bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling relaxation experiments with a mechanistic model of gene expression
Authors: Estavoyer Maxime , Dufeu Marion , Ranson Grégoire , Lefort Sylvain , Voeltzel Thibault , Maguer-Satta Véronique , Gandrillon Olivier , Lepoutre Thomas 
Published: April 2024

AbstractBackgroundIn the present work, we aimed at modeling a relaxation experiment which consists in selecting a subfraction of a cell population and observing the speed at which the entire initial distribution for a given marker is reconstituted.MethodsFor this we first proposed a modification of a previously published mechanistic two-state model of gene expression to which we added a state-dependent proliferation term. This results in a system of two partial differential equations. Under the assumption of a linear proliferation rate, we could derive the asymptotic profile of the solutions of this model.ResultsIn order to confront our model with experimental data, we generated a relaxation experiment of the CD34 antigen on the surface of TF1-BA cells, starting either from the highest or the lowest CD34 expression levels. We observed in both cases that after approximately 25 days the distribution of CD34 returns to its initial stationary state. Numerical simulations, based on parameter values estimated from the dataset, have shown that the model solutions closely align with the experimental data from the relaxation experiments.ConclusionAltogether our results strongly support the notion that cells should be seen and modeled as probabilistic dynamical systems.
PPARG in osteocytes controls cell bioenergetics and systemic energy metabolism independently of sclerostin levels in circulation
Authors: Baroi Sudipta , Czernik Piotr J. , Khan Mohd Parvez , Letson Joshua , Crowe Emily , Chougule Amit , Griffin Patrick R. , Rosen Clifford J. , Lecka-Czernik Beata 
Published: April 2024

AbstractObjectiveThe skeleton is one of the largest organs in the body, wherein metabolism is integrated with systemic energy metabolism. However, the bioenergetic programming of osteocytes, the most abundant bone cells coordinating bone metabolism, is not well defined. Here, using a mouse model with partial penetration of an osteocyte-specific PPARG deletion, we demonstrate that PPARG controls osteocyte bioenergetics and their contribution to systemic energy metabolism independently of circulating sclerostin levels.MethodsIn vivoandin vitromodels of osteocyte-specific PPARG deletion, i.e.Dmp1CrePparγflflmale and female mice (γOTKO) and MLO-Y4 osteocyte-like cells with either siRNA-silenced or CRISPR/Cas9-editedPparγ. As applicable, the models were analyzed for levels of energy metabolism, glucose metabolism, and metabolic profile of extramedullary adipose tissue, as well as the osteocyte transcriptome, mitochondrial function, bioenergetics, insulin signaling, and oxidative stress.ResultsCirculating sclerostin levels of γOTKOmale and female mice were not different from control mice. Male γOTKOmice exhibited a high energy phenotype characterized by increased respiration, heat production, locomotion and food intake. This high energy phenotype in males did not correlate with “beiging” of peripheral adipose depots. However, both sexes showed a trend for reduced fat mass and apparent insulin resistance without changes in glucose tolerance, which correlated with decreased osteocytic responsiveness to insulin measured by AKT activation. The transcriptome of osteocytes isolated from γOTKOmales suggested profound changes in cellular metabolism, fuel transport and usage, mitochondria dysfunction, insulin signaling and increased oxidative stress. In MLO-Y4 osteocytes, PPARG deficiency correlated with highly active mitochondria, increased ATP production, shifts in fuel utilization, and accumulation of reactive oxygen species (ROS).ConclusionsPPARG in male osteocytes acts as a molecular break on mitochondrial function, and protection against oxidative stress and ROS accumulation. It also regulates osteocyte insulin signaling and fuel usage to produce energy. These data provide insight into the connection between osteocyte bioenergetics and their sex-specific contribution to the balance of systemic energy metabolism. These findings support the concept that the skeleton controls systemic energy expenditureviaosteocyte metabolism.HighlightsOsteocytes function as a body energostat via their bioenergeticsPPARG protein acts as a “molecular break” of osteocyte mitochondrial activityPPARG deficiency activates TCA cycle, oxidative stress and ROS accumulationPPARG controls osteocyte insulin signaling and fuel utilization
Spatial proteomics identifies a novel CRTC-dependent viral sensing pathway that stimulates production of Interleukin-11
Authors: Ravenhill Benjamin J. , Oliveira Marisa , Wood George , Di Ying , Davies Colin T.R. , Lu Yongxu , Antrobus Robin , Elliott Gill , Irigoyen Nerea , Hughes David J. , Lyons Paul , Chung Betty , Borner Georg H.H , Weekes Michael P. 
Published: April 2024

ABSTRACTAppropriate cellular recognition of viruses is essential for the generation of effective innate and adaptive antiviral immunity. Viral sensors and their signalling components thus provide a crucial first line of host defence. Many exhibit subcellular relocalisation upon activation, triggering expression of interferon and antiviral genes. To identify novel signalling factors we analysed protein relocalisation on a global scale during viral infection. CREB Regulated Transcription Coactivators-2 and 3 (CRTC2/3) exhibited early cytoplasmic-to-nuclear translocation upon a diversity of viral stimuli, in diverse cell types. This movement was depended on Mitochondrial Antiviral Signalling Protein (MAVS), cyclo-oxygenase proteins and protein kinase A. We identify a key effect of transcription stimulated by CRTC2/3 translocation as production of the pro-fibrogenic cytokine interleukin-11. This may be important clinically in viral infections associated with fibrosis, including SARS-CoV-2.
Metadichol® induced expression of the TLR family of receptors in PBMCs
Authors: Raghavan P.R. 
Published: April 2024

AbstractToll-like receptors (TLRs) are fundamental components of the innate immune system and function as the primary sensors of invading pathogens by recognizing prevalent microbial compounds. The expression of all ten transcription factors belonging to the TLR family (1–10), with the exception of TLR4, exhibited an inverted U-shaped reaction to metadichol, a nanoemulsion composed of long-chain alcohol, as determined by the Q-RT□PCR assay. The response pattern suggested that low, moderate, and high concentrations directly affect TLR expression. This may indicate a dual-phase or dose-dependent effect on the immune system regarding TLR regulation. Compounds targeting TLRs can stimulate or inhibit these receptors, thereby affecting the immune response. Adjusting immunological activation, crucial for therapeutic purposes in conditions such as inflammation, cancer, infection, allergies, and autoimmune diseases, requires an inverse U-shaped response. Currently, no single-molecule examples can elicit the activation of every Toll-like receptor (TLR). This study examined the expression levels of all ten Toll-like receptors (TLRs), MYD88, and the downstream genes IRAK4, TRAF3, and TRIF. Metadichol expresses all the 15 genes.
The distribution ofApis laboriosarevisited: range extensions and biogeographic affinities
Authors: Otis Gard W. , Huang Man-Juan , Kitnya Nyaton , Sheikh Umer Ayyaz Aslam , Faiz Abu ul Hassan , Phung Chinh H. , Warrit Natapot , Peng Yan-Qiong , Zhou Xin , Oo Hliang Min , Acharya Namoona , Devkota Kedar 
Published: April 2024

AbstractApis laboriosa, the Himalayan giant honeybee, inhabits the foothills of the Himalaya and neighboring mountainous regions. Here we revise its distribution in light of recent reports and discoveries. The range now extends from longitude 105.9°E in Cao Bang, Vietnam, in the east to 74.4°E in the Pir Panjal Range of western Himalaya, a linear distance of 3300 km, with the most notable new localities in northeastern Vietnam, central Myanmar, northern Thailand, and AJK-Pakistan. The species generally occurs at lower elevations in the eastern part of its range than in Nepal, northern India, and the border region between India and Pakistan. Most but not all of the new localities are within the range predicted by species distribution modelling. We discuss the new localities that fall outside of the predicted range, the biotic characteristics of the terrestrial ecoregions in which the species occurs, and the remaining regions that may harbor this spectacular honey bee species.
Podocyte exopher-formation as a novel pathomechanism in membranous nephropathy
Authors: Lahme Karen , Sachs Wiebke , Froembling Sarah , Brehler Michael , Loreth Desiree , Surmann Kristin , Gaffling Simone , Wedekind Uta , Böttcher-Dierks Vincent , Adler Marie R. , Sáez Pablo J. , Conze Christian , Thünauer Roland , Skuza Sinah , Neitzel Karen , Zieliniski Stephanie , Brand Johannes , Bonn Stefan , Michalik Stephan , Völker Uwe , Zimmermann Marina , Wiech Thorsten , Meyer Tobias N. , Fester Lars , Meyer-Schwesinger Catherine 
Published: April 2024

ABSTRACTBackgroundMembranous nephropathy (MN) is caused by autoantibody binding to podocyte foot process antigens such as THSD7A and PLA2R1. The mechanisms of the glomerular antigen/autoantibody deposition and clearance are unknown.MethodsWe explore the origin and significance of glomerular accumulations in (1) diagnostic and follow-up biospecimens from THSD7A+and PLA2R1+-MN patients compared to nephrotic non-MN patients, and (2) in experimental models of THSD7A+-MN.ResultsWe discovered podocyte exophers as correlates of histological antigen/autoantibody aggregates found in the glomerular urinary space of MN patients. Exopher vesicle formation represents a novel form of toxic protein aggregate removal inCaenorhabditis elegansneurons. In MN patients, podocytes released exophers to the urine. Enrichment of exophers from MN patient urines established them as a glomerular exit route for antigens and bound autoantibody. Exophers also carried disease-associated proteins such as complement and provided a molecular imprint of podocyte injury pathways. In experimental THSD7A+-MN, exophers were formed from podocyte processes and cell body. Their formation involved the translocation of antigen/autoantibody from the subepithelial to the urinary side of podocyte plasma membranes. Urinary exopher-release correlated with lower albuminuria and lower glomerular antigen/autoantibody burden. In MN patients the prospective monitoring of urinary exopher abundance and of exopher-bound autoantibodies was additive in the assessment of immunologic MN activity.ConclusionsExopher-formation and release is a novel pathomechanism in MN to remove antigen/autoantibody aggregates from the podocyte. Tracking exopher-release will add a non-invasive diagnostic tool with prognostic potential to clinical diagnostics and follow-up of MN patients.
12/15-Lipoxygenases mediate neuropathic-like pain hypersensitivity in female mice
Authors: Brown B , Chen I , Miliano C , Murdaugh LB , Dong Y , Eddinger KA , Yaksh TL , Burton MD , Buczynski MW , Gregus AM 
Published: April 2024

AbstractIt is estimated that chronic neuropathic pain conditions exhibit up to 10% prevalence in the general population, with increased incidence in females. However, nonsteroidal inflammatory drugs (NSAIDs) are ineffective, and currently indicated prescription treatments such as opioids, anticonvulsants, and antidepressants provide only limited therapeutic benefit. In the current work, we extended previous studies in male rats utilizing a paradigm of central Toll-like receptor 4 (TLR4)-dependent, NSAID-unresponsive neuropathic-like pain hypersensitivity to male and female C57BL/6N mice, uncovering an unexpected hyperalgesic phenotype in female mice following intrathecal (IT) LPS. In contrast to previous reports in female C57BL/6J mice, female C57BL/6N mice displayed tactile and cold allodynia, grip force deficits, and locomotor hyperactivity in response to IT LPS. Congruent with our previous observations in male rats, systemic inhibition of 12/15-Lipoxygenases (12/15-LOX) in female B6N mice with selective inhibitors – ML355 (targeting 12-LOX-p) and ML351 (targeting 15-LOX-1) – completely reversed allodynia and grip force deficits. We demonstrate here that 12/15-LOX enzymes also are expressed in mouse spinal cord and that 12/15-LOX metabolites produce tactile allodynia when administered spinally (IT) or peripherally (intraplantar in the paw, IPLT) in a hyperalgesic priming model, similar to others observations with the cyclooxygenase (COX) metabolite Prostaglandin E2(PGE2). Surprisingly, we did not detect hyperalgesic priming following IT administration of LPS, indicating that this phenomenon likely requires peripheral activation of nociceptors. Collectively, these data suggest that 12/15-LOX enzymes contribute to neuropathic-like pain hypersensitivity in rodents, with potential translatability as druggable targets across sexes and species using multiple reflexive and non-reflexive outcome measures.
A “tug-of-war” between the NuRD and SWI/SNF chromatin remodelers regulates the coordinated activation of Epithelial-Mesenchymal Transition and inflammation in oral cancer
Authors: Stabile Roberto , Tucci Francesco A. , Verhagen Mathijs P. , Embregts Carmen , van den Bosch Thierry P.P. , Joosten Rosalie , De Herdt Maria J. , van der Steen Berdine , Nigg Alex L. , Koljenović Senada , Hardillo Jose A. , Verrijzer C. Peter , Biddle Adrian , Baatenburg de Jong Robert J. , Leenen Pieter J.M. , Fodde Riccardo 
Published: April 2024

AbstractPhenotypic plasticity and inflammation, two well-established hallmarks of cancer, play key roles in local invasion and distant metastasis by enabling rapid adaptation of tumor cells to dynamic micro- environmental changes. Here, we show that in oral squamous carcinoma cell carcinoma (OSCC), the competition between the NuRD and SWI/SNF chromatin remodeling complexes plays a pivotal role in regulating both epithelial-mesenchymal plasticity (EMP) and inflammation. By perturbing these complexes, we demonstrate their opposing downstream effects on inflammatory pathways and EMP regulation. In particular, downregulation of the BRG1-specific SWI/SNF complex deregulates key inflammatory genes such as TNF-α and IL6 in opposite ways when compared with loss of CDK2AP1, a key member of the NuRD complex. We show thatCDK2AP1genetic ablation triggers a pro-inflammatory secretome encompassing several chemo- and cytokines thus promoting the recruitment of monocytes into the tumor microenvironment (TME). Furthermore,CDK2AP1deletion stimulates their differentiation into M2-like macrophages, as also validated on tumor microarrays from OSCC patient- derived tumor samples. Further analysis of the inverse correlation between CDK2AP1 expression and TME immune infiltration revealed specific downstream effects on CD68+macrophage abundance and localization. Our study sheds light on the role of chromatin remodeling complexes in OSCC locoregional invasion and points at the potential of CDK2AP1 and other members of the NuRD and SWI/SNF chromatin remodeling complexes as prognostic markers and therapeutic targets.
Direct genome sequencing of respiratory viruses from low viral load clinical specimens using target capture sequencing technology
Authors: Takemae Nobuhiro , Kuba Yumani , Oba Kunihiko , Kageyama Tsutomu 
Published: April 2024

AbstractThe use of metagenomic next-generation sequencing technology to obtain complete viral genome sequences directly from clinical samples with low viral load remains challenging—especially in the case of respiratory viruses—due to the low copy number of viral versus host genomes. To overcome this limitation, target capture sequencing for the enrichment of specific genomes has been developed and applied for direct genome sequencing of viruses. However, as the efficiency of enrichment varies depending on the probes, the type of clinical sample, etc., validation is essential before target capture sequencing can be applied to clinical diagnostics. Here we evaluated the utility of target capture sequencing with a comprehensive viral probe panel for clinical respiratory specimens collected from patients diagnosed with SARS-CoV-2 or influenza type A. We focused on clinical specimens containing low copy numbers of viral genomes. Target capture sequencing yielded approximately 180- and 2000-fold higher read counts of SARS-CoV-2 and influenza A virus, respectively, than metagenomic sequencing when the RNA extracted from specimens contained 59.3 copies/µL of SARS-CoV-2 or 544 copies/µL of influenza A virus, respectively. In addition, the target capture sequencing identified sequence reads in all SARS-CoV-2- or influenza type A-positive specimens with <26 RNA copies/µL, some of which also yielded >70% of the full-length genomes of SARS-CoV-2 or influenza A virus. Furthermore, the target capture sequencing using comprehensive probes identified co-infections with viruses other than SARS-CoV-2, suggesting that this approach will not only detect a wide range of viruses, but also contribute to epidemiological studies.
A Deep Learning-Driven Sampling Technique to Explore the Phase Space of an RNA Stem-Loop
Authors: Gupta Ayush , Ma Heng , Ramanathan Arvind , Zerze Gül H. 
Published: April 2024

AbstractThe folding and unfolding of RNA stem-loops are critical biological processes; however, their computational studies are often hampered by the ruggedness of their folding landscape, necessitating long simulation times at the atomistic scale. Here, we adapted DeepDriveMD (DDMD), an advanced deep learning-driven sampling technique originally developed for protein folding, to address the challenges of RNA stem-loop folding. Although tempering- and order parameter-based techniques are commonly used for similar rare event problems, the computational costs and/or the need fora prioriknowledge about the system often present a challenge in their effective use. DDMD overcomes these challenges by adaptively learning from an ensemble of running MD simulations using generic contact maps as the raw input. DeepDriveMD enables on-the-fly learning of a low-dimensional latent representation and guides the simulation toward the undersampled regions while optimizing the resources to explore the relevant parts of the phase space. We showed that DDMD estimates the free energy landscape of the RNA stem-loop reasonably well at room temperature. Our simulation framework runs at a constant temperature without external biasing potential, hence preserving the information of transition rates, with a computational cost much lower than that of the simulations performed with external biasing potentials. We also introduced a reweighting strategy for obtaining unbiased free energy surfaces and presented a qualitative analysis of the latent space. This analysis showed that the latent space captures the relevant slow degrees of freedom for the RNA folding problem of interest. Finally, throughout the manuscript, we outlined how different parameters are selected and optimized to adapt DDMD for this system. We believe this compendium of decision-making processes will help new users adapt this technique for the rare-event sampling problems of their interest.
Leveraging Large Language Models to Analyze Continuous Glucose Monitoring Data: A Case Study
Authors: Healey Elizabeth , Tan Amelia , Flint Kristen , Ruiz Jessica , Kohane Isaac 
Published: April 2024

AbstractContinuous glucose monitors (CGM) provide patients and clinicians with valuable insights about glycemic control that aid in diabetes management. The advent of large language models (LLMs), such as GPT-4, has enabled real-time text generation and summarization of medical data. Further, recent advancements have enabled the integration of data analysis features in chatbots, such that raw data can be uploaded and analyzed when prompted. Studying both the accuracy and suitability of LLM-derived data analysis performed on medical time series data, such as CGM data, is an important area of research. The objective of this study was to assess the strengths and limitations of using an LLM to analyze raw CGM data and produce summaries of 14 days of data for patients with type 1 diabetes. This study used simulated CGM data from 10 different cases. We first evaluated the ability of GPT-4 to compute quantitative metrics specific to diabetes found in an Ambulatory Glucose Profile (AGP). Then, using two independent clinician graders, we evaluated the accuracy, completeness, safety, and suitability of qualitative descriptions produced by GPT-4 across five different CGM analysis tasks. We demonstrated that GPT-4 performs well across measures of accuracy, completeness, and safety when producing summaries of CGM data across all tasks. These results highlight the capabilities of using an LLM to produce accurate and safe narrative summaries of medical time series data. We highlight several limitations of the work, including concerns related to how GPT-4 may misprioritize highlighting instances of hypoglycemia and hyperglycemia. Our work serves as a preliminary study on how generative language models can be integrated into diabetes care through CGM analysis, and more broadly, the potential to leverage LLMs for streamlined medical time series analysis.
Network localization of pediatric lesion-induced dystonia
Authors: Gelineau-Morel Rose , Dlamini Nomazulu , Bruss Joel , Cohen Alexander Li , Robertson Amanda , Alexopoulos Dimitrios , Smyser Christopher D. , Boes Aaron D. 
Published: April 2024

AbstractObjectiveDystonia is a movement disorder defined by involuntary muscle contractions leading to abnormal postures or twisting and repetitive movements. Classically dystonia has been thought of as a disorder of the basal ganglia, but newer results in idiopathic dystonia and lesion-induced dystonia in adults point to broader motor network dysfunction spanning the basal ganglia, cerebellum, premotor cortex, sensorimotor, and frontoparietal regions. It is unclear whether a similar network is shared between different etiologies of pediatric lesion-induced dystonia.MethodsThree cohorts of pediatric patients with lesion-induced dystonia were identified. The lesion etiologies included hypoxia, kernicterus, and stroke versus comparison subjects with acquired lesions not associated with dystonia. Multivariate lesion-symptom mapping and lesion network mapping were used to evaluate the anatomy and networks associated with dystonia.ResultsMultivariate lesion-symptom mapping showed that lesions of the putamen (stroke: r = 0.50, p <0.01; hypoxia, r = 0.64, p <0.001) and globus pallidus (kernicterus, r = 0.61, p <0.01) were associated with dystonia. Lesion network mapping using normative connectome data from healthy children demonstrated that these regional findings occurred within a common brain-wide network that involves the basal ganglia, anterior and medial cerebellum, and cortical regions that overlap the cingulo-opercular and somato-cognitive-action networks.InterpretationWe interpret these findings as novel evidence for a unified dystonia brain network that involves the somato-cognitive-action network, which is involved in higher order coordination of movement. Elucidation of this network gives insight into the functional origins of dystonia and provides novel targets to investigate for therapeutic intervention.