bluuebunny/crossref_metadata_2025_split huggingface dataset:
Statistical model integrating interactions into genotype-phenotype association mapping: an application to reveal 3D-genetic basis underlying Autism
Authors: Li Qing , Cao Chen , Perera Deshan , He Jingni , Chen Xingyu , Azeem Feeha , Howe Aaron , Au Billie , Yan Jun , Long Quan 
Published: July 2020

AbstractBiological interactions are prevalent in the functioning organisms. Correspondingly, statistical geneticists developed various models to identify genetic interactions through genotype-phenotype association mapping. The current standard protocols in practice test single variants or single regions (that contain multiple local variants) sequentially along the genome, followed by functional annotations that involve various aspects including interactions. The testing of genetic interactions upfront is rare in practice due to the burden of testing a huge number of combinations, which lead to the multiple-test problem and the risk of overfitting. In this work, we developed interaction-integrated linear mixed model (ILMM), a novel model that integrates aprioriknowledge into linear mixed models. ILMM enables statistical integration of genetic interactions upfront and overcomes the problems associated with combination searching.Three dimensional (3D) genomic interactions assessed by Hi-C experiments have led to unprecedented biological discoveries. However, the contribution of 3D genomic interactions to the genetic basis of complex diseases has yet to be quantified. Using 3D interacting regions asa prioriinformation, we conducted both simulations and real data analysis to test ILMM. By applying ILMM to whole genome sequencing data for Autism Spectrum Disorders, or ASD (MSSNG) and transcriptome sequencing data (GTEx), we revealed the 3D-genetic basis of ASD and 3D-eQTLs for a substantial proportion of gene expression in brain tissues. Moreover, we have revealed a potential mechanism involving distal regulation between FOXP2 and DNMT3A conferring the risk of ASD.Software is freely available in our GitHub:https://github.com/theLongLab/Jawamix5
Tumor-stromal IL-1β/ NFκB / ESE3 Signaling Axis Drives Pancreatic Cancer Fibrosis, Chemoresistance, and Poor Prognosis
Authors: Zhao Tiansuo , Xiao Di , Jin Fanjie , Wang Hongwei , Liu Jing , Cai Wenrun , Huang Chongbiao , Wang Xiuchao , Gao Song , Yang Shengyu , Hao Jihui 
Published: July 2020

AbstractPancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis and pancreatic ductal adenocarcinoma (PDAC) progression. The mechanisms controlling PSC activation is not completely understood. Here we investigated the role of ESE3 (Epithelium-Specific ETS factor 3) in PSC activation. We discovered that in PDAC patients ESE3 expression was increased in PSC while decreased in tumor cells. ESE3 overexpression in PSC promoted PSC activation. Condition medium from ESE3-overexprssing PSC promotes PDAC cell migration, chemoresistance, tumor growth and fibrosis. ESE3 directly induced the transcription of α-SMA, Collagen 1 and IL-1β by binding to ESE3 binding sites on their promoters to activate PSC. On the other hand, IL-1β upregulates ESE3 in PSC through NFκB activation and ESE3 is required for PSC activation by tumor cell derived IL-1β. Clinical data showed ESE3 upregulation in PSC was positively correlated with tumor size, pTNM stage, CA19-9, CEA and CA242 level in serum. ESE3 overexpression in PSC was an independent negative prognostic factor for disease-free survival and overall survival among PDAC patients. Inhibition of the IL-1β/ ESE3 (PSC)/ IL-1β positive feedback loop represents a promising therapeutic strategy to reduce tumor fibrosis and increase chemotherapeutic efficacy in PDAC.
Treated wastewater irrigation promotes the spread of antibiotic resistance into subsoil pore-water
Authors: Kampouris Ioannis D. , Klümper Uli , Cacace Damiano , Kunze Steffen , Berendonk Thomas U. 
Published: July 2020

AbstractIn the present study, we investigated the impact of treated wastewater (TWW) irrigation on the prevalence of antibiotic resistance genes (ARGs) in subsoil pore-water, a so-far under-appreciated matrix. We hypothesized that TWW irrigation increases ARG prevalence in subsoil pore-water. This hypothesis was tested using a multiphase approach, which consisted of sampling percolated subsoil pore-water from lysimeter-wells of a real-scale TWW-irrigated field, operated for commercial farming practices, and controlled, laboratory mesocosms irrigated with freshwater or TWW. We monitored the abundance of six selected ARGs (sul1, blaOXA-58,tetM,qnrS,blaCTX-M-32andblaTEM), theintI1gene associated with mobile genetic elements and an indicator for anthropogenic pollution and bacterial abundance (16S rRNA gene) by qPCR. The bacterial load of subsoil pore water was independent of both, irrigation intensity in the field study and irrigation water type in the mesocosms. Among the tested genes in the field study,sul1andintI1exhibited constantly higher relative abundances. Their abundance was further positively correlated with increasing irrigation intensity. Controlled mesocosm experiments verified the observed field study results: the relative abundance of several genes, includingsul1andintI1,increased significantly when irrigating with TWW compared to freshwater irrigation. Overall, TWW irrigation promoted the spread of ARGs andintI1in the subsoil pore-water, while the bacterial load was maintained. The combined results from the real-scale agricultural field and the controlled lab mesocosms indicate that the dissemination of ARGs in various subsurface environments needs to be taken into account during TWW irrigation scenarios.Graphical abstractHighlightsTWW irrigation intensity andsul1&intI1abundance correlate in a real-scale fieldARGs &intI1increase in subsoil pore-water during TWW irrigation in mesocosmsNo increase of ARGs &intI1in freshwater irrigated mesocosmsTWW irrigation does not affect the bacterial load of subsoil pore-water
The common house spider,Parasteatoda tepidariorum, maintains silk gene expression on sub-optimal diet
Authors: Miller Jeremy , Vienneau-Hathaway Jannelle , Dendev Enkhbileg , Lan Merrina , Ayoub Nadia A. 
Published: July 2020

AbstractOrb-web weaving spiders and their relatives spin multiple task-specific fiber types. The unique material properties of each silk type result from differences in amino acid sequence and structure of their component proteins, primarily spidroins (spider fibrous proteins). Amino acid content and gene expression measurements of spider silks suggest some spiders change expression patterns of individual protein components in response to environmental cues. We quantified mRNA abundance of three spidroin encoding genes involved in prey capture in the common house spider,Parasteatoda tepidariorum(Theridiidae), fed different diets. After 10 days of acclimation to the lab on a diet of mealworms, spiders were split into three groups: (1) individuals were immediately dissected, (2) spiders were fed high-energy crickets, or (3) spiders were fed low-energy flies, for 1 month. All spiders gained mass during the acclimation period and cricket-fed spiders continued to gain mass, while fly fed spiders either maintained or lost mass. Using quantitative PCR, we found no significant differences in the absolute or relative abundance of dragline gene transcripts, major ampullate spidroin 1 (MaSp1) and major ampullate spidroin 2 (MaSp2), among groups. In contrast, prey-wrapping minor ampullate spidroin (MiSp)gene transcripts were significantly less abundant in fly-fed than lab-acclimated spiders. However, when measured relative toactin, cricket-fed spiders showed the lowest expression ofMiSp. Our results suggest that house spiders are able to maintain silk production, even in the face of a low-quality diet.
First evidence for an aposematic function of a very common color pattern in small insects
Authors: Mora-Castro Rebeca , Alfaro-Córdoba Marcela , Hernández-Jiménez Marcela , Otárola Mauricio Fernández , Méndez-Rivera Michael , Ramírez-Morales Didier , Rodríguez-Rodríguez Carlos E. , Durán-Rodríguez Andrés , Hanson Paul E. 
Published: July 2020

AbstractMany small parasitoid wasps have a black-orange-black (BOB) color pattern, which is usually present in both sexes. A likely function of this widespread pattern is aposematic (warning) coloration, but this has never been investigated. To test this hypothesis, we presented spider predators(Lyssomanes jemineus), both field-captured and lab-reared individuals, to a species with the BOB pattern and a congeneric all-black species in each of four scelionid genera (Baryconus, Chromoteleia, MacroteleiaandScelio). Each spider/wasp trial was filmed for 40 minutes under controlled conditions and three behavioral responses (detect, attack, avoid) were recorded in each of 136 trials, never using the same predator and prey more than once. In order to better understand the results obtained, two additional studies were performed. First, the reflection spectrum of the cuticle of the wasp and a theoretical visual sensibility model of the spider were used to calculate a parameter we called “absorption contrast” that allowed us to compare the perception contrast between black and orange in each wasp genus as viewed by the spider. Second, acute toxicity trials with the water flea,Daphnia magna, were performed to determine toxicity differences between BOB and non-BOB wasps. By combining the results from the three types of experiments, together with a statistical analysis, we confirmed that BOB color pattern plays an aposematic role.
Modulation of proteasome activity by curcumin and didemethylcurcumin
Authors: Khan Tapan K. , You Youngki , Nelson Thomas J. , Kundu Subrata , Pramanik Saroj , Das Joydip 
Published: July 2020

AbstractModulation of proteasome function by pharmacological interventions and molecular biology tools is an active area of research in cancer biology and neurodegenerative diseases. Curcumin (diferuloylmethane) is a naturally occurring polyphenol that affects multiple signaling pathways and known to modulate PKC activities. The therapeutic significance of curcumin is often considered to reside in its anti-inflammatory, antioxidant, anti-angiogenic, or anti-apoptotic properties. However, recent research suggests that the therapeutic efficacy of curcumin may be due to its activity as a potent inhibitor of the proteasome. In this study, we show that both curcumin and its synthetic polyphenolic derivative (didemethylcurcumin), CUIII modulated proteasome activity in a biphasic manner. Curcumin and CUIII increased proteasome activity at nanomolar concentrations but inhibited proteasome activity at micromolar concentrations. Curcumin was more effective than CUIII in relative proteasome activity increase at nanomolar concentrations. Also, curcumin was more effective than CUIII in relative proteasome activity inhibition at micromolar concentration. The docking study was conducted on the 20S proteasome catalytic subunit. Estimated Kd values for curcumin and didemethylcurcumin are 0.0054μM and 1.3167μM, respectively. These values correlate well with the results of the effectiveness of modulation by curcumin compare to CUIII. The small size of CUIII makes its dock to the narrow cavity of the active site, but the binding interaction is not strong compare to curcumin. This study suggests that curcumin and its didemethyl derivative can be used to modulate proteasome activity. This communication implicates the reason why curcumin and its didemethyl derivative can be used to two different disease mechanisms, neurodegeneration, and cancer.
A novel ultrasound-guided mouse model of sudden cardiac arrest
Authors: Rutledge Cody A. , Chiba Takuto , Redding Kevin , Dezfulian Cameron , Sims-Lucas Sunder , Kaufman Brett A. 
Published: July 2020

AbstractAimMouse models of sudden cardiac arrest are limited by challenges with surgical technique and reliable venous access. To overcome this limitation, we sought to develop a simplified method in the mouse that uses ultrasound-guided injection of potassium chloride directly into the heart.MethodsPotassium chloride was delivered directly into the left ventricular cavity under ultrasound guidance in intubated mice, resulting in immediate asystole. Mice were resuscitated with injection of epinephrine and manual chest compressions and evaluated for survival, body temperature, cardiac function, kidney damage, and diffuse tissue injury.ResultsThe direct injection sudden cardiac arrest model causes rapid asystole with high surgical survival rates and low surgical duration. Sudden cardiac arrest mice with 8-min of asystole have significant cardiac dysfunction at 24 hours and high lethality within the first seven days, where after cardiac function begins to improve. Sudden cardiac arrest mice have secondary organ damage, including significant kidney injury, but no clear evidence of neurologic dysfunction.ConclusionsUltrasound-guided direct injection of potassium chloride allows for rapid and reliable cardiac arrest in the mouse that mirrors human pathology. This technique lowers the barriers to entry for adoption of the mouse model of sudden cardiac arrest, which will improve investigators’ ability to study the mechanisms underlying post-arrest changes.
Genome wide identification of QTL associated with yield and yield components in two popular wheat cultivars TAM 111 and TAM 112
Authors: Yang Yan , Dhakal Smit , Chu Chenggen , Wang Shichen , Xue Qingwu , Rudd Jackie C. , Ibrahim Amir M.H. , Jessup Kirk , Baker Jason , Fuentealba Maria Pilar , Devkota Ravindra , Baker Shannon , Johnson Charles D. , Metz Richard , Liu Shuyu 
Published: July 2020

AbstractTwo drought-tolerant wheat cultivars, ‘TAM 111’ and ‘TAM 112’, have been widely grown in the Southern Great Plains of the U.S. and used as parents in many wheat breeding programs worldwide. This study aimed to reveal genetic control of yield and yield components in the two cultivars under both dryland and irrigated conditions. A mapping population containing 124 F5:7recombinant inbred lines (RILs) was developed from the cross of TAM 112/TAM 111. A set of 5,948 SNPs from the wheat 90K iSelect array and double digest restriction-site associated DNA sequencing was used to construct high-density genetic maps. Data for yield and yield components were obtained from 11 environments. QTL analyses were performed based on 11 individual environments, across all environments, within and across mega-environments. Thirty-six unique consistent QTL regions were distributed on 13 chromosomes including 1A, 1B, 1D, 2A, 2D, 3D, 4B, 4D, 6A, 6B, 6D, 7B, and 7D. Ten unique QTL with pleiotropic effects were identified on four chromosomes and eight were in common with the consistent QTL. These QTL increased dry biomass grain yield by 16.3 g m−2, plot yield by 28.1 g m−2, kernels spike−1by 0.7, spikes m−2by 14.8, thousand kernel weight by 0.9 g with favorable alleles from either parent. TAM 112 alleles mainly increased spikes m−2and thousand kernel weight while TMA 111 alleles increased kernels spike−1, harvest index and grain yield. The saturated genetic map and markers linked to significant QTL from this study will be very useful in developing high throughput genotyping markers for tracking the desirable haplotypes of these important yield-related traits in popular parental cultivars.
Establishing live-cell single-molecule localization microscopy imaging and single-particle tracking in the archaeonHaloferax volcanii
Authors: Turkowyd Bartosz , Schreiber Sandra , Wörtz Julia , Segal Ella Shtifman , Mevarech Moshe , Duggin Iain G. , Marchfelder Anita , Endesfelder Ulrike 
Published: July 2020

AbstractIn recent years, fluorescence microscopy techniques for the localization and tracking of single molecules in living cells have become well-established and indispensable tools for the investigation of cellular biology andin vivobiochemistry of many bacterial and eukaryotic organisms. Nevertheless, these techniques are still not established for imaging archaea. Their establishment as a standard tool for the study of archaea will be a decisive milestone for the exploration of this branch of life and its unique biology.Here we have developed a reliable protocol for the study of the archaeonHaloferax volcanii. We have generated an autofluorescence-freeH. volcaniistrain, evaluated several fluorescent proteins for their suitability to serve as single-molecule fluorescence markers and codon-optimized them to work under optimalH. volcaniicultivation conditions. We found that two of them, Dendra2Hfx and PAmCherry1Hfx, provide state-of-the-art single-molecule imaging. Our strategy is quantitative and allows dual-color imaging of two targets in the same field of view as well as DNA co-staining. We present the first single-molecule localization microscopy (SMLM) images of the subcellular organization and dynamics of two crucial intracellular proteins in livingH. volcaniicells, FtsZ1, which shows complex structures in the cell division ring, and RNA polymerase, which localizes around the periphery of the cellular DNA. This work should provide incentive to develop SMLM strategies for other archaeal organisms in the near future.
A-to-I RNA editing in SARS-COV-2: real or artifact?
Authors: Picardi Ernesto , Mansi Luigi , Pesole Graziano 
Published: July 2020

SummaryADAR1-mediated deamination of adenosines in long double stranded RNAs plays an important role in modulating the innate immune response. However, recent investigations based on metatranscriptomic samples of COVID-19 patients and SARS-COV-2 infected Vero cells have recovered contrasting findings. Using RNAseq data from time course experiments of infected human cell lines and transcriptome data from Vero cells and clinical samples, we prove that A-to-G changes observed in SARS-COV-2 genomes represent genuine RNA editing events, likely mediated by ADAR1. While the A-to-I editing rate is generally low, changes are distributed along the entire viral genome, are overrepresented in exonic regions and are, in the majority of cases, nonsynonymous. The impact of RNA editing on virus-host interactions could be relevant to identify potential targets for therapeutic interventions.
TheE. coliCas1/2 endonuclease complex reduces CRISPR/Cascade guide array stability
Authors: Ye Zhixia , Lebeau Juliana , Moreb Eirik A. , Menacho-Melgar Romel , Lynch Michael D. 
Published: July 2020

AbstractCRISPR based interference has become common in various applications from genetic circuits to dynamic metabolic control. InE. colithe native CRISPR Cascade system can be utilized for silencing by deletion of thecas3nuclease along with expression of guide RNA arrays, where multiple genes can be silenced from a single transcript. We notice the loss of protospacer sequences from guide arrays utilized for dynamic silencing. We report that unstable guide arrays are due to expression of the Cas1/2 endonuclease complex. Acas1deletion improves guide array stability. We propose a model wherein basal Cas1/2 endonuclease activity results in the loss of protospacers from guide arrays. Subsequently, mutant guide arrays can be amplified through selection. Replacing a constitutive promoter driving Cascade complex expression with a tightly controlled inducible promoter improves guide array stability, while minimizing leaky gene silencing.HighlightsCas1/2 endonuclease complex mediates CRISPR/Cascade protospacer loss inE. coliTightly controlled Cascade operon expression increases guide array stability.
Zn2+influx activates ERK and Akt signaling pathways through a common mechanism
Authors: Anson Kelsie J. , Corbet Giulia A. , Palmer Amy E. 
Published: July 2020

AbstractZinc (Zn2+) is an essential metal in biology and its bioavailability is highly regulated. Many cell types exhibit fluctuations in Zn2+that appear to play an important role in cellular function. However, the detailed molecular mechanisms by which Zn2+dynamics influence cell physiology remain enigmatic. Here, we use a combination of fluorescent biosensors and cell perturbations to define how changes in intracellular Zn2+impact kinase signaling pathways. By simultaneously monitoring Zn2+dynamics and kinase activity in individual cells, we quantify changes in labile Zn2+and directly correlate changes in Zn2+with ERK and Akt activity. Under our experimental conditions, Zn2+fluctuations are not toxic and do not activate stress-dependent kinase signaling. We demonstrate that while Zn2+can non-specifically inhibit phosphatases leading to sustained kinase activation, ERK and Akt are predominantly activated via upstream signaling, and through a common node via Ras. We provide a framework for quantification of Zn2+fluctuations and correlate these fluctuations with signaling events in single cells to shed light on the role that Zn2+dynamics play in healthy cell signaling.Significance StatementWhile zinc (Zn2+) is a vital ion for cell function and human health, little is known about the role it plays in regulating cell signaling. Here, we use fluorescent tools to study the interaction between Zn2+and cell signaling pathways that play a role in cell growth and proliferation. Importantly, we use small, non-toxic Zn2+concentrations to ensure that our Zn2+changes are closer to what cells would experience in the body and not stress-inducing. We also demonstrate that these signaling changes are driven by Ras activation, which contradicts one of the major hypotheses in the field. Our sensors shed light on how cells respond to a very important micronutrient in real time.
Widespread non-apoptotic activation ofDrosophilaCaspase-2/9 limits JNK signaling, macrophage proliferation, and growth of wound-like tumors
Authors: Xu Derek Cui , Yamada Kenneth M. , Baena-Lopez Luis Alberto 
Published: July 2020

SummaryResistance to apoptosis due to caspase deregulation is considered one of the main hallmarks of cancer. However, the discovery of novel non-apoptotic caspase functions has revealed unknown intricacies about the interplay between these enzymes and tumor progression. To investigate this biological problem, we capitalized on aDrosophilatumor model highly relevant for humans that relies on the concomitant upregulation of EGFR and the JAK/STAT signaling pathway. Our results indicate that widespread non-apoptotic activation of initiator caspases limits JNK signaling and facilitates cell fate commitment in these tumors, thus preventing the overgrowth and exacerbation of malignant features. Intriguingly, these caspase functions are strongly linked to the ability of these enzymes to control the recruitment and subsequent proliferationin situof macrophage-like cells on the tumor. These findings assign novel tumor-suppressor activities to caspases independent of apoptosis, while providing highly relevant molecular details to understanding their diverse contribution during tumor progression.