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Aim. We sought to profile gut microbiota’s role in combination of Bu Fei Hua Yu (BFHY) with cisplatin treatment. Methods. Non-small cell lung cancer (NSCLC) mice model were constructed followed by treatment with cisplatin alone or combined with BFHY. Mice weight and tumor volume were measured during the experiment. And mice cecum were detected by hematoxylin and eosin, cecum contents were collected for Enzyme Linked ImmuneSorbent Assay, and stool were profiled for metagenomic sequencing. Results. Combination of BFHY with cisplatin treatment decreased the tumor growth and relieved the damage of cecum. Expressions of interleukin-6 (IL-6), interleukin-1β (IL-1β), monocyte chemotactic protein 1 (MCP), and interferon-γ (IFN-γ) were decreased compared with cisplatin treatment alone. Linear discriminant analysis effect size analysis showed that g_Parabacteroides was downregulated and g_Escherichia and g_Blautia were upregulated after cisplatin treatment. After combination with BFHY, g_Bacteroides and g_Helicobacter were decreased. g_Klebsiella, g_Unclssified_Proteobacteria, and g_Unclssified_Clostridiates were increased. Moreover, heatmap results showed that Bacteroides abundance was increased significantly after cisplatin treatment; BFHY combination treatment reversed this state. Function analysis revealed that multiple functions were slightly decreased in cisplatin treatment alone and increased significantly after combination with BFHY. Conclusion. Our study provided evidence of an efficacy of combination of BFHY with cisplatin on treatment of NSCLC and revealed that gut microbiota plays a role in it. The above results provide new ideas on NSCLC treatment.

Phase segregation is ubiquitously observed in immiscible mixtures, such as oil and water, in which the mixing entropy is overcome by the segregation enthalpy1–3. In monodispersed colloidal systems, however, the colloidal–colloidal interactions are usually non-specific and short-ranged, which leads to negligible segregation enthalpy4. The recently developed photoactive colloidal particles show long-range phoretic interactions, which can be readily tuned with incident light, suggesting an ideal model for studying phase behaviour and structure evolution kinetics5,6. In this work, we design a simple spectral selective active colloidal system, in which TiO2 colloidal species were coded with spectral distinctive dyes to form a photochromic colloidal swarm. In this system, the particle–particle interactions can be programmed by combining incident light with various wavelengths and intensities to enable controllable colloidal gelation and segregation. Furthermore, by mixing the cyan, magenta and yellow colloids, a dynamic photochromic colloidal swarm is formulated. On illumination of coloured light, the colloidal swarm adapts the appearance of incident light due to layered phase segregation, presenting a facile approach towards coloured electronic paper and self-powered optical camouflage.

In recent years, research on nanoparticles (NPs) has brought a new phase in the development of medicine. The term “NPs” refers to nanoscale particles, typically between 10 and 1,000 nm in size, that are within the range of cellular and molecular structures. Compared with traditional ophthalmic drugs, NPs can carry drugs to overcome obstacles, target drug delivery, prolong drug release, reduce drug toxicity, and can be used in gene therapy. After a brief introduction to the classification of NPs, we will focus on the potential applications of different NPs in the diagnosis and treatment of different retinal diseases and introduce innovative methods derived from NPs.

Introduction: Observational studies highlight associations of common diseases with individual schizophrenia symptoms. However, it is unclear whether these diseases are associated with individual treatment-resistant schizophrenia (TRS). We aimed to explore the genetic associations between common immune diseases, metabolic diseases, psychiatric disorders, gut microbiota and TRS. Methods: Genome-wide association study (GWAS) summary data of European participants (n = ∼456,327) included TRS, 11 psychiatric disorders, 23 immune and metabolic diseases, body mass index, height, and 211 gut microbiota. In this genetic correlation and two-sample Mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with common immune diseases, metabolic diseases, psychiatric disorders, and gut microbiota with TRS. Results: LDSC revealed candidate associations between attention deficit/hyperactivity disorder (ADHD), schizophrenia, intestinal infectious diseases, obesity and TRS (genetic correlation range, 0.230–0.702; p < 0.05). Two-sample MR analyses suggested that ADHD was positively associated with TRS (estimate [SE] = 0.204 [0.073], p = 0.005), a finding that remained stable across statistical models. Besides, schizophrenia and genus Barnesiella levels were causally associated with TRS but not consistent across MR approaches. Conclusion: This study reports genetic correlations between ADHD, schizophrenia, intestinal infectious diseases, obesity and TRS. The study also found that genus Barnesiella was associated with TRS. These findings may have clinical implications, highlighting the possible strategy for TRS prevention.

Psychiatric disorders have great health hazards and the exact pathogeny remains elusive now. We aim to explore the potential interaction effects of mitochondrial function and human behavior on the risks of anxiety and depression.The genome-wide association study (GWAS) data of mitochondrial function (N = 383,476-982,072) were obtained from published studies. Individual level genotype and phenotype data of anxiety, depression and behavioral factors (including drinking, smoking and physical activity) were all from the UK Biobank (N = 84,805-85,164). We first calculated the polygenic risk scores (PRS) of mitochondrial function as the instrumental variables, and then constructed linear regression analyses to systematically explore the potential interaction effects of mitochondrial function and human behavior on anxiety and depression.In total samples, we observed mitochondrial heteroplasmy (MtHz) vs. Drinking (PConsidering all subjects were from UK Biobank, it should be careful to extrapolate our findings to other populations with different genetic background.Our results suggest the significant impacts of mitochondrial function and human behavior interactions on the development of anxiety and depression, providing new clues for clarifying the pathogenesis of anxiety and depression.

Cu7S4 nanosheets enriched with Cu–S bond can facilitate the kinetics of CO2 electroreduction to HCOO− and suppress the formation of *CO as a result of the high FE of HCOO− (82.7%) and high partial current density (456 mA cm−2).

Searchable encryption (SE) is a powerful technology that enables keyword-based search over encrypted data becomes possible. However, most SE schemes focus on exact keyword search which can not tolerate misspellings and typos. Existing fuzzy keyword search schemes only support fuzzy search within a limited similarity threshold d, the storage cost will grow exponentially or the precision of search results will greatly decrease as $d$ increases. Moreover, the current fuzzy keyword ranked search schemes consider only the keyword weight, and disregard the influence of keyword morphology similarity on the ranking. In this paper, we propose a scalable fuzzy keyword ranked search scheme over encrypted data under hybrid clouds architecture. We use the edit distance to measure the similarity of keywords and design an edit distance algorithm over the encrypted database, in which our scheme achieves fuzzy keyword search for any similarity threshold d with constant storage size and accurate search results. Furthermore, we design a two-factor ranking function combining keyword weight with keyword morphology similarity, which is utilized to rank the search results and enhance system usability. Extensive experiments are performed to demonstrate the trade-off of efficiency and security of the proposed scheme.

Surface and lattice engineered Mo-modified Ru superstructures have been prepared with high performance for bifunctional hydrogen catalysis (HER and HOR).

Previous studies have suggested a potential association between sleep and telomere length (TL), but its genetic basis remains unclear. In this study, we aimed to explore the genetic correlation and potential causal association between TL and insomnia.The genome-wide association study (GWAS) datasets of TL and insomnia-related traits were used, including insomnia, snoring, daytime dozing and napping. Based on the polygenic risk scores (PRS) of TL, linear regression and linkage disequilibrium score (LDSC) regression were used to preliminarily explore the association between TL and insomnia parameters in the UK Biobank cohort. Then, we investigated the causal association between TL and insomnia by mendelian randomization (MR) analysis and colocalization analysis.In the UK Biobank cohort, the association between TL and insomnia was observed in the female samples (t = 2.968, P = 3.00 × 10Our study found no evidence for causal association between insomnia and TL in individuals of European ancestry. We detected a candidate gene associated with both insomnia and TL, providing novel clues for understanding the roles of this association.

OBJECTIVE: The purpose of this study was to assess the effects of moving cupping therapy in people with colorectal cancer (CRC) experiencing chemotherapy-related side effects. METHODS: A prospective observational study was conducted in people diagnosed with CRC who were treated for the side effects of their chemotherapy. Participants received cupping therapy 3 times a week for 10 consecutive weeks at our traditional Chinese medicine ward. Their quality of life and meridian energies were evaluated both at baseline and at 3 months after the treatment course. RESULTS: Forty-six individuals with CRC were enrolled and 34 completed the study. The average number of cycles of chemotherapy during the study was 4.5. The mean number of moving cupping treatments was 25.7. After the moving cupping treatment program, participants exhibited significant improvements in quality of life, physical function, fatigue, nausea/vomiting, sleep disturbance, and pain. CONCLUSION: For the participants in this study, moving cupping therapy relieved some chemotherapy-related side effects and improved quality of life in people with CRC.

Disrupted brain structures and several life environmental factors have been shown to influence depression and anxiety, but their interactions with anxiety and depression remain elusive. Genome-wide association study datasets of 15 brain structure longitudinal changes (N = 15,640) were obtained from the published study. Genotype and phenotype-related data of depression, anxiety, and life environmental factors (including smoking, alcohol drinking, coffee intake, maternal smoking, physical activity, vitamin D, insomnia, sleep duration, and family satisfaction) were collected from UK Biobank. We calculated the polygenic risk scores (PRS) of 15 brain structure changes and then conducted linear regression analyses to explore the interactions of brain structure changes and life environmental factors on depression and anxiety using 15 brain structure change-related PRS, life environmental factors and interactions of them as instrumental variables, and depression score or anxiety score as outcomes. Sex stratification in all analyses was performed to reveal sex-specific differences in the interactions. We found 14 shared interactions related to both depression and anxiety in total sample, such as alcohol drinking × cerebellum white matter 3 (WM; beta = -.003, p = .018 for depression; beta = -003, p = .008 for anxiety) and maternal smoking × nucleus accumbens 2 (beta = .088, p = .002 for depression; beta = .070, p = .008 for anxiety). We also observed sex-specific differences in the interactions, for instance, alcohol drinking × cerebellum WM 3 was negatively associated with depression and anxiety in males (beta = -.004, p = .020 for depression; beta = -.005, p = .002 for anxiety). Our study results reveal the important interactions between brain structure changes and several life environmental factors on depression and anxiety, which may help to explore the pathogenesis of depression and anxiety.

Age-related cognitive slowing is a prominent precursor of cognitive decline. Functional neuroimaging studies found that cognitive processing speed is associated with activation and coupling among frontal, parietal and cerebellar brain networks. However, how the reciprocal influences of inter- and intra-network coupling mediate age-related decline in processing speed remains insufficiently studied. This study examined how inter- and intra-brain network influences mediate age-related slowing. We were interested in the fronto-insular salience network (SN), frontoparietal dorsal attention network (DAN), cerebellar network (CN) and default mode network (DMN). Reaction time (RT) and functional MRI data from 84 participants (aged 18–75) were collected while they were performing the Arrow Task in visual or audial forms. At the subject level, effective connectivities (ECs) were estimated with regression dynamic causal modelling. At the group level, structural equation models (SEMs) were used to model latent speed based on age and the EC mediators. Age was associated with decreased speed and increased inter-network effective connectivity. The CN exerting influence on the DAN (CN → DAN EC) mediated, while the SN → DAN EC suppressed age-related slowing. The DMN and intra-network ECs did not seem to play significant roles in slowing due to ageing. Inter-network connectivity from the CN and SN to the DAN contributes to age-related slowing. The seemingly antagonizing influences of the CN and SN indicate that increased task-related automaticity and decreased effortful control on top-down attention would promote greater speed in older individuals.

Photodynamic therapy (PDT) is a robust cancer treatment modality, and the precise spatiotemporal control of its subcellular action site is crucial for its effectiveness. However, accurate comparison of the efficacy of different organelle-targeted PDT approaches is challenging since it is difficult to find a single system that can achieve separate targeting of different organelles with separable time windows and similar binding amounts. Herein, we conjugated chlorin e6 (Ce6) with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-5000] (ammonium salt) (DSPE-PEG

Haemophilus influenzae (H. influenzae), Streptococcus pneumoniae (pneumococcus) and influenza vaccines are administered in children to prevent infections caused by these pathogens. The benefits of vaccination for asthma control in children and the elicited immune response are not fully understood. This study aimed to investigate the impact of these vaccinations on respiratory infections, asthma symptoms, asthma severity and control status, pathogen colonization and in vitro immune responses to different stimulants mimicking infections in asthmatic children.Children aged 4-6 years were recruited into the multicentre prospective PreDicta study conducted across five European countries. Information about vaccination history, infections, antibiotic use, inhaled corticosteroid (ICS) use and asthma symptoms in the last 12 months were obtained from questionnaires of the study. Nasopharyngeal samples were collected at the first visit to assess bacterial and viral colonization, and venous blood for isolation of peripheral blood mononuclear cells (PBMCs). The PBMCs were stimulated with phytohemagglutinin, R848, Poly I:C and zymosan. The levels of 22 cytokines and chemokines were measured in cell culture supernatants using a luminometric multiplex assay.One-hundred and forty asthmatic preschool children (5.3 ± 0.7 years) and 53 healthy children (5.0 ± 0.8 years) from the PreDicta cohort were included in the current study. Asthmatic children were associated with more frequent upper and lower respiratory infections, and more frequent and longer duration of antibiotic use compared with healthy children. In asthmatic children, sufficient H. influenzae vaccination was associated with a shorter duration of upper respiratory infection (URI) and overall use and average dose of ICS. The airway colonization was characterized by less pneumococcus and more rhinovirus. Pneumococcal vaccination was associated with a reduction in the use rate and average dose of ICS, improved asthma control, and less human enterovirus and more H. influenzae and rhinovirus (RV) airway colonization. Influenza vaccination in the last 12 months was associated with a longer duration of URI, but with a decrease in the occurrence of lower respiratory infection (LRI) and the duration of gastrointestinal (GI) infection and antibiotic use. Asthmatic preschoolers vaccinated with H. influenzae, pneumococcus or influenza presented higher levels of Th1-, Th2-, Th17- and regulatory T cells (Treg)-related cytokines in unstimulated PBMCs. Under stimulation, PBMCs from asthmatic preschoolers with pneumococcal vaccination displayed a predominant anti-inflammatory immune response, whereas PBMCs from asthmatic children with sufficient H. influenzae or influenza vaccination were associated with both pro- and anti-inflammatory immune responses.In asthmatic preschoolers, the standard childhood vaccinations to common respiratory pathogens have beneficial effects on asthma control and may modulate immune responses relevant to asthma pathogenesis.

A multiplex qPCR assay was developed to simultaneously detect duck circovirus (DuCV), duck Tembusu virus (DTMUV), Muscovy duck reovirus (MDRV), and novel duck reovirus (NDRV), but it did not amplify other viruses, including duck virus enteritis (DVE), infectious bursal disease virus (IBDV), avian reovirus (ARV), H5 avian influenza virus (H5 AIV), H7 avian influenza virus (H7 AIV), H9 avian influenza virus (H9 AIV), Newcastle disease virus (NDV), and Muscovy duck parvovirus (MDPV), and the detection limit for DuCV, DTMUV, MDRV, and NDRV was 1.51 × 10

This study aims to numerically investigate the behaviour of corroded circular reinforced concrete (RC) columns strengthened by carbon-fabric-reinforced cementitious matrix (C-FRCM) composites. Three-dimensional finite element (FE) models of the corroded circular RC columns with and without strengthening were set up and validated against previous experimental results. Based on the validated FE models, the parametric studies were carried out to investigate the effects of axial compression ratio, degree of corrosion and layer of carbon fabrics on the behaviour of corroded RC columns under cyclic loading. It shows that the lateral load resistance increased when the axial compression ratio ranged from 0.3 to 0.4, but decreased when the axial compression ratio ranged from 0.4 to 0.6; also the ductility of the corroded RC columns reduced with increasing axial compression ratio. The ultimate capacity of corroded RC columns decreased gradually with the increasing degree of corrosion. Based on the results of parametric studies, equations were developed to estimate the ultimate capacity and displacement of the corroded RC columns repaired by the C-FRCM. The proposed equations can well estimate the ultimate lateral load resisting capacity and ultimate displacement of the corroded circular RC columns strengthened by C-FRCM.

To explore the roles of rare and high-impact variants in sleep duration.Based on the recently released UK Biobank 200k exome dataset, an exome-wide association study was conducted to detect rare variants (minor allele frequency0.01) contributing to sleep duration. Variant annotations were performed by the software tool ANNOVAR. Gene-based burden tests of sleep duration were conducted by the SKAT R-package. After quality control, 137,047 subjects were included in this study. CAUSALdb database was used to explore the related mental traits of identified genes.We detected 730,572 variants with MAF1%, including 3873 frameshift variants, 3977 nonframeshift variants, 449,632 nonsynonymous variants, 1293 startloss variants, 10,254 stopgain variants, 413 stoploss variants, 261,130 synonymous variants, and 3102 variants are annotated as unknown. The burden test of exonic variants detected two exome-wide significant associations for sleep duration including TMIE at 3p21.31 (PThis study reported 2 novel candidate genes for a sleep duration, supporting the roles of rare genetic variants in the regulation of sleep duration.

PurposeThe overuse and scarcity of resources emphasize the importance of the circular economy. The technology facilitated by Industry 4.0 stimulates the implementation of the circular economy that aims to reduce resource use and enhance operational efficiency. This study focuses on enhancing delivery efficiency in an online-to-offline (O2O) context from an Industry 4.0 technology-facilitated personal configuration perspective, that is, comparing in-house and crowdsourced delivery efficiency in China's O2O on-demand food delivery context.Design/methodology/approachThe authors collect 128,152 orders from 38 restaurants of an online restaurant chain in China. The authors adopt multiple regression analysis to examine the delivery efficiency gap between in-house and crowdsourced deliverymen and the determinants of this efficiency gap.FindingsThe findings of this study reveal that crowdsourced deliverymen exhibit higher delivery efficiency, in terms of a shorter delivery time, than in-house deliverymen. In addition, the authors find that platforms providing monetary incentives or implementing late delivery penalties enlarge this efficiency gap. Furthermore, the authors show that external factors, such as working on weekends and bad weather conditions, contribute to the narrowing of this performance efficiency.Practical implicationsThe study's findings suggest that platforms should use advanced technologies facilitated by Industry 4.0 to optimize their personnel configuration to enhance their delivery efficiency and reduce carbon emissions. The effective approaches include using financial incentives and improving working schedules.Originality/valueThe authors' findings contribute to the online fulfillment literature by focusing on delivery efficiency in the O2O context from the Industry 4.0 technology-facilitated personnel configuration perspective. The authors examine how internal and external factors moderate the performance efficiency between these two types of deliverymen.

One of the distinct characteristics in radiologists' reading of multiparametric prostate MR scans, using reporting systems such as PI-RADS v2.1, is to score individual types of MR modalities, T2-weighted, diffusion-weighted, and dynamic contrast-enhanced, and then combine these image-modality-specific scores using standardised decision rules to predict the likelihood of clinically significant cancer. This work aims to demonstrate that it is feasible for low-dimensional parametric models to model such decision rules in the proposed Combiner networks, without compromising the accuracy of predicting radiologic labels: First, it is shown that either a linear mixture model or a nonlinear stacking model is sufficient to model PI-RADS decision rules for localising prostate cancer. Second, parameters of these (generalised) linear models are proposed as hyperparameters, to weigh multiple networks that independently represent individual image modalities in the Combiner network training, as opposed to end-to-end modality ensemble. A HyperCombiner network is developed to train a single image segmentation network that can be conditioned on these hyperparameters during inference, for much improved efficiency. Experimental results based on data from 850 patients, for the application of automating radiologist labelling multi-parametric MR, compare the proposed combiner networks with other commonly-adopted end-to-end networks. Using the added advantages of obtaining and interpreting the modality combining rules, in terms of the linear weights or odds-ratios on individual image modalities, three clinical applications are presented for prostate cancer segmentation, including modality availability assessment, importance quantification and rule discovery., 48 pages, 6 figures

BACKGROUND: Abnormal type I collagen (COL1) expression is associated with the development of many cardiovascular diseases. The TGF-beta/Smad signaling pathway and circRNAs have been shown to regulate COL1 gene expression, but the underlying molecular mechanisms are still not fully understood. METHODS: Gain- and loss-of-function experiments were prformed to study the effect of circZBTB46 on the expression of alpha 2 chain of type I collagen (COL1A2). Co-immunoprecipitation assay was performed to observe the interaction between two proteins. RNA immunoprecipitation assay and biotin pull-down assay were performed to observe the interaction of circZBTB46 with PDLIM5. RESULTS: In this study, we investigated the role of circZBTB46 in regulating COL1A2 expression in human vascular smooth muscle cells (VSMCs). We found that circZBTB46 is expressed in VSMCs and that TGF-beta inhibits circZBTB46 formation by downregulating KLF4 expression through activation of the Smad signaling pathway. CircZBTB46 inhibits the expression of COL1A2 induced by TGF-beta. Mechanistically, circZBTB46 mediates the interaction between Smad2 and PDLIM5, resulting in the inhibition of Smad signaling and the subsequent downregulation of COL1A2 expression. Furthermore, we found that the expression of TGF-beta and COL1A2 is decreased, while circZBTB46 expression is increased in human abdominal aortic aneurysm tissues, indicating that circZBTB46-mediated regulation of TGF-beta/Smad signaling and COL1A2 synthesis in VSMCs plays a crucial role in vascular homeostasis and aneurysm development. CONCLUSIONS: CircZBTB46 was identified as a novel inhibitor of COL1 synthesis in VSMCs, highlighting the importance of circZBTB46 and PDLIM5 in regulating TGF-beta/Smad signaling and COL1A2 expression.

Voriconazole is widely used in the treatment and prevention of invasive fungal diseases. Common drug-induced liver injuries increase the economic burdens and the risks of premature drug withdrawal and disease recurrence. This study estimated the disposal cost of voriconazole-related liver injury, explored the risk factors of voriconazole-related liver injury in hospitalized patients, and established a predictive model of liver injury to assist clinicians and pharmacists in estimating the probability or risk of liver injury after voriconazole administration to allow for early identification and intervention in patients at high risk of liver injury. A retrospective study was conducted on the selected inpatients whose blood concentration of voriconazole was measured in the West China Hospital of Sichuan University from September 2016 to June 2020. The incidence and disposal cost of voriconazole-related liver injuries were calculated. The incidence of voriconazole-related liver injury was 15.82% (217/1372). The disposal cost has been converted to 2023 at a discount rate of 5%. The median (P25, P75) disposal cost of severe liver injury (n = 42), general liver injury (n = 175), and non-liver injury (n = 1155) was 993.59 (361.70, 1451.76) Chinese yuan, 0.00 (0.00, 410.48) yuan, and 0.00 (0.00, 0.00) yuan, respectively, with a statistically significant difference (p < 0.001). Single factor analysis and multiple factor logistic regression were used to analyze the risk factors of voriconazole-related liver injury. The voriconazole-related liver injury was related to the trough concentration (Cmin, OR 1.099, 95% CI 1.058–1.140), hypoproteinemia (OR 1.723, 95% CI 1.126–2.636), and transplantation status (OR 0.555, 95% CI 0.325–0.948). The prediction model of liver injury was Logit (P)= −2.219 + 0.094 × Cmin + 0.544 × Hydroproteinemia − 0.589 × Transplantation, and the prediction model nomogram was established. The model validation results showed that the C-index of the derivation set and validation set was 0.706 and 0.733, respectively. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.705 and 0.733, respectively, indicating that the model had good prediction ability. The prediction model will be helpful to develop clinical individualized medication of voriconazole and to identify and intervene in the cases of patients at high risk of voriconazole-related liver injury early on, in order to reduce the incidence of voriconazole-related liver injuries and the cost of treatment.

Hao Cheng,1 Zhen Yu,1 Cheng-lan Yan,1 Hui-dan Yang,1 Chong Gao,2 Hong-yan Wen1 1Department of Rheumatology, Shanxi Medical University, the Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USACorrespondence: Hong-yan Wen, Email wenhongyan@sxmu.edu.cnBackground: Patients with systemic sclerosis (SSc) have poor prognosis without cure methods. We began, 10 years ago, to relieve active SSc using short-term intravenous high-dose methylprednisolone pulse (MP-Pulse) and then maintain remission using long-term and low-dose oral glucocorticoids (LTLD-GC).Methods: Total 46 of SSc patients with interstitial lung disease (ILD) and induration of skin during January 2006 to December 2019 were analyzed retrospectively, who were followed up for 10 years or more. The patients were treated with MP-Pulse (15 mg/kg/day, 4 days/week, for 2 weeks) with (n=21) or without (n=25) LTLD-GC (prednisone 5– 10 mg/day or methylprednisolone 4– 8 mg/day). The biographic and clinical data, including occurrence of infection or any adverse reactions, were collected at baseline, 6 months, 1 year, and annually through 10 years after treatment.Results: From baseline to 10 years, compared with MP-Pulse alone, MP-Pulse/LTLD-GC significantly reduced skin and lung fibrosis and improved lung function: Rodnan skin score (mRSS: 22.1± 12.4 to 8.16± 2.5, P< 0.001), forced vital capacity (FVC: 71.7% to 89.83%, P< 0.001), forced expiratory volume in the first second (FEV1: 75.7% to 87.88%, P< 0.001), diffusing capacity of the lung for carbon monoxide (DLCO: 63.4% to 87.73%, P< 0.001), and high-resolution chest computerized tomography scan (HRCT score: 3.96± 2.81 to 1.42± 0.83, P< 0.001). None of the 46 patients had femoral head necrosis, compression fracture, death, or life-threatening adverse events.Conclusion: These outcomes indicate that intravenous MP-Pulse combined with oral LTLD-GC could achieve significant remission and better long-term (10 years) efficacy without severe adverse effects in SSc patients with ILD and induration of skin.Keywords: glucocorticoids, low-dose, pulse, systemic sclerosis, safety

Tropical cyclone (TC) annual frequency forecasting is significant for disaster prevention and mitigation in Guangdong Province. Based on the NCEP-NCAR reanalysis and NOAA Extended Reconstructed global sea surface temperature (SST) V5 data in winter, the TC frequency climatic features and prediction models have been studied. During 1951-2019, 353 TCs directly affected Guangdong with an annual average of about 5.1. TCs have experienced an abrupt change from abundance to deficiency in the mid to late 1980 with a slightly decreasing trend and a normal distribution. 338 primary precursors are obtained from statistically significant correlation regions of SST, sea level pressure, 1000hPa air temperature, 850hPa specific humidity, 500hPa geopotential height and zonal wind shear in winter. Then those 338 primary factors are reduced into 19 independent predictors by principal component analysis (PCA). Furthermore, the Multiple Linear Regression (MLR), the Gaussian Process Regression (GPR) and the Long Short-term Memory Networks and Fully Connected Layers (LSTM-FC) models are constructed relying on the above 19 factors. For three different kinds of test sets from 2010 to 2019, 2011 to 2019 and 2010 to 2019, the root mean square errors (RMSEs) of MLR, GPR and LSTM-FC between prediction and observations fluctuate within the range of 1.05-2.45, 1.00-1.93 and 0.71-0.95 as well as the average absolute errors (AAEs) 0.88-1.0, 0.75-1.36 and 0.50-0.70, respectively. As for the 2010-2019 experiment, the mean deviations of the three model outputs from the observation are 0.89, 0.78 and 0.56, together with the average evaluation scores 82.22, 84.44 and 88.89, separately. The prediction skill comparisons unveil that LSTM-FC model has a better performance than MLR and GPR. In conclusion, the deep learning model of LSTM-FC may shed light on improving the accuracy of short-term climate prediction about TC frequency. The current research can provide experience on the development of deep learning in this field and help to achieve further progress of TC disaster prevention and mitigation in Guangdong Province.

Under climate change circumstances, increasing studies have reported the temporal instability of tree growth responses to climate, which poses a major challenge to linearly extrapolating past climate and future growth dynamics using tree-ring data. Space-for-time substitution (SFTS) is a potential solution to this problem that is widely used in the dendrochronology field to project past or future temporal growth response trajectories from contemporary spatial patterns. However, the projected accuracy of the SFTS in the climate effects on tree growth remains uncertain. Here, we empirically test the SFTS method by comparing the effect of spatial and temporal climate variations on climate responses of white spruce (Picea glauca), which has a transcontinental range in North America. We first applied a response surface regression model to capture the variations in growth responses along the spatial climate gradients. The results showed that the relationships between growth and June temperature varied along spatial climate gradients in a predictable way. And their relationships varied mainly along with local temperate condition. Then, the projected correlation coefficients between growth and climate using SFTS were compared against the observed. We found that the growth response changes caused by spatial versus temporal climate variations showed opposite trends. Moreover, the projected correlation coefficients using the SFTS were significantly lower than the observed. This finding suggests that applying the SFTS to project the growth response of white spruce might lead to an overestimation of the degree of tree maladaptation in future climate scenarios. And the overestimation is likely to get weaker from Alaska and Yukon Territory in the west to Quebec in the east. Although this is only a case study of the SFTS method for projecting tree growth response, our findings suggest that direct application of the SFTS method may not be applicable to all regions and all tree species.

Cloud storage attracts a lot of clients to join the paradise. For a high data availability, some clients require their files to be replicated and stored on multiple servers. Because clients are generally charged based on the redundancy level required by them, it is critical for clients to obtain convincing evidence that all replicas are stored correctly and are updated to the up-to-date version. In this paper, we propose a dynamic proof of data possession and replication (DPDPR) scheme, which is proved to be secure in the defined security model. Our scheme shares a single authenticated tree across multiple replicas, which reduces the tree's storage cost significantly. Our scheme allows for batch verification for multiple challenged leaves and can verify multiple replicas in a single batch way, which considerably save bandwidth and computation resources during audit process. We also evaluate the DPDPR's performance and compare it with the most related scheme. The evaluation results show that our scheme saves almost 66% tree's storage cost for three replicas, and obtains almost 60% and 80% efficiency improvements in terms of the overall bandwidth and computation costs, respectively, when three replicas are checked and each challenged with 460 blocks.

N4-methylcytosine (4mC) is a type of DNA modification which could regulate several biological progressions such as transcription regulation, replication and gene expressions. Precisely recognizing 4mC sites in genomic sequences can provide specific knowledge about their genetic roles. This study aimed to develop a deep learning-based model to predict 4mC sites in the Escherichia coli. In the model, DNA sequences were encoded by word embedding technique 'word2vec'. The obtained features were inputted into 1-D convolutional neural network (CNN) to discriminate 4mC sites from non-4mC sites in Escherichia coli genome. The examination on independent dataset showed that our model could yield the overall accuracy of 0.861, which was about 4.3% higher than the existing model. To provide convenience to scholars, we provided the data and source code of the model which can be freely download from https://github.com/linDing-groups/Deep-4mCW2V.

BackgroundVessels encapsulating tumor clusters (VETC) have been considered an important cause of hepatocellular carcinoma (HCC) metastasis.PurposeTo compare the potential of various diffusion parameters derived from the monoexponential model and four non-Gaussian models (DKI, SEM, FROC, and CTRW) in preoperatively predicting the VETC of HCC.Methods86 HCC patients (40 VETC-positive and 46 VETC-negative) were prospectively enrolled. Diffusion-weighted images were acquired using six b-values (range from 0 to 3000 s/mm2). Various diffusion parameters derived from diffusion kurtosis (DK), stretched-exponential (SE), fractional-order calculus (FROC), and continuous-time random walk (CTRW) models, together with the conventional apparent diffusion coefficient (ADC) derived from the monoexponential model were calculated. All parameters were compared between VETC-positive and VETC-negative groups using an independent sample t-test or Mann-Whitney U test, and then the parameters with significant differences between the two groups were combined to establish a predictive model by binary logistic regression. Receiver operating characteristic (ROC) analyses were used to assess diagnostic performance.ResultsAmong all studied diffusion parameters, only DKI_K and CTRW_α significantly differed between groups (P=0.002 and 0.004, respectively). For predicting the presence of VETC in HCC patients, the combination of DKI_K and CTRW_α had the larger area under the ROC curve (AUC) than the two parameters individually (AUC=0.747 vs. 0.678 and 0.672, respectively).ConclusionDKI_K and CTRW_α outperformed traditional ADC for predicting the VETC of HCC.

Despite the growing urgency to curb carbon emissions worldwide, the healthcare industry, particularly the pharmaceutical industry, has received little attention from the sustainability community in terms of its contribution to the global carbon footprint. This paper constructs a differential game model of the secondary pharmaceutical supply chain consisting of pharmaceutical enterprises and medical institutions in the context of centralized drug procurement policy, considering the effects of health insurance reimbursement and consumers’ low-carbon preferences, and compares and analyzes the feedback equilibrium strategies of low-carbon inputs and marketing efforts, supply chain profits, and social welfare levels under four government subsidy models and further discusses them with arithmetic examples. The results illustrated that government subsidies have a significant impact on the low-carbon investment of pharmaceutical enterprises and the low-carbon marketing of medical institutions; subsidies for pharmaceutical enterprises can significantly increase the low-carbon investment and profit level of pharmaceutical enterprises; subsidies for medical institutions can effectively promote the implementation of the “zero-rate” policy and the realization of the emission reduction target under the centralization policy of medical institutions, increase the market demand for low-carbon drugs, and thus gain higher profits; the dual-subsidy model of the government brings higher social welfare than the single-subsidy model, and under a reasonable subsidy ratio, the profit and social welfare of the whole supply chain can be maximized.

Background Immunotherapy is currently applied in the first-line treatment regimens for numerous advanced cancers, especially advanced lung cancer. Immune-related adverse events (irAEs) resulting from immunotherapy can vary in severity and cause a substantial symptom burden to patients. However, there are limited data on symptom burden in patients with advanced lung cancer following immunotherapy. To address this deficit, this study aims to provide insight into the symptom burden and severity through patient-reported outcome measurements and conduct an analysis of temporal trends and clinical consequences of symptom burden in patients with advanced lung cancer receiving combination immunotherapy. Methods We will prospectively recruit 168 eligible patients from 14 hospitals in China. Eligible patients will be aged ≥ 18 years, pathologically diagnosed with locally advanced or stage IV primary lung cancer without surgical indications, and agreed to receive immunotherapy in combination with other therapies. The primary outcome of this study is the symptom burden of patients during the immunotherapy course. Longitudinal symptom data will be collected using the MD Anderson Symptom Inventory–Lung Cancer module (MDASI-LC) and the symptomatic irAEs scale at baseline (once before treatment) and weekly after treatment, until 1 month after the last treatment cycle has been completed. The trajectory of symptom burden following combination immunotherapy will be depicted, and by linking it to clinical outcomes (the secondary outcome and exploratory outcome of this study), the consequence of symptom burden in patients with advanced lung cancer receiving combination immunotherapy will be examined further. Discussion This study intends to establish longitudinal symptom trajectories in patients with lung cancer receiving immunotherapy, and explore its association with clinical outcomes. These findings may serve as an important reference for clinicians in the symptomatic management of patients with lung cancer receiving immunotherapy. Trial registration number ChiCTR2200061540. Registered on June 28, 2022.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, and drug resistance following prolonged treatment leads to downregulation of the efficacy of chemotherapy against CRC. CXCL17 is an inflammatory factor that plays a crucial role in tumorigenesis. However, the function of the CXCL17-GPR35 axis in CRC and resistance to chemotherapy is not entirely clear. Bioinformatic analysis was used to identify differentially expressed genes (DEGs) in oxaliplatin (OXA)-resistant CRC tumour tissues compared to OXA-sensitive counterparts. To further determine the function of CXCL17 in taxol-resistant CRC cells (HCT15), proliferation, migration, invasion, cell cycle, and apoptosis were analysed by CCK-8, wound healing, Transwell(®), and flow cytometry assays, respectively. In addition, RNA sequencing, western blotting, CCK-8, wound healing, and Transwell(®) assays were used to further identify and confirm the downstream effects of CXCL17 regulation on taxol resistance. Our study found that CXCL17 and GPR35 were upregulated in OXA-resistant tumour tissues compared to in OXA-sensitive tissues. CXCL17 silencing significantly decreased the viability, migration, and invasion of taxol-resistant CRC cells. CXCL17 silencing arrested taxol-resistant CRC cells in the G2/M phase and promoted apoptosis. The IL-17 signalling pathway is involved in regulation of the CXCL17-GPR35 biological axis in HCT15 cells, and the addition of IL-17A distinctly reversed the decreased proliferation, migration, and the enhanced apoptosis of HCT15 cells upon CXCL17 deletion. In summary, these findings demonstrate that the CXCL17-GPR35 axis and IL-17 signalling pathway are involved in mediating CRC tumorigenesis and drug-resistance. Inhibition of the CXCL17-GPR35 axis and IL-17 may hence be promising therapeutic targets for CRC resistance to OXA.