ABSTRACT
Post-traumatic stress disorder (PTSD) is a severe stress-dependent psychiatric disorder characterized by impairment of fear memory extinction; however, biological markers to determine impaired fear memory extinction in PTSD remain unclear. In male mice with PTSD-like behaviors elicited by single prolonged stress (SPS), 19 differentially expressed proteins in the hippocampus were identified compared with controls. Among them, a biological macromolecular protein named deleted in colorectal cancer (DCC) was highly upregulated. Specific overexpression of DCC in the hippocampus induced similar impairment of long-term potentiation (LTP) and fear memory extinction as observed in SPS mice. The impairment of fear memory extinction in SPS mice was improved by inhibiting the function of hippocampal DCC using a neutralizing antibody. Mechanistic studies have shown that knocking down or inhibiting µ-calpain in hippocampal neurons increased DCC expression and induced impairment of fear memory extinction. Additionally, SPS-triggered impairment of hippocampal LTP and fear memory extinction could be rescued through activation of the Rac1-Pak1 signaling pathway. Our study provides evidence that calpain-mediated regulation of DCC controls hippocampal LTP and fear memory extinction in SPS mice, which likely through activation of the Rac1-Pak1 signaling pathway.
ABSTRACT
Goal of the review: The utilization of biomarkers to predict cancer risk, prognosis, and treatment outcomes is paramount. Netrin-1 (NTN1), known for its role in commissural axon guidance during embryonic development, has emerged as a versatile molecule with significant implications in cancer and neurobiology. Structurally resembling laminin, Netrin-1 regulates neuronal connectivity and plasticity in adulthood, influencing axonal and dendritic growth, neurotransmission, and cell migration. In addition to its neurological functions, Netrin-1 is increasingly recognized for its involvement in maintaining epithelial tissue and its regulatory roles in fundamental cellular processes, including adhesion, proliferation, differentiation, apoptosis, and angiogenesis. In cancer biology, Netrin-1's interactions with its receptors, such as DCC [Deleted in Colorectal Cancer] and UNC5 (a homolog of DCC), have been implicated in tumor progression across various physiological systems. Elevated levels of Netrin-1 in colorectal cancer and head and neck squamous cell carcinoma are correlated with increased tumorigenic potential, mediated through pathways involving NFκB activation and anti-apoptotic mechanisms. Mechanically induced hypermethylation and downstream signaling cascades that inhibit apoptosis and promote cell survival are observed upon Netrin-1 binding to DCC. Furthermore, Netrin-1 shows promise as a biomarker for detecting inflammatory activity in diseases such as multiple sclerosis and as a potential diagnostic, prognostic, and therapeutic indicator in oral squamous cell carcinoma. Elevated levels of Netrin-1 in bodily fluids, alongside immunohistochemical evidence, support its potential as a valuable clinical marker in cancer management. This abstract emphasizes Netrin-1's diverse biological roles, underscoring its potential as a diagnostic tool and therapeutic target in cancer research. The need for further exploration of Netrin-1's molecular interactions and clinical applications is urgent and crucial to advance personalized medicine approaches and enhance patient outcomes in oncology and neurology.
ABSTRACT
The pursuit of the Sustainable Development Goals (SDGs) requires considerable new green crypto investments. To attract the flow of this investment, it is necessary to develop and apply robotic artificial intelligence (AI) as it has the potential to encourage the adoption of environmental innovation and increase individuals' environmental awareness. Our research employs the DCC-GARCH Copula Model to examine time-varying spillovers and prove interlinkages between the development of AI and green cryptocurrencies in the period from January 1, 2018, to September 8, 2023. Comparing the optimum hedge ratios with the optimal portfolio weights, we demonstrate that the optimal hedge strategy for BOTZ is the most successful one. However, the success of hedging depends on the portfolio's risk profile. Based on our analysis of the cumulative profit profile of different approaches, we continue to believe that the best portfolio weighting strategy is the one that produces positive returns in the middle of 2020 and the first part of 2022 and 2023. This demonstrates that the most profitable diversification approach is not always the most successful one. Our results have important policy implications for investors and governments.
ABSTRACT
Regulation of transcription during embryogenesis is key to development and differentiation. To study transcript expression throughout Caenorhabditis elegans embryogenesis at single-molecule resolution, we developed a high-throughput single-molecule fluorescence in situ hybridization (smFISH) method that relies on computational methods to developmentally stage embryos and quantify individual mRNA molecules in single embryos. We applied our system to sdc-2, a zygotically transcribed gene essential for hermaphrodite development and dosage compensation. We found that sdc-2 is rapidly activated during early embryogenesis by increasing both the number of mRNAs produced per transcription site and the frequency of sites engaged in transcription. Knockdown of sdc-2 and dpy-27, a subunit of the dosage compensation complex (DCC), increased the number of active transcription sites for the X chromosomal gene dpy-23 but not the autosomal gene mdh-1, suggesting that the DCC reduces the frequency of dpy-23 transcription. The temporal resolution from in silico staging of embryos showed that the deletion of a single DCC recruitment element near the dpy-23 gene causes higher dpy-23 mRNA expression after the start of dosage compensation, which could not be resolved using mRNAseq from mixed-stage embryos. In summary, we have established a computational approach to quantify temporal regulation of transcription throughout C. elegans embryogenesis and demonstrated its potential to provide new insights into developmental gene regulation.
ABSTRACT
Introduction: Horizontal gaze palsy with progressive scoliosis-2 (HGPPS2, MIM 617542) with impaired intellectual development aka developmental split-brain syndrome is an ultra-rare congenital disorder caused by pathogenic biallelic variants in the deleted in colorectal cancer (DCC) gene. Case Presentation: We report the clinical and genetic characterization of a Syrian patient with a HGPPS2 phenotype and review the previously published cases of HGPPS2. The genetic screening was performed using exome sequencing on Illumina platform. Genetic analysis revealed a novel DCC c.(?_1912)_(2359_?)dup, p.(Ser788Tyrfs*4) variant segregating recessively in the family. This type of variant has not been described previously in the HGPPS2 patients. To date, including the case reported here, three different homozygous pathogenic frameshift variants, one homozygous missense variant, and an intragenic duplication in the DCC gene have been reported in 8 patients with the HGPPS2 syndrome. Conclusion: The analysis of duplications and deletions in the DCC should be included in the routine genetic diagnostic evaluation of patients with suspected HGPPS2. This report expands the knowledge of phenotypic and genotypic spectrum of pathogenic variants causing HGPPS2.
ABSTRACT
The UNC-5 family of netrin receptor genes, predominantly expressed in brain tissues, plays a pivotal role in various neuronal processes. Mutations in genes involved in axon development contribute to a wide spectrum of human diseases, including developmental, neuropsychiatric, and neurodegenerative disorders. The NTN1/DCC signaling pathway, interacting with UNC5C, plays a crucial role in central nervous system axon guidance and has been associated with psychiatric disorders during adolescence in humans. Whole-exome sequencing analysis unveiled two compound heterozygous causative mutations within the UNC5C gene in a patient diagnosed with psychiatric disorders. In silico analysis demonstrated that neither of the observed variants affected the allosteric linkage between UNC5C and NTN1. In fact, these mutations are located within crucial cytoplasmic domains, specifically ZU5 and the region required for the netrin-mediated axon repulsion of neuronal growth cones. These domains play a critical role in forming the supramodular protein structure and directly interact with microtubules, thereby ensuring the functionality of the axon repulsion process. We emphasize that these mutations disrupt the aforementioned processes, thereby associating the UNC5C gene with psychiatric disorders for the first time and expanding the number of genes related to psychiatric disorders. Further research is required to validate the correlation of the UNC5C gene with psychiatric disorders, but we suggest including it in the genetic analysis of patients with psychiatric disorders.
Subject(s)
Axon Guidance , Mental Disorders , Humans , Axon Guidance/genetics , Netrin-1/genetics , Netrin-1/metabolism , Netrin Receptors/genetics , Netrin Receptors/metabolism , Axons/metabolism , Mental Disorders/metabolismABSTRACT
BACKGROUND: Colorectal cancer (CRC) ranks third in cancer incidence globally and is the second leading cause of cancer-related mortality. The nucleoside diphosphate kinase 1 (NME1) and netrin 1 receptor (DCC) genes have been associated with resistance against tumorigenesis and tumor metastasis. This study investigates the potential association between NME1 (rs34214448 G > T and rs2302254 C > T) and DCC (rs2229080 G > C and rs714 A > G) variants and susceptibility to colorectal cancer development. METHODS: Samples from 232 colorectal cancer patients and 232 healthy blood donors underwent analysis. Variants were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Associations were assessed using odds ratios (OR), and the p values were adjusted with Bonferroni test. RESULTS: Individuals carrying the G/T and T/T genotypes for the NME1 rs34214448 variant exhibited a higher susceptibility for develop colorectal cancer (OR = 2.68, 95% CI: 1.76-4.09, P = 0.001 and OR = 2.47, 95% CI: 1.37-4.47, P = 0.001, respectively). These genotypes showed significant associations in patients over 50 years (OR = 2.87, 95% CI: 1.81-4.54, P = 0.001 and OR = 2.99, 95% CI: 1.54-5.79, P = 0.001 respectively) and with early Tumor-Nodule-Metastasis (TNM) stage (P = 0.001), and tumor location in the rectum (P = 0.001). Furthermore, the DCC rs2229080 variant revealed that carriers of the G/C genotype had an increased risk for develop colorectal cancer (OR = 2.00, 95% CI: 1.28-3.11, P = 0.002) and were associated with age over 50 years, sex, and advanced TNM stages (P = 0.001). CONCLUSIONS: These findings suggest that the NME1 rs34214448 and DCC rs2229080 variants play a significant role in colorectal cancer development.
Subject(s)
Colorectal Neoplasms , Stomach Neoplasms , Humans , Middle Aged , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Genotype , Stomach Neoplasms/genetics , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Case-Control Studies , DCC Receptor/genetics , NM23 Nucleoside Diphosphate Kinases/geneticsABSTRACT
BACKGROUND: Bone cancer pain (BCP) is a common primary or metastatic bone cancer complication. Netrin-1 plays an essential role in neurite elongation and pain sensitization. This study aimed to determine the role of netrin-1 from the metastatic bone microenvironment in BCP development and identify the associated signaling pathway for the strategy of BCP management. METHODS: The rat BCP model was established by intratibial implantation of Walker 256 cells. Von Frey filaments measured the mechanical pain threshold. Movement-induced pain was assessed using limb use scores. Expressions of associated molecules in the affected tibias or dorsal root ganglia (DRG) were measured by immunofluorescence, immunohistochemistry, real-time quantitative polymerase chain reaction, or western blotting. Transduction of deleted in colorectal cancer (DCC) signaling was inhibited by intrathecal injection of DCC-siRNA. RESULTS: In BCP rats, the presence of calcitonin gene-related peptide (CGRP)-positive nerve fibers increased in the metastatic bone lesions. The metastatic site showed enrichment of well-differentiated osteoclasts and expressions of netrin-1 and its attractive receptor DCC. Upregulation of DCC and increased phosphorylation levels of focal adhesion kinase (FAK) and Rac family small GTPase 1/Cell division cycle 42 (Rac1/Cdc42) were found in the DRG. Intrathecal administration of DCC-siRNA led to a significant reduction in FAK and Rac1/Cdc42 phosphorylation levels in the DRG, decreased nociceptive nerve innervation, and improved pain behaviors. CONCLUSIONS: Netrin-1 may contribute to the activation of the BCP by inducing nociceptive nerve innervation and improving pain behaviors.
Subject(s)
Bone Neoplasms , Cancer Pain , Netrin-1 , Animals , Rats , Bone Neoplasms/complications , Cancer Pain/etiology , DCC Receptor/metabolism , Nerve Growth Factors/genetics , Nerve Growth Factors/metabolism , Nerve Growth Factors/pharmacology , Netrin-1/genetics , Nociceptors/metabolism , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , RNA, Small Interfering , Signal Transduction , Tumor Microenvironment , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Background/Objectives: Pathogenic variants in the deleted in colorectal cancer gene (DCC), encoding the Netrin-1 receptor, may lead to mirror movements (MMs) associated with agenesis/dysgenesis of the corpus callosum (ACC) and cognitive and/or neuropsychiatric issues. The clinical phenotype is related to the biological function of DCC in the corpus callosum and corticospinal tract development as Netrin-1 is implicated in the guidance of developing axons toward the midline. We report on a child with a novel inherited, monoallelic, pathogenic variant in the DCC gene. Methods: Standardized measures and clinical scales were used to assess psychomotor development, communication and social skills, emotional and behavioural difficulties. MMs were measured via the Woods and Teuber classification. Exome sequencing was performed on affected and healthy family members. Results: The patient's clinical presentation during infancy consisted of paroxysmal dystonic posturing when asleep, mimicking nocturnal leg cramps. A brain magnetic resonance imaging (MRI) showed complete ACC. He developed typical upper limb MMs during childhood and a progressively evolving neuro-phenotype with global development delay and behavioural problems. We found an intrafamilial clinical variability associated with DCC mutations: the proband's father and uncle shared the same DCC variant, with a milder clinical phenotype. The atypical early clinical presentation of the present patient expands the clinical spectrum associated with DCC variants, especially those in the paediatric age. Conclusions: This study underlines the importance of in-depth genetic investigations in young children with ACC and highlights the need for further detailed analyses of early motor symptoms in infants with DCC mutations.
ABSTRACT
RAGE is a transmembrane receptor of immunoglobulin family that can bind various endogenous and exogenous ligands, initiating the inflammatory downstream signaling pathways, including inflammaging. Therefore, RAGE represents an attractive drug target for age-related diseases. For the development of small-molecule RAGE antagonists, we employed protein-templated dynamic combinatorial chemistry (ptDCC) using RAGE's VC1 domain as a template, the first application of this approach in the context of RAGE. The affinities of DCC hits were validated using microscale thermophoresis. Subsequent screening against AGE2 (glyceraldehyde-modified AGE)-sRAGE (solubleRAGE) (AGE2-BSA/sRAGE) interaction using ELISA tests led to the identification of antagonists with micromolar potency. Our findings not only demonstrate the successful application of ptDCC on RAGE but also highlight its potential to address the pressing need for alternative strategies for the development of small-molecule RAGE antagonists, an area of research that has experienced a slowdown in recent years.
Subject(s)
Signal Transduction , Receptor for Advanced Glycation End Products/chemistry , Receptor for Advanced Glycation End Products/metabolismABSTRACT
Objective: To identify the mutation in codon 201 of the deleted in colorectal cancer gene in colorectal cancer, and to correlate that mutation to the histopathological grading of colorectal cancer. METHODS: The cross-sectional study was conducted from February 2019 to February 2021 after approval from the ethics review board of the Dow University of Health Sciences, Karachi, and comprised biopsy-proven colorectal cancer patients regardless of age and gender. After histopathological reporting, formalin-fixed paraffin-embedded tissue blocks of colorectal cancer were used for deoxyribonucleic acid extraction, followed by polymerase chain reaction optimisation and deoxyribonucleic acid Sanger sequencing for mutational analysis. Data was analysed using SPSS 25. RESULTS: Of the 100 biopsy specimens assessed, 45(45%) were selected. Of them, 13(29%) samples failed to show any band on gel electrophoresis. The remaining 32(71%) samples were used for Sanger sequencing. Of these, 1(3%) sample did not sequence, while 31(97%) showed sequencing. All the sequenced samples identified a mutation in codon 201 of exon 3 in the deleted in colorectal cancer gene; 30(97%) showed homozygosity, and 1(3%) showed heterozygosity. No significant association of point mutation was noted with various demographic and clinicopathological parameters (p>0.05). Conclusion: The deleted in colorectal cancer gene's missense mutation in codon 201 was frequently observed in colorectal cancer patients.
Subject(s)
Colorectal Neoplasms , Genes, DCC , Humans , Colorectal Neoplasms/genetics , Cross-Sectional Studies , Mutation , Codon , DNA , DCC Receptor/geneticsABSTRACT
BACKGROUND: Congenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements on the opposite side. To date, five genes have been associated with CMM, namely DCC, RAD51, NTN1, ARHGEF7, and DNAL4. OBJECTIVE: The aim of this study is to characterize the genetic landscape of CMM in a large group of 80 affected individuals. METHODS: We screened 80 individuals with CMM from 43 families for pathogenic variants in CMM genes. In large CMM families, we tested for presence of pathogenic variants in multiple affected and unaffected individuals. In addition, we evaluated the impact of three missense DCC variants on binding between DCC and Netrin-1 in vitro. RESULTS: Causal pathogenic/likely pathogenic variants were found in 35% of probands overall, and 70% with familial CMM. The most common causal gene was DCC, responsible for 28% of CMM probands and 80% of solved cases. RAD51, NTN1, and ARHGEF7 were rare causes of CMM, responsible for 2% each. Penetrance of CMM in DCC pathogenic variant carriers was 68% and higher in males than females (74% vs. 54%). The three tested missense variants (p.Ile164Thr; p.Asn176Ser; and p.Arg1343His) bind Netrin-1 similarly to wild type DCC. CONCLUSIONS: A genetic etiology can be identified in one third of CMM individuals, with DCC being the most common gene involved. Two thirds of CMM individuals were unsolved, highlighting that CMM is genetically heterogeneous and other CMM genes are yet to be discovered. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Subject(s)
Dyskinesias , Movement Disorders , Male , Female , Humans , Netrin-1/genetics , DCC Receptor/genetics , Movement Disorders/genetics , Mutation, Missense/genetics , Rho Guanine Nucleotide Exchange Factors/geneticsABSTRACT
Analysis of bone marrow aspirates (BMAs) is an essential step in the diagnosis of hematological disorders. This analysis is usually performed based on a visual examination of samples under a conventional optical microscope, which involves a labor-intensive process, limited by clinical experience and subject to high observer variability. In this work, we present a comprehensive digital microscopy system that enables BMA analysis for cell type counting and differentiation in an efficient and objective manner. This system not only provides an accessible and simple method to digitize, store, and analyze BMA samples remotely but is also supported by an Artificial Intelligence (AI) pipeline that accelerates the differential cell counting process and reduces interobserver variability. It has been designed to integrate AI algorithms with the daily clinical routine and can be used in any regular hospital workflow.
Subject(s)
Artificial Intelligence , Hematologic Diseases , Humans , Bone Marrow , Microscopy , Hematologic Diseases/diagnosis , AlgorithmsABSTRACT
The ability of the mammalian brain to maintain spatial representations of external or internal information for short periods of time has been associated with sustained neuronal spiking and reverberatory neural network activity in the medial entorhinal cortex. Here, we show that conditional genetic deletion of netrin-1 or the netrin receptor deleted-in-colorectal cancer (DCC) from forebrain excitatory neurons leads to deficits in short-term spatial memory. We then demonstrate that conditional deletion of either netrin-1 or DCC inhibits cholinergic persistent firing and show that cholinergic activation of muscarinic receptors expressed by entorhinal cortical neurons promotes persistent firing by recruiting DCC to the plasma membrane. Together, these findings indicate that normal short-term spatial memory function requires the synergistic actions of acetylcholine and netrin-1.
Subject(s)
Acetylcholine , Entorhinal Cortex , Animals , Acetylcholine/pharmacology , Netrin-1 , Prosencephalon , Cholinergic Agents , MammalsABSTRACT
Electrochemical transformations are a subject of increasing interest in early drug discovery due to its ability to assemble complex scaffolds under rather mild reaction conditions. In this context, we became interested in electrochemical decarboxylative cross-coupling (DCC) protocols of redox-active esters (RAEs) and halo(hetero)arenes. Starting with the one-step electrochemical synthesis of novel methylamino-substituted heterocycles we recognized the potential of this methodology to deliver a novel approach to ß- and γ- amino acids by starting from the corresponding RAEs. Our work finally resulted in the delivery of novel and highly valuable trifunctional building blocks based on ß- and γ-amino-acid scaffolds.
Subject(s)
Amino Acids , Esters , Electrochemistry , Molecular Structure , Amino Acids/chemistry , Esters/chemistry , Oxidation-ReductionABSTRACT
Direct binding of netrin receptors with dynamic microtubules (MTs) in the neuronal growth cone plays an important role in netrin-mediated axon guidance. However, how netrin-1 (NTN1) regulates MT dynamics in axon turning remains a major unanswered question. Here, we show that the coupling of netrin-1 receptor DCC with tau (MAPT)-regulated MTs is involved in netrin-1-promoted axon attraction. Tau directly interacts with DCC and partially overlaps with DCC in the growth cone of primary neurons. Netrin-1 induces this interaction and the colocalization of DCC and tau in the growth cone. The netrin-1-induced interaction of tau with DCC relies on MT dynamics and TUBB3, a highly dynamic ß-tubulin isotype in developing neurons. Netrin-1 increased cosedimentation of DCC with tau and TUBB3 in MTs, and knockdown of either tau or TUBB3 mutually blocked this effect. Downregulation of endogenous tau levels by tau shRNAs inhibited netrin-1-induced axon outgrowth, branching and commissural axon attraction in vitro, and led to defects in spinal commissural axon projection in vivo. These findings suggest that tau is a key MT-associated protein coupling DCC with MT dynamics in netrin-1-promoted axon attraction.
Subject(s)
Axons , Growth Cones , Netrin-1 , Neurons , MicrotubulesABSTRACT
PURPOSE: The risk of brain exposure to ionizing radiation increases gradually due to the extensive application of nuclear technology in medical, industrial, and aerospace fields. Radiation-induced brain injury (RBI) is highly likely to cause a wide range of neurological complications, including schizophrenia, Alzheimer's disease (AD), depression. Ginkgolide B (GB) is one of the effective active components extracted from ginkgo biloba leaves, exerts protective effects on CNS, which is involved in the regulation of the Hippo signaling pathway. MST1, as one of the core kinases of the Hippo pathway, participated in regulating cell proliferation, differentiation, and apoptosis. However, it remains unclear whether GB attenuates radiation brain injury (RBI) and whether the radioprotective effect of GB refers to MST1 signaling. Hence, our study aimed to explore the radiation protection effect and the potential mechanism of GB. MATERIALS AND METHODS: C57BL/6 mice were stimulated with an X-ray (20 Gy) to establish an RBI model. Then, morris water maze test (MWM) and step-down passive avoidance test (SDPAT) were used to assess the learning and memory function of mice. The open field test (OFT), tail suspension test (TST), and forced swimming test (FST) were used to assess changes in locomotor activity and hopelessness. Besides, X-ray-stimulated SH-SY5Y cells were used to verify the radioprotective effect of GB. Immunofluorescence double staining, Dihydroethidium (DHE), western blot, and flow cytometry were used to explore the role of DCC/MST1 signaling in RBI. RESULTS: In this study, X-ray-treated mice exhibited cognitive impairment and depression-like behavior, which was ameliorated by GB treatment. GB also reduced the ROS production and the number of TUNEL-positive cells in the hippocampus. Moreover, GB increased the protein levels of p-AKT and Bcl2, while decreased the protein levels of MST1, p-p38, p-JNK, cleaved-caspase-3 and Bax both in vivo and in vitro. Additionally, exogenous Netrin-1 alleviated X-ray-induced ROS production and apoptosis, whereas knockout of Netrin-1 receptor DCC abolished the protective effect of GB. CONCLUSION: Oxidative stress and MST1-mediated neuronal apoptosis participated in radiation-induced cognitive impairment and depression-like behaviors, and modulation of DCC by GB was an effective intervention against RBI.
Subject(s)
Brain Injuries , Ginkgolides , Lactones , Neuroblastoma , Radiation Protection , Animals , Humans , Mice , Apoptosis , Brain/metabolism , DCC Receptor/metabolism , Mice, Inbred C57BL , Netrin-1/pharmacology , Reactive Oxygen Species/metabolismABSTRACT
PURPOSE: For pediatric patients, extracorporeal membrane oxygenation (ECMO) remains the predominant mechanical circulatory support (MCS) modality for heart failure (HF) although survival to discharge rates remain between 50 and 60% for these patients. The device-blood interface and disruption of physiologic hemodynamics are significant contributors to poor outcomes. METHODS: In this study, we evaluate the preclinical feasibility of a minimally invasive, non-blood-contacting pediatric DCC prototype for temporary MCS. Proof-of-concept is demonstrated in vivo in an animal model of HF. Hemodynamic pressures and flows were examined. RESULTS: Minimally invasive deployment on the beating heart was successful without cardiopulmonary bypass or anticoagulation. During HF, device operation resulted in an immediate 43% increase in cardiac output while maintaining pulsatile hemodynamics. Compared to the pre-HF baseline, the device recovered up to 95% of ventricular stroke volume. At the conclusion of the study, the device was easily removed from the beating heart. CONCLUSIONS: This preclinical proof-of-concept study demonstrated the feasibility of a DCC device on a pediatric scale that is minimally invasive and non-blood contacting, with promising hemodynamic support and durability for the initial intended duration of use. The ability of DCC to maintain pulsatile MCS without blood contact represents an opportunity to mitigate the mortality and morbidity observed in non-pulsatile, blood-contacting MCS.
Subject(s)
Disease Models, Animal , Feasibility Studies , Heart Failure , Heart-Assist Devices , Proof of Concept Study , Animals , Heart Failure/physiopathology , Heart Failure/therapy , Hemodynamics , Ventricular Function, Left , Time Factors , Equipment Design , Recovery of FunctionABSTRACT
The industrial revolution has dramatically altered the environment and ecosystem. So many scholars have empirically attempted to reveal the most influential anthropogenic factors on environmental degradation. For this purpose, this study examines the leading determinants of CO2 emissions in the context of economic policy uncertainty (EPU) for 14 developed countries within the framework of the extended stochastic impacts by regression on population, affluence and technology (STIRPAT) environmental model from 1997-2018. For empirical modeling, CO2 emission is treated as the dependent variable, which is a strong proxy for environmental degradation. In addition to the GDP per capita, population density, and energy intensity (a proxy for technology), the basic model is extended to include variables such as EPU, renewable energy, trade openness, globalization, and information and communications technology (ICT) index. While the estimation results by the dynamic conditional correlation (DCC) estimator, which are also supported by robustness analysis, suggest that GDP per capita and energy intensity are the main contributors to emission levels, population density has no significant impact on CO2. Furthermore, while renewable energy (in model 2), trade openness (in model 4), and globalization (in model 6) have negative impacts on CO2 emission, technology (in models 5 and 6) and EPU (in model 6) make marginal contributions to CO2.
Subject(s)
Carbon Dioxide , Economic Development , Developed Countries , Carbon Dioxide/analysis , Uncertainty , Ecosystem , Environmental Pollution/analysis , Renewable EnergyABSTRACT
Sustainable investment is widely regarded as an important market-based approach to achieving inclusive green growth. To achieve the inclusive green growth objective, companies providing sustainable products must be profitable enough to attract private capital. Oil price changes can however affect the profitability of such companies. This study assesses volatility transmission between crude oil prices and sustainable investment in the USA. Using the dynamic conditional correlation-generalized autoregressive conditional heteroskedasticity (DCC-GARCH) method, daily data from September 28, 2012, to October 19, 2022, is analyzed. There are several key findings from this analysis. The risk connectedness of crude oil and sustainable investment is found to vary with time. Results further show that the risk connectedness increases in periods of important economic and geopolitical events. The greatest risk connectedness of crude oil and sustainable investment is observed during the outbreak of coronavirus disease (COVID-19). Moreover, the result shows that crude oil is the main risk transmitter, whereas, both the energy efficiency and pollution mitigation indices (i.e., sustainable investment) are risk receivers, and crude oil is constantly dominating sustainable investment. The study findings provide valuable insights for investors and policymakers alike.