bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mark loss can strongly bias demographic rates in multi-state models: a case study with simulated and empirical datasets
Authors: Touzalin Frédéric , Petit Eric J. , Cam Emmanuelle , Stagier Claire , Teeling Emma C. , Puechmaille Sébastien J. 
Published: March 2022

AbstractThe development of methods for individual identification in wild species and the refinement of Capture-Mark-Recapture (CMR) models over the past few decades have greatly improved the assessment of population demographic rates to address ecological and conservation questions. In particular, multi-state models, which offer flexibility in analysing complex study systems, have gained popularity within the ecological community. In this study, we focus on the issue of mark loss and the associated recycling of remarked individuals, which requires further exploration given the increasing use of these models.To fill this knowledge gap, we employed a wide range of simulation scenarios that reflect commonly encountered real case studies, drawing inspiration from the survival rates of 700 vertebrate species. Using a multi-state, Arnason-Schwartz (AS) modelling framework, we estimated the effects of mark loss and recycled individuals on parameter estimates. We assessed parameter bias by simulating a metapopulation system with varying capture and survival rates. Additionally, we demonstrated how mark loss can be easily estimated and accounted for using a 10-year empirical CMR dataset of bats. The bats were individually identified using Passive Integrated Transponder (PIT) tag technology as potentially lost marks and multi-locus genotypes as ’permanent marks’.Our simulation results revealed that the occurrence of bias and the affected parameters were highly dependent on the study system, making it difficult to establish general rules to predict biasa priori. The model structure and the interdependency among parameters pose challenges in predicting the impact of bias on estimates.Our findings underscore the importance of assessing the effect of mark loss when using AS models. Ignoring such violations of model assumptions can have significant implications for ecological inferences and conservation policies. In general, the use of permanent marks, such as genotypes, should always be preferred when modelling population dynamics. If that is not feasible, an alternative is to combine two independent types of temporary marks, such as PIT tags and bands.Analysis of our empirical dataset onMyotis myotisbats revealed that tag loss is higher in juveniles than in adults during the first year after tagging. The use of surgical glue to close the injection hole reduces tag loss rate from 28% to 19% in juveniles, while it has no effect on the tag loss rate in adults (∼10%). The main bias observed in our metapopulation system appears in the survival rate, with up to a 20% underestimation if tag loss is not accounted for.
Peripheral blood T-cell deficiency and hyperinflammatory monocyte responses associate with MAC lung disease
Authors: Lindestam Arlehamn Cecilia S. , Benson Basilin , Kuan Rebecca , Dill-McFarland Kimberley A. , Peterson Glenna J. , Paul Sinu , Nguyen Felicia K. , Gilman Robert H. , Saito Mayuko , Taplitz Randy , Arentz Matthew , Goss Christopher H. , Aitken Moira L. , Horne David J. , Shah Javeed A. , Sette Alessandro , Hawn Thomas R. 
Published: March 2022

AbstractRationaleAlthough nontuberculous mycobacterial (NTM) disease is a growing problem, available treatments are suboptimal and diagnostic tools are inadequate. Immunological mechanisms of susceptibility to NTM disease are poorly understood.ObjectiveTo understand NTM pathogenesis, we evaluated innate and antigen-specific adaptive immune responses to Mycobacterium avium complex (MAC) in individuals with MAC lung disease (MACDZ).MethodsWe synthesized 15mer MAC-, NTM-, or MAC/Mtb-specific peptides and stimulated peripheral blood mononuclear cells (PBMC) with pools of these peptides. We measured T-cell responses by cytokine production, expression of surface markers, and analysis of global gene expression in 27 MACDZ individuals and 32 healthy controls. We also analyzed global gene expression in Mav-infected and uninfected peripheral blood monocytes from 17 MACDZ and 17 healthy controls.Measurements and Main ResultsWe were unable to detect T-cell responses against the peptide libraries or Mav lysate that has increased reactivity in MACDZ subjects compared to controls. T-cell responses to non-mycobacteria derived antigens were preserved.MACDZ individuals had a lower frequency of Th1 and Th1* T-cell populations. By contrast, global gene expression analysis demonstrated upregulation of proinflammatory pathways in uninfected and Mav-infected monocytes derived from MACDZ subjects compared to controls.ConclusionsPeripheral blood T-cell responses to Mycobacterial antigens and the frequency of Th1 and Th1* cell populations are diminished in individuals with MAC disease. In contrast, MACDZ subjects had hyperinflammatory monocyte responses. Together, these data suggest a novel immunologic defect which underlies MAC pathogenesis and includes concurrent innate and adaptive dysregulation.
A Conformation-specific Nanobody Targeting the NMN-activated State of SARM1
Authors: Hou Yun Nan , Cai Yang , Li Wan Hua , He Wei Ming , Zhao Zhi Ying , Zhu Wen Jie , Wang Qiang , Liu Jun , Lee Hon Cheung , Goran Stjepanovic , Zhang Hongmin , Zhao Yong Juan 
Published: March 2022

AbstractUpon axonal injury, Sterile alpha (SAM) and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1) is activated by nicotinamide mononucleotide (NMN) to deplete NAD and consequently promote the process of axon degeneration (AxD). Currently, only the inactive form of SARM1 in its auto-inhibitory conformation has been resolved. The flexibility of the enzymatically active form of SARM1 has so far precluded its structural determination. To solve the problem, we generated a stabilizing nanobody, Nb-C6, that specifically recognized only the NMN-activated form of SARM1. The conformation specificity was verified by immunoprecipitation and surface plasmon resonance. Fluorescently labeled Nb-C6 could immunostain only the activated SARM1 in cells stimulated with CZ-48, a permeant mimetic of NMN. Expression of Nb-C6 in live cells resulted in stabilization of the active form of the endogenous and exogenous SARM1, producing and elevating cellular levels of cyclic ADP-ribose, a calcium messenger. Cryo-EM of the NMN-activated SARM1 complexed by Nb-C6 showed an octameric structure resembling a “blooming lotus” with the ARM domains bending significantly inward and swinging out together with the TIR domains to form the “petals of the lotus”. Nb-C6 bound to the SAM domain of the activated SARM1 and stabilized its Armadillo repeat motif domain. Analyses using hydrogen-deuterium exchange mass spectrometry (HDX-MS), and cross-linking MS (XL-MS) indicate that the activated SARM1 is highly dynamic and flexible and the neighboring TIRs form dimers via the surface close to one BB loop. The Nanobody is thus a valuable tool for delineating the mechanism of activation of SARM1 in AxD and other cellular processes.
Topographic axonal projection at single-cell precision supports local retinotopy in the mouse superior colliculus
Authors: Molotkov Dmitry , Ferrarese Leiron , Boissonnet Tom , Asari Hiroki 
Published: March 2022

AbstractRetinotopy, like all long-range projections, can arise from the axons themselves or their targets. The underlying connectivity pattern, however, remains elusive at the fine scale in the mammalian brain. To address this question, we functionally mapped the spatial organization of the input axons and target neurons in the mouse retinocollicular pathway at single-cell resolution usingin vivotwo-photon calcium imaging. We found a near-perfect retinotopic tiling of retinal ganglion cell axon terminals, with an average error below 30 μm or 2 degrees of visual angle. The precision of retinotopy was relatively lower for local neurons in the superior colliculus. Subsequent data-driven modelling ascribed it to a low input convergence, on average 5.5 retinal ganglion cell inputs to a postsynaptic cell in the superior colliculus. These results indicate that retinotopy arises largely from topographically precise input from presynaptic cells, rather than elaborating local circuitry to reconstruct the topography by postsynaptic cells.
Model biomolecular condensates have heterogeneous structure quantitatively dependent on the interaction profile of their constituent macromolecules
Authors: Shillcock Julian C. , Lagisquet Clément , Alexandre Jérémy , Vuillon Laurent , Ipsen John H. 
Published: March 2022

AbstractBiomolecular condensates play numerous roles in cells by selectively concentrating client proteins while excluding others. These functions are likely to be sensitive to the spatial organization of the scaffold proteins forming the condensate. We use coarse-grained molecular simulations to show that model intrinsically-disordered proteins phase separate into a heterogeneous, structured fluid characterized by a well-defined length scale. The proteins are modelled as semi-flexible polymers with punctate, multifunctional binding sites in good solvent conditions. Their dense phase is highly solvated with a spatial structure that is more sensitive to the separation of the binding sites than their affinity. We introduce graph theoretic measures to show that the proteins are heterogeneously distributed throughout the dense phase, an effect that increases with increasing binding site number, and exhibit multi-timescale dynamics. The simulations predict that the structure of the dense phase is modulated by the location and affinity of binding sites distant from the termini of the proteins, while sites near the termini more strongly affect its phase behaviour. The relations uncovered between the arrangement of weak interaction sites on disordered proteins and the material properties of their dense phase can be experimentally tested to give insight into the biophysical properties and rational design of biomolecular condensates.
Sex-specific effects of chronic paternal stress on offspring development are partially mediated via mothers
Authors: Mashoodh Rahia , Habrylo Ireneusz B. , Gudsnuk Kathryn , Champagne Frances A. 
Published: March 2022

AbstractPaternal stress exposure is known to impact the development of stress-related behaviors in offspring. Previous work has highlighted the importance of sperm mediated factors, such as RNAs, in transmitting the effects of parental stress. However, a key unanswered question is whether mothers’ behavior could drive or modulate the transmission of paternal stress effects on offspring development. Here we investigate how chronic variable stress in Balb/C mice influences the sex-specific development of anxiety- and depression-like neural and behavioral development in offspring. Moreover, we examined how stressed fathers influenced mate maternal investment towards their offspring and how this may modulate the transmission of paternal stress effects on offspring. We show that paternal stress leads to sex-specific effects on offspring behavior. Males that are chronically stressed sire female offspring that show increased anxiety and depression-like behaviors. However, male offspring of stressed fathers show reductions in anxiety- and depression-behaviors and are generally more exploratory. Moreover, we show that females mated with stressed males gain less weight during pregnancy and provide less care towards their offspring which additionally influenced offspring development. These data indicate that paternal stress can influence offspring development directly and indirectly via changes in mothers, with implications for divergent development between male and female offspring.
Petascale pipeline for precise alignment of images from serial section electron microscopy
Authors: Popovych Sergiy , Macrina Thomas , Kemnitz Nico , Castro Manuel , Nehoran Barak , Jia Zhen , Bae J. Alexander , Mitchell Eric , Mu Shang , Trautman Eric T. , Saalfeld Stephan , Li Kai , Seung Sebastian 
Published: March 2022

AbstractThe reconstruction of neural circuits from serial section electron microscopy (ssEM) images is being accelerated by automatic image segmentation methods. Segmentation accuracy is often limited by the preceding step of aligning 2D section images to create a 3D image stack. Precise and robust alignment in the presence of image artifacts is challenging, especially as datasets are attaining the petascale. We present a computational pipeline for aligning ssEM images with several key elements. Self-supervised convolutional nets are trained via metric learning to encode and align image pairs, and they are used to initialize iterative fine-tuning of alignment. A procedure called vector voting increases robustness to image artifacts or missing image data. For speedup the series is divided into blocks that are distributed to computational workers for alignment. The blocks are aligned to each other by composing transformations with decay, which achieves a global alignment without resorting to a time-consuming global optimization. We apply our pipeline to a whole fly brain dataset, and show improved accuracy relative to prior state of the art. We also demonstrate that our pipeline scales to a cubic millimeter of mouse visual cortex. Our pipeline is publicly available through two open source Python packages.
Exosomally targeting microRNA23a ameliorates microvascular endothelial barrier dysfunction following rickettsial infection
Authors: Zhou Changcheng , Bei Jiani , Qiu Yuan , Chang Qing , Nyong Emmanuel , Yang Jun , Krishnan Balaji , Khanipov Kamil , Jin Yang , Fang Xiang , Gaitas Angelo , Gong Bin 
Published: March 2022

AbstractSpotted fever group rickettsioses caused by Rickettsia (R) are devastating human infections, which mainly target microvascular endothelial cells (EC) and can induce lethal EC barrier dysfunction in the brain and lungs. Our previous evidence reveals that exosomes (Exos) derived from rickettsial-infected ECs, namely R-ECExos, can induce disruption of the tight junctional (TJ) protein ZO-1 and barrier dysfunction of human normal recipient brain microvascular endothelial cells (BMECs). However, the underlying mechanism remains elusive. Given that we have observed that microRNA23a (miR23a), a negative regulator of endothelial ZO-1 mRNA, is selectively sorted into R-ECExos, the aim of the present study was to characterize the potential functional role of exosomal miR23a delivered by R-ECExos in normal recipient BMECs. We demonstrated that EC-derived Exos (ECExos) have the capacity to deliver oligonucleotide RNAs to normal recipient BMECs in an RNase-abundant environment. miR23a in ECExos impairs normal recipient BMEC barrier function, directly targeting TJ protein ZO-1 mRNAs. In separate studies using a traditional in vitro model and a novel single living-cell biomechanical assay, our group demonstrated that miR23a anti-sense oligonucleotide-enriched ECExos ameliorate R-ECExo-provoked recipient BMEC dysfunction in association with stabilization of ZO-1 in a dose-dependent manner. These results suggest that Exo-based therapy could potentially prove to be a promising strategy to improve vascular barrier function during bacterial infection and concomitant inflammation.
Targeting tumor stemness switch phenotype by activating pathogen induced stem cell niche defense
Authors: Bhuyan Seema , Pal Bidisha , Pathak Lekhika , Saikia Partha Jyoti , Mitra Shirsajit , Gayan Sukanya , Mokhtari Reza Bayat , Li Hong , Ramana Chilakamarti V , Baishya Debabrat , Das Bikul 
Published: March 2022

AbstractCancer stem cells (CSCs) reside in their tumor microenvironment (TME) niches, which are often hypoxic. Previously, we found that hypoxia and oxidative stress prevalent in TME may reprogram CSCs to a highly aggressive and inflammatory phenotype, the tumor stemness switch (TSS) phenotype. We previously reported a “stem cell niche defense” mechanism in bone marrow and lung mesenchymal stem cell niche against pathogen. Pathogen induced bystander apoptosis (PIBA) of stem cells harboring intracellular pathogen may be part of this defense mechanism. We speculate that the TSS phenotype may also activate this niche defense mechanism to defend their TME niche against pathogen and therefore could be exploited to target CSCs. Here we report that CSCs of TSS phenotype enriched in post-hypoxia ABCG2+ CSCs of several cell lines of diverse tumors including oral squamous cell carcinoma cell line SCC-25 exhibited bystander apoptosis when infected with either Bacillus Calmette Guerin (BCG) or mutantMycobacterium tuberculosis (Mtb) strain 18b. The conditioned media (CM) of the infected cells not only exhibited marked anti-tumor activity in vivo, but also showed significant anti-microbial activity. A detailed mechanisms study revealed that some of the infected ABCG2+ CSCs underwent pyroptosis and released a high mobility group box protein 1 (HMGB1)/p53 death signal that can induce a toll like receptor (TLR) 2/4 mediated bystander apoptosis. Thus, our findings suggest that PIBA can be utilized to activate the “niche defense” mechanism in TSS phenotype, which not only target the TSS, but also exhibit marked anti-tumor activity in vivo.
Structure-guided synthesis of FK506 and FK520 analogs with increased selectivity exhibit in vivo therapeutic efficacy against Cryptococcus
Authors: Hoy Michael J. , Park Eunchong , Lee Hyunji , Lim Won Young , Cole D. Christopher , DeBouver Nicholas D. , Bobay Benjamin G. , Pierce Phillip G. , Fox David , Ciofani Maria , Juvvadi Praveen R. , Steinbach William , Hong Jiyong , Heitman Joseph 
Published: March 2022

AbstractCalcineurin is an essential virulence factor that is conserved across human fungal pathogens includingCryptococcus neoformans,Aspergillus fumigatus, andCandida albicans. Although an excellent target for antifungal drug development, the serine-threonine phosphatase activity of calcineurin is conserved in mammals and inhibition of this activity results in immunosuppression. FK506 (tacrolimus) is a naturally produced macrocyclic compound that inhibits calcineurin by binding to the immunophilin FKBP12. Previously, our fungal calcineurin-FK506-FKBP12 structure-based approaches identified a non-conserved region of FKBP12 that can be exploited for fungal-specific targeting. These studies led to the design of an FK506 analog, APX879, modified at the C22 position that was less immunosuppressive yet maintained antifungal activity. We now report high resolution protein crystal structures of fungal FKBP12 and a human truncated calcineurin-FKBP12 bound to a natural FK506 analog, FK520 (ascomycin). Based on information from these structures and the success of APX879, we synthesized and screened a novel panel of C22-modified compounds derived from both FK506 and FK520. One compound, JH-FK-05 demonstrates broad-spectrum antifungal activityin vitroand is non-immunosuppressivein vivo. In murine models of pulmonary and disseminatedC. neoformansinfection, JH-FK-05 treatment significantly reduced fungal burden and extended animal survival alone and in combination with fluconazole. Furthermore, molecular dynamic simulations performed with JH-FK-05 binding to fungal and human FKBP12 identified additional residues outside of the C22 and C21 positions that could be modified to generate novel FK506 analogs with improved antifungal activity.SignificanceDue to rising rates of antifungal drug resistance and a limited armamentarium of antifungal treatments, there is a paramount need for novel antifungal drugs to treat systemic fungal infections. Calcineurin has been established as an essential and conserved virulence factor in several fungi, making it an attractive antifungal target. However, due to the immunosuppressive action of calcineurin inhibitors, they have not been successfully utilized clinically for antifungal treatment in humans. Recent availability of crystal structures of fungal calcineurin bound inhibitor complexes have enabled the structure-guided design of FK506 analogs and led to a breakthrough in the development of a compound increased for fungal specificity. The development of a calcineurin inhibitor with reduced immunosuppressive activity and therapeutic antifungal activity would add a significant tool to the treatment options for these invasive fungal infections with exceedingly high rates of mortality.
Facultative parthenogenesis: a transient state in transitions between sex and obligate asexuality in stick insects?
Authors: Larose Chloé , Lavanchy Guillaume , Freitas Susana , Parker Darren J. , Schwander Tanja 
Published: March 2022

AbstractTransitions from obligate sex to obligate parthenogenesis have occurred repeatedly across the tree of life. Whether these transitions occur abruptly or via a transient phase of facultative parthenogenesis is rarely known. We discovered and characterised facultatively parthenogenetic populations of the North American stick insectTimema douglasi, a species in which only obligately parthenogenetic populations were known so far. These populations comprised three genetic lineages. Females from all lineages were capable of parthenogenesis (with variable efficiency) but their propensity to reproduce sexually after mating varied extensively. In all three lineages, parthenogenesis resulted in the complete loss of heterozygosity in a single generation. Obligately parthenogeneticTimemahave also lost all heterozygosity, suggesting that the transition to obligate parthenogenesis did not require a modification of the proximate mechanism, but rather involved a gradual increase in frequency. We speculate that facultative parthenogenesis may often be transient and be replaced by obligate strategies (either sex or parthenogenesis) because of a trade-off between the efficiency of the two reproductive modes. Such a trade-off could help explain why facultative parthenogenesis is rare among animals, despite its potential to combine the known benefits of sex and parthenogenesis.
Treatment with an Antigen-Specific Dual Microparticle System Reverses Advanced Multiple Sclerosis in Mice
Authors: Kwiatkowski Alexander J , Helm Eric Y , Stewart Joshua M , Drashansky Theodore T , Cho Jonathan J , Avram Dorina , Keselowsky Benjamin G 
Published: March 2022

AbstractAntigen-specific therapies hold promise for treating autoimmune diseases such as multiple sclerosis while avoiding the deleterious side effects of systemic immune suppression. In this study, an antigen-specific dual-sized microparticle (dMP) immunotherapy reversed hind limb paralysis when administered in mice with advanced experimental autoimmune encephalomyelitis (EAE). Treatment reduced central nervous system (CNS) immune cell infiltration, demyelination and inflammatory cytokine levels. Mechanistic insights using single-cell RNA sequencing showed that treatment impacted the MHC II antigen presentation pathway in dendritic cells, macrophages, B cells and microglia, not only in the draining lymph nodes, but strikingly also in the spinal cord. CD74 and cathepsin S were among the common genes downregulated in most antigen presenting cell (APC) clusters, with B cells also having numerous MHC II genes reduced. Efficacy of the treatment diminished when B cells were absent, suggesting their impact in this therapy, in concert with other immune populations. Activation and inflammation were reduced in both APCs and T cells. This promising antigen-specific therapeutic approach advantageously engaged essential components of both innate and adaptive autoimmune responses, and capably reversed paralysis in advanced EAE without the use of broad immunosuppressant.Significance StatementMultiple sclerosis (MS) is a debilitating autoimmune disease that can lead to paralysis. We demonstrate an antigen-specific microparticle treatment can reverse hind limb paralysis when administered in advanced EAE. Single-cell RNA-sequencing and flow cytometry analysis provide evidence the treatment acts by diminishing Ag presentation in APCs, including B cells in the CNS and the draining lymph nodes. Thus, the antigen-specific dual-sized microparticle treatment is a promising therapy even in advanced EAE, and potentially MS.