bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic β-cell proliferation via phosphorylation of HDAC5 in mice
Authors: Sasaki Shugo , Nian Cuilan , Xu Eric E. , Pasula Daniel J. , Winata Helena , Grover Sanya , Luciani Dan S. , Lynn Francis C. 
Published: December 2022

ABSTRACTObjectiveDiabetes onset is accompanied with β-cell deficiency, and thus restoring functional β-cell mass is a promising therapy for those with diabetes. However, the regulatory mechanisms controlling β-cell mass are not fully understood. Previously, we demonstrated that the transcription factor SOX4 is required for β-cell proliferation in the prediabetic state. To elucidate potential mechanisms by which SOX4 regulates β-cell mass, we performed RNA sequencing (RNA-seq) using pancreatic β-cell specific SOX4 knockout mice (βSOX4 KO). The RNA-seq revealed decreased expression of GRK5, a known type 2 diabetes susceptibility gene whose association with diabetes has not been fully elucidated. Therefore, we aimed to clarify the function of GRK5 in pancreatic β cells.MethodsWe generated a novel pancreatic β cell-specific GRK5 knockout mass (βGRK5 KO) and evaluated glucose tolerance and metabolic changes by body weight measurement, oral glucose tolerance test, and insulin tolerance test. The number of pancreatic β cells was quantified by immunohistochemistry. Glucose loading and Ca2+imaging was performed on isolated islets to evaluate insulin secretory capacity. To elucidate the mechanism of βGRK5 on β cell mass regulation, we performed RNA-seq of isolated islets and identified the signaling pathways that could be regulated by GRK5. Furthermore,in vitroexperiments were conducted using human islets and mouse βGRK5 KO islets to clarify the direct effects of GRK5 on these pathways.ResultsβGRK5 KO islets showed impaired glucose tolerance and insulin secretion, but no change in body weight or insulin resistance, suggesting that the main cause of impaired glucose tolerance is impaired insulin secretion. Isolated islets showed no abnormalities in insulin secretory capacity or changes in calcium influx, but histologically showed a decrease in β cell mass. Consistent with the decreased β cell mass in βGRK5 KO, the cell cycle inhibitor geneCdkn1awas upregulated in βGRK5 KO islets; this phenocopies the βSOX4 KO. Furthermore, we found that Grk5 positively regulates facultative increases in β cell mass through activity-dependent phosphorylation of HDAC5 and subsequent transcription of immediate early genes (IEGs) such asNr4a1,Fosb,Junb,Arc,Egr1andSrf.ConclusionsOur results suggest that GRK5 is associated with type 2 diabetes through regulation of β cell mass. GRK5 could become a potential target of cell therapy to preserve functional β cells during the progression towards frank diabetes.
Curiosity-Motivated Incidental Learning With And Without Incentives: Early Consolidation And Midbrain-Hippocampal Resting-State Functional Connectivity
Authors: Meliss Stefanie , Murayama Kou 
Published: December 2022

AbstractHuman memory is selective and not all experiences are remembered. Both monetary rewards/incentives and curiosity have been found to motivate and facilitate learning by dopaminergic midbrain projections to the hippocampus during encoding. In this study, we examined potential brain mechanisms during early consolidation period that jointly or independently contribute to these facilitating effects. Participants (N = 50) watched 36 videos of magic tricks and rated their “subjective feelings of curiosity” while the availability of extrinsic incentives was manipulated between groups. Functional magnetic resonance imaging (fMRI) data were acquired before, during, and after learning, and memory for magic tricks was assessed one week after. Our analysis focused on the change in resting-state functional connectivity (RSFC) between the dopaminergic midbrain and the anterior hippocampus, a dopaminergic consolidation mechanism previously reported in the context of extrinsically motivated learning. Changes in RSFC were correlated with behavioural measures of learning, i.e., the total number of items encoded and the curiosity-driven memory benefit. We found that brain-behaviour correlations differed depending on the availability of extrinsic incentives. More specifically, the correlation between the total number of items encoded and RSFC change was significantly different in the incentivised compared to the control group. The curiosity-driven memory benefit, however, did not correlate with changes in RSFC in either of the groups. In sum, this suggests that curiosity-motivated learning might be supported by different consolidation mechanisms compared to extrinsically motivated learning and that extrinsic incentives influence consolidation mechanisms supporting learning.Key pointsA new curiosity-motivated incidental encoding paradigm was used to investigate how dopaminergic consolidation mechanisms support learning and whether this is further influenced by the availability of monetary incentives.Changes in resting-state functional connectivity between the dopaminergic midbrain and the anterior hippocampus, a dopaminergic consolidation mechanism, predicted learning outcomes significantly differently if monetary incentives were available.These results might suggest that learning motivated by curiosity might rely on different neural mechanisms during early consolidation than learning motivated by monetary incentives.
Modeling epithelial tissue and cell deformation dynamics using a viscoelastic slab sculpted by surface forces
Authors: Du XinXin , Shelley Michael 
Published: December 2022

I.ABSTRACTDuring morphogenesis, epithelial monolayers actively alter their shape to create future body parts of the animal; this makes the epithelium one of the most active and critical structures in early animal development. Even though epithelial cells exist and move in three dimensions, mathematical models frequently describe them as merely two-dimensional. However, recent imaging technology has begun to reveal pertinent dynamics in the third dimension of the tissue. With the importance of the third dimension in mind, we have developed a self-sculpting, three-dimensional model of epithelia whose dynamics are driven by active forces on its surface. We present a first, fundamental study for a reduced version of epithelia that investigates how surface forces affect its internal dynamics. Our model captures the 3D slab-like geometry of epithelia, viscoelasticity of tissue response, fluid surroundings, and driving from active surface forces. We represent epithelial tissue as a thick slab, a 3D continuum comprised of a Stokes fluid with an extra viscoelastic stress. Employing this model, we present both analytical and numerical solutions of the system and make quantitative predictions about cell shapes, cell dynamics, and the tissue’s response to surface force in a three-dimensional setting. In particular, we elucidate the initiation of ventral furrow invagination and T1 transitions inDrosophilaembryogenesis. In the former, we demonstrate the importance of fluid and geometric surroundings to drive invagination. In the latter, we show the limitations of surface forces alone to drive T1 transitions.
Conformational space exploration of cryo-EM structures by variability refinement
Authors: Afonine Pavel V. , Gobet Alexia , Moissonnier Loïck , Poon Billy K. , Chaptal Vincent 
Published: December 2022

SummaryCryo-EM observation of biological samples enables visualization of sample heterogeneity, in the form of discrete states that are separatable, or continuous heterogeneity as a result of local protein motion before flash freezing. Variability analysis of this continuous heterogeneity describes the variance between a particle stack and a volume, and results in a map series describing the various steps undertaken by the sample in the particle stack. While this observation is absolutely stunning, it is very hard to pinpoint structural details to elements of the maps. In order to bridge the gap between observation and explanation, we designed a tool that refines an ensemble of structures into all the maps from variability analysis. Using this bundle of structures, it is easy to spot variable parts of the structure, as well as the parts that are not moving. Comparison with molecular dynamics simulations highlight the fact that the movements follow the same directions, albeit with different amplitudes. Ligand can also be investigated using this method. Variability refinement is available in thePhenixsoftware suite, accessible under the program namephenix.varref.
Somatomotor Beta Bursts Mediate the Negative Impact of PTSD Severity on Conflict Monitoring
Authors: Rawls Eric , Marquardt Craig A. , Sponheim Scott R. 
Published: December 2022

AbstractCognitive control deficits are associated with posttraumatic stress disorder (PTSD) and may explain how reminders of past traumatic events intrude upon daily experiences of people who have experienced trauma. Lateralized somatomotor beta-band desynchronization, an electrophysiological signature of controlled movement, indexes the downstream output of cognitive control processes. Recent evidence suggests that somatomotor beta activity does not manifest as rhythmic oscillations, but instead as discrete and stochastic burst-like events. Here, we quantified the rates of lateralized somatomotor beta bursts (beta burst rates; BBR) evoked during a flanker cognitive control paradigm among United States military veterans from Operations Iraqi and Enduring Freedom (OEF/OIF) who show varying degrees of PTSD. We found BBR reflected both response direction and conflict monitoring during processing of stimuli that evoked response conflict. Impaired behavioral performance and increased peri-response BBR were related to greater posttraumatic stress symptomatology (PTSS). Critically, increased BBR mediated the link between PTSS and decreased conflict monitoring accuracy. Results suggest that poor cognitive control in PTSS reflects a failure to adaptively disinhibit target motor representations, rather than a failure to inhibit distractor representations. Thus, BBR reveal limited representation of target stimuli as a primary contributor to impaired cognitive control in PTSD. Because BBR were robustly associated with behavioral performance and exhibited high statistical reliability the index may carry utility for appraising individual differences in cognitive control in other brain disorders.
A DNA damage-induced phosphorylation circuit enhances Mec1ATR-Ddc2ATRIPrecruitment to Replication Protein A
Authors: Yates Luke A. , Tannous Elias A. , Morgan R. Marc , Burgers Peter M. , Zhang Xiaodong 
Published: December 2022

AbstractThe cell cycle checkpoint kinase Mec1ATRand its integral partner Ddc2ATRIPare vital for the DNA damage and replication stress response. Mec1-Ddc2 ‘senses’ single-stranded DNA (ssDNA) by being recruited to the ssDNA binding Replication Protein A (RPA) via Ddc2. In this study, we show that a DNA-damage induced phosphorylation circuit modulates checkpoint recruitment and function. We demonstrate that Ddc2-RPA interactions modulate the association between RPA and ssDNA and that Rfa1-phosphorylation aids in the further recruitment of Mec1-Ddc2. We also uncover an underappreciated role for Ddc2 phosphorylation that enhances its recruitment to RPA-ssDNA that is important for the DNA damage checkpoint in yeast. The crystal structure of a phosphorylated Ddc2 peptide in complex with its RPA interaction domain provides molecular details of how checkpoint recruitment is enhanced, which involves Zn2+. Using electron microscopy and structural modelling approaches, we propose that Mec1-Ddc2 complexes can form higher order assemblies with RPA when Ddc2 is phosphorylated. Together, our results provide insight into Mec1 recruitment and suggest that formation of supramolecular complexes of RPA and Mec1-Ddc2, modulated by phosphorylation, would allow for rapid clustering of damage foci to promote checkpoint signalling.Graphical AbstractHighlightsRfa1-S178 phosphorylation promotes Ddc2 recruitment and Ddc2-RPA complexes modulate RPA-ssDNA behaviour.Ddc2 phosphorylation enhances Mec1-Ddc2 recruitment and is important for the DNA damage checkpoint in yeast.Structure of a Ddc2:RPA complex shows phosphorylation-dependent higher order assemblies stabilised by Zn2+.We propose a Mec1-Ddc2 recruitment strategy that allows fast accumulation of Mec1-Ddc2 through DNA damage-induced phosphorylation and promotes autophosphorylation.
Generalised interrelations among mutation rates drive the genomic compliance of Chargaff’s second parity rule
Authors: Pflughaupt Patrick , Sahakyan Aleksandr B. 
Published: December 2022

ABSTRACTChargaff’s second parity rule (PR-2), where the complementary base and k-mer contents are matching within the same strand of a double stranded DNA (dsDNA), is a phenomenon that invited many explanations. The strict compliance of nearly all nuclear dsDNA to PR-2 implies that the explanation should also be similarly adamant. In this work, we revisited the possibility of mutation rates driving PR-2 compliance. Starting from the assumption-free approach, we constructed kinetic equations for unconstrained simulations. The results were analysed for their PR-2 compliance by employing symbolic regression and machine learning techniques. We arrived to a generalised set of mutation rate interrelations in place in most species that allow for their full PR-2 compliance. Importantly, our constraints explain PR-2 in genomes out of the scope of the prior explanations based on the equilibration under mutation rates with simpler no-strand-bias constraints. We thus reinstate the role of mutation rates in PR-2 through its molecular core, now shown, under our formulation, to be tolerant to previously noted strand biases and incomplete compositional equilibration. We further investigate the time for any genome to reach PR-2, showing that it is generally earlier than the compositional equilibrium, and well within the age of life on Earth.
Friend or Foe: Ambrosia Beetle response to volatiles of common threats in their fungus gardens
Authors: Diehl Janina M.C. , Kassie Denicia , Biedermann Peter H.W. 
Published: December 2022

AbstractFungus farming insects encounter multiple microbial threats in their cultivar gardens. They can affect both the nutritional cultivar and the insect’s health. In this study, we explored the potential of ambrosia beetles and their larvae to detect the presence of ubiquitous weed or entomopathogenic fungi. The ability to recognize a threat offers individuals a chance to react. Our study organism, the fruit-tree pinhole borer,Xyleborinus saxesenii, is associated with two mutualistic fungi,Dryadomyces sulphureus(Raffaelea sulphurea)andRaffaelea canadensis. Both symbionts were tested in combinations with two common fungus-garden weeds (Aspergillussp. andPenicillium commune) and the entomopathogenBeauveria bassianain two-choice experiments. Behavioural repellence was found in many, but not all combinations. Larvae and adult females showed an opposite reaction towards the entomopathogen, whereas forAspergillussp., neither provoked repellence nor attraction of larvae and adult females, ifR. canadensiswas used as lure. Our results validate a response of both larvae and adult ambrosia beetles towards other fungal volatiles. Their decision to confront a potential threat or preferably to avoid it could be subject to a more complex context.
Transcriptomic profiling of the adult reptilian dentition sheds light on the genes regulating indefinite tooth replacement
Authors: Henriquez Joaquin Ignacio , Flibotte Stephane , Fu Katherine , Li Edward Zirui-Wang , Richman Joy M. 
Published: December 2022

AbstractThe aim of this study is to profile the transcriptome of teeth and the surrounding tissues of an adult lizard dentition (Eublepharis macularius) that is actively replacing teeth throughout life. Bulk RNAseq was used to compare teeth that are in function versus unerupted, developing teeth and single cell RNA-seq was carried out on jaw segments containing the dental forming tissues. In bulk RNAseq data, we found that functional teeth expressed genes involved in bone and tooth resorption. Indeed, multinucleated odontoclasts were abundant in tissue sections of functional teeth undergoing resorption. Unexpectedly, chemotaxis geneSEMA3Awas expressed within odontoblasts and in adjacent mesenchyme, confirmed using RNAscope. Semaphorins may be involved in regulating odontoclasts during tooth resorption. The scRNA-seq experiment successfully isolated dental mesenchyme and epithelial cells. We confirmed that some of these genes are expressed in the earliest tooth buds within the tooth forming field. In addition, we found evidence of convergent evolution in the tooth eruption trait. Geckos evolved a means for second generation teeth to communicate with the functional teeth. Instead of a dental follicle inducing an eruption pathway as in the mammal, the gecko and other squamate reptiles use the enamel organ of the successional teeth to trigger tooth resorption of the functional teeth, thus creating an eruption pathway. New molecules such as SEMA3A and SFRP2 may also participate in this process. Future studies on the gecko will uncover the molecular basis of convergent evolution in the dentition.
Cognitive and executive impairments in Parkinson’s Disease psychosis: a Bayesian meta-analysis
Authors: Pisani Sara , Gosse Luca , Wieretilo Rita , ffytche Dominic , Velayudhan Latha , Bhattacharyya Sagnik 
Published: December 2022

AbstractBackgroundCognitive and executive deficits lead to worsening of quality of life and are a risk factor for developing dementia in Parkinson’s Disease (PD) patients with psychosis. However, which key cognitive domains are differentially affected in PD patients with psychosis (PDP) compared to those without (PDnP), remains unclear. Here we examined this using a Bayesian meta-analytic approach.MethodsSearches were conducted on PubMed, Web of Science, SCOPUS, Medline and PsycINFO. Hedges’ g effect-size estimates were extracted from eligible studies as a measure of standard mean differences between PDP and PDnP patients. Meta-analyses were conducted separately for each cognitive domain and sub-domain, we examined the effect of age, PD medications, PD duration and severity, depression and psychosis severity for all major domains with meta-regressions.ResultsEffect-size estimates suggest worse performance on all major domains (k=105 studies) in PDP compared to PDnP patients, with global cognition (k=103 studies,g=-0.57), processing speed (k=29 studies,g=-0.58), executive functions (k=33,g=-0.56), episodic memory (k=30 studies,g=-0.58), and perception (k=34 studies,g=-0.55) as the most likely affected domains. Age, depression, and PD duration had moderating effects on task-related performance across most of the major nine domains.ConclusionsWe report extensive deficits across nine domains as well as sub-domains in PD psychosis, with global cognition, processing speed and executive functions as the most likely impaired. Presence of depression may influence task-related performance in PDP, alongside age and PD duration, but not dose of dopamine replacement treatments.
A second update on mapping the human genetic architecture of COVID-19
Authors:   The COVID-19 Host Genetics Initiative, Ganna Andrea 
Published: December 2022

AbstractInvestigating the role of host genetic factors in COVID-19 severity and susceptibility can inform our understanding of the underlying biological mechanisms that influence adverse outcomes and drug development1,2. Here we present a second updated genome-wide association study (GWAS) on COVID-19 severity and infection susceptibility to SARS-CoV-2 from the COVID-19 Host Genetic Initiative (data release 7). We performed a meta-analysis of up to 219,692 cases and over 3 million controls, identifying 51 distinct genome-wide significant loci—adding 28 loci from the previous data release2. The increased number of candidate genes at the identified loci helped to map three major biological pathways involved in susceptibility and severity: viral entry, airway defense in mucus, and type I interferon.
A ferritin-based COVID-19 nanoparticle vaccine that elicits robust, durable, broad-spectrum neutralizing antisera in non-human primates
Authors: Weidenbacher Payton A.-B. , Sanyal Mrinmoy , Friedland Natalia , Tang Shaogeng , Arunachalam Prabhu S. , Hu Mengyun , Kumru Ozan S. , Morris Mary Kate , Fontenot Jane , Shirreff Lisa , Do Jonathan , Cheng Ya-Chen , Vasudevan Gayathri , Feinberg Mark B. , Villinger Francois J. , Hanson Carl , Joshi Sangeeta B. , Volkin David B. , Pulendran Bali , Kim Peter S. 
Published: December 2022

ABSTRACTWhile the rapid development of COVID-19 vaccines has been a scientific triumph, the need remains for a globally available vaccine that provides longer-lasting immunity against present and future SARS-CoV-2 variants of concern (VOCs). Here, we describe DCFHP, a ferritin-based, protein-nanoparticle vaccine candidate that, when formulated with aluminum hydroxide as the sole adjuvant (DCFHP-alum), elicits potent and durable neutralizing antisera in non-human primates against known VOCs, including Omicron BQ.1, as well as against SARS-CoV-1. Following a booster ∼one year after the initial immunization, DCFHP-alum elicits a robust anamnestic response. To enable global accessibility, we generated a cell line that can enable production of thousands of vaccine doses per liter of cell culture and show that DCFHP-alum maintains potency for at least 14 days at temperatures exceeding standard room temperature. DCFHP-alum has potential as a once-yearly booster vaccine, and as a primary vaccine for pediatric use including in infants.
Apical size anddeltaAexpression predict adult neural stem cell decisions along lineage progression
Authors: Mancini Laure , Guirao Boris , Ortica Sara , Labusch Miriam , Cheysson Felix , Bonnet Valentin , Phan Minh Son , Herbert Sébastien , Mahou Pierre , Menant Emilie , Bedu Sébastien , Tinevez Jean-Yves , Baroud Charles , Beaurepaire Emmanuel , Bellaiche Yohanns , Bally-Cuif Laure , Dray Nicolas 
Published: December 2022

SummaryThe maintenance of neural stem cells (NSCs) in the adult brain depends on their activation frequency and division mode. We use long-term intravital imaging of NSCs in the zebrafish adult telencephalon to link activation and division mode with predictive cellular and molecular parameters. We reveal that apical surface area and expression of the Notch ligand DeltaA predict NSC activation frequency, whiledeltaAexpression marks NSC commitment to neurogenesis. We also find thatdeltaA-negative NSCs constitute thebona fideself-renewing NSC pool and systematically engage in asymmetric divisions generating a self-renewingdeltaAnegand a neurogenicdeltaAposNSC. Finally, modulation of Notch signaling during imaging indicates that the prediction of activation frequency by apical size, and the asymmetric divisions ofdeltaAnegNSCs, are functionally independent of Notch. These results provide dynamic qualitative and quantitative readouts of NSC lineage progressionin vivoand support a hierarchical organization of NSCs in differently fated sub-populations.