bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing the dynamics ofMycobacterium bovisinfection in three French badger populations
Authors: Calenge Clément , Payne Ariane , Réveillaud Édouard , Richomme Céline , Girard Sébastien , Desvaux Stéphanie 
Published: June 2023

AbstractThe Sylvatub system is a national surveillance program established in 2011 in France to monitor infections caused byMycobacterium bovis, the main etiologic agent of bovine tuberculosis, in wild species. This participatory program, involving both national and local stakeholders, allowed us to monitor the progression of the infection in three badger populations in clusters covering between 3222 km2and 7698 km2from 2013 to 2019. In each cluster, badgers were trapped and tested forM. bovis. Our first aim was to describe the dynamics of the infection in these clusters. We developed a Bayesian model of prevalence accounting for the spatial structure of the cases, the imperfect and variable sensitivity of the diagnostic tests, and the correlation of the infection status of badgers in the same commune caused by local factors (e.g., social structure and proximity to infected farms). This model revealed that the prevalence increased with time in one cluster (Dordogne/Charentes), decreased in the second cluster (Burgundy), and remained stable in the third cluster (Bearn). In all the clusters, the infection was strongly spatially structured, whereas the mean correlation between the infection status of the animals trapped in the same commune was negligible. Our second aim was to develop indicators for monitoringM. bovisinfection by stakeholders of the program. We used the model to estimate, in each cluster, (i) the mean prevalence level at mid-period, and (ii) the proportion of the badger population that became infected in one year. We then derived two indicators of these two key quantities from a much simpler regression model, and we showed how these two indicators could be easily used to monitor the infection in the three clusters. We showed with simulations that these two simpler indicators were good approximations of these key quantities.
Ribosome clustering and surface layer reorganization in the microsporidian host-invasion apparatus
Authors: Sharma Himanshu , Jespersen Nathan , Ehrenbolger Kai , Carlson Lars-Anders , Barandun Jonas 
Published: June 2023

AbstractDuring host cell invasion, microsporidian spores translocate their entire cytoplasmic content through a thin, hollow superstructure known as the polar tube. To achieve this, the polar tube transitions from a compact spring-like state inside the environmental spore to a long needle-like tube capable of long-range sporoplasm delivery. The unique mechanical properties of the building blocks of the polar tube allow for an explosive transition from compact to extended state and support the rapid cargo translocation process. The molecular and structural factors enabling this ultrafast process and the structural changes during cargo delivery are unknown. Here, we employ light microscopy and in situ cryo-electron tomography to visualize multiple ultrastructural states of the polar tube, allowing us to evaluate the kinetics of its germination and characterize the underlying morphological transitions. We describe a cargo-filled state with a unique ordered arrangement of microsporidian ribosomes, which cluster along the thin tube wall, and an empty post-translocation state with a reduced diameter but a thicker wall. Together with a proteomic analysis of endogenously affinity-purified polar tubes, our work provides comprehensive data on the infection apparatus of microsporidia and demonstrates that ribosomes are efficiently transported through polar tubes in a spiral-like parallel arrangement.
Non-genetic differences underlie variability in proliferation among esophageal epithelial clones
Authors: Reyes Hueros Raúl A. , Gier Rodrigo A. , Shaffer Sydney M. 
Published: June 2023

AbstractThe growth potential of individual epithelial cells is a key determinant of tissue development, homeostasis, and disease progression. Although it is known that epithelial progenitor cells vary in their proliferative capacity, the cell states underlying these differences are yet to be uncovered. Here we performed clonal tracing through imaging and cellular barcoding of an in vitro model of esophageal epithelial cells (EPC2-hTERT). We found that individual clones possess unique growth and differentiation capacities, with a subset of clones growing exponentially. Further, we discovered that this proliferative potential for a clone is heritable through cell division and can be influenced by extrinsic cues from neighboring cells. Combining barcoding with single-cell RNA-sequencing (scRNA-seq), we identified the cellular states associated with the highly proliferative clones, which include genes in the WNT and PI3K pathways. Importantly, we also identified a subset of cells resembling the highly proliferative cell state in the healthy human esophageal epithelium and, to a greater extent, in esophageal squamous cell carcinoma (ESCC). These findings highlight the physiological relevance of our cell line model, providing insights into the behavior of esophageal epithelial cells during homeostasis and disease.
A NanoDam toolkit for tissue-specific transcription factor profiling inC. elegans
Authors: Yee Callista , Xiao Yutong , Katsanos Dimitris , Medwig-Kinney Taylor N. , Zhang Wan , Shen Kang , Matus David Q. , Barkoulas Michalis 
Published: June 2023

AbstractDuring development of multicellular organisms, cells must execute precise molecular decisions to achieve cell fate specification and differentiation. These decisions are orchestrated by networks of transcription factors (TFs) which act to regulate gene expression of specific cohorts of genes to ultimately confer identity. Depending on the cellular context, TF expression can vary dramatically both spatially and temporally. These differences in expression patterns can result in tissue-specific differences in TF binding to downstream targets. To identify targets on a tissue-specific basis, Targeted DamID (TaDa) has been recently introduced to generate TF binding profiles in various models includingC. elegans. However, TaDa suffers from portability such that a new promoter-TF fusion transgene must be constructed for every new experimental condition of interest. Here, we adapt NanoDam for usage inC. elegans, which relies on endogenous TF-GFP knock-ins, a plethora of which have already been generated by the community. We report that NanoDam single copy transgenes consisting of lowly expressed, tissue-specific GFP nanobody-Dam fusions, when combined with endogenous GFP-tagged alleles of TFs, results in robust, tissue-specific profiling. Using an endogenous GFP-tagged allele of EGL-43/EVI1, we performed NanoDam profiling of two disparate tissue types, the anchor cell (AC) and dopaminergic neurons, and identify targets unique to each and shared by both cell types. We also identify two GATA TFs, ELT-6 and EGL-18, as novel regulators of AC invasion. Together, we demonstrate that NanoDam is capable of profiling endogenous GFP-tagged TFs to identify novel downstream targets in specific cell types ofC. elegans.
Behavioral control through the direct, focal silencing of neuronal activity
Authors: Elleman Anna V. , Milicic Nikola , Williams Damian J. , Liu Christine J. , Haynes Allison L. , Simko Jane , Ehrlich David E. , Makinson Christopher D. , Bois J. Du 
Published: June 2023

ABSTRACTVoltage-gated sodium channel (NaV) activity underlies electrical signaling, synaptic release, circuit function, and, ultimately, behavior. Molecular tools that enable precise control of NaVsubpopulations make possible temporal regulation of neuronal activity and cellular communication. To rapidly modulate NaVcurrents, we have rendered a potent NaVinhibitor, saxitoxin, transiently inert through chemical protection with a novel nitrobenzyl-derived photocleavable group. Light-induced uncaging of the photocaged toxin, STX-bpc, effects rapid inhibitor release and focal NaVblock. We demonstrate the efficacy of this reagent for manipulating action potentials in mammalian neurons and brain slice and for altering locomotor behavior in larval zebrafish. Photo-uncaging of STX-bpc is a non-invasive, effective method for reversible, spatiotemporally precise tuning of NaVcurrents, application of which requires no genetic manipulation of the biological sample.
Atg8-LC3 controls systemic nutrient surplus signaling from flies to humans
Authors: Madan Aditi , Kelly Kevin P. , Sullivan Camille E. , Poling Michelle E. , Brent Ava E. , Alassaf Mroj , Dubrulle Julien , Rajan Akhila 
Published: June 2023

AbstractOrganisms experience constant nutritional flux, and homeostatic mechanisms evolved to operate at the nexus of extreme nutritional states - scarcity and surplus. Thus, we surmised that decoding bidirectional molecular switches that operate at the interface of scarcity response and surplus signaling will enable the development of strategies to treat disorders that arise from nutrient imbalance states. Adipocytes secrete leptin, an interleukin protein, which signals nutrient surplus to the central brain to regulate feeding and energy expenditure. We report that Atg8-LC3-family proteins, best known for their role in autophagy, are required for leptin secretion inDrosophilaand human adipocytes. Atg8-LC3 genetic knockdown and point mutations to the Atg8-LC3 interaction motif (AIM/LIR) of leptin, and its functional ortholog inDrosophila, Upd2, disrupt adipokine secretion and increase adipokine retention in human and fly cells. At an organismal level, Atg8-driven Upd2 retention increases organismal resilience to nutrient extremes by rewiring the transcriptome, organismal feeding behavior, and hunger response. Comparative proteomic analyses reveal that LC3 directs leptin to an exosome secretory pathway. We use genetic knockdown in primary human adipocytes to establish that LC3 is required for leptin secretion in a physiologically relevant mammalian system. Hence, we uncover a previously unknown and evolutionarily conserved role for Atg8-LC3 in promoting adipocyte-brain nutrient surplus signaling. We propose that Atg8-LC3’s bidirectional role in nutrient sensing-conveying nutrient surplus and responding to nutrient deprivation-enables organisms to manage nutrient flux effectively.
Offline Two-dimensional Liquid Chromatography-Mass Spectrometry for Deep Annotation of the Fecal Metabolome
Authors: Anderson Brady G. , Raskind Alexander , Hissong Rylan , Dougherty Michael K. , McGill Sarah K. , Gulati Ajay , Theriot Casey M. , Kennedy Robert T. , Evans Charles R. 
Published: June 2023

ABSTRACTCompound identification is an essential task in the workflow of untargeted metabolomics since the interpretation of the data in a biological context depends on the correct assignment of chemical identities to the features it contains. Current techniques fall short of identifying all or even most observable features in untargeted metabolomics data, even after rigorous data cleaning approaches to remove degenerate features are applied. Hence, new strategies are required to annotate the metabolome more deeply and accurately. The human fecal metabolome, which is the focus of substantial biomedical interest, is a more complex, more variable, yet lesser-investigated sample matrix compared to widely studied sample types like human plasma. This manuscript describes a novel experimental strategy using multidimensional chromatography to facilitate compound identification in untargeted metabolomics. Pooled fecal metabolite extract samples were fractionated using offline semi-preparative liquid chromatography. The resulting fractions were analyzed by an orthogonal LC-MS/MS method, and the data were searched against commercial, public, and local spectral libraries. Multidimensional chromatography yielded more than a 3-fold improvement in identified compounds compared to the typical single-dimensional LC-MS/MS approach and successfully identified several rare and novel compounds, including atypical conjugated bile acid species. Most features identified by the new approach could be matched to features that were detectable but not identifiable in the original single-dimension LC-MS data. Overall, our approach represents a powerful strategy for deeper annotation of the metabolome that can be implemented with commercially-available instrumentation, and should apply to any dataset requiring deeper annotation of the metabolome.
Functional ultrasound imaging of stroke in awake rats
Authors: Brunner Clément , Montaldo Gabriel , Urban Alan 
Published: June 2023

AbstractAnesthesia is a major confounding factor in preclinical stroke research as stroke rarely occurs in sedated patients. Moreover, anesthesia affects both brain functions and the stroke outcome acting as neurotoxic or protective agent. So far, no approaches were well suited to induce stroke while imaging hemodynamics along with simultaneous large-scale recording of brain functions in awake animals. For this reason, the first critical hours following the stroke insult and associated functional alteration remain poorly understood. Here, we present a strategy to investigate both stroke hemodynamics and stroke-induced functional alterations without the confounding effect of anesthesia, i.e., under awake condition. Functional ultrasound (fUS) imaging was used to continuously monitor variations in cerebral blood volume (CBV) in +65 brain regions/hemisphere for up to 3hrs after stroke onset. The focal cortical ischemia was induced using a chemo-thrombotic agent suited for permanent middle cerebral artery occlusion in awake rats, and followed by ipsi- and contralesional whiskers stimulation to investigate on the dynamic of the thalamo-cortical functions. Early (0-3hrs) and delayed (day 5) fUS recording enabled to characterize the features of the ischemia (location, CBV loss), spreading depolarizations (occurrence, amplitude) and functional alteration of the somatosensory thalamo-cortical circuits. Post-stroke thalamo-cortical functions were affected not only early after the stroke onset but were also altered secondarly and remotely from the initial insult. Overall, our procedure enables early, continuous, and chronic evaluations of hemodynamics and brain functions which, combined to stroke or other pathologies, aims to better understand physiopathologies toward the development of clinically relevant therapeutic strategies.
Gap junctions arbitrate binocular course control in flies
Authors: Pokusaeva Victoria O. , Satapathy Roshan , Symonova Olga , Jösch Maximilian 
Published: June 2023

AbstractAnimals utilize visual motion cues to maintain stability and navigate accurately. The optomotor response, a reflexive behavior for visual stabilization, has been used to study this visuomotor transformation. However, there is a disparity between the simplicity of this behavior and the intricate circuit components believed to govern it. Here we bridge this divide by exploring the course control repertoire inDrosophilaand establishing a direct link between behavior and the underlying circuit motifs. Specifically, we demonstrate that visual motion information from both eyes plays a crucial role in movement control through bilateral interactions facilitated by gap junctions. These electrical interactions augment the classic stabilization behavior by inverting the response direction and the behavioral strategy. Our findings reveal how animals combine monocular motion cues to generate a variety of behaviors, determine the functional role of the circuit components, and show that gap junctions can mediate non-linear operations with a decisive role in animal behavior.
Proteostatic tuning underpins the evolution of novel multicellular traits
Authors: Montrose Kristopher , Lac Dung T. , Burnetti Anthony J. , Tong Kai , Bozdag G. Ozan , Hukkanen Mikaela , Ratcliff William C. , Saarikangas Juha 
Published: June 2023

AbstractThe evolution of multicellularity paved the way for the origin of complex life on Earth, but little is known about the mechanistic basis of early multicellular evolution. Here, we examine the molecular basis of multicellular adaptation in the Multicellularity Long Term Evolution Experiment (MuLTEE). We demonstrate that cellular elongation, a key adaptation underpinning increased biophysical toughness and organismal size, is convergently driven by downregulation of the chaperone Hsp90. Mechanistically, Hsp90-mediated morphogenesis operates by destabilizing the cyclin-dependent kinase Cdc28, resulting in delayed mitosis and prolonged polarized growth. Reinstatement of Hsp90 or Cdc28 expression resulted in shortened cells that formed smaller groups with reduced multicellular fitness. Together, our results show how ancient protein folding systems can be tuned to drive rapid evolution at a new level of biological individuality by revealing novel developmental phenotypes.TeaserDownregulation of Hsp90 decouples cell cycle progression and growth to drive the evolution of macroscopic multicellularity.
SARS-CoV-2 human challenge reveals single-gene blood transcriptional biomarkers that discriminate early and late phases of acute respiratory viral infections
Authors: Rosenheim Joshua , Gupta Rishi K , Thakker Clare , Mann Tiffeney , Bell Lucy CK , Broderick Claire M , Madon Kieran , Papargyris Loukas , Dayananda Pete , Kwok Andrew J , Greenan-Barrett James , Wagstaffe Helen R , Conibear Emily , Fenn Joe , Hakki Seran , Lindeboom Rik GH , Dratva Lisa M , Lemetais Briac , Weight Caroline M , Venturini Cristina , Kaforou Myrsini , Levin Michael , Kalinova Mariya , Mann Alex , Catchpole Andrew , Knight Julian C , Nikolić Marko Z. , Teichmann Sarah A. , Killingley Ben , Barclay Wendy , Chain Benjamin M , Lalvani Ajit , Heyderman Robert S , Chiu Christopher , Noursadeghi Mahdad 
Published: June 2023

SummaryEvaluation of host-response blood transcriptional signatures of viral infection have so far failed to test whether these biomarkers reflect different biological processes that may be leveraged for distinct translational applications. We addressed this question in the SARS-CoV-2 human challenge model. We found differential time profiles for interferon (IFN) stimulated blood transcriptional responses represented by measurement of single genes. MX1 transcripts correlated with a rapid and transient wave of type 1 IFN stimulated genes (ISG) across all cell types, which may precede PCR detection of replicative infection. Another ISG, IFI27, showed a delayed but sustained response restricted to myeloid peripheral blood mononuclear cells, attributable to gene and cell-specific epigenetic regulation. These findings were reproducible in diverse respiratory virus challenges, and in natural infection with SARS-CoV-2 or unselected respiratory viruses. The MX1 response achieved superior diagnostic accuracy in early infection, correlation with viral load and identification of virus culture positivity, with potential to stratify patients for time sensitive antiviral treatment. IFI27 achieved superior diagnostic accuracy across the time course of symptomatic infection. Compared to blood, measurement of these responses in nasal mucosal samples was less sensitive and did not discriminate between early and late phases of infection.
Flexibly encoded GWAS identifies novel nonadditive SNPs in individuals of African and European ancestry
Authors: Zhou Jiayan , Guare Lindsay , Garao Rico Andre Luis , Zarzar Tomas Gonzalez , Palmiero Nicole , Assimes Themistocles L. , Verma Shefali Setia , Hall Molly Ann 
Published: June 2023

AbstractMost genome-wide association studies (GWASs) assume an additive inheritance model, where heterozygous genotypes (HET) are coded with half the risk of homozygous alternate genotypes (HA), leading to less explained nonadditive genetic effects for complex diseases. Yet, growing evidence indicates that with flexible modeling, many single-nucleotide polymorphisms (SNPs) show nonadditive effects, including dominant and recessive, which will be missed using only the additive model. We developed Elastic Data-Driven Encoding (EDGE) to determine the HET to HA ratio of risk. Simulation results demonstrated that EDGE outperformed traditional methods across all simulated models for power while maintaining a conserved false positive rate. This research lays the necessary groundwork for integrating nonadditive genetic effects into GWAS workflows to identify novel disease-risk SNPs, which may ultimately improve polygenic risk prediction in diverse populations and springboard future applications to thousands of disease phenotypes and other omic domains to improve disease-prediction capability.
Lower nerve growth factor levels in major depression and suicidal behaviors: effects of adverse childhood experiences and recurrence of illness
Authors: Maes Michael , Rachayon Muanpetch , Jirakran Ketsupar , Sodsai Pimpayao , Sughondhabirom Atapol 
Published: June 2023

AbstractBackgroundMajor depressive disorder (MDD) and its severe subtype, major dysmood disorder (MDMD), are distinguished by activation of inflammatory and growth factor subnetworks, which are associated with recurrence of illness (ROI) and adverse childhood experiences (ACE). Nerve growth factor (NGF) plays a crucial role in facilitating neuro-immune communications and may regulate the inflammatory response.MethodsThe present study examined the effects of ACE and ROI on culture supernatant NGF, stem cell factor (SCF), stem cell GF (SCGF), hepatocyte GF (HGF), and macrophage colony stimulating factor (M-CSF), in relation to a neurotoxicity (NT) cytokine profile.ResultsNGF levels are lower in MDD (p=0.003), particularly MDMD (p<0.001), as compared with normal controls. ROI and ACE were significantly and inversely associated with NGF (≤0.003) and the NGF/NT ratio (≤0.001), whereas there are no effects of ACE and ROI on SCF, SCGF, HGF, or M-CSF. Lowered NGF (p=0.003) and the NGF/NT ratio (p<0.001) are highly significantly and inversely associated with the severity of the current depression phenome, conceptualized as a latent vector extracted from the current severity of depression, anxiety, and suicidal behaviors. We found that one validated and replicable latent vector could be extracted from NGF, ROI, and the depression phenome, which therefore constitutes a novel ROI-NGF-pathway-phenotype. ACE explained 59.5% of the variance in the latter pathway phenotype (p<0.001).ConclusionsThe imbalance between decreased NGF and increased neurotoxic cytokines during the acute phase of severe depression may contribute to decreased neuroprotection, increased neuro-affective toxicity, and chronic mild inflammation.