bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smooth muscle expression of RNA editing enzymeADAR1controls activation of RNA sensor MDA5 in atherosclerosis
Authors: Weldy Chad S. , Li Qin , Monteiro João P. , Guo Hongchao , Galls Drew , Gu Wenduo , Cheng Paul P. , Ramste Markus , Li Daniel , Palmisano Brian T. , Sharma Disha , Worssam Matthew D. , Zhao Quanyi , Bhate Amruta , Kundu Ramendra K. , Nguyen Trieu , Li Jin Billy , Quertermous Thomas 
Published: July 2024

AbstractMapping the genomic architecture of complex disease has been predicated on the understanding that genetic variants influence disease risk through modifying gene expression. However, recent discoveries have revealed that a significant burden of disease heritability in common autoinflammatory disorders and coronary artery disease is mediated through genetic variation modifying post-transcriptional modification of RNA through adenosine-to-inosine (A-to-I) RNA editing. This common RNA modification is catalyzed by ADAR enzymes, where ADAR1 edits specific immunogenic double stranded RNA (dsRNA) to prevent activation of the double strand RNA (dsRNA) sensor MDA5 (IFIH1) and stimulation of an interferon stimulated gene (ISG) response. Multiple lines of human genetic data indicate impaired RNA editing and increased dsRNA sensing by MDA5 to be an important mechanism of coronary artery disease (CAD) risk. Here, we provide a crucial link between observations in human genetics and mechanistic cell biology leading to progression of CAD. Through analysis of human atherosclerotic plaque, we implicate the vascular smooth muscle cell (SMC) to have a unique requirement for RNA editing, and that ISG induction occurs in SMC phenotypic modulation, implicating MDA5 activation. Through culture of human coronary artery SMCs, generation of a conditional SMC specificAdar1deletion mouse model on a pro-atherosclerosis background with additional constitutive deletion of MDA5 (Ifih1), and with incorporation of single cell RNA sequencing cellular profiling, we further show that Adar1 controls SMC phenotypic state by regulating Mda5 activation, is required to maintain vascular integrity, and controls progression of atherosclerosis and vascular calcification. Through this work, we describe a fundamental mechanism of CAD, where cell type and context specific RNA editing and sensing of dsRNA mediates disease progression, bridging our understanding of human genetics and disease causality.One Sentence SummarySmooth muscle expression of RNA editing enzyme ADAR1 regulates activation of double strand RNA sensor MDA5 in novel mechanism of atherosclerosis.
Co-activation of selective nicotinic acetylcholine receptor subtypes is required to reverse hippocampal network dysfunction and prevent fear memory loss in Alzheimer’s disease
Authors: Lee Rahmi , Kim Gayeon , Kim Seonil 
Published: July 2024

AbstractAlzheimer’s disease (AD) is the most common form of dementia with no known cause and cure. Research suggests that a reduction of GABAergic inhibitory interneurons’ activity in the hippocampus by beta-amyloid peptide (Aβ) is a crucial trigger for cognitive impairment in AD via hyperexcitability. Therefore, enhancing hippocampal inhibition is thought to be protective against AD. However, hippocampal inhibitory cells are highly diverse, and these distinct interneuron subtypes differentially regulate hippocampal inhibitory circuits and cognitive processes. Moreover, Aβ unlikely affects all subtypes of inhibitory interneurons in the hippocampus equally. Hence, identifying the affected interneuron subtypes in AD to enhance hippocampal inhibition optimally is conceptually and practically challenging. We have previously found that Aβ selectively binds to two of the three major hippocampal nicotinic acetylcholine receptor (nAChR) subtypes, α7- and α4β2-nAChRs, but not α3β4-nAChRs, and inhibits these two receptors in cultured hippocampal inhibitory interneurons to decrease their activity, leading to hyperexcitation and synaptic dysfunction in excitatory neurons. We have also revealed that co-activation of α7- and α4β2-nAChRs is required to reverse the Aβ-induced adverse effects in hippocampal excitatory neurons. Here, we discover that α7- and α4β2-nAChRs predominantly control the nicotinic cholinergic signaling and neuronal activity in hippocampal parvalbumin-positive (PV+) and somatostatin-positive (SST+) inhibitory interneurons, respectively. Furthermore, we reveal that co-activation of these receptors is necessary to reverse hippocampal network dysfunction and fear memory loss in the amyloid pathology model mice. We thus suggest that co-activation of PV+ and SST+ cells is a novel strategy to reverse hippocampal dysfunction and cognitive decline in AD.
Single-nanoparticle electrophoretic mobility determination and trapping using active-feedback 3D tracking
Authors: Johnson Alexis , Welsher Kevin D. 
Published: July 2024

AbstractNanoparticles (NP) are versatile materials with widespread applications across medicine and engineering. Despite rapid incorporation into drug delivery, therapeutics, and many more areas of research and development, there is a lack of robust characterization methods. Light scattering techniques such as dynamic light scattering (DLS) and electrophoretic light scattering (ELS) use an ensemble-averaged approach to the characterization of nanoparticle size and electrophoretic mobility (EM), leading to inaccuracies when applied to polydisperse or heterogeneous populations. To address this lack of single-nanoparticle characterization, this work applies 3D Single-Molecule Active Real-time Tracking (3D-SMART) to simultaneously determine NP size and EM on a per-particle basis. Single-nanoparticle EM is determined by using active feedback to “lock on” to a single particle and apply an oscillating electric field along one axis. A maximum likelihood approach is applied to extract the single-particle EM from the oscillating nanoparticle position along the field-actuated axis, while mean squared displacement is used along the non-actuated axes to determine size. Unfunctionalized and carboxyl-functionalized polystyrene NPs are found to have unique EM based on their individual size and surface characteristics, and it is demonstrated that single-nanoparticle EM is a more precise tool for distinguishing unique NP preparations than diffusion alone, able to determine the charge number of individual NPs to an uncertainty of less than 30. This method also explored individual nanoparticle EM in various ionic strengths (0.25-5 mM) and found decreased EM as a function of increasing ionic strength, in agreement with results determined via bulk characterization methods. Finally, it is demonstrated that the electric field can be manipulated in real time in response to particle position, resulting in one-dimensional electrokinetic trapping. Critically, this new single-nanoparticle EM determination and trapping method does not require microfluidics, opening the possibility for the exploration of single-nanoparticle EM in live tissue and more comprehensive characterization of nanoparticles in biologically relevant environments.
Identifying foraging spatial cues in beehive sound activity using machine learning methods
Authors: Bocanegra David , Galvez Jorge , Di Nayan , Liu Fanglin , Wario Fernando 
Published: July 2024

ABSTRACTThe beehive sound, a continuous signal produced by bees within the hive, has been found to correlate with different behavioral states of the colony, like being queenless and swarming. We investigated the possibility of identifying foraging spatial cues in this signal. We recorded a colony’s sound while foraging from food sources located at three different distances from the hive, one at a time. The recordings were split into frames to obtain six statistics of their Mel Frequency Cepstral Coefficients. Then, we evaluated different autoencoding networks to obtain a latent space that allowed frames from different foraging distances to be easily differentiable. The high accuracy, silhouette score, and F1 score shown in the obtained latent spaces strongly support our approach for identifying foraging spatial cues in beehive sound activity.
Prefrontal and ventral striatal dendritic morphology: effects of life-long complex housing and amphetamine administration
Authors: Kolb Bryan , Robinson Terry E. 
Published: July 2024

AbstractComplex housing is one of the most effective experiences in producing plastic changes in the brain. For example, animals living in complex environments show widespread synaptic changes both in cerebral cortex and the striatum. Similarly, repeatedly treating animals with psychomotor stimulants such as amphetamine also induces changes in prefrontal cortex and the striatum. The purpose of the current study was to determine the effects of life-long housing in complex environments versus standard laboratory caging and this experience influenced the later effects of amphetamine. Both male and female Long-Evans rats were placed in complex environments for about 110 days, beginning at conception, until adulthood at which time they were administered saline or amphetamine daily (1 mg/kg, IP) for 14 days. A week later the brains were harvested and processed for Golgi-Cox staining to analyze dendritic length, branching, and spine density in prefrontal cortex (areas Cg3 and AID) and Nucleus Accumbens (NAcc). The results showed that the prolonged period of enriched housing produced significant synaptic changes in all three measures in all three areas measured, but the effects differed in the two sexes. Amphetamine produced large synaptic changes in Cg3 and NAcc in males but only spine changes in those regions in females. Complex housing did not interact with the later effects of amphetamine administration. Thus, both complex housing and amphetamine can produce a range of synaptic changes depending upon sex and area examined. Furthermore, the effect of complex housing varies depending on the details of when complex housing is begun and how long it lasts.
Computational Insights into the Molecular Dynamics of the Binding of Ligands in the Methanol Dehydrogenase
Authors: Lee One-Sun , Lee Sung Haeng 
Published: July 2024

AbstractMethanol dehydrogenase (MDH) is a promising biocatalyst for industrial use, converting methanol to formaldehyde. Our molecular modeling revealed methanol binds to MDH with ∼7 kcal/mol free energy, while formaldehyde binds with ∼4 kcal/mol. This suggests methanol remains longer in the active site, and formaldehyde exits more readily post-reaction. These insights are crucial for designing more efficient MDH variants for industrial applications.Graphical abstractThe left panel shows methanol and formaldehyde within the active site of methanol dehydrogenase, illustrating entry and release paths. The right panel presents the free energy profiles, indicating methanol’s stronger binding affinity and formaldehyde’s easier release post-reaction.
Cell-Type-Specific Regulation of Cocaine Reward by the E2F3a Transcription Factor in Nucleus Accumbens
Authors: Martínez-Rivera Freddyson J. , Yim Yun Young , Godino Arthur , Minier-Toribio Angélica , Tofani Solange , Holt Leanne M. , Torres-Berrío Angélica , Futamura Rita , Browne Caleb J. , Markovic Tamara , Hamilton Peter J. , Neve Rachael L. , Nestler Eric J. 
Published: July 2024

AbstractThe development of drug addiction is characterized by molecular changes in brain reward regions that lead to the transition from recreational to compulsive drug use. These neurobiological processes in brain reward regions, such as the nucleus accumbens (NAc), are orchestrated in large part by transcriptional regulation. Our group recently identified the transcription factor E2F3a as a novel regulator of cocaine’s rewarding effects and gene expression regulation in the NAc of male mice. Despite this progress, no information is available about the role of E2F3a in regulating cocaine reward at the sex- and cell-specific levels. Here, we used male and female mice expressing Cre-recombinase in either D1- or D2-type medium spiny neurons (MSNs) combined with viral-mediated gene transfer to bidirectionally control levels of E2F3a in a cell-type-specific manner in the NAc during conditioned place preference (CPP) to cocaine. Our findings show that selective overexpression of E2F3a in D1-MSNs increased cocaine CPP in both male and female mice, whereas opposite effects were observed under knockdown conditions. In contrast, equivalent E2F3a manipulations in D2-MSNs had no significant effects. To further explore the role of E2F3a in sophisticated operant and motivated behaviors, we performed viral manipulations of all NAc neurons in combination with cocaine self-administration and behavioral economics procedures in rats and demonstrated that E2F3a regulates sensitivity aspects of cocaine seeking and taking. These results confirm E2F3a as a central substrate of cocaine reward and demonstrate that this effect is mediated in D1-MSNs, thereby providing increased knowledge of cocaine action at the transcriptional level.
Gut metagenomes of Asian octogenarians reveal metabolic potential expansion and distinct microbial species associated with aging phenotypes
Authors: Ravikrishnan Aarthi , Wijaya Indrik , Png Eileen , Chng Kern Rei , Pei Eliza Ho Xin , Qi Amanda Ng Hui , Naim Ahmad Nazri Mohamed , Gounot Jean-Sebastien , Ping Guan Shou , Lee Hanqing Jasinda , Lihuan Guan , Chenhao Li , Yu Jayce Koh Jia , Sessions Paola Florez de , Koh Woon-Puay , Feng Lei , Ng Tze Pin , Larbi Anis , Maier Andrea B. , Kennedy Brian , Nagarajan Niranjan 
Published: July 2024

AbstractWhile rapid demographic changes in Asia are driving the incidence of chronic diseases related to aging, the limited availability of high-qualityin vivodata hampers our ability to understand complex multi-factorial contributions, including gut microbial, to healthy aging. Leveraging the availability of a well-phenotyped cohort of community-living octogenarians in Singapore, we used deep shotgun metagenomic sequencing to do high-resolution taxonomic and functional characterization of their gut microbiomes (n=234). Joint species-level analysis with other Asian cohorts identified a distinct age-associated shift in Asian gut metagenomes, characterized by a reduction in microbial richness, and enrichment of specificAlistipesandBacteroidesspecies (e.g.Alistipes shahiiandBacteroides xylanisolvens). Functional pathway analysis confirmed that these changes correspond to a metabolic potential expansion in aging towards alternate pathways that synthesize and utilize amino-acid precursors, relative to the dominant microbial guilds that typically produce butyrate in the gut from pyruvate (e.g.Faecalibacterium prausnitzii, Roseburia inulinivorans). Extending these observations to key clinical markers helped identify >10 robust gut microbial associations to inflammation, cardiometabolic and liver health, including potential probiotic species such asParabacteroides goldsteiniiand pathobionts such asKlebsiella pneumoniae, highlighting the role of the microbiome as biomarkers and potential intervention targets for promoting healthy aging.
Non-standard proteins in the lenses of AlphaFold3 - case study of amyloids
Authors: Wojciechowska Alicja W. , Wojciechowski Jakub W. , Kotulska Malgorzata 
Published: July 2024

AbstractThe recent release ofAlphaFold3raises a question about its powers and limitations. Here, we analyze the potential ofAlphaFold3for correct reproduction of amyloid structures, which are an example of multimeric proteins with low representation in protein structure databases, which may also be characterized by polymorphism. We show thatAlphaFold3is capable of producing amyloid-like assemblies that have significant similarity to experimental structures (TM-score>0.5), although its results are impacted by the number of monomers forming the predicted fibril and a protein of choice.AlphaFold3produces structurally diverse models of some amyloid proteins, which could reflect their polymorphism observed in nature. We hypothesize that the lower emphasis on multiple sequence analysis (MSA) inAlphaFold3improves the results quality, since for this class of proteins sequence homology may be misleading in their structural similarity. However, the structural landscape obtained from the modeling does not reflect the real one governed by thermodynamics. Finally,AlphaFold3enables for the first time, structural modeling of fibril-like structures to a certain extent, possibly including their polymorphic nature. Still individual benchmarking is necessary for optimal modeling.Graphical Abstract
Perceptual and semantic deficits in face recognition in semantic dementia
Authors: Yadollahikhales Golnaz , Mandelli Maria Luisa , Ezzes Zoe , Pillai Janhavi , Ratnasiri Buddhika , Baquirin David Paul , Miller Zachary , de Leon Jessica , Tee Boon Lead , Seeley William , Rosen Howard , Miller Bruce , Kramer Joel , Sturm Virginia , Gorno-Tempini Maria Luisa , Montembeault Maxime 
Published: July 2024

AbstractState of the artSemantic dementia (SD) patients including semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) patients show semantic difficulties identifying faces and known people related to right anterior temporal lobe (ATL) atrophy. However, it remains unclear whether they also have perceptual deficits in face recognition.MethodologyWe selected 74 SD patients (54 with svPPA and predominant left ATL atrophy and 20 with sbvFTD and predominant right ATL atrophy) and 36 cognitively healthy controls (HC) from UCSF Memory and Aging Center. They underwent a perceptual face processing test (Benton facial recognition test-short version; BFRT-S), and semantic face processing tests (UCSF Famous people battery – Recognition, Naming, Semantic associations – pictures and words subtests), as well as structural magnetic resonance imaging (MRI). Neural correlates with the task’s performance were conducted with a Voxel-based morphometry approach using CAT12.ResultssvPPA and sbvFTD patients were impaired on all semantic face processing tests, with sbvFTD patients performing significantly lower on the famous faces’ recognition task in comparison to svPPA, and svPPA performing significantly lower on the naming task in comparison to sbvFTD. These tasks predominantly correlated with gray matter (GM) volumes in the right and left ATL, respectively. Compared to HC, both svPPA and sbvFTD patients showed preserved performance on the perceptual face processing test (BFRT-S), and performance on the BFRT-S negatively correlated with GM volume in the right posterior superior temporal sulcus (pSTS).ConclusionOur results suggest that early in the disease, with the atrophy mostly restricted to the anterior temporal regions, SD patients do not present with perceptual deficits. However, more severe SD cases with atrophy in right posterior temporal regions might show lower performance on face perception tests, in addition to the semantic face processing deficits. Early sparing of face perceptual deficits in SD patients, regardless of hemispheric lateralization, furthers our understanding of clinical phenomenology and therapeutical approaches of this complex disease.
Mitoregulin self-associates to form likely homo-oligomeric pore-like structures
Authors: Linzer Connor R. , Stein Colleen S. , Witmer Nathan H. , Xu Zhen , Schnicker Nicholas J. , Boudreau Ryan L. 
Published: July 2024

SUMMARYWe and others previously found that a misannotated long noncoding RNA encodes for a conserved mitochondrial transmembrane microprotein named Mitoregulin (Mtln). Beyond an established role for Mtln in lipid metabolism, Mtln has also been shown to more broadly influence mitochondria, boosting respiratory efficiency and Ca2+retention capacity, while lowering ROS, yet the underlying mechanisms remain unresolved. Prior studies have identified possible Mtln protein interaction partners; however, a lack of consensus persists, and no claims have been made about Mtln’s structure. We previously noted two key published observations that seemingly remained overlooked: 1) endogenous Mtln co-immunoprecipitates with epitope-tagged Mtln at high efficiency, and 2) Mtln primarily exists in a ∼66 kDa complex. To investigate if Mtln may self-oligomerize into higher-order complexes, we performed co-immunoprecipitation, protein modeling simulations, and native gel assessments of Mtln-containing complexes in cells and tissues, as well as tested whether synthetic Mtln protein itself forms oligomeric complexes. Our combined results provide strong support that Mtln self-associates and likely forms a hexameric pore-like structure.
An in vivo screen for proteolytic switch domains that can mediate Notch activation by force
Authors: Baker Frederick C. , Harman Jacob , Jordan Trevor , Walton Breana , Ajamu-Johnson Amber , Alashqar Rama F. , Bhikot Simran , Struhl Gary , Langridge Paul D. 
Published: July 2024

AbstractNotch proteins are single pass transmembrane receptors activated by sequential extracellular and intramembrane cleavages that release their cytosolic domains to function as transcription factors in the nucleus. Upon binding, Delta/Serrate/LAG-2 (DSL) ligands activate Notch by exerting a “pulling” force across the intercellular ligand/receptor bridge. This pulling force is generated by Epsin-mediated endocytosis of ligand into the signal-sending cell, and results in the extracellular cleavage of the force-sensing Negative Regulatory Region (NRR) of the receptor by an ADAM10 protease [Kuzbanian (Kuz) inDrosophila]. Here, we have used chimeric Notch and DSL proteins to screen for other domains that can function as ligand-dependent proteolytic switches in place of the NRR in the developingDrosophilawing. While most of the tested domains are either refractory to cleavage or constitutively cleaved, we identify several that mediate Notch activation in response to ligand. These NRR analogues derive from widely divergent source proteins and have strikingly different predicted structures. Yet, almost all depend on force exerted by Epsin-mediated ligand endocytosis and cleavage catalyzed by Kuz. We posit that the sequence space of protein domains that can serve as force-sensing proteolytic switches in Notch activation is unexpectedly large, a conclusion that has implications for the mechanism of target recognition by Kuz/ADAM10 proteases and is consistent with a more general role for force dependent ADAM10 proteolysis in other cell contact-dependent signaling mechanisms. Our results also validate the screen for increasing the repertoire of proteolytic switches available for synthetic Notch (synNotch) therapies and tissue engineering.One sentence summaryA scalable in vivo screen for Epsin and ADAM10 dependent proteolytic switches that can mediate Notch activation in response to force.
Noncanonical roles of ATG5 and membrane atg8ylation in retromer assembly and function
Authors: Paddar Masroor Ahmad , Wang Fulong , Trosdal Einar S , Hendrix Emily , He Yi , Salemi Michelle , Mudd Michal , Jia Jingyue , Duque Thabata L A , Javed Ruheena , Phinney Brett , Deretic Vojo 
Published: July 2024

ABSTRACTATG5 is one of the core autophagy proteins with additional functions such as noncanonical membrane atg8ylation, which among a growing number of biological outputs includes control of tuberculosis in animal models. Here we show that ATG5 associates with retromer’s core components VPS26, VPS29 and VPS35 and modulates retromer function. Knockout of ATG5 blocked trafficking of a key glucose transporter sorted by the retromer, GLUT1, to the plasma membrane. Knockouts of other genes essential for membrane atg8ylation, of which ATG5 is a component, affected GLUT1 sorting, indicating that membrane atg8ylation as a process affects retromer function and endosomal sorting. The contribution of membrane atg8ylation to retromer function in GLUT1 sorting was independent of canonical autophagy. These findings expand the scope of membrane atg8ylation to specific sorting processes in the cell dependent on the retromer and its known interactors.