Search

Abstract PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4CRBN, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes.

Fractures and bone nonunion commonly require surgical intervention. Serious outcomes of non‐healing in the late stages of fracture place a significant financial burden on society and families. Bone nonunion occurs when a fracture stops healing, for many reasons, and leads to a variety of bad outcomes. Numerous factors, including biomechanics and immunology, are involved in the complicated mechanisms of bone nonunion. The immune‐inflammatory response plays a significant part in the emergence of bone nonunion, and the occurrence, control, and remission of inflammation in the bone healing process have a significant influence on the ultimate success of bone tissue repair. In the bone microenvironment, immune cells and associated cytokines control bone repair, which is significantly influenced by macrophages, T cells, and fibroblast growth factor. To limit acute inflammation and balance osteogenesis and osteoblastogenesis for tissue repair and regeneration, immune cells and various cytokines in the local microenvironment must be precisely regulated. As a bad complication of late‐stage fractures, bone nonunion has a significant effect on patients’ quality of life and socioeconomic development. Therefore, in‐depth research on its pathogenesis and treatment methods has important clinical value. To provide more precise, focused therapeutic options for the treatment of bone nonunion, we discuss the regulatory roles of the key immune cells engaged in bone healing within the microenvironment during bone healing and their effect on osteogenesis.

Abstract Plasmonic materials can generate strong electromagnetic fields to boost the Raman scattering of surrounding molecules, known as surface-enhanced Raman scattering. However, these electromagnetic fields are heterogeneous, with only molecules located at the ‘hotspots’, which account for ≈ 1% of the surface area, experiencing efficient enhancement. Herein, we propose patterned plasmonic trimers, consisting of a pair of plasmonic dimers at the bilateral sides and a trap particle positioned in between, to address this challenge. The trimer configuration selectively directs probe molecules to the central traps where ‘hotspots’ are located through chemical affinity, ensuring a precise spatial overlap between the probes and the location of maximum field enhancement. We investigate the Raman enhancement of the Au@Al2O3-Au-Au@Al2O3 trimers, achieving a detection limit of 10−14 M of 4-methylbenzenethiol, 4-mercaptopyridine, and 4-aminothiophenol. Moreover, single-molecule SERS sensitivity is demonstrated by a bi-analyte method. Benefiting from this sensitivity, our approach is employed for the early detection of lung tumors using fresh tissues. Our findings suggest that this approach is sensitive to adenocarcinoma but not to squamous carcinoma or benign cases, offering insights into the differentiation between lung tumor subtypes.

Samantha Lo,1 Ebrahim Mahmoudi,2 Looi Qi Hao,1,3 Fatimah Mohd Nor,4 Mh Busra Fauzi1,5 1Centre for Tissue Engineering Centre and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, 56000, Malaysia; 2Department of Chemical and Process Engineering, Faculty of Engineering and Built Environment, Universiti Kebangsaan Malaysia, Bangi, Selangor Darul Ehsan, 43600, Malaysia; 3My Cytohealth Sdn. Bhd, Kuala Lumpur, 56000, Malaysia; 4Plastic Surgery Department, Kumpulan Perubatan Johor Ampang Puteri Specialist Hospital, Kuala Lumpur, 68000, Malaysia; 5Advance Bioactive Materials-Cells (Adv-BioMaC) UKM Research Group, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor, MalaysiaCorrespondence: Mh Busra Fauzi, Email fauzibusra@ukm.edu.myObjective: Collagen, a widely used natural biomaterial polymer in skin tissue engineering, can be innovatively processed into nanocollagen through cryogenic milling to potentially enhance skin tissue healing. Although various methods for fabricating nanocollagen have been documented, there is no existing study on the fabrication of nanocollagen via cryogenic milling, specifically employing graphene oxide as separators to prevent agglomeration.Methods: In this study, three research groups were created using cryogenic milling: pure nanocollagen (Pure NC), nanocollagen with 0.005% graphene oxide (NC + 0.005% GO), and nanocollagen with 0.01% graphene oxide (NC+0.01% GO). Characterization analyses included transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, x-ray diffraction (XRD), zeta potential (ZP), and polydispersity index (PDI).Results: TEM and SEM analysis revealed that nanocollagen groups alone exhibited particle sizes of less than 100 nm. FTIR spectroscopic investigations indicated the presence of amide A, B, and I, II, and III (1800 to 800 cm− 1) in all nanocollagen study groups, with the characteristic C-O-C stretching suggesting the incorporation of graphene oxide (GO). XRD data exhibited broadening of the major peak as the proportion of GO increased from pure NC to the nanocollagen groups with GO. Zeta potential measurements indicated electrostatic attraction of the samples to negatively charged surfaces, accompanied by sample instability. PDI results depicted size diameters ranging from 800 to 1800 nm, indicating strong polydispersity with multiple size populations.Conclusion: This research demonstrated that collagen can be successfully fabricated into nanoparticles with sizes smaller than 100 nm.Keywords: nanocollagen, cryogenic milling, graphene oxide

Osteoarthritis (OA) is a prevalent joint disease worldwide that significantly impacts the quality of life of individuals, particularly those in middle-aged and elderly populations. OA was initially considered as non-inflammatory arthritis, but recent studies have identified a substantial number of immune responses in OA, leading to the recognition of inflammation as a key factor in its pathogenesis. An increasing number of studies have found that mast cell (MC) and MC-secreted inflammatory mediators and cytokines are notably increased in the synovial fluid of OA patients, indicating a potential association between MCs and the onset and progression of synovial inflammation. The present review aims to summarize the significance and mechanism of MCs in the pathogenesis of OA. Meanwhile, we also discuss the clinical potential of using MCs as therapeutic target for OA therapy. Modulating the activities of MCs or the mediators of MCs in the synovial fluid inflammatory microenvironment will be promising new options for the treatment of OA.

Background: Malaysians, known for their diverse ethnicities, exhibit unique aesthetic features influenced by cultural nuances. Research indicates that factors including ethnicity, culture, and personal experiences affect how people perceive beauty. Objective: This study aims to address the lack of data on the preferred facial aesthetics among women from different ethnic groups in Malaysia. Methods: A questionnaire was administered to 290 Malaysian women, covering multiple regions and dimensions of facial aesthetics, including facial shape, forehead height and slope, cheekbone height, chin shape, eye region features (eyebrow shape, eyelid creases, and inner eye fold), nose (nose bridge shape, nasolabial angle, and nose width-length ratio), and lip thickness. Edited images of Asian models were used as references for facial aesthetic criteria in this study. Results: The survey revealed that the majority of participants were of Malay ethnicity (71.0%) and employed in the private sector (39.3%). The average age of the participants was 31.6±9.2 years, and most of them (66.9%) have not undergone aesthetic procedures before. Furthermore, a significant association was observed between ethnicity and women’s facial aesthetic preferences for facial shape and nasal width-length ratio (p1. However, no significant association was found between ethnicity and other facial aesthetic criteria assessed in the study. Conclusion: This study identified that Malaysian women’s preferences for facial shape and nasal width-to-length ratio are associated with ethnicity. These findings can serve as a valuable reference for aesthetic practitioners, emphasizing the importance of preservation and enhancement of unique ethnic features, customized according to the suitability of each ethnicity, rather than conforming to prevailing beauty standards.

Ethylene vinyl acetate (EVA) foam is widely used as midsole material in athletic footwear due to its lightweight and cushioning properties. However, EVA foam suffers from low mechanical strength, abrasion resistance, and fatigue resistance. Reinforcing EVA foam with graphene nanoplatelets is a promising approach to improving its mechanical performance for footwear applications. This study investigated the effect of 0.1–1 wt% graphene nanoplatelets on the properties of EVA foam composites relevant to midsole performance. The results showed that 0.1–0.2 wt% graphene provided optimal reinforcement, exhibiting 33–40% higher impact energy absorption, 50–60% lower compressive stiffness, 30% higher flexural stiffness, and up to 40% lower abrasion volume loss. Under simulated use conditions, the composites demonstrated higher energy return and fatigue resistance. The graphene nanoplatelets acted as effective reinforcements within the EVA foam by improving stress transfer, inhibiting crack propagation, and shielding the foam surface. The findings indicate that reinforcing EVA foam with small amounts of graphene nanoplatelets can develop midsole materials with enhanced mechanical performance for athletic footwear.

The rock burst frequently occurs in the roadways with top coal, and the roof disasters are particularly severe under dynamic stress in China. In order to explore the classification and instability mechanisms of anchoring structures in the roadways with top-coal, analog simulation experiments, theoretical analysis, and data statistics were used under the engineering background of the large-area rock burst roof failure in the Working Face 301 of a mine in Shaanxi Province, China. The dynamic load response characteristics of the stress, displacement, and surface acceleration of the surrounding rock in the roadways with top coal were analyzed. The classification characteristics of the roof anchoring structure under the influence of top coal thickness and cables were studied. The stress response mechanism of the roadways with top coal under elastic waves was explored, and the instability mechanism of the anchoring “beam arch” structure was proposed. The rock burst resistance of the air-return roadway in the Working Face 301 was evaluated, and the corresponding optimization schemes for the “beam-arch” composite structure were proposed. The results show that ① the monitoring data of stress and displacement of the surrounding rock in the roadways with top coal under dynamic stress verify the existence of internal and external beam or arch anchoring structures in the roof. Due to the increase in the thickness of top coal, there is a transition from “beam” to “arch” in the anchoring structure of the inner layer of the roof; ② based on the relative relationship between the thickness of the top coal and the cables, the roof anchoring structure is divided into “superimposed-beam and arch” for thin top coal, “composite-beam and arch” for thick top coal, and “combined arch” for extra thick top coal. A critical thickness index for the transformation of thick coal beams from “beam” to “arch” is established; ③ the instability mechanism of the beam structure and the arch structure is that they fail after reaching their tensile and shear strength limits under dynamic and static stress, respectively. The amplification effect of the “beam-arch” composite structure on the load stress is significantly affected by its size; ④ the bearing strength of the inner arch in the "combined arch" structure is relatively low. Increasing the length of cables can increase the thickness of the inner arch, and the corresponding “combined arch” structure’s bearing strength increases significantly, which is consistent with the evaluation results of the rock burst resistance.

Objective: To investigate the effect of electroacupuncture (EA) on retinal function in guinea pigs with negative lens-induced myopia (LIM) by inhibiting the RhoA/ROCK2 signaling pathway. Methods: Guinea pigs were randomly divided into normal control (NC) group, LIM group, EA group, SHAM acupoint (SHAM) group, and electro-acupuncture + ROCK pathway inhibitor Y27632 (EA + Y27632) group. The refraction, axial length, retinal blood flow density, choroidal vascular index, retinal physiological function, the contents of total antioxidant capacity (T-AOC), catalase (CAT), glutathione (GSH), superoxide dismutase (SOD) and malondialdehyde (MDA) of each group were determined. The changes in retinal tissue structure were observed by hematoxylin and eosin (H&E) staining, and the expression of the RhoA/ROCK2 signaling pathway-related molecules in the retina was measured by real-time quantitative polymerase chain reaction (qPCR) and Western blot. Results: Myopic refraction, AL, and MDA content in the LIM and SHAM groups were significantly increased, retinal blood flow density and CVI, SOD, GSH, CAT, T-AOC content were decreased. After EA intervention, myopic refraction, AL, and MDA content decreased, retinal blood flow density and CVI, SOD, GSH, CAT, T-AOC content were increased. H&E staining showed that the thickness of the guinea pig retina, the thickness of the inner and outer layers of the nucleus, and the number of cells were significantly increased after EA intervention. qPCR and western blot analyses showed that the expression of RhoA、ROCK2、MLC、CollagenⅠ、MMP-2、TIMP-2 and α-SMA were elevated in the LIM and SHAM group than those in the NC group. Compared with the LIM group, the expression of EA group was significantly decreased. Conclusions: Electroacupuncture can improve retinal function by improving retinal blood flow, reducing retinal oxidative damage, inhibiting RhoA/ROCK2 signaling pathway and controlling extracellular matrix remodeling, thus delaying the occurrence and development of myopia.

Abstract Human papillomavirus (HPV) is a significant contributor to the global cancer burden, and its carcinogenic activity is facilitated in part by the HPV early protein 6 (E6), which interacts with the E3-ligase E6AP, also known as UBE3A, to promote degradation of the tumor suppressor, p53. In this study, we present a single-particle cryoEM structure of the full-length E6AP protein in complex with HPV16 E6 (16E6) and p53, determined at a resolution of ~3.3 Å. Our structure reveals extensive protein-protein interactions between 16E6 and E6AP, explaining their picomolar binding affinity. These findings shed light on the molecular basis of the ternary complex, which has been pursued as a potential therapeutic target for HPV-driven cervical, anal, and oropharyngeal cancers over the last two decades. Understanding the structural and mechanistic underpinnings of this complex is crucial for developing effective therapies to combat HPV-induced cancers. Our findings may help to explain why previous attempts to disrupt this complex have failed to generate therapeutic modalities and suggest that current strategies should be reevaluated.

Remote sensing image classification is pivotal in applications ranging from environmental monitoring to urban planning. However, the scarcity of labeled data in target domains often impedes the generalization of models trained on source domains. To address this challenge, we propose Semantic-Aware Contrastive Adaptation (SACA), a novel framework that leverages contrastive learning to construct a discriminative and class-balanced embedding space. SACA emphasizes semantic details by contrasting samples with category centroids and other samples in a distribution-aware manner. It first identifies distinctive features using category centroids as semantic anchors, then expands the sample scope by incorporating statistical information from the labeled source domain. This approach enables the embedding space to better reflect the true distribution of each semantic class. Our rigorous theoretical analysis reveals that SACA implicitly considers an infinite number of similar and dissimilar sample pairs, leading to a tighter upper bound on the contrastive loss compared to existing methods. This not only improves computational efficiency but also enhances the robustness of learned representations. To demonstrate SACA’s effectiveness, we conduct extensive experiments on three challenging remote sensing datasets: Hyperion, National Center for Airborne Laser Mapping, and Worldview-2. The results show that SACA significantly boosts the performance of self-training methods, outperforming state-of-the-art approaches by a large margin. In-depth ablation studies provide insights into the contribution of each SACA component. SACA represents a significant step towards bridging the domain gap in remote sensing image classification. By leveraging semantic-aware contrastive learning, it enables models to capture consistent semantic concepts across domains, enhancing transferability and robustness. This work opens new avenues for research in domain adaptation and has the potential to benefit a wide range of real-world applications, from precision agriculture to disaster response.

This study examines the frequency attenuation characteristics of elastic waves in marble, granite, and red sandstone through laboratory tests and numerical simulations based on ABAQUS software on eight rock samples. The correlation between the distance of the decay of the peak frequency and the petrophysical and mechanical parameters is also analyzed. The results show that elastic waves undergo stepwise attenuation of their peak frequency during laboratory attenuation tests. This finding was confirmed by numerical simulations. As elastic waves propagate through a rock medium, the amplitude of the high-frequency peak area near the excitation frequency decreases rapidly, while the proportion of low-frequency signals increases. As the propagation continues, the signal spectrum is dominated by low-frequency components, resulting in a stepwise attenuation of the peak frequency. It has been observed that the step decay distance of the peak frequency of elastic waves varies with the degree of particle bonding, which can be used to characterize the attenuation properties of elastic waves in a medium.

Abstract Pregnancy-Associated Plasma Protein A isoforms, PAPP-A and PAPP-A2, are metalloproteases that cleave insulin-like growth factor binding proteins (IGFBPs) to modulate insulin-like growth factor signaling. The structures of homodimeric PAPP-A in complex with IGFBP5 anchor peptide, and inhibitor proteins STC2 and proMBP have been recently reported. Here, we present the single-particle cryo-EM structure of the monomeric, N-terminal LG, MP, and the M1 domains (with the exception of LNR1/2) of human PAPP-A2 to 3.13 Å resolution. Our structure together with functional studies provides insight into a previously reported patient mutation that inactivates PAPP-A2 in a distal region of the protein. Using a combinational approach, we suggest that PAPP-A2 recognizes IGFBP5 in a similar manner as PAPP-A and show that PAPP-A2 cleaves IGFBP5 less efficiently due to differences in the M2 domain. Overall, our studies characterize the cleavage mechanism of IGFBP5 by PAPP-A2 and shed light onto key differences with its paralog PAPP-A.

Abstract Background Lower extremity lymphedema (LEL) staging is mainly assessed by systems that solely depend on physical examinations and lack quantitative assessment based on modern imaging. Objective To explore the value of MRI-based asymmetric volume measurements in the clinical staging of primary LEL. Methods 92 patients with unilateral primary LEL underwent MRI examinations to determine the volume of the mid-calf (Vcl) calculated using the clinical dermatome method as well as the total volume (Vmri), musculoskeletal volume (VM), and subcutaneous volume (VS) volume of the middle calves. The difference between Vmri (DVmri) and VS (DVS) of the affected and unaffected calves was obtained and defined as the asymmetric volume difference. Meanwhile, the volume of the mid-calf (Vcl) and the difference in volume (DVcl) were calculated using the clinical circumferential method. The relationship between the asymmetric volume difference and clinical staging was then evaluated. Interobserver consistency was assessed through the intraclass correlation coefficient (ICC). Volume comparisons between the three groups were performed using the one-way analysis of variance (ANOVA) or the Kruskal-Wallis test. Spearman’s correlation was used to assess volume and clinical stage correlation. The receiver operating characteristic (ROC) curve was used to evaluate the value of asymmetric volume difference for clinical staging. Results The asymmetric volume difference was statistically significant in stage I compared to stages II and III (p

Objective: This study aimed to explore the clinical value of thin slice computed tomography (CT) plain scan in the analysis of CT features of vascular abnormalities associated with coronavirus disease 2019 (COVID-19). Materials and methods: A total of 73 patients with COVID-19 confirmed by the Department of Infection of Beijing Shijitan Hospital from December 5, 2022 to December 17, 2022, were included in the study. Chest thin CT plain scan images showed that the lesions involved blood vessels were retrospectively collected. All patients had complete chest thin CT plain scan and relatively complete clinical data. According to age (>60 and ≤60 years), the patients were divided into the young and elderly groups. The chest imaging manifestations of all patients were observed and statistically analyzed between different age groups. Results: Among the 73 patients with COVID-19, the imaging indexes with statistical significance between the young and elderly groups were as follows: the distribution of the lesion around the central blood vessel, size of the lesion (10~30 mm), size of the lesion (>30 mm), percentage of the lesion to the volume of the lung lobe (≤30), percentage of the lesion to the volume of the lung lobe (>50) (white lung), shape of the lesion was large, the dominant type of the lesion was acinar, vascular distortion, vascular margin fuzzy, and tree-bud sign thick fiber rope. Conclusion: (1) Chest thin-slice CT plain scan can identify the number, location, involved location, scope, vascular abnormality, and pathological type of COVID-19-related vascular abnormality, which has certain significance for the qualitative and differential diagnosis of COVID-19 vascular abnormality. (2) The chest thin CT plain scan is of great significance for finding elderly patients with COVID-19 involving blood vessels. (3) COVID-19-related "blood vessel thickening" can be caused by either the diameter of the blood vessel itself or the inflammatory edema of the perivascular interstitium.

Objective: To explore the imaging characteristics of patients with novel coronavirus pneumonia (COVID-19) combined with different underlying diseases. Materials and methods: COVID-19 was diagnosed in 153 patients at Beijing Shijitan Hospital, Capital Medical University, from November 16, 2022 to December 16, 2022, and data were retrospectively collected. All patients underwent chest CT scan from 1 to 14 days after onset and were divided into two groups based on the presence or absence of underlying diseases. Forty-three patients had underlying diseases, and 110 patients had none. We compared the differences between the two groups. Result: The comparison between the two groups showed statistically significant differences in age, cough, bilateral lung distribution, diffuse distribution, honeycomb-like changes in the lungs, patchy distribution, large patchy distribution, band distribution, crazy-paving sign, air bronchogram sign, traction bronchiectasis, and pleural effusion. Conclusion: Fever and cough are the most common clinical symptoms in patients with COVID-19. Chest CT showed multiple lesions in both lungs. The most common types of lesions were thickening of bronchovascular bundle and GGO. Patients with underlying diseases had more honeycomb-like changes, crazy-paving sign, air bronchogram sign, traction bronchiectasis, and pleural effusion than those without underlying diseases. Chest thin-slice CT scan provides a key reference for the early detection and diagnosis of the disease.

Objective: To investigate the clinical value of thin-section chest computed tomography (CT) in the typing of coronavirus disease 2019 (COVID-19). Methods: A retrospective analysis was performed on 134 patients diagnosed with COVID-19 in our hospital’s Department of Infectious Diseases from December 20, 2022, to December 31, 2022. All patients underwent thin-section chest CT scan with complete clinical data. According to clinical classification, patients were divided into the non-severe and severe groups. Clinical data and imaging features of the two groups were compared and analyzed, and statistical analysis was conducted. Results: There was a statistically significant difference with respect to diabetes mellitus between the two groups, and the incidence of diabetes mellitus in the severe group (45.8%) was higher than that in the non-severe group (25.5%); There were no significant differences in sex, age, average course of disease, and clinical symptoms between the two groups; There were significant differences in the number of lesions, symmetrical distribution, predominant peripheral distribution, diffuse distribution, blurred edge, morphology of large flake and band, vascular bundle thickening, paving stone sign, arcade sign, and fried egg sign between the two groups, the number of lesions >10, diffuse distribution, morphology of large flake and band, vascular bundle thickening, paving stone sign, and arcade sign were more common in the severe group than in the non-severe group, while predominant peripheral distribution, blurred edge, and fried egg sign were more common in the non-severe group than in the severe group. Conclusions: Thin-section chest CT scan can identify the abnormal imaging manifestations of the lung in patients with COVID-19 and evaluate the number, distribution range, and morphological characteristics of the lesions. Combined background diseases, number, distribution characteristics, blurred edge, large flake and band morphology, vascular bundle thickening, paving stone sign, arcade sign, and fried egg sign can effectively indicate the classification of patients with COVID-19. This can provide imaging evidence for the diagnosis and treatment of COVID-19.

Objective: To retrospectively investigate the clinical manifestations and imaging features of heavy novel coronavirus pneumonia (NCP). Materials and methods: Fifty-two patients with positive chest computed tomography (CT) manifestations and a confirmed diagnosis of COVID-19 in the Infection Unit from November 2022 to January 2023 were included in our study. All patients underwent chest thin-section CT examination and had more complete clinical data from 1 to 14 days after onset. Patients were divided into two groups based on the time interval between onset and CT examination (

Objective: To retrospectively analyze the clinical value of chest plain computed tomography (CT) for the initial diagnosis and dynamic changes of early novel coronavirus pneumonia (2019 novel Coronavirus, 2019-nCoV, referred to as new coronavirus pneumonia). Materials and methods: Fifty-two patients with confirmed new coronavirus pneumonia diagnoses and positive chest CT manifestations from November 12, 2022, to January 6, 2023, in the infection department of our hospital were collected. All patients had two chest thin-section CT examinations within 1 month from the onset of the disease and had complete clinical data. Patients were divided into two groups according to their age (≤60 years and >60 years), and the differences in CT performance characteristics between the two groups were compared. The CT review of all patients was also observed. Results: Among the 52 patients, 52 involved the lungs (100%), 24 involved the airways (46.2%), and 21 involved the bloodways (40.4%). Comparison between age groups showed statistically significant differences in lesion location (single/both lungs, airways), tree-in-bud pattern, large morphology, fibrous striae, interstitial changes, and pleural thickening. Among the 52 patients, review CT showed lesion progression in 18 cases (34.6%), which showed an increase in extent in 18 cases (100%), aggravation of solid changes in 7 (38.9), aggravation of GGO in 14 (77.8%), and increase in pleural effusion in 6 (33.3%); review CT showed lesion remission in 18 cases (34.6%), which showed a decrease in extent in 31 (91.2%), 6 (17.6%) with reduced density, 12 (35.3%) with fibrosis, 2 (5.9%) with complete resorption, and 4 (11.8) with reduced pleural effusion. Conclusion: The CT scan of the chest in neocoronary pneumonia has certain characteristics, and for the first time, it mostly showed multiple patchy signs or large patchy ground glass opacity (GGO) with mainly subpleural distribution in the periphery of both lungs, mostly accompanied by "halo sign," "anti-halo sign," and "paving stone sign." The lung is more susceptible to change following treatment. After treatment, the lung lesions change rapidly, with most patients showing absorption and shrinkage, density fading, or fibrosis and a few patients showing increased extent, solidity or aggravation of GGO, and pleural effusion. Chest plain CT helps clinicians in the early diagnosis and dynamic evaluation of neocoronary pneumonia.

Abstract Background Relapsing-remitting multiple sclerosis (RRMS) is the most common phenotype of multiple sclerosis (MS), and its active stage is characterized by active T2 lesions with or without gadolinium (Gd) enhancement on magnetic resonance imaging (MRI). Natalizumab is indicated as monotherapy in adults with active RRMS in Japan. The main objective of this study was to investigate the long-term effect of natalizumab on disease progression in Japanese patients with RRMS using MRI data. Methods This retrospective, chart review study was conducted at a single center in Japan. The main study outcome was the yearly proportion of patients with active T2-weighted image lesions detected with or without Gd enhancement on brain MRI (incidence rate) after treatment initiation for up to 5 years. Additional endpoints included annual relapse rate (ARR) and expanded disability status scale (EDSS) score. Results This study included data from 85 patients with RRMS who had received natalizumab for ≥ 1 year; of these, 65 (76.5%) were female and the mean ± standard deviation (SD) age at baseline was 37.5 ± 10.0 years. The incidence rate of active T2 lesions was 52.9% (45/85) in the year prior to natalizumab treatment (Year − 1), which decreased to 2.4% and 1.6% in Year 0.5–1.5 and Year 1.5–2.5, respectively. No active T2 lesions were detected in Year 2.5–5.5 in patients who continued natalizumab treatment. EDSS score was stable, improved, and worsened in 61.8%, 26.3%, and 11.8% of patients, respectively. The median (range) EDSS score was 2.0 (0.0–7.0) at baseline (n = 85) and remained within a similar range (median score between 1.0 and 2.25 during Years 1–5). ARR decreased from 1.12 relapses per year at baseline to 0.12 relapses per year during Year 1 and remained below 0.15 relapses per year up to Year 5. Conclusion The results of this first long-term study evaluating the effect of natalizumab on MRI activity and clinical outcomes in Japanese patients with RRMS suggest that natalizumab markedly reduced disease activity and maintained effectiveness over several years.

Objective: To compare and analyze the clinical and chest computed tomography (CT) imaging features of COVID-19 patients with different disease courses. Methods: A retrospective analysis was performed for 161 cases with confirmed COVID-19 and positive chest CT lung infections from December 2022 to January 2023 at the fever clinic of Beijing Shijitan Hospital affiliated with Capital Medical University. The patients were divided into two groups based on the time of CT examination:

Objective: This study aimed to investigate the correlation between the neutrophil-to-lymphocyte ratio (NLR) and chest high-resolution computed tomography (HRCT) findings of coronavirus disease 2019 (COVID-19). Materials and Methods: NLR and chest HRCT findings of 132 patients diagnosed with COVID-19 in the department of infectious diseases of Beijing Shijitan Hospital Capital Medical University from December 1, 2022 to February 1, 2023 were retrospectively analyzed. The patients were divided into two groups with NLR cut-off value of 3.0, and their HRCT characteristics and imaging manifestation patterns were analyzed. For the measurement data of normal distribution, the t-test of continuous variables was used between the groups. The data of non-normal distribution are expressed as median and quartile and compared using Mann-Whitney U test. The counting data are expressed as frequency, and the chi-squared or Fisher's exact test was used for comparison between the groups. P10 and the proportion of lesions >50% were higher in the high NLR group than that in the low NLR group. The high NLR group was prone to mixed density shadow, crazy-paving pattern, mosaic sign, anti-halo sign, subpleural black belt, arcade-like sign than that in the low NLR group. The high NLR group was most likely to have nonspecific interstitial pneumonia-like, organizing pneumonia-like, and diffuse alveolar damage-like patterns than that in the low NLR group. Conclusion: Different NLRs have different manifestations of COVID-19 chest HRCT. The high NLR group is more prone to mixed density shadow, crazy-paving pattern, mosaic sign, anti-halo sign, subpleural black belt, and arcade-like sign, as well as most likely to have radiologic patterns of nonspecific interstitial pneumonia, organizing pneumonia, diffuse alveolar damage.

AbstractWith the increase in coal mining depth, many rock bursts triggered by fold structures have been observed, but the disaster mechanism is not clear. This research aims at investigating the influence of upright fold structure(UFS) on rock burst mechanisms. The mechanical model and numerical model of the UFS are constructed, and the mining stress evolution law and rock burst mechanism of working face in a UFS area are studied by utilizing engineering practice. The research shows that the occurrence of rock burst disasters in the fold structure area has obvious regional characteristics. The horizontal and vertical stress of the UFS in the horizontal distribution is similar to the periodic variation characteristics of the sine (cosine) curve. The stress state of the UFS area is divided into five areas. The horizontal and vertical stress concentration factors increase first and then decrease with the working face gradually approaching and away from the upright fold syncline axis. A roadway impact risk index I0 is proposed to determine whether the roadway is damaged, and the mechanism of inducing ground pressure during mining in UFS areas of deep mines is expounded. The control plan effectively reduces the stress levels of surrounding rock in working faces.

Abstract Ensuring a more equitable distribution of vaccines worldwide is an effective strategy to control global pandemics and support economic recovery. We analyze the socioeconomic effects - defined as health gains, lockdown-easing effect, and supply-chain rebuilding benefit - of a set of idealized COVID-19 vaccine distribution scenarios. We find that an equitable vaccine distribution across the world would increase global economic benefits by 11.7% ($950 billion per year), compared to a scenario focusing on vaccinating the entire population within vaccine-producing countries first and then distributing vaccines to non-vaccine-producing countries. With limited doses among low-income countries, prioritizing the elderly who are at high risk of dying, together with the key front-line workforce who are at high risk of exposure is projected to be economically beneficial (e.g., 0.9%~3.4% annual GDP in India). Our results reveal how equitable distributions would cascade more protection of vaccines to people and ways to improve vaccine equity and accessibility globally through international collaboration.

Objective: To explore the characteristics findings of early COVID-19 on chest thin-slice non-enhanced CT. Materials and methods: From November to December 2022, data from 153 patients with COVID-19 with positive chest CT findings confirmed by the Department of Infectious Diseases of our hospital were collected. All patients had relatively complete clinical data and underwent chest CT 1-14 days after the onset. The patients were divided into two groups according to their age (≤60 years old and >60 years old) and the time interval between the onset and CT examination (≤7 days old and >7 days old), and the differences in CT features between the two groups were compared. Result: Among 153 patients with COVID-19, the lung (100%), blood vessels (93.5%), airways (73.4%), and pleura (70.1%) were involved. The comparison between the age groups showed statistically significant differences in the number, location, size, volume, and band shadow of the lesions. There were statistically significant differences in the shape, density, organization, fibrosis, and pleural involvement of the lesions between the patients in the time interval between the onset and CT examination. Conclusion: Chest thin-slice CT can clarify the location and scope of early COVID-19. Some characteristics findings can help for accurate diagnosis and differentiation, such as the diversity of morphology, intrapleural and perivascular distribution, interstitial lesions with alveoli as a unit, early mixed ground-glass shadow often accompanied by obvious organization and fibrosis, localized thickening of the pleura, and few pleural effusions.

There is a very thick water-bearing key strata above the coal seam in the Binchang mining area. When the mining scale is large, it easily breaks and leads to rockburst with a surge of water gushing in the panel. Adopting the layout pattern of a small panel and a large coal pillar can improve the stability of the main key strata, but at present, the research on the layout pattern of a small panel and a large coal pillar under extra-thick water-bearing key strata is still not perfect. Therefore, taking the second and third panels of a mine in Binchang as the engineering background, the width of the coal pillar and the mining scale of the panel are optimized by means of theoretical analysis, field measurement, and numerical simulation to prevent rockburst and control water inflow. The results show: (1) through theoretical calculation, it is deduced that the critical width of instability of the isolated coal pillar in the current mining scale is 257 m, and the critical mining scale of breaking and instability of the main key strata in the third panel is 537 m; (2) considering the bearing capacity of the isolated coal pillar and the recovery rate of coal resources, the reasonable width of the isolated coal pillar is 210~270 m, and when the width is 200 m and 250 m, the reasonable mining scale of the third panel is 490~550 m and 640~700 m, respectively; (3) the field practice shows that the actual width of the coal pillar between the second and third panels is less than the reasonable width, and the stress concentration in the isolated coal pillar area is relatively high, so the roof deep hole blasting and large-diameter drilling in coal seam are adopted to relieve pressure. After taking pressure relief measures, the stress concentration in the isolated coal pillar area is effectively reduced, and the pressure relief effect is remarkable.

PAPP-A substrate selectivity underlies the tight regulation of IGF signaling. Here, the authors report cryo-EM structures of dimeric PAPP-A in its substrate-free form and in complex with a peptide substrate, which combined with biochemical assays provide a mechanism for PAPP-A substrate binding and selectivity.

Abstract Lung endothelial permeability is a key pathological feature of acute respiratory distress syndrome. Hyaluronic acid (HA), a major component of the glycocalyx layer on the endothelium, is generated by HA synthase (HAS) during inflammation and injury and is critical for repair. We hypothesized that administration of exogenous high molecular weight (HMW) HA would restore protein permeability across human lung microvascular endothelial cells (HLMVEC) injured by an inflammatory insult via upregulation of HAS by binding to CD44. A transwell coculture system was used to study the effects of HA on protein permeability across HLMVEC injured by cytomix, a mixture of IL‐1β, TNFα, and IFNγ, with or without HMW or low molecular weight (LMW) HA. Coincubation with HMW HA, but not LMW HA, improved protein permeability following injury at 24 h. Fluorescence microscopy demonstrated that exogenous HMW HA partially prevented the increase in “actin stress fiber” formation. HMW HA also increased the synthesis of HAS2 mRNA expression and intracellular HMW HA levels in HLMVEC following injury. Pretreatment with an anti‐CD44 antibody or 4‐methylumbelliferone, a HAS inhibitor, blocked the therapeutic effects. In conclusion, exogenous HMW HA restored protein permeability across HLMVEC injured by an inflammatory insult in part through upregulation of HAS2.

Objective: To explore the clinical value of CT lymphangiography in diagnosing primary pulmonary lymphedema. Methods: 52 patients who were diagnosed by clinical, imaging and pathology as primary pulmonary lymphedema were analyzed retrospectively. All patients underwent CT lymphangiography. Two experienced radiologists carried out double-blind film reading of the CT lymphangiography manifestations, and observed the abnormal perfomance of lymphatic vessels in the chest as well as CT signs of other chest diseases.Results: CT lymphangiography showed contrast agent abnormity deposited in all 52 patients: the end of thoracic duct was found in 38 cases (73.1%), mediastinum in 34 cases (65.4%), hilar in 22 cases (42.3%), pleura in 18 cases (34.6%), pericardium in 15 cases (28.8%), diaphragm in 5 cases (9.6%), hepatic hilum in 9 cases (17.3%), pancreas in 5 cases (9.6%), retroperitoneum in 12 cases (23.1%). Abnormal CT changes including: (1) alveolar nodule-like ground glass opacity in 19 cases (36.5%), patchy ground glass opacity in 23 cases (44.2%), atelectasis in 11 cases (21.2%), pulmonary nodules in 3 cases (5.8%). (2) the thickening of bronchovascular bundle in 43 cases (82.7%), the thickening of interlobular septum in 43 cases (82.7%), the thickening of intralobular interstitium in 4 cases (7.7%), frog-spawn sign in 7 cases (13.5%). (3) abnormal mediastinum changes in 34 cases (65.4%). (4) other chest CT abnormalities including: the crazy-paving sign in 2 cases (3.8%), pleural effusion in 18 cases (34.6%), pericardial effusion in 18 case (34.6%). Conclusion: CT lymphangiography can indirectly predict the abnormality of lymphatics and the presence or absence of lymphatic reflux by showing the abnormal deposition and distribution of contrast agents, and thus can provide valuable imaging basis for the diagnosis and treatment of primary pulmonary lymphedema.

Objective: To explore the clinical and imaging characteristics and application value CT lymphangiography (CTL) in patients with different types of primary intestinal lymphangiectasia (PIL). Methods: Patients diagnosed as PIL in our center were recruited in this retrospective study from January 2016 to December 2019, All CTL data were blindly reviewed by two radiologists separately, and the evaluation indicators included: sex, onset age, symptoms and signs, serum albumin, wall thickening, serous cavity effusion, abnormal distribution of lymphatics, lymph reflux, lymph nodes, fistula and abnormal lymphatics around neck area. Based on the abnormal lymphatics in intestinal wall and/or mesentery, PIL was classified into type Ⅰ (positive type) and type Ⅱ (negative type). The clinical and imaging features were compared between the two groups. Results: 34 PIL patients were recruited in this study, including 15 cases of Ⅰ and 19 cases of Ⅱ. Type I showed older age of first onset (15.3±9.4 vs. 8.3±3.8), higher rate of diarrhea, and lower rate of limb and/or facial edema than type Ⅱ, with no statistical difference in sex and serum albumin. For imaging features comparisons, type Ⅰ demonstrated higher rate of abnormal dilated lymphatics and fistula, lower rate of increased attenuation of mesentery and lymph nodes, while no statistical difference was found between wall thickening, serous cavity effusion, lymph reflux and abnormal dilated lymphatics around neck area. Conclusion: CTL demonstrated capability of evaluation in detection of location, distribution and range of abnormal lymphatics in PIL. Based on CTL, the imaging classification of PIL was proposed. Different types of PIL showed different clinical and imaging features, which was useful for therapeutic adoptions.

Objective: To investigate the diagnostic value of chest CT and CT lymphangiography (CTL) in congenital pulmonary lymphangiectasia (CPL). Materials and methods: The clinical and imaging datas of 41 patients with CPL diagnosed by clinical and imaging from August 2012 to July 2021 were retrospectively analyzed. All patients underwent chest CT examination before direct lymphangiography (DLG) and CTL after DLG. The CT and CTL imaging manifestations were analyzed and statistically described using the composition ratio in the categorical variable data. Results: Among the 41 patients, CT showed thickening of bronchovascular bundles in 33 cases, interlobular septal thickening in 32 cases, intralobular interstitial thickening in 4 cases, and ground-glass opacity in 26 cases, 5 cases of lung consolidation, 14 cases of atelectasis, 24 cases of pleural effusion. CTL lipiodol was abnormally deposited at the end of the thoracic duct in 35 cases, bronchovascular bundles in 31 cases, hilum in 32 cases, pleura in 17 cases, mediastinum in 36 cases, pericardium in 17 cases, diaphragm in 3 cases, intraperitoneal in 10 cases, and retroperitoneal in 10 cases , 20 cases of pelvis and perineum. Conclusion: CT and CTL can show the extent and distribution of Lymphangiectasia, and provide imaging basis for the diagnosis and treatment of CPL.

Objective: To investigate the application value of CT lymphangiography in diagnosis and grading in patients with primary chyluria. Methods: Clinical and CTL imaging data of 79 patients diagnosed with primary chyluria were collected retrospectively. For CTL, the indexs were (1) Involved kidney and distribution of abnormal lymphatic vessels in the kidney: unilateral or bilateral kidney,renal sinus, renal parenchymal, suprahilar area and subhilar area; (2) Distribution of perirenal and retroperitoneal abnormal lymphatic vessels: retroperitoneal area,lumbar trunk area, renal perivascular area, fatty capsule area, adrenal area, etc; (3) Distribution of dilated lymphatic vessels and lymphatic reflux in chest, abdomen and pelvis; (4) Other abnormal manifestations: lymphatic-related abnormal changes in the chest, abdomen, pelvic cavity and bone; (5) Imaging grading: the imaging grading was carried out according to the range of retroperitoneal involvement, and the retroperitoneal area was divided into 10 areas, including left and right suprahilar area, subhilar area, perirenal area, renal perivascular area and lumbar trunk area, involvement of five or fewer areas were graded as mild, while involvement of six or more were graded as severe. In addition, clinical grading was carried out according to clinical manifestations. The clinical characteristics and CTL signs of patients with primary chyluria were statistically described by the composition ratio of classification variables, and the consistency of imaging grade and clinical grade of patients with primary chyluria was evaluated by Kappa test. Results: CTL showed abnormal lipiodol deposition in kidney in 74 cases (93.7%), unilateral kidney in 55 cases (69.6%), bilateral kidneys in 19 cases (24.1%), renal sinus in 74 cases (93.7%), renal parenchyma in 37 cases (46.8%); suprahilar area in 61 cases (77.2%), 52 cases (65.8%) were unilateral and 9 cases (11.4%) were bilateral; subhilar area in 61 cases (77.2%), 47 cases (59.5%) were unilateral and 14 cases (17.7%) were bilateral; retroperitoneal area in 78 cases (98.7%); lumbar trunk area in 76 cases (96.2%), 20 cases (25.3%) were unilateral and 56 cases (70.9%) were bilateral; perivascular area in 72 cases (91.1%), 45 cases (57.0%) were unilateral and 27 cases (34.2%) were bilateral; fatty capsule in 14 cases (17.7%), 13 cases (16.5%) were unilateral and 1 case (1.3%) was bilateral; adrenal area in 12 cases (15.2%); bladder in 31 cases (39.2%), perivesical area in 12 cases (15.2%), iliac perivascular area in 73 cases (92.4%), abdominal and pelvic wall in 14 cases (17.7%), perineal area in 12 cases (15.2%), perirectal area in 14 cases (17.7%), mesentery in 26 cases (32.9%), intestinal wall in 11 cases (13.9%), intestinal canal in 5 cases (6.3%), peripancreatic area in 15 cases (18.9%), perisplenic area in 2 cases (2.5%), perihepatic area in 7 cases (8.8%), hilus of the lung in 1 case (1.3%), mediastinum in 14 cases (17.7%), pericardium in 1 case (1.3%), extrapleural area in 25 cases (31.6%), chest wall in 2 cases (2.5%), skeleton in 2 cases (2.5%), end of thoracic duct in 70 cases (88.6%). Among the 79 patients with primary chyluria, according to clinical classification, 27 cases were mild and 52 cases were severe; according to imaging classification, 40 cases were mild and 39 cases were severe. The consistency of the two grades was moderate. Conclusion: CTL can evaluate the distribution and range of intrarenal, perirenal and retroperitoneal dilated lymphatic vessels accurately, and evaluate the abnormal lymphatic vessels in the chest, abdomen and pelvis and thoracic duct in patients with primary chyluria.It can provide image basis for the diagnosis, grading and treatment of primary chyluria.

Objective: To investigate the value of MRI-based measurement of calf soft-tissue thickness in assessing the clinical staging of primary lower extremity lymphedema (PLEL). Methods: The clinical and MR imaging data of 90 patients diagnosed with PLEL in our hospital were retrospectively collected, and all patients underwent bilateral lower limb MR examinations. Short Time Inversion Recovery (STIR) sequence was used to measure the total soft tissue thickness (T), musculoskeletal thickness (M) and subcutaneous soft tissue thickness (S) of bilateral lower legs, and the difference between T and S of bilateral lower legs (DT, DS) was calculated respectively. Patients were classified into stages Ⅰ, Ⅱ and Ⅲ with reference to the clinical staging criteria of the International Lymphatic Association 2020 and our lymphatic surgery department for lower limb lymphedema, excluding stage 0. One-way ANOVA was used to compare calf soft tissue thickness among different clinical stages, Spearman correlation was used to analyze the correlation between calf soft tissue thickness and clinical stage, and ROC curves were used to evaluate the efficacy of calf soft tissue thickness in discriminating clinical stage. Results: The differences among T, S, DT and DS of the three stages were statistically significant, while there was no statistical difference among M; when comparing two by two in each subperiod, T, S, DT and DS were statistically different between stage Ⅰ and Ⅱ and stage Ⅰ and Ⅲ, while there was no statistical difference between stage II and III. The correlation between DT (r=0.750) and DS (r=0.772) and clinical stage was significantly greater than that between T (r=0.669) and S (r=0.734), with DS showing the highest correlation with clinical stage; there was no significant correlation between M and clinical stage. ROC curves showed that the AUC values for each parameter to identify stage Ⅰ and Ⅱ were greater than those to identify stage Ⅱ and Ⅲ. The AUC value of DS (AUC=0.945) demonstrated the highest area under the curve (AUC) among all parameters to identify stage Ⅰ and stage Ⅱ. Conclusion: MRI soft-tissue thickness measurement of calf can be used as a quantitative adjunct in the clinical staging of unilateral PLEL, and for patients with unilateral PLEL, we recommend DS as the best thickness index to differentiate stage Ⅰ from Ⅱ lymphedema.

IntroductionThe pathogenesis of sepsis is an imbalance between pro-inflammatory and anti-inflammatory responses. At the onset of sepsis, the lungs are severely affected, and the injury progresses to acute respiratory distress syndrome (ARDS), with a mortality rate of up to 40%. Currently, there is no effective treatment for sepsis. Cellular therapies using mesenchymal stem cells (MSCs) have been initiated in clinical trials for both ARDS and sepsis based on a wealth of pre-clinical data. However, there remains concern that MSCs may pose a tumor risk when administered to patients. Recent pre-clinical studies have demonstrated the beneficial effects of MSC-derived extracellular vesicles (EVs) for the treatment of acute lung injury (ALI) and sepsis.MethodsAfter recovery of initial surgical preparation, pneumonia/sepsis was induced in 14 adult female sheep by the instillation of Pseudomonas aeruginosa (~1.0×1011 CFU) into the lungs by bronchoscope under anesthesia and analgesia. After the injury, sheep were mechanically ventilated and continuously monitored for 24 h in a conscious state in an ICU setting. After the injury, sheep were randomly allocated into two groups: Control, septic sheep treated with vehicle, n=7; and Treatment, septic sheep treated with MSC-EVs, n=7. MSC-EVs infusions (4ml) were given intravenously one hour after the injury.ResultsThe infusion of MSCs-EVs was well tolerated without adverse events. PaO2/FiO2 ratio in the treatment group tended to be higher than the control from 6 to 21 h after the lung injury, with no significant differences between the groups. No significant differences were found between the two groups in other pulmonary functions. Although vasopressor requirement in the treatment group tended to be lower than in the control, the net fluid balance was similarly increased in both groups as the severity of sepsis progressed. The variables reflecting microvascular hyperpermeability were comparable in both groups.ConclusionWe have previously demonstrated the beneficial effects of bone marrow-derived MSCs (10×106 cells/kg) in the same model of sepsis. However, despite some improvement in pulmonary gas exchange, the present study demonstrated that EVs isolated from the same amount of bone marrow-derived MSCs failed to attenuate the severity of multiorgan dysfunctions.

Abstract Surface‐enhanced Raman scattering (SERS), a powerful analysis technique featuring ultrahigh sensitivity and the ability in chemically specific detection, has encountered intrinsic challenges in quantitative analysis due to the signal heterogeneity arising from sample preparation, molecular distribution, and experimental conditions. Herein, the plasmonic Janus nanoparticle, which is curved on one side and flat on the other, as a universal platform for quantitative analysis is proposed. The probe molecules are adsorbed on the curved side as internal standards to correct the signal fluctuation while the target molecules are adsorbed on the flat side for SERS measurement, and thus competitive adsorption between different molecules is prevented. Moreover, the Janus nanoparticles are partially embedded in a flexible and transparent membrane, enabling liquid‐state SERS measurement which is favorable to form a uniform self‐assembly molecular monolayer for quantitative SERS analysis. The quantitation of different biochemical molecules including Rhodamine 6G, crystal violet, and adenine are demonstrated, and an extension in linear response region for quantitative analysis is observed. The findings suggest a robust approach toward quantitative analysis.

Solving the wave equation is one of the most (if not the most) fundamental problems we face as we try to illuminate the Earth using recorded seismic data. The Helmholtz equation provides wavefield solutions that are dimensionally reduced, per frequency, compared to the time domain, which is useful for many applications, like full waveform inversion. However, our ability to attain such wavefield solutions depends often on the size of the model and the complexity of the wave equation. Thus, we use here a recently introduced framework based on neural networks to predict functional solutions through setting the underlying physical equation as a loss function to optimize the neural network (NN) parameters. For an input given by a location in the model space, the network learns to predict the wavefield value at that location, and its partial derivatives using a concept referred to as automatic differentiation, to fit, in our case, a form of the Helmholtz equation. We specifically seek the solution of the scattered wavefield considering a simple homogeneous background model that allows for analytical solutions of the background wavefield. Providing the NN with a reasonable number of random points from the model space will ultimately train a fully connected deep NN to predict the scattered wavefield function. The size of the network depends mainly on the complexity of the desired wavefield, with such complexity increasing with increasing frequency and increasing model complexity. However, smaller networks can provide smoother wavefields that might be useful for inversion applications. Preliminary tests on a two-box-shaped scatterer model with a source in the middle, as well as, the Marmousi model with a source at the surface demonstrate the potential of the NN for this application. Additional tests on a 3D model demonstrate the potential versatility of the approach.

Location of earthquakes is a primary task in seismology and microseismic monitoring, essential for almost any further analysis. Earthquake hypocenters can be determined by the inversion of arrival times of seismic waves observed at seismic stations, which is a non-linear inverse problem. Growing amounts of seismic data and real-time processing requirements imply the use of robust machine learning applications for characterization of seismicity. Convolutional neural networks have been proposed for hypocenter determination assuming training on previously processed seismic event catalogs. We propose an alternative machine learning approach, which does not require any pre-existing observations, except a velocity model. This is particularly important for microseismic monitoring when labeled seismic events are not available due to lack of seismicity before monitoring commenced (e.g., induced seismicity). The proposed algorithm is based on a feed-forward neural network trained on synthetic arrival times. Once trained, the neural network can be deployed for fast location of seismic events using observed P-wave (or S-wave) arrival times. We benchmark the neural network method against the conventional location technique and show that the new approach provides the same or better location accuracy. We study the sensitivity of the proposed method to the training dataset, noise in the arrival times of the detected events, and the size of the monitoring network. Finally, we apply the method to real microseismic monitoring data and show that it is able to deal with missing arrival times in efficient way with the help of fine tuning and early stopping. This is achieved by re-training the neural network for each individual set of picked arrivals. To reduce the training time we used previously determined weights and fine tune them. This allows us to obtain hypocenter locations in near real-time.

Exploring the spatial heterogeneity of urban multi-dimensional networks and influencing factors are of great significance for the integrated development of metropolitan circle. This study took Hangzhou metropolitan circle as an example, using multi-source geospatial big data to obtain urban population, transportation, goods, capital, and information flow information among sub-cities. Then, spatial visualization analysis, social network analysis, and geographical detector were applied to analyze the differences in spatial structure of multiple urban networks and influencing factors in Hangzhou metropolitan circle, respectively. The results showed that (1) the network connections of population, traffic, goods, and capital flows transcended geographical proximity except that of information flow, and population and traffic flow networks were found to be more flattened in Hangzhou metropolitan circle than in other urban networks; (2) the comprehensive urban network of Hangzhou metropolitan circle was imbalanced across sub-cities, presenting hierarchical and unipolar characteristics; and (3) the influence of traffic distance on the network spatial structure of Hangzhou metropolitan was stronger than the geographical distance, and the interactions between traffic distance and socioeconomic factors would further enhance the regional differentiation of the network spatial structure. This study could provide scientific reference for constructing a coordinated and integrated development pattern in a metropolitan circle.

Examining the influence of trust in fostering knowledge sharing behavior (KSB) in virtual teams is of great research value in the current complex, dynamic, and competitive era of a knowledge economy. This study investigated the relationship between trust in coworkers (TC) and KSB. Based on social information processing theory and social cognitive theory, we developed a multilevel moderated mediation model where the team members’ psychological safety (PS) was considered a mediator, while team virtuality (TV) and knowledge sharing self-efficacy (KSSE) acted as team and individual-level moderators, respectively. On surveying 282 individuals in 37 virtual teams of three Chinese internet companies, we found that TC positively affected team members’ KSB and this relationship was fully mediated by team members’ PS. Our findings also demonstrated that the effect of TC on KSB depended on the degree of TV and employees’ KSSE. Specifically, when TV and KSSE were higher, the TC–PS and PS–KSB relationship and the mediating effects of PS in the TC–PS–KSB relationship were all stronger. Our study extends the trust-KSB literature by identifying the psychological mechanism and boundary conditions in the TC-KSB relationship. Moreover, our findings also offer valuable managerial implications for virtual team managers on facilitating team members’ PS and KSB.

The activity of translation initiation factor eIF2B is known to be modulated through stress-responsive phosphorylation of its substrate eIF2. Here, the authors uncover the regulation of eIF2B by the binding of sugar phosphates, suggesting a link between nutrient status and the rate of protein synthesis.

Abstract Background Although promising, clinical translation of human mesenchymal stem or stromal cell-derived extracellular vesicles (MSC EV) for acute lung injury is potentially limited by significant production costs. The current study was performed to determine whether pretreatment of MSC EV with high molecular weight hyaluronic acid (HMW HA) would increase the therapeutic potency of MSC EV in severe bacterial pneumonia. Methods In vitro experiments were performed to determine the binding affinity of HMW HA to MSC EV and its uptake by human monocytes, and whether HMW HA primed MSC EV would increase bacterial phagocytosis by the monocytes. In addition, the role of CD44 receptor on MSC EV in the therapeutic effects of HMW HA primed MSC EV were investigated. In Pseudomonas aeruginosa (PA) pneumonia in mice, MSC EV primed with or without HMW HA were instilled intravenously 4 h after injury. After 24 h, the bronchoalveolar lavage fluid, blood, and lungs were analyzed for levels of bacteria, inflammation, MSC EV trafficking, and lung pathology. Results MSC EV bound preferentially to HMW HA at a molecular weight of 1.0 MDa compared with HA with a molecular weight of 40 KDa or 1.5 MDa. HMW HA primed MSC EV further increased MSC EV uptake and bacterial phagocytosis by monocytes compared to treatment with MSC EV alone. In PA pneumonia in mice, instillation of HMW HA primed MSC EV further reduced inflammation and decreased the bacterial load by enhancing the trafficking of MSC EV to the injured alveolus. CD44 siRNA pretreatment of MSC EV prior to incubation with HMW HA eliminated its trafficking to the alveolus and therapeutic effects. Conclusions HMW HA primed MSC EV significantly increased the potency of MSC EV in PA pneumonia in part by enhancing the trafficking of MSC EV to the sites of inflammation via the CD44 receptor on MSC EV which was associated with increased antimicrobial activity.

Abstract Background Icariin (ICAR) is the main effective component extracted from epimedium, and is reported to have the potential to treat osteoarthritis (OA). However, its pharmacological function on chondrocytes has not been fully clarified. Methods Different doses of ICAR were used to treat chondrocyte cell lines, including CHON-001 and ATDC5. Then the expressions of different lncRNAs were measured by qRT-PCR. Interleukin-1β (IL-1β) was used to simulate the inflammatory response environment of chondrocytes. Overexpression plasmids and short hairpin RNAs of lncRNA CYTOR were used to construct gain-of-function and loss of function models. CCK-8 was conducted to determine the cell viability. Flow cytometry was used to detect the apoptosis of chondrocytes. Enzyme-linked immunosorbent assay (ELISA) was adopted to measure the contents of inflammatory factors (IL-6, IL-8, TNF-α) in the supernatant of the chondrocytes. Results Compared with other lncRNAs, CYTOR was changed most significantly in both CHON-001 and ATDC5 cells after treatment with ICAR. ICAR promotes the viability and inhibits the apoptosis of CHON-001 and ATDC5 cells induced by IL-1β, accompanied with reduced levels of inflammatory factors. Overexpression of CYTOR facilitated the viability of chondrocytes, while repressed their apoptosis and inflammatory response. What’s more, knockdown of CYTOR reversed the protective effects of ICAR on chondrocytes. Conclusion CYTOR was a pivotal lncRNA involved in the protective function of ICAR on chondrocytes.

Neurodegenerative diseases are critical in the healthcare system as patients suffer from progressive diseases despite currently available drug management. Indeed, the growing ageing population will burden the country’s healthcare system and the caretakers. Thus, there is a need for new management that could stop or reverse the progression of neurodegenerative diseases. Stem cells possess a remarkable regenerative potential that has long been investigated to resolve these issues. Some breakthroughs have been achieved thus far to replace the damaged brain cells; however, the procedure’s invasiveness has prompted scientists to investigate using stem-cell small extracellular vesicles (sEVs) as a non-invasive cell-free therapy to address the limitations of cell therapy. With the advancement of technology to understand the molecular changes of neurodegenerative diseases, efforts have been made to enrich stem cells’ sEVs with miRNAs to increase the therapeutic efficacy of the sEVs. In this article, the pathophysiology of various neurodegenerative diseases is highlighted. The role of miRNAs from sEVs as biomarkers and treatments is also discussed. Lastly, the applications and delivery of stem cells and their miRNA-enriched sEVs for treating neurodegenerative diseases are emphasised and reviewed.

【Background】Hebei plain is one of the most important winter wheat production bases in China and plays an critical role in national food security. Most precipitations within wheat growth season in this region fall in July- August and cannot sustain wheat growth. Therefore, supplementary irrigation using groundwater is needed. Over exploitation of groundwater combining with the inefficient flood irrigation over the past few decades has led to serious environmental and ecological degradation, and developing water-saving irrigation techniques has thus become essential to sustaining wheat production in this region. 【Objective】The purpose of this paper is to study how hose-micro-sprinkler irrigation amount impacts water consumption and yield of winter wheat planted in strip pattern, in attempts to improve water use efficacy without undermining crop yield. 【Method】The field experiment was conducted in 2019 with the cultivar Jimai 22 used as the model plant. We compared four irrigation amounts: 15 mm (W1), 22.5 mm (W2), 30 mm(W3) and 37.5 mm(W4), with the 60 mm furrow-irrigation used by local farmers taken as the control (CK). Crops in each treatment were irrigated at jointing, early and middle grain-filling stages, respectively. During the experiment, we measured and calculated water consumption, grain yield and water use efficiency of the wheat. 【Result】The total water consumption during the growth season was 306.46~399.4 mm, varying with treatments, and the proportion of soil water consumed by the crops under W1, W2, W3, W4 and CK was 44.2%, 42.97%, 41.24%, 40.15% and 38.41%, respectively. With the irrigation amount increasing, the proportion of irrigation water consumed by the crops increased. The crops were most water-demanding from the jointing stage to the early filling stage, with 45.33%~53.68% of the total water they consumed occurring in this period. The crops consumed more water from sowing stage to early grouting stage in all treatments, while in CK the crops took up more water they consumed between the early grain-filling stage and the ripening stage. The grain yield increased with irrigation amount, peaking at 9 682.66 kg/hm2 in W4. In contrast, water use efficiency in W3 was the highest, increasing by 7.54% compared to the CK. 【Conclusion】In terms of high-yield and high-water use efficiency, the most appropriate irrigation was 135~157.5 mm, with its associated water consumption being 367.5~400 mm.

Abstract Background Secondary brain damage caused by the innate immune response and subsequent proinflammatory factor production is a major factor contributing to the high mortality of intracerebral haemorrhage (ICH). Nucleotide-binding oligomerization domain 1 (NOD1)/receptor-interacting protein 2 (RIP2) signalling has been reported to participate in the innate immune response and inflammatory response. Therefore, we investigated the role of NOD1/RIP2 signalling in mice with collagenase-induced ICH and in cultured primary microglia challenged with hemin. Methods Adult male C57BL/6 mice were subjected to collagenase for induction of ICH model in vivo. Cultured primary microglia and BV2 microglial cells (microglial cell line) challenged with hemin aimed to simulate the ICH model in vitro. We first defined the expression of NOD1 and RIP2 in vivo and in vitro using an ICH model by western blotting. The effect of NOD1/RIP2 signalling on ICH-induced brain injury volume, neurological deficits, brain oedema, and microglial activation were assessed following intraventricular injection of either ML130 (a NOD1 inhibitor) or GSK583 (a RIP2 inhibitor). In addition, levels of JNK/P38 MAPK, IκBα, and inflammatory factors, including tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS) expression, were analysed in ICH-challenged brain and hemin-exposed cultured primary microglia by western blotting. Finally, we investigated whether the inflammatory factors could undergo crosstalk with NOD1 and RIP2. Results The levels of NOD1 and its adaptor RIP2 were significantly elevated in the brains of mice in response to ICH and in cultured primary microglia, BV2 cells challenged with hemin. Administration of either a NOD1 or RIP2 inhibitor in mice with ICH prevented microglial activation and neuroinflammation, followed by alleviation of ICH-induced brain damage. Interestingly, the inflammatory factors interleukin (IL)-1β and tumour necrosis factor-α (TNF-α), which were enhanced by NOD1/RIP2 signalling, were found to contribute to the NOD1 and RIP2 upregulation in our study. Conclusion NOD1/RIP2 signalling played an important role in the regulation of the inflammatory response during ICH. In addition, a vicious feedback cycle was observed between NOD1/RIP2 and IL-1β/TNF-α, which could to some extent result in sustained brain damage during ICH. Hence, our study highlights NOD1/RIP2 signalling as a potential therapeutic target to protect the brain against secondary brain damage during ICH.

As the overall scale of the constellation system continues to increase,its service capabilities are gradually expanding from traditional mobile communication services to broadband interconnection services,which puts forward new requirements for the operation,maintenance and resource management in the satellite constellation system.The challenges brought by constellation scale,resource dynamics,and resource failure for the performance management-oriented network operation and maintenance and resource management in mega constellation system (MCS) were fi rst analyzed.The key technologies of network operation,maintenance and resource management for MCS were discussed from the aspects of traff c prediction and resource perception and maintenance and dynamic resource slicing.An intelligent network management and control architecture was proposed to realize lightweight operation and maintenance and resource management for MCS,laying a theoretical foundation for the efficient network operation and maintenance and resource management technology for future space-terrestrial integrated networks.

Abstract Background Spinal cord injury (SCI) is the damage to the spinal cord that can lead to temporary or permanent loss of function due to injury to the nerve. The SCI patients are often associated with poor quality of life. Results This review discusses the current status of mesenchymal stem cell (MSC) therapy for SCI, criteria to considering for the application of MSC therapy and novel biological therapies that can be applied together with MSCs to enhance its efficacy. Bone marrow-derived MSCs (BMSCs), umbilical cord-derived MSCs (UC-MSCs) and adipose tissue-derived MSCs (ADSCs) have been trialed for the treatment of SCI. Application of MSCs may minimize secondary injury to the spinal cord and protect the neural elements that survived the initial mechanical insult by suppressing the inflammation. Additionally, MSCs have been shown to differentiate into neuron-like cells and stimulate neural stem cell proliferation to rebuild the damaged nerve tissue. Conclusion These characteristics are crucial for the restoration of spinal cord function upon SCI as damaged cord has limited regenerative capacity and it is also something that cannot be achieved by pharmacological and physiotherapy interventions. New biological therapies including stem cell secretome therapy, immunotherapy and scaffolds can be combined with MSC therapy to enhance its therapeutic effects.

In this paper, Brazilian disc splitting tests on coal rock specimens with bedding planes and corresponding simulations by combined finite/discrete numerical method(FDEM) were carried out.The results show that the angle of bedding plane have a significant influence on fracture pattern and tensile strength of coal.It is clear that as the angle of weak plane increases, the fracture pattern of models can be classified into four types, including stretching failure perpendicular to weak bedding planes, complicated sketching and shear mixed pattern, shear failure along the bedding planes, and sketching damage along weak bedding planes.As for the difference of tensile strength values, it is observed that when the load is perpendicular to the bedding plane, the effect of bedding structure on calculating tensile strength is negligible and the tensile strength value decreases with the angle rising up to the minimum value as angle reaches vertical.In addition, with respect to dissipated energy of coal samples, it is concluded that the dissipated energy gradually decreases when the angle of bedding planes are increased, which have a relationship with varied fracture patterns and strength values.