bluuebunny/crossref_metadata_2025_split huggingface dataset:
Agency as a Bridge to Form Associative Memories
Authors: Ruiz Nicholas A. , DuBrow Sarah , Murty Vishnu P. 
Published: May 2022

AbstractThe perception of agency occurs when individuals feel their decisions exert control over their environment. While agency can increase memory for items, most real-life situations are more complex. The decisions we make not only affect the item we act upon, but all the other items in direct proximity of our decisions. Here, we examined how an individual’s agency to influence a situation affects their ability to learn associations between items that occur prior to and after making a decision. In our paradigm, participants were told they were playing a game show where they had to help a trial unique ‘contestant’ choose between three doors. On ‘agency’ trials, participants were allowed to pick any door they wanted. On ‘forced-choice’ trials, participants were instructed to select a door that was highlighted. They then saw the outcome, a ‘prize’ that was behind the selected door. Across two studies, participants show enhanced memory for contestants they saw in agency vs forced-choice trials. Memory benefits also extended to contestant - door and door - prize associations in both studies. Study 2 found this effect in the contestant - prize association. Notably, we found that agency also shaped the representation of memories such that they were stored as integrated sequences rather than individual relational pairs. Together, these data suggest agency over a situation leads to enhanced memory for all items in that situation. This enhanced binding for items may be occurring by the formation of causal links when an individual has agency over their learning environment.
Improved methods for the large-scale cultivation ofGiardia lambliatrophozoites in the academic laboratory
Authors: Wimberly Brian T. , Bilodeau Danielle , Rissland Olivia S. , Kieft Jeffrey S. 
Published: May 2022

AbstractThe parasitic protistGiardia lambliacauses giardiasis, one of the leading diarrheal diseases worldwide. As a phylogenetically divergent eukaryote,Giardiais also an emerging model organism for exploring the diversity of core eukaryotic metabolic pathways and important molecular structures. To date, methods for the cultivation of large numbers (>109) ofGiardiatrophozoites have been either expensive or cumbersome, hampering structural and biochemical studies. Here, we present two improved strategies for the laboratory-scale growth of billions of adherent trophozoites, with suggestions for the optimization of media components, media preparation, and harvesting methods.
Chimera States among Synchronous Fireflies
Authors: Sarfati Raphaël , Peleg Orit 
Published: May 2022

AbstractSystems of oscillators, whether animate or inanimate, often converge to a state of collective synchrony, when sufficiently interconnected. Twenty years ago, the mathematical study of models of coupled oscillators revealed the possibility for complex phases which exhibit the coexistence of synchronous and asynchronous clusters, since then referred to as “chimera states”. Beyond their recurrence in theoretical models, chimera states have been observed in specifically-designed, non-biological experimental conditions, yet their emergence in nature has remained elusive. Here, we report robust evidence for the occurrence of chimera states in a celebrated realization of natural synchrony: fireflies. In video recordings of collective displays of Photuris frontalis fireflies, we observe, within a single swarm, the spontaneous emergence of different groups flashing with the same periodicity but with a constant time delay between them. From the three-dimensional reconstruction of the swarm, we demonstrate that these states are stable over time and spatially intertwined, but find no evidence of enhanced correlations in their spatial dynamics. We discuss the implications of these findings on the synergy between mathematical models and firefly collective behavior.
The Human Dendritic Cell Atlas: An integrated transcriptional tool to study human dendritic cell biology
Authors: Elahi Zahra , Angel Paul W. , Butcher Suzanne , Rajab Nadia , Choi Jarny , Mintern Justine D. , Radford Kristen J. , Wells Christine A. 
Published: May 2022

SummaryDendritic cells (DCs) are functionally diverse and are present in most adult tissues, however progress in understanding human DC biology is hampered by a relatively small number of these in circulation and by limited access to human tissues. We built a transcriptional atlas of human DCs by combining samples from 14 expression profiling studies derived from 10 laboratories. We identified significant gene expression variation of DC subset-defining markers across tissue-type and upon viral or bacterial stimulation. We further highlight critical gaps between in vitro-derived DC subsets and their in vivo counterparts and provide evidence that monocytes or cord blood progenitor in vitro-differentiated DCs fail to capture the repertoire of primary DC subsets or behaviours. In constructing a reference DC atlas, we provide an important resource for the community wishing to identify and annotate tissue-specific DC subsets from single-cell datasets, or benchmark new in vitro models of DC biology.Key PointsA reference atlas of human DC that allows benchmarking of in vitro DC modelsMeta-analysis of 14 integrated studies demonstrate that human conventional dendritic cells have distinct tissue-of-origin phenotypesUser uploads allow tissue-relevant annotation of human DC subsets from single cell datasetsKey subset markers are altered by tissue or activation statusGaps between in vitro-differentiated DC and in vivo counterparts are partially rescued by humanized mouse models, or coculture with NOTCH-ligands.
Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission
Authors: Stern Shani , Zhang Lei , Wang Meiyan , Wright Rebecca , Cordeiro Diogo , Peles David , Hang Yuqing , Mendes Ana P. D. , Baul Tithi , Roth Julien , Coorapati Shashank , Boks Marco , Pol Hilleke Hulshoff , Brennand Kristen J. , Réthelyi Janos M , Kahn René S. , Marchetto Maria C. , Gage Fred H. 
Published: May 2022

AbstractSchizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. We characterized human-induced pluripotent stem cell (iPSC)-derived hippocampal neurons from two pairs of monozygotic twins that are discordant for a schizophrenia diagnosis. We compared the affected and the non-affected siblings and compared all of them to twin sets where none of the siblings suffered from schizophrenia. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. The neurons in the unaffected co-twin group were also less arborized than the neurons from controls but more arborized than those from affected siblings. Some of their spike features were immature (but less immature than neurons derived from the affected siblings). Importantly, their synaptic activity was not affected. Since schizophrenia is a genetically complex disorder, our twin study allows the measurement of neuronal phenotypes with a similar genetic background. The differences between the siblings may arise due to changes that occurred after the split of the egg into twins. Therefore, our study confirms that dysregulation of synaptic pathways, as well as changes in the rate of synaptic events, distinguishes between individuals affected with schizophrenia and unaffected individuals, even in those having a very similar genetic background.
Translational Activity Controls Ribophagic Flux and Turnover of Distinct Ribosome Pools
Authors: Trendel Jakob , Aleksić Milan , Bertolini Matilde , Jochem Marco , Kramer Günter , Pfeffer Stefan , Bukau Bernd , Krijgsveld Jeroen 
Published: May 2022

SummaryRibosomes are among the most abundant and complex machineries in the cell, however, the turnover of their subunits remains poorly understood. Here, we apply proteomic flux and cryo-electron microscopy analyses to interrogate the ribosome life cycle in human cells. We show that subpopulations of ribosomal subunits coexist, which vary in turnover kinetics and structure. Specifically, 80S ribosomes have a much longer half-life than free 40S and 60S ribosomal subunits, indicating that they represent distinct subunit pools that poorly intermix. Translation inhibition starkly increases the pool-size of 80S ribosomes in a translationally idle state and induces ribophagy of old ribosomes, ultimately rejuvenating the ribosome fleet. Our findings provide a comprehensive model for ribosome turnover and its regulation via translational activity.
Single-cell characterisation of the hematopoietic bone marrow interactome in health and disease
Authors: Ennis Sarah , Conforte Alessandra , O’Reilly Eimear , Cichocka Tatiana , Pal Dhami Sukhraj , Nicholson Pamela , Krebs Philippe , Ó Broin Pilib , Szegezdi Eva 
Published: May 2022

1AbstractThe bone marrow (BM) is a complex microenvironment and the primary site of hematopoiesis, coordinating the production of billions of blood cells every day. Despite the essential role of the hematopoietic niche in maintaining hemostasis and its relevance to hematopoietic diseases, many aspects of this environment remain poorly characterised due to experimental hurdles. Here we present a high-resolution characterisation of the niche in health and acute myeloid leukemia (AML) by establishing a comprehensive single-cell gene expression database of nearly 340,000 BM constituent cells encompassing all disease stages (healthy BM, AML at diagnosis, remission and relapse). We characterised the cell type composition of the BM and found that the proportions of both myeloid and lymphoid lineage cell types are significantly altered in AML. We also determined broadscale dysregulation of gene expression in almost all BM cell types upon establishment of AML, indicating that the entire niche is disrupted by the disease. Given the importance of interactions between hematopoietic cells and their microenvironment in regulating their function and properties, we determined all possible ligand-receptor interactions between hematopoietic stem and progenitor cells (HSPC) and every other BM constituent cell type. This analysis revealed a remarkable expansion of HSPC interactions in AML involving multiple BM constituent cells that can drive dysregulated HSPC-cell adhesion, immunosuppression and enhanced cytokine signalling. In particular, we found that interactions involving TGFB1 become widespread in AML and present evidence that these interactions can drive AML cell quiescence in vitro, thus highlighting TGFB1 signalling as a potential target for increasing drug sensitivity and preventing relapse. Our results shed light on potential mechanisms of enhanced competitiveness of AML HSPCs and an overall skewed microenvironment that fosters AML growth.
High-resolution kinetic gene expression analysis of T helper cell differentiation reveals a STAT-dependent, unique transcriptional program in Th1/2 hybrid cells
Authors: Burt Philipp , Peine Michael , Peine Caroline , Borek Zuzanna , Serve Sebastian , Floßdorf Michael , Hegazy Ahmed N. , Höfer Thomas , Löhning Max , Thurley Kevin 
Published: May 2022

AbstractSelective differentiation of CD4+ T helper (Th) cells into specialized subsets such as Th1 and Th2 cells is a key element of the adaptive immune system driving appropriate immune responses. Besides those canonical Th cell lineages, hybrid phenotypes such as Th1/2 cells arise in vivo, and their generation could be reproduced in vitro. While master-regulator transcription factors like T-bet for Th1 and GATA-3 for Th2 cells drive and maintain differentiation into the canonical lineages, the transcriptional architecture of hybrid phenotypes is less well understood. In particular, it has remained unclear whether a hybrid phenotype implies a mixture of the effects of several canonical lineages for each gene, or rather a bimodal behavior across genes. Th cell differentiation is a dynamic process in which the regulatory factors are modulated over time, but longitudinal studies of Th cell differentiation are sparse. Here, we present a dynamic transcriptome analysis following Th cell differentiation into Th1, Th2 and Th1/2 hybrid cells. We identified an early bifurcation point in gene expression programs, and we found that only a minority of ∼20% of Th cell-specific genes showed mixed effects from both Th1 and Th2 cells on Th1/2 hybrid cells. While most genes followed either Th1 or Th2 cell gene expression, another fraction of ∼20% of genes followed a Th1 and Th2 cell-independent transcriptional program under control of the transcription factors STAT1 and STAT4. Overall, our results emphasize the key role of high-resolution longitudinal data for the characterization of cellular phenotypes.
Echolocation-like model of directed cell migration within growing tissues
Authors: Loo Tricia Y. J. , Mahabaleshwar Harsha , Carney Tom , Saunders Timothy E. 
Published: May 2022

During development and regeneration, cells migrate to specific locations within growing tissues. These cells can respond to both biochemical signals and mechanical cues, resulting in directed migration. Such migration is often highly stereotypic. Yet, how cells respond to migratory signals in a robust manner within a growing domain remains an open problem. Here, we propose a model of directed migration in growing tissues motivated by echolocation. The migrating cells generate a signaling gradient that induces a response signal from the moving system boundary. This response signal mediates cellular adhesion to the surrounding matrix and hence modulates the cell migration. We find that such a mechanism can align a series of cells at stable positions within growing systems and can effectively scale to system size. Finally, we discuss the relevance of such a model to fibroblast migration and location within the developing zebrafish caudal fin, which may be regulated by opposing signaling gradients of Slit-Robo pathway components.Significance StatementHow do cells reliably migrate within growing environments? Here, we show that cells can take advantage of an echolocation-like process, whereby they induce a response from the tissue boundary. As they approach the boundary, the response signal strengthens and brings the cell to a fixed position from the boundary. This simple system may be applicable to fibroblast migration in the fin.
Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency
Authors: Rigoli Marta , Spagnolli Giovanni , Lorengo Giulia , Monti Paola , Potestio Raffaello , Biasini Emiliano , Inga Alberto 
Published: May 2022

ABSTRACTThe formation of a tetrameric assembly is essential for the ability of the tumor suppressor protein p53 to act as a transcription factor. Such a quaternary conformation is driven by a specific tetramerization domain, separated from the central DNA binding domain by a flexible linker. Despite the distance, functional crosstalk between the two domains has been reported. This phenomenon can explain the pathogenicity of some inherited or somatically acquired mutations in the tetramerization domain, including the widespread R337H missense mutation occurring in the population of south Brazil. In this work, we have combined computational predictions through extended all-atom molecular dynamics simulations with functional assays in a genetically defined yeast-based model system to reveal structural features of p53 tetramerization domains and their transactivation capacity and specificity. Besides the germline and cancer-associated R337H and R337C, other rationally designed missense mutations targeting a significant salt bridge interaction that stabilizes the p53 tetramerization domain were studied (R337D, D352R, and the double mutation R337D plus D352R). Simulations revealed a destabilizing effect of pathogenic mutations within the p53 tetramerization domain and highlighted the importance of electrostatic interactions between residues 337 and 352. The transactivation assay performed in yeast by tuning the expression of wild-type and mutant p53 proteins revealed that p53 tetramerization mutations could decrease transactivation potential and alter transactivation specificity, in particular, by better tolerating the negative features in weak DNA binding sites. These results establish the effect of naturally occurring variations at positions 337 and 352 on p53 conformational stability and function.
Melanocyte-secreted Fibromodulin constrains skin inflammation in mice injected with lupus serum
Authors: Halasi Marianna , Nyska Abraham , Rubin Limor , Tal Yuval , Tsokos George C. , Adini Irit 
Published: May 2022

ABSTRACTSkin pigmentation has been linked to the development, prevalence, and severity of several immune-mediated diseases such as SLE. Here, we asked whether fibromodulin (FMOD), which is highly expressed in skin with light complexion, can explain the known differences in the magnitude of inflammation. C57 mice with different levels of pigmentation and FMOD were injected with human lupus serum to induce skin inflammation. Histopathologic studies revealed that black C57 FMOD+/+ that produce low levels of FMOD and white C57 FMOD -/- mice develop more severe inflammation compared with white FMOD +/+ mice. This study also revealed that dark pigmentation and FMOD deletion correlates with the increased numbers of Langerhans cells. Altogether, we identify low pigmentation and FMOD are linked to low severity of inflammation and approaches to promote FMOD expression should offer clinical benefit.
Synonymous codon usage regulates translation initiation
Authors: Barrington Chloe L. , Koch Amanda L. , Galindo Gabriel , Larkin-Gero Emma , Morrison Evan J. , Tisa Samantha , Stasevich Timothy J. , Rissland Olivia S. 
Published: May 2022

ABSTRACTSynonymous codon usage regulates gene expression such that transcripts rich in optimal codons produce significantly more protein than their nonoptimal counterparts. A major unresolved issue has been understanding the mechanisms by which synonymous codons regulate gene expression. We and others have previously shown that nonoptimal codons slow translation elongation speeds and thereby trigger mRNA degradation. However, differences in transcript abundance are not always sufficient to explain differences in protein levels, suggesting there are additional mechanisms by which codon usage regulates gene expression. Using reporter assays in human and Drosophila cells, we found that transcript levels account for less than half of the variation in protein abundance. We demonstrate that the differences at the protein level are not attributable to either protein folding or stability. Instead, we find that mRNAs with nonoptimal codons are bound by fewer ribosomes and that nonoptimal codon usage represses translation initiation. Nonoptimal transcripts are also less bound by the key translation initiation factors eIF4E and eIF4G, providing a mechanistic explanation for their reduced initiation rates. Our results reveal a new mechanism of regulation by codon usage, where nonoptimal codons repress further rounds of translation.
Conformational fluctuations in molten globule state ofα-lactalbumin
Authors: Ghosh Moulick Abhik , Chakrabarti J. 
Published: May 2022

AbstractMolten globule (MG) state is an intermediate state of protein observed during folding into native structure. MG state of protein is induced by various denaturing agent (like Urea), extreme pH, pressure and heat. Experiments suggest that MG state of some protein is functionally relevant even if there is no well-defined tertiary structure. Earlier experimental and theoretical studies suggest that MG state of the protein is dynamic in nature, where conformational states are interconverted in nanosecond time scales. These observations lead us to study and compare conformational fluctuations of MG state to those of intrinsic disordered protein (IDP). We considerα-Lactalbumin(aLA) protein, which shows MG state at low pH upon removal of calcium (Ca2+) ion. We use constant pH molecular dynamics simulation (CpHMD) to maintain low pH during simulation. We use the dihedral principal component analysis, the density based clustering method and the machine learning technique to identify the conformational fluctuations. We observe metastable states in the MG state. The residues containing the essential coordinates responsible for metastability belong to stable helix in crystal structure, but most of them prefer unstructured or bend conformation in MG state. These residues control the exposure of the putative binding residues for fatty acids. Thus, the MG state of protein behaves as intrinsic disorder protein, although the disorder here is induced by external conditions.
Nlrc4 inflammasome is critical for host protection against flagellated Salmonella
Authors: López-Yglesias Américo H. , Lu Chun-Chi , Lai Marvin A. , Quarles Ellen K. , Zhao Xiaodan , Hajjar Adeline M. , Smith Kelly D. 
Published: May 2022

AbstractSalmonella enterica serovar Typhimurium is a leading cause of gastroenteritis worldwide and a deadly pathogen in children, immunocompromised patients, and the elderly. Salmonella induces innate immune responses through the Nlrc4 inflammasome, which has been demonstrated to have distinct roles during systemic and mucosal detection of flagellin and non-flagellin molecules. We hypothesized that Nlrc4 recognition of Salmonella flagellin is the dominant protective pathway during infection. To test this hypothesis, we used wild-type, flagellin-deficient, and flagellin-overproducing Salmonella to establish the role of flagellin in mediating Nlrc4-dependent host resistance during systemic and mucosal infection. We observed that during the systemic phase of infection, Salmonella efficiently evades Nlrc4-mediated innate immunity. However, during mucosal Salmonella infection, flagellin recognition by the Nlrc4 inflammasome pathway is the dominant mediator of protective innate immunity. These data establish that recognition of Salmonella’s flagellin by the Nlrc4 inflammasome during mucosal infection is the dominant innate protective pathway for host resistance against the enteric pathogen.
NMR as a readout to monitor and restore the integrity of complex chemoenzymatic reactions
Authors: Marincin Kenneth A. , Hwang Yousang , Kengmana Everett S. , Meyers David J. , Frueh Dominique P. 
Published: May 2022

AbstractThe non-invasive nature of NMR offers a means to monitor biochemical reactions in situ at the atomic-level. We harness this advantage to monitor a complex chemoenzymatic reaction that sequentially modifies reagents and loads the product on a nonribosomal peptide synthetase carrier protein. We present a protocol including a novel pulse sequence that permits to assess both the integrity of reagents and the completion of each step in the reaction, thus alleviating otherwise time-consuming and costly approaches to debug and repeat inefficient reactions. This study highlights the importance of NMR as a tool to establish reliable and reproducible experimental conditions in biochemical studies.Graphical Abstract