bluuebunny/crossref_metadata_2025 huggingface dataset:
Synoptic Reporting by Summarizing Cancer Pathology Reports using Large Language Models
Authors: Rajaganapathy Sivaraman , Chowdhury Shaika , Buchner Vincent , He Zhe , Jiang Xiaoqian , Yang Ping , Cerhan James R. , Zong Nansu
Published: April 2024

Background

Synoptic reporting, the documenting of clinical information in a structured manner, is known to improve patient care by reducing errors, increasing readability, interoperability, and report completeness. Despite its advantages, manually synthesizing synoptic reports from narrative reports is expensive and error prone when the number of structured fields are many. While the recent revolutionary developments in Large Language Models (LLMs) have significantly advanced natural language processing, their potential for innovations in medicine is yet to be fully evaluated.

Objectives

In this study, we explore the strengths and challenges of utilizing the state-of-the-art language models in the automatic synthesis of synoptic reports.

Materials and Methods

We use a corpus of 7,774 cancer related, narrative pathology reports, which have annotated reference synoptic reports from Mayo Clinic EHR. Using these annotations as a reference, we reconfigure the state-of-the-art large language models, such as LLAMA-2, to generate the synoptic reports. Our annotated reference synoptic reports contain 22 unique data elements. To evaluate the accuracy of the reports generated by the LLMs, we use several metrics including the BERT F1 Score and verify our results by manual validation.

Results

We show that using fine-tuned LLAMA-2 models, we can obtain BERT Score F1 of 0.86 or higher across all data elements and BERT F1 scores of 0.94 or higher on over 50% (11 of 22) of the questions. The BERT F1 scores translate to average accuracies of 76% and as high as 81% for short clinical reports.

Conclusions

We demonstrate successful automatic synoptic report generation by fine-tuning large language models.
The Relationship Between Immune Cells and Heart Failure: A Study Integrating Immune Infiltration Analysis and Bidirectional Mendelian Randomization
Authors: Yu Yiding , Yuan Huajing , Liu Wenwen , Xue Yitao , Liu Xiujuan , Hou Wangjun , Li Yan
Published: April 2024

Background

In recent years, attempts have been made to employ various immunomodulatory therapies as new treatment strategies for heart failure, yet the outcomes have been disappointing. Consequently, unveiling the complexity and causal relationships of the immune system’s role in heart failure has become imperative.

Methods

We first determined the levels of immune cells in failing myocardium using five immune infiltration algorithms: Cibersort, xCell, ssGSEA, MCPcounter, and QuanTIseq. Subsequently, two-sample bidirectional Mendelian Randomization (MR) analysis was conducted between heart failure and 731 immune cell phenotypes using Inverse Variance Weighted (IVW) as the main method, reinforced by MR-Egger, Weighted median, and Weighted mode as secondary analysis methods. Sensitivity analyses were performed to ensure data stability and feasibility.

Results

Immune infiltration analysis revealed changes in the levels of immune cell infiltration in failing myocardium, including T cells, Mast cells, B cells, NK cells, and macrophages. MR analysis indicated that 19 immune cell phenotypes from 5 cell types were associated with an increased risk of heart failure, while 12 immune cell phenotypes from 6 cell types were associated with a decreased risk, without heterogeneity and pleiotropy. Reverse MR analysis did not support a causal relationship between HF and any of the 731 immune cell phenotypes.

Conclusion

Our study highlights the complex pattern and causal relationship between the immune system and heart failure through immune infiltration and MR analyses. This provides new insights for the exploration of immunocyte therapies for heart failure.
Targeting circadian transcriptional programs through a cis-regulatory mechanism in triple negative breast cancer
Authors: Pan Yuanzhong , Chiu Tsu-Pei , Zhou Lili , Chan Priscilla , Kuo Tia Tyrsett , Battaglin Francesca , Soni Shivani , Jayachandran Priya , Li Jingyi Jessica , Lenz Heinz-Josef , Mumenthaler Shannon M. , Rohs Remo , Torres Evanthia Roussos , Kay Steve A.
Published: April 2024

Circadian clock genes are emerging targets in many types of cancer, but their mechanistic contributions to tumor progression are still largely unknown. This makes it challenging to stratify patient populations and develop corresponding treatments. In this work, we show that in breast cancer, the disrupted expression of circadian genes has the potential to serve as biomarkers. We also show that the master circadian transcription factors (TFs) BMAL1 and CLOCK are required for the proliferation of metastatic mesenchymal stem-like (mMSL) triple-negative breast cancer (TNBC) cells. Using currently available small molecule modulators, we found that a stabilizer of cryptochrome 2 (CRY2), the direct repressor of BMAL1 and CLOCK transcriptional activity, synergizes with inhibitors of proteasome, which is required for BMAL1 and CLOCK function, to repress a transcriptional program comprising circadian cycling genes in mMSL TNBC cells. Omics analyses on drug-treated cells implied that this repression of transcription is mediated by the transcription factor binding sites (TFBSs) features in the cis-regulatory elements (CRE) of clock-controlled genes. Through a massive parallel reporter assay, we defined a set of CRE features that are potentially repressed by the specific drug combination. The identification ofcis-element enrichment might serve as a new concept of defining and targeting tumor types through the modulation ofcis-regulatory programs, and ultimately provide a new paradigm of therapy design for cancer types with unclear drivers like TNBC.
Soil carbon in the world’s tidal marshes
Authors: Maxwell Tania L. , Spalding Mark D. , Friess Daniel A. , Murray Nicholas J. , Rogers Kerrylee , Rovai Andre S. , Smart Lindsey S. , Weilguny Lukas , Adame Maria Fernanda , Adams Janine B. , Copertino Margareth S. , Cott Grace M. , Costa Micheli Duarte de Paula , Holmquist James R. , Ladd Cai J.T. , Lovelock Catherine E. , Ludwig Marvin , Moritsch Monica M. , Navarro Alejandro , Raw Jacqueline L. , Ruiz-Fernández Ana-Carolina , Serrano Oscar , Smeaton Craig , Broek Marijn Van de , Windham-Myers Lisamarie , Landis Emily , Worthington Thomas A.
Published: April 2024

Tidal marshes are threatened coastal ecosystems known for their capacity to store large amounts of carbon in their water-logged soils. Accurate quantification and mapping of global tidal marshes soil organic carbon (SOC) stocks is of considerable value to conservation efforts. Here, we used training data from 3,710 unique locations, landscape-level environmental drivers and a newly developed global tidal marsh extent map to produce the first global, spatially-explicit map of SOC storage in tidal marshes at 30 m resolution. We estimate the total global SOC stock to 1 m to be 1.44 Pg C, with a third of this value stored in the United States of America. On average, SOC in tidal marshes’ 0-30 and 30-100 cm soil layers are estimated at 83.1 Mg C ha-1(average predicted error 44.8 Mg C ha-1) and 185.3 Mg C ha-1(average predicted error 105.7 Mg C ha-1), respectively. Our spatially-explicit model is able to capture 59% of the variability in SOC density, with elevation being the strongest driver aside from soil depth. Our study reveals regions with high prediction uncertainty and therefore highlights the need for more targeted sampling to fully capture SOC spatial variability.
Forestwalk: A machine learning workflow brings new insights into posture and balance in rodent beam walking
Authors: Tozzi Francesca , Zhang Yan-Ping , Narayanan Ramanathan , Roquiero Damian , O’Connor Eoin C.
Published: April 2024

The beam walk is widely used to study coordination and balance in rodents. While the task has ethological validity, the main endpoints of ‘foot slip counts’ and ‘time to cross’ are prone to human-rater variability and offer limited sensitivity and specificity. We asked if machine learning-based methods could reveal previously hidden, but biologically relevant, insights from the task. Marker-less pose estimation, using DeepLabCut, was deployed to label 13 anatomical points on mice traversing the beam. Next, we automated classical endpoint detection, including foot slips, with high recall (>90%) and precision (>80%). A total of 395 features were engineered and a random-forest classifier deployed that, together with skeletal visualizations, could test for group differences and identify determinant features. This workflow, named Forestwalk, uncovered pharmacological treatment effects in C57BL/6J mice, revealed phenotypes in transgenic mice used to study Angelman syndrome and SLC6A1-related neurodevelopmental disorder, and will facilitate a deeper understanding of how the brain controls balance in health and disease.
Population genomic analysis reveals cryptic population structure in the commercially important Lake Malawi cichlidCopadichromis mloto
Authors: Sawasawa Wilson , van Huysduynen Alexander Hooft , Gresham Sophie , Sungani Harold , Rusuwa Bosco , De Boeck Gudrun , Turner George F. , Ngochera Maxon , Svardal Hannes
Published: April 2024

Fish is an important source of animal protein for many people living around Lake Malawi. The evaluation of population structure and genetic diversity can yield useful information for management and conservation of fish species but is complicated in Lake Malawi by the close genetic relatedness of species of the recent cichlid adaptive radiation. In this study, we analysed whole-genome sequencing data of “true utaka”, a group of cichlids previously common in fisheries, but that has faced strong decline due to overfishing. Our analysis of 223 individuals collected from fishermen’s catches along the western shoreline of Lake Malawi confirmed thatCopadichromis mloto(C. sp. “virginalis kajose”) is the true utaka most targeted by fisheries. Genetic principal component analysis, phylogenetic inference, and admixture analysis revealed complex patterns of population structure. The presence of at least three geographically widespread genetic clades that have remained separate despite gene flow and partial sympatry hints at the presence of currently undescribed, cryptic species diversity inC. mloto. This result leads us to suggest that, despite the lack of obvious habitat barriers, benthic and pelagic species of Malawi cichlids might harbour unidentified species diversity and calls for further genetic and taxonomic research to define appropriate conservation units.
Insights into dynamic sound localisation: A direction-dependent comparison between human listeners and a Bayesian model
Authors: McLachlan Glen , Majdak Piotr , Reijniers Jonas , Mihocic Michael , Peremans Herbert
Published: April 2024

Self-motion is an essential but often overlooked component of sound localisation. While the directional information of a source is implicitly contained in head-centred acoustic cues, that acoustic input needs to be continuously combined with sensorimotor information about the head orientation in order to decode these cues to a world-centred frame of reference. On top of that, the use of head movement significantly reduces ambiguities in the directional information provided by the incoming sound. In this work, we evaluate a Bayesian model that predicts dynamic sound localisation, by comparing its predictions to human performance measured in a behavioural sound-localisation experiment. Model parameters were set a-priori, based on results from various psychoacoustic and sensorimotor studies, i.e., without any post-hoc parameter fitting to behavioral results. In a spatial analysis, we evaluated the model’s capability to predict spatial localisation responses. Further, we investigated specific effects of the stimulus duration, the spatial prior and sizes of various model uncertainties on the predictions. The spatial analysis revealed general agreement between the predictions and the actual behaviour. The altering of the model uncertainties and stimulus duration revealed a number of interesting effects providing new insights on modelling the human integration of acoustic and sensorimotor information in a localisation task.

Author summary

In everyday life, sound localisation requires both interaural and monaural acoustic information. In addition to this, sensorimotor information about the position of the head is required to create a stable and accurate representation of our acoustic environment. Bayesian inference is an effective mathematical framework to model how humans combine information from different sources and form beliefs about the world. Here, we compare the predictions from a Bayesian model for dynamic sound localisation with data from a localisation experiment. We show that we can derive the model parameter values from previous psychoacoustic and sensorimotor experiments and that the model without any post-hoc fitting, can predict general dynamic localisation performance. Finally, the discrepancies between the modelled data and behavioural data are analysed by testing the effects of adjusting the model parameters.
Common fluorescent Pseudomonas in the phyllosphere can influence aphid behavior in diverse ways
Authors: Herr Kathryn , Schieber Jonah , Hendry Tory A
Published: April 2024

Bacteria in the phyllosphere, the above ground parts of plants, can have complex interactions with plants and their insect visitors. For instance, certain Pseudomonas strains change pea aphid (Acyrthosiphon pisum) feeding behavior. Aphids visually detect and avoid feeding when Pseudomonas produces a compound with blue fluorescent emissions, the siderophore pyoverdine. It is unknown how commonly such interactions occur in nature, so we investigated this potential in pea plant (Pisum sativum) phyllosphere communities. We found a diversity of Pseudomonas taxa with fluorescent potential in pea plant microbiomes. Culture isolates revealed a wide range of fluorescent emissions spectra across taxa, which produced blue to green fluorescence of varying intensities. We tested strains from across this emissions range for pea aphid behavioral responses when given a choice between plants inoculated with a fluorescent isolate or a control treatment. Consistent with previous work, we found that some isolates were avoided by aphids. Surprisingly, some isolates were actually attractive to aphids, causing up to 70% of aphids to settle and feed on bacterially treated plants. Attractive isolates produced green fluorescence in culture, suggesting that attraction could be due to aphid sensory biases. Overall, we found both isolate fluorescence in culture and siderophore potential inferred from gene content to be poor predictors of aphid behavior. We also found very high variability in responses across replicate experiments for some strains, suggesting that environmental conditions may influence outcomes. This shows that bacterial fluorescence may be common on plants and can have context-dependent impacts on herbivorous insects.
Myelin regulatory factor(Myrf) is a critical early regulator of retinal pigment epithelial development
Authors: Brinkmeier Michelle L. , Wang Su Qing , Pittman Hannah , Cheung Leonard Y. , Prasov Lev
Published: April 2024

Myelin regulatory factor (Myrf) is a critical transcription factor in early retinal and retinal pigment epithelial development, and human variants inMYRFare a cause for nanophthalmos. Single cell RNA sequencing (scRNAseq) was performed onMyrfconditional knockout mice (Rx>Cre Myrffl/fl) at 3 developmental timepoints.Myrfwas expressed specifically in the RPE, and expression was abrogated inRx>Cre Myrffl/fleyes. scRNAseq analysis revealed a loss of RPE cells at all timepoints resulting from cell death. GO-term analysis in the RPE revealed downregulation of melanogenesis and anatomic structure morphogenesis pathways, which were supported by electron microscopy and histologic analysis. Novel structural target genes includingErmnandUpk3b, along with macular degeneration and inherited retinal disease genes were identified as downregulated, and a strong upregulation of TGFß/BMP signaling and effectors was observed. Regulon analysis placedMyrfdownstream ofPax6andMitfand upstream ofSox10in RPE differentiation. Together, these results suggest a strong role for Myrf in the RPE maturation by regulating melanogenesis, cell survival, and cell structure, in part acting through suppression of TGFß signaling and activation ofSox10.

SUMMARY STATEMENT

Myrfregulates RPE development, melanogenesis, and is important for cell structure and survival, in part through regulation ofErmn,Upk3bandSox10,and BMP/TGFb signaling.
The allosteric landscape of the Src kinase
Authors: Beltran Antoni , Faure Andre J. , Lehner Ben
Published: April 2024

Enzymes catalyze the reactions of life and are the targets of most small molecule drugs. Most drugs target conserved enzyme active sites, often causing problems of specificity and toxicity. Targeting allosteric sites can increase specificity, overcome resistance mutations, and allow fine-tuning of activity. However, most enzymes have no known allosteric sites and methods do not exist to comprehensively identify them. Here we present a general and fast approach to chart allosteric communication in enzymes and apply it to the Src kinase to produce the first comprehensive map of negative and positive allosteric control of an enzymatic activity. Allostery in the Src kinase domain is pervasive, anisotropic, partially predictable, and modulated by regulatory domains. Multiple surface pockets of Src are allosterically active and so genetically-prioritized for the development of inhibitory and activating drugs. Using this approach it should be possible to chart global allosteric maps of many kinases and other enzymes important for medicine and biotechnology.

Highlights

First comprehensive map of negative and positive allosteric control of an enzymatic activity, the Src kinase.

Allosteric communication is pervasive, distance dependent, and anisotropic.

Allostery is conserved and modulated in the presence of the Src regulatory domains.

Genetic prioritization of druggable surface pockets for Src inhibition and activation.

Allosteric maps can now be constructed for many medically and industrially important kinases and enzymes.
Resolved vs. uncontrolled inflammation: a mathematical model to decipher the role of innate immunity
Authors: García-Martínez Karina , Ledón Nuris , Lage Agustín
Published: April 2024

Neutrophils and macrophages related processes have been described as relevant during the inflammation resolution after an acute damage. Nevertheless, understanding the impact of both cells and the processes in which they are involved is still an open debate. Specifically, several studies have been focused on elucidate their impact in the dynamic outcome of resolution vs uncontrolled response. In this work, we develop a mathematical model that describe the dynamic of the innate immune response after an acute damage. Our model includes all the described processes that mediate this response, including the regulatory mechanisms carried out by type-2 macrophages (M2). Additionally, we estimate the resolution indices to quantify the efficiency of resolution mechanisms by controlling the initial expansion of Neutrophils and/or the subsequent contraction kinetics of the cell response. We predict that the processes of cells influx into the inflamed site, Neutrophil apoptosis and type-1 macrophage (M1)-mediated efferocytosis, are the ones that have an impact on the final outcome, but interfering in different resolution indices. In particular, we predict that the partial reduction of Neutrophil influx and the increase of M1-mediated efferocytosis rate are the best strategies to control the Neutrophil initial expansion. On the other hand, the partial reduction of M1 cells influx or the increase of Neutrophil apoptosis rate are predicted as good strategies to accelerate the Neutrophils decay during the contraction phase of the response.
Transcription of HIV-1 at sites of intact latent provirus integration
Authors: Teixeira Ana Rafaela , Bittar Cintia , Silva Santos Gabriela S. , Oliveira Thiago Y. , Huang Amy S. , Linden Noemi , Ferreira Isabella A.T.M. , Murdza Tetyana , Muecksch Frauke , Jones R. Brad , Caskey Marina , Jankovic Mila , Nussenzweig Michel C.
Published: April 2024

HIV-1 anti-retroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 100-10,000X less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir thereby influencing cytopathic effects and proviral immune evasion.
The muscarinic acetylcholine receptor in dermal papilla cells regulates hair growth
Authors: Yuen Gary Ka-Wing , Leung Ka-Wing , Lai Queenie Wing-Sze , Guo Maggie Suisui , Gao Xiong , Ho Janet Yuen-Man , Chu Harry Chun-Ting , Tsim Karl Wah-Keung
Published: April 2024

The role of cholinergic system in hair biology is poorly understood. In M4 muscarinic receptor (mAChR) knockout mice, the hair follicles have a prolonged telogen phase and failed to produce hair shafts. Here, we reported that hair growth was regulated by cholinergic system via mAChRs. Dermal papilla cells expressed different cholinergic biomarkers. Inhibiting AChE or stimulating mAChR in dermal papilla cells, culture vibrissae and skin epidermis promoted the hair growth. In cultured papilla cells treated with bethanechol, an agonist of mAChR, an activation of Wnt/β-catenin signalling was illustrated by various indicative biomarkers, including phosphorylation of GSK-3β and mRNA expression of various molecules for Wnt/β-catenin signalling. Activation of Wnt/β-catenin signalling was mediated by PI3K/AKT and ERK signalling upon the stimulation of bethanechol. In addition, an increase in hair shaft elongation was observed in mouse vibrissae upon the treatment of bethanechol, suggesting the cholinergic role in hair growth.
Temperature-modulated maternal effects vary with offspring developmental stage inDrosophila melanogaster
Authors: Kohlmeier P , Van Schaik B , Pen I , Billeter JC , Groothuis TGG
Published: April 2024

An organism’s phenotype has the potential to vary in response to environmental factors, allowing it to adjust to environmental fluctuations. Maternal effects on offspring phenotypes have been recognized as important contributors to this phenotypic plasticity, although the extent and duration of this contribution remain elusive. At more advanced developmental stages, offspring may be able to assess their current environment more accurately than at earlier developmental stages, and therefore their reliance on maternal effects may decline over time. This study investigates how the magnitude and direction of maternal effects change between early and late development using the fruit flyDrosophila melanogasteras a model. We employed a split brood design to disentangle the effects of maternal ambient temperature from the effects of offspring ambient temperature at the larval vs. the pupal or early adulthood stage. We subsequently measured offspring phenotypes such as heat shock and cold shock recovery times, survival, and developmental time. Maternal effects on these traits were often substantial during early offspring development, but these effects either diminished in magnitude or even changed direction as development progressed. In conclusion, our study reveals a dynamic shift in the magnitude and direction of maternal effects on offspring phenotypes inD. melanogaster, highlighting the interplay between maternal influence and offspring developmental stage in shaping adaptive responses to environmental variation.
First whole genome assembly ofVaccinium floribundumKunth, an emblematic Andean species
Authors: Albuja-Quintana Martina , Pozo Gabriela , Gordillo-Romero Milton , Armijos Carolina E. , Torres María de Lourdes
Published: April 2024

Background

Vaccinium floribundumKunth, known as "mortiño," is an endemic shrub species of the Andean region adapted to harsh conditions in high-altitude ecosystems. It plays an important ecological role as a pioneer species in the aftermath of deforestation and human-induced fires within paramo ecosystems, emphasizing its conservation value. While previous studies have offered insights into the genetic diversity of mortiño, comprehensive genomic studies are still missing to fully understand the unique adaptations of this species and its population status, highlighting the importance of generating a reference genome for this plant.

Results

ONT and Illumina sequencing were used to establish a reference genome for this species. Three differentde novogenome assemblies were generated and compared for quality, continuity and completeness. The Flye assembly was selected as the best and refined by filtering out short ONT reads, screening for contaminants and genome scaffolding. The final assembly has a genome size of 529 MB, containing 1,317 contigs and 97% complete BUSCOs, indicating a high level of integrity of the genome. Additionally, the LAI Index of 12.93, further categorizes this assembly as a reference genome.

Conclusions

The genome ofV. floribundumreported in this study is the first reference genome generated for this species, providing a valuable tool for further studies. This high-quality genome, based on the quality and completeness parameters obtained, will not only help uncover the genetic mechanisms responsible for its unique traits and adaptations to high-altitude ecosystems, but will also contribute to conservation strategies for a species endemic to the Andes.
Riluzole reverses blood-testis barrier loss to rescue chemotherapy-induced male infertility by binding to TRPC
Authors: Huang Rufei , Xia Huan , Lin Wanqing , Wang Zhaoyang , Li Lu , Deng Jingxian , Ye Tao , Li Ziyi , Yang Yan , Huang Yadong
Published: April 2024

Cancer treatments, including cytotoxic therapy, often result in male infertility, necessitating the development of safe and effective strategies to preserve male reproductive potential during chemotherapy. Notably, our study uncovers the potential of repurposing riluzole, an FDA-approved drug for amyotrophic lateral sclerosis (ALS), in enhancing spermatogenesis. Hence, this research aims to explore the feasibility of utilizing riluzole to alleviate male infertility induced by busulfan (BSF), a commonly used chemotherapy drug. We established a BSF-induced oligospermia model in 4-week-old male mice and found that riluzole could effectively countered the detrimental effects of BSF on sperm production in mice with oligospermia. By restoring blood-testis barrier (BTB) functionality, riluzole improves sperm quality and reduces testicular atrophy. Through transcriptomic and molecular docking analyses, we identify transient receptor potential canonical subfamily member 5 (TRPC5) as a potential target for riluzole-mediated regulation of blood-testis barrier function. These findings propose riluzole as a promising therapeutic option for chemotherapy-induced male infertility, thereby addressing the fertility challenges associated with cancer treatments. Moreover, repurposing riluzole could streamline the drug development process, providing a cost-effective approach with reduced risk compared to developing entirely new drugs.
A morphology and secretome map of pyroptosis
Authors: Lippincott Michael J. , Tomkinson Jenna , Bunten Dave , Mohammadi Milad , Kastl Johanna , Knop Johannes , Schwandner Ralf , Huang Jiamin , Ongo Grant , Robichaud Nathaniel , Dagher Milad , Tsuboi Masafumi , Basualto-Alarcón Carla , Way Gregory P.
Published: April 2024

Pyroptosis represents one type of Programmed Cell Death (PCD). It is a form of inflammatory cell death that is canonically defined by caspase-1 cleavage and Gasdermin-mediated membrane pore formation. Caspase-1 initiates the inflammatory response (through IL-1β processing), and the N-terminal cleaved fragment of Gasdermin D polymerizes at the cell periphery forming pores to secrete pro-inflammatory markers. Cell morphology also changes in pyroptosis, with nuclear condensation and membrane rupture. However, recent research challenges canon, revealing a more complex secretome and morphological response in pyroptosis, including overlapping molecular characterization with other forms of cell death, such as apoptosis. Here, we take a multimodal, systems biology approach to characterize pyroptosis. We treated human Peripheral Blood Mononuclear Cells (PBMCs) with 36 different combinations of stimuli to induce pyroptosis or apoptosis. We applied both secretome profiling (nELISA) and high-content fluorescence microscopy (Cell Painting). To differentiate apoptotic, pyroptotic and healthy cells, we used canonical secretome markers and modified our Cell Painting assay to mark the N-terminus of Gasdermin-D. We trained hundreds of machine learning (ML) models to reveal intricate morphology signatures of pyroptosis that implicate changes across many different organelles and predict levels of many pro-inflammatory markers. Overall, our analysis provides a detailed map of pyroptosis which includes overlapping and distinct connections with apoptosis revealed through a mechanistic link between cell morphology and cell secretome.
GENA-Web - GENomic Annotations Web Inference using DNA language models
Authors: Shmelev Alexey , Petrov Maxim , Penzar Dmitry , Akhmetyanov Nikolay , Tavritskiy Maksim , Mamontov Stepan , Kuratov Yuri , Burtsev Mikhail , Kardymon Olga , Fishman Veniamin
Published: April 2024

The advent of advanced sequencing technologies has significantly reduced the cost and increased the feasibility of assembling high-quality genomes. Yet, the annotation of genomic elements remains a complex challenge. Even for species with comprehensively annotated reference genomes, the functional assessment of individual genetic variants is not straightforward. In response to these challenges, recent breakthroughs in machine learning have led to the development of DNA language models. These transformer-based architectures are designed to tackle a wide array of genomic tasks with enhanced efficiency and accuracy. In this context, we introduce GENA-Web, a web-based platform that consolidates a suite of genome annotation tools powered by DNA language models. The version of GENA-Web presented here encompasses a diverse set of models trained on human data, including the prediction of promoter activity, annotation of splice sites, determination of various chromatin features, and a model for scoring of enhancer activity in Drosophila. GENA-Web is accessible online athttps://dnalm.airi.net/
ZNF574 is a Quality Control Factor For Defective Ribosome Biogenesis Intermediates
Authors: Akers Jared , Bothe Adrian , Suh Hanna , Jung Carmen , Stolp Zachary , Ghosh Tanushree , Yan Liewei , Wang Yuming , Grismer Tarabryn , Reyes Andreas , Hu Tianyi , Xu Shouling , Ban Nenad , Kostova Kamena
Published: April 2024

Eukaryotic ribosome assembly is an intricate process that involves four ribosomal RNAs, 80 ribosomal proteins, and over 200 biogenesis factors that take part in numerous interdependent steps. This complexity creates a large genetic space in which pathogenic mutations can occur. Dead-end ribosome intermediates that result from biogenesis errors are rapidly degraded, affirming the existence of quality control pathway(s) that monitor ribosome assembly. However, the factors that differentiate between on-path and dead-end intermediates are unknown. We engineered a system to perturb ribosome assembly in human cells and discovered that faulty ribosomes are degraded via the ubiquitin proteasome system. We identified ZNF574 as a key component of a novel quality control pathway, which we term the Ribosome Assembly Surveillance Pathway (RASP). Loss of ZNF574 results in the accumulation of faulty biogenesis intermediates that interfere with global ribosome production, further emphasizing the role of RASP in protein homeostasis and cellular health.
HD-ZIP IV genes are essential for embryo initial cell polarization in the radial axis initiation inArabidopsis
Authors: Tanaka Sayuri , Matsushita Yuuki , Hanaki Yuga , Higaki Takumi , Kamamoto Naoya , Matsushita Katsuyoshi , Higashiyama Tetsuya , Fujimoto Koichi , Ueda Minako
Published: April 2024

Plants develop along apical–basal and radial axes. InArabidopsis thaliana, the radial axis becomes evident when the cells of the eight-cell proembryo divide periclinally, forming inner and outer cell layers. Although changes in cell polarity or morphology likely precede this oriented cell division, the initial events and the factors regulating radial axis formation remain elusive. Here, we report that three transcription factors belonging to class IV homeodomain-leucine zipper (HD-ZIP IV) family redundantly regulate radial pattern formation: HOMEODOMAIN GLABROUS11 (HDG11), HDG12, and PROTODERMAL FACTOR2 (PDF2). Thehdg11 hdg12 pdf2triple mutant failed to undergo periclinal division at the eight-cell stage and cell differentiation along the radial axis. Live-cell imaging revealed that this failure in radial axis formation can be traced back to the behavior of the embryo initial cell (apical cell), which is generated by zygote division. In the wild type, the apical cell grows longitudinally and then radially and its nucleus remains at the bottom of the cell, where the vertical cell plate emerges. By contrast, the mutant apical cell elongates longitudinally and its nucleus releases from its basal position, resulting in a transverse division. Computer simulations based on the live-cell imaging data confirmed the importance of the geometric rule (the minimal plane principle and nucleus-passing principle) in determining the cell division plane. We propose that HDG11, HDG12, and PDF2 promote apical cell polarization, i.e., radial cell growth and basal nuclear retention, as the initial event of radial axis formation during embryogenesis.
Cortical Coding of Gustatory and Thermal Signals in Active Licking Mice
Authors: Nash Audrey N. , Shakeshaft Morgan , Bouaichi Cecilia G. , Odegaard Katherine E. , Needham Tom , Bauer Martin , Bertram Richard , Vincis Roberto
Published: April 2024

Eating behaviors are influenced by the integration of gustatory, olfactory, and somatosensory signals, which all contribute to the perception of flavor. Although extensive research has explored the neural correlates of taste in the gustatory cortex (GC), less is known about its role in encoding thermal information. This study investigates the encoding of oral thermal and chemosensory signals by GC neurons compared to the oral somatosensory cortex. In this study, we recorded the spiking activity of more than 900 GC neurons and 500 neurons from the oral somatosensory cortex in mice allowed to freely lick small drops of gustatory stimuli or deionized water at varying non-nociceptive temperatures. We then developed and used a Bayesian-based analysis technique to assess neural classification scores based on spike rate and phase timing within the lick cycle. Our results indicate that GC neurons rely predominantly on rate information, although phase information is needed to achieve maximum accuracy, to effectively encode both chemosensory and thermosensory signals. GC neurons can effectively differentiate between thermal stimuli, excelling in distinguishing both large contrasts (14°C vs. 36°C) and, although less effectively, more subtle temperature differences. Finally, a direct comparison of the decoding accuracy of thermosensory signals between the two cortices reveals that while the somatosensory cortex showed higher overall accuracy, the GC still encodes significant thermosensory information. These findings highlight the GC’s dual role in processing taste and temperature, emphasizing the importance of considering temperature in future studies of taste processing.

Key Points

Flavor perception relies on gustatory, olfactory, and somatosensory integration, with the gustatory cortex (GC) central to taste processing.

GC neurons also respond to temperature, but the specifics of how the GC processes taste and oral thermal stimuli remain unclear.

The focus of this study is on the role of GC neurons in the encoding of oral thermal information, particularly compared to the coding functions of the oral somatosensory cortex.

We found that while the somatosensory cortex shows a higher classification accuracy for distinguishing water temperature, the GC still encodes a substantial amount of thermosensory information.

These results emphasize the importance of including temperature as a key factor in future studies of cortical taste coding.
Targeting IDH1-Mutated Oligodendroglioma with Acid Ceramidase Inhibitors
Authors: Muley Helena , Dowdy Tyrone , Zaibaq Faris , Karadimov George , Li Aiguo , Song Hua , Zhang Meili , Zhang Wei , Wong Zalman , Zhang Laurence , Lita Adrian , Larion Mioara
Published: April 2024

Oligodendroglioma is genetically defined as a tumor harboring isocitrate dehydrogenase 1 or 2 mutations (IDH1mut/IDH2mut) and 1p/19q co-deletions. Previously, we reported that in IDH1mutgliomas, D-2HG, the product of IDH1 mutant enzyme produces an increase in monounsaturated fatty acid levels that are incorporated into ceramides, tilting the S1P-to-ceramide rheostat toward apoptosis. Herein, we exploited this imbalance to further induce and IDHmut-specific glioma cell death. We report for the first time that the inhibition of acid ceramidase (AC) induces apoptosis and provides a benefit in mice survival in IDH1mutoligodendroglioma. We demonstrated an IDH1mut-specific cytotoxicity of SABRAC, an irreversible inhibitor of AC, in patient-derived oligodendroglioma cells. Exploring the mechanism of action of this drug, we found that SABRAC activates both extrinsic and intrinsic apoptosis in an ER stress-independent manner, pointing to a direct action of AC-related ceramides in mitochondria permeability. The activation of apoptosis detected under SABRAC treatment was associated with up to 30-fold increase in some ceramide levels and its derivatives from the salvage pathway. We propose that this novel enzyme, AC, has the potential to increase survival in oligodendroglioma with IDH1mutand should be considered in the future.
Response of protein coding genes and microRNAs to temperature changes in four insect species
Authors: Tsang Stacey S.K. , Nong Wenyan , Xie Yichun , Qu Zhe , Yip Ho Yin , Gaitan-Espitia Juan Diego , Tai Amos P. K. , Yeung Ying Yeung , Tobe Stephen S. , Bendena William G. , Hui Jerome H.L.
Published: April 2024

Insects are the most abundant described living creatures in the world, and they play important roles in our global ecosystem. Climate change affects global biodiversity, and researchers in many fields are striving to better understand the impact of the climate crisis. One such endeavour is the study of temperature-dependent effects on insects. At present, we know little of how climate affects gene expression in insects of different sexes. Here, we took four species of fruit flies of the genusDrosophila(D. melanogaster, D. virilis, D. pseudoobscura,andD. erecta), and subjected the male and female flies of each species to three different temperatures to test their sex-specific gene expression responses. A total of 144 transcriptomic profiles of protein-coding genes and microRNAs were generated. We found that, at the same temperature, there were more male-biased than female-biased protein-coding genes and microRNAs in all four investigated drosophilid species. Interestingly, upon temperature changes, there were more differentially expressed protein-coding genes in females than in males in all four investigated species, while the microRNAs were highly species- and sex-specific. This study provides the first evidence that sex-biased protein-coding gene and microRNA expression responses to temperature change differ between insect species within the same genus, and demonstrates the complexity of sex-specific responses of insects to climate change.

Highlights

At the same temperature, protein coding gene and microRNA expression showed a greater bias towards males than towards females in all four tested insect species.

In response to increasing temperature, females of all 4 tested species exhibited more differentially expressed genes than did males, and enrichment analyses showed that they are species-specific.

Differentially expressed microRNAs did not show a conserved trend between insects upon temperature changes.

Sex-specific gene and microRNA expression of insects in response to climate change evidently involves a complex adaptation mechanism.

Graphical Abstract
Sequential predictive learning is a unifying theory for hippocampal representation and replay
Authors: Levenstein Daniel , Efremov Aleksei , Eyono Roy Henha , Peyrache Adrien , Richards Blake
Published: April 2024

The mammalian hippocampus contains a cognitive map that represents an animal’s position in the environment1and generates offline “replay”2,3for the purposes of recall4, planning5,6, and forming long term memories7. Recently, it’s been found that artificial neural networks trained to predict sensory inputs develop spatially tuned cells8, aligning with predictive theories of hippocampal function9–11. However, whether predictive learning can also account for the ability to produce offline replay is unknown. Here, we find that spatially-tuned cells, which robustly emerge from all forms of predictive learning, do not guarantee the presence of a cognitive map with the ability to generate replay. Offline simulations only emerged in networks that used recurrent connections and head-direction information to predict multi-step observation sequences, which promoted the formation of a continuous attractor reflecting the geometry of the environment. These offline trajectories were able to show wake-like statistics, autonomously replay recently experienced locations, and could be directed by a virtual head direction signal. Further, we found that networks trained to make cyclical predictions of future observation sequences were able to rapidly learn a cognitive map and produced sweeping representations of future positions reminiscent of hippocampal theta sweeps12. These results demonstrate how hippocampal-like representation and replay can emerge in neural networks engaged in predictive learning, and suggest that hippocampal theta sequences reflect a circuit that implements a data-efficient algorithm for sequential predictive learning. Together, this framework provides a unifying theory for hippocampal functions and hippocampal-inspired approaches to artificial intelligence.
Influences of single mutation and retinal binding on the THz absorption spectra of CRABP-II based rhodopsin mimics
Authors: Wang Yunyu , Hu Yongnan , Meng Jiajia , Peng Xubiao , Zhao Qing
Published: April 2024

The collective vibration of many biomolecules such as the skeleton vibration, dipole rotation and conformational bending falls in the terahertz (THz) frequency domain. Terahertz time-domain spectroscopy (THZ-TDS), which is very sensitive to the conformational changes, can be used to characterize the collective vibration of biomolecules. In this study, we investigated the low-frequency THz absorption spectra of two rhodopsin mimics using transmission THz-TDS. Using the normal model analysis (NMA), we successfully modelled the experimental terahertz absorption curve and attributed a unique collective motion pattern to each distinctive terahertz absorption frequency. By comparing the terahertz absorption spectra between without and with retinal, we show that the retinal binding can significantly alters the terahertz absorption spectra as well as the vibration modes. Furthermore, by comparing the terahertz absorption spectra between the two mutants, we observed that the single mutation can significantly change the influence of retinal binding on the terahertz absorption spectrum.
Usage of AMH as a determining test of fertility in women with polycystic ovary 2 syndrome (PCOS)
Authors: Grabowska Rita
Published: April 2024

PCOS is the most common hormonal disorder and cause of infertility in females of reproductive age. The symptoms and their severity vary strongly between particular cases. PCOS is correlated with hormonal, environmental and genetic factors. Complex interactions between genetics and hormonal levels is important to understand the hormonal 31 abnormality and to assess the chance of pregnancy in women with PCOS.

The research was conducted on patients in the age of 27+/-5 years treated in the 33 Gynecology and Oncology Clinic of CMUJ. The research group - PCOS patients (P) n=62. The control group - (C) n=45. The venous blood was collected in volume of 2 ml centrifuged for 15 min at 1400 rpm. Serum was aspirated to 1.5 ml Eppendorf tubes. The ELISA method was used.

The statistical analysis revealed significant differences in the level of selected factors 38 between the two groups at p <0.01. FSH [IU/ml]: P 5,10 (±1,64) vs K 8,96 (±6,15) LH [ IU/ml]: P 8,59 (±6,79) vs K 11,0 (±6,15) AMH [ng/ml]: P 4,06 (±2,43) vs K 1,47 (±2,14). AMH levels in the PCOS group did not show a significant difference in correlation with age. Obese and overweight women in both 42 groups had significantly different levels of AMH compared with normal-weight women. Furthermore, AMH levels were positively correlated with the age of the first period in the PCOS. The studies indicate a high use of the hormones like FSH and AMH in the diagnosis and assessment of ovarian reserve in women with PCOS.
Single-Cell Omics for Transcriptome CHaracterization (SCOTCH): isoform-level characterization of gene expression through long-read single-cell RNA sequencing
Authors: Xu Zhuoran , Qu Hui-Qi , Mu Shizhuo , Kao Charlly , Hakonarson Hakon , Wang Kai
Published: April 2024

Recent development involving long-read single-cell transcriptome sequencing (lr-scRNA-Seq) represents a significant leap forward in single-cell genomics. With the recent introduction of R10 flowcells by Oxford Nanopore, we propose that previous computational methods designed to handle high sequencing error rates are less relevant, and that the traditional approach using short reads to compile "barcode space" (candidate barcode list) to de-multiplex long reads are no longer necessary. Instead, computational methods should now shift focus on harnessing the unique benefits of long reads to analyze transcriptome complexity. In this context, we introduce a comprehensive suite of computational methods named Single-Cell Omics for Transcriptome CHaracterization (SCOTCH). SCOTCH supports both Nanopore and PacBio sequencing platforms, and is compatible with single-cell library preparation protocols from both 10X Genomics and Parse Biosciences. Through a sub-exon identification strategy with dynamic thresholding of read mapping scores, SCOTCH precisely aligns reads to known isoforms and discover novel isoforms, efficiently addressing ambiguous mapping challenges commonly encountered in long-read single-cell data. By addressing the multiple mapping issue with probabilistic inference, SCOTCH allows powerful novel isoform identification and differential transcript usage analysis. Comprehensive simulations and real data analyses across multiple platforms (including 10X Genomics and Parse Bioscience, paired with Illumina or Nanopore sequencing technologies with R9 and R10 flowcells, as well as PacBio sequencing) demonstrated that SCOTCH outperforms existing methods in mapping accuracy, quantification accuracy and novel isoform detection, while also uncovering novel biological insights on transcriptome complexity at the single-cell level.