bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of pasture management on fire ant,Solenopsis invicta(Hymenoptera: Formicidae), abundance and the relationship to arthropod community diversity
Authors: Schmid Ryan B. , Lundgren Jonathan G.
Published: December 2020

The red imported fire ant,Solenopsis invicta, is one of the most prolific invasive species to the Southeastern U.S. These invaders preferentially colonize highly disturbed land and grassland habitat. Management of livestock in pasture systems can have a profound impact on the level of disturbance in grassland habitats, and we hypothesized that pasture management would have a significant effect onS. invictaabundance in the Southeastern U.S., and arthropod diversity would negatively correlate with this invasive species. We studied the effects that pasture management systems (based on stocking density, rotation frequency, and insecticide application rates) have on fire ant mound abundance and arthropod diversity for the soil, foliar, and dung communities.S. invictamounds were quantified and mound areas were documented along transect lines in six pastures. Soil and foliar arthropod communities were collected along the same transect lines, and dung communities sampled from pats within the pasture system. Pastures managed under adaptive multi-paddock (AMP) practices had 3.35× moreS. invictamounds and 4.64× more mound area than their conventionally managed counterparts. However, arthropod diversity did not correlate withS. invictaabundance for any of the three arthropod communities sampled. This study shows pasture management can have a significant impact onS. invictamound abundance, but arthropod communities in AMP managed pastures did not suffer decreased diversity from increased abundance ofS. invicta. Additionally, this study demonstrates that this invasive species does not necessarily contribute to diversity decline, at least under AMP pasture systems.
Redox protein Memo1 coordinates FGF23-driven signaling and small Rho-GTPases in the mouse kidney
Authors: Bartos Katalin , Ramakrishnan Suresh Krishna , Braga-Lagache Sophie , Hänzi Barbara , Durussel Fanny , Prakash Sridharan Arjun , Zhu Yao , Sheehan David , Hynes Nancy E. , Bonny Olivier , Moor Matthias B.
Published: December 2020

Memo1deletion in mice causes premature aging and an unbalanced metabolism partially resemblingFgf23andKlotholoss-of-function animals. We report a role for Memo’s redox function in renal FGF23-Klotho signaling using mice with postnatally induced Memo deficiency in the whole body (cKO). Memo cKO mice showed impaired FGF23-driven renal ERK phosphorylation and transcriptional responses. FGF23 actions involved activation of oxidation-sensitive protein phosphotyrosyl phosphatases (PTP) in the kidney. Redox proteomics revealed excessive thiols of Rho-GDP dissociation inhibitor 1 (Rho-GDI1) in Memo cKO, and we detected a functional interaction between Memo’s redox function and oxidation at Rho-GDI1 Cys79. In isolated cellular systems, Rho-GDI1 did not directly affect FGF23-driven cell signaling, but we detected disturbed Rho-GDI1 dependent small Rho-GTPase protein abundance and activity in the kidney of Memo cKO mice. Collectively, this study reveals previously unknown layers in the regulation of renal FGF23 signaling and connects Memo with the network of small Rho-GTPases.
Comparative analysis of antigen-specific anti-SARS-CoV-2 antibody isotypes in COVID-19 patients
Authors: Fujigaki Hidetsugu , Inaba Masato , Osawa Michiko , Moriyama Saya , Takahashi Yoshimasa , Suzuki Tadaki , Yamase Kenya , Yoshida Yukihiro , Yagura Yo , Oyamada Takayoshi , Takemura Masao , Doi Yohei , Saito Kuniaki
Published: December 2020

Serological tests for detection of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in blood are expected to identify individuals who have acquired immunity against SARS-CoV-2 and indication of seroprevalence of SARS-CoV-2 infection. Many serological tests have been developed to detect antibodies against SARS-CoV-2. However, these tests have considerable variations in their specificity and sensitivity, and whether they can predict levels of neutralizing activity is yet to be determined. This study aimed to investigate the kinetics and neutralizing activity of various antigen-specific antibody isotypes against SARS-CoV-2 in serum of coronavirus disease 2019 (COVID-19) patients confirmed via polymerase chain reaction test. We developed IgG, IgM and IgA measurement assays for each antigen, including receptor-binding domain (RBD) of spike (S) protein, S1 domain, full length S protein, S trimer and nucleocapsid (N) domain, based on enzyme-linked immunosorbent assay. The assays of the S protein for all isotypes showed high specificity, while the assays for all isotypes against N protein showed lower specificity. The sensitivity of all antigen-specific antibody isotypes depended on the timing of the serum collection and all of them, except for IgM against N protein, reached more than 90% at 15-21 days post-symptom onset. The best correlation with virus neutralizing activity was found for IgG against RBD (RBD-IgG), and levels of RBD-IgG in sera from four severe COVID-19 patients increased concordantly with neutralizing activity. Our results provide valuable information regarding the selection of serological test for seroprevalence and vaccine evaluation studies.
A secreted endoribonuclease ENDU-2 from the soma protects germline immortality inC. elegans
Authors: Qi Wenjing , Gromoff Erika D v. , Xu Fan , Zhao Qian , Yang Wei , Pfeifer Dietmar , Maier Wolfgang , Long Lijiang , Baumeister Ralf
Published: December 2020

Multicellular organisms coordinate tissue specific response to environmental information via both cell-autonomous and non-autonomous mechanisms. In addition to secreted ligands, secreted small RNAs have recently been reported to regulate gene expression across tissue boundaries. Here we show that the conserved poly-U specific endoribonuclease ENDU-2 is secreted from the soma and taken-up by the germline to ensure germline immortality at elevated temperature inC. elegans. ENDU-2 binds to mature mRNAs and negatively regulates mRNA abundance both in the soma and the germline. While ENDU-2 promotes RNA decay in the soma directly via its endoribonuclease activity, ENDU-2 prevents misexpression of soma-specific genes in the germline and preserves germline immortality independent of its RNA-cleavage activity. In summary, our results suggest that the secreted RNase ENDU-2 transmits environmental information across tissue boundaries and contributes to maintenance of stem cell immortality probably via retaining a stem cell specific program of gene expression.
Tissue-specific safety mechanism results in opposite protein aggregation patterns during aging
Authors: Jung Raimund , Lechler Marie C. , Rödelsperger Christian , Röseler Waltraud , Sommer Ralf J. , David Della C.
Published: December 2020

During aging, proteostasis capacity declines and aggregation-prone proteins become instable, accumulating in protein aggregates both inside and outside cells. Both in disease and during aging, proteins selectively aggregate in certain tissues and not others. Yet, tissue-specific regulation of protein aggregation remains poorly understood. Surprisingly, we found that the inhibition of three core protein quality control systems, i.e. chaperones, proteasome and macroautophagy, leads to lower levels of age-dependent protein aggregation inC. eleganspharyngeal muscles, but higher levels in body-wall muscles. We describe a novel safety mechanism called SAPA that selectively targets newly synthesized aggregation-prone proteins to suppress aggregation and proteotoxicity.vha-12andscav-3mutants reveal that SAPA relies on macroautophagy-independent lysosomal degradation. Furthermore, SAPA involves several previously uncharacterized components of the intracellular pathogen response. We propose that SAPA represents an anti-aggregation machinery targeting aggregation-prone proteins for lysosomal degradation.
Precision Methylome andin vivoMethylation Kinetics Characterization ofKlebsiella Pneumoniae
Authors: Fu Jing , Zhang Ju , Yang Li , Ding Nan , Yue Liya , Zhang Xiangli , Lu Dandan , Jia Xinmiao , Li Cuidan , Guo Chongye , Yin Zhe , Jiang Xiaoyuan , Zhao Yongliang , Chen Fei , Zhou Dongsheng
Published: December 2020

Klebsiella pneumoniae(K. pneumonia) is an important pathogen that can cause severe hospital-/community-acquired infections. To panoramically analyzeK. pneumoniae’smethylation features, we completed the whole genome sequences of 14K. pneumoniaestrains covering various serotypes, multilocus-sequence typings (MLSTs), clonal groups (CG), viscosity/virulence and drug-resistances, and further characterized their methylomes using PacBio-SMRT and bisulfite technologies. We identified 15 methylation motifs (13 6mA and two 5mC motifs), among which eight were novel ones. Their corresponding MTases were further validated. Additionally, we analyzed the genomic distribution of GATC and CCWGG methylation motifs shared by all strains, and identified differential distributive patterns of some hemi/un-methylated GATC motifs tending to locate in the intergenic regions (IGRs). Specifically, we characterized thein vivomethylation kinetics at single-base resolution on a genome-wide scale by simulating the dynamic processes of replication-mediated passive demethylation and MTase-catalyzed re-methylation. The slower methylation-rates of the GATC motifs in the replication origins (oriC) and IGRs suggest an epigenetic mechanism implicated in the regulation of replication-initiation and transcription. Our findings illustrate the first comprehensive dynamic methylome map ofK. pneumoniaat single base resolution, and provide an efficient means and important reference for a better understanding of epigenetic regulation in bacteria.
Epigenetic alterations underlie airway macrophage differentiation and phenotype during lung fibrosis
Authors: McErlean Peter , Bell Christopher G. , Hewitt Richard J. , Busharat Zabreen , Ogger Patricia P. , Ghai Poonam , Albers Gesa , Kingston Shaun , Molyneaux Philip L. , Beck Stephan , Lloyd Clare M. , Maher Toby M. , Byrne Adam J
Published: December 2020

Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, the epigenetics of AMs development and function in IPF are limited. Here, we characterised the DNA-methylation (DNAm) profile of AMs from IPF (n=30) and healthy (n=14) donors. Our analysis revealed epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm ‘clock’ analysis indicated epigenetic alterations in IPF-AMs was not associated with accelerated ageing. In differential DNAm analysis, we identified numerous differentially methylated positions (DMPs, n=11) and regions (DMRs, n=49) between healthy and IPF AMs respectively. DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKB3) metabolism and importantly, DNAm status was associated with disease severity in IPF. Collectively, our data identify that profound changes in the epigenome underpin the development and function of AMs in the IPF lung.
Optogenetic activation of the serotonergic neural circuit between the dorsal raphe nucleus and pre-Bötzinger complex contributes to inhibition of seizure-induced respiratory arrest in the DBA/1 mouse SUDEP model
Authors: Ma HaiXiang , Yu Qian , Shen Yue , Lian XiTing , Gu LeYuan , lu Han , Zhao HaiTing , Zeng Chang , Nagayasu Kazuki , Zhang HongHai
Published: December 2020

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death among epilepsy patients, occurring even more frequently in cases with anti-epileptic drug resistance. However, the underlying mechanism of SUDEP remains elusive. Our previous study demonstrated that enhancement of serotonin (5-HT) synthesis by intraperitoneal (IP) injection of 5-hydroxytryptophan (5-HTP) significantly reduced the incidence of seizure-induced respiratory arrest (S-IRA) in a DBA/1 mouse SUDEP model. Given that the 5-HT2A receptor (5-HT2AR) plays an important role in mediating the respiration system in the brain, we hypothesized that 5-HT2AR plays a key role in S-IRA and SUDEP. To test this hypothesis, we examined whether the decreased incidence of S-IRA evoked by either acoustic stimulation or pentylenetetrazole (PTZ) injection following 5-HTP administration will be blocked by treatment with ketanserin (KET), a selective antagonist of 5HT2AR, in the DBA/1 mouse SUDEP model. We observed that the reduction in S-IRA by 5-HTP was significantly reversed by IP or intracerebroventricular injection of KET. Considering the localization of 5-HT2AR in the pre-Bötzinger complex (PBC), which plays a key role in regulating respiratory rhythm, we next examined whether KET acts on 5-HT2AR in the PBC. To test this hypothesis, we activated the neural circuit between the dorsal raphe nucleus (DR) and PBC using optogenetics technology. We observed that stimulation of TPH2-ChETA-expressing neurons in the DR reduced the incidence of S-IRA evoked by PTZ, and this suppressant effect was significantly reversed by administration of KET in the bilateral PBC with no changes in electroencephalogram activity. The neural circuit between the DR and PBC was confirmed by injection of cholera toxin subunit B555 (CTB-555), a nerve tracer, in the DR or PBC separately. Calcium signaling evoked by PTZ within neurons of the PBC during seizures was significantly reduced by photostimulation of the DR. Taken together, our findings suggest that 5-HT2AR plays a critical role in regulating S-IRA and targeting the serotonergic neural circuit between the DR and PBC is a promising approach to preventing SUDEP.
The Role of Aquaporin-4 in Optic Nerve Head Astrocytes in Experimental Glaucoma
Authors: Kimball Elizabeth , Schaub Julie , Quillen Sarah , Keuthan Casey , Pease Mary Ellen , Korneva Arina , Quigley Harry
Published: December 2020

Purpose

To study aquaporin channel expression in astrocytes of the mouse optic nerve (ON) and the response to IOP elevation in mice lacking aquaporin 4 (AQP4 null).

Methods

C57BL/6 (B6) and AQP4 null mice were exposed to bead-induced IOP elevation for 3 days (3D-IOP), 1 and 6 weeks. Mouse ocular tissue sections were immunolabeled against aquaporins 1(AQP1), 4(AQP4), and 9(AQP9). Ocular tissue was imaged to identify normal AQP distribution, ON changes, and axon loss after IOP elevation. Ultrastructure examination, cell proliferation, gene expression & transport block was also analyzed.

Results

B6 mice presented abundant AQP4 in Müller cells, astrocytes of retina and myelinated ON (MON), but minimal expression in prelaminar and unmyelinated ON (UON). MON of AQP4 nulls had smaller ON area, smaller axon diameter, higher axon density, and larger proportionate axon area than B6 (all p≤0.05). Bead-injection led to comparable 3D-IOP elevation (p=0.42) and axonal transport blockade in both strains. In B6, AQP4 distribution was unchanged after 3D-IOP. At baseline, AQP1 and AQP9 were present in retina, but not in UON and this was unaffected after IOP elevation in both strains. In 3D-IOP mice, ON astrocytes and microglia proliferated, more in B6 than AQP4 null. After 6 week IOP elevation, axon loss occurred equally in the two mouse types (24.6%, AQP4 null vs. 23.3%, B6).

Conclusion

Lack of AQP4 was neither protective nor detrimental to the effects of IOP elevation. The minimal presence of AQP4 in UON may be a vital aspect of the regionally specific phenotype of astrocytes in the mouse optic nerve head.
Ubiquitin-protein ligaseUbr5cooperates with Hedgehog signalling to promote skeletal tissue homeostasis
Authors: Mellis David , Staines Katherine A , Peluso Silvia , Georgiou Ioanna Ch. , Dora Natalie , Kubiak Malgorzata , Grillo Michela , Farquharson Colin , Kinsella Elaine , Thornburn Anna , Ralston Stuart H , Salter Donald M , Riobo-Del Galdo Natalia A , Hill Robert E , Ditzel Mark
Published: December 2020

Mammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway inDrosophila.To investigate a possible role of UBR5 in regulation of the musculoskeletal system through modulation of mammalian HH signaling, we created a mouse model for specific loss ofUbr5function in limb bud mesenchyme. Our findings revealed a role for UBR5 in maintaining cartilage homeostasis and suppressing metaplasia.Ubr5loss of function resulted in progressive and dramatic articular cartilage degradation, enlarged, abnormally shaped sesamoid bones and extensive heterotopic tissue metaplasia linked to calcification of tendons and ossification of synovium. Genetic suppression of smoothened(Smo), a key mediator of HH signalling, dramatically enhanced theUbr5mutant phenotype. Analysis of HH signalling in both mouse and cell model systems revealed that loss ofUbr5stimulated canonical HH-signalling while also increasing PKA activity. In addition, human osteoarthritic samples revealed similar correlations betweenUBR5expression, canonical HH signalling and PKA activity markers. Our studies identified a crucial function for theUbr5gene in the maintenance of skeletal tissue homeostasis and an unexpected mode of regulation of the HH signalling pathway.

Author Summary

Ubiquitin ligases modify proteins post-translationally which is essential for a variety of cellular processes. UBR5 is an E3 ubiquitin ligase and inDrosophilais a regulator of Hedgehog signaling. In mammals, the Hedgehog (HH) signalling pathway, among many other roles, plays an essential role in tissue maintenance, a process called homeostasis. A murine genetic system was developed to specifically eliminate UBR5 function from embryonic limb tissue that subsequently forms bone and connective tissue (ligaments and tendons). This approach revealed that UBR5 operates as a potent suppressor of excessive growth of normal cartilage and bone and prevents formation of bone in ectopic sites in connective tissue near the knees and ankle joints. In contrast to abnormal growth, UBR5 inhibits degradation of the articular cartilage that cushions the knee joint leading to extensive exposure of underlying bone. Furthermore, Ubr5 interacts with smoothened, a component of the HH pathway, identifying UBR5 as a regulator of mammalian HH signaling in the postnatal musculoskeletal system. In summary, this work shows that UBR5 interacts with the HH pathway to regulate skeletal homeostasis in and around joints of the legs and identifies targets that may be harnessed for biomedical engineering and clinical applications.
BBLN-1 is essential for intermediate filament organization and apical membrane morphology
Authors: Remmelzwaal Sanne , Geisler Florian , Stucchi Riccardo , van der Horst Suzanne , Pasolli Milena , Kroll Jason R. , Jarosinska Olga D. , Akhmanova Anna , Richardson Christine A. , Altelaar Maarten , Leube Rudolf E. , Ramalho João J. , Boxem Mike
Published: December 2020

Epithelial tubes are essential components of metazoan organ systems that control the flow of fluids and the exchange of materials between body compartments and the outside environment. The size and shape of the central lumen confer important characteristics to tubular organs and need to be carefully controlled. Here, we identify the small coiled-coil protein BBLN-1 as a regulator of lumen morphology in theC. elegansintestine. Loss of BBLN-1 causes the formation of bubble-shaped invaginations of the apical membrane into the cytoplasm of intestinal cells, and abnormal aggregation of the subapical intermediate filament (IF) network. BBLN-1 interacts with IF proteins and localizes to the IF network in an IF-dependent manner. The appearance of invaginations is a result of the abnormal IF aggregation, indicating a direct role for the IF network in maintaining lumen homeostasis. Finally, we identify bublin (BBLN) as the mammalian ortholog of BBLN-1. When expressed in theC. elegansintestine, bublin recapitulates the localization pattern of BBLN-1 and can compensate for the loss of BBLN-1. In mouse intestinal organoids, bublin localizes subapically, together with the IF protein keratin 8. Our results therefore may have implications for understanding the role of IFs in regulating epithelial tube morphology in mammals.

We identify BBLN-1 as an evolutionary conserved regulator of lumen morphology in theC. elegansintestine. Loss ofbbln-1causes intermediate filament network reorganization that induces severe apical morphology defects. We also identify bublin (BBLN) as the mammalian ortholog, which can compensate for the loss of BBLN-1 inC. elegans.
The role of sigma-1 receptor in organization of endoplasmic reticulum signaling microdomains
Authors: Zhemkov Vladimir , Ditlev Jonathon A. , Lee Wan-Ru , Liou Jen , Rosen Michael K. , Bezprozvanny Ilya
Published: December 2020

Sigma 1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. S1R modulates activity of multiple effector proteins but its signaling functions are poorly understood. We here test the hypothesis that biological activity of S1R in cells can be explained by its ability to interact with cholesterol and to form cholesterol-enriched microdomains in the ER. Using reduced reconstitution systems, we demonstrate direct effects of cholesterol on S1R clustering. We identify a novel cholesterol-binding motif in the transmembrane region of S1R and demonstrate its importance for S1R clustering. We demonstrate that S1R-induced membrane microdomains have increased local membrane thickness. Increased local cholesterol concentration and membrane thickness in these domains can modulate signaling of inositol-requiring enzyme 1α (IRE1α) in the ER. Further, S1R agonists cause reduction in S1R clusters, suggesting that biological activity of S1R agonists is linked to remodeling of ER membrane microdomains.
Structural Spine Plasticity in Olfaction: Memory and Forgetting, Enhanced vs. Reduced Discriminability after Learning
Authors: Meng John Hongyu , Riecke Hermann
Published: December 2020

How animals learn to discriminate between different sensory stimuli is an intriguing question. An important, common step towards discrimination is the enhancement of differences between the representations of relevant stimuli. This can be part of the learning process. In rodents, the olfac-tory bulb, which is known to contribute to this pattern separation, exhibits extensive structural synaptic plasticity even in adult animals: reciprocal connections between excitatory mitral cells and inhibitory granule cells are persistently formed and eliminated, correlated with mitral cell and granule cell activity. Here we present a Hebbian-type model for this plasticity. It captures the experimental observation that the same learning protocol that enhanced the discriminability of similar stimuli actually reduced that of dissimilar stimuli. The model predicts that the learned bulbar network structure is remembered across training with additional stimuli, unless the new stimuli interfere with the representations of previously learned ones.
Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency inC. elegans
Authors: Zeng Lidan , Li Xuesong , Preusch Christopher B. , He Gary J. , Xu Ningyi , Cheung Tom H. , Qu Jianan , Mak Ho Yi
Published: December 2020

The intracellular level of fatty aldehydes is tightly regulated to minimize the formation of toxic aldehyde adducts of cellular components. Accordingly, deficiency of a fatty aldehyde dehydrogenase FALDH causes the neurologic disorder Sjögren-Larsson syndrome (SLS) in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Based on lipidomic and imaging analysis, we report that the loss of endoplasmic reticulum-, mitochondria- and peroxisomes-associated ALH-4, theC. elegansFALDH ortholog, increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency sincealh-4; nhr-49double mutant animals are not viable. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels, and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy for SLS.
Leveraging auxiliary data from arbitrary distributions to boost GWAS discovery with Flexible cFDR
Authors: Hutchinson Anna , Reales Guillermo , Willis Thomas , Wallace Chris
Published: December 2020

Genome-wide association studies (GWAS) have identified thousands of genetic variants that are associated with complex traits. However, a stringent significance threshold is required to identify robust genetic associations. Leveraging relevant auxiliary covariates has the potential to boost statistical power to exceed the significance threshold. Particularly, abundant pleiotropy and the non-random distribution of SNPs across various functional categories suggests that leveraging GWAS test statistics from related traits and/or functional genomic data may boost GWAS discovery. While type 1 error rate control has become standard in GWAS, control of the false discovery rate can be a more powerful approach. The conditional false discovery rate (cFDR) extends the standard FDR framework by conditioning on auxiliary data to call significant associations, but current implementations are restricted to auxiliary data satisfying specific parametric distributions, typically GWASp-values for related traits. We relax these distributional assumptions, enabling an extension of the cFDR framework that supports auxiliary covariates from arbitrary continuous distributions (“Flexible cFDR”). Our method can be applied iteratively, thereby supporting multi-dimensional covariate data. Through simulations we show that Flexible cFDR increases sensitivity whilst controlling FDR after one or several iterations. We further demonstrate its practical potential through application to an asthma GWAS, leveraging various functional genomic data to find additional genetic associations for asthma, which we validate in the larger, independent, UK Biobank data resource.

Author summary

Genome-wide association studies (GWAS) detect regions of the human genome that are associated with various traits, including complex diseases, but the power to detect these genomic regions is currently limited by sample size. The conditional false discovery rate (cFDR) provides a tool to leverage one GWAS study to improve power in another. The motivation is that if two traits have some genetic correlation, then our interpretation of a low but not significantp-value for the trait of interest will differ depending on whether that SNP shows strong or absent evidence of association with the related trait. Here, we describe an extension to the cFDR framework, called “Flexible cFDR”, that controls the FDR and supports auxiliary data from arbitrary distributions, surpassing current implementations of cFDR which are restricted to leveraging GWASp-values from related traits. In practice, our method can be used to iteratively leverage various types of functional genomic data with GWAS data to increase power for GWAS discovery. We describe the use of Flexible cFDR to supplement data from a GWAS of asthma with auxiliary data from functional genomic experiments. We identify associations novel to the original GWAS and validate these discoveries with reference to a larger, more highly-powered GWAS of asthma.
Exploring Binary Relations for Ontology Extension and Improved Adaptation to Clinical Text
Authors: Slater Luke T , Hoehndorf Robert , Karwath Andreas , Gkoutos Georgios V
Published: December 2020

Background

The controlled domain vocabularies provided by ontologies make them an indispensable tool for text mining. Ontologies also include semantic features in the form of taxonomy and axioms, which make annotated entities in text corpora useful for semantic analysis. Extending those semantic features may improve performance for characterisation and analytic tasks. Ontology learning techniques have previously been explored for novel ontology construction from text, though most recent approaches have focused on literature, with applications in information retrieval or human interaction tasks. We hypothesise that extension of existing ontologies using information mined from clinical narrative text may help to adapt those ontologies such that they better characterise those texts, and lead to improved classification performance.

Results

We develop and present a framework for identifying new classes in text corpora, which can be integrated into existing ontology hierarchies. To do this, we employ the Stanford Open Information Extraction algorithm and integrate its implementation into the Komenti semantic text mining framework. To identify whether our approach leads to better characterisation of text, we present a case study, using the method to learn an adaptation to the Disease Ontology using text associated with a sample of 1,000 patient visits from the MIMIC-III critical care database. We use the adapted ontology to annotate and classify shared first diagnosis on patient visits with semantic similarity, revealing an improved performance over use of the base Disease Ontology on the set of visits the ontology was constructed from. Moreover, we show that the adapted ontology also improved performance for the same task over two additional unseen samples of 1,000 and 2,500 patient visits.

Conclusions

We report a promising new method for ontology learning and extension from text. We demonstrate that we can successfully use the method to adapt an existing ontology to a textual dataset, improving its ability to characterise the dataset, and leading to improved analytic performance, even on unseen portions of the dataset.
Activity of epigenetic inhibitors againstBabesia divergens
Authors: Vanheer Leen N. , Kafsack Björn F.C.
Published: December 2020

Babesiosis in a tick-borne parasitic disease of humans and livestock, that has dramatically increased in frequency and geographical range over the past few decades. Infection of cattle often causes large economic losses, and human infection can be fatal in immunocompromised patients. Unlike for malaria, another disease caused by hemoprotozoan parasites, limited treatment options exist for Babesia infections. As epigenetic regulation is a promising target for new anti-parasitic drugs, we screened 324 epigenetic inhibitors againstBabesia divergensblood stages and identified 75 (23%) and 17 (5%) compounds that displayed ≥90% inhibition at 10 µM and 1 µM, respectively, including over a dozen compounds with activity in the low nanomolar range. We observed differential activity of some inhibitor classes againstBabesia divergensandPlasmodium falciparumparasites and identified pairs of compounds with a high difference in activity, despite a high similarity in chemical structure, highlighting new insights into the development of epigenetic inhibitors as anti-parasitic drugs.
Mechanism for differential recruitment of orbitostriatal transmission during outcomes and actions in alcohol dependence
Authors: Renteria Rafael , Cazares Christian , Baltz Emily T. , Schreiner Drew C. , Yalcinbas Ege A. , Steinkellner Thomas , Hnasko Thomas S. , Gremel Christina M.
Published: December 2020

Psychiatric disease often produces symptoms that have divergent effects on neural activity. For example, in drug dependence, dysfunctional value-based decision-making and compulsive-like actions have been linked to hypo- and hyper-activity of orbital frontal cortex (OFC)-basal ganglia circuits, respectively, however, the underlying mechanisms are unknown. Here we show that alcohol dependence enhanced activity in OFC terminals in dorsal striatum (OFC-DS) associated with actions, but reduced activity of the same terminals during periods of outcome retrieval, corresponding with a loss of outcome control over decision-making. Disrupted OFC-DS terminal activity was due to a dysfunction of dopamine-type 1 receptors on spiny projection neurons (D1R SPNs) that resulted in increased retrograde endocannabinoid (eCB) signaling at OFC-D1R SPN synapses reducing OFC-DS transmission. Blocking CB1 receptors restored OFC-DS activityin vivoand rescued outcome-based control over decision-making. These findings demonstrate a circuit-, synapse-, and computation specific mechanism gating OFC activity following the induction of alcohol dependence.
Fine-tuning of the Smc flux facilitates chromosome organization inB. subtilis
Authors: Anchimiuk Anna , Lioy Virginia S. , Minnen Anita , Boccard Frédéric , Gruber Stephan
Published: December 2020

SMC complexes are widely conserved ATP-powered loop extrusion motors indispensable for the faithful segregation of chromosomes during cell division. How SMC complexes translocate along DNA for loop extrusion and what happens when two complexes meet on the same DNA molecule is largely unknown. Revealing the origins and the consequences of SMC encounters is crucial for understanding the folding process not only of bacterial, but also of eukaryotic chromosomes. Here, we uncover several factors that influence bacterial chromosome organization by modulating the probability of such clashes. These factors include the number, the strength and the distribution of Smc loading sites, the residence time on the chromosome, the translocation rate, and the cellular abundance of Smc complexes. By studying various mutants, we show that these parameters are fine-tuned to reduce the frequency of encounters between Smc complexes, presumably as a risk mitigation strategy. Mild perturbations hamper chromosome organization by causing Smc collisions, implying that the cellular capacity to resolve them is rather limited. Altogether, we identify mechanisms that help to avoid Smc collisions and their resolution by Smc traversal or other potentially risky molecular transactions.
Combined effect of crop rotation and carabid beetles on weed dynamics in arable fields
Authors: Schmucki Reto , Bohan David A. , Pocock Michael J.O.
Published: December 2020

Weed management is a resource-intensive practice in arable agriculture, with direct and long-term impacts on both productivity and biodiversity (e.g. plant, pollinators and farmland wildlife). In conventional systems, weed control relies on crop management and herbicide inputs, but for more sustainable production systems, use of herbicides needs to be reduced. This requires a good understanding of the processes that regulate arable weed dynamics in arable fields.

We adopted a systems framework to understand and model interacting components that drive the weed dynamics in 168 arable fields. Within this framework, we built a structural equation model (SEM) to quantify the direct and indirect effects of crop rotation (i.e. crops in the previous three years and the current year) and carabid beetles (Coleoptera: Carabidae) on weed density, seed abundance and accumulation in the seedbank. We included results from a mechanistic approach to infer interactions between seed-feeding carabid beetles and seeds to estimate predation pressure in each field.

Our results show that weeds in arable fields are regulated by crop type, sowing season, and activity density of carabid beetles. We found a direct effect of crop rotation, including both past and current field management practice, on weed abundance in the field and its seedbank. There was also an indirect effect of crops on weed seed accumulation in the seedbank via the effect of seed-eating carabid beetles. The efficiency of weed control by carabid beetles depended on the cumulative predation pressure, which indicates the importance of functional diversity as well as abundance.

Farmers and agronomists can capitalise on the ecosystem services provided by carabid beetles by adapting agronomic practices and crop rotation to maintain a rich fauna of seed-eating carabids in fields and potentially across the agricultural landscapes. When integrated with rotational management practices, this ecosystem services can improve the efficiency of weed management and contribute to the sustainability of cropping systems.
Social network architecture and the tempo of cumulative cultural evolution
Authors: Cantor Mauricio , Chimento Michael , Smeele Simeon Q. , He Peng , Papageorgiou Danai , Aplin Lucy M. , Farine Damien R.
Published: December 2020

The ability to build upon previous knowledge—cumulative cultural evolution—is a hallmark of human societies. While cumulative cultural evolution depends on the interaction between social systems, cognition and the environment, there is increasing evidence that cumulative cultural evolution is facilitated by larger and more structured societies. However, such effects may be interlinked with patterns of social wiring, thus the relative importance of social network architecture as an additional factor shaping cumulative cultural evolution remains unclear. By simulating innovation and diffusion of cultural traits in populations with stereotyped social structures, we disentangle the relative contributions of network architecture from those of population size and connectivity. We demonstrate that while more structured networks, such as those found in multilevel societies, can promote the recombination of cultural traits into high-value products, they also hinder spread and make products more likely to go extinct. We find that transmission mechanisms are therefore critical in determining the outcomes of cumulative cultural evolution. Our results highlight the complex interaction between population size, structure and transmission mechanisms, with important implications for future research.
Drosophilaneural stem cells show a unique dynamic pattern of gene expression that is influenced by environmental factors
Authors: Goupil Alix , Pennetier Carole , Simon Anthony , Skorski Patricia , Bardin Allison , Basto Renata
Published: December 2020

With the aim of developing a sensor for chromosome lossin vivo, we used the well-established GAL4/GAL80 system combined with a visual GFP marker inDrosophila. We show a low frequency of green cells in mostDrosophilatissues, suggesting low aneuploidy levels. Unexpectedly, in the brain, GFP positive cells are more frequent, but in this case, they do not represent chromosome loss. Using genetic manipulations, RNA FISH and time-lapse microscopy, we uncovered a dynamic and reversible silencing ofGAL80that occurs inDrosophilaneural stem cells. Further, we showed that this novel gene expression regulation is influenced by environmental changes such as temperature variations or food composition. These results have important implications for theDrosophilacommunity, namely the possible interpretation of false positive cells in clonal experiments. Additionally, they also highlight a level of mosaicism and plasticity in the brain, consistent with possible epigenetic regulation of fly chromosomes, which is different from other organs and tissues.
GluA4 enables associative memory formation by facilitating cerebellar expansion coding
Authors: Kita Katarzyna , Albergaria Catarina , Machado Ana S. , Carey Megan R. , Müller Martin , Delvendahl Igor
Published: December 2020

AMPA receptors (AMPARs) mediate excitatory neurotransmission in the CNS and their subunit composition determines synaptic efficacy. Whereas AMPAR subunits GluA1–GluA3 have been linked to particular forms of synaptic plasticity and learning, the functional role of GluA4 remains elusive. Here we used electrophysiological, computational and behavioral approaches to demonstrate a crucial function of GluA4 for synaptic excitation and associative memory formation in the cerebellum. Notably, GluA4-knockout mice had ∼80% reduced mossy fiber to granule cell synaptic transmission. The fidelity of granule cell spike output was markedly decreased despite attenuated tonic inhibition and increased NMDA receptor-mediated transmission. Computational modeling revealed that GluA4 facilitates pattern separation that is important for associative learning. On a behavioral level, while locomotor coordination was generally spared, GluA4-knockout mice failed to form associative memories during delay eyeblink conditioning. These results demonstrate an essential role for GluA4-containing AMPARs in cerebellar information processing and associative learning.
Biogenesis of RNA-containing extracellular vesicles at endoplasmic reticulum membrane contact sites
Authors: Barman Bahnisikha , Ping Jie , Krystofiak Evan , Allen Ryan , Prasad Nripesh , Vickers Kasey , Patton James G. , Liu Qi , Weaver Alissa M.
Published: December 2020

RNA transferred via extracellular vesicles (EVs) can influence cell and tissue phenotypes; however, the biogenesis of RNA-containing EVs is poorly understood and even controversial. Here, we identify the conserved endoplasmic reticulum membrane contact site (MCS) linker protein VAP-A as a major regulator of the RNA and RNA-binding protein content of small and large EVs. We also identify a unique subpopulation of secreted small EVs that is highly enriched in RNA and regulated by VAP-A. Functional experiments revealed that VAP-A-regulated EVs are critical for the transfer of miR-100 between cells and forin vivotumor formation. Lipid analysis of VAP-A-knockdown EVs revealed large alterations in lipids known to regulate EV biogenesis, including ceramides and cholesterol. Knockdown of VAP-A-binding ceramide and cholesterol transfer proteins CERT and ORP1L led to similar defects in biogenesis of RNA-containing EVs. We propose that lipid transfer at VAP-A-positive MCS drives biogenesis of a select RNA-containing EV population.
Highly Multiplexed Immunofluorescence of the Human Kidney using Co-Detection by Indexing (CODEX)
Authors: Neumann Elizabeth K. , Rivera Emilio S. , Patterson Nathan Heath , Allen Jamie L. , Brewer Maya , deCaestecker Mark P. , Fogo Agnes B. , Caprioli Richard M. , Spraggins Jeffrey M.
Published: December 2020

The human kidney is composed of many cell types that vary in their abundance and distribution from organ to organ. As these cell types perform unique and essential functions, it is important to confidently label each within a single tissue to more accurately assess tissue architecture. Towards this goal, we demonstrate the use of co-detection by indexing (CODEX) multiplexed immunofluorescence for visualizing 23 antigens within the human kidney. Using CODEX, many of the major cell types and substructures, such as collecting ducts, glomeruli, and thick ascending limb, were visualized within a single tissue section. Of these antibodies, 19 were conjugated in-house, demonstrating the flexibility and utility of this approach for studying the human kidney using traditional antibody markers. We performed a pilot study showing that the studied tissues had on average 84 ± 11 cells per mm2with the most variance seen within the cells containing vimentin and aquaporin 1, while cells containing α-smooth muscle actin and CD31 possessed a high degree of uniformity between the samples. These precursory data show the power of CODEX multiplexed IF for surveying the cellular diversity of the human kidney and have potential applications within pathology, histology, and building anatomical atlases.
Profiling susceptibility of NIAID Category A and B priority and emerging pathogens to define strain panels for drug discovery and active drug classes
Authors: Cummings Jason E. , Abdo Zaid , Slayden Richard A.
Published: December 2020

Drug susceptibility profiles of NIAID Category A and B priority and emerging pathogens to standard of care drugs were assessed to determine susceptibility against clinical strains in addition to reference laboratory strains to establish a comparison resource for the performance of drug candidates, to define non-redundant minimal strain panels for individual species and the group of species for use in drug screening programs, and provide pharmacophore classification. Profiling of standard of care drugs against strains of each species revealed a broad spectrum of susceptibility among strains in each species with important differences between standard laboratory reference strains and strains sof clinical origin. Unbiased hierarchical clustering analyses of strain susceptibilities within each species group and strains from all the species identified subsets of non-redundant strains that are able to classify the susceptibility range for each species and able to classify all the species. This analysis established a reduced targeted set of Category A and B priority pathogen strains for testing the potency of drug candidates against each species and pan-species. This approach also discriminated pharmacophore classification for each species. This information can be applied to directed screening efforts to guide the selection of drug classes for derivatization and repurposing, and advance drug candidates with the greatest potential for efficacy against NIAID Category A and B priority and emerging pathogens.
Analysis of selection signatures reveals important insights into the adaptability of high-altitude Indian sheep breedChangthangi
Authors: Ahmad Sheikh Firdous , Mehrotra Arnav , Charles Sona , Ganai Nazir Ahmad
Published: December 2020

Changthangiis a high-altitude sheep breed of India that is adapted to cold and hypoxic climate of Himalayas. In the present study, we analysed population structure ofChangthangiand contrasted it with selected Indian and European commercial sheep breeds to detect genomic regions under positive selection. The studied domesticated sheep breeds includedChangthangi, Indian Garole, Deccani, Tibetan, RambouilletandAustralian Merino. While the PCA results revealedChangthangiclustered withTibetansheep; TREEMIX and ADMIXTURE results also detected the introgression of lowland Indian sheep inheritance inChangthangi. Cross-population comparisons ofChangthangiusing XP-EHH showed multiple functional regions present on OAR 7, 15 and 16, to be under selection inChangthangisheep. These regions are related to adaptation to climatic and hypoxic stressors, nervous system and mitochondrial functioning. The genes present in these regions are suitable candidates for future studies on the genetic mechanisms underlying high-altitude adaptation.
Understanding near-surface polymer dynamics by a combination of grazing-incidence neutron scattering and virtual experiments
Authors: Kyrey Tetyana , Ganeva Marina , Witte Judith , von Klitzing Regine , Wellert Stefan , Holderer Olaf
Published: December 2020

Neutron spin-echo spectroscopy is a unique experimental method for the investigation of polymer dynamics. The combination of neutron spin-echo spectroscopy with grazing-incidence geometry (GINSES) opens the possibility to probe the dynamics of soft-matter materials in the vicinity of the solid substrate in the time range up to 100 ns. However, the usage of the GINSES technique has some peculiarities and, due to the novelty of the method and complexity of the scattering geometry, difficulties in further data analysis occur. The current work discusses how virtual experiments within the distorted-wave Born approximation using the BornAgain software can improve GINSES data treatment and aid the understanding of polymer dynamics in the vicinity of the solid surface. With two examples, poly(N-isopropyl acrylamide) brushes and poly(ethylene glycol) microgels on Si surfaces, the simulation as well as the application of the simulation to the GINSES data analysis are presented. The approach allowed a deeper insight to be gained of the background effect and scattering contribution of different layers.