bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sleep deprivation impairs learning and memory by decreasing protein O‐GlcNAcylation in the brain of adult zebrafish
Authors: Lee Yunkyoung , Park Jiwon , Kim Sang‐Min , Nam Kyunghyun , Lee Woojoo , Cho Hyeongjin , Han Inn‐Oc 
Published: November 2019

AbstractSleep is an evolutionarily conserved physiological process implicated in the consolidation of learning and memory (L/M). Here, we report that sleep deprivation (SD)‐induced cognitive deficits in zebrafish are mediated through reduction in O‐GlcNAcylation of brain. Microarray‐based gene expression profiling of zebrafish brain demonstrated significant changes in genes involved in metabolism by SD or fear conditioning (FC), compared to the control group. In particular, it was observed that a marked decrease in the number of genes involved in carboxylic acid and organic acid metabolic processes in the brains of SD group compared to control group. SD downregulated O‐GlcNAc transferase (OGT) and O‐GlcNAcylation, while the expression of O‐GlcNAcase was upregulated. FC activated protein kinase A (PKA) and phosphorylated cAMP response element binding protein (p‐CREB), an effect that was greatly inhibited by SD. Moreover, FC upregulated expressions of OGT and increased O‐GlcNAcylation in the brains of normal but not SD zebrafish. Intriguingly, upregulation of O‐GlcNAcylation by glucosamine restored defects in L/M functions and PKA/p‐CREB activity in SD group. Our findings highlight the O‐GlcNAcylation changes in the brain during the L/M process and further provide a foundation for future studies seeking the molecular and biochemical mechanisms by which HBP of glucose metabolism affects cognitive function.
Ezetimibe ameliorates lipid accumulation during adipogenesis by regulating the AMPK–mTORC1 pathway
Authors: Lee Yu Seol , Park Jeong Su , Lee Da Hyun , Han Jisu , Bae Soo Han 
Published: November 2019

AbstractAdipogenesis, a critical process that converts adipocyte precursors into adipocytes, is considered a potential therapeutic target for the treatment of obesity. Ezetimibe, a drug approved by the United States Food and Drug Administration, is used for the treatment of hypercholesterolemia. Recently, it was reported to ameliorate high fat diet‐induced dyslipidemia in mice and reduce lipid accumulation in hepatocytes through the activation of AMPK. However, the anti‐adipogenic effects of ezetimibe and the underlying molecular mechanism have not yet been elucidated. Here, we found that ezetimibe reduced lipid accumulation via activating AMPK during the early phase of adipogenesis. We also observed that ezetimibe inhibited peroxisome proliferator‐activated receptor γ, which is a major transcription factor of adipogenesis. Furthermore, ezetimibe‐mediated AMPK activation reduced lipid accumulation by inhibiting mTORC1 signaling, leading to the downregulation of lipogenesis‐related genes. Mitotic clonal expansion, required for adipogenesis, accelerates cell cycle progression and cell proliferation. We additionally observed that ezetimibe prevented the progression of mitotic clonal expansion by arresting the cell cycle at the G0/G1 phase, which was followed by the inhibition of cell proliferation. Collectively, ezetimibe‐mediated inhibition of adipogenesis is dependent on the AMPK–mTORC1 pathway. Thus, we suggest that ezetimibe might be a promising drug for the treatment of obesity.
l‐Fucose prevention of renal ischaemia/reperfusion injury in Mice
Authors: Howard Mark C. , Nauser Christopher L. , Farrar Conrad A. , Wallis Russell , Sacks Steven H. 
Published: November 2019

AbstractIn a recent study, we identified a fucosylated damage‐associated ligand exposed by ischemia on renal tubule epithelial cells, which after recognition by collectin‐11 (CL‐11 or collectin kidney 1 (CL‐K1)), initiates complement activation and acute kidney injury. We exploited the ability to increase the local tissue concentration of free l‐fucose following systemic administration, in order to block ligand binding by local CL‐11 and prevent complement activation. We achieved a thirty‐five‐fold increase in the intrarenal concentration of l‐fucose following an IP bolus given before the ischemia induction procedure ‐ a concentration found to significantly block in vitro binding of CL‐11 on hypoxia‐stressed renal tubule cells. At this l‐fucose dose, complement activation and acute post‐ischemic kidney injury are prevented, with additional protection achieved by a second bolus after the induction procedure. CL‐11−/− mice gained no additional protection from l‐fucose administration, indicating that the mechanism of l‐fucose therapy was largely CL‐11‐dependent. The hypothesis is that a high dose of l‐fucose delivered to the kidney obstructs the carbohydrate recognition site on CL‐11 thereby reducing complement‐mediated damage following ischemic insult. Further work will examine the utility in preventing post‐ischemic injury during renal transplantation, where acute kidney injury is known to correlate with poor graft survival.
Highly efficient base editing with expanded targeting scope using SpCas9‐NG in rabbits
Authors: Liu Zhiquan , Shan Huanhuan , Chen Siyu , Chen Mao , Song Yuning , Lai Liangxue , Li Zhanjun 
Published: November 2019

AbstractBase editors, composed of a cytidine deaminase or an evolved adenine deaminase fused to Cas9 nickase, enable efficient C‐to‐T or A‐to‐G conversion in various organisms. However, the NGG protospacer adjacent motif (PAM) requirement of Streptococcus pyogenes Cas9 (SpCas9) substantially limits the target sites suitable for base editing. Quite recently, a new engineered SpCas9‐NG variant, which can recognize minimal NG PAMs more efficiently than the present xCas9 variant. Here, we investigated the efficiency and PAM compatibility of SpCas9‐NG‐assisted cytidine base editors (CBEs) and adenine base editors (ABEs) in rabbits. In this study, we showed that NG‐BE4max and NG‐ABEmax systems can achieve a targeted mutation efficiency of 75%‐100% and 80%‐100% with excellent PAM compatibility of NGN PAMs in rabbit embryos, respectively. In addition, both base editors were successfully applied to create new rabbit models with precise point mutations, demonstrating their high efficiency and expanded genome‐targeting scope in rabbits. Meanwhile, NG‐ABEmax can be used to precisely mimic human Hoxc13 p.Q271R missense mutation in Founder (F0) rabbits, which is arduous for conventional ABEs to achieve due to a NGA PAM requirement. Collectively, NG‐BE4max and NG‐ABEmax systems provide promising tools to perform efficient base editing with expanded targeting scope in rabbits and enhances its capacity to model human diseases.
Production of BBF2H7‐derived small peptide fragments via endoplasmic reticulum stress‐dependent regulated intramembrane proteolysis
Authors: Matsuhisa Koji , Saito Atsushi , Cai Longjie , Kaneko Masayuki , Okamoto Takumi , Sakaue Fumika , Asada Rie , Urano Fumihiko , Yanagida Kanta , Okochi Masayasu , Kudo Yukitsuka , Matsumoto Masaki , Nakayama Keiichi I. , Imaizumi Kazunori 
Published: November 2019

AbstractIntramembrane cleavage of transmembrane proteins is a fundamental cellular process to produce important signals that elicit biological responses. These proteolytic events are known as regulated intramembrane proteolysis (RIP). ATF6 and BBF2H7 are transmembrane basic leucine zipper transcription factors and are subjected to RIP by site‐1 protease (S1P) and site‐2 protease (S2P) sequentially in response to endoplasmic reticulum (ER) stress. However, the detailed mechanisms responsible for RIP of the transcription factors, including the precise cutting sites, are still unknown. In this study, we demonstrated that S1P cleaves BBF2H7 just before the RXXL S1P recognition motif. Conversely, S2P cut at least three different sites in the membrane (next to Leu380, Met381, and Leu385), indicating that S2P cleaves the substrates at variable sites or via a multistep process. Interestingly, we found BBF2H7‐derived small peptide (BSP) fragments located between the S1P and S2P cleavage sites in cells exposed to ER stress. Major type of BSP fragments was composed of 45 amino acid including partial transmembrane and luminal regions and easily aggregates like amyloid β (Aβ) protein. These results advance the understanding of poorly characterized ER stress‐dependent RIP. Furthermore, the aggregable peptides produced by ER stress could link to the pathophysiology of neurodegenerative disorders.
Shifting of economic responsibilities on vulnerable shoulders for survival of families: a scenario from mining industry in India
Authors: Raghav Pankaja , Jaiswal Abhishek , Gupta Manoj Kumar , Rajavel Saranaya , Dhupar Diksha 
Published: November 2019

AbstractContextMining industry has boomed precipitously to provide for demand of metal and minerals for emerging infrastructure. It is major occupation in India involving large work force, although it is hazardous. Aims: To assess the socio-demographic profile of sandstone mine workers in Jodhpur and to identify their major social issues.Material and MethodsStudy design: Cross-sectional study; Setting: Residential area of mine workers, Jodhpur, Rajasthan; Participants: Mine workers residing in residential areas in Jodhpur district for more than 6 months, and who gave consent for participation in study. Data on socioeconomic status and occupation of each family members was collected; Analysis: Data was analysed using SPSS v.23. P value <0.05 was considered as statistically significant.ResultsOne thousand six hundred four mine workers were enrolled in study. More than three fourth (78.7%) of them were male. Their age ranged between 14 to 82 years with mean age of 37.62 ± 12.30 years. Mean age of female workers was significantly higher than of male workers. Average years of working for males was significantly higher than females. Mean age of entry into mines for male workers (20.33 ± 6.69) was significantly lower than females (24.59 ± 8.52). About 2.68% children below 14 years of age were involved in any sort of income generation activity. Conclusions: Majority of mine workers were of young age group. Major socioeconomic issues found were illiteracy, child marriage, child labour, loneliness and shifting economic responsibilities on females.Strengths and limitationsRobust dataset, complete enumeration, large sample size.Key messagesWhat is already known about this subject?The miners work under exploitative conditions and their families live in severe poverty with no access to health services. Families living close to the mines and are prone to developing silicosis from secondary exposure, they are also prone for malnourishment, tuberculosis and other comorbid conditions. Early deaths of the male earning member lead to vulnerable members of family to take the job for their livelihood. There are many reported widow villages where there is no male member due to death of the same by pneumoconiosis.What is the new findings?There is increasing burden on the shoulders of the vulnerable groups (children, females and elderly) among families of sandstone miners in India. Illiteracy, child marriage, child labour and loneliness are among major social problems in these families.How might this impact on policy in the foreseeable future?Families where the main bread earner died of pneumoconiosis could be provided pension to supplement for their food and health expenses requirement. Rajasthan state in India has recently launched “Silicosis Policy”, and this study signifies the importance of implementing such polices in other states in India.
An application of machine learning to assist medication order review by pharmacists in a health care center
Authors: Thibault Maxime , Lebel Denis 
Published: November 2019

AbstractThe objective of this study was to determine if it is feasible to use machine learning to evaluate how a medication order is contextually appropriate for a patient, in order to assist order review by pharmacists. A neural network was constructed using as input the sequence of word2vec embeddings of the 30 previous orders, as well as the currently active medications, pharmacological classes and ordering department, to predict the next order. The model was trained with data from 2013 to 2017, optimized using 5-fold cross-validation, and tested on orders from 2018. A survey was developed to obtain pharmacist ratings on a sample of 20 orders, which were compared with predictions. The training set included 1 022 272 orders. The test set included 95 310 orders. Baseline training set top 1, top 10 and top 30 accuracy using a dummy classifier were respectively 4.5%, 23.6% and 44.1%. Final test set accuracies were, respectively, 44.4%, 69.9% and 80.4%. Populations in which the model performed the best were obstetrics and gynecology patients and newborn babies (either in or out of neonatal intensive care). Pharmacists agreed poorly on their ratings of sampled orders with a Fleiss kappa of 0.283. The breakdown of metrics by population showed better performance in patients following less variable order patterns, indicating potential usefulness in triaging routine orders to less extensive pharmacist review. We conclude that machine learning has potential for helping pharmacists review medication orders. Future studies should aim at evaluating the clinical benefits of using such a model in practice.
A Metabolomics Approach for Early Prediction of Vincristine-Induced Peripheral Neuropathy
Authors: Verma Parul , Devaraj Jayachandran , Skiles Jodi L. , Sajdyk Tammy , Ho Richard H. , Hutchinson Raymond , Wells Elizabeth , Li Lang , Renbarger Jamie , Cooper Bruce , Ramkrishna Doraiswami 
Published: November 2019

AbstractVincristine is a core chemotherapeutic drug administered to pediatric acute lymphoblastic leukemia patients. Despite its efficacy in treating leukemia, it can lead to severe peripheral neuropathy in a sub-group of the patients. Peripheral neuropathy is a debilitating and painful side-effect that can severely impact an individual’s quality of life. Currently, there are no established predictors of peripheral neuropathy incidence during the early stage of chemotherapeutic treatment. As a result, patients who are not susceptible to peripheral neuropathy may receive sub-therapeutic treatment due to an empirical upper cap on the dose, while others may experience severe neuropathy at the same dose. Contrary to previous genomics based approaches, we employed a metabolomics approach to identify small sets of metabolites that can be used to predict a patient’s susceptibility to peripheral neuropathy at different time points during the treatment. Using those identified metabolites, we developed a novel strategy to predict peripheral neuropathy and subsequently adjust the vincristine dose accordingly. In accordance with this novel strategy, we created a free user-friendly tool, VIPNp, for physicians to easily implement our prediction strategy. Our results showed that focusing on metabolites, which encompasses both genotypic and phenotypic variations, can enable early prediction of peripheral neuropathy in pediatric leukemia patients.
Dose and duration of IFNγ pre-licensing interact with donor characteristics to influence the expression and function of IDO in MSCs
Authors: Boyt Devlin , Boland Lauren , Burand Anthony J. , Brown Alex , Ankrum James A. 
Published: November 2019

AbstractHuman mesenchymal stromal cells (MSCs) are a leading cell therapy candidate for the treatment of immune and inflammatory diseases due to their potent regulation of immune cells. MSC expression of indoleamine-2,3-dioxygenase (IDO) upon interferon gamma exposure has been proposed as both a sentinel marker and key mediator of MSC immunomodulatory potency. Rather than wait forin vivoexposure to cytokines, MSCs can be pre-licensed during manufacturing to enhance IDO expression. In this study, we systematically examine the relative role the dose of interferon gamma, the duration of pre-licensing, and the donor of origin plays in dictating MSC production of functional IDO. We find that across three human MSC donors, MSCs increase their expression of IDO in response to both increased dose of interferon gamma and duration of pre-licensing. However, with extended pre-licensing, the expression of IDO no longer predicts MSCs ability to suppress activated peripheral blood mononuclear cells. In addition, pre-licensing dose and duration are revealed to be minor modifiers of MSCs inherent potency, and thus cannot be manipulated to boost poor donors to the levels of high-performing donors. Thus, the dose and duration of pre-licensing should be tailored to optimize performance of specific donors and an emphasis on donor selection is needed to realize significant benefits of pre-licensing.
Distinct microbiome composition of floor and air dust distort richness estimation in university dormitories
Authors: Sun Yu , Li Yanling , Yuan Qianqian , Zhang Zefei , Deng Yiqun , Norbäck Dan , Zhang Xin , Fu Xi 
Published: November 2019

AbstractThe number of culture-independent indoor microbiome study has increased remarkably in recent years, but microbial composition among different sampling strategies remains poorly characterized and their impact to downstream microbiome analysis is also not clear. In this study, we reported a case study of microbial composition of floor and air dust in 87 dormitory rooms of Shanxi University, China. Floor and air dust were collected by vacuum cleaner and petri-dish, respectively, and the bacterial composition was characterized by 16S rRNA sequencing. The composition of floor and air dust differed significantly (R2 = 0.65, p < 0.001, Adonis), and Pseudomonas dominated in floor dust (75.1%) but was less common in air dust (1.9%). The top genera in air dust, including Ralstonia (15.6%), Pelomonas (11.3%), Anoxybacillus (9.3%) and Ochrobactrum (6.2%), all accounted for < 1% abundance in floor dust. The dominant Pseudomonas in floor dust swamped low frequency organisms, leading to significant lower number of operational taxonomic units (OTUs) compared with air dust in the same sequencing depth. The different microbial composition of floor and air dust can lead to differences in downstream bioinformatics analyses. We searched the dormitory microbiome against ~200,000 samples deposited in Microbiome Search Engine (MSE), and found that the compositions of floor dust samples were similar to samples from building environment and human nasopharynx, whereas the compositions of the air dust samples were similar to mosquito tissues.ImportanceIncreasing number of indoor microbiome studies has been conducted in recent years, but the impact of sampling strategy is far from clear. In this study, we reported that the floor and air sampling can lead to drastic variation in microbial composition and downstream analyses in university dormitories, including microbial diversity estimation and compositional similarity search. Thus, the bioinformatics analysis results need to be interpreted with caution in microbiome studies, and it may be necessary to collected samples from different sampling strategies to comprehensively characterize the microbial composition and exposure to human occupants in an indoor environment.
Sensitivity ofListeria monocytogenesto lysozyme predicts ability to proliferate in bovine caruncular epithelial cells
Authors: Blanchard Adam M. , Billenness Rosemarie , Warren Jessica , Glanvill Amy , Roden William , Drinkall Emma , Maboni Grazieli , Robinson Robert S , Rees Catherine E.D. , Pfarrer Christiane , Tötemeyer Sabine 
Published: November 2019

AbstractListeria monocytogenesis an important foodborne pathogen in human and veterinary health, causing significant morbidity and mortality including abortion. It has a particular tropism for the gravid uterus, however, the route of infection in reproductive tissues of ruminants (i.e. placentome), is much less clear. In this study, we aimed to investigate a bovine caruncular epithelial cell (BCEC) line as a model forL. monocytogenesinfection of the bovine reproductive tract. The BCEC infection model was used to assess the ability of 14 differentL. monocytogenesisolates to infect these cells. Lysozyme sensitivity and bacterial survival in 580 µg lysozyme/ml correlated with attenuated ability to proliferate in BCEC (p=0.004 and p=0.02, respectively). Four isolates were significantly attenuated compared to the control strain 10403S. One of these strains (AR008) showed evidence of compromised cell wall leading to increased sensitivity to ß-lactam antibiotics, and another (7644) had compromised cell membrane integrity leading to increased sensitivity to cationic peptides. Whole genome sequencing followed by Multi Locus Sequence Type analysis identified that five invasive isolates had the same sequence type, ST59, despite originating from three different clinical conditions. Virulence gene analysis showed that the attenuated isolate LM4 was lacking two virulence genes (uhpT,virR) known to be involved in intracellular growth and virulence.In conclusion, the BCEC model was able to differentiate between the infective potential of different isolates. Moreover, resistance to lysozyme correlated with the ability to invade and replicate within BCEC, suggesting co-selection for surviving challenging environments as the abomasum.
Choosing between personal values: The Pavlovian substrates of intrinsic preferences
Authors: Viviani Roberto , Dommes Lisa , Bosch Julia , Beschoner Petra , Stingl Julia C. , Schnell Tatjana 
Published: November 2019

AbstractSeveral brain circuits interact in computing the value of choices between options, as when we express our preference between a set of available consumer goods. Here, we used a procedure developed in functional neuroimaging studies of consumer choice to identify the neural substrates activated by choosing between values that, when put into practice, can give meaning to one’s life, such as achievement, community, tradition, or religion, and are unrelated to material needs or financial security. In a first sample (N=18), instead of the neural substrates usually associated with choice between consumer goods, we found activation of the amygdala, a limbic system structure which presides over assignment of values to stimuli according to immediate affective experience and promotes responses according to their association with potential rewards. This unexpected finding was replicated in a second independent sample (N=18). These results are consistent with views arguing for the existential nature of values that give meaning to one’s life here and now, in contrast to maximizing long-term utility.
Early Inhibition of Retinoic Acid Signaling Rapidly Generates Cardiomyocytes Expressing Ventricular Markers from Human Induced Pluripotent Stem Cells
Authors: Machiraju Pranav , Huang Joshua , Iqbal Fatima , Liu Yiping , Wang Xuemei , Bousman Chad , Greenway Steven C. 
Published: November 2019

SUMMARYCurrent protocols for the differentiation of cardiomyocytes from human induced pluripotent stem cells (iPSCs) generally require prolonged time in culture and result in heterogeneous cellular populations. We present a method for the generation of beating cardiomyocytes expressing specific ventricular markers after just 14 days. Addition of the pan-retinoic acid receptor inverse agonist BMS 493 to human iPSCs for the first 8 days of differentiation resulted in increased protein expression of the ventricular isoform of myosin regulatory light chain (MLC2V) from 18.7% ± 1.72% to 55.8% ± 11.4% (p <0.0001) in cells co-expressing the cardiac muscle protein troponin T (TNNT2). Increased MLC2V expression was also accompanied by a slower beating rate (49.4 ± 1.53 vs. 93.0 ± 2.81 beats per minute, p <0.0001) and increased contraction amplitude (201% ± 8.33% vs. 100% ± 10.85%, p <0.0001) compared to untreated cells. Improved directed differentiation will improve in vitro cardiac modeling.