bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Frailty as an Unmeasured Confounder in Observational Studies of Antidiabetic Medications
Authors: Presley Caroline A , Chipman Jonathan , Min Jea Young , Grijalva Carlos G , Greevy Robert A , Griffin Marie R , Roumie Christianne L 
Published: September 2018

Abstract

Background
It is unknown whether observational studies evaluating the association between antidiabetic medications and mortality adequately account for frailty. Our objectives were to evaluate if frailty was a potential confounder in the relationship between antidiabetic medication regimen and mortality and how well administrative and clinical electronic health record (EHR) data account for frailty.

Methods
We conducted a retrospective cohort study in a single Veterans Health Administration (VHA) healthcare system of 500 hospitalizations—the majority due to heart failure—of Veterans who received regular VHA care and initiated type 2 diabetes treatment from 2001 to 2008. We measured frailty using a modified frailty index (FI, >0.21 frail). We obtained antidiabetic medication regimen and time-to-death from administrative sources. We compared FI among patients on different antidiabetic regimens. Stepwise Cox proportional hazards regression estimated time-to-death by demographic, administrative, clinical EHR, and FI data.

Results
Median FI was 0.22 (interquartile range 0.18, 0.27). Frailty differed across antidiabetic regimens (p < .001). An FI increase of 0.05 was associated with an increased risk of death (hazard ratio 1.45, 95% confidence interval 1.32, 1.60). Cox proportional hazards model for time-to-death including demographic, administrative, and clinical EHR data had a c-statistic of 0.70; adding FI showed marginal improvement (c-statistic 0.72).

Conclusions
Frailty was associated with antidiabetic regimen and death, and may confound that relationship. Demographic, administrative, and clinical EHR data, commonly used to balance differences among exposure groups, performed moderately well in assessing risk of death, with minimal gain from adding frailty. Study design and analytic techniques can help minimize potential confounding by frailty in observational studies.
MYCN-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma
Authors: Tjaden Britta , Baum Katharina , Marquardt Viktoria , Simon Mareike , Trajkovic-Arsic Marija , Kouril Theresa , Siebers Bettina , Lisec Jan , Siveke Jens T. , Schulte Johannes H. , Benary Uwe , Remke Marc , Wolf Jana , Schramm Alexander 
Published: September 2018

AbstractMYCN is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of MYC family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of MYC proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of MYCN overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of MYCN induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of MYCN. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of MYCN overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered MYCN induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.
Nicotinic and Cholinergic Modulation of Reward Prediction Error Computations in the Ventral Tegmental Area: a Minimal Circuit Model
Authors: Deperrois Nicolas , Gutkin Boris 
Published: September 2018

AbstractDopamine (DA) neurons in the ventral tegmental area (VTA) are thought to encode reward prediction errors (RPE) by comparing actual and expected rewards. In recent years, much work has been done to identify how the brain uses and computes this signal.While several lines of evidence suggest the the interplay of he DA and the inhibitory interneurons in the VTA implements the RPE computaiton, it still remains unclear how the DA neurons learn key quantities, for example the amplitude and the timing of primary rewards during conditioning tasks. Furthermore, exogenous nicotine and endogenous acetylcholine, acting on both VTA DA and GABA (γ- aminobutyric acid) neurons via nicotinic-acetylcholine receptors (nAChRs), also likely affect these computations. To explore the potential circuit-level mechanisms for RPE computations during classical-conditioning tasks, we developed a minimal computational model of the VTA circuitry. The model was designed to account for several reward-related properties of VTA afferents and recent findings on VTA GABA neuron dynamics during conditioning.With our minimal model, we showed that the RPE can be learned by a two-speed process computing reward timing and magnitude. Including a model of nAChR-mediated currents in the VTA DA-GABA circuit, we also showed that nicotine should reduce the acetylcholine action on the VTA GABA neurons by receptor desensitization and therefore potentially boost the DA responses to reward information. Together, our results delineate the mechanisms by which RPE are computed in the brain, and suggest a hypothesis on nicotine-mediated effects on reward-related perception and decision-making.
Cell competition corrects noisy Wnt morphogen gradients to achieve robust patterning
Authors: Akieda Yuki , Ogamino Shohei , Furuie Hironobu , Ishitani Shizuka , Akiyoshi Ryutaro , Nogami Jumpei , Masuda Takamasa , Shimizu Nobuyuki , Ohkawa Yasuyuki , Ishitani Tohru 
Published: September 2018

SUMMARYMorphogen signaling forms an activity gradient and instructs cell identities in a signaling strength-dependent manner to pattern developing tissues. However, developing tissues also undergo dynamic morphogenesis, which may produce cells with unfit morphogen signaling and consequent noisy morphogen gradient. Here we show that a cell competition-related system corrects such noisy morphogen gradients. Zebrafish imaging analyses of the Wnt/β-catenin signaling-gradient, which acts as a morphogen to establish embryonic anterior-posterior patterning, revealed that unfit cells with abnormal Wnt/β-catenin activity spontaneously appear and produce noise in the Wnt/β-catenin-gradient. Communication between the unfit and neighboring fit cells via cadherin proteins stimulates the apoptosis of the unfit cells by activating Smad signaling and reactive oxygen species production. This unfit cell elimination is required for proper Wnt/β-catenin-gradient formation and consequent anterior-posterior patterning. Because this gradient controls patterning not only in the embryo but also in adult tissues, this system may support tissue robustness and disease prevention.
Transsynaptic interactions between IgSF proteins DIP-α and Dpr10 are required for motor neuron targeting specificity inDrosophila
Authors: Ashley James , Sorrentino Violet , Nagarkar-Jaiswal Sonal , Tan Liming , Xu Shuwa , Xiao Qi , Zinn Kai , Carrillo Robert A. 
Published: September 2018

ABSTRACTTheDrosophilalarval neuromuscular system provides an ideal context in which to study synaptic partner choice, because it contains a small number of pre- and postsynaptic cells connected in an invariant pattern. The discovery of interactions between two subfamilies of IgSF cell surface proteins, the Dprs and the DIPs, provided new candidates for cellular labels controlling synaptic specificity. Here we show that DIP-α is expressed by two identified motor neurons, while its binding partner Dpr10 is expressed by postsynaptic muscle targets. Removal of either DIP-α or Dpr10 results in loss of specific axonal branches and NMJs formed by one motor neuron, MNISN-1s, while other branches of the MNISN-1s axon develop normally. The temporal and spatial expression pattern ofdpr10correlates with muscle innervation by MNISN-1s during embryonic development. We propose a model whereby DIP-α and Dpr10 on opposing synaptic partners interact with each other to generate proper motor neuron connectivity.
Dietary fatty acids promote lipid droplet diversity through seipin enrichment in an ER subdomain
Authors: Cao Zhe , Hao Yan , Lee Yiu Yiu , Wang Pengfei , Li Xuesong , Xie Kang , Lam Wen Jiun , Qiu Yifei , Shui Guanghou , Liu Pingsheng , Qu Jianan , Kang Byung-Ho , Mak Ho Yi 
Published: September 2018

AbstractExogenous metabolites from microbial and dietary origins have profound effects on host metabolism. Here, we report that a sub-population of lipid droplets (LDs), which are conserved organelles for fat storage, is defined by metabolites-driven targeting of theC. elegansseipin ortholog, SEIP-1. Loss of SEIP-1 function reduced the size of a subset of LDs while over-expression of SEIP-1 had the opposite effect. Ultrastructural analysis revealed SEIP-1 enrichment in an endoplasmic reticulum (ER) subdomain, which co-purified with LDs. Analyses ofC. elegansand bacterial genetic mutants indicated a requirement of polyunsaturated fatty acids (PUFAs) and microbial cyclopropane fatty acids (CFAs) for SEIP-1 enrichment, as confirmed by dietary supplementation experiments. In mammalian cells, heterologous expression of SEIP-1 promoted lipid droplet expansion from ER subdomains in a conserved manner. Our results suggest that microbial and polyunsaturated fatty acids serve unexpected roles in regulating cellular fat storage by enforcing LD diversity.
Metatranscriptomic and thermodynamic insights into medium-chain fatty acid production using an anaerobic microbiome
Authors: Scarborough Matthew J. , Lawson Christopher E. , Hamilton Joshua J. , Donohue Timothy J. , Noguera Daniel R. 
Published: September 2018

AbstractBiomanufacturing from renewable feedstocks represents a sustainable strategy to offset fossil fuel-based chemical production. One potential biomanufacturing strategy is production of medium chain fatty acids (MCFA) from organic feedstocks using either pure cultures or microbiomes. While the set of microbes in a microbiome can often metabolize more diverse organic materials than a single species, and the role of specific species may be known, knowledge of the carbon and energy flow within and between organisms in MCFA producing microbiomes is only starting to emerge. Here, we integrate metagenomic, metatranscriptomic, and thermodynamic analyses to predict and characterize the metabolic network of an anaerobic microbiome producing MCFA from organic matter derived from lignocellulosic ethanol fermentation conversion residue. A total of 37 high quality (>80% complete, < 10% contamination) metagenome-assembled genomes (MAGs) were recovered from the microbiome and metabolic reconstruction of the 10 most abundant MAGs was performed. Metabolic reconstruction combined with metatranscriptomic analysis predicted that organisms affiliated with Lactobacillus and Coriobacteriaceae degraded carbohydrates and fermented sugars to lactate and acetate. Lachnospiraceae and Eubacteriaceae affiliated organisms were predicted to transform these fermentation products to MCFA. Thermodynamic analyses identified conditions in which H2 is expected to be either produced or consumed, suggesting a potential role of H2 partial pressure on MCFA production. From an integrated systems analysis perspective, we propose that MCFA production could be improved if microbiomes are engineered to use homofermentative instead of heterofermentative Lactobacillus, and if MCFA-producing organisms are engineered to preferentially use a thioesterase instead of a CoA transferase as the terminal enzyme in reverse β-oxidation.ImportanceMixed communities of microbes play important roles in health, the environment, agriculture, and biotechnology. While tapping the combined activity of organisms within microbiomes may allow the utilization of a wider range of substrate over the use of pure cultures for biomanufacturing, harnessing the metabolism of these mixed cultures remains a major challenge. Here, we predict metabolic functions of bacteria in a microbiome that produces medium-chain fatty acids from a renewable feedstock. Our findings lay the foundation to begin addressing how to engineer and control microbiomes for improved biomanufacturing; to build synthetic mixtures of microbes that produce valuable chemicals from renewable resources; and to better understand microbial communities that contribute to health, agriculture, and the environment.
Precision identification and prediction of high mortality phenotypes and disease progression pathways in severe malaria without requiring longitudinal data
Authors: Hoffmann Till , Johnston Iain , Greenbury Sam , Cominetti Ornella , Jallow Muminatou , Kwiatkowski Dominic , Barahona Mauricio , Jones Nick , Casals-Pascual Climent 
Published: September 2018

AbstractThe parasite Plasmodium falciparum is the main cause of severe malaria (SM). Despite treatment with antimalarial drugs, more than 450,000 SM deaths are reported every year, mainly in African children. The diversity of clinical presentations associated with SM indicate important differences in disease pathogenesis that often require specific treatment, and this clinical heterogeneity of SM is largely unresolved. In this study, we apply new machine learning and inference tools for large-scale data analysis to dissect the heterogeneity in patterns of clinical features associated with SM in 2,695 Gambian children admitted to hospital with Plasmodium falciparum malaria. This quantitative analysis, including the powerful HyperTraPS algorithm for inference of progressive processes, reveals pathways of SM symptom progression and features predicting the severity of individual patient outcomes. Notably, our approach allows the identification and dissection of disease progression pathways without the need for longitudinal observations. Learning these pathways and features from this rich dataset allows us to construct several quantitative measures of the mortality risk associated with a patient presenting with a given set of symptoms. By independently surveying expert practitioners, we show that this data-driven approach agrees with and expands the current state of knowledge on malaria progression, while simultaneously providing a data-supported framework for predicting clinical risk.
Noninvasive prenatal test of methylmalonic academia cblC type through targeted sequencing of cell-free DNA in maternal plasma
Authors: Han Lianshu , Chen Chao , Guo Fengyu , Ye Jun , Peng Zhiyu , Qiu Wenjuan , Wang Yaoshen , Li Wei , Zhang Huiwen , Liang Lili , Wang Yu , Wang Huanhuan , Ji Xing , Sun Jun , Gu Xuefan 
Published: September 2018

AbstractMethylmalonic acidemia (MMA) cblC type is the most frequent inborn error of intracellular cobalamin metabolism which is caused by mutations of MMACHC gene. Non-invasive test of MMA for pregnant women facilitates safe and timely prenatal diagnosis of the disease. In our study, we aimed to design and validate a haplotype-based noninvasive prenatal test (NIPT) method for cblC type of MMA. Targeted capture sequencing using customized hybridization was performed utilizing gDNA (genomic DNA) of trios including parents and an affected proband to determine parental haplotypes associated with the mutant and wild allele. The fetal haplotype was inferred later based on the high depth sequencing data of maternal plasma as well as haplotype linkage analysis. The fetal genotypes deduced by NIPT were further validated by amniocentesis. Haplotype-based NIPT was successfully performed in 21 families. The results of NIPT of 21 families were all consistent with invasive prenatal diagnosis, which was interpreted in a blinded fashion. Three fetuses were identified as compound heterozygosity of MMACHC, 9 fetuses were carriers of MMACHC variant, and 9 fetuses were normal. These results indicated that the haplotype-based NIPT for MMA through small target capture region sequencing is technically accurate and feasible.
Excised linear introns regulate growth in yeast
Authors: Morgan Jeffrey T. , Fink Gerald R. , Bartel David P. 
Published: September 2018

AbstractSpliceosomal introns are ubiquitous non-coding RNAs typically destined for rapid debranching and degradation. Here, we describe 34 excisedSaccharomyces cerevisiaeintrons that, although rapidly degraded in log-phase growth, accumulate as linear RNAs under either saturated-growth conditions or other stresses that cause prolonged inhibition of TORC1, a key integrator of growth signaling. Introns that become stabilized remain associated with components of the spliceosome and differ from the other spliceosomal introns in having a short distance between their lariat branch point and 3′ splice site, which is necessary and sufficient for their stabilization. Deletion of these unusual introns is disadvantageous in saturated conditions and causes aberrantly high growth rates of yeast chronically challenged with the TORC1 inhibitor rapamycin. Reintroduction of native or engineered stable introns suppresses this aberrant rapamycin response. Thus, excised introns function within the TOR growth-signaling network ofS. cerevisiae, and more generally, excised spliceosomal introns can have biological functions.
Critical Limb Ischemia Induces Remodeling of Skeletal Muscle Motor Unit and Myonuclear- and Mitochondrial-Domains
Authors: Mohiuddin Mahir , Lee Nan Hee , Moon June Young , Han Woojin M. , Anderson Shannon E. , Choi Jeongmoon J. , Nakhai Shadi , Tran Thu , Aliya Berna , Kim Do Young , Gerold Aimee , Hansen Laura , Taylor W. Robert , Jang Young C. 
Published: September 2018

AbstractCritical limb ischemia, the most severe form of peripheral artery disease, leads to extensive damage and alterations in skeletal muscle homeostasis. Although recent developments towards revascularization therapies have been introduced, there has been limited research into treatments for ischemic myopathy. To elucidate the regenerative mechanism of the muscle stem cell and its niche components in response to ischemic insults, we explored interactions between the vasculature, motor neuron, muscle fiber, and the muscle stem cell. We first investigated changes in the neuromuscular junction and motor neuron innervation following a surgical hindlimb ischemia model of critical limb ischemia in mice. Along with previous findings that support remodeling of the neuromuscular junction, we report that ischemic injury also causes significant alterations to the myofiber through a muscle stem cell-mediated increase of myonuclei number per fiber, a concomitant decrease in myonuclear domain size, and an increase in relative mitochondrial content per myonucleus. These results indicate that as a regenerative response to critical limb ischemia, myofibers exhibit myonuclear expansion to allow enhanced transcriptional support and an increase in mitochondrial content for bioenergetic need of the energy-demanding tissue regeneration.
Asymmetric ephaptic inhibition between compartmentalized olfactory receptor neurons
Authors: Zhang Ye , Tsang Tin Ki , Bushong Eric A. , Chu Li-An , Chiang Ann-Shyn , Ellisman Mark H. , Reingruber Jürgen , Su Chih-Ying 
Published: September 2018

ABSTRACTIn the Drosophila antenna, different subtypes of olfactory receptor neurons (ORNs) housed in the same sensory hair (sensillum) can inhibit each other non-synaptically. However, the mechanisms underlying this unusual form of lateral inhibition remain unclear. Here we use recordings from pairs of sensilla impaled by the same tungsten electrode to prove that direct electrical (“ephaptic”) interactions mediate lateral inhibition between ORNs. Intriguingly, within individual sensilla, we find that ephaptic lateral inhibition is asymmetric such that one ORN exerts greater influence onto its neighbor. Serial block-face scanning electron microscopy of genetically identified ORNs and circuit modeling indicate that asymmetric lateral inhibition reflects a surprisingly simple mechanism: the physically larger ORN in a pair corresponds to the dominant neuron in ephaptic interactions. Thus, morphometric differences between compartmentalized ORNs account for highly specialized inhibitory interactions that govern information processing at the earliest stages of olfactory coding.
The effect of executive incentives on FDI ambidexterity
Authors: Li Zijie , Gao Qiuling , Shen Kai , Zhang Junyue 
Published: September 2018

PurposeThis paper aims to examine different hypotheses concerning the effects of executive incentive on the degree of Chinese foreign direct investment (FDI) ambidexterity. Specifically, this study provides new insights on how executive equity incentive and executive control right incentive may affect overseas ambidextrous strategy of Chinese enterprises.Design/methodology/approachThis study used panel data of Chinese manufacturing listed companies in 2006-2015 to explore the relationships between related factors. Hypotheses are tested by using regression analysis.FindingsThis study found that executive equity incentive is positively related to the degree of FDI ambidexterity. It also found that the level at which control right incentives of executive are made has a curvilinear relationship with degree of FDI ambidexterity. Higher level of control right incentive of executive will be associated with higher degree of FDI ambidexterity; however, beyond some level, higher control right incentive of executive will be associated with lower degree of FDI ambidexterity.Research limitations/implicationsThis paper has implications to future research and companies’ everyday practice on ambidextrous FDI strategy.Originality/valueBased on the principal-agent framework and incentive theory, this paper offers an interesting insight of achieving balance of ambidextrous strategy for Chinese multinational enterprises by involving the different roles of executive equity incentive and executive control right incentive they played.
A stability controlling-based approach for designing 1-D variable fractional delay all-pass filters
Authors: Zhao Hui , Li Shengnan , Yang Hongyu , Zhou Quan 
Published: September 2018

Purpose
Variable fractional delay filtering is an important technology in signal processing; the research shows that all-pass variable fractional delay (VFD) filters achieve higher design accuracy than FIR VFD filters; therefore, the design, analysis and implementation of all-pass VFD filters are of great importance.

Design/methodology/approach
In this paper, a two-stage approach for the design of general 1-D stable VFD all-pass filters is proposed. The method takes the desired group delay range [N−1, N], where N is the filter order.

Findings
The design algorithm is decomposed into two design stages: first, a set of fixed delay all-pass filters are designed by minimizing a set of objective functions defined in terms of approximating error criterion and filter stability constraint. Then, the design result is determined by fitting each of the fixed delay all-pass filter coefficients as 1-D polynomials. A design example together with its comparisons with those of the recent literature studies is given to justify the effectiveness of the proposed design method.

Originality/value
An illustrating design example shows that the method proposed can achieve better filter performances than the existing ones.