bluuebunny/crossref_metadata_2025 huggingface dataset:
Positive family history of cardiovascular disease and long-term outcomes after coronary artery bypass grafting: a genetic paradox?
Authors: Ruttmann Elfriede , Abfalterer Hannes , Dietl Marion , Wagner Julian , Kilo Juliane , Grimm Michael , Bates Katie , Fritz Josef , Ulmer Hanno
Published: November 2019

OBJECTIVES

Parental cardiovascular disease (CVD) is a known risk factor for premature CVD. It is unknown whether a positive family history (PFH) affects outcomes after coronary artery bypass grafting (CABG).

METHODS

Data come from a retrospective longitudinal study of CABG patients consecutively recruited from 2001 to 2018 (n = 5389). From this study, 2535 patients with premature CVD undergoing CABG under the age of 60 years and information on parental CVD were identified. The Framingham offspring study criteria were used to identify PFH of CVD. Multivariable Cox proportional hazards regression models were used to assess the effect of PFH on overall and major adverse cardiovascular and cerebrovascular event-free survival.

RESULTS

A total of 273 deaths and 428 major adverse cardiovascular and cerebrovascular events occurred during follow-up. PFH of CVD was found in 54.2% of patients (n = 1375). Within these patients, 66.1% had a father who experienced a premature cardiovascular event (n = 909), 27.8% a mother (n = 382) and 6.1% both a mother and a father (n = 84). In the majority of cases, the patient’s parent had experienced a cardiac event (85.9%, n = 1181) and 14.1% of patients with PFH reported parental stroke (n = 194). Following CABG, PFH was associated with improved overall [adjusted hazards ratio (HR) 0.67, 95% confidence interval (CI) 0.50–0.90; P = 0.008] and major adverse cardiovascular and cerebrovascular event-free survival (adjusted HR 0.73, 95% CI 0.68–0.89; P = 0.01). Among the covariates adjusted for age, diabetes, renal insufficiency, peripheral arterial disease, ejection fraction, previous cerebrovascular events and previous mediastinal radiation were all associated with poorer outcomes.

CONCLUSIONS

Although it is well established that a PFH increases the risk of requiring CABG at younger ages, this study shows that, paradoxically, PFH is also protective regarding long-term outcomes.

Registration number local IRB

UN4232 297/4.3 (retrospective study).
Cardiovascular abnormalities in patient with Williams–Beuren syndrome
Authors: Panfilov Dmitry S , Saushkin Viktor V , Kozlov Boris N
Published: November 2019

We present a case of a 42-year-old male patient with severe supravalvular aortic stenosis associated with aortic and mitral valve stenosis as well as an anomalous origin of the right coronary ostium caused by deletion in the q11.23 region of the human chromosome 7 in a patient with Williams–Beuren syndrome.
The O-GalNAcylating enzyme GALNT5 mediates carcinogenesis and progression of cholangiocarcinoma via activation of AKT/ERK signaling
Authors: Detarya Marutpong , Sawanyawisuth Kanlayanee , Aphivatanasiri Chaiwat , Chuangchaiya Sriwipa , Saranaruk Paksiree , Sukprasert Lukkana , Silsirivanit Atit , Araki Norie , Wongkham Sopit , Wongkham Chaisiri
Published: November 2019

Mucin type O-glycosylation is a posttranslational modification of membrane and secretory proteins. Transferring of N-acetylgalactosamine, the first sugar of O-glycosylation, is catalyzed by one of the 20 isoforms of polypeptide N-acetylgalactosaminyltransferases (GALNTs). In this study, Vicia villosa lectin (VVL), a lectin that recognizes O-GalNAcylated glycans, was used to detect VVL-binding glycans (VBGs) in cholangiocarcinoma (CCA). The elevation of VBGs in tumor tissues of the liver fluke associated with CCA from hamsters and patients was noted. VBGs were detected in hyperplastic/dysplastic bile ducts and CCA but not in normal biliary epithelia and hepatocytes, indicating the association of VBGs with CCA development and progression. GALNT5 was shown to be the major isoform found in human CCA cell lines with high VBG expression. Suppression of GALNT5 expression using siRNA significantly reduced VBG expression, signifying the connection of GALNT5 and VBGs observed. Knocked-down GALNT5 expression considerably inhibited proliferation, migration and invasion of CCA cells. Increased expression of GALNT5 using pcDNA3.1-GALNT5 expression vector induced invasive phenotypes in CCA cells with low GALNT5 expression. Increasing of claudin-1 and decreasing of slug and vimentin expression together with inactivation of Akt/Erk signaling were noted in GALNT5 knocked-down cells. These observations were reversed in GALNT5 over-expressing cells. GALNT5-modulated progression of CCA cells was shown to be, in part, via GALNT5-mediated autocrine/paracrine factors that stimulated activations of Akt/Erk signaling and the epithelial to mesenchymal transition process. GALNT5 and its O-GalNAcylated products may have important roles in promoting progression of CCA and could possibly be novel targets for treatment of metastatic CCA.
A CCR4 Association Factor 1, OsCAF1B, Participates in the αAmy3 mRNA Poly(A) Tail Shortening and Plays a Role in Germination and Seedling Growth
Authors: Fang Jhen-Cheng , Liu Hsin-Yi , Tsai Yin-Chuan , Chou Wei-Lun , Chang Chun-Chen , Lu Chung-An
Published: November 2019

Poly(A) tail (PAT) shortening, also termed deadenylation, is the rate-limiting step of mRNA degradation in eukaryotic cells. The carbon catabolite repressor 4-associated factor 1s (CAF1s) were shown to be one of the major enzymes for catalyzing mRNA deadenylation in yeast and mammalian cells. However, the functions of CAF1 proteins in plants are poorly understood. Herein, a sugar-upregulated CAF1 gene, OsCAF1B, is investigated in rice. Using gain–of–function and dominant-negative mutation analysis, we show that overexpression of OsCAF1B resulted in an accelerated α-amylase gene (αAmy3) mRNA degradation phenomenon, while ectopic expression of a form of OsCAF1B that had lost its deadenylase activity resulted in a delayed αAmy3 mRNA degradation phenomenon in transgenic rice cells. The change in αAmy3 mRNA degradation in transgenic rice is associated with the altered lengths of the αAmy3 mRNA PAT, indicating that OsCAF1B acts as a negative regulator of αAmy3 mRNA stability in rice. Additionally, we found that overexpression of OsCAF1B retards seed germination and seedling growth. These findings indicate that OsCAF1B participates in sugar-induced αAmy3 mRNA degradation and deadenylation and acts a negative factor for germination and seedling development.
Root Rot ofJuniperusandMicrobiotabyPhytophthora lateralisin Oregon Horticultural Nurseries
Authors: Peterson Ebba K. , Rupp Franziska , Eberhart Joyce , Parke Jennifer L.
Published: November 2019

Widespread symptoms of root rot and mortality on Juniperus communis and Microbiota decussata were observed in two horticultural nurseries in Oregon, leading to the isolation of a Phytophthora sp. from diseased roots. Based on morphology and sequencing the internal transcribed spacer ITS1-5.8S-ITS2 region, isolates were identified as the invasive pathogen Phytophthora lateralis, causal agent of Port-Orford-cedar (POC; Chamaecyparis lawsoniana) root disease. Additional sequencing of the cytochrome c oxidase subunit 1 and 2 genes identified all isolates as belonging to the PNW lineage. Utilizing recovered isolates plus a POC-wildlands isolate and susceptible POC as controls, we completed Koch’s postulates on potted Juniperus and Microbiota plants. Nursery isolates were more aggressive than the forest isolate, which was used in the POC resistance breeding program. Increased aggressiveness was confirmed using a branch stem dip assay with four POC clones that differed in resistance, although no isolate completely overcame major-gene resistance. Isolates were sensitive to mefenoxam, a fungicide commonly used to suppress Phytophthora spp. growth in commercial nurseries. Although POC resistance is durable against these more aggressive nursery isolates, the expanded host range of P. lateralis challenges POC conservation through the continued movement of P. lateralis by the nursery industry.
High bone microarchitecture, strength, and resistance to bone loss in MRL/MpJ mice correlates with activation of different signaling pathways and systemic factors
Authors: Sun Xuying , Gao Xueqin , Deng Zhenhan , Zhang Linlin , McGilvray Kirk , Gadomski Benjamin C. , Amra Sarah , Bao Gang , Huard Johnny
Published: November 2019

The MRL/MpJ mice have demonstrated an enhanced tissue regeneration capacity for various tissues. In the present study, we systematically characterized bone microarchitecture and found that MRL/MpJ mice exhibit higher bone microarchitecture and strength compared to both C57BL/10J and C57BL/6J WT mice at 2, 4, and 10 months of age. The higher bone mass in MRL/MpJ mice was correlated to increased osteoblasts, decreased osteoclasts, higher cell proliferation, and bone formation, and enhanced pSMAD5 signaling earlier during postnatal development (2‐month old) in the spine trabecular bone, and lower bone resorption rate at later age. Furthermore, these mice exhibit accelerated fracture healing via enhanced pSMAD5, pAKT and p‐P38MAPK pathways compared to control groups. Moreover, MRL/MpJ mice demonstrated resistance to ovariectomy‐induced bone loss as evidenced by maintaining higher bone volume/tissue volume (BV/TV) and lower percentage of bone loss later after ovariectomy. The consistently higher serum IGF1 level and lower RANKL level in MRL/MpJ mice may contribute to the maintenance of high bone mass in uninjured and injured bone. In conclusion, our results indicate that enhanced pSMAD5, pAKT, and p‐P38MAPK signaling, higher serum IGF‐1, and lower RANKL level contribute to the higher bone microarchitecture and strength, accelerated healing, and resistance to osteoporosis in MRL/MpJ mice.
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

Sleep 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

Adipogenesis, 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

In 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

Base 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

Intramembrane 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.
On the selection of endogenous and exogenous signals
Authors: McCormick C. R. , Redden R. S. , Hurst A. J. , Klein R. M.
Published: November 2019

Alerting is one of the three components of attention which involves the eliciting and maintenance of arousal. A seminal study by Posneret al.(Posner MI, Klein R, Summers J, Buggie S. 1973Mem. Cognit.1, 2–12 (doi:10.3758/BF03198062)) focused on how changing the interval between an alerting signal and a target would impact the speed and accuracy of responding. Participants indicated whether targets were presented on the left or right side of the fixation point. Auditory warning signals were played at various intervals prior to the target to alert participants and prepare them to make a response. Reaction times revealed a robust, U-shaped, preparation function. Importantly, a clear speed-accuracy trade-off (SAT) was observed. In the current experiment, we replicated the methodological components of this seminal study while implementing a novel auditory warning signal (Lawrence MA, Klein RM. 2013J. Exp. Psychol. General142, 560 (doi:10.1037/a0029023)) that was either purely endogenous (change in quality without a change in intensity; analogous to isoluminant colour change in vision) or a combination of endogenous and exogenous (change in both quality and intensity). We expected to replicate the U-shaped preparation function and SAT observed by Posner and colleagues. Based on Lawrence and Klein's findings we also expected the SAT to be more robust with the intense signal in comparison to the isointense signal.
What do we know about the fossil record of pinnipeds? A historiographical investigation
Authors: Valenzuela-Toro Ana , Pyenson Nicholas D.
Published: November 2019

The fossil record of pinnipeds (seals, fur seals and walruses) is globally distributed, spanning from the late Oligocene to the Holocene. This record shows a complex evolutionary history that could not otherwise be inferred from their extant relatives, including multiple radiations and iterative ecomorphological specializations among different lineages, many of which are extinct. The fossil record of pinnipeds is not uniformly represented in space and time, however, leaving some gaps in our knowledge. We performed a historiographical investigation of the published fossil record of pinnipeds based on the information available in the Paleobiology Database, with the aim to broadly characterize and evaluate it from a taxonomic, geographical and temporal perspective. We identified major trends, strengths and weaknesses of the pinniped fossil record, including potential biases that may affect our interpretations. We found that 39% of the record corresponds to extant taxa, which are essentially from the Pleistocene and Holocene. There is a larger record from the Northern Hemisphere, suggesting biases in sampling and collection effort. The record is not strongly biased by sedimentary outcrop bias. Specifically, for extinct species, nearly half of them are represented by a single occurrence and a large proportion have type specimens consisting of single isolated postcranial elements. While the pinniped fossil record may have adequate temporal and taxonomic coverage, it has a strong geographical bias and its comparability is hindered by the incompleteness of type specimens. These results should be taken into account when addressing patterns of their past diversity, evolutionary history and paleoecology.
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

Context

Mining 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 Methods

Study 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.

Results

One 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 limitations

Robust dataset, complete enumeration, large sample size.

Key messages

What 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

Abstract

The 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

Vincristine 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

Human 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

The 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.

Importance

Increasing 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

Listeria 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

Several 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

Current 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.
Constricted migration is associated with stable 3D genome structure differences in cancer cell
Authors: Golloshi Rosela , Playter Christopher , Freeman Trevor F. , Das Priyojit , Raines Thomas Isaac , Garretson Joshua H. , Thurston Delaney , McCord Rachel Patton
Published: November 2019

To spread from a localized tumor, metastatic cancer cells must squeeze through constrictions that cause major nuclear deformations. Since chromosome structure affects nucleus stiffness, gene regulation and DNA repair, here we investigate the relationship between 3D genome structure and constricted migration in cancer cells. Using melanoma (A375) cells, we identify phenotypic differences in cells that have undergone multiple rounds of constricted migration. These cells display a stably higher migration efficiency, elongated morphology, and differences in the distribution of Lamin A/C and heterochromatin. Hi-C experiments reveal differences in chromosome spatial compartmentalization specific to cells that have passed through constrictions and related alterations in expression of genes associated with migration and metastasis. Certain features of the 3D genome structure changes, such as a loss of B compartment interaction strength, are consistently observed after constricted migration in clonal populations of A375 cells and in MDA-MB-231 breast cancer cells. Our observations suggest that consistent types of chromosome structure changes are induced or selected by passage through constrictions and that these may epigenetically encode stable differences in gene expression and cellular migration phenotype.
Influence of diffuser grain size on the speckle tracking technique
Authors: Tian Naxi , Jiang Hui , Li Aiguo , Liang Dongxu , Yan Shuai , Zhang Zengyan
Published: November 2019

The speckle-based X-ray imaging technique (SBT), which includes the three imaging modalities of absorption, phase contrast and dark field, is widely used in many fields. However, the influence of the grain size of the diffuser, the coherence of the X-ray source and the pixel size of the detector on the multi-mode imaging quality of SBT is still woefully unclear. In this paper, the whole SBT process is simulated and the influence of these three factors on image quality is discussed. Based on this discussion, the grain size of the diffuser for SBT applications should be limited by the pixel size of the detector and the coherence length of the X-ray source. According to analysis of the noise signal and correlation map, a suitable grain size is an indispensable condition for high-quality SBT images, because an excessively small or large grain size degrades the resolution of the imaging results and generates false signals. In addition, the power spectral density of the measured raw speckle patterns demonstrates that a smaller grain can better retain high-frequency information from an imaged sample. The simulated and experimental results verify these conclusions. The conclusions of this work will be helpful in designing suitable experimental setups for SBT applications and have the potential to promote the performance of SBT in other applications, such as X-ray optics metrology and coherence measurement.
Crystal structure of the Wheat dwarf virus Rep domain
Authors: Everett Blake A. , Litzau Lauren A. , Tompkins Kassidy , Shi Ke , Nelson Andrew , Aihara Hideki , Evans Robert L. , Gordon Wendy R.
Published: November 2019

The Rep domain of Wheat dwarf virus (WDV Rep) is an HUH endonuclease involved in rolling-circle replication. HUH endonucleases coordinate a metal ion to enable the nicking of a specific ssDNA sequence and the subsequent formation of an intermediate phosphotyrosine bond. This covalent protein–ssDNA adduct makes HUH endonucleases attractive fusion tags (HUH-tags) in a diverse number of biotechnological applications. Solving the structure of an HUH endonuclease in complex with ssDNA will provide critical information about ssDNA recognition and sequence specificity, thus enabling rationally engineered protein–DNA interactions that are programmable. The structure of the WDV Rep domain reported here was solved in the apo state from a crystal diffracting to 1.24 Å resolution and represents an initial step in the direction of solving the structure of a protein–ssDNA complex.
Strangers in a seemingly open-to-all website: the gender bias in Wikipedia
Authors: Lir Shlomit Aharoni
Published: November 2019

Purpose

Throughout the years, many scholarly answers were given to the question regarding the gender bias in Wikipedia. However, the research literature seldom explores how different barriers are interconnected and rarely focuses on what prevents women who initially declared their interest from eventually participating in the website. The purpose of this paper is to deal with this lacuna and explore the gender bias in Wikipedia through examining how the different barriers are interlinked in a manner that deters women and prevents them from editing in the website.

Design/methodology/approach

Based on action research with a mixed evaluation method and two rounds of interviews, the research followed the steps of 27 Israeli women activists who participated in editing workshops.

Findings

The findings show that having the will to edit and the knowledge of how to edit are necessary but insufficient conditions for women to participate in Wikipedia. The finding reveals two categories: pre-editing barriers of negative reputation, lack of recognition, anonymity and fear of being erased; and post-editing barriers of experiences of rejection, alienation, lack of time and profit and ownership of knowledge. The research suggests a “Vicious Circle” model, displaying how the five layers of negative reputation, anonymity, fear, alienation and rejection – enhance each other, in a manner that deters women from contributing to the website.

Practical implications

In order for more women to join Wikipedia, the research offers the implantation of a “Virtuous Circle” that consists of nonymity, connection to social media, inclusionist policy, soft deletion and red-flagging harassments.

Originality/value

Throughout the years, many answers were given to the question regarding the gender bias in Wikipedia. However, research literature seldom explores how different barriers are interconnected and rarely focuses on what prevents women who initially declared their interest and who attended editing workshops from eventually participating in the website. The current research has taken upon itself to deal with this lacuna and explores the power-relations in Wikipedia through three questions: first, why an educational intervention did not increase participation? Second, how the different barriers described by research group members are interconnected and enhance each other in a manner that prevents women from editing on the website? and third how can the gap be narrowed?
An investigation of the relationship between lean and well-being based on the job demands-resources model
Authors: Beraldin Andrea Roberto , Danese Pamela , Romano Pietro
Published: November 2019

Purpose

The purpose of this paper is to investigate how just-in-time (JIT)-related job demands, problem-solving job demands and soft lean practices (SLPs) jointly influence employee well-being in terms of work engagement and exhaustion.

Design/methodology/approach

Based on the job demands-resources model, lean-related job characteristics were classified as resources or demands, and a set of hypotheses was developed to test their effect on work engagement and exhaustion, including the potential interaction between job resources and demands. The hypotheses were tested using moderated hierarchical regression and structural equation modelling, based on data from 138 workers.

Findings

SLPs act as job resources in a lean company, increasing work engagement and reducing exhaustion. Conversely, JIT-related job demands act as a hindrance, reducing work engagement and increasing exhaustion. However, SLPs can reduce the effect of JIT-related job demands on exhaustion, and JIT-related job demands may enhance the positive effects of SLPs on work engagement.

Research limitations/implications

The study provides no conclusive evidence on the hypothesized role of problem-solving as a challenge job demand.

Practical implications

The results can guide practitioners’ understanding of how to implement lean without harm to employee well-being.

Originality/value

By employing a well-grounded psychological model to test the link between lean and well-being, the study finds quantitative support for: the buffering effect of SLPs on exhaustion caused by JIT-related job demands, and for the role of JIT as a hindrance. These novel findings have no precedent in previous survey-based research. In addition, it reveals the importance of studying SLPs at an individual level, as what matters is the extent to which workers perceive SLPs as useful and supportive.
Collaboration for transition between TVET and university: a proposal
Authors: Naziz Arjuman
Published: November 2019

Purpose

Despite the growing emphasis on revitalizing the technical and vocational education and training (TVET) sector in Bangladesh, very little discussion has taken place on reforming the current inflexible transition pathways, from TVET to the universities. This paper aims to reflect critically on the existing literature on TVET, in the global and national context, and the experiences of students and TVET experts, to develop a model of collaboration between the polytechnic institutes and the universities in Bangladesh.

Design/methodology/approach

This paper follows a qualitative strategy of enquiry, using a mix of critical reflection on literature on TVET and higher education and unstructured interviews with two TVET experts, four TVET students and four students from a public university. It draws on the theories of collaboration and uses exemplary cases to illustrate and support the line of reasoning.

Findings

This paper identifies that there is resource dependency between the polytechnic institutes and universities in Bangladesh, and their institutional environment necessitates them to form collaboration to ensure flexible transition pathway, from polytechnic institutes to universities; this paper proposes a model for such collaboration.

Practical implications

This paper offers a guideline for forming collaboration among the relevant stakeholders.

Social implications

Collaboration between polytechnic institutes and universities in Bangladesh is likely to address the inequitable nature of TVET, by improving its social status and acceptance, as well as allowing higher income opportunity and greater mobility for the TVET graduates, coming especially from humble socio-economic backgrounds.

Originality/value

This paper contributes in the recent discussions on how collaboration among different stakeholders can contribute in achieving the sustainable development goals, with special emphasis on TVET.