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Diabetic foot ulcer (DFU) is a predominant complication of diabetes mellitus with poor prognosis accompanied by high amputation and mortality rates. Dang-Gui-Si-Ni decoction (DSD), as a classic formula with a long history in China, has been found to improve DFU symptoms. However, mechanism of DSD for DFU therapy remains unclear with no systematic elaboration. In vivo, following establishment of DFU rat model, DSD intervention with low, medium and high doses was done, with Metformin (DM) as a positive control group. With wound healing detection, pathological changes by HE staining, inflammatory factor expression by ELISA and qRT-PCR, oxidative stress levels by ELISA, and AGEs/RAGE/TGF-β/Smad2/3 expression by Western blot were performed. In vitro, intervention with LY2109761 (TGF-β pathway inhibitor) based on DSD treatment in human dermal fibroblast-adult (HDF-a) cells was made. Cell viability by CCK8, migration ability by cell scratch, apoptosis by flow cytometry, and AGEs/RAGE/TGF-β/Smad2/3 expression by Western blot were measured. DFU rats exhibited elevated AGEs/RAGE expression, whereas decreased TGF-β1 and p-Smad3/Smad3 protein expression, accompanied by higher IL-1β, IL-6, TNF-α levels, and oxidative stress. DSD intervention reversed above effects. Glucose induction caused lower cell viability, migration, TGF-β1 and p-Smad3/Smad3 protein expression, with increased apoptosis and AGEs/RAGE expression in HDF-a cells. These effects were reversed after DSD intervention, and further LY2109761 intervention inhibited DSD effects in cells. DSD intervention may facilitate wound healing in DFU by regulating expression of AGEs/RAGE/TGF-β/Smad2/3, providing scientific experimental evidence for DSD clinical application for DFU therapy. [ABSTRACT FROM AUTHOR]

AbstractPrevotella intermedia is a Gram-negative anaerobic bacterium that is a common pathogen of periodontitis. Recent studies have revealed that P. intermedia is closely associated with a variety of diseases involving multiple systems. Under the action of its virulence factors such as cysteine protease and adhesins, P. intermedia has the ability to bind and invade various host cells including gingival fibroblasts. It can also copolymerize a variety of pathogenic bacteria, leading to interference with the host’s immune inflammatory response and causing various diseases. In this article, we review the progress of research on P. intermedia virulence factors and bacterial pathogenesis, and the correlation between P. intermedia and various diseases. [ABSTRACT FROM AUTHOR]

Background: The efficacy and toxicity of KRASG12C inhibitors were evaluated for advanced solid tumors in several studies; however, the results were not fully consistent. Methods: Clinical trials evaluating KRASG12C inhibitors for advanced solid tumors were searched from PubMed, Embase, and Cochrane Library online databases up to 31st December 2023. The characteristics of the studies and the results of objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) rate, overall survival (OS) rate, and treatment-related adverse events (trAEs) were extracted. Results: Ten studies with 925 heavily pretreated advanced patients harboring KRASG12C mutation were included. For total population, the pooled analysis of ORR was 28.6% (95%CI, 21.2-36.6%), DCR was 85.5% (95%CI, 82.2-88.6%), PFS rate at 6 months (PFS6) was 49.6% (95%CI, 41.4-57.9%), PFS rate at 12 months (PFS12) was 26.7% (95%CI, 19.8-34.1%), OS rates at 6 months (OS6) was 76.2% (95%CI, 68.8-82.9%), OS rates at 12 months (OS12) was 47.8% (95%CI, 38.6-57.0%). The pooled analysis of any grade trAEs was 79.3% (95%CI, 66.2-90.0%) and grade three or more trAEs was 24.4% (95%CI, 16.7-32.9%). The median time to response and DoR results from individual data were 1.39 months (95%CI, 1.37–1.41 months) and 10.54 months (95%CI, 7.72–13.36 months). Sotorasib had significantly lower pooled incidences of any trAEs (OR, 0.07, 95%CI, 0.03–0.14) and grade three or more trAES (OR, 0.34, 95%CI, 0.24–0.49) compared with adagrasib. Conclusions: KRASG12C inhibitors have good ORR, DCR, PFS rate, OS rate, tolerable trAEs, and early response with long duration in advanced solid tumors; however, most of the pooled results were heterogeneous. Sotorasib has shown better safety results. [ABSTRACT FROM AUTHOR]

The clogging phenomenon finds extensive application in both industrial processes and daily life events. While this broad spectrum of application motivated extensive research to identify the general factors underlying the clogging mechanism, it results in a fragmented and system-specific understanding of the entire clogging process. Therefore, it is essential to establish a holistic understanding of all contributing factors of clogging based on the microscopic physical mechanisms. In this paper, we experimentally investigate clogging of granular materials in a two-dimensional hopper flow and present a self-consistent physical mechanism of clogging based on precursory chain structures. These chain structures follow a specific modified restricted random walk, and clogging occurs when they are mechanically stable enough to withstand the flow fluctuations. We introduce a single-particle model that can explain the arch-forming probability. Our results provide insight into the microscopic mechanism behind clogging and a broader understanding of the dynamics of dense granular flow. The study of the general factors underlying clogging are fragmented and application-driven due to its broad spectrum of applications. The authors propose a holistic understanding of the clogging process by investigating the clogging of a granular hopper flow using high-speed imaging, finding a signature formation of precursory chain structures. [ABSTRACT FROM AUTHOR]

Education policies align with evolving needs and changes in education. Two years ago, the double reduction policy was widely welcomed. But new challenges have emerged now, it is necessary to examine whether it still meets parental expectations, and whether adjustments in details are needed. We investigated parents' perception of policy implementation intensity; and its relationship with parents' perception of educational involution; and parents' educational anxiety, as well as the roles played by gender. Findings highlight parents who perceive a stronger policy implementation intensity experience higher levels of educational anxiety and are more likely to feel educational involution; education anxiety acts as a mediator, while gender plays a moderating role. We highlighted policy's advantages while emphasizing the necessity to avoid policy rigidity and one‐size‐fits‐all. We recommend establishing a flexible, real‐time parental feedback mechanism and promoting continuous monitoring and evaluation. This approach would enable it to meet the changing demands of education. [ABSTRACT FROM AUTHOR]

Medium optimization and development for selective bacterial cultures are essential for isolating and functionalizing individual bacteria in microbial communities; nevertheless, it remains challenging due to the unknown mechanisms between bacterial growth and medium components. The present study first tried combining machine learning (ML) with active learning to fine-tune the medium components for the selective culture of two divergent bacteria, i.e., Lactobacillus plantarum and Escherichia coli. ML models considering multiple growth parameters of the two bacterial strains were constructed to predict the fine-tuned medium combinations for higher specificity of bacterial growth. The growth parameters were designed as the exponential growth rate (r) and maximal growth yield (K), which were calculated according to the growth curves. The eleven chemical components in the commercially available medium MRS were subjected to medium optimization and specialization. High-throughput growth assays of both strains grown separately were performed to obtain thousands of growth curves in more than one hundred medium combinations, and the resultant datasets linking the growth parameters to the medium combinations were used for the ML training. Repeated rounds of active learning (i.e., ML model construction, medium prediction, and experimental verification) successfully improved the specific growth of a single strain out of the two. Both r and K showed maximized differentiation between the two strains. A further analysis of all the data accumulated in active learning identified the decision-making medium components for growth specificity and the differentiated, determinative manner of growth decisions of the two strains. In summary, this study demonstrated the efficiency and practicality of active learning in medium optimization for selective cultures and offered novel insights into the contribution of the chemical components to specific bacterial growth. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to explore the efficacy and safety of toripalimab combined with anlotinib in patients with advanced non‐small cell lung cancer (NSCLC) who acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs). Materials and Methods: Patients who developed resistance after using first‐ or second‐generation EGFR‐TKIs as their first‐line regimen without EGFR T790M mutation or had disease progression after being treated with third‐generation EGFR‐TKIs as first‐ or second‐line therapy were enrolled. All patients received toripalimab (240 mg/day on Day 1, intravenously) combined with anlotinib (12 mg/day, Days 1–14, orally) once every 3 weeks. Treatment continued until disease progression, or if toxicity was intolerable. The primary endpoint was the objective response rate (ORR) assessed by the investigator. The secondary endpoint was the progression‐free survival (PFS). Results: In total, 19 patients were enrolled between May 2020 and October 2021.The ORR was 0%, and a median PFS was 2.1 months (95% CI 0.251–3.949). Grade ≥3 treatment‐related adverse events (AEs) occurred in 11% patients. Common adverse events included hypothyroidism (12/19), fatigue (9/19), and hypertension (8/19). Patients in stable disease (SD) group had lower abundance of EGFR mutation allele frequency (AF) before enrollment than those in progressive disease (PD) group (p = 0.031). Patients without detectable EGFR mutation (EGFR−) had longer PFS compared to the ones with EGFR mutations (p = 0.059). Patients with high levels of soluble programmed cell death ligand 1 (PD‐L1) at baseline also tended to have longer PFS (p = 0.160). Conclusion: Toripalimab combined with anlotinib was tolerable in EGFR‐TKI‐resistant advanced NSCLC patients not previously treated with chemotherapy. Patients without detectable EGFR mutation and high soluble PD‐L1 levels may benefit from this chemotherapy‐free treatment. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitor (ICI) combined with chemotherapy is one of the standards of care for advanced non–small cell lung cancer (NSCLC) without driver mutations. However, the biomarker of combination therapy is still unknown. Although previous studies have confirmed that low allele frequency adjusted blood‐based tumor mutational burden (LAF‐bTMB) is associated with the efficacy of ICI monotherapy, there has been no report on the correlation between the efficacy of LAF‐bTMB and ICI combined chemotherapy. This study aimed to explore whether LAF‐bTMB can be used as a predictive biomarker for the efficacy of immunotherapy combined with chemotherapy in advanced NSCLC. Methods: This study enrolled patients diagnosed with advanced NSCLC and who received ICI combined with chemotherapy for first‐line therapy from May 2020 to December 2021 at Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Clinical information, treatment information, survival data, and peripheral blood samples of every patient before treatment were collected. Next‐generation sequencing was performed on plasma samples to estimate bTMB and LAF‐bTMB. Results: A total of 42 patients with NSCLC were enrolled. In this cohort, 19 patients achieved partial response (PR), and the objective response rate (ORR) was 45.2%. The median progression‐free survival (PFS) of all patients was 13.4 months (95% CI, 7.49–19.72). Both PFS and the overall survival (OS) were significantly longer in the responder (R) group than in the non‐responder (NR) group (median PFS, 16.4 months vs. 7.2 months, p = 0.028; median OS, NE vs. 9.3 months, p = 0.016). There was no significant difference in bTMB and LAF‐BTMB between the R and NR group. The ORR of patients with LAF‐bTMB≤8muts/Mb was significantly higher than that of patients with LAF‐bTMB >8muts/Mb (ORR, 61% vs. 26%, respectively, p = 0.033). When LAF‐bTMB ≤8muts/Mb or > 20muts/Mb, ORR was significantly higher than that of patients with LAF‐bTMB between 8 and 20muts/Mb (ORR were 57% and 21%, p = 0.047). No correlation has been found between LAF‐bTMB and PFS or OS. Conclusions: This study confirmed that neither bTMB nor LAF‐bTMB is feasible as a potential predictor of first‐line immunochemotherapy for advanced NSCLC. More suitable biomarkers need to be explored to screen patients with better efficacy of immunotherapy combined with chemotherapy in the future. [ABSTRACT FROM AUTHOR]

Bolted joints play a crucial role in mechanical systems by connecting different components and materials. The performance of these systems heavily relies on the behavior of the bolted connections. High-fidelity finite element (FE) models are commonly used to predict their dynamic behavior, but they suffer from long computation times due to large model sizes and iterative solution procedures for contact nonlinearity. To address this, a substructuring-based parametric model order reduction strategy is proposed to improve the computational efficiency of FE models of bolted structures with frictional contact. The strategy involves dividing the model into substructures, including joint substructures, and applying a two-layer Krylov-based Craig-Bampton (CB) method for reduction. The augmented characteristic constraint modes, combined with joint interface modes, are proposed for contact interface reduction. This approach is valid for different numerical representations of contact and does not rely on full model results for bolted joints. Consequently, a sampling-free parametric reduced order model can be generated to analyze changes in pretension and friction coefficient. For time domain simulations, a dual loop contact algorithm integrated in the Newmark-Beta method is present for time integration of the parametric reduced model. The performance of the approach is validated through investigation of overall dynamic responses and local contact variations in two bolted joint structures. [ABSTRACT FROM AUTHOR]

The increased use of plastics and the associated environmental impact has catalyzed research on the development of bio-derived polymers. Bio-based polyesters have gained increased attention due to the abundance of their starting materials and ease of processing. Lignin is naturally occurring in biomass with rich carbon content, whose functionality and rigidity make it an ideal bio-derived candidate for bio-based polyesters. Herein, a lignin-based polyester with good thermal stability and self-repairability was synthesized from carboxylated lignin and epoxidized soybean oil. The synthesized lignin/epoxidized soybean oil (ESO) vitrimer was brittle such that its mechanical performance could not be recorded. However, when polyethylene glycol (PEG) was incorporated as a plasticizer, polymer samples exhibited acceptable ductility. From thermomechanical analysis of the synthesized polyesters, the plasticizer did not impair thermal stability of polymers, but greatly enhanced mechanical properties. Notably, all samples exhibited stability at high temperatures, and good glass transition temperatures (51.0 ± 0.9–78.0 ± 1.2 °C). The highest tensile strength (3.983 ± 0.1 MPa) and storage modulus (1463.67 ± 12.6 MPa) were recorded for the polyester containing 6 % w/w PEG. Moreover, the polymer samples exhibited self-healing capability at 180 °C. This work expands on valorization of lignin through the synthesis of bio-derived materials. [Display omitted] • Cosolvent enhanced lignocellulosic fractionation (CELF) Lignin was modified by carboxylation and characterized. • Lignin-based polyesters with varying polyethylene glycol (PEG) content were synthesized and characterized. • The synthesized polyesters exhibited good thermal stability and self-healing ability at elevated temperature. • Integration of PEG does not lower the thermal stability of lignin-based polyesters. This paper offers insight that can encourage transition to biobased materials as substitutes for fossil fuel based thermosets. [ABSTRACT FROM AUTHOR]

Endometrial cancer is the 6th most common carcinoma as well as the 2nd most common malignancy worldwide in women. It is closely related to fat content, and dyslipidemia is among the most significant metabolic changes in this cancer. Therefore, further understanding of the regulation mechanism in lipid metabolism of endometrial cancer is conducive to the development of better therapeutic strategies and methods. Here, we systematically review the signaling pathways that regulate lipid metabolism in endometrial cancer and the research progress of drugs and targeted therapies that act on lipid metabolism by retrieving relevant articles. The underlying mechanism of occurrence and development of endometrial cancer is relatively clear and comprehensively reviewed here. But following more research studies will help to illuminate more specific regulatory roles of lipid metabolism in endometrial cancer and explore new possible mechanisms, prognostic and therapeutic targets, and subsequent drugs. Our review will provide a full view for the following investigation of lipid metabolism in endometrial cancer. [ABSTRACT FROM AUTHOR]

Coal is a vital energy resource worldwide, but pollutants and greenhouse gases from its combustion cause environmental problems. To explore the non-combustion approach to use and valorize coal, anthracite and lignite were blended with polyamide 12 (PA 12) through FDM printing in this work and compared in the composites. By adding lignite, Young's modulus improved with increasing loading to 50 wt% while tensile strength leveled off among the composites, compared to that of PA 12. By contrast, the addition of anthracite decreased the tensile performance at all loadings. Rheology tests and morphology analyses suggested that the interactions between fillers (anthracite and lignite) and PA 12 may cause differences in tensile properties. In addition, the printed lignite composites showed improved thermal conductivity (~ twofold), indicating lignite demonstrates the potential to build functional composites. This work provides a strategy to use lignite in composites by 3D printing for value-added products and reduces the demand for petroleum-based polymers. Our approach diverts lignite from combustion processes and alleviates the negative impact of lignite use on the environment. [ABSTRACT FROM AUTHOR]

Lignin is a low-cost and renewable bioresource with a huge annual production promising to prepare sustainable materials. However, the poor interfacial adhesion between many lignin-polymer pairs deteriorates the mechanical performance of the composites, which seriously limits the application of lignin in 3D printing via fused depositional modeling. This work examined lignin-polyamide 12 (PA 12) intermolecular interactions (e.g., hydrogen bonding) to address the interface challenge. To realize this goal, the phenolic hydroxyl content was increased for a kraft softwood lignin using a LiBr/HBr demethylation procedure, increasing phenoxy content by 61.7%. Increased hydrogen bonding interactions between modified lignin (Pine-Lig-OH) and PA 12 demonstrated a significantly improved molten dynamic modulus by rheological analysis. Regarding mechanical properties, by adding 20 wt% of Pine-Lig-OH, the tensile strength and Young's modulus reached 46.6 MPa and 1.62 GPa, 30.2% and 33.9% higher than PA 12, respectively. Further morphological analysis proved the interfacial interactions are enhanced by showing the difference in the phase gaps. The dynamic mechanical analysis (DMA) supported the conclusion that Pine-Lig-OH could interact with polymer chains, alternating segmental movements due to the strong interaction. This study presents a method to enhance lignin composite properties by promoting interactions with the polymer matrix through modified functional groups, guiding future lignin composite research. [Display omitted] • More Phenolic structures were designed and modified on kraft softwood lignin by demethylation. • More phenolic hydroxyls improved interfacial adhesion in lignin/PA 12 composites. • Enhanced interaction improved tensile properties. • Phenolic-enhanced lignin altered polymer morphology and dynamic mechanical behaviors. [ABSTRACT FROM AUTHOR]

Background: Low‐grade fetal adenocarcinoma of the lung (L‐FLAC) is a rare subtype of lung adenocarcinoma with undetermined histological features and genetic abnormalities. In this study, we attempted to investigate the pathological characteristics and genomic profiles of L‐FLAC. Methods: Among 9839 cases of primary lung adenocarcinoma resected at Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2011 and June 2016, three cases diagnosed with L‐FLAC were selected. An immunohistochemical profile and whole exome sequencing (WES) using tumor and normal tissues was conducted. The last follow‐up date of patients was January 2021. Results: Three cases diagnosed with L‐FLAC were finally screened, suggesting a percentage of 0.03%. All three patients were male and diagnosed as stage I following radical lobectomy. The missense variant was found to be the major gene mutation type using WES. CTNNB1 and DICER1 were the two most frequent gene mutations. All cases demonstrated positive TTF‐1 expression. In addition, two patients showed positive expression of β‐catenin (nuclear/cytoplasmic expression), CgA and Sny. Negative expression of PD‐L1 in tumor cells was observed in all three cases. One case with a relatively high tumor mutation burden (TMB) (2.18 mut/Mb) had an inferior overall survival of 11.5 months. However, the other two cases with a lower TMB (0.12 and 0.74 mut/Mb) still acquired disease‐free status up to the last follow‐up date. Conclusions: L‐FLAC has a specific molecular background which is different from lung adenocarcinoma. Furthermore, gene heterogeneity was found and might be the reason for a dramatically different prognosis in these L‐FLAC patients. [ABSTRACT FROM AUTHOR]

Biological lignin valorization represents an emerging green approach to upgrade lignin for sustainable and economic biorefineries. However, lignin generally exhibits poor water solubility and inhomogeneous distribution in an aqueous medium, significantly limiting its bioconversion efficiency. Herein, we develop a novel alkali sterilization strategy to effectively enhance the dispersion and fermentation performance of lignin substrates. The colloidal particle size and molecular structure variations of lignin during the sterilization were thoroughly investigated to reveal the mechanisms of enhanced fermentation performance. Results showed that alkali sterilization achieved a completely aseptic effect when mixing lignin medium at an initial pH of 12.7 for 24 h. Dynamic light scattering (DLS) analysis demonstrated that the hydrodynamic volume of colloidal lignin particles decreased by 96.3% by alkali sterilization compared with the conventional thermal sterilization. Moreover, lignin characterizations by nuclear magnetic resonance (NMR) spectroscopy and gel permeation chromatography (GPC) suggested that alkali sterilization modified the lignin molecular structure by generating 50% more hydrophilic carboxyl groups, reducing the weight-average molecular weight (Mw) by 23.0%, and narrowing the molar-mass dispersity (ĐM) by 23.8%. The generation of lignin substrates with more uniform distribution and lower molecular weight improved Rhodococcus opacus PD630 cell growth and metabolism. Microbial cell amount, lignin degradation, and lipid production in alkali sterilized medium increased by 309%, 30.3%, and 48.3%, respectively, compared to those in thermally sterilized medium. These results clearly demonstrated that alkali sterilization dramatically improved the lignin bioconversion performance. This work presents a facile and effective sterilization strategy to overcome inhomogeneous lignin distribution in aqueous fermentation media, showing great potentials as a platform technique for promoting biological lignin valorization. [ABSTRACT FROM AUTHOR]

• Targeted phenolic hydroxyl is enriched on organosolv lignin by a mild modification. • Enhanced interfacial adhesion between the modified lignin and polymer was achieved. • Improved mechanical performance was reached due to enhanced interfacial adhesion. • Modified lignin also promotes the anti-aging of the lignin/polymer composites. Lignin is the most abundant natural aromatic polymer globally but is still underutilized as a renewable material, even with its versatile properties. One approach to using lignin is to incorporate it in polymer composites, but this application is often limited by the poor mechanical performance of the resultant composite due to the poor interfacial adhesion. Following the structure–property relationship, stronger interactions were designed to be enhanced by alternating the functional groups of lignin. This study applied a demethylation method to hardwood lignin (Ori-Lig) to introduce more phenolic hydroxyl groups. Research studies with rheology behavior and molecular simulations demonstrated that an increased phenolic hydroxyl content could improve the adhesion between the modified lignin (OH-Lig) and the polymer matrix at the interface. The tensile performance of the samples from the fused depositional modeling (FDM) 3D printing technique was also improved due to the improved interfacial adhesion. Specifically, by adding 10 wt% of the modified lignin, the tensile strength of the 3D printed samples could reach 46.1 MPa (40.2 MPa of Polyamide 12, PA12), and Young's Modulus could be improved to 1.73 GPa (1.48 GPa of PA12). OH-Lig also improved anti-aging performance so that the tensile strength of the OH-Lig composite after thermo-aging (100 h at 140 °C) remained ∼ 48 MPa. The enhanced mechanical performance with anti-aging properties indicated that the OH-Lig composite may replace PA12 to reduce the use of petrol-based materials. This work showed the method of purposefully designing and modifying lignin structures to fulfill the interaction requirements between lignin and polymer matrix. The as-prepared lignin could be used to prepare functional composites to achieve improved mechanical performance and targeted functions at the same time. [ABSTRACT FROM AUTHOR]

Disruptions in the metro system often result in chaos in the public transport system given their substantial modal share in major metropolitan areas. Metro system disruption can be managed both within the system and by substitute bus (SB) service external to the system. Managing disruption within the metro system typically involves timetable adjustment, rolling stock scheduling, and crew rescheduling, subject to the rail system design and availability of crossovers for turnovers. SB service or bus bridging, on the other hand, is one prominent way to mitigate the negative impact of a metro disruption. In the past decade, research on this topic has grown substantially. In this paper, by conducting a comprehensive search in the Web of Science publications, we identify and review about 70 papers. According to the three aspects of metro system disruption management, we classify the literature into three groups: (i) getting prepared for metro network disruption, (ii) managing disruption within the metro system, and (iii) managing metro disruption with SB service. After summarising the state-of-the-art on this topic, we conclude by identifying gaps and future research directions, primarily on substitute bus service, for this important development effort. [ABSTRACT FROM AUTHOR]

• Uncertain recovery time is considered in Substitute Bus (SB) deployment study. • Cost-benefit analysis is conducted of both the metro and bus companies. • The bus company's profit from providing the SB service is examined. • The metro company's gain of calling for the SB service is evaluated. • Passenger optimal solution is proposed to determine payment rate and SB arrival time. Often serving as the backbone for public transport, any serious metro incident will have a severe impact on passengers. In the aftermath of a disruption, establishing alternative transport means to carry the affected metro passengers, such as via substitute bus (SB) service, is critical. After a particular routing and scheduling plan of SB service is determined, the question is how to assemble the SB fleet, which has different options. Few studies have addressed the issue of designing the contract with a bus company for the provision of SB, including SB availability and service start time guarantee and pricing schemes under uncertain metro system recovery time. This paper attempts to fill this gap. We investigated both the bus company's profit in providing the SB service and the metro company's gain in passenger loss reduction after a metro disruption for setting up the SB service contract. Two payment schemes were considered: fixed payment and linear payment. The objective is to design the SB service contract, which defines the payment scheme and guaranteed SB service start time, from both the perspective of the metro company and that of the bus company to explore feasible solutions. In addition, the scenarios of collaborative decision between the bus and metro companies, nonlinear passenger demand drop, fleet size, arrivals of new passengers, and passengers waiting time are investigated. [ABSTRACT FROM AUTHOR]

Highlights • A modeling platform to determine the optimal initiation time (OIT) was introduced. • Optimal thresholds and OIT in closed-forms were derived for linear arrival case. • Numerical procedure to determine OIT for non-linear arrival case was developed. • Sensitivity analyses were conducted to identify important parameters influencing OIT. Abstract Determining the initiation time of substitute bus (SB) services is critical for metro disruption management, especially under uncertain recovery time. This study develops a mathematical formulation to determine the optimal initiation time (OIT) of SB services by trading-off their initiation cost and passenger delay cost, thereby minimizing the total system cost. Given the probability distribution of metro disruption duration, we determine the OIT by formulating an optimization problem to minimize the expected total system cost. We then conduct sensitivity analyses of the initiation cost of SB services, passenger value of time, and SB services rate. The results show that SB services ought to be activated only if the metro incident lasts longer than a certain time interval, depending on the factors mentioned earlier, and the OIT should advance with the predicted incident duration. This paper derives analytical results for the case of linear passenger arrival, and determines the results numerically for the case of non-linear passenger arrival when analytical closed-form solutions are not available. The findings will facilitate transit operators to develop response plans in the aftermath of a metro disruption. [ABSTRACT FROM AUTHOR]

Increasing demand for effective energy‐storage systems derived from low‐cost and ecofriendly raw materials has aroused wide concern. In this contribution, we propose nitrogen‐abundant amorphous micron‐sized carbon ribbons (AMCRs) originating from biomass raupo as a novel substrate due to their specific quasi 2D morphologies and outstanding dispersion ability. Owing to the innate nitrogen atoms on the surface of AMCRs, ultrathin binary and ternary metal oxide (NiO, CoO, and NiCo2O4) nanosheets can be uniformly developed under benign conditions. These three composites were separately fabricated as electrodes for supercapacitors in a three‐electrode system and exhibited favorable activities. Among them, the ternary metal oxide composites NiCo2O4@AMCRs delivered the supreme specific capacitance of 1691 F g−1 and best cycling stability (89 % capacity retention over 10,000 cycles). Moreover, symmetric supercapacitors (NiCo2O4@AMCRs//NiCo2O4@AMCRs) were assembled inside sleeve devices with 2 m KOH aqueous electrolyte, which demonstrated admirable cyclic stability (79.1 % capacity retention over 8,000 cycles), and an excellent energy density of 26 Wh kg−1 at the power density of 1.8 kW kg−1. Nanotechnology: Nitrogen‐abundant amorphous micron‐sized carbon ribbons (AMCRs), originating from biomass raupo, are proposed as a substrate for electronic storage systems. Among those tested, NiCo2O4@AMCRs delivered a supreme specific capacitance of 1691 F g−1 and the best cycling stability (89 % capacity retention over 10,000 cycles; see figure). [ABSTRACT FROM AUTHOR]

Background: The purpose of the study is to evaluate whether serum cystatin C level is associated with arterial stiffness independent of other risk factors in Chinese general population. Hypothesis: Cystatin C is a predictable marker of arterial stiffness in Chinese general population. Methods: Subjects are 748 persons (mean age, 38.8years) who attended a health checkup in Beijing, China. We measured brachial-ankle PWV (baPWV) by using an automatic oscillometric method, and the concentration of serum cystatin C was quantified. Results: The level of baPWV showed a significantly positive correlation with BMI, SBP, DBP, TG, TC, cystatin C (r = 0.251, p < 0.001), and a negative correlation with HDL-C. And when adjustment for age, BMI, and cigarette smoking, these correlations remain significantly. Conclusion: Arterial stiffness increases with an increase in serum cystatin C level in Chinese general population with normal renal function. [ABSTRACT FROM AUTHOR]

NiO nanosheets were anchored at honeycomb amorphous porous carbon with ultrahigh surface area derived from activated wheat husk to obtain NiO@PC (porous carbon). The ultrahigh surface area of PC (634.4 m 2 g −1 ) promoted the attachment of NiO nanosheets, and this hierarchical nanostructure (NiO@PC) was beneficial for facilitating electron and electrolyte ion transport and accelerating the reversible redox reaction, which successfully demonstrated its high energy storage properties as supercapacitor. The NiO@PC composite exhibited brilliant capacitance of 500 F g −1 at 10 A g −1 after 8000 cycles. Moreover, as symmetric supercapacitor, NiO@PC exhibited high specific capacitance of 76 mF cm −2 at 1 mA cm −2 . The excellent electrochemistry performance of NiO@PC brings the possibility of using biomass waste as electrode materials for energy storage. This process is facile and environmental friendly. [ABSTRACT FROM AUTHOR]

• Parametric model order reduction strategy in context of substructuring proposed for large scale mechanical systems with viscoelasticity. • Krylov subspace based on the approximation of viscoelasticity replaces the interior and interface reduction of the Craig-Bampton method with local characteristic constraint modes. • New expression of the frequency-dependent constraint modes. • Parametric global reduction basis obtained by combination of singular value decomposition and interpolation. • Efficiency and accuracy of the proposed method demonstrated with two numerical examples. Adhesive bonding plays an increasingly important role in mechanical systems to connect different components and multi-material assemblies, and usually exhibits viscoelasticity. To accurately predict their structural dynamic behavior, finite element models are often used. When large systems are considered, these models result in high computational costs. To reduce the computational costs, substructuring combined with model order reduction can be applied. In this context, the well-known Craig-Bampton method is often used. However, due to the frequency-dependency of viscoelastic material properties, it cannot be directly applied to assemblies with adhesive joints. To enable its use for viscoelastic substructures, this work proposes several improvements to the Craig-Bampton method. Moreover, since the dynamic performance of adhesive bonded structures can strongly depend on the viscoelastic properties, the efficient assessment of different material parameters is highly desirable. Therefore, this work also extends the improved Craig-Bampton method towards parametric model order reduction in which a global reduction basis is constructed by singular value decomposition and interpolation of sampling-based local bases. Two numerical examples of adhesive bonded systems are employed to demonstrate the accuracy and computation time reduction which can be achieved with the proposed approach. [ABSTRACT FROM AUTHOR]

The application and performance of ground source heat pump (GSHP) systems in Jiangsu, China are reported in this study. Fifty cases were selected from different areas including office, residence, and other building types. Half of the selected cases was measured in summer, and the other half was measured in winter. The water temperatures, energy efficiency, energy consumption and thermodynamic perfectibility were analyzed statistically. The ground provided an average water temperature of 25.4 °C in summer and 11.7 °C in winter. The temperature difference between the inlet and outlet on the ground side in both the seasons was 3.07 °C. The statistical average values of coefficient of performance (COP), energy efficiency ratio (EER), and thermodynamic perfectibility η were 4.62, 3.41, and 0.38 in summer and 4.34, 3.22, and 0.49 in winter, respectively. The energy used by heat pumps and water pumps was about 3:1 in both the seasons. Furthermore, a comprehensive evaluation was conducted based on the statistical baseline set by the collected data. This method included factors that influence the actual system performance and provided an approach to assess and compare the performance of the cases comprehensively. [ABSTRACT FROM AUTHOR]

On-board hydrogen production via catalytic autothermal reforming is beneficial to vehicles using fuel cells as auxiliary power unit because it eliminates the challenges of hydrogen storage. As the primary fuel for both civilian and military air flight application, Jet-A fuel (after desulfurization) was reformed for making hydrogen-rich fuels in this study using an in-house-made Rh/NiO/K-La-Ce-Al-O X catalyst under various operating conditions. Based on the preliminary thermodynamic analysis of reaction equilibrium, important parameters such as ratios of H 2 O/C and O 2 /C were selected, in the range of 1.1–2.5 and 0.5–1.0, respectively. The optimal operating conditions were experimentally obtained at the reactor's temperature of 696 °C, which gave H 2 O/C = 2.5 and O 2 /C = 0.5, and the obtained fuel conversion percentage, hydrogen yield, and energy efficiency were 0.89, 1.44, and 0.65, respectively. In addition, a discussion of the molar fraction variation of CO and CO 2 at different H 2 O/C, as well as the analysis of fuel conversion profile, leads to the finding of effective approaches for suppression of coke formation. [ABSTRACT FROM AUTHOR]

To conserve energy, ground source heat pump (GSHP) system has been used worldwide for cooling and heating buildings, and there is a persistent concern in the performance of the system. In this study, the performances of five residential GSHP systems in Hot Summer and Cold Winter (HSCW) area in China were examined. Data were acquired through field testing, operation record and long-term monitoring. And outdoor climate parameters, water temperature characteristics, cooling load characteristics, system efficiencies and energy consumptions, heat extraction and rejection imbalance were analyzed. Field test data were used to analyze the dynamic cooling load characteristics and the energy efficiency of the heat pump units and systems. Energy consumption was statistically analyzed. The results show that the weighted average Coefficient of Performance (COP) of the heat pumps and system Energy Efficiency Ratio (EER) varied from 3.36 to 5.94 and 1.95 to 4.35, respectively. Positive correlation of high cooling load and high COP was presented. More heat extraction than rejection was found, which was relevant to domestic hot water supply. Furthermore, long-term distributions of ground side water outlet temperature were used, and the skewness and kurtosis were introduced into the quantization evaluation method. [ABSTRACT FROM AUTHOR]

• Bus bunching occurs much fewer in observations than in conventional models. • Counteraction between link and stop headway deviations can resist bus bunching. • Superposition between link and stop headway deviations destroys headway regularity. • Counteraction is more prominent than superposition with buses moving forward. • The counteraction effect owes to drivers' reactions to bus travel time deviations. Bus headway deviations are the major causes of bus bunching, which is detrimental to bus service reliability and leads to excessive waiting time for passengers. Generally, it is believed that bus bunching is an inevitable result once a service disturbance occurs, as long as the route is long enough. However, in this study, it goes as low as 5% of all trips from the empirical data, contradicting the expectation in theory. This study explores the underlying reasons for this contradiction based on empirical data from two representative bus routes in China. The results show that headway deviations on links and at stops mostly counteract with each other, constraining the occurrence of bus bunching. Under this counteraction effect, the path headway deviations remain within a stable range, normally bounded by the planned headway. It indicates that the bus system has a self-repair ability to resist headway disruptions, which explains why bus bunching happens at a considerably lower frequency in practice than in theory. We further discuss how the counteraction effect works. The insights gained from this study can shed light on preventing bus bunching and generating new ways to recover bus service regularity after a headway disruption. If we can adequately adjust the control methods to make the link and stop headway deviations counteract with each other, the bus system can automatically mitigate the headway deviations. [ABSTRACT FROM AUTHOR]

Polymer grafted nanoparticles with different surface properties have been prepared and widely used in different fields recently. In this study, through the rheological study on the strength of interfacial adhesion relevant to the complex viscoelasticity and relaxation response of the well-defined polymer (polylactide, PLLA) grafted-nanoparticles (silica) mixed with free chains of the same polymer nanocomposites in melt state, we investigated the different interfacial entanglement and relaxation mechanisms of the polymer grafted nanocomposites (PGN), to bridge the relationship between the micro and macro-properties of PGN. The AFM observation illuminated that circles one by one were formed in “grafting from” prepared SiO 2 (GF), while core–shell morphology found in “grafting to” prepared SiO 2 (GT), because of the different surface properties of the modified SiO 2 . The interface relaxation was characterized around 300 s in the GT5 nanocomposites, due to the entanglement between the long grafted and matrix chains, which also contributed lots to the rheology properties enhancement, such as the improving viscosity. Combining the relaxation spectrum and stress relaxation testing, the relaxation units in different time scales, from short time to long time, were illuminated. Also the relaxation of the interfacial chains in different situations, through the introduction of the absorption and reptation models, was proposed to explain our observations. The comparative study reminded us that the strong interfacial interactions or the long interfacial relaxation time aroused by the entanglement, were essential for successfully preparing polymer nanocomposites. [ABSTRACT FROM AUTHOR]

Two types of homemade poly( l-lactide) (PLLA)-grafted SiO nanoparticles with totally different topological structures are introduced into PLLA to prepare PLLA nanocomposites with different interface interactions and study the effect of the topology of polymer grafted nanoparticle on crystallization of PLLA. Differential scanning calorimetry (DSC) and polarized optical photomicrographs (POM) results show that the crystallization rate of PLLA has been greatly improved by the introduction of grafted SiO, due to the improved heterogeneous nucleating effect. The nucleation constant of the two modified nanoparticles is evaluated by Hoffman-Lauritzen analysis; it is suggested that by introducing modified nanoparticles with long grafted chains, the interaction between the nanofiller and PLLA matrix will be enhanced, leading to the improved nucleation effective (the larger nucleation constant Kg), and the changed crystalline morphology, from large spherocrystals to tiny crystals. These observations are explained on the basis of different nucleation mechanism caused by the different surface structures of grafted SiO, through the application of time-resolved Fourier transform infrared (FTIR) spectroscopy in the molecular level. The special long grafted PLLA chains can be acted as a more efficient nucleating agent for PLLA, and the conformational ordering of PLLA during the crystallization is significantly influenced by the topology of modified nanoparticles. [ABSTRACT FROM AUTHOR]

Fuel adaptability of a lab-scale 2.5 kW th autothermal reforming system was experimentally investigated. Analyses of thermodynamics of autothermal reforming of different fuels at various temperatures were provided to determine the associated flow rates of fuel, air, and steam. The tested reformer has a specifically designed mixing chamber and NiO–Rh based bimetallic catalyst with promoters of Ce, K and La, which were originally designed for autothermal reforming of Jet-A fuel. The adaptability of the reformer to multiple fuels, including diesel, gasoline, ethanol, and methanol was experimentally studied at different operating conditions. Molar fractions of H 2 , CO, CO 2 , and CH 4 in the dried reformate were measured and the results were compared with values reported in the literature. The autothermal reforming performance of the reformer for different fuels was evaluated with regard to hydrogen selectivity, CO x selectivity, and energy conversion efficiency. It was concluded that the currently developed reformer and the associated catalyst have great fuel adaptability and high potential being used in a fuel-flexible autothermal reforming system. [ABSTRACT FROM AUTHOR]

Catalytic reforming is a technology to produce hydrogen and syngas from heavy hydrocarbon fuels in order to supply hydrogen to fuel cells. A lab-scale 2.5 kW t autothermal reforming (ATR) system with a specially designed reformer and combined analysis of balance-of-plant was studied and tested in the present study. NiO–Rh based bimetallic catalysts with promoters of Ce, K, and La were used in the reformer. The performance of the reformer was studied by checking the hydrogen selectivity, CO x selectivity, and energy conversion efficiency at various operating temperatures, steam to carbon ratios, oxygen to carbon ratios, and reactants' inlet temperatures. The experimental work firstly tested n -dodecane as the surrogate of Jet-A fuel to optimize operating conditions. After that, desulfurized commercial Jet-A fuel was tested at the optimized operating conditions. The design of the reformer and the catalyst are recommended for high performance Jet-A fuel reforming and hydrogen-rich syngas production. [ABSTRACT FROM AUTHOR]

While clustering has been commonly used to profile the building electricity consumption data, its application to HVAC system data is relatively less. Based on the operation data of a residential ground source heat pump (GSHP) system, a pre-processing procedure was set up, including acquisition, cleaning, missing-data fill-in, and standardization. Then hierarchical clustering was used, based on the dynamic time warping (DTW) distance calculation method. A new index, the sum of squares of errors based on DTW, was used to determine the best cluster number. The patterns were extracted based on clustering results. The heat exchange on the user-side during one cooling season was processed as a case study. We obtained 5 valid clusters and extracted patterns from each. For the studied case, the result based on the DTW method yields a better homogeneity compared to the Euclidean method. The method is then applied to a five-year operation data, where 9 and 6 patterns were obtained for the cooling and heating seasons, respectively. They mainly differed in shape, and the cooling patterns fluctuate more. Overall, clustering and pattern extraction can reduce the data dimension, and provide a data-driven view of how the system supplies the cooling and heating. • A hierarchical clustering was used base on the dynamic time warping method. • Daily patterns of supplied cooling/heating were extracted from massive raw data. • Objectively but briefly profiles the system behavior using the extracted patterns. • Provides reference data for the relative researches. [ABSTRACT FROM AUTHOR]

Lignin is a major bioresource from 2nd generation biorefinery process streams and from pulp and paper production that is still severely underutilized nowadays. Its natural polymeric and aromatic structures make it suitable as a potential building block for biopolymer production. Due to the growing environmental and health concerns over conventional polyurethane (PU) manufacturing processes that utilize toxic isocyanates, there is a great interest to develop a non-isocyanate PU (NIPU) route. Herein, we demonstrate a novel strategy that uses highly pure lignin isolated from co-solvent enhanced lignocellulosic fractionation (CELF) pretreatment of poplar wood to produce biobased NIPUs. In this strategy, hardwood poplar is firstly fractionated via a CELF pretreatment to produce a clean lignin stream that is rich in phenolics. The CELF lignin was then aminated by a Mannich reaction, and the aminated CELF lignin was finally reacted with bicyclic carbonates to yield an advanced NIPU. The structure, mechanical, and thermal properties of these novel NIPUs were elucidated by FTIR, NMR, tensile test, dynamic mechanical analysis (DMA), and thermogravimetric analysis (TGA). The mechanical properties of these lignin based NIPUs could be tuned from highly rigid to elastic polymers by simply modifying the lignin constituents of the polymer. The thermal stabilities of NIPUs were improved because of the addition of aminated lignin, and NIPU containing 55 and 23 wt% lignin showed the highest tensile strength (~1.2 MPa) and elongation at break (~140%), respectively. The results obtained in this study demonstrate that the reaction of cyclic carbonate with aminated lignin represents an interesting pathway for the synthesizing of lignin based NIPU with a relative high lignin content. [Display omitted] • A CELF pretreatment was used to isolate a reactive lignin stream. • A controlled lignin aminated strategy was developed • A green route to synthesis lignin-based non-isocyanate polyurethanes was reported. • The obtained lignin based NIPU was thoroughly characterized [ABSTRACT FROM AUTHOR]

In this work, a reconfigurable ultra-wideband transmissive terahertz polarization rotator based on graphene metamaterial is proposed that can switch between two states of polarization rotation within a broad terahertz band by changing the Fermi level of graphene. The proposed reconfigurable polarization rotator is based on a two-dimensional periodic array of multilayer graphene metamaterial structure, which is composed of metal grating, graphene grating, silicon dioxide thin film, and a dielectric substrate. The graphene metamaterial can achieve high co-polarized transmission of a linearly polarized incident wave at the off-state of the graphene grating without applying the bias voltage. Once the specially designed bias voltage is applied to change the Fermi level of graphene, the polarization rotation angle of linearly polarized waves is switched to 45° by the graphene metamaterial at the on-state. The working frequency band with 45-degree linear polarized transmission remaining above 0.7 and the polarization conversion ratio (PCR) above 90% is from 0.35 to 1.75 THz, and the relative bandwidth reaches 133.3% of the central working frequency. Furthermore, even with oblique incidence at large angles, the proposed device retains high-efficiency conversion in a broad band. The proposed graphene metamaterial offers a novel approach for the design of a terahertz tunable polarization rotator and is expected to be applied in the applications of terahertz wireless communication, imaging, and sensing. [ABSTRACT FROM AUTHOR]

Abstract: This article examines and discusses a promising high performance sulfur adsorbent, NiO–CeO2/Al2O3–SiO2, for the desulfurization of Jet-A fuel at ambient conditions. The authors investigated the effects of the amount of nitric acid added during the preparation of the adsorbent supporter, with pseudo-boehmite (70wt.% Al2O3) and diatomite (SiO2) used as support materials in the adsorbent. Desulfurization performance due to percentage difference of catalyst species, as well as regeneration of the adsorbent, was evaluated. It was discovered that the improved adsorbent, with optimized material composition and processing procedures, can approach a sulfur adsorption capacity of 1.4 and 3.22mg-S/g-ads at breakthrough points of 10 and 50ppmw, respectively. The treated fuel volumes reached 3.02 and 3.58ml/g-ads at 10 and 50ppmw, respectively. The improved adsorbent was also tested for four regeneration times. At a breakpoint of 50ppmw S in effluent fuel, about 75%, 66%, 59% and 51% sulfur adsorption capabilities were recovered in the regenerated adsorbent from cycle 1 to cycle 4. This impressive desulfurization performance at room temperature, and the use of pseudo-boehmite (70wt.% Al2O3) and diatomite (SiO2) other than molecule sieves for the support materials, make this sulfur adsorbent very promising. [Copyright &y& Elsevier]

Highlights: [•] Desulfurization of Jet-A fuel at room temperature using novel adsorbent. [•] Low cost pseudo-boehmite and diatomite mixture are used for support. [•] At breakpoint concentration of 10ppmw adsorption capacity is 0.633mgS/g adsorbent. [•] One cycle regenerated adsorbent recovers 83% of the desulfurization capacity. [Copyright &y& Elsevier]

Highlights: [•] Desulfurization of Jet-A fuel at room temperature using Ni–Ce-based adsorbent. [•] The adsorbent preparation conditions were optimized. [•] The sulfur adsorption equilibrium and kinetics were examined from batch-tests. [•] The achieved sulfur concentration at room temperature in the fuel was 22.13ppmw. [Copyright &y& Elsevier]

[Display omitted] • First study on wood-flour-included composite by stereolithography. • Enhanced mechanical properties of the printed composites. • Stress-whitening was first found after the uniaxial drawing. In this study, poplar wood flour at various concentrations (1–10 wt%) is incorporated into a methacrylate-based resin via solution blending to fabricate wood-reinforced composites using stereolithography apparatus (SLA) 3D printing. Differential scanning calorimetry (DSC) along with Fourier transform infrared spectroscopy (FTIR) analysis shows the presence of a small amount of residual monomer in the printed samples. For the printed composites, the glass transition temperature (T g) from dynamic mechanical analysis (DMA) decreases as more wood flour is incorporated, which indicates an increase in free volume occupied by polymer chains. The tensile strength is improved up to 17.3% from 21.1 MPa (no wood flour) to 24.7 MPa (1.0 wt% wood flour). The highest Young's modulus reaches 323.8 MPa (2.0 wt% wood flour), which is 1.9-fold of that of the sample without wood flour. Moreover, the composites show "stress whitening" with the addition of wood flour during the uniaxial drawing. Morphology analysis of the tested samples show that the formation of microcraze and microvoids likely causing the stress whitening. This is the first study that demonstrates wood flour can be utilized in SLA 3D printed wood plastic composites (WPC) which can reinforce the printed products with a modest loading amount. [ABSTRACT FROM AUTHOR]

Background: Abnormalities in T cell activation play an important role in the pathogenesis of myocarditis, and persistent T cell responses can lead to autoimmunity and chronic cardiac inflammation, as well as even dilated cardiomyopathy. Although previous work has examined the role of T cells in myocarditis in animal models, the specific mechanism for human cardiomyocytes has not been investigated. Methods: In this study, we constructed the human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and established the T cell-mediated cardiac injury model by co-culturing with activated CD4 + T or CD8 + T cells that were isolated from peripheral mononuclear blood to elucidate the pathogenesis of myocardial cell injury caused by inflammation. Results: By combination of quantitative proteomics with tissue and cell immunofluorescence examination, we established a proteome profile of inflammatory myocardia from hiPSC-CMs with obvious cardiomyocyte injury and increased levels of lactate dehydrogenase content, creatine kinase isoenzyme MB and cardiac troponin. A series of molecular dysfunctions of hiPSC-CMs was observed and indicated that CD4 + cells could produce direct cardiomyocyte injury by activating the NOD-like receptor signals pathway. Conclusions: The data presented in our study established a proteome map of inflammatory myocardial based on hiPSC-CMs injury model. These results can provide guidance in the discovery of improved clinical treatments for myocarditis. [ABSTRACT FROM AUTHOR]

Introduction/Aims Methods Results Discussion Severe spinal deformities and previous spinal orthopedic instrumentation may result in substantial technical challenges for nusinersen delivery through lumbar puncture in patients with spinal muscular atrophy (SMA). The aim of this paper was to review our experience with ultrasound‐guided cervical puncture as an alternative approach for the intrathecal administration of nusinersen.This was a retrospective medical record review of transverse interlaminar ultrasound‐guided C1‐C2 puncture for nusinersen delivery in SMA patients. The details of puncture, complications, and success rate of the procedure were summarized.There were four patients who received a total of 13 cervical punctures for nusinersen delivery. All procedures were technically successful with no major complications. Full doses of nusinersen were delivered intrathecally.Transverse interlaminar ultrasound‐guided C1‐C2 puncture is an alternative approach for administering nusinersen if lumbar puncture fails. The success of the technique requires a thorough preprocedural evaluation of cervical spine imaging, sound knowledge of the cervical sonoanatomy and careful manipulation of the needle. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) are widely used in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC); however, the toxicity profiles are inconclusive. Methods: Clinical trials evaluating ICIs for R/M HNSCC were searched from online databases. The characteristics of the studies and the results of incidences of any grade treatment‐related adverse events (trAEs), grade three or more trAEs, treatment‐related deaths, trAEs leading to discontinuation of treatment, and specific trAEs were extracted. Results: Twenty studies with 3756 patients were included. The pooled incidences of any grade trAEs, grade three or more trAEs, treatment‐related deaths, trAEs leading to discontinuation of treatment for overall population were 62.07% (95% CI, 59.07%–65.02%), 13.82% (95% CI, 11.23%–16.62%), 0.39% (95% CI, 0.15%–0.71%), 3.99% (95% CI, 2.36%–5.95%), respectively. Programmed cell death protein 1 (PD‐1) inhibitors monotherapy and ICIs combination therapy had significantly higher incidences of any grade trAEs (odds ratio [OR], 1.25, 95% CI, 1.05–1.49 and 1.36, 95% CI, 1.15–1.60, respectively), grade three or more trAEs (OR, 1.41, 95% CI, 1.08–1.84 and 1.79, 95% CI, 1.39–2.30, respectively), trAEs leading to discontinuation of treatment (OR, 3.98, 95% CI, 2.06–7.70 and 10.14, 95% CI, 5.49–18.70, respectively) compared with programmed death‐ligand 1 (PD‐L1) inhibitors monotherapy. ICIs combination therapy had a significantly higher incidence of grade three or more trAEs compared with PD‐1 inhibitors monotherapy (OR, 1.27, 95% CI, 1.03–1.55); however, the incidences of any grade trAEs and trAEs leading to discontinuation of treatment were not significant different. Conclusions: Our study suggests that the incidences of grade three or more trAEs, treatment‐related deaths, and trAEs leading to discontinuation of treatment are low in R/M HNSCC patients treated with ICIs. PD‐L1 inhibitors monotherapy may be safer compared with PD‐1 inhibitors monotherapy and ICIs combination therapy. [ABSTRACT FROM AUTHOR]

The author comments on the pursuit of excellence in graduate medical education to improve the quality of clinical services in China. He explains the growing conflict between doctors and patients due to shortage of adequately educated health-care workers. The author thinks the standardisation of quality of care remains an enormous challenge for China with health facilities lacking accreditation, certification, and sharing of best practices.

Objective: Long QT syndrome type 7 (Andersen–Tawil syndrome, ATS), which is caused by KCNJ2 gene mutation, often leads to ventricular arrhythmia, periodic paralysis and skeletal malformations. The development, differentiation and electrophysiological maturation of cardiomyocytes (CMs) changes promote the pathophysiology of Long QT syndrome type 7(LQT7). We aimed to specifically reproduce the ATS disease phenotype and study the pathogenic mechanism. Methods and results: We established a cardiac cell model derived from human induced pluripotent stem cells (hiPSCs) to the phenotypes and electrophysiological function, and the establishment of a human myocardial cell model that specifically reproduces the symptoms of ATS provides a reliable platform for exploring the mechanism of this disease or potential drugs. The spontaneous pulsation rate of myocardial cells in the mutation group was significantly lower than that in the repair CRISPR group, the action potential duration was prolonged, and the Kir2.1 current of the inward rectifier potassium ion channel was decreased, which is consistent with the clinical symptoms of ATS patients. Only ZNF528, a chromatin-accessible TF related to pathogenicity, was continuously regulated beginning from the cardiac mesodermal precursor cell stage (day 4), and continued to be expressed at low levels, which was identified by WGCNA method and verified with ATAC-seq data in the mutation group. Subsequently, it indicated that seven pathways were downregulated (all p < 0.05) by used single sample Gene Set Enrichment Analysis to evaluate the overall regulation of potassium-related pathways enriched in the transcriptome and proteome of late mature CMs. Among them, the three pathways (GO: 0008076, GO: 1990573 and GO: 0030007) containing the mutated gene KCNJ2 is involved that are related to the whole process by which a potassium ion enters the cell via the inward rectifier potassium channel to exert its effect were inhibited. The other four pathways are related to regulation of the potassium transmembrane pathway and sodium:potassium exchange ATPase (p < 0.05). ZNF528 small interfering (si)-RNA was applied to hiPSC-derived cardiomyocytes for CRISPR group to explore changes in potassium ion currents and growth and development related target protein levels that affect disease phenotype. Three consistently downregulated proteins (KCNJ2, CTTN and ATP1B1) associated with pathogenicity were verificated through correlation and intersection analysis. Conclusion: This study uncovers TFs and target proteins related to electrophysiology and developmental pathogenicity in ATS myocardial cells, obtaining novel targets for potential therapeutic candidate development that does not rely on gene editing. [ABSTRACT FROM AUTHOR]

Background: Janus kinase 2 (JAK2) mutation plays an important role in T cell immunity. However, the effect of JAK2 mutation on immunotherapy is largely uncharacterized. Methods: In this study, we analyzed the effect of JAK2 mutation on the efficacy and outcomes of immune checkpoint inhibitor (ICI) therapy in the discovery cohort (n = 662) and the verification cohort (n = 1423). Furthermore, we explored the association of JAK2 mutation with the tumor immune microenvironment in a multiomics cohort. Results: In the discovery cohort (n = 662), JAK2 mutant-type patients had a better objective response rate (58.8% vs. 26.7%, P = 0.010), durable clinical benefit (64.7% vs. 38.9%, P = 0.043), progression-free survival (hazard ratio [HR] = 0.431, P = 0.015), and overall survival (HR = 0.378, P = 0.025), relative to JAK2 wild-type patients. Moreover, we further verified the prognostic significance of JAK2 mutation in an independent ICI treatment cohort with a larger sample size (n = 1423). In addition, we discovered that the JAK2 mutation was remarkably related to increased immunogenicity, such as a higher TMB, higher expression of costimulatory molecules and stimulation of antigen processing mechanisms. In addition, JAK2 mutation was positively correlated with activated anticancer immunity, such as infiltration of various immune cells and higher expression of chemokines. Conclusion: Our study demonstrates that JAK2 mutation is a novel marker that can be used to effectively predict prognosis and response to ICI therapy. Highlights: JAK2-mutated patients had a better response to ICI therapy. JAK2 mutation was associated with higher levels of immune cell infiltration and immune checkpoints. JAK2 mutation may be served as a potential predictive biomarker for efficacy of ICI therapy. [ABSTRACT FROM AUTHOR]

Amyloid transthyretin (ATTR) amyloidosis caused by transthyretin misfolded into amyloid deposits in nerve and heart is a progressive rare disease. The unknown pathogenesis and the lack of therapy make the 5-year survival prognosis extremely poor. Currently available ATTR drugs can only relieve symptoms and slow down progression, but no drug has demonstrated curable effect for this disease. The growing volume of pharmacological data and large-scale genome and transcriptome data bring new opportunities to find potential new ATTR drugs through computational drug repositioning. We collected the ATTR-related in the disease pathogenesis and differentially expressed (DE) genes from five public databases and Gene Expression Omnibus expression profiles, respectively, then screened drug candidates by a corrected protein–protein network analysis of the ATTR-related genes as well as the drug targets from DrugBank database, and then filtered the drug candidates on the basis of gene expression data perturbed by compounds. We collected 139 and 56 ATTR-related genes from five public databases and transcriptome data, respectively, and performed functional enrichment analysis. We screened out 355 drug candidates based on the proximity to ATTR-related genes in the corrected interactome network, refined by graph neural networks. An Inverted Gene Set Enrichment analysis was further applied to estimate the effect of perturbations on ATTR-related and DE genes. High probability drug candidates were discussed. Drug repositioning using systematic computational processes on an interactome network with transcriptome data were performed to screen out several potential new drug candidates for ATTR. [ABSTRACT FROM AUTHOR]

A new form of mobile payment, Quick Response (QR) code, has been a popular way of paying bus fares in China since 2017. Compared with conventional payment methods, cash or IC card, QR code shows a lot of differences in response time, recognition accuracy, and payment procedure, which significantly influences the boarding service time (BST) for passengers. However, no research has considered its efficiency. This study, therefore, tries to fill this gap and investigate its influence on BST. Sufficient ride-check data were collected, and the influence of the QR code payment method on BST was examined through a set of regression models. Passengers pay the bus fare with different payment methods as their first choice; nevertheless, when the payment fails, they may transfer among them. According to the payment choice, result, and process, we introduce the first-choice-based, the last-choice-based, and the choice-transfer-based models, respectively. The scenario with delays in calling out the QR code was considered in the choice-transfer-based model. The onboard crowdedness was regarded as a categorical variable to determine the regime of the boarding process in all models. We conduct empirical analysis in Wuhan, and this study can help to identify the influence of the QR code payment method on BST, consequently, improving bus service efficiency. [ABSTRACT FROM AUTHOR]

A putative glutamine synthetase (GS) was detected in a psychrophilic bacterium, Cryobacterium soli GCJ02. For gaining greater insight into its functioning, the gene was cloned and expressed in a heterologous host, Escherichia coli. The monomer enzyme with a molecular weight of 53.03 kDa was expressed primarily in cytosolic compartment. The enzyme activity was detected using glutamate and ATP. The optimum conditions of its biosynthesis were observed to be 60 °C and pH value 7.5. Its thermostability was relatively high with a half-life of 50 min at 40 °C. GS activity was enhanced in the presence of metal ions such as Mg2+ and Mn2+, whereas Fe2+, Cu2+ and Ca2+ proved inhibitory. The consensus pattern [EXE]-D-KP-[XGXGXH] in the GS lies between residues 132 and 272. The catalytic active sites consisting of EAE and NGSGMH were verified by site-directed mutagenesis. Based on the analysis of the consensus pattern, the GS/glutamate synthase cycle of C. soli GCJ02 is expected to contribute to the GS synthesic activity. [ABSTRACT FROM AUTHOR]