bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lifetime development changes in rats tracked by urinary proteome
Authors: Pan Xuanzhen , Liu Yongtao , Bao Yijin , Gao Youhe 
Published: September 2022

AbstractThe existing researches mainly focus on the embryonic stage and a short time after that. However, there was little research about the whole life of an individual from childhood to aging and death. For the first time, we used non-invasive urinary proteome technology to track the changes of several important development timepoints in a batch of rats, covering the 10 timepoints from childhood, adolescence, young, middle adulthood, and to old age death. As previous studies on puberty found, sexual or reproductive maturation, mature spermatozoa in seminiferous tubules(first seen), gonadal hormones, decline of estradiol(E), brain growth and central nervous system myelination, and our differential protein enrichment pathways also included reproductive system development, tube development, response to hormone, response to estradiol, brain development, neuron development.Like previous studies found in young adulthood, musculoskeletal maturity, peak bone mass, development of the immune system, and growth and physical development, and our differential protein enrichment pathway also included skeletal system development, bone regeneration, system development, immune system process, myeloid leukocyte differentiation, growth, and developmental growth. However, at all timepoints in the whole life, there were still many biological pathways of the differential urinary protein enrichment involving multiple organs, tissues, systems, etc., which had not been mentioned by existing studies. This study provided comprehensive and detailed changes in rats’ lifetime development through urinary proteome, supplementing the blank of development research. But also provided a new idea for monitoring the human health change condition and the possibly occurring aging diseases by using the urinary proteome.SummaryAs far as we know, this is the first time that the urinary proteome was used to track the changes of several important developmental timepoints in the lifetime of rats.
Comparing multiscale, presence-only habitat suitability models created with structured survey data and community science data for a rare warbler species at the southern range margin
Authors: Whitenack Lauren E. , Taylor Sara Snell , Tomcho Aimee , Hurlbert Allen H. 
Published: September 2022

AbstractGolden-winged Warblers (Vermivora chrysoptera, Parulidae) are declining migrant songbirds that breed in the Great Lakes and Appalachian regions of North America. Within their breeding range, Golden-winged Warblers are found in early successional habitats adjacent to mature hardwood forest, and previous work has found that Golden-winged Warbler habitat preferences are scale-dependent. Golden-winged Warbler Working Group management recommendations were written to apply to large regions of the breeding range, but there may be localized differences in both habitat availability and preferences. Rapid declines at the southernmost extent of their breeding range in Western North Carolina and Georgia necessitate investigation into landscape characteristics governing distribution in this subregion. We describe patterns of Golden-winged Warbler presence in Western North Carolina by examining habitat variables at multiple spatial scales using data from standardized Audubon North Carolina (NC) surveys and unstructured community scientist checklists submitted to eBird. We compared model performance and predictions between Audubon NC and eBird models and found that Golden-winged Warbler presence is associated with sites which, at a local scale (150m), have more young forest, less mature forest, and more road cover, and at a landscape scale (2.5km), have less road cover. eBird and Audubon models had similar parameter estimates for all of the land cover variables and similar overall performance. Based on parameter estimates, road density at the landscape scale (2.5km) is the primary variable driving the difference between Golden-winged Warbler breeding sites and random background sites in Western North Carolina. Our results show that eBird data can produce species distribution modeling results that are similar to results obtained from more standardized survey methods.
Toroidal displacement of Klebsiella pneumoniae by Pseudomonas aeruginosa is a unique mechanism to avoid competition for iron
Authors: Pradhan Diana , Tanwar Ajay , Parthasarathy Srividhya , Singh Varsha 
Published: September 2022

ABSTRACTCompetition for resources is one of the major drivers for evolution and retention of new traits in microbial communities. Quorum-dependent traits of opportunistic human pathogen Pseudomonas aeruginosa allow it to survive and thrive in nature. Here, we report a unique surfactant-driven pushing mechanism that P. aeruginosa employs specifically against Klebsiella pneumoniae. The pushing is accomplished in a manner that is dependent on nutrient limitation and quorum sensing. We find that P. aeruginosa employs neither proteases nor toxic secondary metabolites against K. pneumoniae. Rhamnolipid biosurfactant appears to be the only factor required to displace Klebsiella effectively. Both rhamnolipid production and the pushing ability of P. aeruginosa are suppressed by iron supplementation. We show that both these bacteria produce several siderophores in minimal medium and rapidly deplete iron. Under these conditions, P. aeruginosa pushes Klebsiella away from the substratum using rhamnolipid, reducing the competition for iron. Our study describes a unique quorum and iron-responsive mechanism in P. aeruginosa to support its own growth during resource competition.
Determining distinct roles of IL-1α through generation of an IL-1α knockout mouse with no defect in IL-1β expression
Authors: Malireddi R.K. Subbarao , Bynigeri Ratnakar , Kancharana Balabhaskararao , Sharma Bhesh Raj , Burton Amanda R. , Pelletier Stephane , Kanneganti Thirumala-Devi 
Published: September 2022

ABSTRACTInterleukin 1α (IL-1α) and IL-1β are the founding members of the IL-1 cytokine family, and these innate immune inflammatory mediators are critically important in health and disease. Early studies on these molecules suggested that their expression was interdependent, with an initial genetic model of IL-1α depletion, the IL-1α KO mouse (Il1a-KOline1), showing reduced IL-1β expression. However, studies using this line in models of infection and inflammation resulted in contrasting observations. To overcome the limitations of this genetic model, we have generated and characterized a new line of IL-1α KO mice (Il1a-KOline2) using CRISPR-Cas9 technology. In contrast to cells from theIl1a-KOline1, where IL-1β expression was drastically reduced, bone marrow-derived macrophages (BMDMs) fromIl1a-KOline2mice showed normal induction and activation of IL-1β. Additionally,Il1a-KOline2BMDMs showed normal inflammasome activation and IL-1β expression in response to multiple innate immune triggers, including both pathogen-associated molecular patterns and pathogens. Moreover, usingIl1a-KOline2cells, we confirmed that IL-1α, independent of IL-1β, is critical for the expression of the neutrophil chemoattractant KC/CXCL1. Overall, we report the generation of a new line of IL-1α KO mice and confirm functions for IL-1α independent of IL-1β. Future studies on the unique functions of IL-1α and IL-1β using these mice will be critical to identify new roles for these molecules in health and disease and develop therapeutic strategies.
In vitro evidence against productive SARS-CoV-2 infection of human testicular cells: Bystander effects of infection mediate testicular injury
Authors: Giannakopoulos Stefanos , Strange Daniel P , Jiyarom Boonyanudh , Abdelaal Omar , Bradshaw Aaron W , Nerurkar Vivek R , Ward Monika A , Bakse Jackson , Yap Jonathan , Vanapruks Selena , Boisvert William , Tallquist Michelle D , Shikuma Cecilia , Sadri-Ardekani Hooman , Clapp Philip , Murphy Sean , Verma Saguna 
Published: September 2022

AbstractThe hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ failure including testicular injury and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury can likely result either from direct virus infection of resident cells or by exposure to systemic inflammatory mediators or virus antigens. We here characterized SARS-CoV-2 infection in different human testicular 2D and 3D models including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not establish a productive infection in any testicular cell types. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma depicted a significant decrease in cell viability and death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 envelope protein, but not Spike or nucleocapsid proteins led to cytopathic effects on testicular cells that was dependent on the TLR2 receptor. A similar trend was observed in the K18h-ACE2 mouse model which revealed gross pathology in the absence of virus replication in the testis. Collectively, data strongly indicates that the testicular injury is not due to direct infection of SARS-CoV-2 but more likely an indirect effect of exposure to systemic inflammation or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.
OCA-B/Pou2af1 is sufficient to promote CD4+T cell memory and prospectively identifies memory precursors
Authors: Sun Wenxiang , Hughes Erik P. , Kim Heejoo , Perovanovic Jelena , Charley Krystal R. , Perkins Bryant , Du Junhong , Ibarra Andrea , Syage Amber R. , Hale J. Scott , Williams Matthew A. , Tantin Dean 
Published: September 2022

AbstractThe molecular mechanisms leading to the establishment of immunological memory are inadequately understood, limiting the development of effective vaccines and durable anti-tumor immune therapies. Here we show that ectopic OCA-B expression is sufficient to improve antiviral memory recall responses, while having minimal effects on primary effector responses. At peak viral response short lived effector T cell populations are expanded but show increasedGadd45bandSocs2expression, while memory precursor effector cells show increased expression ofBcl2,Il7randTcf7on a per-cell basis. Using an OCA-B mCherry reporter mouse line, we observe high OCA-B expression in CD4+TCMcells. We show that early in viral infection, endogenously elevated OCA-B expression prospectively identifies memory precursor cells with increased survival capability and memory recall potential. Cumulatively, the results demonstrate that OCA-B is both necessary and sufficient to promote CD4 T cell memory in vivo and can be used to prospectively identify memory precursor cells.SignificanceCD4+T cell memory is incompletely defined and memory progenitors difficult to identify. Here, we show that expression of the OCA-B transcription coactivator in CD4+T cells is necessary and sufficient to drive productive memory. Using a novel mCherry reporter mouse line, we show that OCA-B expression enriches for responding effector cells with elevated memory potential. The results show that OCA-B expression in T cells is sufficient to promote CD4+memory formation and marks memory precursor cells.
Specific Codons Control Cellular Resources and Fitness
Authors: Love Aaron M. , Nair Nikhil U. 
Published: September 2022

AbstractAs cellular engineering progresses from simply overexpressing proteins to imparting complex metabolic and regulatory phenotypes through multigene expression, judicious appropriation of cellular resources is essential. Since there is degeneracy in codons and their use is biased, codons may control cellular resources at a translational level. We investigate how partitioning tRNA resources by incorporating dissimilar codon usage can drastically alter interdependence of expression level and burden on the host. By isolating the effect of individual codons’ use during elongation, while eliminating confounding factors like mRNA structure, GC content, transcript level, and translation initiation rates, we show that codon choice cantrans-regulate fitness of the host and expression of other heterologous genes. We correlate specific codon usage patterns with host fitness, and derive a coding scheme for multi-gene expression called the Codon Health Index (CHI, χ). This empirically derived coding scheme (χ) enables the design of multi-gene expression systems that avoid catastrophic cellular burden and is robust across multiple growth conditions.
Integration of Gene Expression and DNA Methylation Data Across Different Experiments
Authors: Itai Yonatan , Rappoport Nimrod , Shamir Ron 
Published: September 2022

AbstractIntegrative analysis of multi-omic datasets has proven to be extremely valuable in cancer research and precision medicine. However, obtaining multimodal data from the same samples is often difficult. Integrating multiple datasets of different omics remains a challenge, with only a few available algorithms developed to solve it.Here, we present INTEND (IntegratioN of Transcriptomic and EpigeNomic Data), a novel algorithm for integrating gene expression and DNA methylation datasets covering disjoint sets of samples. To enable integration, INTEND learns a predictive model between the two omics by training on multi-omic data measured on the same set of samples. In comprehensive testing on eleven TCGA cancer datasets spanning 4329 patients, INTEND achieves significantly superior results compared to four state-of-the-art integration algorithms. We also demonstrate INTEND’s ability to uncover connections between DNA methylation and the regulation of gene expression in the joint analysis of two lung adenocarcinoma single-omic datasets from different sources. INTEND’s data-driven approach makes it a valuable multi-omic data integration tool.The code for INTEND is available at https://github.com/Shamir-Lab/INTEND.
Evolution of antibody immunity following Omicron BA.1 breakthrough infection
Authors: Kaku Chengzi I. , Starr Tyler N. , Zhou Panpan , Dugan Haley L. , Khalifé Paul , Song Ge , Champney Elizabeth R. , Mielcarz Daniel W. , Geoghegan James C. , Burton Dennis R. , Andrabi Raiees , Bloom Jesse D. , Walker Laura M. 
Published: September 2022

AbstractUnderstanding the evolution of antibody immunity following heterologous SAR-CoV-2 breakthrough infection will inform the development of next-generation vaccines. Here, we tracked SARS-CoV-2 receptor binding domain (RBD)-specific antibody responses up to six months following Omicron BA.1 breakthrough infection in mRNA-vaccinated individuals. Cross-reactive serum neutralizing antibody and memory B cell (MBC) responses declined by two- to four-fold through the study period. Breakthrough infection elicited minimal de novo Omicron-specific B cell responses but drove affinity maturation of pre-existing cross-reactive MBCs toward BA.1. Public clones dominated the neutralizing antibody response at both early and late time points, and their escape mutation profiles predicted newly emergent Omicron sublineages. The results demonstrate that heterologous SARS-CoV-2 variant exposure drives the evolution of B cell memory and suggest that convergent neutralizing antibody responses continue to shape viral evolution.
Periplasmic coiled coil formed by assembly platform proteins PulL and PulM is critical for function of the Klebsiella type II secretion system
Authors: Li Yuanyuan , Santos-Moreno Javier , Francetic Olivera 
Published: September 2022

ABSTRACTBacteria use type II secretion systems (T2SS) to secrete to their surface folded proteins that confer diverse functions, from nutrient acquisition to virulence. In the Klebsiella species, T2SS-mediated secretion of pullulanase (PulA) requires assembly of a dynamic filament called pseudopilus. The inner membrane assembly platform (AP) complex is essential for PulA secretion and pseudopilus assembly. The AP components PulL and PulM form an inner membrane complex interacting through their C-terminal globular domains and transmembrane segments. Here we investigated the roles of periplasmic helices and cytoplasmic domains of PulL and PulM in their assembly. We found that PulL and PulM variants lacking periplasmic helices were defective for interactions in the bacterial two-hybrid (BACTH) assay. Their function in PulA secretion and assembly of PulG subunits into pseudopilus filaments were strongly reduced. In addition, deleting the cytoplasmic peptide of PulM in variant PulMΔN nearly abolished interaction with PulG in the BACTH assay, without affecting the interaction with PulL. Nevertheless, PulL was degraded in the presence of the PulMΔN variant, suggesting that PulM N-terminal peptide interacts with PulL in the cytoplasm and plays a stabilizing role. We discuss the implication of these results for the mechanism of T2S and type IV pilus assembly.
A hierarchy of cell death pathways confers layered resistance to shigellosis in mice
Authors: Roncaioli Justin L , Babirye Janet Peace , Chavez Roberto A , Liu Fitty L , Turcotte Elizabeth A , Lee Angus Y , Lesser Cammie F , Vance Russell E 
Published: September 2022

AbstractBacteria of the genus Shigella cause shigellosis, a severe gastrointestinal disease driven by bacterial colonization of colonic intestinal epithelial cells. Vertebrates have evolved programmed cell death pathways that sense invasive enteric pathogens and eliminate their intracellular niche. Previously we reported that genetic removal of one such pathway, the NAIP–NLRC4 inflammasome, is sufficient to convert mice from resistant to susceptible to oral Shigella flexneri challenge (Mitchell, Roncaioli et al., 2020). Here, we investigate the protective role of additional cell death pathways during oral mouse Shigella infection. We find that the Caspase-11 inflammasome, which senses Shigella LPS, restricts Shigella colonization of the intestinal epithelium in the absence of NAIP–NLRC4. However, this protection is limited when Shigella expresses OspC3, an effector that antagonizes Caspase-11 activity. TNFα, a cytokine that activates Caspase-8-dependent apoptosis, also provides protection from Shigella colonization of the intestinal epithelium, but only in the absence of both NAIP– NLRC4 and Caspase-11. The combined genetic removal of Caspases-1,-11, and -8 renders mice hyper-susceptible to oral Shigella infection. Our findings uncover a layered hierarchy of cell death pathways that limit the ability of an invasive gastrointestinal pathogen to cause disease.
Host specific sensing of coronaviruses and picornaviruses by the CARD8 inflammasome
Authors: Tsu Brian V. , Agarwal Rimjhim , Gokhale Nandan S. , Kulsuptrakul Jessie , Ryan Andrew P. , Castro Lennice K. , Beierschmitt Christopher M. , Turcotte Elizabeth A. , Fay Elizabeth J. , Vance Russell E. , Hyde Jennifer L. , Savan Ram , Mitchell Patrick S. , Daugherty Matthew D. 
Published: September 2022

AbstractHosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that the 3CL protease (3CLpro) encoded by diverse coronaviruses, including SARS-CoV-2, cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. CARD8 is required for cell death and the release of pro-inflammatory cytokines during SARS-CoV-2 infection. We further find that natural variation alters CARD8 sensing of 3CLpro, including 3CLpro-mediated antagonism rather than activation of megabat CARD8. Likewise, we find that a single nucleotide polymorphism (SNP) in humans reduces CARD8’s ability to sense coronavirus 3CLpros, and instead enables sensing of 3C proteases (3Cpro) from select picornaviruses. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intra-species variation in inflammasome-mediated viral sensing and immunopathology.
Dynamic refinement of behavioural restructure mediates dopamine-dependent credit assignment
Authors: Tang Jonathan C.Y. , Paixao Vitor , Carvalho Filipe , Silva Artur , Klaus Andreas , Alves da Silva Joaquim , Costa Rui M. 
Published: September 2022

AbstractAnimals exhibit a diverse behavioral repertoire when exploring new environments and can learn which actions or action sequences produce positive outcomes. Dopamine release upon encountering reward is critical for reinforcing reward-producing actions1–3. However, it has been challenging to understand how credit is assigned to the exact action that produced dopamine release during continuous behavior. We investigated this problem with a novel self-stimulation paradigm in which specific spontaneous movements triggered optogenetic stimulation of dopaminergic neurons. Dopamine self-stimulation rapidly and dynamically changes the structure of the entire behavioral repertoire. Initial stimulations reinforced not only the stimulation-producing target action, but also actions similar to target and actions that occurred a few seconds before stimulation. Repeated pairings led to gradual refinement of the behavioral repertoire to home in on the target. Reinforcement of action sequences revealed further temporal dependencies of refinement. Action pairs spontaneously separated by long time intervals promoted a stepwise credit assignment, with early refinement of actions most proximal to stimulation and subsequent refinement of more distal actions. Thus, a retrospective reinforcement mechanism promotes not only reinforcement, but gradual refinement of the entire behavioral repertoire to assign credit to specific actions and action sequences that lead to dopamine release.
The relationship between PD-L1 and quiescence in melanocyte stem cell aging
Authors: Palmer Joseph W. , Villavicencio Kyrene M. , Idris Misgana , Weddle Dominique , Filipp Fabian V. ,   NISC Comparative Sequencing Program, Pavan William J. , Harris Melissa L. 
Published: September 2022

SummaryA central aspect of life-long stem cell function in slow cycling stem cells is the proper regulation of cellular quiescence. How the quiescent state is achieved, whether all quiescent cells are equivalent, and if the quiescent stem cell pool changes with age are all questions that remain unanswered. Using quiescent melanocyte stem cells (qMcSC) as a model, we found that stem cell quiescence is neither a singular nor static process and can be heterogeneous. As one example of this heterogeneity, we show that a portion of qMcSCs expresses the immune checkpoint protein PD-L1 at the cell membrane (PD-L1mem+), PD-L1mem+ qMcSCs are better retained with age, and that the aged quiescent McSC pool is transcriptomically more deeply quiescent. Collectively these findings demonstrate that PD-L1 expression is a physiological attribute of quiescence in McSCs and PD-L1mem+ quiescent stem cells may be good targets for reactivation in the context of aging.