bluuebunny/crossref_metadata_2025_split huggingface dataset:
A computational solution for bolstering reliability of epigenetic clocks: Implications for clinical trials and longitudinal tracking
Authors: Higgins-Chen Albert T. , Thrush Kyra L. , Wang Yunzhang , Kuo Pei-Lun , Wang Meng , Minteer Christopher J. , Moore Ann Zenobia , Bandinelli Stefania , Vinkers Christiaan H. , Vermetten Eric , Rutten Bart P.F. , Geuze Elbert , Okhuijsen-Pfeifer Cynthia , van der Horst Marte Z. , Schreiter Stefanie , Gutwinski Stefan , Luykx Jurjen J. , Ferrucci Luigi , Crimmins Eileen M. , Boks Marco P. , Hägg Sara , Hu-Seliger Tina T. , Levine Morgan E. 
Published: April 2021

AbstractEpigenetic clocks are widely used aging biomarkers calculated from DNA methylation data. Unfortunately, measurements for individual CpGs can be surprisingly unreliable due to technical noise, and this may limit the utility of epigenetic clocks. We report that noise produces deviations up to 3 to 9 years between technical replicates for six major epigenetic clocks. The elimination of low-reliability CpGs does not ameliorate this issue. Here, we present a novel computational multi-step solution to address this noise, involving performing principal component analysis on the CpG-level data followed by biological age prediction using principal components as input. This method extracts shared systematic variation in DNAm while minimizing random noise from individual CpGs. Our novel principal-component versions of six clocks show agreement between most technical replicates within 0 to 1.5 years, equivalent or improved prediction of outcomes, and more stable trajectories in longitudinal studies and cell culture. This method entails only one additional step compared to traditional clocks, does not require prior knowledge of CpG reliabilities, and can improve the reliability of any existing or future epigenetic biomarker. The high reliability of principal component-based epigenetic clocks will make them particularly useful for applications in personalized medicine and clinical trials evaluating novel aging interventions.
Megapixel camera arrays for high-resolution animal tracking in multiwell plates
Authors: Barlow Ida , Feriani Luigi , Minga Eleni , McDermott-Rouse Adam , O’Brien Thomas , Liu Ziwei , Hofbauer Maximilian , Stowers John R. , Andersen Erik C. , Ding Siyu Serena , Brown André E.X. 
Published: April 2021

AbstractTracking small laboratory animals such as flies, fish, and worms is used for phenotyping in neuroscience, genetics, disease modelling, and drug discovery. Current imaging systems are limited either in spatial resolution or throughput. A system capable of imaging a large number of animals with sufficient resolution to estimate their pose would enable a new class of experiments where detailed behavioural differences are quantified but at a scale where hundreds of treatments can be tested simultaneously. Here we report a new imaging system consisting of an array of six 12-megapixel cameras that can simultaneously record from all the wells of a 96-well plate with a resolution of 80 pixels/mm at 25 frames per second. We show that this resolution is sufficient to estimate the pose of nematode worms including head identification and to extract high-dimensional phenotypic fingerprints. We use the system to study behavioural variability across wild isolates, the sensitisation of worms to repeated blue light stimulation, the phenotypes of worm disease models, and worms’ behavioural responses to drug treatment. Because the system is compatible with standard multiwell plates, it makes computational ethological approaches accessible in existing high-throughput pipelines and greatly increases the scale of possible phenotypic screening experiments inC. elegans.
Speed tuning in head coordinates as an alternative explanation of depth selectivity from motion parallax in area MT
Authors: Xu Zhe-Xin , DeAngelis Gregory C. 
Published: April 2021

AbstractThere are two distinct sources of retinal image motion: motion of objects in the world and movement of the observer. In cases where an object moves in a scene and the eyes also move, a coordinate transformation that involves smooth eye movements and retinal motion will be needed in order to estimate object motion in world coordinates. More recently, interactions between retinal and eye velocity signals have also been suggested to generate depth selectivity from motion parallax (MP) in the macaque middle temporal (MT) area. We explored whether the nature of the interaction between eye and retinal velocities in MT neurons favors one of these two possibilities or a mixture of both. We analyzed responses of MT neurons to retinal and eye velocities in a viewing context in which the observer translates laterally while maintaining visual fixation on a world-fixed target. In this scenario, the depth of an object can be inferred from the ratio between retinal velocity and eye velocity, according to the motion-pursuit law. Previous studies have shown that MT responses to retinal motion are gain-modulated by the direction of eye movement, suggesting a potential mechanism for depth tuning from MP. However, our analysis of the joint tuning profile for retinal and eye velocities reveals that some MT neurons show a partial coordinate transformation toward head coordinates. We formalized a series of computational models to predict neural spike trains as well as selectivity for depth, and we used factorial model comparisons to quantify the relative importance of each model component. Our findings for many MT neurons reveal that the data are equally well explained by gain modulation or a partial coordinate transformation toward head coordinates, although some responses can only be well fit by the coordinate transform model. Our results highlight the potential role of MT neurons in representing multiple higher-level sensory variables, including depth from MP and object motion in the world.
Evidence that faecal carriage of resistantEscherichia coliby 16-week-old dogs in the United Kingdom is associated with raw feeding
Authors: Mounsey Oliver , Wareham Kezia , Hammond Ashley , Findlay Jacqueline , Gould Virginia C. , Morley Katy , Cogan Tristan A. , Turner Katy M.E. , Avison Matthew B. , Reyher Kristen K. 
Published: April 2021

AbstractWe report a survey (August 2017 to March 2018) and risk factor analysis of faecal carriage of antibacterial-resistant (ABR)Escherichia coliin 223 sixteen-week-old dogs in the United Kingdom. Raw feeding was associated with the presence ofE. coliresistant to fluoroquinolones, tetracycline, amoxicillin, and streptomycin, but not to cefalexin or cefotaxime. Whole genome sequencing of 30 fluoroquinolone-resistant (FQ-R), 22 cefotaxime-resistant (CTX-R) and seven dual FQ-R/CTX-RE. coliisolates showed a wide range of sequence types (STs), an approximately 50:50 split of CTX-M:AmpC-mediated CTX-R, and almost exclusively mutational FQ-R dominated by ST744 and ST162. Comparisons betweenE. coliisolates from puppies known to be located within a 50 x 50 km region with those isolated from human urinary tract and bloodstream infections (isolated in parallel in the same region) identified a clone of ST963E. colicarrying chromosomalblaCMY.2in two puppies and causing two urinary tract infections and one bloodstream infection. Furthermore, an ST744 FQ-R clone was carried by one puppy and caused one urinary tract infection. Accordingly, we conclude that raw feeding is associated with carriage of ABRE. coliin dogs even at sixteen weeks of age and that bacteria carried by dogs are shared with humans.
Gene clustering drives the transcriptional coherence of disparate biological processes in eukaryotes
Authors: Joh Richard I. , Lawrence Michael S. , Aryee Martin J. , Motamedi Mo 
Published: April 2021

AbstractThe establishment of distinct transcriptional states entails coordinated transcriptional coregulation of several disparate biological processes (BP), involving thousands of genes scattered throughout the genome. Linear clustering of genes in a single BP is one strategy for their transcriptional coregulation. However, whether such gene clustering also plays a role in transcriptional coherence of several disparate BPs remains unexplored. Here, by analyzing the genomes of eukaryotes ranging from yeast to human, we report the identification of thousands of conserved and species-specific disparate clustered BP pairs, many of which in normal human tissues are transcriptionally correlated. Strikingly, our results reveal that often this system-level transcriptional coordination is achieved in part by the genic proximity of regulatory nodes of disparate BPs whose coregulation drives the transcriptional coherence of their respective pathways. This, we hypothesize, is one strategy for creating coregulated, tunable modulons in eukaryotes.
Intestinal helminth infection transforms the CD4+ T cell composition of the skin
Authors: Classon C H , Li M , Ma J , Clavero A Lerma , Feng X , Tibbitt C A , Stark J M , Cardoso R , Ringqvist E , Boon L , Villablanca E J , Rothfuchs A Gigliotti , Eidsmo L , Coquet J M , Nylén S 
Published: April 2021

AbstractIntestinal helminth parasites can alter immune responses to vaccines, other infections, allergens and autoantigens, indicating effects on host immune responses in distal barrier tissues. We herein show that C57BL/6 mice infected with the strictly intestinal nematodeHeligmosomoides polygyrushave impaired capacity to initiate skin immune responses and develop skin-resident memory cells to mycobacterial antigens, both during infection and months after deworming therapy. Surprisingly, and in contrast to a previously noted loss of T cells in peripheral lymph nodes, the skin of worm-infected mice harboured higher numbers of CD4+ T cells compared to skin of uninfected controls.H. polygyrus-specific TH2 cells accumulated during infection and remained after worm expulsion. Accumulation of TH2 cells in the skin was associated with increased expression of the skin-homing chemokine receptors CCR4 and CCR10 on CD4+ T cells in blood and mesenteric lymph nodes draining intestinal tissues, indicating gut-to-skin trafficking of cells. In conclusion, we show that infection by a strictly intestinal helminth has long-term effects on immune cell composition and local immune responses to unrelated antigens in the skin, revealing a novel mechanism for T cell colonization and worm-mediated immunosuppression in this organ.
Sequence determinants ofin cellcondensate assembly morphology, dynamics, and oligomerization as measured by number and brightness analysis
Authors: Emenecker Ryan J. , Holehouse Alex S. , Strader Lucia C. 
Published: April 2021

AbstractBackgroundBiomolecular condensates are non-stoichiometric assemblies that are characterized by their capacity to spatially concentrate biomolecules and play a key role in cellular organization. Proteins that drive the formation of biomolecular condensates frequently contain oligomerization domains and intrinsically disordered regions (IDRs), both of which can contribute multivalent interactions that drive higher-order assembly. Our understanding of the relative and temporal contribution of oligomerization domains and IDRs to the material properties of in vivo biomolecular condensates is limited. Similarly, the spatial and temporal dependence of protein oligomeric state inside condensates has been largely unexplored in vivo.MethodsIn this study, we combined quantitative microscopy with number and brightness analysis to investigate the aging, material properties, and protein oligomeric state of biomolecular condensates in vivo. Our work is focused on condensates formed by AUXIN RESPONSE FACTOR 19 (ARF19), which is a transcription factor integral to the signaling pathway for the plant hormone auxin. ARF19 contains a large central glutamine-rich IDR and a C-terminal Phox Bem1 (PB1) oligomerization domain and forms cytoplasmic condensates.ResultsOur results reveal that the IDR amino acid composition can influence the morphology and material properties of ARF19 condensates. In contrast the distribution of oligomeric species within condensates appears insensitive to the IDR composition. In addition, we identified a relationship between the abundance of higher- and lower-order oligomers within individual condensates and their apparent fluidity.ConclusionsIDR amino acid composition affects condensate morphology and material properties. In ARF condensates, altering the amino acid composition of the IDR did not greatly affect the oligomeric state of proteins within the condensate.
Exosome component 1 cleaves single-stranded DNA and sensitizes kidney renal clear cell carcinoma cells to poly(ADP-ribose) polymerase inhibitor
Authors: Xiao Qi , Liu Qiaoling , Wang Lina , Wang Na , Wang Kai , Song Chengli , Yang Qingkai 
Published: April 2021

AbstractTargeting DNA repair pathway offers an important therapeutic strategy for cancers. However, the failure of DNA repair inhibitors to markedly benefit patients necessitates the development of new strategies. Here, we show that exosome component 1 (EXOSC1) promotes DNA damages and sensitizes kidney renal clear cell carcinoma (KIRC) cells to DNA repair inhibitor. Considering that endogenous source of mutation (ESM) constantly assaults genomic DNA and likely sensitize cancer cells to the inhibitor, we first analyzed the statistical relationship between the expression of individual genes and the mutations for KIRC. Among the candidates, EXOSC1 most notably promoted DNA damages and subsequent mutations via preferentially cleaving C site(s) in single-stranded DNA. Consistently, EXOSC1 was more significantly correlated with C>A transversions in coding strands than these in template strands in KIRC. Notably, KIRC patients with high EXOSC1 showed a poor prognosis, and EXOSC1 sensitized cancer cells to poly(ADP-ribose) polymerase inhibitor. These results show that EXOSC1 acts as an ESM in KIRC, and targeting EXOSC1 might be a potential therapeutic strategy.
Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses
Authors: West Johanna , Röder Juliane , Matrosovich Tatyana , Beicht Jana , Baumann Jan , Kouassi Nancy Mounogou , Doedt Jennifer , Bovin Nicolai , Zamperin Gianpiero , Gastaldelli Michele , Salviato Annalisa , Bonfante Francesco , Pond Sergei Kosakovsky , Herfst Sander , Fouchier Ron , Wilhelm Jochen , Klenk Hans-Dieter , Matrosovich Mikhail 
Published: April 2021

AbstractThe hemagglutinin (HA) of A/H3N2 pandemic influenza viruses (IAVs) of 1968 differed from its inferred avian precursor by eight amino acid substitutions. To determine their phenotypic effects, we studied recombinant variants of A/Hong Kong/1/1968 virus containing either human-type or avian-type amino acids in the corresponding positions of HA. The precursor HA displayed receptor binding profile and high conformational stability typical for duck IAVs. Substitutions Q226L and G228S, in addition to their known effects on receptor specificity and replication, marginally decreased HA stability. Substitutions R62I, D63N, D81N and N193S reduced HA binding avidity. Substitutions R62I, D63N, D81N and A144G promoted virus replication in human airway epithelial cultures. Analysis of HA sequences revealed that substitutions D63N and D81N accompanied by the addition of N-glycans represent common markers of avian H3 HA adaptation to mammals. Our results advance understanding of genotypic and phenotypic changes in IAV HA required for avian-to-human adaptation and pandemic emergence.
Computer-Vision Stabilized Intravital Imaging Reveals Lung Capillary Neutrophil Dynamics Crucial for Lung Host-Defense Function
Authors: Tsukasaki Yoshikazu , Bachmaier Kurt , Joshi Jagdish C. , Joshi Bhagwati , Toth Peter T. , Hong Zhigang , Nepal Saroj , Gunzer Matthias , Cho Jaehyung , Mehta Dolly , Tiruppathi Chinnaswamy , Pinho Sandra , Mo Gary , Rehman Jalees , Malik Asrar B. 
Published: April 2021

AbstractPolymorphonuclear neutrophils (PMN) are highly dynamic innate immune cells which are essential for lung host defense. However,in vivointravital imaging in moving organs such as the lung remains challenging due to motion artifacts. Here we describe a novel intravital imaging method with high-throughput analytical capability based on a computer vision stabilization algorithm, Computer-vision-Assisted STabilized intravital imaging (CASTii). The sub-micron precision of this approach enables analysis of compartmentalized intravital PMN dynamics. We quantified in real-time a novel patrolling function of lung intracapillary circulating PMN. We also describe the dynamics of intracapillary PMN pooling (marginated PMN pool) using direct imaging of PMNs. The pool was formed by repeated catch-and-release kinetics involving PMN deformation inside microvessels during the passage of PMNs in vessels. We observed rapid PMN recruitment into the lung tissue compartments from pooled PMNs in response to alveolar chemoattract exposure. In contrast, endotoxemia-induced intracapillary sequestration of PMN impaired PMN transmigration into the alveolar space and defective phagocytosis of live bacteria. Intravital imaging of PMN dynamics with CASTii provides fundamental insights into host-defense functions of lung capillary PMN.
The SARS CoV-1 3a protein disrupts Golgi complex morphology and cargo trafficking
Authors: Gonzales Rex R. , Machamer Carolyn E. 
Published: April 2021

AbstractCoronaviruses assemble by budding into the endoplasmic reticulum-Golgi intermediate compartment, but the pathway of egress from infected cells is not well understood. Efficient egress of infectious bronchitis virus (a gamma coronavirus, CoV) requires neutralization of Golgi pH by the envelope (E) protein. This results in reduced rates of cargo traffic and disrupts Golgi morphology, but it protects the spike protein from aberrant proteolysis. The severe acute respiratory syndrome (SARS) CoV-1 E protein does not disrupt the Golgi, however. We show here that in transfected cells, the ORF3a protein of SARS CoV-1 disrupts Golgi morphology, cargo trafficking and luminal pH. Unlike the infectious bronchitis virus E protein, these functions of the SARS CoV-1 3a protein appear to require its viroporin activity. Thus, neutralization of acidic compartments may be a universal feature of CoV infection, although different viral proteins and mechanisms may be used to achieve this outcome.
Cumulative effects of spruce budworm and moose herbivory on boreal forest ecosystems
Authors: Leroux Shawn J. , Charron Louis , Hermanutz Luise , Feltham Janet 
Published: April 2021

Abstract

Ungulate herbivory is a key natural disturbance in many ecosystems. In forest ecosystems, ungulate herbivory often co‐occurs with other disturbances yet there are few studies looking at the cumulative impacts of ungulates and other natural disturbances on forest dynamics.

We report on an 18‐year experiment to investigate the combined effects of introduced, non‐native moose and native spruce budworm herbivory on balsam fir forest recruitment and regeneration. Specifically, we measured inputs into early life‐history components of balsam fir dominant boreal forest ecosystems such as seed density, seedbed quality, seedling and sapling height and density, as well as adult density in eight paired moose exclosure and control sites across a spruce budworm disturbance gradient (i.e. no outbreak, recent outbreak, old outbreak) that resulted in closed, partially open and open canopies.

Piecewise structural equation models (SEMs) revealed a strong negative effect of spruce budworm disturbance on balsam fir adult density and indirect effects of this budworm disturbance on balsam fir seedling and sapling density mediated through adult density. We observed a similar pattern of budworm disturbance effects on balsam fir seed density with the lowest densities in sites with open canopy, then partially open and closed canopies. As expected, the SEM showed a positive effect of bryophyte seedbed cover on balsam fir seedling density. The SEM showed support for a positive effect of moose exclusion on balsam fir sapling height and density. Specifically, saplings were on average taller and denser in exclosure than control plots and these differences are most pronounced at sites with partially open canopies created by spruce budworm disturbance and undisturbed or closed canopy sites. Overall, we show evidence for cumulative and interactive effects of spruce budworm and moose herbivory on all life stages of balsam fir and such effects are negatively affecting regeneration of balsam fir forests.

Human activities are creating conditions that facilitate the expansion and increased impacts of herbivores on boreal ecosystem functioning. A greater understanding of how ungulate herbivory interacts with other disturbances is needed to improve our predictions of forest ecosystem dynamics under global change.

A free Plain Language Summary can be found within the Supporting Information of this article.
Global resorption efficiencies of trace elements in leaves of terrestrial plants
Authors: Chen Hao , Reed Sasha C. , Lü Xiaotao , Xiao Kongcao , Wang Kelin , Li Dejun 
Published: April 2021

Abstract

Leaf nutrient resorption is a critical nutrient conservation strategy. Previous studies focus mainly on resorption patterns of macronutrients, but resorption patterns of trace elements remain poorly understood.

A meta‐analysis was conducted to explore the general patterns of the leaf resorption of eight trace elements [i.e. copper (Cu), molybdenum (Mo), zinc (Zn), boron (B), manganese (Mn), sodium (Na), aluminium (Al) and iron (Fe)], and a macronutrient [i.e. sulphur (S)] using data collected from 53 published studies.

Sulphur (49.6%) had the highest average resorption efficiency followed by Cu (30.3%), Mo (29.5%), Zn (19.5%) and B (17.6%). Two structural elements, Na and Mn, were not resorbed, whereas two potentially toxic elements, Al (−55.6%) and Fe (−25.4%), were accumulated in senesced leaves. Both climatic factors and growth types affected leaf nutrient resorption efficiency, but the magnitudes and directions of the effects differed greatly between S and the trace elements. The resorption efficiencies of S, Cu, Mo and Zn decreased as leaf nutrient concentrations increased, but the structural or potentially toxic elements (i.e. B, Mn, Na, Fe and Al) presented no response or opposite trends.

Our results provide global mean resorption efficiencies of trace elements for the first time, and highlight that structural and potentially toxic elements have relatively lower or no leaf resorption, which should be fully considered in biogeochemical models.

A free Plain Language Summary can be found within the Supporting Information of this article.