bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-cancer organoid validation of tumor outlier chromosomal amplification events
Authors: Salahudeen Ameen A. , Yuki Kanako , Seoane Jose A. , Mah Amanda T. , Smith Amber R. , Kolahi Kevin , De la O Sean M. , Hart Daniel J. , Ding Jie , Ma Zhicheng , Barkal Sammy , Shukla Navika D. , Zhang Chuck , Cantrell Michael A. , Batish Arpit , Usui Tatsuya , Root David , Hahn William , Curtis Christina , Kuo Calvin J 
Published: October 2021

SUMMARYSomatic copy number gains are pervasive in many cancer types, yet their roles in oncogenesis are often poorly explored. This lack of understanding is in part due to broad extensions of copy gains across cancer genomes spanning large chromosomal regions, obscuring causal driver loci. Here we employed a multi-tissue pan-organoid modeling approach to validate candidate oncogenic loci identified within pan-cancer TCGA data by the overlap of extreme copy number amplifications with extreme expression dysregulation for each gene. The candidate outlier loci nominated by this integrative computational analysis were functionally validated by infecting cancer type-specific barcoded full length cDNA lentiviral libraries into cognate minimally transformed human and mouse organoids bearing initial oncogenic mutations from esophagus, oral cavity, colon, stomach, pancreas and lung. Presumptive amplification oncogenes were identified by barcode enrichment as a proxy for increased proliferation. Iterative analysis validatedDYRK2at 12q15, encoding a serine-threonine kinase, as an amplified head and neck squamous carcinoma oncogene inp53-/-oral mucosal organoids. Similarly,FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, was validated inp53-/-esophageal organoids in vitro and in vivo with pharmacologic inhibition by small molecule and soluble receptor FGFR antagonists. Our studies establish the feasibility of pan-organoid contextual modeling of pan-cancer candidate genomic drivers, enabling oncogene discovery and preclinical therapeutic modeling.
NFkB-signaling promotes glial reactivity and suppresses Müller glia-mediated neuron regeneration in the mammalian retina
Authors: Palazzo Isabella , Todd Levi J. , Hoang Thanh V. , Reh Thomas A. , Blackshaw Seth , Fischer Andy J. 
Published: October 2021

AbstractMüller glia (MG) in mammalian retinas are incapable of regenerating neurons after damage, whereas the MG in lower vertebrates regenerate functional neurons. Identification networks that regulate MG-mediated regeneration is key to harnessing the regenerative potential of MG. Here we study how NFkB-signaling influences glial responses to damage and reprogramming of MG into neurons in the rodent retina. We find activation of NFkB and dynamic expression of NFkB-associated genes in MG after damage, however NFkB activity is inhibited by microglia ablation. Knockout of NFkB in MG suppressed the accumulation of immune cells after damage. Inhibition of NFkB following NMDA-damage significantly enhanced the reprogramming of Ascl1-overexpressing MG into neuron-like cells. scRNA-seq of retinal glia following inhibition of NFkB reveals coordination with signaling via TGFβ2 and suppression of NFI and Id transcription factors. Inhibition of Smad3 or Id transcription factors increased numbers of neuron-like cells produced by Ascl1-overexpressing MG. We conclude that NFkB is a key signaling hub that is activated in MG after damage, mediates the accumulation of immune cells, and suppresses the neurogenic potential of MG.
Transient definitive host presence is sufficient to sustain avian schistosome populations
Authors: Rudko Sydney P , McPhail Brooke A , Reimink Ronald L , Froelich Kelsey , Turnbull Alyssa , Hanington Patrick C 
Published: October 2021

AbstractTo control swimmer’s itch in northern Michigan inland lakes, one species of bird, the common merganser (Mergus merganser), has been relocated from several lakes since 2015. Relocation efforts are driven by a desire to reduce the prevalence of the swimmer’s itch-causing parasite Trichobilharzia stagnicolae. The intention of this state-sponsored control effort was to interrupt the life cycle of T. stagnicolae and reduce parasite egg contribution into the environment from summer resident mergansers such that infections of the intermediate snail host Stagnicola emarginata declined. Reduced snail infection prevalence was expected to greatly reduce abundance of the swimmer’s itch-causing cercarial stage of the parasite in water. With no official program in place to assess the success of this relocation effort, we sought to study the effectiveness and impact of the removal of a single definitive host from a location with high definitive host and parasite diversity. This was assessed through a comprehensive, lake-wide monitoring study measuring longitudinal changes in the abundance of three species of avian schistosome cercariae in four inland Michigan lakes. Environmental measurements were also taken at these lakes to understand how they can affect swimmer’s itch incidence. Results from this study demonstrate that the diversity of avian schistosomes at the study lakes would likely make targeting of a single species of swimmer’s itch-causing parasite meaningless from a swimmer’s itch control perspective. Our data also suggest that removal of the common merganser is not an effective control strategy for the T. stagnicolae parasite, likely due to parasite contributions of migratory birds in the fall and spring. This suggests that only minimal contact time between the definitive host and the lake ecosystem is required to contribute sufficient parasite numbers to maintain a thriving population of parasite species with a high host-specificity.
MetAMDB: Metabolic Atom Mapping Database
Authors: Starke Collin , Wegner Andre 
Published: October 2021

AbstractMetAMDB (https://metamdb.tu-bs.de/) is an open source metabolic atom mapping database, providing atom mappings for around 75000 metabolic reactions. Each atom mapping can be inspected and downloaded either as a RXN file or as a graphic in SVG format. In addition, MetAMDB offers the possibility of automatically creating atom mapping models based on user-specified metabolic networks. These models can be of any size (small to genome scale) and can subsequently be used in standard 13C metabolic flux analysis software.
The kinectome: a comprehensive kinematic map of human motion in health and disease
Authors: Lopez Emahnuel Troisi , Sorrentino Pierpaolo , Liparoti Marianna , Minino Roberta , Carotenuto Anna , Amico Enrico , Sorrentino Giuseppe 
Published: October 2021

AbstractEffective human movement requires the coordinated participation of the whole musculoskeletal system. Here we propose to represent the human body movements as a network (that we named “kinectome”), where nodes are body parts, and edges are defined as the correlations of the accelerations between each pair of body parts during gait. We apply this framework in healthy individuals and patients with Parkinson’s disease (PD). The network dynamics in Parkinson’s display high variability, as conveyed by the high variance and the modular structure in the patients’ kinectomes. Furthermore, our analysis identified a set of anatomical elements that are specifically related to the balance impairment in PD. Furthermore, each participant could be identified based on its kinectome patterns, akin to a “fingerprint” of movement, confirming that our approach captures relevant features of gait. We hope that applying network approaches to human kinematics yields new insights to characterize human movement.
Isotopic signatures induced by upwelling reveal regional fish populations in Lake Tanganyika
Authors: Ehrenfels Benedikt , Junker Julian , Namutebi Demmy , Callbeck Cameron M. , Dinkel Christian , Kalangali Anthony , Kimirei Ismael A. , Mbonde Athanasio S. , Mosille Julieth B. , Sweke Emmanuel A. , Schubert Carsten J. , Seehausen Ole , Wagner Catherine E. , Wehrli Bernhard 
Published: October 2021

AbstractLake Tanganyika’s pelagic fish sustain the second largest inland fishery in Africa and are under pressure from heavy fishing and global warming related increases in stratification. Only little is known about whether basin-scale hydrodynamics – including a more stratified north and an upwelling-driven south – induce ecological and genetic differences among populations of highly mobile, pelagic fish inhabiting these different areas. Here, we examine whether the basin-scale dynamics leave distinct isotopic imprints in the pelagic fish of Lake Tanganyika, which may reveal differences in habitat, diet, or lipid content. We conducted two lake-wide campaigns during different seasons and collected physical, nutrient, chlorophyll, phytoplankton and zooplankton data. Additionally, we analyzed the pelagic fish – the clupeids Stolothrissa tanganicae, Limnothrissa miodon and four Lates species – for their isotopic and elemental carbon (C) and nitrogen (N) compositions. The δ13C values were significantly higher in the productive south after the upwelling/mixing period across all trophic levels, implying that the fish have regional foraging grounds, and thus record these latitudinal isotope gradients. By combining our isotope data with genetics, we demonstrate that the fish form regional populations on a seasonal to multiannual time scale. Based on δ15N and C:N ratios, we found no strong evidence for varying diets or lipid contents between those regional populations.Additional analyses revealed that isotopic variations between specimens from the same location are not linked to genetic differences. We suggest that the development of basinscale ecological differences in response to the prevailing hydrodynamic regimes may be inhibited by lake-wide gene flow on the long term. Our findings show that the pelagic fish species are genetically adapted to the whole lake, but they form regional populations on short time scales. This implies that sustainable management strategies may adopt basin-scale fishing quotas.
High-content profiling reveals a unified model of copper ionophore dependent cell death in oesophageal adenocarcinoma
Authors: Hughes Rebecca E. , Elliott Richard J. R. , Li Xiaodun , Munro Alison F. , Makda Ashraff , Carter Roderick N. , Morton Nicholas M. , Fujihara Kenji , Clemons Nicholas J. , Fitzgerald Rebecca , O’Neill J. Robert , Hupp Ted , Carragher Neil O. 
Published: October 2021

AbstractBackground and AimsOesophageal adenocarcinoma (OAC) is of increasing global concern due to increasing incidence, a lack of effective treatments, and poor prognosis. Therapeutic target discovery and clinical trials have been hindered by the heterogeneity of the disease, lack of driver mutations, and the dominance of large-scale genomic rearrangements. In this work we have characterised three potent and selective hit compounds identified in an innovative high-content phenotypic screening assay. The three hits include two approved drugs; elesclomol and disulfiram, and another small molecule compound, ammonium pyrrolidinedithiocarbamate. We uncover their mechanism of action, discover a targetable vulnerability, and gain insight into drug sensitivity for biomarker-based clinical trials in OAC.MethodsElesclomol, disulfiram, and ammonium pyrrolidinedithiocarbamate were systematically characterised across panels of oesophageal cell lines and patient-derived organoids. Drug treated oesophageal cell lines were morphologically profiled using a high-content, imaging platform. Compounds were assessed for efficacy across patient-derived organoids. Metabolomics and transcriptomics were assessed for the identification of oesophageal-cancer specific drug mechanisms and patient stratification hypotheses.ResultsHigh-content profiling revealed that all three compounds were highly selective for OAC over tissue-matched controls. Comparison of gene expression and morphological signatures unveiled a unified mechanism of action involving the accumulation of copper selectively in cancer cells, leading to dysregulation of proteostasis and cancer cell death. Basal omic analyses revealed proteasome and metabolic markers of drug sensitivity, forming the basis for biomarker-based clinical trials in OAC.ConclusionsIntegrated analysis of high-content imaging, transcriptomic and metabolomic data has revealed a new therapeutic mechanism for the treatment of OAC and represents an alternative target-agnostic drug discovery strategy.
DeepSTARR predicts enhancer activity from DNA sequence and enables thede novodesign of enhancers
Authors: de Almeida Bernardo P. , Reiter Franziska , Pagani Michaela , Stark Alexander 
Published: October 2021

AbstractEnhancer sequences control gene expression and comprise binding sites (motifs) for different transcription factors (TFs). Despite extensive genetic and computational studies, the relationship between DNA sequence and regulatory activity is poorly understood and enhancerde novodesign is considered impossible. Here we built a deep learning model, DeepSTARR, to quantitatively predict the activities of thousands of developmental and housekeeping enhancers directly from DNA sequence inDrosophila melanogasterS2 cells. The model learned relevant TF motifs and higher-order syntax rules, including functionally non-equivalent instances of the same TF motif that are determined by motif-flanking sequence and inter-motif distances. We validated these rules experimentally and demonstrated their conservation in human by testing more than 40,000 wildtype and mutantDrosophilaand human enhancers. Finally, we designed and functionally validated synthetic enhancers with desired activitiesde novo.
Network Segregation Predicts Processing Speed in the Cognitively Healthy Oldest-old
Authors: Nolin SA , Faulkner ME , Stewart P , Fleming L , Merritt S , Rezaei RF , Bharadwaj PK , Franchetti MK , Raichlen DA , Jessup CJ , Edwards L , Hishaw GA , Van Etten EJ , Trouard TP , Geldmacher D , Wadley VG , Alperin N , Porges EC , Woods AJ , Cohen RA , Levin BE , Rundek T , Alexander GE , Visscher KM 
Published: October 2021

AbstractFunctional connections among groups of brain areas give insight into the brain’s organization. The cognitive effects of aging may relate to the brain’s large-scale organization. Examining the relationship between individual differences in brain organization and cognitive function in healthy older adults can help us understand how these networks support healthy cognitive aging. We investigated functional network segregation in 146 cognitively healthy participants aged 85+ in the McKnight Brain Aging Registry. We found that the segregation of the cortical association system and the segregation of individual networks within that system [the fronto-parietal network (FPN), cingulo-opercular network (CON) and default mode network (DMN)], were strong predictors of overall cognition and processing speed. We also provide a healthy oldest-old (85+) cortical parcellation that can be used in future work in this age group. This study shows that network segregation of the oldest-old brain is closely linked to cognitive performance. This work adds to the growing body of knowledge about differentiation in the aged brain by demonstrating that cognitive ability is associated with differentiated functional networks in very old individuals experiencing successful cognitive aging.
Comprehensive characterization of the antibody responses to SARS-CoV-2 Spike protein after infection and/or vaccination
Authors: Garrett Meghan E. , Galloway Jared G. , Wolf Caitlin , Logue Jennifer K. , Franko Nicholas , Chu Helen Y. , Matsen Frederick A. , Overbaugh Julie 
Published: October 2021

ABSTRACTBackgroundControl of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including different vaccine platforms, is needed to achieve this goal.MethodsThe epitopes and pathways of escape for Spike-specific antibodies in individuals with diverse infection and vaccination history were profiled using Phage-DMS. Principal component analysis was performed to identify regions of antibody binding along the Spike protein that differentiate the samples from one another. Within these epitope regions we determined potential escape mutations by comparing antibody binding of peptides containing wildtype residues versus peptides containing a mutant residue.ResultsIndividuals with mild infection had antibodies that bound to epitopes in the S2 subunit within the fusion peptide and heptad-repeat regions, whereas vaccinated individuals had antibodies that additionally bound to epitopes in the N- and C-terminal domains of the S1 subunit, a pattern that was also observed in individuals with severe disease due to infection. Epitope binding appeared to change over time after vaccination, but other covariates such as mRNA vaccine dose, mRNA vaccine type, and age did not affect antibody binding to these epitopes. Vaccination induced a relatively uniform escape profile across individuals for some epitopes, whereas there was much more variation in escape pathways in in mildly infected individuals. In the case of antibodies targeting the fusion peptide region, which was a common response to both infection and vaccination, the escape profile after infection was not altered by subsequent vaccination.ConclusionsThe finding that SARS-CoV-2 mRNA vaccination resulted in binding to additional epitopes beyond what was seen after infection suggests protection could vary depending on the route of exposure to Spike antigen. The relatively conserved escape pathways to vaccine-induced antibodies relative to infection-induced antibodies suggests that if escape variants emerge, they may be readily selected for across vaccinated individuals. Given that the majority of people will be first exposed to Spike via vaccination and not infection, this work has implications for predicting the selection of immune escape variants at a population level.FundingThis work was supported by NIH grants AI138709 (PI Overbaugh) and AI146028 (PI Matsen). Julie Overbaugh received support as the Endowed Chair for Graduate Education (FHCRC). The research of Frederick Matsen was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute and the Simons Foundation. Scientific Computing Infrastructure at Fred Hutch was funded by ORIP grant S10OD028685.
Ultra-precise all-optical manipulation of neural circuits with multifunctional Cre-dependent transgenic mice
Authors: Bounds Hayley A. , Sadahiro Masato , Hendricks William D. , Gajowa Marta , Gopakumar Karthika , Quintana Daniel , Tasic Bosiljka , Daigle Tanya L. , Zeng Hongkui , Oldenburg Ian Antón , Adesnik Hillel 
Published: October 2021

SummaryDetermining which features of the neural code drive perception and behavior requires the ability to simultaneous read out and write in neural activity patterns with high precision across many neurons. All-optical systems that combine two photon (2p) calcium imaging and targeted 2p photostimulation enable the activation of specific, functionally defined groups of neurons in behaving animals. However, these techniques do not yet have the ability to reveal how the specific distribution of firing rates across a relevant neural population mediates neural computation and behavior. The key technical obstacle is the inability to transform single-cell calcium signals into accurate estimates of firing rate changes and then write in these cell-specific firing rate changes to each individual neuron in a targeted population. To overcome this challenge, we made two advances: first we introduce a new genetic line of mice for robust Cre-dependent co-expression of a high-performance calcium indicator and a potent soma-targeted microbial opsin. Second, using this line, we developed a pipeline that enables the read-out and write-in of precise population vectors of neural activity across a targeted group of neurons. The combination of the new multifunctional transgenic line and the photostimulation paradigm offer a powerful and convenient platform for investigating the neural codes of computation and behavior. It may prove particularly useful for probing causal features of the geometry of neural representations where the ability to directly control the topology of population activity is essential.
At a snail’s pace: the influence of habitat disturbance on terrestrial snail movement using experimentally manipulated mesocosms
Authors: Denief Emily E. , Turner Julie W. , Prokopenko Christina M. , Robitaille Alec L. , Wal Eric Vander 
Published: October 2021

AbstractThe Anthropocene marks great changes to environments and the animals that inhabit them. Changes, such as disturbance, can affect the manner in which animals interact with their environments, such as moving and selecting habitats. To test how animals might respond to changing disturbance regimes, we employ an experimental approach to movement ecology. We used integrated step selection analysis (iSSA) to test the behavioural responses of individually-marked grove snails (Cepaea nemoralis) exposed to a gradient of physical disturbance in their habitat. We used a before-after control-impact (BACI) experimental design within semi-controlled mesocosms to manipulate edge and disturbance variables by altering the area of the mesocosm covered by bricks. We showed that grove snails perceive edges of enclosures and edges of bricks as risks, and responded to such risks by altering their movement. Grove snails displayed a bimodal response to risk by taking shelter in place or moving faster to be farther from the disturbance. Furthermore, individuals tended to modulate their behavioural response to the degree of risk. Our study highlights the usefulness of experimental mesocosms in movement ecology and in determining the effects of habitat alteration and human-imposed risk on movement behaviour.
Metabolic regulation inferred from Jacobian and Hessian matrices of metabolic functions
Authors: Nägele Thomas 
Published: October 2021

AbstractQuantitative analysis of experimental metabolic data is frequently challenged by non-intuitive, complex patterns which emerge from regulatory networks. Quantitative output of metabolic regulation can be summarised by metabolic functions which comprise information about dynamics of metabolite concentrations. They reflect the sum of biochemical reactions which affect a metabolite concentration. Derivatives of metabolic functions provide essential information about system dynamics. The Jacobian matrix of a reaction network summarises first-order partial derivatives of metabolic functions with respect to metabolite concentrations while Hessian matrices summarise second-order partial derivatives. Here, a simple model of invertase-driven sucrose hydrolysis is simulated and both Jacobian and Hessian matrices of metabolic functions are derived for quantitative analysis of kinetic regulation of sucrose metabolism. Based on previous experimental observations, metabolite dynamics are quantitatively explained in context of underlying metabolic functions. Their potential regulatory role during plant cold acclimation is derived from Jacobian and Hessian matrices.