The activation of transcriptional coactivators YAP and its paralog TAZ has been shown to promote resistance to anti‐cancer therapies. YAP/TAZ activity is tightly coupled to actin cytoskeleton ...architecture. However, the influence of actin remodeling on cancer drug resistance remains largely unexplored. Here, we report a pivotal role of actin remodeling in YAP/TAZ‐dependent BRAF inhibitor resistance in BRAF V600E mutant melanoma cells. Melanoma cells resistant to the BRAF inhibitor PLX4032 exhibit an increase in actin stress fiber formation, which appears to promote the nuclear accumulation of YAP/TAZ. Knockdown of YAP/TAZ reduces the viability of resistant melanoma cells, whereas overexpression of constitutively active YAP induces resistance. Moreover, inhibition of actin polymerization and actomyosin tension in melanoma cells suppresses both YAP/TAZ activation and PLX4032 resistance. Our siRNA library screening identifies actin dynamics regulator TESK1 as a novel vulnerable point of the YAP/TAZ‐dependent resistance pathway. These results suggest that inhibition of actin remodeling is a potential strategy to suppress resistance in BRAF inhibitor therapies.
Synopsis
BRAF V600E mutant melanoma cells undergo active actin cytoskeletal remodeling in response to the BRAF inhibitor PLX4032, and the remodeling promotes nuclear localization of YAP/TAZ oncoproteins, conferring adaptive resistance to PLX4032.
The development of PLX4032 resistance in melanoma cell lines is accompanied by increases in both actin stress fiber formation and cell spreading on substrates.
PLX4032‐resistant melanoma cells exhibit higher levels of YAP/TAZ nuclear localization and transcriptional activity.
Inhibition of actin filament assembly or actin cytoskeletal tension suppresses YAP/TAZ activation and PLX4032 resistance in melanoma cells.
Depletion of YAP/TAZ restores PLX4032 sensitivity in resistant cells, whereas overexpression of constitutively active YAP induces PLX4032 resistance in non‐resistant melanoma cells.
Adaptive resistance to the BRAF inhibitor PLX4032 in BRAF V600E mutant melanoma cells involves increased actin stress fiber formation, impinging on the growth‐regulating YAP/TAZ signaling axis.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Ciliopathies are clinically overlapping genetic disorders involving structural and functional abnormalities of cilia. Currently, there are no small-molecule drugs available to treat ciliary defects ...in ciliopathies. Our phenotype-based screen identified the flavonoid eupatilin and its analogs as lead compounds for developing ciliopathy medication. CEP290, a gene mutated in several ciliopathies, encodes a protein that forms a complex with NPHP5 to support the function of the ciliary transition zone. Eupatilin relieved ciliogenesis and ciliary receptor delivery defects resulting from deletion of CEP290. In rd16 mice harboring a blinding Cep290 in-frame deletion, eupatilin treatment improved both opsin transport to the photoreceptor outer segment and electrophysiological responses of the retina to light stimulation. The rescue effect was due to eupatilin-mediated inhibition of calmodulin binding to NPHP5, which promoted NPHP5 recruitment to the ciliary base. Our results suggest that deficiency of a ciliopathy protein could be mitigated by small-molecule compounds that target other ciliary components that interact with the ciliopathy protein.
Cortical circuits process both sensory and motor information in animals performing perceptual tasks. However, it is still unclear how sensory inputs are transformed into motor signals in the cortex ...to initiate goal-directed actions. In this study, we found that a visual-to-motor inhibitory circuit in the anterior cingulate cortex (ACC) triggers precise action in mice performing visual Go/No-go tasks. Three distinct features of ACC neurons-visual amplitudes of sensory neurons, suppression times of motor neurons and network activity from other neurons-predicted response times of the mice. Moreover, optogenetic activation of visual inputs in the ACC, which drives fast-spiking sensory neurons, prompted task-relevant actions in mice by suppressing ACC motor neurons and disinhibiting downstream striatal neurons. Notably, when mice terminated actions in response to stop signals, both motor neuron and network activity increased. Collectively, our data demonstrate that visual inputs to the frontal cortex trigger gated feedforward inhibition to initiate goal-directed actions.
Full text
Available for:
GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Objective The aim of the present study was to investigate the influence of comorbid oppositional defiant disorder (ODD) on clinical features and neuropsychological profiles of children with ...attention-deficit/hyperactivity disorder (ADHD).Methods We divided the participants into three groups: the ADHD with ODD (ADHD/ODD) (n=36), ADHD without ODD (ADHD/noODD) (n=307), and control groups (n=128). Parents of the participants completed the ADHD Rating Scale, Social Responsiveness Scale (SRS), Korean Personality Rating Scale for Children (K-PRC), and 10-item mania scale from the Parent General Behavior Inventory (P-GBI-10M). Neuropsychological profiles were assessed using the Advanced Test of Attention (ATA), Children’s Color Trails Test, and Stroop Color and Word Test.Results The ADHD/ODD group had more ADHD symptoms and functional impairments in relationships with teachers and peers, and self-esteem than the ADHD/noODD group. The ADHD/ODD group scored higher in Social Communication (p<0.001) and Autistic Mannerisms (p<0.001) subscales of SRS, P-GBI-10M (p<0.001), and Delinquency (p<0.001) and Psychosis (p<0.001) subscales of K-PRC than the ADHD/noODD group. Commission Errors (p<0.001) and Response-Time Variability (p<0.001) in Visual ATA and Commission Errors (p<0.001) in Auditory ATA were significantly higher in the ADHD/ODD group than in the ADHD/noODD group.Conclusion The present study suggests that patients with ADHD with ODD experience more ADHD symptoms and neuropsychological deficits than those with ADHD without ODD. These results also imply that comorbid ODD is associated with greater social impairment and emotional dysregulation.
This study compared parenting stress in preschool children with developmental disabilities (DD) or typical development (TD). We also investigated children's factors that affect parenting stress.
A ...total of 196 preschool children participated in the study (aged 54.8±9.2 months). There were 79 children with DD (59 with autism spectrum disorder, 61 with intellectual disability, 12 with language disorder) and 117 with TD. The high parenting stress and the low parenting stress groups were divided based on the Total Stress of Korean Parenting Stress Index Fourth Edition (K-PSI-4) with an 85-percentile cutoff score. Pearson's correlation analysis was conducted to calculate the correlation between K-PSI-4 and the children's or parents' measures.
The difference in parenting stress between DD and TD was significant in the Total Stress of K-PSI-4 (p<0.001). The Total Stress scale of K-PSI-4 represented a modest to strong correlation with cognitive development, adaptive functioning, social communication, and behavioral problems in children with DD. Our results showed that caregivers of children with DD reported higher parenting stress than those with TD. Parenting stress was strongly associated with cognitive development, adaptive functioning, social communication, and behavioral problems in children with DD. Among the children's factors, especially social communication, attention problems, and aggressive behavior had association with caregivers' higher parenting stress.
These findings suggest the need for early intervention for parenting stress in caregivers by assessing child characteristics, including social cognition, awareness, communication, and inattention and hyperactivity, in the evaluation of children with DD.
While acute treatment with beetroot juice (BRJ) containing nitrate (NO3 (-)) can lower systolic blood pressure (SBP), afterload, and myocardial O2 demand during submaximal exercise, effects of ...chronic supplementation with BRJ (containing a relatively low dose of NO3 (-), 400 mg) on cardiac output (CO), SBP, total peripheral resistance (TPR), and the work of the heart in response to dynamic exercise are not known. Thus, in 14 healthy males (22 ± 1 yr), we compared effects of 15 days of both BRJ and nitrate-depleted beetroot juice (NDBRJ) supplementation on plasma concentrations of NOx (NO3 (-)/NO2 (-)), SBP, diastolic blood pressure (DBP), mean arterial pressure (MAP), CO, TPR, and rate pressure product (RPP) at rest and during progressive cycling exercise. Endothelial function was also assessed via flow-mediated dilation (FMD). BRJ supplementation increased plasma NOx from 83.8 ± 13.8 to 167.6 ± 13.2 μM. Compared with NDBRJ, BRJ reduced SBP, DBP, MAP, and TPR at rest and during exercise (P < 0.05). In addition, RPP was decreased during exercise, while CO was increased, but only at rest and the 30% workload (P < 0.05). BRJ enhanced FMD-induced increases in brachial artery diameter (pre: 12.3 ± 1.6%; post: 17.8 ± 1.9%). We conclude that 1) chronic supplementation with BRJ lowers blood pressure and vascular resistance at rest and during exercise and attenuates RPP during exercise and 2) these effects may be due, in part, to enhanced endothelium-induced vasodilation in contracting skeletal muscle. Findings suggest that BRJ can act as a dietary nutraceutical capable of enhancing O2 delivery and reducing work of the heart, such that exercise can be performed at a given workload for a longer period of time before the onset of fatigue.
The understanding of the essential environmental factors affecting the spatiotemporal variation in methylmercury (MeHg) in river water is limited to date, despite its importance for predicting the ...effect of ongoing climate change on MeHg accumulation in freshwater ecosystems. This study aimed to explore the variation in MeHg concentration and related environmental factors in the downstream zone of the Yeongsan River under highly dynamic hydrologic conditions by using water quality and hydrologic data collected from 1997 to 2022, and Hg and MeHg data collected from 2017 to 2022. The mean concentration of unfiltered MeHg was 35.7 ± 13.7 pg L−1 (n = 24) in summer and 26.7 ± 7.43 pg L−1 (n = 24) in fall. Dissolved oxygen (DO), conductivity, nitrate, and dissolved organic carbon (DOC) were determined to be the most influential variables in terms of MeHg variation based on the partial least squares regression model, and their effects on the MeHg concentration were negative, except for DOC. Heatmaps representing the similarity distances between temporal trends of hydrologic and water quality variables were constructed to determine fundamental factors related to the time-based variations in DO, conductivity, nitrate, and DOC using a dynamic time warping algorithm. The heatmap cluster analysis showed that the temporal trends of these variables were closely related to rainfall variation rather than irradiance or water temperature. Overall, biogeochemical factors directly related to in situ methylation rate of Hg(II)—rather than transport of Hg(II) and MeHg from external sources—mainly control the spatiotemporal variation of MeHg in the downstream zone of the Yeongsan River.
Display omitted
•A consistent decline in MeHg concentration was noted in the Yeongsan River.•DO, conductivity, nitrate and DOC were primary influencers of this variation.•Rainfall was a factor leading to temporal variations of the primary influencers.•Rainfall should be considered to better understand the long-term MeHg variation.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A new robot-to-robot communication system is designed for operation in the middle of highways/roads to support mobile safety of approaching vehicles. Robot devices capable of directing a vehicle on a ...bypass route using the proposed vehicle guidance method are detailed. The safety device includes a detector configured to detect a vehicle approaching the sensor robot and an image projector configured to project an image onto the road surface of the approaching vehicle when the vehicle is recognized. Robots can interact in two ways: (1) directly with drivers in the car to avoid the lane problem and (2) among sensor robots in ad-hoc networks, to transfer the information to the cloud to distribute via the mobile app for users far away from the location. In summary, the research results show that the sensor robots and mobile app mainly operated from 6 a.m. to 10 a.m. and provided customized service by modifying/solving uncommon sudden events on the road quickly.
Tobacco and alcohol are risk factors for human papillomavirus-negative head and neck squamous cell carcinoma (HPV
HNSCC), which arises from the mucosal epithelium of the upper aerodigestive tract. ...Notably, despite the mutagenic potential of smoking, HPV
HNSCC exhibits a low mutational load directly attributed to smoking, which implies an undefined role of smoking in HPV
HNSCC. Elevated
(Yes-associated protein) mRNA is prevalent in HPV
HNSCC, irrespective of the
gene amplification status, and the mechanism behind this upregulation remains elusive. Here, we report that oxidative stress, induced by major risk factors for HPV
HNSCC such as tobacco and alcohol, promotes
transcription via TM4SF19 (transmembrane 4 L six family member 19). TM4SF19 modulates
transcription by interacting with the GABP (Guanine and adenine-binding protein) transcription factor complex. Mechanistically, oxidative stress induces TM4SF19 dimerization and topology inversion in the endoplasmic reticulum membrane, which in turn protects the GABPβ1 subunit from proteasomal degradation. Conversely, depletion of TM4SF19 impairs the survival, proliferation, and migration of HPV
HNSCC cells, highlighting the potential therapeutic relevance of targeting TM4SF19. Our findings reveal the roles of the key risk factors of HPV
HNSCC in tumor development via oxidative stress, offering implications for upcoming therapeutic approaches in HPV
HNSCC.
PDF
