bluuebunny/crossref_metadata_2025_split huggingface dataset:
The future of artificial intelligence in digital pathology - results of a survey across stakeholder groups
Authors: Heinz Céline N. , Echle Amelie , Foersch Sebastian , Bychkov Andrey , Kather Jakob Nikolas 
Published: December 2021

AbstractArtificial intelligence (AI) provides a powerful tool to extract information from digitized histopathology whole slide images. In the last five years, academic and commercial actors have developed new technical solutions for a diverse set of tasks, including tissue segmentation, cell detection, mutation prediction, prognostication and prediction of treatment response. In the light of limited overall resources, it is presently unclear for researchers, practitioners and policymakers which of these topics are stable enough for clinical use in the near future and which topics are still experimental, but worth investing time and effort into. To identify potentially promising applications of AI in pathology, we performed an anonymous online survey of 75 computational pathology domain experts from academia and industry. Participants enrolled in 2021 were queried about their subjective opinion on promising and appealing sub-fields of computational pathology with a focus on solid tumors. The results of this survey indicate that the prediction of treatment response directly from routine pathology slides is regarded as the most promising future application. This item was ranked highest in the overall analysis and in sub-groups by age and professional background. Furthermore, prediction of genetic alterations, gene expression and survival directly from routine pathology images scored consistently high across subgroups. Together, these data demonstrate a possible direction for the development of computational pathology systems in clinical, academic and industrial research in the near future.
Effects of footshock stress on social behavior and neuronal activation in the medial prefrontal cortex and amygdala of male and female mice
Authors: Dorofeikova Mariia , Borkar Chandrashekhar D , Weissmuller Katherine , Smith-Osborne Lydia , Basavanhalli Samhita , Bean Erin , Smith Avery , Duong Anh , Resendez Alexis , Fadok Jonathan P 
Published: December 2021

AbstractSocial behavior is complex and fundamental, and its deficits are common pathological features for several psychiatric disorders including anxiety, depression, and posttraumatic stress disorder. Acute stress may have a negative impact on social behavior, and these effects can vary based on sex. The aim of this study was to explore the effect of two days of footshock stress on the sociability of male and female C57Bl/6J mice measured using a standard social interaction test. Animals were divided into two main groups of footshock exposure or context exposure control. Each group had mice that were treated with either the benzodiazepine alprazolam, or vehicle. In all groups, neuronal activation during social interaction was assessed using immunohistochemistry against the immediate early gene product cFos. Although footshock stress did not significantly alter sociability or latency to approach a social interaction counterpart, it did increase defensive tail-rattling behavior specifically in males. This stress-induced increase in tail-rattling was alleviated by alprazolam, yet alprazolam had no effect on female tail-rattling behavior in the stress group. Alprazolam lowered cFos expression in the medial prefrontal cortex, and social interaction induced sex-dependent differences in cFos activation in the ventromedial intercalated cell clusters. Overall, our results suggest that acute footshock stress induces sex-dependent alterations in defensiveness and patterns of cFos activation during social interaction tests.
Modeling the dynamics of within-host viral infection and evolution predicts quasispecies distributions and phase boundaries separating distinct classes of infections
Authors: Lewis Greyson R. , Marshall Wallace F. , Jones Barbara A. 
Published: December 2021

AbstractWe use computational modeling to study within-host viral infection and evolution. In our model, viruses exhibit variable binding to cells, with better infection and replication countered by a stronger immune response and a high rate of mutation. By varying host conditions (permissivity to viral entry T and immune clearance intensity A) for large numbers of cells and viruses, we study the dynamics of how viral populations evolve from initial infection to steady state and obtain a phase diagram of the range of cell and viral responses. We find three distinct replicative strategies corresponding to three physiological classes of viral infections: acute, chronic, and opportunistic. We show similarities between our findings and the behavior of real viral infections such as common flu, hepatitis, and SARS-CoV-2019. The phases associated with the three strategies are separated by a phase transition of primarily first order, in addition to a crossover region. Our simulations also reveal a wide range of physical phenomena, including metastable states, periodicity, and glassy dynamics. Lastly, our results suggest that the resolution of acute viral disease in patients whose immunity cannot be boosted can only be achieved by significant inhibition of viral infection and replication.Author summaryVirus, in particular RNA viruses, often produce offspring with slightly altered genetic composition. This process occurs both across host populations and within a single host over time. Here, we study the interactions of viruses with cells inside a host over time. In our model, the viruses encounter host cell defenses characterized by two parameters: permissivity to viral entry T and immune response A). The viruses then mutate upon reproduction, eventually resulting in a distribution of related viral types termed a quasi-species distribution. Across varying host conditions (T, A), three distinct viral quasi-species types emerge over time, corresponding to three classes of viral infections: acute, chronic and opportunistic. We interpret these results in terms of real viral types such as common flu, hepatitis, and also SARS-CoV-2019. Analysis of viral of viral mutant populations over a wide range of permissivity and immunity, for large numbers of cells and viruses, reveals phase transitions that separate the three classes of viruses, both in the infection-cycle dynamics and at steady state. We believe that such a multiscale approach for the study of within-host viral infections, spanning individual proteins to collections of cells, can provide insight into developing more effective therapies for viral disease.
Electrobehavioral phenotype and seizure pharmacosensitivity in a novel mouse model of patient-derived SLC6A1 S295L mutation-associated neurodevelopmental epilepsy
Authors: Lindquist Britta E. , Voskobiynyk Yuliya , Paz Jeanne T. 
Published: December 2021

AbstractSolute carrier family 6 member 1 (SLC6A1) gene encodes GAT-1, a GABA transporter expressed on glia and presynaptic terminals of inhibitory neurons. Mutations in SLC6A1 are associated with myoclonic atonic epilepsy, absence epilepsy, autism, and intellectual disability. However, the mechanisms leading to these defects are unknown. Here, we used a novel mouse model harboring a point mutation (S295L) recently identified in the human SLC6A1 gene that results in impaired membrane trafficking of the GAT-1 protein. We performed chronic wireless telemetry recordings of heterozygous (GAT-1S295L/+) mice, and of mice lacking one or both copies of the gene (GAT-1+/− and GAT-1−/−). We assessed their behaviors and pharmacosensitivity, and investigated the relationship between seizure burden and behavioral performance. GAT-1S295L/+ mice exhibited frequent spikewave discharges (SWDs) associated with behavioral arrest, and there was a dose-effect relationship between GAT-1 gene copy number and the severity of electrocorticogram (ECoG) abnormalities. Seizure burden was inversely correlated with behavioral performance. Forelimb grip strength was reduced in female mice. Acute administration of GAT-1 antagonist NO-711 induced SWDs in wildtype mice, exacerbated the phenotype in GAT-1S295L/+ and GAT-1+/− mice, and had no effect on GAT-1−/− mice lacking the drug target. By contrast, ethosuximide normalized the ECoG in GAT-1S295L/+ and GAT-1+/− mice. In conclusion, GAT-1S295L/+ mice show haploinsufficiency with evidence of GAT-1 hypofunction. This mouse model reconstitutes major aspects of human disease and thus provides a useful preclinical model for drug screening and gene therapy.Significance StatementThe SLC6A1 gene encodes for GAT-1, a major GABA transporter. Mutations in SLC6A1 lead to a spectrum of neurodevelopmental disorders and epilepsies collectively referred to as SLC6A1-related disorders (SRD). A critical contributor to disability in SRD patients is the burden of seizures and their sequelae. There is an urgent need to understand the mechanisms of SRD as they will inform therapeutic interventions. Mouse models can provide critical information allowing both the assessment of candidate therapies and the design of next generations therapies. Here we used behavioral assessments and wireless electrophysiology in a new mouse model of SRD to understand the disease pathogenesis and the association between seizure burden and behavioral deficits.
Brain intrinsic connection patterns underlying tool processing in human adults are present in neonates and not in macaques
Authors: Wen Haojie , Xu Ting , Wang Xiaoying , Yu Xi , Bi Yanchao 
Published: December 2021

AbstractTool understanding and use are supported by a dedicated left-lateralized, intrinsically connected network in the human adult brain. To examine this network’s phylogenic and ontogenetic origins, we compared resting-state functional connectivity (rsFC) among regions subserving tool processing in human adults to rsFC among homologous regions in human neonates and macaque monkeys (adolescent and mature). These homologous regions formed an intrinsic network in human neonates, but not in macaques. Network topological patterns were highly similar between human adults and neonates, and significantly less so between humans and macaques. The premotor-parietal rsFC had most significant contribution to the formation of the neonate tool network. These results suggest that an intrinsic brain network potentially supporting tool processing exists in the human brain prior to individual tool use experiences, and that the premotor-parietal functional connection in particular offers a brain basis for complex tool behaviors specific to humans.
An exploratory study on the microbiome of northern and southern populations of Ixodes scapularis ticks predicts changes and unique bacterial interactions
Authors: Kumar Deepak , Downs Latoyia P. , Adegoke Abdulsalam , Machtinger Erika , Oggenfuss Kelly , Ostfeld Richard S. , Embers Monica , Karim Shahid 
Published: December 2021

AbstractThe black-legged tick (Ixodes scapularis) is the primary vector of Borrelia burgdorferi, the causative agent of Lyme disease in North America. However, the prevalence of Lyme borreliosis is clustered around the northern states of the United States of America. This study utilized a metagenomic sequencing approach to compare the microbial communities residing within Ix. scapularis populations from north and southern geographic locations in the USA. Using a SparCC network construction model, potential interactions between members of the microbial communities from Borrelia burgdorferi-infected tissues of unfed and blood-fed ticks were performed. A significant difference in bacterial composition and diversity among northern and southern tick populations was found between northern and southern tick populations. The network analysis predicted a potential antagonistic interaction between endosymbiont Rickettsia buchneri and Borrelia burgdorferi sensu lato. Network analysis, as expected, predicted significant positive and negative microbial interactions in ticks from these geographic regions, with the genus Rickettsia, Francisella, and Borreliella playing an essential role in the identified clusters. Interactions between Rickettsia buchneri and Borrelia burgdorferi sensu lato needs more validation and understanding. Understanding the interplay between the micro-biome and tick-borne pathogens within tick vectors may pave the way for new strategies to prevent tick-borne infections.
The genome of the Balearic shearwater (Puffinus mauretanicus), a Critically Endangered seabird: a valuable resource for evolutionary and conservation genomics
Authors: Cuevas-Caballé Cristian , Obiol Joan Ferrer , Vizueta Joel , Genovart Meritxell , Gonzalez-Solís Jacob , Riutort Marta , Rozas Julio 
Published: December 2021

AbstractThe Balearic shearwater (Puffinus mauretanicus) is the most threatened seabird in Europe. The fossil record suggests that human colonisation of the Balearic Islands resulted in a sharp decrease of the population size. Currently, populations continue to be decimated mainly due to predation by introduced mammals and bycatch in longline fisheries, and some studies predict their extinction by 2070. We present the first high-quality reference genome for the species which was obtained by a combination of short and long-read sequencing. Our hybrid assembly includes 4,169 scaffolds, with a scaffold N50 of 2.1 Mbp, a genome length of 1.2 Gbp, and BUSCO completeness of 96%, which is amongst the highest across sequenced avian species. This reference genome allowed us to study critical aspects relevant to the conservation status of the species, such as an evaluation of overall heterozygosity levels and the reconstruction of its historical demography. Our phylogenetic analysis using whole-genome information resolves current uncertainties in the order Procellariiformes systematics. Comparative genomics analyses uncover a set of candidate genes that may have played an important role into the adaptation to a pelagic lifestyle of Procellariiformes, including those for the enhancement of fishing capabilities, night vision and the development of natriuresis. This reference genome will be the keystone for future developments of genetic tools in conservation efforts for this Critically Endangered species.
Rapid profiling of protein complex re-organization in perturbed systems
Authors: Bludau Isabell , Nicod Charlotte , Martelli Claudia , Xue Peng , Heusel Moritz , Fossati Andrea , Uliana Federico , Frommelt Fabian , Aebersold Ruedi , Collins Ben C. 
Published: December 2021

AbstractProtein complexes constitute the primary functional modules of cellular activity. To respond to perturbations, complexes undergo changes in their abundance, subunit composition or state of modification. Understanding the function of biological systems requires global strategies to capture this contextual state information on protein complexes and interaction networks. Methods based on co-fractionation paired with mass spectrometry have demonstrated the capability for deep biological insight but the scope of studies using this approach has been limited by the large measurement time per biological sample and challenges with data analysis. As such, there has been little uptake of this strategy beyond a few expert labs into the broader life science community despite rich biological information content. We present a rapid integrated experimental and computational workflow to assess the re-organization of protein complexes across multiple cellular states. It enables complex experimental designs requiring increased sample/condition numbers. The workflow combines short gradient chromatography and DIA/SWATH mass spectrometry with a data analysis toolset to quantify changes in complex organization. We applied the workflow to study the global protein complex rearrangements of THP-1 cells undergoing monocyte to macrophage differentiation and a subsequent stimulation of macrophage cells with lipopolysaccharide. We observed massive proteome organization in functions related to signaling, cell adhesion, and extracellular matrix during differentiation, and less pronounced changes in processes related to innate immune response induced by the macrophage stimulation. We therefore establish our integrated differential pipeline for rapid and state-specific profiling of protein complex organization with broad utility in complex experimental designs.
Insights into standards of care – dexamethasone and antibodies against COVID-19 in hamster models
Authors: Wyler Emanuel , Adler Julia M. , Eschke Kathrin , Alves Gustavo Teixeira , Peidli Stefan , Pott Fabian , Kazmierski Julia , Michalick Laura , Kershaw Olivia , Bushe Judith , Andreotti Sandro , Pennitz Peter , Abdelgawad Azza , Postmus Dylan , Goffinet Christine , Kreye Jakob , Reincke S Momsen , Prüss Harald , Blüthgen Nils , Gruber Achim D. , Kuebler Wolfgang M. , Witzenrath Martin , Landthaler Markus , Nouailles Geraldine , Trimpert Jakob 
Published: December 2021

AbstractRationaleIn face of the ongoing SARS-CoV-2 pandemic, effective and well-understood treatment options are still scarce. While vaccines have proven instrumental in fighting SARS-CoV-2, their efficacy is challenged by vaccine hesitancy, novel variants and short-lasting immunity. Therefore, understanding and optimization of therapeutic options remains essential.ObjectivesWe aimed at generating a deeper understanding on how currently used drugs, specifically dexamethasone and anti-SARS-CoV-2 antibodies, affect SARS-CoV-2 infection and host responses. Possible synergistic effects of both substances are investigated to evaluate combinatorial treatments.MethodsBy using two COVID-19 hamster models, pulmonary immune responses were analyzed to characterize effects of treatment with either dexamethasone, anti-SARS-CoV-2 spike monoclonal antibody or a combination of both. scRNA sequencing was employed to reveal transcriptional response to treatment on a single cell level.Measurements and main resultsDexamethasone treatment resulted in similar or increased viral loads compared to controls. Anti-SARS-CoV-2 antibody treatment alone or combined with dexamethasone successfully reduced pulmonary viral burden. Dexamethasone exhibited strong anti-inflammatory effects and prevented fulminant disease in a severe COVID-19-like disease model. Combination therapy showed additive benefits with both anti-viral and anti-inflammatory potency. Bulk and single-cell transcriptomic analyses confirmed dampened inflammatory cell recruitment into lungs upon dexamethasone treatment and identified a candidate subpopulation of neutrophils specifically responsive to dexamethasone.ConclusionsOur analyses i) confirm the anti-inflammatory properties and indicate possible modes of action for dexamethasone, ii) validate anti-viral effects of anti-SARS-CoV-2 antibody treatment, and iii) reveal synergistic effects of a combination therapy and can thus inform more effective COVID-19 therapies.
Proteome allocation and the evolution of metabolic cross-feeding
Authors: Labourel Florian J. F. , Daubin Vincent , Menu Frédéric , Rajon Etienne 
Published: December 2021

AbstractMetabolic cross-feeding (MCF) is a widespread type of ecological interaction where organisms share nutrients. In a common instance of MCF, an organism incompletely metabolises sugars and releases metabolites that are used by another as a carbon source to produce energy. Why would the former waste edible food, and why does this preferentially occur at specific locations in the sugar metabolic pathway (acetate and glycerol are preferentially exchanged) have challenged evolutionary theory for decades. Addressing these questions requires to model the cellular features involved; to this end, we built an explicit model of metabolic reactions, including their enzyme-driven catalysis and the cellular constraints acting on the proteome that may incur a cost to expressing all enzymes along a pathway. After showing that cells should in principle prioritise upstream reactions when metabolites are restrained inside the cell, we investigate how the diffusivity of these metabolites may trigger the emergence of MCF in a population. We find that the occurrence of MCF is rare and requires that an intermediate metabolite be extremely diffusive: indeed, up to high membrane permeability coefficients, the expected evolutionary outcome is not a diversification that resembles MCF but a single genotype that instead overexpresses downstream enzymes. Only at very high levels of membrane permeability and under distinctive sets of parameters should the population diversify and MCF evolve. These results help understand the origins of simple microbial communities, and may later be extended to investigate how evolution has progressively built up today’s extremely diverse communities.Significance statementCan two species thrive on a single energetic resource? While the competitive exclusion principle predicts that one in the pair should go extinct, it may occur that an organism releases partly metabolised molecules in the environment, securing an ecological niche for a second organism in a specialisation process called metabolic cross-feeding. Here we investigate how evolution may favor the waste of a useful resource using a model that considers how a cell packed with proteins may be less efficient, hence favoring a shortening of metabolic pathways in order to reduce cell packing. Our model indicates that such specialisation only occurs under restricted conditions. Incidentally, this makes the signatures of cross-feeding, such as which metabolites are preferentially involved, quite predictable.
Targeting macrophages with CAR-T cells delays solid tumor progression and enhances anti-tumor immunity
Authors: Sánchez-Paulete Alfonso R. , Mateus-Tique Jaime , Mollaoglu Gurkan , Nielsen Sebastian R. , Marks Adam , Lakshmi Ashwitha , Pia Luisanna , Baccarini Alessia , Merad Miriam , Brown Brian D. 
Published: December 2021

ABSTRACTTumor-associated macrophages (TAMs) are one of the most abundant cell types in many solid tumors and typically exert protumor effects. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials. Here, we report the development of a strategy for TAM depletion in mouse solid tumor models using chimeric antigen receptor (CAR) T cells targeting the macrophage marker F4/80 (F4.CAR-T). F4.CAR-T cells effectively killed macrophages in vitro and in vivo without toxicity. When injected into mice bearing orthotopic lung tumors, F4.CAR-T cells infiltrated tumor lesions and delayed tumor growth comparably to PD1 blockade, and significantly extended mouse survival. Anti-tumor effects were mediated by F4.CAR-T-produced IFN-γ, which promoted upregulation of MHC molecules on cancer cells and tumor-infiltrating myeloid cells. Notably, F4.CAR-T promoted expansion of endogenous CD8 T cells specific for tumor-associated antigens and led to immune editing of highly antigenic tumor cell clones. Antitumor impact was also observed in mouse models of ovarian and pancreatic cancer. These studies provide proof-of-principle evidence to support CAR-T targeting of TAMs as a means to enhance antitumor immunity.