bluuebunny/crossref_metadata_2025_split huggingface dataset:
Network-based Translation of GWAS Findings to Pathobiology and Drug Repurposing for Alzheimer’s Disease
Authors: Fang Jiansong , Zhang Pengyue , Wang Quan , Zhou Yadi , Chiang Chien-Wei , Chen Rui , Zhang Bin , Li Bingshan , Lewis Stephen J. , Pieper Andrew A. , Li Lang , Cummings Jeffrey , Cheng Feixiong 
Published: January 2020

AbstractGenome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer’s disease (AD). However, utilizing GWAS to identify high-confidence AD risk genes (ARGs) that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful. To address this critical problem in the field, we have developed a genotype-informed, network-based methodology that interrogates pathogenesis to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and preclinical AD models, drug-target networks, and the human protein-protein interactome, along with large-scale patient database validation andin vitromechanistic observations in human microglia cells. Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.895, 95% confidence interval [CI] 0.841-0.951, P = 3.97 × 10−4) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR =0.921, 95% CI 0.861-0.983,P= 0.0146), an insulin secretagogue that is also used to treat type 2 diabetes.In vitroexperiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD. In summary, we present an integrated, network-based methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD.
The Concurrent Initiation of Medications Is Associated with Discontinuation of Buprenorphine Treatment for Opioid Use Disorder
Authors: Zhang Pengyue , Chiang Chien-Wei , Quinney Sara , Donneyong Macarius , Lu Bo , Huang Lei Frank , Cheng Feixiong 
Published: January 2020

ABSTRACTIntroductionRetention in buprenorphine treatment for opioid use disorder (OUD) yields better opioid abstinence and reduces all-cause mortality for patients with OUD. Despite significant efforts have been made to expand the availability and use of buprenorphine in the United States, its retention rates remain on a low level. The current study examines discontinuation of buprenorphine with respect to concurrent initiation of other medications using real-world evidence.MethodsCase-crossover study was conducted to examine discontinuation of buprenorphine using a large-scale longitudinal health dataset including 148,306 commercially-insured individuals initiated on medications for opioid use disorder (MOUD). Odds ratios and Bonferroni adjusted p-values were calculated for medications and therapeutic classes of medications.ResultsClonidine was associated with increased discontinuation risk of buprenorphine both using the buprenorphine dataset alone (OR = 1.583 and adjusted p-value = 1.22 × 10−6) and using naltrexone as a comparison drug (OR = 2.706 and adjusted p-value = 4.11 × 10−5). Opioid medications (oxycodone, morphine and fentanyl) and methocarbamol were associated with increased discontinuation risk of buprenorphine using the buprenorphine dataset alone (adjusted p-value < 0.05), but not significant using naltrexone as a comparison drug. 6 drug therapeutic classes were associated with increased discontinuation risk of buprenorphine both using the buprenorphine dataset alone and using naltrexone as a comparison drug (adjusted p-value < 0.05).ConclusionConcurrent initiation of medications is associated with increased discontinuation risk of buprenorphine. Opioid medications are prescribed among patients on MOUD and associated with increased discontinuation risk of buprenorphine. Analgesics is associated with increased discontinuation risk of buprenorphine for patients without previous exposure of pain medications.
Development of Gene Editing Strategies for Humanβ-Globin (HBB) Gene Mutations
Authors: Kalkan Batuhan Mert , Kala Ezgi Yagmur , Yuce Melek , Alpaslan Medine Karadag , Kocabas Fatih 
Published: January 2020

AbstractRecent developments in gene editing technology have enabled scientists to modify DNA sequence by using engineered endonucleases. These gene editing tools are promising candidates for clinical applications, especially for treatment of inherited disorders like sickle cell disease (SCD). SCD is caused by a point mutation in human β-globin gene (HBB). Clinical strategies have demonstrated substantial success, however there is not any permanent cure for SCD available. CRISPR/Cas9 platform uses a single endonuclease and a single guide RNA (gRNA) to induce sequence-specific DNA double strand break (DSB). When this accompanies a repair template, it allows repairing the mutated gene. In this study, it was aimed to target HBB gene via CRISPR/Cas9 genome editing tool to introduce nucleotide alterations for efficient genome editing and correction of point mutations causing SCD in human cell line, by Homology Directed Repair (HDR). We have achieved to induce target specific nucleotide changes on HBB gene in the locus of mutation causing SCD. The effect of on-target activity of bone fide standard gRNA and newly developed longer gRNA were examined. It is observed that longer gRNA has higher affinity to target DNA while having the same performance for targeting and Cas9 induced DSBs. HDR mechanism was triggered by co-delivery of donor DNA repair templates in circular plasmid form. In conclusion, we have suggested methodological pipeline for efficient targeting with higher affinity to target DNA and generating desired modifications on HBB gene.Graphical abstractHighlightsHBB gene were targeted by spCas9 in close proximity to the SCD mutationLong gRNA, which is designed to target SCD mutation, is sickle cell disease specific and exhibits indistinguishable level of cleavage activity on target locus.Functional HBB HDR repair templates with 1 Kb and 2 Kb size were generated to cover all known mutations in the HBB gene.Replacement of PAM sequence in HDR template with HindIII recognition sequence allowed a quick assessment of the HDR efficiency.HDR template: Cas9-GFP vector 2:1 ratio yielded the highest HDR events/GFP+ cells.
A gradient from long-term memory to novel cognition: transitions through default mode and executive cortex
Authors: Wang Xiuyi , Margulies Daniel S. , Smallwood Jonathan , Jefferies Elizabeth 
Published: January 2020

AbstractHuman cognition flexibly guides decision-making in familiar and novel situations. Although these decisions are often treated as dichotomous, in reality, situations are neither completely familiar, nor entirely new. Contemporary accounts of brain organization suggest that neural function is organized along a gradient from unimodal regions of sensorimotor cortex, through executive regions to transmodal default network. We examined whether this graded view of neural organization helps to explain how decision-making changes across situations that vary in their alignment with long-term knowledge. Functional magnetic resonance imaging found that as decisions are made in an increasingly familiar context, the BOLD signal follows this neural gradient, with stronger responses in default regions when items are linked in long-term memory. In this way, neural organization is optimized to support decision-making in both highly familiar and less familiar situations.
Flight demand and environmental niche are associated with molecular evolutionary rates in a large avian radiation
Authors: Duchene David A. , Montoya Paola , Claramunt Santiago , Cadena Daniel A. 
Published: January 2020

AbstractAmong the macroevolutionary drivers of molecular evolutionary rates, metabolic demands and environmental energy have been a central topic of discussion. The large number of studies examining these associations have found mixed results, and have rarely explored the interactions among various factors impacting molecular evolutionary rates. Taking the diverse avian family Furnariidae as a case study, we examined the association between several estimates of molecular evolutionary rates with proxies of metabolic demands imposed by flight (wing loading and the hand-wing index) and proxies of environmental energy across the geographic ranges of species (temperature and UV radiation). We found evidence that species that fly less have greater wing loading and this is associated with accelerated rates of mutation. An elongated wing morphology is associated with greater flight activity and with molecular signatures of positive selection or reduced population sizes. Meanwhile, environmental temperature and UV radiation interact to explain molecular rates at sites affected by selection and population size, contrary to the expectation of their impact on mutation rates. Our results suggest that the demands of flight and environmental energy pose multiple evolutionary pressures on the genome either by driving mutation rates or via their association with natural selection or population size.
Mental compression of spatial sequences in human working memory using numerical and geometrical primitives
Authors: Al Roumi Fosca , Marti Sébastien , Wang Liping , Amalric Marie , Dehaene Stanislas 
Published: January 2020

AbstractHow does the human brain store sequences of spatial locations? The standard view is that each consecutive item occupies a distinct slot in working memory. Here, we formulate and test the alternative hypothesis that the human brain compresses the whole sequence using an abstract, language-like code that captures the numerical and geometrical regularities of the sequence at multiple nested levels. We exposed participants to spatial sequences of fixed length but variable regularity, and asked them to remember the sequence in order to detect deviants, while their brain activity was recorded using magneto-encephalography. Using multivariate decoders, each successive location could be decoded from brain signals, and upcoming locations were anticipated prior to their actual onset. Crucially, sequences with lower complexity, defined as the minimal description length provided by the formal language, and whose memory representation was therefore predicted to be more compressed, led to lower error rates and to increased anticipations. Furthermore, neural codes specific to the numerical and geometrical primitives of the postulated language could be detected, both in isolation and within the sequences. These results suggest that the human brain detects sequence regularities at multiple nested levels and uses them to compress long sequences in working memory.
Type-1 IFN primed monocytes in pathogenesis of idiopathic pulmonary fibrosis
Authors: Fraser Emily , Denney Laura , Blirando Karl , Vuppusetty Chaitanya , Antanaviciute Agne , Zheng Yuejuan , Repapi Emmanouela , Iotchkova Valentina , Taylor Stephen , Ashley Neil , St Noble Victoria , Benamore Rachel , Hoyles Rachel , Clelland Colin , Rastrick Joseph M D , Hardman Clare S , Alham Nasullah K , Rigby Rachel E , Rehwinkel Jan , Ho Ling-Pei 
Published: January 2020

ABSTRACTIdiopathic pulmonary fibrosis (IPF) is the most severe form of lung fibrosis. It is progressive, and has an extremely poor outcome and limited treatment options. The disease exclusively affects the lungs, and thus less attention has been focused on blood-borne immune cells. which could be a more effective therapeutic target than lung-based cells. Here, we questioned if circulating monocytes, which has been shown to be increased in IPF, bore abnormalities that might contribute to its pathogenesis. We found that levels of circulating monocytes correlated directly with the extent of fibrosis in the lungs, and increased further during acute clinical deterioration. Monocytes in IPF were phenotypically distinct, displaying increased expression of CD64, a type 1 IFN gene expression signature and a greater magnitude of type 1 IFN response when stimulated. These abnormalities were accompanied by markedly raised CSF-1 levels in the serum, prolonged survival of monocytesex vivo, and increased numbers of monocytes in lung tissue. Our study defines the key monocytic abnormalities in IPF, proposing type 1 IFN-primed monocytes as a potential driver of an aberrant repair response and fibrosis. It provides a rationale for targeting monocytes and identifies monocytic CD64 as a potential specific therapeutic target for IPF.
Multiplex genetic engineering exploiting pyrimidine salvage pathway-based self-encoded selectable markers
Authors: Birštonas Lukas , Dallemulle Alex , López-Berges Manuel S. , Jacobsen Ilse D. , Offterdinger Martin , Abt Beate , Straßburger Maria , Bauer Ingo , Schmidt Oliver , Sarg Bettina , Lindner Herbert , Haas Hubertus , Gsaller Fabio 
Published: January 2020

ABSTRACTSelectable markers are indispensable for genetic engineering, yet their number and variety is limited. Most selection procedures for prototrophic cells rely on the introduction of antibiotic resistance genes. New minimally invasive tools are needed to facilitate sophisticated genetic manipulations. Here, we characterized three endogenous genes in the human fungal pathogenAspergillus fumigatusfor their potential as markers for targeted genomic insertions of DNAs-of-interest (DOIs). Since these genes are involved in uptake and metabolization of pyrimidines, resistance to the toxic effects of prodrugs 5-fluorocytosine and 5-fluorouracil can be used to select successfully integrated DOIs. We show that DOI integration, resulting in the inactivation of these genes, caused no adverse effects with respect to nutrient requirements, growth or virulence. Beside the individual use of markers for site-directed integration of reporter cassettes including the 17-kb penicillin biosynthetic cluster, we demonstrate their sequential use inserting three fluorescent protein encoding genes into a single strain for simultaneous multicolor localization microscopy. In addition toA. fumigatus, we validated the applicability of this novel toolbox inPenicillium chrysogenumandFusarium oxysporum.Enabling multiple targeted insertions of DOIs without the necessity for exogenous markers, this technology has the potential to significantly advance genetic engineering.
Serum α-Klotho levels correlate with episodic memory changes related to cardiovascular exercise in older adults
Authors: Becke Andreas , Maass Anne , Kreutz Michael R. , Duezel Emrah 
Published: January 2020

AbstractAerobic exercise is a potential life-style intervention to delay cognitive decline and neurodegeneration. Elevated serum levels of the anti-aging protein α-Klotho (αKL) are a potential mediating factor of exercise benefits on cognition. Here, we examined in older adults how exercise-related changes of αKL levels in serum relate to changes in cerebral blood flow (CBF), hippocampal volumes and episodic memory. We analyzed data from a previously published intervention study in which forty cognitively healthy subjects were pseudo-randomly assigned to either a cardiovascular exercise group (treadmill training, n=21) or control group (indoor progressive-muscle relaxation/stretching, n=19). 3-Tesla gadolinium perfusion imaging was used to track hippocampal CBF changes and high resolution 7-Tesla-T1-images were used to track hippocampal volume changes. Changes in episodic memory performance were measured using the complex figure test (CFT). Longitudinal changes were compared between groups and analyzed with a multiple linear regression approach. CFT and hippocampal volume changes significantly predicted changes in serum αKL levels. For CFT, this effect was found in the exercise but not the control group. Collectively the data suggest that αKL level increases induced by exercise can be associated with improved hippocampal function in older adults.
Early life stress causes persistent impacts on the microbiome of Atlantic salmon
Authors: Webster Tamsyn M. Uren , Consuegra Sofia , de Leaniz Carlos Garcia 
Published: January 2020

AbstractIntensively farmed fish are commonly stressed, often leading to immune impairment and increased susceptibility to disease. Microbial communities associated with the gut and skin are vital to host immune function, but little is known about how stress affects the fish microbiome, especially during the sensitive early life stages. We compared the effects of two aquaculture-relevant stressors on the gut and skin microbiome of Atlantic salmon fry: an acute cold stress during late embryogenesis, and a chronic environmental stress during the larval stage. Acute cold stress had a lasting effect on the structure of both the gut and the skin microbiome, likely due to disruption of the egg shell microbial communities which seed the initial colonisation of the teleost microbiome upon hatching. In contrast, chronic post hatch stress altered the structure of the gut microbiome, but not that of the skin. Both types of stressors promoted similar Gammaproteobacteria ASVs, particularly within the generaAcinetobacterandAeromonaswhich include several important fish pathogens and, in the gut, reduced the abundance of Lactobacillales. This suggests that there may be common signatures of stress in the salmon microbiome, which may represent useful stress biomarkers in aquaculture.
Enhancing georeferenced biodiversity inventories: automated information extraction from literature records reveal the gaps
Authors: Kopperud Bjørn Tore , Lidgard Scott , Liow Lee Hsiang 
Published: January 2020

AbstractWe use natural language processing (NLP) to retrieve location data for cheilostome bryozoan species (text-mined occurrences [TMO]) in an automated procedure. We compare these results with data from the Ocean Biogeographic Information System (OBIS). Using OBIS and TMO data separately and in combination, we present latitudinal species richness curves using standard estimators (Chao2 and the Jackknife) and range-through approaches. Our combined OBIS and TMO species richness curves quantitatively document a bimodal global latitudinal diversity gradient for cheilostomes for the first time, with peaks in the temperate zones. 79% of the georeferenced species we retrieved from TMO (N = 1780) and OBIS (N = 2453) are non-overlapping and underestimate known species richness, even in combination. Despite clear indications that global location data compiled for cheilostomes should be improved with concerted effort, our study supports the view that latitudinal species richness patterns deviate from the canonical LDG. Moreover, combining online biodiversity databases with automated information retrieval from the published literature is a promising avenue for expanding taxon-location datasets.
Contrasting population structure and demographic history of cereal aphids in different environmental and agricultural landscapes
Authors: Morales-Hojas Ramiro , Sun Jingxuan , Iraizoz Fernando Alvira , Tan Xiaoling , Chen Julian 
Published: January 2020

AbstractGenetic diversity of populations has important ecological and evolutionary consequences, which are fundamental to improve the sustainability of agricultural production. Studies of how differences in agricultural management and environment influence the population structure of insect pests are fundamental to predict outbreaks and optimise control programmes. Here, we have studied the population genetic diversity and evolution ofSitobion avenaeandSitobion miscanthi(previously mistaken forS. avenae), which are among the most relevant aphid pests of cereals across Europe and China, respectively. We have used a genomic approach that allows the identification of weak geographic structure and migration patterns at scales that were previously not discernible. In the present study, we show that the population structure in present day populations are different from that described in previous studies, which suggests that they have evolved recently possibly as a response to human-induced changes in agriculture. In the UK,S. avenaeis predominantly anholocyclic and, as a result of the evolution of insecticide resistance, a superclone is now dominant across the geographic distribution in the country and the genetic diversity is low. In China,S. miscanthipopulations are mostly holocyclic, with one sexual stage in autumn to produce overwintering eggs, and there are six genetically differentiated subpopulations and high genetic differentiation between geographic locations, which suggests that further taxonomical research is needed. Unlike in the case ofS. avenaein England, there is no evidence for insecticide resistance and there is no predominance of a single lineage inS. miscanthiin China.
Fear conditioning prompts sparser representations of conditioned threat in primary visual cortex
Authors: Yin Siyang , Bo Ke , Liu Yuelu , Thigpen Nina , Keil Andreas , Ding Mingzhou 
Published: January 2020

AbstractRepeated exposure to threatening stimuli alters sensory responses. We investigated the underlying neural mechanism by recording simultaneous EEG-fMRI from human participants viewing oriented gratings during Pavlovian fear conditioning. In acquisition, one grating (the CS+) was paired with a noxious noise, the unconditioned stimulus (US). The other grating (CS-) was never paired with US. In habituation, which preceded acquisition, and in final extinction, the same two gratings were presented without the US. Using fMRI-BOLD multivoxel patterns in primary visual cortex during habituation as reference, we found that during acquisition, aversive learning selectively prompted systematic changes in multivoxel patterns evoked by the CS+. Specifically, CS+ evoked voxel patterns in V1 became sparser as aversive learning progressed, and the sparse pattern was preserved in extinction. Concomitant with the voxel pattern changes, occipital alpha oscillations were increasingly more desynchronized during CS+ (but not CS-) trials. Across acquisition trials, the rate of change in CS+-related alpha desynchronization was correlated with the rate of change in multivoxel pattern representations of the CS+. Furthermore, alpha oscillations co-varied with BOLD in the right temporal-parietal junction, but not with BOLD in the amygdala. Thus, fear conditioning prompts persistent sparsification of threat cue representations, likely mediated by attention-related mechanisms.