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In severe few-shot scenarios, fault samples are extremely limited, challenging the health management of the chiller significantly. Generative adversarial network (GAN), a common data augmentation method, suffers from a feature shift issue in severe few-shot scenarios. This is because the extremely limited fault samples cannot provide sufficient distribution paradigms for GANs. Therefore, a severe few-shot fault diagnosis method for chillers based on an extended conditional mapping feature generation network (ECMFGN) is proposed to tackle this issue. In ECMFGN, the ECM module is built to provide an extended distribution paradigm for the generator. This extended distribution paradigm can adequately reflect class-specific characteristics. Then, through adversarial supervised learning, the feature similarity between the samples synthesized by the generator and the real samples is improved. Experiments demonstrate that the feature shift issue in severe few-shot scenarios is solved effectively. In addition, the characteristics of different fault modes for chillers are close. Thus, insufficient intraclass cohesion and interclass separation can lead to interclass confusion of generated samples, which directly affects diagnostic accuracy. To conquer this challenge, a smooth $L_{1}$ triplet loss (TL) is designed to promote intraclass cohesion while improving the separability between classes. The experimental results indicate that the performance of the fault diagnosis model is significantly improved in the chiller dataset with similar characteristics among the fault modes, benefiting the health management and maintenance decisions of the equipment.

Supplemental Digital Content is Available in the Text.The influence of interleukin (IL)-17 inhibition on blood pressure in patients with autoimmune diseases remains inconclusive. Our objective is to examine the risk of hypertension in patients with autoimmune diseases undergoing IL-17 inhibition therapies through meta-analysis of randomized, placebo-controlled trials. We obtained integrated data from PubMed, Embase, and ClinicalTrials.gov. Incident hypertension rates were calculated, and hazard ratios with 95% confidence intervals were analyzed, along with Ι2statistics to assess heterogeneity. Sequential analysis ensured conclusion reliability. In 30 randomized controlled trials involving 9909 patients with diverse autoimmune diseases treated with anti-IL-17 agents, our meta-analysis revealed a significant increase in hypertension risk (risk ratio 1.69, 95% confidence interval 1.24–2.31, P= 0.001), robustly supported by trial sequential analysis. Among the 4 agents (secukinumab, ixekizumab, bimekizumab, and brodalumab), only secukinumab exhibited a notable association with hypertension. Patients with various primary autoimmune diseases, particularly those with psoriatic arthritis, had a higher likelihood of developing hypertension; in rheumatic arthritis patient cohorts, anti-IL-17 agents did not elevate hypertension risk. Prolonged treatment duration correlated with an increased hypertension risk. Stratifying by sex, studies with a female predominance demonstrated a higher risk ratio for hypertension compared with male-predominant studies. This highlights that anti-IL-17 treatment escalates hypertension risk, emphasizing the need for extra caution when managing patients with autoimmune diseases (Registered by PROSPERO, CRD42016053112).

Recently, immunotherapy has emerged as a promising and effective method for treating triple-negative breast cancer (TNBC). However, challenges still persist. Immunogenic cell death (ICD) is considered a prospective treatment and potential combinational treatment strategy as it induces an anti-tumor immune response by presenting the antigenic epitopes of dead cells. Nevertheless, the ICD process in TNBC and its impact on disease progression and the response to immunotherapy are not well understood. In this study, we observed dysregulation of the ICD process and verified the altered expression of prognostic ICD genes in TNBC through quantitative real-time polymerase chain reaction (qRT-PCR) analysis. To investigate the potential role of the ICD process in TNBC progression, we determined the ICD-dependent subtypes, and two were identified. Analysis of their distinct tumor immune microenvironment (TIME) and cancer hallmark features revealed that Cluster 1 and 2 corresponded to the immune “cold” and “hot” phenotypes, respectively. In addition, we constructed the prognostic signature ICD score of TNBC patients and demonstrated its clinical independence and generalizability. The ICD score could also serve as a potential biomarker for immune checkpoint blockade and may aid in the identification of targeted effective agents for individualized clinical strategies.

AbstractAimsTo determine the association between all-cause mortality and low-density lipoprotein cholesterol (LDL-C) in patients with idiopathic cardiomyopathy (iDCM).BackgroundLDL-C had long been considered as a dangerous predictor of cardiovascular diseases; however, the correlation between them was not fully clarified.MethodsA total of 1058 patients who met the World Health Organization criteria for iDCM in West China Hospital (2009–2016) were enrolled in this retrospective study. Baseline demographic characteristics and correlations between variables were calculated and analyzed, and potential predictors were explored using univariate and multivariate regressions. Cox proportional hazards models were used to determine correlation on a continuous scale.ResultsLDL-C is an independent prognostic factor and higher LDL-C levels are associated with better prognosis in iDCM patients according to cox regression analysis. Compared with individuals which LDL > 2.28 mmol/L (75th–100th percentile), the multivariable-adjusted hazard ratio for all-cause mortality was 1.52 (95%CI: 1.03–2.26) in patients with LDL-C < 1.78 mmol/L (0–25th percentile). In patients with New York Heart Association function III and IV, LDL-C levels have a hazard ratio of 0.83 (confidence interval 0.73–0.95).ConclusionsIn patients with iDCM, lower LDL-C level was associated with an increased risk of all-cause mortality. The correlation between mortality and LDL-C level was stronger in patients with worse heart function. LDL-C levels have a potential predictive value in iDCM patients.

The extreme unbalance of training samples among different working conditions caused by complex and variable external environments makes the fault diagnosis of a chiller based on domain adaptation (DA) poor performance. Although recently emerging fault diagnosis methods based on domain generalization (DG) can learn domain-invariant knowledge from multiple source domains and can generalize to unseen target domains, these methods still rely on multiple similar source domain data and rarely consider how to enhance the ability to distinguish the joint distribution of features extracted from the source domain samples. To address these problems, a generative domain-generalized framework for chillers fault diagnosis, namely, vision transformer generative adversarial DG (VIT-GADG), is proposed. In VIT-GADG, a novel VIT domain generation network (VIT-DGN) is first designed to reduce DG’s dependence on multisource domain data by improving the diversity of the distribution of the source domain samples. Then, a new adversarial DG network called VIT conditional adversarial DG network (VIT-CADGN) is designed to extract domain-invariant knowledge from the source domain and latent domains that can be generalized to unseen target domains. Specifically, the VIT module can effectively extract the global statistical feature of input samples, which is conducive to the identification of joint distribution. Simultaneously, the collaborative conditional domain discrimination strategy is introduced to improve the distribution discrimination ability of the extracted global statistical features while simultaneously aligning its conditional distribution. In addition, a personalized adaptive weight strategy is proposed to improve the performance of VIT-CADGN. Finally, the comprehensive case study shows that VIT-GADG has a satisfactory ability to extract invariant features, which improves the diagnosis accuracy in the unseen target domain.

Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous β-phenylethylamine (β-PEA)1as well as methamphetamine2, an abused substance that has posed a severe threat to human health and society3. Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction2,4,5. Here we report structures of human TAAR1–G-protein complexes bound to methamphetamine and β-PEA as well as complexes bound to RO5256390, a TAAR1-selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HT1AR (refs. 6,7). Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of methamphetamine recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like extracellular loop 2 helix/loop structure and a hydrogen-bonding network in the ligand-binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders.

Cold brew coffee is popular with consumers due to its simple preparation and unique taste. However, traditional cold brew coffee extraction is time consuming and inefficient, which can be improved by ultrasound-assisted extraction to enhance the product market potential. In this study, the flavor profiles and sensory differences of coffee prepared at three different ultrasonic temperatures, as well as traditional cold brew and hot brew coffee, were evaluated by consumer-based sensory evaluation, Rate-All-That-Apply, combined with the determination of the content of volatile and non-volatile components. The results showed that ultrasound assisted cold brew coffee prepared at 25 °C had a good extraction effect, with chlorogenic acid (CGA) and organic acid contents of 1.05 mg/mL and 0.97 mg/mL, respectively, which were higher than the traditional cold brew coffee obtained after 12 h of preparation, with contents of 0.53 mg/mL and 0.85 mg/mL, respectively. And the total content of volatile compounds can almost reach the results of traditional cold brew for 12 h, which were 1.25 mg/kg and 1.42 mg/kg, respectively. Sensory evaluation indicated that ultrasonic treatment enhanced the sensory attributes such as nutty and cocoa flavors in the coffee. Consumers preferred the cold brew coffee obtained via ultrasound-assisted extraction. These samples presented higher levels of sweetness, floral, and fruity flavors, which were associated with 2,5-Dimethyl-3-(2-methylpropyl)pyrazine, 2,3-Dimethyl-5-(3-methylbutyl)pyrazine, (S)-(+)-4-sec-Butylpyrazole, and styrene. In this study, we demonstrated that ultrasound-assisted extraction can help reduce the time to prepare cold brew coffee and make it possible to commercialize ultrasound-assisted cold brew coffee.

Public opinion surveys over the past thirty years show that public opinion is split on the issue of global warming. One of the problems with “solicited” opinion polls is that the findings may be selectively interpreted in favour of the political goals of a particular interest group. To gain a better understanding of the general public’s unsolicited responses to climate change news, the current study examined Twitter messages containing the words “global warming” spanning 16 months. Using a framework combining a sentiment analysis technique, Hedonometer from the perspective of natural language processing, and Appraisal Theory from a discourse analysis perspective, the study shows that the demonstrated happiness level in tweets containing the words “global warming” is consistently lower than the general level on Twitter, due to increased use of negative words and decreased use of positive words. The Appraisal analysis shows that Appreciation is used most frequently and Affect least.

Increasing global concerns about psychoactive substance addiction and psychotic disorders highlight the need for comprehensive research into the structure-function relationship governing ligand recognition between these substances and their receptors in the brain. Recent studies indicate the significant involvement of trace amine-associated receptor 1 (TAAR1) in the signaling regulation of the hallucinogen lysergic acid diethylamide (LSD) and other antipsychotic drugs. This study presents structures of the TAAR1-Gs protein complex recognizing LSD, which exhibits a polypharmacological profile, and the partial agonist RO5263397, which is a drug candidate for schizophrenia and addiction. Moreover, we elucidate the cross-species recognition and partial activation mechanism for TAAR1, which holds promising implications from a drug discovery perspective. Through mutagenesis, functional studies, and molecular dynamics (MD) simulations, we provide a comprehensive understanding of a versatile TAAR1 pocket in recognizing various ligands as well as in the ligand-free state, underpinning the structural basis of its high adaptability. These findings offer valuable insights for the design of antipsychotic drugs.

Estrogen-related receptor α (ERRα), a member of nuclear receptors (NRs), plays a role in the regulation of cellular energy metabolism and is reported to be a novel potential target for type 2 diabetes therapy. To date, only a few agonists of ERRα have been identified to improve insulin sensitivity and decrease blood glucose levels. Herein, the discovery of novel potent agonists of ERRα determined using a combined virtual screening approach is described. Molecular dynamics (MD) simulations were used to obtain structural ensembles that can consider receptor flexibility. Then, an efficient virtual screening strategy with a combination of similarity search and ensemble docking was performed against the Enamine, SPECS, and Drugbank databases to identify potent ERRα agonists. Finally, a total of 66 compounds were purchased for experimental testing. Biological investigation of promising candidates identified seven compounds that have activity against ERRα with EC50values ranging from 1.11 to 21.70 μM, with novel scaffolds different from known ERRα agonists until now. Additionally, the molecule GX66 showed micromolar inverse activity against ERRα with an IC50of 0.82 μM. The predicted binding modes showed that these compounds were anchored in ERRα-LBP via interactions with several residues of ERRα. Overall, this study not only identified the novel potent ERRα agonists or an inverse agonist that would be the promising starting point for further exploration but also demonstrated a successful molecular dynamics-guided approach applicable in virtual screening for ERRα agonists.

ABSTRACTRadiation therapy (RT) is widely applied in cancer treatment. The sensitivity of tumor cells to RT is the key to the treatment. This study probes the role and mechanism of miR-20b-5p in Pembrolizumab’s affecting the radiosensitivity of tumor cells. After Pembrolizumab treatment or cell transfection (miR-20b-5p mimics and miR-20b-5p inhibitors), tumor cells (NCI-H460 and ZR-75-30) were exposed to RT. The sensitivity of NCI-H460 and ZR-75-30 to RT was evaluated by monitoring cell proliferation and apoptosis. The dual-luciferase reporter assay and RNA immunoprecipitation (RIP) were adopted to evaluate the binding relationship between miR-20b-5p and CD274 (PD-L1). The xenograft model was established in nude mice to examine the mechanism of action of Pembrolizumab in vivo. Our outcomes exhibited that either Pembrolizumab treatment or miR-20b-5p overexpression potentiated radiosensitivity of tumor cells. Overexpressing miR-20b-5p enhanced radiosensitization of Pembrolizumab in vivoand in vitroby targeting PD-L1 and inactivating PD-L1/PD1. Overall, miR-20b-5p overexpression combined with Pembrolizumab potentiated cancer cells’ sensitivity to RT by repressing PD-L1/PD1.AbbreviationsAkt: serine/threonine kinase 1; cDNA: complementary DNA; CO2: carbon dioxide; EDTA: Ethylene Diamine Tetraacetic Acid; ENCORI: The Encyclopedia of RNA Interactomes; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IGF2BP2: insulin like growth factor 2 mRNA binding protein 2; IHC: Immunohistochemistry; LncRNA MALAT1: Long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1; miRNAs: MicroRNAs; Mt: Mutant type; MTT: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide; NC: negative control; NR2F2: nuclear receptor subfamily 2 group F member 2; NSCLC: non-small cell lung cancer; OD: optical density; PBS: phosphate-buffered saline; PD-L1: Programmed death-ligand 1; PD-1: programmed death 1; PI3K: phosphatidylinositol 3-kinase; qRT-PCR: Quantitative reverse transcription-polymerase chain reaction; RIP: RNA immunoprecipitation; RIPA: Radio Immunoprecipitation Assay; RRM2: ribonucleotide reductase regulatory subunit M2; RT: Radiation therapy; U6: U6 small nuclear RNA; V: volume; WB: Western blot; Wt: wild type; x ± sd: mean ± standard deviation.

AbstractRegulators of G protein signaling (RGSs) are proteins that negatively regulate G protein signal transduction. In this study, seven putative RGSs were characterized in the nematode-trapping (NT) fungus, Arthrobotrys oligospora. Deleting Rgsgenes significantly increased intracellular cAMP levels, and caused defects in mycelia growth, stress resistance, conidiation, trap formation, and nematocidal activity. In particular, the ΔAoFlbAmutant was unable to produce conidia and traps. Transcriptomic analysis showed that amino acid metabolic and biosynthetic processes were significantly enriched in the ΔAoFlbAmutant compared to WT. Interestingly, Gas1family genes are significantly expanded in A. oligosporaand other NT fungi that produce adhesive traps, and are differentially expressed during trap formation in A. oligospora. Disruption of two Gas1genes resulted in defective conidiation, trap formation, and pathogenicity. Our results indicate that RGSs play pleiotropic roles in regulating A. oligosporamycelial growth, development, and pathogenicity. Further, AoFlbA is a prominent member and required for conidiation and trap formation, possibly by regulating amino acid metabolism and biosynthesis. Our results provide a basis for elucidating the signaling mechanism of vegetative growth, lifestyle transition, and pathogenicity in NT fungi.

This study investigated the impact of masticatory behavior, including variations in chewing duration (D) and chewing frequency (F), on the bolus characteristics of biscuits with different chia seed powder (CSP) additions. Five distinct biscuits were prepared with varying amounts of CSP (0%, 5%, 10%, 15%, and 20%, w/w) and their physicochemical indexes and sensory properties were conducted. Subsequently, six types of bolus were obtained under different conditions of chewing duration (15, 30, or 45s) and chewing frequencies (70 or 90 times per minute). The moisture content, texture properties, and in vitro starch digestion of bolus were also determined. The findings indicated a significant decrease in the spread ratio, with a reduction of approximately 25% in biscuits enriched with 20% (w/w) CSP compared to the control (0%). And the 15% added CSP biscuits had the highest overall acceptance rating. After chewing, the particle size decreased significantly (p<0.05), with increased surface inhomogeneity and a decline in rapidly digestible starch (RDS) levels. The moisture content, salivary uptake, and resistant starch (RS) of bolus chewed for a long duration (D45) were at least 1.3 times higher than those chewed for a short duration (D15). Nevertheless, the salivary flow rate and RDS were found to be significantly lower. Changes in chewing frequency for the bolus with CSP did not significantly alter the bolus texture and image texture properties. However, the discomfort associated with high-frequency reduced the saliva flow rate. This study discusses how CSP addition and masticatory behavior affect the characteristics of CSP biscuit bolus, providing insights for innovative chia seed nutritious food research and understanding consumer masticatory behavior.

Colon leakage is one of the most severe complications in abdominal trauma or surgery cases. It can lead to severe abdominal infection and abdominal adhesions, resulting in prolonged hospital stays and increased mortality. In this study, a photosensitive hydrogel is proposed, which can swiftly form a strong adhesion coating on the damaged colon after UV irradiation, to realize quick cure and suture‐free repair of colon leakage. The newly developed biological gel consists of hyaluronic acid methacryloyl (HAMA) and hyaluronic acid o‐nitroso benzaldehyde (HANB) in the optimal ratio of 3: 1, which exerts both the rapid photocuring properties of HAMA and the strong tissue adhesion properties of HANB. HAMA/HANB shows excellent adhesion stability on wet surfaces, presenting controllable mechanical properties, ductility, adhesion stability, and chemical stability; it also evades foreign body response, which relieves the degree of abdominal adhesion. The underlying mechanism for HAMA/HANB promoting wound healing in colon leakage involves the reconstruction of the colon barrier, as well as the regulation of the immune reaction and neovascularization. In all, HAMA/HANB is a promising alternative suture‐free approach for repairing colon leakage; it has a reliable healing effect and is expected to be extended to clinical application for other organ injuries. Colon leakage is a serious complication in abdominal trauma or surgery. A photosensitive hydrogel, HAMA/HANB, for suture‐free repair is developed. It forms a strong adhesive coating on the damaged colon, promoting healing and reducing adhesions. HAMA/HANB regulates immune reactions, neovascularization, and colon barrier reconstruction. It offers a promising approach for colon leakage and organ injuries.

Citri Reticulatae Pericarpium (CRP) is a very well-known foodstuff. It can not only be drunk directly like tea, but also be used as a condiment for cooking food. This study used headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS), gas chromatography-olfactometry-mass spectrometry (GC-O-MS), and sensory evaluation to analyze and evaluate CRP over a six-year aging process (2, 5, 10, 15, 20, and 25 years). HS-SPME-GC-MS identified 93 volatile components, while GC-O-MS detected 42 aroma compounds. The results indicated that the aroma intensity (AI) of the spicy, woody, and herbal aroma compounds remained unchanged, while those with citrus and fruity notes gradually decreased and even disappeared with extended storage time, which could explain the unique CRP aroma. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed that the CRP in the six-year aging process was clearly divided into three groups: young-aged samples (2Y), middle-aged samples (5Y and 10Y), and old-aged samples (15Y, 20Y, and 25Y). In addition, combining sensory evaluation and GC-O-MS fully reflected the changes during the different CRP aging stages. This study confirmed the potential of combining GC-O-MS and OPLS-DA as a reliable analytical selection technique to distinguish CRP age. Finally, 13 key aroma compounds were screened using VIP >1 and p < 0.05, including isopulegol, dodecanal, and α-calacorene.

During spontaneous fermentation of light-flavor Baijiu, the microbial diversity decreased gradually. Lactic acid bacteria (LAB) and yeast predominated at the end of fermentation and showed a strong positive correlation with esters in Baijiu. Exploring the metabolic characteristics of LAB and interactions with yeast are important for revealing the mechanism of Baijiufermentation. The carbon source utilization heatmap showed that Lactobacillus acetotolerans, Lactobacillus brevis, and Lactobacillus hilgardiicould utilize various organic acids. Lactobacillus plantarumcould utilize a variety of amino acids. The utilization efficiency of different substrates was supposed to be an important factor for different LAB species dynamics during fermentation. The effects of pH, temperature and ethanol on the esterase activity of LAB were further analyzed. The results showed that pH was the most significant factor on esterase activity, and all the strains showed the highest activity at pH 7.0. Principal component analysis indicated that co-culture of LAB and Saccharomyces cerevisiaecould promote the formation of esters, and the co-culture of Lactobacillus acetotoleransor Leuconostoc mesenteroideswith Pichia anomalacould promote the production of esters and alcohols. LAB showed a weak inhibitory effect on the growth of yeast, whereas the growth of LAB was significantly inhibited by yeast in the co-culture system. The results of this work will broaden our knowledge regarding the esterase activity, carbon source utilization efficiency of LAB and interactions with predominant yeast, which will provide a theoretical basis for the dynamics of different LAB species and their effects on the flavor of Baijiu.