bluuebunny/crossref_metadata_2025 huggingface dataset:
Hemoglobin alpha is a redox-sensitive mitochondrial-related protein in T-lymphocytes
Authors: Reed Emily C. , Silva Valeria A. , Giebel Kristen R. , Natour Tamara , Lauten Tatlock H. , Jojo Caroline N. , Schleiker Abigail E. , Case Adam J.
Published: September 2024

Abstract

Hemoglobin subunits, which form the well-characterized, tetrameric, oxygen-carrying protein, have recently been described to be expressed in various non-canonical cell types. However, the exact function of hemoglobin subunits within these cells remains to be fully elucidated. Herein, we report for the first time, the expression of hemoglobin alpha-a1 (Hba-a1) in T-lymphocytes and describe its role as a mitochondrial- associated antioxidant. Within naïve T-lymphocytes, Hba-a1 mRNA and HBA protein are present and highly induced by redox perturbations, particularly those arising from the mitochondria. Additionally, preliminary data using a T-lymphocyte specific Hba-a1 knock-out mouse model indicated that the loss of Hba-a1 led to an exacerbated production of mitochondrial reactive oxygen species and inflammatory cytokines after a stress challenge, further supporting the role of HBA acting to buffer the mitochondrial redox environment. Interestingly, we observed Hba-a1 expression to be significantly upregulated or downregulated depending on T-lymphocyte polarization and metabolic state, which appeared to be controlled by both transcriptional regulation and chromatin remodeling. Altogether, these data suggest Hba-a1 may function as a crucial mitochondrial-associated antioxidant and appears to possess critical and complex functions related to T- lymphocyte activation and differentiation.
TX-Phase: Secure Phasing of Private Genomes in a Trusted Execution Environment
Authors: Dokmai Natnatee , Zhu Kaiyuan , Sahinalp S. Cenk , Cho Hyunghoon
Published: September 2024

Genotype imputation servers enable researchers with limited resources to extract valuable insights from their data with enhanced accuracy and ease. However, the utility of these services is limited for those with sensitive study cohorts or those in restrictive regulatory environments due to data privacy concerns. Although privacy-preserving analysis tools have been developed to broaden access to these servers, none of the existing methods support haplotype phasing, a critical component of the imputation workflow. The complexity of phasing algorithms poses a significant challenge in maintaining practical performance under privacy constraints. Here, we introduce TX-Phase, a secure haplotype phasing method based on the framework of Trusted Execution Environments (TEEs). TX-Phase allows users’ private genomic data to be phased while ensuring data confidentiality and integrity of the computation. We introduce novel data-oblivious algorithmic techniques based on compressed reference panels and dynamic fixed-point arithmetic that comprehensively mitigate side-channel leakages in TEEs to provide robust protection of users’ genomic data throughout the analysis. Our experiments on a range of datasets from the UK Biobank and Haplotype Reference Consortium demonstrate the state-of-the-art phasing accuracy and practical runtimes of TX-Phase. Our work enables secure phasing of private genomes, opening access to large reference genomic datasets for a broader scientific community.
Multilevel selection on individual and group social behaviour in the wild
Authors: Philson Conner S. , Martin Julien G. A. , Blumstein Daniel T.
Published: September 2024

The degree to which phenotypes are shaped by multilevel selection – the theoretical framework proposing natural selection occurs at more than one level of biological organisation – is a classic debate in biology. Though social behaviours are a common theoretical example for multilevel selection, it is unknown if and how multilevel selection acts on sociality in the wild. We studied the relative strength of multilevel selection on both individual behaviour and group social structure, quantified with social networks and 19 years of data from a wild, free-living mammal, the yellow-bellied marmot (Marmota flaviventer). Contextual analysis revealed multilevel selection in specific fitness and life history contexts, with selection for group social structure being just as strong, if not stronger, than individual social behaviour. We also found antagonistic multilevel selection within and between levels, potentially explaining why increased sociality is not as beneficial or heritable in this system comparatively to other social taxa. Thus, the evolutionary dynamics of hierarchal or nested biological traits should be assessed at multiple levels simultaneously to tell a more accurate and comprehensive story. Overall, we provide empirical evidence suggesting that multilevel selection acts on social relationships and structures in the wild, and provide direct evidence for a classic, unanswered question in biology.
Modeling integration site data for safety assessment with MELISSA
Authors: Lin Tsai-Yu , Ceoldo Giacomo , House Kimberley , Welty Matthew , Dang Thao Thi , Klatt Denise , Brendel Christian , Murphy Michael P. , Cornetta Kenneth , Pellin Danilo
Published: September 2024

Gene and cell therapies pose safety concerns due to potential insertional mutagenesis by viral vectors. We introduce MELISSA, a statistical framework for analyzing Integration Site (IS) data to assess insertional mutagenesis risk. MELISSA employs regression models to estimate and compare gene-specific integration rates and their impact on clone fitness. We tested MELISSA under three settings. First, we conducted simulation studies to verify its performance under controlled conditions. Second, we characterized the IS profile of a lentiviral vector on Mesenchymal Stem Cells (MSCs) and compared it with that of Hematopoietic Stem and Progenitor Cells (HSPCs), in addition to comparing the in vitro clonal dynamics of MSCs isolated from alternative tissues. Finally, we applied MELISSA to published IS data from patients enrolled in gene therapy clinical trials, successfully identifying both known and novel genes that drive changes in clone growth through vector integration. MELISSA identifies over– and under-targeted genes, estimates IS impact and explores biological relevance through pathway analysis. This offers a quantitative tool for researchers, clinicians, and regulators to bridge the gap between IS data and safety and efficacy evaluation, facilitating the generation of comprehensive data packages supporting Investigational New Drug (IND) and Biologics License (BLA) applications and the development of safe and effective gene and cell therapies.
Sodium Benzoate Promotes Fat Accumulation and Aging via the SKN-1/Nrf2 Signaling Pathway: Evidence from theCaenorhabditis elegansModel
Authors: Lee Jiah D. , Lee Jiwoo , Vang Jerry , Pan Xiaoping
Published: September 2024

Sodium benzoate (SB) is widely used in food products, cosmetics, and medical solutions due to its antimicrobial properties. While it is generally considered safe and has potential neuroprotective benefits, SB has also been linked to adverse effects, including hepatic oxidative stress and inflammation. However, the potential effects of SB on obesity and aging remain poorly understood. In this study, we investigated the effects of SB on fat accumulation and aging using the nematodeCaenorhabditis elegans(C. elegans) as a model system. Wild-type worms were exposed to various SB concentrations (0%, 0.0004%, 0.0008%, 0.004%, and 0.1%) and 0.016% glucose as a positive control for 72 hours in liquid or on NGM agar plates. Fat accumulation was assessed through the Oil Red O staining, which revealed that SB induced more fat accumulation compared to vehicle control, even at low concentrations, including the dosage of 0.0004%. Lifespan analysis also demonstrated that SB significantly accelerated aging in wild-type worms in a dose-dependent manner. Further investigations found that SKN-1 (an Nrf2 homolog) is necessary for SB-induced fat accumulation and aging. Moreover, SB inhibited the nuclear localization of SKN-1 under oxidative stress conditions. These findings suggest that SB may induce fat accumulation and aging by inhibiting the oxidative stress-mediated SKN-1 signaling pathway.
Antipsychotic-like effects of the selective Rho-kinase 2 inhibitor KD025 in genetic and pharmacological mouse models of schizophrenia
Authors: Tanaka Rinako , Liao Jingzhu , Liu Yue , Zhu Wenjun , Fukuzawa Kisa , Kondo Masamichi , Sawahata Masahito , Mori Daisuke , Mouri Akihiro , Kubota Hisayoshi , Tachibana Daiki , Kobayashi Yohei , Matsuzaki Tetsuo , Nagai Taku , Nabeshima Toshitaka , Kaibuchi Kozo , Ozaki Norio , Mizoguchi Hiroyuki , Yamada Kiyofumi
Published: September 2024

1

Copy number variations in theARHGAP10gene encoding Rho GTPase–activating protein 10 are significantly associated with schizophrenia. ARHGAP10 negatively regulates RhoA/Rho-kinase (ROCK) signaling. We previously demonstrated that fasudil, a non-selective ROCK inhibitor, exhibited antipsychotic-like effects in several mouse models of schizophrenia. ROCK has two subtypes, ROCK1 and ROCK2. ROCK1 is mainly expressed in the thymus and blood, while ROCK2 is predominantly expressed in the brain. Therefore, it is expected that like fasudil, selective ROCK2 inhibitors will exhibit antipsychotic-like effects, accompanied by a lower incidence of adverse effects due to ROCK1 inhibition. Here, we used genetic and pharmacological models of schizophrenia to investigate whether the selective ROCK2 inhibitor KD025 would show antipsychotic-like effects with a favorable adverse effect profile. Oral administration of KD025 suppressed the abnormal increase in the phosphorylation level of myosin phosphatase–targeting subunit 1, a substrate of ROCK, and ameliorated the decreased spine density of layer 2/3 pyramidal neurons in the medial prefrontal cortex ofArhgap10S490P/NHEJ mice. Furthermore, KD025 mitigated the methamphetamine-induced impairment of visual discrimination (VD) inArhgap10S490P/NHEJ and wild-type mice. KD025 also reduced MK-801–induced impairments of VD, novel object recognition, and hyperlocomotion. Regarding side effects that are commonly seen with typical antipsychotics, KD025 did not affect systolic blood pressure and did not induce extrapyramidal symptoms, hyperprolactinemia, or hyperglycemia at the effective dosage in naïve wild-type mice. Taken together, KD025 shows antipsychotic-like effects with a favorable adverse effect profile in genetic and pharmacological mouse models of schizophrenia.
Detection of statistically robust interactions from diverse RNA-DNA ligation data
Authors: Zehr Simonida , Seredinski Sandra , Walsh Emma C. , Bonetti Alessandro , Leisegang Matthias S. , Brandes Ralf P. , Schulz Marcel H. , Warwick Timothy
Published: September 2024

Chromatin-localized RNAs play diverse roles in gene regulation and nuclear architecture. Mapping genome-wide RNA-DNA interactions is possible using a variety of molecular methods, including using bridging oligonucleotides to ligate RNA and DNA in proximity. While molecular methods have progressed, a robust computational method for calling biologically meaningful RNA-DNA interactions from these data is lacking. Herein, we presentRADIAnT, a reads-to-interactions pipeline for analyzing RNA-DNA ligation data.RADIAnTcalls interactions against a dataset-specific, unified background which considers RNA binding site-TSS distance and genomic region bias. By scaling the background by RNA abundance,RADIAnTis sensitive enough to detect specific interactions of lowly expressed transcripts, while remaining specific enough to discount false positive interactions of highly abundant RNAs.RADIAnToutperforms previously proposed methods in the accurate recall of genome-wideMalat1-DNA interactions, and in a use case, was utilized to identify dynamic chromatin-associated RNAs in the physiologically- and pathologically-relevant process of endothelial-to-mesenchymal transition.
Post-transcriptional control of homeostatic B-cell signalling by HuR is required for innate B cell maintenance and function
Authors: Capitan-Sobrino Dunja , Mouysset Mailys , Maloudi Orlane , Aubert Yann , Osma-Garcia Ines C. , Nestor-Martin Maia , Nguyen Trang-My M. , Dunga Greta , Diaz-Muñoz Manuel D.
Published: September 2024

Innate B-1 cells constitute a self-maintained layer of defence for early detection of bacteria, clearance of apoptotic cell debris and removal of autoantigens driving autoimmunity. B-1 cells are originated from foetal tissues but, as opposed to B-2 cells, the molecular mechanisms behind their development and homeostatic maintenance remain largely unknown. Here we demonstrate that post-transcriptional regulation by the RNA binding protein HuR is essential for the homeostatic self-replenishment of innate B-1 cells, the expansion of B-1 cell clones targeting self-antigens and the production of natural autoantibodies. HuR KO B-1 cells fail to express the high levels of surface BCR, TACI and BAFFR required for tonic signalling and cell survival. Mechanistically, HuR binds to the 3’UTRs of mRNAs encoding these surface receptors and of pro-survival molecules, like BCL-2 and MCL-1, promoting their translation into protein. In summary, we reveal the need of post-transcriptional regulation in BCR expression, tonic signalling and homeostatic maintenance of functional B-1 cells.
Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3/BP4 criteria
Authors: Bergquist Timothy , Stenton Sarah L. , Nadeau Emily A.W. , Byrne Alicia B. , Greenblatt Marc S. , Harrison Steven M. , Tavtigian Sean V. , O’Donnell-Luria Anne , Biesecker Leslie G. , Radivojac Predrag , Brenner Steven E. , Pejaver Vikas ,   ClinGen Sequence Variant Interpretation Working Group
Published: September 2024

Purpose

We previously developed an approach to calibrate computational tools for clinical variant classification, updating recommendations for the reliable use of variant impact predictors to provide evidence strength up toStrong. A new generation of tools using distinctive approaches have since been released, and these methods must be independently calibrated for clinical application.

Method

Using our local posterior probability-based calibration and our established data set of ClinVar pathogenic and benign variants, we determined the strength of evidence provided by three new tools (AlphaMissense, ESM1b, VARITY) and calibrated scores meeting each evidence strength. Results

All three tools reached theStronglevel of evidence for variant pathogenicity andModeratefor benignity, though sometimes for few variants. Compared to previously recommended tools, these yielded at best only modest improvements in the tradeoffs of evidence strength and false positive predictions.

Conclusion

At calibrated thresholds, three new computational predictors provided evidence for variant pathogenicity at similar strength to the four previously recommended predictors (and comparable with functional assays for some variants). This calibration broadens the scope of computational tools for application in clinical variant classification. Their new approaches offer promise for future advancement of the field.
Mitigating Cellular Dysfunction by Addressing Contaminants in Synthetic circRNA
Authors: Zhang Ziwei , Li Weiyu , Luo Dengwang , Yuan Xiushuang , Yu Li , Wang Daming , Cao Yuhong
Published: September 2024

Synthetic circular RNA (circRNA) shows great potential in biomedical research and therapies, but impurities introduced during its synthesis can undermine circRNA efficacy. This study investigated the immunogenic potential of byproducts generated during its production. We found that trace amounts of double-stranded RNA in high molecular weight impurities, 5’ triphosphates of uncircularized RNA or small intron fragments, and hydrolyzed RNA fragments significantly impact the functionality of circRNA by activating innate immune responses through the sensory molecules involved in RNA sensing. To address this, we developed a novel multi-step purification process that employs enzymatic treatments and cellulose-based filtration to selectively remove these detrimental contaminants. This tailored approach minimizes cellular immune reactions and substantially improves circRNA yields with up to more than 10 times increase. Our findings underscore the critical impact of precise contaminant management in enhancing the expression and potential therapeutic utility of circRNA. This suggests a new direction for optimizing their production for both research and clinical applications.
BrainSTEM: A multi-resolution fetal brain atlas to assess the fidelity of human midbrain cultures
Authors: Toh Hilary SY , Xu Lisheng , Chen Carissa , Yang Pengyi , Sun Alfred X , Ouyang John F
Published: September 2024

Many midbrain dopaminergic neuron (mDA) differentiation protocols aimed at Parkinson’s disease (PD) modeling and cell replacement therapy have been developed. However, comprehensive evaluations of the transcriptomic fidelity of these protocols at the single-cell level against a commonin vivoreference have been lacking. To this end, we constructed an integrated human fetal whole-brain atlas and a midbrain subatlas to use as a standard of comparison. From the whole-brain atlas, we observed distinct brain-region-specific gene expression in most neural cell types, emphasizing the need to first evaluatein vitroprotocols at the whole-brain level to identify midbrain-associated cells. These cells are then mapped to the midbrain subatlas for more refined neuronal subtype specification and trajectory analysis specific to the midbrain. We surveyed all publicly available single-cell datasets of human midbrain culture models and performed the two-tier mapping. Using this biologically-driven multi-resolution mapping strategy which we termed BrainSTEM (brain Single-cell Two tiEr Mapping), we confirmed the presence of multiple midbrain cell types (‘on-target’), but also a substantial proportion of cells associated with non-midbrain regions and subtypes (‘off-target’). This leads to an overall ‘inflation’ of mDA presence, stemming from non-midbrain-associated cells, across all published protocols. BrainSTEM thus offers an unbiased framework for understanding the current state of midbrain models and aids the improvement of midbrain differentiation protocols for PD studies.
The dynamics of capillary flow in an open-channel system featuring trigger valves
Authors: Tokihiro Jodie C. , Robertson Ingrid H. , Gregucci Denise , Shin Albert , Michelini Elisa , Nicholson Tristan M. , Olanrewaju Ayokunle , Theberge Ashleigh B. , Berthier Jean , Berthier Erwin
Published: September 2024

Trigger valves are fundamental features in capillary-driven microfluidic systems that stop fluid at an abrupt geometric expansion and release fluid when there is flow in an orthogonal channel connected to the valve. The concept was originally demonstrated in closed-channel capillary circuits. We show here that trigger valves can be successfully implemented in open channels. We also show that a series of open-channel trigger valves can be placed alongside or opposite a main channel resulting in a layered capillary flow. We developed a closed form model for the dynamics of the flow at trigger valves based on the concept of average friction length and successfully validated the model against experiments. For the main channel, we discuss layered flow behavior in the light of the Taylor-Aris dispersion theory and in the channel turns by considering Dean theory of mixing. This work has potential applications in autonomous microfluidics systems for biosensing, at-home or point-of-care sample preparation devices, hydrogel patterning for 3D cell culture and organ-on-a-chip models.
A new comparative framework for estimating selection on synonymous substitutions
Authors: Verdonk Hannah , Pivirotto Alyssa , Pavinato Vitor , Hey Jody , Pond Sergei LK
Published: September 2024

Selection on synonymous codon usage is a well known and widespread phenomenon, yet existing models often do not account for it or its effect on synonymous substitution rates. In this article, we develop and expand the capabilities of Multiclass Synonymous Substitution (MSS) models, which account for such selection by partitioning synonymous substitutions into two or more classes and estimating a relative substitution rate for each class, while accounting for important confounders like mutation bias. We identify extensive heterogeneity among relative synonymous substitution rates in an empirical dataset of ∼12,000 gene alignments from twelveDrosophilaspecies. We validate model performance using data simulated under a forward population genetic simulation, demonstrating that MSS models are robust to model misspecification. MSS rates are significantly correlated with other covariates of selection on codon usage (population-level polymorphism data and tRNA abundance data), suggesting that models can detect weak signatures of selection on codon usage. With the MSS model, we can now study selection on synonymous substitutions in diverse taxa, independent of anya prioriassumptions about the forces driving that selection.
Reconstruction of ancestral protein sequences using autoregressive generative models
Authors: De Leonardis Matteo , Pagnani Andrea , Barrat-Charlaix Pierre
Published: September 2024

Ancestral sequence reconstruction (ASR) is an important tool to understand how protein structure and function changed over the course of evolution. It essentially relies on models of sequence evolution that can quantitatively describe changes in a sequence over time. Such models usually consider that sequence positions evolve independently from each other and neglect epistasis: the context-dependence of the effect of mutations. On the other hands, the last years have seen major developments in the field of generative protein models, which learn constraints associated with structure and function from large ensembles of evolutionarily related proteins. Here, we show that it is possible to extend a specific type of generative model to describe the evolution of sequences in time while taking epistasis into account. We apply the developed technique to the problem of Ancestral Sequence Reconstruction (ASR): given a protein family and its evolutionary tree, we try to infer the sequences of extinct ancestors. Using both simulations and data coming from experimental evolution we show that our method outperforms state-of-the-art ones. Moreover, it allows for sampling a greater diversity of potential ancestors, allowing for a less biased characterization of ancestral sequences.
Entangled Evolution Model: Application to Adaptive Mutation
Authors: Ross Patrick
Published: September 2024

Adaptive mutation, the phenomenon where organisms appear to increase beneficial mutation rates in response to environmental stress, has challenged the traditional understanding of random mutations in evolutionary biology. Here, we present a novel computational model, the Entangled Evolution Model, which integrates quantum game theory and quantum walks to provide a new approach to understanding mutation dynamics. By applying the Clauser-Horne-Shimony-Holt (CHSH) quantum game within a modified Lotka-Volterra framework, we simulate how quantum entanglement can accelerate the rate of adaptive mutations inEscherichia colipopulations. Our simulations reveal that entangled bacterial populations achieve successful adaptive mutations with an 85% probability, significantly surpassing the classical theoretical maximum. These results introduce a new perspective on computational approaches to evolutionary adaptation, offering an efficient algorithmic framework to explore the role of quantum effects in biological systems.
Ex vivoDHA supplementation suppresses prostaglandin E2 formation in primary human macrophages
Authors: Kirchhoff Rebecca , Kampschulte Nadja , Rothweiler Carina , Rohwer Nadine , Weylandt Karsten-Henrich , Schebb Nils Helge
Published: September 2024

Scope

There is evidence that intake of long-chain n-3 polyunsaturated fatty acids (PUFA) is associated with improved prognosis for inflammatory diseases. However, the underlying mechanisms are still subject of ongoing research. For this purpose, we developed anex vivon-3 PUFA supplementation strategy to test n-3 PUFA supplementation under controlled conditions in primary human macrophages.

Methods and results

Cells were supplemented with docosahexaenoic acid (DHA). Quality parameters to account for possible confounders were established for a reproducible and reliable supplementation. Following supplementation, PUFA pattern of cells was shifted towards a pattern reflecting that of subjects with a high n-3 PUFA status. This was accompanied by a decrease of arachidonic acid-derived oxylipins in a dose- and time-dependent manner in favor of n-3 PUFA ones. Stimulation with LPS resulted in decreased levels of pro-inflammatory prostaglandins in the DHA-supplemented cells, but no changes in cytokines.

Conclusion

In vitrosupplementation studies with n-3 PUFA need rigorous controls to exclude background formation of oxylipins. By accounting for these possible confounders the desribedex vivoapproach is a promising tool for the mechanistic investigation of n-3 PUFA in primary human immune cells, offering an alternative for intervention studies in humans.
Beyond associations: A benchmark Causal Relation Extraction Dataset (CRED) of disease-causing genes, its comparative evaluation, interpretation and application
Authors: Bansal Nency , Sri Dhinesh R C , Pathak Ayush , Narayanan Manikandan
Published: September 2024

Information on causal relationships is essential to many sciences (including biomedical science, where knowing if a gene-disease relation is causal vs. merely associative can lead to better treatments); and can foster research on causal side-information-based machine learning as well. Automatically extracting causal relations from large text corpora remains less explored though, despite much work on Relation Extraction (RE). The few existing CRE (Causal RE) studies are limited to extracting causality within a sentence or for a particular disease, mainly due to the lack of a diverse benchmark dataset. Here, we carefully curate a new CRE Dataset (CRED) of 3553 (causal and non-causal) gene-disease pairs, spanning 284 diseases and 500 genes, within or across sentences of 267 published abstracts. CRED is assembled in two phases to reduce class imbalance and its inter-annotator agreement is 89%. To assess CRED’s utility in classifying causal vs. non-causal pairs, we compared multiple classifiers and found SVM to perform the best (F1 score 0.70). Both in terms of classifier performance and model interpretability (i.e., whether the model focuses importance/attention on words with causal connotations in abstracts), CRED outperformed a state-of-the-art RE dataset. To move from benchmarks to real-world settings, our CRED-trained classification model was applied on all PubMed abstracts on Parkinson’s disease (PD). Genes predicted to be causal for PD by our model in at least 50 abstracts got validated in textbook sources. Besides these well-studied genes, our model revealed less-studied genes that could be explored further. Our systematically curated and evaluated CRED, and its associated classification model and CRED-wide gene-disease causality scores, thus offer concrete resources for advancing future research in CRE from biomedical literature.
Optimizing the use of cryopreserved genetic resources for the selection and conservation of animal populations
Authors: Jacques Alicia , Tixier-Boichard Michèle , Restoux Gwendal
Published: September 2024

Abstract

Background

Genetic diversity is essential for the sustainability and adaptability of populations, and is thus a central pillar of the agro-ecological transition. However, within a population it is inevitable that some amount of genetic variability is lost, and efforts must be made to limit this as much as possible. A valuable tool in this endeavor could be the use of cryopreserved genetic resources in cryobanks, which could assist in the management of various animal populations in the contexts of both selection and conservation.

Results

We performed simulations that revealed that the most appropriate use ofex situgenetic resources differs radically depending on characteristics of the target population and its management objectives. With populations under conservation, the aim is the management of genetic diversity, which was optimized by the regular use of cryopreserved genetic resources at each generation. For populations under selection, instead, the concern is the addition of additive genetic variability, which benefited from the use of cryopreserved collections over only a few generations based primarily on the genetic values of donors. In both cases, the use of cryopreserved individuals in animal populations requires a large amount of material: for breeds under selection because the number of offspring is high, and for breeds under conservation because the frozen semen is used repeatedly over a long period.

Conclusions

The use of cryopreserved material appears to be an effective means of managing the genetic variability of an animal population, either by slowing down the erosion of variability or by helping to redirect a selection objective. However, care must be taken with populations under selection to limit the disadvantages associated with the reintroduction of old genetic material, in particular the gap in breeding values for traits of interest. Finally, our study highlights the need for a sufficiently large stock of cryopreserved material in collections (e.g., number of doses, straws) to ensure the most efficient use.
BirdNET is as good as experts for acoustic bird monitoring in a European city
Authors: Fairbairn Andrew J. , Burmeister Josija-Simeon , Weisser Wolfgang W. , Meyer Sebastian T.
Published: September 2024

BirdNET has become a leading AI for recognising bird species in audio recordings. However, the effect of parameter settings on the algorithm’s performance is not well understood, leaving questions about its applicability in ecological research. We compared the species identification of BirdNET against expert identification using an acoustic dataset consisting of 930 minutes of recordings collected in Munich, Germany. The performance of BirdNET was evaluated using three performance metrics: precision, recall, and F1-score. The metrics were calculated using 24 combinations of the parameters week, sensitivity, and overlap at four temporal aggregations, to also test the effects of recording length. We found that BirdNET closely matched expert identification, particularly when given more data (higher temporal aggregation) and when including the parameters week of the year, a suitable sensitivity, and an overlap of one to two seconds. Thus, our study shows that BirdNET can provide species lists and richness comparable to that of expert ornithologists in acoustic surveys in urban environments. We provide a set of recommendations and parameter settings for BirdNET.
Differences in growth features between species are driving cereal-legume intercrop yield: a statistical learning approach based on aggregated dataset
Authors: Mahmoud Rémi , Gaudio Noémie , Gendre Xavier , Hilgert Nadine , Casadebaig Pierre
Published: September 2024

Increasing crop diversification is crucial for developing more sustainable agricultural systems, and cereal-legume intercropping is a promising strategy. This study investigates the factors influencing the yield of cereal-legume intercrops using data from six field experiments in southwestern France, where durum wheat was intercropped with either faba bean or pea. We assessed how differences in plant traits between the associated species (e.g., height or biomass growth rates) are related to the intercrop productivity. Additionally, we developed a novel modeling approach, combining machine learning and mixed-effects models, to identify the key traits driving intercrop performance based on variable importance.

Our results show that interspecific differences in plant traits, particularly in biomass accumu-lation rate, maximum leaf area index, and elongation rate, were the most important factors explaining intercrop yield. These traits and their differences mainly suggest that compet-itive processes shape the outcome of a mixture and highlight the importance of dynamic measurements in agronomic experiments. The relationship between species yield and trait differences was symmetric for both intercropped species. Furthermore, these relationships were scale-dependent, with trends observed at the aggregate level not always consistent at the level of individual experiments.

Our study highlights the importance of considering trade-offs when designing intercropping systems for practical applications and demonstrates the value of combining machine learning with ecological knowledge to gain insights into complex agricultural systems from aggregated datasets.

Highlights

Joint analysis of experimental datasets provided new insights into crop mixtures func-tioning.

Differences in growth traits between species in the mixture predicted their perfor-mance.

The strength of the correlation between performance and trait distance was similar for both species.

Farmers and researchers need to consider trade-offs when designing intercropping sys-tems.
Single-cell Landscape of Immune Cells in Blood and Skin in Psoriasis
Authors: Deng Jingwen , Nordkamp Michel Olde , Ye Shuyan , Yu Jingjie , Balak Deepak , Yu Wanlin , Radstake Timothy , Borghans José A. M. , Lu Chuanjian , Pandit Aridaman , Gerritsen Bram
Published: September 2024

Background

Psoriasis is a systemic inflammatory disease for which there is currently no cure, in part due to an incomplete understanding of its pathophysiology.

Methods

To better understand the immune response in psoriasis, we performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) and on lesional and non-lesional skin samples from a cohort of 11 psoriasis patients and 8 healthy controls. Additionally, we conducted flow cytometry on PBMCs from a separate cohort of 13 psoriasis patients and 11 ankylosing spondylitis.

Findings

Our study revealed altered immune signatures of specific myeloid and lymphocyte subsets in blood and skin, both in terms of cell numbers and gene expression. Specifically, we discovered elevated proportions of circulating CD14++monocytes, increased expression of major histocompatibility complex (MHC) class II molecule by circulating CD16+monocytes, as well as increased expression of genes related to skin homing and to pro-inflammatory responses in psoriasis by circulating plasmacytoid dendritic cells (pDCs). Circulating CD8+T effector memory cells in psoriasis patients exhibited reduced abundance but increased skin-homing potential. In psoriatic lesions, we observed a hyperinflammatory myeloid-cell state and enrichment of IL17-producing cells with a tissue-resident memory T-cell signature.

Interpretation

The changes in immune cell numbers and gene expression indicate a significant alteration in the immune landscape of psoriasis patients. This suggests that the immune system in psoriasis is reprogrammed, affecting both innate and adaptive branches. These findings provide new insights into the aberrant immune-cell signatures in the circulation and skin lesions in psoriasis, and thereby help to understand its pathophysiology.

Funding

This study was financially supported by the National Natural Science Foundation of China (U23A6012), Science and Technology Planning Project of Guangzhou (2024A03J0055, 202206080005), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202204).
Evaluation of genomic and phenomic prediction for application in apple breeding
Authors: Jung Michaela , Hodel Marius , Knauf Andrea , Kupper Daniela , Neuditschko Markus , Bühlmann-Schütz Simone , Studer Bruno , Patocchi Andrea , Broggini Giovanni AL
Published: September 2024

Apple breeding schemes can be improved by using genomic prediction models to forecast the performance of breeding material. These models’ predictive ability depends on factors like trait genetic architecture, training set size, relatedness of the selected material to the training set, and the validation method used. Alternative genotyping methods such as RADseq and complementary data from near-infrared spectroscopy could help improve the cost-effectiveness of genomic selection. However, the impact of these factors and alternative approaches on predictive ability beyond experimental populations still need to be investigated. In this study, we evaluated 137 prediction scenarios varying the described factors and alternative approaches, offering recommendations for implementing genomic selection in apple breeding. Our results show that extending the training set with germplasm related to the predicted breeding material can improve average predictive ability across eleven studied traits by up to 0.08. The study emphasizes the usefulness of leave-one-family-out validation, reflecting the application of genomic selection to a new family, although it reduced average predictive ability across traits by up to 0.24 compared to cross-validation. Similar average predictive abilities across traits indicate that imputed RADseq data could be a suitable genotyping alternative to SNP array datasets. The best-performing scenario using near-infrared spectroscopy data for phenomic prediction showed a 0.35 decrease in average predictive ability across traits compared to conventional genomic prediction, suggesting that the tested phenomic selection approach is impractical. These findings offer valuable guidance for applying genomic selection in apple breeding, ultimately leading to the development of breeding material with improved quality.
The evolution, diversity, and genetic architecture of sex in waterhemp (Amaranthus tuberculatus)
Authors: Kreiner Julia M. , Todesco Marco , Bercovich Natalia , Gong Yunchen , Elphinstone Cassandra , Tranel Patrick J. , Rieseberg Loren H. , Wright Stephen I.
Published: September 2024

The evolution of separate sexes is hypothesized to occur through distinct pathways involving few large-effect or many small-effect alleles. However, the genetic architecture of sex may itself evolve through selection to suppress recombination in order to maintain beneficial combinations of alleles, potentially at the cost of losing functional genetic variation. To explore these processes, we leveraged the recent transition ofAmaranthus tuberculatusto dioecy within a predominantly monoecious genus, along with a sex-phenotyped population genomic dataset, and six newly generated chromosome-level haplotype phased assemblies. We identify a ~4 Mb region strongly associated with sex through genotype and sequence-depth based analyses. Comparative genomics of these proto-sex chromosomes within the species and across the Amaranthus genus demonstrates remarkable variability in their structure and genic content, including numerous polymorphic inversions. No such inversion underlies the extended linkage we observe associated with sex determination. Instead, we identify a complex copy number polymorphism that is differentiated across sexes, is variable across ancestral lineages, geographical scales, and habitats, but incompletely explains sex as phenotyped--over 10% of individuals show phenotype-genotype mismatch in the sex-linked region. Together with our novel observation of leakiness in expression of sex within the species, these findings imply the presence of multiple interacting determinants of sex. The evolution of separate sexes and its genetic architecture inA. tuberculatustherefore appears to be ongoing, with modifiers of sex that permit gene exchange and the maintenance of diversity in proto-sex chromosomes.
Tenascin-C in the early lung cancer tumor microenvironment promotes progression through integrin αvβ1 and FAK
Authors: Samson Shiela C. , Rojas Anthony , Zitnay Rebecca G. , Carney Keith R. , Hettinga Wakeiyo , Schaelling Mary C. , Sicard Delphine , Zhang Wei , Gilbert-Ross Melissa , Dy Grace K. , Cavnar Michael J. , Furqan Muhammad , Browning Robert F. , Naqash Abdul R. , Schneider Bryan P. , Tarhini Ahmad , Tschumperlin Daniel J. , Venosa Alessandro , Marcus Adam I. , Emerson Lyska L. , Spike Benjamin T. , Knudsen Beatrice S. , Mendoza Michelle C.
Published: September 2024

Pre-cancerous lung lesions are commonly initiated by activating mutations in the RAS pathway, but do not transition to lung adenocarcinomas (LUAD) without additional oncogenic signals. Here, we show that expression of the extracellular matrix protein Tenascin-C (TNC) is increased in and promotes the earliest stages of LUAD development in oncogenic KRAS-driven lung cancer mouse models and in human LUAD. TNC is initially expressed by fibroblasts and its expression extends to tumor cells as the tumor becomes invasive. Genetic deletion of TNC in the mouse models reduces early tumor burden and high-grade pathology and diminishes tumor cell proliferation, invasion, and focal adhesion kinase (FAK) activity. TNC stimulates cultured LUAD tumor cell proliferation and migration through engagement of αv-containing integrins and subsequent FAK activation. Intringuingly, lung injury causes sustained TNC accumulation in mouse lungs, suggesting injury can induce additional TNC signaling for early tumor cell transition to invasive LUAD. Biospecimens from patients with stage I/II LUAD show TNC in regions of FAK activation and an association of TNC with tumor recurrence after primary tumor resection. These results suggest that exogenous insults that elevate TNC in the lung parenchyma interact with tumor-initiating mutations to drive early LUAD progression and local recurrence.
Advancing Clinical Response Against Glioblastoma: Evaluating SHP1705 CRY2 Activator Efficacy in Preclinical Models and Safety in Phase I Trials
Authors: Chan Priscilla , Nagai Yoshiko , Wu Qiulian , Hovsepyan Anahit , Mkhitaryan Seda , Wang Jiarui , Karapetyan Gevorg , Kamenecka Theodore , Solt Laura A. , Cope Jamie , Moats Rex A. , Hirota Tsuyoshi , Rich Jeremy N. , Kay Steve A.
Published: September 2024

Background

It has been reported that circadian clock components, Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), are uniquely essential for glioblastoma (GBM) stem cell (GSC) biology and survival. Consequently, we developed a novel Cryptochrome (CRY) activator SHP1705, which inhibits BMAL1-CLOCK transcriptional activity.

Methods

We analyzed buffy coats isolated from Phase 1 clinical trial subjects’ blood to assess any changes to circadian, housekeeping, and blood transcriptome-based biomarkers following SHP1705 treatment. We utilized GlioVis to determine which circadian genes are differentially expressed in non-tumor versus GBM tissues. We employedin vitroandin vivomethods to test the efficacy of SHP1705 against patient-derived GSCs and xenografts in comparison to earlier CRY activator scaffolds. Additionally, we applied a novel-REV-ERB agonist SR29065, which inhibitsBMAL1transcription, to determine whether targeting both negative limbs of the circadian transcription-translation feedback loop (TTFL) would yield synergistic effects against various GBM cells.

Results

SHP1705 is safe and well-tolerated in Phase I clinical trials. SHP1705 has increased selectivity for the CRY2 isoform and potency against GSC viability compared to previously published CRY activators. SHP1705 prolonged survival in mice bearing GBM tumors established with GSCs. When combined with the novel REV-ERB agonist SR29065, SHP1705 displayed synergy against multiple GSC lines and differentiated GSCs (DGCs).

Conclusions

These demonstrate the efficacy of SHP1705 against GSCs, which pose for GBM patient outcomes. They highlight the potential of novel circadian clock compounds in targeting GBM as single agents or in combination with each other or current standard-of-care.

KEY POINTS

SHP1705 is a novel CRY2 activator that has shown success in Phase 1 safety trials

SHP1705 has a significantly improved efficacy against GSCs and GBM PDX tumors

Novel REV-ERB agonist SR29065 and SHP1705 display synergistic effects against GSCs

IMPORTANCE OF THE STUDY

CRY2is decreased in GBM tissues compared toCRY1suggesting that promoting CRY2 activity will be an efficacious GBM treatment paradigm. SHP1705, a CRY2 activator that has shown success in Phase 1 safety trials, has significantly improved preclinical efficacy. Novel REV-ERB agonist SR29065 displays synergistic effects against diverse GBM cells.
Myofiber-specific FoxP1 knockout protects against pancreatic cancer-induced muscle wasting in male but not female mice
Authors: Schonk Martin M , Ducharme Jeremy B , Neyroud Daria , Nosacka Rachel L , Tucker Haley O , Judge Sarah M , Judge Andrew R
Published: September 2024

Cancer cachexia affects up to 80% of cancer patients and results in reduced quality of life and survival. We previously demonstrated that the transcriptional repressor Forkhead box P1 (FoxP1) is upregulated in skeletal muscle of cachectic mice and people with cancer, and when overexpressed in skeletal muscle is sufficient to induce pathological features characteristic of cachexia. However, the role of myofiber-derived FoxP1 in both normal muscle physiology and cancer-induced muscle wasting remains largely unexplored. To address this gap, we generated a conditional mouse line with myofiber-specific ablation of FoxP1 (FoxP1SkmKO) and found that in cancer-free mice, deletion of FoxP1 in skeletal myofibers resulted in increased myofiber size in both males and females, with a significant increase in muscle mass in males. In response to murine KPC pancreatic tumor burden, we found that myofiber-derived FoxP1 is required for cancer-induced muscle wasting and diaphragm muscle weakness in male mice. In summary, our findings identify myofiber-specific FoxP1 as a negative regulator of skeletal muscle with sex-specific differences in the context of cancer.

NEW & NOTEWORTHY

Here we identify myofiber-derived FoxP1 as a negative regulator of skeletal muscle with sex-specific effects in cancer. Under cancer-free conditions, FoxP1 knockout increased myofiber size in male and female mice. However, in response to pancreatic cancer, FoxP1 was required for muscle wasting and weakness in males but not females. This highlights the need to consider sexual dimorphism in cancer-induced muscle pathologies and provides evidence suggesting that targeting FoxP1 could help mitigate these effects in males.
Inactivity-mediated molecular adaptations: insights from a pre-clinical model of physical activity reduction
Authors: Meyer Alice , Kim Nicole , Nguyen Melissa , Misch Monica , Marmo Kevin , Dowd Jacob , Will Christian , Janosevic Milica , Stephenson Erin J
Published: September 2024

Insufficient physical activity is associated with increased relative risk of cardiometabolic disease and is an independent risk factor for mortality. Experimentally reducing physical activity rapidly induces insulin resistance, impairs glucose handling, and drives metabolic inflexibility. These adaptations manifest during the early stages of physical inactivity, even when energy balance is maintained, suggesting that inactivity-mediated metabolic reprogramming is an early event that precedes changes in body composition. To identify mechanisms that promote metabolic adaptations associated with physical inactivity, we developed a mouse model of physical activity reduction that permits the study of inactivity in animals prior to the onset of overt changes in body composition. Adult mice were randomized into three groups: an inactive control group (standard rodent housing), an active control group (treadmill running 5 d/week for 6-weeks), and an activity reduction group (treadmill running for 4-weeks, followed by 2-weeks of inactivity). Transcriptional profiling of gastrocnemius muscle identified seven transcripts uniquely altered by physical activity reduction compared to the inactive and active control groups. Most identified transcripts had reported functions linked to bioenergetic adaptation. Future studies will provide deeper characterization of the function(s) of each the identified transcripts while also determining how inactivity affects transcriptional regulation in other tissues.