bluuebunny/crossref_metadata_2025_split huggingface dataset:
The L-alanosine gene cluster encodes a pathway for diazeniumdiolate biosynthesis
Authors: Ng Tai L. , McCallum Monica E. , Zheng Christine R. , Wang Jennifer X. , Wu Kelvin J. Y. , Balskus Emily P. 
Published: September 2019

AbstractN-nitroso-containing natural products are bioactive metabolites with antibacterial and anticancer properties. In particular, compounds containing the diazeniumdiolate (N-nitrosohydroxylamine) group display a wide range of bioactivities ranging from cytotoxicity to metal chelation. Despite the importance of this structural motif, knowledge of its biosynthesis is limited. Herein, we describe the discovery of a biosynthetic gene cluster in Streptomyces alanosinicus ATCC 15710 responsible for producing the diazeniumdiolate natural product L-alanosine. Gene disruption and stable isotope feeding experiments identified essential biosynthetic genes and revealed the nitrogen source of the N-nitroso group. Additional biochemical characterization of the biosynthetic enzymes revealed that the non-proteinogenic amino acid L-2,3-diaminopropionic acid (L-Dap) is synthesized and loaded onto a peptidyl carrier protein (PCP) domain in L-alanosine biosynthesis, which we propose may be a mechanism of handling unstable intermediates generated en route to the diazeniumdiolate. This research framework will facilitate efforts to determine the biochemistry of diazeniumdiolate formation.
Leveraging genome-wide data to investigate differences between opioid usevs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium
Authors: Polimanti Renato , Walters Raymond K. , Johnson Emma C. , McClintick Jeanette N. , Adkins Amy E. , Adkins Daniel E. , Bacanu Silviu-Alin , Bierut Laura J. , Bigdeli Tim B. , Brown Sandra , Bucholz Kathy , Copeland William E. , Costello E. Jane , Degenhardt Louisa , Farrer Lindsay A , Foroud Tatiana M. , Fox Louis , Goate Alison M. , Grucza Richard , Hack Laura M. , Hancock Dana B. , Hartz Sarah M. , Heath Andrew C. , Hewitt John K. , Hopfer Christian J. , Johnson Eric O. , Kendler Kenneth S. , Kranzler Henry R. , Krauter Ken , Lai Dongbing , Madden Pamela A. F. , Martin Nicholas G. , Maes Hermine H. , Nelson Elliot C. , Peterson Roseann E. , Porjesz Bernice , Riley Brien P. , Saccone Nancy , Stallings Michael , Wall Tamara , Webb Bradley T. ,   Leah Wetherill the Psychiatric Genomics Consortium Substance Use Disorders Workgroup, Edenberg Howard J. , Agrawal Arpana , Gelernter Joel 
Published: September 2019

AbstractTo provide novel insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing up to 4,503 OD cases, 4,173 opioid-exposed controls, and 32,500 opioid-unexposed controls. Among the variants identified, rs9291211 was associated with OE (a comparison of exposed vs. unexposed controls; z=-5.39, p=7.2×10−8). This variant regulates the transcriptomic profiles ofSLC30A9andBEND4in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N>360,000) found association of this variant with propensity to use dietary supplements (p=1.68×10−8). With respect to the same OE phenotype in the gene-based analysis, we identifiedSDCCAG8(z=4.69, p=10−6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (z=5.55, p=2.9×10−8) and a significant association with musculoskeletal disorders in the UK Biobank (p=4.88×10−7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (N=466,571) was positively associated with OD (OD cases vs. unexposed controls, p=8.1×10−5; OD cases vs. exposed controls, p=0.054) and OE (exposed controls vs. unexposed controls, p=3.6×10−5). A PRS based on a GWAS of neuroticism (N=390,278) was positively associated with OD (OD cases vs. unexposed controls, p=3.2×10−5; OD cases vs. exposed controls, p=0.002) but not with OE (p=0.671). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls (exposed vs. unexposed) in studies of addiction.
RNA Helicase DDX5 Negatively Regulates Wnt Signaling and Hepatocyte Reprogramming in Hepatitis B Virus-related Hepatocellular Carcinoma
Authors: Mani Saravana Kumar Kailasam , Cui Zhibin , Yan Bingyu , Utturkar Sagar , Foca Adrien , Fares Nadim , Durantel David , Lanman Nadia , Merle Philippe , Kazemian Majid , Andrisani Ourania 
Published: September 2019

ABSTRACTBackground and AimsRNA helicase DEAD box protein 5 (DDX5) is downregulated during hepatitis B virus (HBV) replication, and associates with poor prognosis HBV-related hepatocellular carcinoma (HCC). The aim of this study is to determine the mechanism and significance of DDX5 downregulation for HBV-driven HCC.Approach & ResultsWe used established cellular models of HBV replication, HBV infection, as well as HBV-related liver tumors. HBV replicating DDX5 knockdown hepatocytes were analyzed by RNAseq; differentially expressed genes were validated by qRT-PCR, and bioinformatic analyses of HCCs from The Cancer Genome Atlas. Our results show reduced expression of DDX5 in HCCs of all etiologies is associated with poor survival. In HBV replicating hepatocytes, downregulation of DDX5 is mediated by miR17∼92 and miR106b∼25, induced by HBV infection. Increased expression of these miRNAs was quantified in HBV-associated HCCs expressing a hepatic cancer stem cell (hCSC)-like gene signature and reduced DDX5 mRNA, suggesting a role for DDX5 in hCSC formation. Interestingly, DDX5 knockdown in HBV replicating hepatocyte cell lines resulted in hepatosphere formation, sorafenib and cisplatin resistance, Wnt signaling activation and pluripotency gene expression, all characteristics of hCSCs. Moreover, DDX5 knockdown increased viral replication. RNA-seq analyses of HBV-replicating DDX5 knockdown cells, identified enhanced expression of key genes of the Wnt/β-catenin pathway, including Frizzled7 (FZD7) and Matrix Metallopeptidase7 (MMP7), indicative of Wnt signaling activation. Clinically, elevated FZD7 expression correlates with poor patient survival. Importantly, inhibitors to miR17∼92 and miR106b∼25 restored DDX5 levels and suppressed both Wnt/β-catenin activation and viral replication.ConclusionDDX5 is a negative regulator of Wnt signaling and hepatocyte reprogramming in HCCs. Restoration of DDX5 levels in HBV-infected patients can exert both antitumor and antiviral effects.
Ancient DNA reconstructs the genetic legacies of pre-contact Puerto Rico communities
Authors: Nieves-Colón Maria A. , Pestle William J. , Reynolds Austin W. , Llamas Bastien , de la Fuente Constanza , Fowler Kathleen , Skerry Katherine M. , Crespo-Torres Edwin , Bustamante Carlos D. , Stone Anne C. 
Published: September 2019

AbstractIndigenous peoples have occupied the island of Puerto Rico since at least 3000 B.C. Due to the demographic shifts that occurred after European contact, the origin(s) of these ancient populations, and their genetic relationship to present-day islanders, are unclear. We use ancient DNA to characterize the population history and genetic legacies of pre-contact Indigenous communities from Puerto Rico. Bone, tooth and dental calculus samples were collected from 124 individuals from three pre-contact archaeological sites: Tibes, Punta Candelero and Paso del Indio. Despite poor DNA preservation, we used target enrichment and high-throughput sequencing to obtain complete mitochondrial genomes (mtDNA) from 45 individuals and autosomal genotypes from two individuals. We found a high proportion of Native American mtDNA haplogroups A2 and C1 in the pre-contact Puerto Rico sample (40% and 44%, respectively). This distribution, as well as the haplotypes represented, support a primarily Amazonian South American origin for these populations, and mirrors the Native American mtDNA diversity patterns found in present-day islanders. Three mtDNA haplotypes from pre-contact Puerto Rico persist among Puerto Ricans and other Caribbean islanders, indicating that present-day populations are reservoirs of pre-contact mtDNA diversity. Lastly, we find similarity in autosomal ancestry patterns between pre-contact individuals from Puerto Rico and the Bahamas, suggesting a shared component of Indigenous Caribbean ancestry with close affinity to South American populations. Our findings contribute to a more complete reconstruction of pre-contact Caribbean population history and explore the role of Indigenous peoples in shaping the biocultural diversity of present-day Puerto Ricans and other Caribbean islanders.
Dissociating cholinergic influence on alertness and temporal attention in primates in a simple reaction time paradigm
Authors: Oláh Vilmos , Knakker Balázs , Trunk Attila , Lendvai Balázs , Hernádi István 
Published: September 2019

AbstractThe ability to promptly respond to behaviourally relevant events depends on both general alertness and phasic changes in attentional state driven by temporal expectations. Using a variable foreperiod simple reaction time (RT) task in four adult male rhesus macaques, we investigated the role of the cholinergic system in alertness and temporal expectation. Foreperiod-effects on RT reflect temporal expectation, while alertness is quantified as overall response speed. We measured these RT parameters under vehicle treatment and systemic administration of the muscarinic receptor antagonist scopolamine. We also investigated whether and to what extent the effects of scopolamine were reversed by donepezil, a cholinesterase inhibitor widely used for the treatment of dementia. In the control condition, RT showed a continuous decrease as the foreperiod duration increased, which clearly indicated the effect of temporal expectation on RT. This foreperiod effect was mainly detectable on the faster tail of the RT distribution and was eliminated by scopolamine. Furthermore, scopolamine treatment slowed down the average RT. Donepezil treatment was efficient on the slower tail of the RT distribution and improved scopolamine-induced impairments only on the average RT reflecting a general beneficial effect on alertness without any improvement in temporal expectation. The present results highlight the role of the cholinergic system in temporal expectation and alertness in primates and help delineate the efficacy and scope of donepezil and other cholinomimetic agents as cognitive enhancers in present and future clinical practice.
Empirical evaluation of fused EEG-MEG source reconstruction. Application to auditory mismatch generators
Authors: Lecaignard Françoise , Bertrand Olivier , Caclin Anne , Mattout Jérémie 
Published: September 2019

AbstractSince their introduction in the late eighties, Bayesian approaches for neuroimaging have opened the way to new powerful and quantitative analysis of brain data. Here, we apply this statistical framework to evaluate empirically the gain of fused EEG-MEG source reconstruction, compared to unimodal (EEG or MEG) one. Combining EEG and MEG information for source reconstruction has been consistently evidenced to enhance localization performances using simulated data. However, given considerable efforts to conduct simultaneous recordings, empirical evaluation becomes necessary to quantify the real information gain. And this is obviously not straightforward due to the ill-posedness of the inverse problem. Here, we consider Bayesian model comparison to quantify the ability of EEG, MEG and fused (EEG/MEG) inversions of individual data to resolve spatial source models. These models consisted in group-level cortical distributions inferred from real EEG, MEG and EEG/MEG brain responses. We applied this comparative evaluation to the timely issue of the generators of auditory mismatch responses evoked by unexpected sounds. These included the well-known Mismatch Negativity (MMN) but also earlier deviance responses. As expected, fused localization was evidenced to outperform unimodal inversions with larger model separability. The present methodology confirms with real data the theoretical interest of simultaneous EEG/MEG recordings and fused inversion to highly inform (spatially and temporally) source modeling. Precisely, a bilateral fronto-temporal network could be identified for both the MMN and early deviance response. Interestingly, multimodal inversions succeeded in revealing spatio-temporal details of the functional organization within the supratemporal plane that have not been reported so far, nor were visible here with unimodal inversions. The present refined auditory network could serve as priors for auditory modeling studies.
The effects of carnosine pretreatment on the inflammatory response and the PI3K/Akt signaling pathway following hypoxia-ischemia in neonatal rats
Authors: Zhang Xiangmin , Xia Lei , Huang Zhiheng , Xu Falin 
Published: September 2019

AbstractAn increasing number of studies have demonstrated that carnosine plays a neuroprotective role in many types of brain injury. We have previously shown that carnosine has both short-term and long-lasting neuroprotective effects in a hypoxia–ischemia(HI) rat model. In the mature brain, post-ischemia neuronal survival involves in activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, whether the activation of PI3K/Akt pathway also plays an important role in the immature brain still remain unclear.The goal of this study is to detect the effection of carnosine on inflammation response following HI, further evidencing neuroprotection of carnosine. We measured total Akt, phospho-Akt (p-AKT) and tumor necrosis factor receptor 1 (TNFR1) protein levels by western blot assay and tumor necrosis factor-α (TNF-α) and TNFR1 mRNA expression using real-time RT-PCR. We found the carnosine-pretreated group had statistically significant downregulation of TNF-α mRNA levels 24 h after HI (P < 0.05). Similar results were observed when we measured TNFR1 mRNA levels both 24h and 72h after HI (P < 0.05). And the TNFR1 protein expression after HI was markedly decreased at 24 and 72 h post-HI in the carnosine-pretreated rats(P < 0.05). Nevertheless, the rats pretreated with carnosine showed a marked increase in p-Akt levels (P< 0.05). And the pro-apoptotic protein Bad was also examined using immunohistochemistry after 24 and 72 h of all groups. We found significantly fewer Bad-positive cells in the carnosine-pretreated group at each time point after HI (P < 0.05). These findings suggest that carnosine pretreatment inhibits the HI-induced inflammatory response, and neuroprotection mechanism of carnosine involved in activation of the PI3K/Akt signaling pathway.
A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC--derived microglia
Authors: Piers Thomas M , Cosker Katharina , Mallach Anna , Johnson Gabriel Thomas , Guerreiro Rita , Hardy John , Pocock Jennifer M 
Published: September 2019

AbstractLoss-of-function genetic variants oftriggering receptor expressed on myeloid cells 2 (TREM2)are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2 and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on microglial metabolic function in human patient iPSC-derived-microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC-microglia, including the Alzheimer’s disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signalling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β-Amyloid phagocytosis. These findings have ramifications for microglial focussed-treatments in AD.
Evaluation of six phase encoding based susceptibility distortion correction methods for diffusion MRI
Authors: Gu Xuan , Eklund Anders 
Published: September 2019

PurposeSusceptibility distortions impact diffusion MRI data analysis and is typically corrected during preprocessing. Correction strategies involve three classes of methods: registration to a structural image, the use of a fieldmap, or the use of images acquired with opposing phase encoding directions. It has been demonstrated that phase encoding based methods outperform the other two classes, but unfortunately, the choice of which phase encoding based method to use is still an open question due to the absence of any systematic comparisons.MethodsIn this paper we quantitatively evaluated six popular phase encoding based methods for correcting susceptibility distortions in diffusion MRI data. We employed a framework that allows for the simulation of realistic diffusion MRI data with susceptibility distortions. We evaluated the ability for methods to correct distortions by comparing the corrected data with the ground truth. Four diffusion tensor metrics (FA, MD, eigenvalues and eigenvectors) were calculated from the corrected data and compared with the ground truth. We also validated two popular indirect metrics using both simulated data and real data. The two indirect metrics are the difference between the corrected LR and AP data, and the FA standard deviation over the corrected LR, RL, AP and PA data.ResultsWe found that DR-BUDDI and TOPUP offered the most accurate and robust correction compared to the other four methods using both direct and indirect evaluation metrics. EPIC and HySCO performed well in correcting b0 images but produced poor corrections for diffusion weighted volumes, and also they produced large errors for the four diffusion tensor metrics. We also demonstrate that the indirect metric (the difference between corrected LR and AP data) gives a different ordering of correction quality than the direct metric.ConclusionWe suggest researchers to use DR-BUDDI or TOPUP for susceptibility distortion correction. The two indirect metrics (the difference between corrected LR and AP data, and the FA standard deviation) should be interpreted together as a measure of distortion correction quality. We also suggest that indirect metrics must be interpreted cautiously when evaluating methods for correcting susceptibility distortions in diffusion MRI data.
Molecular architecture of the DNA‐binding sites of the P‐loop ATPases MipZ and ParA fromCaulobacter crescentus
Authors: Refes Yacine , He Binbin , Corrales-Guerrero Laura , Steinchen Wieland , Panis Gaël , Viollier Patrick H. , Bange Gert , Thanbichler Martin 
Published: September 2019

ABSTRACTTwo related P-loop ATPases, ParA and MipZ, mediate the spatiotemporal regulation of chromosome segregation and cell division inCaulobacter crescentus. Both of these proteins share the ability to form dynamic concentration gradients that control the positioning of regulatory targets within the cell. Their proper localization relies on their nucleotide-dependent cycling between a monomeric and a dimeric state, driven by interaction with the chromosome partitioning protein ParB, and on the ability of the dimeric species to associate non-specifically with the nucleoid. In this study, we use a combination of genetic screening, biochemical analysis and hydrogen/deuterium exchange mass spectrometry to identify the residues mediating the interaction of MipZ with DNA. Our results show that the DNA-binding activity of MipZ relies on a series of positively charged and hydrophobic residues lining both sides of the dimer interface. MipZ thus appears to associate with DNA in a sequence-independent manner through electrostatic interactions with the DNA phosphate backbone. In support of this hypothesis, chromatin immunoprecipitation analyses did not reveal any specific target sitesin vivo. When extending our analysis to ParA, we found that the architectures of the MipZ and ParA DNA-binding sites are markedly different, although their relative positions on the dimer surface and their mode of DNA binding are conserved. Importantly, bioinformatic analysis suggests that the same principles apply to other members of the P-loop ATPase family. ParA-like ATPases thus share common mechanistic features, although their modes of action have diverged considerably during the course of evolution.SIGNIFICANCEParA-like P-loop ATPases are involved in a variety of cellular processes in bacteria, including chromosome and plasmid segregation, chemoreceptor and carboxysome positioning, and division site placement. Many members of this large protein family depend on the ability to bind non-specific DNA for proper function. Although previous studies have yielded insights in the DNA-binding properties of some ParA-like ATPases, a comprehensive view of the underlying mechanisms is still lacking. Here, we combine state-of-the-art cell biological, biochemical and biophysical approaches to localize the DNA-binding regions of the ParA-like ATPases MipZ and ParA fromCaulobacter crescentus. We show that the two proteins use the same interface and mode of action to associate with DNA, suggesting that the mechanistic basis of DNA binding may be conserved in the ParA-like ATPase family.
Tree congruence: quantifying similarity between dendrogram topologies
Authors: Vidovic Steven U. 
Published: September 2019

AbstractTree congruence metrics are typically global indices that describe the similarity or dissimilarity between dendrograms. This study principally focuses on topological congruence metrics that quantify similarity between two dendrograms and can give a normalised score between 0 and 1. Specifically, this article describes and tests two metrics the Clade Retention Index (CRI) and the MASTxCF which is derived from the combined information available from a maximum agreement subtree and a strict consensus. The two metrics were developed to study differences between evolutionary trees, but their applications are multidisciplinary and can be used on hierarchical cluster diagrams derived from analyses in science, technology, maths or social sciences disciplines. A comprehensive, but non-exhaustive review of other tree congruence metrics is provided and nine metrics are further analysed. 1,620 pairwise analyses of simulated dendrograms (which could be derived from any type of analysis) were conducted and are compared in Pac-man piechart matrices. Kendall’s tau-b is used to demonstrate the concordance of the different metrics and Spearman’s rho ranked correlations are used to support these findings. The results support the use of the CRI and MASTxCF as part of a suite of metrics, but it is recommended that permutation metrics such as SPR distances and weighted metrics are disregarded for the specific purpose of measuring similarity.