bluuebunny/crossref_metadata_2025 huggingface dataset:
Broader functions of TIR domains in Arabidopsis immunity
Authors: Jacob Pierre , Hige Junko , Song Lijiang , Bayless Adam , Russ Dor , Bonardi Vera , El-Kasmi Farid , Wünsch Lisa , Yang Yu , Fitzpatrick Connor R. , McKinney Brock J. , Nishimura Marc T. , Grant Murray R. , Dangl Jeffery L.
Published: December 2022

TIR domains are NAD-degrading enzymes that function during immune signaling in prokaryotes, plants, and animals. In plants, most TIR domains are incorporated into intracellular immune receptors. In Arabidopsis, TIR-derived small molecules bind and activate EDS1 heterodimers, which in turn activate RNLs, a class of cation channel-forming immune receptors. RNL activation drives cytoplasmic Ca2+influx, transcriptional reprogramming, pathogen resistance and host cell death. We screened for mutants that suppress an RNL activation mimic allele and identified a TIR-containing immune receptor, SADR1. Despite functioning downstream of an auto-activated RNL, SADR1 is not required for defense signaling triggered by other tested TIR-containing immune receptors. SADR1 is required for defense signaling initiated by some trans-membrane pattern recognition receptors and contributes to the unbridled spread of cell death inlesion simulating disease 1. Together with RNLs, SADR1 regulates defense gene expression at infection site borders, likely in a non-autonomous manner. RNL mutants that cannot sustain this pattern of gene expression are unable to prevent disease spread beyond localized infection sites, suggesting that this pattern corresponds to a pathogen containment mechanism. SADR1 potentiates RNL-driven immune signaling partially through the activation of EDS1, but also partially independently of EDS1. We studied EDS1-independent TIR function using nicotinamide, an NADase inhibitor. We observed decreased defense induction from trans-membrane pattern recognition receptors and decreased calcium influx, pathogen growth restriction and host cell death following intracellular immune receptor activation. We demonstrate that TIR domains can potentiate calcium influx and defense and are thus broadly required for Arabidopsis immunity.
Extracellular vesicle-associated cholesterol dictates the regenerative functions of macrophages in the brain
Authors: Vanherle Sam , Guns Jeroen , Loix Melanie , Mingneau Fleur , Dierckx Tess , Vangansewinkel Tim , Wolfs Esther , Lins Paula Pincela , Bronckaers Annelies , Lambrichts Ivo , Dehairs Jonas , Swinnen Johannes V. , Verberk Sanne G.S. , Haidar Mansour , Hendriks Jerome J.A. , Bogie Jeroen F.J.
Published: December 2022

Macrophages play major roles in the pathophysiology of various neurological disorders, being involved in seemingly opposing processes such as lesion progression and resolution. Yet, the molecular mechanisms that drive their harmful and benign effector functions remain poorly understood. Here, we demonstrate that extracellular vesicles (EVs) secreted by repair-associated macrophages (RAMs) enhance remyelinationex vivoandin vivoby promoting the differentiation of oligodendrocyte precursor cells (OPCs). Guided by lipidomic analysis and applying cholesterol depletion and enrichment strategies, we find that EVs released by RAMs show markedly elevated cholesterol levels and that cholestserol abundance controls their reparative impact on OPC maturation and remyelination. Mechanistically, EV-associated cholesterol was found to promote OPC differentiation through direct membrane fusion. Collectively, our findings highlight that EVs are essential for cholesterol trafficking in the brain and that changes in cholesterol abundance dictate the reparative impact of EVs released by macrophages in the brain, potentially having broad implications for therapeutic strategies aimed at promoting repair in neurodegenerative disorders.
Differential and overlapping effects between exogenous and endogenous attention shape perceptual facilitation during visual processing
Authors: Landry Mathieu , Da Silva Castanheira Jason , Jerbi Karim
Published: December 2022

Visuospatial attention is not a monolithic process and can be divided into different functional systems. In this framework, exogenous attention reflects the involuntary orienting of attention resources following a salient event, whereas endogenous attention corresponds to voluntary orienting based on the goals and intentions of individuals. Previous work shows that these attention processes map onto distinct functional systems, yet evidence suggests that they are not fully independent. In the current work, we investigated the differential and overlapping effects of exogenous and endogenous attention on visual processing. We combined spatial cueing of visuospatial attention, electroencephalography (EEG), and multivariate pattern analysis (MVPA) to examine where and when the effects of exogenous and endogenous attention were maximally different and maximally similar. Critically, MVPA provided new insights by examining whether classifiers trained to decode the cueing effect for one attention process (e.g., exogenous attention) can successfully decode the cueing effect for the other attention process (e.g., endogenous attention). These analyses uncovered differential and overlapping effects between exogenous and endogenous attention. Next, we combined principal component analyses, single-trial event-related potentials, and mediation analysis to determine whether these effects facilitate perception, as indexed by the behavioral spatial cueing effects of exogenous and endogenous attention. This approach revealed that three EEG components shape the cueing effects of exogenous and endogenous attention at various times after target onset. Altogether, our study provides a comprehensive account about how overlapping and differential processes of endogenous and exogenous relate to perceptual facilitation in the context of visuospatial attention.

Significance Statement

Top-down and bottom-up attention represent separate functional systems in the brain. Previous research suggests, however, that they are not fully independent, and can interfere with each other. In the present study, the authors use machine learning techniques and recordings of brain activity to investigate differences and similarities between top-down and bottom-up attention during the visual processing of stimuli. This approach allowed them to explore how top-down and bottom-up attention processes facilitate perception. Their results show that top-down and bottom-up attention operate differently as early as 100ms after the onset of a target. In contrast, they operate similarly 200ms after the target onset. Most importantly, these effects are directly related to the participants’ perceptual behavior. In sum, our study shows that top-down and bottom-up attention support the perception of stimuli through overlapping and distinct spatio-temporal brain patterns.
MYSM1 co-activates ERα action via histone and non-histone deubiquitination to confer antiestrogen resistance in breast cancer
Authors: Luan Ruina , Sun Ge , Zhou Baosheng , Wang Manlin , Bai Yu , Wang Chunyu , Wang Shengli , Zeng Kai , Feng Jianwei , He Mingcong , Lin Lin , Wei Yuntao , Zhang Qiang , Zhao Yue
Published: December 2022

Endocrine resistance is a crucial challenge in estrogen receptor alpha (ERα)-positive breast cancer (BCa) therapy. Aberrant alteration in modulation of E2/ERα signaling pathway has emerged as the putative contributor for endocrine resistance in BCa. Thus, identification the efficient ERα cofactor remains necessary for finding a potential therapeutic target for endocrine resistance. Herein, we have demonstrated that Myb like, SWIRM and MPN domains 1 (MYSM1) as a histone deubiquitinase is a novel ERα co-activator with establishedDrosophilaexperimental model. Our results showed that MYSM1 participated in up-regulation of ERα action via histone and non-histone deubiquitination. We provided the evidence to show that MYSM1 was involved in maintenance of ERα stability via ERα deubiquitination. Furthermore, silencing MYSM1 induced enhancement of histone H2A ubiquitination as well as reduction of histone H3K4me3 and H3Ac levels atcisregulatory elements on promoter of ERα-regulated gene. In addition, MYSM1 depletion attenuated cell proliferation/growth in BCa-derived cell lines and xenograft models. Knockdown of MYSM1 increased the sensitivity of antiestrogen agents in BCa cells. MYSM1 was highly expressed in clinical BCa samples, especially in aromatase inhibitor (AI) non-responsive tissues. These findings clarify the molecular mechanism of MYSM1 as an epigenetic modifier in regulation of ERα action and provide a potential therapeutic target for endocrine resistance in BCa.
Prokaryote communities associated with different types of tissue formed and substrates inhabited bySerpula lacrymans
Authors: Embacher Julia , Zeilinger Susanne , Kirchmair Martin , Neuhauser Sigrid
Published: December 2022

The basidiomyceteSerpula lacrymansis responsible for timber destruction in houses. Basidiomycetes are known to harbor a diverse but poorly understood microbial community of bacteria, archaea, yeasts, and filamentous fungi in their fruiting bodies. In this study, we used amplicon-sequencing to analyze the abundance and composition of prokaryotic communities associated with fruiting bodies ofS. lacrymansand compared them to communities of surrounding material to access the ‘background’ community structure. Our findings indicate that bacterial genera cluster depended on sample type, and that the main driver for microbial diversity is specimen, followed by sample origin. The most abundant bacterial phylum identified in the fruiting bodies was Pseudomonadota, followed by Actinomycetota and Bacteroidota. The prokaryote community of the mycelium was dominated by Actinomycetota, Halobacterota, and Pseudomonadota. Actinomycetota was the most abundant phylum in both environment samples (infested timber and underground scree), followed by Bacillota in wood and Pseudomonadota in underground scree.Nocardioides, Pseudomonas, Pseudonochardia, StreptomycesandRubrobacterspp. were among others found to comprise the core microbiome ofS. lacrymansbasidiocarps. This research contributes to the understanding of the holobiontS. lacrymansand gives hints to potential bacterial phyla important for its development and life style.

Highlights

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The prokaryote communities associated withS. lacrymansmycelia and fruiting bodies as well as wood and non-woody substrate form distinct clusters.

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Across all samples 30% of OTU’s were shared (core microbiome) while the number of unique OTUs was small.

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Fruiting bodies (n= 8) ofS. lacrymansshared a core set of 365 OTU’s, dominated by Actinobacteriodota (44%), Pseudomonadota (28%), and Acidobacteriodota (9%).

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Tissue/sample type is the main factor influencing diversity, followed by sample origin.
Modulation of lysosomal Cl-mediates migration and apoptosis through the TRPML1 as a lysosomal Cl-sensor
Authors: Lee Dongun , Shin Dong Min , Hong Jeong Hee
Published: December 2022

Lysosomes are responsible for protein degradation and clearance in cellular recycling centers. It has been known that the lysosomal chloride level is enriched and involved in intrinsic lysosomal function. However, the mechanism by which chloride levels can be sensed and the chloride-mediated lysosomal function is unknown. In this study, we verified that reduced chloride levels acutely induced lysosomal calcium release through TRPML1 and lysosomal repositioning toward juxtanuclear region. Functionally, low chloride-induced lysosomal calcium release attenuated cellular migration. In addition, spontaneous exposure to low chloride levels dysregulated lysosomal biogenesis and subsequently induced the delayed migration and promoted apoptosis. Two chloride-sensing GXXXP motifs in the TRPML1 were identified. Mutations in the GXXXP motif of TRPML1 did not affect chloride levels and no changes in migratory ability. In this study, we demonstrated that the depleted chloride approach induces reformation of the lysosomal calcium pool, and subsequent dysregulated cancer progression will assist in improving therapeutic strategies for lysosomal accumulation-associated diseases or cancer cell apoptosis.
Membrane association is required for Stmn2-mediated axon protection
Authors: Thornburg-Suresh Emma J.C. , Richardson Jerianne E. , Summers Daniel W.
Published: December 2022

Axon integrity is essential for functional connectivity in the nervous system. The degeneration of stressed or damaged axons is a common and sometimes initiating event in neurodegenerative disorders. Cellular factors that preserve axon integrity have an important influence on the fate of a damaged axon. Stathmin-2 (Stmn2) is an axon maintenance factor that is depleted in Amyotrophic Lateral Sclerosis and replenishment of Stmn2 can restore neurite outgrowth in diseased neurons. Stathmins have a well-documented role in microtubule dynamics during neurodevelopment, yet mechanisms responsible for Stmn2-mediated axon maintenance in injured neurons are not known. We demonstrate that membrane association of Stmn2 is critical for its axon-protective activity. Axonal enrichment of Stmn2 is driven by palmitoylation as well as tubulin interaction. We discover that another Stathmin, Stmn3, co-migrates with Stmn2-containing vesicles and undergoes regulated degradation through DLK-JNK signaling. The Stmn2 membrane targeting domain is both necessary and sufficient for localization to a specific vesicle population and confers sensitivity to DLK-dependent degradation. Our findings reveal a broader role for DLK in tuning the local abundance of palmitoylated Stathmins in axon segments. Moreover, palmitoylation is a critical component of Stathmin-mediated axon protection and defining the Stmn2-containing vesicle population will provide important clues toward mechanisms of axon maintenance.
Expanded Multiplexing on Sensor-Constrained Microfluidic Partitioning Systems
Authors: Kota Pavan K. , Vu Hoang-Anh , LeJeune Daniel , Han Margaret , Syed Saamiya , Baraniuk Richard G. , Drezek Rebekah A.
Published: December 2022

Microfluidics can split samples into thousands or millions of partitions such as droplets or nanowells. Partitions capture analytes according to a Poisson distribution, and in diagnostics, the analyte concentration is commonly calculated with a closed-form solution via maximum likelihood estimation (MLE). Here, we present a generalization of MLE with microfluidics, an extension of our previously developed Sparse Poisson Recovery (SPoRe) algorithm, and anin vitrodemonstration with droplet digital PCR (ddPCR) of the new capabilities that SPoRe enables. Many applications such as infection diagnostics require sensitive detection and broad-range multiplexing. Digital PCR coupled with conventional target-specific sensors yields the former but is constrained in multiplexing by the number of available measurement channels (e.g., fluorescence). In our demonstration, we circumvent these limitations by broadly amplifying bacteria with 16S ddPCR and assigning barcodes to nine pathogen genera using only five nonspecific probes. Moreover, we measure only two probes at a time in multiple groups of droplets given our two-channel ddPCR system. Although individual droplets are ambiguous in their bacterial content, our results show that the concentrations of bacteria in the sample can be uniquely recovered given the pooled distribution of partition measurements from all groups. We ultimately achieve stable quantification down to approximately 200 total copies of the 16S gene per sample, enabling a suite of clinical applications given a robust upstream microbial DNA extraction procedure. We develop new theory that generalizes the application of this framework to a broad class of realistic sensors and applications, and we prove scaling rules for system design to achieve further expanded multiplexing. This flexibility means that the core principles and capabilities demonstrated here can generalize to most biosensing applications with microfluidic partitioning.
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

Objective

Diabetes 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.

Methods

We 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.

Results

βGRK5 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.

Conclusions

Our 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

Human 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 points

A 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.

During 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

Cryo-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

Cognitive 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

The 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 Abstract

Highlights

Rfa1-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

Chargaff’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

Fungus 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

The 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

Background

Cognitive 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.

Methods

Searches 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.

Results

Effect-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.

Conclusions

We 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

Investigating 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

While 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

The 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.
Independent inhibitory control mechanisms for aggressive motivation and action
Authors: Minakuchi Tomohito , Guthman Eartha Mae , Acharya Preeta , Hinson Justin , Fleming Weston , Witten Ilana B. , Oline Stefan N. , Falkner Annegret L.
Published: December 2022

Social behaviors, like other motivated behaviors, frequently consist of a flexible motivated-seeking or approach phase followed by social action. Dysregulated social behavior may arise from changes to motivation, wherein individuals fail to enter a motivated seeking state, or may be in the execution of the social action itself. However, it is unclear how the brain generates and gates this flexible motivation-to-action sequence, and whether aggressive motivation and action are controlled by separate circuit mechanisms. Here, we record populations of neurons in the ventromedial hypothalamus ventrolateral area (VMHvl) of male mice at cellular resolution during “free” aggression and also during an aggression operant task, where the behaviors that precede attack are stereotyped. We find that this population encodes the temporal sequence of aggressive motivation to action and that the temporal selectivity of neurons is invariant to differences in motivated behavior. To test whether motivation and action could be independently regulated, we focused on two key inhibitory inputs to the VMHvl: a source of local inhibition (VMHvl shell) and the primary source of long-range inhibition (the medial preoptic area, MPO). While we find that the VMHvl receives broad monosynaptic inhibitory input from both inputs, optogenetic perturbation of these inputs during recording reveals temporal selectivity during aggressive motivation and action, suggesting specificity of function. Encoding models applied to population calcium recordings of these inhibitory inputs during naturalistic social interactions and during the social operant task further reveal that these inputs have different temporal dynamics during aggression: VMHvl shellvgat+activity peaks at the start of aggressive interactions, while MPO-VMHvlvgat+activity peaks at behaviorally aligned endpoints of aggressive interactions. Finally, using closed-loop optogenetic stimulation timed to specific phases of the aggression-operant task, we find a double-dissociation of the effects on aggressive motivation and action: activation of MPO-VMHvlvgat+, even briefly and temporally distant from the initiation of aggression, produces long-lasting motivational deficits, delaying the initiation of aggression and generating behaviors consistent with an unmotivated state. In contrast, activation of VMHvl shellvgat+produces acute action-related deficits, causing an exit from an attack state. Fitting a Hidden Markov Model (HMM) to behavior further corroborates these findings by showing that MPO-VMHvlvgat+stimulation prolongs a low motivation state and VMHvl shellvgat+promotes exit from an attack state. Together, these data demonstrate how separable inhibitory circuits in the hypothalamus can independently gate the motivational and action phases of aggression through a single locus of control.
Extending norm activation theory to understand publics' support for environmentally responsible organizations
Authors: Oh Jeyoung , Ki Eyun-Jung
Published: December 2022

Purpose

Previous studies have empirically examined the positive outcomes organizations can achieve by engaging in environmentally responsible actions, but the underlying mechanism of the reasons why publics engage in supportive behaviors for those organizations has not been examined in light of theoretical foundations. To fill this gap, this paper builds on a foundation of norm activation theory to explore the effect of publics' awareness of environmental consequences on perceived environmental responsibility of organizations and organizational norm, which can have an impact on publics' supportive behavior toward environmentally responsible organizations. The potential relationships between social media use for environmental information and other variables are also explored.

Design/methodology/approach

Drawing on norm activation theory, an online survey was conducted among 288 adults in the United States. Participants were recruited from Amazon Mechanical Turk.

Findings

Findings indicate the impact of individuals' awareness of environmental consequences on their ascription of responsibility to organizations, which influences organizational norm and supportive behavior intention toward organizations.

Originality/value

This study is one of the first attempts to explore the underlying mechanism of publics' support for environmentally responsible organizations.
How do developmental I-deals promote team creativity: the role of team creative-efficacy and error management atmosphere
Authors: Fan Zili , Sun Hao , Zhu Pingli , Zhu Mengting , Zhang Xuan
Published: December 2022

Purpose

As a new human resource management practice, developmental idiosyncratic deals (developmental I-deals) play an important role in attracting, retaining and motivating employees to promote creativity. Based on the social cognitive theory, the purpose of this study is to examine the impact of developmental I-deals on team creativity through team creative-efficacy and the moderating role of error management atmosphere in this process.

Design/methodology/approach

To reduce the effects of common method biases and causal lag effect, this study was divided into three stages for data collection, with a time interval of a month. A total of 365 employee samples (72 team samples) from seven internet enterprises in Shanghai and Wuhan were selected, and Bootstrap method and Johnson-Neyman method were used to test the hypothesis.

Findings

The results of this study show that developmental I-deals positively affect team creativity, and team creative-efficacy mediates the relationship between developmental I-deals and team creativity. Error management atmosphere strengthens the impact of developmental I-deals on team creative-efficacy and further strengthens the indirect effect of developmental I-deals on team creativity through team creative-efficacy.

Originality/value

Based on the social cognitive theory, this study examines the impact of developmental I-deals on team creativity through team creative-efficacy and the moderating role of error management atmosphere in this process. First, the study of I-deals category was further refined. The existing research defines the concept of I-deals in a general way and does not classify it in detail. Second, the internal mechanism of I-deals is revealed. Third, it expands the multi-level research of I-deals.
The impact of the Celtic Tiger and Great Recession on drug consumption
Authors: Windle James , Cambridge Graham , Leonard James , Lynch Orla
Published: December 2022

Purpose

This paper aims to explore how the Celtic Tiger economic boom and Great Recession influenced drug and alcohol use in one Irish city.

Design/methodology/approach

Semi-structured interviews were conducted with 48 people, living in Cork City, who had previously used drugs and/or alcohol problematically. All participants had engaged with services for their problematic use and had at least one year of abstinence at time of interview.

Findings

Some participants reported that their drug and/or alcohol consumption increased during the economic boom; others, who were already in (self-defined) active addiction, reported how full employment lessened some of the harms of their problematic use. For others, problematic use struck once the economy entered a downturn and, heavy drink and drug use became a means of soothing the strains of economic recession.

Originality/value

The paper provides two key contributions. Methodologically, it demonstrates how large-scale national quantitative data can mask local idiosyncratic tendencies, suggesting the need for mixed-method approaches for understanding drug market trends. The paper also provides insights into the impact of global and local economic conditions on drug and alcohol consumption in Ireland.