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Mesenchymal stem cell (MSC)-based therapies have emerged as promising methods for regenerative medicine; however, how to precisely enhance their tissue repair effects is still a major question in the field. Circulating extracellular vesicles (EVs) from diseased states carry diverse pathological information and affect the functions of recipient cells. Based on this unique property, we report that disease-derived circulating EV (disease-EV) preconditioning is a potent strategy for precisely enhancing the tissue repair potency of MSCs in diverse disease models. Briefly, plasma EVs from lung or kidney tissue injuries were shown to contain distinctly enriched molecules and were shown to induce tissue injury-specific gene expression responses in cultured MSCs. Disease-EV preconditioning improved the performance (including proliferation, migration, and growth factor production) of MSCs through metabolic reprogramming (such as via enhanced oxidative phosphorylation and lipid metabolism) without inducing an adverse immune response. Consequently, compared with normal MSCs, disease-EV-preconditioned MSCs exhibited superior tissue repair effects (including anti-inflammatory and antiapoptotic effects) in diverse types of tissue injury (such as acute lung or kidney injury). Disease-derived EVs may serve as a type of “off-the-shelf” product due to multiple advantages, such as flexibility, stability, long-term storage, and ease of shipment and use. This study highlights the idea that disease-EV preconditioning is a robust strategy for precisely enhancing the regenerative capacity of MSC-based therapies.

BackgroundImmunotherapy has shown considerable promise in cancer treatment, yet only a minority of osteosarcoma patients derive benefits from this approach. Hypoxia and lactate metabolism are two predominant characteristics of the tumor microenvironment. These features are crucial for molding the immune landscape and thus have the potential to act as predictive indicators for immunotherapy response.MethodsPrognostic modeled genes were identified through univariate and multivariate Cox regression as well as LASSO regression analyses. The tumor microenvironment was evaluated using ESTIMATE, CIBERSORT, and ImmuCellAI analyses. Tide prediction and expression of immune checkpoints, MHC molecules, chemokines, interleukins, interferons, receptors, and other cytokines were utilized to estimate immunotherapy efficacy. Single-cell analysis was performed to demonstrate the expression of modeled genes among various immune cell types. Experimental validation was carried out to verify the expression and functions of SFXN4 and SQOR.ResultsA potent signature was constructed with 8 genes related to hypoxia and lactate metabolism, including MAFF, COL5A2, FAM162A, SQOR, UQCRB, SFXN4, PFKFB2 and COX6A2. A nomogram incorporating risk scores and other clinical features demonstrated excellent predictive capacity. Osteosarcoma patients with high-risk scores exhibited poor prognosis and more “cold” tumor characteristics. According to the ESTIMATE algorithm, these patients displayed lower immune, stromal, and ESTIMATE scores, partially attributed to inadequate infiltration of key immunocytes. The Ciborsort analysis similarly indicated that high-risk individuals had diminished infiltration of critical anti-tumor immune cells such as Cytotoxic T cells, CD4+ T cells, and NK cells. The low expression levels of certain immune checkpoints, MHC molecules, chemokines, interleukins, interferons, receptors, and other cytokines in high-risk cases suggested their unsatisfactory responses to immune treatment. Tide prediction further demonstrated that fewer individuals classified as high risk may exhibit sensitivity to immune checkpoint inhibitor therapy. Notably, SFXN4 was found to be highly expressed in osteosarcoma tissues and cells; it promoted the growth, migration, and invasion of osteosarcoma cells, while SQOR had the opposite effect.ConclusionOur research has developed a robust hypoxia- and lactate metabolism-related gene signature, providing a solid theoretical foundation for prognosis prediction, classification of “cold” and “hot” tumors, accessing immunotherapy response, and directing personalized treatment for osteosarcoma.

Abstract Single-cell RNA sequencing (scRNA-seq) technology has been widely used to study the differences in gene expression at the single cell level, providing insights into the research of cell development, differentiation, and functional heterogeneity. Various pipelines and workflows of scRNA-seq analysis have been developed but few considered multi-timepoint data specifically. In this study, we develop CASi, a comprehensive framework for analyzing multiple timepoints’ scRNA-seq data, which provides users with: (1) cross-timepoint cell annotation, (2) detection of potentially novel cell types emerged over time, (3) visualization of cell population evolution, and (4) identification of temporal differentially expressed genes (tDEGs). Through comprehensive simulation studies and applications to a real multi-timepoint single cell dataset, we demonstrate the robust and favorable performance of the proposal versus existing methods serving similar purposes.

Microglia are essential for maintaining homeostasis and responding to pathological events in the central nervous system (CNS). Their dynamic and multidimensional states in different environments are pivotal factors in various CNS disorders. However, therapeutic modulation of microglial states is challenging due to the intricate balance these cells maintain in the CNS environment and the blood–brain barrier’s restriction of drug delivery. Nanomedicine presents a promising avenue for addressing these challenges, offering a method for the targeted and efficient modulation of microglial states. This review covers the challenges faced in microglial therapeutic modulation and potential use of nanoparticle-based drug delivery systems. We provide an in-depth examination of nanoparticle applications for modulating microglial states in a range of CNS disorders, encompassing neurodegenerative and autoimmune diseases, infections, traumatic injuries, stroke, tumors, chronic pain, and psychiatric conditions. This review highlights the recent advancements and future prospects in nanomedicine for microglial modulation, paving the way for future research and clinical applications of therapeutic interventions in CNS disorders.

Abstract Background To compare the expression levels of long non-coding RNA (lncRNA) and messenger RNA (mRNA) in pre-receptive endometrium between patients with Polycystic Ovary Syndrome (PCOS)and normal ovulation undergoing in vitro fertilization-embryo transfer (IVF-ET). Methods Endometrial tissues were collected with endometrial vacuum curette in pre-receptive phase (3 days after oocytes retrieval) from PCOS and control groups. LncRNAs and mRNAs of endometrium were identified via RNA sequencing and alignments. A subset of 9 differentially expressed lncRNAs and 11 mRNAs were validated by quantitative reverse transcription polymerase chain reaction(qRT-PCR)in 22 PCOS patients and 18 ovulation patients. The function of mRNAs with differential expression patterns were explored using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Results We found out 687 up-regulated and 680 down-regulated mRNAs, as well as 345 up-regulated and 63 down-regulated lncRNAs in the PCOS patients in contrast to normal ovulation patients. qRT-PCR was used to detect the expression of 11 mRNAs, and validated that the expression of these 6 mRNAs CXCR4, RABL6, OPN3, SYBU, IDH1, NOP10 were significantly elevated among PCOS patients, and the expression of ZEB1 was significantly decreased. qRT-PCR was performed to detect the expression of 9 lncRNAs, and validated that the expression of these 7 lncRNAs IDH1-AS1, PCAT14, FTX, DANCR, PRKCQ-AS1, SNHG8, TPT1-AS1 were significantly enhanced among PCOS patients. Bioinformatics analysis showed that differentially expressed genes (DEGs) involved KEGG pathway were tyrosine metabolism, PI3K-Akt pathway, metabolic pathway, Jak-STAT pathway, pyruvate metabolism, protein processing in endoplasmic reticulum, oxidative phosphorylation and proteasome. The up-regulation of GO classification was involved in ATP metabolic process, oxidative phosphorylation, RNA catabolic process, and down-regulation of GO classification was response to corticosteroid, steroid hormone, and T cell activation. Conclusion Our results determined the characteristics and expression profile of endometrial lncRNAs and mRNAs in PCOS patients in pre-receptive phase, which is the day 3 after oocytes retrival. The possible pathways and related genes of endometrial receptivity disorders were found, and those lncRNAs may be developed as a predictive biomarker of endometrium in pre-receptive phase.

Background: The primary objective of this investigation was to assess the impact of pyrroline-5-carboxylate reductase 1 (PYCR1) on the progression of gastric cancer (GC), specifically focusing on tumor growth and metastatic potential. Methods: Surgical specimens from patients with different stages of GC were assayed for PYCR1 expression using immunohistochemistry. PYCR1 expression was manipulated by depletion or overexpression approaches in GC cells, and these cells were applied to explore the functional roles of PYCR1. Expression of apoptosis– and metastasis–related markers was quantified through quantitative real-time PCR and Western blot. Results: Higher PYCR1 expression was ascertained in surgical specimens from patients with GC as compared to noncancerous adjacent tissues. Additionally, PYCR1 overexpression in GC tissues was linked to adverse clinical outcomes. The depletion of PYCR1 in GC cells resulted in a pronounced reduction in proliferation, the induction of apoptosis, and the attenuation of invasion and metastasis. Conversely, its ectopic expression notably augmented proliferation, restricted apoptosis, and stimulated invasion and metastasis. In addition, the knockdown of PYCR1 resulted in a significant elevation in the activation of caspase 3, a key protein involved in apoptosis. This depletion also led to a decrease in the activation or expression of proteins associated with metastasis, such as phosphorylated (p)-phosphatidylinositol 3-kinase (PI3K), p-AKT serine/threonine kinase (AKT), and snail family transcriptional repressor 1 (Snail). Additionally, it resulted in an upregulation of E-cadherin expression. Conversely, the overexpression of PYCR1 notably increased the levels of p-PI3K, p-AKT, and Snail, while simultaneously reducing E-cadherin expression. Conclusion: PYCR1, by activating PI3K/AKT signaling, assumes a crucial role in governing malignant characteristics of GC cells, including proliferation, apoptosis, and metastasis. These findings underscore the promising potential of PYCR1 as a diagnostic biomarker and a target for tailored therapeutic interventions in patients with GC.

Abstract REY‐rich mud, consisting of deep‐sea sediments with high concentrations of rare‐earth elements and yttrium (REY), holds significant economic potential. Many studies have been conducted on biogenic apatite, ferromanganese micronodule, and phillipsite within these deposits to ascertain the REY enrichment mechanisms. However, the knowledge of clay minerals in REY‐rich mud, which is the predominant component of pelagic sediments, is still limited. In this study, two adjacent gravity cores (core GC02: REY‐rich mud; core GC03: typical sediments of equatorial Pacific) were collected from the Clarion‐Clipperton Fracture Zone (CCFZ) of the Eastern Pacific to study the role of different clay minerals in REY enrichment. The clay minerals in core GC03 and core GC02 are primarily illite (averaging 60%) and smectite (averaging 63%), respectively, and the smectite in core GC02 was mainly Fe‐rich, which was probably formed via the reaction between opal and FeOOH. Moreover, multiple studies have reported similar smectite enrichment in REY‐rich mud, suggesting that it is a common characteristic. The presumed hydrothermal or volcanic origination of smectite in REY‐rich layers of core GC02 indicates the essential role of hydrothermal and volcanic activities in REY‐rich mud formation during the Oligocene in the western CCFZ.

ABSTRACTObjectives There is no meta-analysis about the effects of pegfilgrastim on the occurrence of febrile neutropenia (FN) in pediatric/adolescent cancer patients. The study explored the efficacy of prophylactic pegfilgrastim in preventing FN in children/adolescents with cancer.Methods PubMed, Embase, and the Cochrane Library were searched for studies published before April 7, 2020. The primary outcome was the rate of FN. Effect size (ES) and odds ratio (OR) with 95% confidence intervals (CIs) were used to evaluate the outcome. The ES represented the rate of FN, and the STATA ‘metaprop’ command was used to synthesize the rate.Results Eight studies were included, comprising 167 patients and 550 courses of treatment. There was no difference between pegfilgrastim and filgrastim for the rate of FN in children receiving chemotherapy (OR = 0.68, 95% CI: 0.20–2.23, P = 0.520). In patients receiving pegfilgrastim, the rate of FN was 25.6% (95% CI: 14.9%−36.3%), the rate of grade 4 FN was 38.3% (95% CI: 19.2%−59.5%), the rate of severe neutropenia (SN) was 40.5% (95% CI: 35.1%−46.1%), and the rate of treatment delays due to FN was 4.8% (95% CI: 0.8%−11.3%).Discussion The number of studies that could be included was small; therefore, a specific type of cancer or a specific treatment could be studied. Heterogeneity was high.Conclusion There was no difference between pegfilgrastim and filgrastim for the rate of FN. The use of pegfilgrastim was still associated with rates of FN, grade 4 FN, severe neutropenia, and treatment delays due to FN in pediatric cancer patients.

Abstract Background To summarize the characteristics and treatment, and analyze the prognosis of large number of infants with retinoblastoma (RB) in China through a multicenter, 10-year retrospective analysis. Methods The data of RB infants were collected from multiple centers. The characteristics and survival prognosis were analyzed. The overall survival (OS) rate was estimated by the Kaplan–Meier method. Multivariate Cox survival analysis was to evaluate the independent risk factors affecting the prognosis of RB infants. Results A total of 373 RB infants (202 boys and 171 girls) were included, the median age was 6.22 months (10 days to 11.93 months). The median follow-up time of RB infants was 18.4 (1.02–122.81 months). After excluding the lost to follow-up cases, the OS rate was 97.7% (345/353). Kaplan–Meier survival analysis indicated that 9 cases died and the median survival time was not reached. Univariate analysis of prognostic factors revealed eye affected, presenting signs, left eye stage and recurrence to be poor prognostic factors for OS rate in RB infants (all P

IntroductionsIdentifying biological markers of colorectal cancer (CRC) development and prognosis and exploring the intrinsic connection between these molecular markers and CRC progression is underway. However, a single molecular tumor marker is often difficult to assess and predict the progression and prognosis of CRC. Consequently, a combination of tumor-related markers is much needed. Ki67, Her-2, and mutant P53 (MutP53) proteins play pivotal roles in CRC occurrence, progression and prognosis.MethodsBased on the expressions by immunochemistry, we developed a risk model, nomogram and lymph node metastasis model by R software and Pythons to explore the value of these proteins in predicting CRC progression, prognosis, and examined the relationship of these proteins with the CRC clinicopathological features from 755 (training set) and 211 CRC (validation set) patients collected from the hospital.ResultsWe found that Ki67 expression was significantly correlated with T-stage, N-stage, TNM-stage, vascular invasion, organization differentiation, and adenoma carcinogenesis. Moreover, Her-2 expression was significantly correlated with T-stage, N-stage, TNM-stage, vascular and nerve invasion, pMMR/dMMR, signet ring cell carcinoma, and organization differentiation. MutP53 expression was significantly correlated with T-stage, N-stage, TNM-stage, vascular and nerve invasion, adenoma carcinogenesis, signet ring cell carcinoma, organization differentiation, and pMMR/dMMR. Increased expression of each of the protein indicated a poor prognosis. The established risk model based on the three key proteins showed high predictive value for determining the pathological characteristics and prognosis of CRC and was an independent influencer for prognosis. The nomogram prediction model, which was based on the risk model, after sufficient evaluation, showed more premium clinical value for predicting prognosis. Independent cohort of 211 CRC patients screened from the hospital verified the strong predictive efficacy of these models. The utilization of the XGBoost algorithm in a lymph node metastasis model, which incorporates three crucial proteins, demonstrated a robust predictive capacity for lymph node metastasis.DiscussionThe risk model, nomogram and lymph node metastasis model have all provided valuable insights into the involvement of these three key proteins in the progression and prognosis of CRC. Our study provides a theoretical basis for further screening of effective models that utilize biological markers of CRC.

The paleoproductivity in the Southern Ocean plays a crucial role in controlling the atmospheric CO2 concentration. Here, we present the sediment record of gravity core ANT37-C5/6-07, which was retrieved from the Cosmonaut Sea (CS), Indian Ocean sector of the Southern Ocean. We found that the change in the oxygen concentration in the CS bottom water is strongly correlated with the atmospheric CO2 fluctuations since the Last Glacial Maximum (LGM). Based on the change in the export production, we reconstructed the evolution history of the deep-water ventilation/upwelling in the study area. During the LGM, a large amount of respiratory carbon was stored in the deep Southern Ocean due to the effect of the low export productivity and restricted ventilation. The oxygen concentration was also low at this time. Despite the increase in paleoproductivity, the biological pump efficiency remained at a low level during the Last Deglaciation. Vast quantities of CO2 were released into the atmosphere through enhanced upwelling. The recovery of ventilation during this period facilitated the supply of oxygen-rich surface water to the deep ocean. Moreover, signals were identified during the transitions between the Heinrich Stage 1 (HS1), Antarctic Cold Reverse (ACR), and Younger Drays (YD) periods. During the Holocene, the productivity increased overall, and the oxygen in the bottom water was consumed but still remained at a high level. This may have been caused by the enhanced ventilation and/or the prevalence of East Cosmonaut Polynya (ECP) near Cape Ann.

Synthesizing ring structure aviation fuels from biomass-derived platform molecules is challenging, especially for bridged ring structure aviation fuels which are typically achieved from fossil-derived chemicals. Herein, we report the synthesis of a series of ring structure biofuels in two steps by a combination of a solvent-free Michael-cyclization reaction and a hydrodeoxygenation (HDO) reaction from lignocellulose-derived 5,5-dimethyl-1,3-cyclohexanedione. These biofuels are obtained with high overall yields up to 90%, which exhibit high densities of 0.81 g cm−3-0.88 g cm−3 and high volumetric neat heat of combustion (VNHOC) values of 36.0 MJ L−1-38.6 MJ L−1. More importantly, bridged-ring structure hydrocarbons can also be achieved in two steps by a combination of a Robinson annulation reaction and an HDO reaction to afford the final products at high overall yields up to 90%. The bridged-ring structure products have comparable high densities and high VNHOC values to the best artificial fuel JP-10 (0.94 g cm−3 and 39.6 MJ L−1). The results demonstrate a promising way for the synthesis of high-density aviation fuels with different fuel properties at high yields.

Exploiting the electrical and mechanical properties of CNT films remain elusive because of the difficult material process. Here, Wang et al. report multifunctional MWCNT films with crystalline structure which exhibited great electromagnetic interference shielding efficiency, high thermoelectric power factor, and large ampacity.

Summary: Influenza A virus poses a constant challenge to human health. The highly conserved influenza matrix-2 (M2) protein is an attractive target for the development of a universal antibody-based drug. However, screening using antigens with subphysiological conformation in a nonmembrane environment significantly reduces the generation of efficient antibodies. Here, M2(1-46) was incorporated into nanodiscs (M2-nanodiscs) with M2 in a membrane-embedded tetrameric conformation, closely resembling its natural physiological state in the influenza viral envelope. M2-nanodisc generation, an antigen, was followed by Chiloscyllium plagiosum immunization. The functional vNARs were selected by phage display panning strategy from the shark immune library. One of the isolated vNARs, AM2H10, could specifically bind to tetrameric M2 instead of monomeric M2e (the ectodomain of M2 protein). Furthermore, AM2H10 blocked ion influx through amantadine-sensitive and resistant M2 channels. Our findings indicated the possibility of developing functional shark nanobodies against various influenza viruses by targeting the M2 protein.

Organ fibrosis is a serious health challenge worldwide, and its global incidence and medical burden are increasing dramatically each year. Fibrosis can occur in nearly all major organs and ultimately lead to organ dysfunction. However, current clinical treatments cannot slow or reverse the progression of fibrosis to end-stage organ failure, and thus advanced anti-fibrotic therapeutics are urgently needed. As a type of naturally derived nanovesicle, native extracellular vesicles (EVs) from multiple cell types (e.g., stem cells, immune cells, and tissue cells) have been shown to alleviate organ fibrosis in many preclinical models through multiple effective mechanisms, such as anti-inflammation, pro-angiogenesis, inactivation of myofibroblasts, and fibrinolysis of ECM components. Moreover, the therapeutic potency of native EVs can be further enhanced by multiple engineering strategies, such as genetic modifications, preconditionings, therapeutic reagent-loadings, and combination with functional biomaterials. In this review, we briefly introduce the pathology and current clinical treatments of organ fibrosis, discuss EV biology and production strategies, and particularly focus on important studies using native or engineered EVs as interventions to attenuate tissue fibrosis. This review provides insights into the development and translation of EV-based nanotherapies into clinical applications in the future.

ObjectiveThe aim of this study is to investigate the optimal estradiol (E2) level on the day of gonadotropin-releasing hormone antagonist (GnRH-ant) initiation to maximize the clinical pregnancy rate (CPR) after fresh embryo transfer among patients with simple tubal factor infertility.MethodsA retrospective cohort study was conducted in the Reproductive Medicine Center, the Second Hospital of Hebei Medical University. A total of 1,493 IVF-ET cycles of patients diagnosed with single tubal factor infertility from August 2016 to August 2021 were included and equally allocated into five distinct groups according to the quintile serum E2 levels on the day of GnRH-ant initiation. The five groups had similar baseline data except for antral follicle count.Result(s)The serum E 2 level on GnRH-ant initiation day was determined as an independent predictor of clinical pregnancy after adjusting for confounding factors such as age, infertility duration, body mass index, cycle number, antral follicle count, and the number of transferred embryos. Through smooth curve fitting, we found that, with the increase of serum E2 levels on the day of GnRH-ant initiation, CPR showed a trend of slight increase and then slight decrease. The maximal CPR was achieved when the serum E2 level on GnRH-ant initiation day was 498 pg/ml. When E2 was less than 498 pg/ml, the odds ratio (OR) of clinical pregnancy was 1.05 (95% CI: 1.00, 1.11, P = 0.0583). When E2 was greater than 498 pg/ml, the OR of clinical pregnancy was 0.97 (95% CI: 0.95, 0.98, P = 0.0003). Furthermore, CPR remained high when E2 was 436.8–658.6 pg/ml but declined significantly by more than 40% when E2 was ≥ 894.4 pg/ml (P < 0.05).Conclusion(s)The serum E2 level should be considered as an adjuvant parameter for GnRH-ant initiation. The best E2 value was 498 pg/ml, and GnRH-ant administration could be recommended to initiate when serum E2 was 436.8–658.6 pg/ml. If GnRH-ant was initiated when serum E2 was above 894.4 pg/ml, then the CPR after fresh embryo transfer may decline dramatically, and thus, cancellation of fresh embryo transfer and earlier initiation of GnRH-ant in future cycles should be considered.

Abstract Background Approximately 5.0–24.2% of colorectal cancers (CRCs) have inactivating mutations in SMAD4, making it one of the frequently mutated genes in CRC. We thus carried out a comprehensive system review and meta-analysis investigating the prognostic significance and clinicopathological features of SMAD4 gene mutation in CRC patients. Methods A detailed literature search was conducted in PubMed, Web of Science and Embase databases to study the relationship between SMAD4 mutations and the demographic and clinicopathological characteristics in CRC patients. The hazard ratios (HRs) with 95% confidence intervals (CI) were used to evaluate the effect of SMAD4 mutations on overall survival (OS) and progression-free survival (PFS)/recurrence-free survival (RFS). Results Ten studies enrolling 4394 patients were eligible for inclusion. Data on OS were available from 5 studies and data on PFS/RFS were available from 3 studies. Comparing SMAD4-mutated CRC patients with SMAD4 wild-type CRC patients, the summary HR for OS was 1.46 (95% CI 1.28–1.67, P = 0.001), the summary HR for PFS/RFS was 1.59 (95% CI 1.14–2.22, P = 0.006). In terms of clinicopathology parameters, 9 studies have data that can be extracted, SMAD4 mutations were associated with tumor location (odds ratio [OR] = 1.15, colon/rectum, 95% CI 1.01–1.31, P = 0.042), TNM stage (OR = 1.28, stage IV/I–III, 95% CI 1.03–1.58, P = 0.025), lymph node metastasis (OR = 1.42, N1 + N2/N0, 95% CI 1.20–1.67, P

The application of anticoagulants and immune agents in assisted reproduction technology has been in a chaotic state, and no clear conclusion has been reached regarding the effectiveness and safety of this treatment. We aimed to explore the potential association between adjuvant medication and pregnancy outcomes and offspring safety in a retrospective cohort study including 8,873 frozen-thawed embryo transfer cycles. The included cycles were divided into three groups according to the drugs used, namely, the routine treatment group (without anticoagulant agents and immune agents), the anticoagulant agent group, and the immunotherapy group. Among normal ovulatory patients, those who used immune agents had a 1.4-fold increased risk of miscarriage (≤13 weeks), but a 0.8-fold decreased chance of birth (≥28 weeks) compared with the routine treatment group. Among patients with more than 1 embryo transferred, those who used anticoagulant agents showed a 1.2-fold higher risk of multiple birth than those undergoing routine treatment. Among patients without pregnancy complications, anticoagulant treatment was associated with a 2.1-fold increased risk of congenital anomalies. Among young patients (

Smoothened (SMO) protein is a member of the G protein-coupled receptor (GPCR) family that is involved in the Hedgehog (Hh) signaling pathway. It is a putative target for treating various cancers, including medulloblastoma and basal cell carcinoma (BCC). Characterizing membrane proteins such as SMO in their native state is highly beneficial for the development of effective pharmaceutical drugs, as their structures and functions are retained to the highest extent in this state. Therefore, although SMO protein is conventionally solubilized in detergent micelles, incorporating the protein in a lipid-based membrane mimic is still required. In this study, we used styrene maleic acid (SMA) copolymer that directly extracted membrane protein and surrounding lipids as well as formed the so-called polymer nanodiscs, to solubilize and purify the SMO transmembrane domain encapsulated by SMA-nanodiscs. The obtained SMA-nanodiscs showed high homogeneity and maintained the physiological activity of SMO protein, thereby enabling the measurement of the dissociation constant (Kd) for SMO ligands SMO-ligands Shh Signaling Antagonist V (SANT-1) and Smoothened Agonist (SAG) using ligand-based solution nuclear magnetic resonance spectroscopy. This work paves the way for investigating the structure, function, and drug development of SMO proteins in a native-like lipid environment.

Streaming computing attracts intense attention because of the demand for massive data analyzing in real-time. Due to unbounded and continuous input, the volume of streaming data is so high that all the data cannot be permanently stored. Piecewise polynomial fitting is a popular data compression method that approximately represents the raw data stream with multiple polynomials. The polynomial coefficients corresponding to the best-fitting curve can be calculated by the method of least squares, which minimizes the sum of the squared residuals between observed and fitted values. However, built on several matrix calculations, the method of least squares always leads to high time complexity and is difficult to be applied to streaming computing. This paper puts forward a fast piecewise polynomial fitting for time-series data in streaming computing. The input data stream is dynamically segmented according to a given residual bound. Meanwhile, the data points in each segment are fitted using an improved polynomial fitting method, which has less time overhead than general polynomial fitting by reusing the intermediate calculation results. Experimental results on four time-series datasets show that our algorithm can achieve the highest speedup to the general piecewise polynomial fitting of 2.82x for periodically sampled time-series data and 1.85x for aperiodically sampled time-series data, without affecting the compression ratio and fitting accuracy. Moreover, the event-time latency comparison in a streaming environment indicates that the improved method can endure higher throughput than general piecewise polynomial fitting with the same latency.

The coordinated development of ecology and economy is one of the key issues of sustainable development. A full understanding of the relationship between ecology and economy is necessary for the coordinated development of the two. This paper takes Sichuan Province as the research area and county-level administrative districts as the research unit. Based on the medium value of the ecological quality index and economic growth index of each unit, Sichuan Province is divided into dual pressure zones (DPZ), economic backward zones (EBZ), ecological crisis zones (ECZ), and coordinated development zones (CDZ) and the coupling coordination degree (CCD) of each unit is studied. The results show that: (1) On the whole, the eastern part of Sichuan Province has a better level of economic development, and the southern part of the western region has a higher ecological quality. The ecological quality and economic growth pattern are highly correlated with topographical conditions. (2) The distribution characteristics of the four types of partitions are significantly different. The EBZ are more distributed in the western and southern of Sichuan Province, the ECZ are more distributed in the eastern, the DPZ and CDZ are relatively more sporadic. More than 90% of the partition changed zones are distributed in the eastern area. (3) The CCD of more than 95% units belongs to moderate coordination and high coordination. The overall CCD of the four types of zones has shown an upward trend from 2010 to 2015. Based on the results, Sichuan Province should follow the path of clear waters and green mountains are as good as mountains of gold and silver, and targeted sustainable development suggestions for DPZ, EBZ, ECZ, and CDZ are put forward. This paper provides guidance for formulating regional sustainable development strategies, especially in areas with unbalanced development due to congenital topographical conditions.

With the development of industry in recent years, heavy metal contamination in water and substrate, which may pose a serious threat to human health if left untreated, has attracted increasing attention. Biochar is commonly used as an adsorbent/immobilizer for heavy metals in water and substrates because of its wide range of raw materials, low production cost, and good adsorption performance. In this paper, we selected abundant Moso bamboo as the raw material to make biochar (bamboo charcoal), modified bamboo charcoal using different methods to find the modified product with the best adsorption effect, assessed the adsorption performance of modified bamboo charcoal on Cu(II) and Cd(II) in solution, and investigated the effects of the solution concentration, adsorption time, pH, and temperature on the adsorption effect of KAM500-400-3 on Cu(II) and Cd(II). The effect of the solution concentration, adsorption time, pH, and temperature on the adsorption effect of KAM500-400-3 on Cu(II) and Cd(II) was investigated, and the adsorption mechanism of KAM500-400-3 on heavy metals Cu(II) and Cd(II) was analyzed by fitting the adsorption kinetics, adsorption isotherms, and adsorption thermodynamics. The adsorption/fixation characteristics of modified bamboo charcoal on heavy metals Cu(II) and Cd(II) in water and substrate were investigated. This study aimed to identify an effective material for the treatment of heavy metals in water and substrates and provide a reference for their application in practical engineering.

Mutations in KRAS (codon 12/13), NRAS, BRAFV600E, and amplification of ERBB2 and MET account for 70–80% of anti-epidermal growth factor receptor (EGFR) monoclonal antibody primary resistance. However, the list of anti-EGFR monoclonal antibody primary resistance biomarkers is still incomplete. Herein, we report a case of wild-type RAS/BRAF metastatic colorectal cancer (CRC) with resistance to anti-EGFR monoclonal antibody and chemotherapy. Initially, mutation detection in postoperative tumor tissue by using amplification-refractory mutation system polymerase chain reaction indicated wild-type RAS/BRAF without point mutations, insertion deletions, or fusion mutations. Therefore, we recommended combined therapy of cetuximab and FOLFIRI after failure of platinum-based adjuvant chemotherapy, but the disease continued to progress. Next generation sequencing analysis of the postoperative tumor tissue revealed that KRAS copy number was increased and detected SMAD4, RNF43, and PREX2 mutations. This is the first case of advanced CRC with increased copy numbers of KRAS resistant to cetuximab and chemotherapy, which results in poor patient survival, and other mutated genes may be associated with the outcomes. Our findings indicate KRAS copy number alterations should also be examined, especially with anti-EGFR monoclonal antibody therapy in CRC, since it may be related with the primary resistance to these drugs.

Camptothecin (CPT) is a cytotoxic quinoline alkaloid isolated from the bark and branches of the Chinese tree Camptotheca acuminata. CPT inhibits topoisomerase I. It possesses various antitumor activities and is mainly used in the treatment of colon, ovarian, liver, and bone cancers as well as leukemia. CPT inhibits the expressions of inflammatory genes and can prevent death from chronic inflammation. Therefore, we investigated the effect of CPT treatment in ulcerative colitis (UC) using DSS-induced UC mouse model; after that, we explored its potential mechanisms. Here, we found that CPT exerted protection on DSS-induced UC in rats. In addition, the administration prominently reduced the disease activity index as well as colon length of the model rats and remarkably reduced the inflammatory cytokines. Further, CPT significantly reduced several vital proinflammatory proteins in LPS-induced RAW264.7 cells. In summary, our findings demonstrate that CPT is hopefully to act as a therapeutic agent for UC.

In the whole lunar surface drilling and sampling task, it is critical to make the operation of the drilling and sampling impact system efficient and reliable. This paper focuses on how to improve the impact stress obtained at the cutting edge of the drill bit. Firstly, with the objective of maximizing the output impact energy, the design parameters of the percussive mechanism are optimally selected; based on the one-dimensional stress wave transfer theory, the collision input model and transfer models of impact stress in the drilling tool are established. Secondly, in order to verify the above design parameters and theoretical models, the percussive drive characteristics’ test and the transfer characteristics’ tests of impact stress in the drill stem and drilling tool joints are carried out in turn. The experimental results are consistent with the theoretical analysis, which clarifies the transfer characteristics of the impact stress at the various stages of generation, incidence, and transfer to the cutting edge. It was finally found that increasing the percussive frequency and impact energy of the percussive mechanism as well as the contact stiffness of the collision surface can increase the incident impact stress of the drilling tool, while reducing the length of the screw connection between the drill bit and the drill stem can reduce the impact stress loss. This provides a theoretical reference for the design of the percussive mechanism and drilling tools in lunar surface drilling and sampling tasks.

The discovery of epidermal growth factor receptor ( EGFR ) somatic mutations and the availability of tyrosine kinase inhibitors (TKIs) as targeted therapies have altered the therapeutic prospects of advanced non-small-cell lung cancer (NSCLC). G719X and S768I are uncommon mutations, and they often exist as compound mutations. A few reports have described the efficacy of first- and second-generation EGFR-TKIs. However, the efficacy of osimertinib in patients with these uncommon compound mutations is unknown. In this study, we reported the postoperative outcome of a patient with NSCLC and uncommon compound EGFR G719X and S768I mutations. After postoperative recurrence, the patient was treated with osimertinib, and an excellent and long-lasting clinical response was achieved. The patient has taken osimertinib for 31.0 months and exhibited a partial response, and her follow-up is ongoing.

Pluripotent stem cells have broad applications in regenerative medicine and offer ideal models for understanding the biological process of embryonic development and specific diseases. Studies suggest that the self-renewal and multi-lineage differentiation of stem cells are regulated by a complex network consisting of transcription factors, chromatin regulators, signaling factors, and non-coding RNAs. It is of great interest to identify RNA regulatory factors that determine the fate of stem cells. Long non-coding RNA (lncRNA), a class of non-coding RNAs with more than 200 bp in length, has been shown to act as essential epigenetic regulators of stem cell pluripotency and specific lineage commitment. In this review, we focus on recent research progress related to the function and epigenetic mechanisms of lncRNA in determining the fate of stem cells, particularly pluripotency maintenance and lineage-specific differentiation. We discuss the role of the Oct4 and Sox2 promoter-interacting lncRNA as identified by Chromatin RNA In Situ reverse Transcription sequencing (CRIST-seq). Further understanding of their potential actions will provide a basis for the development of regenerative medicine for clinical application. This work offers comprehensive details and better understanding of the role of lncRNA in determining the fate of stem cells and paves the way for clinical stem cell applications.

In this paper, the microstructure and properties of a Ti/Mg alloy clad plate manufactured by explosive welding were studied. The bonding interface was inspected by ultrasonic examination (US). The microstructure and the composition of the clad were characterized by OM and SEM. Properties were inspected by tensile test, shearing test, microhardness test and electrochemical corrosion. The results showed that the bonding interface of the clad plate was made up of straight areas and wavy areas. In straight areas, element diffusion occurred across the bonding interface. Additionally, in wavy areas, a melting zone occurred in the Mg alloy layer near to the bonding interface. Lots of light particles embedded on the melting zone. Tensile test results were comparable with the Ti sheet and the ultimate tensile strength of the clad plate demonstrated an 18% increase. The shearing strength of the clad plate was about 68–87 MPa. The microhardness of the clad plate was higher than that of the original sheets from the interface to 300 μm away. At over 300 μm, the microhardness of the clad plate decreased and approached the original sheets. Compared with the straight area, the hardness of the Mg alloy layer in the wavy area close to the interface increased by 12%. Corrosion results showed that the corrosion potential (Ecorr) absolute value of the clad plate increased by 24%, and the corrosion current density (icorr) value was 4 orders of magnitude lower, compared with the Mg alloy sheet. It was clear that the corrosion resistance of the clad plate was higher than that of the Mg alloy sheet. Cladding Mg alloy and Ti by explosive welding would improve the industrial applications of magnesium materials.

Abstract Background Retinoblastoma is the most common primary intraocular tumor and more and more attention has been paid to the developing countries. This study was aimed to evaluate the clinical features, treatment, and prognosis of retinoblastoma patients with central nervous system (CNS) metastasis in Beijing Tongren Hospital, one of the largest tertiary eye centers in China. Methods Clinical data of 31 consecutive retinoblastoma patients with CNS metastases, who were diagnosed at the Department of Pediatrics in Beijing Tongren Hospital between September 2005 and December 2015, were retrospective analyzed. Results The median age at presentation was 29 months (range from 5 to 108 months). Magnetic resonance imaging (MRI) results indicated that 16 patients (56.6%, 16/31) presented with meningeal involvement, 12 (38.7%, 12/31) presented with intracranial mass, 11 (35.5%, 11/31) presented with thickened optic nerve, and 5 (16.1%, 5/31) presented with concurrent meningeal and spinal cord membrane involvement. Retinoblastoma cells were detected in the cerebrospinal fluid (CSF) of 12 patients (44.4%, 12/27). Laboratory examinations on the blood and CSF were performed for 11 patients who had received six cycles of systemic chemotherapy, indicated that the serum level of neurone-specific enolase (NSE) after chemotherapy was significantly lower than that before chemotherapy (P

Abstract Objectives Influenza causes a spectrum of disease from asymptomatic infection to fatal outcome, and pre‐existing immunity can alter susceptibility and disease severity. In a household transmission study, we recruited outpatients with confirmed influenza virus infection and prospectively identified secondary infections in their household contacts, therefore identifying infection cases with baseline samples for determining immune‐mediated protection from influenza infection. Methods We examined baseline broadly reactive immune correlates of relevance to universal vaccine development, specifically antibody‐dependent cytotoxic (ADCC) antibodies and T‐cell responses in functional assays. Antibodies were assessed in a cell‐based NK cell degranulation assay by flow cytometry, and T‐cell responses were assessed by IFN‐γ intracellular cytokine staining flow cytometry assay. Results The magnitude of antibody responses and ADCC function for multiple influenza‐specific proteins was lower in participants who became infected, consolidating the role of pre‐existing antibodies in protection from seasonal influenza virus infection. Among H1N1‐infected contacts, we found that higher levels of pre‐existing H1‐haemagglutinin ADCC responses correlated with reduced symptom severity. Recent infection boosted the titre and magnitude of haemagglutinin‐, neuraminidase‐ and nucleoprotein‐specific ADCC antibodies. Limited T‐cell samples precluded conclusions on the role of pre‐existing T‐cell responses. Conclusions Overall, ADCC responses are a protective correlate against influenza virus infection that should be considered in future vaccine development and evaluation. Influenza‐specific ADCC responses are elevated in uninfected subjects, associated with reduced symptoms and boosted by recent infection, whilst HA stem and NA IgG are also elevated in uninfected participants irrespective of ADCC function.

In this paper, we consider the following Emden-Fowler type dynamic equations on time scales \begin{equation*} \big(a(t)|x^\Delta(t)|^\alpha \operatorname{sgn} x^\Delta(t)\big)^\Delta+b(t)|x(t)|^\beta \operatorname{sgn}x(t)=0, \end{equation*} when $\alpha

Histone deacetylase 7 (HDAC7) is a member of the class IIa family of classical HDACs with important roles in cell development, differentiation, and activation, including in macrophages and other innate immune cells. HDAC7 and other class IIa HDACs act as transcriptional repressors in the nucleus but, in some cell types, they can also act in the cytoplasm to modify non-nuclear proteins and/or scaffold signalling complexes. In macrophages, HDAC7 is a cytoplasmic protein with both pro- and anti-inflammatory functions, with the latter activity involving activation of the pentose phosphate pathway (PPP) enzyme 6-phosphogluconate dehydrogenase (6PGD) and the generation of antiinflammatory metabolite ribulose-5-phosphate. Here, we used ectopic expression systems and biochemical approaches to investigate the mechanism by which HDAC7 promotes 6PGD enzyme activity. We reveal that HDAC7 enzyme activity is not required for its activation of 6PGD and that the N-terminal protein-protein interaction domain of HDAC7 is sufficient to initiate this response. Mechanistically, the N-terminus of HDAC7 increases the affinity of 6PGD for NADP+, promotes the generation of a shorter form of 6PGD, and enhances the formation of higher order protein complexes, implicating its scaffolding function in engagement of the PPP. This contrasts with the pro-inflammatory function of HDAC7 in macrophages, in which it promotes deacetylation of the glycolytic enzyme pyruvate kinase M2 for inflammatory cytokine production. [ABSTRACT FROM AUTHOR]