Search

Introduction: Orthodontic tooth movement (OTM) involves complex interactions between mechanical forces and periodontal tissue adaptation, mainly mediated by periodontal ligament cells, including periodontal ligament stem cells (PDLSCs), osteoblasts, and osteoclasts. Dopamine (DA), a neurotransmitter known for its critical role in bone metabolism, is investigated in this study for its potential to enhance osteogenic differentiation in PDLSCs, which are pivotal in OTM. This study examined the potential of DA to facilitate OTM by binding to DA receptors (D1R and D2R) and activating the ERK1/2 signaling pathway. We propose that DA's interaction with these receptors on PDLSCs could enhance osteogenic differentiation, thereby accelerating bone remodeling and reducing the duration of orthodontic treatments, which offering a novel approach to improve clinical outcomes in orthodontic care. Methods: This study utilized a rat OTM model, micro-CT, histological analyses, and in vitro assays to investigate dopamine's effect on osteogenesis. PDLSCs were cultured and treated with DA, and cytotoxicity, osteogenic differentiation, gene and protein expression assessed. Results: Dopamine administration significantly increased trabecular bone density and osteogenic marker expression in an OTM rat model. In vitro, DA at 10 nM optimally promoted human PDLSCs osteogenesis without affecting proliferation. Blocking DA receptors or inhibiting the ERK1/2 pathway attenuated these effects, underscoring the importance of dopaminergic signaling in tension-induced osteogenesis during OTM. Conclusion: Taken together, our study reveals that local dopamine administration at a concentration of 10 nM not only enhances tension-induced osteogenesis in vivo but also significantly promotes osteogenic differentiation of PDLSCs in vitro through D1 and D2 receptor-mediated ERK1/2 signaling pathway activation.

Abstract Background Temporomandibular joint osteoarthritis (TMJOA) has a high incidence rate, but its pathogenesis remains unclear. Circadian rhythm is an important oscillation in the human body and influences various biological activities. However, it is still unclear whether circadian rhythm affects the onset and development of TMJOA. Methods We disrupted the normal rhythm of rats and examined the expression of core clock genes in the mandibular condylar cartilage of the jaw and histological changes in condyles. After isolating rat mandibular condylar chondrocytes, we upregulated or downregulated the clock gene Per1, examined the expression of cartilage matrix-degrading enzymes, tested the activation of the GSK3β/β-CATENIN pathway and verified it using agonists and inhibitors. Finally, after downregulating the expression of Per1 in the mandibular condylar cartilage of rats with jet lag, we examined the expression of cartilage matrix-degrading enzymes and histological changes in condyles. Results Jet lag led to TMJOA-like lesions in the rat mandibular condyles, and the expression of the clock gene Per1 and cartilage matrix-degrading enzymes increased in the condylar cartilage of rats. When Per1 was downregulated or upregulated in mandibular condylar chondrocytes, the GSK3β/β-CATENIN pathway was inhibited or activated, and the expression of cartilage matrix-degrading enzymes decreased or increased, which can be rescued by activator and inhibitor of the GSK3β/β-CATENIN pathway. Moreover, after down-regulation of Per1 in mandibular condylar cartilage in vivo, significant alleviation of cartilage degradation, cartilage loss, subchondral bone loss induced by jet lag, and inhibition of the GSK3β/β-CATENIN signaling pathway were observed. Circadian rhythm disruption can lead to TMJOA. The clock gene Per1 can promote the occurrence of TMJOA by activating the GSK3β/β-CATENIN pathway and promoting the expression of cartilage matrix-degrading enzymes. The clock gene Per1 is a target for the prevention and treatment of TMJOA.

Objective: To explore the effect of amyloid-β peptide (Aβ) on mandibular condyle to develop a new treatment for postmenopausal women with Temporomandibular joint osteoarthritis. Methods: A murine bone loss model was established by ovariectomy. Microstructure parameters of the condyle were measured by microcomputed tomography before and after intraperitoneal injection with Aβ. Flow cytometry, Alizarin red staining, RT-qPCR assays, FITC/PI staining, Oil Red O staining and western blotting were used to evaluate the effect of Aβ on the osteogenic differentiation of mouse bone marrow stromal stem cells (mBMSCs). Results: In vivo, condylar microstructure parameters increased. Serum osteoprotegerin and procollagen type 1 N propeptide increased in a dose-dependent manner after the injection of Aβ, which were opposite the changes observed in c-terminal telopeptides of type I collagen, tumor necrosis factor-α and the high serum level of leptin. In vitro, Aβ promoted calcium nodule formation in the cells. The expression of ALP, Runx2, osteorix and osteocalcin increased significantly. The expression of mRNAs related to the Wnt signaling pathway was significantly upregulated, which could be blocked by DKK1. Conclusion: Aβ can reverse bone loss in the mandibular condyle in ovariectomized mice through promoting the osteogenic differentiation of mBMSCs via the Wnt pathway.

Abstract Intensification of northern hemisphere glaciation (iNHG), ~2.7 million years ago (Ma), led to establishment of the Pleistocene to present-day bipolar icehouse state. Here we document evolution of orbital- and millennial-scale Asian winter monsoon (AWM) variability across the iNHG using a palaeomagnetically dated centennial-resolution grain size record between 3.6 and 1.9 Ma from a previously undescribed loess-palaeosol/red clay section on the central Chinese Loess Plateau. We find that the late Pliocene–early Pleistocene AWM was characterized by combined 41-kyr and ~100-kyr cycles, in response to ice volume and atmospheric CO2 forcing. Northern hemisphere ice sheet expansion, which was accompanied by an atmospheric CO2 concentration decline, substantially increased glacial AWM intensity and its orbitally oscillating amplitudes across the iNHG. Superposed on orbital variability, we find that millennial AWM intensity fluctuations persisted during both the warmer (higher-CO2) late Pliocene and colder (lower-CO2) early Pleistocene, in response to both external astronomical forcing and internal climate dynamics.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with a global prevalence of 25%. Patients with NAFLD are more likely to suffer from advanced liver disease, cardiovascular disease, or type II diabetes. However, unfortunately, there is still a shortage of FDA-approved therapeutic agents for NAFLD. Lian-Mei-Yin (LMY) is a traditional Chinese medicine formula used for decades to treat liver disorders. It has recently been applied to type II diabetes which is closely related to insulin resistance. Given that NAFLD is another disease involved in insulin resistance, we hypothesize that LMY might be a promising formula for NAFLD therapy. Herein, we verify that the LMY formula effectively reduces hepatic steatosis in diet-induced zebrafish and NAFLD model mice in a time- and dose-dependent manner. Mechanistically, LMY suppresses Yap1-mediated Foxm1 activation, which is crucial for the occurrence and development of NAFLD. Consequently, lipogenesis is ameliorated by LMY administration. In summary, the LMY formula alleviates diet-induced NAFLD in zebrafish and mice by inhibiting Yap1/Foxm1 signaling-mediated NAFLD pathology.

Kashin-Beck disease (KBD) is an endemic osteochondropathy. A specific gene called SRY-box transcription factor 6 (SOX6) is important for forming cartilage. This study aims to explore the potential correlation between SOX6 single nucleotide polymorphisms (SNPs) and KBD risk for the first time. In the case–control study, 735 unrelated Chinese Han individuals were enrolled. The four mutation sites of the SOX6 gene (rs4539287 G/A, rs3203295 C/A, rs7928675 C/A, and rs10832681 A/G) were screened and genotyped on the Agena MassARRAY platform. The correlation between SOX6 SNPs and KBD risk was explored based on logistic regression analysis. The interaction between SNP and SNP was analyzed based on the multi-factor dimensionality reduction (MDR) method. Overall analysis revealed a remarkable correlation between rs7928675 and rs10832681 and the reduction of KBD risk (p < 0.05). Subgroup analyses further indicated that these two SNPs have a significant protective effect on KBD risk among participants aged ≤65 years, males, and non-smokers (p < 0.05). MDR displayed a marked interaction between rs3203295 and rs10832681. Our study revealed that SOX6 rs7928675 and rs10832681 are markedly correlated with a reduced risk of KBD in the Chinese Han population, providing a new direction for the prevention, diagnosis, and treatment of KBD.

During the development of neural circuits, axons are guided by a variety of molecular cues to navigate through the brain and establish precise connections with correct partners at the right time and place. Many axon guidance cues have been identified and they play pleiotropic roles in not only axon guidance but also axon fasciculation, axon pruning, and synaptogenesis as well as cell migration, angiogenesis, and bone formation. In search of receptors for Sema3E in axon guidance, we unexpectedly found that Plexin B3 is highly expressed in retinal ganglion cells of zebrafish embryos when retinal axons are crossing the midline to form the chiasm. Plexin B3 has been characterized to be related to neurodevelopmental disorders. However, the investigation of its pathological mechanisms is hampered by the lack of appropriate animal model. We provide evidence that Plexin B3 is critical for axon guidance in vivo. Plexin B3 might function as a receptor for Sema3E while Neuropilin1 could be a co-receptor. The intracellular domain of Plexin B3 is required for Semaphorin signaling transduction. Our data suggest that zebrafish could be an ideal animal model for investigating the role and mechanisms of Sema3E and Plexin B3 in vivo.

Abstract Purpose Temporomandibular joint osteoarthritis (TMJOA) is a common disease that negatively affects the life quality of human beings. Circadian rhythm acts an important role in life activities. However, whether the clock genes are rhythmic expressed in mandibular condylar chondrocytes, or the clock genes have an effect on the progression of TMJOA remains unknown. In this study, we aim to explore expression of clock genes and regulatory mechanism of TMJOA in rat mandibular condylar chondrocytes. Methods After synchronized by dexamethasone, the expression of core clock genes Per1, Per2, Clock, Cry1, Cry2 and Bmal1 and cartilage matrix degrading factor gene Mmp13 were analyzed in mandibular condylar chondrocytes every 4 h with RT-qPCR. The mandibular condylar chondrocytes were stimulated with IL-1β, and expression of Per1, Mmp13, P65 and p-P65 was assessed by RT-qPCR and Western blot. Sh-Per1 lentivirus was used to assess the effect of clock gene Per1 in IL-1β-induced chondrocytes, and expression of Mmp13, P65 and p-P65 was measured. After establishing a rat TMJOA model using unilateral anterior crossbite (UAC), micro-CT, H & E, Alcian Blue & Nuclear Fast Red and Safranin O & Fast Green, cartilage thickness was utilized to assess the damage of cartilage and subchondral bone. Immunohistochemistry of PER1, MMP13 and P65 was performed in condylar sections. Results All core clock genes and Mmp13 were rhythmically expressed. And Mmp13 expression curve was closed in phase and amplitude with Per1. After stimulation with IL-1β, the expression of MMP13, PER1 and P65 and ratio of p-P65/P65 increased in condylar chondrocytes. After Per1 was down-regulated in condylar chondrocytes, the expression of MMP13 and P65 and ratio of p-P65/P65 decreased. Compared with the condyles of Sham group, the bony parameters of UAC group were significantly worse. The thickness of cartilage in UAC group significantly reduced. The modified Mankin scores and the expression of PER1, MMP13 and P65 in cartilage of UAC group significantly increased compared with Sham group. Conclusion Core clock genes and Mmp13 are rhythmic expressed in rat mandibular condylar chondrocytes. PER1 can regulate the expression of MMP13 through NF-κB pathway in IL-1β-induced mandibular condylar chondrocytes.

Matthew M Mirsky,1 Carley Mitchell,1 Augustine Hong,1 Shufen Cao,2 Pingfu Fu,2 Seunghee Margevicius,2 Sulin Wu,1 Afshin Dowlati,1 Ariel Nelson,1 J Eva Selfridge,1 Nikhil Ramaiya,1 Christopher Hoimes,1 Asrar Alahmadi,1,&ast; Debora S Bruno1,&ast; 1University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; 2Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA&ast;These authors contributed equally to this workCorrespondence: Debora S Bruno, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, OH, 44106, USA, Tel +1 216 844-3951, Email Debora.Bruno@uhhospitals.orgPurpose: Disparities in cancer care delivery remain a pressing health-care crisis within the United States (US). The use of immune checkpoint inhibitors (ICIs) and their management may be a disparity generator that impacts survival. This retrospective study assessed disparities in a cohort of patients with a variety of solid tumors treated with ICIs within a single health-care organization focusing on the impact of race, socioeconomic status (SES) and site of care delivery on survival and the development of severe immune-related adverse events (irAEs).Patients and Methods: Manual chart review was performed on all patients with solid tumors treated with ICIs within a health-care organization from 2012 to 2018. Care delivery was dichotomized as DOP (disease-oriented provider at academic center) and COP (community oncology provider). Primary and secondary outcomes were overall survival (OS) and rates of grade 3– 4 irAEs, respectively. Relationships with covariates of interest, including race, socioeconomic status and type of care delivery, were assessed among both outcomes.Results: A total of 1070 eligible patients were identified. Of those, 11.4% were of Black race, 59.7% had either non-small cell lung cancer (NSCLC) or melanoma and 82.8% had stage IV disease. Patients of Black race and lower SES were more likely to be treated by DOPs (p< 0.0001). A superior OS was associated with care delivered by DOPs when compared to COPs (HR 0.68; 95% CI 0.56– 0.84; p=0.0002), which was durable after accounting for race, SES, histopathologic diagnosis and disease stage. Melanoma patients experienced higher rates of severe irAEs (HR 2.37; 95% CI 1.42– 3.97; p=0.001). Race, SES and site of care delivery were not related to rates of severe irAEs.Conclusion: In a large health-care organization, patients treated with checkpoint inhibitors by DOPs benefited from a significant OS advantage that was durable after controlling for racial and socioeconomic factors, providing evidence that disease-oriented care has the potential to mitigate racial and socioeconomic disparities.Keywords: disparities, healthcare delivery, immunotherapy outcomes

Abstract Background Chronic lymphoproliferative disorders of natural killer cells (CLPD-NK) is a rare lymphoproliferative disease. Peripheral neuropathy is an unusual symptom of CLPD-NK. We report a case of peripheral neuropathy associated with CLPD-NK and perform a review of literatures. Case presentation a 62-year‐old woman presented with progressive numbness and weakness in both extremities. Electrophysiological examinations indicated a sensorimotor polyneuropathy. Peripheral blood examination revealed that the number of white blood cells (WBC) and lymphocytes were significantly increased. Flow cytometry analysis identified that 84% of the lymphocytes are NK cells that mainly expressed CD56, combined with variable expression of CD16, CD2, CD7, CD94, granzyme B, perforin, and CD158 but negative for CD3. Sural nerve biopsy revealed that a plethora of NK cells infiltrated into nerve fascicles. On treatment with combined cyclophosphamide and corticosteroids, her symptoms rapidly improved. Moreover, the absolute lymphocyte count and its proportion recovered to normal range after 3 months’ treatment. Conclusion To the best of our knowledge, this is the first case report of peripheral neuropathy associated with CLPD-NK from Chinese. This rare lymphoproliferative disease should be considered if peripheral neuropathy combines with increased WBC or lymphocytes. Immunosuppressive drugs are the major treatment and most patients can achieve a good prognosis.

Recent advances in deep learning have shown significant potential for accurate cell detection via density map regression using point annotations. However, existing deep learning models often struggle with multi-scale feature extraction and integration in complex histopathological images. Moreover, in multi-class cell detection scenarios, current density map regression methods typically predict each cell type independently, failing to consider the spatial distribution priors of different cell types. To address these challenges, we propose CellRegNet, a novel deep learning model for cell detection using point annotations. CellRegNet integrates a hybrid CNN/Transformer architecture with innovative feature refinement and selection mechanisms, addressing the need for effective multi-scale feature extraction and integration. Additionally, we introduce a contrastive regularization loss that models the mutual exclusiveness prior in multi-class cell detection cases. Extensive experiments on three histopathological image datasets demonstrate that CellRegNet outperforms existing state-of-the-art methods for cell detection using point annotations, with F1-scores of 86.38% on BCData (breast cancer), 85.56% on EndoNuke (endometrial tissue) and 93.90% on MBM (bone marrow cells), respectively. These results highlight CellRegNet’s potential to enhance the accuracy and reliability of cell detection in digital pathology.

Umbilical cord blood (UCB) is an advantageous source for hematopoietic stem/progenitor cell (HSPC) transplantation, yet the current strategies for large-scale and cost-effective UCB-HSPC preparation are still unavailable. To overcome these obstacles, we systematically evaluate the feasibility of our newly identified CH02 peptide for ex vivo expansion of CD34+ UCB-HSPCs. We herein report that the CH02 peptide is specifically enriched in HSPC proliferation via activating the FLT3 signaling. Notably, the CH02-based cocktails are adequate for boosting 12-fold ex vivo expansion of UCB-HSPCs. Meanwhile, CH02-preconditioned UCB-HSPCs manifest preferable efficacy upon wound healing in diabetic mice via bidirectional orchestration of proinflammatory and anti-inflammatory factors. Together, our data indicate the advantages of the CH02-based strategy for ex vivo expansion of CD34+ UCB-HSPCs, which will provide new strategies for further development of large-scale HSPC preparation for clinical purposes.

Hybridization coupled to polyploidy, or allopolyploidy, has dramatically shaped the evolution of flowering plants, teleost fishes, and other lineages. Studies of recently formed allopolyploid plants have shown that the two subgenomes that merged to form that new allopolyploid do not generally express their genes equally. Instead, one of the two subgenomes expresses its paralogs more highly on average. Meanwhile, older allopolyploidy events tend to show biases in duplicate losses, with one of the two subgenomes retaining more genes than the other. Since reduced expression is a pathway to duplicate loss, understanding the origins of expression biases may help explain the origins of biased losses. Because we expect gene expression levels to experience stabilizing selection, our conceptual frameworks for how allopolyploid organisms form tend to assume that the new allopolyploid will show balanced expression between its subgenomes. It is then necessary to invoke phenomena such as differences in the suppression of repetitive elements to explain the observed expression imbalances. Here we show that, even for phenotypically identical diploid progenitors, the inherent kinetics of gene expression give rise to biases between the expression levels of the progenitor genes in the hybrid. Some of these biases are expected to be gene-specific and not give rise to global differences in progenitor gene expression. However, particularly in the case of allopolyploids formed from progenitors with different genome sizes, global expression biases favoring one subgenome are expected immediately on formation. Hence, expression biases are arguably the expectation upon allopolyploid formation rather than a phenomenon needing explanation. In the future, a deeper understanding of the kinetics of allopolyploidy may allow us to better understand both biases in duplicate losses and hybrid vigor.

Multiple boiler system (MBS) is commonly applied in the industry to cater to the process steam demand reliably and flexibly. Optimising load allocation among the boilers is significant for the routine boiler system efficiency and carbon emission reduction. This aligns with the objective of “RENKEI control” to achieve the optimum cooperative energy efficiency between multiple elements that interact with one another. MBS can be implemented in a centralised or decentralised manner, depending on the unit allocation and process extension planning. Generally, the boiler load allocation is optimized via the complex engineering mathematic approach or modelling, which might not be user-friendly for the in-house engineer without sound mathematical knowledge and optimization background. Therefore, a user-friendly tool and method to handle problems of high combinatorial complexity with a low computational burden are needed. In this paper, the graph theoretic tool, Process Graph (P-graph), which was initially used for Process Network Synthesis (PNS), is applied to optimize the load allocation of both centralised and decentralised MBS considering the non-linear boiler part-load efficiency and existing steam piping network constraint. Besides, the fuel consumption by the existing on-site boiler operation strategy, such as parallel, tandem, and user-assigned mode, can be checked by simply modifying the P-graph structure to identify the potential improvement of MBS load optimization. The methodology proposed achieves 2.48 % and 2.37 % fuel savings in both centralised and decentralised MBS optimisation. Former case demonstrates a similar result (different by 0.02 %) compared to other authors’ work.

The dry and windy Asian glacials during the mid-Pleistocene transition were probably due to the Northern Hemisphere ice sheet expansion, suggest records of grain size and magnetic susceptibility from the Chinese Loess Plateau and model simulations.

Over the past four decades, therapeutic hypothermia (TH) has long been suggested as a promising neuroprotective treatment of acute ischemic stroke (AIS). Much attention has focus on keeping the hypothermic benefits and removing side effects of systemic hypothermia. In the past few years, the advent of intravenous thrombolysis and endovascular thrombectomy has taken us into a reperfusion era of AIS treatment. With recent research emphasizing ways to plus neuroprotective treatments to reperfusion therapy, the spotlight is now shifting toward the study of how selective brain hypothermia can offset the drawbacks of systemic hypothermia and be applied in prehospital condition. This mini-review summarizes current brain cooling methods that can be used for inducing selective hypothermia in prehospital care. It will guide the future development of selective cooling methods, extend the application of TH in prehospital care, and provide insights into the prospects of selective hypothermia in AIS.

Students’ learning experiences are considered useful indicators to evaluate the effectiveness of teaching in tertiary education. With limited theory-driven research, this study aimed to examine whether the educational environment is able to mediate the relationship between student workload and generic skills. A cross-sectional study was conducted among 1347 nursing students in ten nursing schools across Vietnam from November 2021 to January 2022. The results showed that the total score of the students’ workload and the generic skills were 3.25 ± 0.59 and 3.84 ± 0.56 (possible score: 1-5), respectively. Students were at an “agree” level with statements like “the sheer volume of work to be got through in this course means you can’t comprehend it” and “as results of doing this course, I feel more confident about tackling unfamiliar problem”. Most nursing students rated the educational environment at levels of “more positive educational environment” (N=1018, 75.58%), with a total score of 120.75 ± 20.78 (possible score: 0-200). The educational environment was identified as a mediator in the relationships between the workload and the generic skills. The direct effect on workload was -0.00035 which was not significant (p=0.987) with the generic skills. The indirect effect of workload that passes through the educational environment was -0.07 and is also statistically significant, at p= 0.002. As such, the study suggests that, to enhance students’ generic skills, it is necessary to instruct students in efficient learning strategies to help them manage their academic workload, particularly during unexpected situations such as the COVID-19 pandemic. Additionally, despite the occurrence of a high level of student workload, nursing schools could focus on efficient tactics and interventions to improve the educational environment, which subsequently helps to improve students’ outcomes.

Brain tumor segmentation using neural networks presents challenges in accurately capturing diverse tumor shapes and sizes while maintaining real-time performance. Additionally, addressing class imbalance is crucial for achieving accurate clinical results. To tackle these issues, this study proposes a novel N-shaped lightweight network that combines multiple feature pyramid paths and U-Net architectures. Furthermore, we ingeniously integrate hybrid attention mechanisms into various locations of depth-wise separable convolution module to improve efficiency, with channel attention found to be the most effective for skip connections in the proposed network. Moreover, we introduce a combination loss function that incorporates a newly designed weighted cross-entropy loss and dice loss to effectively tackle the issue of class imbalance. Extensive experiments are conducted on four publicly available datasets, i.e., UCSF-PDGM, BraTS 2021, BraTS 2019, and MSD Task 01 to evaluate the performance of different methods. The results demonstrate that the proposed network achieves superior segmentation accuracy compared to state-of-the-art methods. The proposed network not only improves the overall segmentation performance but also provides a favorable computational efficiency, making it a promising approach for clinical applications.

In 2020 early summer, a historically severe rainy season struck East Asia, causing extensive damage to life and property. Subseasonal forecast of this event challenges the limits of rainy season predictability. Employing the integrated atmospheric model across scales and the Sunway supercomputer, we conducted ensemble one-month forecasts at global 3 km, variable 4–60 km, and global 60 km resolutions. The global convection-permitting forecast accurately captures the rainband, while other forecasts exhibited northward and weaker shifts due to the northward shifts of the atmospheric rivers over Japan, attributed to intensified Western North Pacific Subtropical High (WNPSH). Further, the double-ITCZ-like tropical rainfall pattern in Western Pacific in global convection-permitting forecast contributes to a more accurate WNPSH and rainband. In contrast, other forecasts show a single-ITCZ-like pattern in Western Pacific, leading to a northward-shifted WNPSH and rainband, advocating the importance of accurately representing tropical convections, as they can significantly affect mid-/high-latitude weather and climate.

Radiation therapy (RT) for melanoma brain metastases, delivered either as whole brain radiation therapy (WBRT) or as stereotactic radiosurgery (SRS), is an established component of treatment for this condition. However, evidence allowing comparison of the outcomes, advantages and disadvantages of the two RT modalities is scant, with very few randomised controlled trials having been conducted. This has led to considerable uncertainty and inconsistent guideline recommendations. The present systematic review identified 112 studies reporting outcomes for patients with melanoma brain metastases treated with RT. Three were randomised controlled trials but only one was of sufficient size to be considered informative. Most of the evidence was from non-randomised studies, either specific treatment series or disease cohorts. Criteria for determining treatment choice were reported in only 32 studies and the quality of these studies was variable. From the time of diagnosis of brain metastasis, the median survival after WBRT alone was 3.5 months (IQR 2.4–4.0 months) and for SRS alone it was 7.5 months (IQR 6.7–9.0 months). Overall patient survival increased over time (pre-1989 to 2015) but this was not apparent within specific treatment groups.

Abstract SARS-CoV-2 infection triggers profound and variable immune responses in human hosts. Chromatin remodeling has been observed in individuals severely ill or convalescing with COVID-19, but chromatin remodeling early in disease prior to anti-spike protein IgG seroconversion has not been defined. We performed the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and RNA-seq on peripheral blood mononuclear cells (PBMCs) from outpatients with mild or moderate symptom severity at different stages of clinical illness. Early in the disease course prior to IgG seroconversion, modifications in chromatin accessibility associated with mild or moderate symptoms were already robust and included severity-associated changes in accessibility of genes in interleukin signaling, regulation of cell differentiation and cell morphology. Furthermore, single-cell analyses revealed evolution of the chromatin accessibility landscape and transcription factor motif accessibility for individual PBMC cell types over time. The most extensive remodeling occurred in CD14+ monocytes, where sub-populations with distinct chromatin accessibility profiles were observed prior to seroconversion. Mild symptom severity was marked by upregulation of classical antiviral pathways, including those regulating IRF1 and IRF7, whereas in moderate disease, these classical antiviral signals diminished, suggesting dysregulated and less effective responses. Together, these observations offer novel insight into the epigenome of early mild SARS-CoV-2 infection and suggest that detection of chromatin remodeling in early disease may offer promise for a new class of diagnostic tools for COVID-19.

Malus plants are frequently devastated by the apple rust caused by Gymnosporangium yamadae Miyabe. When rust occurs, most Malus spp. and cultivars produce yellow spots, which are more severe, whereas a few cultivars accumulate anthocyanins around rust spots, forming red spots that inhibit the expansion of the affected area and might confer rust resistance. Inoculation experiments showed that Malus spp. with red spots had a significantly lower rust severity. Compared with M. micromalus, M. ‘Profusion’, with red spots, accumulated more anthocyanins. Anthocyanins exhibited concentration-dependent antifungal activity against G. yamadae by inhibiting teliospores germination. Morphological observations and the leakage of teliospores intracellular contents evidenced that anthocyanins destroyed cell integrity. Transcriptome data of anthocyanins-treated teliospores showed that differentially expressed genes were enriched in cell wall and membrane metabolism-related pathways. Obvious cell atrophy in periodical cells and aeciospores was observed at the rust spots of M. ‘Profusion’. Moreover, WSC, RLM1, and PMA1 in the cell wall and membrane metabolic pathways were progressively downregulated with increasing anthocyanins content, both in the in vitro treatment and in Malus spp. Our results suggest that anthocyanins play an anti-rust role by downregulating the expression of WSC, RLM1, and PMA1 to destroy the cell integrity of G. yamadae.

Introduction: This study aimed to determine whether miR-20 promoted osteogenic differentiation in bone marrow-derived mesenchymal stem/stromal cells (BMSCs) and accelerated bone formation in the maxillary sinus bone defect model in rabbits.Methods: BMSCs were transfected with miR-20a or anti-miR-20a for 12 h, followed by detection of RUNX2, Sp7 mRNA, bone morphogenetic protein 2 (BMP2), and RUNX2 protein expression. Alkaline phosphatase (ALP) activity and Alizarin Red S staining were used to detect calcified nodule deposition. In the rabbit maxillary sinus bone defect model, miR-20a loaded with AAV and BMP2 protein were mixed with Bio-Oss bone powder for filling the bone defect. At 4 weeks and 8 weeks, bone density was detected by cone beam computed tomography (CBCT), and new bone, osteoblasts, and collagen type 1 were evaluated by hematoxylin and eosin (HE) staining and immunohistochemical (IHC) staining.Results: Overexpression of miR-20a enhanced the mRNA and protein levels of BMP2, RUNX2, and SP7, the activity of ALP, and the levels of matrix mineralization, whereas the levels and activity of the aforementioned factors were decreased by anti-miR-20a treatment of BMSCs. Furthermore, miR-20a significantly increased the bone density, the number of osteoblasts, and the secretion of collagen type 1 in bone defects compared with Bio-Oss bone powder in the rabbit maxillary sinus bone defect model.Conclusion: Overall, miR-20a can induce osteogenic differentiation in BMSCs and accelerate bone formation of maxillary sinus defects in rabbits.

It is challenging to make precise assessments of real estate prices due to its elevated individual prices, complicated influencing factors, and ambiguous attribute selection. As a result of the high demand for owner-occupied and investment properties, real estate is also a substantial concern for society. A hot topic for research by major institutions has been how to accurately estimate its price. Real-world applications of real estate valuation impose stringent requirements on the acquisition of datasets and the generalizability of models. On the basis of SRGCNN, a spatial regression model with excellent generalizability, this paper introduces an external attention mechanism to construct the A-SRGCNN model and compares it to the benchmark model utilizing data from Shanghai, Melbourne, and San Diego. For spatial regression, A-SRGCNN employs graph convolutional neural networks, and the external attention mechanism implicitly considers the relationship between property data. Experiments indicate that the A-SRGCNN model outperforms the benchmark model and has improved real estate price estimation accuracy. In the meantime, this paper employs the A-SRGCNN model to conduct zonal experiments and time-division experiments on the secondary real estate market in Shanghai to analyze the real estate price linkages between different zones and the real estate price linkages at different times. It is revealed that Shanghai real estate prices exhibit spatial aggregation and price aggregation, with comparable prices within the same zones, and that the A-SRGCNN model is effective at predicting house prices.

The purpose of this research was to investigate the possibilities and opportunities for ASEAN and Korea student exchange programs in the post-COVID-19 pandemic era, by focusing on the needs of non-participating ASEAN students. To do so, this study conducted an online survey to analyze ASEAN students' understanding, views, expectations, and reasons for not participating in student exchange programs to Korea, while investigating their considerations and preferences for future participation. The findings revealed significant differences between ASEAN students in terms of nationality (especially Vietnamese students), academic field, and gender. They also highlighted the rising role and importance of hybrid and online modes of student mobility, that grew in the wake of the COVID-19 pandemic. Therefore, there is a need for universities, government policy makers and educational scholars to reflect the emerging new needs of students concerning ASEAN-Korea exchange programs in the post-COVID-19 pandemic era.

Fluvial floods endure as one of the most catastrophic weather-induced disasters worldwide, leading to numerous fatalities each year and significantly impacting socio-economic development and the environment. Hence, the research and development of new methods and algorithms focused on improving fluvial flood prediction and devising robust flood management strategies are essential. This study explores and assesses the potential application of 1D-Convolution Neural Networks (1D-CNN) for spatial prediction of fluvial flood in the Quang Nam province, a high-frequency tropical cyclone area in central Vietnam. To this end, a geospatial database with 4156 fluvial flood locations and 12 flood indicators was considered. The ADAM algorithm and the MSE loss function were used to train the 1D-CNN model, whereas popular performance metrics, such as Accuracy (Acc), Kappa, and AUC, were used to measure the performance. The results indicated remarkable performance by the 1D-CNN model, achieving high prediction accuracy with metrics such as Acc = 90.7%, Kappa = 0.814, and AUC = 0.963. Notably, the proposed 1D-CNN model outperformed benchmark models, including DeepNN, SVM, and LR. This achievement underscores the promise and innovation brought by 1D-CNN in the realm of susceptibility mapping for fluvial floods.

Periodontal ligament stem cells (PDLSCs) are considered ideal cell sources for the regeneration of periodontal and alveolar bone tissue. Cytoskeleton Regulator RNA (CYTOR), a newly discovered long noncoding RNA, has been reported to function as competing endogenous RNA (ceRNA) and to be involved in many biological processes. However, its roles in PDLSC osteogenic differentiation remain unclear. Here, we firstly found CYTOR was mainly sublocalized in the cytoplasm of PDLSCs and CYTOR expression was increased during osteogenic differentiation of PDLSCs. By employing gain- and loss-of-function approaches, we then identified CYTOR overexpression promoted osteogenic differentiation of PDLSCs while CYTOR knockdown inhibited this process. Furthermore, bioinformatics analysis was utilized to show that both CYTOR and SOX11 mRNA contained the same seed sites for miR-6512-3p, which was further confirmed by dual luciferase reporter assay and RNA-binding protein immunoprecipitation. Notably, CYTOR conferred its functions by directly binding to miR-6512-3p and an inverse correlation between CYTOR and miR-6512-3p on the level on SOX11 and osteogenic differentiation of PDLSCs was obtained. Additionally, miR-6512-3p could bind to SOX11 mRNA 3′ UTR and repressed SOX11 expression. Moreover, level of SOX11 was significantly increased during osteogenic differentiation of PDLSCs. Knockdown of SOX11 attenuated the increasing effect of CYTOR overexpression on osteogenic differentiation of PDLSCs. Collectively, these data supported that CYTOR positively modulated the expression of SOX11 through competitively binding to miR-6512-3p, thus promoting osteogenic differentiation of PDLSCs. The CYTOR/miR-6512-3p/SOX11 axis could be a novel therapeutic target for periodontal regeneration medicine.

Summary: Background & aims: Disease-associated undernutrition is common among hospitalized adults around the world, but risk is expected to be even greater in regions of food insecurity, as in Southeast Asia. Our study, which was based in a large Vietnamese hospital, aimed to determine the prevalence of undernutrition and its associated health and economic burdens. Methods: We conducted a retrospective analysis of medical records for a cohort of 1600 adult patients who were admitted to the University Medical Center (UMC) hospital in Ho Chi Minh City, Vietnam over a 2.5-year interval. Undernutrition or its risk was identified as [1] a diagnosis of malnutrition by a physician, and/or [2] a body mass index (BMI) < 18.5, and/or [3] a score ≥ 3 on the Nutritional Risk Screening (NRS)-2002, and/or [4] in-hospital use of oral nutritional supplements, as recorded in the patient's medical chart. Our study also tracked comorbidities and their severity and compiled data on hospital length of stay and infectious complications during the hospital stay or within 30-days post-hospitalization. We determined costs for the full study population, and we also stratified results by admission source. Results: We found that 2 of every 3 hospital study patients were undernourished or at risk for malnutrition, based primarily on BMI < 18.5 kg/m2 or NRS-2002 score ≥ 3. The highest prevalence of malnutrition risk occurred in patients undergoing gastrointestinal surgery (84.8%), and the lowest among cardiology patients (48.9%). On average, patients were 80.2 years of age, predominantly female (58%), of Kinh ethnicity (95%), with 2.1 comorbid conditions, and public health insurance (84%). Infectious complications occurred in 4% of patients, and hospital length of stay was 8.4 (±4.6) days. Of patients contacted in post-discharge follow-up (N=987), 20.6% had been readmitted to the hospital within 30-days post-discharge. The average total episode cost was 31.6x106 (±28.1x106) VND. Conclusions: Among hospitalized patients in Vietnam, we found that disease-related undernutrition is highly prevalent, which can worsen patient outcomes, increase healthcare resource use, and elevate healthcare costs. To address these problems, we propose use of a nutrition-focused action plan that aims to enhance awareness of nutrition gaps and improve professional training for identification of undernutrition and for delivery of needed nutrition care.

Walnut (Juglans) species are economically important hardwood trees cultivated worldwide for both edible nuts and high-quality wood. Broad-scale assessments of species diversity, evolutionary history, and domestication are needed to improve walnut breeding. In this study, we sequenced 309 walnut accessions from around the world, including 55 Juglans relatives, 98 wild Persian walnuts (J. regia), 70 J. regia landraces, and 86 J. regia cultivars. The phylogenetic tree indicated that J. regia samples (section Dioscaryon) were monophyletic within Juglans. The core areas of genetic diversity of J. regia germplasm were southwestern China and southern Asia near the Qinghai-Tibet Plateau and the Himalayas, and the uplift of the Himalayas was speculated to be the main factor leading to the current population dynamics of Persian walnut. The pattern of genomic variation in terms of nucleotide diversity, linkage disequilibrium, single nucleotide polymorphisms, and insertions/deletions revealed the domestication and selection footprints in Persian walnut. Selective sweep analysis, GWAS, and expression analysis further identified two transcription factors, JrbHLH and JrMYB6, that influence the thickness of the nut diaphragm as loci under selection during domestication. Our results elucidate the domestication and selection footprints in Persian walnuts and provide a valuable resource for the genomics-assisted breeding of this important crop.

Global warming drove ‘wet gets wetter and dry gets drier’ climate shifts in Asia ~5.3 million years ago with monsoon pacing by ~400,000 and ~ 100,000 year cycles. This could be a template for future Asian climate response to anthropogenic warming.