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Summary Legume–rhizobia symbiosis enables biological nitrogen fixation to improve crop production for sustainable agriculture. Small heat shock proteins (sHSPs) are involved in multiple environmental stresses and plant development processes. However, the role of sHSPs in nodule development in soybean remains largely unknown. In the present study, we identified a nodule‐localized sHSP, called GmHSP17.9, in soybean, which was markedly up‐regulated during nodule development. GmHSP17.9 was specifically expressed in the infected regions of the nodules. GmHSP17.9 overexpression and RNAi in transgenic composite plants and loss of function in CRISPR‐Cas9 gene‐editing mutant plants in soybean resulted in remarkable alterations in nodule number, nodule fresh weight, nitrogenase activity, contents of poly β‐hydroxybutyrate bodies (PHBs), ureide and total nitrogen content, which caused significant changes in plant growth and seed yield. GmHSP17.9 was also found to act as a chaperone for its interacting partner, GmNOD100, a sucrose synthase in soybean nodules which was also preferentially expressed in the infected zone of nodules, similar to GmHSP17.9. Functional analysis of GmNOD100 in composite transgenic plants revealed that GmNOD100 played an essential role in soybean nodulation. The hsp17.9 lines showed markedly more reduced sucrose synthase activity, lower contents of UDP‐glucose and acetyl coenzyme A (acetyl‐CoA), and decreased activity of succinic dehydrogenase (SDH) in the tricarboxylic acid (TCA) cycle in nodules due to the missing interaction with GmNOD100. Our findings reveal an important role and an unprecedented molecular mechanism of sHSPs in nodule development and nitrogen fixation in soybean.

The study was intended to determine the antineoplastic effects of two new iridium(III) complexes [Ir(ppy)2(PTTP)](PF6) (1) (ppy = 2-phenylpyridine) and [Ir(piq)2(PTTP)](PF6) (2) (piq = 1-phenylisoquinoline, PTTP = 2-phenoxy-1,4,8,9-tetraazatriphenylene). In MTT assay, the ligand PTTP displayed ineffective inhibition on cell growth in SGC-7901, BEL-7402, HepG2 as well as NIH3T3 cell lines, while complexes 1 and 2 showed high cytotoxic activity on SGC-7901 cells with an IC50 value of 0.5 ± 0.1 µM and 4.4 ± 0.6 µM, respectively. Cellular uptake, cell cloning experiments, wound healing assay and cell cycle arrest indicated that the two complexes can inhibit the cell proliferation in SGC-7901 and induce cell cycle arrest at G0/G1 phase. Additionally, reactive oxygen species (ROS) and mitochondrial membrane potential suggested that the two complexes induced cell apoptosis through disrupting mitochondrial functions. Further, western blot analysis illustrated that the two complexes caused apoptosis via regulating expression levels of Bcl-2 family proteins. Moreover, complex 1 could suppress tumor growth in vivo with an inhibitory rate of 49.41%. Altogether, these results demonstrated that complexes 1 and 2 exert a potent anticancer effect against SGC-7901 cells via mitochondrial apoptotic pathway and have a potential to be developed as antineoplastic drug candidates for human gastric cancer.

Objective Physical exercise has obvious effects on bone loss, pain relief, and improvement of bone metabolism indexes in patients with osteoporosis, but currently lacks sufficient evidence. The aim of this systematic review and meta‐analysis was to synthesize and present the best available evidence on the effectiveness and safety of exercises in the treatment of primary osteoporosis. Methods Publications pertaining to the effectiveness of exercise on bone mineral density (BMD), visual analog scores (VAS), and biochemical markers of bone metabolism in primary osteoporosis (POP) from PubMed, Cochrane Library, Embase, VIP, CNKI, and Wanfang Database were retrieved from their inception to April 2020. Results A total of 20 studies with 1824 participants were included. The results of the meta‐analysis revealed that exercise therapy for lumbar spine and femoral neck BMD is statistically different from conventional therapy (lumbar spine BMD: SMD = 0.78, 95%CI: 0.46, 1.10, P, The results of this meta‐analysis show that different types of exercise therapies significantly improved lumbar spine and femoral neck BMD, and relieve the pain of patients in the current low‐quality evidence. Additional high‐quality evidence is required to confirm the effect of exercise therapy on the biochemical markers of bone metabolism in POP patients. Therefore, more multicenters, larger samples, long‐term, single‐blind RCTs are needed to evaluate the effects of exercise therapy on BMD, VAS and biochemical markers of bone metabolism in POP patients.

Objective The aim of the present study was to reveal the case characteristics of osteonecrosis of the femoral head (ONFH) in Mainland China. Methods This cross‐sectional epidemiological study derived data for ONFH patients from July 2016 to December 2018 from the China Osteonecrosis of the Femoral Head Database (CONFHD). The derived data included gender, age, body mass index (BMI), height, occupation, region, and etiology of femoral head necrosis. A descriptive analysis was performed to summarize the epidemiological characteristics of the case data in the CONFHD. Results A total of 1844 ONFH patients (2945 hips) were included in this study, comprising 1302 men and 542 women. The age of patients ranged from 18 to 95 years, with a median of 50 years, and the male to female ratio was 2.4. Male patients are younger than female patients (48.26 ± 12.56 years old and 55.56 ± 14.94 years old, respectively). Among the 1844 patients (2945 hips), there were 528 (17.92%) hips at ARCO stage I, 941 (31.99%) hips at ARCO stage II, 873 (29.63%) hips at ARCO stage III, and 603 (20.46%) hips at ARCO stage IV. In the subclassification of ARCO stages I and II, the majority of cases were type C; type A comprised the majority in the subclassification of ARCO stage III. According to the Kellgren–Lawrence classification system, among the 603 ARCO stage IV hips, there were 178 (29.52%) grade 1 hips, 201 (33.34%) grade 2 hips, 176 (29.18%) grade 3 hips, and 48 (7.96%) grade 4 hips. Most were from three provinces: Henan (27.3%), Shanxi (13.9%), and Shandong (11.9%). Regarding BMI, 982 patients (53.25%) were overweight or obese. Among all patients, the largest proportion of patients engaged in level IV manual work. Of all the patients, there were 495 (26.84%) with steroid‐induced ONFH, 685 (37.15%) were alcoholics, and 290 (15.73%) had traumatic ONFH. The 495 patients with steroid‐induced ONFH included 278 men (56.16%) and 217 women (43.84 %), had a complete history of hormone use. Among the primary diseases, there were 195 cases (39.39%) of immune system diseases, followed by dermatological diseases, respiratory diseases, nephropathy, and other diseases. There were a total of 685 patients with alcoholic ONFH, 589 of these patients (85.99%) were men. A total of 188 (27.45%) patients had drunk alcohol for 6–10 years (comprising the highest proportion), and 280 patients (40.88%) consumed 3001–3500 mL of alcohol each week (the highest proportion). Conclusion Osteonecrosis of the femoral head most commonly occurs after the age of 40. Male patients have an earlier onset than female patients, and the number of male patients is approximately twice that of female patients. The BMI of patients was mainly in the overweight and obese range, and half of these patients engaged in level IV manual work. From the imaging findings, the numbers of hips at ARCO stages II and III were greatest, and the number at stage I was relatively small. Among all the causes of disease, alcohol, steroid use and trauma were the three most common reasons for ONFH., This is the first Internet‐based ONFH patient case registration study for mainland China. It presents epidemiological characteristics of osteonecrosis of the femoral head in mainland China.

Objective The purpose of the present study was to evaluate the present situation and risk factors for the misdiagnosis of osteonecrosis of femoral head (ONFH), providing the basis for accurate diagnosis of ONFH. Methods For this retrospective study, 1471 patients with ONFH were selected from the China Osteonecrosis of Femoral Head Database (CONFHD). These patients had been recruited between July 2016 and December 2018. According to whether or not they were misdiagnosed, the patients were divided into two groups, with 1168 cases (22–84 years old) included in the diagnosis group and 303 cases (21–80 years old) in the misdiagnosis group. Misdiagnosis was measured using the following criteria: (i) the patient had the same symptoms and signs, and the second diagnosis was not consistent with the initial diagnosis within 6 months; and (ii) the patient was admitted to a hospital participating in CONFHD and the previous diagnosis was inconsistent with the diagnosis given by the expert group. Comparisons of age, visual analogue scale for pain, and body mass index between the two groups were performed using a t‐test. Gender, causes of ONFH, primary diseases requiring corticosteroids, methods of corticosteroid use, corticosteroid species, type of trauma, onset side of the disease, pain side, whether symptoms are hidden, and type of imaging examination at the initial visit were compared using the χ2‐test. Years of alcohol consumption, weekly alcohol consumption, and physician title at the initial visit were compared using a Mann–Whitney U‐test. Furthermore, the statistically significant factors were evaluated using multiple regression analysis to investigate the risk factors of misdiagnosis. Results A total of 303 patients (20.6%) were misdiagnosed: 118 cases were misdiagnosed as lumbar disc herniation, 86 cases as hip synovitis, 48 cases as hip osteoarthritis, 32 cases as rheumatoid arthritis, 11 cases as piriformis syndrome, 5 cases as sciatica, and 3 cases as soft‐tissue injury. Whether symptoms are hidden (P = 0.038, odds ratio [OR] = 1.546, 95% confidence interval [CI] = 1.025–2.332), physician title at the initial visit (P, Patient history of corticosteroid use or alcohol abuse and MRI examination at the initial diagnosis may be protective factors for misdiagnosis. Hidden symptoms, first visit physician title as attending doctor or resident doctor, and only X‐ray examination at the initial diagnosis may be the risk factors for misdiagnosis.

Objective To investigate the application of treatment modalities for patients with osteonecrosis of the femoral head (ONFH) in mainland China. Methods This cross‐sectional study was based on the online application of China Osteonecrosis of the Femoral Head Database (CONFHD). Between July 2016 to December 2018, the CONFHD program planned to recruit ONFH patients from 12 administrative areas across mainland China. Real‐world medical records of treatment regimens for these patients, including surgeries and prescriptions, were approved to upload to the CONFHD application for further analysis. The surgeries performed on these patients were classified into total hip arthroplasty and hip‐preserving procedures, and the latter was further classified into core decompression, bone grafting, and tantalum rod implantation. Prescription medications were classified into chemical medicine and Chinese herbal medicine (CHM); chemical medicine was further classified according to their chemical compounds, and CHM was classified according to therapeutic functions based on traditional Chinese medicine theory. Descriptive analysis was performed to summarize the application of different treatment regimens on the overall sample. Results A total of 1491 patients (2381 hips) who fulfilled the protocol criteria were included. There were 1039 males and 452 females with a mean age of 47.29 ± 12.69 years. The causes of ONFH were alcoholism in 642 patients (43%), corticosteroid in 439 patients (29%), trauma in 239 patients (16%), and idiopathic ONFH in 171 patients (11%). Operative treatments (including total hip arthroplasty and hip‐preserving procedures) were performed on 49% of patients (43% of hips), chemical medicine therapy (including bisphosphonate, statins, and prostacyclin) was given to 37% of patients (37% of hips), and CHM was administrated to 72% of patients (75% of hips). The aforementioned interventions were not always used alone, since 47% of patients (52% of hips) received combined regimens with multiple interventions. Among hips treated by surgery, all hips with ARCO stage IV ONFH received THA (305 hips), and THA was also performed on 63 hips with stage II ONFH. Over half of hips with stage I (81%), II (91%), and III (92%) ONFH had received pharmacological treatments. Prostacyclin and bisphosphonate were the top two most prescribed medicines used alone. CHM therapies with multiple CHM functions were more commonly prescribed. Conclusion Current treatment modalities for ONFH patients in mainland China include operative treatment, chemical medicine, and CHM. Combined regimens with different treatment modalities are common in real‐world clinical practices., A cross‐sectional study to investigate the application of treatment modalities for patients with osteonecrosis of the femoral head in mainland China based on the China Osteoncrosis of the Femoral Head Database's (CONFHD) online platform.

Objective: To investigate the association between gastrointestinal heat retention syndrome (GHRS) and adult chronic eczema. Methods: This case–control study compared GHRS/GHRS accompanied by damp-heat syndrome (GHRS-DHS) and other patient characteristics between subjects with (cases) and without chronic eczema (controls) to identify potential factors associated with this condition. Semi-structured questionnaires were used to collect data via face-to-face interviews. Participants were recruited from Dongzhimen Hospital affiliated with Beijing University of Chinese Medicine. A logistic regression analysis was performed on the collected data, and odds ratios (ORs) were calculated. Results: A total of 168 cases and 172 controls were recruited. Among the cases of adult chronic eczema, there were 79 subjects with GHRS and 68 with GHRS-DHS. Sex (P = .02, OR = 0.54, 95% confidence interval [CI]: 0.32–0.91), GHRS (P = .04, OR = 1.90, 95% CI: 1.02–3.51), GHRS-DHS (P

The application of the wide-spectrum antibiotic sulfadiazine (SD) in veterinary medicine has created serious environmental issues due to its high mobility and non-degradability. This research details the investigation of SD biodegradation in soil, as well as the degradation pathways of SD by immobilized SD-degrading bacterial strains on a biomass carrier. Soil remediation is generally expected to be more difficult compared with in an aqueous and air environment because of the stealth and diversity of pollutants and the complexity of soil matrices (soil texture, pH and organic matter). In this study, an immobilization system consisting of bagasse and a microorganism is proven to have a high degradation potential, and is non-toxic, low-cost, renewable and applicable for SD biodegradation in soil. Single colonies were obtained by repeatedly streaking cultures supplemented with increment (50 mg L−1) of SD concentration. According to biochemical tests, 16S rDNA gene sequence homology and internal transcribed spacer (ITS) sequence analysis, they are identified as T2 (Enterobacter cloacae) and Z3 (fungal entophyte), respectively. Batch tests were conducted to establish a link between the SD degradation rate and environmental conditions, such as the temperature, pH and heavy metal ions. Under optimum conditions (28 °C, pH = 3.5, 15% inoculation amounts of T2), the degradation of SD in soil reached 78.19%. The degradation pathway of SD is summarized on the basis of the ultra-high performance liquid chromatography-quadrupole time-of-flight (UPLC-Q-TOF) analyses of the biodegradation products.

Rural areas are crucial to the realization of sustainable development goals (SDGs). Rural social capital is indispensable for these areas to fulfil the SDGs. As China pursues rural revitalization, it is essential to achieve the sustainable development of rural areas within the agropastoral transition zone (APTZ) in northern China. The same applies to the SDGs’ realization in other APTZs across the globe. From the micro perspective of individual farmers and herdsmen, this article collected 732 microscopic datapoints through repeated rural surveys, and adopted the multivariate ordered probit model to empirically analyze how the subjective well-being of farmers and herdsmen in northern China’s APTZ was affected by the individual (person) and collective (community) layers of rural social capital. Specifically, the production mode was introduced to study the relationship between social capital and subjective well-being, and social capital was measured by a self-designed theoretical analysis framework, which covered six dimensions and two layers (person and community). It was verified that the individual social capital and collective social capital were mutually replaceable in terms of the effect on the subjective well-being of farmers and herdsmen. Additionally, this article examined the influence of different production modes on the social capital and subjective well-being of farmers and herdsmen, and discussed how the same amount of social capital contributes differently to the subjective well-being of farmers and herdsmen under different production models. The results showed that: (1) Social capital significantly promoted the subjective well-being of farmers and herdsmen, and social network was the leading contributor among the dimensions of individual social capital, while social trust was the leading contributor among the dimensions of collective social capital. By the contribution to the subjective well-being of farmers and herdsmen, the six dimensions of social capital can be ranked as social network > social trust > social participation > social standard > social fame > common vision. (2) Individual social capital and collective social capital were mutually replaceable in terms of enhancing the subjective well-being of farmers and herdsmen; when the individual social capital was insufficient, the collective social capital would exert a much greater influence on the subjective well-being of farmers and herdsmen; when the individual social capital grows, the farmers and herdsmen would depend less on collective social capital. (3) The same amount of social capital contributes differently to the subjective well-being of farmers and herdsmen under different production models; by contribution strength, the production models can be ranked as pure herdsmen (PH) > pure farmers (PF) > non-farmers/herdsmen (NFH) > farmers + herdsmen (FH). Finally, several policy suggestions were provided to improve the subjective well-being of farmers and herdsmen in APTZ. The results show that collective social capital eliminates the negative effect of individual social capital shortage on the subjective well-being of farmers and herdsmen. Thus, it is suggested to consider not only the construction of macroscopic hardware environment, but also to roll out policies and measures to improve the subjective well-being from the micro perspective of farmers and herdsmen. These suggestions are concentrated on the implementation of China’s rural revitalization strategy, and the creation of relevant institutions and cultural environments, as well as the optimization of the internal hierarchy of farmers and herdsmen’s social capital. The research results may help to promote the subjective well-being of farmers and herdsmen in rural areas within the APTZs of China and the world, and provide a reference and a path to realize SDGs in China and similar places across the globe.

The sandstorm in 2021 in East Asia demonstrated the ecological issues that culminated for decades in Mongolia. Mongolia is facing challenges to realize green and sustainable development. This article aims to increase the understanding of eco-efficiency and its influencing factors in Mongolia and to provide a reference for similar developing countries and regions to achieve green and sustainable development. This article used the Slacks-Based Measure of Efficiency (SBM) model with advantages of dimension freedom and unit variable to estimate the economic efficiency and eco-efficiency of 22 provinces in Mongolia from 2007 to 2016, energy consumption and undesirable environmental outputs were taken as ecological/environmental indicators in the input and output system of regional eco-efficiency in Mongolia, combining traditional indicators of economic efficiency to build Mongolia’s eco-efficiency input–output framework. This article applied hot spot analysis and gravity center analysis to reveal the temporal and spatial evolution characters of eco-efficiency in Mongolia. Finally, the article applied panel Tobit regression to analyze the influencing factors of eco-efficiency. We were found that Mongolia’s eco-efficiency slightly improved from 0.7379 in 2007 to 0.7673 in 2016, lower than the economic efficiency. The high eco-efficiency provinces appeared in the capital Ulaanbaatar and its surrounding areas, showing an obvious spatial spillover effect. The low eco-efficiency provinces were mainly in the undeveloped western region. The relationship between per capita GDP and eco-efficiency was U-shaped and consistent with environmental Kuznets theory. Accelerating economic growth, optimizing population distribution, and improving energy structure and green technology can improve Mongolia’s eco-efficiency.

Identifying epigenetic changes is essential for an in-depth understanding of phenotypic diversity and pigs as the human medical model for anatomizing complex diseases. Abnormal sperm DNA methylation can lead to male infertility, fetal development failure, and affect the phenotypic traits of offspring. However, the whole genome epigenome map in pig sperm is lacking to date. In this study, we profiled methylation levels of cytosine in three commercial pig breeds, Landrace, Duroc, and Large White using whole-genome bisulfite sequencing (WGBS). The results showed that the correlation of methylation levels between Landrace and Large White pigs was higher. We found that 1,040–1,666 breed-specific hypomethylated regions (HMRs) were associated with embryonic developmental and economically complex traits for each breed. By integrating reduced representation bisulfite sequencing (RRBS) public data of pig testis, 1743 conservated HMRs between sperm and testis were defined, which may play a role in spermatogenesis. In addition, we found that the DNA methylation patterns of human and pig sperm showed high similarity by integrating public data from WGBS and chromatin immunoprecipitation sequencing (ChIP-seq) in other mammals, such as human and mouse. We identified 2,733 conserved HMRs between human and pig involved in organ development and brain-related traits, such as NLGN1 (neuroligin 1) containing a conserved-HMR between human and pig. Our results revealed the similarities and diversity of sperm methylation patterns among three commercial pig breeds and between human and pig. These findings are beneficial for elucidating the mechanism of male fertility, and the changes in commercial traits that undergo strong selection.

Healthcare‐acquired infections as well as increasing antimicrobial resistance have become an urgent global challenge, thus smart alternative solutions are needed to tackle bacterial infections. Antibacterial materials in biomedical applications and hospital hygiene have attracted great interest, in particular, the emergence of surface design strategies offer an effective alternative to antibiotics, thereby preventing the possible development of bacterial resistance. In this review, recent progress on advanced surface modifications to prevent bacterial infections are addressed comprehensively, starting with the key factors against bacterial adhesion, followed by varying strategies that can inhibit biofilm formation effectively. Furthermore, “super antibacterial systems” through pre‐treatment defense and targeted bactericidal system, are proposed with increasing evidence of clinical potential. Finally, the advantages and future challenges of surface strategies to resist healthcare‐associated infections are discussed, with promising prospects of developing novel antimicrobial materials., This review provides a systematic overview of recent progress on advanced surface modifications to prevent bacterial infections, starting with the key factors against bacterial adhesion, followed by varying strategies that can inhibit biofilm formation effectively. Finally, the advantages and future challenges of surface strategies to resist healthcare‐associated infections are discussed, with promising prospects of developing novel antimicrobial materials.

The studies of iridium (III) complexes as potent anticancer reagents have attracted great attention. Here, a new iridium (III) complex [Ir(bzq)2(PYIP)](PF6) (Ir1, bzq = benzo[h]quinoline, PYIP = 2-(pyren-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) was synthesized and its liposomes (Ir1Lipo) was prepared. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used to detect the cytotoxic activity of Ir1 and Ir1Lipo on HepG2, SGC-7901, BEL-7402, HeLa, B16, A549 and normal NIH3T3 cells. The complex Ir1 displays no obvious inhibitory effect on the growth of BEL-7402 cells, while the Ir1Lipo shows significant cytotoxic activity on BEL-7402 cells (IC50 = 2.6 ± 0.03 μM). In further studies, Ir1Lipo induced apoptosis by the mitochondrial pathways, such as increasing intracellular reactive oxygen species (ROS) content and intracellular Ca2+ level, decreasing the mitochondrial membrane potential (MMP). In addition, after incubation with Ir1Lipo, the colony formation of BEL-7402 cells was significantly inhibited. Moreover, flow cytometry was used to detect the impact of Ir1Lipo on cell cycle distribution, and western blot was used to detect the expression of caspases and Bcl-2 (B-cell lymphoma-2) family proteins. Furthermore, Ir1Lipo exhibited significant antitumor activity in vivo with an inhibitory rate of 65.8%. These results indicated that Ir1Lipo induces apoptosis in BEL-7402 cells through intrinsic mitochondrial pathway.

Background/objective Coronavirus disease 2019 (COVID-19) is a disaster in human medical history and glucocorticoids remain the most promising therapy. Osteonecrosis is a disease caused by reduced intraosseous blood flow to bones in the joints, which will rapidly induce joint destruction. Approximately one-third patients with severe acute respiratory syndrome (SARS) who received high cumulative doses and long treatment durations of glucocorticoids occurred osteonecrosis. Considering the similarity of SARS and COVID-19 on their pathogen, clinical characteristics, and therapeutic strategies, it is particularly desirable to investigate whether osteonecrosis will become a common sequela among convalescent COVID-19 patients. Methods This multi-strategy study was designed by integrating different research methods, such as meta-analysis, systematic review, and cross-sectional investigations to address above study objectives. At first, two meta-analyses were performed on the osteonecrosis incidence among SARS patients and the clinical data of glucocorticoid exposure among COVID-19 patients. Then, a systematic review of low-dosage glucocorticoid associated osteonecrosis and a cross-sectional investigation of glucocorticoid exposure of COVID-19 patients in Wuhan city of China were also conducted. Moreover, the pathogenesis, diagnosis, prevention, and treatment options for osteonecrosis patients with COVID-19 infection were further presented and discussed. Results Our meta-analysis showed that 32% of SARS patients had developed osteonecrosis after receiving glucocorticoid treatment with high dose, and our system review supported that low level glucocorticoid exposure might also lead to the occurrence of osteonecrosis. Similarly, 40% of COVID-19 patients had undergone glucocorticoid treatment according to our meta-analysis. The cross-sectional investigation in Wuhan city of China found that the average of cumulative glucocorticoid exposure level was 504 ​mg calculated by the dosage of methylprednisolone. Notably, a confirmed osteonecrosis case was identified from 1406 patients with COVID-19 during our cross-sectional investigation, implying that preventive management of osteonecrosis should be better started with regular clinical follow-up observation. Conclusion Growing evidence of the glucocorticoid therapy for COVID-19 patients prompts us to establish risk-classification-based early screening and to introduce early prevention protocol of its associated osteonecrosis that will be of clinical significance in favor of improved prognosis of this disease. The translational potential of this article To establish risk-classification-based early screening and to introduce early prevention protocol of glucocorticoid-induced osteonecrosis will be of clinical significance in favor of improved prognosis of COVID-19.

Human norovirus, an RNA virus of the family Caliciviridae, is a common viral pathogen causing acute gastroenteritis of all age groups worldwide. To date, tens of thousands genome sequences of norovirus have been uploaded to NCBI database, more than half of them were epidemic strains of GII.4 or GII.17 genotype. However, sequence information on the non-epidemic norovirus strains remains poorly studied. In this study, an uncommon norovirus genotype, GIX.1[GII.P15], was isolated using Raji cells and the full-genome sequence of the strain was extensively characterized. The norovirus virus particles with a diameter of approximately 30 nm and a morphology of spherical and lace-like appearance were observed by electron microscopy. Viral genome replication in Raji cells were confirmed by real-time quantitative reverse transcription-PCR from viral replication kinetics and passaging experiments of the primary virus. Phylogenetic analysis showed that the strain (KMN1) belonged to the GIX.1[GII.P15] genotype and indicated that no recombination has occurred in this strain thus far. Further compared analysis of the full genome sequence with the consensus sequence of GIX.1[GII.P15] genomes revealed a total of 81 nucleotide substitutions (53 in ORF1, 20 in ORF2, and 8 in ORF3) across the genome, but only 6 substitutions resulted in amino acid changes (3 in ORF1, 1 in ORF2, and 2 in ORF3). Moreover, one amino acid substitution at the 302 amino acid site (P302S) was observed in the P2 domain of the capsid protein, and the site was around one of the predicted conformational epitopes on the VP1 protein structure. The genomic information obtained from the novel strain may extend the understanding of the non-epidemic GIX.1[GII.P15] strains.

Quantitative and multiparametric blood analysis is of great clinical importance in cardiovascular disease diagnosis. Current blood analysis methods are typically restricted to invasiveness, bulky instruments and complicated clinical procedures. Wearable devices can realize on-skin assessment of several vital signals but generally exhibit very limited blood analyzing functions. Here, we report a flexible optoacoustic blood stethoscope (OBS) for multiparametric cardiovascular monitoring, bypassing the need for invasive procedures. The device features the light delivery elements for blood illumination and the piezoelectric acoustic elements capable of capturing the light-induced acoustic waves. This flexible device can adhere to the skin for continuous and non-invasive in-situ monitoring of multiple cardiovascular biomarkers, including hypoxia, drug concentration decay, and hemodynamics, which can be further visualized with the tailored 3D algorithm. Demonstrations on both in-vivo animal trials and human subjects highlight the OBS's unique potential to provide a new avenue for cardiovascular disease diagnosis and prediction.

Nonhealing wounds have become a major healthcare burden worldwide. Chronic wound healing is universally hampered by the presence of bacterial infections that form biofilms. Therefore, in this study, a novel nanoliquid dressing based on a mild photothermal heating strategy was designed to provide safe healing of biofilm-infected wounds. Dilute nitric acid (HNO3) solution was employed to induce a redox process triggered by copper sulfide (CuS) nanoplates in the nanoliquid dressing. This redox process was further promoted by the mild photothermal effect (≤47.5 °C) that generated a sufficient amount of reactive oxygen species, resulting in less thermal injury to normal tissues. Correspondingly, with the safe concentration of CuS nanoplates (0.4 mg/mL), excellent bactericidal efficiencies up to 98.3 and 99.3% against ampicillin-resistant Escherichia coli (Ampr E. coli) and Staphylococcus aureus (S. aureus) were achieved, respectively. Moreover, the nanoliquid dressing exhibited a near-infrared enhanced destructive effect on mature biofilms. According to in vivo wound healing experiments in mice, the nanoliquid dressing increased the healing rate and reduced the inflammatory response. This study provides a novel insight into treating the biofilm-infected chronic wounds in the "post-antibiotic era".

To prolong the service life of asphalt pavement in coastal areas, firstly, the continuous immersion, dry-wet cycle and freeze-thaw cycle in 0% (pure water), 5% and 10% NaCl solution were selected to speed up the corrosion of salty and humid environment on asphalt mixture. The changing law of mechanical property of asphalt mixture was studied by splitting test. Then the deterioration of microstructure and road performance of asphalt mixture in salty and humid environment was tested by laboratory tests. Finally, the effects of additives such as anti-stripping agent, fiber and hydrated lime on water stability and mechanical property of asphalt mixture were studied. The test results show that the splitting strength of asphalt mixture gradually decreases with the increase of action number after treated by different ways. The method of dry-wet cycle reflects the adverse effect of salty and humid environment on the performance of asphalt mixture better. Dry-wet cycle in 10% NaCl solution for twelve times is recommended to simulate the corrosion effect of salty and humid environment. After treated by dry-wet cycle in 10% NaCl solution, the high temperature performance, low temperature crack resistance and water stability of asphalt mixture all decrease by various degrees. Especially the water stability declines seriously, which residual stability and freeze-thaw splitting strength ratio cannot meet the requirement of specification. The void ratio of asphalt mixture increases first and then stabilizes with the increase of dry-wet cycles. The chloride crystal precipitates and continues to expand in the mixture, which eventually leads to the performance deterioration of asphalt mixture. Among different additives, basalt fiber achieves best effect in combating the deterioration of asphalt mixture in salty and humid environment.

Liver cirrhosis of hepatitis B is an immune-related disease in which liver cells die during the body’s immune system activation to clear the virus, and the progress is closely related to T lymphocytes. T lymphocyte cells recognise antigens, specifically by major histocompatibility complex (MHC), through a membrane protein T cell receptor (TCR). Here, we used high throughput immune repertoire sequencing technique to study the characteristics and diversity of the TCR repertoire between patients who underwent liver transplantation and healthy controls (NC). We sequenced the TCR β-chain complementary-determining region 3 (CDR3) repertoire in peripheral blood mononuclear cells (PBMCs) from 6 liver transplantation patients before transplantation (Pre) and on the first (Post1) and seventh days (Post7) after transplantation along with 6 NC. We observed that the distributions of CDR3, VD indel, and DJ indel lengths were similar among the Pre, Post1, Post7 and NC groups. We found that the TCR repertoire diversity of transplantation groups was relatively lower compared to NC group. The Pre-group had more highly expanded T cell clones compared to Post1, Post7 and NC groups, and the diversity of the T cell repertoire of the Post7 group was significantly decreased compared to the Pre, Post1 and NC groups. In addition, we found our results also show that various TRBV expression increased and some public sequences at different time points after liver transplantation, and the expression levels of 3 TRBV segments and 2 TRBJ segments were also significantly different in Pre, Post1, Post7 and NC groups. Moreover, 1 aa sequence shared by all liver transplantation patients and 2 aa sequences shared by at least two groups, which may serve as biomarkers to monitor the immune status of liver transplant patients.

Polycyclic aromatic hydrocarbons (PAHs) are of high concern to public health due to their carcinogenic and mutagenic properties. Here, we present the first comprehensive and quantitative analysis of sources, potential source regions according to source sectors and source-related human health risks of multi-year atmospheric measurements of PAHs in the Canadian Great Lakes Basin (GLB). The highest PAH concentrations were observed at a rural residential site (Egbert), followed by two regionally representative remote sites [Point Petre (PPT) and Burnt Island]. The levels of most PAHs in the GLB atmosphere significantly decreased between 1997 and 2017, broadly consistent with the decreasing trends of anthropogenic emissions. Coal, liquid fossil fuel, and biomass burning were the most common potential sources. The potential source regions for most source sectors were identified south or southwest of the sampling sites. Risk assessment suggests potential health risks associated with the inhalation of atmospheric PAHs. On a positive note, health risks from coal combustion, liquid fossil fuel combustion, and petrogenic sources at PPT significantly decreased, directly demonstrating the success of emission control in reducing health impacts. In contrast, the health risk from forest fire-related PAH emissions may play an increasing role in the future due to climate change.

Background: Coronavirus disease 2019 (COVID-19) is an emerging global medical challenge and glucocorticoids remain the most promising therapy. Osteonecrosis (ON) is a disease caused by reduced blood flow to bones in the joints, which will rapidly induce joint destroy. ON had been frequently identified among convalescent patients after Severe Acute Respiratory Syndrome (SARS). Considering the similarity of SARS and COVID-19 on their pathogen, clinical characteristics and therapeutic strategies, it is particularly worrying whether ON will be a common sequela among convalescent COVID-19 patient. Methods: This multi-strategy study integrating different research methods, such as meta-analysis, systematic review and cross-sectional investigation. At first, two meta-analyses were performed on the incidence of osteonecrosis among SARS patients and the clinical data of glucocorticoid exposure among COVID-19 patients. Then, a systematic review of low-dosage glucocorticoid associated osteonecrosis and a real-world cross-sectional investigation of glucocorticoid exposure of COVID-19 patients in China Wuhan were also provided. Moreover, the pathogenesis, diagnosis, prevention, and treatment options for osteonecrosis after COVID-19 infection were further described. Findings: Our meta-analysis showed that 32% of SARS patients had developed ON after receiving glucocorticoid treatment with high dose, and our system review also supported that low level glucocorticoid exposure may lead to the occurrence of ON. Similarly, 40% of COVID-19 patients had undergone glucocorticoid treatment according to our meta-analysis. The cross-sectional investigation in China Wuhan found that the average of cumulative glucocorticoid exposure level was 504 mg calculated by the dosage of methylprednisolone. Notably, a confirmed osteonecrosis case after COVID-19 was identified during our investigation. Preventive management of ON shall better start with regular clinical followup observation. Interpretation: Growing evidence of the glucocorticoid therapy for COVID-19 patients prompts us to put forward the risk-classification-based early screening and early prevention protocol of ON, which may be of clinical significance in favorable prognosis of this disease. Registration Details: PROSPERO, registration number CRD42020203536. Funding Information: This study was supported by the Special Project For COVID-19 Prevention and Management of Ministry of Education of China (2020-JYB-YJ-023), the National Key Research and Development Program of China (2019ZX09731-002) and the State Key Program of National Natural Science Foundation of China (82030122). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The protocol for the investigation study has been registered in the Chinese Clinical Trial Registry (ChiCTR), (URL: http://www.chictr.org.cn/showproj.aspx?proj=61769, No. ChiCTR2000038333). This study was approved by the Ethics Institutional Review Board of the Third Affiliated Hospital of Beijing University of Chinese Medicine (No. BZYSY-2020KYKTPJ-06), and informed consent was obtained from every participant patient.

SUMMARY Patients with chronic myeloid leukaemia and chronic lymphocytic leukaemia are now predominantly managed in an outpatient setting, with infrequent need for hospital-based therapy. New targeted oral treatments have transformed survival outcomes. An increasing number of patients now have a life expectancy approaching that of the general population. Suboptimal drug adherence is common and a key reason for therapy failure and poor clinical outcomes. The pharmacokinetics of new oral targeted drugs are significantly impacted by drug–drug interactions and an altered gastric pH. Long-term use of some of the new oral drugs is associated with complications, including cardiovascular events and infections, which can be fatal if not recognised.

The leaf epidermis is a dynamic biomechanical shell that integrates growth across spatial scales to influence organ morphology. Pavement cells, the fundamental unit of this tissue, morph irreversibly into highly lobed cells that drive planar leaf expansion. Here we define how tissue-scale cell wall tensile forces and the microtubule-cellulose synthase systems pattern interdigitated growth in real-time. A morphologically potent subset of cortical microtubules span the periclinal and anticlinal cell faces to pattern cellulose fibers that generate a patch of anisotropic wall. The result is local polarized growth that is mechanically coupled to the adjacent cell via a pectin-rich middle lamella, and this drives lobe formation. Finite element pavement cell models revealed cell wall tensile stress as an upstream patterning element that links cell- and tissue-scale biomechanical parameters to interdigitated growth. Cell lobing in leaves is evolutionarily conserved, occurs in multiple cell types, and is associated with important agronomic traits. Our general mechanistic models of lobe formation provide a foundation to analyze the cellular basis of leaf morphology and function.

A series of novel isocombretapyridines were designed and synthesized based on a lead compound isocombretastatin A-4 (isoCA-4) by replacing 3,4,5-trimethoxylphenyl with substituent pyridine nucleus. The MTT assay results showed that compound 20a possessed the most potent activities against all tested cell lines with IC50 values at nanomolar concentration ranges. Moreover, 20a inhibited tubulin polymerization at a micromolar level and also displayed potent anti-vascular activity in vitro. Further mechanistic studies were conducted to demonstrate that compound 20a could bind to the colchicine site of tubulin,and disrupte the cell microtubule networks, induce G2/M phase arrest, promote apoptosis and depolarize mitochondria of K562 cells in a dose-dependent manner. Notably, 20a exhibited more potent tumor growth inhibition activity with 68.7% tumor growth inhibition than that of isoCA-4 in H22 allograft mouse model without apparent toxicity. The present results suggested that compound 20a may serve as a promising potent microtubule-destabilizing agent candidate for the development of therapeutics to treat cancer.

Background: Environmental risk factors, including environmental noise stress, and genetic factors, have been associated with the occurrence and development of Alzheimer’s disease (AD). However, the exact role and mechanism of AD-like pathology induced by environment-gene interactions between environmental noise and APP/PS1 gene remain elusive. Methods: Herein, we investigated the impact of chronic noise exposure on AD-like neuropathology in APP/PS1 transgenic mice. The Morris water maze (MWM) task was conducted to evaluate AD-like changes. The hippocampal phosphorylated Tau, amyloid-β (Aβ), and neuroinflammation were assessed. We also assessed changes in positive feedback loop signaling of the voltage-dependent anion channel 1 (VDAC1) to explore the potential underlying mechanism linking AD-like neuropathology to noise-APP/PS1 interactions. Results: Long-term noise exposure significantly increased the escape latency and the number of platform crossings in the MWM task. The Aβ overproduction was induced in the hippocampus of APP/PS1 mice, along with the increase of Tau phosphorylation at Ser396 and Thr231 and the increase of the microglia and astrocytes markers expression. Moreover, the VDAC1-AKT (protein kinase B)-GSK3β (glycogen synthase kinase 3 beta)-VDAC1 signaling pathway was abnormally activated in the hippocampus of APP/PS1 mice after noise exposure. Conclusion: Chronic noise exposure and APP/PS1 overexpression may synergistically exacerbate cognitive impairment and neuropathological changes that occur in AD. This interaction may be mediated by the positive feedback loop of the VDAC1-AKT-GSK3β-VDAC1 signaling pathway.

Protein-protein interactions (PPIs) are important for almost all cellular processes, including metabolic cycles, DNA transcription and replication, and signaling cascades. The experimental methods for identifying PPIs are always time-consuming and expensive. Therefore, it is important to develop computational approaches for predicting PPIs. In this paper, an improved model is proposed to use a machine learning method in the study of protein-protein interactions. With the consideration of the factors affecting the prediction of the PPIs, a method of feature extraction and fusion is proposed to improve the variety of the features to be considered in the prediction. Besides, with the consideration of the effect affected by the different input order of the two proteins, we propose a “Y-type” Bi-RNN model and train the network by using a method which both needs backward and forward training. In order to insure the training time caused on the extra training either a backward one or a forward one, this paper proposes a weight-sharing policy to minimize the parameters in the training. The experimental results show that the proposed method can achieve an accuracy of 99.57%, recall of 99.36%, sensitivity of 99.76%, precision of 99.74%, MCC of 99.14%, and AUC of 99.56% under the benchmark dataset.

Aim: A series of novel isothio- and isoselenochromanone derivatives bearing N-benzyl pyridinium moiety were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Results: Most of the target compounds exhibited potent anti-AChE activities with IC50 values in nanomolar ranges. Among them, compound 15a exhibited the most potent anti-AChE activity (IC50 = 2.7 nM), moderate antioxidant activity and low neurotoxicity. Moreover, the kinetic and docking studies revealed that compound 15a was a mixed-type inhibitor, which bounds to peripheral anionic site and catalytic active site of AChE. Conclusion: Those results suggested that compound 15a might be a potential candidate for AD treatment.

Aim To investigate the effect of propofol on the migration and invasion of oral squamous cell carcinoma (OSCC) cells and explore the underlying mechanism. Main methods Cal-27 and SCC-25 cells treated with or without propofol, then the cells metastasis were determined. The levels of SNAI1 mRNA and protein were detected by real-time PCR and western blot. Cell migration ability was evaluated by wound healing assay, and the invasion of cells was measured using transwell assay. Key findings Propofol treatment significantly promoted cell migration and invasion of OSCC. Further mechanistic studies of the stimulating effects of propofol on OSCC cell metastasis revealed that propofol treatment dose-dependently upregulated the expression of SNAI1, a member of the Snail superfamily of zinc-finger transcription factors. Additionally, the inhibition of endogenous SNAI1 expression reversed the effect of propofol on cell migration and invasion in Cal-27 and SCC-25 cells. Significance Our results demonstrate that propofol at clinically relevant concentrations facilitates cell migration and invasion through up-regulation of SNAI1 in OSCC cells, and suggest propofol may not be suitable for anesthesia management in OSCC patients.

Background People with biomarkers above cut-off values normally have higher risk to develop pre-malignancies and malignancies. Objective Here we investigate if serological TK1 protein (STK1p), AFP, CEA and PSA below cut-off values predict development of pre-cancer. Methods The mean values and the concentration distribution of STK1p, AFP, CEA and PSA were determined in a cohort of 56,178 persons participating a health screening group, consist of people with non-tumor diseases, pre-malignancy and diseases associated with the risk process of malignancy. A health disease-free group (n= 428) was selected among the 56,178 participants and used as controls. Results The STK1p below cut-off value (⩽ 2 pM) showed partly (51.6%) an almost normal concentration distribution and partly (43.9%) an extensive tail in the health screening group, which was not found in the disease-free group. Due to the extensive tail in the distribution, the mean value of STK1p increased significantly (p= 0.0001) from 0.38 ± 0.30 pM in the health disease-free group to 0.69 ± 0.55 pM in the group below the cut-off value. No significantly differences in the concentration distribution and the mean values among gender and ages were observed. On the other hand, there were no difference in the concentration distributions and the mean values of AFP, CEA and PSA between the health disease - free group and the group below cut-off values, as well as between gender and ages. Of interest, the elevated mean value of STK1p of the group below the cut-off value was correlated to pre-malignancy and diseases associated with the risk process of malignancy in liver and prostate. No such correlations were found with AFP, CEA and PSA. Conclusion STK1p is a potential proliferating biomarker for early discover of persons in the risk to develop or already have pre-malignancies or diseases associated with the risk process of malignancy.

Outpatient parenteral antibiotic therapy (OPAT) is a widely accepted and safe therapeutic option for carefully selected patients. This study reviewed the practice of an OPAT service in a large Australian tertiary teaching hospital in Western Sydney over a 10-year period. Data were retrieved from a prospectively maintained electronic database which included information on patient demographics, clinical diagnosis, microbiological identity, antimicrobial therapy, complications and readmissions. Data were analysed using descriptive statistics. There were 3435 referrals made to the service between January 2004 and June 2014, amounting to 25,289 antibiotic days. The most frequent referral was for Skin and Soft Tissue Infections (SSTIs), 61.28%, followed by Bone and Joint Infections (BJIs), 15.30%. The most common organism identified was methicillin-sensitive Staphylococcus aureus. Readmission was uncommon (5.15%), with the highest rate of readmission noted for Cardiovascular System Infections (16.67%) followed by BJIs (10.31%). Line infection, aseptic thrombophlebitis and drug hypersensitivity or reaction were the cause of 68.55% of all complications. There was a decline in line-related complications throughout the study period. OPAT service is in increasing demand in Australia, providing a significant relief in in-hospital days. Growth in referrals was seen not only with SSTIs and BJIs, but also a diverse range of other infective entities with limited literature in its treatment in an OPAT setting. This study highlights the need to improve data collection, develop risk stratification strategies and standardisation of OPAT services in Australia.