Miracle-dz/UniFAR-FTUs huggingface dataset:
Interference at Influenza Hemagglutinin Antigenic-Sites Determines Antibody Levels and Specificities after Repeat Vaccination

Background It is recommended that children receive a dose of the influenza vaccine at 6 months of age and a second dose the following season. In some years, the second dose will be the same vaccine formulation, in others years it with be re-formulated to include HA proteins derived from antigenically drifted or shifted circulating influenza strains. In addition, natural exposure to influenza can create permanent changes to the memory B cell repertoire and specificities. The effect that the specificity of pre-existing humoral immunity has on antibody levels and specificity after repeat vaccination is an ongoing research area. Methods We used a computational framework (ssMod.v1) to simulate scenarios that occurred during the 2009 influenza pandemic: children receiving a second dose who have previously exposed to the 2009 influenza HA antigen, children previously exposed to an HA antigen antigenically similar to the 2009 influenza HA antigen, and children previously exposed to an antigenically dissimilar strain. To assess the contribution of pre-existing immunity, two experimental permutations in the sMod.v1 were made: elimination of antibody-mediated antibody clearance of vaccine (HA) antigen by pre-existing antibodies and elimination of the ability of memory B cells to form germinal centers. In the simulation, 30 days after repeat vaccination antibody specificities were examined against 12 antigenically historical vaccine/HA variant influenza strains for each of the five canonical antigenic-sites and the subdominant, conserved, stalk antigenic-site. Results We found that elimination of antibody-mediated antigen clearance significantly increased antibody levels while elimination of the ability of memory B cells to form germinal center reactions significantly decreased the total antibody levels, but this was dependent on the antigenic relationship between the original vaccine and repeat vaccine and the particular antigenic-site. Moreover, highly-cross-reactive antibody was highest when the antigenic distance between original vaccine HA antigen and repeat vaccine HA antigen was larger and antibody-mediated antigen clearance was eliminated.
Analysis of SARS-CoV-2 mutations reveals three types of temporal dynamics and one is correlated with international travels

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This disease has spread globally, causing more than 161.5 million cases and 3.3 million deaths. Keeping on the identification, surveillance and the study of the temporal dynamics of mutations with significant representation is central to understand the adaptation of SARS-CoV-2. Furthermore, how lockdown policies influence the dynamics of SARS-CoV-2 mutations is poorly understood. Here, using 1 058 020 SARS-CoV-2 genomes and COVID-19 cases from 714 country-month combinations representing 98 countries, we performed a normalization by COVID-19 cases calculation of relative frequency of SARS-CoV-2 mutations. We found 115 mutations estimated to be present in more than 3 % of global COVID-19 cases and determined three types of mutation dynamics: High-Frequency, Medium-Frequency, and Low-Frequency. Classification of mutations based on temporal dynamics helps to study viral adaptation and can be used to evaluate the effects of human behaviors in the pandemic. For instance, we report a negative and positive correlation of the frequency change of High-Frequency mutations with the level of international movement controls and the number of flight departures, respectively.
Dynamic genome plasticity during unisexual reproduction in the human fungal pathogen Cryptococcus deneoformans

Genome copy number variation occurs during each mitotic and meiotic cycle and it is crucial for organisms to maintain their natural ploidy. Defects in ploidy transitions can lead to chromosome instability, which is a hallmark of cancer. Ploidy in the haploid human fungal pathogen Cryptococcus neoformans is exquisitely orchestrated and ranges from haploid to polyploid during sexual development and under various environmental and host conditions. However, the mechanisms controlling these ploidy transitions are largely unknown. During C. deneoformans (formerly C. neoformans var. neoformans, serotype D) unisexual reproduction, ploidy increases prior to the onset of meiosis, can be independent from cell-cell fusion and nuclear fusion, and likely occurs through an endoreplication pathway. To elucidate the molecular mechanisms underlying this ploidy transition, we identified twenty cell cycle-regulating genes encoding cyclins, cyclin-dependent kinases (CDK), and CDK regulators. We characterized four cyclin genes and two CDK regulator genes that were differentially expressed during unisexual reproduction and contributed to diploidization. To detect ploidy transition events, we generated a ploidy reporter, called NURAT, which can detect copy number increases via double selection for nourseothricin-resistant, uracil-prototrophic cells. Utilizing this ploidy reporter, we showed that ploidy transition from haploid to diploid can be detected during the early phases of unisexual reproduction. Interestingly, selection for the NURAT reporter revealed several instances of segmental aneuploidy of multiple chromosomes, which conferred azole resistance in some isolates. These findings provide further evidence of ploidy plasticity in fungi with significant biological and public health implications. Author Summary Ploidy is an intrinsic fundamental feature of all eukaryotic organisms, and ploidy variation and maintenance are critical to the organism survival and evolution. Fungi exhibit exquisite plasticity in ploidy variation in adaptation to various environmental stresses. For example, the haploid opportunistic human fungal pathogen C. deneoformans can generate diploid blastospores during unisexual reproduction and also forms polyploid titan cells during host infection, however, the mechanisms underlying these ploidy transitions are largely unknown. In this study, we elucidated the genetic regulatory circuitry governing ploidy duplication during C. deneoformans unisexual reproduction through the identification and characterization of cell cycle regulators that are differentially expressed during unisexual reproduction. We showed that four cyclin and two cyclin-dependent kinase regulator genes function in concert to orchestrate ploidy transition during unisexual reproduction. To trace and track ploidy transition events, we also generated a ploidy reporter and revealed the formation of segmental aneuploidy in addition to diploidization, illustrating the diverse mechanisms of genome plasticity in C. deneoformans.
Heterogeneity and molecular programming of progenitors for motor neurons and oligodendrocytes

The pMN domain is a restricted domain in the ventral spinal cords, defined by the expression of olig2 gene. The fate determination of pMN progenitors is highly temporally and spatially regulated, with motor neurons and oligodendrocyte progenitor cells (OPCs) developing sequentially. Insight into the heterogeneity and molecular programs of pMN progenitors is currently lacking. With the zebrafish model, we identified multiple states of neural progenitors using single-cell sequencing: proliferating progenitors, common progenitors for both motor neurons and OPCs, and restricted precursors for either motor neurons or OPCs. We found specific molecular programs for neural progenitor fate transition, and manipulations of representative genes in the motor neuron or OPC lineage confirmed their critical role in cell fate determination. The transcription factor NPAS3 is necessary for the development of the OPC lineage and can interact with many known genes associated with schizophrenia. Deciphering progenitor heterogeneity and molecular mechanisms for these transitions will elucidate the formation of complex neuron-glia networks in the central nervous system during development, and understand the basis of neurodevelopmental disorders.
A functionally divergent intrinsically disordered region underlying the conservation of stochastic signaling

Stochastic signaling dynamics expand living cells’ information processing capabilities. An increasing number of studies report that regulators encode information in their pulsatile dynamics. The evolutionary mechanisms that lead to complex signaling dynamics remain uncharacterized, perhaps because key interactions of signaling proteins are encoded in intrinsically disordered regions (IDRs), whose evolution is difficult to analyze. Here we focused on the stochastic pulsing dynamics of Crz1, a transcription factor in fungi downstream of the widely conserved calcium signaling pathway. We find that Crz1 IDRs from anciently diverged fungi can all respond transiently to calcium stress; however, only Crz1 IDRs from the Saccharomyces clade support pulsatility, encode extra information, and rescue fitness, while the Crz1 IDRs from distantly related fungi do none of the three. On the other hand, we find that Crz1 pulsing is conserved in the distantly related fungi, consistent with the evolutionary model of stabilizing selection. Further, we show that a calcineurin docking site in a specific part of the IDRs appears to be sufficient for pulsing and show evidence for a beneficial increase in the relative calcineurin affinity of this docking site. We propose that evolutionary flexibility of functionally divergent IDRs underlies the conservation of stochastic signaling by stabilizing selection.
Attention networks and the intrinsic network structure of the human brain

Attention network theory states that attention is not a unified construct but consists of three independent systems that are supported by separable distributed networks: an alerting network to deploy attentional resources in anticipation of upcoming events, an orienting network to direct attention to a cued location, and a control network to select relevant information at the expense of concurrently available information. Ample behavioral and neuroimaging evidence supports the dissociation of the three attention domains. The strong assumption that each attentional system is realized through a separable network, however, raises the question how these networks relate to the intrinsic network structure of the brain. Our understanding of brain networks has advanced majorly in the past years due to the increasing focus on brain connectivity. It is well established that the brain is intrinsically organized into several large-scale networks whose modular structure persists across task states. Existing proposals on how the presumed attention networks relate to intrinsic networks rely mostly on anecdotal and partly contradictory arguments. We addressed this issue by mapping different attention networks with highest spatial precision at the level of cifti-grayordinates. Resulting group maps were compared to the group-level topology of 23 intrinsic networks which we reconstructed from the same participants’ resting state fMRI data. We found that all attention domains recruited multiple and partly overlapping intrinsic networks and converged in the dorsal fronto-parietal and midcingulo-insular network. While we observed a preference of each attentional domain for its own set of intrinsic networks, implicated networks did not match well to those proposed in the literature. Our results indicate a necessary refinement of the attention network theory.
Genome-wide identiﬁcation and analysis of prognostic features in human cancers

SUMMARY Clinical decisions in cancer rely on precisely assessing patient risk. To improve our ability to identify the most aggressive malignancies, we constructed genome-wide survival models using gene expression, copy number, methylation, and mutation data from 10,884 patients. We identiﬁed more than 100,000 signiﬁcant prognostic biomarkers and demonstrate that these genomic features can predict patient outcomes in clinically ambiguous situations. While adverse biomarkers are commonly believed to represent cancer driver genes and promising therapeutic targets, we show that cancer features associated with shorter survival times are not enriched for either oncogenes or for successful drug targets. Instead, the strongest adverse biomarkers represent widely expressed cell-cycle and housekeeping genes, and, correspondingly, nearly all therapies directed against these features have failed in clinical trials. In total, our analysis establishes a rich resource for prognostic biomarker analysis and clariﬁes the use of patient survival data in preclinical cancer research and therapeutic development.
Inducible and reversible inhibition of miRNA-mediated gene repression in vivo

Although virtually all gene networks are predicted to be controlled by miRNAs, the contribution of this important layer of gene regulation to tissue homeostasis in adult animals remains unclear. Gain and loss of function experiments have provided key insights into the specific function of individual miRNAs, but effective genetic tools to study the functional consequences of global inhibition of miRNA activity in vivo are lacking. Here we report the generation and characterization of a genetically engineered mouse strain in which miRNA-mediated gene repression can be reversibly inhibited without affecting miRNA biogenesis or abundance. We demonstrate the usefulness of this strategy by investigating the consequences of acute inhibition of miRNA function in adult animals. We find that different tissues and organs respond differently to global loss of miRNA function. While miRNA-mediated gene repression is essential for the homeostasis of the heart and the skeletal muscle, it is largely dispensable in the majority of other organs. Even in tissues where it is not required for homeostasis, such as the intestine and hematopoietic system, miRNA activity can become essential during regeneration following acute injury. These data support a model where many metazoan tissues primarily rely on miRNA function to respond to potentially pathogenic events.
Subcellular proteomics of dopamine neurons in the mouse brain reveals axonal enrichment of proteins encoded by Parkinson’s disease-linked genes

Dopaminergic neurons modulate neural circuits and behaviors via dopamine release from expansive, long range axonal projections. The elaborate cytoarchitecture of these neurons is embedded within complex brain tissue, making it difficult to access the neuronal proteome using conventional methods. Here, we demonstrate APEX2 proximity labeling within genetically targeted neurons in the mouse brain, enabling subcellular proteomics with cell type-specificity. By combining APEX2 biotinylation with mass spectrometry, we mapped the somatodendritic and axonal proteomes of midbrain dopaminergic neurons. Our dataset reveals the proteomic architecture underlying proteostasis, axonal metabolism, and neurotransmission in these neurons. We find a significant enrichment of proteins encoded by Parkinson’s disease-linked genes in striatal dopaminergic axons, including proteins with previously undescribed axonal localization. These proteomic datasets provide a resource for neuronal cell biology, and this approach can be readily adapted for study of other neural cell types.
Brief exposure of neuronal cells to levels of short chain fatty acids observed in human systemic circulation impair the cell lipid metabolism resulting in associated cell death by apoptosis

Communication between gut microbiota and the brain is an enigma. Alterations in the gut microbial community affects enteric metabolite levels, such as SCFAs. SCFAs have been proposed as a possible mechanism through which the gut microbiome modulate brain health and function. This study analyzed for the first time the effects of SCFAs at levels reported in human systemic circulation on human neuronal cell energy metabolism, viability, survival and the brain lipidome. Cell and rat brain lipidomics was done using UHPLC-HESI-HRAMS/MS. Neuronal cells viability, survival and energy metabolism were analyzed via flow cytometer, immunofluorescence, and SeahorseXF platform. Lipidomics analysis demonstrated that SCFAs significantly remodeled the brain lipidome in vivo and in vitro. The most notable remodulation was observed in the metabolism of phosphatidylethanolamine plasmalogens, and mitochondrial lipids carnitine and cardiolipin. Increased mitochondrial mass, fragmentation, and hyperfusion occurred concomitant with the altered mitochondrial lipid metabolism resulting in decreased neuronal cell respiration, ATP production, and increased cell death. This suggests SCFAs at levels observed in human systemic circulation can adversely alter the brain lipidome and neuronal cell function potentially negatively impacting brain health outcomes.
ESR Investigations of (BaSnO3)x/(Cu, Tl) 1223 composite in the normal and superconducting state

ABSTRACT (BaSnO3)x/Cu0.5Tl0. 5Ba2Ca2Cu3O10-δ superconducting composites (0.00 ≤ x ≤ 1.50 wt.%) were prepared by the solid-state reaction technique. The crystalline structure and superconducting transition temperature were investigated by X-ray powder diffraction (XRD) and dc-electrical resistivity measurements, respectively. X-Band electron spin resonance (ESR) measurements were carried out at different temperatures 103 ≤ T ≤ 298 K. ESR spectra are dominated by a single asymmetric line corresponding to Cu2+ ions at the rhombic site. The temperature dependence of the g factors allowed the determination of the pseudo-gap onset temperature T*. The results of T* are compatible with those obtained from resistivity and thermoelectric power measurements. The contribution of delocalized electrons from Cu2+ ions in the disordered part of the impurity phases BaCuO2 and Ba2CuO3 is significant for the high addition of nanoparticles. Moreover, the number of spins N participating in ESR and the activation energy Ea were enhanced with the addition of BaSnO3.
Formation des eaux thermales sulfurées des pyrénées orientales. Origine du soufre. Géochimie du fer et du cuivre

Les eaux geothermales sulfurees des Pyrenees Orientales sont des eaux d'origine meteoriques qui acquierent de l'enthalpie en profondeur. Les temperatures profondes sont de l'ordre de 90 a 120 °C. La composition des eaux est sans doute fixee par une serie d'equilibres avec le quartz (ou la calcedoine), la kaolinite, l'adulaire, le chrysotile et la calcite. Les especes du soufre sont issues pour une partie des sulfates des eaux meteoriques et pour l'autre du lessivage de la pyrite qui fournit de l'hydrogene sulfure (HS- ), du sulfate (SO4 2- ) et des traces de thiosulfate (SO2 O3 2- ). L'application du geothermometre base sur le fractionnement isotopique du soufre entre sulfure et sulfate donne des resultats en accord avec les determinations des temperatures profondes. La concentration en fer depend de l'equilibre avec FeS qui est realise en profondeur. La concentration en cuivre depend sans doute de la formation de CuFeS2 en profondeur.
The Role of Guilt, Shame, and Social Distance in Bystander-Focused Prevention of Campus Sexual Violence

Abstract Guided by the appraisal-tendency framework and construal level theory, this study investigates how emotional appeals (guilt vs. shame) and social distance frames (distant vs. proximal) influence college students’ attitude toward bystander action campaign and intention to intervene in sexual violence situations. The findings indicated a two-way interaction effect between these two message factors on campaign attitude and behavior intention. Additionally, self-efficacy was found to be the mediator that underlying the proposed match-based effects. The findings provide theoretical implications into persuasive communication in the context of campus sexual violence bystander intervention and offer practical insights to advertisers and social/health marketers.
Different responses to climate change of the hydrological regime of Lake Hańcza, the deepest lake in the Central European Plain

ABSTRACT The study presents changes in the elements of the hydrological regime of Lake Hańcza in the period 1960–2019, including water temperature, ice cover characteristics and water level. It was determined that statistically significant changes resulted in an increase in water temperature (0.11°C·dec−1), a decrease in maximum ice thickness (5 cm·dec−1) and an increase in water levels (6.7 cm·dec−1). Changes in water temperature and ice cover in the analysed case are different from those in other lakes of the region. As the tests conducted in this study and in previous research have shown, the lake has resisted global warming for a relatively long time, and the change in thermal conditions occurred a decade later than in other lakes in this part of Europe. The analysed case leads to the conclusion that the morphometric features of lakes significantly modify the influence of overriding factors, such as climate conditions.
α-Ketoglutarate Upregulates Collecting Duct (Pro)renin Receptor Expression, Tubular Angiotensin II Formation, and Na+ Reabsorption During High Glucose Conditions

Diabetes mellitus (DM) causes high glucose (HG) levels in the plasma and urine. The (pro)renin receptor (PRR) is a key regulator of renal Na+ handling. PRR is expressed in intercalated (IC) cells of the collecting duct (CD) and binds renin to promote angiotensin (Ang) II formation, thereby contributing to Na+ reabsorption. In DM, the Kreb's cycle is in a state of suppression in most tissues. However, in the CD, expression of glucose transporters is augmented, boosting the Kreb's cycle and consequently causing α-ketoglutarate (αKG) accumulation. The αKG receptor 1 (OXGR1) is a Gq-coupled receptor expressed on the apical membrane of IC cells of the CD. We hypothesize that HG causes αKG secretion and activation of OXGR1, which increases PRR expression in CD cells. This effect then promotes intratubular AngII formation and Na+ reabsorption. To test this hypothesis, streptozotocin (STZ)-induced diabetic mice were treated with or without montelukast (ML), an OXGR1 antagonist, for 6 days. STZ mice had higher urinary αKG and PRR expression along with augmented urinary AngII levels and Na+ retention. Treatment with ML prevented all these effects. Similarly, primary cultured inner medullary CD cells treated with HG showed increased PRR expression, while OXGR1 antagonist prevented this effect. αKG increases PRR expression, while treatments with ML, PKC inhibition, or intracellular Ca2+ depletion impair this effect. In silico analysis suggested that αKG binds to mouse OXGR1. These results indicate that HG conditions promote increased levels of intratubular αKG and OXGR1-dependent PRR upregulation, which impact AngII formation and Na+ reabsorption.