bluuebunny/crossref_metadata_2025 huggingface dataset:
Vimentin regulates mitochondrial ROS production and inflammatory responses of neutrophils
Authors: Huynh Thao Ngoc , Toperzer Jody , Scherer Allison , Gumina Anne , Brunetti Tonya , Mansour Michael K. , Markovitz David M. , Russo Brian C.
Published: April 2024

The intermediate filament vimentin is present in immune cells and is implicated in proinflammatory immune responses. Whether and how it supports antimicrobial activities of neutrophils is not well established. Here, we developed an immortalized neutrophil model to examine the requirement of vimentin. We demonstrate that vimentin restricts the production of proinflammatory cytokines and reactive oxygen species (ROS), but enhances phagocytosis and swarming. We observe that vimentin is dispensable for neutrophil extracellular trap (NET) formation, degranulation, and inflammasome activation. Moreover, gene expression analysis demonstrated that the presence of vimentin was associated with changes in expression of multiple genes required for mitochondrial function and ROS overproduction. Treatment of wild-type cells with rotenone, an inhibitor for complex I of the electron transport chain, increases the ROS levels. Likewise, treatment with mitoTEMPO, a SOD mimetic, rescues the ROS production in cells lacking vimentin. Together, these data show vimentin regulates neutrophil antimicrobial functions and alters ROS levels through regulation of mitochondrial activity.
Functional Analysis of G6PD Variants Associated With Low G6PD Activity in the All of Us Research Program
Authors: Powell Nicholas R. , Geck Renee C. , Lai Dongbing , Shugg Tyler , Skaar Todd C. , Dunham Maitreya
Published: April 2024

Glucose-6-phosphate dehydrogenase (G6PD) protects red blood cells against oxidative damage through regeneration of NADPH. Individuals withG6PDpolymorphisms (variants) that produce an impaired G6PD enzyme are usually asymptomatic, but at risk of hemolytic anemia from oxidative stressors, including certain drugs and foods. Prevention of G6PD deficiency-related hemolytic anemia is achievable throughG6PDgenetic testing or whole-genome sequencing (WGS) to identify affected individuals who should avoid hemolytic triggers. However, accurately predicting the clinical consequence ofG6PDvariants is limited by over 800G6PDvariants which remain of uncertain significance. There also remains significant variability in which deficiency-causing variants are included in pharmacogenomic testing arrays across institutions: many panels only include c.202G>A, even though dozens of other variants can also cause G6PD deficiency. Here, we seek to improveG6PDgenotype interpretation using data available in the All of Us Research Program and using a yeast functional assay. We confirm thatG6PDcoding variants are the main contributor to decreased G6PD activity, and that 13% of individuals in the All of Us data with deficiency-causing variants would be missed if only the c.202G>A variant were tested for. We expand clinical interpretation forG6PDvariants of uncertain significance; reporting that c.595A>G, known as G6PD Dagua or G6PD Açores, and the newly identified variant c.430C>G, reduce activity sufficiently to lead to G6PD deficiency. We also provide evidence that five missense variants of uncertain significance are unlikely to lead to G6PD deficiency, since they were seen in hemi- or homozygous individuals without a reduction in G6PD activity. We also applied the new WHO guidelines and were able to classify two synonymous variants as WHO class C. We anticipate these results will improve the accuracy, and prompt increased use, ofG6PDgenetic tests through a more complete clinical interpretation ofG6PDvariants. As the All of Us data increases from 245,000 to 1 million participants, and additional functional assays are carried out, we expect this research to serve as a template to enable complete characterization of G6PD deficiency genotypes. With an increased number of interpreted variants, genetic testing ofG6PDwill be more informative for preemptively identifying individuals at risk for drug- or food-induced hemolytic anemia.
Artificial Intelligence in Diabetes Care: Evaluating GPT-4’s Competency in Reviewing Diabetic Patient Management Plan in Comparison to Expert Review
Authors: Mondal Agnibho , Naskar Arindam
Published: April 2024

Background

The escalating global burden of diabetes necessitates innovative management strategies. Artificial intelligence, particularly large language models like GPT-4, presents a promising avenue for improving guideline adherence in diabetes care. Such technologies could revolutionize patient management by offering personalized, evidence-based treatment recommendations.

Methods

A comparative, blinded design was employed, involving 50 hypothetical diabetes mellitus case summaries, emphasizing varied aspects of diabetes management. GPT-4 evaluated each summary for guideline adherence, classifying them as compliant or non-compliant, based on the ADA guidelines. A medical expert, blinded to GPT-4’s assessments, independently reviewed the summaries. Concordance between GPT-4 and the expert’s evaluations was statistically analyzed, including calculating Cohen’s kappa for agreement.

Results

GPT-4 labelled 30 summaries as compliant and 20 as non-compliant, while the expert identified 28 as compliant and 22 as non-compliant. Agreement was reached on 46 of the 50 cases, yielding a Cohen’s kappa of 0.84, indicating near-perfect agreement. GPT-4 demonstrated a 92% accuracy, with a sensitivity of 86.4% and a specificity of 96.4%. Discrepancies in four cases highlighted challenges in AI’s understanding of complex clinical judgments related to medication adjustments and treatment modifications.

Conclusion

GPT-4 exhibits promising potential to support health-care professionals in reviewing diabetes management plans for guideline adherence. Despite high concordance with expert assessments, instances of non-agreement underscore the need for AI refinement in complex clinical scenarios. Future research should aim at enhancing AI’s clinical reasoning capabilities and exploring its integration with other technologies for improved healthcare delivery.
Evaluating General Vision-Language Models for Clinical Medicine
Authors: Jiang Yixing , Omiye Jesutofunmi A. , Zakka Cyril , Moor Michael , Gui Haiwen , Alipour Shayan , Mousavi Seyed Shahabeddin , Chen Jonathan H. , Rajpurkar Pranav , Daneshjou Roxana
Published: April 2024

Recently emerging large multimodal models (LMMs) utilize various types of data modalities, including text and visual inputs to generate outputs. The incorporation of LMMs into clinical medicine presents unique challenges, including accuracy, reliability, and clinical relevance. Here, we explore clinical applications of GPT-4V, an LMM that has been proposed for use in medicine, in gastroenterology, radiology, dermatology, and United States Medical Licensing Examination (USMLE) test questions. We used standardized robust datasets with thousands of endoscopy images, chest x-ray, and skin lesions to benchmark GPT-4V’s ability to predict diagnoses. To assess bias, we also explored GPT-4V’s ability to determine Fitzpatrick skin tones with dermatology images. We found that GPT-4V is limited in performance across all four domains, resulting in decreased performance compared to previously published baseline models. The macro-average precision, recall, and F1-score for gastroenterology were 11.2%, 9.1% and 6.8% respectively. For radiology, the best performing task of identifying cardiomegaly had precision, recall, and F1-score of 28%, 94%, and 43% respectively. In dermatology, GPT-4V had an overall top-1 and top-3 diagnostic accuracy of 6.2% and 21% respectively. There was a significant accuracy drop when predicting images of darker skin tones (p<0.001). GPT-4V accurately identified Fitzpatrick skin tones for 56.5% of images. For the multiple-choice-styled USMLE image-based test questions, GPT-4V had an accuracy of 59%. Our findings demonstrate that the current version of GPT-4V is limited in its diagnostic abilities across multiple image-based medical specialties. Future work should be done to explore LMM’s sensitivity to prompting as well as hybrid models that can combine LMM’s capabilities with other robust models.
Premorbid predictors of death at initial presentation of coronary heart disease in the Women’s Health Initiative study
Authors: Chen Ming-Li , Li Jin , Iyer Kruthika R. , Tcheandjieu Catherine , Jimenez Shirin , Salfati Elias Levy Itshak , Gobbo Liana C. Del , Stefanick Marcia L , Desai Manisha , Xue Xiaonan , Assimes Themistocles L
Published: April 2024

Background

Premorbid health traits that predispose to a fatal initial presentation of coronary heart disease (CHD) remain poorly characterized.

Methods

We followed 148,230 post-menopausal participants in the Women’s Health Initiative for a median of 13.3 years. We ascertained the first occurrence of CHD and performed a joint Cox multivariate regression to identify premorbid predictors for a fatal rather than a non-fatal incident event.

Results

A total of 10,714 incident CHD events including 513 fatal events accrued during follow up. A five-year increase in age, smoking 5 to 34 cigarettes per day, and a standard deviation (SD) increase in the Cornel voltage product on electrocardiography each independently increased the relative risk (RR) of dying from one’s initial presentation of CHD by 46% (95% confidence interval [CI], 35 to 58%), 30% (8 to 51%,), and 17% (7 to 28%), respectively. A high level of recreational physical activity (>1200 metabolic equivalent (MET) minutes per week) reduced one’s relative risk by 32% (12 to 49%). A significant dose-response effect was observed for both physical activity and smoking and the reduction in absolute risk of presenting with fatal CHD associated with a healthy lifestyle was roughly equivalent to the difference in risk observed among women separated in age by approximately 10 years.

Conclusions

Modifiable factors affect a post-menopausal woman’s risk of dying from her initial presentation of CHD. Our findings may reduce case-fatality rates of CHD by motivating individuals at risk to adopt and/or adhere to established primary prevention strategies.
Utilising activity patterns of a complex biophysical network model to optimise intra-striatal deep brain stimulation
Authors: Spiliotis Konstantinos , Appali Revathi , Fontes Gomes Anna Karina , Payonk Jan Philipp , Adrian Simon , van Rienen Ursula , Starke Jens , Köhling Rüdiger
Published: April 2024

Abstract

In this study, we develop a large-scale biophysical network model for the isolated striatal body to optimise potential intrastriatal deep brain stimulation applied in, e.g. obsessive-compulsive disorder by using spatiotemporal patterns produced by the network. The model uses modified Hodgkin-Huxley models on small-world connectivity, while the spatial information, i.e. the positions of neurons, is obtained from a detailed human atlas. The model produces neuronal activity patterns segregating healthy from pathological conditions. Three indices were used for the optimisation of stimulation protocols regarding stimulation frequency, amplitude and localisation: the mean activity of the entire network, the mean activity of the ventral striatal area (emerging as a defined community using modularity detection algorithms), and the frequency spectrum of the entire network activity. By minimising the deviation of the aforementioned indices from the normal state, we guide the optimisation of deep brain stimulation parameters regarding position, amplitude and frequency.
Systematic perturbation screens decode regulators of inflammatory macrophage states and identify a role forTNFmRNA m6A modification
Authors: Haag Simone M , Xie Shiqi , Eidenschenk Celine , Fortin Jean-Philippe , Callow Marinella , Costa Mike , Lun Aaron , Cox Chris , Wu Sunny Z , Pradhan Rachana N , Lock Jaclyn , Kuhn Julia A , Holokai Loryn , Thai Minh , Freund Emily , Nissenbaum Ariane , Keir Mary , Bohlen Christopher J , Martin Scott , Geiger-Schuller Kathryn , Hejase Hussein A , Yaspan Brian L , Carlos Sandra Melo , Turley Shannon J , Murthy Aditya
Published: April 2024

Macrophages adopt dynamic cell states with distinct effector functions to maintain tissue homeostasis and respond to environmental challenges. During chronic inflammation, macrophage polarization is subverted towards sustained inflammatory states which contribute to disease, but there is limited understanding of the regulatory mechanisms underlying these disease-associated states. Here, we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human monocyte-derived macrophages (hMDMs) to uncover regulatory circuits of inflammatory macrophage states. This process identifies regulators of five distinct inflammatory states associated with key features of macrophage function. Among these, the mRNA m6A writer components emerge as novel inhibitors of a TNFα-driven cell state associated with multiple inflammatory pathologies. Loss of m6A writer components in hMDMs enhancesTNFtranscript stability, thereby elevating macrophage TNFα production. A PheWAS on SNPs predicted to impact m6A installation onTNFrevealed an association with cystic kidney disease, implicating an m6A-mediated regulatory mechanism in human disease. Thus, systematic phenotypic characterization of primary human macrophages describes the regulatory circuits underlying distinct inflammatory states, revealing post-transcriptional control of TNF mRNA stability as an immunosuppressive mechanism in innate immunity.
Control without cause: How covariate control biases our insights into brain architecture and pathology
Authors: Sperber Christoph , Gallucci Laura , Arnold Marcel , Umarova Roza M.
Published: April 2024

Inferential analysis of normal or pathological brain imaging data – as in brain mapping or the identification of neurological imaging markers – is often controlled for secondary variables. However, a rationale for covariate control is rarely given and formal criteria to identify appropriate covariates in such complex data are lacking. We investigated the impact and adequacy of covariate control in large-scale imaging data using the example of stroke lesion-deficit mapping. In 183 stroke patients, we evaluated control for age, sex, hypertension, or lesion volume when mapping real or simulated deficits. We found that the impact of covariate control varies and can be strong, but it does not necessarily improve the precision of results. Instead, it systematically shifts results towards the inversed associations between imaging features and the covariate. This effect of covariate control can bias results and, as shown in another experiment, can even create effects out of nothing. The widespread use of covariate control in the statistical analysis of clinical brain imaging data – and, likely, other biological high-dimensional data as well – may not generally improve statistical results, but it may just change them. Therefore, covariate control constitutes a problematic degree of freedom in the analysis of brain imaging data and may often not be justified at all.
Intrinsic Units: Identifying a system’s causal grain
Authors: Marshall William , Findlay Graham , Albantakis Larissa , Tononi Giulio
Published: April 2024

Integrated information theory (IIT) aims to account for the quality and quantity of consciousness in physical terms. According to IIT, a substrate of consciousness must be a system of units that is a maximum of intrinsic, irreducible cause-effect power, quantified by integrated information (φs). Moreover, the grain of each unit must be the one— from micro (finer) to macro (coarser)—that maximizes the system’s intrinsic irreducibility (i.e., maximizesφs). The units that maximizeφsare called the intrinsic units of the system. This work extends the mathematical framework of IIT 4.0 to assess cause-effect power at different grains and thereby determine a system’s intrinsic units. Using simple, simulated systems, we show that the cause-effect power of a system of macro units can be higher than the cause-effect power of the corresponding micro units. Two examples highlight specific kinds of macro units, and how each kind can increase cause-effect power. The implications of the framework are discussed in the broader context of IIT, including how it provides a foundation for tests and inferences about consciousness.
Compliant DNA Origami Nanoactuators as Size-Selective Nanopores
Authors: Yu Ze , Baptist Anna V. , Reinhardt Susanne C. M. , Bertosin Eva , Dekker Cees , Jungmann Ralf , Heuer-Jungemann Amelie , Caneva Sabina
Published: April 2024

Biological nanopores crucially control the import and export of biomolecules across lipid membranes in cells. They have found widespread use in biophysics and biotechnology, where their typically narrow, fixed diameters enable selective transport of ions and small molecules as well as DNA and peptides for sequencing applications. Yet, due to their small channel sizes, they preclude the passage of large macromolecules, e.g., therapeutics. Here, we harness the unique combined properties of DNA origami nanotechnology, machine-inspired design, and synthetic biology, to present a structurally reconfigurable DNA origami MechanoPore (MP) that features a lumen that is tuneable in size through molecular triggers. Controllable switching of MPs between three stable states is confirmed by 3D-DNA-PAINT super-resolution imaging and through dye-influx assays, after reconstitution of the large MPs in the membrane of liposomes via an inverted-emulsion cDICE technique. Confocal imaging of transmembrane transport shows size-selective behaviour with adjustable thresholds. Importantly, the conformational changes are fully reversible, attesting to the robust mechanical switching that overcomes pressure from the surrounding lipid molecules. These MPs advance nanopore technology, offering functional nanostructures that can be tuned on-demand – thereby impacting fields as diverse as drug-delivery, biomolecule sorting and sensing, as well as bottom-up synthetic biology.
Changes in SWEET-mediated sugar partitioning affect photosynthesis performance and plant response to drought
Authors: Aubry Emilie , Clément Gilles , Gilbault Elodie , Dinant Sylvie , Le Hir Rozenn
Published: April 2024

Sugars, produced through photosynthesis, are at the core of all organic compounds synthesized and used for plant growth and response to environmental changes. Their production, transport, and utilization are highly regulated and integrated throughout the plant life cycle. The maintenance of sugar partitioning between the different subcellular compartments and between cells is important in adjusting the photosynthesis performance and response to abiotic constraints. Here, we investigated, in Arabidopsis, the consequences of the disruption of four genes coding for SWEET sugar transporters (SWEET11, SWEET12, SWEET16, and SWEET17) on plant photosynthesis and response to drought. Our results show that mutations in bothSWEET11andSWEET12genes lead to an increase of cytosolic sugars in mesophyll cells and phloem parenchyma cells, which impacts several photosynthesis-related parameters. Further, our results suggest that in theswt11swt12double mutant, the sucrose-induced feedback mechanism on stomatal closure is poorly efficient. On the other hand, changes in fructose partitioning in mesophyll and vascular cells, measured in theswt16swt17double mutant, positively impact gas exchanges, probably through an increased starch synthesis together with higher vacuolar sugar storage. Finally, we propose that the impaired sugar partitioning, rather than the total amount of sugar observed in the quadruple mutant, is responsible for the enhanced sensitivity upon drought. This work highlights the importance of considering SWEET-mediated sugar partitioning rather than global sugar content in photosynthesis performance and plant response to drought. Such knowledge will pave the way to design new strategies to maintain plant productivity in a challenging environment.
Legumain is a paracrine regulator of osteoblast differentiation and mediates the inhibitory effect of TGF-β1 on osteoblast maturation
Authors: Forbord Karl Martin , Lunde Ngoc Nguyen , Bosnjak Tatjana , Johansen Harald Thidemann , Solberg Rigmor , Jafari Abbas
Published: April 2024

1.

Transforming growth factor-beta 1 (TGF-β1) is a critical regulator of skeletal homeostasis and has diverse promoting effects on osteoblastogenesis. However, the mechanisms behind the intriguing inhibitory effect of TGF-β1 on osteoblast maturation are not fully understood. Here, we demonstrate a novel mechanism by which TGF-β1 modulates osteoblast maturation through lysosomal protease legumain. We observed that presence of TGF-β1 in osteogenic cultures of human bone marrow derived mesenchymal stromal (stem) cells enhanced legumain activity and secretion, in-spite of decreased legumain mRNA expression, suggesting post-transcriptional regulation. We further showed that osteogenic cells internalize and activate prolegumain, associated with inhibited osteoblast maturation, revealing legumain as a paracrine regulator of osteoblast maturation. Interestingly, TGF-β1 treatment exacerbated legumain internalization and activity, and showed an additive effect on legumain-induced inhibition of osteoblast maturation. Importantly, legumain inhibition abolished the inhibitory effect of TGF-β1 on osteoblast maturation. Our findings reveal that TGF-β1 inhibits osteoblast maturation through stimulating secretion and activity of endogenous legumain, as well as increasing the internalization and activation of extracellular legumain. Therefore, our study provides a deeper understanding of the complex regulation of osteoblastogenesis and unveils a novel TGF-β1-legumain axis in regulation of osteoblast maturation and offer novel insights for possible therapeutic interventions related to bone diseases associated with aberrant TGF-β1 signaling.
In-depth study of MPV17: a molecular travel unveiling a mitochondrial calcium regulation function
Authors: Meurant Sébastien , Amato Ilario , Mauclet Lorris , Dieu Marc , Chevrollier Arnaud , Ledoux Benjamin , Caruso Marino , Lenaers Guy , Arnould Thierry , Renard Patricia
Published: April 2024

Mitochondrial DNA depletion syndromes are severe genetic disorders associated with mutations in a variety of genes includingMPV17,encoding a protein of the inner mitochondrial membrane with an unclear function. In this study, using BioID technology, we identified MPV17 interacting partners among which proteins from the MICOS complex. However, MPV17 knockout did not impact mitochondrial ultrastructure, but led to increased mitochondria-derived vesicles formation and altered mitochondrial permeability transition pore. Furthermore, MPV17 KO cells exhibited higher mitochondrial calcium levels and reactive oxygen species, leading to mtDNA degradation, a phenomenon prevented by blocking mitochondrial calcium entry or treating cells with antioxidant. We thus propose a function for MPV17 as a potential additional member of the mitochondrial permeability transition pore, whereas in the absence of the protein, the build-up of calcium inside the mitochondria would lead to mtDNA degradation caused by increased oxidative damages.
Temporally controlled nervous system-to-gut signaling bidirectionally regulates longevity inC. elegans
Authors: Xu Lingxiu , Han Chengxuan , Chun Lei , Xu X.Z. Shawn , Liu Jianfeng
Published: April 2024

The nervous system modulates aging by secreting signaling molecules to cell-nonautonomously regulate the physiological state of distal tissues such as the gut. However, the underlying mechanisms are not well understood. Here, usingC. elegansas a model, we identified two distinct neuroendocrine signaling circuits through which motor neurons signal the gut in early life to shorten lifespan but in mid-late life to extend lifespan. Both circuits employ the same neurotransmitter acetylcholine (ACh), while recruiting two different gut ACh receptors ACR-6 and GAR-3 to regulate the transcription factor DAF-16 and HSF-1 in early and mid-late life, respectively. Strikingly, the gut expression of ACR-6 is restricted to early life, whereas that of GAR-3 is confined to mid-late life, providing a potential mechanism for the temporal control of the two circuits. These results identify a novel mechanism that empowers the nervous system to bidirectionally regulate longevity by differentially signaling the gut at different life stages.
TRPV4 stimulates colonic afferents through mucosal release of ATP and glutamate
Authors: Meng Michelle Y , Paine Luke W , Sagnat David , Bello Ivana , Oldroyd Sophie , Javid Farideh , Harper Matthew T , Hockley James RF , Smith Ewan St. J , Owens Róisín M , Alric Laurent , Buscail Etienne , Welsh Fraser , Vergnolle Nathalie , Bulmer David C
Published: April 2024

Background and Purpose

Abdominal pain is a leading cause of morbidity for people living with gastrointestinal disease. While the vanilloid transient receptor potential 4 (TRPV4) ion channel has been implicated in the pathogenesis of abdominal pain, the relative paucity of TRPV4 expression in colon-projecting sensory neurons suggests that non-neuronal cells may also contribute to TRPV4-mediated nociceptor stimulation.

Experimental Approach

Changes in murine colonic afferent activity were examined usingex vivoelectrophysiology in tissues with the gut mucosa present or removed. ATP and glutamate release were measured by bioluminescence assay from human colon organoid cultures and mouse colon. Dorsal root ganglion sensory neuron activity was evaluated by Ca2+imaging when cultured alone or co-cultured with colonic mucosal cells.

Key Results

The TRPV4 agonist GSK1016790A elicited a robust increase in murine colonic afferent activity, which was abolished by removal of the gut mucosa. GSK1016790A promoted ATP and glutamate release from human colon organoid cultures and mouse colon. Inhibition of ATP degradation in mouse colon enhanced the afferent response to GSK1016790A. Pre-treatment with purinoreceptor or glutamate receptor antagonists attenuated and abolished the response to GSK1016790A when given alone or in combination, respectively. Sensory neurons co-cultured with colonic mucosal cells produced a marked increase in intracellular Ca2+to GSK1016790A compared to neurons cultured alone.

Conclusions and Implications

Our data indicate that mucosal release of ATP and glutamate is responsible for the stimulation of colonic afferents following TRPV4 activation. These findings highlight an opportunity to target the gut mucosa for the development of new visceral analgesics.

Bullet Point Summary

What is already known?

Activation of TRPV4 causes visceral hypersensitivity via the stimulation of colonic afferents.

What does this study add?

TRPV4-mediated colonic afferent activation is dependent on mucosal release of ATP and glutamate.

What is the clinical significance?

Mucosal TRPV4-mediated colonic afferent activation provides a gut restricted target for treating abdominal pain.
Discordance between phylogenomic datasets in aphids: who is telling the truth?
Authors: Jousselin Emmanuelle , Coeur d’acier Armelle , Clamens Anne-Laure , Galan Maxime , Cruaud Corinne , Barbe Valérie , Manzano-Marin Alejandro
Published: April 2024

Aphids (Hemiptera: Aphididae) are intensively studied due to their significance as pests and their captivating biological traits. Despite this considerable research interest, the evolutionary history of this insect family is poorly understood. Recent phylogenomic analyses have produced conflicting topologies, particularly at deep nodes, complicating our understanding of aphid trait evolution. In this work, we aimed to produce new data to unravel the backbone phylogeny of aphids. We sequenced partial and whole mitochondrial genomes from 87 species that were added to 31 published mitochondria. We additionally sequenced 42 nuclear loci across 95 aphid species and sourced 146 genes from 12 new and 61 published genomes from the primary aphid obligate endosymbiont, Buchnera aphidicola. We obtain data from these three sources for a subset of 51 aphid species, facilitating a comparative analysis of their phylogenetic signals. Our analyses confirm the monophyly of subfamilies, validating current taxonomic classifications, except for Eriosomatinae and Calaphidinae. However, relationships between subfamilies remain contentious in both mitochondrial and nuclear phylogenies. The topologies obtained withBuchneraappear fully resolved but exhibit some discordance with host phylogenies at deep evolutionary scales and conflict with views on the evolution of aphid morphology. We discuss alternative hypotheses for these discrepancies. Finally, the paucity of phylogenetic information at deep phylogenetic scales may stem from an initial rapid radiation. Though challenging to establish, this scenario may inherently hinder resolution in aphid phylogenetics.
KMAP: Kmer Manifold Approximation and Projection for visualizing DNA sequences
Authors: Fu Chengbo , Niskanen Einari A. , Wei Gong-Hong , Yang Zhirong , Sanvicente-García Marta , Güell Marc , Cheng Lu
Published: April 2024

Identifying and illustrating patterns in DNA sequences is a crucial task in various biological data analyses. In this task, patterns are often represented by sets of kmers, the fundamental building blocks of DNA sequences. To visually unveil these patterns, we could project each kmer onto a point in two-dimensional (2D) space. However, this projection poses challenges due to the high-dimensional nature of kmers and their unique mathematical properties. Here, we established a mathematical system to address the peculiarities of the kmer manifold. Leveraging this kmer manifold theory, we developed a statistical method named KMAP for detecting kmer patterns and visualizing them in 2D space. We applied KMAP to three distinct datasets to showcase its utility. KMAP achieved a comparable performance to the classical method MEME, with approximately 90% similarity in motif discovery from HT-SELEX data. In the analysis of H3K27ac ChIP-seq data from Ewing Sarcoma (EWS), we found that BACH1, OTX2 and ERG1 might affect EWS prognosis by binding to promoter and enhancer regions across the genome. We also found that FLI1 bound to the enhancer regions after ETV6 degradation, which showed the competitive binding between ETV6 and FLI1. Moreover, KMAP identified four prevalent patterns in gene editing data of the AAVS1 locus, aligning with findings reported in the literature. These applications underscore that KMAP could be a valuable tool across various biological contexts. KMAP is freely available at:https://github.com/chengl7-lab/kmap.
A single-nucleus RNA sequencing atlas of the postnatal retina of the sharkScyliorhinus canicula
Authors: Vidal-Vázquez Nicolás , Hernández-Núñez Ismael , Carballo-Pacoret Pablo , Salisbury Sarah , Villamayor Paula R. , Hervas-Sotomayor Francisca , Yuan Xuefei , Lamanna Francesco , Schneider Céline , Schmidt Julia , Mazan Sylvie , Kaessmann Henrik , Adrio Fátima , Robledo Diego , Barreiro-Iglesias Antón , Candal Eva
Published: April 2024

The retina, whose basic cellular structure is highly conserved across vertebrates, constitutes an accessible system for studying the central nervous system. In recent years, single-cell RNA-sequencing studies have uncovered cellular diversity in the retina of a variety of species, providing new insights on retinal evolution and development. However, similar data in cartilaginous fishes, the sister group to all other extant jawed vertebrates, are still lacking. Here, we present a single-nucleus RNA-sequencing atlas of the postnatal retina of the catsharkScyliorhinus canicula, consisting of the expression profiles for 17,438 individual cells from three female, juvenile catshark specimens. Unsupervised clustering revealed 22 distinct cell types comprising all major retinal cell classes, as well as retinal progenitor cells (whose presence reflects the persistence of proliferative activity in postnatal stages in sharks) and oligodendrocytes. Thus, our dataset serves as a foundation for further studies on the development and function of the catshark retina. Moreover, integration of our atlas with data from other species will allow for a better understanding of vertebrate retinal evolution.
Precision and Accuracy of Single-Cell/Nuclei RNA Sequencing Data
Authors: Dai Rujia , Zhang Ming , Chu Tianyao , Kopp Richard , Zhang Chunling , Liu Kefu , Wang Yue , Wang Xusheng , Chen Chao , Liu Chunyu
Published: April 2024

Single-cell/nuclei RNA sequencing (sc/snRNA-Seq) is widely used for profiling cell-type gene expressions in biomedical research. An important but underappreciated issue is the quality of sc/snRNA-Seq data that would impact the reliability of downstream analyses. Here we evaluated the precision and accuracy in 18 sc/snRNA-Seq datasets. The precision was assessed on data from human brain studies with a total of 3,483,905 cells from 297 individuals, by utilizing technical replicates. The accuracy was evaluated with sample-matched scRNA-Seq and pooled-cell RNA-Seq data of cultured mononuclear phagocytes from four species. The results revealed low precision and accuracy at the single-cell level across all evaluated data. Cell number and RNA quality were highlighted as two key factors determining the expression precision, accuracy, and reproducibility of differential expression analysis in sc/snRNA-Seq. This study underscores the necessity of sequencing enough high-quality cells per cell type per individual, preferably in the hundreds, to mitigate noise in expression quantification.
Cell wall digestibility outperforms ear in maintaining digestibility even under severe combined water and heat stress
Authors: Main Oscar , López-Malvar Ana , Meunier Florence , Guillaume Sophie , Jacquemot Marie-Pierre , Lopez-Marnet Paul-Louis , Barotin Charlène , Marmagne Anne , Cézard Laurent , Fargier Sébastien , Rey Sébastien , Larsonneau Pierre , Reymond Matthieu , Mangel Nathalie , Uijttewaal Anthony , Coursol Sylvie , Méchin Valérie
Published: April 2024

Forage maize is a central pillar of dairy cow feeding in France, directly influencing milk production. Drought significantly affects both its yield and digestibility, which are essential for registration purposes. Research on inbred lines revealed droughts notable effect on dry matter and cell wall digestibilities, directly impacting forage quality. Nevertheless, further investigation is warranted due to increasing frequency of drought. To delve deeper, we grew a range of modern forage maize hybrids for two years under four different field water-monitored modalities, representing a total of eight environmental conditions. The resulting dataset allowed us to perform a multiscale analysis, integrating agroclimatic, agronomic, biochemical and histological traits. By establishing a comprehensive heat and water stress index, we classified the environmental conditions. We demonstrated that under severe stress, ear production decreases significantly, but dry matter digestibility can be maintained through increased cell wall digestibility. This boost in cell wall digestibility was due to a reduction inp-hydroxycinnamic acid content, while lignin content remained relatively stable between environments. The significance of lignin distribution increased with the severity of the stress, reaching an extreme threshold where biochemical parameters solely account for digestibility variations.
TAM receptors control actomyosin dynamics in osteoclasts via RHOA-COFILIN-MYOSIN II signaling
Authors: Engelmann Janik , Zarrer Jennifer , Schmerder Max , Mess Christian , Ragipoglu Deniz , Riecken Kristoffer , Burstyn-Cohen Tal , Alberto Emily J. , Ghosh Sourav , Rothlin Carla , Pantel Klaus , Bokemeyer Carsten , Hesse Eric , Taipaleenmäki Hanna , Loges Sonja , Ben-Batalla Isabel
Published: April 2024

The TAM family of receptor tyrosine kinases were recently identified to regulate bone homeostasis by controlling osteoblasts and bone formation. Despite extensive knowledge of TAM receptor function in the mononuclear phagocyte system, the role of TAM receptors in osteoclasts remains largely unknown. Here, we identify a physiological regulatory system including MERTK and TYRO3 in osteoclasts controlling RHOA-ROCK-COFILIN/Myosin II signaling, thereby antagonistically regulating osteoclast-mediated bone remodeling to maintain bone homeostasis. Myeloid-specificlysozyme M-mediated deletion ofMertkled to increased bone mass in mice. In early stages of RANKL-induced osteoclast differentiation MERTK promotes amoeboid migration mode in osteoclast precursor cells by inducing RHOA-COFILIN-MLC2 pathway leading to increased osteoclast formation. In contrast, TYRO3 inhibits RHOA-ROCK signaling in osteoclast precursor cells thereby inhibiting these processes. Furthermore, we unraveled an inhibitory role of MERTK as well as TYRO3 in osteoclast differentiation and function. In line with this, mice withcathepsin K-mediated deletion ofMertkandTyro3exhibited an osteoporotic bone phenotype. We found that osteoclast precursor cell morphology dictates its fusion capacity and identified MERTK as a negative regulator of osteoclast fusion. In multinucleated cells, deletion ofMertkinhibits actin ring formation by mediating central actomyosin contraction and inactivation of COFILIN. In contrast, spatially well-ordered RHOA activation at adhesion structures, induced by loss ofTyro3,improves osteoclast biomechanotransduction to ameliorate podosome belt formation and enhance osteoclast function. By using a syngeneic breast cancer bone metastasis osteolysis models we identified TYRO3 as a bone protective receptor for osteolytic bone diseases, whereas MERTK represents a pharmacologic accessible target to inhibit osteoclast formation because its stimulatory effects of osteoclast precursors prevail the inhibitory effects on mature osteoclasts. Next to the recently uncovered role of MERTK as a target for osteoanabolic therapy MERTK may represent a one-drug two-target treatment strategy to increase osteoblast function and reduce osteoclast formation for treatments of bone diseases.
In VitroAnti-cancer potential of Aloe emodin against Oral Squamous Cell Carcinoma
Authors: T Jesse Joel , Suluvoy Jagadish Kumar , Kolla Harish babu
Published: April 2024

Oral squamous cell carcinoma is caused due to smoking, chewing of tobacco, high exposure of UV radiation and infectious agents such as human papilloma virus (HPV). Epigenetic dysregulation and uncontrolled cell growth are main factors that drives towards tumor development. Risk factors such as smoking, tobacco and viral agent’s up regulates its activity and leads to the cancer. Although chemotherapy, surgery and radiation were preferred for treating cancer but patients, feel extreme psychological stress and depression. Natural products are been investigated for their numerous diseases and in that they can be treated against cancer without side effects. Aloe emodin is one such natural molecule available, which possess various pharmacological activities for human beneficial. In this current study, we investigated the anti-cancer activity of aloe emodinin vitro. The KB 3-1 cell line were treated with different concentrations of Aloe emodin and its anti-cancer potential was determined through DNA fragmentation and cell viability assays.
Confinement in fibrous environments positions and orients mitotic spindles
Authors: Sarkar Apurba , Jana Aniket , Agashe Atharva , Wang Ji , Kapania Rakesh , Gov Nir S. , DeLuca Jennifer G. , Paul Raja , Nain Amrinder S.
Published: April 2024

Accurate positioning of the mitotic spindle within the rounded cell body is critical to physiological maintenance. Adherent mitotic cells encounter confinement from neighboring cells or the extracellular matrix (ECM), which can cause rotation of mitotic spindles and, consequently, titling of the metaphase plate (MP). To understand the positioning and orientation of mitotic spindles under confinement by fibers (ECM-confinement), we use flexible ECM-mimicking nanofibers that allow natural rounding of the cell body while confining it to differing levels. Rounded mitotic bodies are anchored in place by actin retraction fibers (RFs) originating from adhesion clusters on the ECM-mimicking fibers. We discover the extent of ECM-confinement patterns RFs in 3D: triangular and band-like at low and high confinement, respectively. A stochastic Monte-Carlo simulation of the centrosome (CS), chromosome (CH), membrane interactions, and 3D arrangement of RFs on the mitotic body recovers MP tilting trends observed experimentally. Our mechanistic analysis reveals that the 3D shape of RFs is the primary driver of the MP rotation. Under high ECM-confinement, the fibers can mechanically pinch the cortex, causing the MP to have localized deformations at contact sites with fibers. Interestingly, high ECM-confinement leads to low and high MP tilts, which mechanistically depend upon the extent of cortical deformation, RF patterning, and MP position. We identify that cortical deformation and RFs work in tandem to limit MP tilt, while asymmetric positioning of MP leads to high tilts. Overall, we provide fundamental insights into how mitosis may proceed in fibrous ECM-confining microenvironments in vivo.
CCDC113 stabilizes sperm axoneme and head-tail coupling apparatus to ensure male fertility
Authors: Wu Bingbing , Long Chenghong , Yang Yuzhuo , Zhang Zhe , Ma Shuang , Ma Yanjie , Wei Huafang , Li Jinghe , Jiang Hui , Li Wei , Liu Chao
Published: April 2024

The structural integrity of the sperm is crucial for male fertility, defects in sperm head-tail linkage and flagellar axoneme are associated with acephalic spermatozoa syndrome (ASS) and the multiple morphological abnormalities of the sperm flagella (MMAF). Notably, impaired head-tail coupling apparatus (HTCA) often accompanies defects in the flagellum structure, however, the molecular mechanisms underlying this phenomenon remain elusive. Here, we identified an evolutionarily conserved coiled-coil domain-containing (CCDC) protein, CCDC113, and found the disruption of CCDC113 produced spermatozoa with disorganized sperm flagella and HTCA, which caused male infertility. Further analysis revealed that CCDC113 could bind to CFAP57 and CFAP91, and function as an adaptor protein for the connection of radial spokes, nexin-dynein regulatory complex (N-DRC) and doublet microtubules (DMTs) in the sperm axoneme. Moreover, CCDC113 was identified as a structural component of HTCA, collaborating with SUN5 and CENTLEIN to connect sperm head to tail during spermiogenesis. Together, our studies reveal that CCDC113 serve as a critical hub for sperm axoneme and HTCA stabilization, providing insights into the potential pathogenesis of infertility associated with humanCCDC113mutations.
Toll-like receptor 3orchestrates a conserved mechanism of heart regeneration
Authors: Fiegl Manuel , Roehrs Bernhard , Hau Dominik , Mair Sophia , Niederwanger Philipp , Regele Dominik , Merotto Lorenzo , Toechterle Sonja , Engler Clemens , Graber Michael , Kirchmair Elke , Niedrist Veronika , Muller Lynn , Poelzl Leo , Hirsch Jakob , Naegele Felix , Happacher Isidor , Oberegger Simon , Bonaros Nikolaos , Grimm Michael , Tancevski Ivan , Finotello Francesca , Meyer Dirk , Holfeld Johannes , Gollmann-Tepekoeylue Can
Published: April 2024

The human’s heart responds to tissue damage with persistent fibrotic scarring. Unlike humans, zebrafish can repair cardiac injury and re-grow heart tissue throughout life. Recently,Toll-like receptor 3(Tlr3) was identified as an important mediator of cardiac regeneration in neonatal mice. However, no functional analysis oftlr3knock-out mutant zebrafish in respect to cardiac regeneration has yet been performed.

We hypothesize that TLR3 signalling plays a central, conserved role in driving cardiac regeneration upon injury. Therefore, we focused ontlr3mediated cardiac regeneration in zebrafish, ultimately discovering an evolutionary conserved mechanism of heart repair. Using histological, behavioural, and RNA-Sequencing analysis, we uncovered a conserved mechanism oftlr3mediated cardiac repair after myocardial injury.

Upon myocardial cryoinjury subjection, survival is decreased intlr3-/-fish as compared to wildtype controls.Tlr3-/-zebrafish fail to recruit immune cells to the injured ventricle, resulting in impaired DNA repair and transcriptional reprogramming of cardiomyocytes.

Mechanistically, we uncover an evolutionary conserved mechanism oftlr3activation in fibroblasts promoting monocyte migration towards an injured ventricular area. Our data revealtlr3as a novel therapeutic target to promote cardiac regeneration.

Every experiment including human participants has been approved by the ethics committee of the Medical University of Innsbruck (Ref. Nr.: 1262/2023). All experiments including the use of laboratory animals have been approved by the federal ministry of education, science, and research of Austria (Ref. Nr.: 2020-0.345.504).
Cortico-Spinal Intermittent Theta Burst Stimulation Propelling Sensorimotor Function Recovery in Complete Spinal Cord Injury: Randomized Control Trial Protocol
Authors: Patel Deeksha , Banerjee Rohit , Farooque Kamran , Gupta Deepak , Garg Bhavuk , Kumar Nand , Kocchar KP , Jain Suman
Published: April 2024

Background

Intermittent theta burst stimulation (iTBS) is a non-invasive stimulation technique to induce neuronal and synaptic plasticity. The induced cortical plasticity is imperative in the recovery of motor and sensory functions. Spinal cord injury (SCI) causes damage to neurons and results in sensorimotor dysfunction. The effect of iTBS on recovery of motor and sensory dysfunction in complete SCI (cSCI) is still elusive.

AIM

This study aims to assess the effect of iTBS on cortico-spinal tract integrity, plasticity, and regaining of motor and sensory function in cSCI patients. The rationale behind using an iTBS protocol is to modify and augment the communication between spared neurons of the cortico-spinal tract and strengthen the synaptic transmission, which will improve motor function in underlying muscles.

Method

A total of 48 patients will be recruited and randomly divided into placebo and real stimulation groups. iTBS along with a rehabilitation program will be administered to the placebo and real stimulation groups. Follow-up will be done at 1 month, 2 months, and 3 months after the intervention.

Result

The outcome of the study will be defined by electrophysiological parameters elicited by single and paired-pulse stimulation, ASIA score, pain, activities of daily life, quality of life, anxiety, depression, and biomarkers related to SCI. The results of this study will uncover the effectiveness of iTBS stimulation on (i) recovery of motor and sensory function in cSCI (ii) excitability of cortico-spinal tract (iii) neurological recovery and modulation of pain (iv) cortical reorganization after injury.

Conclusion

Intermittent theta-burst stimulation (iTBS) in conjunction with an individualized rehabilitation program may serve as an integrated strategy to rejuvenate locomotor abilities and improve the overall quality of life for people with complete spinal cord injuries (SCI).

Key Points

iTBS is a novel neurostimulation technique aimed to restore sensorimotor function after a complete SCI

The primary objective of the trial is to evaluate the efficacy of iTBS in promoting sensorimotor function recovery

Assessment of the potential impact of iTBS on SCI rehabilitation

Understand the underlying mechanism of excitatory-inhibitory circuits associated with SCI

Unlock the importance of neuronal plasticity in regaining mobility