Neurodevelopmental disorder-associated CYFIP2 regulates membraneless organelles and eIF2α phosphorylation via protein interactors and actin cytoskeleton.

De novo variants in the Cytoplasmic FMR1-interacting protein 2 (CYFIP2) have been repeatedly associated with neurodevelopmental disorders and epilepsy, underscoring its critical role in brain development and function. While CYFIP2's role in regulating actin polymerization as part of the WAVE regulatory complex (WRC) is well-established, its additional molecular functions remain relatively unexplored. In this study, we performed unbiased quantitative proteomic analysis, revealing 278 differentially expressed proteins (DEPs) in the forebrain of Cyfip2 knock-out embryonic mice compared to wild-type mice. Unexpectedly, these DEPs, in conjunction with previously identified CYFIP2 brain interactors, included not only other WRC components but also numerous proteins associated with membraneless organelles (MLOs) involved in mRNA processing and translation within cells, including the nucleolus, stress granules, and processing bodies. Additionally, single-cell transcriptomic analysis of the Cyfip2 knock-out forebrain revealed gene expression changes linked to cellular stress responses and MLOs. We also observed morphological changes in MLOs in Cyfip2 knock-out brains and CYFIP2 knock-down cells under basal and stress conditions. Lastly, we demonstrated that CYFIP2 knock-down in cells, potentially through WRC-dependent actin regulation, suppressed the phosphorylation levels of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α), thereby enhancing protein synthesis. These results suggest a physical and functional connection between CYFIP2 and various MLO proteins and also extend CYFIP2's role within the WRC from actin regulation to influencing eIF2α phosphorylation and protein synthesis. With these dual functions, CYFIP2 may fine-tune the balance between MLO formation/dynamics and protein synthesis, a crucial aspect of proper mRNA processing and translation.

Continuous Template Growth of Large-Scale Tellurene Films on 1T'-MoTe2.

Use of a template triggers an epitaxial interaction with the depositing material during synthesis. Recent studies have demonstrated that two-dimensional tellurium (tellurene) can be directionally oriented when grown on transition metal dichalcogenide (TMD) templates. Specifically, employing a T-phase TMD, such as WTe2, restricts the growth direction even further due to its anisotropic nature, which allows for the synthesis of well-oriented tellurene films. Despite this, producing large-area epitaxial films still remains a significant challenge. Here, we report the continuous synthesis of a 1T'-MoTe2 template via chemical vapor deposition and tellurene via vapor transport. The interaction between helical Te and the 1T'-MoTe2 template facilitates the Te chains to collapse into ribbon shapes, enhancing lateral growth at a rate approximately 6 times higher than in the vertical direction, as confirmed by scanning electron microscopy and atomic force microscopy. Interestingly, despite the predominance of the lateral growth, cross-sectional transmission electron microscopy analysis of the tellurene ribbons revealed a consistent 60-degree incline at the edges. This suggests that the edges of the tellurene ribbons, where they contact the template surface, are favorable sites for additional Te absorption, which then stacks along the incline angle to expand. Furthermore, controlling the synthesis temperature, duration, and preheating time has facilitated the successful synthesis of tellurene films. The resultant tellurene exhibited hole mobility as high as ∼400 cm2/V s. After removing the underlying metallic template with plasma treatment, the film showed a current on/off ratio of ∼103. This ratio was confirmed by two-terminal field-effect transistor measurements and supported by near-field terahertz (THz) spectroscopy mapping.

Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer: Updated Overall Survival Outcomes From Phase III PRODIGY.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy (CSC) improved progression-free survival (PFS) compared with surgery followed by adjuvant S-1 (SC) for patients with resectable locally advanced gastric cancer (LAGC) with clinical T2-3N+ or T4Nany disease. The primary end point was PFS. Overall survival (OS) was the secondary end point. We herein report the long-term follow-up outcomes, including OS, from this trial. A total of 238 and 246 patients were randomly assigned to the CSC and SC arms, respectively, and were treated (full analysis set). As of the data cutoff (September 2022), the median follow-up duration of the surviving patients was 99.5 months. Compared with SC, CSC significantly increased the OS (adjusted hazard ratio [HR], 0.72; stratified log-rank P = .027) with an 8-year OS rate of 63.0% and 55.1% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (HR, 0.70; stratified log-rank P = .016). In conclusion, neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, prolonged the OS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1. It should be considered one of the standard treatment options for patients with LAGC in Asia.

Does an untreated peri-implant dehiscence defect affect the progression of peri-implantitis?: A preclinical in vivo experimental study.

OBJECTIVE: To investigate the early impact of plaque accumulation in a buccal dehiscence defect on peri-implant marginal bone resorption. MATERIALS AND METHODS: In six male Mongrel dogs, four dental implants were placed in the posterior maxilla on both sides (two implants per side). Based on the group allocation, each implant was randomly assigned to one of the following four groups to decide whether buccal dehiscence defect was prepared and whether silk ligation was applied at 8 weeks post-implant placement for peri-implantitis induction: UC (no defect without ligation); UD (defect without ligation); LC (no defect with ligation); and LD (defect with ligation) groups. Eight weeks after disease induction, the outcomes from radiographic and histologic analyses were statistically analyzed (p < .05). RESULTS: Based on radiographs, the exposed area of implant threads was smallest in group UC (p < .0083). Based on histology, both the distances from the implant platform to the first bone-to-implant contact point and to the bone crest were significantly longer in the LD group (p < .0083). In the UD group, some spontaneous bone fill occurred from the base of the defect at 8 weeks after implant placement. The apical extension of inflammatory cell infiltrate was significantly more prominent in the LD and LC groups compared to the UC group (p < .0083). CONCLUSION: Plaque accumulated on the exposed implant surface had a negative impact on maintaining the peri-implant marginal bone level, especially when there was a dehiscence defect around the implant.

Magnetically Controlled Intraocular Delivery of Dexamethasone Using Silica-Coated Magnetic Nanoparticles.

Although the number of patients with eye diseases is increasing, efficient drug delivery to the posterior segment of the eyeball remains challenging. The reasons include the unique anatomy of the eyeball, the blood-aqueous barrier, the blood-retina barrier, and drug elimination via the anterior chamber and uveoscleral routes. Solutions to these obstacles for therapeutic delivery to the posterior segment will increase the efficacy, efficiency, and safety of ophthalmic treatment. Micro/nanorobots are promising tools to deliver therapeutics to the retina under the direction of an external magnetic field. Although many groups have evaluated potential uses of micro/nanorobots in retinal treatment, most experiments have been performed under idealized in vitro laboratory conditions and thus do not fully demonstrate the clinical feasibility of this approach. This study examined the use of magnetic nanoparticles (MNPs) to deliver dexamethasone, a drug widely used in retinal disease treatment. The MNPs allowed sustainable drug release and successful magnetic manipulation inside bovine vitreous humor and the vitreous humor of living rabbits. Therefore, controlled drug distribution via magnetic manipulation of MNPs is a promising strategy for targeted drug delivery to the retina.

Vertically Phase Separated Photomultiplication Organic Photodetectors with p-n Heterojunction Type Ultrafast Dynamic Characteristics.

Photomultiplication (PM)-type organic photodetectors (OPDs), which typically form a homogeneous distribution (HD) of n-type dopants in a p-type polymer host (HD PM-type OPDs), have achieved a breakthrough in device responsivity by surpassing a theoretical limit of external quantum efficiency (EQE). However, they face limitations in higher dark current and slower dynamic characteristics compared to p-n heterojunction (p-n HJ) OPDs due to inherent long lifetime of trapped electrons. To overcome this, we have developed a new PM-type OPD that demonstrates ultrafast dynamic properties through a vertical phase separation (VPS) strategy between the p-type polymer (host) and n-type acceptor (dopant), referred to as VPS PM-type OPDs. Notably, VPS PM-type OPDs show a remarkable increase (by three orders of magnitude) in -3 dB cut-off frequency (120 kHz) and over a 200-fold faster response time (rising time = 4.8 µs, falling time = 8.3 µs) compared to HD PM-type OPDs, while maintaining high EQE of 1,121% and specific detectivity of 2.53 × 1013 Jones at -10 V. The VPS PM OPD represents a groundbreaking advancement by demonstrating the coexistence of p-n HJ and PM modes within a single photoactive layer for the first time. This innovative approach holds the potential to enhance both static and dynamic properties of OPDs. This article is protected by copyright. All rights reserved.

Correction: Gallbladder polyps: Correlation of size and clinicopathologic characteristics based on updated definitions.

[This corrects the article DOI: 10.1371/journal.pone.0237979.].

In vivo experimental study comparing alveolar ridge preservation versus guided bone regeneration after unassisted socket healing at intact and damaged sites in narrow alveolar ridges.

BACKGROUND: To compare bone regeneration and dimensional alteration of alveolar ridge at intact and damaged extraction sockets after alveolar ridge preservation (ARP) and implant placement versus unassisted socket healing followed by guided bone regeneration (GBR) with simultaneous implant placement. METHODS: In 6 beagle dogs, 3 types of extraction sockets in the mandible were created: (1) intact sockets, (2) 1-wall defect sockets and (3) 2-wall defect sockets. The sockets were allocated to undergo either (1) ARP and implant placement 8 weeks later (ARP group) or (2) GBR with simultaneous implant placement after 8 weeks of unassisted socket healing (GBR group). After an additional healing period of 8 weeks, bone regeneration and dimensional changes were evaluated radiographically and histologically. RESULTS: GBR showed superior bone formation and greater bone gains compared to ARP, regardless of the initial extraction-socket configuration. Although ARP maintained the preexisting alveolar ridge dimensions, peri-implant bone defects were still detected at 8 weeks of follow-up. Histomorphometric analyses confirmed that GBR increased dimensions of the alveolar ridge compared to baseline, and the augmentation and bone regeneration were greater with GBR than with ARP. CONCLUSION: Early implant placement with ARP can mitigate alveolar ridge changes in the narrow alveolar ridge. However, early implant placement with simultaneous GBR creates the conditions for enhanced bone regeneration around the implant and greater ridge augmentation compared to ARP, irrespective of the extraction-socket configuration.

Non-isocyanate Synthesis of Covalent Adaptable Networks Based on Dynamic Hindered Urea Bonds: Sequential Polymerization and Chemical Recycling.

The development of environmentally sustainable processes for polymer recycling is of paramount importance in the polymer industry. In particular, the implementation of chemical recycling for thermoset polymers via covalent adaptable networks (CANs), particularly those based on the dynamic hindered urea bond (HUB), has garnered intensive attention from both the academic and industrial sectors. This interest stems from its straightforward chemical structure and reaction mechanism, which are well-suited for commercial polyurethane and polyurea applications. However, a substantial drawback of these CANs is the requisite use of toxic isocyanate curing agents for their synthesis. Herein, we propose a new HUB synthesis pathway involving thiazolidin-2-one and a hindered amine. This ring-opening reaction facilitates the isocyanate-free formation of a HUB and enables sequential reactions with acrylate and epoxide monomers via thiol-Michael and thiol-epoxy click chemistry. The CANs synthesized using this methodology exhibit superior reprocessability, chemical recyclability, and reutilizability, facilitated by specific catalytic and solvent conditions, through the reversible HUB, thiol-Michael addition, and transesterification processes.

Re-evaluation of risk and oncological outcomes of resection of veins and arteries in the resection of pancreatic cancer.

BACKGROUND: Advances in chemotherapy have led to increasing major vascular resection during pancreatectomy which has been contraindicated due to high morbidity. This study aimed to verify the safety and oncological outcomes of vascular resection during pancreatectomy in the era of neoadjuvant therapy. METHODS: Data from patients who underwent surgery for pancreatic cancer at Seoul National University Hospital between 2001 and 2021 were reviewed. Clinicopathological outcomes were analyzed according vessel resection. A propensity-score-matched (PSM) analysis was performed to evaluate survival outcomes. RESULTS: Of 1596 patients, the proportion of those who underwent vascular resection increased from 9.2% to 23.4% over time divided into 5-year intervals. There were no differences in major complications (15.6% vs. 13.0%; p = .266) and 30-day mortality rate (0.3% vs. 0.6%; p = .837) between the vascular and nonvascular resection groups. After PSM, the vascular resection group demonstrated comparable survival outcome with the nonvascular resection group (5 year-survival-rate 20.4 vs. 23.7%; p = .194). Arterial resection yielded comparable survival outcome with nonvascular resection (5 year-survival-rate 38.1% vs. 23.7%; p = .138). CONCLUSIONS: Appropriate vascular resection-even arterial-is safe and effective in patients carefully selected for radical surgery in the era of neoadjuvant therapy. Further studies are needed to determine the optimal indication and method for vascular resection in patients with pancreatic cancer.

Analyzing small RNA sequences from canine stem cell-derived extracellular vesicles primed with TNF-α and IFN-γ and exploring their potential in lung repair.

Acute lung injury is an acute inflammation disorder that disrupts the lung endothelial and epithelial barriers. In this study, we investigated the extracellular vesicles (EVs) obtained via priming inflammatory cytokines such as tumor necrosis factor (TNF)-α and interferon (IFN)-γ on canine adipose mesenchymal stem cells in improving their anti-inflammatory and/or immunosuppressive potential, and/or their ability to alleviate lipopolysaccharide-induced lung injury in vitro. We also explored the correlation between epithelial-to-mesenchymal transition and the inflammatory repressive effect of primed EVs. Using small RNA-Seq, we confirmed that miR-16 and miR-502 significantly increased in EVs from TNF-α and IFN-γ-primed canine adipose mesenchymal stem cells. The pro and anti-inflammatory cytokines were analyzed in a lipopolysaccharide-induced lung injury model and we found that the EV anti-inflammatory effect improved on priming with inflammatory cytokines. EVs obtained from primed stem cells effectively suppress endothelial-to-mesenchymal transition in a lung injury model. Our results suggest a potential therapeutic approach utilizing EVs obtained from adipose mesenchymal stem cells primed with TNF-α and IFN-γ against lung inflammation and endothelial to mesenchymal transition.

Femoral artery occlusion induced vasculopathy following herpes zoster: a case report.

BACKGROUND: Reactivation of the varicella zoster virus (VZV) results in herpes zoster (HZ), which is a painful unilateral rash with a typical dermatomal distribution. HZ may be followed by postherpetic neuralgia (PHN), vasculopathy, myelopathy, retinal necrosis, and cerebellitis. Vasculopathy can cause ischemic stroke, aneurysms, arterial dissection, transient ischemic attack, and rarely, peripheral arterial disease (PAD). The possible mechanism is that the VZV travels to the arteries through the sensory ganglia, leading to inflammation and pathological vascular remodeling, which result in vasculopathy. CASE DESCRIPTION: Here, we describe a rare case of femoral artery occlusion induced vasculopathy 5 years after HZ. A 65-year-old woman visited our pain clinic with persistent pain following HZ that occurred 3 months earlier. She had several rash scars on the right thigh along with a continuous throbbing, shooting, and sharp pain. The patient was diagnosed with PHN and prescribed with medications that relieved the leg pain. The symptoms remained stationary for almost 5 years. She presented again with complaints of a paroxysmal tingling sensation in the right thigh and claudication due to increased pain, which had begun 6 months prior. She reported leg pain after walking for 10 minutes. Lumbar spine magnetic resonance imaging (MRI) revealed foraminal stenosis at the level of right L2, with no abnormality below L2. Subsequently, the patient was evaluated for vascular diseases. Lower extremity ultrasonography and computed tomography (CT) angiography revealed stenosis and thrombotic occlusions in the right superficial femoral and tibial arteries as well as the left middle femoral and tibial arteries. Surgical revascularization via percutaneous angioplasty was performed bilaterally. The leg pain was relieved after the procedure and the claudication improved. CONCLUSIONS: Peripheral artery occlusion is a rare phenomenon following HZ. In cases involving changes in HZ symptoms, further evaluation is required for potential vasculopathy.

Improving the diagnostic performance of inexperienced readers for thyroid nodules through digital self-learning and artificial intelligence assistance.

Background: Data-driven digital learning could improve the diagnostic performance of novice students for thyroid nodules. Objective: To evaluate the efficacy of digital self-learning and artificial intelligence-based computer-assisted diagnosis (AI-CAD) for inexperienced readers to diagnose thyroid nodules. Methods: Between February and August 2023, a total of 26 readers (less than 1 year of experience in thyroid US from various departments) from 6 hospitals participated in this study. Readers completed an online learning session comprising 3,000 thyroid nodules annotated as benign or malignant independently. They were asked to assess a test set consisting of 120 thyroid nodules with known surgical pathology before and after a learning session. Then, they referred to AI-CAD and made their final decisions on the thyroid nodules. Diagnostic performances before and after self-training and with AI-CAD assistance were evaluated and compared between radiology residents and readers from different specialties. Results: AUC (area under the receiver operating characteristic curve) improved after the self-learning session, and it improved further after radiologists referred to AI-CAD (0.679 vs 0.713 vs 0.758, p<0.05). Although the 18 radiology residents showed improved AUC (0.7 to 0.743, p=0.016) and accuracy (69.9% to 74.2%, p=0.013) after self-learning, the readers from other departments did not. With AI-CAD assistance, sensitivity (radiology 70.3% to 74.9%, others 67.9% to 82.3%, all p<0.05) and accuracy (radiology 74.2% to 77.1%, others 64.4% to 72.8%, all p <0.05) improved in all readers. Conclusion: While AI-CAD assistance helps improve the diagnostic performance of all inexperienced readers for thyroid nodules, self-learning was only effective for radiology residents with more background knowledge of ultrasonography. Clinical Impact: Online self-learning, along with AI-CAD assistance, can effectively enhance the diagnostic performance of radiology residents in thyroid cancer.

Telecommuting during the COVID-19: the role of job demand and control on health outcomes.

Background: The coronavirus disease 2019 (COVID-19) pandemic drastically modified the occupational system wherein telecommuting has risen as the major form of work. Few studies have incorporated Karasek's job demand-control (JDC) model into explaining the health effects of telecommuting. This study aimed to investigate the health risk in South Korean telecommuters during the pandemic, and its distribution according to the job stress-related factors. Methods: A nationwide population-based cross-sectional study of South Korean laborers was conducted, utilizing the 6th Korean Working Conditions Survey (2020-2021). Following the previously described concept of telecommuting, 14,478 white-collar employees were eligible study participants. Telecommuting, job demand, job control, and various health indicators were measured by the responses to the survey. Participants were stratified into 4 job profiles classified by the JDC model. We conducted multiple logistic regression analyses between telecommuting and health-related outcomes to estimate the odds ratio (OR) with a 95% confidence interval (CI). Results: One hundred forty-six low-strain, 223 active, 69 passive, and 148 high-strain workers were screened as telecommuters. Compared to office workers, telecommuters had a higher proportion in high job control groups. Subgroup analysis demonstrated different relationships between telecommuting and health, where only active telecommuters showed a higher prevalence of depression (OR: 1.980, 95% CI: 1.126-3.481), and high-strain telecommuters were affected in most outcomes including insomnia (OR: 2.555, 95% CI: 1.473-4.433), musculoskeletal pain (OR: 2.786, 95% CI: 1.719-4.517), headache/eye strain (OR: 3.074, 95% CI: 1.992-4.745) and presenteeism (OR: 1.932, 95% CI: 1.193-3.131). Conclusions: This study revealed significantly increased odds of multiple health outcomes among South Korean telecommuters during the COVID-19 pandemic era. High-strain job holders were prominently susceptible to the negative health impacts of telecommuting. Occupational health management towards telecommuters should approach mitigating high job demand and low job control.

Energy Transfer Between i-Motif DNA Encapsulated Silver Nanoclusters and Fluorescein Amidite Efficiently Visualizes the Redox State of Live Cells.

The redox regulation, maintaining a balance between oxidation and reduction in living cells, is vital for cellular homeostasis, intricate signaling networks, and appropriate responses to physiological and environmental cues. Here, a novel redox sensor, based on DNA-encapsulated silver nanoclusters (DNA/AgNCs) and well-defined chemical fluorophores, effectively illustrating cellular redox states in live cells is introduced. Among various i-motif DNAs, the photophysical property of poly-cytosines (C20)-encapsulated AgNCs that sense reactive oxygen species (ROS) is adopted. However, the sensitivity of C20/AgNCs is insufficient for evaluating ROS levels in live cells. To overcome this drawback, the ROS sensing mechanism of C20/AgNCs through gel electrophoresis, mass spectrometry, and small-angle X-ray scattering is primarily defined. Then, by tethering fluorescein amidite (FAM) and Cyanine 5 (Cy5) dyes to each end of the C20/AgNCs sensor, an Energy Transfer (ET) between AgNCs and FAM is achieved, resulting in intensified green fluorescence upon ROS detection. Taken together, the FAM-C20/AgNCs-Cy5 redox sensor enables dynamic visualization of intracellular redox states, yielding insights into oxidative stress-related processes in live cells.

Decreased aggressive care at the end of life among advanced cancer patients in the Republic of Korea: a nationwide study from 2012 to 2018.

BACKGROUND: This study aimed to investigate the trends of aggressive care at the end-of-life (EoL) for patients with advanced cancer in Korea and to identify factors affecting such care analyzing nationwide data between 2012 to 2018. METHODS: This was a population-based, retrospective nationwide study. We used administrative data from the National Health Insurance Service and the Korea Central Cancer Registry to analyze 125,350 patients aged 20 years and above who died within one year of a stage IV cancer diagnosis between 2012 and 2018. RESULTS: The overall aggressiveness of EoL care decreased between 2012 and 2018. In patients' last month of life, chemotherapy use (37.1% to 32.3%; p < 0.05), cardiopulmonary resuscitation (13.2% to 10.4%; p < 0.05), and intensive care unit admission (15.2% to 11.1%; p < 0.05) decreased during the study period, although no significant trend was noted in the number of emergency room visits. A steep increase was seen in inpatient hospice use in the last month of life (8.6% to 26.6%; p < 0.05), while downward trends were observed for hospice admission within three days prior to death (13.9% to 11%; p < 0.05). Patients were more likely to receive aggressive EoL care if they were younger, women, had treatment in tertiary hospitals, or had hematologic malignancies. In the subgroup analysis, the overall trend of aggressive EoL care decreased for all five major cancer types. CONCLUSION: The aggressiveness of EoL care in stage IV cancer patients showed an overall decrease during 2012-2018 in Korea.