bluuebunny/crossref_metadata_2025 huggingface dataset:
Tracking spatial patterns and nocturnal arousal in an undisturbed natural population of the pulse-type weakly electric fishGymnotus omarorum
Authors: Migliaro Adriana , Pedraja Federico , Mucha Stefan , Benda Jan , Silva Ana
Published: July 2024

Assessing animals’ locomotor and activity-rest patterns in natural populations is challenging. It requires individual identification and behavioral tracking in sometimes complex and inaccessible environments. Weakly electric fish are advantageous models for remote monitoring due to their continuous emission of electric signals (EODs).Gymnotus omarorumis a South American freshwater pulse-type weakly electric fish. Previous manual recordings of restrained individuals in the wild showed a spatial distribution compatible with territoriality and a nocturnal increase in EOD rate interpreted as arousal. This interdisciplinary study presents the development of low-cost amplifiers for remote EOD recordings and the refinement of tracking algorithms that provide individual recognition ofGymnotus omarorumin the wild. We describe natural daily spacing patterns of undisturbed individuals that are compatible with territoriality, although heterogeneous across sampling sites, and confirm that all resident fish showed a robust nocturnal increase of EOD rate likely associated with daily variations of water temperature.

HIGHLIGHTS

Successful remote individual tracking of wild pulse type weakly electric fish

G. omarorumspacing patterns are compatible with known nocturnality and territoriality

Residents keep their diurnal resting sites and move within small areas during the night

The robust nocturnal electric arousal of residents is linked to water temperature peak
Are circulating levels of the myokine irisin linked to type 2 diabetes? A systematic review and meta-analysis
Authors: Aminov E. , Folan P. , Pisconti A.
Published: July 2024

Background

Type II diabetes (T2DM) is one of the most prevalent metabolic disorders, and its multisystemic health consequences are widely known. Due to skeletal muscle’s ability to sequester a vast amount of glucose, muscle function and exercise have become a subject of much research into strategies to prevent and treat T2DM. Myokines are bioactive molecules released by muscle during contraction and involved in several biological processes such as metabolism, inflammation and behavior. Irisin, a recently discovered myokine, has been implicated in a vast array of physiological roles, including the ability to induce fat beiging. Since beige and brown fat both serve important roles in metabolic regulation, irisin’s role in the context of T2DM is the subject of ongoing investigations.

Methods

We systematically reviewed articles indexed in PubMed, Scopus and Web of Science that were published between 2011 and 2024, and compared circulating irisin levels in patients affected by T2DM and healthy subjects. As part of our systematic review of the literature, we performed meta-analysis of the data across all included articles, as well as stratified by body mass index (BMI), country of origin and by average irisin concentration in the control group.

Results

We discovered great variability across the included studies in the average irisin levels detected, which spanned four orders of magnitude, hence the attempt at reducing variability by stratifying based on average levels in the control group. While the statistical power of our meta-analysis was decreased by the great variability in reported irisin concentrations, we nonetheless detected a consistent trend of decreased irisin concentration in T2DM patients compared with healthy controls, regardless of BMI, country of origin or average irisin concentration in the control group.

Conclusion

With almost 60 articles included, ours is the first extensive systematic review and meta-analysis of irisin in T2DM, yet a highly statistically significant association between circulating irisin levels and T2DM could not be established due to the great variability of the data across include articles. Nonetheless we noticed a trend that is independent of BMI, suggesting a direct relationship between T2DM and irisin that is likely not secondary to diabetic sarcopenia. While our work encourages further research into irisin’s potential role in T2DM pathogenesis, the reproducibility of irisin detection methods in biological samples should be determined and standardized protocols should be made available to the research and clinical communities.
Modular organization of synapses within a neuromere for distinct axial locomotion inDrosophilalarvae
Authors: Fukumasu Kazushi , Nose Akinao , Kohsaka Hiroshi
Published: July 2024

The ability to generate diverse patterns of behavior is advantageous for animal survival. However, it is still unclear how interneurons in a single nervous system are organized to exhibit distinct motions by coordinating the same set of motor neurons. In this study, we analyze the populational dynamics of synaptic activity when fly larvae exhibit two distinct fictive locomotion, forward and backward waves. Based on neurotransmitter phenotypes, the hemi-neuromere is demarcated into ten domains. Calcium imaging analysis shows that one pair of the domains exhibits a consistent recruitment order in synaptic activity in forward and backward waves, while most other domains show the opposite orders in the distinct fictive locomotion. Connectomics-based mapping indicates that these two domains contain pre- and post-synaptic terminals of interneurons involved in motor control. These results suggest that the identified domains serve as a convergence region of forward and backward crawling programs.
Color-barcoded Super-multiplex RNA FISH in Three-dimensional Tissues through Single-round Imaging
Authors: Chang Tianyi , Zhao Shihui , Deng Kunyue , Liao Zhizhao , Tang Mingchuan , Zhu Yanxi , Han Wuji , Yu Chenxi , Fan Wenyi , Jiang Mengcheng , Wang Guanbo , Liu Dongfang , Peng Jirun , Pang Yuhong , Fei Peng , Wang Jianbin , Zheng Chunhong , Huang Yanyi
Published: July 2024

To resolve diverse RNA species in situ, cyclic reactions are often required to increase multiplexity, as conventional fluorescence microscopy is limited to only a few channels. This typically necessitates sophisticated instrumentation for techniques such as in-situ sequencing or sequential fluorescence in-situ hybridization (FISH) imaging, which has hindered the widespread adoption of spatial RNA imaging in biological research. Here, we introduce ‘Profiling of RNA In-situ through Single-round iMaging’ (PRISM), a method that expands coding capacity by leveraging color intensity grading. Using a radius vector filtering strategy to ensure the distinguishability of codewords in color space, PRISM achieves up to 64-plex color-barcoded RNA imaging in a single imaging round with conventional microscopes. We validated PRISM’s versatility across various tissues, including mouse brains, mouse embryos, and human hepatocellular carcinoma (HCC) samples, collectively annotating over 5.6 million cells. Through quasi-3D spatial landscapes, we tracked major cell types in multiple organs during embryonic development from E12.5 to E14.5. Additionally, we uncovered the critical role of cancer-associated fibroblasts (CAFs) in mediating immune infiltration and immune response heterogeneity within and between tumor microenvironments. PRISM was further applied to 100-µm-thick mouse brain slices, generating an accurate 3D cell atlas and subcellular RNA localization landscapes. Robust, user-friendly, and capable of fast turnaround times with sub-cellular resolution, PRISM provides biologists with a powerful super-multiplex FISH toolkit.
WITHDRAWN: Unveiling the Family of Optimal Accelerations in Minimax Optimization and Fixed-Point Algorithms
Authors: Li Chris Junchi
Published: July 2024

WITHDRAWAL STATEMENT

bioRxiv has withdrawn this manuscript because it inappropriately listed Peter L. Bartlett, Jingfeng Wu, and Bin Yu as authors. Therefore, this work should not be cited as reference for the project. If you have any questions, please contact the corresponding author.
Maternal dietary deficiencies in folic acid and choline change metabolites levels in offspring after ischemic stroke
Authors: Anwar Fazian , Mosley Mary-Tyler , Jasbi Paniz , Chi Jinhua , Gu Haiwei , Jadavji Nafisa M.
Published: July 2024

Ischemic stroke is a debilitating disease, with nutrition being a modifiable risk factor. Changes in levels of metabolites can be used to measure the alterations in the gut, a significant marker for the etiology of diseases. This study utilized untargeted metabolomics to investigate changes in fecal samples of offspring in response to maternal dietary deficiencies and ischemic stroke. Female mice were placed on control (CD), folic acid- (FADD), or choline-deficient (ChDD) diets prior to, during pregnancy, and lactation. Offspring were weaned on to CD and at 2 months of age an ischemic stroke was induced. Fecal samples were collected prior to ischemic stroke, and at 1- and 4-weeks post-stroke for analysis. Sex and maternal dietary differences in metabolites were observed at both the 1- and 4-week post-stroke timepoints. At the 1-week post-stroke, female FADD offspring had more changes in metabolites than males. Comparatively, at the 4-week post-stroke timepoint, female offspring on either FADD or ChDD demonstrated metabolite changes. This study demonstrates a long-lasting impact of maternal dietary deficiencies on central nervous system and gut microbiome function after ischemic stroke.

Summary Statement

Our study investigated metabolite changes in female and male offspring fecal samples from mothers maintained on folic acid or choline deficient diet. We report that female offspring metabolite levels were impacted.
Peering into the world of wild passerines with 3D-SOCS: synchronized video capture and posture estimation
Authors: Chimento Michael , Chan Alex Hoi Hang , Aplin Lucy M. , Kano Fumihiro
Published: July 2024

1

Collection of large behavioral data-sets on wild animals in natural habitats is vital in ecology and evolution studies. Recent progress in machine learning and computer vision, combined with inexpensive microcomputers, have unlocked a new frontier of fine-scale markerless measurements.

Here, we leverage these advancements to develop a 3D Synchronized Outdoor Camera System (3D-SOCS): an inexpensive, mobile and automated method for collecting behavioral data on wild animals using synchronized video frames from Raspberry Pi controlled cameras. Accuracy tests demonstrate 3D-SOCS’ markerless tracking can estimate postures with a 3mm tolerance.

To illustrate its research potential, we place 3D-SOCS in the field and conduct a stimulus presentation experiment. We estimate 3D postures and trajectories for multiple individuals of different bird species, and use this data to characterize the visual field configuration of wild great tits (Parus major), a model species in behavioral ecology. We find their optic axes at approximately±60◦azimuth and−5◦elevation. Furthermore, birds exhibit functional lateralization in their use of the right eye with conspecific stimulus, and show individual differences in lateralization. We also show that birds’ convex hulls predicts body weight, highlighting 3D-SOCS’ potential for non-invasive population monitoring.

3D-SOCS is a first-of-its-kind camera system for wild research, presenting exciting potential to measure fine-scaled behavior and morphology in wild birds.
Layer-specific reorganization of mnemonic representations in primate retrosplenial cortex during learning
Authors: Kambi Niranjan A , Afrasiabi Mohsen , Phillips Jessica M , Kenchappa Shobha C , Cleveland Duncan , Redinbaugh Michelle , Mohanta Sounak , Wang Bekah , Fayyad Matt , Saalmann Yuri B
Published: July 2024

Rapid learning of associations between co-occurring stimuli is essential for episodic memory formation. The retrosplenial cortex (RSC) is strongly interconnected with the hippocampus, and in rodents, the RSC has been shown to support spatial navigation and fear conditioning. Although lesion and neuroimaging studies in humans and macaques have further implicated the RSC in episodic memory, it is unclear how memory representations form and evolve in the RSC. Here we show that representations of memorized contexts in primate RSC form within minutes. These initial representations reorganize as the memory matures, with a shift in the weight of neuronal contributions from superficial to deep RSC layers across an hour and increased local connectivity between deep layer neurons. Because RSC superficial and deep layers represent input and output layers respectively, it suggests that hippocampal inputs provide context information to superficial layers during early learning, and this context information consolidates in deep RSC layers.
Cellular Dynamics Upon Immune Checkpoint Inhibition
Authors: Lin Zhongyang , Petrenko Ekaterina , Chandra Mitalee , Srinivas Nalini , Ugurel Selma , Becker Jürgen C. , Aran Dvir
Published: July 2024

Cellular dynamics in the tumor microenvironment upon immune checkpoint inhibition (ICIs) treatment remain largely known. To elucidate these dynamics and associated mechanisms of response and resistance, we analyzed a large-scale single-cell RNA-sequencing dataset of 326 samples from 163 patients across multiple cancer types, with longitudinally site-matched samples. We developed a robust, integration-free deep phenotyping framework, and annotated 1,022,526 cells into 83 granular cell states. Our analysis revealed consistent compositional changes in 19 cell subtypes during ICI treatment, including enhanced adaptive immune responses (e.g., CD8+ IL7R+ central memory T cells, GZMK+ effector memory T cells, germinal center B cells), reduced interferon-responsive immune cells, quiescent CD4+CREM- memory T cells, and angiogenesis tip cells. Co-regulatory network analysis revealed a continuum between two patterns resembling tertiary lymphoid structure maturity. Accumulation of interferon-responsive subtypes was associated with T cell expansion. We further identified a B cell- centric response-specific pattern indicating an enhanced early-phase adaptive immune response favored treatment efficacy, which was subsequently validated through supervised subgroup analysis. Our study presents a comprehensive landscape of TME cellular dynamics during ICI treatment, showcasing the importance of a systems-level understanding in improving patient stratification and advancing personalized cancer immunotherapy.
Different phylogenetic characteristics of Icterids: would they be evolutionary strategies to avoid parasitism by Molothrus spp.?
Authors: Barbosa Vinícius Munhoz , Dinis da Silva Bianca , Xavier da Silva Vinícius , Hasui Érica
Published: July 2024

Some birds exhibit the behavior of nest parasitism, which involves laying their eggs in the nests of other species to be incubated and cared for by the adoptive parents. Among all the studies conducted on this subject, there is a gap regarding the nest type of nest parasites and their hosts. Therefore, using species from the Icteridae family, this study aimed to identify if there is a tendency for more closed nests to be less parasitized than open nests and if there is a phylogenetic relationship between them. In this context, we expected open nests to be an ancestral condition to closed nests, serving as an evolutionary feature to avoid nest parasitism. We also analyzed other characteristics such as the number of eggs, nest type and parental care. As a result, we observed that open nests were more common, while closed nests were predominant in a specific clade and some isolated species. The analyses indicated a phylogenetic signal clustered within the Icteridae family concerning nest types, which may imply a selective pressure. However, we cannot assert that it is a direct response to nest parasitism, as closed nests are also parasitized, specifically byM. oryzivorus. Parental care and diet type also showed phylogenetic signal, indicating that these changes were not random. However, we did not observe associations in host selection by the parasites based on these characteristics. Furthermore, we found a progression in the number of species parasitized byMolothrusspp. along the phylogenetic lineage. We also observed a similarity in host choice betweenM. aterandM. aeneus, indicating evolutionary convergence, as they are not sister groups.
Does Emergency Department point-of-care ultrasound in the evaluation of possible small bowel obstruction lead to meaningful improvements in patient-centric milestones?
Authors: Chen Yi-Ru , Sierra Melva Morales , Nasir Rida , Mahabir Naya , Iyeke Lisa , Jordan Lindsay , Shah Trupti , Burke Kevin , Friedman Matthew , Dexeus Daniel , Mihailos Athena , Richman Mark , Guttman Joshua
Published: July 2024

Introduction

Point-of-care ultrasound (POCUS) has 90-95% sensitivity and specificity for small bowel obstruction (SBO) compared with computed tomography (CT). ED clinicians might reasonably use a positive POCUS to progress to patient-centric milestones (eg, nasogastric tube (NGT) placement, general surgery consult, and disposition). Awaiting CT performance and interpretation before moving to such milestones may delay care. Literature is limited concerning the effects of POCUS vs. CT alone on such patient-centric milestones for patients with SBO. This study compared time to patient-centric milestones (NGT, general surgery consult, and disposition) among ED patients suspected of having SBO who underwent POCUS vs. CT only in their SBO diagnostic process.

Methods

Data from 11,801 SBO patients seen among 14 EDs between 2017-2022 was queried. Patients were categorized into two groups according to diagnostic method (POCUS + CT vs. CT alone). Patients were included if they had a POCUS positive for SBO and an ED diagnosis of SBO; they were excluded from analysis of any specific/particular milestone (NGT, general surgery consult, or disposition) if they had that milestone prior to POCUS. Median time from ED arrival to each milestone was calculated for both groups (POCUS + CT vs. CT alone).

Results

Compared to CT-only patients, patients with POCUS plus CT had a non-statistically-significant longer wait time from ED arrival to NGT (414 vs. 390, p=0.7) and from ED arrival to general surgery consult (487.5 vs. 442 minutes, p = 0.07). They had statistically-significantly longer time to from ED arrival to disposition (475.5 vs. 377 minutes, p=0.009). Among cases in which POCUS was performed, 80% of the time the NGT was placed, 77% of the time the general surgery consult was performed, and 100% of time disposition was made only after CT result rather than after POCUS but before CT result.

Conclusion

Use of POCUS was not associated with earlier achievement of patient-centric milestones (NGT or general surgery consult) and was associated with longer time to disposition. This is most-likely because, despite POCUS suggesting SBO, clinicians waited for CT results prior to placing the NGT, consulting general surgery, and entering the disposition. Such results suggest that, despite POCUS’s high sensitivity and specificity, ED and/or general surgery clinicians rely on CT scan results to confirm SBO, delaying patient-centric milestones.
Plasmodium falciparum multidrug resistance 1gene polymorphisms associated with outcomes after antimalarial treatment
Authors: Laird Veronika R. , Plucinski Mateusz M. , Venkatesan Meera , Rondini Kelsey A. , Randrianarivelojosia Milijaona , Andriamananjara Mauricette N. , Moonga Hawela , Ishengoma Deus S. , Chidimatembue Arlindo , Dimbu Pedro Rafael , Adeothy Adicatou-Laï , Beavogui Abdoul Habib , Kariuki Simon , Nsobya Sam L. , Uwimana Aline , Kahunu Gauthier Mesia , Assefa Ashenafi , Koita Ousmane A. , Lucchi Naomi W. , Souza Samaly S. Svigel , Zhou Zhiyong , Moriarty Leah F. , Halsey Eric S.
Published: July 2024

Article summary

This study suggests that: 1) patients given AL infected with parasites carrying N86 were statistically more likely to experience a recurrent infection; 2) patients given ASAQ infected with parasites carrying 86Y were statistically more likely to experience a recurrent infection.

Background

Plasmodium falciparum multidrug resistance transporter 1(Pfmdr1) gene mutations are associated with altered response to artemisinin-based combination therapies (ACTs), particularly those containing the partner drugs lumefantrine and amodiaquine (i.e., artemether-lumefantrine [AL] and artesunate-amodiaquine [ASAQ]). Past studies ofPfmdr1single nucleotide polymorphisms (SNPs) at codons 86, 184, and 1246 have shown different responses to AL and ASAQ.

Methods

To determine whether infection with parasites carrying specificPfmdr1SNPs leads to increased risk of recurrent parasitemia (recrudescent or new infection), data from 4,129 samples from 16 therapeutic efficacy studies from 13 African countries between 2013–2019 were analyzed.

Results

Patients treated with AL and infected with parasites carryingPfmdr1N86 were at greater risk of treatment failure than those whose parasites carried 86Y. After treatment with ASAQ, individuals infected with parasites that carriedPfmdr186Y were more likely to experience a recurrent infection.

Conclusions

Our results support prior studies that suggested: 1) patients given AL and infected with parasites carrying N86 were more likely to experience a recurrent infection; 2) patients given ASAQ and infected with parasites carrying 86Y were more likely to experience recurrent infection. These findings suggest that ACT andPfmdr1genotype may influence outcome afterP. falciparuminfection.
Trajectories of physical activity after ischemic stroke: exploring prediction of change
Authors: Damsbo Andreas Gammelgaard , Blauenfeldt Rolf Ankerlund , Andersen Grethe , Johnsen Søren P. , Mortensen Janne Kaergaard
Published: July 2024

Background and aims

Physical activity (PA) is associated with lower risk of stroke and better functional outcome. However, sedentary behavior after stroke is prevalent. We aimed to identify predictors for PA after first-time ischemic stroke and to develop prediction models to assess change in PA after stroke.

Methods

We used the Physical Activity Scale for the Elderly (PASE) to quantify PA prior to stroke and six months after stroke. Demographic and clinical data were enriched with registry data on socioeconomic status (SES). Associations with post-stroke PA were analyzed using linear regression. Elastic net regression models were used to predict decrease from higher PASE quartile to the lowest and increase from lowest to higher.

Results

A total of 523 patients, from The Efficacy of Citalopram Treatment in Acute Ischemic Stroke (TALOS) trial, had complete PASE data. Median [IQR] age was 69 years [59, 77], 181 (35%) were female and median [IQR] National Institute of Health Stroke Scale score was 3 [2, 5]. Overall, median PASE score did not change, but 20 % of patients decreased to the lowest PASE quartile whereas 48% from the lowest PASE quartile increased to a higher level. The prediction model performance, as represented by the area under receiver operating curve, was 0.679 for predicting a decrease and 0.619 for predicting an increase in PA. SES was the most consistent predictor for both decrease and for a lack of increase in PA.

Conclusions

Almost 1/2 of the least active patients increased their PA after stroke whereas 1/5 decreased to the least active level with socioeconomic factors being the most consistent predictors for change. Despite including comprehensive data, the PA prediction models had a modest predictive performance. Efforts to optimize PA should include all stroke survivors to improve PA for previously inactive patients and prevent PA decrease.
Genome-wide association studies of thyroid-related hormones, dysfunction, and autoimmunity among 85,421 Chinese pregnancies
Authors: Wei Yuandan , Zhen Jianxin , Hu Liang , Gu Yuqin , Liu Yanhong , Guo Xinxin , Yang Zijing , Zheng Hao , Cheng Shiyao , Wei Fengxiang , Xiong Likuan , Liu Siyang
Published: July 2024

Maintaining normal thyroid function is crucial in pregnancy, yet thyroid dysfunction and the presence of thyroid peroxidase antibodies (TPOAb) affect 0.5% to 18% of pregnant women. Here, we conducted a genome-wide association study (GWAS) of eight thyroid traits, including two thyroid-related hormones, four thyroid dysfunctions, and two thyroid autoimmunity measurements among 85,421 Chinese pregnant women to investigate the genetic basis of thyroid function during pregnancy. Our study identified 176 genetic loci, including 125 previously unknown genome-wide associations. Joint epidemiological and Mendelian randomization analyses revealed significant associations between the gestational thyroid phenotypes and gestational complications, birth outcomes, and later-age health outcomes. Specifically, genetically elevated thyroid-stimulating hormone (TSH) levels during pregnancy correlated with lower glycemic levels, reduced blood pressure, and longer gestational duration. Additionally, TPOAb and thyroid functions during pregnancy share genetic correlations with later-age thyroid and cardiac disorders. These findings provide novel insights into the genetic determinants of thyroid traits during pregnancy, which may lead to new therapeutics, early pre-diagnosis and preventive strategies starting from early adulthood.
A transphyletic study of metazoan β-catenin protein complexes
Authors: Mbogo Ivan , Kawano Chihiro , Nakamura Ryotaro , Tsuchiya Yuko , Villar-Briones Alejandro , Hirao Yoshitoshi , Yasuoka Yuuri , Hayakawa Eisuke , Tomii Kentaro , Watanabe Hiroshi
Published: July 2024

β-catenin is essential for various biological processes, such as body axis determination and cell differentiation, during embryonic development in metazoans. β-catenin functions are thought to be exerted through complexes formed with various types of proteins. Although β-catenin complex proteins have been identified in several bilaterians, little is known about the structural and functional properties of β-catenin complexes in early metazoan evolution. In this study, we performed a comparative analysis of β-catenin sequences in nonbilaterian lineages that diverged early in metazoan evolution. We also carried out transphyletic function experiments with β-catenin from nonbilaterian metazoans using developingXenopusembryos, which included secondary axis induction in embryos and proteomic analysis of β-catenin protein complexes. Comparative functional analysis of nonbilaterian β-catenins demonstrated sequence characteristics important for β-catenin functions, and the deep origin and evolutionary conservation of the cadherin-catenin complex. Proteins co-immunoprecipitated with β-catenin included several proteins conserved among metazoans. These data provide new insights into the conserved repertoire of β-catenin complexes.
Unravelling the progression of the zebrafish primary body axis with reconstructed spatiotemporal transcriptomics
Authors: Dong Yang , Cheng Tao , Liu Xiang , Fu Xin-Xin , Hu Yang , Yang Xian-Fa , Yang Ling-En , Li Hao-Ran , Bian Zhi-Wen , Jing Naihe , Liao Jie , Fan Xiaohui , Xu Peng-Fei
Published: July 2024

Elucidating the spatiotemporal dynamics of gene expression is essential for understanding complex physiological and pathological processes. Traditional technologies likein situhybridization (ISH) and immunostaining have been restricted to analyzing expression patterns of a limited number of genes. Spatial transcriptomics (ST) has emerged as a robust alternative, enabling the investigation of spatial patterns of thousands of genes simultaneously. However, current ST methods are hindered by low read depths and limited gene detection capabilities. Here, we introduce Palette, a pipeline that infers detailed spatial gene expression patterns from bulk RNA-seq data, utilizing existing ST data as only reference. This method identifies more precise expression patterns by smoothing, imputing and adjusting gene expressions. We applied Palette to construct theDaniorerioSpatioTemporalExpressionProfiles (DreSTEP)by integrating 53-slice serial bulk RNA-seq data from three developmental stages with existing ST references and 3D zebrafish embryo images.DreSTEP provides a comprehensive cartographic resource for examining gene expression and spatial cell-cell interactions within zebrafish embryos. Utilizing machine learning-based screening, we identified key morphogens and transcription factors (TFs) essential for anteroposterior (AP) axis development and characterized their dynamic distribution throughout embryogenesis. In addition, among these TFs, Hox family genes were found to be pivotal in AP axis refinement. Their expression was closely correlated with cellular AP identities, andhoxbgenes may act as central regulators in this process.
The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4
Authors: Feringa Femke M. , Koppes-den Hertog Sascha J. , Wang Lian , Derks Rico J.E. , Kruijff Iris , Erlebach Lena , Heijneman Jorin , Miramontes Ricardo , Pömpner Nadine , Blomberg Niek , Olivier-Jimenez Damien , Johansen Lill Eva , Cammack Alexander J. , Giblin Ashling , Toomey Christina E , Rose Indigo V.L. , Yuan Hebao , Ward Michael , Isaacs Adrian M. , Kampmann Martin , Kronenberg-Versteeg Deborah , Lashley Tammaryn , Thompson Leslie M. , Ori Alessandro , Mohammed Yassene , Giera Martin , van der Kant Rik
Published: July 2024

Lipid changes in the brain have been implicated in many neurodegenerative diseases including Alzheimer’s Disease (AD), Parkinson’s disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named the Neurolipid Atlas, that we have pre-populated with novel human, mouse and isogenic induced pluripotent stem cell (iPSC)-derived lipidomics data for different brain diseases. We show that iPSC-derived neurons, microglia and astrocytes display distinct lipid profiles that recapitulatein vivolipotypes. Leveraging multiple datasets, we show that the AD risk gene ApoE4 drives cholesterol ester (CE) accumulation in human astrocytes recapitulating CE accumulation measured in the human AD brain. Multi-omic interrogation of iPSC-derived astrocytes revealed that cholesterol plays a major role in astrocyte interferon-dependent pathways such as the immunoproteasome and major histocompatibility complex (MHC) class I antigen presentation. We show that through enhanced cholesterol esterification ApoE4 suppresses immune activation of astrocytes. Our novel data commons, available at neurolipidatlas.com, provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.
A novel behavioral paradigm using mice to study predictive postural control
Authors: Doi Yurika , Asaka Meiko , Born Richard T. , Yanagihara Dai , Uchida Naoshige
Published: July 2024

Postural control circuitry performs the essential function of maintaining balance and body position in response to perturbations that are either self-generated (e.g. reaching to pick up an object) or externally delivered (e.g. being pushed by another person). Human studies have shown that anticipation of predictable postural disturbances can modulate such responses. This indicates that postural control could involve higher-level neural structures associated with predictive functions, rather than being purely reactive. However, the underlying neural circuitry remains largely unknown. To enable studies of predictive postural control circuits, we developed a novel experimental paradigm formice. In this paradigm, modeled after human studies, a dynamic platform generated reproducible translational perturbations. While mice stood bipedally atop a perch to receive water rewards, they experienced backward translations that were either unpredictable or preceded by an auditory cue. To validate the paradigm, we investigated the effect of the auditory cue on postural responses to perturbations across multiple days in three mice. These preliminary results serve to validate a new postural control experimental paradigm, opening the door to the types of neural recordings and circuit manipulations that are currently possible in mice.

Significance Statement

The ability to anticipate disturbances and adjust one’s posture accordingly—known as “predictive postural control”—is crucial for preventing falls and for advancing robotics. While human balance is often assessed via floor perturbations, rodent studies typically use rotarod tests. Here, we developed a postural perturbation task for freely moving mice, modeled after those used in human studies. Using a dynamic platform, we delivered reproducible perturbations with or without preceding auditory cues and quantified how the auditory cue affects postural responses to perturbations. Our work provides validation of a new postural control experimental paradigm, which opens the door to the types of neural population recordings and circuit manipulation that are currently possible in mice.
Early ctDNA kinetics as a dynamic biomarker of cancer treatment response
Authors: Li Aaron , Lou Emil , Leder Kevin , Foo Jasmine
Published: July 2024

Circulating tumor DNA assays are promising tools for the prediction of cancer treatment response. Here, we build a framework for the design of ctDNA biomarkers of therapy response that incorporate variations in ctDNA dynamics driven by specific treatment mechanisms. We develop mathematical models of ctDNA kinetics driven by tumor response to several therapy classes, and utilize them to simulate randomized virtual patient cohorts to test candidate biomarkers. Using this approach, we propose specific biomarkers, based on ctDNA longitudinal features, for targeted therapy, chemotherapy and radiation therapy. We evaluate and demonstrate the efficacy of these biomarkers in predicting treatment response within a randomized virtual patient cohort dataset. These biomarkers are based on novel proposals for ctDNA sampling protocols, consisting of frequent sampling within a compact time window surrounding therapy initiation – which we hypothesize to hold valuable prognostic information on longer-term treatment response. This study highlights a need for tailoring ctDNA sampling protocols and interpretation methodology to specific biological mechanisms of therapy response, and it provides a novel modeling and simulation framework for doing so. In addition, it highlights the potential of ctDNA assays for making early, rapid predictions of treatment response within the first days or weeks of treatment, and generates hypotheses for further clinical testing.
Nepali oral microbiomes reflect a gradient of lifestyles from traditional to industrialized
Authors: Ryu Erica P , Gautam Yoshina , Proctor Diana M , Bhandari Dinesh , Tandukar Sarmila , Gupta Meera , Gautam Guru Prasad , Relman David A , Shibl Ahmed A , Sherchand Jeevan Bahadur , Jha Aashish R , Davenport Emily R
Published: July 2024

Background: Lifestyle plays an important role in shaping the gut microbiome. However, its contributions to the oral microbiome remains less clear, due to the confounding effects of geography and methodology in investigations of populations studied to date. Furthermore, while the oral microbiome seems to differ between foraging and industrialized populations, we lack insight into whether transitions to and away from agrarian lifestyles shape the oral microbiota. Given the growing interest in so-called 'vanishing microbiomes' potentially being a risk factor for increased disease prevalence in industrialized populations, it is important that we distinguish lifestyle from geography in the study of microbiomes across populations. Results: Here, we investigate salivary microbiomes of 63 Nepali individuals representing a spectrum of lifestyles: foraging, subsistence farming (individuals that transitioned from foraging to farming within the last 50 years), agriculturalists (individuals that have transitioned to farming for at least 300 years), and industrialists (expatriates that immigrated to the United States within the last 20 years). We characterize the role of lifestyle in microbial diversity, identify microbes that differ between lifestyles, and pinpoint specific lifestyle factors that may be contributing to differences in the microbiomes across populations. Contrary to prevailing views, when geography is controlled for, oral microbiome alpha diversity does not differ significantly across lifestyles. Microbiome composition, however, follows the gradient of lifestyles from foraging through agrarianism to industrialism, supporting the notion that lifestyle indeed plays a role in the oral microbiome. Relative abundances of several individual taxa, including Streptobacillus and an unclassified Porphyromonadaceae genus, also mirror lifestyle. Finally, we identify specific lifestyle factors associated with microbiome composition across the gradient of lifestyles, including smoking and grain source. Conclusion: Our findings demonstrate that by controlling for geography, we can isolate an important role for lifestyle in determining oral microbiome composition. In doing so, we highlight the potential contributions of several lifestyle factors, underlining the importance of carefully examining the oral microbiome across lifestyles to improve our understanding of global microbiomes.
Polyunsaturated Fatty Acid - mediated Cellular Rejuvenation for Reversing Age-related Vision Decline
Authors: Gao Fangyuan , Tom Emily , Rydz Cezary , Cho William , Kolesnikov Alexander V. , Sha Yutong , Papadam Anastasios , Jafari Samantha , Joseph Andrew , Ahanchi Ava , Saraei Nika Balalaei Someh , Lyon David , Foik Andrzej , Nie Qing , Grassmann Felix , Kefalov Vladimir J. , Skowronska-Krawczyk Dorota
Published: July 2024

The retina is uniquely enriched in polyunsaturated fatty acids (PUFAs), which are primarily localized in cell membranes, where they govern membrane biophysical properties such as diffusion, permeability, domain formation, and curvature generation. During aging, alterations in lipid metabolism lead to reduced content of very long-chain PUFAs (VLC-PUFAs) in the retina, and this decline is associated with normal age-related visual decline and pathological age-related macular degeneration (AMD).ELOVL2(Elongation of very-long-chain fatty acids-like 2) encodes a transmembrane protein that produces precursors to docosahexaenoic acid (DHA) and VLC-PUFAs, and methylation level of its promoter is currently the best predictor of chronological age. Here, we show that mice lacking ELOVL2-specific enzymatic activity (Elovl2C234W) have impaired contrast sensitivity and slower rod response recovery following bright light exposure. Intravitreal supplementation with the direct product of ELOVL2, 24:5n-3, in aged animals significantly improved visual function and reduced accumulation of ApoE, HTRA1 and complement proteins in sub-RPE deposits. At the molecular level, the gene expression pattern observed in retinas supplemented with 24:5n-3 exhibited a partial rejuvenation profile, including decreased expression of aging-related genes and a transcriptomic signature of younger retina. Finally, we present the first human genetic data showing significant association of several variants in the humanELOVL2locus with the onset of intermediate AMD, underlying the translational significance of our findings. In sum, our study identifies novel therapeutic opportunities and defines ELOVL2 as a promising target for interventions aimed at preventing age-related vision loss.
Genetic hypogonadal (Gnrh1hpg) mouse model uncovers influence of reproductive axis on maturation of the gut microbiome during puberty
Authors: Sisk-Hackworth Laura , Akhavan Shayan R. , Krutkin Dennis D. , Kelley Scott T. , Thackray Varykina G.
Published: July 2024

The gut microbiome plays a key role in human health and gut dysbiosis is linked to many sex-specific diseases including autoimmune, metabolic, and neurological disorders. Activation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty leads to sexual maturation and development of sex differences through the action of gonadal sex steroids. While the gut microbiome also undergoes sex differentiation, the mechanisms involved remain poorly understood. Using a genetic hypogonadal (hpg) mouse model, we sampled the fecal microbiome of male and female wild-type and hpg mutant mice before and after puberty to determine how microbial taxonomy and function are influenced by age, sex, and the HPG axis. We showed that HPG axis activation during puberty is required for sexual maturation of the gut microbiota composition, community structure, and metabolic functions. We also demonstrated that some sex differences in taxonomic composition and amine metabolism developed independently of the HPG axis, indicating that sex chromosomes are sufficient for certain sex differences in the gut microbiome. In addition, we showed that age, independent of HPG axis activation, led to some aspects of pubertal maturation of the gut microbiota community composition and putative functions. These results have implications for microbiome-based treatments, indicating that sex, hormonal status, and age should be considered when designing microbiome-based therapeutics.
APCCdh1-mediated degradation of Cdh1 is necessary for faithful meiotic chromosome segregation inS. cerevisiae
Authors: Ostapenko Denis , Solomon Mark J.
Published: July 2024

The Anaphase-Promoting Complex/Cyclosome (APC/C) is a ubiquitin ligase that promotes the ubiquitination and subsequent degradation of numerous cell cycle regulators during mitosis and in G1. Proteins are recruited to the APC/C by activator proteins such as Cdh1. During the cell cycle, Cdh1 is subject to precise regulation so that substrates are not degraded prematurely. We have explored the regulation of Cdh1 during the developmental transition into meiosis and sporulation in the budding yeastS. cerevisiae. Transition to sporulation medium triggers the degradation of Cdh1. Cdh1 degradation is mediated by the APC/C itself in a “trans” mechanism in which one molecule of Cdh1 recruits a second molecule of Cdh1 to the APC/C for ubiquitination. Degradation requires an intact glucose-sensing SNF1 protein kinase complex (orthologous to the mammalian AMPK nutritional sensor), which directly phosphorylates Cdh1 on Ser-200 within an unstructured N-terminal region. In the absence of phosphorylation, expression of a Cdh1-S200A mutant is fully stabilized, leading to chromosome instability and loss of viability. We hypothesize that Cdh1 degradation is necessary for the preservation of cell cycle regulators and chromosome cohesion proteins between the reductional and equational meiotic divisions, which occur without the intervening Gap or S phases found in mitotic cell cycles.
Preparatory attentional templates in prefrontal and sensory cortex encode target-associated information
Authors: Zhou Zhiheng , Geng Joy J.
Published: July 2024

Visual search relies on the ability to use information about the target in working memory to guide attention and make target-match decisions. The representation of target features is referred to as the “attentional” or “target” template and is thought to be encoded within an IFJ-visual cortical network (Baldauf & Desimone, 2014; Bichot et al., 2015b). The contents of the template typically contain veridical target information that is used to modulate sensory processing in preparation for guiding attention during search. However, many behavioral studies have shown that target-associated information is used to guide attention, especially when target discrimination is difficult (Battistoni et al., 2017; de Lange et al., 2018; Peelen et al., 2024; Vo et al., 2019; Yu et al., 2023; Zhou & Geng, 2024). Thus, while target-associated information is known to impact search performance, its presence within the IFJ-visual attentional network during the preparatory period has never been demonstrated. Here, we use fMRI and multivariate pattern analysis, to test if attentional guidance by target-associated information is explicitly represented in the preparatory period before search begins, either in conjunction with the target or even in place of it. Participants were first trained on four face-scene category pairings after which they completed a cued visual search task for the same faces. Each trial began with a face cue, followed by a delay period, and then a search display with two lateralized faces superimposed on scene images. The critical results showed that while face information could be decoded in the fusiform face area (FFA), superior parietal lobule (SPL), and dorsolateral prefrontal cortex (dLPFC), during the cue period, face information could not be decoded in any brain regions during the delay period. In contrast, the associated scene was decoded only in ventrolateral prefrotnal cortex (vLPFC) curing the cue period but most importantly, in the inferior frontal junction (IFJ) and the parahippocampal place area (PPA) during the delay period. Our results are a novel demonstration that target-associated information from memory can supplant veridical target information in the brain’s “target template” in anticipation of difficult visual search.
The Mediating Role of Sleep in the Association Between Environmental Noise and Mental Health
Authors: Grocott Kaya , Mansour Adelle , Bentley Rebecca , Mason Kate E.
Published: July 2024

Exposure to environmental noise in residential areas has been associated with adverse mental health outcomes; however, the mechanisms of this relationship remain underexplored. This study investigates the contribution of reduced sleep quality to the negative association between perceived neighbourhood environmental noise exposure and poor mental health. We used the Household Income and Labour Dynamics in Australia (HILDA) survey and applied causal mediation methods to examine the role of sleep in the association between self-reported exposure to road traffic noise and plane, train and industry (PTI) noise and mental wellbeing at three time points between 2012 and 2021. Road traffic noise was associated with poorer mental health in 2012-13 and 2016-17, while no evidence of an association was observed in 2020-2021 (the period of COVID-related lockdowns in Australia). For the years where a significant association was observed, mediation analyses suggest that reduced sleep quality accounts for 21% (in 2012-13; 95% CI: 7–35%) and 33% (in 2016-17; 95% CI: 26–64%) of the total effect of perceived traffic noise on mental health. Perceived PTI noise was associated with poorer mental health in 2016-2017 and 2020-2021, with mediation through sleep observed in 2016-2017 (proportion mediated 20% (95% CI:3–38%)). Mediation by sleep quality was stronger among people reporting exposure to multiple noise sources than among people reporting exposure to a single noise source. As much as a third of the association between road traffic noise and poor mental wellbeing may be due to poorer sleep quality following exposure to unwanted noise.