors: Zhytnik Lidiia , Maasalu Katre , Reimann Ene , Märtson Aare , Kõks Sulev
Published: November 2020

Background

Osteogenesis imperfecta (OI) is a rare genetic disorder in which the patients suffer from numerous fractures, skeletal deformities and bluish sclera. The disorder ranges from a mild form to severe and lethal cases. The main objective of this pilot study was to compare the blood transcriptional landscape of OI patients with COL1A1 pathogenic variants and their healthy relatives, in order to find out different gene expression and dysregulated molecular pathways in OI.

Methods

We performed RNA sequencing analysis of whole blood in seven individuals affected with different OI severity and their five unaffected relatives from the three families. The data was analyzed using edgeR package of R Bioconductor. Functional profiling and pathway analysis of the identified differently expressed genes was performed with g:GOSt and MinePath web-based tools.

Results

We identified 114 differently expressed genes. The expression of 79 genes was up-regulated, while 35 genes were down-regulated. The functional analysis identified a presence of dysregulated interferon signaling pathways (IFI27, IFITM3, RSAD12, GBP7). Additionally, the expressions of the genes related to extracellular matrix organization, Wnt signaling, vitamin D metabolism and MAPK-ERK 1/2 pathways were also altered.

Conclusions

The current pilot study successfully captured the differential expression of inflammation and bone metabolism pathways in OI patients. This work can contribute to future research of transcriptional bloodomics in OI. Transcriptional bloodomics has a strong potential to become a major contributor to the understanding of OI pathological mechanisms, the discovery of phenotype modifying factors, and the identification of new therapeutic targets. However, further studies in bigger cohorts of OI patients are needed to confirm the findings of the current work.
Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk
Authors: Giorgino Francesco , Vora Jiten , Fenici Peter , Solini Anna
Published: November 2020

Approximately half of all patients with type 2 diabetes (T2D) develop a certain degree of renal impairment. In many of them, chronic kidney disease (CKD) progresses over time, eventually leading to end-stage kidney disease (ESKD) requiring dialysis and conveying a substantially increased risk of cardiovascular morbidity and mortality. Even with widespread use of renin–angiotensin system blockers and tight glycemic control, a substantial residual risk of nephropathy progression remains. Recent cardiovascular outcomes trials investigating sodium–glucose cotransporter 2 (SGLT2) inhibitors have suggested that these therapies have renoprotective effects distinct from their glucose-lowering action, including the potential to reduce the rates of ESKD and acute kidney injury. Although patients in most cardiovascular outcomes trials had higher prevalence of existing cardiovascular disease compared with those normally seen in clinical practice, the proportion of patients with renal impairment was similar to that observed in a real-world context. Patient cardiovascular risk profiles did not relevantly impact the renoprotective benefits observed in these studies. Benefits were observed in patients across a spectrum of renal risk, but were evident also in those without renal damage, suggesting a role for SGLT2 inhibition in the prevention of CKD in people with T2D. In addition, recent studies such as CREDENCE and DAPA-CKD offer a greater insight into the renoprotective effects of SGLT2 inhibitors in patients with moderate-to-severe CKD. This review outlines the evidence that SGLT2 inhibitors may prevent the development of CKD and prevent and delay the worsening of CKD in people with T2D at different levels of renal risk.
Association of serum Cyr61 levels with peripheral arterial disease in subjects with type 2 diabetes
Authors: Feng Bin , Xu Guidong , Sun Kangyun , Duan Kaipeng , Shi Bimin , Zhang Nannan
Published: November 2020

Background

The prevalence of peripheral artery disease (PAD) is obviously increased in patients with diabetes. Existing evidence shows that cysteine-rich angiogenic inducer 61 (Cyr61), a 40-kD secreted protein, plays important roles in regulating cellular physiological processes. Recent studies have demonstrated a significant correlation between serum Cyr61 and atherosclerosis. However, the relationship between Cyr61 levels and PAD in patients with type 2 diabetes (T2DM) remains obscure.

Methods

Data from a total of 306 subjects with T2DM were cross-sectionally analysed. The extent of PAD was determined by using the Fontaine classification, which defines four stages. We measured serum Cyr61 concentrations by ELISA in subjects with and without PAD at Fontaine’s stage II, III, or IV. Logistic regression models were used to examine the independent association of Cyr61 with PAD.

Results

Out of the 306 subjects enrolled, 150 were free from PAD, while 156 had clinically significant PAD. In subjects with PAD, the prevalences of Fontaine classification stages II, III and IV were 48.7%, 32.1%, and 19.2%, respectively. Patients with more advanced PAD had significantly higher Cyr61 (P for trend < 0.001). The prevalence of PAD on the basis of severity increased with increasing Cyr61 quartiles (all P values for trends < 0.001), and the severity of PAD was positively correlated with Cyr61 quartiles (r = 0.227, P = 0.006). The association of Cyr61 levels with PAD remained after adjusting for major risk factors in a logistic regression analysis.

Conclusions

Our results demonstrated that Cyr61 was significantly increased in PAD patients with T2DM and that Cyr61 levels were positively associated with disease severity. Cyr61 could be a promising biomarker and further studies are needed to assess its clinical utility.
CD44 cross-linking increases malignancy of breast cancer via upregulation of p-Moesin
Authors: Hu Song , Shi Xiaoxing , Liu Yiwen , He Yiqing , Du Yan , Zhang Guoliang , Yang Cuixia , Gao Feng
Published: November 2020

Background

CD44 is highly expressed in most cancer cells and its cross-linking pattern is closely related to tumor migration and invasion. However, the underlying molecular mechanism regarding CD44 cross-linking during cancer cell metastasis is poorly understood. Therefore, the purpose of this study was to explore whether disruption of CD44 cross-linking in breast cancer cells could prevent the cells migration and invasion and determine the effects of CD44 cross-linking on the malignancy of the cancer cells.

Methods

The expression of CD44, CD44 cross-linking and Moesin phosphorylation in breast cancer cells was assessed by Western Blot assays. Effects of CD44 cross-linking on tumor metastasis were evaluated by Transwell assay. The effects of CD44 cross-linking disruption on cell viability were assessed using CCK-8 assays. The expression of p-Moesin between normal and breast cancer tissues was examined by immunohistochemical staining.

Results

High expression of CD44 cross-linking was found in invasive breast cancer cells (BT-549 and MDA-MB-231), which is associated with the malignancy of breast cancer. The expressions of ERM complex in a panel of breast cancer cell lines indicate that Moesin and its phosphorylation may play a significant role in cell metastasis. Moesin phosphorylation was inhibited by CD44 de-crosslinking in breast cancer cells and Moesin shRNA knockdown attenuated the promotion of CD44 cross-linking on cell migration and invasion. Finally, immunohistochemistry results demonstrated that p-Moesin was overexpressed in primary and metastatic cancers.

Conclusions

Our study suggested that CD44 cross-linking could elevate p-Moesin expression and further affect migration and invasion of breast cancer cells. These results also indicate that p-Moesin may be useful in future targeted cancer therapy.
Ex vivo infection of murine precision-cut lung tissue slices with Mycobacterium abscessus: a model to study antimycobacterial agents
Authors: Molina-Torres Carmen Amelia , Flores-Castillo Oscar Noé , Carranza-Torres Irma Edith , Guzmán-Delgado Nancy Elena , Viveros-Valdez Ezequiel , Vera-Cabrera Lucio , Ocampo-Candiani Jorge , Verde-Star Julia , Castro-Garza Jorge , Carranza-Rosales Pilar
Published: November 2020

Background

Multidrug-resistant infections due toMycobacterium abscessusoften require complex and prolonged regimens for treatment. Here, we report the evaluation of a new ex vivo antimicrobial susceptibility testing model using organotypic cultures of murine precision-cut lung slices, an experimental model in which metabolic activity, and all the usual cell types of the organ are found while the tissue architecture and the interactions between the different cells are maintained.

Methods

Precision cut lung slices (PCLS) were prepared from the lungs of wild type BALB/c mice using the Krumdieck®tissue slicer. Lung tissue slices were ex vivo infected with the virulentM. abscessusstrain L948. Then, we tested the antimicrobial activity of two drugs: imipenem (4, 16 and 64 μg/mL) and tigecycline (0.25, 1 and 4 μg/mL), at 12, 24 and 48 h. Afterwards, CFUs were determined plating on blood agar to measure the surviving intracellular bacteria. The viability of PCLS was assessed by Alamar Blue assay and corroborated using histopathological analysis.

Results

PCLS were successfully infected with a virulent strain ofM. abscessusas demonstrated by CFUs and detailed histopathological analysis. The time-course infection, including tissue damage, parallels in vivo findings reported in genetically modified murine models forM. abscessusinfection. Tigecycline showed a bactericidal effect at 48 h that achieved a reduction of > 4log10CFU/mL against the intracellular mycobacteria, while imipenem showed a bacteriostatic effect.

Conclusions

The use of this new organotypic ex vivo model provides the opportunity to test new drugs againstM. abscessus, decreasing the use of costly and tedious animal models.
N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling
Authors: Xu Junjie , Wan Zhe , Tang Minyue , Lin Zhongjie , Jiang Shi , Ji Lin , Gorshkov Kirill , Mao Qijiang , Xia Shunjie , Cen Dong , Zheng Junhao , Liang Xiao , Cai Xiujun
Published: November 2020

Background and aims

Accumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafenib therapy.

Methods

In vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation.

Results

In this study, we found that a circular RNA, circRNA-SORE, which is up-regulated insorafenib-resistant HCC cells, was necessary for the maintenance of sorafenib resistance, and that silencing circRNA-SORE substantially increased the efficacy of sorafenib-induced apoptosis. Mechanistic studies determined that circRNA-SORE sequestered miR-103a-2-5p and miR-660-3p by acting as a microRNA sponge, thereby competitively activating the Wnt/β-catenin pathway and inducing sorafenib resistance. The increased level of circRNA-SORE in sorafenib-resistant cells resulted from increased RNA stability. This was caused by an increased level of N6-methyladenosine (m6A) at a specific adenosine in circRNA-SORE. In vivo delivery of circRNA-SORE interfering RNA by local short hairpin RNA lentivirus injection substantially enhanced sorafenib efficacy in animal models.

Conclusions

This work indicates a novel mechanism for maintaining sorafenib resistance and is a proof-of-concept study for targeting circRNA-SORE in sorafenib-treated HCC patients as a novel pharmaceutical intervention for advanced HCC.
Inverse association between triglyceride glucose index and muscle mass in Korean adults: 2008–2011 KNHANES
Authors: Ahn Sung-Ho , Lee Jun-Hyuk , Lee Ji-Won
Published: November 2020

Background

Since sarcopenia is an important risk factor for falls or cardiovascular disease, early detection and prevention of sarcopenia are being increasingly emphasized. Emerging evidence has indicated relationships between sarcopenia, insulin resistance, and inflammation. The triglyceride glucose (TyG) index, a novel surrogate marker of insulin resistance and systemic inflammation, has not yet been shown to be associated with sarcopenia. This study aimed to examine the relationship between the TyG index and muscle mass in Korean adults.

Methods

This study included 15,741 non-diabetic adults over 19 years old using data from the 2008–2011 Korea National Health and Nutrition Examination Survey. Participants were divided into three groups according to tertiles of the TyG index. A low skeletal muscle mass index (LSMI) was defined by the Foundation for the National Institutes of Health Sarcopenia Project criteria. A weighted multivariate logistic regression model was used to analyze relationships between TyG index tertiles and LSMI.

Results

The ORs (95% CIs) for LSMI in the second and third TyG tertiles, compared to the first tertile, were 1.463 (1.131–1.892) and 1.816 (1.394–2.366), respectively, after adjusting for confounding factors. Higher TyG index values were also associated with increased odds of LSMI in adults under 65 years who did not exercise regularly, who consumed less than 30 g of alcohol per day, who did not currently smoke, and who ate less than 1.5 g of protein/kg/day.

Conclusion

The TyG index was significantly and positively associated with LSMI in Korean adults.
Association between the non-HDL-cholesterol to HDL-cholesterol ratio and non-alcoholic fatty liver disease in Chinese children and adolescents: a large single-center cross-sectional study
Authors: Yang Shouxing , Zhong Jinwei , Ye Mengsi , Miao Lei , Lu Guangrong , Xu Changlong , Xue Zhanxiong , Zhou Xinhe
Published: November 2020

Background

The non-HDL-cholesterol to HDL-cholesterol (NHDLC/HDLC) ratio is closely related to a variety of dyslipidemia-related diseases. This study examined the relationship between the NHDLC/HDLC ratio and non-alcoholic fatty liver (NAFLD) in children and adolescents.

Methods

This cross-sectional survey included a total of 7759 eligible Chinese children and adolescents (5692 boys and 2067 girls) who received routine medical examinations. The anthropometric and laboratory data of the subjects were collected. NAFLD was diagnosed by liver ultrasonography. Binary logistic regression analysis was performed on the NHDLC/HDLC ratio, NHDLC, HDLC and NAFLD. Receiver operating characteristic (ROC) curve analysis was used to compare the diagnostic significance of the above parameters for NAFLD.

Results

The total prevalence of NAFLD was 4.36%, and the prevalence in boys was higher than that in girls (5.61% vs. 1.9%, P < 0.001). The prevalence of NAFLD was positively correlated with the NHDLC/HDLC ratio (P < 0.001). The binary logistic regression analysis demonstrated that the OR was 8.61 (95% CI, 5.90–12.57, P < 0.001) in tertile 3 (highest NHDLC/HDLC ratio) compared with tertile 1 (lowest NHDLC/HDLC ratio). After adjustment for age, sex, body mass index (BMI), alanine aminotransferase (ALT), uric acid (UA), total bilirubin (TB), fasting plasma glucose (FPG) and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), the OR for tertile 3 (OR = 1.83, 95% CI, 1.04–3.22, P = 0.035) was still significantly higher than that of tertile 1. The area under the curve (AUC) of the NHDLC/HDLC ratio of boys was 0.787, which was significantly greater than NHDLC and HDLC (0.719 and 0.726, P < 0.001). For girls, the AUC of the NHDLC/HDLC ratio was 0.763, which was also significantly greater than NHDLC (0.661, P < 0.001). The cutoff point of the NHDLC/HDLC ratio was 2.475 in boys and 2.695 in girls. In addition, the AUC of the NHDLC/HDLC ratio was 0.761 in subjects with normal ALT levels (ALT ≤40 U/L), which was significantly higher than NHDLC (0.680, P < 0.001) and HDLC (0.724, P = 0.007). For subjects with elevated ALT levels (ALT > 40 U/L), the AUC of the NHDLC/HDLC ratio (0.746) was also significantly greater than NHDLC (0.646, P < 0.001).

Conclusions

The NHDLC/HDLC ratio was positively correlated with NAFLD in Chinese children and adolescents. It may serve as an effective indicator to help identify NAFLD in children and adolescents.
PD-1/PD-L1 expression profiles within intrahepatic cholangiocarcinoma predict clinical outcome
Authors: Tian Lingyu , Ma Jiaqiang , Ma Lijie , Zheng Bohao , Liu Longzi , Song Danjun , Wang Yining , Zhang Zhao , Gao Qiang , Song Kang , Wang Xiaoying
Published: November 2020

Objective

Immunotherapy targeting the programmed cell death protein-1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) pathway has been observed to be efficient in several solid tumors. We aim to investigate the prognostic significance of PD-1/PD-L1 expression profile in intrahepatic cholangiocarcinoma (ICC).

Materials and methods

We investigated the expression of PD-1, PD-L1, CD8+ T cells, and CD68+ macrophages in paired tumor and adjacent normal tissues from 322 ICC patients using tyramide signal amplification (TSA)-based multiplexed immunohistochemistry.

Results

We found that high proportion of tumor-infiltrating CD8+ PD-1High within CD8+ PD-1+ T cells significantly correlated with advanced TNM stage (P = 0.035). ICC patients with high proportion of CD8+ PD-1High in CD8+ PD-1+ had worse postoperative survival than low proportion patients (P = 0.0037), which was an independently prognostic factor for OS (P = 0.025,). The density of CD68+ PD-L1+ significantly and positively correlated with the density of CD8+ PD-1High (P < 0.0001, r = 0.5927). The proportion of CD68+ PD-L1+ within CD68+ ICC was the risk factor for OS and TTR but not an independently factor for prognosis. The CD68+ PD-L1+ macrophages and CD8+ PD-1High T cells may cooperatively play a role in inhibiting anti-tumor immunity.

Conclusion

CD68+ PD-L1+ macrophages and CD8+ PD-1High T cells predict unfavorable prognosis, which could also bring new progress about immune target therapy in ICC research.
Factors affecting the technical efficiency of rural primary health care centers in Hamadan, Iran: data envelopment analysis and Tobit regression
Authors: Mohammadpour Saeed , Javan-Noughabi Javad , Vafaee Najar Ali , Zangeneh Moharram , Yousefi Shaghayegh , Nouhi Mojtaba , Jahangiri Reza
Published: November 2020

Background

Studying and monitoring the efficiency of primary health care centers has a special place in the health system. Although studies have been conducted in the field of efficiency in Iran, few have focused on rural primary health care centers. In addition, previous studies have not used the child mortality rate and Behvarzes as input and output.

Objective

The present study was conducted aimed to estimate the technical efficiency of rural primary health care centers and determinant factors in Hamadan using data envelopment analysis and Tobit regression.

Methods

This is a Longitudinal study of rural primary health care centers in Hamadan province (2002–2016). Data Envelopment Analysis was employed to estimate technical efficiency of sampled health facilities while Panel Tobit Analysis was applied to predict factors associated with efficiency levels. The outputs were child mortality rate under 1 year of age and child mortality rate 1 year to 5 years of age. The input was Behvarzes (rural health workers).

Results

The results of efficiency analysis showed that the average efficiency scores of the centers had a fluctuating trend during the period of the study, but the average performance scores generally decreased in 2016, as compared with 2002. The highest and lowest average performance scores were observed in 2003 (0.78) and 2013 (0.56), respectively. Number of physicians and rural primary healthcare centers per population had a positive statistically significant and the number of midwives and the total fertility per population had a negative statistically significant effect on efficiency.

Conclusions

The findings suggest some level of wastage of health resources in primary health centers. Findings indicate a level of waste of health resources in primary health centers. Behvarz functions in providing primary care services can be considered in the reallocation and optimal use of available resources at the level of rural health centers.
Tyrosine 192 within the SH2 domain of the Src-protein tyrosine kinase p56Lck regulates T-cell activation independently of Lck/CD45 interactions
Authors: Kästle Matthias , Merten Camilla , Hartig Roland , Kaehne Thilo , Liaunardy-Jopeace Ardiyanto , Woessner Nadine M. , Schamel Wolfgang W. , James John , Minguet Susana , Simeoni Luca , Schraven Burkhart
Published: November 2020

Background

Upon engagement of the T-cell receptor (TCR), the Src-family protein tyrosine kinase p56Lck phosphorylates components of the TCR (e.g. the TCRζ chains), thereby initiating T-cell activation. The enzymatic activity of Lck is primarily regulated via reversible and dynamic phosphorylation of two tyrosine residues, Y394 and Y505. Lck possesses an additional highly conserved tyrosine Y192, located within the SH2 domain, whose role in T-cell activation is not fully understood.

Methods

Knock-in mice expressing a phospho-mimetic (Y192E) form of Lck were generated. Cellular and biochemical characterization was performed to elucidate the function of Y192 in primary T cells. HEK 293T and Jurkat T cells were used for in vitro studies.

Results

Co-immunoprecipitation studies and biochemical analyses using T cells from LckY192Eknock-in mice revealed a diminished binding of LckY192Eto CD45 and a concomitant hyperphosphorylation of Y505, thus corroborating previous data obtained in Jurkat T cells. Surprisingly however, in vitro kinase assays showed that LckY192Epossesses a normal enzymatic activity in human and murine T cells. FLIM/FRET measurements employing an LckY192Ebiosensor further indicated that the steady state conformation of the LckY192Emutant is similar to Lckwt. These data suggest that Y192 might regulate Lck functions also independently from the Lck/CD45-association. Indeed, when LckY192Ewas expressed in CD45−/−/Csk−/−non-T cells (HEK 293T cells), phosphorylation of Y505 was similar to Lckwt, but LckY192Estill failed to optimally phosphorylate and activate the Lck downstream substrate ZAP70. Furthermore, LckY19Ewas recruited less to CD3 after TCR stimulation.

Conclusions

Taken together, phosphorylation of Y192 regulates Lck functions in T cells at least twofold, by preventing Lck association to CD45 and by modulating ligand-induced recruitment of Lck to the TCR.

Major findings

Our data change the current view on the function of Y192 and suggest that Y192 also regulates Lck activity in a manner independent of Y505 phosphorylation.
Diesel exhaust impairs TREM2 to dysregulate neuroinflammation
Authors: Greve Hendrik J. , Mumaw Christen L. , Messenger Evan J. , Kodavanti Prasada R. S. , Royland Joyce L. , Kodavanti Urmila P. , Block Michelle L.
Published: November 2020

Background

Air pollution has been linked to neurodegenerative diseases, including Alzheimer’s disease (AD), and the underlying neuroimmune mechanisms remain poorly understood. TREM2 is a myeloid cell membrane receptor that is a key regulator of disease-associated microglia (DAM) cells, where loss-of-functionTREM2mutations are associated with an increased risk of AD. At present, the basic function of TREM2 in neuroinflammation is a point of controversy. Further, the impact of air pollution on TREM2 and the DAM phenotype is largely unknown. Using diesel exhaust (DE) as a model of urban air pollution exposure, we sought to address its impact on TREM2 expression, the DAM phenotype, the association of microglia with the neurovasculature, and the role of TREM2 in DE-induced neuroinflammation.

Methods

WYK rats were exposed for 4 weeks to DE (0, 50, 150, 500 μg/m3) by inhalation. DE particles (DEP) were administered intratracheally once (600 μg/mouse) or 8 times (100 μg/mouse) across 28 days to male mice (Trem2+/+,Trem2−/−, PHOX+/+, and PHOX−/−).

Results

Rats exposed to DE exhibited inverted-U patterns ofTrem2mRNA expression in the hippocampus and frontal cortex, while TREM2 protein was globally diminished, indicating impaired TREM2 expression. Analysis of DAM markersCx3Cr1,Lyz2, andLplin the frontal cortex and hippocampus showed inverted-U patterns of expression as well, supporting dysregulation of the DAM phenotype. Further, microglial-vessel association decreased with DE inhalation in a dose-dependent manner. Mechanistically, intratracheal administration of DEP increasedTnf(TNFα),Ncf1(p47PHOX), andNcf2(p67PHOX) mRNA expression in onlyTrem2+/+mice, whereIl1b(IL-1β) expression was elevated in onlyTrem2−/−mice, emphasizing an important role for TREM2 in DEP-induced neuroinflammation.

Conclusions

Collectively, these findings reveal a novel role for TREM2 in how air pollution regulates neuroinflammation and provides much needed insight into the potential mechanisms linking urban air pollution to AD.
K284-6111 alleviates memory impairment and neuroinflammation in Tg2576 mice by inhibition of Chitinase-3-like 1 regulating ERK-dependent PTX3 pathway
Authors: Ham Hyeon Joo , Lee Yong Sun , Yun Jaesuk , Son Dong Ju , Lee Hee Pom , Han Sang-Bae , Hong Jin Tae
Published: November 2020

Background

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders characterized by gradual memory loss and neuropsychiatric symptoms. We have previously demonstrated that the 2-({3-[2-(1-cyclohexene-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), the inhibitor of CHI3L1, has the inhibitory effect on memory impairment in Αβ infusion mouse model and on LPS-induced neuroinflammation in the murine BV-2 microglia and primary cultured astrocyte.

Methods

In the present study, we investigated the inhibitory effect of K284-6111 on memory dysfunction and neuroinflammation in Tg2576 transgenic mice, and a more detailed correlation of CHI3L1 and AD. To investigate the effects of K284-6111 on memory dysfunction, we administered K284-6111 (3 mg/kg, p.o.) daily for 4 weeks to Tg2576 mice, followed by behavioral tests of water maze test, probe test, and passive avoidance test.

Results

Administration of K284-6111 alleviated memory impairment in Tg2576 mice and had the effect of reducing the accumulation of Aβ and neuroinflammatory responses in the mouse brain. K284-6111 treatment also selectively inactivated ERK and NF-κB pathways, which were activated when CHI3L1 was overexpressed, in the mouse brain and in BV-2 cells. Web-based gene network analysis and our results of gene expression level in BV-2 cells showed that CHI3L1 is closely correlated with PTX3. Our result revealed that knockdown of PTX3 has an inhibitory effect on the production of inflammatory proteins and cytokines, and on the phosphorylation of ERK and IκBα.

Conclusion

These results suggest that K284-6111 could improve memory dysfunction by alleviating neuroinflammation through inhibiting CHI3L1 enhancing ERK-dependent PTX3 pathway.