bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal genome-wide methylation study of PTSD treatment using prolonged exposure and hydrocortisone
Authors: Yang Ruoting , Xu Changxin , Bierer Linda M. , Flory Janine D. , Gautam Aarti , Bader Heather N. , Lehrner Amy , Makotkine Iouri , Desarnaud Frank , Miller Stacy A. , Jett Marti , Hammamieh Rasha , Yehuda Rachel
Published: July 2021

Epigenetic changes are currently invoked as explanations for both the chronicity and tenacity of post-traumatic stress disorder (PTSD), a heterogeneous condition showing varying, sometimes idiosyncratic responses to treatment. This study evaluated epigenetic markers in the context of a randomized clinical trial of PTSD patients undergoing prolonged-exposure psychotherapy with and without a hydrocortisone augmentation prior to each session. The purpose of the longitudinal epigenome-wide analyses was to identify predictors of recovery (from pretreatment data) or markers associated with symptom change (based on differences between pre- and post-therapy epigenetic changes). The results of these analyses identified the CREB–BDNF signaling pathway, previously linked to startle reaction and fear learning and memory processes, as a convergent marker predicting both symptom change and severity. Several previous-reported resilience markers were also identified (FKBP5, NR3C1, SDK1, and MAD1L1) to associate with PTSD recovery in this study. Especially, the methylation levels of FKBP5 in the gene body region decreased significantly as CAPS score decreased in responders, while no changes occurred in nonresponders. These biomarkers may have future utility in understanding clinical recovery in PTSD and potential applications in predicting treatment effects.
The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study
Authors: Onwordi Ellis Chika , Whitehurst Thomas , Mansur Ayla , Statton Ben , Berry Alaine , Quinlan Marina , O’Regan Declan P. , Rogdaki Maria , Marques Tiago Reis , Rabiner Eugenii A. , Gunn Roger N. , Vernon Anthony C. , Natesan Sridhar , Howes Oliver D.
Published: July 2021

Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [11C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [11C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.
Reduced cortical thickness of the paracentral lobule in at-risk mental state individuals with poor 1-year functional outcomes
Authors: Sasabayashi Daiki , Takayanagi Yoichiro , Takahashi Tsutomu , Nishiyama Shimako , Mizukami Yuko , Katagiri Naoyuki , Tsujino Naohisa , Nemoto Takahiro , Sakuma Atsushi , Katsura Masahiro , Ohmuro Noriyuki , Okada Naohiro , Tada Mariko , Suga Motomu , Maikusa Norihide , Koike Shinsuke , Furuichi Atsushi , Kido Mikio , Noguchi Kyo , Yamasue Hidenori , Matsumoto Kazunori , Mizuno Masafumi , Kasai Kiyoto , Suzuki Michio
Published: July 2021

Although widespread cortical thinning centered on the fronto-temporal regions in schizophrenia has been reported, the findings in at-risk mental state (ARMS) patients have been inconsistent. In addition, it remains unclear whether abnormalities of cortical thickness (CT) in ARMS individuals, if present, are related to their functional decline irrespective of future psychosis onset. In this multicenter study in Japan, T1-weighted magnetic resonance imaging was performed at baseline in 107 individuals with ARMS, who were subdivided into resilient (77, good functional outcome) and non-resilient (13, poor functional outcome) groups based on the change in Global Assessment of Functioning scores during 1-year follow-up, and 104 age- and sex-matched healthy controls recruited at four scanning sites. We measured the CT of the entire cortex and performed group comparisons using FreeSurfer software. The relationship between the CT and cognitive functioning was examined in an ARMS subsample (n = 70). ARMS individuals as a whole relative to healthy controls exhibited a significantly reduced CT, predominantly in the fronto-temporal regions, which was partly associated with cognitive impairments, and an increased CT in the left parietal and right occipital regions. Compared with resilient ARMS individuals, non-resilient ARMS individuals exhibited a significantly reduced CT of the right paracentral lobule. These findings suggest that ARMS individuals partly share CT abnormalities with patients with overt schizophrenia, potentially representing general vulnerability to psychopathology, and also support the role of cortical thinning in the paracentral lobule as a predictive biomarker for short-term functional decline in the ARMS population.
IRF-8/miR-451a regulates M-MDSC differentiation via the AMPK/mTOR signal pathway during lupus development
Authors: Shi Guoping , Li Dan , Zhang Dongya , Xu Yujun , Pan Yuchen , Lu Li , Li Jingman , Xia Xiaoyu , Dou Huan , Hou Yayi
Published: July 2021

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease. Myeloid-derived suppressor cells (MDSCs) have been found to be involved in the regulation of SLE development. However, little is known about the association between MDSC subsets and the factors that draw MDSCs into abnormal expansion. This study found that the percentage of M-MDSCs increased in mice with pristane-induced lupus. Toll-like receptor (TLR)7 signal activation and high interferon-α (IFN-α) level promoted M-MDSC differentiation in vitro. Moreover, both AMP-activated protein kinase (AMPK) agonist metformin and two mammalian targets of rapamycin (mTOR) inhibitors (INK128 and rapamycin) inhibited the percentage of M-MDSCs in lupus mice as well as in the TLR7- and IFN-α-induced bone marrow (BM) differentiation into MDSCs in vitro. In terms of mechanism, whole-genome transcriptome profiling was performed by RNA sequencing, revealing that the expression of the transcription factor IRF-8 was higher in M-MDSCs isolated from pristane-induced lupus mice, compared with control mice. IRF-8 was identified to be crucial for TLR7- and IFN-α-induced BM differentiation into MDSCs in vitro. Furthermore, interferon (IFN) regulatory factor8 (IRF-8) was targeted by miR-451a in M-MDSC differentiation. Of note, metformin-modified M-MDSCs could relieve lupus symptoms in pristane-induced lupus mice. The findings revealed a novel mechanism linking IRF-8/miR-451a to M-MDSC differentiation via the AMPK/mTOR signal pathway during lupus development. This study might provide an important reference for SLE therapy by targeting M-MDSCs.
Development of a fixed module repertoire for the analysis and interpretation of blood transcriptome data
Authors: Altman Matthew C. , Rinchai Darawan , Baldwin Nicole , Toufiq Mohammed , Whalen Elizabeth , Garand Mathieu , Syed Ahamed Kabeer Basirudeen , Alfaki Mohamed , Presnell Scott R. , Khaenam Prasong , Ayllón-Benítez Aaron , Mougin Fleur , Thébault Patricia , Chiche Laurent , Jourde-Chiche Noemie , Phillips J. Theodore , Klintmalm Goran , O’Garra Anne , Berry Matthew , Bloom Chloe , Wilkinson Robert J. , Graham Christine M. , Lipman Marc , Lertmemongkolchai Ganjana , Bedognetti Davide , Thiebaut Rodolphe , Kheradmand Farrah , Mejias Asuncion , Ramilo Octavio , Palucka Karolina , Pascual Virginia , Banchereau Jacques , Chaussabel Damien
Published: July 2021

As the capacity for generating large-scale molecular profiling data continues to grow, the ability to extract meaningful biological knowledge from it remains a limitation. Here, we describe the development of a new fixed repertoire of transcriptional modules, BloodGen3, that is designed to serve as a stable reusable framework for the analysis and interpretation of blood transcriptome data. The construction of this repertoire is based on co-clustering patterns observed across sixteen immunological and physiological states encompassing 985 blood transcriptome profiles. Interpretation is supported by customized resources, including module-level analysis workflows, fingerprint grid plot visualizations, interactive web applications and an extensive annotation framework comprising functional profiling reports and reference transcriptional profiles. Taken together, this well-characterized and well-supported transcriptional module repertoire can be employed for the interpretation and benchmarking of blood transcriptome profiles within and across patient cohorts. Blood transcriptome fingerprints for the 16 reference cohorts can be accessed interactively via: https://drinchai.shinyapps.io/BloodGen3Module/.
Myofibroblast transcriptome indicates SFRP2hi fibroblast progenitors in systemic sclerosis skin
Authors: Tabib Tracy , Huang Mengqi , Morse Nina , Papazoglou Anna , Behera Rithika , Jia Minxue , Bulik Melissa , Monier Daisy E. , Benos Panayiotis V. , Chen Wei , Domsic Robyn , Lafyatis Robert
Published: July 2021

Skin and lung fibrosis in systemic sclerosis (SSc) is driven by myofibroblasts, alpha-smooth muscle actin expressing cells. The number of myofibroblasts in SSc skin correlates with the modified Rodnan skin score, the most widely used clinical measure of skin disease severity. Murine fibrosis models indicate that myofibroblasts can arise from a variety of different cell types, but their origin in SSc skin has remained uncertain. Utilizing single cell RNA-sequencing, we define different dermal fibroblast populations and transcriptome changes, comparing SSc to healthy dermal fibroblasts. Here, we show that SSc dermal myofibroblasts arise in two steps from an SFRP2hi/DPP4-expressing progenitor fibroblast population. In the first step, SSc fibroblasts show globally upregulated expression of transcriptome markers, such as PRSS23 and THBS1. A subset of these cells shows markers indicating that they are proliferating. Only a fraction of SFRP2hi SSc fibroblasts differentiate into myofibroblasts, as shown by expression of additional markers, SFRP4 and FNDC1. Bioinformatics analysis of the SSc fibroblast transcriptomes implicated upstream transcription factors, including FOSL2, RUNX1, STAT1, FOXP1, IRF7 and CREB3L1, as well as SMAD3, driving SSc myofibroblast differentiation.
The effect of water on colloidal quantum dot solar cells
Authors: Shi Guozheng , Wang Haibin , Zhang Yaohong , Cheng Chen , Zhai Tianshu , Chen Botong , Liu Xinyi , Jono Ryota , Mao Xinnan , Liu Yang , Zhang Xuliang , Ling Xufeng , Zhang Yannan , Meng Xing , Chen Yifan , Duhm Steffen , Zhang Liang , Li Tao , Wang Lu , Xiong Shiyun , Sagawa Takashi , Kubo Takaya , Segawa Hiroshi , Shen Qing , Liu Zeke , Ma Wanli
Published: July 2021

Almost all surfaces sensitive to the ambient environment are covered by water, whereas the impacts of water on surface-dominated colloidal quantum dot (CQD) semiconductor electronics have rarely been explored. Here, strongly hydrogen-bonded water on hydroxylated lead sulfide (PbS) CQD is identified. The water could pilot the thermally induced evolution of surface chemical environment, which significantly influences the nanostructures, carrier dynamics, and trap behaviors in CQD solar cells. The aggravation of surface hydroxylation and water adsorption triggers epitaxial CQD fusion during device fabrication under humid ambient, giving rise to the inter-band traps and deficiency in solar cells. To address this problem, meniscus-guided-coating technique is introduced to achieve dense-packed CQD solids and extrude ambient water, improving device performance and thermal stability. Our works not only elucidate the water involved PbS CQD surface chemistry, but may also achieve a comprehensive understanding of the impact of ambient water on CQD based electronics.
SARS-CoV-2 antibody dynamics and transmission from community-wide serological testing in the Italian municipality of Vo’
Authors: Dorigatti Ilaria , Lavezzo Enrico , Manuto Laura , Ciavarella Constanze , Pacenti Monia , Boldrin Caterina , Cattai Margherita , Saluzzo Francesca , Franchin Elisa , Del Vecchio Claudia , Caldart Federico , Castelli Gioele , Nicoletti Michele , Nieddu Eleonora , Salvadoretti Elisa , Labella Beatrice , Fava Ludovico , Guglielmo Simone , Fascina Mariateresa , Grazioli Marco , Alvisi Gualtiero , Vanuzzo Maria Cristina , Zupo Tiziano , Calandrin Reginetta , Lisi Vittoria , Rossi Lucia , Castagliuolo Ignazio , Merigliano Stefano , Unwin H. Juliette T. , Plebani Mario , Padoan Andrea , Brazzale Alessandra R. , Toppo Stefano , Ferguson Neil M. , Donnelly Christl A. , Crisanti Andrea
Published: July 2021

In February and March 2020, two mass swab testing campaigns were conducted in Vo’, Italy. In May 2020, we tested 86% of the Vo’ population with three immuno-assays detecting antibodies against the spike and nucleocapsid antigens, a neutralisation assay and Polymerase Chain Reaction (PCR). Subjects testing positive to PCR in February/March or a serological assay in May were tested again in November. Here we report on the results of the analysis of the May and November surveys. We estimate a seroprevalence of 3.5% (95% Credible Interval (CrI): 2.8–4.3%) in May. In November, 98.8% (95% Confidence Interval (CI): 93.7–100.0%) of sera which tested positive in May still reacted against at least one antigen; 18.6% (95% CI: 11.0–28.5%) showed an increase of antibody or neutralisation reactivity from May. Analysis of the serostatus of the members of 1,118 households indicates a 26.0% (95% CrI: 17.2–36.9%) Susceptible-Infectious Transmission Probability. Contact tracing had limited impact on epidemic suppression.
Structures of ABCG2 under turnover conditions reveal a key step in the drug transport mechanism
Authors: Yu Qin , Ni Dongchun , Kowal Julia , Manolaridis Ioannis , Jackson Scott M. , Stahlberg Henning , Locher Kaspar P.
Published: July 2021

ABCG2 is a multidrug transporter that affects drug pharmacokinetics and contributes to multidrug resistance of cancer cells. In previously reported structures, the reaction cycle was halted by the absence of substrates or ATP, mutation of catalytic residues, or the presence of small-molecule inhibitors or inhibitory antibodies. Here we present cryo-EM structures of ABCG2 under turnover conditions containing either the endogenous substrate estrone-3-sulfate or the exogenous substrate topotecan. We find two distinct conformational states in which both the transport substrates and ATP are bound. Whereas the state turnover-1 features more widely separated NBDs and an accessible substrate cavity between the TMDs, turnover-2 features semi-closed NBDs and an almost fully occluded substrate cavity. Substrate size appears to control which turnover state is mainly populated. The conformational changes between turnover-1 and turnover-2 states reveal how ATP binding is linked to the closing of the cytoplasmic side of the TMDs. The transition from turnover-1 to turnover-2 is the likely bottleneck or rate-limiting step of the reaction cycle, where the discrimination of substrates and inhibitors occurs.
Elimination of noise in optically rephased photon echoes
Authors: Ma You-Zhi , Jin Ming , Chen Duo-Lun , Zhou Zong-Quan , Li Chuan-Feng , Guo Guang-Can
Published: July 2021

Photon echo is a fundamental tool for the manipulation of electromagnetic fields. Unavoidable spontaneous emission noise is generated in this process due to the strong rephasing pulse, which limits the achievable signal-to-noise ratio and represents a fundamental obstacle towards their applications in the quantum regime. Here we propose a noiseless photon-echo protocol based on a four-level atomic system. We implement this protocol in a Eu3+:Y2SiO5 crystal to serve as an optical quantum memory. A storage fidelity of 0.952 ± 0.018 is obtained for time-bin qubits encoded with single-photon-level coherent pulses, which is far beyond the maximal fidelity achievable using the classical measure-and-prepare strategy. In this work, the demonstrated noiseless photon-echo quantum memory features spin-wave storage, easy operation and high storage fidelity, which should be easily extended to other physical systems.
Untargeted metabolomics and transcriptomics identified glutathione metabolism disturbance and PCS and TMAO as potential biomarkers for ER stress in lung
Authors: Wang Zijing , Ma Peng , Wang Yisa , Hou Biyu , Zhou Can , Tian He , Li Bowen , Shui Guanghou , Yang Xiuying , Qiang Guifen , Yin Chengqian , Du Guanhua
Published: July 2021

Endoplasmic reticulum (ER) stress is a cellular state that results from the overload of unfolded/misfolded protein in the ER that, if not resolved properly, can lead to cell death. Both acute lung infections and chronic lung diseases have been found related to ER stress. Yet no study has been presented integrating metabolomic and transcriptomic data from total lung in interpreting the pathogenic state of ER stress. Total mouse lungs were used to perform LC–MS and RNA sequencing in relevance to ER stress. Untargeted metabolomics revealed 16 metabolites of aberrant levels with statistical significance while transcriptomics revealed 1593 genes abnormally expressed. Enrichment results demonstrated the injury ER stress inflicted upon lung through the alteration of multiple critical pathways involving energy expenditure, signal transduction, and redox homeostasis. Ultimately, we have presented p-cresol sulfate (PCS) and trimethylamine N-oxide (TMAO) as two potential ER stress biomarkers. Glutathione metabolism stood out in both omics as a notably altered pathway that believed to take important roles in maintaining the redox homeostasis in the cells critical for the development and relief of ER stress, in consistence with the existing reports.
Development and validation in 500 female samples of a TP-PCR assay to identify AFF2 GCC expansions
Authors: Silva Cecília , Maia Nuno , Santos Flávia , Rodrigues Bárbara , Marques Isabel , Santos Rosário , Jorge Paula
Published: July 2021

Over 100 X-linked intellectual disability genes have been identified, with triplet repeat expansions at the FMR1 (FRAXA) and AFF2 (FRAXE) genes being the causative agent in two of them. The absence of FRAXE pathognomonic features hampers early recognition, delaying testing and molecular confirmation. Hence, our laboratory uses a multiplex PCR-based strategy to genotype both FRAXA and FRAXE. However, AFF2 expansions are missed giving rise to an uninformative result in around 20% of female samples. To rule out undetected expansions and confirm homozygosity Southern blot analysis is performed being labour- and resource-intensive. The aim of this study is to develop a timely and economic triplet-primed amplification (TP-PCR) screening strategy to size the AFF2 GCC repeat and accurately assess homozygosity as well as pinpoint multiplex-PCR false negatives in female samples. In order to achieve this, validation was performed in a cohort of 500 females with a previous uninformative FRAXE PCR result. Interestingly, the presence of a T > C SNP (rs868949662), contiguous to the GCC repetitive tract, allows triplet primer binding in two additional repeats, increasing the discrimination power of the TP-PCR assay in heterozygous and homozygous samples. Twelve alleles outside the normal range were recognized: eight intermediate and four premutated, which seems relevant considering the rarity of the AFF2 expansions. All genotypes are concordant with that obtained by Southern blotting, confirming this as a strict, reproducible and low-cost homozygosity screening strategy that enables the identification of small expanded alleles missed by the routine multiplex-PCR due to allele dropout. Overall, this assay is capable of spotting multiplex-PCR false negatives besides identifying alleles up to > 80 GCC repeats. Furthermore, the occurrence of intermediate repeat sizes with unexpected frequency, introduces new areas of clinical research in this cohort in understanding these less explored AFF2 repeat sizes and newly associated phenotypes.
Neuroanatomical correlates of the perception of body axis orientation during body tilt: a voxel-based morphometry study
Authors: Tani Keisuke , Tanaka Satoshi
Published: July 2021

Accurate perception of the orientations of the body axis and gravity is essential for actions. The ability to perceive these orientations during head and body tilt varies across individuals, and its underlying neural basis is unknown. To address this, we investigated the association between inter-individual differences in local gray matter (GM) volume and inter-individual differences in the ability to estimate the directions of body longitudinal axis or gravity during whole-body tilt using voxel-based morphometry (VBM) analysis in 50 healthy adults (20–46 years, 25 men and 25 women). Although no anatomical regions were identified relating to performance requiring estimates of gravitational direction, we found a significant correlation between the GM volume in the right middle occipital gyrus and the ability to estimate the body axis orientation. This finding provides the first evidence on neuroanatomical substrates of the perception of body axis orientation during body tilt.
An integrated machine learning framework for a discriminative analysis of schizophrenia using multi-biological data
Authors: Ke Peng-fei , Xiong Dong-sheng , Li Jia-hui , Pan Zhi-lin , Zhou Jing , Li Shi-jia , Song Jie , Chen Xiao-yi , Li Gui-xiang , Chen Jun , Li Xiao-bo , Ning Yu-ping , Wu Feng-chun , Wu Kai
Published: July 2021

Finding effective and objective biomarkers to inform the diagnosis of schizophrenia is of great importance yet remains challenging. Relatively little work has been conducted on multi-biological data for the diagnosis of schizophrenia. In this cross-sectional study, we extracted multiple features from three types of biological data, including gut microbiota data, blood data, and electroencephalogram data. Then, an integrated framework of machine learning consisting of five classifiers, three feature selection algorithms, and four cross validation methods was used to discriminate patients with schizophrenia from healthy controls. Our results show that the support vector machine classifier without feature selection using the input features of multi-biological data achieved the best performance, with an accuracy of 91.7% and an AUC of 96.5% (p < 0.05). These results indicate that multi-biological data showed better discriminative capacity for patients with schizophrenia than single biological data. The top 5% discriminative features selected from the optimal model include the gut microbiota features (Lactobacillus, Haemophilus, and Prevotella), the blood features (superoxide dismutase level, monocyte-lymphocyte ratio, and neutrophil count), and the electroencephalogram features (nodal local efficiency, nodal efficiency, and nodal shortest path length in the temporal and frontal-parietal brain areas). The proposed integrated framework may be helpful for understanding the pathophysiology of schizophrenia and developing biomarkers for schizophrenia using multi-biological data.
Implication of FDG-PET/CT without synchronous colonic lesion in patients with stenotic left-sided colorectal cancer
Authors: Lee Jong Il , Cho Sang Sik , Shin Ui Sup , Jeon Byong Ho , Moon Sun Mi , Kim Younjoo , Yang Ki Young , Kim Byung Il
Published: July 2021

Although 18-fluoro-2-deoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is useful for detecting synchronous colorectal cancer (CRC) in stenotic CRC, long-term outcomes of patients without synchronous FDG-avid lesions are not well reported. We investigated postoperative colonoscopy results in patients with left-sided stenosing CRC without synchronous FDG-avid lesions. In this retrospective review, 754 patients with left-sided CRC without synchronous FDG-avid lesions on preoperative 18F-FDG PET/CT were divided into two groups based on the completeness of preoperative colonoscopy. Propensity score matching was performed to balance baseline characteristics. Results of postoperative colonoscopy were compared in both the unmatched and matched cohorts. At 1 and 5 years after surgery, the cumulative risk of advanced adenoma (AA) or carcinoma (CA) in all patients, risk of CA, and additional surgical risk were 1.8% and 10.1%, 0.1% and 0.4%, and 0% and 0.5%, respectively. In both cohorts, the AA risk was significantly higher in the incomplete colonoscopy group. However, the risk of CA showed no between-group difference in the matched cohort. Additional surgical risk did not differ between the two groups. Thus, the finding of negative FDG-avid lesions in the proximal colon in addition to the target CRC ensures the absence of additional lesions warranting surgical plan changes.
The role of FOSL1 in stem-like cell reprogramming processes
Authors: Pecce Valeria , Verrienti Antonella , Fiscon Giulia , Sponziello Marialuisa , Conte Federica , Abballe Luana , Durante Cosimo , Farina Lorenzo , Filetti Sebastiano , Paci Paola
Published: July 2021

Cancer stem-like cells (CSCs) have self-renewal abilities responsible for cancer progression, therapy resistance, and metastatic growth. The glioblastoma stem-like cells are the most studied among CSC populations. A recent study identified four transcription factors (SOX2, SALL2, OLIG2, and POU3F2) as the minimal core sufficient to reprogram differentiated glioblastoma (GBM) cells into stem-like cells. Transcriptomic data of GBM tissues and cell lines from two different datasets were then analyzed by the SWItch Miner (SWIM), a network-based software, and FOSL1 was identified as a putative regulator of the previously identified minimal core. Herein, we selected NTERA-2 and HEK293T cells to perform an in vitro study to investigate the role of FOSL1 in the reprogramming mechanisms. We transfected the two cell lines with a constitutive FOSL1 cDNA plasmid. We demonstrated that FOSL1 directly regulates the four transcription factors binding their promoter regions, is involved in the deregulation of several stemness markers, and reduces the cells’ ability to generate aggregates increasing the extracellular matrix component FN1. Although further experiments are necessary, our data suggest that FOSL1 reprograms the stemness by regulating the core of the four transcription factors.
Age period cohort analysis of chewing ability in Korea from 2007 to 2018
Authors: Kim Nam-Hee , Kawachi Ichiro
Published: July 2021

There have been marked improvements in oral health in Korea during the past 10 years, including chewing ability. We sought to disentangle age, period, and cohort effects in chewing ability between 2007 and 2018. We analyzed data from the Korea National Health and Nutrition Examination Survey. The main variable was chewing difficulty, which was assessed among participants aged 20 years and older. APC analysis revealed three trends in chewing difficulty: (1) there was an increase in chewing difficulty starting at around 60 years of age (age effect), (2) there was a steady decrease in chewing difficulty during the observation period (period effect), and (3) chewing ability improved with each successive generation born after 1951 (cohort effect). Regarding recent improvements in chewing ability, cohort effects were somewhat more important than period effects.
Circulating miRNA is a useful diagnostic biomarker for nonalcoholic steatohepatitis in nonalcoholic fatty liver disease
Authors: Kim Tae Hyung , Lee Yoonseok , Lee Young-Sun , Gim Jeong-An , Ko Eunjung , Yim Sun Young , Jung Young Kul , Kang SeongHee , Kim Moon Young , Kim Hayeon , Kim Baek-hui , Kim Ji Hoon , Seo Yeon Seok , Yim Hyung Joon , Yeon Jong Eun , Um Soon Ho , Byun Kwan Soo
Published: July 2021

Nonalcoholic steatohepatitis (NASH) is considered as a progressive form of nonalcoholic fatty liver disease (NAFLD). To distinguish NASH from nonalcoholic fatty liver (NAFL), we evaluated the diagnostic value of circulating miRNAs. Small RNA sequencing was performed on 12 NAFL patients and 12 NASH patients, and the miRNA expression was compared. After selecting miRNAs for the diagnosis of NASH, we analyzed the diagnostic accuracy of each miRNA and the combination of miRNAs. External validation was performed using quantitative reverse transcription PCR. Among the 2,588 miRNAs, 26 miRNAs significantly increased in the NASH group than in the NAFL group. Among the 26 elevated miRNAs in the NASH group, 8 miRNAs were selected, and in silico analysis was performed. Only four miRNAs (miR-21-5p, miR-151a-3p, miR-192-5p, and miR-4449) showed significant area under the receiver operating characteristic curve (AUC) values for NASH diagnosis. The combination of the four miRNAs showed satisfactory diagnostic accuracy for NASH (AUC 0.875; 95% CI 0.676–0.973). External validation revealed similar diagnostic accuracy for NASH (AUC 0.874; 95% CI 0.724–0.960). NASH represents significantly distinct miRNA expression profile compared with NAFL. The combination of serum circulating miRNAs can be used as a novel biomarker for the NASH diagnosis in NAFLD.
Genetic characterization and implications for conservation of the last autochthonous Mouflon population in Europe
Authors: Satta Valentina , Mereu Paolo , Barbato Mario , Pirastru Monica , Bassu Giovanni , Manca Laura , Naitana Salvatore , Leoni Giovanni Giuseppe
Published: July 2021

Population genetic studies provide accurate information on population structure, connectivity, and hybridization. These are key elements to identify units for conservation and define wildlife management strategies aimed to maintain and restore biodiversity. The Mediterranean island of Sardinia hosts one of the last autochthonous mouflon populations, descending from the wild Neolithic ancestor. The first mouflon arrived in Sardinia ~ 7000 years ago and thrived across the island until the twentieth century, when anthropogenic factors led to population fragmentation. We analysed the three main allopatric Sardinian mouflon sub-populations, namely: the native sub-populations of Montes Forest and Mount Tonneri, and the reintroduced sub-population of Mount Lerno. We investigated the spatial genetic structure of the Sardinian mouflon based on the parallel analysis of 14 highly polymorphic microsatellite loci and mitochondrial D-loop sequences. The Montes Forest sub-population was found to harbour the ancestral haplotype in the phylogeny of European mouflon. We detected high levels of relatedness in all the sub-populations and a mitochondrial signature of hybridization between the Mount Lerno sub-population and domestic sheep. Our findings provide useful insights to protect such an invaluable genetic heritage from the risk of genetic depletion by promoting controlled inter-population exchange and drawing informed repopulation plans sourcing from genetically pure mouflon stocks.
Elevated S-adenosylhomocysteine induces adipocyte dysfunction to promote alcohol-associated liver steatosis
Authors: Arumugam Madan Kumar , Chava Srinivas , Rasineni Karuna , Paal Matthew C. , Donohue Terrence M. , Osna Natalia A. , Kharbanda Kusum K.
Published: July 2021

It has been previously shown that chronic ethanol administration-induced increase in adipose tissue lipolysis and reduction in the secretion of protective adipokines collectively contribute to alcohol-associated liver disease (ALD) pathogenesis. Further studies have revealed that increased adipose S-adenosylhomocysteine (SAH) levels generate methylation defects that promote lipolysis. Here, we hypothesized that increased intracellular SAH alone causes additional related pathological changes in adipose tissue as seen with alcohol administration. To test this, we used 3-deazaadenosine (DZA), which selectively elevates intracellular SAH levels by blocking its hydrolysis. Fully differentiated 3T3-L1 adipocytes were treated in vitro for 48 h with DZA and analysed for lipolysis, adipokine release and differentiation status. DZA treatment enhanced adipocyte lipolysis, as judged by lower levels of intracellular triglycerides, reduced lipid droplet sizes and higher levels of glycerol and free fatty acids released into the culture medium. These findings coincided with activation of both adipose triglyceride lipase and hormone sensitive lipase. DZA treatment also significantly reduced adipocyte differentiation factors, impaired adiponectin and leptin secretion but increased release of pro-inflammatory cytokines, IL-6, TNF and MCP-1. Together, our results demonstrate that elevation of intracellular SAH alone by DZA treatment of 3T3-L1 adipocytes induces lipolysis and dysregulates adipokine secretion. Selective elevation of intracellular SAH by DZA treatment mimics ethanol’s effects and induces adipose dysfunction. We conclude that alcohol-induced elevations in adipose SAH levels contribute to the pathogenesis and progression of ALD.
Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo
Authors: Goldshmit Yona , Perelroizen Rita , Yakovchuk Alex , Banyas Evgeni , Mayo Lior , David Sari , Benbenishty Amit , Blinder Pablo , Shalom Moshe , Ruban Angela
Published: July 2021

Inhibition of extracellular glutamate (Glu) release decreases proliferation and invasion, induces apoptosis, and inhibits melanoma metastatic abilities. Previous studies have shown that Blood-glutamate scavenging (BGS), a novel treatment approach, has been found to be beneficial in attenuating glioblastoma progression by reducing brain Glu levels. Therefore, in this study we evaluated the ability of BGS treatment to inhibit brain metastatic melanoma progression in-vivo. RET melanoma cells were implanted in C56BL/6J mice to induce brain melanoma tumors followed by treatment with BGS or vehicle administered for fourteen days. Bioluminescent imaging was conducted to evaluate tumor growth, and plasma/CSF Glu levels were monitored throughout. Immunofluorescence staining of Ki67 and 53BP1 was used to analyze tumor cell proliferation and DNA double-strand breaks. In addition, we analyzed CD8, CD68, CD206, p-STAT1 and iNOS expression to evaluate alterations in tumor micro-environment and anti-tumor immune response due to treatment. Our results show that BGS treatment reduces CSF Glu concentration and consequently melanoma growth in-vivo by decreasing tumor cell proliferation and increasing pro-apoptotic signaling in C56BL/6J mice. Furthermore, BGS treatment supported CD8+ cell recruitment and CD68+ macrophage invasion. These findings suggest that BGS can be of potential therapeutic relevance in the treatment of metastatic melanoma.
Mechanical properties of CAD/CAM-fabricated in comparison to conventionally fabricated functional regulator 3 appliances
Authors: Roser Christoph , Hodecker Lutz D. , Koebel Chris , Lux Christopher J. , Ruckes Dorothee , Rues Stefan , Zenthöfer Andreas
Published: July 2021

Manufacturing of Fränkel's functional regulator 3 (FR3) is complicated and requires extensive knowledge from the dental technician. To determine whether FR3s produced by CAD/CAM techniques (CAD-FR3) meet similar mechanical properties like conventional FR3s (Con-FR3), for each of 10 patient cases, three CAD-FR3 designs (palatal connector cross-section 3 × 3 mm, 4 × 1 mm or 5 × 2 mm) and one Con-FR3 were subjected to cyclic loading and subsequent fracture testing in a universal testing device. Transversal load capacity (Fmax(FR3)) and stiffness were compared among the different CAD-FR3 designs and Con-FR3s using Friedman and Wilcoxon tests with a significance level of α = 0.05. All CAD-FR3 designs had significantly higher mean Fmax(FR3) (p ≤ 0.007) and stiffness (p ≤ 0.005) than the Con-FR3s. The CAD-FR33×3 had the highest mean Fmax(FR3) (98.2 ± 26.2 N) and stiffness (37.1 ± 15.5 N/mm), closely followed by the CAD-FR35×2 (Fmax(FR3): 90.3 ± 24.7 N; stiffness: 30.0 ± 12.3 N/mm). Among the CAD appliances, CAD-FR34×1 had the lowest values (p ≤ 0.007 for all pairwise tests) with Fmax(FR3) of 45.8 ± 17.9 N and stiffness of 12.5 ± 7.3 N/mm. CAD-FR3s have superior mechanical properties in comparison to Con-FR3s if certain design parameters are followed. Further clinical investigations have to examine if they can serve as an alternative in practice.
Inhibitory control mediates the interaction between serotonin transporter gene (5-HTTLPR) and peer victimization on adolescent depressive symptoms
Authors: Lin Xiaonan , Cao Yanmiao , Ji Linqin , Zhang Wenxin
Published: July 2021

Many efforts have been devoted to investigating the effect of the interaction between the serotonin transporter gene (5-HTTLPR) and environment (G × E) on depression, but they yield mixed results. The inconsistency has suggested that G × E effects may be more complex than originally conceptualized, and further study is warranted. This study explored the association among5-HTTLPR, peer victimization and depressive symptoms and the underlying mediating role of inhibitory control in this association. A total of 871 Chinese Han adolescents (Mage = 15.32 years, 50.3% girls) participated and provided saliva samples from which the5-HTTLPRwas genotyped. This study found that5-HTTLPRinteracted with peer victimization in predicting depressive symptoms. Adolescents carrying L allele reported more depressive symptoms than SS carriers when exposed to higher level of peer victimization. Furthermore, adolescents’ inhibitory control deficits mediated the association between5-HTTLPR × peer victimization and depressive symptoms. These findings suggested that one pathway in which G × E may confer vulnerability to depressive symptoms is through disruptions to adolescents’ inhibitory control system.
Extracellular detection of neuronal coupling
Authors: Guzman Elmer , Cheng Zhuowei , Hansma Paul K. , Tovar Kenneth R. , Petzold Linda R. , Kosik Kenneth S.
Published: July 2021

We developed a method to non-invasively detect synaptic relationships among neurons from in vitro networks. Our method uses microelectrode arrays on which neurons are cultured and from which propagation of extracellular action potentials (eAPs) in single axons are recorded at multiple electrodes. Detecting eAP propagation bypasses ambiguity introduced by spike sorting. Our methods identify short latency spiking relationships between neurons with properties expected of synaptically coupled neurons, namely they were recapitulated by direct stimulation and were sensitive to changing the number of active synaptic sites. Our methods enabled us to assemble a functional subset of neuronal connectivity in our cultures.
Zinc systematics quantify crustal thickness control on fractionating assemblages of arc magmas
Authors: Chiaradia M.
Published: July 2021

Understanding the processes leading to the broad chemical variability of arc magmas is an essential, yet not fully elucidated, issue in Earth Sciences. Here, I show that Zn–MgO–SiO2 systematics of magmatic arc rocks correlate significantly with arc thickness. Because Zn–MgO–SiO2 systematics are mostly controlled by fractionation of different mineral phases, this suggests a systematic change in the proportions of fractionating mineral assemblages depending on arc thickness. Using a mass balance model with a Monte Carlo approach, I show that Zn–MgO–SiO2 systematics can be quantitatively explained by a continuous transition from plagioclase-dominated fractionating assemblages in thin arcs to amphibole-garnet-magnetite-dominated assemblages in increasingly thicker arcs. Most likely, such a systematic change results from the increase of average depth of magma differentiation that is ultimately controlled by arc thickness. Results presented have implications on the causes of different geochemical trends in arcs, the role of arcs as H2O filters, and their association with porphyry deposits.
Outer retinal tubulation formation and clinical course of advanced age-related macular degeneration
Authors: Arrigo Alessandro , Aragona Emanuela , Battaglia Ottavia , Saladino Andrea , Amato Alessia , Borghesan Federico , Pina Adelaide , Calcagno Francesca , Hassan Farah Rashid , Bandello Francesco , Battaglia Parodi Maurizio
Published: July 2021

Outer retinal tubulations (ORT) are a relatively new finding characterizing outer retinal atrophy. The main aim of the present study was to describe ORT development in advanced age-related macular degeneration (AMD) and to assess its relationship with disease’s severity. Patients with advanced AMD characterized either by macular neovascularization or geographic atrophy, showing signs of outer retinal disruption or retinal pigment epithelium atrophy on structural optical coherence tomography (OCT) at the inclusion examination were prospectively recruited. All the patients underwent complete ophthalmologic evaluation, structural OCT scans and fundus autofluorescence imaging. The planned follow-up was of 3-years. Main outcome measures were ORT prevalence, mechanism of ORT formation, mean time needed for complete ORT formation, best-corrected visual acuity (BCVA), definitely decreased autofluorescence (DDAF) area, questionably decreased autofluorescence (QDAF) area, retinal layer thickness, foveal sparing, number of intravitreal injections. We also assessed the possible role of external limiting membrane (ELM) and Müller cells in ORT pathogenesis. Seventy eyes (70 patients) were included; 43 showed dry AMD evolving to geographic atrophy, while 27 displayed the features of wet AMD. Baseline BCVA was 0.5 ± 0.5 LogMAR, decreasing to 0.9 ± 0.5 LogMAR at the 3-year follow-up (p < 0.01). We detected completely formed ORT in 26/70 eyes (37%), subdivided as follows: 20 eyes (77%) wet AMD and 6 eyes (23%) dry AMD (p < 0.01). ORT took 18 ± 8 months (range 3–35 months) to develop fully. We described the steps leading to ORT development, characterized by progressive involvement of, and damage to the photoreceptors, the ELM and the RPE. Eyes displaying ORT were associated with a smaller QDAF area, less retinal layers damage and lower rate of foveal sparing than eyes free of ORT (p < 0.01). We also described pigment accumulations simulating ORT, which were detected in 16/70 eyes (23%), associated with a greater loss of foveal sparing, increased DDAF area and smaller QDAF area at the 3-year follow-up (p < 0.01). In conclusion, this study provided a description of the steps leading to ORT development in AMD. ELM and Müller cells showed a role in ORT pathogenesis. Furthermore, we described a subtype of pigment hypertrophy mimicking ORT, evaluating its clinical utility.
Sequencing for germline mutations in Swedish breast cancer families reveals novel breast cancer risk genes
Authors: Helgadottir Hafdis T. , Thutkawkorapin Jessada , Lagerstedt-Robinson Kristina , Lindblom Annika
Published: July 2021

Identifying genetic cancer risk factors will lead to improved genetic counseling, cancer prevention and cancer care. Analyzing families with a strong history of breast cancer (BC) has been a successful method to identify genes that contribute to the disease. This has led to discoveries of high-risk genes like the BRCA-genes. Nevertheless, many BC incidences are of unknown causes. In this study, exome sequencing on 59 BC patients from 24 Swedish families with a strong history of BC was performed to identify variants in known and novel BC predisposing genes. First, we screened known BC genes and identified two pathogenic variants in the BRIP1 and PALB2 genes. Secondly, to identify novel BC genes, rare and high impact variants and segregating in families were analyzed to identify 544 variants in novel BC candidate genes. Of those, 22 variants were defined as high-risk variants. Several interesting genes, either previously linked with BC or in pathways that when flawed could contribute to BC, were among the detected genes. The strongest candidates identified are the FANCM gene, involved in DNA double-strand break repair, and the RAD54L gene, involved in DNA recombination. Our study shows identifying pathogenic variants is challenging despite a strong family history of BC. Several interesting candidates were observed here that need to be further studied.
Association of self-rated health with chronic disease, mental health symptom and social relationship in older people
Authors: Yang Hongling , Deng Qin , Geng Qingshan , Tang Yanfei , Ma Jun , Ye Weitao , Gan Qiangsheng , Rehemayi Rehemutula , Gao Xiaoli , Zhu Chunyan
Published: July 2021

Chronic disease, mental health symptoms and poor social relations are reported common causes for poor self-rated health in older people. To assess the co-occurrence rate of chronic diseases, poor mental health and poor social relationships in older people, and determine their association with self-rated health. 6,551 older people in Zhongshan, China, participated a large health surveillance program were randomly selected and questioned about their SRH, chronic conditions, mental health symptoms and social relationships. The association between self-rated health and chronic conditions, poor mental health, social relationships, and their co-occurrence were analyzed. 56.4% of participants reported poor self-rated health. 39.1% experienced at least one chronic disease. 29.0% experienced one or more mental health symptoms; 19.5% experienced at least one poor social relationship. 7.8% had co-occurrence of chronic diseases, mental health problems, and poor social relationships. Logistic regressions showed that poor self-rated health was associated with chronic diseases, poor mental health, poor social relationships and their co-occurrence. The findings indicate the importance of managing chronic disease, poor mental health and poor social relationships for older people.
Evidence-based recommender system for high-entropy alloys
Authors: Ha Minh-Quyet , Nguyen Duong-Nguyen , Nguyen Viet-Cuong , Nagata Takahiro , Chikyow Toyohiro , Kino Hiori , Miyake Takashi , Denœux Thierry , Huynh Van-Nam , Dam Hieu-Chi
Published: July 2021

Existing data-driven approaches for exploring high-entropy alloys (HEAs) face three challenges: numerous element-combination candidates, designing appropriate descriptors, and limited and biased existing data. To overcome these issues, here we show the development of an evidence-based material recommender system (ERS) that adopts Dempster–Shafer theory, a general framework for reasoning with uncertainty. Herein, without using material descriptors, we model, collect and combine pieces of evidence from data about the HEA phase existence of alloys. To evaluate the ERS, we compared its HEA-recommendation capability with those of matrix-factorization- and supervised-learning-based recommender systems on four widely known datasets of up-to-five-component alloys. Thek-fold cross-validation on the datasets suggests that the ERS outperforms all competitors. Furthermore, the ERS shows good extrapolation capabilities in recommending quaternary and quinary HEAs. We experimentally validated the most strongly recommended Fe–Co-based magnetic HEA (namely, FeCoMnNi) and confirmed that its thin film shows a body-centered cubic structure.
Surface-initiated polymerization of mussel-inspired dopamine for hydrophilic coatings
Authors: Kuo Tzu-Yu , Chung Yi-Chang
Published: July 2021

Inspired by mussels, dopamine with catechol and amino groups in the molecular structure has been broadly studied for its universal attachment, biocompatibility and ease of use.