bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunosuppression is a conserved driver of tuberculosis susceptibility
Authors: Kotov Dmitri I. , Lee Ophelia V. , Ji Daisy X. , Jaye David L. , Suliman Sara , Gabay Cem , Vance Russell E.
Published: November 2023

Mycobacterium tuberculosis(Mtb) causes 1.6 million deaths a year1. However, no individual mouse model fully recapitulates the hallmarks of human tuberculosis disease. Here we report that a comparison across three different susceptible mouse models identifiesMtb-induced gene signatures that predict active TB disease in humans significantly better than a signature from the standard C57BL/6 mouse model. An increase in lung myeloid cells, including neutrophils, was conserved across the susceptible mouse models, mimicking the neutrophilic inflammation observed in humans2,3. Myeloid cells in the susceptible models and non-human primates exhibited high expression of immunosuppressive molecules including the IL-1 receptor antagonist, which inhibits IL-1 signaling. Prior reports have suggested that excessive IL-1 signaling impairsMtbcontrol4–6. By contrast, we found that enhancement of IL-1 signaling via deletion of IL-1 receptor antagonist promoted bacterial control in all three susceptible mouse models. IL-1 signaling enhanced cytokine production by lymphoid and stromal cells, suggesting a mechanism for IL-1 signaling in promotingMtbcontrol. Thus, we propose that myeloid cell expression of immunosuppressive molecules is a conserved mechanism exacerbatingMtbdisease in mice, non-human primates, and humans.
Detection, characterization, and phylogenetic analysis of a near-whole genome sequence of a novel astrovirus in an endemic Malagasy fruit bat,Rousettus madagascariensis
Authors: Horigan Sophia , Kistler Amy , Ranaivoson Hafaliana Christian , Andrianianina Angelo , Andry Santino , Kettenburg Gwenddolen , Raharinosy Vololoniaina , Randriambolamanantsoa Tsiry Hasina , Tato Cristina M. , Lacoste Vincent , Heraud Jean-Michel , Dussart Philippe , Brook Cara E.
Published: November 2023

Bats (order:Chiroptera) are known to host a diverse range of viruses, some of which present a public health risk. Thorough viral surveillance is therefore essential to predict and potentially mitigate zoonotic spillover. Astroviruses (family:Astroviridae) are an understudied group of viruses with a growing amount of indirect evidence for zoonotic transfer. Astroviruses have been detected in bats with significant prevalence and diversity, suggesting that bats may act as important astrovirus hosts. Most astrovirus surveillance in wild bat hosts has, to date, been restricted to single-gene PCR detection and concomitant Sanger sequencing; additionally, many bat species and many geographic regions have not yet been surveyed for astroviruses at all. Here, we use metagenomic Next Generation Sequencing (mNGS) to detect astroviruses in three species of Madagascar fruit bats,Eidolon dupreanum, Pteropus rufus,andRousettus madagascariensis. We detect numerous partial sequences from all three species and one near-full length astrovirus sequence fromRousettus madagascariensis, which we use to characterize the evolutionary history of astroviruses both within bats and the broader mammalian clade,Mamastrovirus. Taken together, applications of mNGS implicate bats as important astrovirus hosts and demonstrate novel patterns of bat astrovirus evolutionary history, particularly in the Southwest Indian Ocean region.
HeterozygousKmt2dloss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation
Authors: Dhar Shilpa S. , Brown Calena , Rizvi Ali , Reed Lauren , Kotla Sivareddy , Zod Constantin , Abraham Janak , Abe Jun-Ichi , Rajaram Veena , Chen Kaifu , Lee Min Gyu
Published: November 2023

The histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in medulloblastoma (MB) and many other types of cancer. Notably, heterozygous loss ofKMT2Dis prevalent in MB and other cancer types. However, what role heterozygousKMT2Dloss plays in tumorigenesis has not been well characterized. Here, we show that heterozygousKmt2dloss highly promotes MB driven by heterozygous loss of the MB suppressor genePtchin mice. HeterozygousKmt2dloss upregulated tumor-promoting programs, including oxidative phosphorylation and G-protein-coupled receptor signaling, inPtch+/−-driven MB genesis. Mechanistically, both downregulation of the transcription-repressive tumor suppressor gene NCOR2 by heterozygousKmt2dloss and upregulation of the oncogeneMycNby heterozygousPtchloss increased the expression of tumor-promoting genes. Moreover, heterozygousKmt2dloss extensively diminished enhancer signals (e.g., H3K27ac) and H3K4me3 signature, including those for tumor suppressor genes (e.g.,Ncor2). Combinatory pharmacological inhibition of oxidative phosphorylation and the enhancer-decommissioning H3K4 demethylase LSD1 drastically reduced tumorigenicity of MB cells bearing heterozygousKmt2dloss. These findings reveal the mechanistic basis underlying the MB-promoting effect of heterozygousKMT2Dloss, provide a rationale for a therapeutic strategy for treatment of KMT2D-deficient MB, and have mechanistic implications for the molecular pathogenesis of other types of cancer bearing heterozygousKMT2Dloss.
MethylBERT: A Transformer-based model for read-level DNA methylation pattern identification and tumour deconvolution
Authors: Jeong Yunhee , Gerhäuser Clarissa , Sauter Guido , Schlomm Thorsten , Rohr Karl , Lutsik Pavlo
Published: November 2023

DNA methylation (DNAm) is a key epigenetic mark that shows profound alterations in cancer. Read-level methylomes enable more in-depth DNAm analysis due to the broad coverage and preservation of rare cell-type signals, compared to array-based data such as 450K/EPIC array. Here, we propose MethylBERT, a novel Transformer-based model for read-level methylation pattern classification. MethylBERT identifies tumour-derived sequence reads based on their methylation patterns and genomic sequence. Using the read classification probability, the method estimates tumour cell fractions within bulk samples and provides an assessment of the model precision. In our evaluation, MethylBERT outperforms existing deconvolution methods and demonstrates high accuracy regardless of methylation pattern complexity, read length and read coverage. Moreover, we show its applicability to cell-type deconvolution as well as its potential for accurate non-invasive early cancer diagnostics using liquid biopsy samples. MethylBERT represents a significant advancement in read-level methylome analysis and enables accurate tumour purity estimation. The broad applicability of MethylBERT will enhance studies on both solid tumour tissues and circulating tumour DNA as well as non-cancerous bulk methylomes.
Sex-dependent effects of infection on guppy reproductive fitness and offspring parasite resistance
Authors: Weiler Isabella L. G. , Kramp Rachael D. , Rovenolt Faith , Stephenson Jessica F.
Published: November 2023

Infection imposes energetic costs on hosts. Hosts typically respond by shifting resources, potentially affecting the quantity and quality of offspring they produce. As the sexes differ in their optimal reproductive strategies, infection of mothers versus fathers may affect offspring quantity and quality in different ways.

Here, we test how experimental infection of guppiesPoecilia reticulatawith the ectoparasiteGyrodactylus turnbulliaffects parental reproductive fitness and offspring parasite resistance. We compared breeding pairs in which one or neither parent had previously been infected.

In terms of reproductive fitness, parental infection experience did not affect the size, body condition, or number of offspring produced, but fathers who experienced the heaviest infections produced offspring ∼55 days sooner than average. This result may represent terminal investment by the males most affected by infection, or may indicate that these males have a faster pace of life, investing in reproduction at the expense of parasite defence.

We found that offspring age, parental infection experience, and parental infection severity together strongly predicted offspring parasite resistance. Only among pairs in which one parent had been infected, older offspring, which were those born soonest after the parent’s infection, tended to experience heavier infections. This result may therefore reflect temporary infection-induced reductions in parental investment in offspring quality. Beyond this effect of offspring age, offspring of infected mothers experienced 105 fewer worm days than those of infected fathers: fathers, but not mothers, that experienced heavy infections themselves produced offspring that also experienced heavy infections. The parent-offspring regression for infected fathers is therefore consistent with previous evidence that parasite resistance is heritable in this system, and yields a narrow sense heritability estimate of 0.69±0.13. By contrast, the mother-offspring regression (slope: -0.13±0.17) provides novel insight that mothers may engage in transgenerational immune priming.

Overall, our results suggest that the sexes strike a different balance between offspring quantity and quality when faced with infection, with potentially broad implications for disease and host-parasite coevolutionary dynamics in nature.
Unearthing SRSF1’s Novel Function in Binding and Unfolding of RNA G-Quadruplexes
Authors: De Silva Naiduwadura Ivon Upekala , Lehman Nathan , Fargason Talia , Paul Trenton , Zhang Zihan , Zhang Jun
Published: November 2023

SRSF1 governs splicing of over 1,500 mRNA transcripts. SRSF1 contains two RNA-recognition motifs (RRMs) and a C-terminal Arg/Ser-rich region (RS). It has been thought that SRSF1 RRMs exclusively recognize single-stranded exonic splicing enhancers, while RS lacks RNA-binding specificity. With our success in solving the insolubility problem of SRSF1, we can explore the unknown RNA-binding landscape of SRSF1. We find that SRSF1 RS prefers purine over pyrimidine. Moreover, SRSF1 binds to the G-quadruplex (GQ) from the ARPC2 mRNA, with both RRMs and RS being crucial. Our binding assays show that the traditional RNA-binding sites on the RRM tandem and the Arg in RS are responsible for GQ binding. Interestingly, our FRET and circular dichroism data reveal that SRSF1 unfolds the ARPC2 GQ, with RS leading unfolding and RRMs aiding. Our saturation transfer difference NMR results discover that Arg residues in SRSF1 RS interact with the guanine base but other nucleobases, underscoring the uniqueness of the Arg/guanine interaction. Our luciferase assays confirm that SRSF1 can alleviate the inhibitory effect of GQ on gene expression in the cell. Given the prevalence of RNA GQ and SR proteins, our findings unveil unexplored SR protein functions with broad implications in RNA splicing and translation.
Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer
Authors: Klein Lukas , Tu Mengyu , Krebs Niklas , Urbach Laura , Grimm Daniela , Latif Muhammad Umair , Penz Frederike , Chan Nathan , Aliar Kazeera , Vyas Foram , Kishore Uday , Hessmann Elisabeth , Trumpp Andreas , Espinet Elisa , Papantonis Argyris , Khokha Rama , Ellenrieder Volker , Grünwald Barbara T. , Singh Shiv K.
Published: November 2023

Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity. This intratumoral co-existence of classical and basal-like programs is evident in multi-scale transcriptomic and spatial analyses of resected, advanced-stage and chemotherapy-treated specimens and reciprocally linked to a diverse stromal immune microenvironment as well as worse clinical outcome. However, the underlying mechanisms of intratumoral subtype heterogeneity remain largely unclear. Here, by combining preclinical models, multi-center clinical, bulk and compartment-specific transcriptomic, proteomic, and bioimaging data from human specimens, we identified an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic CD68+macrophages as a driver of intratumoral subtype co-existence along with an immunosuppressive tumor microenvironment with T cell exclusion. Our ATAC-, ChIP-, and RNA-seq analyses revealed that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory immune signatures in tumor cells, antagonizing cJUN/AP1 signaling to favor a therapy-responsive classical neoplastic identity. Through the tumor microenvironment, this dichotomous regulation was further amplified via regional macrophage populations. Moreover, CD68+/TNF-α+cells associated with a reactive phenotype and reduced CD8+T cell infiltration in human PDAC tumors. Consequently, combined anti-TNF-α immunotherapy and chemotherapy resulted in reduced macrophage counts and promoted CD3+/CD8+T cell infiltration in basal-like PDAC, leading to improved survival in preclinical murine models. We conclude that tumor cell intrinsic epigenetic programs, together with extrinsic microenvironmental cues, facilitate intratumoral subtype heterogeneity and disease progression.
Superovulation and aging perturb oocyte-granulosa cell communication
Authors: Daugelaite Klaudija , Lacour Perrine , Winkler Ivana , Koch Marie-Luise , Schneider Anja , Schneider Nina , Tolkachov Alexander , Nguyen Xuan Phuoc , Vilkaite Adriana , Rehnitz Julia , Odom Duncan T. , Goncalves Angela
Published: November 2023

In vitrofertilization has been developed to overcome reduced fertility, which is increasingly due to a decline in reproductive cell quality during aging. Here, we quantitatively investigated the interplay between superovulation and aging in mouse oocytes and their paired granulosa cells using newly adapted isolation techniques. We tested the hypothesis that superovulation disrupts oocyte maturation, revealing the key intercellular communication pathways dysregulated by forced hormonal stimulation. We further demonstrated that granulosa cell transcriptional markers can prospectively predict an associated oocyte’s early developmental potential. By using naturally ovulated old mice as a non-stimulated reference, we showed that aging and superovulation dysregulate similar genes and interact with each other. By comparing mice and human transcriptional responses of granulosa cells, we found that age-related dysregulation of hormonal responses and cell cycle pathways was shared, though substantial divergence exists in other pathways.

Highlights

Superovulation perturbs cumulus-oocyte communication

Granulosa cell transcription predicts superovulated oocyte quality

Superovulation and aging non-additively perturb similar sets of genes
Robustly interrogating machine learning-based scoring functions: what are they learning?
Authors: Durant Guy , Boyles Fergus , Birchall Kristian , Marsden Brian , Deane Charlotte M.
Published: November 2023

Motivation

Machine learning-based scoring functions (MLBSFs) have been found to exhibit inconsistent performance on different benchmarks and be prone to learning dataset bias. For the field to develop MLBSFs that learn a generalisable understanding of physics, a more rigorous understanding of how they perform is required.

Results

In this work, we compared the performance of a diverse set of popular MLBSFs (RFScore, SIGN, OnionNet-2, Pafnucy, and PointVS) to our proposed baseline models that can only learn dataset biases on a range of benchmarks. We found that these baseline models were competitive in accuracy to these MLBSFs in almost all proposed benchmarks, indicating these models only learn dataset biases. Our tests and provided platform, ToolBoxSF, will enable researchers to robustly interrogate MLBSF performance and determine the effect of dataset biases on their predictions.

Availability and Implementation

https://github.com/guydurant/toolboxsf

Contact

deane@stats.ox.ac.uk

Supplementary information

Supplementary data are available at Bioinformatics online.
Beacon-based sleep status and physical activity monitoring in humans
Authors: Kikusui Takefumi , Yagisawa Mizuho , Koyama Kahori , Fujiwara Koichi , Kume Kazuhiko , Nomoto Kensaku , Nagasawa Miho
Published: November 2023

One out of every five people in Japan is dissatisfied with their sleep and various diseases caused by lack of exercise have been pointed out, but there are few effective remedies for these problems. In this study, we aimed to develop a simple method for measuring behavioral sleep patterns and physical activity using a beacon accelerometer wirelessly connected with a smartphone. A sleep prediction model was created comparing the data obtained from the accelerometer with the sleep status data obtained by a previously validated sleep monitoring system. The Random Forest model was able to classify sleep and wakefulness with a 97.4% and 85.4% precision, respectively, which were comparable to those of conventional acceleration-based sleep monitoring devices. Additionally, the same data acquisition method was used to classify exercise intensity into seven levels and a high correlation (r=0.813, p<0.0001) was found when comparing the classified exercise intensity to metabolic equivalent (MET) values. This suggests that the proposed method can be used for accurate measurement of both behavioral sleep and physical activity classifying over a long period of time.
Non-canonical ORFs are an important source of tumor-specific antigens in a liver cancer meta-cohort
Authors: Camarena Marta E. , Theunissen Patrick , Ruiz Marta , Ruiz-Orera Jorge , Calvo-Serra Beatriz , Castelo Robert , Sarobe Pablo , Fortes Puri , Perera-Bel Júlia , Albà M. Mar
Published: November 2023

The expression of tumor-specific antigens during cancer progression can trigger an immune response against the tumor. Antigens that have been used as cancer vaccines are those originated by non- synonymous mutations and those derived from cancer/testis antigens. However, the first class is predominantly patient-specific, preventing the development of therapies than can benefit multiple patients, and the second one offers a limited set of actionable targets. A possible alternative is the use of peptides derived from non-canonical ORFs (ncORFs). While many ncORFs have been shown to be translated in cancer cells, their tumor-specificity and patient distribution remains to be determined. Here we analyze RNA sequencing data 117 hepatocellular carcinoma (HCC) tumors and matched healthy tissue, together with ribosome profiling data from an additional 10 HCC tumors, to answer these open questions. Combining HLA-epitope binding predictions and experimental validation experiments we conclude that around 40% of the tumor-specific antigens in HCC are likely to be derived from ncORFs in lncRNAs, including two peptides that can trigger an immune response in mice. We identify a subset of 33 tumor-specific lncRNAs expressing novel cancer antigens shared by more than 10% of the HCC analyzed, which could be combined to target a large proportion of the patients. The results of the study open new avenues for extending the range of anti-cancer vaccines.
Accelerated design ofEscherichia coligenomes with reduced size using a whole-cell model and machine learning
Authors: Gherman Ioana M. , Rees-Garbutt Joshua , Pang Wei , Abdallah Zahraa S. , Gorochowski Thomas E. , Grierson Claire S. , Marucci Lucia
Published: November 2023

Whole-cell models (WCMs) are multi-scale computational models that aim to simulate the function of all genes and biological processes within a cell. While WCMs offer deeper insights into how cells behave, they also require significant computational resources to run. Here, we show how machine learning (ML) surrogates can be used to address this limitation by training them on WCM outputs to accurately predict whether cells divide successfully across several generations when a subset of genes are removed (knocked out). Our ML surrogate achieves a 95% reduction in computational time when compared to the original WCM. We then used the surrogate and a genome-design algorithm to generate anin silicoreducedE. colicell, where 40% of the genes included in the WCM were removed. This approach illustrates how the holistic understanding provided by the WCM can be leveraged for synthetic biology tasks, while mitigating its computational burden through machine learning.
A Computational Model of Coarctation of the Aorta in Rabbits: Ventricular and Ascending Aortic Remodeling
Authors: Hiebing Ashley A. , Culver Matthew A. , LaDisa John F. , Witzenburg Colleen M.
Published: November 2023

Coarctation of the aorta (CoA) is a common congenital cardiovascular lesion that typically presents as a localized narrowing of the proximal descending thoracic aorta just distal to the left subclavian artery. While improvements in surgical and catheter-based techniques have increased short-term survival, there is a high long-term risk of hypertension after CoA correction and a reduced average lifespan despite treatment. Computational models can be used to estimate ventricular and arterial remodeling, potentially serving as key tools in developing a mechanistic understanding of the interplay between pre-correction hemodynamics, post-correction recovery, and long-term hypertension risk. In this study, we developed a lumped parameter model of the heart and circulation to simulate aortic coarctation. We then used the model to estimate changes in ventricular thickness and ascending aortic compliance from imaging and catheterization data collected in rabbits with untreated and corrected CoA that used the current putative clinical treatment threshold (≥20 mmHg). Model outputs were compared to reported stroke volume, ejection fraction, systolic and diastolic ascending aortic pressures, peak ascending aortic flow, mean and peak aortic blood pressure gradients, and upper-to-lower body flow split, with all results falling within one standard deviation of the data for control, untreated CoA, and corrected CoA groups. In the untreated CoA and corrected simulations, a decrease in ascending aortic compliance was necessary to match reported hemodynamics, suggesting the rabbits exposed to CoA ≥20 mmHg underwent vascular remodeling that persisted after repair.
Interactive visualization of whole eukaryote genome alignments using NCBI’s Comparative Genome Viewer (CGV)
Authors: Rangwala Sanjida H , Rudnev Dmitry V , Ananiev Victor V , Asztalos Andrea , Benica Barrett , Borodin Evgeny A , Bouk Nathan , Evgeniev Vladislav I , Kodali Vamsi K , Lotov Vadim , Mozes Eyal , Oh Dong-Ha , Omelchenko Marina V , Savkina Sofya , Sukharnikov Ekaterina , Virothaisakun Joël , Murphy Terence D. , Pruitt Kim D , Schneider Valerie A.
Published: November 2023

We report a new visualization tool for analysis of whole genome assembly-assembly alignments, the Comparative Genome Viewer (CGV) (https://ncbi.nlm.nih.gov/genome/cgv/). CGV visualizes pairwise same-species and cross-species alignments provided by NCBI using assembly alignment algorithms developed by us and others. Researchers can examine the alignments between the two assemblies using two alternate views: a chromosome ideogram- based view or a 2D genome dotplot. Whole genome alignment views expose large structural differences spanning chromosomes, such as inversions or translocations. Users can also navigate to regions of interest, where they can detect and analyze smaller-scale deletions and rearrangements within specific chromosome or gene regions. RefSeq or user-provided gene annotation is displayed in the ideogram view where available. CGV currently provides approximately 700 alignments from over 300 animal, plant, and fungal species. CGV and related NCBI viewers are undergoing active development to further meet needs of the research community in comparative genome visualization.
Salience-dependent disruption of sustained auditory attention can be inferred from evoked pupil responses and neural tracking of task-irrelevant sounds
Authors: Fiedler Lorenz , Johnsrude Ingrid , Wendt Dorothea
Published: November 2023

Stimulus-driven attention allows us to react to relevant stimuli (and imminent danger!) outside our current focus of attention. But irrelevant stimuli can also disrupt attention; for example, during listening to speech. The degree to which sound captures attention is called salience, which can be estimated by existing, behaviorally validated, computational models (Huang & Elhilali, 2017). Here we examined whether neurophysiological responses to task-irrelevant sounds indicate the degree of distraction during a sustained-listening task and how much this depends on individual hearing thresholds. N = 47 Danish-speaking adults (28/19 female/male; mean age: 60.1, SD: 15.9 years) with heterogenous hearing thresholds (PTA; mean: 25.5, SD: 18.0 dbHL) listened to continuous speech while one-second-long, task-irrelevant natural sounds (distractors) of varying computed salience were presented at unpredictable times and locations. Eye tracking and electroencephalography were used to estimate pupil response and neural tracking, respectively. The task-irrelevant sounds evoked a consistent pupil response (PR), distractor-tracking (DT) and a drop of target-tracking (ΔTT), and statistical modelling of these three measures within subjects showed that all three are enhanced for sounds with higher computed salience. Participants with larger PR showed a stronger drop in target tracking (ΔTT) and performed worse in target speech comprehension. We conclude that distraction can be inferred from neurophysiological responses to task-irrelevant stimuli. These results are a first step towards neurophysiological assessment of attention dynamics during continuous listening, with potential applications in hearing-care diagnostics.

Significance statement

Successful speech-in-noise comprehension in daily life does not only depend on the acuity of the auditory input, but also cognitive factors like attentional control. Being able to measure distraction-dependent neurophysiological responses to peripheral, task-irrelevant stimuli would enable monitoring the extent to which the attentional focus is instantaneously captured away from a target under sustained attention. Here we show that especially pupil response and neural tracking of distractor sounds reflect the degree to which people with both normal and elevated hearing thresholds are distracted. Such a measure could be used to non-invasively track the focus of attention and thus could find application in hearing care diagnostics, where cognitive factors like attentional control are being increasingly recognized as important.
Spatial and single-cell transcriptomics illuminate bat immunity and barrier tissue evolution
Authors: Levinger Roy , Tussia-Cohen Dafna , Friedman Sivan , Lender Yan , Nissan Yomiran , Fraimovitch Evgeny , Gavriel Yuval , Tearle Jacqueline , Kolodziejczyk Aleksandra A. , Gomes Tomás , Kunowska Natalia , Weinberg Maya , Donati Giacomo , James Kylie R , Yovel Yossi , Hagai Tzachi
Published: November 2023

The Egyptian fruit bat displays tolerance to lethal viruses and unique dietary adaptations, but the molecular basis for this is poorly understood. To this end, we generated detailed maps of bat gut, lung and blood cells using spatial and single-cell transcriptomics. We compared bat with mouse and human cells to reveal divergence in genetic programs associated with environmental interactions and immune responses. Complement system genes are transcriptionally divergent, uniquely expressed in bat lung and gut epithelium, and undergo rapid coding-sequence evolution. Specifically in the tip of the gut villus, bat enterocytes express evolutionarily young genes while lacking expression of genes related to specific nutrient absorption. Profiling immune stimulation of PBMCs revealed a monocyte subset with conserved cross-species interferon expression, suggesting strong constraints to avoid an excessive immune response. Our study thus uncovers conserved and divergent immune pathways in bat tissues, providing a unique resource to study bat immunity and evolution.
Multi-region calcium imaging in freely behaving mice with ultra-compact head-mounted fluorescence microscopes
Authors: Xue Feng , Li Fei , Zhang Ke-ming , Ding Lufeng , Wang Yang , Zhao Xingtao , Xu Fang , Zhang Danke , Sun Mingzhai , Lau Pak-Ming , Zhu Qingyuan , Zhou Pengcheng , Bi Guo-Qiang
Published: November 2023

To investigate the circuit-level neural mechanisms of behavior, simultaneous imaging of neuronal activity in multiple cortical and subcortical regions is highly desired. Miniature head-mounted microscopes offer the capability of calcium imaging in freely behaving animals. However, implanting multiple microscopes on a mouse brain remains challenging due to space constraints and the cumbersome weight of equipment. Here, we present TINIscope, a Tightly Integrated Neuronal Imaging microscope optimized for electronic and opto-mechanical design. With its compact and lightweight design of 0.43 g, TINIscope enables unprecedented simultaneous imaging of behavior-relevant activity in up to four brain regions in mice. Proof-of-concept experiments with TINIscope recorded over 1000 neurons in four hippocampal subregions and revealed concurrent activity patterns spanning across these regions. Moreover, we explored potential multi-modal experimental designs by integrating additional modules for optogenetics, electrical stimulation or local field potential recordings. Overall, TINIscope represents a timely and indispensable tool for studying the brain-wide interregional coordination that underlies unrestrained behaviors.
Shifted levels of sleep and activity under darkness as mechanisms underlying ectoparasite resistance
Authors: Benoit Joshua B. , Ajayi Oluwaseun M. , Webster Ashley , Grieshop Karl , Lewis David , Talbott Hailie , Bose Joy , Polak Michal
Published: November 2023

Parasites harm host fitness and are pervasive agents of natural selection capable of driving the evolution of host resistance traits. Indeed, host resistance in natural populations typically shows ample genetic variation, which may be maintained when parasite resistance imposes fitness costs on the host in the absence of parasites. Previously we demonstrated significant evolutionary responses to artificial selection for increasing behavioral immunity toGamasodes queenslandicusmites in replicate lines ofDrosophila melanogaster. Here, we report transcriptional shifts in metabolic processes between selected and control fly lines based on RNA-seq analyses. We also show decreased starvation resistance and increased use of nutrient reserves in flies from mite-resistant lines. Additionally, resistant lines exhibited increased behavioral activity, reduced sleep and elevated oxygen consumption under conditions of darkness. Using an independent panel ofD. melanogastergenetic lines exhibiting variable sleep durations, we found a positive correlation between mite resistance and reduced sleep, providing additional support for a link between resistance and sleep. Experimentally restraining the activity of artificially selected mite-resistant flies during exposure to parasites under dark conditions reduced their resistance advantage relative to control flies. The results suggest that ectoparasite resistance in this system involves increased dark-condition activity and metabolic gene expression at the expense of nutrient reserves and starvation resistance.

Significance statement

Parasites are potent agents of selection, yet resistance may often be constrained evolutionarily because of trade-offs involving other fitness-related traits. Using artificial selection, we show that resistance to ectoparasites directly increases metabolism and decreases starvation resistance, predominantly through altered sleep and activity patterns at night. These studies highlight that active-resting patterns of the host are a significant driving force in ectoparasite resistance, but may have a negative impact on fitness during periods of low food availability. Our strongly integrative work suggests that parasite pressure may influence the evolution of host sleep and activity patterns.
The brittle star genome illuminates the genetic basis of animal appendage regeneration
Authors: Parey Elise , Ortega-Martinez Olga , Delroisse Jérôme , Piovani Laura , Czarkwiani Anna , Dylus David , Arya Srishti , Dupont Samuel , Thorndyke Michael , Larsson Tomas , Johannesson Kerstin , Buckley Katherine M. , Martinez Pedro , Oliveri Paola , Marlétaz Ferdinand
Published: November 2023

Species within nearly all extant animal lineages are capable of regenerating body parts. However, it remains unclear whether the gene expression programme controlling regeneration is evolutionarily conserved. Brittle stars are a species-rich class of echinoderms with outstanding regenerative abilities, but investigations into the genetic bases of regeneration in this group have been hindered by the limited genomic resources. Here, we report a chromosome-scale genome assembly for the brittle starAmphiura filiformis.We show that the brittle star genome is the most rearranged amongst echinoderms sequenced to date, featuring a reorganised Hox cluster reminiscent of the rearrangements observed in sea urchins. In addition, we performed an extensive profiling of gene expression during brittle star adult arm regeneration and identified sequential waves of gene expression governing wound healing, proliferation and differentiation. We conducted comparative transcriptomic analyses with other invertebrate and vertebrate models for appendage regeneration and uncovered hundreds of genes with conserved expression dynamics, particularly during the proliferative phase of regeneration. Our findings emphasise the crucial importance of echinoderms to detect long-range expression conservation between vertebrates and classical invertebrate regeneration model systems.
A new family of statistical tests for neuronal spiking and autocorrelated timeseries data
Authors: Montijn Jorrit S. , Meijer Guido T. , Heimel J. Alexander
Published: November 2023

Quantifying whether and when signals are modulated by autonomous or external events is ubiquitous in the field of neuroscience. Existing statistical approaches, however, are not ideally suited to do this, especially when the signals under scrutiny show temporal autocorrelations. For example, a standard approach in the analysis of calcium imaging data is to use a t-test on predetermined time-windows to quantify whether neurons respond (differently) to an event of interest. While this is attractive because of its simplicity, only average signal differences can be detected. In practice, neurons often show complex response dynamics which are missed by conventional statistical tests. More advanced methods, such as bin-wise ANOVAs, do not share this drawback, but can suffer from high false-positive rates or “ghost correlations” when applied to temporally autocorrelated data. To solve this issue, we have developed three novel statistical tests extending the original ZETA-test to other use cases: 1) a test for time-series data; 2) a two-sample test to detect differences in neural responses between two conditions; and 3) a two-sample test to detect differences in time-series data between two conditions. In addition, we have improved upon the original ZETA-test. We show that our methods have a statistical sensitivity superior to t-tests and ANOVAs and work well with temporally autocorrelated data where other approaches fail. Our methods are widely applicable and we present example applications to Neuropixels data, two-photon GCaMP imaging data, and human electrocorticogram data. Open-source code for implementations in MATLAB and Python is available on GitHub and PyPi.

Significance Statement

Neurophysiology involves the detection of weak signals in a noisy background. Often these signals, as well as the background, are temporally autocorrelated. This means that many statistical methods, such as the ANOVA, are inappropriate. In some cases, these statistical tests produce “ghost” signals that mislead researchers into thinking there is an effect of their experiment, when in reality there is none. We have therefore developed a new family of statistical tests, the ZETA-tests, that are not negatively impacted by temporal autocorrelations. They do not use arbitrary (hyper)parameters, like bin size, and show superior statistical sensitivity compared to other methods like t-tests and ANOVAs. We provide easy-to-use implementations and expect our methods to be useful for many neuroscientists from various disciplines.
Different complex regulatory phenotypes underlie hybrid male sterility in divergent rodent crosses
Authors: Hunnicutt Kelsie E. , Callahan Colin , Keeble Sara , Moore Emily C. , Good Jeffrey M. , Larson Erica L.
Published: November 2023

Hybrid incompatibilities are a critical component of species barriers and may arise due to negative interactions between divergent regulatory elements in parental species. We used a comparative approach to identify common themes in the regulatory phenotypes associated with hybrid male sterility in two divergent rodent crosses, dwarf hamsters and house mice. We investigated three potential characteristic gene expression phenotypes in hybrids including the propensity of transgressive differentially expressed genes towards over or underexpression, the influence of developmental stage on patterns of misexpression, and the role of the sex chromosomes on misexpression phenotypes. In contrast to near pervasive overexpression in hybrid house mice, we found that misexpression in hybrid dwarf hamsters was dependent on developmental stage. In both house mouse and dwarf hamster hybrids, however, misexpression increased with the progression of spermatogenesis, although to varying extents and with potentially different consequences. In both systems, we detected sex-chromosome specific overexpression in stages of spermatogenesis where inactivated X chromosome expression was expected, but the hybrid overexpression phenotypes were fundamentally different. Importantly, misexpression phenotypes support the presence of multiple developmental blocks to spermatogenesis in dwarf hamster hybrids, including a potential role of meiotic stalling or breakdown early in spermatogenesis. Collectively, we demonstrate that while there are some similarities in hybrid expression phenotypes of house mice and dwarf hamsters, there are also clear differences that point towards unique mechanisms underlying hybrid male sterility. Our results highlight the potential of comparative approaches in helping to understand the causes and consequences of disrupted gene expression in speciation.
Cerebellar deep brain stimulation as a dual-function therapeutic for restoring movement and sleep in dystonic mice
Authors: Leon Luis E. Salazar , Kim Linda H. , Sillitoe Roy V.
Published: November 2023

Dystonia arises with cerebellar dysfunction, which plays a key role in the emergence of multiple pathophysiological deficits that range from abnormal movements and postures to disrupted sleep. Current therapeutic interventions typically do not simultaneously address both the motor and non-motor (sleep-related) symptoms of dystonia, underscoring the necessity for a multi-functional therapeutic strategy. Deep brain stimulation (DBS) is effectively used to reduce motor symptoms in dystonia, with existing parallel evidence arguing for its potential to correct sleep disturbances. However, the simultaneous efficacy of DBS for improving sleep and motor dysfunction, specifically by targeting the cerebellum, remains underexplored. Here, we test the effect of cerebellar DBS in two genetic mouse models with dystonia that exhibit sleep defects—Ptf1aCre;Vglut2fx/fxandPdx1Cre;Vglut2fx/fx—which have overlapping cerebellar circuit miswiring defects but differing severity in motor phenotypes. By targeting DBS to the cerebellar fastigial and interposed nuclei, we modulated sleep dysfunction by enhancing sleep quality and timing in both models. This DBS paradigm improved wakefulness (decreased) and rapid eye movement (REM) sleep (increased) in both mutants. Additionally, the latency to reach REM sleep, a deficit observed in human dystonia patients, was reduced in both models. Cerebellar DBS also induced alterations in the electrocorticogram (ECoG) patterns that define sleep states. As expected, DBS reduced the severe dystonic twisting motor symptoms that are observed in thePtf1aCre;Vglut2fx/fxmutant mice. These findings highlight the potential for using cerebellar DBS to improve sleep and reduce motor dysfunction in dystonia and uncover its potential as a dual-effectin vivotherapeutic strategy.
“Technical Note: DeepLabCut-Display: open-source desktop application for visualizing and analyzing two-dimensional locomotor data in livestock”
Authors: Shirey Jacob , Smythe Madelyn P. , Dewberry L. Savannah , Allen Kyle , Jain Eakta , Brooks Samantha A.
Published: November 2023

Gait assessments are a key part of determining the wellbeing of livestock. Techniques for gait assessment have traditionally involved human-eye inspections or reflective markers, but markerless computer vision methods have been developed in recent years. Despite many computer vision tools providing high-quality pose estimations in an efficient manner, they lack post-processing functionality. A review of model performance and calculation of gait parameters is a necessary step to fully harness the capability of this new technology. Thus, this study developed DeepLabCut-Display, an open-source desktop software application. DeepLabCut-Display allows a user to upload the video and coordinate data associated with the output of DeepLabCut, a prominent pose-estimation software tool. A user can review the video and coordinate data in parallel, filter points by a likelihood threshold, and automatically calculate gait parameters. Specific video frames, filtered data, and gait parameters can be exported from the application for further usage. The source code is publicly hosted on GitHub alongside installation and usage instructions. DeepLabCut-Display, the product of interdisciplinary and collaborative design between software developers and animal scientists, will alleviate a critical bottleneck in processing of data for locomotor analysis in livestock.

Summary Statement

DeepLabCut-Display is a utility to dynamically visualize raw marker coordinates, and to automatically produce gait parameters for locomotion analysis of horses and other livestock.

Lay Summary

Artificial intelligence systems that can predict and track the positions of objects are now being applied in many fields, including animal science. Veterinarians and animal scientists use these systems to create pose estimations, a digital label of anatomical landmarks overlaid on a video of an animal in motion. They are used to quantify the subject’s motion and detect anomalies that may be indicative of disease or injury. Pose estimation systems are efficient and accurate, but they lack features like data visualization and post-processing analysis that are necessary to make determinations about the animal’s motion. This study developed DeepLabCut-Display, a software application that can visualize the data from a pose estimation system and provides a set of tools for further analysis. After a user is done with analysis, they can save the results to their computer. The application was made by a collaboration between software developers and animal scientists, highlighting how interdisciplinary teams are effective at producing useful software.
Physical performance and telomere length in older adults
Authors: Martínez-Ezquerro José Darío , Ortiz-Ramírez Mauricio , García-delaTorre Paola , González-Covarrubias Vanessa , Sánchez-García Sergio
Published: November 2023

Background

The fast-paced aging demographic prompts studying risk factors and markers that could predict healthy aging. Telomere length shows promise for assessing a broad spectrum of aging-related phenotypes.

Aim of the study

To assess the association between physical performance and telomere length in Mexican older adults.

Methods

In this observational cross-sectional study, we recruited 323 older adults affiliated with the Instituto Mexicano del Seguro Social (IMSS) and members of the “Cohort of Obesity, Sarcopenia, and Frailty of Older Mexican Adults’’ (COSFOMA). To assess physical performance, we used the Short Physical Performance Battery (SPPB) and stratified individuals into two groups according to their SPPB score into low ≤7 (L-SPPB) and high >7 (H-SPPB). Absolute telomere length (aTL) was determined by using qPCR. Next, we classified individuals according to their aTL into short ≤4.22 kb (S-TL) and long >4.22 kb (L-TL). For both SPPB and aTL categories, we calculated the mean and adjusted mean by sex, age, marital status, education, remunerated work, smoking, drinking, cognitive decline, depression, and polypharmacy with 95% CI, including the lower and upper CI (LCImeanUCI). We estimated the effect size between physical performance and telomere length with Cohen’s d for unequal group sizes. Also, we calculated the odds ratio with 95% confidence intervals, including the lower and upper CI (LCIORUCI) for physical performance according to telomere length categories.

Results

Participants in the low physical performance category had significantly shorter telomeres (4.14.44.7mean and3.54.04.5kb adjusted mean, p<0.001), in opposition to the high physical performance category (score >7) with longer telomeres (5.55.75.9mean and4.75.35.8kb adjusted mean, p<0.001), with a medium-to-high telomere length effect size (d= 0.762). Finally, the odds of being classified in the low physical activity category increased2.13.66.1times per kb of telomere (adjOR1.73.36.3, p<0.001) compared to the high physical activity group (p<0.001).

Conclusion

Decreased physical functioning is associated with lower telomere length. Absolute telomere length (aTL) as a possible biomarker for differential diagnosis of healthy and unhealthy aging should be explored further.
Fortune may favor the flexible: Environment-dependent behavioral shifts in invasive coquí frogs
Authors: Soto Katharina M , Edmonds Devin , Colton Andrea L , Hardin Faith O , Fischer Eva K
Published: November 2023

Biological invasions are a major driver of global biodiversity loss, impacting endemic species, ecosystems, and economies. While the influence of life history traits on invasive success is well-established, the role of behavior in the invasive potential of animals is less studied. The common coquí frog,Eleutherodactylus coqui, is a highly successful invader in Hawaii. We build on previous research characterizing changes in physiology and morphology to explore behavioral variation across the invasive range of coquí in Hawaii. We hypothesized that behavioral traits contributing to invasion expansion would be reflected in behavioral differences at the invasive center versus invasive edge. To investigate whether differences in the field represent local adaptation or behavioral plasticity, we additionally evaluated behavior following acclimation to a shared laboratory environment. While we identified only subtle behavioral variation among populations in the field, we found that individuals from all populations became less bold, active, and exploratory in the laboratory, converging on a similar behavioral phenotype. Alongside previous work, our results suggest that coquí adjust their behavior to local environmental conditions across their invasive range, and that behavioral flexibility may contribute to invasive success.