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BioRxiv : the Preprint Server For... Jun 2024G protein-coupled receptors (GPCRs) modulate various physiological functions by re-wiring cellular gene expression in response to extracellular signals. Control of gene...
G protein-coupled receptors (GPCRs) modulate various physiological functions by re-wiring cellular gene expression in response to extracellular signals. Control of gene expression by GPCRs has been studied almost exclusively at the transcriptional level, neglecting an extensive amount of regulation that takes place translationally. Hence, little is known about the nature and mechanisms of gene-specific post-transcriptional regulation downstream of receptor activation. Here, we apply an unbiased multiomics approach to delineate an extensive translational regulatory program initiated by the prototypical beta2-adrenergic receptor (β2-AR) and provide mechanistic insights into how these processes are orchestrated. Using ribosome profiling (Ribo-seq), we identify nearly 120 novel gene targets of adrenergic receptor activity which expression is exclusively regulated at the level of translation. We next show that all translational changes are induced selectively by endosomal β2-ARs. We further report that this proceeds through activation of the mammalian target of rapamycin (mTOR) pathway. Specifically, within the set of translational GPCR targets we discover significant enrichment of genes with 5' terminal oligopyrimidine (TOP) motifs, a gene class classically known to be translationally regulated by mTOR. We then demonstrate that endosomal β2-ARs are required for mTOR activation and subsequent mTOR-dependent TOP mRNA translation. Together, this comprehensive analysis of drug-induced translational regulation establishes a critical role for location-biased GPCR signaling in fine-tuning the cellular protein landscape.
PubMed: 38948806
DOI: 10.1101/2024.06.17.599400 -
BioRxiv : the Preprint Server For... Jun 2024Drugs of abuse activate defined neuronal ensembles in brain reward structures such as the nucleus accumbens (NAc), which are thought to promote the enduring synaptic,...
Drugs of abuse activate defined neuronal ensembles in brain reward structures such as the nucleus accumbens (NAc), which are thought to promote the enduring synaptic, circuit, and behavioral consequences of drug exposure. While the molecular and cellular effects arising from experience with drugs like cocaine are increasingly well understood, the mechanisms that sculpt NAc ensemble participation are largely unknown. Here, we leveraged unbiased single-nucleus transcriptional profiling to identify expression of the secreted glycoprotein Reelin (encoded by the gene) as a marker of cocaine-activated neuronal ensembles within the rat NAc. Multiplexed in situ detection confirmed selective expression of the immediate early gene in neurons after cocaine experience, and also revealed enrichment of mRNA in + medium spiny neurons (MSNs) in both the rat and human brain. Using a novel CRISPR interference strategy enabling selective knockdown in the adult NAc, we observed altered expression of genes linked to calcium signaling, emergence of a transcriptional trajectory consistent with loss of cocaine sensitivity, and a striking decrease in MSN intrinsic excitability. At the behavioral level, loss of prevented cocaine locomotor sensitization, abolished cocaine place preference memory, and decreased cocaine self-administration behavior. Together, these results identify Reelin as a critical mechanistic link between ensemble participation and cocaine-induced behavioral adaptations.
PubMed: 38948801
DOI: 10.1101/2024.06.17.599348 -
BioRxiv : the Preprint Server For... Jun 2024Premature aging is a hallmark of Down syndrome, caused by trisomy of human chromosome 21, but the reason is unclear and difficult to study in humans. We used an...
Premature aging is a hallmark of Down syndrome, caused by trisomy of human chromosome 21, but the reason is unclear and difficult to study in humans. We used an aneuploid model in wild yeast to show that chromosome amplification disrupts nutrient-induced cell-cycle arrest, quiescence entry, and healthy aging, across genetic backgrounds and amplified chromosomes. We discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). Compared to euploids, aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates. Although they have normal proteasome capacity, aneuploids show signs of ubiquitin dysregulation, which impacts cyclin abundance to disrupt arrest. Remarkably, inducing ribosome stalling in euploids produces similar aberrations, while up-regulating limiting RQC subunits or proteins in ubiquitin metabolism alleviates many of the aneuploid defects. Our results provide implications for other aneuploidy disorders including Down syndrome.
PubMed: 38948718
DOI: 10.1101/2024.06.22.600216 -
BioRxiv : the Preprint Server For... Jun 2024Normal endothelial cell dependent vascular smooth muscle cell function is mediated by nitric oxide (NO), which stimulates soluble guanylyl cyclase (sGC) production of...
VERICIGUAT RESCUES CYCLIC GUANOSINE MONOPHOSPHATE PRODUCTION IN HUMAN AORTIC VASCULAR SMOOTH MUSCLE CELLS AND AUGMENTS VASORELAXATION IN AORTIC RINGS EXPOSED TO HIGH GLUCOSE.
BACKGROUND
Normal endothelial cell dependent vascular smooth muscle cell function is mediated by nitric oxide (NO), which stimulates soluble guanylyl cyclase (sGC) production of the second messenger, cyclic guanosine monophosphate (cGMP) leading to increased protein kinase G (PKG) activity and vascular smooth muscle relaxation. NO bioavailability is impaired in inflammatory settings, such as high glucose (HG). We examined whether the direct sGC sensitizer/stimulator vericiguat, augments cGMP production in human vascular smooth muscle cells (HVSMC) exposed to high glucose and explored its effect on vasorelaxation.
METHODS
Aortic HVSMCs were exposed to HG for 24h. In the treatment group, cells also received 1uM vericiguat for 24h. After incubation, cGMP and PKG activity were measured. Additionally, thoracic murine aortas were exposed to HG or to normal glucose (NG) control. The rings were then placed in an organ chamber bath and dose response curves to increasing doses of acetylcholine (Ach) and sodium nitroprusside were constructed for three groups: control (normal glucose), HG alone, and HG + vericiguat.
RESULTS
HVSMCs exposed to HG produced significantly less cGMP than those exposed to NG. cGMP production in the presence of HG was rescued when treated with 1uM vericiguat. Additionally, PKG activity was impaired in the presence of HG and enzyme activity was restored with vericiguat. In isolated mouse aortic rings, ACh mediated relaxation was impaired following treatment with HG, but was improved when a HG group was treated with vericiguat.
CONCLUSIONS
The sGC sensitizer/stimulator vericiguat restored cGMP production and PKG activity in the setting of HG. Vericiguat enhanced ACh-mediated vasorelaxation in the setting of HG. The findings suggest clinical studies are warranted to investigate the potential of sGC sensitization/stimulation as a therapeutic intervention to improve vascular endothelial-dependent function that is impaired in pro-inflammatory settings that are associated with the development of atherosclerotic disease.
PubMed: 38948704
DOI: 10.1101/2024.06.21.600154 -
Innovation in Aging 2024In most western countries, older adults depend on private cars for transportation and do not proactively plan for driving cessation. The objective of this review was to... (Review)
Review
BACKGROUND AND OBJECTIVES
In most western countries, older adults depend on private cars for transportation and do not proactively plan for driving cessation. The objective of this review was to examine current research studies outlining effective interventions and strategies to assist older adults during their transition from driver to driving retirement or cessation.
RESEARCH DESIGN AND METHODS
A search was completed across 9 databases using key words and MeSH terms for drivers, cessation of driving, and older adult drivers. Eligibility screening of 9,807 titles and abstracts, followed by a detailed screening of 206 papers, was completed using the Covidence platform. Twelve papers were selected for full-text screen and data extraction, comprising 3 papers with evidence-based intervention programs and 9 papers with evidence-informed strategies.
RESULTS
Three papers met the research criteria of a controlled study for programs that support and facilitate driving cessation for older adults. Nine additional studies were exploratory or descriptive, which outlined strategies that could support older drivers, their families, and/or healthcare professionals during this transition. Driving retirement programs/toolkits are also presented.
DISCUSSION AND IMPLICATIONS
The driver retirement programs had promising results, but there were methodological weaknesses within the studies. Strategies extracted contributed to 6 themes: of the topic, is important, is critical, away from assessment to proactive planning, is needed, and should be the end result. Meeting the transportation needs of older adults will be essential to support aging in place, out-of-home mobility, and participation, particularly in developed countries where there is such a high dependency on private motor vehicles.
PubMed: 38948542
DOI: 10.1093/geroni/igae054 -
Frontiers in Surgery 2024Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive... (Review)
Review
Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive comprehension of the pathophysiology, genetics, and surgical techniques related to mCRC has paved the way for the introduction of novel therapeutic modalities. These advancements not only have augmented the overall survival but have also positively impacted the quality of life (QoL) for affected individuals. Despite the remarkable progress made in the last two decades in the development of chemotherapy, immunotherapy, and target therapies, mCRC remains an incurable disease, with a 5-year survival rate of 14%. In this comprehensive review, our primary goal is to present an overview of mCRC treatment methods following the latest guidelines provided by the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the American Society of Colon and Rectal Surgeons (ASCRS). Emphasis has been placed on outlining treatment approaches encompassing chemotherapy, immunotherapy, targeted therapy, and surgery's role in managing mCRC. Furthermore, our review delves into prospective avenues for developing new therapies, offering a glimpse into the future of alternative pathways that hold potential for advancing the field.
PubMed: 38948479
DOI: 10.3389/fsurg.2024.1398289 -
Data in Brief Aug 2024Within the study of the urban heat island (UHI) in Echirolles and Grenoble (France, the eastern part of the alpine arc), two temperature measurement networks have been...
A new high spatial density temperature dataset in the Grenoble alpine valley (France) for urban heat island investigation and climate services dedicated to municipalities purposes.
Within the study of the urban heat island (UHI) in Echirolles and Grenoble (France, the eastern part of the alpine arc), two temperature measurement networks have been deployed. The aim is to measure the temperature gradients associated with the UHI in summer. A total of 62 measurement points has been installed in the various neighborhoods on 3-meter-high streetlights, starting in summer 2019. The preliminary classification of the different neighborhood typologies according to ``Local Climate Zone'' guided the choice of location for the temperature sensors. These urban observations respond to a dual challenge: firstly, to observe temperature located in complex topographical situations with valleys, and secondly, to observe the urban climate in neighborhoods where social considerations are important. Municipalities of Echirolles and Grenoble were involved in the investigation. The ADEME-funded (The French Agency for Ecological Transition) CASSANDRE research program analyzes and processes these observations to study the vulnerability of inhabitants to heat waves and more generally to summer heat stress.
PubMed: 38948403
DOI: 10.1016/j.dib.2024.110553 -
Asian Journal of Pharmaceutical Sciences Jun 2024Autophagy and mitophagy pose unresolved challenges in understanding the pathology of diabetic heart condition (DHC), which encompasses a complex range of cardiovascular... (Review)
Review
Autophagy and mitophagy pose unresolved challenges in understanding the pathology of diabetic heart condition (DHC), which encompasses a complex range of cardiovascular issues linked to diabetes and associated cardiomyopathies. Despite significant progress in reducing mortality rates from cardiovascular diseases (CVDs), heart failure remains a major cause of increased morbidity among diabetic patients. These cellular processes are essential for maintaining cellular balance and removing damaged or dysfunctional components, and their involvement in the development of diabetic heart disease makes them attractive targets for diagnosis and treatment. While a variety of conventional diagnostic and therapeutic strategies are available, DHC continues to present a significant challenge. Point-of-care diagnostics, supported by nanobiosensing techniques, offer a promising alternative for these complex scenarios. Although conventional medications have been widely used in DHC patients, they raise several concerns regarding various physiological aspects. Modern medicine places great emphasis on the application of nanotechnology to target autophagy and mitophagy in DHC, offering a promising approach to deliver drugs beyond the limitations of traditional therapies. This article aims to explore the potential connections between autophagy, mitophagy and DHC, while also discussing the promise of nanotechnology-based theranostic interventions that specifically target these molecular pathways.
PubMed: 38948399
DOI: 10.1016/j.ajps.2024.100927 -
PeerJ 2024Burmese amber preserves a diverse assemblage of Cretaceous arachnids, and among pseudoscorpions (Arachnida: Pseudoscorpiones), ten species in five families have already...
Burmese amber preserves a diverse assemblage of Cretaceous arachnids, and among pseudoscorpions (Arachnida: Pseudoscorpiones), ten species in five families have already been named. Here, we describe a new fossil species from Burmese amber in the pseudoscorpion family Hyidae, providing detailed measurements, photographs and 3D-models from synchrotron scanning. Based on morphology, the new fossil, sp. nov. is placed in the genus , and is nearly identical to extant species in the genus, except for the position of trichobothrium on the pedipalpal chela, thereby indicating extreme morphological stasis in this invertebrate lineage over the last 99 million years. represents the first described fossil species in Hyidae, and the third described Burmese fossil in the superfamily Neobisioidea. It also joins the garypinid, , in representing the oldest fossil records for extant pseudoscorpion genera. Considering proposed divergence dates, the newly described fossil species bolsters a Gondwanan origin for Hyidae, and provides evidence for the "" hypothesis for the Burma Terrane, in which this landmass rifted from Gondwana in the Late Jurassic and collided with Eurasia by the Cretaceous/Eocene. Like species today, likely inhabited humicolous microhabitats in tropical forests on the Burma Terrane, supporting ecological niche stasis for this family since the Mesozoic.
Topics: Animals; Fossils; Arachnida; Amber; Biological Evolution; Myanmar; Phylogeny
PubMed: 38948233
DOI: 10.7717/peerj.17515 -
Imaging Science in Dentistry Jun 2024The aim of this study was to evaluate image artifacts in the vicinity of dental implants in cone-beam computed tomography (CBCT) scans obtained with different spatial...
Impact of the spatial orientation of the patient's head, metal artifact reduction, and tube current on cone-beam computed tomography artifact expression adjacent to a dental implant: A laboratory study using a simulated surgical guide.
PURPOSE
The aim of this study was to evaluate image artifacts in the vicinity of dental implants in cone-beam computed tomography (CBCT) scans obtained with different spatial orientations, tube current levels, and metal artifact reduction algorithm (MAR) conditions.
MATERIALS AND METHODS
One dental implant and 2 tubes filled with a radiopaque solution were placed in the posterior region of a mandible using a surgical guide to ensure parallel alignment. CBCT scans were acquired with the mandible in 2 spatial orientations in relation to the X-ray projection plane (standard and modified) at 3 tube current levels: 5, 8, and 11 mA. CBCT scans were repeated without the implant and were reconstructed with and without MAR. The mean voxel and noise values of each tube were obtained and compared using multi-way analysis of variance and the Tukey test (α=0.05).
RESULTS
Mean voxel values were significantly higher and noise values were significantly lower in the modified orientation than in the standard orientation (<0.05). MAR activation and tube current levels did not show significant differences in most cases of the modified spatial orientation and in the absence of the dental implant (>0.05).
CONCLUSION
Modifying the spatial orientation of the head increased brightness and reduced spatial orientation noise in adjacent regions of a dental implant, with no influence from the tube current level and MAR.
PubMed: 38948193
DOI: 10.5624/isd.20240016