bluuebunny/crossref_metadata_2025 huggingface dataset:
The signalling axis CDK12-BRCA1 mediates dinaciclib associated radiosensitivity through p53-mediated cellular senescence
Authors: Flores Natalia García , Fernández-Aroca Diego M. , Garnés-García Cristina , Domínguez-Calvo Andrés , Sabater Sebastia , Andrés Ignacio , Jiménez-Suárez Jaime , Fernández-Aroca Pablo , Cimas Francisco , de Cárcer Guillermo , Belandia Borja , Palmero Ignacio , Huertas Pablo , Ruiz-Hidalgo María José , Prieto Ricardo Sánchez
Published: April 2024

Pan-CDK inhibitors are a new class of targeted therapies that can act on multiple CDKs, with dinaciclib being one of the most promising compounds. Although used as monotherapy, an interesting approach could be to combine it with radiotherapy. Here we show that dinaciclib increases radiosensitivity in some experimental models of lung and colon cancer (A549 or HCT 116) but not in others (H1299 or HT-29). Dinaciclib did not alter responses such as ATM signalling, apoptosis or cell cycle profiling after ionising radiation exposure that have been described for other CDK inhibitors. Mechanistically, inhibition of CDK12 by dinaciclib abolishes BRCA1 expression, which blocks homologous recombination (HR), leaving only the non-homologous end joining repair process (NHEJ), which ultimately promotes the induction of ionising radiation-associated cellular senescence in a p53-dependent manner, explaining the lack of effect observed in some experimental models. In conclusion, our report explains the molecular mechanism involved in this novel therapeutic effect of dinaciclib and provides a rationale for more selective and personalised chemo/radiotherapy treatment according to the genetic background of the tumour.

Highlights

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Dinaciclib is a radiosensitising agent in lung and colon cancer cell lines.

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Dinaciclib promotes radiosensitivity by inhibiting CDK12 leading to a decrease in BRCA1 expression.

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Lack of BRCA1 blocks homologous recombination response to DNA damage, enhancing ionising radiation-associated senescence in a p53-dependent fashion.

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The combination of dinaciclib plus radiotherapy could be a novel treatment for tumours holding functional BRCA1 and p53 signalling.
Genetic tuning of intrinsically photosensitive retinal ganglion cell subtype identity to drive visual behavior
Authors: Aranda Marcos L. , Bhoi Jacob D. , Parra Omar A. Payán , Lee Seul Ki , Yamada Tomoko , Yang Yue , Schmidt Tiffany M.
Published: April 2024

The melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) comprise a subset of the ∼40 retinal ganglion cell types in the mouse retina and drive a diverse array of light-evoked behaviors from circadian photoentrainment to pupil constriction to contrast sensitivity for visual perception. Central to the ability of ipRGCs to control this diverse array of behaviors is the distinct complement of morphophysiological features and gene expression patterns found in the M1-M6 ipRGC subtypes. However, the genetic regulatory programs that give rise to subtypes of ipRGCs are unknown. Here, we identify the transcription factor Brn3b (Pou4f2) as a key genetic regulator that shapes the unique functions of ipRGC subtypes and their diverse downstream visual behaviors.
Recent adaptation in an imperiled salmonid revealed by museum genomics
Authors: Sharo Andrew G. , Supple Megan A. , Cabrera Randy , Seligmann William E. , Sacco Samuel , Columbus Cassondra D. , Pearse Devon E. , Shapiro Beth , Garza John Carlos
Published: April 2024

Steelhead/rainbow trout (Oncorhynchus mykiss) is an imperiled salmonid with two main life history strategies: migrate to the ocean or remain in freshwater. Domesticated hatchery forms of this species have been stocked into almost all California waterbodies, possibly resulting in introgression into natural populations and altered population structure.

We compared whole-genome sequence data from contemporary populations against a set of museum population samples of steelhead from the same locations that were collected prior to most hatchery stocking.

We observed minimal introgression and few steelhead-hatchery trout hybrids despite a century of extensive stocking. Our historical data show signals of introgression with a sister species and indications of an early hatchery facility. Finally, we found that migration-associated haplotypes have become less frequent over time, a likely adaptation to decreased opportunities for migration. Since contemporary migration-associated haplotype frequencies have been used to guide species management, we consider this to be a rare example of shifting baseline syndrome that has been validated with historical data.

We suggest cautious optimism that a century of hatchery stocking has had minimal impact on California steelhead population genetic structure, but we note that continued shifts in life history may lead to further declines in the ocean-going form of the species.
Resource competition affects the developmental outcome of the acoustic parasitoid flyOrmia ochracea
Authors: Dominguez Jimena A. , Latham Brendan , Mongui Laura C. , Rossinow Addie , Xiong Yeng , Schmidt Briella V. , Vu Quang , Torres-Lopez Blanca L. , Henderson Parker A. , Mason Andrew C. , Lee Norman
Published: April 2024

Ormia ochraceais an acoustic parasitoid fly where the adults are free-living, but their larval young depend on nutritional resources within host crickets for growth and development. In nature, gravid female flies rely on their ability to recognize and localize cricket calling songs to find suitable host species to parasitize. In depth investigations of fly behavior and the mechanistic bases of auditory perception require a reliable approach to propagate stable fly colonies in the laboratory. Previous work has demonstrated that flies can be propagated using a number of natural host cricket species, as well as cricket species that flies do not parasitize in nature. However, we lack a complete understanding of fly developmental outcomes when non-host cricket species are utilized to propagate fly colonies. In this study, we document the feasibility of using commercially suppliedAcheta domesticusas a host species. We specifically test the hypothesis that host size and resource competition can affect developmental outcomes ofO. ochracea. We performed manual parasitizations on crickets that varied in size, and resource competition was varied by manipulating the number of larvae used to parasitize a host cricket. A series of morphometric analyses were conducted on host crickets, and developmental outcomes were measured in terms of pupation success and eclosion success, pupal width, and eclosed adult fly size. In the absence of resource competition, we found that host cricket size did not affect pupation or eclosion success. In the presence of resource competition between two developing larvae within a host cricket, pupation and eclosion successes were impacted negatively, and the developing pupae were more likely to be smaller. These results confirm that resource competition among developing parasitoids can negatively affect developmental outcomes, andAcheta domesticuscan be used effectively to propagate colonies ofO. ochraceain the laboratory.

Highlights

The acoustic parasitoid flyOrmia ochraceacan successfully develop within the house cricketAcheta domesticus.

Pupal size and eclosed adult fly size varies positively with the size of host cricket.

Resource competition negatively affects pupation and eclosion success.

Resource competition resulted in smaller fly pupae that were less likely to eclose.

Graphical Abstract
Genome sequence and characterization of a hypervirulent BI/NAP1/027Clostridioides difficile(CDC20121308)
Authors: Español Laureano A. , Palumbo Miranda C. , Barbero Angela M. , Palma Sabina , Serral Federico , Ruggeri Diego , Martí Marcelo A. , Fernández Do Porto Darío , Hernández Del Pino Rodrigo E. , Pasquinelli Virginia
Published: April 2024

Clostridioides difficileis a gram-positive bacterium implicated in antibiotic-associated diarrhea. The use of antibiotics alters the gut microbiota, rendering the host susceptible to infection byC. difficile.This pathogen colonizes the large intestine of humans and animals leading to asymptomatic carriage or clinical manifestations such as toxic megacolon and fulminant colitis depending on a wide range of pathogen and host factors. The emergence of BI/NAP1/027 strains in North America and the spread of these hypervirulent ribotypes worldwide have been linked to the increase in incidence and severity ofC. difficileinfections (CDI) over the last decade. In this work, we aimed to characterize the BI/NAP1/027C. difficilecommercial strain CDC20121308 widely employed in the study of host-pathogen interactions.

The genome sequence was obtained using a whole-genome shotgun strategy. A total of 3,717 coding sequences (CDS) and 45 tRNAs were predicted. The annotation of the CDC20121308 strain identified 26% of CDS into RAST subsystems. We also detected the presence of RT 027 lineage markers such asthyA, cdtA, cdtB and tcdC 18bp-deletion. Moreover, the genome of CDC20121308 had 11 genes devoted to resistance to toxic compounds, antibiotics (e.g. Tetracycline (Tet) and Vancomycin (Van)) and disinfecting agents as predicted using CARD.C. difficileCDC20121308 resistance to Van and Tet was confirmed by broth microdilution assay. Crystal violet staining demonstrated biofilm formation, which could be associated with antibiotic resistance and pathogenicity. Additionally, we observed a spreading diffuse growth in soft agar tubes, suggesting a motile phenotype. Lastly, a genomic region containing Type 4 Secretory System components such as virD4, virB4, and virB6 was identified.

In conclusion, our results allowed a genomic and functional characterization of the BI/NAP1/027C. difficileCDC20121308 strain. We demonstrated the presence of several genes associated with pathogenesis that were validated by experimental assays. This study provides additional data for the use of this highly virulence commercial strain of epidemiological relevance in research works involvingin vitroandin vivoapproaches.
Perturbation-Specific Transcriptional Mapping for unbiased target elucidation of antibiotics
Authors: Romano Keith P , Bagnall Josephine , Warrier Thulasi , Sullivan Jaryd , Ferrara Kristina , Orzechowski Marek , Nguyen Phuong H , Raines Kyra , Livny Jonathan , Shoresh Noam , Hung Deborah T
Published: April 2024

The rising prevalence of antibiotic resistance threatens human health. While more sophisticated strategies for antibiotic discovery are being developed, target elucidation of new chemical entities remains challenging. In the post-genomic era, expression profiling can play an important role in mechanism-of-action (MOA) prediction by reporting on the cellular response to perturbation. However, the broad application of transcriptomics has yet to fulfill its promise of transforming target elucidation due to challenges in identifying the most relevant, direct responses to target inhibition. We developed an unbiased strategy for MOA prediction, called Perturbation-Specific Transcriptional Mapping (PerSpecTM), in which large-throughput expression profiling of wildtype or hypomorphic mutants, depleted for essential targets, enables a computational strategy to address this challenge. We applied PerSpecTM to perform reference-based MOA prediction based on the principle that similar perturbations, whether chemical or genetic, will elicit similar transcriptional responses. Using this approach, we elucidated the MOAs of three new molecules with activity againstPseudomonas aeruginosaby comparing their expression profiles to those of a reference set of antimicrobial compounds with known MOAs. We also show that transcriptional responses to small molecule inhibition resemble those resulting from genetic depletion of essential targets by CRISPRi by PerSpecTM, demonstrating proof-of-concept that correlations between expression profiles of small molecule and genetic perturbations can facilitate MOA prediction when no chemical entities exist to serve as a reference. Empowered by PerSpecTM, this work lays the foundation for an unbiased, readily scalable, systematic reference-based strategy for MOA elucidation that could transform antibiotic discovery efforts.

Significance Statement

New antibiotics are critically needed in the face of increasing antibiotic resistance. However, mechanism-of-action (MOA) elucidation remains challenging and imposes a major bottleneck in antibiotic discovery and development. Building on the principle that molecules with similar MOAs elicit similar transcriptional responses, we have developed a highly scalable strategy for MOA prediction in the important bacterial pathogenPseudomonas aeruginosabased on correlations between the expression profiles of new molecules and known perturbations, either small molecule inhibition by known antibiotics or transcriptional repression of essential targets by CRISPRi. By rapidly assigning MOAs to three new molecules with anti-pseudomonal activity, we provide proof-of-concept for a rapid, comprehensive, systematic, reference-based approach to MOA prediction with the potential to transform antibiotic discovery efforts.
Missing cell types in single-cell references impact deconvolution of bulk data but are detectable
Authors: Ivich Adriana , Davidson Natalie R. , Grieshober Laurie , Li Weishan , Hicks Stephanie C. , Doherty Jennifer A. , Greene Casey S.
Published: April 2024

Advancements in RNA-sequencing have dramatically expanded our ability to study gene expression profiles of biological samples in bulk tissue and single cells. Deconvolution of bulk data with single-cell references provides the ability to study relative cell-type proportions, but most methods assume a reference is present for every cell type in bulk data. This is not true in all circumstances--cell types can be missing in single-cell profiles for many reasons. In this study, we examine the impact of missing cell types on deconvolution methods. Our experimental designs are simulation-based, using paired single-cell and single-nucleus data, since single-nucleus RNA-sequencing is able to preserve the nucleus of cell types that would otherwise be missing in a single-cell counterpart. These datasets allow us to examine the missing-cell-type phenomenon in deconvolution with realistic proportions. We apply three deconvolution methods that vary from straightforward to state-of-the-art: non-negative least squares, BayesPrism, and CIBERSORTx. We find that the performance of deconvolution methods is influenced by both the number and the similarity of missing cell types, consistent with prior results. Additionally, we find that missing cell-type profiles can be recovered from residuals using a simple non-negative matrix factorization strategy. We expect our simulation strategies and results to provide a starting point for those developing new deconvolution methods and help improve their to better account for the presence of missing cell types. Building off of our findings on simulated data, we then analyzed data from high-grade serous ovarian cancer; a tumor that has regions of highly variable levels of adipocytes dependent on the region from which it is sampled. We observe results consistent with simulation, namely that expression patterns from cell types likely to be missing appear present in residuals. Our results suggests that deconvolution methods should consider the possibility of missing cell types and provide a starting point to address this. Our source code for data simulation and analysis is freely available athttps://github.com/greenelab/pred_missing_celltypes.
CAIM: Coverage-based Analysis for Identification of Microbiome
Authors: Acheampong Daniel A. , Jenjaroenpun Piroon , Wongsurawat Thidathip , Krulilung Alongkorn , Pomyen Yotsawat , Kandel Sangam , Kunadirek Pattapon , Chuaypen Natthaya , Kusonmano Kanthida , Nookaew Intawat
Published: April 2024

Accurate taxonomic profiling of microbial taxa in a metagenomic sample is vital to gain insights into microbial ecology. Recent advancements in sequencing technologies have contributed tremendously toward understanding these microbes at species resolution through a whole shotgun metagenomic (WMS) approach. In this study, we developed a new bioinformatics tool, CAIM, for accurate taxonomic classification and quantification within both long- and short-read metagenomic samples using an alignment-based method. CAIM depends on two different containment techniques to identify species in metagenomic samples using their genome coverage information to filter out false positives rather than the traditional approach of relative abundance. In addition, we propose a nucleotide-count based abundance estimation, which yield lesser root mean square error than the traditional read-count approach. We evaluated the performance of CAIM on 28 metagenomic mock communities and 2 synthetic datasets by comparing it with other top-performing tools. CAIM maintained a consitently good performance across datasets in identifying microbial taxa and in estimating relative abundances than other tools. CAIM was then applied to a real dataset sequenced on both Nanopore (with and without amplification) and Illumina sequencing platforms and found high similality of taxonomic profiles between the sequencing platforms. Lastly, CAIM was applied to fecal shotgun metagenomic datasets of 232 colorectal cancer patients and 229 controls obtained from 4 different countries and primary 44 liver cancer patients and 76 controls. The predictive performance of models using the genome-coverage cutoff was better than those using the relative-abundance cutoffs in discriminating colorectal cancer and primary liver cancer patients from healthy controls with a highly confident species markers.

Key Points

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Metagenomic coverage is an important index to obtain highly accurate species identification by reducing false positives from whole shotgun metagenomic data.

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Comparative analyses of CAIM and other bioinformatics tools for species identification on many mock community whole shotgun metagenomic datasets generated by short-read and long-read sequencing and synthetic datasets were performed, showing that CAIM has a very good performance compared with the other tools.

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Using the metagenomic coverage approach through CAIM improves the predictive power of species biomarkers identified from in stool samples of colorectal cancer and primary liver datasets.
ACTN3genotype influences androgen response in skeletal muscle
Authors: Roeszler Kelly N. , See Michael , Meehan Lyra R. , Lima Giscard , Kolliari-Turner Alexander , Alexander Sarah E. , Landen Shanie , Wood Harrison D. , Tiong Chrystal F. , Chen Weiyi , Mustafa Tomris , Houweling Peter J. , Eynon Nir , Lamon Severine , Pitsiladis Yannis , Handelsman David J. , Rossello Fernando J. , Ramialison Mirana , North Kathryn N. , Seto Jane T.
Published: April 2024

Abstract

Androgens are vital for the maintenance of muscle mass and their anabolic effects are primarily exerted through the androgen receptor (AR). Accumulating evidence in humans and mice suggests that circulating androgens, AR and androgen response are influenced byACTN3 (α- actinin-3), also known as “the gene for speed”. One in 5 people worldwide are α-actinin-3 deficient due to homozygous inheritance of a common null polymorphism (577X) inACTN3. In this study, we show that α-actinin-3 deficiency decreases baseline AR in skeletal muscles of mice and humans, in both males and females, and that AR expression directly correlates withACTN3in a dosage dependent manner. We further demonstrate inActn3knockout mice that α- actinin-3 deficiency increases muscle wasting induced by androgen deprivation and reduces the muscle hypertrophic response to dihydrotestosterone and this is mediated by differential activation of pathways regulating amino acid metabolism, intracellular transport, MAPK signalling, autophagy, mitochondrial activity and calcineurin signalling. Gene set enrichment and protein analyses indicate that the absence of α-actinin-3 results in a failure to coactivate many of these pathways in response to changes in androgens, and relies on leveraging mitochondrial remodelling and calcineurin signalling to restore muscle homeostasis. We further identified 7 genes that are androgen sensitive and α-actinin-3-dependent in expression, and whose functions correspond to these processes. Our results highlight the pivotal role of α- actinin-3 in various processes associated with the regulation of protein turnover and muscle mass, and suggest thatACTN3genotype is a genetic modifier of androgen action in skeletal muscle.
Limosilactobacillus fermentumATG-V5 stimulates the immune response by enhancing gut microbiome and metabolite in a cyclophosphamide-induced immunosuppression mouse model
Authors: Park Arum , Park Yeon-Hwa , Kang Yewon , Park Juyi , Park Gun-Seok , Ju Yo-Han , Hwang Won , Kang Jihee
Published: April 2024

Limosilactobacillus fermentumis known to exert immunomodulatory effects. In this study, we elucidated the immunoenhancing effects and mechanisms of a novel strain ofLimosilactobacillus fermentumATG-V5. Our findings demonstrate that ATG-V5 regulates the activation and proliferation of natural killer (NK) and T cells. It induced activation effects such as increased nitric oxide (NO) production, phagocytic capacity, and cytokine generation in Raw264.7 cells, which were confirmed to occur through the ERK and pp65 pathways. Furthermore, using a cyclophosphamide (CPP) mouse model, we demonstrated the immunomodulatory efficacy of ATG-V5, including enhanced activation of NK cells, increased levels of antibodies and cytokine secretion, in mice with immunosuppression induced by CPP. Additionally, by analyzing the gut bacterial community in the mouse model, we confirmed the ability of ATG-V5 consumption to regulate the gut microbiota, thereby substantiating the potential of this strain as a promising immunoenhancing agent.
Birth of protein-coding exons by ancient domestication of LINE retrotransposon
Authors: Kitao Koichi , Ichiyanagi Kenji , Nakagawa So
Published: April 2024

Transposons, occasionally domesticated as novel host protein-coding genes, are responsible for the lineage-specific functions in vertebrates. LINE-1 (L1) is one of the most active transposons in the vertebrate genomes. Despite its abundance, the contribution of L1 to the birth of vertebrate proteins remains unelucidated. Here, we present a novel mechanism for the origination ofde novoproteins, in which the L1 retrotransposons are incorporated into host genes as protein-coding exons by alternative splicing. L1 ORF1 protein (ORF1p) is an RNA-binding protein that binds to L1 RNA and is required for retrotransposition by acting as an RNA chaperone. We identified a splicing variant ofmyosin light chain 4(MYL4) containing an L1 ORF1-derived exon and encoding a chimeric protein of L1 ORF1p and MYL4, named Lyosin. Molecular evolutionary analysis revealed that Lyosin was acquired in the common ancestor of reptiles and birds during the Paleozoic era. The amino acid sequence of Lyosin had undergone purifying selection although it was lost in some lineages, including the Neognathae birds and snakes. The transcripts encoding Lyosin were expressed in the testes of two lizard species, suggesting that its function is different from that of the canonical MYL4 expressed specifically in the heart. Furthermore, sequence searches revealed other evolutionarily conserved chimeric isoforms fused to the L1 ORF1p in three genes in vertebrates. Our findings suggest a novel evolutionary mechanism for the birth of lineage-specific proteins derived from transposons and implicate the previously unrecognized adaptive functions of L1 ORF1p.
Genome of tropical bed bugCimex hemipterus(Cimicidae, Hemiptera) reveals tetraspanin expanded in bed bug ancestor
Authors: Law Sean Tsz Sum , Nong Wenyan , Li Chade , Chong Tze Kiu , Yip Ho Yin , Swale Thomas , Chiu Siu Wai , Chung Roger Yat-Nork , Lam Hon-Ming , Wong Samuel Y.S. , Wong Hung , Hui Jerome H.L.
Published: April 2024

Cimexspecies are ectoparasites that exclusively feed on warm-blooded animals such as birds and mammals. Three cimicid species are known to be persistent pests for humans, including the tropical bed bugC. hemipterus, common bed bugC. lectularius, and Eastern bat bugLeptocimex boueti. To date, genomic information is restricted to the common bed bugC. lectularius, which limits understand their biology and to provide controls of bed bug infestations. Here, a chromosomal-level genome assembly ofC. hemipterus(495 Mb) containing on 16 pseudochromosomes (scaffold N50 = 34 Mb), together with 9 messenger RNA and small RNA transcriptomes were obtained. Comparison between hemipteran genomes, we found that the tetraspanin superfamily were expanded in theCimexancestor. This study provides the first genome assembly for the tropical bed bugC. hemipterus, and offers an unprecedented opportunity to address to questions relating to bed bug infestations, as well as genomic evolution to hemipterans more widely.
Optimal filtering strategies for task-specific functional PET imaging
Authors: Reed Murray Bruce , León Magdalena Ponce de , Klug Sebastian , Milz Christian , Silberbauer Leo Robert , Falb Pia , Godbersen Godber Mathis , Jamadar Sharna , Chen Zhaolin , Nics Lukas , Hacker Marcus , Lanzenberger Rupert , Hahn Andreas
Published: April 2024

Functional Positron Emission Tomography (fPET) has advanced as an effective tool for investigating dynamic processes in glucose metabolism and neurotransmitter action, offering potential insights into brain function, disease progression, and treatment development. Despite significant methodological advances, extracting stimulation-specific information presents additional challenges in optimizing signal processing across both spatial and temporal domains, which are essential for obtaining clinically relevant insights. This study aims to provide a systematic evaluation of state-of-the-art filtering techniques for fPET imaging.

Forty healthy participants underwent a single [18F]FDG PET/MR scan, engaging in the cognitive task Tetris®. Twenty thereof also underwent a second PET/MR session. Eight filtering techniques, including 3D and 4D Gaussian smoothing, highly constrained backprojection (hypr), iterative hypr (Ihypr4D), two MRI-Markov Random Field (MRI-MRF) filters (L=10 and 14 mm neighborhood) as well as static and dynamic Non-Local Means (sNLM and dNLM respectively) approaches, were applied to fPET data. Test-retest reliability (intraclass correlation coefficient), the identifiability of the task signal (temporal signal-to-noise ratio (tSNR)), spatial task-based activation (group level t-values), and sample size calculations were assessed.

Results indicate distinct performance between filtering techniques. Compared to standard 3D Gaussian smoothing, dNLM, sNLM, MRI-MRF L=10 and Ihypr4D filters exhibited superior tSNR, while only dNLM and hypr showed improved test-retest reliability. Spatial task-based activation was enhanced by both NLM filters and MRI-MRF approaches. The dNLM enabled a minimum reduction of 15.4% in required sample size.

The study systematically evaluated filtering techniques in fPET data processing, highlighting their strengths and limitations. The dNLM filter emerges as a promising choice, with improved performance across all metrics. However, filter selection should align with specific study objectives, considering factors like processing time and resource constraints.
ALTERATIONS IN PEROXISOMAL-MITOCHONDRIAL INTERPLAY IN SKELETAL MUSCLE ACCELERATES MUSCLE DYSFUNCTION
Authors: Scalabrin Marco , Turco Eloisa , Nogara Leonardo , Gherardi Gaia , Trani Giulia , Negro Samuele , Romero Anais Franco , Jaspers Yorrick , Baschiera Elisa , De Cegli Rossella , Del Prete Eugenio , Cali Tito , Blaauw Bert , Salviati Leonardo , Rigoni Michela , Mammucari Cristina , Caspar-Bauguil Sylvie , Moro Cedric , Sandri Marco , Kemp Stephan , Romanello Vanina
Published: April 2024

Whole-body energy expenditure, as well as glucose and lipid metabolism, are regulated by skeletal muscles, which account for 40-50% of human body mass. Peroxisomes are dynamic organelles that play a crucial role in lipid metabolism and clearance of reactive oxygen species, however their role in muscles remains poorly understood.

To clarify this issue, we generated a muscle-specific transgenic mouse line with peroxisome import deficiency resulting from deletion of peroxisomal biogenesis factor 5 (Pex5). Pex5 inhibition disrupted the tethering between peroxisomes and mitochondria, impaired lipid metabolism and reduced muscle force and exercise performance. Moreover, mitochondrial content and function were also altered, accelerating age-related structural defects, neuromuscular junction degeneration, and muscle atrophy. Altogether, our findings show the importance of preserving peroxisomal function and their contact sites with mitochondria to maintain muscle health during aging.
Plaque-associated endogenous IgG and its impact on immunohistochemical detection of mouse monoclonal IgG antibodies in mouse models of Alzheimer’s disease
Authors: Ito Shogo , Yamauchi Kenta , Hama Hiroshi , Koike Masato , Miyawaki Atsushi , Hioki Hiroyuki
Published: April 2024

Experimental studies for Alzheimer’s disease (AD) have largely depended on transgenic mice with β-amyloidosis. Here, we report plaque-associated endogenous immunoglobulin G (PA-IgG) and its impact on indirect immunohistochemical detection of mouse monoclonal IgG antibodies (Ms monoclonal IgG Abs) in the brain of AD mouse models. Immunostaining for Ms IgG in AD mouse models demonstrated endogenous IgG in the brain parenchyma accumulated on microglia associated with amyloid β (Aβ) plaques and/or Aβ plaques themselves. This PA-IgG caused robust off-target binding of secondary Abs against Ms IgG (H+L) in indirect immunohistochemistry using Ms monoclonal IgG Abs. Blocking with Fab fragments of anti-Ms IgG (H+L) Ab was not effective against off-target binding. Unexpectedly, we found that secondary Abs that specifically recognize Ms IgG1, 2a, 2b, and 3 did not cause off-target binding on frozen brain sections ofAppNL-G-F/NL-G-Fmice, and enabled specific labeling of Ms monoclonal IgG Abs in the AD mouse model brains. We further demonstrated that indirect detection with a conventional secondary Ab against Ms IgG (H+L) Ab could lead to erroneous conclusions regarding Aβ plaque burden and phosphorylated tau accumulation inAppNL-G-F/NL-G-Fmice, and the use of Ms IgG subclass specific secondary Abs allowed to avoid the inevitable impediment caused by the endogenous IgG accumulation. Specific indirect detection of Ms monoclonal IgG Abs in AD mouse models by the use of secondary Abs against Ms IgG subclass would accelerate AD research by expanding the choice of Abs available for histochemical analysis in AD studies.
Human adipose stromal cells differentiate towards a tendon phenotype with adapted visco-elastic properties in a 3D-culture system
Authors: Hordé Maxime , Fouchard Jonathan , Laffray Xavier , Blavet Cédrine , Béréziat Véronique , Lagathu Claire , Gaut Ludovic , Duprez Delphine , Havis Emmanuelle
Published: April 2024

Tendon cell differentiation relies on molecular and mechanical parameters that control the expression of tendon-associated transcription factors and extracellular matrix proteins. However, the minimal cues able to initiate tendon differentiation from progenitor cells remains unknown. We analysed the tendon differentiation program in human adipose stromal cells (hASCs) cultured in a minimal 3D-system. We generated 3D-hASC constructs by embedding hASCs in a type-I collagen gel under a static uniaxial geometrical constraint with no additional molecular and mechanical cues, and assessed tendon-associated gene expression and mechanical properties for up to three weeks in culture. Analysis of tendon-associated genes revealed a molecular progression consistent with the acquisition of a tendon phenotype. The analysis of viscoelastic properties of 3D-hASC constructs by nano-indentation indicated a progressive increase in tissue stiffness up to 10 kPa, concomitant with a reduced stress relaxation indicative of solid-like mechanical properties. These changes in mechanical properties parallel the molecular change of matrix genes during the time of cultures. In summary, we have established that hASCs cultured in a minimal 3D-system progress into the tendon differentiation program associated with variations of mechanical properties.
CN-model: A dynamic model for the coupled carbon and nitrogen cycles in terrestrial ecosystems
Authors: Stocker Benjamin D. , Prentice I. Colin
Published: April 2024

Reducing uncertainty in carbon cycle projections relies on reliable representations of interactions between the carbon and nutrient cycles. Here, we build on a set of principles and hypotheses, funded in established theoretical understanding and supported by empirical evidence, to formulate and implement a dynamic model of carbon-nitrogen cycle (C-N) interactions in terrestrial ecosystems. The model combines a representation of photosynthetic acclimation to the atmospheric environment with implications for canopy and leaf N, a representation of functional balance for modelling C allocation and growth different tissues, and a representation of plant N uptake based on a first principles-informed, simplified description of solute transport in the soil. Here, we provide a comprehensive description of the model and its implementation and demonstrate the stability and functionality of the model for simulating seasonal variations of ecosystem C and N fluxes and pools. This may provide a way forward for representing key ecosystem processes related to C and N cycling based on established theoretical concepts with strong empirical support.
SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria
Authors: Pellegrini Joaquín Miguel , Keriel Anne , Gorvel Laurent , Hanniffy Sean , Arce-Gorvel Vilma , Bosilkovski Mile , Solera Javier , Méresse Stéphane , Mémet Sylvie , Gorvel Jean-Pierre
Published: April 2024

Plasmacytoid dendritic cells (pDC), professional type I interferon (IFN) producing cells, have been implicated in host responses against bacterial infections. However, their role in host defense is debated and the operating molecular mechanisms are unknown. Certain Signaling Lymphocyte Activation Molecule Family (SLAMF) members act as microbial sensors and modulate immune functions in response to infection. Here by analyzing multiple human blood transcriptomic datasets, we report the involvement of SLAMF7 and SLAMF8 in many infectious diseases, with elevated levels associated with type I IFN responses in salmonellosis and brucellosis patients. We further identify SLAMF7 and SLAMF8 as key regulators of human pDC function. Silencing of these receptors hinders pDC maturation and abrogates cytokine production during infection with acute (Salmonella) or chronic (Brucella) inflammation-inducing bacteria. Mechanistically, we show that SLAMF7 and SLAMF8 signal through NF-κB, IRF7 and STAT-1, and limit mitochondrial ROS accumulation uponSalmonellainfection. This SLAMF7/8-dependent control of mitochondrial ROS levels favors bacterial persistence and NF-κB activation. Overall, our results unravel essential shared roles of SLAMF7 and SLAMF8 in finely tuning human pDC responses to intracellular bacterial infections with high diagnosis and therapeutic perspectives.
Socialization causes long-lasting behavioral changes
Authors: Gil-Martí Beatriz , Isidro-Mézcua Julia , Poza-Rodriguez Adriana , Asti Tello Gerson S. , Treves Gaia , Turiégano Enrique , Beckwith Esteban J. , Martin Francisco A
Published: April 2024

In modern human societies, social isolation acts as a negative factor for health and life quality. On the other hand, social interaction also has profound effects on animal and human behaviors, reducing aggressiveness, feeding and loss of sleep. Here, we observe that in the flyDrosophila melanogasterthese behavioral changes long-last even after social interaction has ceased, suggesting that the socialization experience triggers behavioral plasticity. We find that impairing long-term memory mechanisms either genetically or by anesthesia abolishes the expected behavioral changes in response to social interaction. Furthermore, we show that socialization increases CREB-dependent neuronal activity and synaptic plasticity in the mushroom body, the main insect memory center analogous to mammalian hippocampus. We propose that social interaction triggers socialization awareness, understood as long-lasting changes in behavior caused by experience with mechanistic similarities to long-term memory formation.
Common neural mechanisms supporting time judgements in humans and monkeys
Authors: Rodriguez-Larios Julio , Rassi Elie , Mendoza Germán , Merchant Hugo , Haegens Saskia
Published: April 2024

There has been an increasing interest in identifying the biological underpinnings of human time perception, for which purpose research in non-human primates (NHP) is common. Although previous work, based on behaviour, suggests that similar mechanisms support time perception across species, the neural correlates of time estimation in humans and NHP have not been directly compared. In this study, we assess whether brain evoked responses during a time categorization task are similar across species. Specifically, we assess putative differences in post-interval evoked potentials as a function of perceived duration in human EEG (N = 24) and local field potential (LFP) and spike recordings in pre-supplementary motor area (pre-SMA) of one monkey. Event-related potentials (ERPs) differed significantly after the presentation of the temporal interval between “short” and “long” perceived durations in both species, even when the objective duration of the stimuli was the same. Interestingly, the polarity of the reported ERPs was reversed for incorrect trials (i.e., the ERP of a “long” stimulus looked like the ERP of a “short” stimulus when a time categorization error was made). Hence, our results show that post-interval potentials reflect the perceived (rather than the objective) duration of the presented time interval in both NHP and humans. In addition, firing rates in monkey’s pre-SMA also differed significantly between short and long perceived durations and were reversed in incorrect trials. Together, our results show that common neural mechanisms support time categorization in NHP and humans, thereby suggesting that NHP are a good model for investigating human time perception.
Amblyopic deficits in monocular processing and binocular interactions revealed by submillimeter 7T fMRI and EEG frequency tagging
Authors: Wang Yue , Qian Chencan , Gao Yige , Zhou Yulian , Zhang Xiaotong , Wen Wen , Zhang Peng
Published: April 2024

Disruption of retinal input early in life can lead to amblyopia, a condition characterized by reduced visual acuity despite corrected optics. Although extensive losses of neural activity have been found in the early visual cortex, it remains unclear whether they reflect deficits in feedforward or feedback processing, or abnormal binocular interactions. Combining submillimeter 7T fMRI and EEG frequency tagging, our study revealed the precise neural deficits in monocular processing and binocular interactions in human adults with unilateral amblyopia. Cortical depth-dependent fMRI revealed monocular response deficits in cortical layers of the primary visual cortex (V1) receiving thalamic input, which carried over to the downstream areas (V2-V4) in feedforward processing. Binocular stimulation produced a greater signal loss in the superficial layers of V1, consistent with suppression from the fellow eye by lateral inhibition. EEG data further demonstrate reduced suppression from the amblyopic eye, weakened binocular integration, and delayed monocular and binocular processing. Our results support attenuated and delayed monocular processing in V1 layers receiving thalamic input in human amblyopia, followed by imbalanced binocular suppression and weakened binocular integration in the superficial layers, which further reduced signal strength and processing speed. These precise neural deficits can help developing more targeted and effective treatments for the vision disorder.

Significance

Cortical depth-dependent 7T fMRI and EEG frequency tagging revealed attenuated and delayed neural activity in monocular processing and binocular interactions in human amblyopia. Neural deficits in monocular processing arise from the input layers of V1, followed by imbalanced binocular suppression and weakened binocular integration in the superficial layers. The precise neural deficits at high spatiotemporal resolution can help developing more targeted and effective treatment for amblyopia.

Graphical abstract

This figure illustrates the precise neural deficits of amblyopia in monocular processing and binocular interactions based on the main findings of the current study. Attenuated and delayed neural activity arises from V1 cortical layers receiving thalamic input in monocular processing, followed by imbalanced binocular suppression and weakened binocular integration in the superficial layers, further reducing visual signal strength and processing speed.
Embodiment of an artificial limb in the mouse model
Authors: Hayatou Zineb , Wang Hongkai , Chaillet Antoine , Shulz Daniel E. , Ego-Stengel Valérie , Estebanez Luc
Published: April 2024

Body ownership disorders can be triggered by disease or body damage. Methods to probe limb embodiment are required to address those disorders. This includes the development of neuroprostheses that better integrate into the body scheme of the user. To this end, the “rubber hand illusion” protocol is a key behavioural method to probe the powerful embodiment that can be triggered by congruent somatosensory and visual inputs from the limb.

So far, the neurophysiology of limb embodiment remains poorly known, in part because translating the rubber hand illusion to animal models such as the mouse remains challenging. Yet, mapping out the brain circuits of embodiment thanks to the use of genetic and optogenetic research tools would allow to propose novel embodiment restoration strategies.

Here we show that the rubber hand illusion described in humans can be translated to the mouse forelimb model using an automated, videography-based procedure. We exposed head-fixed mice to a visible, static 3D-printed replica of the right forelimb, while their own forelimb was hidden from their sight. We synchronously brushed their hidden forelimb and the replica. Following these visuo-tactile associations, the replica was visually threatened, and we probed the reaction of the mice using automated tracking of pupils and facial expression. The mice focused significantly more their gaze towards the threatened forelimb replica after receiving synchronous tactile and visual information compared to asynchronous. More generally, across test and control conditions, the mouse pupillary response was consistent with the human overt response to the rubber hand illusion. Thus, our results show that mice exhibit quantifiable behavioural markers of the embodiment of an artificial forelimb.
Exposure to light supresses the activity of the medial and superior amygdala during emotional processing
Authors: Campbell Islay , Aizpurua Jose Fermin Balda , Sharifpour Roya , Paparella Ilenia , Beckers Elise , Berger Alexandre , Koshmanova Ekaterina , Mortazavi Nasrin , Read John , Phillips Christophe , Collette Fabienne , Sherif Siya , Talwar Puneet , Zubkov Mikhail , Lamalle Laurent , Vandewalle Gilles
Published: April 2024

Background

Light can influence several non-image-forming biological effects including the modulation of mood and emotional processing through neural circuitry that remains to be fully established. Rodent data showed that nuclei the amygdala, known to be important to mood regulation and emotional processing, receive direct inputs from the retina and mediate part of the affective impact of light. Here, we wanted to assess whether these animal findings translate to human beings. We determine the dynamics of the impact of light exposure on the activity of the amygdala, and whether the dynamics varied across its volume, during the processing of emotional stimulation.

Methods

We used 7 Tesla functional magnetic resonance imaging to assess the impact of variations in light illuminance on the regional activity of the amygdala in healthy young adults (N = 29; 18 women; 24 ± 3.1y) during an auditory emotional task.

Results

We find that several subregions of the amygdala, including the medial nucleus that receives direct retinal projection, showed a marked and linear reduction of activity with increasing illuminance when processing emotionally charged stimuli.

Conclusion

We speculate that it is through the medial nucleus that light affects the emotional state of healthy individuals. These findings shed more light on the mechanisms that underlie the biological impact of light on the brain and may contribute to the benefits of light therapy in the treatment of mood disorders.
Unveiling the complete invasion history ofD. melanogaster: three horizontal transfers of transposable elements in the last 30 years
Authors: Pianezza Riccardo , Scarpa Almorò , Haider Anna , Signor Sarah , Kofler Robert
Published: April 2024

Transposable elements (TEs) are repetitive sequences capable of mobilizing within genomes, exerting significant influence on evolution throughout the tree of life. Using a novel approach that does not require prior knowledge about the sequence of repeats, we identified three novel TE invasions inD. melanogaster:MLEspread between 1990-2000,Souslikbetween 2009-2012, andTransib1between 2013-2016. We recapitulate prior findings, revealing that a total of 11 TEs invadedD. melanogasterover the past two centuries. Leveraging data from over 1400 arthropod genomes, we provide evidence that the TE invasions were triggered by horizontal transfers, withD. simulansand species of theD. willistonigroup acting as putative donors. Through analysis of∼600 short-read datasets spanning diverse geographic regions, we reveal the rapidity of TE invasions:Transib1swiftly multiplied from three isolated epicenters in 2014 to all investigated populations within just two years. Our findings suggest that anthropogenic activities, facilitating habitat and population expansions ofD. melanogaster, might have accelerated the rate of horizontal transposon transfer as well the spread of the TEs into the worldwide population. Given the significant impact of TEs in genomes and the potential involvement of humans in their dispersal, our research has crucial implications for both evolution and ecology.