bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neonatal Peyer’s patch cDC activation as a pacemaker of postnatal immune maturation
Authors: Torow N. , Li R. , Hitch T. , Mingels C. , Bounny S. al , van Best N. , Stange E.-L. , Benabid A. , Rüttger L. , Gadermayr M. , Runge S. , Treichel N. , Merhof D. , Rosshart S. , Jehmlich N. , von Bergen M. , Heymann F. , Clavel T. , Tacke F. , Lelouard H. , Costa I. , Hornef M. W. 
Published: March 2022

AbstractMarked differences exist between the mucosal immune system of the neonate and adult host. The pronounced influence of the enteric microbiota in adults suggests a causal relationship between postnatal colonization and immune maturation. However, using metagenomic, metaproteomic, and functional immunological analyses we demonstrate an early presence of bacteria and immunogenic microbial antigens preceding immune maturation in the small intestine, the primary inductive site of intestinal immunity. Instead, transcriptomic, flow cytometric and histological analysis indicated neonatal Peyer’s patch (PP) mononuclear phagocytes (MNP) as rate limiting factor of postnatal immune maturation. Despite the early presence of MNPs, conventional dendritic cells (cDC) of type 1, 2a and 2b exhibited significant age-dependent differences in tissue distribution and cellular composition. Single cell transcriptional profiling and functional assays revealed decreased antimicrobial and antigen processing/presentation capacity, an overall retarded cell maturation and reduced antigen uptake. In cDC2a this resulted in a reduced proportion of CCR7+migratory cells and a consequent defect in CD4 T cell priming. Interestingly, transcriptional profiling of neonatal DC subsets identified reduced expression of type I interferon (IFN)-stimulated genes (ISG). Type I IFN induction by oral administration of the TLR7 agonist R848 accelerated MNP maturation and enhanced cognate antigen CD4 T cell priming. However, humoral responses to oral vaccination in the presence of R848 were significantly reduced. Together, our results identify PP MNP maturation as pacemaker of postnatal mucosal immune priming, indicate the biological role of delayed maturation and demonstrate that targeted interventional strategies allow manipulation of mucosal responses in early life.
Cardio-audio synchronization elicits neural and cardiac surprise responses in human wakefulness and sleep
Authors: Pelentritou Andria , Pfeiffer Christian , Schwartz Sophie , De Lucia Marzia 
Published: March 2022

AbstractThe human brain can infer temporal regularities in auditory sequences with fixed sound-to-sound intervals and in pseudo-regular sequences where sound onsets are locked to cardiac inputs. Here, we investigated auditory and cardio-audio regularity encoding during sleep, when reduced vigilance may result in altered bodily and environmental stimulus processing. Using electroencephalography and electrocardiography in healthy volunteers (N=26) during wakefulness and sleep, we measured the response to unexpected sound omissions within three auditory regularity conditions: synchronous, where sound and heartbeat are temporally locked, isochronous, with fixed sound-to-sound intervals, and a control condition without specific regularity. During wakefulness and all sleep stages, the cardiac signal following sound omissions exhibited a deceleration over time in the synchronous condition only. At the neural level, both the synchronous and isochronous sequences gave rise to a neural omission response in wakefulness and N2 sleep. Regularity encoding in the synchronous and isochronous conditions was characterized by a modulation of the background oscillatory activity in N2 sleep, outlining a possible mechanism through which the brain aligns periods of high neuronal excitability to the expected sound onset. The violation of auditory and cardio-audio regularity elicits cardiac and neural surprise responses across vigilance stages.Significance StatementAcross vigilance states, the human brain can generate predictions about the future based on past sensory regularities. While this is evident for environmental stimuli, the role of bodily signals in forming sensory prediction remains unknown. Here, we show that the human brain utilizes the temporal relationship between cardiac and auditory inputs in order to anticipate upcoming sounds during wakefulness and sleep. After presenting sounds in synchrony with the ongoing heartbeat, a sound omission elicited both a heartbeat deceleration and a prediction error signal as measured by the electroencephalographic response. Heartbeat signals support auditory regularity encoding during sleep and wakefulness, highlighting one mechanism for optimizing the detection of unexpected stimuli by taking advantage of the continuously monitored cardiac signals.
Dynamic nucleosome organization after fertilization reveals regulatory factors for mouse zygotic genome activation
Authors: Wang Chenfei , Chen Chuan , Liu Xiaoyu , Li Chong , Wu Qiu , Chen Xiaolan , Yang Lingyue , Kou Xiaochen , Zhao Yanhong , Wang Hong , Gao Yawei , Zhang Yong , Gao Shaorong 
Published: March 2022

AbstractChromatin remodeling is essential for epigenome reprogramming after fertilization. However, the underlying mechanisms of chromatin remodeling remain to be explored. Here, we investigated the dynamic changes in nucleosome occupancy and positioning in pronucleus-stage zygotes using ultra low-input MNase-seq. We observed distinct features of inheritance and reconstruction of nucleosome position in both paternal and maternal genomes. Genome-wide de novo nucleosome occupancy in the paternal genome was observed as early as 1 hour after the injection of sperm into ooplasm. The nucleosome positioning pattern was continually rebuilt to form nucleosome depletion regions (NDRs) at promoters and transcription factor (TF) binding sites with differential dynamics in paternal and maternal genomes. NDRs formed more quickly on the promoters of genes involved in zygotic genome activation (ZGA), and this formation is closely connected with histone acetylation, but not transcription elongation or DNA replication. Importantly, we found that NDR establishment on the binding motifs of specific TFs might be associated with their potential pioneer functions in ZGA. Further investigations suggested that the predicted factors MLX and RFX1 played important roles in regulating minor and major ZGA, respectively. Our data not only elucidate the nucleosome positioning dynamics in both male and female pronuclei following fertilization, but also provide an efficient method for identifying key transcription regulators during development.
Mouse Genomic Associations withEx VivoSensitivity to Simulated Space Radiation
Authors: Cekanaviciute Egle , Tran Duc , Nguyen Hung , Macha Alejandra Lopez , Pariset Eloise , Langley Sasha , Babbi Giulia , Malkani Sherina , Penninckx Sébastien , Schisler Jonathan C. , Nguyen Tin , Karpen Gary H. , Costes Sylvain. V. 
Published: March 2022

AbstractExposure to ionizing radiation is considered by NASA to be a major health hazard for deep space exploration missions. Ionizing radiation sensitivity is modulated by both genomic and environmental factors. Understanding their contributions is crucial for designing experiments in model organisms, evaluating the risk of deep space (i.e. high-linear energy transfer, or LET, particle) radiation exposure in astronauts, and also selecting therapeutic irradiation regimes for cancer patients. We identified single nucleotide polymorphisms in 15 strains of mice, including 10 collaborative cross model strains and 5 founder strains, associated with spontaneous and ionizing radiation-inducedex vivoDNA damage quantified based on immunofluorescent 53BP1+nuclear foci. Statistical analysis suggested an association with pathways primarily related to cellular signaling, metabolism, tumorigenesis and nervous system damage. We observed different genomic associations in early (4 and 8 hour) responses to different LET radiation, while later (24 hour) DNA damage responses showed a stronger overlap across all LETs. Furthermore, a subset of pathways was associated with spontaneous DNA damage, suggesting 53BP1+foci as a potential biomarker for DNA integrity in mouse models. Based on our results, we suggest several mouse strains as new models to further study the impact of ionizing radiation and validate the identified genetic loci. We also highlight the importance of future humanex vivostudies to refine the association of genes and pathways with the DNA damage response to ionizing radiation and identify targets for space travel countermeasures.
The Flexible Linker of Decorin Binding Protein A from Borrelia burgdorferi is a Target of Antibodies in Lyme disease
Authors: Movahed Elaheh , Vance David J , Van Slyke Greta , Ehrbar Dylan , Yates Jennifer , Kullas Karen , Rudolph Michael , Mantis Nicholas J 
Published: March 2022

ABSTRACTDecorin binding protein A (DbpA) is a surface adhesin expressed by Borrelia burgdorferi, the causative agent of Lyme disease. While DbpA is one of the most immunogenic B. burgdorferi antigens in Lyme disease patients, the B cell epitopes recognized over the course of infection have not been defined. In this report we profiled ∼300 human serum samples from early, mid, and late-stage Lyme disease for IgM and IgG reactivity with DbpA and a tiled DbpA 18-mer peptide array derived from B.b. strains B31 and 297. Using ELISA and multiplex immunoassays (MIA), we identified 12 DbpA-derived peptides whose reactivity was elevated in Lyme disease patients as compared to healthy controls. The most reactive peptide (“A7”) corresponds to the flexible loop between DbpAB31 α-helix 1 and α-helix 2, implicated in influencing DbpA binding to heparin and dermatan sulfate. An A7-like peptide is also reportedly a target of antibodies in Lyme neuroborreliosis patients. The remaining peptides, while highly reactive in serum samples across disease stages, likely represent non-native epitopes, as antibody reactivity to a subset of peptides in competition assays was unaffected by the addition of soluble DbpA. Moreover, peptide reactivity of any given patient sample rarely correlated with overall DbpA antibody levels, suggesting the antibodies were raised against DbpA degradation products. Insights into B cell epitopes on DbpA elicited during Lyme disease have important implications for understanding how B.burgdorferi persists in the face of an overwhelming antibody response.IMPORTANCEThe bacterium, Borrelia burgdorferi, is the causative agent of Lyme disease, the most reported tick-borne illness in the United States. In humans, clinical manifestations of Lyme disease are complex and can persist for months, even in the face of a robust antibody response directed against numerous B. burgdorferi surface proteins, including decorin binding protein A (DbpA), which is involved in early stages of infection. In this study we employed ∼300 serum samples from Lyme disease patients to better understand antibody reactivity with specific regions (“epitopes”) of DbpA. We identified one epitope on DbpA recognized by antibodies from almost half of the serum samples tested and that, theoretically, should block DbpA’s ability to function in promoting B. burgdorferi colonization of human hosts.
Protective antibodies and T cell responses to Omicron variant three months after the booster dose of BNT162b2 vaccine
Authors: Naaber Paul , Tserel Liina , Kangro Kadri , Sepp Epp , Jürjenson Virge , Kärner Jaanika , Haljasmägi Liis , Haljasorg Uku , Kuusk Marilin , Gerhold Joachim M. , Planken Anu , Ustav Mart , Kisand Kai , Peterson Pärt 
Published: March 2022

AbstractThe high number of mutations in the Omicron variant of SARS-CoV-2 cause its immune escape when compared to the earlier variants of concern (VOC). At least three vaccine doses are required for the induction of Omicron neutralizing antibodies and further reducing the risk for hospitalization. However, most of the studies have focused on the immediate response after the booster vaccination while the duration of immune response is less known. We here studied longitudinal serum samples from the vaccinated individuals up to three months after their third dose of the BNT162b2 vaccine for their capacity to produce protective antibodies and T cell responses to Wuhan and Omicron variants. After the second dose, the antibody levels to the unmutated spike protein were significantly decreased at three months, and only 4% of the individuals were able to inhibit Omicron spike interaction compared to 47%, 38%, and 14% of individuals inhibiting wild-type, delta, and beta variants’ spike protein. Nine months after the second vaccination, the antibody levels were similar to the levels before the first dose and none of the sera inhibited SARS-CoV-2 wild-type or any of the three VOCs. The booster dose remarkably increased antibody levels and their ability to inhibit all variants. Three months after the booster the antibody levels and the inhibition activity were trending lower but still up and not significantly different from their peak values at two weeks after the third dose. Although responsiveness towards mutated spike peptides was lost in less than 20 % of vaccinated individuals, the wild-type spike-specific CD4+ and CD8+ memory T cells were still present at three months after the booster vaccination in the majority of studied individuals. Our data show that two doses of the BNT62b2 vaccine are not sufficient to protect against the Omicron variant, however, the spike-specific antibodies and T cell responses are strongly elicited and well maintained three months after the third vaccination dose.
Neural representations of vicarious rewards are linked to interoception and prosocial behaviour
Authors: Contreras-Huerta Luis Sebastian , Coll Michel-Pierre , Bird Geoffrey , Yu Hongbo , Prosser Annayah , Lockwood Patricia L. , Murphy Jennifer , Crockett Molly J. , Apps Matthew A.J. 
Published: March 2022

AbstractEvery day we constantly observe other people receiving rewards. Theoretical accounts posit that vicarious reward processing might be linked to people’s sensitivity to internal body states (interoception) and facilitates a tendency to act prosocially. However, the neural processes underlying the links between vicarious reward processing, interoception and prosocial behaviour are poorly understood. Previous research has linked vicarious reward processing to the anterior cingulate gyrus (ACCg) and the anterior insula (AI). Can we predict someone’s propensity to be prosocial or to be aware of interoceptive signals from variability in how the ACCg and AI process rewards? Here, participants monitored rewards being delivered to themselves or a stranger during functional magnetic resonance imaging. Later, they performed a task measuring their willingness to exert effort to obtain rewards for others, and a task measuring their propensity to be aware and use interoceptive signals. Using multivariate similarity analysis, we show that people’s willingness to be prosocial is predicted by greater similarity between self and other representations in the ACCg. Moreover, greater dissimilarity in self-other representations in the AI is linked to interoceptive propensity. These findings highlight that vicarious reward is linked to bodily signals in AI, and foster prosocial tendencies through the ACCg.
RNA G-quadruplex structure contributes to cold adaptation in plants
Authors: Yang Xiaofei , Yu Haopeng , Duncan Susan , Zhang Yueying , Cheema Jitender , Miller J. Benjamin , Zhang Jie , Kwok Chun Kit , Zhang Huakun , Ding Yiliang 
Published: March 2022

AbstractNucleotide composition is suggested to infer gene functionality and ecological adaptation of species to distinct environments. However, the underlying biological function of nucleotide composition dictating environmental adaptations is largely unknown. Here, we systematically analyzed the nucleotide compositions of transcriptomes across 1000 plants (1KP) and their corresponding habitats. Intriguingly, we found that plants growing in cold climates have guanine (G)-enriched transcriptomes, which are prone to forming RNA G-quadruplex structures. Both immunofluorescence detection and in vivo structure profiling revealed that RNA G-quadruplex formation in plants was globally enhanced in response to cold. Cold-responsive RNA G-quadruplexes strongly enhanced mRNA stability, rather than affecting translation. Disruption of individual RNA G-quadruplex promoted mRNA decay in the cold, leading to impaired plant cold response. Therefore, we propose that plants adopted RNA G-quadruplex structure as a molecular marker to facilitate their adaptation to the cold during evolution.
DNA supercoiling restricts the transcriptional bursting of neighboring eukaryotic genes
Authors: Patel Heta P. , Coppola Stefano , Pomp Wim , Brouwer Ineke , Lenstra Tineke L. 
Published: March 2022

AbstractDNA supercoiling has emerged as a major contributor to gene regulation in bacteria. The impact of DNA supercoiling on transcription dynamics in eukaryotes is less clear. Here, using single-molecule dual-color RNA imaging in budding yeast, we show that transcriptional bursting of the divergent and tandem GAL genes is coupled. Upon topoisomerase degradation, supercoils that buildup from transcription inhibit subsequent transcription at neighboring genes, thereby reducing their simultaneous bursting. GAL gene transcription is inhibited more by negative than by positive supercoiling accumulation. Unlike bacteria, wildtype yeast has sufficient topoisomerase levels to minimize inhibition from supercoils at adjacent genes. Overall, we discover fundamental differences in supercoiling-mediated gene regulation between bacteria and yeast and show that rapid supercoiling release in eukaryotes ensures proper gene expression of neighboring genes.One sentence summaryTranscription causes twisting of the DNA double helix, which can inhibit transcription of adjacent genes.
Loss of NF1 causes tactile hypersensitivity and impaired synaptic transmission in a Drosophila model of autism spectrum disorder
Authors: Dyson Alex , Garg Shruti , Evans D. Gareth , Baines Richard A. 
Published: March 2022

SummaryAutism Spectrum Disorder (ASD) is a neurodevelopmental condition in which the mechanisms underlying its core symptomatology are largely unknown. Studying animal models of monogenic syndromes associated with ASD, such as neurofibromatosis type 1 (NF1), can offer insights into its aetiology. Here, we show that loss of function of the Drosophila NF1 ortholog results in larval tactile hypersensitivity, paralleling the sensory abnormalities observed in individuals with ASD. Mutant larvae also exhibit synaptic transmission deficits at the glutamatergic neuromuscular junction (NMJ), with increased spontaneous but reduced evoked release. Diminished expression of NF1 specifically within central cholinergic neurons induces both excessive neuronal firing and tactile hypersensitivity, suggesting the two may be linked. Furthermore, both impaired synaptic transmission and behavioural deficits are fully rescued via knockdown of Ras proteins. These findings validate NF1-/-Drosophila as a tractable model of ASD with the potential to elucidate important pathophysiological mechanisms.
Lipobiotin-capture magnetic bead assay for isolation, enrichment and detection of Mycobacterium tuberculosis from saliva
Authors: Hansen Julia , Kolbe Katharina , König Inke R. , Scherliess Regina , Hellfritzsch Marie , Malm Sven , Zallet Julia , Hillemann Doris , Wiesmüller Karl-Heinz , Herzmann Christian , Brandenburg Julius , Reiling Norbert 
Published: March 2022

AbstractBackgroundPulmonary Tuberculosis (TB) is diagnosed through sputum samples. As sputum sampling is challenging in children and cachexic patients, the development of diagnostic tests using saliva appears promising but has been discouraged due to low bacterial load and the poor sensitivity. We present a novel and rapid method to enrich Mycobacterium tuberculosis (Mtb) from saliva, which may serve as a basis for a diagnostic saliva test.MethodsLipobiotin-functionalized magnetic beads (LMBs) were incubated with Mtb-spiked PBS and saliva from healthy donors as well as with saliva from TB patients. Flow cytometry was used to evaluate the capacity of the beads to bind Mtb, while real-time quantitative polymerase chain reaction (qPCR) was utilized to detect Mtb and estimate the amount of mycobacterial DNA in different sample types.ResultsWe found that LMBs bind Mtb efficiently when compared to non-functionalized beads. The development of an qPCR assay based on the use of LMBs (LMB assay) allowed us to enrich mycobacterial DNA in spiked sample types, including PBS and saliva from healthy donors (enrichment of up to 8.7 fold). In Mtb-spiked saliva samples, we found that the LMB assay improved the detection rate of 102 bacteria in a volume of 5 ml from 0 out of 15 (0%) to 6 out of 15 (40%). Consistent with that, the LMB assay increased the rate of correctly identified saliva samples from TB patients in two independent cohorts.ConclusionsImplementation of the principle of the LMB-based assay may improve the sensitivity of existing diagnostic techniques, e.g. by functionalizing materials that facilitate Mtb sampling from the oral cavity.
Profiling Genetic Diversity Reveals the Molecular Basis for Balancing Function with Misfolding in Alpha-1 Antitrypsin
Authors: Wang Chao , Zhao Pei , Sun Shuhong , Wang Xi , Balch William E. 
Published: March 2022

AbstractGenetic variation of alpha-1 antitrypsin (AAT) is responsible for alpha-1-antitrypsin deficiency (AATD) leading to gain-of-toxic aggregation in the liver and loss-of-function onneutrophilelastase (NE) inhibitory activity in the lung contributing tochronicobstructivepulmonarydisease (COPD) during aging. To probe the molecular basis for how biology designs the protein fold to achieve balance between sequence, function and structure contributing to AATD in the population, we measured the intracellular monomer and polymer, secreted monomer and polymer and NE inhibitory activity of 75 alpha-1-antitrypsin (AAT) variants. To address the complex folding dynamics affecting the form and function of the protein fold that is differentially impacted by variants in the population, we applied aGaussianprocessregression (GPR) based machine learning approach termedvariationspatialprofiling (VSP). By using a sparse collection of extant variants to link genotype to phenotype, VSP mapsspatialcovariance (SCV) relationships that quantitate the functional value of every residue in the wild-type (WT) AAT sequence with defined uncertainty in the context of its protein fold design. The SCV-based uncertainty allows us to pinpoint critical short- and long-range residue interactions involving 3 regions-the N-terminal (N1), middle (M2) and carboxyl-terminal (C3) of AAT polypeptide sequence that differentially contribute to the balance between function and misfolding of AAT, thus providing an unanticipated platform for precision therapeutic development for liver and lung disease. By understanding mechanistically the complex fold design of the metastable WT AAT fold, we posit that GPR-based SCV provides a foundation for understanding the evolutionary design of the fold from the ensemble of structures found in the population driving biology for precision management of AATD in the individual.