bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroanatomical dissection of the MC3R circuitry regulating energy rheostasis
Authors: Possa-Paranhos Ingrid Camila , Butts Jared , Pyszka Emma , Nelson Christina , Cho Dajin , Sweeney Patrick 
Published: April 2024

AbstractAlthough mammals resist both acute weight loss and weight gain, the neural circuitry mediating bi-directional defense against weight change is incompletely understood. Global constitutive deletion of the melanocortin-3-receptor (MC3R) impairs the behavioral response to both anorexic and orexigenic stimuli, with MC3R knockout mice demonstrating increased weight gain following anabolic challenges and increased weight loss following anorexic challenges (i.e. impaired energy rheostasis). However, the brain regions mediating this phenotype remain incompletely understood.Here, we utilized MC3R floxed mice and viral injections of Cre-recombinase to selectively delete MC3R from medial hypothalamus (MH) in adult mice. Behavioral assays were performed on these animals to test the role of MC3R in MH in the acute response to orexigenic and anorexic challenges. Complementary chemogenetic approaches were used in MC3R-Cre mice to localize and characterize the specific medial hypothalamic brain regions mediating the role of MC3R in energy homeostasis. Finally, we performed RNAscope in situ hybridization to map changes in the mRNA expression of MC3R, POMC, and AgRP following energy rheostatic challenges.Our results demonstrate that MC3R deletion in MH increased feeding and weight gain following acute high fat diet feeding in males, and enhanced the anorexic effects of semaglutide, in a sexually dimorphic manner. Additionally, activation of DMH MC3R neurons increased energy expenditure and locomotion. Together, these results demonstrate that MC3R mediated effects on energy rheostasis result from the loss of MC3R signaling in the medial hypothalamus of adult animals and suggest an important role for DMH MC3R signaling in energy rheostasis.Key Points:MC3R signaling regulates energy rheostasis in adult miceMedial hypothalamus regulates energy rheostasis in adult miceEnergy rheostasis alters mRNA levels of AgRP and MC3R in DMHDMH MC3R neurons increase locomotion and energy expenditureMC3R expression in DMH is sexually dimorphic
Force-Enhanced Sensitive Detection of New DNA-Interactive Agents from Microorganisms at the Single-Molecule Level
Authors: Liu Tianyu , Cai Teng , Liu Hongwei , Li Aiying , Yin Meng , Mei Yan , Zhou Yueyue , Fan Sijun , Lu Yao , Wan Luosheng , You Huijuan , Cai Xiaofeng 
Published: April 2024

AbstractThe discovery of microbial-derived DNA-interacting agents, which hold broad therapeutic potential, is inherently challenging due to the limited sensitivity and specificity of conventional methodologies. Our study introduces a pioneering application of single-molecule stretching assay (SMSA) in natural product chemistry to identify DNA-intercalating agents directly from microbial cultures or extracts. We demonstrate that mechanical force can enhance sensitivity by increasing both the binding affinityKa and the quantity of ligands bound. The changes induced by intercalators in the counter length and overstretching transition of dsDNA yield a distinctive and highly specific signature indicative of DNA intercalative binding, thereby enabling straightforward detection of DNA intercalators even in trace amounts from microbial cultures. This methodology eliminates the need for extensive large-scale fermentation and purification processes, thus offering a more streamlined approach to DNA-intercalating natural product discovery. By applying SMSA to 17 microorganisms, we identified two DNA intercalator-producing strains:Streptomyces tanashiensisandTalaromyces funiculosus. Subsequently, three DNA intercalators, namely medermycin, kalafungin, and ligustrone B, were isolated and characterized. Among them, medermycin and kalafungin showed significant inhibitory effects against HCT-116 cancer cells, withIC50values of 52 ± 6 nM and 70 ± 7 nM, respectively.
Perfusion-Independent Tissue Hypoxia in Cardiac Hypertrophy in Mice Measured by64Cu-CTS PET Imaging
Authors: Baark Friedrich , Michaels Aidan M. , Waters Edward C. T. , Rigby Alex , Kim Jana , Yu Zilin , Pell Victoria R. , Clark James E. , Blower Philip J. , Eykyn Thomas R. , Southworth Richard 
Published: April 2024

AbstractBackgroundHypoxia is central to many cardiac pathologies, but clinically its presence can only be inferred by indirect biomarkers including hypoperfusion and energetic compromise. Imaging hypoxia directly could offer new opportunities for the diagnosis and sub-stratification of cardiovascular diseases.ObjectivesTo determine whether [64Cu]CuCTS Positron Emission Tomography (PET) can identify hypoxia in a murine model of cardiac hypertrophy.MethodsMale C57BL/6 mice underwent abdominal aortic constriction (AAC) to induce cardiac hypertrophy, quantified by echocardiography over 4 weeks. Hypoxia and perfusion were quantified in vivo using [64Cu]CuCTS and [64Cu]CuGTSM PET, respectively, and radiotracer biodistribution was quantified post-mortem. Cardiac radiotracer retention was correlated with contractile function (measured by echocardiography), cardiac hypertrophy (measured by histology), HIF-1α stabilization and NMR-based metabolomics. The effect of anesthesia on [64Cu]CuCTS uptake was additionally investigated in a parallel cohort of mice injected with radiotracer while conscious.ResultsHearts showed increased LV wall thickness, reduced ejection fraction and fractional shortening following AAC. [64Cu]CuCTS retention was 317% higher in hypertrophic myocardium (p<0.001), despite there being no difference in perfusion measured by64CuGTSM. Radiotracer retention correlated on an animal-by-animal basis with severity of hypertrophy, contractile dysfunction, HIF1α stabilization and metabolic signatures of hypoxia. [64Cu]CuCTS uptake in hypertrophic hearts was significantly higher when administered to conscious animals.Conclusions[64Cu]CuCTS PET can quantify cardiac hypoxia in hypertrophic myocardium, independent of perfusion, suggesting the hypoxia is caused by increased oxygen diffusion distances at the subcellular level. Alleviation of cardiac workload by anesthesia in preclinical models partially alleviates this effect.
A metabolic-dysfunction associated steatotic liver acinus biomimetic induces pancreatic islet dysfunction in a coupled microphysiology system
Authors: Aleman Julio , Ravikumar K , Wiegand Connor , Schurdak Mark E. , Vernetti Lawrence , Gavlock Dillon , Reese Celeste , DeBiasio Richard , LaRocca Greg , Angarita Yulder Daniel , Gough Albert , Soto-Gutierrez Alejandro , Behari Jaideep , Yechoor Vijay , Miedel Mark T. , Stern Andrew M. , Banerjee Ipsita , Taylor D. Lansing 
Published: April 2024

AbstractPreclinical and clinical studies suggest that lipid-induced hepatic insulin resistance is a primary defect that predisposes to dysfunction in pancreatic islets, implicating a perturbed liver-pancreas axis underlying the comorbidity of T2DM and MASLD. To investigate this hypothesis, we developed a human biomimetic microphysiological system (MPS) coupling our vascularized liver acinus MPS (vLAMPS) with primary islets on a chip (PANIS) enabling MASLD progression and islet dysfunction to be quantitatively assessed. The modular design of this system (vLAMPS-PANIS) allows intra-organ and inter-organ dysregulation to be deconvoluted. When compared to normal fasting (NF) conditions, under early metabolic syndrome (EMS) conditions, the standalone vLAMPS exhibited characteristics of early stage MASLD, while no significant differences were observed in the standalone PANIS. In contrast, with EMS, the coupled vLAMPS-PANIS exhibited a perturbed islet-specific secretome and a significantly dysregulated glucose stimulated insulin secretion (GSIS) response implicating direct signaling from the dysregulated liver acinus to the islets. Correlations between several pairs of a vLAMPS-derived and a PANIS-derived secreted factors were significantly altered under EMS, as compared to NF conditions, mechanistically connecting MASLD and T2DM associated hepatic factors with islet-derived GLP-1 synthesis and regulation. Since vLAMPS-PANIS is compatible with patient–specific iPSCs, this platform represents an important step towards addressing patient heterogeneity, identifying complex disease mechanisms, and advancing precision medicine.
FREDDIE: A comprehensive tool for detecting exonization of retrotransposable elements in short and long RNA sequencing data
Authors: Mercuri Rafael L. V. , Miller Thiago L. A. , dos Santos Filipe F. , de Lima Matheus F. , Rangel-Pozzo Aline , Galante Pedro A. F. 
Published: April 2024

BackgroundTransposable elements (TEs) constitute a significant portion of mammalian genomes, accounting for about 50% of the total DNA. Intragenic TEs are of particular interest as they are co-transcribed with their host genes in pre-mRNA, potentially leading to the formation of novel chimeric transcripts and the exonization of TEs. The abundance of RNA sequencing data currently available offers a unique opportunity to explore transcriptomic variations. However, a significant limitation is the capability of existing computational tools. Here, we introduce FREDDIE, an innovative algorithm designed to detect the exonization of retrotransposable elements using RNA-seq data. FREDDIE can process short and long RNA sequencing data, assemble and quantify transcripts, evaluate coding potential, and identify protein domains in chimeric transcripts involving exonized TEs and retrocopies.ResultsTo demonstrate the efficacy of FREDDIE, we analyzed and validated TE exonization in two human cancer cell lines, K562 and U251. We have identified 322 chimeric transcripts, of which 126 were from K562, and 196 were from U251. Among these chimeric transcripts, there were 35 that showed similar exonization patterns and host genes. These transcripts involve protein-coding genes of the host and exonization of LINE-1 (L1), Alu elements, and retrocopies of coding genes. We have selected some candidates and validated them experimentally through RT-PCR. The validation rate for these candidates was 70%, later confirmed by long-read sequencing.Additionally, we applied FREDDIE to analyze TE exonization across 157 glioblastoma samples, identifying 1,010 chimeric transcripts. The majority of these transcripts involved the exonization of Alu elements (69.8%), followed by L1 (20.6%) and retrocopies (9.6%). Notably, we discovered a highly expressed L1 exonization within the ROS gene, resulting in a truncated open reading frame (ORF) with the deletion of two protein domains.ConclusionsFREDDIE is an efficient and user-friendly tool for identifying chimeric transcripts that involve exonization of intragenic TEs. Overall, FREDDIE enables comprehensive investigations into the contributions of TEs to transcriptome evolution, variation, and disease-associated abnormalities, and it operates effectively on standard computing systems.FREDDIE is publicly available:https://github.com/galantelab/freddie
A flexible intracortical brain-computer interface for typing using finger movements
Authors: Shah Nishal P. , Willsey Matthew S. , Hahn Nick , Kamdar Foram , Avansino Donald T. , Fan Chaofei , Hochberg Leigh R. , Willett Francis R. , Henderson Jaimie M. 
Published: April 2024

AbstractKeyboard typing with finger movements is a versatile digital interface for users with diverse skills, needs, and preferences. Currently, such an interface does not exist for people with paralysis. We developed an intracortical brain-computer interface (BCI) for typing with attempted flexion/extension movements of three finger groups on the right hand, or both hands, and demonstrated its flexibility in two dominant typing paradigms. The first paradigm is “point-and-click” typing, where a BCI user selects one key at a time using continuous real-time control, allowing selection of arbitrary sequences of symbols. During cued character selection with this paradigm, a human research participant with paralysis achieved 30-40 selections per minute with nearly 90% accuracy. The second paradigm is “keystroke” typing, where the BCI user selects each character by a discrete movement without real-time feedback, often giving a faster speed for natural language sentences. With 90 cued characters per minute, decoding attempted finger movements and correcting errors using a language model resulted in more than 90% accuracy. Notably, both paradigms matched the state-of-the-art for BCI performance and enabled further flexibility by the simultaneous selection of multiple characters as well as efficient decoder estimation across paradigms. Overall, the high-performance interface is a step towards the wider accessibility of BCI technology by addressing unmet user needs for flexibility.
Epigenetic cross-talk between Sirt1 and Dnmt1 promotes axonal regeneration after spinal cord injury in zebrafish
Authors: Gupta Samudra , Hui Subhra Prakash 
Published: April 2024

AbstractThough spinal cord injury (SCI) causes irreversible sensory and motor impairments in human, adult zebrafish retain the potent regenerative capacity by injury-induced proliferation of central nervous system (CNS)-resident progenitor cells to develop new functional neurons at the lesion site. The hallmark of SCI in zebrafish lies in a series of changes in the epigenetic landscape, specifically DNA methylation and histone modifications. Decoding the post-SCI epigenetic modifications is therefore critical for the development of therapeutic remedies that boost SCI recovery process. Here, we have studied on Sirtuin1 (Sirt1), a non-classical histone deacetylase that potentially play a critical role in neural progenitor cells (NPCs) proliferation and axonal regrowth following SCI in zebrafish. We investigated the role of Sirt1 in NPC proliferation and axonal regrowth in response to injury in the regenerating spinal cord and found that Sirt1 is involved in the induction of NPC proliferation along with glial bridging during spinal cord regeneration. We also demonstrate that Sirt1 plays a pivotal role in regulating the HIPPO pathway through deacetylation-mediated inactivation of Dnmt1 and subsequent hypomethylation ofyap1promoter, leading to the induction ofctgfaexpression, which drives the NPC proliferation and axonal regrowth to complete the regenerative process. In conclusion, our study reveals a novel cross-talk between two important epigenetic effectors, Sirt1 and Dnmt1, in the context of spinal cord regeneration, establishing a previously undisclosed relation between Sirt1 and Yap1 which provides a deeper understanding of the underlying mechanisms governing injury-induced NPC proliferation and axonal regrowth. Therefore, we have identified Sirt1 as a novel, major epigenetic regulator of spinal cord regeneration by modulating the HIPPO pathway in zebrafish.
Comparative Analysis of Machine Learning Algorithms for Breast Cancer Classification: SVM Outperforms XGBoost, CNN, RNN, and Others
Authors: Ghosh Prithwish , Chatterjee Debashis 
Published: April 2024

ABSTRACTThis study evaluates ten machine learning algorithms for classifying breast cancer cases as malignant or benign based on physical attributes. Algorithms tested include XGBoost, CNN, RNN, AdaBoost, Adaptive Decision Learner, fLSTM, GRU, Random Forest, SVM, and Logistic Regression. Using a robust dataset from UCI machine learning Breast Cancer, SVM emerged as the most accurate, achieving 98.2456% accuracy. While AdaBoost, Logistic Regression, Neural Networks, and Random Forest showed promise, none matched SVM’s accuracy. These findings underscore the potential of machine learning, particularly SVMs, in cancer diagnosis and treatment by analyzing physical attributes for improved diagnostics and targeted therapies.
Autophosphorylation of the Tousled-like kinases TLK1 and TLK2 regulates recruitment to damaged chromatin via PCNA interaction
Authors: West Kirk L. , Kreiling Natasha , Raney Kevin D. , Ghosal Gargi , Leung Justin W 
Published: April 2024

AbstractTousled-like kinases 1 and 2 (TLK1 and 2) are cell cycle-regulated serine/threonine kinases that are involved in multiple biological processes. Mutation of TLK1 and 2 confer neurodegenerative diseases. Recent studies demonstrate that TLK1 and 2 are involved in DNA repair. However, there is no direct evidence that TLK1 and 2 function at DNA damage sites. Here, we show that both TLK1 and TLK2 are hyper-autophosphorylated at their N-termini, at least in part, mediated by their homo-or hetero-dimerization. We found that TLK1 and 2 hyper-autophosphorylation suppresses their recruitment to damaged chromatin. Furthermore, both TLK1 and 2 associate with PCNA specifically through their evolutionarily conserved non-canonical PCNA-interacting protein (PIP) box at the N-terminus, and mutation of the PIP-box abolishes their recruitment to DNA damage sites. Mechanistically, the TLK1 and 2 hyper-autophosphorylation masks the PIP-box and negatively regulates their recruitment to the DNA damage site. Overall, our study dissects the detailed genetic regulation of TLK1 and 2 at damaged chromatin, which provides important insights into their emerging roles in DNA repair.
Radiation resistance in cervical cancer: An insight on mitochondrial associated membranes and its related proteins
Authors: Lakshminarasimhan Harini , Santhoshkumar Rashmi , Srivastava Sweta 
Published: April 2024

ABSTRACTRadiation therapy proves ineffective against radiation-resistant cancers, exacerbating the disease. The Mitochondrial Associated Membrane (MAM) forms through the tethering of the endoplasmic reticulum to the mitochondrial membrane. Under stress conditions such as radiation, mitochondrial function becomes impaired, prompting the recruitment of endoplasmic reticulum proteins for cell survival. Therefore, understanding the role of ER and mitochondria interactions is crucial for the development of inhibitors or drugs to sensitize cancer cells to radiation. In this study, we focused on ultrastructural alterations in radiation-resistant cells. The main structural changes observed included mitochondrial elongation, mitophagy, the presence of lipid droplets, and shortened ER segments. While MAM formation (the interaction between the ER and mitochondria) was observed in SiHa cells not exposed to radiation, it was disrupted in radiation-resistant cells. We analysed genes associated with mitochondrial elongation, mitophagy, lipid droplet formation, short ER fragments, and ER stress using a dataset from cervical cancer patients in The Cancer Genome Atlas (TCGA). Our analyses suggest that BNIP3L is implicated in therapy failure and tumour recurrence. In future, inhibiting BNIP3L could potentially sensitize resistant cells to radiation therapy.
Neural circuit basis of adolescent THC-induced potentiation of opioid responses later in life
Authors: Hubbard Elizabeth , Galinato Vivienne Mae , Derdeyn Pieter , Bartas Katrina , Mahler Stephen V. , Beier Kevin T. 
Published: April 2024

ABSTRACTUse of one drug of abuse typically influences the behavioral response to other drugs, either administered at the same time or a subsequent time point. The nature of the drugs being used, as well as the timing and dosing, also influence how these drugs interact. Here, we tested the effects of adolescent THC exposure on the development of morphine-induced behavioral adaptations following repeated morphine exposure during adulthood. We found that adolescent THC administration potentiated reward, and paradoxically impaired the development of morphine reward. Following a forced abstinence period, we then mapped the whole-brain response to a moderate dose of morphine, and found that adolescent THC administration led to increased morphine-induced activity in the basal ganglia and increased functional connectivity between frontal cortical regions and the ventral tegmental area. Last, we show using rabies virus-based circuit mapping that adolescent THC exposure triggers a long-lasting elevation in connectivity from the frontal cortex regions onto ventral tegmental dopamine cells. Our study adds to the rich literature on the interaction between drugs of abuse, including THC and opioids, and provides potential circuit substates by which adolescent THC exposure influences responses to morphine later in life.
Heme allocation in eukaryotic cells relies on mitochondrial heme export through FLVCR1b to cytosolic GAPDH
Authors: Jayaram Dhanya Thamaraparambil , Sivaram Pranav , Biswas Pranjal , Dai Yue , Sweeny Elizabeth A. , Stuehr Dennis J. 
Published: April 2024

AbstractHeme is an iron-containing cofactor essential for life. In eukaryotes heme is generated in the mitochondria and must leave this organelle to reach protein targets in other cell compartments. Mitochondrial heme binding by cytosolic GAPDH was recently found essential for heme distribution in eukaryotic cells. Here, we sought to uncover how mitochondrial heme reaches GAPDH. Experiments involving a human cell line and a novel GAPDH reporter construct whose heme binding in live cells can be followed by fluorescence revealed that the mitochondrial transmembrane protein FLVCR1b exclusively transfers mitochondrial heme to GAPDH through a direct protein-protein interaction that rises and falls as heme transfers. In the absence of FLVCR1b, neither GAPDH nor downstream hemeproteins received any mitochondrial heme. Cell expression of TANGO2 was also required, and we found it interacts with FLVCR1b to likely support its heme exporting function. Finally, we show that purified GAPDH interacts with FLVCR1b in isolated mitochondria and triggers heme transfer to GAPDH and its downstream delivery to two client proteins. Identifying FLVCR1b as the sole heme source for GAPDH completes the path by which heme is exported from mitochondria, transported, and delivered into protein targets within eukaryotic cells.
Bridging verbal coordination and neural dynamics
Authors: Schwab-Mohamed Isaïh , Mercier Manuel R. , Trébuchon Agnès , Morillon Benjamin , Lancia Leonardo , Schön Daniele 
Published: April 2024

AbstractOur use of language, which is profoundly social in nature, essentially takes place in interactive contexts and is shaped by precise coordination dynamics that interlocutors must observe. Thus, language interaction is highly demanding on fast adjustment of speech production. Here, we developed a real-time coupled-oscillators virtual partner that allows - by changing the coupling strength parameters - to modulate the ability to synchronise speech with a virtual speaker. Then, we recorded the intracranial brain activity of 16 patients with drug-resistant epilepsy while they performed a verbal coordination task with the virtual partner (VP). More precisely, patients had to repeat short sentences synchronously with the VP. This synchronous speech task is efficient to highlight both the dorsal and ventral language pathways. Importantly, combining time-resolved verbal coordination and neural activity shows more spatially differentiated patterns and different types of neural sensitivity along the dorsal pathway. More precisely, high-frequency activity in left secondary auditory regions is highly sensitive to verbal coordinative dynamics, while primary regions are not. Finally, the high-frequency activity of the IFG BA44 (bilaterally) seems to specifically index the online coordinative adjustments that are continuously required to compensate deviation from synchronisation. These findings illustrate the possibility and value of using a fully dynamic, adaptive and interactive language task to gather deeper understanding of the subtending neural dynamics involved in speech perception, production as well as their interaction.