bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polydopamine Nanoparticles as Mimicking RPE Melanin for the Protection of Retinal Cells Against Blue Light-Induced Phototoxicity
Authors: Kwon Yong-Su , Zheng Min , Smirnov Alex I. , Han Zongchao 
Published: January 2024

AbstractExposure of the eyes to blue light can induce the overproduction of reactive oxygen species (ROS) in the retina and retinal pigment epithelium (RPE) cells, potentially leading to pathological damage of age-related macular degeneration (AMD). While the melanin in RPE cells absorbs blue light and prevents ROS accumulation, the loss and dysfunction of RPE melanin due to age-related changes may contribute to photooxidation toxicity. Herein, we present a novel approach utilizing a polydopamine-replenishing strategy via a single-dose intravitreal (IVT) injection to protect retinal cells against blue light-induced phototoxicity. To investigate the effects of overexposure to blue light on retinal cells, we created a blue light exposure Nrf2-deficient mouse model, which are susceptible to light-induced retinal lesions. After blue light irradiation, we observed retina degeneration and an overproduction of ROS. The Polydopamine-replenishing strategy demonstrated effectiveness in maintaining retinal structural integrity and preventing retina degeneration by reducing ROS production in retinal cells against the phototoxicity of blue light exposure. Our findings highlight the potential of polydopamine as a simple and effective replenishment for providing photoprotection against high-energy blue light exposure.Graphical AbstractThe graphic illustration of PDA-mediated photoprotection strategies to mimic natural melanin in RPE cells against blue light-induced phototoxicity in an Nrf2-deficient mouse model via a single-dose intravitreal (IVT) administration.
Noxious stimulation induces self-protective behaviour in bumblebees
Authors: Gibbons Matilda , Pasquini Elisa , Kowalewska Amelia , Read Eva , Gibson Sam , Crump Andrew , Solvi Cwyn , Versace Elisabetta , Chittka Lars 
Published: January 2024

AbstractSelf-grooming directed towards a noxiously-stimulated body part is one indicator that an animal may feel pain. In insects, the lack of evidence for such behaviour has been widely argued to reflect the absence of pain experiences. Here, we tested whether bumblebees (Bombus terrestris) selectively groom one of their antennae that was touched with a noxiously-heated (65 □C) probe. In the first two minutes after being touched with the noxiously-heated probe, bees groomed their touched antenna a) more than their untouched antenna, b) more than bees that were touched on the antenna with an unheated probe, and c) more than control (untouched) bees groomed either of their antennae. Our results clearly show that bumblebees can direct grooming towards a site of noxious stimulation. Our findings thus refute arguments that claim that insects do not feel pain because of their lack of displaying this behaviour.
Single dopaminergic neuron DAN-c1 inDrosophilalarval brain mediates aversive olfactory learning through D2-like receptors
Authors: Qi Cheng , Qian Cheng , Steijvers Emma , Colvin Robert A. , Lee Daewoo 
Published: January 2024

AbstractThe intricate relationship between the dopaminergic system and olfactory associative learning inDrosophilahas been an intense scientific inquiry. Leveraging the formidable genetic tools, we conducted a screening of 57 dopaminergic drivers, leading to the discovery of DAN-c1 driver, uniquely targeting the single dopaminergic neuron (DAN) in each brain hemisphere. While the involvement of excitatory D1-like receptors is well-established, the role of D2-like receptors (D2Rs) remains underexplored. Our investigation reveals the expression of D2Rs in both DANs and the mushroom body (MB) of third instar larval brains. Silencing D2Rs in DAN-c1 via microRNA disrupts aversive learning, further supported by optogenetic activation of DAN-c1 during training, affirming the inhibitory role of D2R autoreceptor. Intriguingly, D2R knockdown in the MB impairs both appetitive and aversive learning. These findings elucidate the distinct contributions of D2Rs in diverse brain structures, providing novel insights into the molecular mechanisms governing associative learning inDrosophilalarvae.
Neural Dynamics and Seizure Correlations: Insights from Neural Mass Models in a Tetanus Toxin Rat Model of Epilepsy
Authors: Zarei Eskikand Parvin , Soto-Breceda Artemio , Cook Mark J. , Burkitt Anthony N. , Grayden David B. 
Published: January 2024

AbstractThis study focuses on the use of a neural mass model to investigate potential relationships between functional connectivity and seizure frequency in epilepsy. We fitted a three-layer neural mass model of a cortical column to intracranial EEG (iEEG) data from a Tetanus Toxin rat model of epilepsy, which also included responses to periodic electrical stimulation. Our results show that some of the connectivity weights between different neural populations correlate significantly with the number of seizures each day, offering valuable insights into the dynamics of neural circuits during epileptogenesis. We also simulated single-pulse electrical stimulation of the neuronal populations to observe their responses after the connectivity weights were optimized to fit background (non-seizure) EEG data. The recovery time, defined as the time from stimulation until the membrane potential returns to baseline, was measured as a representation of the critical slowing down phenomenon observed in nonlinear systems operating near a bifurcation boundary. The results revealed that recovery times in the responses of the computational model fitted to the EEG data were longer during 5 min periods preceding seizures compared to 1 hr before seizures in four out of six rats. Analysis of the iEEG recorded in response to electrical stimulation revealed results similar to the computational model in four out of six rats. This study supports the potential use of this computational model as a model-based biomarker for seizure prediction when direct electrical stimulation to the brain is not feasible.
FAK and p130Cas modulate stiffness-mediated early transcription and cellular metabolism
Authors: Tumenbayar Bat-Ider , Tutino Vincent M. , Brazzo Joseph A. , Yao Peng , Bae Yongho 
Published: January 2024

SUMMARYCellular metabolism is influenced by the stiffness of the extracellular matrix. Focal adhesion kinase (FAK) and its binding partner, p130Cas, transmit biomechanical signals about substrate stiffness to the cell to regulate a variety of cellular responses, but their roles in early transcriptional and metabolic responses remain largely unexplored. We cultured mouse embryonic fibroblasts with or without siRNA-mediated FAK or p130Cas knockdown and assessed the early transcriptional responses of these cells to placement on soft and stiff substrates by RNA sequencing and bioinformatics analyses. Exposure to the stiff ECM altered the expression of genes important for metabolic and biosynthetic processes, and these responses were influenced by knockdown of FAK and p130Cas. Our findings reveal that FAK-p130Cas signaling mechanotransduces ECM stiffness to early transcriptional changes that alter cellular metabolism and biosynthesis.
Adaptive thermogenesis is mediated by GDF15 via the GFRAL neuronal axis in mice
Authors: Kim Ji Eun , Ju Sang-Hyeon , Lee Min Hee , Hong Hyun Jung , Yaseen Uzma , Kim Jung Tae , Zhang Benyuan , Yi Hyon-Seung , Lee Seong Eun , Kang Yea Eun , Yi Yoon-Sun , Jun Sangmi , Park Minsung , Kim Jinkuk , Auwerx Johan , Sohn Jong-Woo , Lee Ju Hee , Shong Minho 
Published: January 2024

AbstractAdaptive thermogenesis is a key homeostatic mechanism that primarily occurs in brown adipocytes and enables the maintenance of body temperature. Although this process involves coordinated responses in multiple tissues, including the browning of white adipocytes, the precise inter-organ crosstalk underlying adaptive thermogenesis is unclear. Here, we investigate the pivotal role of the GDNF family receptor alpha-like (GFRAL) neuronal axis in modulating compensatory thermogenic responses in brown and white adipose depots under stress conditions, specifically the mitochondrial unfolded protein response resulting from genetic modification and cold exposure. We employed a mouse model with targeted deletion ofCrif1in the mitoribosomes of brown adipocytes, and cold-exposed mice and immortalized adipocytes, to uncover the mechanism by which mitochondrial stress-induced growth differentiation factor 15 (GDF15) expression affects metabolism and facilitates adaptive thermogenesis. We found thatCrif1deletion resulted in browning of inguinal white adipose depots, increased energy expenditure, reduced food intake, and resistance to weight gain. Retrograde neuronal tracing established that GFRAL-positive neurons in the hindbrain and sympathetic preganglionic neurons in the spinal cord mediated the GDF15-associated browning of inguinal white adipose tissue. Intervention studies using antisense oligonucleotides to inhibitGfralexpression blunted the effect ofCrif1deletion on energy expenditure and food intake, further confirming the essential role the GFRAL axis plays in GDF15-driven thermogenic adaptation in white adipose tissue. Our findings suggest that the GFRAL neuronal axis is key in coordinating the adaptive thermogenic response across multiple tissues and adipose depots, thereby ensuring metabolic homeostasis during mitochondrial stress.
Proliferative History Is a Novel Driver of Clinical Outcome in Splenic Marginal Zone Lymphoma
Authors: Parker Helen , Mirandari Amatta , Oquendo Carolina Jaramillo , Duran-Ferrer Martí , Stevens Benjamin , Buermann Lara , Amarasinghe Harindra E. , Thomas Jaya , Kadalayil Latha , Carr Louise , Syeda Shama , Sakthipakan Methusha , Parry Marina , Davis Zadie , McIver-Brown Neil , Xochelli Aliki , Ennis Sarah , Scarfo Lydia , Ghia Paolo , Kalpadakis Christina , Pangalis Gerassimos , Rossi Davide , Wagner Simon , Ahearne Matthew , Seifert Marc , Plass Christoph , Weichenhan Dieter , Kimby Eva , Sutton Lesley-Ann , Rosenquist Richard , Forconi Francesco , Stamatopoulos Kostas , Salido Marta , Ferrer Ana , Thieblemont Catherine , Ljungström Viktor , Amini Rose-Marie , Oscier David , Walewska Renata , Rose-Zerilli Matthew J.J. , Gibson Jane , Martín-Subero José Ignacio , Oakes Christopher , Bryant Dean , Strefford Jonathan C 
Published: January 2024

AbstractThe epiCMIT (epigenetically-determined Cumulative MIToses) mitotic clock traces B-cell mitotic history via DNA methylation changes in heterochromatin and H3K27me3-containing chromatin. While high scores correlated with poor outcomes in CLL and MCL, its prognostic significance in SMZL remains unknown. Derived from 142 SMZL cases using DNA methylation microarrays, epiCMIT values were correlated with genomic, transcriptomic, and clinical data. EpiCMIT as a continuous variable was significantly higher in females (p=0.02), patients with IGHV1-2*04 allele usage (p<0001), intermediate IGHV somatic hypermutation load (97-99.9% identity,p=0.04), elevated mutational burden (25 vs. 17 mut/Mb,p=0.001), driver gene mutations [KLF2(p<0.001),NOTCH2(p<0.01),TP53(p=0.01),KMT2D(p<0.001)], and del(7q) (p=0.01). Negative correlation between epiCMIT and telomere length (r=-0.29p<0.001) supported the association between cumulated proliferation and telomere attrition. While univariate analysis highlighted epiCMIT as robust predictor of shorter treatment-free survival (TFS), multivariate analysis confirmed epiCMIT as an independent marker for shorter TFS. In summary, our matched multi-omic datasets facilitate the clinico-biological characterization of SMZL and introduces epiCMIT as a strong prognostic marker, identifying high-risk patients and predicting reduced treatment-free survival, hence providing a new tool for risk-adapted patient management.
Molecular basis for the transcriptional regulation of an epoxide-based virulence circuit inPseudomonas aeruginosa
Authors: He Susu , Taher Noor M. , Hvorecny Kelli L. , Ragusa Michael J. , Bahl Christopher D. , Hickman Alison B. , Dyda Fred , Madden Dean R. 
Published: January 2024

ABSTRACTThe opportunistic pathogenPseudomonas aeruginosainfects cystic fibrosis (CF) patient airways and produces a virulence factor Cif that is associated with worse outcomes. Cif is an epoxide hydrolase that reduces cell-surface abundance of the cystic fibrosis transmembrane conductance regulator (CFTR) and sabotages pro-resolving signals. Its expression is regulated by a divergently transcribed TetR family transcriptional repressor. CifR represents the first reported epoxide-sensing bacterial transcriptional regulator, but neither its interaction with cognate operator sequences nor the mechanism of activation has been investigated. Using biochemical and structural approaches, we uncovered the molecular mechanisms controlling this complex virulence operon. We present here the first molecular structures of CifR alone and in complex with operator DNA, resolved in a single crystal lattice. Significant conformational changes between these two structures suggest how CifR regulates the expression of the virulence genecif. Interactions between the N-terminal extension of CifR with the DNA minor groove of the operator play a significant role in the operator recognition of CifR. We also determined that cysteine residue Cys107 is critical for epoxide sensing and DNA release. These results offer new insights into the stereochemical regulation of an epoxide-based virulence circuit in a critically important clinical pathogen.
Nobiletin, a Polymethoxyflavonoid, Activates the Desuccinylase Activity of SIRT5 and Prevents the Development of Heart Failure
Authors: Sunagawa Yoichi , Funamoto Masafumi , Hamabe-Horiike Toshihide , Hieda Kehima , Yabuki Seiichiro , Tomino Midori , Ikai Yoshimi , Suzuki Anna , Ogawahara Shintaro , Yabuta Asami , Sasaki Hana , Ebe Ayaka , Naito Shiomi , Takai Hidemichi , Shimizu Kana , Shimizu Satoshi , Kawase Yuto , Naruta Ryuya , Katanasaka Yasufumi , Asakawa Tomohiro , Kan Toshiyuki , Mori Kiyoshi , Murakami Akira , Ogura Masahito , Inagaki Nobuya , Hasegawa Koji , Morimoto Tatsuya 
Published: January 2024

AbstractNobiletin is a natural compound useful for the prevention and treatment of several diseases. However, the precise role of nobiletin in heart failure is unclear. Nobiletin treatment prevents pressure overload- and myocardial infarction-induced heart failure. Using affinity purification of biotinylated nobiletin from rat heart cell lysates, we identified sirtuin 5 (SIRT5) as a novel nobiletin-binding protein. Nobiletin enhanced the desuccinylase activity of SIRT5in vitro. Compared to wild-type mice, SIRT5-overexpressing transgenic mice resisted pressure overload-induced systolic dysfunction. Conversely, SIRT5 knockout disrupted the nobiletin-mediated therapeutic effects on heart failure in mice. SIRT5 desuccinylated p300 at lysine 1568 and reduced the histone acetyltransferase (HAT) activity of p300. The desuccinylated p300 mutant suppressed the phenylephrine-induced cardiomyocyte hypertrophic responses. These findings suggest that nobiletin prevents heart failure development through SIRT5-dependent inhibition of p300-HAT activity. Nobiletin, a nontoxic dietary compound, is a potential therapeutic agent for heart failure in humans.
Community successional patterns and inter-kingdom interactions during granular biofilm development
Authors: de Celis Miguel , Modin Oskar , Arregui Lucía , Persson Frank , Santos Antonio , Belda Ignacio , Wilén Britt-Marie , Liébana Raquel 
Published: January 2024

AbstractAerobic granular sludge is a compact and efficient biofilm process used for wastewater treatment which has received much attention and is currently being implemented worldwide. The microbial associations and their ecological implications occurring during granule development, especially those involving inter-kingdom interactions, are poorly understood. In this work, we monitored the prokaryote and eukaryote community composition and structure during the granulation of activated sludge for 343 days in a sequencing batch reactor (SBR), and investigated the influence of abiotic and biotic factors on the granule development. Sludge granulation was accomplished with low-wash out dynamics at long settling times, allowing for the microbial communities to adapt to the SBR environmental conditions. The sludge granulation and associated changes in microbial community structure could be divided into three stages: floccular, intermediate, and granular. The eukaryotic and prokaryotic communities showed parallel successional dynamics, with three main sub-communities identified for each kingdom, dominating in each stage of sludge granulation. Although inter-kingdom interactions were shown to affect community succession during the whole experiment, during granule development random factors like the availability of settlement sites or drift acquired increasing importance. The prokaryotic community was more affected by deterministic factors, including reactor conditions, while the eukaryotic community was to a larger extent shaped by biotic interactions (including inter-kingdom interactions) and stochasticity.
Genome streamlining to improve performance of a fast-growing cyanobacteriumSynechococcus elongatusUTEX 2973
Authors: Sengupta Annesha , Bandyopadhyay Anindita , Sarkar Debolina , Hendry John I. , Schubert Max G. , Liu Deng , Church George M. , Maranas Costas D. , Pakrasi Himadri B. 
Published: January 2024

AbstractCyanobacteria are photosynthetic organisms that have garnered significant recognition as potential hosts for sustainable bioproduction. However, their complex regulatory networks pose significant challenges to major metabolic engineering efforts, thereby limiting their feasibility as production hosts. Genome streamlining has been demonstrated to be a successful approach for improving productivity and fitness in heterotrophs but is yet to be explored to its full potential in phototrophs. Here we present the systematic reduction of the genome of the cyanobacterium exhibiting the fastest exponential growth,Synechococcus elongatusUTEX 2973. This work, the first of its kind in a photoautotroph, involved an iterative process using state-of-the-art genome-editing technology guided by experimental analysis and computational tools. CRISPR/Cas3 enabled large, progressive deletions of predicted dispensable regions and aided in the identification of essential genes. The large deletions were combined to obtain a strain with 55 kb genome reduction. The strains with streamlined genome showed improvement in growth (up to 23%) and productivity (by 22.7%) as compared to the WT. This streamlining strategy not only has the potential to develop cyanobacterial strains with improved growth and productivity traits but can also facilitate a better understanding of their genome to phenome relationships.ImportanceGenome streamlining is an evolutionary strategy used by natural living systems to dispense unnecessary genes from their genome as a mechanism to adapt and evolve. While this strategy has been successfully borrowed to develop synthetic heterotrophic microbial systems with desired phenotype, it has not been extensively explored in photoautotrophs. Genome streamlining strategy incorporates both computational predictions to identify the dispensable regions and experimental validation using genome editing tool and in this study we have employed a modified strategy with the goal to minimize the genome size to an extent that allows optimal cellular fitness under specified conditions. Our strategy has explored a novel genome-editing tool in photoautotrophs which, unlike other existing tools, enables large, spontaneous optimal deletions from the genome. Our findings demonstrate the effectiveness of this modified strategy in obtaining strains with streamlined genome, exhibiting improved fitness and productivity.
Monocytic fibrocyte-like cell enrichment and myofibroblastic adaptation causes nucleus pulposus fibrosis and associates with disc degeneration severity
Authors: Sun Yi , Peng Yan , Su Zezhuo , So Kyle KH , Lu Qiu-ji , Lyu Mao-jiang , Zuo Jianwei , Huang Yong-can , Guan Zhi-ping , Cheung Kenneth MC , Zheng Zhao-min , Zhang Xin-tao , Leung Victor YL 
Published: January 2024

AbstractFibrotic remodeling of nucleus pulposus (NP) leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration, leading to low back pain incidence and disability. Emergence of fibroblastic cells in disc degeneration has been reported, yet their nature and origin remain elusive. In this study, we performed an integrative analysis of multiple single-cell RNA sequencing datasets to interrogate the cellular heterogeneity and fibroblast-like entities in degenerative human NP specimens. We found that disc degeneration severity is associated with an enrichment of fibrocyte-like phenotype, characterized by CD45 and collagen I dual positivity, and expression of myofibroblast marker α-smooth muscle actin. Refined clustering and classification distinguished the fibrocyte-like populations as subtypes in the NP cells - and immunocytes-clusters, expressing disc degeneration markersHTRA1andANGPTL4and genes related to response to TGF-β. In injury-induced mouse disc degeneration model, fibrocyte-like cells were found recruited into the NP undergoing fibrosis and adopted a myofibroblast phenotype. Depleting the fibrocyte-like cells in CD11b-DTR mice in which monocytic lineages were ablated by diphtheria toxin could markedly attenuate fibrous modeling and myofibroblast formation in the NP of the degenerative discs, and prevent disc height loss and histomorphological abnormalities. Marker analysis supports that disc degeneration progression is dependent on a function of CD45+COL1A1+and αSMA+cells. Our findings reveal that fibrocyte-like cells play a pivotal role in NP fibrosis and may therefore be a target for modifying disc degeneration and promoting its repair.
General mechanisms of task engagement in the primate frontal cortex
Authors: Grohn Jan , Khalighinejad Nima , Jahn Caroline , Bongioanni Alessandro , Schuffelgen Urs , Sallet Jerome , Rushworth Matthew , Kolling Nils 
Published: January 2024

AbstractStaying engaged with a task is necessary to maintain goal-directed behaviors. Although engagement varies with the specific task at hand it also exhibits continuous, intrinsic fluctuations widely. This intrinsic component of engagement is difficult to isolate behaviorally or neurally in controlled experiments with humans. By contrast, animals spontaneously move between periods of complete task engagement and disengagement, even in experimental settings. We, therefore, looked at behavior in macaques in a series of four tasks while recording fMRI signals. We identified consistent autocorrelation in task disengagement. This made it possible to build models capturing task-independent engagement and to link it to neural activity. Across all tasks, we identified common patterns of neural activity linked to impending task disengagement in mid-cingulate gyrus. By contrast, activity centered in perigenual anterior cingulate cortex (pgACC) was associated with maintenance of task performance. Importantly, we were able to carefully control for task-specific factors such as the reward history, choice value, and other motivational effects, such as response vigor, as indexed by response time, when identifying neural activity associated with task engagement. Moreover, we showed pgACC activity had a causal link to task engagement; in one of our tasks, transcranial ultrasound stimulation of pgACC, but not of control regions, changed task engagement/disengagement patterns.