Search

Abstract Background The aim of the study was to establish a weighted comprehensive evaluation model (WCEM) of image registration for cone‐beam computed tomography (CBCT) guided lung cancer radiotherapy that considers the geometric accuracy of gross target volume (GTV) and organs at risk (OARs), and assess the registration accuracy of different image registration methods to provide clinical references. Methods The planning CT and CBCT images of 20 lung cancer patients were registered using diverse algorithms (bony and grayscale) and regions of interest (target, ipsilateral, and body). We compared the coverage ratio (CR) of the planning target volume (PTVCT) to GTVCBCT, as well as the dice similarity coefficient (DSC) of the GTV and OARs, considering the treatment position across various registration methods. Furthermore, we developed a mathematical model to assess registration results comprehensively. This model was evaluated and validated using CRFs across four automatic registration methods. Results The grayscale registration method, coupled with the registration of the ipsilateral structure, exhibited the highest level of automatic registration accuracy, the DSC were 0.87 ± 0.09 (GTV), 0.71 ± 0.09 (esophagus), 0.74 ± 0.09 (spinal cord), and 0.91 ± 0.05 (heart), respectively. Our proposed WCEM proved to be both practical and effective. The results clearly indicated that the grayscale registration method, when applied to the ipsilateral structure, achieved the highest CRF score. The average CRF scores, excellent rates, good rate and qualification rates were 58 ± 26, 40%, 75%, and 85%, respectively. Conclusions This study successfully developed a clinically relevant weighted evaluation model for CBCT‐guided lung cancer radiotherapy. Validation confirmed the grayscale method's optimal performance in ipsilateral structure registration.

Summary: Cartilage maintains the structure and function of joints, with disturbances leading to potential osteoarthritis. N6-methyladenosine (m6A), the most widespread post-transcriptional modification in eukaryotes, plays a crucial role in regulating biological processes. While current research has indicated that m6A affects the progression of osteoarthritis, its function in the development and homeostasis of articular cartilage remains unclear. Here we report that Mettl3 deficiency in chondrocytes leads to mandibular condylar cartilage morphological alterations, early temporomandibular joint osteoarthritis, and diminished adaptive response to abnormal mechanical stimuli. Mechanistically, METTL3 modulates Lats1 mRNA methylation and facilitates its degradation in an m6A-YTHDF2-dependent manner, which subsequently influences the degradation and nuclear translocation of YAP1. Intervention with the Hippo pathway inhibitor XMU-MP-1 alleviates condylar abnormality caused by Mettl3 knockout. Our findings demonstrate the role of METTL3 in cartilage development and homeostasis, offering insights into potential treatment strategies for osteoarthritis.

Abstract Acceleration of tooth movement during orthodontic treatment is challenging, with osteoclast-mediated bone resorption on the compressive side being the rate-limiting step. Recent studies have demonstrated that mechanoreceptors on the surface of monocytes/macrophages, especially adhesion G protein-coupled receptors (aGPCRs), play important roles in force sensing. However, its role in the regulation of osteoclast differentiation remains unclear. Herein, through single-cell analysis, we revealed that CD97, a novel mechanosensitive aGPCR, was expressed in macrophages. Compression upregulated CD97 expression and inhibited osteoclast differentiation; while knockdown of CD97 partially rescued osteoclast differentiation. It suggests that CD97 may be an important mechanosensitive receptor during osteoclast differentiation. RNA sequencing analysis showed that the Rap1a/ERK signalling pathway mediates the effects of CD97 on osteoclast differentiation under compression. Consistently, we clarified that administration of the Rap1a inhibitor GGTI298 increased osteoclast activity, thereby accelerating tooth movement. In conclusion, our results indicate that CD97 suppresses osteoclast differentiation through the Rap1a/ERK signalling pathway under orthodontic compressive force.

Abstract The tissue-resident skeletal stem cells (SSCs), which are self-renewal and multipotent, continuously provide cells (including chondrocytes, bone cells, marrow adipocytes, and stromal cells) for the development and homeostasis of the skeletal system. In recent decade, utilizing fluorescence-activated cell sorting, lineage tracing, and single-cell sequencing, studies have identified various types of SSCs, plotted the lineage commitment trajectory, and partially revealed their properties under physiological and pathological conditions. In this review, we retrospect to SSCs identification and functional studies. We discuss the principles and approaches to identify bona fide SSCs, highlighting pioneering findings that plot the lineage atlas of SSCs. The roles of SSCs and progenitors in long bone, craniofacial tissues, and periosteum are systematically discussed. We further focus on disputes and challenges in SSC research.

Objectives: Alpha-ketoglutarate (αKG) is an essential metabolite that plays a crucial role in skeletal homeostasis. Here we aim to investigate the effect of αKG on alveolar socket healing and reveal the underlying mechanism in the view of macrophage polarization. Methods: In a murine model pretreated with or without αKG, mandibular first molars were extracted. Mandibular tissues were harvested for microCT and histological analyses. Immunofluorescence was used to evaluate macrophage polarization during healing process. Macrophages with αKG/vehicle supplementation in vitro were proceeded to quantitative real-time PCR and flow cytometry to further elucidate the mechanism. Results: MicroCT and histological analyses showed accelerated healing and enhanced bone regeneration of extraction sockets in experimental group. αKG increased new bone volume in alveolar sockets and promoted the activity of both osteoblastogenesis and osteoclastogenesis. αKG administration reduced M1 pro-inflammatory macrophages in an early phase and promoted anti-inflammatory M2 macrophage polarization in a later phase. Consistently, the expressions of M2 marker genes were augmented in αKG group, while M1 marker genes were downregulated. Flow cytometry revealed the increased ratio of M2/M1 macrophages in cells treated with αKG. Conclusions: αKG accelerates the healing process of extraction sockets via orchestrating macrophage activation, with promising therapeutic potential in oral clinics.

CHD7 is chromatin remodeler and mutations of CHD7 are the main cause of CHARGE syndrome. Here the authors show that conditional knockout of Chd7 in bone marrow mesenchymal stem cells (MSCs) and pre-osteoblasts leads to a skeletal system development disorder in mice and upregulated PPAR signaling, disrupting the balance between osteogenic and adipogenic differentiation.

BackgroundHospital-acquired pneumonia (HAP) has a significant and detrimental impact on schizophrenia patients. Non-antipsychotic medicines and modified electroconvulsive therapy (MECT) are frequently used in conjunction with antipsychotics to treat schizophrenia. Whether non-antipsychotic medicines or MECT are risk factors for HAP in schizophrenia treated with antipsychotics is still unknown.MethodsPatients with schizophrenia who were admitted to the Fourth People's Hospital of Chengdu between January 2015 and April 2022 were included in this retrospective cohort study. Individuals with HAP were 1:1 matched to individuals without HAP (non-HAP) using propensity score matching (PSM). The risk factors for HAP were analyzed by comparing the two groups.ResultsA total of 7,085 schizophrenia patients were included in this study, with a mean age of 39.77 ± 14.45 years. 193 patients developed HAP on an average of 22.26 ± 21.68 days after admission with an incidence of 2.73%. After 1:1 PSM, 192 patients from each group (HAP and non-HAP) were included. The HAP group had significantly more patients with MECT and taking benzodiazepines, antidepressants, mood stabilizers, and anti-parkinsonians both before and after PSM by Bonferroni correction (P < 0.001). Multivariate logistic regression analysis showed that, combined with antipsychotics, non-antipsychotic medicines including benzodiazepines (OR = 3.13, 95%CI = 1.95-5.03, P < 0.001), mood stabilizers (OR =3.33, 95%CI =1.79–6.20, P < 0.001) and MECT (OR =2.58, 95%CI =1.49–4.46, P = 0.001) were associated with a significantly increased incidence of HAP.ConclusionThe incidence of HAP in schizophrenia patients in our cohort was 2.73%. MECT and non-antipsychotic medicines, including benzodiazepines and mood stabilizers were risk factors for HAP in schizophrenia patients treated with antipsychotics.

Transcriptional elongation is a universal and critical step during gene expression. The super elongation complex (SEC) regulates the rapid transcriptional induction by mobilizing paused RNA polymerase II (Pol II). Dysregulation of SEC is closely associated with human diseases. However, the physiological role of SEC during development and homeostasis remains largely unexplored. Here we studied the function of SEC in adipogenesis by manipulating an essential scaffold protein AF4/FMR2 family member 4 (AFF4), which assembles and stabilizes SEC. Knockdown of AFF4 in human mesenchymal stem cells (hMSCs) and mouse 3T3-L1 preadipocytes inhibits cellular adipogenic differentiation. Overexpression of AFF4 enhances adipogenesis and ectopic adipose tissue formation. We further generate Fabp4-cre driven adipose-specific Aff4 knockout mice and find that AFF4 deficiency impedes adipocyte development and white fat depot formation. Mechanistically, we discover AFF4 regulates autophagy during adipogenesis. AFF4 directly binds to autophagy-related protein ATG5 and ATG16L1, and promotes their transcription. Depleting ATG5 or ATG16L1 abrogates adipogenesis in AFF4-overepressing cells, while overexpression of ATG5 and ATG16L1 rescues the impaired adipogenesis in Aff4-knockout cells. Collectively, our results unveil the functional importance of AFF4 in regulating autophagy and adipogenic differentiation, which broaden our understanding of the transcriptional regulation of adipogenesis.

Forest roads, haul roads, and especially skid trails have been associated with sedimentation and soil erosion risk. Despite the widespread small shovel harvesting system on steep terrains in South Korea, the subsequent risks of deep (rut depth >5 cm) and compact disturbances, and erosion rates in skid trails are largely unknown. Therefore, the main objectives of this study were to compare the soil erosion rate in each skid trail and predict the total soil erosion rate in a small shovel harvesting area. The soil erosion rate was measured at the plot scale (5 × 3 m) in different skid trail parts (bladed skid trail by small-shovel loader passage, BT; and compacted skid trail CT by carrier passage with construction by a small-shovel loader) using a silt fence experiment. In addition, we investigated the applicability of the Water Erosion Prediction Project (WEPP) model to each disturbance. Among all disturbances, the highest erosion rate (average value of 9.13 ± 0.96 kg m−2 4 months−1) was because of CT. The model predictions were over- and under-estimated and showed particularly poor performance where uncovered soil was exposed (less than 1%) to high machine traffic frequency and excavation. Further, the annual soil erosion rates ranged from 11.59 to 28.94 ton ha−1 year−1. The results suggested that the WEPP model could partially validate the soil erosion results, and further research is still required to improve the accuracy of the model.

Background: Recent studies have demonstrated benefits from adjuvant tyrosine-kinase inhibitors (TKIs) compared with chemotherapy in non-small cell lung cancer. We launched a multi-center retrospective study to evaluate the efficacy and toxicity of adjuvant TKIs with or without chemotherapy in epidermal growth factor receptor (EGFR)-mutant stage III-pN2 lung adenocarcinoma. Methods: Two hundred and seventy-four consecutive cases with stage III-pN2 lung adenocarcinoma and complete resection have been investigated. Clinic-pathologic characteristics, adjuvant treatments, long-term survivals, and toxicities were documented. Risk factors of distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were evaluated. Results: There were 52 (19.0%) patients treated with adjuvant TKIs alone, 199 (72.6%) with adjuvant chemotherapy alone, and 23 (8.4%) with both. After a median follow-up time of 29 months, the two-year DMFS, DFS, and OS was 61.2%, 54.1%, and 91.2%, respectively. According to univariable analyses, the risk factors were lymphovascular invasion (p < 0.001), extranodal extension (p = 0.005), and adjuvant systemic therapy (p = 0.006) for DMFS, EGFR mutation type (p = 0.025), lymphovascular invasion (p = 0.013), extranodal extension (p = 0.004), and adjuvant systemic therapy (p < 0.001) for DFS, and EGFR mutation type (p < 0.001) for OS. Multivariable analyses indicated that the independent prognostic factors were adjuvant systemic therapy (TKIs vs. TKIs+chemotherapy, Harzard ratio (HR) = 0.40; p = 0.036; TKIs vs. chemotherapy, HR = 0.38; p = 0.004), lymphovascular invasion (yes vs. no, HR = 2.22; p = 0.001) for DMFS, and adjuvant systemic therapy (TKIs vs. TKIs+chemotherapy, HR = 0.42; p = 0.034; TKIs vs. chemotherapy, HR = 0.33; p < 0.001) for DFS. No significant difference was found in the incidence of Grade 3–4 toxicities between groups (p = 0.445). Conclusions: Adjuvant TKIs might be a beneficial choice compared with adjuvant chemotherapy or combination systemic treatments.

Abstract Alveolar bone is the thickened ridge of jaw bone that supports teeth. It is subject to constant occlusal force and pathogens invasion, and is therefore under active bone remodeling and immunomodulation. Alveolar bone holds a distinct niche from long bone considering their different developmental origin and postnatal remodeling pattern. However, a systematic explanation of alveolar bone at single-cell level is still lacking. Here, we construct a single-cell atlas of mouse mandibular alveolar bone through single-cell RNA sequencing (scRNA-seq). A more active immune microenvironment is identified in alveolar bone, with a higher proportion of mature immune cells than in long bone. Among all immune cell populations, the monocyte/macrophage subpopulation most actively interacts with mesenchymal stem cells (MSCs) subpopulation. Alveolar bone monocytes/macrophages express a higher level of Oncostatin M (Osm) compared to long bone, which promotes osteogenic differentiation and inhibits adipogenic differentiation of MSCs. In summary, our study reveals a unique immune microenvironment of alveolar bone, which may provide a more precise immune-modulatory target for therapeutic treatment of oral diseases.

Abstract Background Aberrant activation of the Wnt/β-catenin signaling pathway is one of the most frequent abnormalities in human cancer, including colorectal cancer (CRC). Previous studies revealed pivotal functions of WNT family members in colorectal cancer, as well as their prognostic values. Nevertheless, the prognostic role and mechanisms underlying WNT7b in colorectal cancer development remains unclear. Methods In this study, WNT7b expression was measured by immunohistochemical staining of 100 cases of surgically resected human colorectal cancerous tissues as well as matched adjacent normal tissues constructed as tissue microarrays. In vitro studies, we attempted to substantiate the WNT7b expressional pattern previously found in immunohistochemistry staining. We used the colorectal cancer cell-line HCT116 and normal colorectal cell-line FHC for immunofluorescence staining and nuclear/cytoplasmic separated western blotting. We measured epithelial–mesenchymal transition (EMT) markers and migration capacity of HCT116 in the context of WNT7b knocked-down using short interfering RNA. Finally, clinical and prognostic values of WNT7b activation levels were examined. Results WNT7b was expressed in the nucleus in adjacent normal tissues. In CRC tissues, nuclear expression of WNT7b was similar; however, membrane and cytoplasmic expression was strikingly enhanced. Consistently, in vitro analysis confirmed the same expression pattern of WNT7b. Compared with FHC cells, HCT116 cells displayed higher levels of WNT7b membrane and cytoplasmic enrichment, as well as higher migration capacity with a sensitized EMT process. Either partial knockdown of WNT7b or blockade of the Wnt/β-catenin signaling pathway reversed EMT process and inhibited the migration of HCT116 cells. Finally, elevated secretion levels of WNT7b were significantly associated with lymphatic and remote metastasis and predicted worse prognosis in the CRC cohort. Conclusion In summary, we demonstrated that the activation of WNT7b autocrine probably contributes to CRC metastasis by triggering EMT process through the Wnt/β-catenin signaling pathway. High levels of WNT7b autocrine secretion predicts poor outcome in patients with CRC. This molecule is a promising candidate for clinical CRC treatments.

α-ketoglutarate is an intermediate of the Krebs Cycle that was recently reported to extend lifespan in C.Elegans. Here, the authors show that administration of α-ketoglutarate to mice reduces age-related bone loss, by ameliorating senescence of bone-marrow derived mesenchymal stem cells.

Abstract Background Tibet is located in the high-altitude area of Southwest China, where the health level is influenced by specific factors such as the natural environment and living habits. However, there has been little research that has focused on Tibetan health conditions. The two-week prevalence rate is an important indicator of the health level of residents. The purpose of this study was to understand the health status of the residents and the health service needs in Tibet. Methods The two-week prevalence rate was calculated using data from a population of 10,493 individuals aged 15 and above that was obtained from the 2018 Sixth National Health Service Survey of Tibet. We initially analysed the types and associated factors of two-week illnesses in Tibetan. The influencing factors for the two-week prevalence rate in Tibet were determined by multivariate logistic regression analysis. Subsequently, we assessed the severity of two-week illnesses by calculating the average days of the duration of the disease, the days of being bedridden and the days of being off work. Results The two-week illness prevalence rate was 20.1% in Tibet. Digestive system diseases were frequent, and hypertension was the most common disease. According to the multivariate logistic regression analysis, the two-week prevalence rate was associated with gender, age, residence, marital status, and employment status. In addition, the severity of two-week illnesses differed among the residents. Conclusion This study identified that health service needs have increased in Tibet and that the health status of the local residents needs to be improved. Moreover, hypertension has become a major health hazard for the residents and should be considered in the utilization of health services.

Changes in water quality were examined during selected rainfall events in a headwater stream severely damaged by a forest fire on 21–23 February 2021. Seven water quality parameters were analyzed: pH, electrical conductivity, biochemical oxygen demand, chemical oxygen demand, total suspended solids (TSS), total nitrogen, and total phosphorous. First-flush effect and event mean concentration analyses were conducted in spring (dry season) and summer (wet season) immediately after the forest fire. In spring, the non-biodegradable organic matter concentrations increased along with pollutants related to ash-enhanced soil water repellency in water affected by first-flush effects. In summer, TSS and nutrient concentrations increased along with pollutants related to fire-induced soil surface disturbances after a series of rainfall events. First-flush analyses indicated that cumulative pollutant loads were greater in the spring than in the summer due to a higher concentration of forest fire ash in the early storm runoff immediately after the forest fire. The event mean concentrations revealed that pollutant loads were associated with both forest fire ash and storm events in the immediate post-fire period. Therefore, this study indicated that water quality along a headwater stream is affected by short-term effects of large and intense forest fires and rainfall seasonality.

BackgroundTo explore the efficacy and toxicity of simultaneous modulated accelerated radiotherapy (SMART) concurrently with cisplatin (CDDP) and S1 (tegafur/gimeracil/oteracil) in elderly patients with esophageal squamous cell carcinoma (ESCC).MethodsThis single-arm, phase II study enrolled pathologically confirmed, stage II–IVa ESCC of 70–80 years old and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2. Patients received SMART (64 Gy to gross tumor volume and 48 Gy to clinical target volume in 30 fractions) with concurrent CDDP (day 1 of each week) and S1 (days 1–14, 22–35). The primary endpoint was objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicities.ResultsThirty-seven eligible patients were analyzed with median follow-up of 25.7 months for all and 46.1 months for survivors. The ORR was 88.9%. Patients with baseline weight loss

Introduction: Pneumonia is an important cause of death in patients with schizophrenia. It is critical to understand the risk factors of hospital-acquired pneumonia (HAP) and determine prevention strategies to reduce HAP. The aim of this study is to elucidate the risk factors for HAP in the middle-aged and elderly hospitalized patients with schizophrenia.Methods: We retrospectively reviewed the medical records of 2,617 the middle-aged and elderly patients (age ≥ 50) with schizophrenia who were admitted for the first time to a large-scale psychiatric hospital between 2016 and 2020. The factors related to the incidence of HAP in patients were analyzed, including personal characteristics, antipsychotics, and non-antipsychotics.Results: The HAP infection rate of hospitalized the middle-aged and elderly patients with schizophrenia was 7.8%. Chi-square analyses showed that older age, male, and ≥60 days of hospitalization were risk factors for HAP infection (χ2 = 94.272, p < 0.001; χ2 = 22.110, p < 0.001; χ2 = 8.402, p = 0.004). Multivariate logistic regression showed that quetiapine, clozapine, and olanzapine significantly increased the incidence of HAP (OR = 1.56, 95% CI = 1.05–2.32, p = 0.029; OR = 1.81, 95% CI = 1.26–2.60, p = 0.001; OR = 1.68, 95% CI = 1.16–2.42, p = 0.006). Antipsychotic drugs combined with aceglutamide had an effect on HAP (OR = 2.19, 95% CI = 1.38–3.47, p = 0.001).Conclusion: The high HAP infection rate in hospitalized the middle-aged and elderly patients with schizophrenia may be related to the increase of age and the use of antipsychotic drugs. The types and dosages of antipsychotic drugs should be minimized while paying attention to the mental symptoms of patients.

Introduction: Schizophrenia is a mental disease with a profound impact on human health. Patients with schizophrenia have poor oral hygiene, increasing their risk of systemic diseases, such as respiratory infections, and declining their quality of life. Therefore, this study aims to assess the oral health status of inpatients with schizophrenia, analyze its related factors, and thus provide scientific evidence for further exploration of corresponding control strategies.Methods: A total of 425 inpatients older than 50 years with a diagnosis of schizophrenia from two psychiatric hospitals (mean age 58.49 ± 5.72 years) were enrolled. The demographic data of the patients were checked on admission. Two independent dentists examined caries, missing teeth, and fillings. Mini-Mental State Examination (MMSE) and Global Deterioration Scale were performed as cognitive tests. Positive and Negative Syndrome Scale and Repeatable Battery for the Assessment of Neuropsychological Status rating scale were used to determine their mental status.Results: The average decayed, missing, and filled teeth index was 12.99 ± 8.86. Linear regression analysis showed that the decayed, missing, and filled teeth index had a significantly positive relationship with age (p < 0.001) and smoking (p < 0.001) and a negative relationship with MMSE (p = 0.029). The missing teeth index had a positive relationship with age (p < 0.001), smoking (p < 0.001), and Global Deterioration Scale (p = 0.014) and a negative relationship with MMSE (p = 0.004).Conclusion: The oral health of elderly patients with schizophrenia is poor, which may be related to the cognitive level of patients and affect their quality of life. The focus should be provided to the oral care of patients with schizophrenia, and investment in their specialized oral treatment should be increased.

Machine learning models are now capable of delivering coveted digital soil mapping (DSM) benefits (e.g., field capacity (FC) prediction); therefore, determining the optimal sample sites and sample size is essential to maximize the training efficacy. We solve this with a novel optimal sampling algorithm that allows the authentic augmentation of insufficient soil features using machine learning predictive uncertainty. Nine hundred and fifty-three forest soil samples and geographically referenced forest information were used to develop predictive models, and FCs in South Korea were estimated with six predictor set hierarchies. Random forest and gradient boosting models were used for estimation since tree-based models had better predictive performance than other machine learning algorithms. There was a significant relationship between model predictive uncertainties and training data distribution, where higher uncertainties were distributed in the data scarcity area. Further, we confirmed that the predictive uncertainties decreased when additional sample sites were added to the training data. Environmental covariate information of each grid cell in South Korea was then used to select the sampling sites. Optimal sites were coordinated at the cell having the highest predictive uncertainty, and the sample size was determined using the predictable rate. This intuitive method can be generalized to improve global DSM.

Abstract Background The periodontal ligament is essential for homeostasis of periodontal tissue. A hypoxic milieu of the periodontal tissue is generated under periodontitis or during orthodontic treatment, which affects the periodontal and bone remodelling process. Here, we provide a comprehensive proteomic characterization of periodontal ligament cells under hypoxic conditions, aiming to reveal previously unappreciated biological changes and to help advance hypoxia-based therapeutic strategies for periodontal diseases. Methods Human periodontal ligament cells (hPDLCs) were characterized using immunohistochemistry (IHC) and flow cytometry (FACS). Successful hypoxia treatment of hPDLCs with 1% O2 was confirmed by qRT-PCR. Proliferation was evaluated using an MTT assay. The proteomic expression profile under hypoxia was studied with the isobaric tags for relative and absolute quantification (iTRAQ) approach followed by protein identification and bioinformatic analysis, and western blot verification was performed. Results The hPDLCs were positive for vimentin, CD73 and CD105 and negative for keratin, CD34 and CD45. After hypoxia treatment, the mRNA expression of hypoxia-inducible factor 1a (HIF1a) was upregulated. The proliferation rate was elevated during the first 6 h but decreased from 6 h to 72 h. A total of 220 differentially expressed proteins were quantified in hPDLCs under hypoxia (1% O2, 24 h), including 153 upregulated and 67 downregulated proteins, five of which were verified by western blot analysis. The Gene Ontology enriched terms included the energy metabolic process, membrane-bound organelle and vesicle, and protein binding terms. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated several involved pathways, including glycolysis/gluconeogenesis, biosynthesis of amino acids, the HIF-1 signalling pathway, and focal adhesion. A protein–protein interaction (PPI) network demonstrated the dominant role of autophagy over apoptosis under hypoxia. Conclusion The proteomic profile of hPDLCs under hypoxia was mainly related to energy metabolism, autophagy, and responses to stimuli such as adhesion and inflammation. Previously unrecognized proteins including solute carrier family proteins, heat shock proteins, ubiquitination-related enzymes, collagen and S100 family proteins are involved in adaptive response to hypoxia in hPDLCs and are thus of great research interest in future work.

In this paper, we focus on the millimeter-wave (mmWave) band multiple-input and multiple-output (MIMO) channel estimation in the satellite-based Internet of Things (S-IoT). At first, we establish a sparse geometric-based mmWave MIMO channel model between a high throughput satellite (HTS) and multiple terrestrial user equipments (UEs) for the S-IoT downlink system. By exploiting the sparsity inherent to the mmWave band channel, we propose an efficient adaptive random-selected multi-beamforming (ARM) estimation scheme, which can simultaneously estimate the mmWave MIMO channel state information (CSI) for multiple UEs in angle domain. The ARM estimation scheme measures of the CSI between the HTS and multiple UEs by utilizing a series of random combinations of transmitting beamforming vectors and receiving UEs' antennas and the required number of measurements can adaptively reduce as well as the signal-to-noise ratios (SNR) increases. To further improve the performance of ARM estimation scheme, the number of each beamforming been selected for the channel measurement is buffered, and modify the probability of the random selection of beams and UEs. Two improved ARM estimation schemes are proposed, one is ARM forcing adaptation beam selection (ARM-FABS) scheme, and the other is ARM partially estimated beam selection (ARM-PEBS) scheme. The simulation results show that the proposed ARM estimation schemes can reduce the required number of measurements and achieve a better tracking performance over a wide range of SNRs.

Bone fractures and defects are a major health issue and have reportedly affected over 455 million individuals globally to date. Bone tissue engineering has gained great success in bone defect repair and bone reconstruction based on the use of nano-hydroxyapatite (nHA) or collagen (COL). Both nHA and COL exhibit osteogenic induction capacity to support bone tissue regeneration; however, the former suffers from poor flexibility and the latter lacks mechanical strength. Biological scaffolds created by combining nHA and COL (nHA/COL) can overcome the drawbacks imposed by individual materials and, therefore, have become widely applied in tissue engineering. The composite scaffolds can further promote tissue reconstruction by allowing the loading of various growth factors. Naringin (NG) is a natural flavonoid. Its molecular weight is 580.53 Da, lower than that of many growth factors, and it causes minimal immune responses when being introduced in vivo. In addition, naringin is safe, non-toxic, inexpensive to produce, and has superior bio-properties. In this study, we introduced NG into a nHA/COL scaffold (NG/nHA/COL) and exploited the potentials of the NG/nHA/COL scaffold in enhancing bone tissue regeneration. NG/nHA/COL scaffolds were fabricated by firstly combining nHA and collagen at different compositional ratios, followed by NG encapsulation. NG release tests showed that the scaffold with a nHA/COL mass ratio of 7:3 exhibited the optimal property. The in vitro cell study showed the desirable biocompatibility of the NG/nHA/COL scaffold, and its effective promotion for the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), as proved by an increased alkaline phosphatase (ALP) activity, the formation of more calcium nodules, and a higher expression of osteogenic-related genes involving Osteocalcin (OCN), BMP-2, and Osteopontin (OPN), compared with the control and nHA/COL groups. When administered into rats with skull defects, the NG/nHA/COL scaffold significantly promoted the reconstruction of bone tissues and the early repair of skull defects, indicating the great potential of NG/nHA/COL scaffolds in bone tissue engineering.

ObjectiveTo improve the assessment of primary tumor heterogeneity in magnetic resonance imaging (MRI) of non-small cell lung cancer (NSCLC), we proposed a method using basic measurements from T1- and T2-weighted MRI.MethodsOne hundred and four NSCLC patients with different T stages were studied. Fifty-two patients were analyzed as training group and another 52 as testing group. The ratios of standard deviation (SD)/mean signal value of primary tumor from T1-weighted (T1WI), T1-enhanced (T1C), T2-weighted (T2WI), and T2 fat suppression (T2fs) images were calculated. In the training group, correlation analyses were performed between the ratios and T stages. Then an ordinal regression model was built to generate the tumor heterogeneous index (THI) for evaluating the heterogeneity of tumor. The model was validated in the testing group.ResultsThere were 11, 32, 40, and 21 patients with T1, T2, T3, and T4 disease, respectively. In the training group, the median SD/mean on T1WI, T1C, T2WI, and T2fs sequences was 0.11, 0.19, 0.16, and 0.15 respectively. The SD/mean on T1C (p=0.003), T2WI (p=0.000), and T2fs sequences (p=0.002) correlated significantly with T stages. Patients with more advanced T stage showed higher SD/mean on T2-weighted, T2fs, and T1C sequences. The median THI in the training group was 2.15. THI correlated with T stage significantly (p=0.000). In the testing group, THI was also significantly related to T stages (p=0.001). Higher THI had relevance to more advanced T stage.ConclusionsThe proposed ratio measurements and THI based on MRI can serve as functional radiomic markers that correlated with T stages for evaluating heterogeneity of lung tumors.

Capsule-forming extracellular polysaccharides are crucial for bacterial host colonization, invasion, immune evasion, and ultimately pathogenicity. Due to warming ocean waters and human encroachment of coastal ecosystems, Vibrio parahaemolyticus has emerged as a globally important foodborne enteropathogen implicated in acute gastroenteritis, wound infections, and septic shock. Conventionally, the antigenic properties of lipopolysaccharide (LPS, O antigen) and capsular polysaccharide (CPS, K antigen) have provided a basis for serotyping V. parahaemolyticus, whereas disclosure of genetic elements encoding 13 O-serogroups have allowed molecular serotyping methods to be developed. However, the genetic structure of CPS loci for 71 K-serogroups has remained unidentified, limiting progress in understanding its roles in V. parahaemolyticus pathophysiology. In this study, we identified and characterized the genetic structure and their evolutionary relationship of CPS loci of 40 K-serogroups through whole genome sequencing of 443 V. parahaemolyticus strains. We found a distinct pattern of CPS gene cluster across different K-serogroups and expanded its new 3′-border by identifying glpX as a key gene conserved across all K-serogroups. A total of 217 genes involved in CPS biosynthesis were annotated. Functional contents and genetic structure of the 40 K-serogroups were analyzed. Based on inferences from species trees and gene trees, we proposed an evolution model of the CPS gene clusters of 40 K-serogroups. Horizontal gene transfer by recombination from other Vibrio species, gene duplication is likely to play instrumental roles in the evolution of CPS in V. parahaemolyticus. This is the first time, to the best of our knowledge, that a large scale of CPS gene clusters of different K-serogroups in V. parahaemolyticus have been identified and characterized in evolutionary contexts. This work should help advance understanding on the variation of CPS in V. parahaemolyticus and provide a framework for developing diagnostically relevant serotyping methods.

Typical small shovel logging system, using manual felling and extraction by small crawler excavator with grapple and crawler carriers, is the predominant logging method in the Republic of Korea, due to the associated high productivity. The trails with ground pressure and one more passes of the shovel and carriers may lead to soil compaction. However, impacts of these bunching-extraction technologies on physical and hydrological properties of soils are not well known. The main objectives of this study were to: (1) determine the bulk density, porosity, and saturated hydraulic conductivity of soils in logging operation areas with three different disturbance types (i.e., undisturbed areas [UAs], bladed trails [BTs], and skid trails [STs]), and (2) compare soil compaction between these disturbance types. The most intense compaction occurred within BTs and STs, with increased bulk density and reduced porosity and hydraulic conductivity. Soil bulk density increased by 27–53% at all depths in BTs and STs compared to UAs, while porosity decreased by 23–49%. On average, saturated hydraulic conductivity at depths of 0–20 cm decreased from 337.5 mm h−1 to 30.5 mm h−1 in the most compacted sections of BTs and STs. Skid trails, which are characterized by trail construction and frequent vehicle movement, also caused greater impacts on soil compaction than BTs. This study provides useful insights to aid forest consultants and field managers in planning more environmentally sound mechanized logging operations.

Stem cells play an irreplaceable role in the development, homeostasis, and regeneration of the craniofacial bone. Multiple populations of tissue-resident craniofacial skeletal stem cells have been identified in different stem cell niches, including the cranial periosteum, jawbone marrow, temporomandibular joint, cranial sutures, and periodontium. These cells exhibit self-renewal and multidirectional differentiation abilities. Here, we summarized the properties of craniofacial skeletal stem cells, based on their spatial distribution. Specifically, we focused on the in vivo genetic fate mapping of stem cells, by exploring specific stem cell markers and observing their lineage commitment in both the homeostatic and regenerative states. Finally, we discussed their application in regenerative medicine.

Chromodomain helicase DNA-binding protein 7 (CHD7) is an ATP-dependent chromatin remodeling enzyme, functioning as chromatin reader to conduct epigenetic modification. Its effect on osteogenic differentiation of human dental follicle cells (hDFCs) remains unclear. Here, we show the CHD7 expression increases with osteogenic differentiation. The knockdown of CHD7 impairs the osteogenic ability of hDFCs, characterized by reduced alkaline phosphatase activity and mineralization, and the decreased expression of osteogenesis-related genes. Conversely, the CHD7 overexpression enhances the osteogenic differentiation of hDFCs. Mechanically, RNA-seq analyses revealed the downregulated enrichment of PTH (parathyroid hormone)/PTH1R (parathyroid hormone receptor-1) signaling pathway after CHD7 knockdown. We found the expression of PTH1R positively correlates with CHD7. Importantly, the overexpression of PTH1R in CHD7-knockdown hDFCs partially rescued the impaired osteogenic differentiation. Our research demonstrates that CHD7 regulates the osteogenic differentiation of hDFCs by regulating the transcription of PTH1R.

Abstract Background The concept of establishing a dental stem cell (DSC) bank for oral and maxillofacial regeneration has become of great interest but it remains at a primitive stage. The routine application of serum-containing conditions for human DSC (hDSC) culture is in great controversy considering that the animal-originated serum can cause serious ethical concerns and lead to increasingly irrelevant variables, errors, and poor repeatability of experiment results. Thus, this study aimed to establish a safe, stable and efficient hDSC serum-free culturing system for future DSC bank usage. Methods Dental pulp stem cells (DPSCs) from human permanent tooth pulp were isolated, expanded, passaged, and divided into two groups according to their culture conditions: group 1 was the serum-containing medium (SCM) group; and group 2 was the serum-free Essential 8 medium (E8) group. DPSCs were characterized first, followed by cell proliferation, pluripotency, and migration study in SCM and E8 medium. Results Human DPSCs (hDPSCs) in E8 medium demonstrated greater proliferation, pluripotency, migration ability and less apoptosis. hDPSCs could be successfully induced to the adipogenic, osteogenic, neurogenic, and chondrogenic lineages in E8 group. Real-time polymerase chain reaction indicated that the expression of PPAR-γ, RUNX2, OCN and MAP-2 was higher in E8 group. Conclusions Compared with serum-containing medium, E8 medium exhitibed higher ability in maintaining the cell proliferation, pluripotency, migration, and stability. This new serum-free culture environment might be applicable for hDSC culture in the future.

Abstract Background To investigate the incidence of radiation esophagitis (RE) and tumor local control using esophagus sparing technique in locally advanced non-small cell lung cancer (LANSCLC) treated by simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) and concurrent chemotherapy. Methods Eighty-seven patients with stage IIIA/B NSCLC who received definitive SIB-IMRT and concurrent chemotherapy had been divided into two groups: 1.with esophagus sparing technique; 2.without esophagus sparing technique. Chi-square test was performed to compare sex, clinical stage, histology, concurrent chemotherapy, RE and nutrition status between two groups. T-test was used to compare the dosimetric parameters. Overall survival (OS) and loco-regional failure free survival (LRFS) were calculated by the Kaplan–Meier method and compared by a log-rank test. Results There were 44 patients in the esophagus sparing group and 43 in the non-sparing group. The incidence of severe RE (Grade 3) was significantly lower in patients with esophagus sparing technique (p = 0.002). Patients in esophagus sparing group had better nutrition status (p = 0.045). With a median follow-up of 18 months (range 1–51 months), the 1-year, 2-year and 3-year OS of all the patients was 86.6, 65.4 and 43.7%. The 1-year, 2-year LRFS was 78.4, 65.9%. OS time (p = 0.301) and LRFS (p = 0.871) was comparable between two groups. Conclusions Esophagus-sparing technique is an effective and essential method to limit RE in LANSCLC treated by SIB-IMRT and concurrent chemotherapy without compromising local control.

Floor litter can reduce the amount of water reaching the soil layer through rainfall interception. The rainfall interception capacity of floor litter varies with the physical features of the litter and rainfall characteristics. This study aimed to define the maximum and minimum interception storages (Cmx, Cmn) of litter layers using rainfall simulation experiments, and examine the effects of litter type and rainfall characteristics on rainfall retention and drainage processes that occur in the litter layer. Different types of needle-leaf and broadleaf litters were used: Abies holophylla, Pinus strobus, Pinus rigida, Quercus acutissima, Quercus variabilis, and Sorbus alnifolia. Our results indicate a wide variation in interception storage values of needle leaf litter, regardless of the rainfall intensity and duration. The A. holophylla needle-leaf litter showed the highest Cmx and Cmn values owing to its short length and low porosity. Conversely, the lowest interception storage values were determined for the P. strobus needle leaf litter. No significant differences in interception storage were established for the broadleaf litter. Moreover, except for A. holophylla litter, the broadleaf litter retained more water than the needle leaf litter. An increase in the intensity or duration of rainfall events leads to an increase in the water retention storage of litter. However, these factors do not influence the litter’s drainage capacity, which depends primarily on the force of gravity.

Marrow adipose tissue (MAT) is a unique fat depot in the bone marrow and exhibits close relationship with hematopoiesis and bone homeostasis. MAT is distinct from peripheral adipose tissue in respect of its heterogeneous origin, site-specific distribution, and complex and perplexing function. Though MAT is indicated to function in hematopoiesis, skeletal remodeling, and energy metabolism, its explicit characterization still requires further research. In this review, we highlight recent advancement made in MAT regarding the origin and distribution of MAT, the local interaction with bone homeostasis and hematopoietic niche, the systemic endocrine regulation of metabolism, and MAT-based strategies to enhance bone formation.

To investigate the effects of consolidation radiation in patients with stage IE-IIE, non-bulky primary gastric diffuse large B-cell lymphoma (DLBCL).A cohort consisted of 71 consecutive patients with stage IE-IIE, non-bulky primary gastric DLBCL was retrospectively analyzed. All of them had been in complete remission after receiving at least four cycles of chemotherapy, containing rituximab or not. Consolidation radiation was delivered thereafter in 28 patients while other 43 received clinical observation only. Locoregional relapse-free survival (LRFS), disease-free survival (DFS), overall survival (OS) and distant metastasis-free survival (DMFS) were compared between patients with or without radiotherapy.The 10-year LRFS, DFS, OS and DMFS were 100% and 81.4% (p = 0.028), 91.7% and 77.1% (p = 0.14), 91.7% and 77.8% (p = 0.67), 91.7% and 78.0% (p = 0.42) for patients with or without radiotherapy.Radiotherapy is associated with improved locoregional control of patients with early stage primary gastric DLBCL, who have achieved complete remission following at least four cycles of chemotherapy.

TiO2 was intensively researched especially for photocatalystic applications. The nitrogen-doped TiO2 films prepared by pulsed laser deposition (PLD) method were reviewed, and some recent new experimental results were also presented in this paper. A new optical transmission method for evaluating the photocatalystic activity was presented. The main results are (1) PLD method is versatile for preparing oxide material or complex component films with excellent controllability and high reproducibility. (2) Anatase nitrogen-doped TiO2 films were prepared at room temperature, 200°C, and 400°C by PLD method using novel ceramic target of mixture of TiN and TiO2. UV/Vis spectra, AFM, Raman spectra, and photocatalystic activity for decomposition of methyl orange (MO) tests showed that visible light response was improved at higher temperature. (3) The automatic, continuous optical transmission autorecorder method is suitable for detecting the photodecomposition dynamic process of organic compound.

Mutations modification enzymes including the tRNA N7-methylguanosine (m7G) methyltransferase complex component WDR4 were frequently found in patients with neural disorders, while the pathogenic mechanism and therapeutic intervention strategies are poorly explored. In this study, we revealed that patient-derived WDR4 mutation leads to temporal and cell-type-specific neural degeneration, and directly causes neural developmental disorders in mice. Mechanistically, WDR4 point mutation disrupts the interaction between WDR4 and METTL1 and accelerates METTL1 protein degradation. We further uncovered that impaired tRNA m7G modification caused by Wdr4 mutation decreases the mRNA translation of genes involved in mTOR pathway, leading to elevated endoplasmic reticulum stress markers, and increases neural cell apoptosis. Importantly, treatment with stress-attenuating drug Tauroursodeoxycholate (TUDCA) significantly decreases neural cell death and improves neural functions of the Wdr4 mutated mice. Moreover, adeno-associated virus mediated transduction of wild-type WDR4 restores METTL1 protein level and tRNA m7G modification in the mouse brain, and achieves long-lasting therapeutic effect in Wdr4 mutated mice. Most importantly, we further demonstrated that both TUDCA treatment and WDR4 restoration significantly improve the survival and functions of human iPSCs-derived neuron stem cells that harbor the patient's WDR4 mutation. Overall, our study uncovers molecular insights underlying WDR4 mutation in the pathogenesis of neural diseases and develops two promising therapeutic strategies for treatment of neural diseases caused by impaired tRNA modifications. [ABSTRACT FROM AUTHOR]

Translation of mRNA to protein is tightly regulated by transfer RNAs (tRNAs), which are subject to various chemical modifications that maintain structure, stability, and function. Deficiency of tRNA N7 -methylguanosine (m7 G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report that the loss of m7 G rewires cellular metabolism, leading to the pathogenesis of primordial dwarfism. Conditional deletion of the catalytic enzyme Mettl1 or missense mutation of the scaffold protein Wdr4 severely impaired endochondral bone formation and bone mass accrual. Mechanistically, Mettl1 knockout decreased abundance of m7 G-modified tRNAs and inhibited translation of mRNAs relating to cytoskeleton and Rho GTPase signaling. Meanwhile, Mettl1 knockout enhanced cellular energy metabolism despite incompetent proliferation and osteogenic commitment. Further exploration revealed that impairment of Rho GTPase signaling upregulated the level of branched-chain amino acid transaminase 1 (BCAT1) that rewired cell metabolism and restricted intracellular α-ketoglutarate (αKG). Supplementation of αKG ameliorated the skeletal defect of Mettl1-deficient mice. In addition to the selective translation of metabolism-related mRNAs, we further revealed that Mettl1 knockout globally regulated translation via integrated stress response (ISR) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Restoring translation by targeting either ISR or mTORC1 aggravated bone defects of Mettl1-deficient mice. Overall, our study unveils a critical role of m7 G tRNA modification in bone development by regulation of cellular metabolism and indicates suspension of translation initiation as a quality control mechanism in response to tRNA dysregulation. [ABSTRACT FROM AUTHOR]

The roof-caving step scale goaf behind the working face is sensitive to the region's spontaneous combustion and gas concentration distribution, including many rock block cracks and holes. A severe deviation from the dynamics of fluids in porous media by representative element volume (REV), leading to the results of Computational Fluid Dynamics (CFD) simulation, has a significant error. A heterogeneous two-dimensional pore network model was established to simulate the goaf flow accurately. The network was first created using the simple cubic lattice in the OpenPNM package, and the spatial distribution of the "O-ring" bulking factor was mapped to the network. The bulking factor and Weibull distribution were combined to produce the size distribution of the pore and throat in the network. The constructed pore network model was performed with single-phase flow simulations. The study determined the pore structure parameters of the pore network through the goaf's risked falling characteristics and described the flow field's distribution characteristics in the goaf. The permeability coefficient increases as pore diameter, throat diameter, pore volume and throat volume increase and increases as throat length decreases. The correlation between throat volume and permeability coefficient is the highest, which indicates that the whole throat is the main control factor governing the air transport capacity in the goaf. These results may provide some guidelines for controlling thermodynamic disasters in the goaf. [ABSTRACT FROM AUTHOR]