bluuebunny/crossref_metadata_2025 huggingface dataset:
The Prevalence of Skin Tears in an Acute Care Hospital
Authors: Werth Sherry Lynn , Justice Rachel
Published: July 2024

PURPOSE:

The purpose of this quality improvement project was to determine the prevalence of skin tears (STs) within an acute care hospital.

PARTICIPANTS AND SETTING:

The setting was a 676-bed Midwestern urban teaching hospital with Magnet designation in the United States. All adult, children, and neonatal patients were assessed during the data collection period with the exclusion of the mother/baby unit and patients who were unsafe to move, actively dying, off the unit during the survey assessment, or those who declined participation.

APPROACH:

ST prevalence data were collected concurrently with the quarterly Pressure Injury Prevalence Survey over a period of 12-months (beginning the third quarter of 2017 through the second quarter of 2018) by the Pressure Injury Prevalence Survey Skin Care Champions using the revised Payne-Martin classification system for STs. A data collection form developed by the Wound, Ostomy, and Continence nurse was also completed for the patients with ST(s).

OUTCOMES:

The prevalence of STs was 2.92% (46/1576 patients). Twenty-one patients were women and 25 were men, with a mean age of 69.90 years (age range: 8 days-96 years). The majority of STs were found on the extremities (60 STs, 86.96%) and hospital-acquired (30 patients, 65.22%). Thirty STs (43.48%) were category III according to the revised Payne-Martin classification system for STs with major risk factors identified as frail skin (n = 34), advanced age (n = 30), and impaired mobility (n = 24).

IMPLICATIONS FOR PRACTICE:

STs are a common finding in the acute care setting spanning all age groups and are frequently overlooked by health care providers. This project provides a strategy to determine ST prevalence in a health care setting. Additional studies should focus on risk factor assessment and prevention strategies as these may decrease the incidence of this painful wound.
Spatially explicit predictions of food web structure from regional-level data
Authors: Dansereau Gabriel , Barros Ceres , Poisot Timothée
Published: July 2024

Knowledge about how ecological networks vary across global scales is currently limited given the complexity of acquiring repeated spatial data for species interactions. Yet, recent developments in metawebs highlight efficient ways to first document possible interactions within regional species pools. Downscaling metawebs towards local network predictions is a promising approach to using the current data to investigate the variation of networks across space. However, issues remain in how to represent the spatial variability and uncertainty of species interactions, especially for large-scale food webs. Here, we present a probabilistic framework to downscale a metaweb based on the Canadian mammal metaweb and species occurrences from global databases. We investigated how our approach can be used to represent the variability of networks and communities between ecoregions in Canada. Species richness and interactions followed a similar latitudinal gradient across ecoregions but simultaneously identified contrasting diversity hotspots. Network motifs revealed additional areas of variation in network structure compared with species richness and number of links. Our method offers the potential to bring global predictions down to a more actionable local scale, and increases the diversity of ecological networks that can be projected in space.

This article is part of the theme issue 'Connected interactions: enriching food web research by spatial and social interactions'.
On formal limitations of causal ecological networks
Authors: Damos Petros T.
Published: July 2024

Causal multivariate time-series analysis, combined with network theory, provide a powerful tool for studying complex ecological interactions. However, these methods have limitations often underestimated when used in graphical modelling of ecological systems. In this opinion article, I examine the relationship between formal logic methods used to describe causal networks and their inherent statistical and epistemological limitations. I argue that while these methods offer valuable insights, they are restricted by axiomatic assumptions, statistical constraints and the incompleteness of our knowledge. To prove that, I first consider causal networks as formal systems, define causality and formalize their axioms in terms of modal logic and use ecological counterexamples to question the axioms. I also highlight the statistical limitations when using multivariate time-series analysis and Granger causality to develop ecological networks, including the potential for spurious correlations among other data characteristics. Finally, I draw upon Gödel’s incompleteness theorems to highlight the inherent limits of fully understanding complex networks as formal systems and conclude that causal ecological networks are subject to initial rules and data characteristics and, as any formal system, will never fully capture the intricate complexities of the systems they represent.

This article is part of the theme issue ‘Connected interactions: enriching food web research by spatial and social interactions’.
Societies with fission–fusion dynamics as complex adaptive systems: the importance of scale
Authors: Madsen Anastasia , de Silva Shermin
Published: July 2024

In this article, we argue that social systems with fission–fusion (FF) dynamics are best characterized within a complex adaptive systems (CAS) framework. We discuss how different endogenous and exogenous factors drive scale-dependent network properties across temporal, spatial and social domains. Importantly, this view treats the dynamics themselves as objects of study, rather than variously defined notions of static ‘social groups’ that have hitherto dominated thinking in behavioural ecology. CAS approaches allow us to interrogate FF dynamics in taxa that do not conform to more traditional conceptualizations of sociality and encourage us to pose new types of questions regarding the sources of stability and change in social systems, distinguishing regular variations from those that would lead to system-level reorganization.

This article is part of the theme issue ‘Connected interactions: enriching food web research by spatial and social interactions’.
Delving deep into the draft genome of Mangrovibacter sp. SLW1, isolated from Sundarbans mangrove
Authors: Roy Arindam , Ghosh Anwesha , Bhadury Punyasloke
Published: July 2024

Mangrovibacter sp. SLW1, a Gram-negative, aerobic, motile bacterium was isolated from mangrove litterfall in Sundarbans mangrove. The draft genome is 5.5 Mbp in size with 49.45 mol% GC content. The linear chromosome of the bacterium consists of 27 contigs with 7,339 coding sequences. The detailed in silico analyses of the genome of Mangrovibacter sp. SLW1 provide information on their ecological adaptation. The genome is a reservoir for multiple heavy metals and metalloids resistance gene clusters as well as exhibit metabolic capabilities for utilization of a wide range of carbohydrates. It also encodes for tris-catecholate siderophore and can regulate uptake of iron and plant growth such as for mangrove vegetation.
Programming aliphatic polyester degradation by engineered bacterial spores
Authors: Cui Ziyu , Kawada Masamu , Hui Yue , Sim Seunghyun
Published: July 2024

Enzymatic degradation of plastics is a sustainable approach to addressing the growing issue of plastic accumulation. The primary challenges for using enzymes as catalysts are issues with their stability and recyclability, further exacerbated by their costly production and delicate structures. Here, we demonstrate an approach that leverages engineered spores that display target enzymes in high density on their surface to catalyze aliphatic polyester degradation and create self-degradable materials. Engineered spores display recombinant enzymes on their surface, eliminating the need for costly purification processes. The intrinsic physical and biological characteristics of spores enable easy separation from the reaction mixture, repeated reuse, and renewal. Engineered spores displaying lipases completely degrade aliphatic polyesters and retain activity through four cycles, with full activity recovered through germination and sporulation. Directly incorporating spores into polyesters results in robust materials that are completely degradable. Our study offers a straightforward and sustainable biocatalytic approach to plastic degradation.
Blocking the ability of huntingtin to bind membranes: a therapeutic strategy for Huntington’s disease
Authors: Siriwardhana Chathuranga , Adegbuyiro Adewale , Sedighi Faezeh , Stonebraker Alyssa R. , Leonard Sharon , Beasley Maryssa , Skeens Adam , Mertz Blake , Geldenhuys Werner , Legleiter Justin
Published: July 2024

The ordered aggregation of proteins into amyloid fibrils is a hallmark of numerous neurodegenerative diseases. A common strategy in developing therapeutics for amyloid-based diseases relies on preventing or manipulating the aggregation process. However, many amyloid-forming proteins and their aggregates bind and damage organelle and cellular membranes. As such, blocking the ability of these proteins from directly interacting with membranes represents a unique therapeutic strategy. Using a mutant huntingtin (htt) protein associated with Huntington’s disease (HD) as a model system, the viability of this strategy was evaluated. Screening over 1200 compounds for their ability to block htt binding to lipid vesicles, two compounds, Ro90-7501 (Ro) and Benzamil (Ben), were identified and validated. Despite directly interacting with htt, neither compound prevented fibril formation. Molecular dynamics simulations suggested each compound has a unique mechanism of action, consistent with experimental data. Importantly, both compounds ameliorated phenotype in aC. elegansmodel of HD.
Cell state and transcription factor modulation during extended ex vivo CD8+T-cell expansion
Authors: Lui Yuan , Jenkins Edward , Ng Emily Zhi Qing , Kotowski Mateusz , Mullin Sydney J , Clarke Joseph , Davis Simon J , Santos Ana Mafalda , Sharma Sumana
Published: July 2024

Adoptive cell therapy is becoming a cornerstone of tumour immunotherapy. It relies on the relatively long-term (> 2 week) ex vivo expansion of T cells either in the form of tumour-infiltrating cells, or bulk cells modified with the expression of heterologous signalling proteins, e.g., chimeric antigen receptors. However, relatively little is known about the developmental trajectories of T cells under these conditions at the system level, or whether the pathways governing these trajectories could be manipulated for clinical advantage. Using bulk RNA-seq analysis of T cells expanded and rested over a 17-day period, we produce a resource revealing how gene expression changes as cells transition through distinct cellular states over the course of activation and ex vivo expansion. By integrating this resource with published single-cell RNA-seq data, we identify a member of the AP1 transcription factor (TF) family, FOSL1, that primes CD8+T-cells towards an effector/killing phenotype. Remarkably, FOSL1 over-expression during T-cell expansion produced ‘super engager-like’ T-cells, evidenced by their gene-expression signatures and enhanced cancer-cell killing capacity. This establishes proof-of-principle for the rational engineering of T cells via TF modification during ex vivo expansion, offering a route to improving adoptive T-cell therapy.
MENTOR: Multiplex Embedding of Networks for Team-Based Omics Research
Authors: Sullivan Kyle A. , Miller J. Izaak , Townsend Alice , Morgan Mallory , Lane Matthew , Pavicic Mirko , Shah Manesh , Cashman Mikaela , Jacobson Daniel A.
Published: July 2024

While the proliferation of data-driven omics technologies has continued to accelerate, methods of identifying relationships among large-scale changes from omics experiments have stagnated. It is therefore imperative to develop methods that can identify key mechanisms among one or more omics experiments in order to advance biological discovery. To solve this problem, here we describe the network-based algorithm MENTOR - Multiplex Embedding of Networks for Team-Based Omics Research. We demonstrate MENTOR’s utility as a supervised learning approach to successfully partition a gene set containing multiple ontological functions into their respective functions. Subsequently, we used MENTOR as an unsupervised learning approach to identify important biological functions pertaining to the host genetic architectures inPopulus trichocarpaassociated with microbial abundance of multiple taxa. Moreover, as open source software designed with scientific teams in mind, we demonstrate the ability to use the output of MENTOR to facilitate distributed interpretation of omics experiments.
Double Trouble: Multiple infections and the coevolution of virulence-resistance in structured host-parasite populations
Authors: Lombard Julien D. , Massol François , Lion Sébastien
Published: July 2024

Parasite evolution is expected to modulate selective pressures acting upon host, and alter its response to infection. In such a context, parasite competition seems be a key variable for the evolutionary dynamics and epidemic features. We develop a nested coevolutionary model of host resistance and parasite virulence. From individual-based traits, we define a within-host model and derive from the within-host equilibrium the main epidemiological features of interest -transmission, virulence, recovery-. We use this first model to build an adaptive dynamics model in order to assess the joint evolution of the parasite virulence and host resistance. We compared the coevolutionarily stable states predicted by the model under different competition regimes, including single infections (preemption), superinfection (dominance) and coinfections (mixed). We find that parasite virulence under coinfections evolved towards higher values than under superinfections, while the opposite trend was observed for host resistance. The local coexistence of parasites enables a kin selection effects that reduce both virulence and the subsequent host response. We showed that the magnitude of multiple infections effects varies with the ecological context, and that the coevolutionary outcomes deviate from simple optimization of persistence depending on the degree of spatial coupling of hosts.
The inhibition of three distinct signaling pathways eliminates the oncogenic Tribbles homolog 2 from melanoma cells
Authors: Mayoral-Varo Victor , Orea-Soufi Alba , Jiménez Lucía , Santos Bruno , Serrão Gisela , Jociles Miguel , Obeso Sara , Ferreira Bibiana I. , Link Wolfgang
Published: July 2024

Tribbles homolog 2 (TRIB2) is one of three members of the Tribbles family of pseudo serine/threonine kinases. It acts as an oncogene whose expression is correlated with tumor stage and therapy response in melanoma. While metastatic melanoma, the most aggressive form of skin cancer now has two effective treatment options, namely MAPK pathway and immune checkpoint inhibitors, the majority of patients primarily fail to respond or acquire secondary resistance. Hence, innovative approaches to identify disease-relevant, druggable targets to remove the roadblock of therapy resistance are urgently needed. TRIB2 has been implicated in conferring resistance to various anti-cancer therapies suggesting TRIB2 as a therapeutic target for resistant tumors. This study explores the pharmacological targeting of TRIB2, revealing several independent routes of pharmacological manipulations. TRIB2 is a short-lived protein stabilized by inhibition of the PI3K/AKT pathway. Conversely, inhibitors of BRAF, MEK and ERK significantly decrease TRIB2 expression by a mechanism that involves transcription. Strikingly, increasing concentrations of the kinase inhibitor PIK75 effectively eliminate TRIB2 in melanoma cells surpassing its PI3K inhibitory activity. Additionally, Polo-Like Kinases (PLKs) inhibitors significantly reduce TRIB2 protein expression and stability. We demonstrate that inhibition or silencing of PLK2 leads to a decrease in TRIB2 levels. Overall, we identify three distinct classes of compounds that efficiently eliminate the oncogenic TRIB2 protein from melanoma cells based on different molecular mechanisms and exhibiting 40 to 200 times greater potency than the previously reported afatinib.
SpeSpeNet: An interactive and user-friendly tool to create and explore microbial correlation networks
Authors: van Eijnatten A.L. , van Zon L. , Manousou E. , Bikineeva M. , Wubs J. , van der Putten W. , Morriën E. , Dutilh B.E. , Snoek B.L.
Published: July 2024

Correlation networks are commonly used to explore microbiome data. In these networks, nodes are taxa and edges represent correlations between their abundance patterns across samples. As clusters of correlating taxa (co-abundance clusters) often indicate a shared response to environmental drivers, network visualization contributes to system understanding. Currently, most tools for creating and visualizing co-abundance networks from microbiome data either require the researcher to have coding skills, or they are not user-friendly, with high time expenditure and limited customizability. Furthermore, existing tools lack focus on the relationship between environmental drivers and the structure of the microbiome, even though many edges in correlation networks can be understood through a shared relationship of two taxa with the environment. For these reasons we developed SpeSpeNet (Species-Species Network,https://tbb.bio.uu.nl/SpeSpeNet), a practical and user-friendly R-shiny tool to construct and visualize correlation networks from taxonomic abundance tables. The details of data preprocessing, network construction, and visualization are automated, require no programming ability for the web version, and are highly customizable, including associations with user-provided environmental data. Here, we present the details of SpeSpeNet and demonstrate its utility using three case studies.
Atypical soluble guanylyl cyclases control brain size inDrosophila
Authors: Prieto Daniel , Egger Boris , Cantera Rafael
Published: July 2024

Hypoxia-induced proliferation of neural stem cells has a crucial role in brain development. In the brain ofDrosophila melanogaster, the optic lobe exhibits progressive hypoxia during larval development. Here, we investigate an alternative oxygen-sensing mechanism within this brain compartment, distinct from the canonical hypoxia signaling pathway mediated by HIF. Using genetic tools, immunostaining, and confocal microscopy, we demonstrate that the loss of the atypical soluble guanylyl cyclase (asGC) subunitGyc88E, or the ectopic expression ofGyc89Dbin neural stem cells leads to increased optic lobe volume. We propose the existence of a link between cGMP signaling and neurogenesis in the developing brain.
Adolescent alcohol exposure alters age-related progression of behavioral and neurotrophic dysfunction in the TgF344-AD model in a sex-specific manner
Authors: Reitz Nicole L. , Nunes Polliana T. , Savage Lisa M.
Published: July 2024

Alzheimer’s Disease (AD) and heavy alcohol use are widely prevalent and lead to brain pathology. Both alcohol-related brain damage (ABRD) and AD result in cholinergic dysfunction, reductions in hippocampal neurogenesis, and the emergence of hippocampal-dependent cognitive impairments. It is still unknown how ARBD caused during a critical developmental timepoint, such as adolescence, interacts with AD-related pathologies to accelerate disease progression later in life. The current study utilized a longitudinal design to characterize behavioral and pathological changes in a transgenic rat model of AD (TgF344-AD) following adolescent intermittent ethanol (AIE) exposure. We found that AIE accelerates cognitive decline associated with AD transgenes in female rats at 6 months of age, and male AD-rats are impaired on spatial navigation by 3-months with no additional deficits due to AIE exposure. Protein levels of various AD-pathological markers were analyzed in the dorsal and ventral hippocampus of male and female rats. The data suggests that AIE-induced alterations of the tropomyosin-related kinase A receptor (TrkA) / p75 neurotrophin receptor (p75NTR) ratio creates a brain that is vulnerable to age- and AD-related pathologies, which leads to an acceleration of cognitive decline, particularly in female rats.
Computational investigation of missense somatic mutations in cancer and potential links to pH-dependence and proteostasis
Authors: Sallah Shalaw , Warwicker Jim
Published: July 2024

Metabolic changes during tumour development lead to acidification of the extracellular environment and a smaller increase of intracellular pH. Searches for somatic missense mutations that could reveal adaptation to altered pH have focussed on arginine to histidine changes, part of a general arginine depletion that originates from DNA mutational mechanisms. Analysis of mutations to histidine, potentially a simple route to the introduction of pH-sensing, shows no clear biophysical separation overall of subsets that are more and less frequently mutated in cancer genomes. Within the more frequently mutated subset, individual sites predicted to mediate pH-dependence upon mutation include NDST1 (a Golgi-resident heparan sulphate modifying enzyme), the HLA-C chain of MHCI complex, and the water channel AQP-7. Arginine depletion is a general feature that persists in the more frequently mutated subset, and is complemented by over-representation of mutations to lysine. Arginine to lysine balance is a known factor in determining protein solubility, with higher lysine content being more favourable. Proteins with greater change in arginine to lysine balance are enriched for cell periphery location, where proteostasis is likely to be challenged in tumour cells. Somatic missense mutations in a cancer genome number only in the 10s typically, although can be much higher. Whether the altered arginine to lysine balance is of sufficient scale to play a role in tumour development is unknown.
Quantifying higher-order epistasis: beware the chimera
Authors: Chitra Uthsav , Arnold Brian J. , Raphael Benjamin J.
Published: July 2024

Epistasis, or interactions in which alleles at one locus modify the fitness effects of alleles at other loci, plays a fundamental role in genetics, protein evolution, and many other areas of biology. Epistasis is typically quantified by computing the deviation from the expected fitness under an additive or multiplicative model using one of several formulae. However, these formulae are not all equivalent. Importantly, one widely used formula – which we call thechimericformula – measures deviations from amultiplicativefitness model on anadditivescale, thus mixing two measurement scales. We show that for pairwise interactions, the chimeric formula yields a different magnitude, but the same sign (synergistic vs. antagonistic) of epistasis compared to the multiplicative formula that measures both fitness and deviations on a multiplicative scale. However, for higher-order interactions, we show that the chimeric formula can have both different magnitudeandsign compared to the multiplicative formula — thus confusing negative epistatic interactions with positive interactions, and vice versa. We resolve these inconsistencies by deriving fundamental connections between the different epistasis formulae and the parameters of themultivariate Bernoulli distribution. Our results demonstrate that the additive and multiplicative epistasis formulae are more mathematically sound than the chimeric formula. Moreover, we demonstrate that the mathematical issues with the chimeric epistasis formula lead to markedly different biological interpretations of real data. Analyzing multi-gene knockout data in yeast, multi-way drug interactions inE. coli, and deep mutational scanning (DMS) of several proteins, we find that 10 − 60% of higher-order interactions have a change in sign with the multiplicative or additive epistasis formula. These sign changes result in qualitatively different findings on functional divergence in the yeast genome, synergistic vs. antagonistic drug interactions, and and epistasis between protein mutations. In particular, in the yeast data, the more appropriate multiplicative formula identifies nearly 500 additional negative three-way interactions, thus extending the trigenic interaction network by 25%.
Using state space models to understand trait evolution in fossil lineages
Authors: Hunt Gene , Martinez Rivera Wilmer , Hopkins Melanie , Fricks John , Sterner Beckett
Published: July 2024

Linear state space models provide a useful framework for investigating phenotypic evolution in fossil lineages in a wide variety of models including Brownian motion, Ornstein-Uhlenbeck processes, and models that incorporate potentially explanatory environmental covariates. A state space framework also provides access to residuals for the predicted and observed values at each time point as well as improved numerical stability. We illustrate the value of the state space approach by re-analyzing a classic dataset of diatom evolution in Yellowstone Lake. We find that number of spines is best explained by adaptation to changing solar insolation as an exogenous environmental covariate.
Single laboratory evaluation of the (Q20+) nanopore sequencing kit for bacterial outbreak investigations
Authors: Hoffmann Maria , Jang Jay Hee , Tallent Sandra , Gonzalez-Escalona Narjol
Published: July 2024

This study aimed to evaluate the potential of Oxford Nanopore Technologies (ONT) GridION with Q20+ chemistry as a rapid and accurate method for identifying and clustering foodborne pathogens. The study focuses on assessing whether ONT Q20+ technology could offer near real-time pathogen identification, including SNP differences, serotypes, and antimicrobial resistance genes, to overcome the drawbacks of existing methodologies. This pilot study evaluated different combinations of two DNA extraction methods (Maxwell RSC Cultured Cell DNA kit, and Monarch high molecular weight extraction kits) and two ONT library preparation protocols (ligation and the rapid barcoding sequencing kit) using five well-characterized strains representing diverse foodborne pathogens. The results showed that any combination of extraction and sequencing kits produced high-quality closed bacterial genomes. However, there were variations in assembly length and genome completeness based on different combinations of methods, indicating the need for further optimization.in silicoanalyses demonstrated that the Q20+ nanopore sequencing chemistry accurately identified species, genotyped, and detected virulence factors comparable to Illumina sequencing. Phylogenomic clustering methods showed that ONT assemblies clustered with reference genomes, although some indels and SNP differences were observed. There were also differences on SNP accuracy among the different species. The observed SNP differences were likely due to sequencing and analysis processes rather than genetic variations in the sampled bacteria. The study also compared a change in the basecaller model with the previous model (SUP 4Khz 260 bps) and found no significant difference in accuracy (SUP 5Khz 400 bps). In conclusion, the evaluation of ONT Q20+ nanopore sequencing chemistry demonstrated its potential as an alternative for rapid and comprehensive bacterial genome analysis in outbreak investigations. However, further research, verification studies, and optimization efforts are needed to address the observed limitations to adopt and fully realize the impact of nanopore sequencing on public health outcomes and more efficient responses to foodborne disease threats.
EngineeringCandida boidiniiformate dehydrogenase for activity with NMN(H)
Authors: Vainstein Salomon , Banta Scott
Published: July 2024

Multi-step enzymatic reaction cascades often involve cofactors that serve as electron donors/acceptors in addition to the primary substrates. The co-localization of cascades can lead to cross-talk and competition, which can be unfavorable for the production of a targeted product. Orthogonal pathways allow reactions of interest to operate independently from the metabolic reactions within a cell; non-canonical cofactor analogs have been explored as a means to create these orthogonal pathways. Here, we aimed to engineer the formate dehydrogenase fromCandid boidinii(CbFDH) for activity with the non-canonical cofactor nicotinamide adenine mononucleotide (NMN(H)). We used PyRosetta and structural alignment to design mutations that enable CbFDH to use NMN+for the oxidation of formate. Although the suggested mutations did not result in enhanced activity with NMN+, we found that PyRosetta was able to easily design single mutations that disrupted all enzymatic activity.
A neurofunctional signature of affective arousal generalizes across valence domains and distinguishes subjective experience from autonomic reactivity
Authors: Zhang Ran , Gan Xianyang , Xu Ting , Yu Fangwen , Wang Lan , Song Xinwei , Jiao Guojuan , Liu Xiqin , Zhou Feng , Becker Benjamin
Published: July 2024

Arousal is fundamental for affective experience and, together with valence, defines the core affective space. Precise brain models of affective arousal are lacking, leading to continuing debates of whether the neural systems generalize across valence domains and are separable from those underlying autonomic arousal or wakefulness. Here, we combined naturalistic fMRI with predictive modeling to develop a brain affective arousal signature (BAAS, discovery-validation design, n=60, 36). We demonstrate its (1) sensitivity and generalizability across mental processes and valence, and (2) neural distinction from autonomic arousal, wakefulness, and stimulation modality (24 studies, n=868). Affective arousal was encoded in distributed cortical-subcortical (e.g., prefrontal, PAG) systems with local similarities in thalamo-amygdala-insula systems between affective and autonomous arousal. We demonstrate application of the BAAS to improve specificity of established valence-specific neuromarkers. Our study provides a biologically plausible model for affective arousal that aligns with the affective space and has a high application potential.
Dnmt1 determines bone length by regulating energy metabolism of growth plate chondrocytes
Authors: Yanagihara Yuta , Takahashi Masatomo , Izumi Yoshihiro , Kinoshita Tomofumi , Takao Masaki , Bamba Takeshi , Imai Yuuki
Published: July 2024

Chondrocytes differentiated from mesenchymal stem cells play a role in determining skeletal patterns by ossification. However, the mechanism by which maintenance DNA methylation in chondrocytes regulates differentiation and skeletal formation is unclear. In the Musculoskeletal Knowledge Portal, Dnmt1 was significantly associated with “Height”. Long bones in the limbs of Dnmt1-deficient (Dnmt1ΔPrx1) mice are significantly shortened due to decreased chondrocyte proliferation and accelerated differentiation. Integrated analysis of RNA-Seq and MBD-Seq revealed that inDnmt1ΔPrx1chondrocytes reduced DNA methylation resulted in increased expression of genes related to energy metabolism and to ossification. Metabolomic analyses confirmed that levels of nearly all energy metabolites were increased inDnmt1ΔPrx1chondrocytes. These results indicate that Dnmt1-mediated maintenance DNA methylation governs chondrocyte differentiation by regulating energy metabolism through both gene expression and modulation of metabolite supplies. Taken together, this study suggests that appropriate DNA methylation status in chondrocytes can orchestrate growth plate mineralization and subsequently determine bone length.
Genetic and functional characterization of inherited complex chromosomal rearrangements in a family with multisystem anomalies
Authors: Fang He , Eacker Stephen M. , Wu Yu , Neufeld-Kaiser Whitney , Laurino Mercy , Keel Siobán , Horwitz Marshall S. , Liu Yajuan J.
Published: July 2024

Purpose

Complex chromosomal rearrangements (CCRs) are rare structural variants involving three or more chromosomal breakpoints. Most de novo reported CCRs pose challenges for diagnosis and management. They often require karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray analysis (CMA) for clinical diagnosis because of the limitations of each method. Here we report an inherited exceptionally complex CCR involving 4 chromosomes and 11 breakpoints in a family with multisystem anomalies.

Methods

We evaluated the CCRs using karyotyping, FISH, CMA, and two emerging genomic technologies: high-throughput chromosome conformation capture sequencing (Hi-C; aka genomic proximity mapping, GPM) and optical genome mapping (OGM). We also performed functional studies using transcriptome and methylome analyses.

Results

The proband, who had intellectual disability and immune deficiency, shared CCRs with her unaffected mother involving chromosomes 1, 7, and 11 by karyotyping. However, CMA revealed a duplication and three deletions in the proband in contrast to her mother’s balanced genome. Hi-C (GPM) and OGM detected the CCRs and copy number alterations but also uncovered additional breakpoints at high resolution, including an insertion in 4p and two cryptic rearrangements at 7p. Transcriptome and methylome analyses identified likely biological pathways associated with the proband’s phenotypes.

Conclusion

Combining cytogenetic and genomic methods provided comprehensive characterization and defined the breakpoints at high resolution in both proband and mother. This underscores the value of novel cytogenetic and genomic techniques in deciphering complex genome rearrangements and the significance of integrative genomic analysis and functional characterization in understanding clinical phenotypes.
Bone pain in Fibrous dysplasia does not rely on aberrant sensory nerve sprouting or neuroma formation
Authors: Palmisano Biagio , Tavanti Chiara , Farinacci Giorgia , Gosti Giorgio , Leonetti Marco , Donsante Samantha , Giannicola Giuseppe , Appelman-Dijkstra Natasha , Corsi Alessandro , Ippolito Ernesto , Riminucci Mara
Published: July 2024

Bone pain is a major symptom of many skeletal disorders. Fibrous dysplasia (FD) is a genetic disease with mono or polyostotic skeletal phenotype due to the post-zygotic occurrence of the causative Gsα mutation. Bone pain in FD often associates with skeletal deformities and fractures or nerve impingement by the pathological tissue. However, even in the absence of complications, FD patients often complain of a chronic pain that does not correlate with their disease burden. Multiple hypotheses have been made to explain this pain. However, its pathogenetic mechanisms remain, as yet, largely unexplored.

In this study, we first demonstrate that the FD mouse model EF1α-GsαR201Cdevelops a painful-like behavior and an altered response to nociceptive stimuli that, as in FD patients, do not correlate with the severity of their phenotype, thus providing a reliable model to study bone pain in FD. Then, we show that in EF1α-GsαR201Cmice, the overall pattern of skeletal innervation is preserved and that within FD lesions, sensory fibers are variably and focally distributed, mainly at perivascular sites. Finally, we provide the first analysis of a series of human FD bone biopsies showing that sensory nerve fibers are rarely detected within the pathological tissue.

These data confirm that bone pain is an intrinsic and reproducible feature of FD. They also show that, albeit sensory nerve fibers are found within FD lesions and may contribute to the unpleasant sensation that accompanies the disease, pathological sensory nerve sprouting or formation of neuromas are not detected in the Gsα-mutated skeleton.
Cell wall-resident PIR proteins show an inverted architecture inNeurospora crassa, but keep their role as wall stabilizers
Authors: Montaño-Silva Paul , Callejas-Negrete Olga A. , Pereira-Santana Alejandro , Verdín Jorge
Published: July 2024

Proteins with internal repeats (PIRs) are the second most abundant class of fungal cell wall resident proteins. In yeasts, PIRs preserve the wall stability under stressful conditions. They are characterized by conserved N-terminal amino acid sequences repeated in tandem (PIR domains), and a Cys-rich C-terminal domain. Despite PIRs have been inferred in several filamentous fungi genomes, they have not been studied beyond yeasts. In this work, PIRs diversity, evolution and biological role, focused on a new PIRs class, were addressed. Bioinformatic inference of PIRs in fungi indicated they were an innovation in Ascomycota. Predicted PIRs clustered in two main groups: classical yeasts PIRs (N-terminal PIR domains; C-terminal Cys-rich domain), and PIRs from filamentous fungi with an inverted architecture (N-terminal Cys-rich domain; C-terminal PIR domains), which could harbor additional GPI-signals. As representatives of the second group,Neurospora crassa(Nc) PIR-1 (NCU04033) and PIR-2 (NCU07569) were studied. Confocal microscopy of eGFP-labeled PIR-1 and PIR-2 revealed they accumulate in apical plugs; additionally, PIR-1 requires the Kex2 processing site for correct maturation, and its predicted C-terminal GPI modification signal resulted functional. Moreover, Nc Δpir-1and Δpir-2single mutants showed a growth rate similar to that of Nc WT, but the double mutant Nc Δpir-1/Δpir-2grew significatively slower. Similarly, Nc Δpir-1and Nc Δpir-2were mildly sensitive to calcofluor white, although Nc Δpir-1/Δpir-2double mutant was severely impaired. Despite the inverted architecture of PIR-1 and PIR-2, they resulted in cell wall stabilizers as classical yeast PIRs.
Choose your partner: Social evaluation of skilfulness at cooperative co-action tasks in Tonkean macaques (Macaca tonkeana)
Authors: Hirel Marie , Meunier Hélène , Mundry Roger , Rakoczy Hannes , Fischer Julia , Keupp Stefanie
Published: July 2024

Social evaluation – inferring individual characteristics of others from their past behaviours – is an adaptive strategy that helps to inform social decisions. However, how nonhuman primates form and use impressions about others to select their social partners strategically is still unclear. In this study, we investigated whether Tonkean macaques,Macaca tonkeana, can spontaneously use information, acquired by observation, to choose the optimal partners for cooperation in two co-action tasks from the same domain. The subjects (N=5) did not prefer to cooperate with the skilful partner compared to the unskilled partner, irrespective of the task or how much attention they paid to the partners’ actions solving a solo version of one task prior to the test. The probability of optimal choices did not increase through trials either, indicating no learning by experience with the partners across the 16 test trials. Our results contradict findings of previous studies that tested monkeys in different domains of competence and contexts, and thus encourage further investigation on monkeys’ social evaluation abilities. Our experimental design presents a promising way to investigate different contexts, the inter-individual differences, the different types of social information involved, and the cognitive mechanisms underlying social evaluation and partner selectivity in nonhuman primates.
Tumor-derived colorectal cancer organoids induce a unique Treg cell population through direct modulation of CD4+T cell differentiation
Authors: Aristin Revilla Sonia , Frederiks Cynthia Lisanne , Prekovic Stefan , Mocholi Enric , Kranenburg Onno , Coffer Paul James
Published: July 2024

In colorectal cancer (CRC), increased numbers of tumor-infiltrating CD4+regulatory T (Treg) cells correlate with tumor development and immunotherapy failure, leading to poor prognosis. However, the molecular and cellular mechanisms governing Treg recruitment, expansion, or differentiation remain unclear. Here, we developed anin vitroco-culture system to assess the capacity of CRC tumors to directly modulate Treg cell differentiation. CD4+T cells from Foxp3eGFP mice were co-cultured with murine tumor-derived CRC organoids, resulting in a significant increase in Treg cell numbers. This induction of Treg cells was not due to increased proliferation, but rather through differentiation of CD4+T cells in a TGFβ-dependent manner. Human CRC tumor organoids similarly induced Treg cells that exhibited enhanced suppressive capacity compared to TGFβ-induced Treg cells. RNA-sequencing analysis identified distinct transcriptional profiles between CRC organoid-induced Treg cells and TGFβ-induced Treg cells, with upregulation of key functional signature genes linked to CRC Treg cellsin vivo. High expression of genes upregulated in CRC organoid-induced Treg cells correlates with shorter progression free interval and overall survival of CRC patients, highlighting their prognostic potential. Taken together, CRC tumor organoids drive CD4+differentiation to Treg cells with a phenotype resembling tumor-infiltrating Treg cells. This model can be applied to both understand the molecular mechanisms by which tumors can directly modulate CD4+T cell differentiation and identify approaches to disrupt Treg cell function and stimulate anti-tumor immunity.
The temporal refinement ofDach1is a key step in the functional maturation of primary somatosensory neurons
Authors: Szemes Tünde , San José Alba Sabaté , Azouz Abdulkader , Sitte Maren , Salinas Gabriela , Achouri Younes , Kricha Sadia , Ris Laurence , Red-Horse Kristy , Bellefroid Eric J. , Desiderio Simon
Published: July 2024

During somatosensory neurogenesis, neurons are born in an unspecialized transcriptional state, with several transcription factors following a broad-to-restricted expression dynamic as development proceeds, supporting neuron subtype identities. The relevance of this temporal refinement remains however unclear, these broad-to-restricted transcription factors being selectively involved in neurons in which they are ultimately maintained. Here we found thatDach1encodes for abona fidebroad-to-restricted transcription factor retained and required in tactile somatosensory neurons. Within developing nociceptors, we demonstrate that Prdm12 contributes toDach1extinction. Using genetic approaches to prevent its temporal restriction during somatosensory development, we reveal thatDach1refinement is a prerequisite for the appropriate transcriptional maturation of somatosensory subtypes from which it becomes ultimately excluded. These findings highlight the essential role played by Dach1 during somatosensory neuron development. They further demonstrate that the broad-to-restricted temporal pattern followed by several transcription factors is physiologically relevant to achieve appropriate transcriptional maturation of somatosensory neurons.
Thermal preconditioning modulates coral physiology and heat tolerance: A multi-species perspective
Authors: Ferrara Erik F. , Roik Anna , Wöhrmann-Zipf Franziska , Ziegler Maren
Published: July 2024

Global warming threatens reef-building corals by challenging their natural adaptive capacity. Therefore, interventions such as stress hardening by thermal preconditioning could become crucial for their survival. Stress-hardening approaches recognize that organisms living in thermally variable environments are better able to withstand marine heat waves. However, a systematic assessment of preconditioning effects on the baseline physiology and thermal tolerance across coral species is lacking. We assessed the changes of thermal tolerance in six stony coral species (Galaxea fascicularis, Porites rus, Acropora muricata, Montipora digitata, andStylophora pistillata) in three thermal preconditioning treatments of stable-high 29 °C and variable-high 29 °C with a daily oscillation of ± 1.5 °C, compared to corals in stable-ambient 26 °C. We quantified changes in photosynthetic efficiency and coral bleaching intensity before and after a short-term heat stress assay and up to 30 days later. Stress-hardening success after preconditioning was observed in nearly all preconditioned corals, but the increases in thermal tolerance were species-specific. The greatest increase was recorded inG. fascicularisandA. muricata, with stress responses reduced by over 80 %. In contrast, preconditioning regimes had minor effects on stress tolerance ofS. pistillata, making it least receptive to this intervention. After 30 days, most stress-hardened species demonstrated higher survival and recovery rates than their conspecifics from the stable-ambient regime. Notably, both preconditioning regimes affected baseline physiology, especially in the branching species, as indicated by minor tissue paling and decreased photosynthetic efficiency. We conclude that implementing thermal stress hardening protocols will require careful consideration of the species-specific receptiveness and evaluation of the potential trade-offs that can be inflicted with the post-conditioning shifts in physiological baselines.
Metabolites reflect variability introduced by mesoscale eddies in the North Pacific Subtropical Gyre
Authors: Kumler William , Qin Wei , Lundeen Rachel A. , Barone Benedetto , Carlson Laura T. , Ingalls Anitra E.
Published: July 2024

Mesoscale eddies significantly alter open ocean environments such as those found in the subtropical gyres that cover a large fraction of the global ocean. Previous studies have explored eddy effects on biogeochemistry and microbial community composition but not on the molecular composition of particulate organic matter. This study reports the absolute concentration of 67 metabolites and relative abundances for 640 molecular features to understand how mesoscale eddies impact the metabolome of the North Pacific Subtropical Gyre during two cruises in 2017 and 2018. We find that many metabolites track biomass trends, but metabolites like isethionic acid, homarine, and trigonelline linked to eukaryotic phytoplankton were enriched at the deep chlorophyll maximum of the cyclonic features, while degradation products such as arsenobetaine were enriched in anticyclones. In every analysis, metabolites with the strongest responses were detected via untargeted mass spectrometry, indicating that the molecules most sensitive to environmental perturbation were not among the characterized metabolome. By analyzing depth variability (accounting for 20-40% of metabolomic variability across ∼150 meters) and the vertical displacement of isopycnal surfaces (explaining 10-20% of variability across a sea level anomaly range of 40 centimeters and a spatial distance of 300 kilometers), this analysis constrains the importance of mesoscale eddies in shaping the chemical composition of particulate matter in the largest biomes on the planet.

Importance

Mesoscale eddies are common ocean surface currents that circulate seawater vertically and horizontally. This stirring effect alters biogeochemistry and planktonic community composition. Here, we use metabolomics to determine how these eddy-induced changes influence the nature of organic carbon across an eddy dipole. We found that many small, polar molecules track with the overall particulate carbon in the system and that there were significant differences in metabolite composition between eddy states. A few metabolites reflected the increased importance of eukaryotic phytoplankton that were enriched by the higher nutrient supply from depth in the cyclonic eddies. Anticyclones contained more compounds that reflected a higher degree of degradation. This work answers outstanding questions about the importance of these common ocean features in shaping microbial community function.