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Supramolecular chemistry enables the manipulation of functional components on a molecular scale, facilitating a “bottom-up” approach to govern the sizes and structures of supramolecular materials. Using dynamic non-covalent interactions, supramolecular polymers can create materials with reversible and degradable characteristics and the abilities to self-heal and respond to external stimuli. Pillar[n]arene represents a novel class of macrocyclic hosts, emerging after cyclodextrins, crown ethers, calixarenes, and cucurbiturils. Its significance lies in its distinctive structure, comparing an electron-rich cavity and two finely adjustable rims, which has sparked considerable interest. Furthermore, the straightforward synthesis, uncomplicated functionalization, and remarkable properties of pillar[n]arene based on supramolecular interactions make it an excellent candidate for material construction, particularly in generating interpenetrating supramolecular polymers. Polymers resulting from supramolecular interactions involving pillar[n]arene find potential in various applications, including fluorescence sensors, substance adsorption and separation, catalysis, light-harvesting systems, artificial nanochannels, and drug delivery. In this context, we provide an overview of these recent frontier research fields in the use of pillar[n]arene-based supramolecular polymers, which serves as a source of inspiration for the creation of innovative functional polymer materials derived from pillar[n]arene derivatives.

This study utilized a combination of FLIC(1D3.2C) and FLUENT(2021R2) software to optimize the primary air distribution along the grate and the performance of a straw briquette combustion furnace of a 7 MW unit in China used to produce hot air for drying grain. Three air distribution modes, namely front-enhanced, uniform, and rear-enhanced modes, were analyzed to determine their effect on the flue gas components above the grate, the temperature field in the furnace, and the nitrogen oxide concentration at the furnace outlet. The results of the calculations showed that the NOx emissions for the front-enhanced, uniform, and rear-enhanced modes were 133.5 mg/Nm3, 104.4 mg/Nm3, and 76.6 mg/Nm3, respectively. It was found that the rear-enhanced mode can expand the biomass drying, devolatilization, and combustion zone, thus improving the furnace combustion performance and decreasing NOx emissions. These findings can provide useful guidance for optimizing biomass chain-grate-firing furnaces.

In wastewater treatment, a low C/N ratio highly inhibits the bioremoval of nitrogen, and commercial external carbon sources are widely used. In order to obtain an economical substitute, fermentation broth of spent mushroom substrates (SMS) was employed here as a carbon source for denitrification in a sequencing batch reactor (SBR). During the domestication process, the SMS fermentation broth-feeding treatment presented comparable nitrogen removal ability (74.44%) with a commercial carbon source group (77.99%). Rhodobacter, Lactobacillus and Pseudomonas were the dominant bacteria in the fermentation broth, and Saccharomycetales Gymnopilus dilepis was the dominant fungi. At the early domestication stage, the relatively high concentration of fermentation broth led to a much lower abundance of typical nitrate reductase genes than the control group. Furthermore, extracellular polymeric substance (EPS) formation was observed in the broth-feeding sample. The microbial structure dynamic was investigated, which showed a high influent effect when 20% fermentation broth was added. As domestication proceeded, similar dominant species in the control and broth-feeding treatments were observed. Overall, SMS fermentation broth can be used as a promising substitute to replace a costly commercial carbon source.

The frequency of cetacean strandings is increasing, with multiple causes identified. We examined temporal and spatial trends in stranding numbers along the coastal areas of the East China Sea from 1990 to 2021. Using structural equation models, we analyzed the relationships between strandings and climate, oceanic properties, and human activities. Our findings revealed time-dependent interannual variability in strandings but no linear trend, indicating relative stability in cetacean strandings. Seasonal patterns were observed only in narrow-ridged finless porpoises (Neophocaena asiaeorientalis), with significant spring increases (March to May). Clustering of strandings occurred in central Fujian and northern/southern Taiwan, according to spatial analysis. The impact of variables on cetacean strandings varied across time periods. Storm surges, coastal fishing, and the Pacific decadal oscillation were associated with stranding events from 1990 to 2006. However, from 2006 to 2021, the influence of storm surges weakened, while the climate index only indirectly affected strandings through sea surface temperature and salinity, with an increased intensity in the effects of winter sea surface temperature and salinity. Structural equation models unveiled the cascading effects of environmental changes on strandings. This study reports changing trends in cetacean strandings and identifies relevant variables. Although not exhaustive, understanding the reasons behind strandings enhances our comprehension of cetacean responses to environmental changes, supporting targeted conservation and management efforts.

Neuroblastoma is the most common extracranial solid tumor in children. Patients with neuroblastoma have a poor prognosis. The development of therapy targets and the ability to predict prognosis will be enhanced through further exploration of the genetically related genes of neuroblastoma. The present investigation utilized CRISPR-Cas9 genome-wide screening based on the DepMap database to determine essential genes for neuroblastoma cells’ continued survival. WGCNA analysis was used to determine the progression-related genes, and a prognostic signature was constructed. The signature gene, NCAPG, was downregulated in neuroblastoma cells to explore its impact on various cellular processes. This research used DepMap and WGCNA to pinpoint 45 progression-related essential genes for neuroblastoma. A risk signature comprising NCAPG and MAD2L1 was established. The suppression of NCAPG prevented neuroblastoma cells from proliferating, migrating, and invading. The results of flow cytometric analysis demonstrated that NCAPG inhibition caused cell cycle arrest during the G2 and S phases and the activation of apoptosis. Additionally, NCAPG downregulation activated the p53-mediated apoptotic pathway, inducing cell apoptosis. The present work showed that NCAPG knockdown reduced neuroblastoma cell progression and may serve as a basis for further investigation into diagnostic indicators and therapy targets for neuroblastoma.

The lack of a direct and linear relation between inclusion removal from tundishes and the design of their turbulence inhibitors is a difficult challenge. In contrast to the traditional method of optimizing flow control devices based on the residence time distribution curve, this study used the inclusion/flow field database production clustering mining algorithm to conduct step-by-step data mining on the tundish flow field; to produce relevant facts of the flow field characteristics in the inclusion aggregation zone; and to extract the data mining results from the fact database to screen a digital twin algorithm that forecasts the inclusion aggregation area in a tundish to optimize the flow control device. The results showed that the inclusion aggregation area in the tundish impact zone is above the turbulence inhibitor and that the inclusion aggregation area outside the tundish impact zone is at the vortex center of the flow field. According to the mining results, a pseudo-code for screening the inclusion aggregation area was developed, and the turbulence inhibitor was optimized with the help of the digital convergence of the digital and physical models. Finally, in a tundish, the inclusion removal rate in molten steel was increased by 14.4%. The turbulence inhibitor designed by the digital twin method is currently being used in a Chinese steel mill.

Sea cucumber peptides have been proven to exhibit a variety of biological activities. Ulcerative colitis (UC) is a chronic disease characterized by diffuse inflammation of the mucosa of the rectum and colon with increasing incidence and long duration, and is difficult to cure. The effect of sea cucumber peptide on UC is currently unknown. In this study, 1.5% dextran sulfate sodium (DSS) was added to the drinking water of mice to induce a UC model, and the daily doses of sea cucumber peptide (SP) solution of 200 mg/kg·BW, 500 mg/kg·BW, and 1000 mg/kg·BW were given to UC mice to detect the relieving effect of SP. The results showed that SP can reduce the disease activity index (DAI) of UC mice induced by DSS and can alleviate colon shortening, intestinal tissue damage, and the loss of intestinal tight junction proteins (Claudin-1, Occludin). SP decreased the spleen index, pro-inflammatory factors (IL-1β, IL-6, TNF-α), and myeloperoxidase (MPO) levels in UC mice. SP can alleviate the imbalance of gut microbiota in UC mice, increase the abundance of the Lachnospiraceae NK4A136 group, Prevotellaceae UCG-001, and Ligilactobacillus, and reduce the abundance of Bacteroides and the Eubacterium rum group, as well as alleviating the decrease in short-chain fatty acid (SCFA) content in the feces of UC mice. Notably, SP inhibited miR-155 expression in the colon tissue of UC mice and increased its target protein, suppressor of cytokine signaling 1 (SOCS1), which acts as an inflammatory inhibitor. In summary, the ameliorative effect of SP on UC may be achieved by improving the imbalance of gut microbiota and regulating the miR-155/SOCS1 axis. This study provides a new idea for developing SP as a nutritional supplement to maintain intestinal health.

Abstract Background PTEN is one of the most frequently mutated genes in human cancer. Although the roles of canonical PTEN protein and PTEN isoforms have been extensively explored, the current understanding of PTEN family members cannot fully illustrate the diversity of their roles in biological processes and tumor development. Notably, the function of noncoding RNAs arising from PTEN has been less elucidated. Methods We searched circBase and circInteractome to analyze the potential of PTEN for generating circRNAs. Then, Sanger sequencing, RNase R and Actinomycin D assays were used to verify the ring structure of circPTEN1. In situ hybridization and qRT-PCR were used to determine the level of circPTEN1 in peritumor and tumor tissues of colorectal cancer (CRC). Furthermore, functional experiments, including Transwell assay, 3D multicellular tumor spheroid invasion assay and metastasis models, were performed using circPTEN1 knockdown and overexpression cell lines in vitro and in vivo to investigate the effects of circPTEN1 on tumor metastasis in CRC. Mechanistically, luciferase reporter assay, fluorescence in situ hybridization, electrophoretic mobility shift assay, RNA immunoprecipitation, RNA pull-down and mass spectrometry were executed. Results We identified a circular RNA generated from the PTEN gene, designated circPTEN1, that is frequently downregulated in colorectal cancer, and decreased expression of circPTEN1 predicts poor survival. Low expression of circPTEN1 promotes metastasis in PDX models in vivo and accelerates cancer cell invasion in vitro, whereas overexpression of circPTEN1 reveals opposite roles. Mechanically, we found that circPTEN1 is capable of binding the MH2 domain of Smad4 to disrupt its physical interaction with Smad2/3, which reduces the formation and subsequent nucleus translocation of Smad complexes and consequently suppresses the expression of its downstream genes associated with epithelial-mesenchymal transition upon TGF-β stimulation. Furthermore, we found that eIF4A3 suppresses the cyclization of circPTEN1 by directly binding to the circPTEN1 flanking region. Conclusions Our study uncovered a novel PTEN gene-generated circRNA with a tumor suppression function, and further revealed the mechanism of circPTEN1 in CRC metastasis mediated by TGF-β. The identification of circPTEN1 provides a new direction for PTEN investigation, and elucidation of circPTEN1/TGF-β/Smad signaling may pave the way for the development of a potential therapeutic strategy for the suppression of cancer progression.

Abstract Background The combined positive score (CPS) of the programmed death ligand‐1 (PD‐L1) 22C3 assay is a predictive marker of pembrolizumab monotherapy for advanced esophageal cancer (EC) patients. However, little is known about the association of the PD‐L1 22C3 CPS with the clinicopathological features and heterogeneity of PD‐L1 expression in EC in the Chinese population in a real‐world setting. Methods We examined the association of the PD‐L1 22C3 CPS with clinicopathological characteristics in 533 EC specimens. Further, we compared 37 cases' different blocks of the same specimen and 50 paired primary/metastatic lymph node lesions to investigate the heterogeneity of PD‐L1 expression. Results PD‐L1 positive expression was observed in 45.0% of 533 EC patients, including 46.8% with squamous cell carcinoma, 15.4% with adenocarcinoma, 28.6% with basaloid squamous carcinoma, 42.9% with spindle cell carcinoma, and 33.3% with neuroendocrine tumors. PD‐L1 positive expression was positively associated with lymph node metastasis (59.2% chance, p = 0.021) and venous/lymphatic invasion (66.3% chance, p = 0.029). PD‐L1 expression was highly consistent in different paraffin blocks of the same surgically resected specimen (concordance rate: 86.5%, p = 0.000016) and a moderate consistency (concordance rate: 78.0%, p = 0.000373) for the primary and metastatic lymph node lesion comparison. Conclusions This is a novel study which demonstrated a positive correlation between a high PD‐L1 22C3 CPS and invasion/metastasis risk in EC surgical specimens. Both paired blocks and paired primary/metastatic lymph node lesions showed significant concordance. PD‐L1 heterogeneity was inferred to be mainly related to positive mononuclear inflammatory cells (MICs), which might have substantial implications for clinical practice.

Abstract Background and aims Inflammation plays a key role in the initiation and progression of atrial fibrillation (AF). The systemic inflammation indexes are easily evaluated and predict AF development. However, it’s role in prediction of recurrence of AF is unknown. We aim to explore the association between the systemic inflammation indexes and recurrence of AF in patients underwent cryoablation (CryoMaze) concomitant with mitral valve surgery. Methods We examined systemic inflammation indexes during perioperative period in 122 patients between 2015 and 2018. Systemic inflammation indexes were developed by systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocytes to monocytes ratio. Univariate and multivariate analyses were performed to examine the association of each markers with recurrence of AF. Results Of the 122 patients included in this study, 22 patients (18%) experienced AF recurrence after CryoMaze concomitant with mitral valve surgery. There is no significant difference between each systemic inflammation indexes before surgery and recurrence of AF. In univariate analysis, MLR after surgery 3 days, PLR, MPLR, NLR, SII after surgery 7 days were able to predict recurrence of AF. In multivariate analyses, SII ≥ 1696 independently predicted recurrence (OR, 3.719; 95% CI, 1.417–9.760). Interestingly, baseline SII showed no significant in prediction of recurrence. It was sharply elevated after surgery and dropped slowly. In patients of recurrence, SII after 7 days of surgery increased again. Conclusions The raised SII again was associated with an increased risk of the postoperative recurrence of AF and independently predicted the late recurrence of AF after CryoMaze concomitant with mitral valve surgery.

Bacterial infection is one of serious problems hindering tissue regeneration, but strategies able to perform proper antibiosis with spatiotemporal controllability to manipulate the local inflammation and immunity for effective healing of infected wound is still a challenge. Herein, we fabricated a smart hydrogel (CNMs@HA-PDA-PL) with multiple responsiveness to near infrared radiation, visible light, hyaluronidase and hydrogen peroxide for promoted healing of the infected wound via controllable anti-bacteria at designed locations and time periods as well as the on-demand regulation of local inflammation and immunity. The hydrogel consists of hyaluronic acid (HA) modified graphitic carbon nitride (g-C3N4) microsphere (CNMs), antimicrobial peptides (ε-Poly-l-lysine, ε-PL) and polydopamine (PDA). The PDA framework and CNMs respectively serve as photothermal agent and photodynamic agent to generate heat and radical for instant damage of major bacteria on/surrounding the hydrogel, while the ε-PL is in charge of the sustained antibiosis in long term to eliminate the deep bacteria away from the hydrogel via biochemical process. Once the hydrogel was located at infected area, the over-expressed hyaluronidase and hydrogen peroxide would sequentially spread CNMs and ε-PL to start photodynamic therapy and biochemical therapy in designed range after initial photothermal therapy, resulting in synergistic antibiosis with spatiotemporal controllability. This stepwise anti-bacteria process meanwhile manipulated the local inflammatory microenvironment to promote tissue regeneration, in which the hydrogel gradually performed effective recruitment of inflammatory (M1) macrophages and continuous phenotypic transition of these M1 macrophages toward pro-reparative (M2) macrophages, leading to a rapid healing of the infectious cutaneous wound.

Abstract Recent developments in 3D-printing technology have provided a time-efficient and inexpensive alternative to the fabrication of microfluidic devices. At present, 3D-printed microfluidic systems face the challenges of post-processing, non-transparency, and being time consuming, limiting their practical application. In this study, a time-efficient and inexpensive fabrication method was developed for 3D-printed microfluidic devices. The material for 3D-printed microfluidic chips is Dowsil 732, which is used as a sealant or encapsulant in various industries. The curing time and surface hydrophobicity of the materials were evaluated. The results indicated that the surface of Dowsil 732 is hydrophilic. An optimization model of the direct ink writing method is proposed to establish a time-efficient and accurate fabrication method for microfluidic devices. The results indicate that the optimization model can effectively describe the change trend between printing speed, printing pressure, and channel wall accuracy, and the model accuracy rate exceeds 95%. Three examples—a micromixer, concentration gradient generator, and droplet generator—were printed to demonstrate the functionality and feasibility of the fabrication method.

Chinese yam polysaccharide (CYP) has received attention in recent years owing to its positive nutritional and medicinal characteristics. Copper is an essential trace metal in animals, which plays an important role in iron absorption and hemoglobin synthesis. However, no published study has evaluated Chinese yam polysaccharide copper complex (CYP-Cu) as a dietary additive in broilers. This study was conducted to investigate the effects of dietary CYP-Cu on growth performance, immunity, and oxidative resistance in broilers. A total of 360 1-day-old 817 broiler chickens were randomly divided into 4 groups, with 3 replicates of 30 birds each and were fed a basal diet with the addition of 0 (control group), 0.02, 0.10, and 0.50 g/kg CYP-Cu. The feeding trial lasted 48 days. On day 28 and day 48, 6 broilers in each group were slaughtered, respectively. Then the parameters of growth and carcass, serum biochemistry, immunity, and antioxidation, and the expression level of hepatic antioxidative genes were investigated. The results showed that compared with the control group, the supplementation of dietary CYP-Cu could improve the indexes of the growth, carcass, serum biochemistry, immunity and oxidation resistance in broilers, such as average daily gain (ADG), the slaughter percentage (SP), semi-evisceration weight percentage (SEWP), eviscerated carcass weight percentage (EWP), breast muscle percentage (BMP), leg muscle percentage (LMP), serum albumin (ALB), high density lipoprotein (HDL), insulin-like growth factor I (IGF-I), triiodothyronine (T3), thyroxine (T4), growth hormone (GH), insulin (INS), immunoglobulin M (IgM), immunoglobulin G (IgG), immunoglobulin A (IgA), interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 6 (IL-6), complement 3 (C3), complement 4 (C4), total superoxide dismutase (T-SOD), total antioxidative capacity (T-AOC), glutathione peroxidase (GSH-Px), and glutathione s-transferase (GSH-ST); these parameters in the 0.10 g/kg CYP-Cu treated group were significantly increased (P < 0.05) in the total trial period, with the exceptions that feed conversion ratio (FCR) and serum low density lipoprotein (LDL), malondialdehyde (MDA) were decreased in the total trial period. In addition, the antioxidative gene mRNA expression of Nuclear factor E2-related factor 2 (Nrf2), Superoxide dismutase 1 (SOD1), Superoxide dismutase 2 (SOD2), and Catalase (CAT) were upregulated in the liver (P < 0.05). These results indicated that the supplementation of dietary CYP-Cu improved the growth, immunity, and oxidation resistance of broilers, and the addition of 0.10 g/kg CYP-Cu in broiler diets is recommended, which suggests that CYP-Cu may be a promising green feed additive in the poultry industry.

Vitamin B6 (VB6) exhibits therapeutic effects towards autism spectrum disorder (ASD), but its specific mechanism is poorly understood. Rat dams were treated with VB6 standard, VB6 deficiency, or VB6 supplementary diet, and the same treatment was provided to their offspring, with their body weights monitored. Three-chambered social test and open field test were employed to evaluate the effect of VB6 on autism-like behaviors. Gamma-aminobutyric acid (GABA) generation and synaptic inhibition of neurons in the hippocampus of rat were detected via immunofluorescence staining, followed by the measurement of GABA concentration through high-performance liquid chromatography (HPLC). The role of VB6 in the autophagy and apoptosis of cells was determined via Western blot and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL). In order to conduct rescue experiments, the inhibition of mammalian target of rapamycin (mTOR) or the activation of GABA was achieved by drug administration to the offspring rats with VB6 deficiency. As a result, no evident difference in weight was observed in the offspring with varied VB6 treatments. VB6 deficiency impaired social interaction; aggravated self-grooming and bowel frequency; decreased GABA concentration, VIAAT, GAD67, vGAT expressions, and LC3 II/LC3 I ratio; increased p62 level and p-mTOR/mTOR ratio; and promoted cell apoptosis. Inhibition of mTOR reversed the effect of VB6 deficiency on cell autophagy. GABA activation or mTOR inhibition offset the role of VB6 deficiency in autism-like behaviors and hippocampal GABA expression. Collectively, VB6 deficiency induces autism-like behaviors in rats by regulating mTOR-mediated autophagy in the hippocampus.

ObjectiveThis study aimed to analyze the association between the activity of daily living (ADL), coronavirus disease (COVID-19), and the value of the Barthel Index in predicting the prognosis of patients.MethodsThis study included 398 patients with COVID-19, whose ADL at admission to hospital were assessed with the Barthel Index. The relationship between the index and the mortality risk of the patients was analyzed. Several regression models and a decision tree were established to evaluate the prognostic value of the index in COVID-19 patients.ResultsThe Barthel Index scores of deceased patients were significantly lower than that of discharged patients (median: 65 vs. 90, P < 0.001), and its decrease indicated an increased risk of mortality in patients (P < 0.001). After adjusting models for age, gender, temperature, pulse, respiratory rate, mean arterial pressure, oxygen saturation, etc., the Barthel Index could still independently predict prognosis (OR = 0.809; 95% CI: 0.750–0.872). The decision tree showed that patients with a Barthel Index of below 70 had a higher mortality rate (33.3–40.0%), while those above 90 were usually discharged (mortality: 2.7–7.2%).ConclusionThe Barthel Index is of prognostic value for mortality in COVID-19 patients. According to their Barthel Index, COVID-19 patients can be divided into emergency, observation, and normal groups (0–70; 70–90; 90–100), with different treatment strategies.

Pain is commonly comorbid with anxiety; however, the neural and molecular mechanisms underlying the comorbid anxiety symptoms in pain (CASP) have not been fully elucidated. In this study, we explored the role of acid-sensing ion channel 1a (ASIC1a), located in GABAergic neurons from the central nucleus of the amygdala (GABACeA), in the regulation of CASP in an acute pain mouse model. We found that the mice displayed significant mechanical pain sensitization and anxiety-like behaviors one day post injection of complete Freud’s adjuvant (CFA1D). Electrophysiological recordings from acute brain slices showed that the activity of GABACeA neurons increased in the CFA1D mice compared with that in the saline mice. In addition, chemogenetic inhibition of GABACeA neurons relieved mechanical pain sensitization and anxiety-like behaviors in the CFA1D mice. Interestingly, through pharmacological inhibition and genetic knockdown of ASIC1a in the central nucleus amygdala, we found that downregulation of ASIC1a relieved the hypersensitization of mechanical stimuli and alleviated anxiety-related behaviors, accompanied with reversing the hyperactivity of GABACeA neurons in the CFA 1D mice. In conclusion, our results provide novel insights that ASIC1a in GABACeA neurons regulates anxiety-like behaviors in a mouse model of acute pain.

Psychological stress emerges to be a common health burden in the current society for its highly related risk of mental and physical disease outcomes. However, how the quickly-adaptive stress response process connects to the long-observed organismal alterations still remains unclear. Here, we investigated the profile of circulatory extracellular vesicles (EVs) after acute stress (AS) of restraint mice by phenotypic and proteomic analyses. We surprisingly discovered that AS-EVs demonstrated significant changes in size distribution and plasma concentration compared to control group (CN) EVs. AS-EVs were further characterized by various differentially expressed proteins (DEPs) closely associated with biological, metabolic and immune regulations and were functionally important in potentially underlying multiple diseases. Notably, we first identified the lipid raft protein Stomatin as an essential biomarker expressed on the surface of AS-EVs. These findings collectively reveal that EVs are a significant function-related liquid biopsy indicator that mediate circulation alterations impinged by psychological stress, while also supporting the idea that psychological stress-associated EV-stomatin can be used as a biomarker for potentially predicting acute stress responses and monitoring psychological status. Our study will pave an avenue for implementing routine plasma EV-based theranostics in the clinic.

In view of the disadvantages of the traditional environmental monitoring system, such as high power consumption, high maintenance cost and no real-time monitoring, an environmental temperature and humidity monitoring system based on narrow band Internet of things (NB-IoT) technology was developed, which is mainly controlled by singlechip microcomputer.The work flow of the main controller and the working mode of the communication module were optimized to reduce the power consumption of the system.NB-IoT communication technology was utilized for data transmission to the cloud platform through the base station and core network.China Mobile IoT open platform (OneNET platform) was adopted to achieve the connection between the terminal device and the application, and expanded functions provided by the platform was used to design a mobile phone application to achieve the remote real-time monitoring of environmental parameters and improve the user’s convenience.

Background: The rapid spread of C. difficile 027 has become one of the leading threats of healthcare-associated infections wordwild. However, C. difficile 027 infections have rarely been reported in China. The objective of this study was to strengthen the understanding of the molecular characterizations of C. difficile 027 in China. Methods: In this study, stool specimens from 176 suspected CDI cases were collected from 1 Jan 2018 to 30 Jun 2019. These specimens were measured by GeneXpert test and C.difficile colonies were identified and analyzed. Results: There were five samples positive for tcdA, tcdB, binary toxin genes and had deletions in tcdC gene. These five Clostridioides difficile isolates belonged to ST1 and confirmed as Clostridioides difficile 027 strains by PCR ribotyping. Through using whole genome sequencing, , we found that these five strains were closely clustered into the same predominant evolutionary branch and were highly similar to C. difficile 027 strain R20291. Antimicrobial susceptibility testing result showed they were highly resistant to fluoroquinolones. Conclusions: In Our study, five C. difficile 027 isolates were identified and characterized using MLST, PCR ribotyping and whole genome sequencing. We proposed that C. difficile 027 infections are probably neglected in China. Further epidemiological studies across the country together with the introduction of routine diagnostic testing and multi-center or national level surveillance are needed to ascertain the size of this potentially significant problem.

Remifentanil-induced hyperalgesia (RIH) is a severe but common postoperative clinical problem with elusive underlying neural mechanisms. Here, we discovered that glutamatergic neurons in the thalamic ventral posterolateral nucleus (VPLGlu) exhibited significantly elevated burst firing accompanied by upregulation of Cav3.1 T-type calcium channel expression and function in RIH model mice. In addition, we identified a glutamatergic neuronal thalamocortical circuit in the VPL projecting to hindlimb primary somatosensory cortex glutamatergic neurons (S1HLGlu) that mediated RIH. In vivo calcium imaging and multi-tetrode recordings revealed heightened S1HLGlu neuronal activity during RIH. Moreover, preoperative suppression of Cav3.1-dependent burst firing in VPLGlu neurons or chemogenetic inhibition of VPLGlu neuronal terminals in the S1HL abolished the increased S1HLGlu neuronal excitability while alleviating RIH. Our findings suggest that remifentanil induces postoperative hyperalgesia by upregulating T-type calcium channel-dependent burst firing in VPLGlu neurons to activate S1HLGlu neurons, thus revealing an ion channel–mediated neural circuit basis for RIH that can guide analgesic development.

Chronic pain is a disease of long-lasting pain with unpleasant feelings mediated by central and (or) peripheral sensitization, its duration usually lasts more than 3 months or longer than the expected recovery time. The patients with chronic pain are manifested with enhanced sensitivity to noxious and non-noxious stimuli. Due to an incomplete understanding of the mechanisms, patients are commonly insensitive to the treatment of first line analgesic medicine in clinic. Thus, the exploration of non-opioid-dependent analgesia are needed. Recent studies have shown that “sinomenine,” the main active ingredient in the natural plant “sinomenium acutum (Thunb.) Rehd. Et Wils,” has a powerful inhibitory effect on chronic pain, but its underlying mechanism still needs to be further elucidated. A growing number of studies have shown that various immune cells such as T cells, B cells, macrophages, astrocytes and microglia, accompanied with the relative inflammatory factors and neuropeptides, are involved in the pathogenesis of chronic pain. Notably, the interaction of the immune system and sensory neurons is essential for the development of central and (or) peripheral sensitization, as well as the progression and maintenance of chronic pain. Based on the effects of sinomenine on immune cells and their subsets, this review mainly focused on describing the potential analgesic effects of sinomenine, with rationality of regulating the neuroimmune interaction.

IntroductionGangliosides play an essential role in cancer development and progression. However, the involvement of gangliosides in the prognosis and tumor microenvironment (TME) of neuroblastoma is not entirely understood.MethodsConsensus clustering analysis was performed to identify ganglioside-mediated molecular subtypes. LASSO-Cox analysis was conducted to identify independent prognostic genes, and a novel risk signature was constructed. The risk signature was validated internally and externally. We further explored the independent prognosis value, immune landscape, drug susceptibility, and tumor dedifferentiation of the risk signature. The role of the signature gene B3GALT4 in neuroblastoma was explored in vitro.ResultsSeventeen ganglioside-related genes were differentially expressed between INSS stage 4 and other stages, and two ganglioside-related clusters with distinct prognoses were identified. A novel risk signature integrating ten ganglioside-related prognostic genes was established. Across the train set and external validation sets, the risk signature presented high predictive accuracy and discrimination. The risk signature was an independent prognostic factor and constructed a nomogram combining multiple clinical characteristics. In the high-score group, the deficiency in antigen processing and presenting machinery, lack of immune cell infiltration, and escaping NK cells contributed substantially to immune escape. The low-score group was more responsive to immune checkpoint blockade therapy, while the high-score group showed substantial sensitivity to multiple chemotherapeutic drugs. Besides, the risk score was significantly positively correlated with the stemness index and reduced considerably in all-trans retinoic acid-treated neuroblastoma cell lines, indicating high dedifferentiation in the high-score group. Additionally, neuroblastoma cells with downregulation of B3GALT4 present with increased proliferation, invasion, and metastasis abilities in vitro.ConclusionThe novel ganglioside-related risk signature highlights the role of ganglioside in neuroblastoma prognosis and immune landscape and helps optimize chemotherapy and immunotherapy for neuroblastoma.

Summary: Apoptotic vesicles (apoVs) are specific extracellular vesicles generated during apoptosis and play important roles in multiple physiological and pathophysiological settings. Here, we present a protocol using differential centrifugation to separate apoVs from human mesenchymal stem cells (MSCs) after induction of apoptosis. We describe how to characterize apoV size and morphology by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM), and determination of specific biomarker expression by immunoblotting. Our protocol will be useful for preparing apoVs for further functional analysis.For complete details on the use and execution of this protocol, please refer to Zheng et al. (2021). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Summary: Glioma-associated oncogene homolog 1 (Gli1) marks a subpopulation of endogenous mesenchymal stem cells (MSCs) characterized by perivascular location. Here, we present an optimized immunofluorescence staining protocol to identify resident Gli1+ MSCs in fixed/frozen bone sections from LacZ transgenic mice. This protocol describes the preparation of fixed/frozen tissue sections and the use of LacZ immunofluorescent staining for the in vivo characterization of endogenous MSCs, regarding their specific identity and specialized niches, and is applicable to LacZ-expressing cells of diverse organs.For complete details on the use and execution of this protocol, please refer to Chen et al. (2020). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Objective To explore the sensitivity of median and ulnar nerve sensory latency differences in diagnosing carpal tunnel syndrome (CTS) at different severities. Methods CTS patients were divided into three groups based on disease severity (mild, moderate, and severe). Distal latency of sensory nerve action potential (SNAP) for the median and ulnar nerves was recorded. The sensitivity of SNAP distal latency to CTS and its correlation with CTS severity were analyzed. Results Significant differences were found in the median nerve sensory action potential distal latency (MSDL) and in the median and ulnar sensory latency difference to ring finger (MUD) but not in the ulnar nerve sensory action potential distal latency (USDL) between CTS and control. The sensitivity and specificity were 92.2 and 99.4% with an MSDL cutoff value of 2.40 ms, respectively, and were both 100% with a MUD cutoff value of 0.33 ms. There was no significant difference in USDL among the CTS and control groups. Significant differences were found in MSDL and MUD among the CTS severities and between mild and moderate CTS, but not between mild and severe CTS or between moderate and severe CTS. Correlations with CTS severity were observed for MSDL and MUD but not for USDL. Conclusion The ulnar nerve of the CTS patients was not damaged. A smaller MSDL reflected median nerve damage, which can be used for the early diagnosis of CTS. MUD correlated with CTS severity with a higher sensitivity than MSDL, which can provide therapeutic insight without pain to patients.

Abstract Background It has been noticed for years that ultrafiltration (UF) is important for survival in peritoneal dialysis. On the other hand, precise and convenient UF measurement suitable for patient daily practice is not as straight forward as it is to measure UF in the lab. Both overfill and flush before fill used to be source of measurement error for clinical practice. However, controversy finding around UF in peritoneal dialysis still exists in some situation. The current study was to understand the difference between clinical measured UF and real UF. The effect of evaporation and specific gravity in clinical UF measurement were tested in the study. Methods Four different brands of dialysate were purchased from the market. The freshest dialysate available in the market were intentionally picked. The bags were all 2 L, 2.5% dextrose and traditional lactate buffered PD solution. They were stored in four different conditions with controlled temperature and humidity. The bags were weighted at baseline, 6 months and 12 months of storage. Specific gravity was measured in mixed 24 h drainage dialysate from 261 CAPD patients when they come for their routine solute clearance test. Results There was significant difference in dialysate bag weight at baseline between brands. The weight declined significantly after 12 month’s storage. The weight loss was greater in higher temperature and lower humidity. The dialysate in non-PVC package lose less weight than PVC package. The specific gravity of dialysate drainage was significantly higher than pure water and it was related to dialysate protein concentration. Conclusion Storage condition and duration, as well as the type of dialysate package have significant impact in dialysate bag weight before use. Evaporation is likely to be the reason behind. The fact that specific gravity of dialysate drainage is higher than 1 g/ml overestimates UF in manual exchanges, which contributes to systemic measurement error of ultrafiltration in CAPD. Trial registration ClinicalTrials.gov ID: NCT03864120 (March 8, 2019) (Understand the Difference Between Clinical Measured Ultrafiltration and Real Ultrafiltration).

Estrogen deficiency is one of the most frequent causes of osteoporosis in postmenopausal women. Under chronic inflammatory conditions caused by estrogen deficiency, activated T cells contribute to elevated levels of proinflammatory cytokines, impaired osteogenic differentiation capabilities of bone marrow mesenchymal stem cells (BMMSCs), and disturbed regulatory T cell (Treg)/Th17 cell balance. However, therapeutic strategies that re-establish immune homeostasis in this disorder have not been well developed. Here, we produced T cell-depleting nanoparticles (TDNs) that ameliorated the osteopenia phenotype and rescued the osteogenic deficiency of BMMSCs in ovariectomized (OVX) mice. TDNs consist of monocyte chemotactic protein-1 (MCP-1)-encapsulated mesoporous silica nanoparticles as the core and Fas-ligand (FasL) as the corona. We showed that the delicate design of the TDNs enables rapid release of MCP-1 to recruit activated T cells and then induces their apoptosis through the conjugated FasL both in vitro and in vivo. Apoptotic signals recognized by macrophages help skew the Treg/Th17 cell balance and create an immune tolerant state, further attenuating the osteogenic deficiency of BMMSCs and the osteopenia phenotype. Mechanistically, we found that the therapeutic effects of TDNs were partially mediated by apoptotic T cell-derived extracellular vesicles (ApoEVs), which promoted macrophage transformation towards the M2 phenotype. These findings demonstrate that TDNs may represent a promising strategy for treating osteoporosis and other immune disorders.

Abstract Cervical adenocarcinoma is an important disease that affects young women and it has a high mortality and poor prognosis. Denticleless E3 ubiquitin protein ligase homolog (DTL) gene with oncogenic function has been evaluated in several cancers. Through this study, we aimed to clarify the clinical and molecular characteristics of cervical adenocarcinoma involving overexpression of DTL and elucidate its molecular mechanism. Bioinformatics analysis was performed through multiple databases. RNA sequencing was used to obtain differentially expressed genes after DTL was overexpressed in cells. The role of DTL in cervical adenocarcinoma was explored through in vitro and in vivo experiments. We found that DTL has an unfavorable prognostic implication for patients with cervical adenocarcinoma. Overexpression of DTL induced the migration and invasion of tumor cells in vitro and promoted intra-pulmonary metastasis in vivo. In addition, DTL activated JNK through RAC1 and upregulated FOXO1 to induce epithelial–mesenchymal transition, and the migration and invasion of tumor cells. Therefore, we conclude that overexpression of DTL enhanced cell motility and promoted tumor metastasis of cervical adenocarcinoma by regulating the RAC1-JNK-FOXO1 axis. These results suggest that DTL may become a potential therapeutic target for antitumor metastasis of cervical adenocarcinoma.

Abstract The effective production of shale oil is important for the cost‐effectiveness in the oil and gas industry. Oil price volatility and uncertainty require suitable hydraulic fracturing schemes to maximize production and to minimize fracturing costs. Since the reduction of fracture stage saves bridge plugs and fracturing costs, it is considered as a possible method to improve the cost‐effectiveness. To maintain the stimulated reservoir volume, cluster numbers per stage are consequently increased, which may induce nonuniform fracture propagation and interference which affects the stimulation efficiency. This study conducts a comparative study for single‐stage (reduced) and two‐stage (not reduced) fracturing schemes with the same fracturing fluid volume. Reservoir geomechanics and rock mechanics analyses are conducted for Jimsar shale oil in north‐western China with a single‐stage multicluster fracturing model established. Fracture geometries and key factors are investigated followed by the evaluation of the fractured well production. The relationship between multicluster parameters and production is quantified. Meanwhile, two‐stage fracturing modeling is also set up to compare with single‐stage fracturing modeling. Fracturing results show that although single‐stage fracturing results in nonuniform fracture propagation, the overall stimulation is satisfactory. Production results show that the nonuniform growth of fracture clusters leads to different contributions to the production from individual clusters and the production from inner fractures is significantly inhibited. Compared with two‐stage fracturing with the same pumping volume, it is found out that single‐stage fracturing can lead to cost‐effective horizontal well production in Jimsar shale oil given certain values of hydraulic fracturing costs, and the reduced stage scheme is preferable in low oil price and high uncertainty scenarios.

Yearly administration of influenza vaccine with recommendations can help control seasonal influenza epidemics in adults aged ≥60 years. Here, we describe the results of a prospective study observing the immunogenicity and persistence of induced immunity of a trivalent inactivated split-virion influenza vaccine (TIV) in adults aged ≥60 years during the 2018–2019 season in Taizhou City, Zhejiang Province in China. A total of 422 participants completed the study period. Vaccinated participants (284) received a single dose of TIV, but unvaccinated participants (138) didn’t receive any vaccine. Study participants vaccinated with TIV had significantly higher GMTs of Hemagglutination Inhibition (HI) antibodies against AH1N1, AH2N3, and B/Victoria strains (all p

Research on noncoding ribonucleic acids (ncRNAs) is mostly and broadly focused on microRNAs (miRNAs), cyclic RNAs (circRNAs), and long ncRNAs (lncRNAs), which have been confirmed to play important roles in tumor cell proliferation, invasion, and migration. Specifically, recent studies have shown that ncRNAs contribute to tumorigenesis and tumor development by mediating changes in enzymes related to lipid metabolism. The purpose of this review is to discuss the characterized ncRNAs involved in the lipid metabolism of tumors to highlight ncRNA-mediated lipid metabolism-related enzyme expression in malignant tumors and its importance to tumor development. In this review, we describe the types of ncRNA and the mechanism of tumor lipid metabolism and analyze the important role of ncRNA in tumor lipid metabolism and its future prospects from the perspectives of ncRNA biological function and lipid metabolic enzyme classification. However, several critical issues still need to be resolved. Because ncRNAs can affect tumor processes by regulating lipid metabolism enzymes, in the future, we can study the unique role of ncRNAs from four aspects: disease prevention, detection, diagnosis, and treatment. Therefore, in the future, the development of ncRNA-targeted therapy will become a hot direction and shoulder a major task in the medical field.

In the year of 2016 to 2017, record-breaking marine heatwave (MHW) events occurred along the Chinese coast, exerting severe impacts on coastal fishes and fisheries. However, the response of the nekton community to MHW events still remains poorly understanding. Thus, to investigate the influences of the MHW events on species composition dynamics, this study conducted a survey on nekton communities in the northern East China Sea in the summers during 2014 to 2017. The recently-developed “heatwaveR” package was adopted to describe the variation characteristics of heatwaves within the study area, based on high-resolution remote-sensing sea surface temperature products. We also compared variations in the community structures of different biological groups before (2014–2015) and during the occurrence of the MHW events (2016–2017). During the MHW events, temperature increased by approximately 2.3°C in both 2016 and 2017. Compared with those before the MHW events, the biomass and dominance of several important crustaceans decreased, and the biomass of warm water affinity species increased significantly, while their richness and diversity decreased; the biomass of warm temperature affinity species declined significantly, while their diversity increased slightly. These results show the difference in the response rates of species with different thermal preferences and different species compositions to the extreme climate change. Beta diversity analysis revealed that the inter-group variation before and during the MHW event exceeded the intra-group variation, proving that MHWs changed the community structure to a certain extent. PERMANOVA test showed that the species compositions of planktivorous fish (FG1) and small-omnivorous fish (FG2) in the feeding-functional groups were significantly different before and during the MHW event, which may be attributed to the impact of MHWs on oligotrophic fishes through thermal preference and the trophic cascade effect. There was no significant change in the species compositions of other functional groups, indicating that medium-trophic and eutrophic fishes possessed certain adaptability to MHWs. Regarding fisheries management under extreme warming events, it would be advisable to diagnose temperature anomalies in the early stage, monitor changes in species abundance in the early life cycle, and then rapidly develop suitable fishing strategies.

Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies and exhibits a high rate of relapse and unfavorable outcomes. Ferroptosis, a relatively recently described type of cell death, has been reported to be involved in cancer development. However, the prognostic value of ferroptosis-related genes (FRGs) in AML remains unclear. In this study, we found 54 differentially expressed ferroptosis-related genes (DEFRGs) between AML and normal marrow tissues. 18 of 54 DEFRGs were correlated with overall survival (OS) (P

Backward-in-time Lagrangian model can identify potential spawning areas by reconstructing egg drift trajectories, contributing to accurately designing potential priority conservation plans for spawning areas. In this study, we apply this approach to investigate the small yellow croaker (Larimichthys polyactis) with commercial value in China. A two-step spatial random forest (RF) model is used to predict the occurrence probability and abundance of their eggs and describe the optimal ecological range of environmental factors. A priority protection index (BPPI) of the spawning areas is established by combining the sites with the optimal occurrence and abundance and integrating backward tracking pathways. The result indicates that the model with 1-2 day time lags of environmental variables shows the optimum explanatory power. Temperature and salinity are the most important factors affecting oogenesis and show a regime shift in the response curve. They reflect the physiological regulation of parental sexual maturation by the environment. In addition, egg abundance correlates more strongly with chlorophyll-a (Chl a) concentration and depth, suggesting that parents prefer environments with shallow water and high prey density for spawning activities. The egg retrieval shows that the potential spawning sources are distributed near the southeastern part of the oogenesis site, with a maximum egg dispersal distance of no more than 30 km. This finding confirms that the coastal regions of Jiangsu Province are an important spawning ground for the small yellow croaker, making a significant contribution to the productivity and resilience of the fish.

To aid in addressing global climate change and reduce automobile carbon emissions, the thermal efficiency of engines must be improved. By altering the structural design of an engine body (including the cylinder blocks and cylinder heads), a rapid combustion model with a compression ratio of 16 and a maximum tumble ratio of 3.94 was developed that improved the combustion speed. Through synergistic matching of cooled exhaust gas recirculation with lean burn technology, when the exhaust gas recirculation rate was 20% and the air-fuel ratio was 20, the effect of reducing NO x emission and knocking reached the optimum level. When an electronic water pump and dual thermostat technology were used, the temperature change at the combustion chamber wall of each cylinder was

Necroptosis has been indicated as a key regulator of tumor progression. However, the prognostic regulatory role of necroptosis in clear cell renal cell carcinoma (ccRCC) needs to be further investigated. In this study, necroptosis-related subtypes were identified by mining the public cohort (n = 530) obtained from The Cancer Genome Atlas. By applying Principal Component Analysis (PCA), the necroptosis-related scores (N-Score) were developed to assess the prognosis procession of ccRCC. The results were further validated by an external clinical cohort (n = 116) obtained from the First Affiliated Hospital of Wenzhou Medical University. It has been found that N-Score could precisely distinguish the prognostic outcomes of patients as an independent risk factor (Hazard ratio = 4.990, 95% confidence interval (CI) = 2.007–12.403, p < 0.001). In addition, changes in N-Score were associated with differences in tumor mutational burden as well as immune infiltration characterization. Moreover, higher N-Scores were also correlated significantly molecular drug sensitivity and stronger immune checkpoint activity. Notably, the prognosis of ccRCC could be effectively guided by combining the N-Scores and external clinical indicators. In conclusion, N-Scores could be served as a robust and effective biomarker to improve the prognosis outcomes and targeted therapy of ccRCC.

The functional group structures of coal molecules are one of the most important factors affecting spontaneous combustion. However, it is difficult to determine the exact effects of such structures. Extraction technology is able to modify the functional groups in coal as a means of inhibiting spontaneous combustion reactions. The present work extracted coal from the Caojiatan mine in northern Shaanxi, China, with various solvents. The extraction effectiveness of these solvents was found to decrease in the order of dioctyl sulfosuccinate (AOT) > water > n-hexane > cyclohexane + AOT + ethanol > cyclohexane > ethanol > methanol. With the exception of the AOT, the concentration of functional groups in the extracted coal was decreased compared with that in a control specimen extracted using only water. Ethanol, n-hexane, and methanol provided the optimal extraction efficiencies in terms of capturing coal molecules with aromatic structures, aliphatic structures, and oxygen-containing groups, respectively. The results of this work are expected to assist in future research concerning the extraction of coal molecules with specific functional groups. This work also suggests new approaches to the active prevention and control of spontaneous combustion during the mining, storage, and transportation of coal.

Detecting foodborne pathogens on-site is crucial for ensuring food safety, necessitating the development of rapid, cost-effective, highly sensitive, and portable devices. This paper presents an integrated microfluidic biosensing system designed for the rapid and sensitive detection of Salmonella typhimurium (S. typhimurium). The biosensing system comprises a microfluidic chip with a versatile valve, a recombinase polymerase amplification (RPA) for nucleic acid detection, and a customized real-time fluorescence detection system. The versatile valve combines the functions of an active valve and a magnetic actuation mixer, enabling on-demand mixing and controlling fluid flow. Quantitative fluorescence is processed and detected through a custom-built smartphone application. The proposed integrated microfluidic biosensing system could detect Salmonella at concentrations as low as 1.0 × 102 copies/µL within 30 min, which was consistent with the results obtained from the real-time quantitative polymerase chain reaction (qPCR) tests. With its versatile valve, this integrated microfluidic biosensing system holds significant potential for on-site detection of foodborne pathogens.

Artemisia absinthium, an important herb of the Artemisia genus, was evaluated in this study for its potential as an alternative to classical antibiotics. The antimicrobial activity of methanol extracts of A. absinthium (MEAA) was evaluated using the broth microdilution method, revealing that A. absinthium exhibited broad-spectrum antibacterial and antifungal activity. Ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF-MS) was used to analyze the chemical profile of the MEAA, with a focus on flavonoids, quinic acids, and glucaric acids. A total of 90 compounds were identified, 69 of which were described for the first time in A. absinthium. Additionally, a new class of caffeoyl methyl glucaric acids was identified. The main active compounds were quantified and screened for antimicrobial activity. A. absinthium was found to be rich in quinic acids and flavonoids. The screening for antimicrobial activity also revealed that salicylic acid, caffeic acid, casticin, and 3,4-dicaffeoylquinic acid had varying degrees of antimicrobial activity. The acute toxicity of MEAA was examined following OECD guidelines. The administration of 5000 mg/kg bw of MEAA did not result in mortality in male and female mice. Furthermore, there were no observed effects on the visceral organs or general behavior of the mice, demonstrating the good safety of MEAA. This study provides new evidence for the use of A. absinthium as an alternative to classical antibiotics in addressing the problem of bacterial resistance.

Abstract Background Inflammatory bowel disease (IBD) is a kind of intestinal immune dysfunction disease, and its occurrence and prevalence are on the rise worldwide. As a chronic gastrointestinal disease, its pathogenesis is still unknown. Exosomes are vesicles in various body fluids that carry a variety of substances. They can mediate intercellular communication and long-distance transport of multiple media. In this study, we investigated the protein profile of serum exosomes from healthy people and IBD patients to explore a new serological biomarker for IBD. Methods Initially, exosomes were extracted from serum samples, and the proteins within the exosomes were identified by label-free liquid chromatography/mass spectrometry (LC-MS/MS). Western blot and ELISA were used to assess the identified protein. To further analyze the target protein, an acute colitis mouse model was established, and exosomes in colonic tissue and serum were extracted to investigate the protein in them. Results Firstly, serum exosomes were extracted from samples, and proteins in exosomes were identified by LC-MS/MS. Through statistical analysis, we identified 633 proteins. Among these proteins, pregnancy zone protein (PZP) showed a marked difference between patients with IBD and healthy people, in that its expression level was much higher in the IBD patients This exosomal protein was associated with immunosuppressive effects. Also, the level of PZP in colon tissue exosomes and serum exosomes of acute colitis mice was significantly higher than that of the control group. Conclusions Our findings indicated that serum exosome PZP was present at a high level in the IBD patients. Hence it might be a promising biomarker and enhance auxiliary diagnosis of IBD.

Clarifying the flow laws of shale gas under high temperature and high pressure is the prerequisite to accurately predicting the productivity of deep shale gas wells. In this paper, a self-diffusion flow model of flow field and temperature field coupling (referred to as self-diffusion flow and heat coupling model) was established based on the previously proposed self-diffusion flow model, while considering the influence of the temperature field change. Then, its calculation result was compared with that of the flow model based on Darcy's law and Knudsen diffusion (referred to as modified Darcy flow model). Based on the self-diffusion flow and heat coupling model, the self-diffusion flow behaviors of deep shale gas under the influence of temperature field change were analyzed, and the influence of bottomhole temperature on the degree of reserve recovery of deep shale gas was discussed. Finally, the self-diffusion flow and heat coupling model was applied to simulate the production of one shale-gas horizontal well in the Upper Ordovician Wufeng Formation–Lower Silurian Longmaxi Formation in the Changning Block of the Sichuan Basin. And the following research results were obtained. First, at the same parameters, the shale gas production calculated by the self-diffusion flow and heat coupling model is higher than the result calculated by the modified Darcy flow model. Second, when temperature field change is taken into consideration, the self–dviffusion coefficient profile presents a peak, the gas density profile presents a valley and the data points corresponding to the peak/valley move synchronously to the internal formation, which indicates that the self–diffusion coefficient influences the gas mass transfer rate, and the influence range of near well low temperature on gas self-diffusion increases continuously as the production continues. Third, when the bottomhole temperature is lower than the formation temperature, the self–diffusion coefficient of the gas near the well decreases and the gas is blocked near the well, which reduces the gas well production. Fourth, the production simulation result of the case well shows that the self-diffusion flow and heat coupling model can predict the production of deep shale gas more accurately if temperature field change is taken into consideration. In conclusion, the self-diffusion flow and heat coupling model established in this paper is of higher reliability and accuracy and can be used for productivity simulation and prediction of deep shale gas wells. The conclusion of this paper has certain guiding significance for deep shale gas production and gas well productivity prediction.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes a broad clinical spectrum of coronavirus disease 2019 (COVID-19). The development of COVID-19 may be the result of a complex interaction between the microbial, environmental, and host genetic components. To reveal genetic determinants of susceptibility to COVID-19 severity in the Chinese population, we performed a genome-wide association study on 885 severe or critical COVID-19 patients (cases) and 546 mild or moderate patients (controls) from two hospitals, Huoshenshan and Union hospitals at Wuhan city in China. We identified two loci on chromosome 11q23.3 and 11q14.2, which are significantly associated with the COVID-19 severity in the meta-analyses of the two cohorts (index rs1712779: odds ratio [OR] = 0.49; 95% confidence interval [CI], 0.38–0.63 for T allele; P = 1.38 × 10−8; and index rs10831496: OR = 1.66; 95% CI, 1.38–1.98 for A allele; P = 4.04 × 10−8, respectively). The results for rs1712779 were validated in other two small COVID-19 cohorts in the Asian populations (P = 0.029 and 0.031, respectively). Furthermore, we identified significant eQTL associations for REXO2, C11orf71, NNMT, and CADM1 at 11q23.3, and CTSC at 11q14.2, respectively. In conclusion, our findings highlight two loci at 11q23.3 and 11q14.2 conferring susceptibility to the severity of COVID-19, which might provide novel insights into the pathogenesis and clinical treatment of this disease.

Abstract Programmed cell death ligend-1 (PD-L1) expression by immunohistochemistry (IHC) assays is a predictive marker of anti-PD-1/PD-L1 therapy response. With the popularity of anti-PD-1/PD-L1 inhibitor drugs, quantitative assessment of PD-L1 expression becomes a new labor for pathologists. Manually counting the PD-L1 positive stained tumor cells is an obviously subjective and time-consuming process. In this paper, we developed a new computer aided Automated Tumor Proportion Scoring System (ATPSS) to determine the comparability of image analysis with pathologist scores. A three-stage process was performed using both image processing and deep learning techniques to mimic the actual diagnostic flow of the pathologists. We conducted a multi-reader multi-case study to evaluate the agreement between pathologists and ATPSS. Fifty-one surgically resected lung squamous cell carcinoma were prepared and stained using the Dako PD-L1 (22C3) assay, and six pathologists with different experience levels were involved in this study. The TPS predicted by the proposed model had high and statistically significant correlation with sub-specialty pathologists’ scores with Mean Absolute Error (MAE) of 8.65 (95% confidence interval (CI): 6.42–10.90) and Pearson Correlation Coefficient (PCC) of 0.9436 ( $$p < 0.001$$ p < 0.001 ), and the performance on PD-L1 positive cases achieved by our method surpassed that of non-subspecialty and trainee pathologists. Those experimental results indicate that the proposed automated system can be a powerful tool to improve the PD-L1 TPS assessment of pathologists.

Chaolong Wang and colleagues report a large genome-wide association study for COVID-19 severity in Chinese individuals. By meta-analysis with European data, they identify 3 loci associated with severe disease that suggest key roles for the adaptive immune system and the ABO blood group system in development of severe COVID-19.

PTENα is an N-terminally extended isoform of PTEN, a gene frequently mutated in human cancers. Here the authors show that PTENα remains active in PTEN-mutant cancers and is associated with tumor immune escape by promoting tumor cell resistance to T cell cytotoxicity.

Abstract Introduction Programmed cell death ligand-1 (PD-L1) expression is a promising biomarker for identifying treatment related to non-small cell lung cancer (NSCLC). Automated image analysis served as an aided PD-L1 scoring tool for pathologists to reduce inter- and intrareader variability. We developed a novel automated tumor proportion scoring (TPS) algorithm, and evaluated the concordance of this image analysis algorithm with pathologist scores. Methods We included 230 NSCLC samples prepared and stained using the PD-L1(SP263) and PD-L1(22C3) antibodies separately. The scoring algorithm was based on regional segmentation and cellular detection. We used 30 PD-L1(SP263) slides for algorithm training and validation. Results Overall, 192 SP263 samples and 117 22C3 samples were amenable to image analysis scoring. Automated image analysis and pathologist scores were highly concordant [intraclass correlation coefficient (ICC) = 0.873 and 0.737]. Concordances at moderate and high cutoff values were better than at low cutoff values significantly. For SP263 and 22C3, the concordances in squamous cell carcinomas were better than adenocarcinomas (SP263 ICC = 0.884 vs 0.783; 22C3 ICC = 0.782 vs 0.500). In addition, our automated immune cell proportion scoring (IPS) scores achieved high positive correlation with the pathologists TPS scores. Conclusions The novel automated image analysis scoring algorithm permitted quantitative comparison with existing PD-L1 diagnostic assays and demonstrated effectiveness by combining cellular and regional information for image algorithm training. Meanwhile, the fact that concordances vary in different subtypes of NSCLC samples, which should be considered in algorithm development.