bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross-sectional and longitudinal associations of family income-to-needs ratio with cortical and subcortical brain volume in adolescent boys and girls
Authors: King Lucy S. , Dennis Emily L. , Humphreys Kathryn L. , Thompson Paul M. , Gotlib Ian H. 
Published: January 2020

AbstractDeviations in neurodevelopment may underlie the association between lower childhood socioeconomic status and difficulties in cognitive and socioemotional domains. Most previous investigations of the association between childhood socioeconomic status and brain morphology have used cross-sectional designs with samples that span wide age ranges, occluding effects specific to adolescence. Sex differences in the association between childhood socioeconomic status and neurodevelopment may emerge or intensify during adolescence. We used tensor-based morphometry, a whole brain approach, to examine sex differences in the cross-sectional association between normative variation in family income-to-needs ratio (INR) and cortical and subcortical gray and white matter volume during early adolescence (ages 9-13 years, N=147), as well as in the longitudinal association between in INR and change in volume from early to later adolescence (ages 11-16 years, N=109). Biological sex interacted with INR to explain variation in volume in several areas cross-sectionally and longitudinally. Effects were primarily in cortical gray matter areas, including regions of the association cortex and sensorimotor processing areas. Effect sizes tended to be larger in boys than in girls. Biological sex may be an important variable to consider in analyses of the effects of family income on structural neurodevelopment during adolescence.HighlightsSex-specific associations of SES with neurodevelopment may emerge in adolescence.We used a whole-brain approach to examine gray and white matter volume.Sex interacted with SES to explain variation in volume across adolescence.Sex is an important variable to consider in analyses of SES and brain volume.
Chlorotoxin Redirects Chimeric Antigen Receptor T Cells for Specific and Effective Targeting of Glioblastoma
Authors: Wang Dongrui , Starr Renate , Chang Wen-Chung , Aguilar Brenda , Alizadeh Darya , Wright Sarah L. , Yang Xin , Brito Alfonso , Sarkissian Aniee , Ostberg Julie R. , Shi Yanhong , Gutova Margarita , Aboody Karen , Badie Behnam , Forman Stephen J. , Barish Michael E. , Brown Christine E. 
Published: January 2020

AbstractWhile chimeric antigen receptor (CAR) T cells have demonstrated antitumor activity against glioblastoma (GBM), tumor heterogeneity remains a critical challenge. To more effectively target heterogeneous GBMs, we report the development of a novel peptide-based CAR exploiting the GBM-binding potential of chlorotoxin (CLTX). CLTX bound a greater proportion of tumor cells than GBM-associated antigens EGFR, HER2 and IL13Rα2. CAR T cells bearing CLTX as the targeting domain (CLTX-CAR), mediated potentin vitroandin vivoanti-GBM activity, and efficiently targeted tumors lacking expression of other GBM-associated antigens. Importantly, CLTX-CAR T cells exhibited no observable off-target effector activity against normal cells, or when adoptively transferred into mice. Effective targeting by CLTX-CAR T cells required cell surface expression of matrix metalloproteinase-2 (MMP-2). Our results are the first demonstration of a peptide toxin utilized as a CAR targeting domain, expanding the repertoire of tumor-selective CAR T cells with the potential to reduce antigen escape.One Sentence SummaryChimeric antigen receptors incorporating chlorotoxin as the tumor targeting domain recognize and kill glioblastoma with high specificity and potency.
AITL: Adversarial Inductive Transfer Learning with input and output space adaptation for pharmacogenomics
Authors: Sharifi-Noghabi Hossein , Peng Shuman , Zolotareva Olga , Collins Colin C. , Ester Martin 
Published: January 2020

AbstractMotivationThe goal of pharmacogenomics is to predict drug response in patients using their single- or multi-omics data. A major challenge is that clinical data (i.e. patients) with drug response outcome is very limited, creating a need for transfer learning to bridge the gap between large pre-clinical pharmacogenomics datasets (e.g. cancer cell lines), as a source domain, and clinical datasets as a target domain. Two major discrepancies exist between pre-clinical and clinical datasets: 1) in the input space, the gene expression data due to difference in the basic biology, and 2) in the output space, the different measures of the drug response. Therefore, training a computational model on cell lines and testing it on patients violates the i.i.d assumption that train and test data are from the same distribution.ResultsWe propose Adversarial Inductive Transfer Learning (AITL), a deep neural network method for addressing discrepancies in input and output space between the pre-clinical and clinical datasets. AITL takes gene expression of patients and cell lines as the input, employs adversarial domain adaptation and multi-task learning to address these discrepancies, and predicts the drug response as the output. To the best of our knowledge, AITL is the first adversarial inductive transfer learning method to address both input and output discrepancies. Experimental results indicate that AITL outperforms state-of-the-art pharmacogenomics and transfer learning baselines and may guide precision oncology more accurately.Availability of codes and supplementary materialhttps://github.com/hosseinshn/AITLContactccollins@prostatecentre.comandester@cs.sfu.ca
Effect of short-term prescription opioids on DNA methylation of the OPRM1 promoter
Authors: Sandoval-Sierra Jose Vladimir , Salgado García Francisco I , Brooks Jeffrey H , Derefinko Karen J , Mozhui Khyobeni 
Published: January 2020

AbstractBackgroundLong-term opioid use has been associated with hypermethylation of the opioid receptor mu 1 (OPRM1) promoter. Very little is currently known about the early epigenetic response to therapeutic opioids. Here we examine whether we can detect DNA methylation changes associated with few days use of prescribed opioids. Genome-wide DNA methylation was assayed in a cohort of 33 opioid-naïve participants who underwent standard dental surgery followed by opioid self-administration. Saliva samples were collected before surgery (visit 1), and at two postsurgery visits at 2.7 ± 1.5 days (visit 2), and 39 ± 10 days (visit 3) after the discontinuation of opioid analgesics.ResultsThe perioperative methylome underwent significant changes over the three visits that was primarily due to postoperative inflammatory response and cell heterogeneity. To specifically examine the effect of opioids, we started with a candidate gene approach and evaluated 10 CpGs located in the OPRM1 promoter. There was significant cross-sectional variability in opioid use, and for participants who self-administered the prescribed drugs, the total dosage ranged from 5–210 morphine milligram equivalent (MME). Participants were categorized by cumulative dosage into three groups: <25 MME, 25–90 MME, ≥90 MME. Using mixed effects modeling, 4 CpGs had significant positive associations with opioid dose at 2-tailed p-value < 0.05, and overall, 9 of the 10 OPRM1 promoter CpGs showed the predicted higher methylation in the higher dose groups relative to the lowest dose group. After adjustment for age, cellular heterogeneity, and past tobacco use, the promoter mean methylation also had positive associations with cumulative MME (regression coefficient = 0.0002, 1-tailed p-value = 0.02), and duration of opioid use (regression coefficient = 0.003, 1-tailed p-value = 0.001), but this effect was significant only for visit 3. A preliminary epigenome-wide association study identified a significant CpG in the promoter of the RAS-related signaling gene, RASL10A, that may be predictive of opioid dosage.ConclusionThe present study provides evidence that the hypermethylation of the OPRM1 promoter is in response to opioid use, and that epigenetic differences in OPRM1 and other sites are associated with short-term use of therapeutic opioids.
Edaravone-Loaded Mesoscale Nanoparticles Treat Cisplatin-Induced Acute Kidney Injury
Authors: Williams Ryan M. , Shah Janki , Mercer Elizabeth , Tian Helen S. , Cheung Justin M. , Dorso Madeline , Jaimes Edgar A. , Heller Daniel A. 
Published: January 2020

AbstractCisplatin-induced acute kidney injury (CI-AKI) is a significant co-morbidity of chemotherapeutic regimens. While this condition is associated with substantially lower survival and increased economic burden, there is no pharmacological agent to effectively treat CI-AKI. The disease is hallmarked by acute tubular necrosis of the proximal tubular epithelial cells primarily due to increased oxidative stress. In our prior work, we developed a highly-selective kidney-targeted mesoscale nanoparticle (MNP) that accumulates primarily in the renal proximal tubular epithelial cells while exhibiting no toxicity. Here, we found that MNPs exhibit renal-selective targeting in multiple mouse models of tumor growth with virtually no tumor accumulation. We then evaluated the therapeutic efficacy of MNPs loaded with the reactive oxygen species scavenger edaravone in a mouse model of CI-AKI. We found a marked and significant therapeutic effect with this approach as compared to free drug or empty control MNPs, including improved renal function, histology, and diminution of oxidative stress. These results indicated that renal-selective MNP edaravone delivery holds substantial potential in the treatment of acute kidney injury among patients undergoing cisplatin-based chemotherapy.
Arabidopsis LTR retrotransposons and their regulation by epigenetically activated small RNA
Authors: Lee Seung Cho , Ernst Evan , Berube Benjamin , Borges Filipe , Parent Jean-Sebastien , Ledon Paul , Schorn Andrea , Martienssen Robert A. 
Published: January 2020

AbstractIn Arabidopsis, LTR-retrotransposons are activated by mutations in the chromatin remodeler DECREASE in DNA METHYLATION 1 (DDM1), giving rise to 21-22nt epigenetically activated siRNAs (easiRNAs) that depend on RNA DEPENDENT RNA POLYMERASE 6 (RDR6). We purified virus-like-particles (VLPs) from ddm1 and ddm1rdr6 mutants in which genomic RNA is reverse transcribed into complementary DNA. Next generation short-read and long-read sequencing of VLP DNA (VLP DNA-seq) revealed a comprehensive catalog of active LTR-retrotransposons without the need for mapping transposition, and independent of genomic copy number. Linear replication intermediates of a functionally intact copia element EVADE revealed multiple central polypurine tracts (cPPT), a feature shared with HIV where cPPT promote nuclear localization. For one member of the ATCOPIA52 subfamily (SISYPHUS), cPPT intermediates were not observed, but abundant circular DNA indicated transposon “suicide” by auto-integration within the VLP. easiRNA targeted EVADE genomic RNA, polysome association of GYPSY (ATHILA) subgenomic RNA, and transcription via histone H3 lysine-9 dimethylation. VLP DNA-seq provides a comprehensive landscape of LTR-retrotransposons, and their control at transcriptional, post-transcriptional and reverse transcriptional levels.
Restricted sequence variation inStreptococcus pyogenespenicillin binding proteins
Authors: Hayes Andrew , Lacey Jake A. , Morris Jacqueline M. , Davies Mark R. , Tong Steven Y.C. 
Published: January 2020

AbstractA recent clinical report has linkedStreptococcus pyogenesβ-lactam antibiotic resistance to mutations in the Penicillin Binding Protein PBP2x. To determine whether this is an isolated case or reflects a broader prevalence of mutations that might confer reduced β-lactam susceptibility, we investigated the relative frequency of penicillin binding protein (PBP) sequence variation within a global database of 9,667S. pyogenesisolates. We found that mutations inS. pyogenesPBPs (PBP2x, PBP1a, PBP1b and PBP2a) occur infrequently across this global database with less than 3 amino acid changes differing between >99% of the global population. Only 4 of the 9,667 strains contained mutations near transpeptidase active sites. The reported PBP2x T553K substitution was not identified. These findings are in contrast to those of 2,520S. pneumococcussequences where PBP mutations are relatively frequent and are often located in key β-lactam binding pockets. These data, combined with the general lack of penicillin resistance reported inS. pyogenesworldwide, suggests that extensive, unknown, constraints restrictS. pyogenesPBP sequence plasticity. These findings imply that while heavy antibiotic pressure may select for mutations in the PBPs, there is currently no evidence of such mutations becoming fixed in theS. pyogenespopulation nor that mutations are being sequentially acquired in the PBPs.ImportancePenicillin is the first line therapeutic option forStreptococcus pyogenesinfections. Despite the global high prevalence ofS. pyogenesinfections and widespread use of penicillin, reports of resistance to penicillin have been incredibly rare. Recently, penicillin resistance was detected in two clinicalS. pyogenesisolates with accompanying mutations in the active site of the penicillin binding protein PBP2x, raising concerns that penicillin resistance may become more widespread. We screened a global database ofS. pyogenesgenome sequences to investigate the frequency of penicillin binding protein (PBP) mutations, identifying that PBP mutations are uncommon relative toStreptococcus pneumoniae. These findings support clinical observations that penicillin resistance is rare inS. pyogenes, and suggest that there are considerable constraints onS. pyogenesPBP sequence variation.
Time varying connectivity across the brain changes as a function of nicotine abstinence state
Authors: Fedota John R. , Ross Thomas J. , Castillo Juan , McKenna Michael R. , Matous Allison L. , Salmeron Betty Jo , Menon Vinod , Stein Elliot A. 
Published: January 2020

ABSTRACTBackgroundThe Nicotine Withdrawal Syndrome (NWS) includes affective and cognitive disruptions whose incidence and severity vary across time during acute abstinence. However, most network-level neuroimaging employs static measures of resting state functional connectivity (rsFC), assuming time-invariance, and unable to capture dynamic brain-behavior relationships. Recent advances in rsFC signal processing allow characterization of “time varying connectivity” (TVC), which characterizes network communication between sub-networks that reconfigure over the course of data collection. As such, TVC may more fully describe network dysfunction related to the NWS.MethodsTo isolate alterations in the frequency and diversity of communication across network boundaries as a function of acute nicotine abstinence we scanned cigarette smokers in the nicotine sated and abstinent states and applied a previously-validated method to characterize TVC at a network and nodal level within the brain.ResultsDuring abstinence, we found brain wide decreases in the frequency of interactions between network nodes in different modular communities (i.e. temporal flexibility; TF). In addition, within a subset of the networks examined the variability of these interactions across community boundaries (i.e. spatiotemporal diversity; STD) also decreased. Finally, within two of these networks the decrease in STD was significantly related to NWS clinical symptoms.ConclusionsEmploying multiple measures of TVC in a within subjects’ design, we characterized a novel set of changes in network communication and link these changes to specific behavioral symptoms of the NWS. These reductions in TVC provide a meso-scale network description of the relative inflexibility of specific large-scale brain networks as a result of acute abstinence.
Liquid-liquid phase separation of full-length prion protein initiates conformational conversionin vitro
Authors: Tange Hiroya , Ishibashi Daisuke , Nakagaki Takehiro , Taguchi Yuzuru , Kamatari Yuji O. , Ozawa Hiroki , Nishida Noriyuki 
Published: January 2020

AbstractPrion diseases are characterized by accumulation of amyloid fibrils. The causative agent is an infectious amyloid that is comprised solely of misfolded prion protein (PrPSc). Prions can convert PrPCto proteinase-resistant PrP (PrP-res)in vitro; however, the intermediate steps involved in the spontaneous conversion remain unknown. We investigated whether recombinant prion protein (rPrP) can directly convert into PrP-resvialiquid-liquid phase separation in the absence of PrPSc. We found that rPrP underwent liquid-liquid phase separation at the interface of the aqueous two-phase system (ATPS) of polyethylene glycol (PEG) and dextran, whereas single-phase conditions were not inducible. Fluorescence recovery assay after photobleaching revealed that the liquid-solid phase transition occurred within a short time. The aged rPrP-gel acquired proteinase-resistant amyloid accompanied by β-sheet conversion, as confirmed by western blotting, Fourier transform infrared spectroscopy, and Congo red staining. The reactions required both the N-terminal region of rPrP (amino acids 23-89) and kosmotropic salts, suggesting that the kosmotropic anions may interact with the N-terminal region of rPrP to promote liquid-liquid phase separation. Thus, structural conversionvialiquid–liquid phase separation and liquid–solid phase transition are intermediate steps in the conversion of prions.
Profiling the microbial community structure and functional diversity of a dam-regulated river undergoing gravel bar restoration
Authors: Serrana Joeselle M. , Li Bin , Sumi Tetsuya , Takemon Yasuhiro , Watanabe Kozo 
Published: January 2020

AbstractBackgroundRiver restoration efforts are expected to influence and change the diversity and functions of microbial communities following the recovery of habitat characteristics in the river ecosystem. The recreation or restoration of gravel bars in the Trinity River in California aims to rehabilitate the environmental heterogeneity downstream of the dam impounded channel. Here, we profiled the community composition, estimated diversity, and annotated putative metabolic functions of the sediment microbial communities to assess whether the construction and restoration of gravel bars in the Trinity River in California enhanced environmental heterogeneity, with the increase in the microbial beta diversity of these in-channel structures against the free-flowing reach of the main channel with comparison to its undisturbed tributaries.ResultsMicrobial community composition of the free-flowing (i.e., no gravel bars) communities were relatively closer regardless of dam influence, whereas the Trinity River gravel bar and tributaries’ gravel bar communities were highly dissimilar. Proteobacteria, Bacteroidetes, and Acidobacteria were the highly abundant sediment microbial phyla on most sites, specifically in the Trinity River gravel bar communities. Putative functional annotation of microbial taxa revealed that chemoheterotrophy and aerobic chemoheterotrophy were the most prevalent microbial processes, with the Trinity River gravel bars having relatively higher representations. The considerably large abundance of heterotrophic taxa implies that gravel bars provide suitable areas for heterotrophic microorganisms with metabolic functions contributing to the net respiration in the river.ConclusionsOur results provide supporting evidence on the positive impact of habitat restoration being conducted in the Trinity River with the non-dam influenced, undisturbed tributaries as the basis of comparison. Gravel bar recreation and restoration contributed to the increased microbial biodiversity through the restoration of environmental heterogeneity at the river scale. We provided valuable insights into the potential microbial processes in the sediment that might be contributing to the biogeochemical processes carried out by the microbial communities in the Trinity River. The significant positive correlation between the functional diversity of the identified microbial taxa and beta diversity suggests that differences in the detected metabolic functions were closely related to dissimilarities in community composition.
Divergent thermal challenges elicit convergent stress signatures in aposymbioticAstrangia poculata
Authors: Wuitchik DM , Almanzar A , Benson BE , Brennan SA , Chavez JD , Liesegang MB , Reavis JL , Reyes CL , Schniedewind MK , Trumble IF , Davies SW 
Published: January 2020

AbstractAnthropogenic climate change threatens corals globally and both high and low temperatures are known to induce coral bleaching. However, coral stress responses across wide thermal breadths are rarely explored. In addition, it is difficult to disentangle the role of symbiosis on the stress response of obligately symbiotic coral hosts. Here, we leverage aposymbiotic colonies of the facultatively symbiotic coral,Astrangia poculata, which lives naturally with and without its algal symbiont, to examine how broad thermal challenges influence coral hosts.A. poculatawere collected from their northern range limit and thermally challenged in two independent 16-day common garden experiments (heat and cold challenge) and behavioral responses to food stimuli and genome-wide gene expression profiling (TagSeq) were performed. Both thermal challenges elicited significant reductions in polyp extension. However, five times as many genes were differentially expressed under cold challenge compared to heat challenge. Despite more genes responding to cold challenge, there was significant overlap in which genes were differentially expressed across thermal challenges. These convergently responding genes (CRGs) were associated with downregulation of motor functions and nematocysts while others were consistent with stress responses previously identified in tropical corals. The fact that these responses were observed in aposymbiotic colonies highlights that many genes previously implicated in stress responses in symbiotic species may simply represent the coral’s stress response in or out of symbiosis.
Variation in root secondary metabolites is shaped by past climatic conditions
Authors: Bont Zoe , Züst Tobias , Huber Meret , Erb Matthias 
Published: January 2020

AbstractPlants can adapt to changing environments by adjusting the production and maintenance of diverse sets of bioactive secondary metabolites. To date, the impact of past climatic conditions relative to other factors such as soil abiotic factors and herbivore pressure on the evolution of plant secondary metabolites is poorly understood, especially for plant roots.We explored associations between root latex secondary metabolites in 63Taraxacum officinalepopulations across Switzerland and past climatic conditions, soil abiotic parameters, and root herbivore pressure. To assess the contribution of environmental effects, root secondary metabolites were measured in F0 plants in nature and F2 plants under controlled greenhouse conditions.Concentrations of root latex secondary metabolites were most strongly associated with past climatic conditions, while current soil abiotic factors or root herbivore pressure did not show a clear association with root latex chemistry. Results were identical for natural and controlled conditions, suggesting heritable trait variation rather than environmental plasticity as underlying factor.Synthesis.We conclude that climatic conditions likely play a major role in the evolution of root secondary metabolites. Direct abiotic effects are likely underlying this pattern, hinting at a novel role of root latex metabolites the tolerance of abiotic stress.