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Abstract Background There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Methods We performed a multicentre, open-label, randomized, phase 3 study. Eligible patients (aged 15 years or older, had received allo-HSCT for a haematological malignancy, developed aGVHD, and received no previous therapies for aGVHD) were randomly assigned (1:1) to receive either 5 mg/m2 MTX on Days 1, 3, or 8 and then combined with corticosteroids or corticosteroids alone weekly. Results The primary endpoint was the overall response rate (ORR) on Day 10. A total of 157 patients were randomly assigned to receive either MTX plus corticosteroids (n = 78; MTX group) or corticosteroids alone (n = 79; control group). The Day 10 ORR was 97% for the MTX group and 81% for the control group (p = .005). Among patients with mild aGVHD, the Day 10 ORR was 100% for the MTX group and 86% for the control group (p = .001). The 1-year estimated failure-free survival was 69% for the MTX group and 41% for the control group (p = .002). There were no differences in treatment-related adverse events between the two groups. Conclusions In conclusion, mini-dose MTX combined with corticosteroids can significantly improve the ORR in patients with aGVHD and is well tolerated, although it did not achieve the prespecified 20% improvement with the addition of MTX. Trial registration The trial was registered with clinicaltrials.gov (NCT04960644).

Nitrogen is an essential macronutrient for plant growth and development. Nitrate is the major form of nitrogen acquired by most crops and also serves as a vital signaling molecule. Nitrate is absorbed from the soil into root cells usually by the low-affinity NRT1 NO3- transporters and high-affinity NRT2 NO3- transporters, with NRT2s serving to absorb NO3- under NO3–limiting conditions. Seven NRT2 members have been identified in Arabidopsis, and they have been shown to be involved in various biological processes. In this review, we summarize the spatiotemporal expression patterns, localization, and biotic and abiotic responses of these transporters with a focus on recent advances in the current understanding of the functions of the seven AtNRT2 genes. This review offers beneficial insight into the mechanisms by which plants adapt to changing environmental conditions and provides a theoretical basis for crop research in the near future.

Abstract Carbon supported intermetallic compound nanoparticles with high activity and stability are promising cathodic catalysts for oxygen reduction reaction in proton-exchange-membrane fuel cells. However, the synthesis of intermetallic catalysts suffers from large diffusion barrier for atom ordering, resulting in low ordering degree and limited performance. We demonstrate a low-melting-point metal doping strategy for the synthesis of highly ordered L10-type M-doped PtCo (M = Ga, Pb, Sb, Cu) intermetallic catalysts. We find that the ordering degree of the M-doped PtCo catalysts increases with the decrease of melting point of M. Theoretic studies reveal that the low-melting-point metal doping can decrease the energy barrier for atom diffusion. The prepared highly ordered Ga-doped PtCo catalyst exhibits a large mass activity of 1.07 A mgPt −1 at 0.9 V in H2-O2 fuel cells and a rated power density of 1.05 W cm−2 in H2-air fuel cells, with a Pt loading of 0.075 mgPt cm−2.

In the era of marine big data, making full use of multi-source satellite observations to accurately retrieve and predict the temperature structure of the ocean subsurface layer is very significant in advancing the understanding of oceanic processes and their dynamics. Considering the time dependence and spatial correlation of marine characteristics, this study employed the convolutional long short-term memory (ConvLSTM) method to retrieve the subsurface temperature in the Western Pacific Ocean from several types of satellite observations. Furthermore, considering the temperature’s vertical distribution, the retrieved results for the upper layer were iteratively used in the calculation for the deeper layer as input data to improve the algorithm. The results show that the retrieved results for the 100 to 500 m depth temperature using the 50 m layer in the calculation resulted in higher accuracy than those retrieved from the standard ConvLSTM method. The largest improvement was in the calculation for the 100 m layer, where the thermocline was located. The results indicate that our improved ConvLSTM method can increase the accuracy of subsurface temperature retrieval without additional input data.

Abstract Background Rectal cancer is one of the most lethal of gastrointestinal malignancies. Metabonomics has gradually developed as a convenient, inexpensive and non-destructive technique for the study of cancers. Methods A total of 150 tissue samples from 25 rectal cancer patients were analyzed by liquid chromatography–mass spectrometry (LC–MS), and 6 tissue samples were collected from each patient (group 1: tumor; group 2: 0.5 cm from tumor; group 3:1 cm from tumor; group 4:2 cm from tumor; group 5:3 cm from tumor and group 6:5 cm from tumor). The differential metabolites of tumor tissues and 5 cm from the tumor (normal tissues) were first selected. The differential metabolites between tumor tissues and normal tissues were regrouped by hierarchical clustering analysis, and further selected by discriminant analysis according to the regrouping of clustering results. The potential safe margin of clinical T(cT)1,cT2 stage rectal cancer and cT3,cT4 stage rectal cancer at the metabolomic level was further identified by observing the changes in the level of differential metabolites within the samples from group 1 to group 6. Results We found 22 specific metabolites to distinguish tumor tissue and normal tissue. The most significant changes in metabolite levels were observed at 0.5 cm (cT1, cT2) and 2.0 cm (cT3, cT4) from the tumor, while the changes in the tissues afterwards showed a stable trend. Conclusions There are differential metabolites between tumor tissues and normal tissues in rectal cancer. Based on our limited sample size, the safe distal incision margin for rectal cancer surgery in metabolites may be 0.5 cm in patients with cT1 and cT2 stage rectal cancer and 2.0 cm in patients with cT3 and cT4 stage rectal cancer.

Background & aims: Traditional Chinese medicine and radiofrequency ablation are becoming increasingly important in the treatment of primary liver cancer. However, the clinical outcome of traditional Chinese medicine plus radiofrequency ablation is contentious. This study aimed to conduct a meta-analysis of randomized controlled clinical trials to address this gap. Methods: Short-term efficacy, alpha-fetoprotein level, immune function, liver function, and quality of life outcomes in patients with primary liver cancer treated with Chinese herbal medicine adjuvant radiofrequency ablation were systematically reviewed. Results: Eighteen randomized controlled clinical trials with 1488 patients with primary liver cancer were included. The combination treatment significantly increased the objective remission rate and quality of patient survival compared to the control group. Combination treatment significantly improved immunity and liver function factors, including CD3, CD4, CD4/CD8, alanine aminotransferase, aspartate aminotransferase, total bilirubin, and albumin levels. However, there were no statistical differences in CD8 levels across treatments. Trial sequential analysis showed that the cumulative Z-curve of the Objective response rate crossed the conventional and test sequence monitoring boundaries; however, it did not cross the required information size line. Conclusions: Traditional Chinese medicine combined with radiofrequency ablation for primary liver cancer can effectively reduce alpha-fetoprotein and improve clinical efficacy, immune function, liver function, as well as the quality of life.

While single-atom catalysts offer well-defined structures, the homogeneity of the active sites is determined by localized coordination environments. Here, authors anchor Ir single atoms onto different sites on CoOOH and show how their distinct coordinations activate oxygen-evolving electrocatalysis

Abstract Background Poor graft function (PGF) or prolonged isolated thrombocytopenia (PT), which are characterized by pancytopenia or thrombocytopenia, have become serious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous single-arm trial suggests that N-acetyl-L-cysteine (NAC) prophylaxis reduced PGF or PT after allo-HSCT. Therefore, an open-label, randomized, phase 3 trial was performed to investigate the efficacy and tolerability of NAC prophylaxis to reduce PGF or PT after allo-HSCT. Methods A phase 3, open-label randomized trial was performed. Based on the percentage of CD34+VEGFR2 (CD309)+ endothelial cells (ECs) in bone marrow (BM) detected by flow cytometry at 14 days before conditioning, patients aged 15 to 60 years with acute leukemia undergoing haploidentical HSCT were categorized as low-risk (EC ≥ 0.1%) or high-risk (EC < 0.1%); patients at high risk were randomly assigned (2:1) to receive NAC prophylaxis or nonprophylaxis. The primary endpoint was PGF and PT incidence at +60 days post-HSCT. Results Between April 18, 2019, and June 24, 2021, 120 patients with BM EC

Abstract Background Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal disorders characterized by ineffective haematopoiesis and immune deregulation. Emerging evidence has shown the effect of bone marrow (BM) endothelial progenitor cells (EPCs) in regulating haematopoiesis and immune balance. However, the number and functions of BM EPCs in patients with different stages of MDS remain largely unknown. Methods Patients with MDS (N = 30), de novo acute myeloid leukaemia (AML) (N = 15), and healthy donors (HDs) (N = 15) were enrolled. MDS patients were divided into lower-risk MDS (N = 15) and higher-risk MDS (N = 15) groups according to the dichotomization of the Revised International Prognostic Scoring System. Flow cytometry was performed to analyse the number of BM EPCs. Tube formation and migration assays were performed to evaluate the functions of BM EPCs. In order to assess the gene expression profiles of BM EPCs, RNA sequencing (RNA-seq) were performed. BM EPC supporting abilities of haematopoietic stem cells (HSCs), leukaemia cells and T cells were assessed by in vitro coculture experiments. Results Increased but dysfunctional BM EPCs were found in MDS patients compared with HDs, especially in patients with higher-risk MDS. RNA-seq indicated the progressive change and differences of haematopoiesis- and immune-related pathways and genes in MDS BM EPCs. In vitro coculture experiments verified that BM EPCs from HDs, lower-risk MDS, and higher-risk MDS to AML exhibited a progressively decreased ability to support HSCs, manifested as elevated apoptosis rates and intracellular reactive oxygen species (ROS) levels and decreased colony-forming unit plating efficiencies of HSCs. Moreover, BM EPCs from higher-risk MDS patients demonstrated an increased ability to support leukaemia cells, characterized by increased proliferation, leukaemia colony-forming unit plating efficiencies, decreased apoptosis rates and apoptosis-related genes. Furthermore, BM EPCs induced T cell differentiation towards more immune-tolerant cells in higher-risk MDS patients in vitro. In addition, the levels of intracellular ROS and the apoptosis ratios were increased in BM EPCs from MDS patients, especially in higher-risk MDS patients, which may be therapeutic candidates for MDS patients. Conclusion Our results suggest that dysfunctional BM EPCs are involved in MDS patients, which indicates that improving haematopoiesis supporting ability and immuneregulation ability of BM EPCs may represent a promising therapeutic approach for MDS patients.

Mesoscale eddies are a common occurrence in the Kuroshio Extension (KE) that have a major impact on the levels of salinity and heat transport in the Northwest Pacific, the strength of the Kuroshio jet, and the fluctuations of the Kuroshio’s trajectory. In this study, a purely data-driven machine learning model, Temporal Modes-Enhanced Neural Network (TMENN), is proposed to forecast the spatiotemporal variation of mesoscale eddies based on daily sea surface height (SSH) data over a 20-year period (2000–2019) in the Kuroshio Extension. To reduce computational costs and facilitate faster forecasting, raw SSH data are decomposed into spatial modes and temporal modes (principal components, PCs) by empirical orthogonal functions (EOF) analysis, and the first 117 PCs (a total of 8384 PCs), wherein the cumulative variance contribution rate reaches 95%, are selected solely as the predictors of TMENN to train and forecast. Forecasting reconstruction results show that the model can reliably forecast the evolution of the eddy in the KE for about 30 days. Additionally, three classical mesoscale eddy processes are selected to verify the accuracy of the model, namely cold eddy attachment, warm eddy shedding, and attachment, and the results indicate that the model can well capture the evolution process of mesoscale eddies.

Artificial photosynthesis offers an integrated means to convert light to fuel, but efficiencies are often low. Here, authors report a Z-scheme system utilizing Ir and FeCoOx co-catalysts to enhance charge separation on BiVO4 facets that achieves high quantum efficiencies for overall water splitting.

Abstract Background In patients with papillary thyroid cancer (PTC), cervical lymph node metastasis (LNM) must be carefully assessed to determine the extent of lymph node dissection required and patient prognosis. Few studies attempted to determine whether the ultrasound (US) appearance of the primary thyroid tumor could be used to predict cervical lymph node involvement. This study aimed to identify the US features of the tumor that could predict cervical LNM in patients with PTC. Methods This was a retrospective study of patients with pathologically confirmed PTC. We evaluated the following US characteristics: lobe, isthmus, and tumor size; tumor position; parenchymal echogenicity; the number of lesions (i.e., tumor multifocality); parenchymal and lesional vascularity; tumor margins and shape; calcifications; capsular extension; tumor consistency; and the lymph nodes along the carotid vessels. The patients were grouped as no LNM (NLNM), central LNM (CLNM) alone, and lateral LNM (LLNM) with/without CLNM, according to the postoperative pathological examination. Results Totally, 247 patients, there were 67 men and 180 women. Tumor size of > 10 mm was significantly more common in the CLNM (70.2%) and LLNM groups (89.6%) than in the NLNM group (45.4%). At US, capsular extension > 50% was most common in the LLNM group (35.4%). The multivariable analysis revealed that age (OR = 0.203, 95%CI: 0.095–0.431, P

Microbial communities and their associated metabolic activities, methanogenesis and anaerobic oxidation of methane (AOM), are the key components of carbon biocycles in continental margin sediments. The composition and diversity of microbial communities in a methanic environment have been widely investigated, but identifying direct correlations between microbial communities and their activities remains a challenge. Here, we investigated shifting microbial communities that performed methanogenesis and AOM in long-term incubations (the longest is up to 199 days). AOM, methanogenesis, sulfate reduction and iron reduction occurred during the incubation, and 16S rRNA gene sequencing showed that some bacteria were maintained or even enriched during the incubation compared to the environmental samples. In contrast, archaeal diversity was reduced, and only some uncultured archaea belonging to the phylum Bathyarchaeota were enriched after treatment with a high sulfate concentration (29.38 mM), suggesting that sulfate might promote their enrichment. Well-known anaerobic methanotrophic archaea (ANME) were not detected, and SEEP-SRB1, which is in syntrophy with ANME, decreased to approximately zero after the incubation. The abundance of known methanogens, such as genera Methanococcoides and Methanosarcina, increased slightly in some incubations but was still present at a low relative abundance (

Abstract Dysfunctional megakaryopoiesis hampers platelet production, which is closely associated with thrombocytopenia (PT). Macrophages (MФs) are crucial cellular components in the bone marrow (BM) microenvironment. However, the specific effects of M1 MФs or M2 MФs on regulating megakaryocytes (MKs) are largely unknown. In the current study, aberrant BM-M1/M2 MФ polarization, characterized by increased M1 MФs and decreased M2 MФs and accompanied by impaired megakaryopoiesis-supporting abilities, was found in patients with PT post-allotransplant. RNA-seq and western blot analysis showed that the PI3K-AKT pathway was downregulated in the BM MФs of PT patients. Moreover, in vitro treatment with PI3K-AKT activators restored the impaired megakaryopoiesis-supporting ability of MФs from PT patients. Furthermore, we found M1 MФs suppress, whereas M2 MФs support MK maturation and platelet formation in humans. Chemical inhibition of PI3K-AKT pathway reduced megakaryopoiesis-supporting ability of M2 MФs, as indicated by decreased MK count, colony-forming unit number, high-ploidy distribution, and platelet count. Importantly, genetic knockdown of the PI3K-AKT pathway impaired the megakaryopoiesis-supporting ability of MФs both in vitro and in a MФ-specific PI3K-knockdown murine model, indicating a critical role of PI3K-AKT pathway in regulating the megakaryopoiesis-supporting ability of M2 MФs. Furthermore, our preliminary data indicated that TGF-β released by M2 MФs may facilitate megakaryopoiesis through upregulation of the JAK2/STAT5 and MAPK/ERK pathways in MKs. Taken together, our data reveal that M1 and M2 MФs have opposing effects on MKs in a PI3K-AKT pathway-dependent manner, which may lead to new insights into the pathogenesis of thrombocytopenia and provide a potential therapeutic strategy to promote megakaryopoiesis.

Abstract Background The ankle joint complex (AJC) is of fundamental importance for balance, support, and propulsion. However, it is particularly susceptible to musculoskeletal and neurological injuries, especially neurological injuries such as drop foot following stroke. An important factor in ankle dysfunction is damage to the central nervous system (CNS). Correspondingly, the fundamental goal of rehabilitation training is to stimulate the reorganization and compensation of the CNS, and to promote the recovery of the motor system’s motor perception function. Therefore, an increasing number of ankle rehabilitation robots have been developed to provide long-term accurate and uniform rehabilitation training of the AJC, among which the parallel ankle rehabilitation robot (PARR) is the most studied. The aim of this study is to provide a systematic review of the state of the art in PARR technology, with consideration of the mechanism configurations, actuator types with different trajectory tracking control techniques, and rehabilitation training methods, thus facilitating the development of new and improved PARRs as a next step towards obtaining clinical proof of their rehabilitation benefits. Methods A literature search was conducted on PubMed, Scopus, IEEE Xplore, and Web of Science for articles related to the design and improvement of PARRs for ankle rehabilitation from each site’s respective inception from January 1999 to September 2020 using the keywords “ parallel”, “ ankle”, and “ robot”. Appropriate syntax using Boolean operators and wildcard symbols was utilized for each database to include a wider range of articles that may have used alternate spellings or synonyms, and the references listed in relevant publications were further screened according to the inclusion criteria and exclusion criteria. Results and discussion Ultimately, 65 articles representing 16 unique PARRs were selected for review, all of which have developed the prototypes with experiments designed to verify their usability and feasibility. From the comparison among these PARRs, we found that there are three main considerations for the mechanical design and mechanism optimization of PARRs, the choice of two actuator types including pneumatic and electrically driven control, the covering of the AJC’s motion space, and the optimization of the kinematic design, actuation design and structural design. The trajectory tracking accuracy and interactive control performance also need to be guaranteed to improve the effect of rehabilitation training and stimulate a patient’s active participation. In addition, the parameters of the reviewed 16 PARRs are summarized in detail with their differences compared by using figures and tables in the order they appeared, showing their differences in the two main actuator types, four exercise modes, fifteen control strategies, etc., which revealed the future research trends related to the improvement of the PARRs. Conclusion The selected studies showed the rapid development of PARRs in terms of their mechanical designs, control strategies, and rehabilitation training methods over the last two decades. However, the existing PARRs all have their own pros and cons, and few of the developed devices have been subjected to clinical trials. Designing a PARR with three degrees of freedom (DOFs) and whereby the mechanism’s rotation center coincides with the AJC rotation center is of vital importance in the mechanism design and optimization of PARRs. In addition, the design of actuators combining the advantages of the pneumatic-driven and electrically driven ones, as well as some new other actuators, will be a research hotspot for the development of PARRs. For the control strategy, compliance control with variable parameters should be further studied, with sEMG signal included to improve the real-time performance. Multimode rehabilitation training methods with multimodal motion intention recognition, real-time online detection and evaluation system should also be further developed to meet the needs of different ankle disability and rehabilitation stages. In addition, the clinical trials are in urgent need to help the PARRs be implementable as an intervention in clinical practice.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

Background: The responses of intravenous immunoglobulin (IVIg) or corticosteroids as the initial treatment on pregnancy with ITP were unsatisfactory. This study aimed to assess the safety and effectiveness of prednisone plus IVIg versus prednisone or IVIg in pregnant patients with immune thrombocytopenia (ITP). Methods: Between 1 January 2010 and 31 December 2020, 970 pregnancies diagnosed with ITP at 19 collaborative centers in China were reviewed in this observational study. A total of 513 pregnancies (52.89%) received no intervention. Concerning the remaining pregnancies, 151 (33.04%) pregnancies received an initial treatment of prednisone plus IVIg, 105 (22.98%) pregnancies received IVIg alone, and 172 (37.64%) pregnancies only received prednisone. Results: Regarding the maternal response to the initial treatment, no differences were found among the three treatment groups (41.1% for prednisone plus IVIg, 33.1% for prednisone, and 38.1% for IVIg). However, a significant difference was observed in the time to response between the prednisone plus IVIg group (4.39 ± 2.54 days) and prednisone group (7.29 ± 5.01 days; p

Bone marrow (BM) endothelial progenitor cell (EPC) damage of unknown mechanism delays the repair of endothelial cells (EC) and recovery of hematopoiesis after chemo-radiotherapy. We found increased levels of the glycolytic enzyme PFKFB3 in the damaged BM EPC of patients with poor graft function, a clinical model of EPC damage-associated poor hematopoiesis after allogeneic hematopoietic stem cell transplantation. Moreover, in vitro the glycolysis inhibitor 3-(3-pyridinyl)- 1-(4-pyridinyl)-2-propen-1-one (3PO) alleviated the damaged BM EPC from patients with poor graft function. Consistently, PFKFB3 overexpression triggered BM EPC damage after 5-fluorouracil treatment and impaired hematopoiesis-supporting ability in vitro. Mechanistically, PFKFB3 facilitated pro-apoptotic transcription factor FOXO3A and expression of its downstream genes, including p21, p27, and FAS, after 5-fluorouracil treatment in vitro. Moreover, PFKFB3 induced activation of NF-κB and expression of its downstream adhesion molecule E-selectin, while it reduced hematopoietic factor SDF-1 expression, which could be rescued by FOXO3A silencing. High expression of PFKFB3 was found in damaged BM EC of murine models of chemo-radiotherapy-induced myelosuppression. Furthermore, a murine model of BM EC-specific PFKFB3 overexpression demonstrated that PFKFB3 aggravated BM EC damage, and impaired the recovery of hematopoiesis after chemotherapy in vivo, effects which could be mitigated by 3PO, indicating a critical role of PFKFB3 in regulating BM EC damage. Clinically, PFKFB3-induced FOXO3A expression and NF-κB activation were confirmed to contribute to the damaged BM EPC of patients with acute leukemia after chemotherapy. 3PO repaired the damaged BM EPC by reducing FOXO3A expression and phospho-NF-κB p65 in patients after chemotherapy. In summary, our results reveal a critical role of PFKFB3 in triggering BM EPC damage and indicate that endothelial-PFKFB3 may be a potential therapeutic target for myelosuppressive injury.

AbstractAuthigenic carbonate in seep environments, as a direct byproduct of sulfate-driven anaerobic oxidation of methane (SD-AOM), is usually absent within the sediment column because of the requirement of a strict formation condition. In this case, the lack of a reliable carbon signal may impede the identification of SD-AOM and methane leakage. Here, carbon and oxygen isotopes, elemental compositions, AMS 14C dates in sediments, and porewater geochemistry were investigated from two sites (A27 and SH1) of the Shenhu area, northern South China Sea (SCS), to discuss how SD-AOM affects the carbon isotope in methane-affected marine sediments. Porewater results at both sites indicate the occurrence of methane diffusion from the sulfate-methane transition zone (SMTZ) below. The carbon isotopes of bulk-sediment carbonate and foraminifera show no distinctly negative excursion, reflecting that these signals are invalid in response to SD-AOM in the investigated sites. Then, a mass balance model is adopted to evaluate the δ13C value of authigenic carbonate (δ13CAC). Consequently, three intervals (A2 and A3 from site A27 and S2 from site SH1) are identified, featuring negative δ13CAC values, high TS/TOC ratios, and enhanced contents of authigenic carbonate, which are most likely influenced by SD-AOM. Considering the current SMTZ located at deeper layers, intervals A2 and S2 represent the locations of paleo-SMTZ, while interval A3 is thought to be influenced by the current methane diffusion. Interestingly, the δ13C values of total organic matter (δ13CTOC) show positive excursions within the paleo-SMTZs, which can be explained herein by the diagenetic modification. In the course of SD-AOM at the SMTZ, high rate of (methylotrophic) methanogenesis preferentially consumes lighter carbon atoms in organic matter, with the remainder being gradually more positive. Our results indicate that the exploration of a reliable methane-carbon response in systems lacking seep carbonates plays an important role in constraining SD-AOM and methane release.

Abstract Background Horseshoe crabs are ancient marine arthropods with a long evolutionary history extending back approximately 450 million years, which may benefit from their innate immune systems. However, the genetic mechanisms underlying their abilities of distinguishing and defending against invading microbes are still unclear. Results Here, we describe the 2.06 Gbp genome assembly of Tachypleus tridentatus with 24,222 predicted protein-coding genes. Comparative genomics shows that T. tridentatus and the Atlantic horseshoe crab Limulus polyphemus have the most orthologues shared among two species, including genes involved in the immune-related JAK-STAT signalling pathway. Divergence time dating results show that the last common ancestor of Asian horseshoe crabs (including T. tridentatus and C. rotundicauda) and L. polyphemus appeared approximately 130 Mya (121–141), and the split of the two Asian horseshoe crabs was dated to approximately 63 Mya (57–69). Hox gene analysis suggests two clusters in both horseshoe crab assemblies. Surprisingly, selective analysis of immune-related gene families revealed the high expansion of conserved pattern recognition receptors. Genes involved in the IMD and JAK-STAT signal transduction pathways also exhibited a certain degree of expansion in both genomes. Intact coagulation cascade-related genes were present in the T. tridentatus genome with a higher number of coagulation factor genes. Moreover, most reported antibacterial peptides have been identified in T. tridentatus with their potentially effective antimicrobial sites. Conclusions The draft genome of T. tridentatus would provide important evidence for further clarifying the taxonomy and evolutionary relationship of Chelicerata. The expansion of conserved immune signalling pathway genes, coagulation factors and intact antimicrobial peptides in T. tridentatus constitutes its robust and effective innate immunity for self-defence in marine environments with an enormous number of invading pathogens and may affect the quality of the adaptive properties with regard to complicated marine environments.

Accurate and reliable short-term electric load forecasting (STLF) plays a critical role in power system to enhance its routine management efficiency and reduce operational costs. However, most of the existing STLF methods suffer from lack of appropriate feature selection procedure. In this paper, a multifactorial framework (MF) possessing the potential to contribute more satisfactory forecasting results and computational speed is proposed. Moreover, a graphical tool for easy and accurate computation of day-ahead load forecast is implemented via MATLAB App Designer. Firstly, we choose the candidate feature set by analyzing the raw electricity consumption data. Then, partial mutual information is adopted as criterion to eliminate these irrelevant and redundant ones among candidate features for the purpose of reducing the input subset and retaining these most relevant. At last, the selected features are used as the input of the well-established artificial neural network (ANN) model optimized by genetic algorithm and cross validation to implement prediction. The MF is applied for the load data measured from 2016 to 2018 in Jinan, and then some competitive experiments and extensive simulations are carried out and results indicates that the ANN-based model with selected features significantly outperforms other alternative models with single features or a few of features regarding mean absolute percent error. In addition, the parallel structure of ANN and the lower dimension of the input space enable the model to achieve faster calculation speed.

Hirota’s direct method is one significant way to obtain solutions of soliton equations, but it is rarely studied under the time scale framework. In this paper, the generalized KdV equation on time-space scale is deduced from one newly constructed Lax equation and zero curvature equation by using the AKNS method, which can be reduced to the classical and discrete KdV equation by considering different time scales. What is more, it is the first time that the single-soliton solution of the KdV equation under the time scale framework is obtained by using the idea of Hirota’s direct method.

Ultrasonic technology is an environment-friendly method in algae-laden water treatment with the advantages of wonderful efficiency and no chemical additions. However, ultrasonic technology is costly and can lead to the release of algae organic matter (AOM). Few studies considered algae removal efficiency, water safety, and economy. In this study, a Response Surface Methodology (RSM) and Elitist Non-dominated Sorting Genetic Algorithm (NSGA-II) integrated method was used to investigate the influence of ultrasound parameters on algal removal efficiency band AOM release and conduct the multi-objective optimization of ultrasonic technology for satisfactory algal removal, environment protection, and improved economy. The maximum algae removal rate (ρ), minimal energy consumption, and minimal UV254 value of algal solution were calculated. Quadratic polynomial models were obtained to illustrate the relationship between ultrasonic parameters and the responses. Ultrasonic frequency was the most important factor affecting algal removal efficiency, and high frequency was beneficial for algal removal because of its contribution to the break of air bubbles. High power density significantly increased the UV254 value, and the concentration of soluble microbial metabolites and humic acid-like substances significantly increased after ultrasound. The optimization solutions calculated by NSGA-II showed low deviation from single-objective optimization solution by RSM, demonstrating that the multi-objective optimization results were reliable. This study presents a novel RSM and NSGA-II combined method in optimizing ultrasonic technology for effective, safe, and economic algal removal. The optimization results can provide references for ultrasonic parameters to be selected in practical applications.

Locust plagues are still worldwide problems. Selecting active enantiomers from current chiral insecticides is necessary for controlling locusts and mitigating the pesticide pollution in agricultural lands. Herein, two enantiomers of isocarbophos (ICP) were separated and the enantioselectivity in insecticidal activity against the pest Locusta migratoria manilensis (L. migratoria) and mechanisms were investigated. The significant difference of LD50 between (+)-ICP (0.609 mg/kg bw) and (−)-ICP (79.412 mg/kg bw) demonstrated that (+)-ICP was a more effective enantiomer. The enantioselectivity in insecticidal activity of ICP enantiomers could be attributed to the selective affinity to acetylcholinesterase (AChE). Results of in vivo and in vitro assays suggested that AChE was more sensitive to (+)-ICP. In addition, molecular docking showed that the -CDOKER energies of (+)-ICP and (−)-ICP were 25.6652 and 24.4169, respectively, which suggested a stronger affinity between (+)-ICP and AChE. Significant selectivity also occurred in detoxifying enzymes activities (carboxylesterases (CarEs) and glutathione S-transferases (GSTs)) and related gene expressions. Suppression of detoxifying enzymes activities with (+)-ICP treatment suggested that (−)-ICP may induce the detoxifying enzyme-mediated ICP resistance. A more comprehensive understanding of the enantioselectivity of ICP is necessary for improving regulation and risk assessment of ICP.

Summary:. Soft tissue reconstruction around joints such as the knee requires a few additional considerations compared with other regions. The overlying skin must be pliable, with adequate distensibility to maintain the range of motion as a hinge joint, and ideally be replaced with “like-for-like” tissue to restore its delicate contour. The advent of perforator flaps has provided reconstructive surgeons with thin, pliable flaps conferring superior aesthetic results, good preservation of joint range of motion, and less donor site morbidity. Utilizing locoregional options also allows replacement with “like-for-like.” We retrospectively reviewed lower medial thigh perforator flaps performed for traumatic and debrided infected knee wounds, using a free-style approach to flap harvest. The described technique was found to be reliable, with consistent anatomy. All flaps survived and successfully covered small- to medium-sized critical defects in healthy individuals and those with multiple comorbidities.

Patients with prolonged isolated thrombocytopenia (PT) after allogeneic stem cell transplantation (allo-SCT) are known to have a poor prognosis. However, there is no standard treatment for PT. The present study aimed to investigate the potential effect of a novel recombinant human thrombopoietin (rhTPO) in a cohort of patients with PT following allo-SCT. A total of 24 patients with PT (including delayed platelet engraftment and secondary failure of platelet recovery) were treated with rhTPO from July 1, 2016 to May 31, 2017. rhTPO injections were administered at 300 IU/kg/d for 28 consecutive days or until platelet counts were ≥ 50 × 109/L, independent of platelet transfusion. Response was defined as platelet recovery to ≥ 20 × 109/L for seven consecutive days without transfusion support during or within 7 days of the end of rhTPO treatment. All patients completed the 28 days of treatment, and none were withdrawn due to adverse effects. The overall response was 45.8%, which was significantly higher than historical data (12.2%, p

Bisphenol analogues including bisphenol A (BPA), bisphenol AF (BPAF), bisphenol F (BPF), and bisphenol S (BPS) share similar chemical structures and endocrine disrupting effects. Their effects on metabolisms, however, are so far only marginally understood. In this study, NMR-based metabonomic profiles of HepG2 cell culture media and PCR array were used to assess the metabolomics disturbances and gene expression levels of HepG2 in response to four BPs (BPA, BPAF, BPF, and BPS). The results indicated that BP analogues resulted in disturbances in 7–15 metabolites that were classified as amino acid (alanine, glutamine, glutamate), intermediates and end-products in the glycolysis (pyruvate) and the tricarboxylic acid cycle (acetate, lactate). Their rank in order according to the number of metabolites and pathways was BPF > BPA > BPAF > BPS. The common disrupted pathways (pyruvate metabolism; alanine, aspartate, and glutamate metabolism) indicated enhanced glycolysis. The following glucometabolic PCR array analysis suggested that although four BPs shared the capability of disrupting glucose metabolism, they may act through different mechanisms: BPAF has increased the pyruvate kinase (PKLR) expression level, which implied enhanced glycolysis that was agreed with NMR results. The other three BP analogues, however, decreased the expression level of glucokinase (GCK) that indicated glucose sensing impairment. Our results demonstrated the potential for using metabolomic and PCR array to understand the underlying action of mechanisms and identify the potential targets for future targeted risk assessment. Keywords: Bisphenol analogues, Metabolomic modulations, HepG2, PCR array

Abstract Background Although the prognosis of chronic myeloid leukemia (CML) has dramatically improved, the pathogenesis of CML remains elusive. Studies have shown that sustained phosphorylation of AKT1 plays a crucial role in the proliferation of CML cells. Evidence indicates that in tongue cancer cells, FAM168A, also known as tongue cancer resistance-associated protein (TCRP1), can directly bind to AKT1 and regulate AKT1/NFκB signaling pathways. This study aimed to investigate the role of FAM168A in regulation of AKT1/NFκB signaling pathway and cell cycle in CML. Methods FAM168A interference was performed, and the expression and phosphorylation of FAM168A downstream proteins were measured in K562 CML cell line. The possible roles of FAM168A in the proliferation of CML cells were investigated using in vitro cell culture, in vivo animal models and clinical specimens. Results We found that the expression of FAM168A significantly increased in the peripheral blood mononuclear cells of CML patients, compared with normal healthy controls. FAM168A interference did not change AKT1 protein expression, but significantly decreased AKT1 phosphorylation, significantly increased IκB-α protein level, and significantly reduced nuclear NFκB protein level. Moreover, there was a significant increase of G2/M phase cells and Cyclin B1 level. Immunoprecipitation results showed that FAM168A interacts with breakpoint cluster region (BCR) -Abelson murine leukemia (ABL1) fusion protein and AKT1, respectively. Animal experiments confirmed that FAM168A interference prolonged the survival and reduced the tumor formation in mice inoculated with K562 cells. The results of clinical specimens showed that FAM168A expression and AKT1 phosphorylation were significantly elevated in CML patients. Conclusion This study demonstrates that FAM168A may act as a linker protein that binds to BCR-ABL1 and AKT1, which further mediates the downstream signaling pathways in CML. Our findings demonstrate that FAM168A may be involved in the regulation of AKT1/NFκB signaling pathway and cell cycle in CML.

Polyhalogenated carbazoles (PHCZs) are an emerging class of persistent, bioaccumulative compounds that are structurally and chemically related to dioxins. They have been detected widely in sediment, river, and soil samples, but their environmental risks are largely unknown. Therefore, seven common PHCZs were tested for their endocrine disrupting potential in silico, in vitro, and in vivo. A dual-luciferase reporter gene assay was used to detect receptor-mediated (agonist or antagonistic) activity (concentration range: 10−9–10−5 M) against the estrogen receptor α (ERα), glucocorticoid receptor α (GRα), and mineralocorticoid receptor (MR). The alterations in the steroidogenesis pathway were investigated in H295R cells. Antagonistic effects against GRα were observed with five PHCZs, along with an increase in the cortisol levels of H295R cells. The most common effect observed was that of the agonistic activity of ERα, with the molecular docking analysis further indicating that hydrogen bonding and hydrophobic interactions may stabilize the interaction between PHCZs and the estrogen receptor binding pocket. In addition, a seven-day exposure of young female rats to three PHCZs (27-BCZ, 3-BCZ, and 36-BCZ) resulted in changes in serum E2 levels, uterine epithelium cell heights, and relative uterus weights. In conclusion, endocrine-disrupting effects, especially the estrogenic effects, were observed for the tested PHCZs. Such adverse effects of PHCZs on humans and wildlife warrant further thorough investigation.

Background: Endothelial cells (ECs) function as an instructive platform to support haematopoietic stem cell (HSC) homeostasis. Our recent studies found that impaired bone marrow (BM) ECs are responsible for the defective haematopoiesis in patients with poor graft function (PGF), which is characterised by pancytopenia post-allotransplant. Although activated autophagy was reported to benefit ECs, whether EC autophagy plays a critical role in supporting HSCs and its effect on PGF patients post-allotransplant remain unclear. Methods: To evaluate whether the autophagy status of ECs modulates their ability to support haematopoiesis, human umbilical vein endothelial cells (HUVECs) and primary BM ECs derived from healthy donors were subjected to knockdown or overexpression of Beclin-1 (an autophagy-related protein). Moreover, BM ECs derived from PGF patients were studied. Findings: Beclin-1 knockdown significantly reduced the haematopoiesis-supporting ability of ECs by suppressing autophagy, which could be restored by activating autophagy via Beclin-1 upregulation. Moreover, autophagy positively regulated haematopoiesis-related genes in HUVECs. Subsequently, a prospective case-control study demonstrated that defective autophagy reduced Beclin-1 expression and the colony-forming unit (CFU) plating efficiency in BM ECs from PGF patients compared to matched patients with good graft function. Rapamycin, an autophagy activator, quantitatively and functionally improved BM ECs from PGF patients in vitro and enhanced their ability to support HSCs by activating the Beclin-1 pathway. Interpretation: Our results suggest that the autophagy status of ECs modulates their ability to support haematopoiesis by regulating the Beclin-1 pathway. Defective autophagy in BM ECs may be involved in the pathogenesis of PGF post-allotransplant. Rapamycin provides a promising therapeutic approach for PGF patients. Funding: Please see funding sources. Keywords: Autophagy, Endothelial cells, Haematopoietic stem cells, Poor graft function, Allotransplant

Repetitive and intensive physiotherapy is indispensable to patients with ankle disabilities. Increasingly robot-assisted technology has been employed in the treatment to reduce the burden of the therapists and the related costs of the patients. This paper proposes a configuration of a wearable parallel mechanism to supplement the equipment selection for ankle rehabilitation. The kinematic analysis, i.e., the inverse position solution and Jacobian matrices, is elaborated. Several performance indices, including the reachable workspace index, motion isotropy index, force transfer index, and maximum torque index, are developed based on the derived kinematic solution. Moreover, according to the proposed kinematic configuration and wearable design concept, the mechanical structure that contains a basic machine-drive system and a multi-model position/force data collection system is designed in detail. Finally, the results of the performance evaluation indicate that the wearable parallel robot possesses sufficient motion isotropy, high force transfer performance, and large maximum torque performance within a large workspace that can cover all possible range of motion of human ankle complex, and is suitable for ankle rehabilitation.

We integrated multiple geochemical analysis of a 13.75 m-long core 973-4 recovered from the northeastern South China Sea (SCS) to detect the response of deep-sea sediment archives to sea-level change spanning the last 42 kyr. The age-depth model based on AMS 14C dating, together with the sediment grain size, shows an occurrence of turbidity current at around 14 kyr, which was associated with submarine landslides caused by gas hydrate dissociation. A dominantly terrigenous sediment input was supplied from southwestern Taiwan rivers. By synthesizing environment-sensitive indexes, four distinct stages of paleoenvironmental evolutions were recognized throughout the studied interval. Well-oxygenated condition occurred during the stage I (42.4-31.8 kyr) with low sea-level stand below -80 m, accompanied by flat terrigenous input. The largest amounts of terrigenous sediment input occurred during the late phase of stage II (31.8-20.4 kyr) with the lowest sea-level stand below -120 m because of a short distance from paleo-Taiwan river estuaries to the core location. An occurrence of Ca-enriched turbidity current disturbed the original sediments during the stage III (20.4-13.9 kyr). The stepwise elevated sea-level stand resulted in an enclosed (semi-enclosed) system and contributed to a relatively low-oxygen environment in deep ocean during the stage IV (13.9 kyr—present). Temporal variations of TOC and CaCO3 display contrary pattern synchronously, indicating a decoupled relationship between organic carbon burial and carbonate productivity. Our results highlight that these sedimentary records as reflected in the paleoenvironmental changes in the northeastern SCS were mainly driven by sea-level fluctuations and later, since the mid-Holocene, the strengthening East Asian summer monsoon (EASM) overwhelmed the stable sea level in dominating the environmental changes.

Mesoscale eddies occur frequently in the Luzon Strait and its adjacent area, and accurate prediction of eddy structure changes is of great significance. In recent years, artificial neural network (ANN) has been widely applied in the study of physical oceanography with the continuous accumulation of satellite remote sensing data. This study adopted an ANN approach to predict the evolution of eddies around the Luzon Strait, based on 25 years of sea level anomaly (SLA) data, 85% of which are used for training and the remaining 15% are reserved for testing. The original SLA data were firstly decomposed into spatial modes (EOFs) and time-dependent principal components (PCs) by the empirical orthogonal function (EOF) analysis. In order to calculate faster and save costs, only the first 35 PCs were selected as predictors, whereas their variance contribution rate reached 96%. The results of predicted reconstruction indicated that the neural network-based model can reliably predict eddy structure evaluations for about 15 days. Importantly, the position and variation of four typical eddy events were reconstructed, and included a cyclone eddy event, an eddy shedding event, an anticyclone eddy event, and an abnormal anticyclone eddy event.

Abstract Background As one of the major treatment obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), relapse of Ph+ALL may result from the persistence of leukemia-propagating cells (LPCs). Research using a xenograft mouse assay recently determined that LPCs were enriched in the CD34+CD38−CD58− fraction in human Ph+ALL. Additionally, a cohort study demonstrated that Ph+ALL patients with a LPCs phenotype at diagnosis exhibited a significantly higher cumulative incidence of relapse than those with the other cell phenotypes even with uniform front-line imatinib-based therapy pre- and post-allotransplant, thus highlighting the need for novel LPCs-based therapeutic strategies. Methods RNA sequencing (RNA-Seq) and real-time quantitative polymerase chain reaction (qRT-PCR) were performed to analyze the gene expression profiles of the sorted LPCs and other cell fractions from patients with de novo Ph+ALL. In order to assess the effects of the selective BCR–ABL and/or Janus kinase (JAK)2 inhibition therapy by the treatment with single agents or a combination of ruxolitinib and imatinib or nilotinib on Ph+ALL LPCs, drug-induced apoptosis of LPCs was investigated in vitro, as well as in vivo using sublethally irradiated and anti-CD122-conditioned NOD/SCID xenograft mouse assay. Moreover, western blot analyses were performed on the bone marrow cells harvested from the different groups of recipient mice. Results RNA-Seq and qRT-PCR demonstrated that JAK2 was more highly expressed in the sorted LPCs than in the other cell fractions in de novo Ph+ALL patients. Combination treatment with a selective JAK1/JAK2 inhibitor (ruxolitinib) and nilotinib more effectively eliminated LPCs than either therapy alone or both in vitro and in humanized Ph+ALL mice by reducing phospho-CrKL and phospho-JAK2 activities at the molecular level. Conclusions In summary, this pre-clinical study provides a scientific rationale for simultaneously targeting BCR–ABL and JAK2 activities as a promising anti-LPCs therapeutic approach for patients with de novo Ph+ALL.

Enhanced peripheral complement activation has long been considered as one of the major pathogenic elements of immune thrombocytopenia. A dysfunctional bone marrow microenvironment, especially with regards to mesenchymal stem cells, has been observed in patients with immune thrombocytopenia. However, the potential role of the complement system in the dysfunctional bone marrow microenvironment remains poorly understood. In this study, bone marrow samples from patients with immune thrombocytopenia were divided into two groups based on whether or not complement components were deposited on the surfaces of their mesenchymal stem cells. The mesenchymal cells from the group with complement deposition were less numerous, dysfunctional, had a reduced capacity to proliferate, and showed increased apoptosis as well as abnormal secretion of interleukin-1β and C-X-C motif chemokine ligand 12. In vitro treatment with all-trans retinoic acid increased the number and improved the function of the complement-positive bone marrow mesenchymal stem cells by upregulating DNA hypermethylation of the interleukin-1β promoter. In vivo studies showed that all-trans retinoic acid could rescue the impaired mesenchymal stem cells to support the thrombopoietic niche in both patients with immune thrombocytopenia and a murine model of this disease. Taken together, these results indicate that impairment of mesenchymal stem cells, mediated by the complement–interleukin-1β loop, plays a role in the pathogenesis of immune thrombocytopenia. All-trans retinoic acid represents a promising therapeutic approach in patients with immune thrombocytopenia through its effect of repairing mesenchymal stem cell impairment.

To overcome the shortage of appropriate-sized whole liver grafts for children, technical variant liver transplantation has been practiced for decades. We perform a meta-analysis to compare the survival rates and incidence of surgical complications between pediatric whole liver transplantation and technical variant liver transplantation.To identify relevant studies up to January 2014, we searched PubMed/Medline, Embase, and Cochrane library databases. The primary outcomes measured were patient and graft survival rates, and the secondary outcomes were the incidence of surgical complications. The outcomes were pooled using a fixed-effects model or random-effects model.The one-year, three-year, five-year patient survival rates and one-year, three-year graft survival rates were significantly higher in whole liver transplantation than technical variant liver transplantation (OR = 1.62, 1.90, 1.65, 1.78, and 1.62, respectively, p