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Abstract Insufficient tumor immunogenicity and immune escape from tumors remain common problems in all tumor immunotherapies. Recent studies have shown that pyroptosis, a form of programmed cell death that is accompanied by immune checkpoint inhibitors, can induce effective immunogenic cell death and long‐term immune activation. Therapeutic strategies to jointly induce pyroptosis and reverse immunosuppressive tumor microenvironments are promising for cancer immunotherapy. In this regard, a dual‐responsive supramolecular polymeric nanomedicine (NCSNPs) to self‐cascade amplify the benefits of cancer immunotherapy is designed. The NCSNPs are formulated by β‐cyclodextrin coupling nitric oxide (NO) donor, a pyroptosis activator, and NLG919, an indoleamine 2,3‐dioxygenase (IDO) inhibitor, and self‐assembled through host–guest molecular recognition and hydrophobic interaction to obtain nanoparticles. NCSNPs possess excellent tumor accumulation and bioavailability attributed to ingenious supramolecular engineering. The study not only confirms the occurrence of NO‐triggered pyroptosis in tumors for the first time but also reverses the immunosuppressive microenvironment in tumor sites via an IDO inhibitor by enhancing the infiltration of cytotoxic T lymphocytes, to achieve remarkable inhibition of tumor proliferation. Thus, this study provides a novel strategy for cancer immunotherapy.

The reverse water-gas shift reaction (rWGS) is of particular interest as it is the first step to producing high-added-value products from carbon dioxide (CO2) and renewable hydrogen (H2), such as synthetic fuels or other chemical building blocks (e.g. methanol) through a modified Fischer-Tropsch process. However, side reactions and material deactivation issues, depending on the conditions used, still make it challenging. Efforts have been put into developing and improving scalable catalysts that can deliver high selectivity while at the same time being able to avoid deactivation through high temperature sintering and/or carbon deposition. Here we design a set of perovskite ferrites specifically tailored to the hydrogenation of CO2 via the reverse water-gas shift reaction. We tailor the oxygen vacancies, proven to play a major role in the process, by partially substituting the primary A-site element (Barium, Ba) with Praseodymium (Pr) and Samarium (Sm), and also dope the B-site with a small amount of Nickel (Ni). We also take advantage of the exsolution process and manage to produce highly selective Fe-Ni alloys that suppress the formation of any by-products, leading to up to 100% CO selectivity.

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Xanthelasma palpebrarum (XP) is the most common form of cutaneous xanthoma, with a prevalence of 1.1%~4.4% in the population. However, the cause of XP remains largely unknown. In the present study, we used Mendelian randomization to assess the genetic association between plasma lipids, metabolic traits, and circulating protein with XP, leveraging summary statistics from large genome-wide association studies (GWAS). Genetically predicted plasma cholesterol and LDL-C, but not HDL-C or triglyceride, were significantly associated with XP. Metabolic traits, including BMI, fasting glucose, type 2 diabetes, systolic and diastolic blood pressure, were not significantly associated with XP. Furthermore, we found genetically predicted 12 circulating proteins were associated with XP, including FN1, NTM, FCN2, GOLM1, ICAM5, PDE5A, C5, CLEC11A, CXCL1, CCL2, CCL11, CCL13. In conclusion, this study identified plasma cholesterol, LDL-C, and 12 circulating proteins to be putative causal factors for XP, highlighting the role of plasma cholesterol and inflammatory response in XP development.

Abstract For around half of the pediatric B-lineage acute lymphoblastic leukemia (B-ALL) patients, the molecular mechanism of relapse remains unclear. To fill this gap in knowledge, here we characterize the chromatin accessibility landscape in pediatric relapsed B-ALL. We observe rewired accessible chromatin regions (ACRs) associated with transcription dysregulation in leukemia cells as compared with normal B-cell progenitors. We show that over a quarter of the ACRs in B-ALL are in quiescent regions with high heterogeneity among B-ALLs. We identify subtype-specific and allele-imbalanced chromatin accessibility by integrating multi-omics data. By characterizing the differential ACRs between diagnosis and relapse in B-ALL, we identify alterations in chromatin accessibility during drug treatment. Further analysis of ACRs associated with relapse free survival leads to the identification of a subgroup of B-ALL which show early relapse. These data provide an advanced and integrative portrait of the importance of chromatin accessibility alterations in tumorigenesis and drug responses.

Purpose: Vitiligo is a chronic depigmentation disease caused by a loss of functioning melanocytes and melanin from the epidermis. Oxidative stress-induced damage to melanocytes is key in the pathogenesis of vitiligo. WSY6 is a caffeic acid derivative synthesized from epigallocatechin-3-gallate (EGCG). This study is to investigate whether the new chemical WSY6 protected melanocytes from H2O2-induced cell damage and to elucidate the underlying molecular mechanism. Patients and methods: The present study compared the antioxidative potential of WSY6 with EGCG in hydrogen peroxide (H2O2)-treated PIG1 cells. Western blotting was used to study the protein expression of cyto-c, cleaved-caspase3, cleaved-caspase9, and the activation of MAPK family members, including p38, ERK1/2, JNK and their phosphorylation in melanocytes. ROS assay kit to detect intracellular reactive oxygen species production; CCK8 and lactate dehydrogenase leak assay to detect cytotoxicity. Results: EGCG and WSY6 ameliorated H2O2-induced oxidative stress damage in PIG1 cells in a does-dependent manner, while WSY6 was much more effective. WSY6 reduced cellular ROS production, cytochrome c release, downregulated caspase-3 and caspase-9 activation. MAPK pathway signaling including phosphorylated p38, ERK and JNK were observed under oxidative stress and can be much protected by pre-treatment of WSY6. Conclusion: These results indicated that WSY6 could be a more powerful antioxidant than EGCG and protect melanocytes against oxidative cytotoxicity.

Chemical looping ammonia synthesis is a promising pathway to synthesise ammonia with lower energy and economic costs than the current Haber-Bosch process, for example, by lowering the operating temperature and/or pressure, whilst maintaining comparable NH3 yield. A solid nitrogen carrier is used to mediate the reaction and form ammonia in consecutive steps. In contrast to the Haber-Bosch process, the thermodynamics and kinetics of the reaction are dependent on the properties of the nitrogen carrier. This introduces additional opportunities for novel designs, though finding suitable materials becomes the challenge. Herein, nitrides from the Materials Project database are screened based on their equilibrium nitrogen pressures and nitrogen exchange capacities. The equilibrium nitrogen pressure was used as a proxy to determine the equilibrium ammonia mole fraction of the reaction, a key performance indicator for chemical looping ammonia synthesis. Using high-throughput gas-solid equilibrium calculations, 2515 nitrides were screened, and 111 nitrides were found to achieve sufficiently high ammonia mole fraction at equilibrium to compete with the Haber-Bosch process. Due to large inaccuracies associated with theoretical material properties, the viability of screened candidates cannot be adequately ascertained. The quality and quantity of theoretical and experimental data for nitrogen carriers, respectively, must be improved further to identify suitable materials for chemical looping ammonia synthesis.

Abstract Purpose Studies of the association between body mass index (BMI) at diagnosis and treatment outcome in children with acute lymphoblastic leukemia (ALL) have yielded inconsistent results. Hence, we conducted a retrospective study in a large cohort of Chinese children with ALL treated with contemporary protocols. Patients and Methods A total of 1437 children (62.1% male; median age at diagnosis 5.7 years, range: 2.3–16.3 years) were enrolled in two consecutive clinical trials at the Shanghai Children's Medical Center. The rates of overall survival, event‐free survival, relapse, treatment‐related mortality, and adverse events were compared among patients who were underweight (BMI 85th to

IntroductionTemporin-GHa obtained from the frog Hylarana guentheri showed bactericidal efficacy against Streptococcus mutans. To enhance its antibacterial activity, the derived peptides GHaR and GHa11R were designed, and their antibacterial performance, antibiofilm efficacy and potential in the inhibition of dental caries were evaluated.MethodsBacterial survival assay, fluorescent staining assay and transmission electron microscopy observation were applied to explore how the peptides inhibited and killed S. mutans. The antibiofilm efficacy was assayed by examining exopolysaccharide (EPS) and lactic acid production, bacterial adhesion and cell surface hydrophobicity. The gene expression level of virulence factors of S. mutans was detected by qRT-PCR. Finally, the impact of the peptides on the caries induced ability of S. mutans was measured using a rat caries model.ResultsIt has been shown that the peptides inhibited biofilm rapid accumulation by weakening the initial adhesion of S. mutans and reducing the production of EPS. Meanwhile, they also decreased bacterial acidogenicity and aciduricity, and ultimately prevented caries development in vivo.ConclusionGHaR and GHa11R might be promising candidates for controlling S. mutans infections.

PurposeThis meta-analysis was exerted in assessing the anticancer efficacy and safety of nab-paclitaxel (nab-P) when combined with platinum compound agents for therapy in patients with non-small cell lung cancer (NSCLC).MethodWe systematically searched the following seven electronic databases: PubMed, Cochrane Library, Web of Science, Embase, CNKI, Wan Fang, and China Science and Technology Journal Data. Randomized comparative clinical [randomized controlled clinical trial (RCT)] studies on nab-P plus platinum and carboplatin or cisplatin in combination with conventional chemotherapy agents or traditional paclitaxel were searched.ResultsA total of 19 RCT studies involving 6,011 patients were analyzed. The primary outcome includes the overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). The secondary outcome includes adverse events (AEs). Nab-P combined with platinum (carboplatin/cisplatin) had a better ORR [odds ratio (OR) = 1.66, 95% confidence interval (CI) (1.34, 2.05), p < 0.001] and improved PFS [hazard ratio (HR) = 0.84, 95% CI: (0.74, 0.94), p = 0.01] and OS [HR = 0.86, 95% CI: (0.78, 0.96), p = 0.008] in NSCLC patients. ORR [OR = 2.18, 95% CI: (1.07, 4.43)], PFS [HR = 0.62, 95% CI: (0.40, 0.97)], and OS [HR = 0.63, 95% CI: (0.49, 0.81)] were significantly improved among patients aged >70 years, and ORR [OR = 1.80, 95% CI: (1.20, 2.70)] and PFS [HR = 0.74, 95% CI: (0.56, 0.97)] were significantly elevated with SCC rate ≥65% in NSCLC patients (all p > 0.05). Among the adverse effects, the prevalence of neutropenia, neuralgia, and arthralgia/myalgia (≥ grade 3) compared to that of the control group. On the other hand, the prevalence of anemia and thrombocytopenia was higher in the nab-P plus platinum (carboplatin/cisplatin) compared to that of controls. It is worth noting that fatigue did not show statistical significance.ConclusionNab-P in combination with carboplatin/cisplatin regimen improves efficacy and tolerability in patients with NSCLC.Systematic review registrationhttp://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022288499.

Aim: This study focusses on the anti-inflammatory and immune-modulatory roles of berberine (BBR) in ulcerative colitis (UC) treatment. Additionally, the underlying mechanisms of BBR were systematically explored. Methods: A 3% (w/v) dextran sodium sulphate (DSS) solution was used for establishing the mice UC model. M2 macrophage polarisation was induced in RAW 264.7 cells using interleukin 4 (IL-4), whereas M1 macrophage polarisation was induced using lipopolysaccharide. Colon length, colon mucosa damage index (CMDI), and haematoxylin–eosin (HE) staining were used to evaluate colon damage induced by DSS. M1/M2 macrophages in the colon tissue were identified using immunofluorescence (IF) staining with CD86+ or CD163+. M1/M2 macrophages in the abdomen were examined using flow cytometry. An enzyme-linked immunosorbent assay was conducted to identify M1/M2 macrophage supernatant biomarkers in RAW 264.7 cells. Western blotting, immunohistochemical staining, and real-time PCR were performed to investigate the potential mechanisms of BBR for treating UC in vivo and in vitro. Results: BBR was found to prolong colon length, ameliorate CMDI and alleviate the colon's pathological changes in UC mice. In DSS-induced UC mice, M1 macrophages predominated. BBR promoted M2 macrophages and suppressed M1 macrophages in the colon and abdomen of DSS-induced UC mice. Additionally, BBR significantly decreased M1-specific markers (IFN-γ and IL-1β) while increasing M2-specific markers (IL-10 and TGF-β) in the supernatants of RAW 264.7 cells. BBR upregulated the mRNA expression of IL-4, STAT6, and Chil3 while downregulating TNF-α, IFN-γ, and NOS2 expression in vivo. Moreover, BBR activated the downstream targets of the IL-4-STAT6 signalling pathway and enhanced the phosphorylation of STAT6 in vivo and in vitro to polarise M2 macrophage. Conclusion: In UC mice, BBR suppressed M1 macrophages while promoting M2 macrophages. M1 macrophage suppression and M2 macrophage activation were strongly correlated with the anti-inflammatory and immune-modulating activities of BBR. BBR induced the polarisation of M2 macrophages by activating the IL-4-STAT6 signalling pathway, which contributed to its therapeutic efficacy against UC.

As preconditions and consequences of the globalization of higher education, multilingualism has reconfigured language ecology, language policy and planning, and multilingual management in the contemporary world. However, studies of multilingualism focusing on real-language scenarios in Sino-foreign cooperative education institutions (SCEIs) are rare. This study explores the multilingual ecology, language policy and planning, and language management of three leading SCEIs in China. It also investigates the attitudes of SCEIs’ stakeholders toward language use and language policy in multilingual contexts. A case study was conducted by analyzing a significant number of language policy documents, semi-structured interviews with stakeholders, and partial participant observations. The research results reveal the main features of multilingual coexistence and intense competition in the three leading SCEIs by identifying the micro, meso, and macro issues of language management. The effects of language policy and planning mechanisms are also identified in SCEIs of higher education. Potential conflicts in multilingual environments are interpreted from the perspective of global cooperation. Last, recommendations are offered for the advancement of the language evolution of SCEIs in China.

During the late Ming Dynasty period, the Jesuits carried out a cultural accommodation strategy in China, commonly known as Ricci’s Strategy, due to the significant role played by Matteo Ricci (1552–1610) during this process. This strategy encompassed three elements: evangelizing through science and technology, establishing connections with the upper class, and compiling books to spread evangelism, all of which helped Catholicism to be promoted in China and be accepted by the Chinese people collectively. But the strategy also drew a lot of opposition within and outside of the Society of Jesus, some of which even led to the Rites Controversy. The extant literature primarily focuses on the conflicts that arose between the Society of Jesus and other religious orders, as well as the divergent viewpoints within the Society itself, like Niccolò Longobardo (1559–1654)’s well-documented anti-Riccian position. However, this approach largely ignored the disputes that arose within the Jesuit community in Beijing during the 17th century, mainly involving Ludovico Buglio (1606–1682) and Adam Schall (1592–1666) as two key figures on opposing sides. These disputes primarily centered around three points: the inclusion of superstitious elements in the calendar, the identities of the Jesuits in Early Qing, and the approach to inculturating theology. Although these historical events offered new perspectives and materials for the study of Ricci’s Strategy, they have received limited scholarly attention. This paper focuses on the disputes between Buglio and Schall, analyzing how Matteo Ricci’s Strategy was investigated during that time.

Abstract Background Using embedded sensors, instrumented walkways provide clinicians with important information regarding gait disturbances. However, because raw data are summarized into standard gait variables, there may be some salient features and patterns that are ignored. Multiple sclerosis (MS) is an inflammatory neurodegenerative disease which predominantly impacts young to middle-aged adults. People with MS may experience varying degrees of gait impairments, making it a reasonable model to test contemporary machine leaning algorithms. In this study, we employ machine learning techniques applied to raw walkway data to discern MS patients from healthy controls. We achieve this goal by constructing a range of new features which supplement standard parameters to improve machine learning model performance. Results Eleven variables from the standard gait feature set achieved the highest accuracy of 81%, precision of 95%, recall of 81%, and F1-score of 87%, using support vector machine (SVM). The inclusion of the novel features (toe direction, hull area, base of support area, foot length, foot width and foot area) increased classification accuracy by 7%, recall by 9%, and F1-score by 6%. Conclusions The use of an instrumented walkway can generate rich data that is generally unseen by clinicians and researchers. Machine learning applied to standard gait variables can discern MS patients from healthy controls with excellent accuracy. Noteworthy, classifications are made stronger by including novel gait features (toe direction, hull area, base of support area, foot length and foot area).

Abstract The Tibetan Plateau (TP) is known as one of the most sensitive regions to climate change, and it has experienced accelerated warming in recent decades. However, to what degree the TP warming amplification relates to remote forcing such as sea ice loss in the Arctic sea ice remains unclear. Here, we found that the decline of sea ice concentration over the Barents-Kara Sea (BKS) could account for 18–32% of the winter warming over the TP by comparing observational data and ensemble experiments from an atmospheric general circulation model. The reduced BKS sea ice and resultant upward turbulent heat fluxes can intensify a Rossby wave train propagating equatorward to the TP. As a result, the enhanced southwesterlies towards the TP strengthen the warm advection over most parts of the TP and lead to TP warming. In addition, an atmospheric teleconnection between the Arctic and the TP also exists in the interannual variability. That is, a tripole mode in air temperature, with warm centers in the Arctic and TP but a cold center in the mid-high latitudes of the Eurasian continent in between. Our results imply that the BKS sea ice loss could intensify such a tripole mode and thus enhancing the winter TP warming.

The genomic landscape of pediatric acute myeloid leukemia (AML) has mostly been characterised for Western populations. Here, the authors identify potential driver alterations in Chinese pediatric AML, which differ from Western populations, and propose a prognostic risk classification model.

As the main components of the atmospheric heat source/sink over the Tibetan Plateau (TP), up-to-date spatiotemporal fields of surface sensible heat flux and latent heat release by precipitation are vital for investigating the local land–atmosphere interaction and the effect of the thermal forcing of the TP on global weather and climate. This study recalculates the long-term daily dataset of surface sensible heat flux and latent heat release of condensation over the TP based on 293 routine meteorological observations, with the latest date being 31 December 2019. Most stations have adequate and valid records during the period 1981–2019, and the results for 1951–1980 are also calculated if the observations are available. Moreover, a brief evaluation of the climatology and long-term variation during 1981–2019 is conducted. By providing the most continuous and longest set of observational surface sensible heat flux and latent heat release of condensation data over the TP with a high degree of credibility, this new dataset will support research concerning the multi-timescale variation of diabatic heating/cooling over the TP and its remote influence. It is openly available on the LASG data-sharing platform (http://data.lasg.ac.cn/TPSHLH/).

This meta-analysis assessed the clinical significance of omega-3 polyunsaturated fatty acids (PUFAs) in the management of patients with colorectal cancer (CRC) after radical resection. We comprehensively searched electronic databases, such as EMBASE, PubMed, MEDLINE and Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biomedical Database (CBM), Wanfang Electronic Database, and VIP Medical Information System (VIP) from inception to 10 April 2022. Randomized controlled trials (RCTs) of omega-3 PUFAs and conventional nutrition or blank treatments were selected. The following were evaluated in the pooled analysis: immune function-related indices (IgA, IgG, IgM, CD3+, CD4+, CD8+, and ratio of CD4+/CD8+), nutritional status-related indices [total protein (TP), albumin (ALB), and prealbumin (PA)], and their corresponding 95% confidence intervals (CIs). Next, we conducted heterogeneity detection, sensitivity analysis, contour-enhanced funnel plot to detect possible publication bias, and meta-regression analysis. In all, 20 studies, including 1,613 patients (809 in the omega-3 PUFAs group and 804 in the control group), were selected in the final analysis. The results of the pooled analysis showed that omega-3 PUFAs significantly increased the humoral immune function indices, including IgA [standardized mean difference (SMD) = 0.54, 95% CI 0.10–0.99], IgM (SMD = 0.52, 95% CI 0.05–0.99), IgG (SMD = 0.65, 95% CI 0.47–0.84); T cell immune function indices, including CD3+ (SMD = 0.73, 95% CI 0.54–0.92), CD4+ (SMD = 0.76, 95% CI 0.53–0.98), and ratio of CD4+/CD8+ (SMD = 0.66, 95% CI 0.39–0.92). However, CD8+ was markedly reduced after intervention of omega-3 PUFAs (SMD = –0.28, 95% CI –0.66–0.09). In addition, pooled analysis indicated that omega-3 PUFAs markedly improved the nutritional status indicators, including TP (SMD = 0.53, 95% CI 0.17–0.88), ALB (SMD = 0.43, 95% CI 0.15–0.70), and PA (SMD = 0.46, 95% CI 0.01–0.90). The meta-regression analysis revealed that the covariates of the small sample affected the robustness and credibility of the CD4+ results. Conclusively, this study suggested that omega-3 PUFAs have the potential to be used as a valid immunonutritional therapy/support for treating patients with CRC postoperatively. This meta-analysis protocol was registered in PROSPERO (no. CRD42021288487).Systematic review registration[https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021288487], identifier [CRD42021288487].

Abstract This study aimed to investigate the potential biomarkers of vitiligo by evaluating the disease activity and curative effect of autologous cultured pure melanocyte transplantation (CMT) on patients. Altogether, 36patients with stable vitiligo were treated with CMT. Blister fluid samples were collected from patients with stable vitiligo. Patients with active vitiligo were matched with healthy controls. The chemokine levels in the serum and blister fluid samples were measured using Luminex. The curative effect on patients with stable vitiligo was evaluated 6 months after treatment. Treatment responses were defined according to the extent of repigmentation as effective (if 50% or more repigmentation was achieved) or ineffective (if less than 50% or worse repigmentation was achieved). Patients received re-transplantation if the initial treatment was ineffective. The levels of C-X-C motif chemokine ligand (CXCL)9 and CXCL10 in blister fluid samples were significantly lower in stable patients than in active participants. Receiver operating characteristic analysis revealed that the levels of CXCL9 and CXCL10 were sensitive and specific in diagnosing active vitiligo. Further, 65.6% (21/32) of patients who received CMT had effective treatment responses. The high CXCL9 level in the blister fluid was a significant predictor of ineffective treatment responses. The treatment response was significantly enhanced after treatment. Four patients with ineffective treatment responses received anti-inflammatory treatment and re-transplantation. The CXCL9 and CXCL10 levels in the blister fluid were related to the presence of active vitiligo. Also, the CXCL9 level was a predictor of the effectiveness of CMT in treating vitiligo.

This meta-analysis intended to systematically evaluate the clinical implications of indocyanine green fluorescence (ICG) in patients undergoing laparoscopic colorectal surgery. PubMed, MEDLINE, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Medical Information System and China Biomedical Database were synthetically searched for studies published from inception to April 14, 2022. The randomized controlled trials comparing ICG-use with controls were selected. The incidence of anastomotic leakage (AL), lymph node detection, operation duration, intraoperative bleeding, postoperative morbidity, and hospitalization time were evaluated in summary analysis, and calculated the corresponding 95% confidence intervals (CI). Subsequently, in addition to subgroup analyses, studies for heterogeneity, sensitivity, and publication bias were carried out. Consequently, 3453 patients in the enrolled 15 studies were included; 1616 patients were allocated to the experimental group, and 1837 patients were assigned to the control group. The ICG group had a significantly decreased risk of AL (RR: 0.50, 95% CI: 0.37–0.67) and shorter hospitalization time (SMD: -0.31, 95% CI: -0.54–0.08) compared to the control group. Meanwhile, the ICG showed clearly better lymph node detection (SMD: 0.19, 95% CI: 0.02–0.36). However, when the content of operation duration (SMD: -0.07, 95% CI: -0.30–0.15) and intraoperative bleeding (SMD: -0.16, 95% CI: -0.35–0.04) were compared, no statistical significance was found. Furthermore, the pooled analysis of postoperative morbidity was not statistically significant (RR:0.79, 95% CI: 0.58–1.08). The results of the subgroup analysis of AL indicated that there may be regional variations in AL (RR: 0.50, 95% CI: 0.37–0.67) but not in postoperative morbidity (RR: 0.79, 95% CI: 0.58–1.08). In conclusion, the application of ICG in laparoscopic colorectal surgery can effectively reduce the AL, lymph node detection, and hospitalization time. However, more multicenter large-sample randomized controlled trials are required to further confirm its advantages. The meta-analysis was registered in PROSPERO (no. CRD42022288054).

Machine learning can discern meaningful information from large datasets. Applying machine learning techniques to raw sensor data from instrumented walkways could automatically detect subtle changes in walking and balance. Multiple sclerosis (MS) is a neurological disorder in which patients report varying degrees of walking and balance disruption. This study aimed to determine whether machine learning applied to walkway sensor data could classify severity of self-reported symptoms in MS patients. Ambulatory people with MS (n = 107) were asked to rate the severity of their walking and balance difficulties, from 1-No problems to 5-Extreme problems, using the MS-Impact Scale-29. Those who scored less than 3 (moderately) were assigned to the “mild” group (n = 35), and those scoring higher were in the “moderate” group (n = 72). Three machine learning algorithms were applied to classify the “mild” group from the “moderate” group. The classification achieved 78% accuracy, a precision of 85%, a recall of 90%, and an F1 score of 87% for distinguishing those people reporting mild from moderate walking and balance difficulty. This study demonstrates that machine learning models can reliably be applied to instrumented walkway data and distinguish severity of self-reported impairment in people with MS.

With the development of personalized medical demands for precise diagnosis, rational management and effective cancer treatment, supramolecular theranostic systems have received widespread attention due to their reversibly switchable structures, sensitive response to biological stimuli and integration ability for multiple capabilities in a single platform with a programmable fashion. Cyclodextrins (CDs), benefiting from their excellent characteristics, such as non-toxicity, easy modification, unique host–guest properties, good biocompatibility, etc., as building blocks, serve as an all-purpose strategy for the fabrication of a supramolecular cancer theranostics nanodevice that is capable of biosafety, controllability, functionality and programmability. This review focuses on the supramolecular systems of CD-bioimaging probes, CD-drugs, CD-genes, CD-proteins, CD-photosensitizers and CD-photothermal agents as well as multicomponent cooperation systems with regards to building a nanodevice with functions of diagnosis and (or) therapeutics of cancer treatment. By introducing several state-of-the-art examples, emphasis will be placed on the design of various functional modules, the supramolecular interaction strategies under the fantastic topological structures and the hidden “bridge” between their structures and therapeutic efficacy, aiming for further comprehension of the important role of a cyclodextrin-based nanoplatform in advancing supramolecular cancer theranostics.

BackgroundThiopurines are widely used as anti-cancer and immunosuppressant agents, but have a narrow therapeutic index owing to frequent toxicity and life-threatening bone marrow suppression. The nudix hydrolase 15 (NUDT15) genetic polymorphism is strongly associated with the tolerance and myelosuppressive effect of mercaptopurine administration, but the frequency of NUDT15 variants is known to vary among different ethnic groups or nationalities. At present, the NUDT15 gene polymorphism in ethnic minorities such as the Uighur, Kirghiz, and Dai nationalities in China is unclear.ProcedureDNA samples were isolated from 1,071 Chinese children, including 675 Han children with acute lymphoblastic leukemia and 396 healthy minority children, including 118 Uighur, 126 Kirghiz, and 152 Dai participants. The coding regions of NUDT15 exons 1 to 3 were amplified by polymerase chain reaction. NUDT15 genotypes were identified by Sanger sequencing.ResultsFive NUDT15 genetic variants of coding regions including rs746071566 (c.55_56insGAGTCG), rs186364861 (c.52G > A), c.137C > G, and c.138T > G in exon 1, and the variant rs116855232 (c.415C > T) in exon 3 were found among the participants. The frequency of NUDT15 rs746071566 variants was lower in the Uighur and Kirghiz populations than in the Han population and in other East Asian nationalities, while the frequency of c.415C > T variants was lower in the Dai population. The c.52G > A variant was relatively uncommon in children of the Han, Uighur, Kirghiz, and Dai ethnic groups. Notably, the rare variants c.137C > G and c.138T > G in a Uighur child were predicted to be disruptive sites.ConclusionIn summary, our results illustrate the NUDT15 polymorphisms in Chinese children of Han, Uighur, Kirghiz, and Dai nationalities, and provide the most effective detection recommendations for different ethnic groups to predict thiopurine-related toxicity, which could be used to guide future clinical thiopurine dose adjustment.

Abstract Future projection of temperature extremes in the “Earth's three poles” (the Arctic, Antarctica, and Third Pole‐Tibetan Plateau [TP]) is of importance to risk assessment and policymaking owing to the high sensitivity to climate change in these regions. In this study, future projections of four extreme temperature indices were constructed after the application of a bias correction method in models of Phase 6 of the Coupled Model Intercomparison Project (CMIP6). The reduced intensification of temperature extremes in the Earth's three poles if warming can be limited to 1.5°C instead of 2°C above the pre‐industrial level was examined. Results showed that all the extreme temperature indices show significant increasing trends under both the SSP2–4.5 and SSP5–8.5 scenarios over the Earth's three poles (SSP: Shared Socioeconomic Pathway). For the coldest night (TNn), warmest night (TNx), and warmest day (TXx), the greatest increase by the end of the 21st century under SSP5–8.5 occurs in the Arctic, followed by the TP and finally Antarctica. For the coldest day (TXn), the greatest increase occurs in the Arctic, followed by Antarctica and finally the TP. If global warming can be limited to 1.5°C rather than 2°C, the intensification of TNn, TNx, TXn, and TXx in the Arctic (Antarctica/TP) under SSP5–8.5 is projected to reduce by 66% (21.7%/44.26%), 50.31% (54.79%/60.52%), 71.58% (12.91%/65.81%), and 41.73% (81.3%/57.34%), respectively, and the results are similar for SSP2–4.5. Therefore, keeping a lower warming target is essential for reducing the risk of extreme events in the Earth's three poles.

Background/Objectives Most of the studies on functional outcomes in pediatric survivors of cancers and bone marrow failure disorders have been conducted in North American, European, and Oceanian populations, with few studies having been performed in China. The objective of this study was to evaluate psychosocial outcomes in a cohort of Chinese pediatric survivors diagnosed with cancer or conditions requiring hematopoietic stem cell transplantation (HSCT), and to identify clinical and behavioral factors associated with adverse psychosocial outcomes. Methods This was a cross-sectional survey study. We recruited pediatric survivors of cancer or inherited disorder requiring HSCT at ≤18 years old and were ≥6 months post-treatment. Parents completed the St. Jude Children’s Research Hospital After Completion of Therapy questionnaire to report their child’s emotional functioning, social functioning, attention/concentration and behavior. Multivariable general linear modeling was used to identify clinical, treatment and behavioral factors associated with psychosocial outcomes, adjusting for sex, age and cancer diagnoses. Results Ninety-five pediatric survivors were recruited (62.1% male; mean [standard deviation] age 9.7 [3.4] years; 4.1 [2.6] years post-diagnosis). They were diagnosed with bone marrow failure disorders (23.2%), hematological malignancies (45.3%) or solid tumors (23.2%). Compared with survivors with no current health problems, those with more than one current health problem performed worse in emotional functioning (Estimate = 2.42, SE = 0.88, P = 0.008) and social functioning (Estimate = 2.90, SE = 1.64, P = 0.03). Higher pain interference was significantly associated with worse emotional functioning (Estimate = 0.19, SE = 0.08, P = 0.03) and attention functioning (Estimate = 0.26, SE = 0.11, P = 0.03). Compared with survivors who reported less sleep problems, those who had more sleep problems demonstrated poorer emotional functioning (Estimate = 0.30, SE = 0.08, P = 0.001). Survivors who had a longer duration of screen usage per day reported more impairment on attention and behavior functioning than those who had a shorter duration of screen usage per day (both PConclusion Survivors who were diagnosed at a younger age or had unaddressed/untreated health problems may require additional psychological evaluation. The implementation of psychosocial assessments during routine long-term follow-up care may help to identify high-risk patients during the early phase of survivorship. Rehabilitation interventions should address modifiable behavioral factors (e.g. sleep habits, screen time and chronic pain).

Overloading of road freight vehicles accelerates road damage, creates unfair competition in the transport market, and increases safety risk. There is a dearth of research on the mining of data of highway Freight Weight (FW), and this paper therefore aims to discover factors affecting road freight overloading based on highway FW data, with a view of developing strategies to mitigate such occurrences. A comprehensive sampling survey of road freight transportation was conducted in Anhui Province (China). Vehicle Characteristics (VC), Operation Mode (OM), and transportation information from a total of 3248 trucks were collected. In order to take advantage of the strengths associated with both statistical modelling techniques and non-parametric methods, a Classification And Regression Tree (CART) technique was integrated with Binary Logistic Regression (BLR) to reveal the factors affecting road freight overloading. The classification efficacy test shows that the BLR–CART method outperformed the BLR method in term of accuracy. It is also revealed that the factors affecting overloading of freight vehicles are the Type of Transportation (ToT), Rated Load (RL), OM, FW during the investigation period, interaction between RL and FW, and interaction among RL, FW, and Average Haul Distance (AHD). Road transport authorities should pay greater attention to these factors in order to improve efficiency and effectiveness of overloading inspection.

Abstract In this paper, we study the commutators generated by Lipschitz functions and fractional type integral operators with kernels of the form Kα(x,y)=κ1(x−A1y)κ2(x−A2y)⋯κm(x−Amy), $$ K_{\alpha }(x,y) = \kappa _{1}(x - A_{1}y) \kappa _{2}(x - A_{2}y)\cdots \kappa _{m}(x - A_{m}y), $$ where 0≤α=α1+⋯+αm

Background: Relapse is the major reason for death in pediatric acute lymphoblastic leukemia (ALL) patients. It may be worse because of refusing re-treatment in developing countries. So, we investigated the influencing factors for re-treatment decision made by parents and survival data of patients with relapsed pediatric ALL in China. Methods: Clinical characteristics, choice of re-treatment, survival status at the last follow-up time were collected, survival data and prognostic factors were analyzed. Results: Among 390 relapsed cases which were collected from five centers in China, 230 (59.0%) were re-treated. Fifty-eight were alive, 249 had died, and 83 were lost to follow up (median follow up 73.0 months). Receiving retreatment was not associated with gender, initial immunophenotype, or era of relapse, but was associated with age, initial risk group, and recurrence time and site. The 5-year OS rate of patients who received re-treatment or not was 35.5% and 4.5%, respectively. In re-treatment group, the survival analysis showed that initial risk group, site of relapse, time from diagnosis to relapse, and whether the patient achieved CR2 were closely related to 5-year OS, while WBC count (50 × 109/L), and immunophenotype at diagnosis were not. Fortyeight cases received transplantation and 20 (41.7%) survived, while only 36 (19.8%) of 182 patients who did survived. Conclusions: The estimated 5-year OS rate was only 24.4% ± 2.5% for all 390 relapsed cases in China. Of them, 59% patients, 230 cases, were re-treated with 5-year OS 35.5%. Patients who were indicated and performed for HSCT had a 5-year OS of 52.2%. Keywords: Children, Leukemia, Lymphoblastic, Acute, Relapse

The Tibetan Plateau (TP) is known as one of the sentinels of global climate change. Substantial winter warming over the TP will likely lead, directly or indirectly, to a series of geological disasters such as snow and glacial avalanches. Hence, for better adaptation to climate change, it is vital to project the future change in winter temperature over the TP. However, the current state-of-the-art climate models involved in the sixth phase of the Coupled Model Intercomparison Project (CMIP6) still produce strong cold biases over most parts of the TP in their historical simulations. On the basis of selecting the optimal models, here we use the statistical downscaling method to constrain the projected winter temperature in CMIP6 models. The results show that the regions with the strongest winter warming over the TP will be near the Himalayas and the densely populated eastern regions. The constrained warming magnitude is much greater than that in the ensemble mean of the original 32 CMIP6 models or six best models over these regions. Therefore, early warning and forecasting services should be strengthened for the future temperature over these regions. Moreover, the long-term spatial warming varies greatly under four different future emission scenarios. Under the most severe scenario, the increase in winter temperature near the Himalayas exceeds 10 °C, which will greatly destabilize glaciers in the region, while the increase is only 4 °C–6 °C under the weakest scenario. Therefore, it is urgent to reduce greenhouse gas emissions to control the future temperature increase at hotspots of climate vulnerability such as the TP.

The Tibetan Plateau (TP), acting as a large elevated land surface and atmospheric heat source during spring and summer, has a substantial impact on regional and global weather and climate. To explore the multi-scale temporal variation in the thermal forcing effect of the TP, here we calculated the surface sensible heat and latent heat release based on 6-h routine observations at 80 (32) meteorological stations during the period 1979–2016 (1960–2016). Meanwhile, in situ air-column net radiation cooling during the period 1984–2015 was derived from satellite data. This new dataset provides continuous, robust, and the longest observational atmospheric heat source/sink data over the third pole, which will be helpful to better understand the spatial-temporal structure and multi-scale variation in TP diabatic heating and its influence on the earth’s climatic system.

Targeting at enhancing reverse cholesterol transport (RCT) is apromising strategy for treating atherosclerosis via infusion of reconstitute high density lipoprotein (HDL) as cholesterol acceptors or increase of cholesterol efflux by activation of macrophage liver X receptors (LXRs). However, systemic activation of LXRs triggers excessive lipogenesis in the liver and infusion of HDL downregulates cholesterol efflux from macrophages. Here we describe an enlightened strategy using phospholipid reconstituted apoA-I peptide (22A)-derived synthetic HDL (sHDL) to deliver LXR agonists to the atheroma and examine their effect on atherosclerosis regression in vivo. A synthetic LXR agonist, T0901317 (T1317) was encapsulated in sHDL nanoparticles (sHDL-T1317). Similar to the T1317 compound, the sHDL-T1317 nanoparticles upregulated the expression of ATP-binding cassette transporters and increased cholesterol efflux in macrophages in vitro and in vivo. The sHDL nanoparticles accumulated in the atherosclerotic plaques of ApoE-deficient mice. Moreover, a 6-week low-dose LXR agonist-sHDL treatment induced atherosclerosis regression while avoiding lipid accumulation in the liver. These findings identify LXR agonist loaded sHDL nanoparticles as a promising therapeutic approach to treat atherosclerosis by targeting RCT in a multifaceted manner: sHDL itself serving as both a drug carrier and cholesterol acceptor and the LXR agonist mediating upregulation of ABC transporters in the aorta.

Longitudinal-connected air suspension has been proven to have desirable dynamic load-sharing performances for multi-axle heavy vehicles. However, optimization approaches towards the improvement of comprehensive vehicle performance through the geometric design of longitudinal-connected air suspension have been considerably lacking. To address this, based on a 5-degrees-of-freedom nonlinear model of a three-axle semi-trailer with longitudinal air suspension, taking the changes of driving conditions (road roughness, speed, and load) into account, a height control strategy of the longitudinal-connected air suspension was proposed. Then, in view of the height of the air spring under various driving conditions, the support vector regression method was employed to fit the relationship models between the performance indices and the driving conditions, as well as the suspension geometric parameters (inside diameters of the air line and the connectors). Finally, to tackle the uncertainties of driving conditions in the optimization of suspension geometric parameters, a double-loop multi-objective particle swarm optimization algorithm (DL-MOPSO) was put forward based on the interval uncertainty theory. The simulation results indicate that compared with the longitudinal-connected air suspension using two traditional geometric parameters, the optimization ratios for dynamic load sharing coefficient and root-mean-square acceleration at various spring heights are between −1.04% and 20.75%, and 1.44% and 35.1%, respectively. Therefore, based on the signals measured from the suspension height sensors, through integrated control of inflation/deflation valves of air suspensions, as well as the valves’ inside connectors and air lines, the proposed DL-MOPSO algorithm can improve the comprehensive driving performance of the longitudinal-connected three-axle semi-trailer effectively, and in response to changes in driving conditions.