bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing data quality on fetal brain MRI reconstruction: a multi-site and multi-rater study
Authors: Sanchez Thomas , Mihailov Angeline , Gomez Yvan , Juan Gerard Martí , Eixarch Elisenda , Jakab Andras , Dunet Vincent , Koob Mériam , Auzias Guillaume , Cuadra Meritxell Bach
Published: July 2024

Quality assessment (QA) has long been considered essential to guarantee the reliability of neuroimaging studies. It is particularly important for fetal brain MRI, where unpredictable fetal motion can lead to substantial artifacts in the acquired images. Multiple images are then combined into a single volume through super-resolution reconstruction (SRR) pipelines, a step that can also introduce additional artifacts. While multiple studies designed automated quality control pipelines, no work evaluated the reproducibility of the manual quality ratings used to train these pipelines. In this work, our objective is twofold. First, we assess the inter- and intra-rater variability of the quality scoring performed by three experts on over 100 SRR images reconstructed using three different SRR pipelines. The raters were asked to assess the quality of images following 8 specific criteria like blurring or tissue contrast, providing a multi-dimensional view on image quality. We show that, using a protocol and training sessions, artifacts like bias field and blur level still have a low agreement (ICC below 0.5), while global quality scores show very high agreement (ICC = 0.9) across raters. We also observe that the SRR methods are influenced differently by factors like gestational age, input data quality and number of stacks used by reconstruction. Finally, our quality scores allow us to unveil systematic weaknesses of the different pipelines, indicating how further development could lead to more robust, well rounded SRR methods.
A high-throughput approach for the efficient prediction of perceived similarity of natural objects
Authors: Kaniuth Philipp , Mahner Florian P. , Perkuhn Jonas , Hebart Martin N.
Published: July 2024

Perceived similarity offers a window into the mental representations underlying our ability to make sense of our visual world, yet, the collection of similarity judgments quickly becomes infeasible for larger datasets, limiting their generality. To address this challenge, here we introduce a computational approach that predicts perceived similarity from neural network activations through a set of 49 interpretable dimensions learned on 1.46 million triplet odd-one-out judgments. The approach allowed us to predict separate, independently-sampled similarity scores with an accuracy of up to 0.898. Combining this approach with human ratings of the same dimensions led only to small improvements, indicating that the neural network used similar information as humans in this task. Predicting the similarity of highly homogeneous image classes revealed that performance critically depends on the granularity of the training data. Our approach allowed us to improve the brain-behavior correspondence in a large-scale neuroimaging dataset and visualize candidate image features humans use for making similarity judgments, thus highlighting which image parts may carry behaviorally-relevant information. Together, our results demonstrate that current neural networks carry information sufficient for capturing broadly-sampled similarity scores, offering a pathway towards the automated collection of similarity scores for natural images.
ExploringPorphyromonas gingivalisPathogenesis and Antibody Pool Effect Using a Novel Mouse Reproductive Model
Authors: Shi Xiaoju , Xu Maria
Published: July 2024

This study introduces a novel animal model consisting of two phases. In phase I, Balb/c mice received three intraperitoneal injections of antibodies and two subcutaneous challenges withPorphyromonas gingivalis. The mice were divided into seven groups: G1, G2, and G3 received a single monoclonal antibody targeting the major outer membrane protein RagB ofP. gingivalisand infection; G4 was infected without antibody; G5 and G6 received a mixture of monoclonal antibodies and infection; and G7 served as the healthy control. In phase II, one male was paired with one female from the same group and one healthy female. Fertility was assessed using maximum body weight growth rate (MWGR) and alive pup rate (APR).

Results indicated that the APR of neonatal mice in G5+G6 significantly lower than G1-G3 and G7 (P < 0.05). Similarly, the MWGR of G5+G6 significantly lower than G7 (P < 0.05). Notably, the APR and MWGR in G4, which received no antibody, were lower than in G7 but higher than in G5-G6. These findings suggest that a mixture of antibodies coexisting withP. gingivalisinfection leads to more detrimental reproductive damage than infection alone. The so-called Antibody Pool Effect plays a role in the pathogenesis ofP. gingivalis. Understanding the mechanisms of this immunopathological damage may provide insights into the correlation betweenP. gingivalisinfection and systemic diseases.
Population genetic consequences of the seasonal migrations of birds
Authors: Pegan T.M. , Kimmitt A.A. , Benz B.W. , Weeks B.C. , Aubry Y. , Burg T.M. , Hudon J. , Jones A.W. , Kirchman J.J. , Ruegg K. , Winger B.M.
Published: July 2024

Differences in life history can cause co-distributed species to display discordant population genetic patterns. In high-latitude animals, evolutionary processes may be especially influenced by long-distance seasonal migration, a widespread adaptation to seasonality. Although migratory movements are intuitively linked to dispersal, their evolutionary genetic consequences remain poorly understood. Using ∼1700 genomes from 35 co-distributed boreal-breeding bird species, we reveal that most long-distance migrants exhibit spatial genetic structure, revealing evolutionary effects of philopatry rather than dispersal. We further demonstrate that migration distance and genetic diversity are strongly positively correlated in our study species. This striking relationship suggests that the adaptive seasonal shifts in biogeography that long-distance migratory species undergo each year lends them enhanced population stability that preserves genetic diversity relative to shorter-distance migrants that winter at higher latitudes. Our results suggest that the major impact of long-distance seasonal migration on population genetic evolution occurs through promotion of demographic stability, rather than facilitation of dispersal.
Nucleus accumbens sub-regions experience distinct dopamine release responses following acute and chronic morphine exposure
Authors: Gooding Sarah Warren , Lewis Elinor , Chau Christine , Sandhu Suhail , Glienke Julianna , Whistler Jennifer L.
Published: July 2024

It is well established that dopamine neurons of the ventral tegmental area (VTA) play a critical role in reward and aversion as well as pathologies including drug dependence and addiction. The distinct effects of acute and chronic opioid exposure have been previously characterized at VTA synapses. Recent work suggests that distinct VTA projections that target the medial and lateral shell of the nucleus accumbens (NAc), may play opposing roles in modulating behavior. It is possible that these two anatomically and functionally distinct pathways also have disparate roles in opioid reward, tolerance, and withdrawal in the brain. In this study we monitored dopamine release in the medial or lateral shell of the NAc of male mice during a week-long morphine treatment paradigm. We measured dopamine release in response to an intravenous morphine injection both acutely and following a week of repeated morphine. We also measured dopamine in response to a naloxone injection both prior to and following repeated morphine treatment. Morphine induced a transient increase in dopamine in the medial NAc shell that was much larger than the slower rise observed in the lateral shell. Surprisingly, chronic morphine treatment induced a sensitization of the medial dopamine response to morphine that opposed a diminished response observed in the saline-treated control group. This study expands on our current understanding of the medial NAc shell as hub of opioid-induced dopamine fluctuation. It also highlights the need for future opioid studies to appreciate the heterogeneity of dopamine neurons.

Significance Statement

The social and economic consequences of the opioid epidemic are tragic and far-reaching. Yet, opioids are indisputably necessary in clinical settings where they remain the most useful treatment for severe pain. To combat this crisis, we must improve our understanding of opioid function in the brain, particularly the neural mechanisms that underlie opioid dependence and addictive behaviors. This study uses fiber photometry to examine dopamine changes that occur in response to repeated morphine, and morphine withdrawal, at multiple stages of a longitudinal opioid-dependence paradigm. We reveal key differences in how dopamine levels respond to opioid administration in distinct sub-regions of the ventral striatum and lay a foundation for future opioid research that appreciates our contemporary understanding of the dopamine system.
A graph-based practice of evaluating collective identities of cell clusters
Authors: Okano Yuji , Kase Yoshitaka , Okano Hideyuki
Published: July 2024

The rise of single-cell RNA-sequencing (scRNA-seq) and evolved computational algorithms have significantly advanced biomedical science by revealing and visualizing the multifaceted and diverse nature of single cells. These technical advancements have also highlighted the pivotal role of cell clusters as representations of biologically universal entities such as cell types and cell states. However, to some extent, these clusterings remain dataset-specific and method-dependent. To improve comparability across different datasets or compositions, we previously introduced a graph-based representation of cell collections that captures the statistical dependencies of their characteristic genes.

While our earlier work focused on theoretical insights, it was not sufficiently adapted and fine-tuned for practical implementation. To address this, the present paper introduces an improved practice to define and evaluate cellular identities based on our theory. First, we provide a concise summary of our previous theory and workflow. Then, point-by-point, we highlight the issues that needed fixing and propose solutions. The framework’s utility was enhanced by leveraging alternative formats of cellular features such as gene ontology (GO) terms and effectively handling dropouts. Supplemental techniques are offered to reinforce the versatility and robustness of our method.
Knock out of the intracellular calcium conducting ion channel Mitsugumin 23 (MG23) protects against pressure overload induced left ventricular hypertrophy and cardiac dysfunction
Authors: Dorward Amy M. , Robertson Gavin B. , Sneddon Claire , O’Rourke Chloe L. , Um In Hwa , Harrison David J. , Nishi Miyuki , Takeshima Hiroshi , Murdoch Colin E. , Pitt Samantha J.
Published: July 2024

Background

In cardiac dysfunction, intracellular Ca2+-dynamics are disrupted leading to leakage of Ca2+from the sarcoplasmic reticulum (SR). This results in diminished cardiac contractility and impaired cardiac function. In cardiac tissue, the underlying molecular mechanisms responsible for RyR2-independent Ca2+leak are poorly understood. Mitsugumin 23 (MG23) is an intracellular Ca2+-conducting ion channel located on ER/SR and nuclear membranes. We propose that MG23 contributes to regulation of intracellular Ca2+-homeostasis, and that altered MG23 function may drive progression of cardiac dysfunction. The aim of this research was to investigate the role of MG23 in SR Ca2+leak, and whether knock out ofMg23protects the heart against pressure-overload induced left ventricular hypertrophy.

Methods

Cardiac pressure-overload was induced in wild type (WT) andMg23-knock out (KO) mice through subcutaneous Angiotensin II (AngII, 1.1 mg/kg/day) infusion via osmotic pump. After 10-days infusion,in vivopressure-volume dynamics were measured by insertion of a pressure-volume catheter into the left ventricle. MG23 protein expression was assessed through Western blot analysis. Ventricular fibrosis and cardiomyocyte size were measured using histological and immunofluorescence approaches. Cardiomyocytes were isolated from WT andMg23-KO hearts and intracellular Ca2+dynamics assessed through live cell imaging using the Ca2+indicator Fluo-4.

Results

AngII-induced cardiac pressure-overload increased expression of MG23 in WT mouse hearts. Knock out ofMg23protected hearts against AngII-induced cardiac hypertrophy. Compared to WT animals, AngII treatedMg23-KO mice displayed a significant reduction in left ventricular fibrosis and displayed normal cardiac functioning. InMg23-KO hearts, no alteration in expression of key Ca2+handling proteins was identified, but cardiomyocytes displayed altered Ca2+spark profiles consistent with a role for MG23 in SR Ca2+leak.

Conclusion

MG23 plays a key role in driving Ca2+dysregulation observed in the early pathological stages of pressure-overload induced heart failure.
e3SIM: epidemiological-ecological-evolutionary simulation framework for genomic epidemiology
Authors: Xu Peiyu , Liang Shenni , Hahn Andrew , Zhao Vivian , Lo Wai Tung 'Jack' , Haller Benjamin C. , Sobkowiak Benjamin , Chitwood Melanie H. , Colijn Caroline , Cohen Ted , Rhee Kyu Y. , Messer Philipp W. , Wells Martin T. , Clark Andrew G. , Kim Jaehee
Published: July 2024

Infectious disease dynamics are driven by the complex interplay of epidemiological, ecological, and evolutionary processes. Accurately modeling these interactions is crucial for understanding pathogen spread and informing public health strategies. However, existing simulators often fail to capture the dynamic interplay between these processes, resulting in oversimplified models that do not fully reflect real-world complexities in which the pathogen's genetic evolution dynamically influences disease transmission. We introduce the epidemiological-ecological-evolutionary simulator (e3SIM), an open-source framework that concurrently models the transmission dynamics and molecular evolution of pathogens within a host population while integrating environmental factors. Using an agent-based, discrete-generation, forward-in-time approach, e3SIM incorporates compartmental models, host-population contact networks, and quantitative-trait models for pathogens. This integration allows for realistic simulations of disease spread and pathogen evolution. Key features include a modular and scalable design, flexibility in modeling various epidemiological and population-genetic complexities, incorporation of time-varying environmental factors, and a user-friendly graphical interface. We demonstrate e3SIM's capabilities through simulations of realistic outbreak scenarios with SARS-CoV-2 and Mycobacterium tuberculosis, illustrating its flexibility for studying the genomic epidemiology of diverse pathogen types.
The aging musician: Evidence of a downward trend in song tempo as a function of artist age
Authors: Luck Geoff , Ansani Alessandro
Published: July 2024

Correspondences between the timing of motor behavior and that of musical performance are well-established. Motor behavior, however, is known to degrade across the adult lifespan due to neurobiological decay. In particular, performance on speed-dependent motor tasks deteriorates, spontaneous motor tempo (SMT) slows, and upper motor rate limit falls. Here, we examine whether this slowdown in motor behavior impacts tempo of musical performance as a function of age. We analyzed 14,556 songs released between 1956 and 2020 by artists with careers spanning at least 20 years. Generalized Additive Mixed Models (GAMMs) and Linear Mixed Models (LMMs) were employed to assess the effects of age, operationalized by subtracting birth year from release year of each track, on musical tempo. Results revealed a slight tempo increase from early adulthood to age 30, followed by a marked, linear slowdown with age across the remainder of the lifespan. From artists’ thirties to their eighties, tempo decreased by almost 10 bpm, averaging around 2 bpm per decade. This decrease aligns with the slowing-with-age hypothesis and mirrors rates of decline observed in studies of spontaneous motor tempo (SMT) and gait speed. Our findings highlight a significant gap in understanding of creative performance across the lifespan, particularly the role of age as a mediating factor in musical tempo. Moreover, that a discernible decrease in tempo is apparent even in commercial recordings further emphasizes the inescapable connection between dynamics of motor behavior and timing of musical performance.
TGFβ-ANGPT2-Tie2 axis in cancer-associated fibroblasts reprograms oral cancer cells to embryonic-like cell state with predictive significance of poor prognosis
Authors: Mitra Paromita , Saha Uday , Stephen Kingsly Joshua , Prasad Priyanka , Patel Ankit Kumar , Harshvardhan BV , Mondal Santosh Kumar , Kurkalang Sillarine , Roy Sumitava , Ghosh Arnab , Roy Shantanu Saha , Das Sarma Jayasri , Biswas Nidhan Kumar , Acharya Moulinath , Sharan Rajeev , Arun Pattatheyil , Jolly Mohit Kumar , Maitra Arindam , Singh Sandeep
Published: July 2024

Myofibroblastic cancer-associated fibroblasts (CAFs) in tumor stroma is identified as poor-prognostic indicator in oral cancer; however, biological mechanisms are largely unexplored. Here, we discovered the role of autocrine or exogenous transforming growth factor beta (TGFβ) in inducing Tunica Interna Endothelial cell kinase 2 (Tie2) -signaling through histone deacetylase-mediated downregulation of Tie2-antagonist, Angiopoietin-2 in CAFs, responsible for induction and maintenance of myofibroblastic differentiation. To understand the influence of CAF-specific Tie2-signaling on cancer cell properties, we performed CAF-Cancer cell co-culture and its single-cell RNA sequencing (scRNA-Seq). Distinct clustering of CAFs suggested their transcriptional heterogeneity, driven by TGFβ-Tie2 activation. Interestingly, CAF-specific Tie2-signaling was responsible to reprogram cancer cells, producing embryonic-like cell state with increased stemness and EMT signatures. Importantly, both the Tie2-specific gene expression signature as well as reprogrammed cancer cell specific gene expression modules were validated respectively in fibroblasts clusters and malignant cell clusters in two independent earlier reported scRNAseq studies of HNSCC tumors. Highlighting the translatability of our study, the gene expression signature derived from reprogrammed cancer cells showed significant association with poor prognosis in HNSCC patient of TCGA cohort. Pharmacological inhibition of Tie2-signaling in CAFs, significantly abrogated the tumor initiating ability of co-cultured oral cancer cell lines. Overall, combining our molecular and computational analysis, we may propose Tie2 as a novel factor responsible for CAF mediated cancer cell plasticity, associated with aggressive nature of oral cancer.

Teaser

Tie2-signaling is activated in myofibroblasts which impacts the behaviour of malignant cells by inducing cancer cell plasticity to acquire stemness.
Autoimmunity and clinical pathology amelioration in SLE by Dexamethasone primed Mesenchymal Stem Cell derived conditioned media
Authors: Priya Khushbu , Rawat Sonali , Das Doli , Chaubey Manaswi , Thacker Hiral , Giri Kiran , Singh Shambhavi , Rai Madhukar , Mohanty Sujata , Rai Geeta
Published: July 2024

This study proposes a novel approach, utilizing cell-free dexamethasone (Dex) primed Whartons jelly mesenchymal stem cells derived conditioned media (DW), offering improved efficacy, simplicity, and alternative medicine for addressing complications associated with systemic lupus erythematosus (SLE). This study explores the immunomodulatory effects of DW treatment on immune cell populations in SLE patients and a pristane-induced lupus (PIL) mouse model. DW induces significant expansion of Tregs, Bregs, suppressing Th17, double-negative T cells, and inflammatory neutrophils through modulating IL-10 and IL-17A production. Comparisons with the standard drug hydroxychloroquine reveal similar effects, suggesting TGF beta; pathway mediation in DW’s actions. Compared with the immunosuppressive drug Dex, DW better attenuated autoantibody production, increased anti-inflammatory cytokines and maintained a balanced Th17/Treg ratio. In the preclinical in vivo studies, DW exhibits therapeutic efficacy, reducing mortality, preventing proteinuria, and reversing limb inflammation, seizure and alopecia. Organ specific evaluations using advanced live imaging or histopathological analysis highlighted DW’s protective effects on kidneys, liver, lungs, heart, and spleen. This provided insight into the immunomodulatory benefits of DW at various levels and suggested that it could be a potential therapeutic avenue for managing complications related to SLE.
Temporally resolved growth patterns reveal novel information about the polygenic nature of complex quantitative traits
Authors: Sweet Dorothy D. , Tirado Sara B. , Cooper Julian , Springer Nathan M. , Hirsch Cory D. , Hirsch Candice N.
Published: July 2024

Plant height can be an indicator of plant health across environments and used to identify superior genotypes or evaluate abiotic stress factors. Typically plant height is measured at a single time point when plants have reached terminal height for the season. Evaluating plant height using unoccupied aerial vehicles (UAVs) is faster, allowing for measurements throughout the growing season, which facilitates a better understanding of plant-environment interactions and the genetic basis of this complex trait. To assess variation throughout development, plant height data was collected weekly for a panel of ∼500 diverse maize inbred lines over four growing seasons. The variation in plant height throughout the season was significantly explained by genotype, year, and genotype-by-year interactions to varying extents throughout development. Genome-wide association studies revealed significant SNPs associated with plant height and growth rate at different parts of the growing season specific to certain phases of vegetative growth that would not be identified by terminal height associations alone. When plant height growth rates were compared to growth rates estimated from canopy cover, greater Fréchet distance stability was observed in plant height growth curves than for canopy cover. This indicated canopy cover may be more useful for understanding environmental modulation of overall plant growth and plant height better for understanding genotypic modulation of overall plant growth. This study demonstrated that substantial information can be gained from high temporal resolution data to understand how plants differentially interact with the environment and can enhance our understanding of the genetic basis of complex polygenic traits.
Feeders and Expellers, Two Types of Animalcules With Outboard Cilia, Have Distinct Surface Interactions
Authors: Prakash Praneet , Vona Marco , Goldstein Raymond E.
Published: July 2024

Within biological fluid dynamics, it is conventional to distinguish between “puller” and “pusher” microswimmers on the basis of the forward or aft location of the flagella relative to the cell body: typically, bacteria are pushers and algae are pullers. Here we note that since many pullers have “outboard” cilia or flagella displaced laterally from the cell centerline on both sides of the organism, there are two important subclasses whose far-field is that of a stresslet, but whose near field is qualitatively more complex. The ciliary beat creates not only a propulsive force but also swirling flows that can be represented by paired rotlets with two possible senses of rotation, either “feeders” that sweep fluid toward the cell apex, or “expellers” that push fluid away. Experimental studies of the rotiferBrachionus plicatilisin combination with earlier work on the green algaeChlamydomonas reinhardtiishow that the two classes have markedly different interactions with surfaces. When swimming near a surface, expellers such asC. reinhardtiiscatter from the wall, whereas a feeder likeB. plicatilisstably attaches. This results in a stochastic “run-and-stick” locomotion, with periods of ballistic motion parallel to the surface interrupted by trapping at the surface.
Chromosome X Dosage Modulates Development of Aneuploidy in Genetically Diverse Mouse Embryonic Stem Cells
Authors: Stanton Alexander , Aydin Selcan , Skelly Daniel A. , Stavish Dylan , Leonhard Kim , Taapken Seth , McIntire Erik , Pankratz Matthew , Czechanski Anne , Ludwig Tenneille , Choi Ted , Gygi Steven P. , Barbaric Ivana , Munger Steven C. , Reinholdt Laura G. , Pera Martin F.
Published: July 2024

The genetic integrity of pluripotent stem cells (PSC) is critical to their applications in research and therapy, but it is compromised by frequent development of structural chromosome variants associated with malignancy. Many cell lines exhibit remarkable genetic stability, but little is known about the basis of the known variation in genomic integrity amongst different PSC isolates. Here we identify aneuploidies using RNA-seq and proteomics data from a panel of mouse embryonic stem cell (mESC) lines derived from 170 Diversity Outbred mice. We found 62 lines with detectable aneuploid subpopulations and a subset of originally XX lines that lost one Chromosome X (XO). Strikingly, a much lower proportion of XX lines were aneuploid, compared to XY or XO lines. Two single-cell RNA-seq data sets demonstrated that aneuploid XY DO mESC also show lower Chromosome X gene expression, and a prospective study confirmed that XY mESC accumulate higher aneuploid proportions in culture than isogenic XX lines. We identify potential mechanisms for this protective effect of X chromosome dosage, including our findings that the lines with two active X Chromosomes have a higher proportion of 2-cell-like cells, a state associated with maintenance of genetic integrity of mESC, and that they show differential expression of X-linked tumor suppressor genes associated with the DNA damage response.

Highlights

First genetic analysis of predisposition to aneuploidy in pluripotent stem cell cultures

Chromosomal regions duplicated in aneuploid mouse embryonic stem cells are syntenic with regions overrepresented in human pluripotent stem cell lines bearing recurrent genetic abnormalities

X-Chromosome dosage strongly influences susceptibility to aneuploidy in mouse embryonic stem cells and to a lesser degree in human pluripotent stem cells

XX mouse embryonic stem cell lines show a higher proportion of cells in 2 cell-like state and higher expression of tumor suppressor genes associated with DNA damage response
A positive list administered immunity system restricts the body size of insects
Authors: Ogata Norichika , Matsuda Tomoko
Published: July 2024

There are several explanations for the extinction of ancient giant insects. Here, we present a new hypothesis suggesting that the innate immune system limits the body sizes of insects. In this study, we co-cultured bacteria, fungi, and insect blood cells, and performed single-cell RNA sequencing analyses of insect blood cells to determine their division of labor. In the innate immune system, prohibited molecules are listed as signals of invasion. The increasing diversity of organisms makes this list extensive. The burden of managing such an extensive list leads to a division of labor among blood cells and reduces the effective number of blood cells. Our simulation indicates that a reduced number of effective blood cells cannot protect a giant body from invaders.
Scene context and attention independently facilitate MEG decoding of object category
Authors: Leticevscaia Olga , Brandman Talia , Peelen Marius V.
Published: July 2024

Many of the objects we encounter in our everyday environments would be hard to recognize without any expectations about these objects. For example, a distant silhouette may be perceived as a car because we expect objects of that size, positioned on a road, to be cars. Reflecting the influence of such expectations on visual processing, neuroimaging studies have shown that when objects are poorly visible, expectations derived from scene context facilitate the representations of these objects in visual cortex from around 300 ms after scene onset. The current magnetoencephalography (MEG) study tested whether this facilitation occurs independently of attention and task relevance. Participants viewed degraded objects alone or within their original scene context while they either attended the scenes (attended condition) or the fixation cross (unattended condition), temporally directing attention away from the scenes. Results showed that at 300 ms after stimulus onset, multivariate classifiers trained to distinguish clearly visible animate vs inanimate objects generalized to distinguish degraded objects in scenes better than degraded objects alone, despite the added clutter of the scene background. Attention also modulated object representations at this latency, with better category decoding in the attended than the unattended condition. The modulatory effects of context and attention were independent of each other. Finally, data from the current study and a previous study were combined (N=51) to provide a more detailed temporal characterization of contextual facilitation. These results extend previous work by showing that facilitatory scene-object interactions are independent of the specific task performed on the visual input.
PTEN Regulates Myofibroblast Activation in Valvular Interstitial Cells based on Subcellular Localization
Authors: Batan Dilara , Tseropoulos Georgios , Kirkpatrick Bruce E. , Bera Kaustav , Khang Alex , Weiser-Evans Mary , Anseth Kristi S.
Published: July 2024

Aortic valve stenosis (AVS) is characterized by altered mechanics of the valve leaflets, which disrupts blood flow through the aorta and can cause left ventricle hypotrophy. These changes in the valve tissue result in activation of resident valvular interstitial cells (VICs) into myofibroblasts, which have increased levels of αSMA in their stress fibers. The persistence of VIC myofibroblast activation is a hallmark of AVS. In recent years, the tumor suppressor gene phosphatase and tensin homolog (PTEN) has emerged as an important player in the regulation of fibrosis in various tissues (e.g., lung, skin), which motivated us to investigate PTEN as a potential protective factor against matrix-induced myofibroblast activation in VICs. In aortic valve samples from humans, we found high levels of PTEN in healthy tissue and low levels of PTEN in diseased tissue. Then, using pharmacological inducers to treat VIC cultures, we observed PTEN overexpression prevented stiffness-induced myofibroblast activation, whereas genetic and pharmacological inhibition of PTEN further activated myofibroblasts. We also observed increased nuclear PTEN localization in VICs cultured on stiff matrices, and nuclear PTEN also correlated with smaller nuclei, altered expression of histones and a quiescent fibroblast phenotype. Together, these results suggest that PTEN not only suppresses VIC activation, but functions to promote quiescence, and could serve as a potential pharmacological target for the treatment of AVS.
Tissue-specific immune transcriptional signatures in the bordering tissues of the mouse brain and retina
Authors: Etebar Fazeleh , Whatmore Paul , Harkin Damien G. , Dando Samantha J.
Published: July 2024

Background

Bordering the central nervous system (CNS) parenchyma are the pia mater (the innermost layer of the meninges enveloping the brain) and the choroid (underlying the retina). While near the neural parenchyma, the pia mater and choroid are external to the immune privileged environment of the brain and retina and thus are distinct immune compartments. This study aimed to characterise the transcriptomic signatures of immune cells within the pia mater and choroid bordering the healthy adult mouse CNS.

Methods

Brains and eyes were obtained from 7-week-old female C57Bl/6J mice. Pia mater-enriched tissue and choroid were dissected and processed for fluorescence activated cell sorting of CD45+immune cells and single cell RNA-sequencing. Additionally, single cell RNA-sequencing was performed on immune cells isolated from choroid obtained from human donor eye tissue. Immunostaining and confocal microscopy of wholemount tissue were used to validate selected immune cell populationsin situ.

Results

A total of 3,606 cells were sequenced from mouse tissues, including 1,481 CD45+cells from pia mater-enriched tissue and 2,125 CD45+cells from choroid. Clustering and differential gene expression analysis revealed heterogeneous subtypes of monocytes/macrophages, dendritic cells, T cells and B cells. While some clusters were common to both pia mater and choroid, others exhibited tissue-specific gene expression profiles and potential functional specialisations. Analysis of 6,501 CD45+ cells sequenced from human choroid identified similar immune cell populations to mouse choroid.

Conclusions

This study provides a detailed characterisation of the molecular signatures of immune cells within the vascular connective tissues bordering the healthy brain and retina, and their potential roles in immune protection.
Identification of cuproptosis and ferroptosis-related subtypes and development of a prognostic signature in colon cancer
Authors: He Yinghao , Liu Fuqiang , Jiang Zheng
Published: July 2024

Colon cancer, as a highly prevalent malignant tumor globally, poses a significant threat to human health. In recent years, ferroptosis and cuproptosis, as two novel forms of cell death, have attracted widespread attention for their potential roles in the development and treatment of colon cancer. However, the investigation into the subtypes and their impact on the survival of colon cancer patients remains understudied. In this study, utilizing data from TCGA and GEO databases, we examined the expression differences of ferroptosis and cuproptosis-related genes in colon cancer and identified two subtypes. Through functional analysis and bioinformatics methods, we elucidated pathway differences and biological characteristics between these two subtypes. By leveraging differential genes between the two subtypes, we constructed a prognostic model using univariate Cox regression and multivariate Cox regression analysis as well as LASSO regression analysis. Further survival analysis and receiver operating characteristic curve analysis demonstrated the model’s high accuracy. To enhance its clinical utility, we evaluated the clinical significance of the model and constructed a nomogram, significantly improving the predictive ability of the model and providing a new tool for prognostic assessment of colon cancer patients. Subsequently, through immune-related analysis, we revealed differences in immune cell infiltration and immune function between high- and low-risk groups. Further analysis of the relationship between the model and immune cells and functions revealed potential therapeutic targets. Drug sensitivity analysis revealed associations between the expression of model-related genes and drug sensitivity, suggesting their involvement in tumor resistance through certain mechanisms. AZD8055_1059, Bortezomib_1191, Dihydrorotenone_1827, and MG-132_1862 were more sensitive in the high-risk group. Finally, we analyzed differential expression of model-related genes between tumor tissues and normal tissues, validated through real-time quantitative PCR. In summary, our study provides a relatively accurate prognostic tool for colon cancer patients, offering guidance for treatment selection and indicating the potential of immunotherapy in colon cancer.
Geometry based gene expression signatures detect cancer treatment responders in clinical trials
Authors: Chachólski Wojciech , Ramanujam Ryan
Published: July 2024

Abstract

Aim

The overall aim of this project is to determine if gene expression signatures of tumors, constructed from geometrical attributes of data, could be used to predict patient treatment response by detecting subgroups of responders. This is tested in Pfizer clinical trial data and compared with standard clustering methods (n= 726).

Results

Geometrical gene expression signature analysis demonstrated high utility to detect sub-groups with enhanced treatment response. In the Pfizer trial, gene expression signatures were able to detect three subgroups of responders (p= 0.012), containing 52.9% of patients and accounting for nearly all the observed treatment effect. Standard techniques following a similar methodology were able to partition a single subgroup containing 21.3% of patients.

Conclusions

Gene expression based geometrical signatures yielded vastly superior performance over standard clustering techniques, as demonstrated in Pfizer’s Phase III clinical trial data. These can be used to determine subgroups of enhanced treatment response in oncology clinical trials, and might lead to personalized treatment recommendations in the future.
Social predation by a nudibranch mollusc
Authors: Otter Kate , Gomidova Saida , Katz Paul S.
Published: July 2024

Social predation is a common strategy used by predators to subdue and consume prey. Animals that use this strategy have many ways of finding each other, organizing behaviors and consuming prey. There is wide variation in the extent to which these behaviors are coordinated and the stability of individual roles. This study characterizes social predation by the nudibranch mollusc,Berghia stephanieae, which is a specialist predator that eats only the sea anemone,Exaiptasia diaphana. A combination of experimental and modeling approaches showed thatB. stephanieaedoes predate uponE. diaphanain groups. The extent of social feeding was not altered by length of food deprivation, suggesting that animals are not shifting strategies based on internal state. It was unclear what cues the individualBerghiaused to find each other; choice assays testing whether they followed slime trails, were attracted to injured anemones, or preferred conspecifics feeding did not reveal any cues. Individuals did not exhibit stable roles, such as leader or follower, rather the population exhibited fission-fusion dynamics with temporary roles during predation. Thus, theBerghiaprovides an example of a specialist predator of dangerous prey that loosely organizes social feeding, which persists across hunger states and uses temporary individual roles; however, the cues that it uses for aggregation are unknown.

Significance Statement

Social predation is a strategy to hunt dangerous prey and minimize injury. Many nudibranchs specialize as predators of cnidarians, which are dangerous to them. Although nudibranchs are typically characterized as solitary hunters, we provide evidence that social predation strategies may be used by a species that specializes on one species of sea anemone. The study showed that the individual sea slugs assumed temporary roles for establishing groups and that the group dynamics were unstable. However, the cues that the nudibranchs use to aggregate remain elusive.
Speciation completion rates have limited impact on macroevolutionary diversification
Authors: Veron Pierre , Andréoletti Jérémy , Giraud Tatiana , Morlon Hélène
Published: July 2024

Standard birth-death processes used in macroevolutionary studies assume instantaneous speciation, an unrealistic premise that limits the interpretation of speciation and extinction rates. The protracted birth-death (PBD) model instead assumes that speciation involves two steps: initiation and completion. In order to understand their respective influence on macroevolutionary speciation rates, we compute a standard time-varying birth-death scenario that is “equivalent” to the PBD model in terms of speciation and extinction probabilities. First, we find a sharp decline in the equivalent birth rate near the present, indicating that rates estimated at the tips of phylogenies may not accurately reflect the underlying speciation process. Second, the completion rate controls the timing of the decay rather than the asymptotic equivalent rates. The equivalent birth rate in the past scales with the speciation initiation rate, with a scaling factor depending mostly on the population extinction rate. Our results suggest that the rates of population formation and extinction may often play a larger role than the speed of accumulation of reproductive isolation in modulating speciation rates. Our study establishes a theoretical framework for understanding how microevolutionary processes combine to explain the diversification of species on macroevolutionary time scales.
Sphingosine kinase 1 is integral for elastin deficiency-induced arterial hypermuscularization
Authors: Saito Junichi , Dave Jui M. , Gallardo-Vara Eunate , Kabir Inamul , Tellides George , Riemer Robert K. , Urban Zsolt , Hla Timothy , Greif Daniel M.
Published: July 2024

Defective elastin and smooth muscle cell (SMC) accumulation characterize both arterial diseases (e.g., atherosclerosis, restenosis and supravalvular aortic stenosis [SVAS]), and physiological ductus arteriosus (DA) closure. Elastin deficiency induces SMC hyperproliferation; however, mechanisms underlying this effect are not well elucidated. Elastin (ELN) is expressed from embryonic day (E) 14 in the mouse aorta. Immunostains ofEln(+/+)andEln(-/-)aortas indicate that SMCs of theElnnull aorta are first hyperproliferative at E15.5, prior to morphological differences. Bulk RNA-seq reveals that sphingosine kinase 1 (Sphk1) is the most upregulated transcript inEln(-/-)aortic SMCs at E15.5. Reduced ELN increases levels of transcription factor early growth response 1 (EGR1), resulting in increased SPHK1 levels in cultured human aortic SMCs and in the mouse aorta at E15.5 and P0.5. Aortic tissue from Williams-Beuren Syndrome patients, who have elastin insufficiency and SVAS, also has upregulated SPHK1 expression. SMC-specificSphk1deletion or pharmacological inhibition of SPHK1 attenuates SMC proliferation and mitigates aortic disease, leading to extended survival ofEln(-/-)mice. In addition, EGR1 and SPHK1 are increased in the wild-type mouse DA compared to adjacent descending aorta. Treatment with a SPHK1 inhibitor attenuates SMC proliferation and reduces SMC accumulation, leading to DA patency. In sum, SPHK1 is a key node in elastin deficiency-induced hypermuscularization, and inhibiting this kinase may be a therapeutic strategy for SVAS and select congenital heart diseases in which a patent DA maintains circulation.

One Sentence Summary

Sphingosine kinase 1-induced by defective elastin promotes muscularization in pathological aortic stenosis and physiological ductus arteriosus occlusion.
Development of a Deep Learning model Tailored for HER2 Detection in Breast Cancer to aid pathologists in interpreting HER2-Low cases
Authors: Bannier Pierre-Antoine , Broeckx Glenn , Herpin Loïc , Dubois Rémy , Praet Lydwine Van , Maussion Charles , Deman Frederik , Amonoo Ellen , Mera Anca , Timbres Jasmine , Gillett Cheryl , Sawyer Elinor , Gazińska Patrycja , Ziolkowski Piotr , Lacroix-Triki Magali , Salgado Roberto , Irshad Sheeba
Published: July 2024

Introduction

Over 50% of breast cancer cases are "Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC)", characterized by HER2 immunohistochemistry (IHC) scores of 1+ or 2+ alongside no amplification on fluorescence in situ hybridization (FISH) testing. The development of new anti-HER2 antibody-drug conjugates (ADCs) for treating HER2-low breast cancers illustrates the importance of accurately assessing HER2 status, particularly HER2-low breast cancer. In this study, we evaluated the performance of a deep learning (DL) model for the assessment of HER2, including an assessment of the causes of discordances of HER2-Null between a pathologist and the DL model. We specifically focussed on aligning the DL model rules with the ASCO/CAP guidelines, including stained cells’ staining intensity and completeness of membrane staining.

Methods

We trained a DL model on a multi-centric cohort of breast cancer cases with HER2- immunohistochemistry scores (n=299). The model was validated on 2 independent multi- centric validation cohorts (n=369 and n=92), with all cases reviewed by 3 senior breast pathologists. All cases underwent a thorough review by three senior breast pathologists, with the ground truth determined by a majority consensus on the final HER2 score among the pathologists. In total, 760 breast cancer cases were utilized throughout the training and validation phases of the study.

Results

The model’s concordance with the ground truth (ICC = 0.77 [0.68 - 0.83]; Fisher P = 1.32e-10) is higher than the average agreement among the 3 senior pathologists (ICC = 0.45 [0.17 - 0.65]; Fisher P = 2e-3). In the two validation cohorts, the DL model identifies 95% [93%- 98%] and 97% [91% - 100%] of HER2-low and HER2-positive tumors respectively. Discordant results were characterized by morphological features such as extended fibrosis, a high number of tumor-infiltrating lymphocytes, and necrosis, whilst some artifacts such as non- specific background cytoplasmic stain in the cytoplasm of tumor cells also cause discrepancy.

Conclusion

Deep learning can support pathologists’ interpretation of difficult HER2-low cases. Morphological variables and some specific artifacts can cause discrepant HER2-scores between the pathologist and the DL Model.
Cognitive neuropsychological and neuroanatomic predictors of naturalistic action performance in left hemisphere stroke: a retrospective analysis
Authors: Thibault Simon , Wong Aaron L. , Buxbaum Laurel J.
Published: July 2024

Individuals who have experienced a left hemisphere cerebrovascular accident (LCVA) have been shown to make errors in naturalistic action tasks designed to assess the ability to perform everyday activities such as preparing a cup of coffee. Naturalistic action errors in this population are often attributed to limb apraxia, a common deficit in the representation and performance of object-related actions. However, naturalistic action impairments are also observed in right hemisphere stroke and traumatic brain injury, populations infrequently associated with apraxia, and errors across all these populations are influenced by overall severity. Based on these and other data, an alternative (though not mutually exclusive) account is that naturalistic action errors in individuals with LCVA are also a consequence of deficits in general attentional resource availability or allocation. In this study, we conducted a retrospective analysis of data from a group of 51 individuals with LCVA who had completed a test of naturalistic action, along with a battery of tests assessing praxis, attention allocation and control, reasoning, and language abilities to determine which of these capacities contribute uniquely to naturalistic action impairments. Using a regularized regression method, we found that naturalistic action impairments are predicted by both praxis deficits (hand posture sequencing and gesture recognition), as well as attention allocation and control deficits (orienting and dividing attention), along with language comprehension ability and age. Using support vector regression-lesion symptom mapping, we demonstrated that naturalistic action impairments are associated with lesions to posterior middle temporal gyrus and anterior inferior parietal lobule regions known to be implicated in praxis; as well the middle frontal gyrus that has been implicated in both praxis and attention allocation and control. Together, these findings support the hypothesis that naturalistic action impairments in people with LCVA are a consequence of apraxia as well as deficits in attention allocation and control.