bluuebunny/crossref_metadata_2025 huggingface dataset:
Causality and signalling of garden-path sentences
Authors: Wang Daphne , Sadrzadeh Mehrnoosh
Published: January 2024

Sheaves are mathematical objects that describe the globally compatible data associated with open sets of a topological space. Original examples of sheaves were continuous functions; later they also became powerful tools in algebraic geometry, as well as logic and set theory. More recently, sheaves have been applied to the theory of contextuality in quantum mechanics. Whenever the local data are not necessarily compatible, sheaves are replaced by the simpler setting of presheaves. In previous work, we used presheaves to model lexically ambiguous phrases in natural language and identified the order of their disambiguation. In the work presented here, we model syntactic ambiguities and study a phenomenon in human parsing called garden-pathing. It has been shown that the information-theoretic quantity known as ‘surprisal’ correlates with human reading times in natural language but fails to do so in garden-path sentences. We compute the degree of signalling in our presheaves using probabilities from the large language modelBERTand evaluate predictions on two psycholinguistic datasets. Our degree of signalling outperforms surprisal in two ways: (i) it distinguishes between hard and easy garden-path sentences (with ap-value<10−5), whereas existing work could not, (ii) its garden-path effect is larger in one of the datasets (32 ms versus 8.75 ms per word), leading to better prediction accuracies.

This article is part of the theme issue ‘Quantum contextuality, causality and freedom of choice’.
Hidden variables, free choice, context-independence and all that
Authors: Dzhafarov Ehtibar N.
Published: January 2024

This paper provides a systematic account of the hidden variable models (HVMs) formulated to describe systems of random variables with mutually exclusive contexts. Any such system can be described either by a model with free choice but generally context-dependent mapping of the hidden variables into observable ones, or by a model with context-independent mapping but generally compromised free choice. These two types of HVMs are equivalent, one can always be translated into another. They are also unfalsifiable, applicable to all possible systems. These facts, the equivalence and unfalsifiability, imply that freedom of choice and context-independent mapping are no assumptions at all, and they tell us nothing about freedom of choice or physical influences exerted by contexts as these notions would be understood in science and philosophy. The conjunction of these two notions, however, defines a falsifiable HVM that describes non-contextuality when applied to systems with no disturbance or to consistifications of arbitrary systems. This HVM is most adequately captured by the term ‘context-irrelevance’, meaning that no distribution in the model changes with context.

This article is part of the theme issue ‘Quantum contextuality, causality and freedom of choice’.
Student experiences with an interactive 3D immersive biotechnology simulation and its impact on motivational beliefs
Authors: Spencer Dan , McKeown Caitlin , Tredwell David , Huckaby Benjamin , Wiedner Andrew , Dums Jacob T. , Cartwright Emily L. , Potts Colin M. , Sudduth Nathan , Brown Evan , Albright Phillips , Jhala Arnav , Srougi Melissa C.
Published: January 2024

The development and use of virtual laboratories to augment traditional in-person skills training continues to grow. Virtual labs have been implemented in a number of diverse educational settings, which have many purported benefits including their adaptability, accessibility, and repeatability. However, few studies have evaluated the impact of virtual laboratories outside of academic achievement and skills competencies, especially in biotechnology. In this study, an interdisciplinary team of content experts, video game researchers, instructional designers, and assessment experts developed a 3D immersive simulation designed to teach novice scientists the technical skills necessary to perform sterile mammalian cell culture technique. Unique to the simulation development process is the recreation of an immersive experience through the capture of details in the real-world lab where participants have the freedom of choice in their actions, while receiving immediate feedback on their technical skills as well as procedural execution. However, unlike an in-person laboratory course, students are able to iterate and practice their skills outside of class time and learn from their mistakes. Using a mixed-methods study design, over the course of two semesters we evaluated student attitudes of the simulation and their science motivational beliefs including self-efficacy and science identity after engaging with the simulation prior to the physical laboratory. Our results show that students’ science identity remained unchanged while their science self-efficacy increased. Furthermore, students had positive perceptions of the benefits of the virtual simulation. These data suggest that the virtual cell culture simulation can be a useful pedagogical training tool to bolster students’ motivational beliefs that is both accessible and easy to implement.
MYC is sufficient to generate mid-life high-grade serous ovarian and uterine serous carcinomas in a p53-R270H mouse model
Authors: Blackman Alexandra , Rees Amy C , Bowers Robert R , Jones Christian M , Vaena Silvia G , Clark Madison A , Carter Shelby , Villamor Evan D , Evans Della , Emanuel Anthony J , Fullbright George , Long David T , Spruill Laura , Romeo Martin J , Helke Kristi L , Delaney Joe R
Published: January 2024

Genetically engineered mouse models (GEMM) have fundamentally changed how ovarian cancer etiology, early detection, and treatment is understood. However, previous GEMMs of high-grade serous ovarian cancer (HGSOC) have had to utilize genetics rarely or never found in human HGSOC to yield ovarian cancer within the lifespan of a mouse.MYC, an oncogene, is amongst the most amplified genes in HGSOC, but it has not previously been utilized to drive HGSOC GEMMs. We coupledMycand dominant negative mutant p53-R270H with a fallopian tube epithelium-specific promoterOvgp1to generate a new GEMM of HGSOC. Female mice developed lethal cancer at an average of 15.1 months. Histopathological examination of mice revealed HGSOC characteristics including nuclear p53 and nuclear MYC in clusters of cells within the fallopian tube epithelium and ovarian surface epithelium. Unexpectedly, nuclear p53 and MYC clustered cell expression was also identified in the uterine luminal epithelium, possibly from intraepithelial metastasis from the fallopian tube epithelium (FTE). Extracted tumor cells exhibited strong loss of heterozygosity at the p53 locus, leaving the mutant allele. Copy number alterations in these cancer cells were prevalent, disrupting a large fraction of genes. Transcriptome profiles most closely matched human HGSOC and serous endometrial cancer. Taken together, these results demonstrate theMycandTrp53-R270Htransgene was able to recapitulate many phenotypic hallmarks of HGSOC through the utilization of strictly human-mimetic genetic hallmarks of HGSOC. This new mouse model enables further exploration of ovarian cancer pathogenesis, particularly in the 50% of HGSOC which lack homology directed repair mutations. Histological and transcriptomic findings are consistent with the hypothesis that uterine serous cancer may originate from the fallopian tube epithelium.
Immune-neuroendocrine phenotypic expression changes through life inCoturnix japonicaquails
Authors: Marozzi Antonela , Correa Silvia G. , Palme Rupert , Cantarelli Veronica I. , Ponzio Marina F. , Marin Raul H. , Nazar F. Nicolas
Published: January 2024

Immune-neuroendocrine characteristics can be used to classify individuals according to their physiological profiles or phenotypes (INPs). In avian models such as quail and domestic chickens, three subgroups based on INPs have been defined: Lewis-like (pro-inflammatory polarization), Fischer-like (anti-inflammatory polarization), and an intermediate INP. This study investigates the stability and alterations of INPs throughout ontogeny, from juvenile to adult stages in four time-points including an exposure to unpredictable and diverse chronic stress (CS) during early adulthood. We measured corticosterone levels, pro-(IFN-γ and IL-1β) and anti-inflammatory (IL-13, IL-4) cytokines, phytohemagglutinin (PHA-P) lymphoproliferative response, anti-sheep red blood cells antibody (Ab SRBC) response, and leukocyte distribution frequency. Cluster analyses were conducted to classify bird based on their similarities across all analyzed variables, to thereby establish their INP at each time point. The extreme Lewis- or Fischer-like profiles were less represented in juvenile and pre-stress adult birds showing a higher proportion of individuals with an intermediate profile. Following CS exposure, the prevalence of Lewis-like and Fischer-like profiles increased. This shift persisted 10 weeks later as birds matured to an advanced egg-laying stage, with females predominantly exhibiting the Fischer-like INP, and males the Lewis-like INP. The observed shift in INP distribution following CS towards more polarized Lewis- and Fisher-like profiles implies a more even representation of the three observed profiles and may reflect inter-individual differences in physiological response to CS associated to particular coping strategies. A more even INPs distribution could provide the population with a greater advantage when facing diverse environmental challenges.
Using splines for point spread function calibration at non-uniform depths in localization microscopy
Authors: Korovin Serafim , Kalisvaart Dylan , Hung Shih-Te , Cnossen Jelmer , de Visser Coen , Smith Carlas S.
Published: January 2024

Single-molecule localization microscopy methods extensively leverage the microscope point spread function (PSF) for fitting the molecules. Calibrating an accurate PSF model is especially difficult in the presence of depth-dependent aberrations which alter the PSF shape depending on the imaging depth. The aberrations at depths of a few micrometers become substantial enough to considerably impoverish the conventional calibration methods’ performance. In our work, we propose a novel spline model which enables the depth-dependent PSF model calibration by interpolating between the beads at arbitrary depths. We show that diffspline reduces the PSF intensity overestimation by 67.8 percentage points and underestimation by 21.8 percentage points. Moreover, it eliminates the depth-dependent bias and improves the localization precision two-fold compared to previous approaches.
CODEX: COunterfactual Deep learning for thein-silicoEXploration of cancer cell line perturbations
Authors: Schrod Stefan , Beißbarth Tim , Zacharias Helena U. , Hauschild Anne-Christin , Altenbuchinger Michael
Published: January 2024

Motivation

High-throughput screens (HTS) provide a powerful tool to decipher the causal effects of chemical and genetic perturbations on cancer cell lines. Their ability to evaluate a wide spectrum of interventions, from single drugs to intricate drug combinations and CRISPR-interference, has established them as an invaluable resource for the development of novel therapeutic approaches. Nevertheless, the combinatorial complexity of potential interventions makes a comprehensive exploration intractable. Hence, prioritizing interventions for further experimental investigation becomes of utmost importance.

Results

We propose CODEX as a general framework for the causal modeling of HTS data, linking perturbations to their downstream consequences. CODEX relies on a stringent causal modeling strategy based on counterfactual reasoning. As such, CODEX predicts drug-specific cellular responses, comprising cell survival and molecular alterations, and facilitates thein-silicoexploration of drug combinations. This is achieved for both bulk and single-cell HTS. We further show that CODEX provides a rationale to explore complex genetic modifications from CRISPR-interferencein silicoin single cells.

Availability and Implementation

Our implementation of CODEX is publicly available athttps://github.com/sschrod/CODEX. All data used in this article are publicly available.
GPX3 supports ovarian cancer tumor progressionin vivoand promotes expression of GDF15
Authors: Chang Caroline , Cheng Ya-Yun , Kamlapurkar Shriya , White Sierra R. , Tang Priscilla W. , Elhaw Amal T. , Javed Zaineb , Aird Katherine M. , Mythreye Karthikeyan , Phaëton Rébécca , Hempel Nadine
Published: January 2024

Objective

We previously reported that high expression of the extracellular glutathione peroxidase GPX3 is associated with poor patient outcome in ovarian serous adenocarcinomas, and that GPX3 protects ovarian cancer cells from oxidative stress in culture. Here we tested if GPX3 is necessary for tumor establishmentin vivoand to identify novel downstream mediators of GPX3’s pro-tumorigenic function.

Methods

GPX3 was knocked-down in ID8 ovarian cancer cells by shRNA to test the role of GPX3 in tumor establishment using a syngeneic IP xenograft model. RNA sequencing analysis was carried out in OVCAR3 cells following shRNA-mediated GPX3 knock-down to identify GPX3-dependent gene expression signatures.

Results

GPX3 knock-down abrogated clonogenicity and intraperitoneal tumor developmentin vivo, and the effects were dependent on the level of GPX3 knock-down. RNA sequencing showed that loss of GPX3 leads to decreased gene expression patterns related to pro-tumorigenic signaling pathways. Validation studies identified GDF15 as strongly dependent on GPX3. GDF15, a member of the TGF-β growth factor family, has known oncogenic and immune modulatory activities. Similarly, GPX3 expression positively correlated with pro-tumor immune cell signatures, including regulatory T-cell and macrophage infiltration, and displayed significant correlation with PD-L1 expression.

Conclusions

We show for the first time that tumor produced GPX3 is necessary for ovarian cancer growthin vivoand that it regulates expression of GDF15. The immune profile associated with GPX3 expression in serous ovarian tumors suggests that GPX3 may be an alternate marker of ovarian tumors susceptible to immune check-point inhibitors.
MuPET-Flow: Multiple Ploidy Estimation Tool from Flow cytometry data
Authors: Gómez-Muñoz C. , Fischer G.
Published: January 2024

Ploidy, representing the number of homologous chromosome sets, can be estimated from flow cytometry data acquired on cells stained with a fluorescent DNA dye. This estimation relies on a combination of tools that often require scripting, individual sample curation, and additional analyses. To automate the ploidy estimation for multiple flow cytometry files, we developed MuPET-Flow—a Shiny graphical user interface tool. MuPET-Flow allows users to visualize cell fluorescence histograms, detect the peaks corresponding to the different cell cycle phases, perform a linear regression using standards, make ploidy or genome size predictions, and export results as figures and table files. The tool was benchmarked with known ploidy datasets, yielding consistent ploidy results. MuPET-Flow produces ploidy results comparable to those from other available tools; however, MuPET-Flow stands out for its user-friendly interface, which allows the whole process to be carried out in one place, considerably speeding up analysis, particularly in projects involving large numbers of samples.

Availability and implementation:https://github.com/CintiaG/MuPET-Flow.
SMARCD1 is a “Goldilocks” metastasis modifier
Authors: Ross Christina , Gong Li-Yun , Jenkins Lisa M. , Ha Ngoc-han , Majocha Megan , Hunter Kent
Published: January 2024

Abstract

Breast cancer is the most frequently diagnosed cancer worldwide, constituting around 15% of all diagnosed cancers in 2023. The predominant cause of breast cancer-related mortality is metastasis to distant essential organs, and a lack of metastasis-targeted therapies perpetuates dismal outcomes for late-stage patients. However, through our use of meiotic genetics to study inherited transcriptional network regulation, we have identified a new class of “Goldilocks” genes that are promising candidates for the development of metastasis-targeted therapeutics. Building upon previous work that implicated the CCR4-NOT RNA deadenylase complex in metastasis, we now demonstrate that the RNA-binding proteins (RNA-BPs) NANOS1, PUM2, and CPSF4 also regulate metastatic potential. Using cell lines, 3D culture, mouse models, and clinical data, we pinpointSmarcd1mRNA as a key target of all three RNA-BPs. Strikingly, both high and low expression ofSmarcd1is associated with positive clinical outcomes, while intermediate expression significantly reduces the probability of survival. Applying the theory of “essential genes” from evolution, we identify an additional 50 genes that span several cellular processes and must be maintained within a discrete window of expression for metastasis to occur. In the case ofSmarcd1, small perturbations in its expression level significantly reduce metastasis in laboratory mouse models and alter splicing programs relevant to the ER+/HER2-enriched breast cancer subtype. The identification of subtype-specific “Goldilocks” metastasis modifier genes introduces a new class of genes and potential catalogue of novel targets that, when therapeutically “nudged” in either direction, may significantly improve late-stage patient outcomes.
Somatic epigenetic drift during shoot branching: a cell lineage-based model
Authors: Chen Yifan , Burian Agata , Johannes Frank
Published: January 2024

Plant architecture is shaped by the continuous production of new organs, most of which emerge post-embryonically. This process includes the formation of new lateral branches along existing shoots. Shoot branching is fundamental to plant development, plant-environment interactions, and vegetative propagation. Current empirical evidence supports a “detached meristem” model as the cellular basis of lateral shoot initiation. In this model, a small number of undifferentiated cells are “sampled” from the periphery of the shoot apical meristem (SAM) to act as precursors for axillary buds, which eventually develop into new shoots. Repeated branching thus creates a series of cellular bottlenecks (i.e. somatic drift) that affect howde novogenetic and epigenetic mutations propagate through the plant body during development. Somatic drift could be particularly relevant for epigenetic changes in the form of stochastic DNA methylation gains and losses (i.e. spontaneous epimutations), as they have been shown to arise rapidly with each cell division.

Here, we formalize a special case of the “detached meristem” model, where pre-cursor cells are randomly sampled from the SAM periphery in a way that maximizes cell lineage independence. By following a population of SAM cells through repeated branching processes, we show that somatic drift gives rise to a complex mixture of cellular phylogenies, which shape the evolution of cell-to-cell DNA methylation heterogeneity within the SAM over time. This process is dependent on the number of branch points, the strength of somatic drift as well as the epimutation rate. For many realistic cell biological settings, our model predicts that cell-to-cell DNA methylation heterogeneity in the SAM converges to non-zero states during development, suggesting that epigenetic variation is an inherent property of the SAM cell population.

Our insights have direct implications for empirical studies of somatic (epi)genomic diversity in long-lived perennial and clonal species using bulk or single-cell sequencing approaches.
The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons
Authors: Arcas José Miguel , Oudaha Khalid , González Alejandro , Fernández-Trillo Jorge , Peralta Francisco Andrés , Castro-Marsal Júlia , Poyraz Seyma , Taberner Francisco , Sala Salvador , de la Peña Elvira , Gomis Ana , Viana Félix
Published: January 2024

Background and Purpose

The mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator of cell growth and metabolism. Its deregulation is implicated in several diseases. The macrolide rapamycin (RAP), a specific inhibitor of mTOR, has immunosuppressive, anti-inflammatory and antiproliferative properties. Recently, we identified tacrolimus, another macrolide immunosuppressant, as a novel activator of TRPM8 ion channels, involved in cold temperature sensing, thermoregulation, tearing and cold pain. We hypothesized that RAP may also have agonist activity on TRPM8.

Experimental approach

Using calcium imaging and electrophysiology in transfected HEK293 cells and wildtype orTrpm8KO mouse DRG neurons, we characterized RAP effects on TRPM8. We also examined the effects of RAP on tearing in mice.

Key Results

Micromolar concentrations of RAP activate rat and mouse TRPM8 directly and potentiate cold-evoked responses. These effects were also observed in human TRPM8.

In cultured mouse DRG neurons, RAP evoked an increase in intracellular calcium almost exclusively in cold-sensitive neurons. Responses were drastically blunted inTrpm8KO mice or by TRPM8 antagonists. Cutaneous cold thermoreceptor endings were also activated by RAP. Topical application of RAP to the eye surface evokes tearing in mice by a TRPM8-dependent mechanism.

Conclusion and implications

These results identify TRPM8 cationic channels in sensory neurons as novel molecular targets of the immunosuppressant RAP. These findings may help explain some of its therapeutic effects after topical application to the skin and the eye surface. Moreover, RAP could be used as an experimental tool in the clinic to explore cold thermoreceptors.

Bullet point summary

WHAT IS ALREADY KNOWN

TRPM8 is a polymodal channel involved in cold detection, thermoregulation, tearing and cold pain

Tacrolimus, a macrolide immunosupressor, is an agonist of cold-activated TRPM8 channels

WHAT THIS STUDY ADDS

The macrolide rapamycin also activates directly TRPM8 channels in mouse sensory neurons and human TRPM8

Rapamycin stimulates tearing in mice in a TRPM8-dependent manner CLINICAL SIGNIFICANCE

Rapamycin, an FDA-approved drug, shows agonist activity on TRPM8 channels

Beneficial effects of rapamycin and other macrolides on inflammatory ocular disorders may involve TRPM8 activation
Analyzing the intrastate and interstate swine movement network in the United States
Authors: Cardenas Nicolas C. , Valencio Arthur , Sanchez Felipe , O’Hara Kathleen C. , Machado Gustavo
Published: January 2024

Disease prevention and control tactics rely on identifying and restricting animal movement to attenuate the between-premises spread of disease in livestock systems. Therefore, it is essential to uncover between-premises movement dynamics, including shipment distances and network-based control strategies. Here, we analyzed three years of between-premises pig movements, which include 197,022 unique animal shipments, 3,973 premises, and 391,625,374 pigs shipped across 20 U.S. states. We constructed unweighted, directed, temporal networks at 180-day intervals to calculate premises-to-premises movement distances, the size of connected components, network loyalty, and degree distributions, and, based on the out-going contact chains, identified network-based control actions. Our results show that the median distance between premises pig movements was 74.37 km, with median intrastate and interstate movements of 52.71 km and 328.76 km, respectively. On average, 2,842 premises were connected via 6,705 edges, resulting in a weak giant connected component that included 91% of the premises. The premises-level network exhibited loyalty, with a median of 0.65 (IQR: 0.45 – 0.77). Results highlight the effectiveness of node targeting and disease spread; we demonstrated that targeting 25% of farms with the highest degree or betweenness limited spread to 1.23% and 1.7% of premises, respectively. While there is no complete shipment data for the entire U.S., our multi-state movement analysis demonstrated the value and the needs of such data for enhancing the design and implementation of proactive-disease control tactics.
Toward mastering the cell language by learning to generate
Authors: Chen Yixin , Bian Haiyang , Wei Lei , Jia Jinmeng , Dong Xiaomin , Li Yuzhuo , Zhao Yubo , Wu Xinze , Li Chen , Luo Erpai , Xiao Chuxi , Hao Minsheng , Zhang Xuegong
Published: January 2024

Cells can be viewed as complex stories written by coordinated expression of genes. The success of AI large language models (LLMs) in mastering the human language inspired us to develop a large AI model scMulan with 368 million parameters to generate cell transcriptomics with designated attributes by learning the cell language. We defined a unified c-sentence to incorporate cell transcriptomics and meta-attributes, and pre-trained scMulan on the equivalence of 100 million human cells. Experiments showed that scMulan can generate designated pseudo transcriptomics, predict missing attributes of cells, reconstruct unobserved cells along functional gradients, and can help to identify driving regulators of cell fates. The generated data passed tests of current tools and can reflect the underlying biology.
MORE interpretable multi-omic regulatory networks to characterize phenotypes
Authors: Aguerralde-Martin Maider , Clemente-Císcar Mónica , Conesa Ana , Tarazona Sonia
Published: January 2024

The identification of phenotype-specific regulatory mechanisms is crucial for understanding the molecular basis of diseases and other complex traits. However, the lack of tools capable of constructing multi-omic, condition-specific regulatory networks remains a significant limitation. He re, we introduce MO RE (Multi-Omics Regulation), a novel R package for the inference and comparison of multi-modal regulatory networks publicly available athttps://github.com/BiostatOmics/MORE. MORE supports any number and type of omics layers, integrates prior regulatory knowledge, and employs advanced regression-based modelling and variable selection techniques to identify significant regulators of target features.

We evaluated MORE on simulated datasets and benchmarked it against state-of-the-art tools. Our tool exhibited superior accuracy in identifying key regulators, model goodness-of-fit, and computational efficiency. Additionally, we applied MORE to an ovarian cancer dataset to uncover tumour subtype-specific regulatory mechanisms associated with distinct survival outcomes.

By providing a comprehensive and user-friendly framework for constructing phenotype-specific regulatory networks, MORE addresses a critical gap in the field of multi-omics data integration. Its versatility and effectiveness make it a valuable resource for advancing our understanding of complex molecular interactions and regulatory systems.
Transgenerational chromosome repair in the asexual bdelloid rotiferAdineta vaga
Authors: Houtain Antoine , Derzelle Alessandro , Llirós Marc , Hespeels Boris , Nicolas Émilien , Simion Paul , Virgo Julie , Lenormand Thomas , Hallet Bernard , Van Doninck Karine
Published: January 2024

Homologous recombination is an essential DNA repair mechanism that promotes chromosome pairing and ensures allele segregation during meiosis in sexual organisms. Here, we explore the dual function of homologous recombination in the bdelloid rotiferAdineta vaga, an ancient asexual species known for its remarkable resilience to extreme genotoxic stresses. Genomic analyses reveal thatA. vagauses meiotic recombination, both to promote spontaneous crossovers and gene conversion during oogenesis and to repair the genome in response to DNA damage. Our study identifies a novel transgenerational DNA repair mechanism, termed break-induced homologous extension repair (BIHER), which operates on single DNA ends to repair fragmented chromosomes over successive generations. Our findings suggest that meiotic BIHER, coupled with the holocentric structure of chromosomes, represents a key adaptation of life in extreme environments.
Shoring up the base: the development and regulation of cortical sclerenchyma in grass nodal roots
Authors: McCahill Ian W. , Khahani Bahman , Probert Cassandra F. , Flockhart Eleah L. , Abushal Logayn T. , Gregory Greg A. , Zhang Yu , Baumgart Leo A. , O’Malley Ronan C. , Hazen Samuel P.
Published: January 2024

Plants depend on the combined action of a shoot-root-soil system to maintain their anchorage to the soil. Mechanical failure of any component of this system results in lodging, a permanent and irreversible inability to maintain vertical orientation. Models of anchorage in grass crops identify the compressive strength of roots near the soil surface as key determinant of resistance to lodging. Indeed, studies of disparate grasses report a ring of thickened, sclerenchyma cells surrounding the root cortex, present only at the base of nodal roots. Here, in the investigation of the development and regulation of this agronomically important trait, we show that development of these cells is uncoupled from the maturation of other secondary cell wall-fortified cells, and that cortical sclerenchyma wall thickening is stimulated by mechanical forces transduced from the shoot to the root. We also show that exogenous application of gibberellic acid stimulates thickening of lignified cell types in the root, including cortical sclerenchyma, but is not sufficient to establish sclerenchyma identity in cortex cells. Leveraging the ability to manipulate cortex development via mechanical stimulus, we show that cortical sclerenchyma development alters root mechanical properties and improves resistance to lodging. We describe transcriptome changes associated with cortical sclerenchyma development under both ambient and mechanically stimulated conditions and identify SECONDARY WALL NAC7 as a putative regulator of mechanically responsive cortex cell wall development at the root base.
Refining Spatial Proteomics by Mass Spectrometry: An Efficient Workflow Tailored for Archival Tissue
Authors: Daucke Rune , Rift Charlotte V. , Bager Nicolai S. , Saxena Kartikey , Koffeldt Peter R. , Woessmann Jakob , Petrosius Valdemaras , Santoni-Rugiu Eric , Kristensen Bjarne W. , Klausen Pia , Schoof Erwin M.
Published: January 2024

Background

Formalin-fixed, paraffin-embedded (FFPE) tissue remains the gold standard for extensively archiving biological specimens, providing biobanks with large repositories of retrospective potential. However, while formalin crosslinking is effective at preserving tissue, it poses significant challenges for extracting molecular information, including the proteome. Traditionally, this process required high levels of input material, which, in turn, limited the ability to preserve cell-type heterogeneity and spatial information. To address these limitations, we developed an easily adaptable and highly efficient workflow for extracting deep proteomes from low-input materials, such as biopsies used in routine histopathological diagnostics.

Methods

We compared the extraction efficiency of pancreatic acinar cells identified in FFPE tissue samples stained with conventional hematoxylin-eosin (H&E) against that of cells isolated from tissue samples immunostained for the epithelial cell adhesion molecule (EpCAM) across material inputs ranging from 1,166 to 800,000µm2(estimated to 2 to 1,310 cells in volume). Cells were isolated using laser capture microdissection and subsequently analyzed using Liquid Chromatography-Tandem Mass Spectrometry.

Results

Similar yields for both methods were observed, with EpCAM-positive cells yielding slightly higher results—approximately 1,200 unique protein groups at the lowest input and up to 5,900 at the highest. In cells isolated from H&E-stained tissue, ∼900 to ∼5,200 protein groups were identified. We decided that the optimal balance for our workflow, ensuring maximum protein identification while minimizing input material, lies within the range of approximately 50,000 to 100,000µm2. With these results, we tested spatial capabilities and biological relevance by isolating cancer cells from biopsies of pancreatic cancer, lung cancer, or glioblastoma, with the first two being stained with EpCAM and the latter being stained against the tumor-suppressor protein p53. We successfully identified tissue-specific protein expressions and observed prominent clustering of all cell populations.

Discussion

Our results highlight the feasibility of performing spatial proteomics on FFPE tissue using minimal input material. This adaptable methodology opens up possibilities for investigating cell-type-specific biology while preserving spatial and histological information.
Age and Sex Differences of Virtual Reality Pain Alleviation Therapeutic During Pediatric Burn Care: A Randomized Clinical Trial
Authors: Jones Katarina , Armstrong Megan , Luna John , Thakkar Rajan K , Fabia Renata , Groner Jonathan I , Noffsinger Dana , Ni Ai , Griffin Bronwyn , Xiang Henry
Published: January 2024

Virtual reality (VR) effectively alleviates pain for pediatric patients during many medical care procedures, such as venipuncture and burn wound care. Whether VR pain alleviation therapeutics (VR-PAT) differ by a patient’s age or sex remains unresolved. This randomized clinical trial evaluated how age and sex affect VR pain alleviation during dressing care for pediatric burns. Ninety patients aged 6-17 years (inclusive) with burn injuries were recruited from an outpatient burn clinic of an American Burn Association-verified pediatric burn center. Before randomization, expectations of VR helpfulness and need were assessed on a visual analog scale (VAS, 0-100). Participants were randomly assigned to active or passive VR for one burn dressing change. Immediately following the dressing change, participants self-reported pain and the time spent thinking about pain and rated the VR features on the degrees of realism experienced, pleasure/fun, and perceived engagement level. Path analyses assessed how these VR features were interrelated and how they affected self-reported pain by age and sex. Patients aged 6–9 years reported higher mean expectations of VR helpfulness and need (mean=73.6 and 94.5, respectively) than 10–12-year-olds (mean=55.7 and 84.2, respectively) and 13-17-year-olds (mean=68.6 and 77.4, respectively). The path analysis indicated VR engagement and fun were significantly correlated (p-value <0.05). VR engagement significantly negatively impacted overall pain scores during burn dressing (coefficient=-0.45, −0.41; p-value <0.05) and significantly positively impacted time thinking of pain (coefficient=0.38, 0.32; p-value <0.05). Younger patients had the highest expectations of VR pain alleviation’s helpfulness and need. VR game realism, fun, and engagement features were not statistically different between age groups and sexes. VR engagement and thinking of pain during burn dressing significantly positively affected self-reported pain (p-value <0.05), suggesting an analgesic mechanism beyond distraction alone. Younger patients benefited more from VR pain alleviation therapeutics than older patients.
Studies on Geographic Variations and Gender Bias in Thyroid Cancer at National Guard Hospitals in Saudi Arabia
Authors: Alanazi Nawaf , Alabbad Zainab Ibrahim , Almutairi Nahal Hamad , Alhulaymi Rahmah Abdulwahab , Alfalah Jawaher Raed , Alkhalifa Eithar Qasim , Abubaker Rehab Ibrahim , Adeel Kanza , Balghonaim Sarah , Alshayeb Alzahra , Al-Mukhaylid Sarah , Iqbal Zafar
Published: January 2024

Thyroid cancer (TC) is one of the most prevalent cancers in the world, ranked as ninth worldwide and third in Saudi Arabia. This report reviews the incidence of TC at National Guard Hospitals (Riyadh, Jeddah, and Ahsa), in relation to gender, geographic variation and age. The study design is quantitative cross-sectional retrospective review; data of 2166 patients with TC diagnosed in National Guard Hospitals (Ahsa -Jeddah- Riyadh) in the period of 2015-2021 was received from King Abdullah International Medical Research Center (KAIMRC). Chi- square, t-test, and ANOVA-tests were used in analyzing the relationship between variables. Out of the 2166 patient records, (79.78%) were females, and (46.6%) were in the age group of 40-60 with a mean age of 47.28 years. Riyadh had the highest incidence of TC (49.8%), while Ahsa had the lowest (5.6%). the commonest TC type was papillary (83.5%) followed by follicular (4.0%), medullary (1.2%), anaplastic (1.1%), hurthle cell carcinoma (0.8%) and thyroid lymphoma (0.1%). Females were more suspected to have TC, and the risk of having TC increases as age increases until the age of 60, where it decreases. The registered cases were more in Riyadh, Jeddah and Ahsa, respectively, except for lymphoma and hurthle cell, as they were high in Jeddah. Lymphoma was reported in Jeddah and in males only. The mortality rate was low (2.4%). However, increased death risk was observed in patients diagnosed above the age of 60. Mortality was seen in papillary, anaplastic and a single death case was reported in follicular TC.

Research highlights

Females are at higher risk to develop thyroid cancer than males.

The risk of having thyroid cancer increased by age in both genders until the age of 60 where it decreased.

The registered cases were higher in Riyadh then Jeddah, and it was the lowest in Ahsa.

Lymphoma and hurtle cell were higher in Jeddah.

Mortality was low and seen in papillary, anaplastic and a single death case was reported in follicular thyroid cancer.
The Accuracy of Cardiac Surface Conduction Velocity Measurements
Authors: Vigmond Edward J. , Roney Caroline , Bayer Jason , Nanthakumar Kumaraswamy
Published: January 2024

Background:Conduction velocity (CV) is a measure of the health of myocardial tissue. It can be measured by taking differences in activation times from intracardiac electrodes. Several factors introduce error into the measurement, amongst which, ignoring the three dimensional aspect is a major detriment. The purpose of this paper was to determine if, nonetheless, there was a specific region where CV could be accurately measured.Methods:Computer simulations of three dimensional ventricles with a realistic His-Purkinje system were performed. Ventricles also included a dense scar or diffuse fibrosis.Results:A finer spatial sampling produced better agreement with true CV. Using a error limit of 10 cm/s as a threshold, measurements taken within a region less than 2 cm from the pacing site proved to be accurate. Error increased abruptly beyond this distance. The Purkinje system and tissue fibre orientation played equally major roles in leading to a surface CV which was not reflective of the CV propagation through the tissue.Conclusions:Surface CV measurements close to the pacing site taken with an electrode spacing of at most 1 mm, give reasonable estimates of tissue CV.
Point-of-care cardiac elastography with external vibration for quantification of diastolic myocardial stiffness
Authors: Meyer Tom , Wellge Brunhilde , Barzen Gina , Knebel Fabian , Hahn Katrin , Elgeti Thomas , Fischer Thomas , Braun Jürgen , Tzschätzsch Heiko , Sack Ingolf
Published: January 2024

Background

Heart failure is an increasing health problem in Western societies. Approximately 50% of patients with heart failure have preserved ejection fraction (HFpEF) and concomitant diastolic dysfunction (DD), in part caused by increased myocardial stiffness not detectable by standard echocardiography. While elastography can map tissue stiffness, cardiac applications are currently limited, especially in patients with a higher body mass index (BMI). Therefore, we developed point-of-care cardiac elastography to detect abnormal diastolic myocardial stiffness associated with DD.

Methods

Cardiac time-harmonic elastography (THE) using standard medical ultrasound and continuous external vibration was developed and applied to healthy controls and participants with DD due to wild-type transthyretin amyloidosis (ATTR) in this prospective single-center study between June 2020 and December 2022. A subgroup of participants with ATTR was on tafamidis treatment. Diastolic shear wave speed (SWS) was determined as surrogate marker of myocardial stiffness in different cardiac regions including the septum, posterior wall and automatically detected global left ventricular wall.

Results

A total of 130 participants were screened and 44 participants with ATTR (4 women, mean age: 80±7 years, BMI range: 20-37) and 54 healthy controls (26 women, mean age: 47±16 years, BMI range: 15-32) were included. In all analyzed regions, SWS was higher in patients than in controls providing area-under-the-curve (AUC) values (septum: 1.8±0.3m/s versus 2.9±0.6m/s, AUC=0.996; posterior wall: 1.9±0.3m/s versus 2.7±0.5m/s, AUC=0.938; global left ventricular wall: 2.0±0.3m/s versus 2.6±0.4m/s, AUC=0.912). Furthermore, SWS was reduced in participants treated with tafamidis (septum: 2.6±0.4 m/s; posterior wall: 2.4±0.3m/s; global left ventricular wall: 2.3±0.3m/s, all p<.005) suggesting the use of THE for therapy monitoring and patient management.

Conclusions

Cardiac THE detects abnormal myocardial stiffness in patients with DD, independent of BMI and ROI selection. Because it uses standard ultrasound components, THE can be cost-effectively implemented as a point-of-care device for widespread clinical use.
Predicting social experience from dyadic interaction dynamics: the BallGame, a novel paradigm to study social engagement
Authors: Lübbert Annika , Sengelmann Malte , Heimann Katrin , Schneider Till R. , Engel Andreas K. , Göschl Florian
Published: January 2024

Theories of embodied cognition suggest that a shared environment and ongoing sensorimotor interaction are central for interpersonal learning and engagement. To investigate the embodied, distributed and hence dynamically unfolding nature of social cognitive capacities, we present a novel laboratory-based coordination task: the BallGame. Our paradigm requires continuous sensing and acting between two players who jointly steer a virtual ball around obstacles towards as many targets as possible. By analysing highly resolved measures of movement coordination and gaming behaviour, game-concurrent experience ratings, semi-structured interviews, and personality questionnaires, we reveal contributions from different levels of observation on social experience. In particular, successful coordination (number of targets collected) and intermittent periods of high versus low movement coordination (variability of relation) emerged as prominent predictors of social experience. Importantly, having the same (but incomplete) view on the game environment strengthened interpersonal coordination, whereas complementary views enhanced engagement and tended to generate more complex interactive behaviour. Overall, we find evidence for a critical balance between similarity and synchrony on the one hand, and variability and difference on the other, for successful engagement in social interactions. Finally, following participant reports, we highlight how interpersonal experience emerges from specific histories of coordination that are closely related to the interaction context in both space and time.
Development of non-sedating antischistosomal benzodiazepines
Authors: Mian Md Yeunus , Sharmin Dishary , Mondal Prithu , Belayet Jawad Bin , Hossain M Mahmun , McCusker Paul , Ryan Kaetlyn T. , Fedorov Alexander Y , Green Heather A , Ericksen Spencer S. , Zamanian Mostafa , Tiruveedhula V. V. N. Phani Babu , Cook James M. , Chan John D.
Published: January 2024

The neglected tropical disease schistosomiasis infects over 200 million people worldwide and is treated with just one broad spectrum antiparasitic drug (praziquantel). Alternative drugs are needed in the event of emerging praziquantel resistance or treatment failure. One promising lead that has shown efficacy in animal models and a human clinical trial is the benzodiazepine meclonazepam, discovered by Roche in the 1970’s. Meclonazepam was not brought to market because of dose-limiting sedative side effects. However, the human target of meclonazepam that causes sedation (GABAARs) are not orthologous to the parasite targets that cause worm death. Therefore, we were interested in whether the structure of meclonazepam could be modified to produce antiparasitic benzodiazepines that do not cause host sedation. We synthesized 18 meclonazepam derivatives with modifications at different positions on the benzodiazepine ring system and tested them forin vitroantiparasitic activity. This identified five compounds that progressed toin vivoscreening in a murine model, two of which cured parasite infections with comparable potency to meclonazepam. When these two compounds were administered to mice that were run on the rotarod test, both were less sedating than meclonazepam. These findings demonstrate the proof of concept that meclonazepam analogs can be designed with an improved therapeutic index, and point to the C3 position of the benzodiazepine ring system as a logical site for further structure-activity exploration to further optimize this chemical series.
Density dependence shapes life-history trade-offs in a food limited ungulate population
Authors: Jaggi Harman , Zuo Wenyun , Kentie Rosemarie , Gaillard Jean-Michel , Coulson Tim , Tuljapurkar Shripad
Published: January 2024

Quantifying trade-offs within populations is an important goal in life-history and evolutionary theory. However, most studies focusing on life-history variation assume trade-offs to be static. In this paper, we provide a framework for understanding life-history variation at different densities while enabling us to reveal trade-offs that are often masked due to individual heterogeneity. We use published individual-based data from a population of Soay sheep and find density dependence strongly shapes life-history trade-offs and the distribution of lifetime reproductive success. We find trade-offs between juvenile survival and growth structures life-history variation for Soay sheep at all densities, but the intensity of the trade-offs increases with population density. At carrying capacity (K), a new trade-off appears between reproduction and juvenile survival. In addition, we find the distribution of LRS to be highly constrained atK, with mothers of prime adult sizes (∼ 25kg) contributing the most to reproduction. We also find the effects of density-dependence on demographic measures such as net reproductive rate, stable size distribution, and average vital rate functions. Our results suggest high density limits the diversity of individual life history strategies and has implications for better understanding the evolution of reproductive tactics via density-dependent selection and management of ungulates in food limited environments.