bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug resistant gliomas
Authors: Tiek Deanna M , Erdogdu Beril , Razaghi Roham , Jin Lu , Sadowski Norah , Alamillo-Ferrer Carla , Hogg J Robert , Haddad Bassem R , Drewry David H , Wells Carrow I , Pickett Julie E. , Song Xiao , Goenka Anshika , Hu Bo , Goldlust Samuel L , Zuercher William J , Pertea Mihaela , Timp Winston , Cheng Shi-Yuan , Riggins Rebecca B 
Published: June 2019

AbstractTemozolomide (TMZ) is a chemotherapeutic agent that has been the first-line standard of care for the aggressive brain cancer glioblastoma (GBM) since 2005. Though initially beneficial, TMZ- resistance is universal and second-line interventions are an unmet clinical need. Here we took advantage the mechanism of action of TMZ to target guanines (G) and investigated G-rich g- quadruplex (G4) and splice site changes that occur upon TMZ-resistance. We report TMZ-resistant GBM has guanine mutations that disrupt the G-rich DNA G4s and splice sites that lead to deregulated alternative splicing. These alterations create vulnerabilities, which are selectively targeted by either the G4 stabilizing drug TMPyP4 or a novel splicing kinase inhibitor of cdc2- like kinase. Finally, we show that the G4 and RNA-binding protein EWSR1 aggregates in the cytoplasm in TMZ-resistant GBM cells and patient samples. Together, our findings provide insight into targetable vulnerabilities of TMZ-resistant GBM and present cytoplasmic EWSR1 as a putative biomarker.TeaserTargeting temozolomide mutations in drug resistant glioma via g-quadruplex and splicing modulators with a putative biomarker.
Methylation at nucleotide C62 in spliceosomal RNA U6 alters mRNA splicing which is important for embryonic development
Authors: Ogren Allison , Kibiryeva Nataliya , Marshall Jennifer , O’Brien James E. , Bittel Douglas C. 
Published: June 2019

AbstractUnderstanding the regulation of development can help elucidate the pathogenesis behind many developmental defects found in humans and other vertebrates. Evidence has shown that alternative splicing of messenger RNA (mRNA) plays a role in developmental regulation, but our knowledge of the underlying mechanisms that regulate alternative splicing are inadequate. Notably, a subset of small noncoding RNAs known as scaRNAs (small cajal body associated RNAs) contribute to spliceosome maturation and function through covalently modifying spliceosomal RNAs by either methylating or pseudouridylating specific nucleotides, but the developmental significance of these modifications is not well understood. Our focus is on one such scaRNA, known as SNORD94 or U94, that methylates one specific cytosine (C62) on spliceosomal RNA U6, thus potentially altering spliceosome function during embryogenesis. We previously showed that mRNA splicing is significantly different in myocardium from infants with congenital heart defects (CHD) compared to controls. Furthermore, we showed that modifying expression of scaRNAs alters mRNA splicing in human cells, and zebrafish embryos. Here we present evidence that SNORD94 levels directly influence levels of methylation at C62 in U6, which we have previously shown is associated with altered splicing and congenital heart defects. The potential importance of scaRNAs as a developmentally important regulatory mechanism controlling alternative splicing of mRNA is unappreciated and needs more research.Author summarySplicing of mRNA transcripts by removal of introns and some non-critical exons is a crucial part of mRNA processing, gene expression, and cell function, and regulation of this process is still under investigation. Alternative splicing of mRNA transcripts of genes is tissue and time specific throughout life, although this process occurs everywhere in the body according to local tissue needs and signals. The spliceosome, the large ribonucleoprotein complex that carries out splicing, is biochemically modified by small noncoding RNAs, which is important for its structure and function. Here we show that the amount of 2’-O-ribose methylation at nucleotide C62 in spliceosomal RNA U6 is dependent on the level of the scaRNA SNORD94. We hypothesize that alternative splicing is dependent, at least in part, on biochemical modification to the spliceosomal RNAs. Furthermore, when scaRNA directed modifications are dysregulated, the result causes inappropriate alternative splicing that may contribute to developmental defects such as congenital heart defects. To our knowledge, this is the first demonstration that 2’-O-ribose methylation is indeed dependent on scaRNA levels in human cells and tissues.
Schistosomiasis among pregnant women in the Njombe-Penja health district, Littoral region of Cameroon: A cross sectional study
Authors: Tonga Calvin , Bayoi Charlie Ngo , Tchanga Flore Chanceline , Yengue Jacqueline Félicité , Wepnje Godlove Bunda , Nyabeyeu Hervé Nyabeyeu , Kangam Lafortune , Kouodjip Larissa Nono , Akono Patrick Ntonga , Lehman Léopold Gustave 
Published: June 2019

AbstractBackgroundSchistosomiasis is a Neglected Tropical Disease with endemic foci in Cameroon. Epidemiological data on schistosomiasis in pregnancy are scarce in the country. This study is about schistosomiasis among pregnant women in the Njombe-Penja health district, where schistosomiasis was reported since 1969.MethodologyOverall, 282 pregnant women were enrolled upon informed consent at first antenatal consultation. A questionnaire was administered to document socio-economic and obstetric information. Stool and terminal urine samples were collected and analysed using the Kato-Katz/formol-ether concentration techniques and centrifugation method respectively. Haemoglobin concentration was measured with finger prick blood, using a URIT-12® electronic haemoglobinometer.Principal findingsThe overall prevalence of schistosomiasis was 31.91%. Schistosoma guineensis, S. haematobium and S. mansoni infections were found in 0.35%, 04.96% and 28.01% of participants respectively. Co-infection with 2 species of Schistosoma was found in 04.44% of these women. The prevalence of schistosomiasis was significantly higher in younger women (≤20) and among residents of Njombe. All S. haematobium infected women were anemic and infection was associated with significantly lower haemoglobin levels (p=0.02).ConclusionThe prevalence of schistosomiasis is high in pregnant women of the Njombe-Penja health district, with possible adverse pregnancy outcomes. Female of childbearing age should be considered for mass drug administration.Author summaryPregnant women are known to be more vulnerable to infectious diseases and in their case, at least two lives are at risk. Although schistosomiasis remains a major public health issue in Cameroon, epidemiological data on schistosomiasis in pregnancy are scarce. These data are of high interest for informed decision-making. We examined stools and urines from 282 women of the Njombe-Penja Health district and measured their blood levels. Overall, 31.91% of women were infected, mostly younger ones and those living in the town of Njombe. Three species of Schistosoma parasite were identified. Women having urinary schistosomiasis had lower blood levels. These results show that the prevalence of schistosomiasis is high in pregnant women of Njombe. Also, because of the anemia it induces, the disease can lead to adverse pregnancy outcomes on the woman and her foetus. Treating female of childbearing age would cure the disease and prevent adverse outcomes.
Analysis of meiosis in Pristionchus pacificus reveals plasticity in homolog pairing and synapsis in the nematode lineage
Authors: Rillo-Bohn Regina , Adilardi Renzo S. , Mitros Therese , Avşaroğlu Bariş , Stevens Lewis , Köhler Simone , Bayes Joshua , Wang Clara , Lin Sabrina , Baskevitch K. Alienor , Rokhsar Daniel S. , Dernburg Abby F. 
Published: June 2019

ABSTRACTMeiosis is conserved across eukaryotes yet varies in the details of its execution. Here we describe a new comparative model system for molecular analysis of meiosis, the nematode Pristionchus pacificus, a distant relative of the widely studied model organism Caenorhabditis elegans. P. pacificus shares many anatomical and other features that facilitate analysis of meiosis in C. elegans. However, while C. elegans has lost the meiosis-specific recombinase Dmc1 and evolved a recombination-independent mechanism to synapse its chromosomes, P. pacificus expresses both DMC-1 and RAD-51. We find that SPO-11 and DMC-1 are required for stable homolog pairing, synapsis, and crossover formation, while RAD-51 is dispensable for these key meiotic processes. RAD-51 and DMC-1 localize sequentially to chromosomes during meiotic prophase and show nonoverlapping functions. We also present a new genetic map for P. pacificus that reveals a crossover landscape very similar to that of C. elegans, despite marked divergence in the regulation of synapsis and crossing-over between these lineages.
BAGSE: a Bayesian hierarchical model approach for gene set enrichment analysis
Authors: Hukku Abhay , Quick Corbin , Luca Francesca , Pique-Regi Roger , Wen Xiaoquan 
Published: June 2019

AbstractGene set enrichment analysis has been shown to be effective in identifying relevant biological pathways underlying complex diseases. Existing approaches lack the ability to quantify the enrichment levels accurately, hence preventing the enrichment information to be further utilized in both upstream and downstream analyses. A modernized and rigorous approach for gene set enrichment analysis that emphasizes both hypothesis testing and enrichment estimation is much needed. We propose a novel computational method, Bayesian Analysis of Gene Set Enrichment (BAGSE), for gene set enrichment analysis. BAGSE is built on a Bayesian hierarchical model and fully accounts for the uncertainty embedded in the association evidence of individual genes. We adopt an empirical Bayes inference framework to fit the proposed hierarchical model by implementing an efficient EM algorithm. Through simulation studies, we illustrate that BAGSE yields accurate enrichment quantification while achieving similar power as the state-of-the-art methods. Further simulation studies show that BAGSE can effectively utilize the enrichment information to improve the power in gene discovery. Finally, we demonstrate the application of BAGSE in analyzing real data from a differential expression experiment and a Transcriptome-wide Association Study (TWAS). Our results indicate that the proposed statistical framework is effective in aiding the discovery of potentially causal pathways and gene networks. BAGSE is implemented using the C++ programming language and is freely available from https://github.com/xqwen/bagse/. Simulated and real data used in this paper are also available at the Github repository for reproducibility purposes.
The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia
Authors: Metzner Christoph , Zurowski Bartosz , Steuber Volker 
Published: June 2019

AbstractDespite an increasing body of evidence demonstrating subcellular alterations in parvalbumin-positive (PV+) interneurons in schizophrenia, their functional consequences remain elusive. Since PV+ interneurons are involved in the generation of fast cortical rhythms, these changes have been hypothesized to contribute to well-established alterations of beta and gamma range oscillations in patients suffering from schizophrenia. However, the precise role of these alterations and the role of different subtypes of PV+ interneurons is still unclear. Here we used a computational model of auditory steady-state response (ASSR) deficits in schizophrenia. We investigated the differential effects of decelerated synaptic dynamics, caused by subcellular alterations at two subtypes of PV+ interneurons: basket cells and chandelier cells. Our simulations suggest that subcellular alterations at basket cell synapses rather than chandelier cell synapses are the main contributor to these deficits Particularly, basket cells might serve as target for innovative therapeutic interventions aiming at reversing the oscillatory deficits.
Essential roles of Hdac1 and 2 in lineage development and genome-wide DNA methylation during mouse preimplantation development
Authors: Zhao Panpan , Wang Huanan , Wang Han , Dang Yanna , Luo Lei , Li Shuang , Shi Yan , Wang Lefeng , Wang Shaohua , Mager Jesse , Zhang Kun 
Published: June 2019

AbstractEpigenetic modifications, including DNA methylation and histone modifications, are reprogrammed considerably following fertilization during mammalian early embryonic development. Incomplete epigenetic reprogramming is a major factor leading to poor developmental outcome in embryos generated by assisted reproductive technologies, such as somatic cell nuclear transfer. However, the role of histone modifications in preimplantation development is poorly understood. Here, we show that co-knockdown (cKD) of Hdac1 and 2 (but not individually) resulted in developmental failure during the morula to blastocyst transition. This outcome was also confirmed with the use of small-molecule Hdac1/2-specific inhibitor FK228. We observed reduced cell proliferation and increased incidence of apoptosis in cKD embryos, which were likely caused by increased acetylation of Trp53. Importantly, both RNA-seq and immunostaining analysis revealed a failure of lineage specification to generate trophectoderm and pluripotent cells. Among many gene expression changes, a substantial decrease of Cdx2 may be partly accounted for by the aberrant Hippo pathway occurring in cKD embryos. In addition, we observed an increase in global DNA methylation, consistent with increased DNA methyltransferases and Uhrf1. Interestingly, deficiency of Rbbp4 and 7 (both are core components of several Hdac1/2-containing epigenetic complexes) results in similar phenotypes as those of cKD embryos. Overall, Hdac1 and 2 play redundant functions required for lineage specification, cell viability and accurate global DNA methylation, each contributing to critical developmental programs safeguarding a successful preimplantation development.SignificanceSubstantial changes to epigenetic modifications occur during preimplantation development and can be detrimental when reprogrammed incompletely. However, little is known about the role of histone modifications in early development. Co-knockdown of Hdac1 and 2, but not individually, resulted in developmental arrest during morula to blastocyst transition, which was accompanied by reduced cell number per embryo and increased incidence of apoptosis. Additionally, we observed a failure of first lineage specification to generate trophectoderm and pluripotent cells, which were associated with reduced expression of key lineage-specific genes and aberrant Hippo pathway. Moreover, an increase in global DNA methylation was found with upregulated Dnmts and Uhrf1. Thus, Hdac1 and 2 play overlapping roles in lineage development, apoptosis, and global methylation during preimplantation development.
Long-term single-cell passaging of human iPSC fully supports pluripotency and high-efficient trilineage differentiation capacity
Authors: Cruvinel Estela , Ogusuku Isabella , Cerioni Rosanna , Gonçalves Jéssica , Góes Maria Elisa , Alvim Juliana Morais , Silva Anderson Carlos , Pereira Alexandre , Dariolli Rafael , Valadares Marcos , Biagi Diogo 
Published: June 2019

ABSTRACTObjectivesTo validate a straightforward single-cell passaging cultivation method that enables high-quality maintenance of hiPSC without the appearance of karyotypic abnormalities or loss of pluripotency.MethodsCells were kept in culture for over 50 passages, following a structured chronogram of passage and monitoring cell growth by population doubling time (PDT) calculation and cell confluence. Standard procedures for iPSC monitoring as embryonic body (EB) formation, karyotyping and pluripotency markers expression were evaluated in order to monitor the cellular state in the long-term culture. Cells that underwent these tests were then subjected to differentiation into keratinocytes and cardiomyocytes to evaluate its differentiation capacity.ResultshiPSC clones maintained its pluripotent capability as well as chromosomal integrity and were able to generate derivatives from the three germ layers at high passages by embryoid body formation and high-efficient direct differentiation into keratinocytes and cardiomyocytes.ConclusionOur findings support the routine of hiPSC single-cell passaging as a reliable procedure even after long-term cultivation, providing healthy PSCs to be used in drugs discovery, toxicity and disease modeling as well as for therapeutic approaches.
Hypertriglyceridemia and obesity exacerbate the course of SIRS induced by SAP in Rats
Authors: Hua Kelei , Li RuiXia , Cao LiYing , Lao WanSheng 
Published: June 2019

AbstractThe aim of the present study was to explore the mechanism underlying how HTG (hypertriglyceridaemia) and obesity exacerbate the course of the systemic inflammatory response syndrome (SIRS) induced by severe acute pancreatitis (SAP) in rats. Seventy-two rats were fed a normal or high-fat diet to induce HTG and obesity, and SAP was induced by retrograde injection of 5% sodium taurocholate solution at a volume of 1 ml/kg into the biliopancreatic duct. The injury to the pancreas was assessed by macroscopic observation, pancreatic histological evaluation and serum levels of amylase and lipase. SIRS was estimated by measuring SIRS scores and interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α) and interleukin-10 (IL-10) expression. The results showed that the SIRS scores and pancreatic histological scores increased significantly and the blood calcium level decreased significantly in the hypertriglyceridaemia SAP (HSAP) group compared with those of the SAP group. In addition, HTG and obesity significantly increased plasma levels of the proinflammatory cytokines IL-6 and TNF-α and significantly downregulated the proinflammatory cytokine IL-10. Our findings showed that HSAP rats exhibited more severe pancreatic injury and more serious SIRS scores than the SAP rats did. The underlying mechanism may be that HTG and obesity intensify early-stage SIRS by regulating the levels of inflammatory and anti-inflammatory cytokines.
Understanding cross-border crime: the value of international business research
Authors: Enderwick Peter 
Published: June 2019

PurposeBased on a considerable degree of commonality between multinational enterprises (MNEs) and cross-border criminal organisations, the purpose of this paper is to identify ways and areas in which international business (IB) research could be of value in improving understanding of the operations of cross-border criminal organisations and in the development of effective countermeasures to global crime.Design/methodology/approachA review of the characteristics of legitimate MNEs and cross-border criminal organisations is undertaken to assess the applicability of IB research approaches in understanding the strategies and structures of organised criminal groups.FindingsDespite some obvious differences there appears to be sufficient commonality between legitimate and illegitimate international commerce so that the firm-centric focus of IB research could provide valuable insights complementing the policy-oriented approach of criminology. Some adaptation of IB research tools may be required. The exchange is not one-way: studies of cross-border crime also offer lessons for IB scholars.Research limitations/implicationsIB scholarly work on cross-border crime could enrich both the fields of IB and transnational criminology. Better understanding of criminal enterprises could also facilitate the design of more effective interdiction policies.Originality/valueDespite their commonalities and interactions, the two sectors of international enterprise have developed separately, and this paper identifies and explores possible synergies between the two.
Accuracy estimation of a stretch-retractable single section continuum manipulator based on inverse kinematics
Authors: Wang Hao , Gao GuoHua , Xia Qixiao , Ren Han , Li LianShi , Zheng Yuhang 
Published: June 2019

Purpose
The purpose of this paper is to present a novel stretch-retractable single section (SRSS) continuum manipulator which owns three degrees of freedom and higher motion range in three-dimension workspace than regular single continuum manipulator. Moreover, the motion accuracy was analyzed based on the kinematic model. In addition, the experiments were carried out for validation of the theory.

Design/methodology/approach
A kinematics model of the SRSS continuum manipulator is presented for analysis on bending, rotating and retracting in its workspace. To discuss the motion accuracy of the SRSS continuum manipulator, the dexterity theory was introduced based on the decomposing of the Jacobian matrix. In addition, the accuracy of motion is estimated based on the inverse kinematics and dexterity theory. To verify the presented theory, the motion of free end was tracked by an electromagnetic positioning system. According to the comparison of experimental value and theoretical analysis, the free end error of SRSS continuum manipulator is less than 6.24 per cent in the region with favorable dexterity.

Findings
This paper presents a new stretch-retractable continuum manipulator that the structure was composed of several springs as the backbone. Thus, the SRSS continuum manipulator could own wide motion range depending on its retractable structure. Then, the motion accuracy character of the SRSS continuum manipulator in the different regions of its workspace was obtained both theoretically and experimentally. The results show that the high accuracy region distributes in the vicinity of the outer boundary of the workspace. The motion accuracy gradually decreases with the motion position approaching to the center of its workspace.

Research limitations/implications
The presented SRSS continuum manipulator owns three degrees of freedom. The future work would be focused on the two-section structure which will own six degrees of freedom.

Practical implications
In this study, the SRSS continuum manipulator could be extended to six degrees of freedom continuum robot with two sections that is less one section than regular six degrees of freedom with three single section continuum manipulator.

Originality/value
The value of this study is to propose a SRSS continuum manipulator which owns three degrees of freedom and could stretch and retract to expend workspace, for which the accuracy in different regions of the workspace was analyzed and validated based on the kinematics model and experiments. The results could be feasible to plan the motion space of the SRSS continuum manipulator for keeping in suitable accuracy region.