bluuebunny/crossref_metadata_2025 huggingface dataset:
Prostate-derived circulating microRNAs add prognostic value to prostate cancer risk calculators
Authors: Zenner Morgan L. , Kirkpatrick Brenna , Leonardo Trevor R. , Schlicht Michael J. , Saldana Alejandra Cavazos , Loitz Candice , Valyi-Nagy Klara , Maienschein-Cline Mark , Gann Peter H. , Abern Michael , Nonn Larisa
Published: May 2023

Prostate cancer is the second leading cause of malignancy-related deaths among American men. Active surveillance is a safe option for many men with less aggressive disease, yet definitively determining low-risk cancer is challenging with biopsy alone. Herein, we sought to identify prostate-derived microRNAs in patient sera and serum extracellular vesicles, and determine if those microRNAs improve upon the current clinical risk calculators for prostate cancer prognosis before and after biopsy. Prostate-derived intracellular and extracellular vesicle-contained microRNAs were identified by small RNA sequencing of prostate cancer patient explants and primary cells. Abundant microRNAs were included in a custom microRNA PCR panel that was queried in whole serum and serum extracellular vesicles from a diverse cohort of men diagnosed with prostate cancer. The levels of these circulating microRNAs significantly differed between indolent and aggressive disease and improved the area under the curve for pretreatment nomograms of prostate cancer disease risk. The microRNAs within the extracellular vesicles had improved prognostic value compared to the microRNAs in the whole serum. In summary, quantifying microRNAs circulating in extracellular vesicles is a clinically feasible assay that may provide additional information for assessing prostate cancer risk stratification.
Streamlined intravital imaging approach for long-term monitoring of epithelial cell dynamics on an inverted confocal microscope
Authors: Hamersky Michael , Tekale Khushi , Winfree L. Matthew , Rowan Matthew JM , Seldin Lindsey
Published: May 2023

Understanding normal and aberrant in vivo cell behaviors is necessary to develop clinical interventions to thwart disease initiation and progression. It is therefore critical to optimize imaging approaches that facilitate the observation of cell dynamics in situ, where tissue structure and composition remains unperturbed. The epidermis is the body’s outermost barrier as well as the source of the most prevalent human cancers, namely cutaneous skin carcinomas. The accessibility of skin tissue presents a unique opportunity to monitor epithelial and dermal cell behaviors in intact animals using noninvasive intravital microscopy. Nevertheless, this sophisticated imaging approach has primarily been achieved using upright multiphoton microscopy, which represents a significant barrier-for-entry for most investigators. In this study, we present a custom-designed 3D-printed microscope stage insert suitable for use with inverted confocal microscopes that streamlines long-term intravital imaging of ear skin in live transgenic mice. We believe this invention, which may be readily customized to image other organ systems, will prove invaluable to the cell biology community by significantly enhancing the accessibility of intravital microscopy. This technological advancement is critical to bolster our understanding of live cell dynamics in both normal and disease contexts.
The E3 ubiquitin ligase Itch regulates death receptor and cholesterol trafficking to affect TRAIL-mediated apoptosis
Authors: Holloway James , Turkington Richard C. , Longley Daniel B. , Evergren Emma
Published: May 2023

The activation of apoptosis signalling by TRAIL (TNF-related apoptosis-inducing ligand) through receptor binding is a fundamental mechanism of cell death induction and is often perturbed in cancer cells to enhance their cell survival and treatment resistance. Ubiquitination plays an important role in the regulation of TRAIL-mediated apoptosis, and here we investigate the role of the E3 ubiquitin ligase Itch in TRAIL-mediated apoptosis in oesophageal cancer cells. Knockdown of Itch expression resulted in resistance to TRAIL-induced apoptosis, caspase-8 activation, Bid cleavage and also promoted cisplatin resistance. Whilst the assembly of the death-inducing signalling complex (DISC) at the plasma membrane was not perturbed relative to the control, the TRAIL-R2 receptor was mis-localised in the Itch-knockdown cells. Further, we observed significant mitochondrial widening with an increased cholesterol content. An inhibitor of cholesterol trafficking, U18666A, was able to replicate some of the effects of Itch knockdown, including protection from TRAIL-induced apoptosis, reduced caspase-8 activation, Bid cleavage and Cisplatin resistance. This study highlights the importance of Itch in regulating the crosstalk between mitochondrial cholesterol and TRAIL-induced apoptosis.
dsRNA-based viromics: A novel tool unveiled hidden soil viral diversity and richness
Authors: Poursalavati A. , Larafa A. , Fall M.L.
Published: May 2023

Viruses play a crucial role in agroecosystem functioning. However, few studies have examined the diversity of the soil virome, especially when it comes to RNA viruses. Despite the great progress in viral metagenomics and metatranscriptomics (metaviromics) toward RNA viruses characterization, soil RNA viruses’ ecology is embryonic compared to DNA viruses. We currently lack a wet lab. method to accurately unhide the true soil viral diversity. To overcome this limitation, we developed dsRNA-based methods capitalizing on our expertise in soil RNA extraction and dsRNA extraction ported from studies of phyllosphere viral diversity. This proposed method detected both RNA and DNA viruses and is proven to capture a greater soil virus diversity than existing methods, virion-associated nucleic enrichment, and metaviromics. Indeed, using this method we detected 284 novel RNA-dependent RNA polymerases and expanded the diversity ofBirnaviridaeandRetroviridaeviral families to agricultural soil, which, to our knowledge, have never been reported in such ecosystem. The dsRNA-based method is cost-effective in terms of affordability and requirements for data processing, facilitating large-scale and high-throughput soil sample processing to unlock the potential of the soil virome and its impact on biogeochemical processes (e.g. carbon and nutrient cycling). This method can also benefit future studies of viruses in complex environments, for example, to characterize RNA viruses in the human gut or aquatic environment where RNA viruses are less studied mainly because of technical limitations.
Changing awareness and sources of tobacco and e-cigarettes among children in Great Britain
Authors: Parnham Jennie C. , Vrinten Charlotte , Cheeseman Hazel , Bunce Laura , Hopkinson Nicholas S , Filippidis Filippos T , Laverty Anthony A.
Published: May 2023

Introduction

It is illegal in the UK to sell tobacco or nicotine e-cigarettes to people under the age of 18 years, as is displaying tobacco cigarettes at the point of sale. This paper examined changes in exposure to display of these products in shops and sources of these products among adolescent users over time.

Methods

Data from representative repeated online cross-sectional surveys of youth in Great Britain (11-18 years) were used (2018-2022; n=12,445). Outcome measures included noticing product displays and sources of e-cigarettes and tobacco cigarettes. Logistic regressions examined the associations of these outcome variables over time and with sociodemographic variables.

Results

Of 12,040 participants with complete data, 10.1% used some form of nicotine product (4.2% cigarettes, 2.9% e-cigarettes, 3.0% both) at least occasionally. The likelihood of noticing tobacco cigarettes on display fell over time for both supermarkets (2018: 67.1% to 2022: 58.5%) and small shops (2018: 81.3% to 2022: 66.3%), but the likelihood of noticing e-cigarettes in supermarkets rose (2018: 57.4% to 2022: 66.5%). Sources of tobacco cigarettes did not differ over time, but e-cigarette users were more likely to get their e-cigarettes from small shops in 2022 (51.2%) vs. 2019 (34.2%) (Odds ratio 2.02; 95%CI 1.24, 3.29).

Conclusion

This study provides evidence that current policies to limit awareness of and access to both tobacco and e-cigarettes among adolescents in the UK may not be effective. UK policy on the advertising, promotion and sale of both tobacco and e-cigarettes need to be reinforced to deter use among children.
Bile acid fitness determinants of aBacteroides fragilisisolate from a human pouchitis patient
Authors: Fiebig Aretha , Schnizlein Matthew K. , Pena-Rivera Selymar , Trigodet Florian , Dubey Abhishek Anil , Hennessy Miette , Basu Anindita , Pott Sebastian , Dalal Sushila , Rubin David , Sogin Mitchell L. , Eren A. Murat , Chang Eugene B. , Crosson Sean
Published: May 2023

Bacteroides fragiliscomprises 1-5% of the gut microbiota in healthy humans but can expand to >50% of the population in ulcerative colitis (UC) patients experiencing inflammation. The mechanisms underlying such microbial blooms are poorly understood, but the gut of UC patients has physicochemical features that differ from healthy patients and likely impact microbial physiology. For example, levels of the secondary bile acid deoxycholate (DC) are highly reduced in the ileoanal J-pouch of UC colectomy patients. We isolated aB. fragilisstrain from a UC patient with pouch inflammation (i.e. pouchitis) and developed it as a genetic model system to identify genes and pathways that are regulated by DC and that impactB. fragilisfitness in DC and crude bile. Treatment ofB. fragiliswith a physiologically relevant concentration of DC reduced cell growth and remodeled transcription of one-quarter of the genome. DC strongly induced expression of chaperones and select transcriptional regulators and efflux systems and downregulated protein synthesis genes. Using a barcoded collection of ≈50,000 unique insertional mutants, we further definedB. fragilisgenes that contribute to fitness in media containing DC or crude bile. Genes impacting cell envelope functions including cardiolipin synthesis, cell surface glycosylation, and systems implicated in sodium-dependent bioenergetics were major bile acid fitness factors. As expected, there was limited overlap between transcriptionally regulated genes and genes that impacted fitness in bile when disrupted. Our study provides a genome-scale view of aB. fragilisbile response and genetic determinants of its fitness in DC and crude bile.

Importance

The Gram-negative bacterium,Bacteroides fragilis, is a common member of the human gut microbiota that colonizes multiple host niches and can influence human physiology through a variety of mechanisms. Identification of genes that enableB. fragilisto grow across a range of host environments has been impeded in part by the relatively limited genetic tractability of this species. We have developed a high-throughput genetic resource for aB. fragilisstrain isolated from a UC pouchitis patient. Bile acids limit microbial growth and are altered in abundance in UC pouches, whereB. fragilisoften blooms. Using this resource, we uncovered pathways and processes that impactB. fragilisfitness in bile and that may contribute to population expansions during bouts of gut inflammation.
A unified neural representation model for spatial and semantic computations
Authors: Haga Tatsuya , Oseki Yohei , Fukai Tomoki
Published: May 2023

Hippocampus and entorhinal cortex encode spaces by spatially local and hexagonal grid activity patterns (place cells and grid cells), respectively. In addition, the same brain regions also implicate neural representations for non-spatial, semantic concepts (concept cells). These observations suggest that neurocomputational mechanisms for spatial knowledge and semantic concepts are related in the brain. However, the exact relationship remains to be understood. Here we show a mathematical correspondence between a value function for goal-directed spatial navigation and an information measure for word embedding models in natural language processing. Based on this relationship, we integrate spatial and semantic computations into a neural representation model called as “disentangled successor information” (DSI). DSI generates biologically plausible neural representations: spatial representations like place cells and grid cells, and concept-specific word representations which resemble concept cells. Furthermore, with DSI representations, we can perform inferences of spatial contexts and words by a common computational framework based on simple arithmetic operations. This computation can be biologically interpreted by partial modulations of cell assemblies of non-grid cells and concept cells. Our model offers a theoretical connection of spatial and semantic computations and suggests possible computational roles of hippocampal and entorhinal neural representations.
Chemical protein unfolding - A simple cooperative model
Authors: Seelig Joachim , Seelig Anna
Published: May 2023

Chemical unfolding with guanidineHCl or urea is a common method to study the conformational stability of proteins. The analysis of unfolding isotherms is usually performed with an empirical linear extrapolation method (LEM). The method contradicts however, common expectations. A large positive free energy is assigned to the native protein which is usually considered to be a minimum of the free energy. Here we present a multistate cooperative model, which addresses specifically the binding of the denaturant to the protein and the cooperativity of the protein unfolding equilibrium. The model is based on a molecular statistical-mechanical partition function of the ensemble but simple solutions for the calculation of the binding isotherm and the associated free energy are presented. The model is applied to 23 published unfolding isotherms of small and large proteins. For a given denaturant, the binding constant depends on temperature and pH, but shows little protein specificity. Chemical unfolding is less cooperative than thermal unfolding. The cooperativity parameter σ is two orders of magnitude larger than that of thermal unfolding. The multistate cooperative model predicts a zero free energy for the native protein, which becomes strongly negative beyond the midpoint concentration of unfolding. The free energy to unfold a cooperative unit corresponds exactly to the diffusive energy of the denaturant concentration gradient necessary for unfolding. The temperature dependence of unfolding isotherms yields the denaturant-induced unfolding entropy and, in turn, the unfolding enthalpy. The multistate cooperative model provides molecular insight, is as simple to apply as the LEM, but avoids the conceptual difficulties of the latter.
Temporal dynamics of gut microbiomes in non-industrialized urban Amazonia
Authors: Schaan Ana Paula , Vidal Amanda , Zhang An-Ni , Poyet Mathilde , Alm Eric J , Groussin Mathieu , Ribeiro-dos-Santos Ândrea
Published: May 2023

Background

Increasing levels of industrialization have been associated with changes in gut microbiome structure and loss of features thought to be crucial for maintaining gut ecological balance. The stability of gut microbial communities over time within individuals seems to be largely affected by this transition but has been overlooked among transitioning populations from low to middle-income countries. Here, we used shotgun sequencing to characterize the temporal dynamics of gut microbiomes of 24 individuals living in an urban non-industrialized lifestyle in the Brazilian Amazon and contextualized our data with 165 matching longitudinal samples from an urban industrialized and a rural non-industrialized population.

Results

We show that gut microbiome composition and diversity have greater variability over time among non-industrialized individuals when compared to industrialized counterparts and that taxa may present diverse temporal dynamics across human populations. Enterotype classifications show community types are generally stable over time despite shifts in microbiome structure. Further, by tracking genomes over time, we show that levels of bacterial population replacements are more frequent among Amazonian individuals and non-synonymous variants accumulate in genes associated with degradation of host dietary polysaccharides.

Conclusions

Our results suggest that the stability of gut microbiomes is influenced by levels of industrialization and that tracking microbial population dynamics is important to understand how the microbiome will adapt to these transitions.
L. pneumophilaresists its self-harming metabolite HGA via secreted factors and collective peroxide scavenging
Authors: Holland Mische , Farinella Danielle N. , Cruz-Lorenzo Emily , Laubscher Madelyn I. , Doakes Darian A. , Ramos Maria A. , Kubota Nanami , Levin Tera C.
Published: May 2023

Many pathogenic bacteria, includingLegionella pneumophila, infect humans from environmental reservoirs. To survive in these reservoirs, bacteria must withstand microbe-on-microbe competition. We previously discovered thatL. pneumophilacan compete with neighboring bacteria via an antimicrobial metabolite called homogentisic acid (HGA) (Levin, Goldspiel, and Malik 2019). Curiously,L. pneumophilastrains that secrete HGA are not wholly immune to its effects: low-density bacteria are strongly inhibited by HGA whereas high-density cells are tolerant. How do these bacteria tolerate HGA and avoid self-harm during interbacterial competition? Here, we find that HGA toxicity occurs via the production of toxic hydroperoxides and multiple factors facilitate high-density tolerance. First, HGA only becomes fully toxic after >1 hour of oxidation. While this manifests as a delay in killing within well-mixed liquid cultures, in a biofilm environment, this could provide time for HGA to diffuse away before becoming toxic. Second, HGA generates quantities of hydroperoxides that can be collectively scavenged by high-density, but not low-density cells. And third, high-density cells produce one or more secreted factors that are transiently protective from HGA. In combination, we propose that the bacteria are able to deploy HGA to generate a pool of reactive oxygen species surrounding their own biofilms, while maintaining non-toxic conditions within them. Overall, these findings help to explain how broadly toxic molecules can be used as inter-bacterial weapons. They also provide insights about why some of our current decontamination methods to controlL. pneumophilaare ineffective, leading to recurrent disease outbreaks.
Guild and Niche Determination Enable Targeted Alteration of the Microbiome
Authors: Moyne Oriane , Al-Bassam Mahmoud , Lieng Chloe , Thiruppathy Deepan , Norton Grant J. , Kumar Manish , Haddad Eli , Zaramela Livia S. , Zengler Karsten
Published: May 2023

Microbiome science has greatly contributed to our understanding of microbial life and its essential roles for the environment and human health1–5. However, the nature of microbial interactions and how microbial communities respond to perturbations remains poorly understood, resulting in an often descriptive and correlation-based approach to microbiome research6–8. Achieving causal and predictive microbiome science would require direct functional measurements in complex communities to better understand the metabolic role of each member and its interactions with others. In this study we present a new approach that integrates transcription and translation measurements to predict competition and substrate preferences within microbial communities, consequently enabling the selective manipulation of the microbiome. By performing metatranscriptomic (metaRNA-Seq) and metatranslatomic (metaRibo-Seq) analysis in complex samples, we classified microbes into functional groups (i.e. guilds) and demonstrated that members of the same guild are competitors. Furthermore, we predicted preferred substrates based on importer proteins, which specifically benefited selected microbes in the community (i.e. their niche) and simultaneously impaired their competitors. We demonstrated the scalability of microbial guild and niche determination to natural samples and its ability to successfully manipulate microorganisms in complex microbiomes. Thus, the approach enhances the design of pre- and probiotic interventions to selectively alter members within microbial communities, advances our understanding of microbial interactions, and paves the way for establishing causality in microbiome science.
Gene expression genetics of the striatum of Diversity Outbred mice
Authors: Philip Vivek M. , He Hao , Saul Michael C. , Dickson Price E. , Bubier Jason A. , Chesler Elissa J.
Published: May 2023

Brain transcriptional variation is a heritable trait that mediates complex behaviors, including addiction. Expression quantitative trait locus (eQTL) mapping reveals genomic regions harboring genetic variants that influence transcript abundance. In this study, we profiled transcript abundance in the striatum of 386 Diversity Outbred (J:DO) mice of both sexes using RNA-Seq. All mice were characterized using a behavioral battery of widely-used exploratory and risk-taking assays prior to transcriptional profiling. We performed eQTL mapping, incorporated the results into a browser-based eQTL viewer, and deposited co-expression network members in GeneWeaver. The eQTL viewer allows researchers to query specific genes to obtain allelic effect plots, analyze SNP associations, assess gene expression correlations, and apply mediation analysis to evaluate whether the regulatory variant is acting through the expression of another gene. GeneWeaver allows multi-species comparison of gene sets using statistical and combinatorial tools. This data resource allows users to find genetic variants that regulate differentially expressed transcripts and place them in the context of other studies of striatal gene expression and function in addiction-related behavior.
Differentiation-dependent chromosomal organization changes in normal myogenic cells are absent in rhabdomyosarcoma cells
Authors: Ibarra Joe , Hershenhouse Tyler , Almassalha Luay , MacQuarrie Kyle L.
Published: May 2023

Myogenesis, the progression of proliferating skeletal myoblasts to terminally differentiated myotubes, regulates thousands of target genes. Uninterrupted linear arrays of such genes are differentially associated with specific chromosomes, suggesting chromosome specific regulatory roles in myogenesis. Rhabdomyosarcoma (RMS), a tumor of skeletal muscle, shares common features with normal muscle cells. We hypothesized that RMS and myogenic cells possess differences in chromosomal organization related to myogenic gene arrangement. We compared the organizational characteristics of chromosomes 2 and 18, chosen for their difference in myogenic gene arrangement, in cultured RMS cell lines and normal myoblasts and myotubes. We found chromosome-specific differences in organization during normal myogenesis, with increased area occupied and a shift in peripheral localization specifically for chromosome 2. Most strikingly, we found a differentiation-dependent difference in positioning of chromosome 2 relative to the nuclear axis, with preferential positioning along the major nuclear axis present only in myotubes. RMS cells demonstrated no preference for such axial positioning, but induced differentiation through transfection of the pro-myogenic miRNA miR-206 resulted in an increase of major axial positioning of chromosome 2. Our findings identify both a differentiation-dependent, chromosome-specific change in organization in normal myogenesis, and highlight the role of chromosomal spatial organization in myogenic differentiation.
The Origin Recognition Complex requires chromatin tethering by a hypervariable intrinsically disordered region that is functionally conserved from sponge to man
Authors: Adiji Olubu A. , McConnell Brendan S. , Parker Matthew W.
Published: May 2023

The first step towards eukaryotic genome duplication is loading of the replicative helicase, the Mcm2-7 complex, onto chromatin. This so-called “licensing” step is executed by the Pre-Replication Complex (Pre-RC) whose assembly on chromatin is nucleated by the DNA-binding activity of the Origin Recognition Complex (ORC). It is thought that metazoan ORC, like the yeast complex, is recruited directly to chromatin by its ATP-dependent DNA binding and encirclement activity. However, we have previously shown that this DNA binding mode is dispensable for chromatin recruitment of fly ORC, raising the question of how metazoan ORC binds chromosomes. We show here that the intrinsically disordered region (IDR) of fly Orc1 is both necessary and sufficient for recruitment of ORC to chromosomesin vivoand demonstrate that this activity is regulated by IDR phosphorylation.In vitrostudies show that the IDR alone binds DNA and this bestows the ORC holocomplex with a high-affinityATP-independentDNA binding mode. Interestingly, we find that Orc1 IDRs have diverged so markedly across metazoans that they are unrecognizable as orthologs and yet we find that these compositionally homologous sequences retain DNA and chromatin binding activity down to basal metazoans. Altogether, these data suggest that chromatin is recalcitrant to ORC’s ATP-dependent DNA binding activity and we propose that this necessitates IDR-dependent chromatin tethering which poises ORC to opportunistically encircle nucleosome free regions as they become available. This work reveals a novel step in metazoan replication licensing and expands our understanding of disordered protein homology and evolution by stretching the relationship between primary structure and function.
Molecular features driving condensate formation and gene expression by the BRD4-NUT fusion oncoprotein are overlapping but distinct
Authors: Kosno Martyna , Currie Simon L. , Kumar Ashwani , Xing Chao , Rosen Michael K.
Published: May 2023

Aberrant formation of biomolecular condensates has been proposed to play a role in several cancers. The oncogenic fusion protein BRD4-NUT forms condensates and drives changes in gene expression in Nut Carcinoma (NC). Here we sought to understand the molecular elements of BRD4-NUT and its associated histone acetyltransferase (HAT), p300, that promote these activities. We determined that a minimal fragment of NUT (MIN) in fusion with BRD4 is necessary and sufficient to bind p300 and form condensates. Furthermore, a BRD4-p300 fusion protein also forms condensates and drives gene expression similarly to BRD4-NUT(MIN), suggesting the p300 fusion may mimic certain features of BRD4-NUT. The intrinsically disordered regions, transcription factor-binding domains, and HAT activity of p300 all collectively contribute to condensate formation by BRD4-p300, suggesting that these elements might contribute to condensate formation by BRD4-NUT. Conversely, only the HAT activity of BRD4-p300 appears necessary to mimic the transcriptional profile of cells expressing BRD4-NUT. Our results suggest a model for condensate formation by the BRD4-NUT:p300 complex involving a combination of positive feedback and phase separation, and show that multiple overlapping, yet distinct, regions of p300 contribute to condensate formation and transcriptional regulation.
Orientia tsutsugamushi:analysis of the mobilome of a highly fragmented and repetitive genome reveals ongoing lateral gene transfer in an obligate intracellular bacterium
Authors: Giengkam Suparat , Kullapanich Chitrasak , Wongsantichon Jantana , Adcox Haley E. , Gillespie Joseph J. , Salje Jeanne
Published: May 2023

The rickettsial human pathogenOrientia tsutsugamushi(Ot) is an obligate intracellular Gram-negative bacterium with one of the most highly fragmented and repetitive genomes of any organism. Around 50% of its ∼2.3 Mb genome is comprised of repetitive DNA that is derived from the highly proliferated Rickettsiales amplified genetic element (RAGE). RAGE is an integrative and conjugative element (ICE) that is present in a single Ot genome in up to 92 copies, most of which are partially or heavily degraded. In this report, we analysed RAGEs in eight fully sequenced Ot genomes and manually curated and reannotated all RAGE-associated genes, including those encoding DNA mobilisation proteins, P-type (vir) and F-type (tra)type IV secretion system (T4SS) components, Ankyrin repeat- and tetratricopeptide repeat-containing effectors, and other piggybacking cargo. Originally, the heavily degraded Ot RAGEs led to speculation that they are remnants of historical ICEs that are no longer active. Our analysis, however, identified two Ot genomes harbouring one or more intact RAGEs with complete F-T4SS genes essential for mediating ICE DNA transfer. As similar ICEs have been identified in unrelated rickettsial species, we assert that RAGEs play an ongoing role in lateral gene transfer within the Rickettsiales. Remarkably, we also identified in several Ot genomes remnants of prophages with no similarity to other rickettsial prophages. Together these findings indicate that, despite their obligate intracellular lifestyle and host range restricted to mites, rodents and humans, Ot genomes are highly dynamic and shaped through ongoing invasions by mobile genetic elements and viruses.
Torsion of the heart tube by shortage of progenitor cells : identification ofGreb1las a genetic determinant of criss-cross hearts in mice
Authors: Bernheim Ségolène , Borgel Adrien , Garrec Jean-François Le , Perthame Emeline , Desgrange Audrey , Krezel Wojciech , Raimondi Francesca , Bonnet Damien , Houyel Lucile , Meilhac Sigolène M.
Published: May 2023

Despite their burden and impact, most congenital defects remain poorly understood by lack of knowledge of the embryological mechanisms. Here, we identifyGreb1lmutants as the first mouse model of criss-cross heart. Based on 3D quantifications of shape changes, we demonstrate that torsion of the atrioventricular canal occurs together with supero-inferior ventricles at E10.5, after heart looping. Mutants phenocopy specific features of partial deficiency in retinoic acid signalling, suggesting that GREB1L is a novel modulator of this signalling. Spatio-temporal gene mapping and cross-correlated transcriptomic analyses further reveal the role ofGreb1lin maintaining a pool of precursor cells during heart tube elongation, by controlling ribosome biogenesis and cell differentiation. Growth arrest and malposition of the outflow tract are predictive of abnormal tube remodelling in mutants. Our work on a rare cardiac malformation opens novel perspectives on the origin of a broader spectrum of congenital defects associated withGREB1Lin humans.

Highlights

Greb1linactivation is the first model of criss-cross heart

Growth arrest of the outflow tract and reduced pole distance are predictive of the torsion of the atrioventricular canal, and also account for associated defects of supero-inferior ventricles and malposition of the great vessels

Ventricle position needs to be maintained after heart looping

GREB1L, which is associated in humans with a spectrum of congenital defects, is required to maintain precursor cells, by promoting ribosome biogenesis and restricting cell differentiation.

GREB1L is a novel factor involved in retinoic acid signalling.

In Brief

GREB1Lis associated with a spectrum of congenital defects in humans. Bernheim et al now uncover its function in maintaining a reservoir of precursor cells. Inactivation ofGreb1lin the mouse impairs the elongation of the heart tube leading to criss-cross heart with supero-inferior ventricles.
LTP2hypomorphs show genotype-by-environment interaction in early seedling traits inArabidopsis thaliana
Authors: Alexandre Cristina M , Bubb Kerry L , Schultz Karla M , Lempe Janne , Cuperus Josh T , Queitsch Christine
Published: May 2023

Isogenic individuals can display seemingly stochastic phenotypic differences, limiting the accuracy of genotype-to-phenotype predictions. The extent of this phenotypic variation depends in part on genetic background, raising questions about the genes involved in controlling stochastic phenotypic variation. Focusing on early seedling traits inArabidopsis thaliana, we found that hypomorphs of the cuticle-related geneLTP2greatly increased variation in seedling phenotypes, including hypocotyl length, gravitropism and cuticle permeability. Manyltp2hypocotyls were significantly shorter than wild-type hypocotyls while others resembled the wild type. Differences in epidermal properties and gene expression betweenltp2seedlings with long and short hypocotyls suggest a loss of cuticle integrity as the primary determinant of the observed phenotypic variation. We identified environmental conditions that reveal or mask the increased variation inltp2hypomorphs, and found that increased expression of its closest paralogLTP1is necessary forltp2phenotypes. Our results illustrate how decreased expression of a single gene can generate starkly increased phenotypic variation in isogenic individuals in response to an environmental challenge.
Social navigation: distance and grid-like codes support navigation of abstract social space in human brain
Authors: Liang Zilu , Wu Simeng , Wu Jie , Wang Wenxu , Qin Shaozheng , Liu Chao
Published: May 2023

People form impressions about others during daily social encounters and infer personality traits from others’ behaviors. Such trait inference is thought to rely on two universal dimensions, i.e., competence and warmth. These two dimensions can be used to construct a ‘social cognitive map’ organizing massive information obtained from social encounters efficiently. Originated from spatial cognition, the neural codes supporting representation and navigation of spatial cognitive map has been widely studied. Recent studies suggest similar neural mechanism subserves the map-like architecture in social cognition as well. Here we investigated how spatial codes operate beyond physical environment and support the representation and navigation of social cognitive map. We designed a social value space defined by two dimensions of competence and warmth. Behaviorally, participants were able to navigate to a learned location from random starting locations in this abstract social space. At neural level, we identified representation of distance in precuneus, fusiform gyrus and middle occipital gyrus. We also found partial evidence of grid-like representation patterns in medial prefrontal cortex and entorhinal cortex. Moreover, the intensity of grid-like response scaled with performance of navigating in social space and social avoidance trait scores. Our findings suggest a neurocognitive mechanism by which social information can be organized into a structured representation namely cognitive map and its relevance to social well-being.
Hippocampal contextualization of social rewards
Authors: Duarte Joana Mendes , Li Kaizhen , Nguyen Robin , Ciocchi Stéphane
Published: May 2023

Acquiring and exploiting memories of rewarding experiences is critical for survival. The spatial environment in which a rewarding stimulus is encountered regulates memory retrieval. The ventral hippocampus (vH) has been implicated in contextual memories involving rewarding stimuli such as food, social cues or drugs. Yet, the spatial representations and circuits underlying contextual memories of socially rewarding stimuli are poorly understood. Here, usingin vivoelectrophysiological recordings during a social reward contextual conditioning paradigm in mice, we showed that vH neurons discriminate between contexts with neutral or acquired social reward value and exhibit a preferential remapping of their place fields to the context previously paired with social reward cues. The formation of context-discriminating vH neurons following learning was contingent upon the presence of salient reinforcers. Moreover, vH neurons showed different contextual representations during retrieval of social reward and fear contextual memories, suggesting different vH circuits underlie positively and negatively valenced contextual memories. Finally, optogenetic inhibition of locus coeruleus (LC) projections in the vH selectively disrupted social reward contextual memory by impairing vH contextual representations. Collectively, our findings reveal that the vH integrates contextual and social reward information, with memory encoding of these representations supported by input from the LC.
Cryo-EM structures of both ends of the actin filament explain why the barbed end elongates faster than the pointed end
Authors: Chou Steven Z. , Pollard Thomas D.
Published: May 2023

Actin filament ends are the sites of subunit addition during elongation and subunit loss during depolymerization. Prior work established the kinetics and thermodynamics of the assembly reactions at both ends but not the structural basis of their differences. Cryo-EM reconstructions of the barbed end at 3.1 Å resolution and the pointed end at 3.5 Å reveal distinct conformations at the two ends. These conformations explain why barbed ends elongate faster than pointed ends and why pointed ends rapidly dissociate the γ-phosphate released from ATP hydrolysis during assembly. The D-loop of the penultimate subunit at the pointed end is folded onto the terminal subunit, precluding its binding incoming actin monomers, and gates on the phosphate release channels of both subunits are wide open. The samples were prepared with FH2 dimers from fission yeast formin Cdc12. The barbed end reconstruction has extra density that may be partial occupancy by the FH2 domains.

Significance Statement

Cells depend cytoplasmic filaments assembled from the protein actin for their physical integrity, as tracks for myosin motor proteins and movements of the whole cell and internal organelles. Actin filaments elongate and shrink at their ends by adding or dissociating single actin molecules. We used cryo-electron microscopy to determine the structures of the two ends of actin filaments at 3.5 Å resolution for the slowly growing pointed end and 3.1 Å for the rapidly growing barbed end. These structures reveal why barbed ends grow faster than the pointed ends, why the rate at the pointed end is not diffusion-limited and why the pointed end has a low affinity for the γ-phosphate released from bound ATP inside the filament.
Lipid-anchored Proteasomes Control Membrane Protein Homeostasis
Authors: Zhang Ruizhu , Pan Shuxian , Zheng Suya , Liao Qingqing , Jiang Zhaodi , Wang Dixian , Li Xuemei , Hu Ao , Li Xinran , Zhu Yezhang , Shen Xiaoqi , Lei Jing , Zhong Siming , Zhang Xiaomei , Huang Lingyun , Wang Xiaorong , Huang Lan , Shen Li , Song Bao-Liang , Zhao Jingwei , Wang Zhiping , Yang Bing , Guo Xing
Published: May 2023

Protein degradation in eukaryotic cells is mainly carried out by the 26S proteasome, a macromolecular complex not only present in the cytosol and nucleus but also associated with various membranes. How proteasomes are anchored to the membrane and the biological meaning thereof have been largely unknown in higher organisms. Here we show that N-myristoylation of the Rpt2 subunit is a general mechanism for proteasome-membrane interaction. Loss of this modification in the Rpt2-G2A mutant cells leads to profound changes in the membrane-associated proteome, perturbs the endomembrane system and undermines critical cellular processes such as cell adhesion, endoplasmic reticulum-associated degradation (ERAD) and membrane protein trafficking. Rpt2G2A/G2Ahomozygous mutation is embryonic lethal in mice and is sufficient to abolish tumor growth in a nude mice xenograft model. These findings have defined an evolutionarily conserved mechanism for maintaining membrane protein homeostasis and underscored the significance of compartmentalized protein degradation bymyristoyl-anchoredproteasomes (MAPs) in health and disease.
Spatiotemporal velocities, aggregation, and false dispersion: numerical considerations for the modeling of colonial and motile harmful algae
Authors: Opfer Jackie , Hondzo Miki , Voller V.R.
Published: May 2023

Purpose

The purpose of this study is to investigate the errors arising from the numerical treatment of model processes, paying particular attention to the impact of key system features including widely variable dispersion coefficients, spatiotemporal velocities of algal cells, and the aggregation of algae from single cells to large colonies. An advection–dispersion model has been presented to describe the vertical transport of colonial and motile harmful algae in a lake environment.

Design/methodology/approach

Model performance is examined for two different numerical treatments of the advective term: first-order upwind and quadratic upwind with a stability-preserving flux limiter (SMART). To determine how these schemes impact predictions, comparisons are made across a sequence of models with increasing complexity.

Findings

Using first-order upwinding for advection–dispersion calculations with a time oscillating velocity field leads to oscillatory numerical dispersion. Subjecting an initially uniform distribution of large-sized algal colonies to a spatiotemporal velocity creates a concentration pulse, which reaches a steady-state width at high-grid Peclet numbers when using the SMART scheme; the pulse exhibits contraction–expansion behavior throughout a velocity cycle at all Peclet numbers when using first-order upwinding. When aggregation dynamics are included with advection-dominated spatiotemporal transport, results indicate the SMART scheme predicts larger peak concentration values than those predicted by first-order upwind, but peak location and the time to large colony appearance remain largely unchanged between the two advective schemes.

Originality/value

To the best of the authors’ knowledge, this study is the first numerical investigation of a novel advection–dispersion model of vertical algal transport. In addition, a generalized expression for the effective dispersion coefficient of temporally variable flow fields is presented.
Industrial revolution and environmental sustainability: an analytical interpretation of research constituents in Industry 4.0
Authors: Malik Arun , Sharma Shamneesh , Batra Isha , Sharma Chetan , Kaswan Mahender Singh , Garza-Reyes Jose Arturo
Published: May 2023

Purpose

Environmental sustainability is quickly becoming one of the most critical issues in industry development. This study aims to conduct a systematic literature review through which the author can provide various research areas to work on for future researchers and provide insight into Industry 4.0 and environmental sustainability.

Design/methodology/approach

This study accomplishes this by performing a backward analysis using text mining on the Scopus database. Latent semantic analysis (LSA) was used to analyze the corpus of 4,364 articles published between 2013 and 2023. The authors generated ten clusters using keywords in the industrial revolution and environmental sustainability domain, highlighting ten research avenues for further exploration.

Findings

In this study, three research questions discuss the role of environmental sustainability with Industry 4.0. The author predicted ten clusters treated as recent trends on which more insight is required from future researchers. The authors provided year-wise analysis, top authors, top countries, top sources and network analysis related to the topic. Finally, the study provided industrialization’s effect on environmental sustainability and the future aspect of automation.

Research limitations/implications

The reliability of the current study may be compromised, notwithstanding the size of the sample used. Poor retrieval of the literature corpus can be attributed to the limitations imposed by the search words, synonyms, string construction and variety of search engines used, as well as to the accurate exclusion of results for which the search string is insufficient.

Originality/value

This research is the first-ever study in which a natural language processing technique is implemented to predict future research areas based on the keywords–document relationship.
Empowering leadership for contextual performance: serial mediation of organizational support and commitment
Authors: Pazetto Celliane Ferraz , Luiz Thiago Tomaz , Beuren Ilse Maria
Published: May 2023

Purpose

This study analyzes, from the perspective of social exchange theory, the influence of empowering leadership on contextual performance mediated by perceived organizational support (POS) and affective organizational commitment (AOC).

Design/methodology/approach

A survey was carried out with 182 employees of the Best Companies to Work in Brazil. Data analysis was performed by structural equation modeling (SEM) and by fuzzy set qualitative comparative analysis (fsQCA).

Findings

Results demonstrate that empowering leadership directly influences higher contextual performance and indirectly through the mediation of AOC, but not through POS. Serial mediation confirms that the model's variables self-promote each other to ultimately foster higher performance. Furthermore, all solutions to obtain high contextual performance include empowering leadership in the dimension of trust in the high performance of employees.

Research limitations/implications

The statistical support for the serial mediation indicates that empowering leadership promotes POS, which influences AOC that finally promotes the employee's contextual performance. However, this study's model does not include employees' task performance; our results add to the contextual performance literature.

Practical implications

The study highlights the role of the empowering leadership style in the organizational context, an aspect that deserves attention from the managers and organizations due to its effect on employee performance.

Originality/value

The study adds a new framework to the literature, which can be used by organizations to promote contextual performance. The variables, which include contextual and individual factors, foster the employee's contextual performance in a joint and self-promoting way. Contextual performance exceeds the manager's technical attributions; it covers psychological and discretionary behaviors.
Does CSR contribute to the financial sector's financial stability? The moderating role of a sustainability committee
Authors: Orazalin Nurlan , Kuzey Cemil , Uyar Ali , Karaman Abdullah S.
Published: May 2023

Purpose

This study tests whether corporate social responsibility (CSR) performance is a predictor of the financial sector's financial stability (FS), with the moderation of a sustainability committee.

Design/methodology/approach

The sample covers financial sector firms included in the Thomson Reuters Eikon database. The analyses are based on 8,840 firm-year observations for the years between 2002 and 2019 and the country-firm-year fixed-effects (FE) regression analysis is executed.

Findings

The results reveal that CSR initiatives contribute to the financial sector's FS as a whole and the sector's three individual sub-sectors. This proven significant association holds for all sub-sectors, namely insurance, banking, and investment banking. Moreover, the moderation analysis reveals the prominent role of a sustainability committee in bridging CSR performance (CSRP) with FS.

Research limitations/implications

The findings highlight that meeting societies' expectations pays back in the form of greater FS in the financial sector.

Practical implications

The findings suggest that CSR engagement helps the financial sector firms manage their risks and alleviates exposure to insolvency. This is because CSR performance promotes firms' accountability and transparency toward stakeholders. The results help motivate managers to pursue CSR goals more seriously to ensure FS. The moderation analysis implies that sustainability committees develop policies and practices to integrate the non-financial and financial goals of the firm.

Originality/value

Although prior studies have examined the link between CSR and financial performance (FP) in the financial sector, those studies have largely ignored FS in terms of risk-adjusted performance. Besides, prior studies have exclusively focused on the banking sector, but the authors concentrate on the banking, insurance, and investment banking sectors.