bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Characterization of the Human Islet Microvasculature Using Living Pancreas Slices
Authors: Mateus Gonçalves Luciana , Almaça Joana
Published: January 2021

Pancreatic islets are clusters of endocrine cells that secrete different hormones to regulate blood glucose levels. Efficient hormone secretion requires a close interaction of endocrine cells with their vascular system. Islets receive blood through feeding arteriole(s) that branch into capillaries made of endothelial cells covered by pericytes. While a lot is known about rodent islet blood vessels, the structure and function of the human islet microvasculature has been less investigated. In this study, we used living pancreas slices from non-diabetic human donors to examine the function of human islet blood vessels. Living human pancreas slices were incubated with a membrane permeant calcium indicator and pericytes/smooth muscle cells were visualized with a fluorescent antibody against the mural cell marker NG2 proteoglycan. By confocal microscopy, we simultaneously recorded changes in the diameter of lectin-labeled blood vessels and cytosolic calcium levels in mural cells in islets. We tested several stimuli with vasoactive properties, such as norepinephrine, endothelin-1 and adenosine and compared human vascular responses with those previously published for mouse islet blood vessels. Norepinephrine and endothelin-1 significantly constricted human islet feeding arterioles, while adenosine dilated them. Islet capillaries were less responsive and only 15–20% of the mouse and human islet capillary network showed vasomotion. Nevertheless, in these responsive regions, norepinephrine and endothelin-1 decreased both mouse and human islet capillary diameter. Changes in islet blood vessel diameter were coupled to changes in cytosolic calcium levels in adjacent mouse and human islet mural cells. Our study shows that mural cells in islets are the targets of different regulatory mechanisms of islet blood perfusion. Several alterations of the human islet microvasculature occur during diabetes progression. Elucidating their functional consequences in future studies will be critical for our understanding of disease pathogenesis.
Preparation of Li2-3xAlxS for All-Solid-State Li-S Battery
Authors: Phuc Nguyen Huu Huy , Takaki Maeda , Hiroyuki Muto , Atsunori Matsuda
Published: January 2021

Li2-3xAlxS (0 ≤ x ≤ 0.1667) was prepared via the planetary ball-milling method. Diffuse reflection UV-Vis measurements revealed that the band gap and electronic structure of Li2S changed with the formation of defective Li2-3xAlxS. Compared with x = 0, the ionic conductivity for the sample with x = 0.1334 improved by ∼3 orders of magnitude. The lithium movement activation energy and pre-exponential factor A were found to be dependent on the x value. Compared with Li2S, a ∼10-fold improvement in the electronic conductivity was realized with the addition of Al2S3. Additionally, the all-solid-state Li-S battery cell performance also displayed an enhancement in both the initial capacity and stability for sample x = 0.1667 compared with x = 0. This study highlighted the importance of the intrinsic electronic conductivity of the active materials (but not the electrode) on the performance of the all-solid-state Li-S battery.
The Digenic Causality in Familial Hypercholesterolemia: Revising the Genotype–Phenotype Correlations of the Disease
Authors: Kamar Amina , Khalil Athar , Nemer Georges
Published: January 2021

Genetically inherited defects in lipoprotein metabolism affect more than 10 million individuals around the globe with preponderance in some parts where consanguinity played a major role in establishing founder mutations. Mutations in four genes have been so far linked to the dominant and recessive form of the disease. Those players encode major proteins implicated in cholesterol regulation, namely, the low-density lipoprotein receptor (LDLR) and its associate protein 1 (LDLRAP1), the proprotein convertase substilin/kexin type 9 (PCSK9), and the apolipoprotein B (APOB). Single mutations or compound mutations in one of these genes are enough to account for a spectrum of mild to severe phenotypes. However, recently several reports have identified digenic mutations in familial cases that do not necessarily reflect a much severe phenotype. Yet, data in the literature supporting this notion are still lacking. Herein, we review all the reported cases of digenic mutations focusing on the biological impact of gene dosage and the potential protective effects of single-nucleotide polymorphisms linked to hypolipidemia. We also highlight the difficulty of establishing phenotype–genotype correlations in digenic familial hypercholesterolemia cases due to the complexity and heterogeneity of the phenotypes and the still faulty in silico pathogenicity scoring system. We finally emphasize the importance of having a whole exome/genome sequencing approach for all familial cases of familial hyperlipidemia to better understand the genetic and clinical course of the disease.
A Novel Transcriptome Integrated Network Approach Identifies the Key Driver lncRNA Involved in Cell Cycle With Chromium (VI)-Treated BEAS-2B Cells
Authors: Zheng Pai , Kang Yulin , Han Shuo , Feng Huimin , Ha Feizai , Long Changmao , Zhou Di , Hu Guiping , Chen Zhangjian , Wang Zengmiao , Wang Tiancheng , Jia Guang
Published: January 2021

Hexavalent chromium [Cr(VI)] is a well-known occupational carcinogen, but the mechanisms contributing to DNA damage and cell cycle alternation have not been fully characterized. To study the dose-response effects of Cr(VI) on transcription, we exposed BEAS-2B cells to Cr(VI) at concentrations of 0.2, 0.6, and 1.8 μmol/L for 24 h. Here, we identified 1,484 differentially expressed genes (DEGs) in our transcript profiling data, with the majority of differentially expressed transcripts being downregulated. Our results also showed that these DEGs were enriched in pathways associated with the cell cycle, including DNA replication, chromatin assembly, and DNA repair. Using the differential expressed genes related to cell cycle, a weighted gene co-expression network was constructed and a key mRNA-lncRNA regulation module was identified under a scale-free network with topological properties. Additionally, key driver analysis (KDA) was applied to the mRNA-lncRNA regulation module to identify the driver genes. The KDA revealed that ARD3 (FDR = 1.46 × 10–22), SND1 (FDR = 5.24 × 10–8), and lnc-DHX32-2:1 (FDR = 1.43 × 10–17) were particularly highlighted in the category of G2/M, G1/S, and M phases. Moreover, several genes we identified exhibited great connectivity in our causal gene network with every key driver gene, including CDK14, POLA1, lnc-NCS1-2:1, and lnc-FOXK1-4:1 (all FDR < 0.05 in those phases). Together, these results obtained using mathematical approaches and bioinformatics algorithmics might provide potential new mechanisms involved in the cytotoxicity induced by Cr.
Identification of Potential Diagnostic and Prognostic Biomarkers for Colorectal Cancer Based on GEO and TCGA Databases
Authors: Wang Zhenjiang , Guo Mingyi , Ai Xinbo , Cheng Jianbin , Huang Zaiwei , Li Xiaobin , Chen Yuping
Published: January 2021

Colorectal cancer (CRC) is one of the most common neoplastic diseases worldwide. With a high recurrence rate among all cancers, treatment of CRC only improved a little over the last two decades. The mortality and morbidity rates can be significantly lessened by earlier diagnosis and prompt treatment. Available biomarkers are not sensitive enough for the diagnosis of CRC, whereas the standard diagnostic method, endoscopy, is an invasive test and expensive. Hence, seeking the diagnostic and prognostic biomarkers of CRC is urgent and challenging. With that order, we screened the overlapped differentially expressed genes (DEGs) of GEO (GSE110223, GSE110224, GSE113513) and TCGA datasets. Subsequent protein–protein interaction network analysis recognized the hub genes among these DEGs. Further functional analyses including Gene Ontology and KEGG pathway analysis and gene set enrichment analysis were processed to investigate the role of these genes and potential underlying mechanisms in CRC. Kaplan–Meier analysis and Cox hazard ratio analysis were carried out to clarify the diagnostic and prognostic role of these genes. In conclusion, our present study demonstrated that CCNA2, MAD2L1, DLGAP5, AURKA, and RRM2 are all potential diagnostic biomarkers for CRC and may also be potential treatment targets for clinical implication in the future.
Role of Endothelial and Mesenchymal Cell Transitions in Heart Failure and Recovery Thereafter
Authors: Wang Guangyu , Cruz Ana Sofia , Youker Keith , Marcos-Abdala Hernan G. , Thandavarayan Rajarajan A. , Cooke John P. , Torre-Amione Guillermo , Chen Kaifu , Bhimaraj Arvind
Published: January 2021

Background: Mechanisms of myocardial recovery are not well elucidated.

Methods: 3-month-old C57/BL6 mice were treated with Angiotensin-II infusion and N (w)-nitro-L-arginine methyl ester in drinking water to induce HF at 5 weeks. These agents were discontinued, and animals studied with echocardiographic, histological and genetic assessment every 2 weeks until week 19. mRNA was extracted from these samples and human pre-post LVAD samples.

Results: Histologic and echo characteristics showed progressive worsening of cardiac function by week 5 and normalization by week 19 accompanied by normalization of the transcriptional profile. Expression of 1,350 genes were upregulated and 3,050 genes down regulated in HF compared to controls; during recovery, this altered gene expression was largely reversed. We focused on genes whose expression was altered during HF but reverted to control levels by Week 19. A gene ontology (GO) analysis of this cohort of genes implicated pathways involved in EndoMT and MEndoT. The cohort of genes that were differentially regulated in heart failure recovery in the murine model, were similarly regulated in human myocardial samples obtained pre- and post-placement of a left ventricular assist device (LVAD). Human end stage HF myocardial samples showed cells with dual expressed VE-Cadherin and FSP-1 consistent with cell fate transition. Furthermore, we observed a reduction in fibrosis, and an increase in endothelial cell density, in myocardial samples pre- and post-LVAD.

Conclusions: Cell fate transitions between endothelial and mesenchymal types contribute to the pathophysiology of heart failure followed by recovery.
LncRNA H19 Suppresses Osteosarcomagenesis by Regulating snoRNAs and DNA Repair Protein Complexes
Authors: Xu An , Huang Mo-Fan , Zhu Dandan , Gingold Julian A. , Bazer Danielle A. , Chang Betty , Wang Donghui , Lai Chien-Chen , Lemischka Ihor R. , Zhao Ruiying , Lee Dung-Fang
Published: January 2021

Osteosarcoma is one of the most frequent common primary malignant tumors in childhood and adolescence. Long non-coding RNAs (lncRNAs) have been reported to regulate the initiation and progression of tumors. However, the exact molecular mechanisms involving lncRNA in osteosarcomagenesis remain largely unknown. Li-Fraumeni syndrome (LFS) is a familial cancer syndrome caused by germline p53 mutation. We investigated the tumor suppressor function of lncRNA H19 in LFS-associated osteosarcoma. Analyzing H19-induced transcriptome alterations in LFS induced pluripotent stem cell (iPSC)-derived osteoblasts, we unexpectedly discovered a large group of snoRNAs whose expression was significantly affected by H19. We identified SNORA7A among the H19-suppressed snoRNAs. SNORA7A restoration impairs H19-mediated osteogenesis and tumor suppression, indicating an oncogenic role of SNORA7A. TCGA analysis indicated that SNORA7A expression is associated with activation of oncogenic signaling and poor survival in cancer patients. Using an optimized streptavidin-binding RNA aptamer designed from H19 lncRNA, we revealed that H19-tethered protein complexes include proteins critical for DNA damage response and repair, confirming H19's tumor suppressor role. In summary, our findings demonstrate a critical role of H19-modulated SNORA7A expression in LFS-associated osteosarcomas.
An Eight-CpG-based Methylation Classifier for Preoperative Discriminating Early and Advanced-Late Stage of Colorectal Cancer
Authors: Hu Ji , Zhao Fu-ying , Huang Bin , Ran Jing , Chen Mei-yuan , Liu Hai-lin , Deng You-song , Zhao Xia , Han Xiao-fan
Published: January 2021

Aim

To develop and validate a CpG-based classifier for preoperative discrimination of early and advanced-late stage colorectal cancer (CRC).

Methods

We identified an epigenetic signature based on methylation status of multiple CpG sites (CpGs) from 372 subjects in The Cancer Genome Atlas (TCGA) CRC cohort, and an external cohort (GSE48684) with 64 subjects by LASSO regression algorithm. A classifier derived from the methylation signature was used to establish a multivariable logistic regression model to predict the advanced-late stage of CRC. A nomogram was further developed by incorporating the classifier and some independent clinical risk factors, and its performance was evaluated by discrimination and calibration analysis. The prognostic value of the classifier was determined by survival analysis. Furthermore, the diagnostic performance of several CpGs in the methylation signature was evaluated.

Results

The eight-CpG-based methylation signature discriminated early stage from advanced-late stage CRC, with a satisfactory AUC of more than 0.700 in both the training and validation sets. This methylation classifier was identified as an independent predictor for CRC staging. The nomogram showed favorable predictive power for preoperative staging, and the C-index reached 0.817 (95% CI: 0.753–0.881) and 0.817 (95% CI: 0.721–0.913) in another training set and validation set respectively, with good calibration. The patients stratified in the high-risk group by the methylation classifier had significantly worse survival outcome than those in the low-risk group. Combination diagnosis utilizing only four of the eight specific CpGs performed well, even in CRC patients with low CEA level or at early stage.

Conclusions

Our classifier is a valuable predictive indicator that can supplement established methods for more accurate preoperative staging and also provides prognostic information for CRC patients. Besides, the combination of multiple CpGs has a high value in the diagnosis of CRC.
Identification of Common Genes and Pathways in Eight Fibrosis Diseases
Authors: Gu Chang , Shi Xin , Dang Xuening , Chen Jiafei , Chen Chunji , Chen Yumei , Pan Xufeng , Huang Tao
Published: January 2021

Acute and chronic inflammation often leads to fibrosis, which is also the common and final pathological outcome of chronic inflammatory diseases. To explore the common genes and pathogenic pathways among different fibrotic diseases, we collected all the reported genes of the eight fibrotic diseases: eye fibrosis, heart fibrosis, hepatic fibrosis, intestinal fibrosis, lung fibrosis, pancreas fibrosis, renal fibrosis, and skin fibrosis. We calculated the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment scores of all fibrotic disease genes. Each gene was encoded using KEGG and GO enrichment scores, which reflected how much a gene can affect this function. For each fibrotic disease, by comparing the KEGG and GO enrichment scores between reported disease genes and other genes using the Monte Carlo feature selection (MCFS) method, the key KEGG and GO features were identified. We compared the gene overlaps among eight fibrotic diseases and connective tissue growth factor (CTGF) was finally identified as the common key molecule. The key KEGG and GO features of the eight fibrotic diseases were all screened by MCFS method. Moreover, we interestingly found overlaps of pathways between renal fibrosis and skin fibrosis, such as GO:1901890-positive regulation of cell junction assembly, as well as common regulatory genes, such as CTGF, which is the key molecule regulating fibrogenesis. We hope to offer a new insight into the cellular and molecular mechanisms underlying fibrosis and therefore help leading to the development of new drugs, which specifically delay or even improve the symptoms of fibrosis.
Role of TLR4 in Persistent Leptospira interrogans Infection: A Comparative In Vivo Study in Mice
Authors: Nair Nisha , Guedes Mariana S. , Hajjar Adeline M. , Werts Catherine , Gomes-Solecki Maria
Published: January 2021

Toll-Like Receptor (TLR) 4, the LPS receptor, plays a central role in the control of leptospirosis and absence of TLR4 results in lethal infection in mice. Because human TLR4 does not sense the atypical leptospiral-LPS, we hypothesized that TLR4/MD-2 humanized transgenic mice (huTLR4) may be more susceptible to leptospirosis than wild-type mice, and thus may constitute a model of acute human leptospirosis. We infected huTLR4 mice, which express human TLR4 but not murine TLR4, with a high dose ofL. interrogansserovar Copenhageni FioCruz (Leptospira) in comparison to C57BL/6J wild-type (WT) and, as a control, a congenic strain in which thetlr4coding sequences are deleted (muTLR4Lps-del). We show that the huTLR4 gene is fully functional in the murine background. We found that dissemination ofLeptospirain blood, shedding in urine, colonization of the kidney and overall kinetics of leptospirosis progression is equivalent between WT and huTLR4 C57BL/6J mice. Furthermore, inflammation of the kidney appeared to be subdued in huTLR4 compared to WT mice in that we observed less infiltrates of mononuclear lymphocytes, less innate immune markers and no relevant differences in fibrosis markers. Thus, huTLR4 mice showed less inflammation and kidney pathology, and are not more susceptible to leptospirosis than WT mice. This study is significant as it indicates that one intact TLR4 gene, be it mouse or human, is necessary to control acute leptospirosis.
Broadband Frequency and Spatial On-Demand Tailoring of Topological Wave Propagation Harnessing Piezoelectric Metamaterials
Authors: Dorin Patrick , Wang K. W.
Published: January 2021

Many engineering applications leverage metamaterials to achieve elastic wave control. To enhance the performance and expand the functionalities of elastic waveguides, the concepts of electronic transport in topological insulators have been applied to elastic metamaterials. Initial studies showed that topologically protected elastic wave transmission in mechanical metamaterials could be realized that is immune to backscattering and undesired localization in the presence of defects or disorder. Recent studies have developed tunable topological elastic metamaterials to maximize performance in the presence of varying external conditions, adapt to changing operating requirements, and enable new functionalities such as a programmable wave path. However, a challenge remains to achieve a tunable topological metamaterial that is comprehensively adaptable in both the frequency and spatial domains and is effective over a broad frequency bandwidth that includes a subwavelength regime. To advance the state of the art, this research presents a piezoelectric metamaterial with the capability to concurrently tailor the frequency, path, and mode shape of topological waves using resonant circuitry. In the research presented in this manuscript, the plane wave expansion method is used to detect a frequency tunable subwavelength Dirac point in the band structure of the periodic unit cell and discover an operating region over which topological wave propagation can exist. Dispersion analyses for a finite strip illuminate how circuit parameters can be utilized to adjust mode shapes corresponding to topological edge states. A further evaluation provides insight into how increased electromechanical coupling and lattice reconfiguration can be exploited to enhance the frequency range for topological wave propagation, increase achievable mode localization, and attain additional edge states. Topological guided wave propagation that is subwavelength in nature and adaptive in path, localization, and frequency is illustrated in numerical simulations of thin plate structures. Outcomes from the presented work indicate that the easily integrable and comprehensively tunable proposed metamaterial could be employed in applications requiring a multitude of functions over a broad frequency bandwidth.
Dislocation-Controlled Low-Temperature Superplastic Deformation of Ti-6Al-4V Alloy
Authors: Liu Chao , Wang Xin , Zhou Ge , Li Feng , Zhang Siqian , Zhang Haoyu , Chen Lijia , Liu Haijian
Published: January 2021

The superplastic tension and deformation mechanism of Ti-6Al-4V alloy at 923 K and a tensile speed of 10−3, 5 × 10−3, or 5 × 10−2 s−1 was studied on an AG 250KNE electronic tension tester. Through theoretical modeling, the unit dislocation count of this alloy during superplastic deformation was introduced into the Ruano–Wadsworth–Sherby (R-W-S) deformation mechanism map, and a new deformation mechanism map involving dislocation count was plotted. Thereby, the mechanism underling the low-temperature superplastic deformation of this alloy was predicted. It was found the superplastic tension of Ti-6Al-4V at the tested temperature was controlled by dislocation movement, and with an increase in strain rate, the deformation transited from the dislocation-controlled mechanism with a stress index of 4 to the dislocation glide mechanism with a stress index of 5 or 7. At the strain rate of 10−3 s−1, this alloy reached the largest tension rate of 790% and strain rate sensitivity index of 0.52 and had excellent low-temperature superplastic properties.
Inhaled Gases as Therapies for Post–Cardiac Arrest Syndrome: A Narrative Review of Recent Developments
Authors: Hayashida Kei , Miyara Santiago J. , Shinozaki Koichiro , Takegawa Ryosuke , Yin Tai , Rolston Daniel M. , Choudhary Rishabh C. , Guevara Sara , Molmenti Ernesto P. , Becker Lance B.
Published: January 2021

Despite recent advances in the management of post–cardiac arrest syndrome (PCAS), the survival rate, without neurologic sequelae after resuscitation, remains very low. Whole-body ischemia, followed by reperfusion after cardiac arrest (CA), contributes to PCAS, for which established pharmaceutical interventions are still lacking. It has been shown that a number of different processes can ultimately lead to neuronal injury and cell death in the pathology of PCAS, including vasoconstriction, protein modification, impaired mitochondrial respiration, cell death signaling, inflammation, and excessive oxidative stress. Recently, the pathophysiological effects of inhaled gases including nitric oxide (NO), molecular hydrogen (H2), and xenon (Xe) have attracted much attention. Herein, we summarize recent literature on the application of NO, H2, and Xe for treating PCAS. Recent basic and clinical research has shown that these gases have cytoprotective effects against PCAS. Nevertheless, there are likely differences in the mechanisms by which these gases modulate reperfusion injury after CA. Further preclinical and clinical studies examining the combinations of standard post-CA care and inhaled gas treatment to prevent ischemia–reperfusion injury are warranted to improve outcomes in patients who are being failed by our current therapies.
Genome-Wide Profiling of Diadegma semiclausum Ichnovirus Integration in Parasitized Plutella xylostella Hemocytes Identifies Host Integration Motifs and Insertion Sites
Authors: Wang Ze-hua , Zhou Yue-nan , Yang Jing , Ye Xi-qian , Shi Min , Huang Jian-hua , Chen Xue-xin
Published: January 2021

Polydnaviruses (PDVs), classified into two genera, bracoviruses (BVs) and ichnoviruses (IVs), are large, double-stranded DNA viruses, which are beneficial symbionts of parasitoid wasps. PDVs do not replicate in their infected lepidopteran hosts. BV circles have been demonstrated to be integrated into host genomic DNA after natural parasitization. However, the integrations of IV circles in vivo remain largely unknown. Here, we analyzed the integration of Diadegma semiclausum ichnovirus (DsIV) in the genomic DNA of parasitized Plutella xylostella hemocytes. We found that DsIV circles are present in host hemocytes with non-integrated and integrated forms. Moreover, DsIV integrates its DNA circles into the host genome by two distinct strategies, conservatively, and randomly. We also found that four conserved-broken circles share similar motifs containing two reverse complementary repeats at their breaking sites, which were host integration motifs (HIMs). We also predicted HIMs of eight circles from other ichnoviruses, indicating that a HIM-mediated specific mechanism was conserved in IV integrations. Investigation of DsIV circle insertion sites of the host genome revealed the enrichment of microhomologies between the host genome and the DsIV circles at integration breakpoints. These findings will deepen our understanding of the infections of PDVs, especially IVs.
Fungal Community and Biodeterioration Analysis of Hull Wood and Its Storage Environment of the Nanhai No. 1 Shipwreck
Authors: Han Yeqing , Huang Xinduo , Wang Yu , Du Jing , Ma Kaixuan , Chen Yue , Li Naisheng , Zhang Zhiguo , Pan Jiao
Published: January 2021

The Nanhai No. 1 shipwreck is a Chinese merchant ship in the Southern Song Dynasty, and now it is stored in a huge enclosed glass warehouse in Maritime Silk Road Museum in Guangdong Province. At present, the hull of the Nanhai No. 1 shipwreck is still being excavated, and a small part of the hull wood is soaked in a specific solution to desalt. Through long-term exploration, we found that the above two states of hull wood had undergone biodeterioration, so the purpose of this study is to analyze the fungal community of exposed and soaked wood from the Nanhai No. 1 shipwreck. We sampled 10 exposed hull wood and sea mud samples, two wood storage water samples, and air samples in the glass warehouse. We used scanning electron microscope and optical microscope to find that there were obvious fungal structures in exposed wood and wood storing water samples. High-throughput sequencing of fungi revealed that the most abundant genera in exposed and soaked wood were Fusarium sp., and Scedosporium sp., respectively. In addition, Fusarium solani and Scedosporium apiospermum were successfully isolated from the hull wood surface and wood storing water samples, and the degradation tests of lignin and cellulose, the sensitivity tests of biocides and growth curve assay were carried out. We also found that Penicillium sp. and Cladosporium sp. are the most abundant in the glass warehouse air. Our research results show that F. solani and S. apiospermum should be regarded as a major threat to the preservation of the Nanhai No. 1 shipwreck. These results provide a reference for our protection of shipwrecks and other similar artifacts.
Untargeted Metabolomic Analysis Combined With Multivariate Statistics Reveal Distinct Metabolic Changes in GPR40 Agonist-Treated Animals Related to Bile Acid Metabolism
Authors: Doerfler Hannes , Botesteanu Dana-Adriana , Blech Stefan , Laux Ralf
Published: January 2021

Metabolomics has been increasingly applied to biomarker discovery, as untargeted metabolic profiling represents a powerful exploratory tool for identifying causal links between biomarkers and disease phenotypes. In the present work, we used untargeted metabolomics to investigate plasma specimens of rats, dogs, and mice treated with small-molecule drugs designed for improved glycemic control of type 2 diabetes mellitus patients via activation of GPR40. The in vivo pharmacology of GPR40 is not yet fully understood. Compounds targeting this receptor have been found to induce drug-induced liver injury (DILI). Metabolomic analysis facilitating an integrated UPLC-TWIMS-HRMS platform was used to detect metabolic differences between treated and non-treated animals within two 4-week toxicity studies in rat and dog, and one 2-week toxicity study in mouse. Multivariate statistics of untargeted metabolomics data subsequently revealed the presence of several significantly upregulated endogenous compounds in the treated animals whose plasma level is known to be affected during DILI. A specific bile acid metabolite useful as endogenous probe for drug–drug interaction studies was identified (chenodeoxycholic acid-24 glucuronide), as well as a metabolic precursor indicative of acidic bile acid biosynthesis (7α-hydroxy-3-oxo-4-cholestenoic acid). These results correlate with typical liver toxicity parameters on the individual level.
Decreased Retinal Vascular Density in Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI): An Optical Coherence Tomography Angiography (OCTA) Study
Authors: Wang Xi , Zhao Qianhua , Tao Rui , Lu Huimeng , Xiao Zhenxu , Zheng Li , Ding Ding , Ding Saineng , Ma Yichen , Lu Zhaozeng , Xiao Yiqin
Published: January 2021

Background

To explore the retinal vascular density changes in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients using optical coherence tomography angiography (OCTA).

Methods

We recruit 62 AD patients, 47 MCI patients, and 49 cognitively healthy controls (HC) in this study. All participants in the study received a comprehensive ophthalmological and neurological evaluation, including global cognitive screening, as well as the Mini-Mental State Examination (MMSE), and completed the following eye examinations: visual acuity (VA), intraocular pressure (IOP), examination with slit-lamp, fundus photography (Version 1.5.0.0, NIDEK CO, LTD) and Optical coherence tomography imaging (software ReVue version 2017.1.0.155, Optovue Inc., Fremont, CA, United States). The visual rating scales for atrophy and white matter lesion in MRI was evaluated for all the patients with AD and MCI.

Results

In the AD patient group, the superficial vascular density in the superior, inferior and whole retina was 44.64 ± 3.34, 44.65 ± 3.55, and 44.66 ± 3.36, respectively. These values were 44.24 ± 3.15, 43.72 ± 3.16, and 44 ± 3.07, respectively, in the MCI patient group. After multivariate analysis of the generalized linear model, adjustments for the confounding factors of sex, age, hypertension, diabetes and the quality index of OCTA image, the superficial vascular density in the AD and MCI patient groups was significantly lower than that in the HC group (P < 0.05): 46.94 ± 2.04, 46.67 ± 2.26, and 46.82 ± 2.08, respectively. No difference in the area of the FAZ among the three groups was observed (AD group: 0.34 ± 0.11 mm2; MCI group: 0.36 ± 0.12 mm2; control group: 0.33 ± 0.12 mm2, p > 0.05). The ganglion cell complex (GCC) thickness, inner parafovea thickness, and peripapillary retinal nerve fiber layer (p-RNFL) thickness were associated with the superficial vascular density. We found no significant correlation between the global cognition (MMSE scores) or between the Fazekas score and retinal OCT angiogram flow density.

Conclusion

The superficial vascular density in the AD and MCI patient groups was significantly lower than that in the HC group. Our findings suggest the retinal microvascular dysfunction occurred in MCI and AD.
Atorvastatin Attenuates Isoflurane-Induced Activation of ROS-p38MAPK/ATF2 Pathway, Neuronal Degeneration, and Cognitive Impairment of the Aged Mice
Authors: Liu Pengfei , Gao Quansheng , Guan Lei , Sheng Weixuan , Hu Yanting , Gao Teng , Jiang Jingwen , Xu Yongxing , Qiao Hui , Xue Xinying , Liu Sanhong , Li Tianzuo
Published: January 2021

Isoflurane, a widely used volatile anesthetic, induces neuronal apoptosis and memory impairments in various animal models. However, the potential mechanisms and effective pharmacologic agents are still not fully understood. The p38MAPK/ATF-2 pathway has been proved to regulate neuronal cell survival and inflammation. Besides, atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, exerts neuroprotective effects. Thus, this study aimed to explore the influence of atorvastatin on isoflurane-induced neurodegeneration and underlying mechanisms. Aged C57BL/6 mice (20 months old) were exposed to isoflurane (1.5%) anesthesia for 6 h. Atorvastatin (5, 10, or 20 mg/kg body weight) was administered to the mice for 7 days. Atorvastatin attenuated the isoflurane-induced generation of ROS and apoptosis. Western blotting revealed a decrease in cleaved caspase-9 and caspase-3 expression in line with ROS levels. Furthermore, atorvastatin ameliorated the isoflurane-induced activation of p38MAPK/ATF-2 signaling. In a cellular study, we proved that isoflurane could induce oxidative stress and inflammation by activating the p38MAPK/ATF-2 pathway in BV-2 microglia cells. In addition, SB203580, a selected p38MAPK inhibitor, inhibited the isoflurane-induced inflammation, oxidative stress, and apoptosis. The results implied that p38MAPK/ATF-2 was a potential target for the treatment of postoperative cognitive dysfunction.
Cognitive and Behavioral Inhibition Deficits in Parkinson’s Disease: The Hayling Test as a Reliable Marker
Authors: Siquier Antònia , Andrés Pilar
Published: January 2021

Objective

The present study seeks to provide an overview of executive (inhibition and flexibility) deficits in Parkinson’s disease (PD) by combining a cognitive and behavioral approach.

Methods

Fifteen PD patients and 15 healthy controls underwent a neuropsychological and behavioral assessment including the Hayling and Trails Tests, the Questionnaire for Impulsive–Compulsive Disorders in Parkinson’s Disease (QUIP-RS), the Behavior Rating Inventory of Executive Function (BRIEF-A), and the Short Form-36 Health Survey (SF-36). The level of awareness of executive functioning was also analyzed. We finally explored how these neuropsychological and clinical outcomes could relate to each other.

Results

PD patients performed significantly worse in both neuropsychological tasks designed to evaluate inhibition abilities. They also reported more inhibition difficulties in everyday life and poorer quality of life. Associations between neuropsychological measures and self-reports were found. Moreover, as indicated by the discrepancy score, PD patients were as accurate as their relatives in self-reporting their executive daily difficulties.

Conclusion

Inhibition and cognitive flexibility impairments assessed by the neuropsychological tests (Hayling and Trails tests) seem to capture daily life executive problems in PD. Furthermore, our study provides a deeper understanding of PD patients’ and their relatives’ experience of these executive dysfunctions.
Fluoxetine Promotes Hippocampal Oligodendrocyte Maturation and Delays Learning and Memory Decline in APP/PS1 Mice
Authors: Chao Feng-lei , Zhang Yi , Zhang Lei , Jiang Lin , Zhou Chun-ni , Tang Jing , Liang Xin , Fan Jin-hua , Dou Xiao-yun , Tang Yong
Published: January 2021

Oligodendrogenesis dysfunction impairs memory consolidation in adult mice, and an oligodendrocyte abnormality is an important change occurring in Alzheimer's disease (AD). While fluoxetine (FLX) is known to delay memory decline in AD models, its effects on hippocampal oligodendrogenesis are unclear. Here, we subjected 8-month-old male amyloid precursor protein (APP)/presenilin 1 (PS1) mice to the FLX intervention for 2 months. Their exploratory behaviors and general activities in a novel environment, spatial learning and memory and working and reference memory were assessed using the open-field test, Morris water maze, and Y maze. Furthermore, changes in hippocampal oligodendrogenesis were investigated using stereology, immunohistochemistry, immunofluorescence staining, and Western blotting techniques. FLX delayed declines in the spatial learning and memory, as well as the working and reference memory of APP/PS1 mice. In addition, APP/PS1 mice exhibited immature hippocampal oligodendrogenesis, and FLX increased the numbers of 2′3′cyclic nucleotide 3′-phosphodiesterase (CNPase)+ and newborn CNPase+ oligodendrocytes in the hippocampi of APP/PS1 mice. Moreover, FLX increased the density of SRY-related HMG-box 10 protein (SOX10)+ cells and reduced the percentage of oligodendrocyte lineage cells displaying the senescence phenotype (CDKN2A/p16INK4a) in the hippocampus of APP/PS1 mice. Moreover, FLX had no effect on the serotonin (5-HT) 1A receptor (5-HT1AR) content or number of 5-HT1AR+ oligodendrocytes, but it reduced the content and activity of glycogen synthase kinase 3β (GSK3β) in the hippocampus of APP/PS1 transgenic mice. Taken together, FLX delays the senescence of oligodendrocyte lineage cells and promotes oligodendrocyte maturation in the hippocampus of APP/PS1 mice. FLX may regulate GSK3β through a mechanism other than 5-HT1AR and then inhibit the negative effect of GSK3β on oligodendrocyte maturation in the hippocampus of an AD mouse model.
High Contrast Allows the Retina to Compute More Than Just Contrast
Authors: Yedutenko Matthew , Howlett Marcus H. C. , Kamermans Maarten
Published: January 2021

The goal of sensory processing is to represent the environment of an animal. All sensory systems share a similar constraint: they need to encode a wide range of stimulus magnitudes within their narrow neuronal response range. The most efficient way, exploited by even the simplest nervous systems, is to encode relative changes in stimulus magnitude rather than the absolute magnitudes. For instance, the retina encodes contrast, which are the variations of light intensity occurring in time and in space. From this perspective, it is easy to understand why the bright plumage of a moving bird gains a lot of attention, while an octopus remains motionless and mimics its surroundings for concealment. Stronger contrasts simply cause stronger visual signals. However, the gains in retinal performance associated with higher contrast are far more than what can be attributed to just a trivial linear increase in signal strength. Here we discuss how this improvement in performance is reflected throughout different parts of the neural circuitry, within its neural code and how high contrast activates many non-linear mechanisms to unlock several sophisticated retinal computations that are virtually impossible in low contrast conditions.
Clinical Features, Radiological Characteristics, and Outcomes of Patients With Intracranial Alveolar Echinococcosis: A Case Series From Tibetan Areas of Sichuan Province, China
Authors: Li Sisi , Chen Jiani , He Yongqiao , Deng Yongyi , Chen Jie , Fang Wenyu , Zeren Zhamu , Liu Yadong , Abdulaziz Ammar Taha Abdullah , Yan Bo , Zhou Dong
Published: January 2021

Objectives: Intracranial alveolar echinococcosis (IAE), a zoonotic disease, is a critical health problem in the Tibetan region. We aimed to describe the clinical and radiological characteristics and outcomes among patients with IAE.

Methods: We screened patients diagnosed with IAE between March 2015 and May 2019 at the Ganzi Tibetan Autonomous Prefecture People's Hospital. Detailed demographics, clinical characteristics, neuroimaging features, and outcomes were recorded.

Results: A total of 21 patients with an average age of 44.1 ± 12.7 years were included. Thirteen (61.9%) patients were male. The most common chief neurological complaint was headache (n = 17, 81.0%), followed by dizziness, seizure, visual disturbances, hemiparesis, disturbed consciousness, and dysphasia. All the patients had coexisting liver localizations. The typical neuroimaging features of IAE on cerebral magnetic resonance imaging scans showed obvious low-signal shadow with multiple small vesicles inside the lesions on T2-weighted images and FLAIR images. The pathological HE staining demonstrates vesicular lesions with several internal sacs. For hepatic alveolar echinococcosis (AE), the hepatic portal was invaded in six (28.6%) patients, and the portal vein (n = 5, 23.8%) was the mostly commonly involved vessel. As for treatment, 11 patients (52.4%) had poor compliance with albendazole. The duration of patients taken albendazole ranged from 2 months to 3 years. Cerebral AE surgery was performed in 11 patients, five of them underwent partial resection of AE lesions, and six patients received total resection. One patient with primary IAE underwent radical surgery. Ten patients (47.6%) died during the follow-up for a mean of 21.7 ± 11.9 (3–46) months. In total, 28.9% of the patients died within 5 years, and 71.6% died within 10 years. The median interval between the date of diagnosis as AE and death was 84 (19–144) months.

Conclusion: Despite substantial advances in diagnostic and therapeutic methods, the treatment of IAE remains difficult and results in unsatisfactory outcomes. The major critical issue is surgical treatment of IAE although the disease is disseminated. Besides, lifelong albendazole would be indicated, but most patients had poor medication compliance. It is important to educate patients about the necessity of medical treatment.
Objective Dual-Task Turning Measures for Return-to-Duty Assessment After Mild Traumatic Brain Injury: The ReTURN Study Protocol
Authors: Fino Peter C. , Weightman Margaret M. , Dibble Leland E. , Lester Mark E. , Hoppes Carrie W. , Parrington Lucy , Arango Jorge , Souvignier Alicia , Roberts Holly , King Laurie A.
Published: January 2021

Determining readiness for duty after mild traumatic brain injury (mTBI) is essential for the safety of service members and their unit. Currently, these decisions are primarily based on self-reported symptoms, objective measures that assess a single system, or standardized physical or cognitive tests that may be insensitive or lack ecological validity for warrior tasks. While significant technological advancements have been made in a variety of assessments of these individual systems, assessments of isolated tasks are neither diagnostically accurate nor representative of the demands imposed by daily life and military activities. Emerging evidence suggests that complex tasks, such as dual-task paradigms or turning, have utility in probing functional deficits after mTBI. Objective measures from turning tasks in single- or dual-task conditions, therefore, may be highly valuable for clinical assessments and return-to-duty decisions after mTBI. The goals of this study are to assess the diagnostic accuracy, predictive capacity, and responsiveness to rehabilitation of objective, dual-task turning measures within an mTBI population. These goals will be accomplished over two phases. Phase 1 will enroll civilians at three sites and active-duty service members at one site to examine the diagnostic accuracy and predictive capacity of dual-task turning outcomes. Phase 1 participants will complete a series of turning tasks while wearing inertial sensors and a battery of clinical questionnaires, neurocognitive testing, and standard clinical assessments of function. Phase 2 will enroll active-duty service members referred for rehabilitation from two military medical treatment facilities to investigate the responsiveness to rehabilitation of objective dual-task turning measures. Phase 2 participants will complete two assessments of turning while wearing inertial sensors: a baseline assessment prior to the first rehabilitation session and a post-rehabilitation assessment after the physical therapist determines the participant has completed his/her rehabilitation course. A variable selection procedure will then be implemented to determine the best task and outcome measure for return-to-duty decisions based on diagnostic accuracy, predictive capacity, and responsiveness to rehabilitation. Overall, the results of this study will provide guidance and potential new tools for clinical decisions in individuals with mTBI.

Clinical Trial Registration:clinicaltrials.gov, Identifier NCT03892291.
Neurodegenerative Disease and the Experience of Homelessness
Authors: Piña-Escudero Stefanie Danielle , López Lucía , Sriram Sandeepa , Longoria Ibarrola Erika Mariana , Miller Bruce , Lanata Serggio
Published: January 2021

Introduction: Today, half of the American homeless population is older than 50 years of age. This shift in age distribution among people experiencing homelessness has challenged our long-held views of the causes of homelessness. Age-related neurological diseases, especially neurodegenerative diseases of the brain (NDDB), may play a role eliciting homelessness in a significant proportion of vulnerable older adults. This article aims to explore relationships between homelessness and NDDB in a cohort of research participants enrolled in observational studies on NDDB at an academic center.

Methods: We reviewed charts of the Memory and Aging Center (MAC) of the University of California, San Francisco's database searching for research participants with NDDB that had direct relationship to homelessness. We reviewed all research visits conducted between 2004 and 2018 (N = 5,300). Research participants who had any relationship to homelessness were included in this analysis. NDDB was diagnosed via comprehensive neurological, functional, neuropsychological, and biomarker assessments. Non-parametric tests were used for analysis. Thirteen participants were found to have a direct relationship with homelessness. Seven were female and the median of education was 16 (IR: 12.0–19.5) years. Participants were divided into two groups: Those who experienced homelessness while symptomatic from a NDDB but before formal diagnosis (n = 5, Group 1); and participants with formally diagnosed NDDB who exhibited a new propensity toward homelessness (n = 8, Group 2). Compared to Group 2, participants in Group 1 were younger (p = 0.021) and showed similar results in the neuropsychological evaluation. In both groups, the most prevalent diagnosis was frontotemporal dementia. In Group 1, the majority of participants became homeless in the setting of a fragile socioeconomic situation and informants believed that NDDB contributed or caused their homeless state. In Group 2, a new propensity toward homelessness became manifest in different ways and it stood out that all of these participants were well-supported by family and friends during their illness.

Conclusions and Relevance: This case series highlights the role that NDDB may have in precipitating homelessness among vulnerable older adults, particularly in the setting of challenging socioeconomic circumstances and unsupportive living environments. Social ramifications of these findings, particularly pertaining to challenges around rehousing these individuals is discussed.