Defining high bleeding risk in patients undergoing transcatheter aortic valve implantation: a VARC-HBR consensus document.

The identification and management of patients at high bleeding risk (HBR) undergoing transcatheter aortic valve implantation (TAVI) are of major importance, but the lack of standardised definitions is challenging for trial design, data interpretation, and clinical decision-making. The Valve Academic Research Consortium for High Bleeding Risk (VARC-HBR) is a collaboration among leading research organisations, regulatory authorities, and physician-scientists from Europe, the USA, and Asia, with a major focus on TAVI-related bleeding. VARC-HBR is an initiative of the CERC (Cardiovascular European Research Center), aiming to develop a consensus definition of TAVI patients at HBR, based on a systematic review of the available evidence, to provide consistency for future clinical trials, clinical decision-making, and regulatory review. This document represents the first pragmatic approach to a consistent definition of HBR evaluating the safety and effectiveness of procedures, devices and drug regimens for patients undergoing TAVI..

Single-Cell Transcriptional Profile Construction of Rat Pituitary Glands before and after Sexual Maturation and Identification of Novel Marker Spp1 in Gonadotropes.

The mammalian pituitary gland drives highly conserved physiological processes such as somatic cell growth, pubertal transformation, fertility, and metabolism by secreting a variety of hormones. Recently, single-cell transcriptomics techniques have been used in pituitary gland research. However, more studies have focused on adult pituitary gland tissues from different species or different sexes, and no research has yet resolved cellular differences in pituitary gland tissue before and after sexual maturation. Here, we identified a total of 15 cell clusters and constructed single-cell transcriptional profiles of rats before and after sexual maturation. Furthermore, focusing on the gonadotrope cluster, 106 genes were found to be differentially expressed before and after sexual maturation. It was verified that Spp1, which is specifically expressed in gonadotrope cells, could serve as a novel marker for this cell cluster and has a promotional effect on the synthesis and secretion of follicle-stimulating hormone. The results provide a new resource for further resolving the regulatory mechanism of pituitary gland development and pituitary hormone synthesis and secretion.

Risk factors and prediction model for new-onset hypertensive disorders of pregnancy: a retrospective cohort study.

Background and aims: Hypertensive disorders of pregnancy (HDP) is a significant cause of maternal and neonatal mortality. This study aims to identify risk factors for new-onset HDP and to develop a prediction model for assessing the risk of new-onset hypertension during pregnancy. Methods: We included 446 pregnant women without baseline hypertension from Liyang People's Hospital at the first inspection, and they were followed up until delivery. We collected maternal clinical parameters and biomarkers between 16th and 20th weeks of gestation. Logistic regression was used to determine the effect of the risk factors on HDP. For model development, a backward selection algorithm was applied to choose pertinent biomarkers, and predictive models were created based on multiple machine learning methods (generalised linear model, multivariate adaptive regression splines, random forest, and k-nearest neighbours). Model performance was evaluated using the area under the curve. Results: Out of the 446 participants, 153 developed new-onset HDP. The HDP group exhibited significantly higher baseline body mass index (BMI), weight change, baseline systolic/diastolic blood pressure, and platelet counts than the control group. The increase in baseline BMI, weight change, and baseline systolic and diastolic blood pressure significantly elevated the risk of HDP, with odds ratios and 95% confidence intervals of 1.10 (1.03-1.17), 1.10 (1.05-1.16), 1.04 (1.01-1.08), and 1.10 (1.05-1.14) respectively. Restricted cubic spline showed a linear dose-dependent association of baseline BMI and weight change with the risk of HDP. The random forest-based prediction model showed robust performance with the area under the curve of 0.85 in the training set. Conclusion: This study establishes a prediction model to evaluate the risk of new-onset HDP, which might facilitate the early diagnosis and management of HDP.

Microenvironment Responsive Hydrogel Exerting Inhibition of Cascade Immune Activation and Elimination of Synovial Fibroblasts for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a progressive autoimmune disease and drug therapy has been restricted due to poor therapeutic efficacy and adverse effects. In RA synovium, dendritic cells present self-antigens to activate cascade immune pathway. Furthermore, downstream macrophages secrete high levels of pro-inflammatory cytokines; Hyperplasia of activated synovial fibroblasts (FLS) is responsible for hypoxic synovium microenvironment, secretion of cytokines/chemokines and erosion of bone/cartilage tissues. Positive feedback loop of inflammation between macrophages and FLS independent of antigen-presentation is constructed. Herein, an injectable pH-sensitive peptide hydrogel encapsulating siRNA/Methotrexate-polyethyleneimine (siMP, including sip65MP, sip38MP, siCD86MP) and Bismuthene nanosheet/Methotrexate-polyethyleneimine (BiMP) is successfully developed. Among them, siCD86MP reduces protein level of co-stimulatory molecule CD86 while sip65MP and sip38MP separately inhibit NF-κB and MAPK-p38 pathways of macrophages and FLS to suppress secretion of cytokines and MMPs. Meanwhile, reduction in anti-apoptotic property of FLS induced by inhibition of NF-κB pathway has a synergistic effect with photodynamic therapy (PDT) and photothermal therapy (PTT) mediated by BiMP for FLS elimination, effectively ameliorating hypoxic synovium microenvironment. After being injected into synovium, hydrogel responds to acidic microenvironment and serves as a reservoir for sustained drug release and inherent retention capacity of which enables cationic nanoparticles to bypass tissue barrier for precise synovium targeting. This brand-new drug delivery system combines modulating cascade immune pathway from beginning to end by RNAi and eliminating FLS for improving synovium microenvironment by phototherapy together, providing a robust strategy for clinical RA treatment.

Hydroxyl-Bonded Co Single Atom Site on Boroncarbonitride Surface Realizes Nonsacrificial H2O2 Synthesis in the Near-Infrared Region.

Photocatalytic synthesis of hydrogen peroxide (H2O2) from O2 and H2O under near-infrared light is a sustainable renewable energy production strategy, but challenging reaction. The bottleneck of this reaction lies in the regulation of O2 reduction path by photocatalyst. Herein, the center of the one-step two-electron reduction (OSR) pathway of O2 for H2O2 evolution via the formation of the hydroxyl-bonded Co single-atom sites on boroncarbonitride surface (BCN-OH2/Co1) is constructed. The experimental and theoretical prediction results confirm that the hydroxyl group on the surface and the electronic band structure of BCN-OH2/Co1 are the key factor in regulating the O2 reduction pathway. In addition, the hydroxyl-bonded Co single-atom sites can further enrich O2 molecules with more electrons, which can avoid the one-electron reduction of O2 to •O2 -, thus promoting the direct two-electron activation hydrogenation of O2. Consequently, BCN-OH2/Co1 exhibits a high H2O2 evolution apparent quantum efficiency of 0.8% at 850 nm, better than most of the previously reported photocatalysts. This study reveals an important reaction pathway for the generation of H2O2, emphasizing that precise control of the active site structure of the photocatalyst is essential for achieving efficient conversion of solar-to-chemical.

The impact of Yoga on patients with knee osteoarthritis: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The objective of this review is to conduct a comprehensive and systematic assessment of the efficacy of Yoga as an intervention for knee osteoarthritis (KOA). METHODS: We searched PubMed, Cochrane Library, Embase, Web of Science, and PEDro as of January 3, 2024. Retrieved a total of 200 articles. Standardised mean differences (SMDs) and 95% confidence intervals (CI) were calculated. RESULTS: The study included a total of 8 trials and involved 756 KOA patients. The results indicated that compared to the control group, Yoga exercise showed significant improvements in alleviating pain (SMD = -0.92; 95% CI = -1.64 ~ - 0.20; P = 0.01, I2 = 94%), stiffness (SMD = -0.51; 95% CI = -0.91 ~ -0.12; P = 0.01; I2 = 66%) and physical function (SMD = -0.53; 95% CI = -0.89 ~ -0.17; P = 0.004; I2 = 59%) among KOA patients. However, there was no significant improvement observed in terms of activities of activity of daily living (ADL) (SMD = 1.03; 95% CI = -0.01 ~ 2.07; P = 0.05; I2 = 84%), and quality of life (QOL) (SMD = 0.21; 95% CI = -0.33 ~ 0.74; P = 0.44; I2 = 83%) with the practice of Yoga. CONCLUSIONS: In general, Yoga has been found to be effective in reducing pain and stiffness in KOA patients, it can also improve the physical function of patients. However, there is limited evidence to suggest significant improvements in terms of ADL and QOL.

Does the liver facilitate aging-related cognitive impairment: Conversation between liver and brain during exercise?

Liver, an important regulator of metabolic homeostasis, is critical for healthy brain function. In particular, age-related neurodegenerative diseases seriously reduce the quality of life for the elderly. As population aging progresses rapidly, unraveling the mechanisms that effectively delay aging has become critical. Appropriate exercise is reported to improve aging-related cognitive impairment. Whereas current studies focused on exploring the effect of exercise on the aging brain itself, ignoring the persistent effects of peripheral organs on the brain through the blood circulation. The aim of this paper is to summarize the communication and aging processes of the liver and brain and to emphasize the metabolic mechanisms of the liver-brain axis about exercise ameliorating aging-related neurodegenerative diseases. A comprehensive understanding of the potential mechanisms about exercise ameliorating aging is critical for improving adaptation to age-related brain changes and formulating effective interventions against age-related cognitive decline.

TRIF-dependent signaling and its role in liver diseases.

TIR domain-containing adaptor inducing IFN-ß (TRIF) is a crucial adaptor molecule downstream of toll-like receptors 3 (TLR3) and 4 (TLR4). TRIF directly binds to TLR3 through its TIR domain, while it associates with TLR4 indirectly through the bridge adaptor molecule TRIF-related adaptor molecule (TRAM). TRIF plays a pivotal role in regulating interferon beta 1 (IFN-ß) response, nuclear factor kappa B (NF-κB) signaling, apoptosis, and necroptosis signaling mediated by TLR3 and TLR4. It accomplishes these by recruiting and activating various kinases or transcription factors via its distinct domains. In this review, we comprehensively summarize the TRIF-dependent signaling pathways mediated by TLR3 and TLR4, elucidating key target molecules and downstream pathways. Furthermore, we provide an overview of TRIF's impact on several liver disorders, including drug-induced liver injury, ischemia-reperfusion liver injury, autoimmune hepatitis, viral hepatitis, alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). We also explore its effects on liver steatosis, inflammation, fibrosis, and carcinogenesis. A comprehensive understanding of the TRIF-dependent signaling pathways, as well as the intricate relationship between TRIF and liver diseases, can facilitate the identification of potential drug targets and the development of novel and effective therapeutics against hepatic disorders.

Generation and characterization of mature hepatocyte organoids for liver metabolic studies.

Hepatocyte organoids (HOs) generated in vitro recently are powerful tools for liver regeneration. However, the reported HOs were mostly fetal in nature with low expression levels of metabolic genes characteristic of adult liver functions, hampering their application in studying metabolic regulations and therapeutic testing for liver disorders. We report development of novel culture conditions that contains optimized levels of Triiodothyronine (T3) with the removal of growth factors, enabled successful generation of mature hepatocyte organoids (MHOs) with metabolic functions characteristic of adult livers of both mouse and human origins. We showed that the MHOs can be used to study various metabolic functions including bile and urea production, zonal metabolic gene expression, and metabolic alterations in both alcoholic and non-alcoholic fatty liver diseases as well hepatocyte proliferation, injury, and cell fate changes. Notably, the MHOs derived from human fetal hepatoblasts also showed improved hepatitis B virus (HBV) infection. Therefore, these MHOs provide a powerful in vitro model for studies of human liver physiology and diseases. The human MHOs are potentially a robust research tools for therapeutic development as well.

Monocyte-Derived Macrophages Aggravate Cardiac Dysfunction After Ischemic Stroke in Mice.

BACKGROUND: Cardiac damage induced by ischemic stroke, such as arrhythmia, cardiac dysfunction, and even cardiac arrest, is referred to as cerebral-cardiac syndrome (CCS). Cardiac macrophages are reported to be closely associated with stroke-induced cardiac damage. However, the role of macrophage subsets in CCS is still unclear due to their heterogeneity. Sympathetic nerves play a significant role in regulating macrophages in cardiovascular disease. However, the role of macrophage subsets and sympathetic nerves in CCS is still unclear. METHODS AND RESULTS: In this study, a middle cerebral artery occlusion mouse model was used to simulate ischemic stroke. ECG and echocardiography were used to assess cardiac function. We used Cx3cr1GFPCcr2RFP mice and NLRP3-deficient mice in combination with Smart-seq2 RNA sequencing to confirm the role of macrophage subsets in CCS. We demonstrated that ischemic stroke-induced cardiac damage is characterized by severe cardiac dysfunction and robust infiltration of monocyte-derived macrophages into the heart. Subsequently, we identified that cardiac monocyte-derived macrophages displayed a proinflammatory profile. We also observed that cardiac dysfunction was rescued in ischemic stroke mice by blocking macrophage infiltration using a CCR2 antagonist and NLRP3-deficient mice. In addition, a cardiac sympathetic nerve retrograde tracer and a sympathectomy method were used to explore the relationship between sympathetic nerves and cardiac macrophages. We found that cardiac sympathetic nerves are significantly activated after ischemic stroke, which contributes to the infiltration of monocyte-derived macrophages and subsequent cardiac dysfunction. CONCLUSIONS: Our findings suggest a potential pathogenesis of CCS involving the cardiac sympathetic nerve-monocyte-derived macrophage axis.

Radiating blood flow signal: A new ultrasound feature of thyroid carcinoma.

OBJECTIVE: To summary radiating blood flow signals and evaluate their diagnostic value in differentiating benign and malignant thyroid nodules. MATERIALS AND METHODS: We retrospectively recruited consecutive patients undergoing US at 4 hospitals from 2018 to 2022. In a training dataset, the correlations of US features with malignant thyroid nodules were assessed by multivariate logistic analysis. Multivariate logistic regression models involving the ACR TI-RADS score, radiating blood flow signals and their combination were built and validated internally and externally. The AUC with 95% asymptotic normal confidence interval as well as sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) with 95% exact binomial confidence intervals were calculated. RESULTS: Among 2475 patients (1818 women, age: 42.47 ± 11.57; 657 men, age: 42.16 ± 11.69), there were 3187 nodules (2342 malignant nodules and 845 benign nodules). Radiating blood flow signals were an independent risk factor for diagnosing thyroid carcinoma. In the training set, the AUC of the model using the combination of radiating blood flow signals and the ACR TI-RADS score (0.95 95 % CI: [0.94, 0.97]; P < 0.001) was significantly higher than that of the ACR TI-RADS model (0.91 [0.89, 0.93]). In the two internal validation sets and the external validation set, the AUCs of the combination model were 0.97 [0.96, 0.98], 0.92 [0.88, 0.96], and 0.91 [0.86, 0.95], respectively, and were all significantly higher than that of the ACR TI-RADS score (0.92 [0.90, 0.95], 0.86 [0.81, 0.91], 0.84 [0.79, 0.89]; P < 0.001). CONCLUSION: Radiating blood flow is a new US feature of thyroid carcinomas that can significantly improve the diagnostic performance vs. the ACR TI-RADS score.

Fabrication of SERS composite substrates using Ag nanotriangles-modified SiO2 photonic crystal and the application of malachite green detection.

A novel surface-enhanced Raman scattering (SERS) composite substrates on the basis of Ag triangular nanoplates(Ag TNPs)-modified SiO2 photonic crystals (PC) is fabricated and applied to the SERS detection of malachite green (MG). It consists of uniformly arranged Ag TNP@SiO2, a new PC. Notably, Ag TNP are uniformly aligned on the SiO2 surface, forming a three-dimensional high-density hotspot nanostructure. With the tip "hot spots" of Ag TNPs, Bragg diffraction of SiO2 and coupling enhancement between Ag TNPs and SiO2, the SERS enhancement of this composite substrates was multiplied. The effect on the SERS of Ag TNP@SiO2 composite substrate was systematically optimized by tuning Ag TNP size, size of SiO2 microspheres, coverage of Ag TNPs on SiO2 and fabrication method of Ag TNPs and PC. Moreover, the uniform of SERS composite substrates and Raman signal was dramatically increased by the method of vertical deposition. Eventually, the SERS composite substrates were employed in MG detection. Its broad detection range of 1 pM-1 µM and low limit of detection (LOD) of 0.49 pM indicated acceptable sensitivity and repeatability. This work illustrates the promising applicability in food safety analysis based on SERS composite substrates composed by Ag TNP@SiO2 with numerous SERS enhancements and excellent stability.

A novel multilevel iterative training strategy for the ResNet50 based mitotic cell classifier.

The number of mitotic cells is an important indicator of grading invasive breast cancer. It is very challenging for pathologists to identify and count mitotic cells in pathological sections with naked eyes under the microscope. Therefore, many computational models for the automatic identification of mitotic cells based on machine learning, especially deep learning, have been proposed. However, converging to the local optimal solution is one of the main problems in model training. In this paper, we proposed a novel multilevel iterative training strategy to address the problem. To evaluate the proposed training strategy, we constructed the mitotic cell classification model with ResNet50 and trained the model with different training strategies. The results showed that the models trained with the proposed training strategy performed better than those trained with the conventional strategy in the independent test set, illustrating the effectiveness of the new training strategy. Furthermore, after training with our proposed strategy, the ResNet50 model with Adam optimizer has achieved 89.26% F1 score on the public MITOSI14 dataset, which is higher than that of the state-of-the-art methods reported in the literature.

Molecular mechanisms and potential therapeutic targets in the pathogenesis of hypertension in visceral adipose tissue induced by a high-fat diet.

Background: Hypertension (HTN) presents a significant global public health challenge with diverse causative factors. The accumulation of visceral adipose tissue (VAT) due to a high-fat diet (HFD) is an independent risk factor for HTN. While various studies have explored pathogenic mechanisms, a comprehensive understanding of impact of VAT on blood pressure necessitates bioinformatics analysis. Methods: Datasets GSE214618 and GSE188336 were acquired from the Gene Expression Omnibus and analyzed to identify shared differentially expressed genes between HFD-VAT and HTN-VAT. Gene Ontology enrichment and protein-protein interaction analyses were conducted, leading to the identification of hub genes. We performed molecular validation of hub genes using RT-qPCR, Western-blotting and immunofluorescence staining. Furthermore, immune infiltration analysis using CIBERSORTx was performed. Results: This study indicated that the predominant characteristic of VAT in HTN was related to energy metabolism. The red functional module was enriched in pathways associated with mitochondrial oxidative respiration and ATP metabolism processes. Spp1, Postn, and Gpnmb in VAT were identified as hub genes on the pathogenic mechanism of HTN. Proteins encoded by these hub genes were closely associated with the target organs-specifically, the resistance artery, aorta, and heart tissue. After treatment with empagliflozin, there was a tendency for Spp1, Postn, and Gpnmb to decrease in VAT. Immune infiltration analysis confirmed that inflammation and immune response may not be the main mechanisms by which visceral adiposity contributes to HTN. Conclusions: Our study pinpointed the crucial causative factor of HTN in VAT following HFD. Spp1, Postn, and Gpnmb in VAT acted as hub genes that promote elevated blood pressure and can be targets for HTN treatment. These findings contributed to therapeutic strategies and prognostic markers for HTN.

Ferroptosis biomarkers predict tumor mutation burden's impact on prognosis in HER2-positive breast cancer.

BACKGROUND: Ferroptosis has recently been associated with multiple degenerative diseases. Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases. However, the association of iron proliferation-related genes with prognosis in HER2+ breast cancer (BC) patients is unclear. AIM: To identify and evaluate fresh ferroptosis-related biomarkers for HER2+ BC. METHODS: First, we obtained the mRNA expression profiles and clinical information of HER2+ BC patients from the TCGA and METABRIC public databases. A four-gene prediction model comprising PROM2, SLC7A11, FANCD2, and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort. Patients were stratified into high-risk and low-risk groups based on their median risk score, an independent predictor of overall survival (OS). Based on these findings, immune infiltration, mutations, and medication sensitivity were analyzed in various risk groupings. Additionally, we assessed patient prognosis by combining the tumor mutation burden (TMB) with risk score. Finally, we evaluated the expression of critical genes by analyzing single-cell RNA sequencing (scRNA-seq) data from malignant vs normal epithelial cells. RESULTS: We found that the higher the risk score was, the worse the prognosis was (P < 0.05). We also found that the immune cell infiltration, mutation, and drug sensitivity were different between the different risk groups. The high-risk subgroup was associated with lower immune scores and high TMB. Moreover, we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses. HRisk-HTMB patients had the worst prognosis, whereas LRisk-LTMB patients had the best prognosis (P < 0.0001). Analysis of the scRNA-seq data showed that PROM2, SLC7A11, and FANCD2 were significantly differentially expressed, whereas FH was not, suggesting that these genes are expressed mainly in cancer epithelial cells (P < 0.01). CONCLUSION: Our model helps guide the prognosis of HER2+ breast cancer patients, and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.

Effective dose of intranasal remimazolam for preoperative sedation in preschool children: a dose-finding study using Dixon's up-and-down method.

Background: Most preschool children are distressed during anesthesia induction. While current pharmacological methods are useful, there is a need for further optimization to an "ideal" standard. Remimazolam is an ultra-short-acting benzodiazepine, and intranasal remimazolam for pre-induction sedation may be promising. Methods: This study included 32 preschool children who underwent short and minor surgery between October 2022 and January 2023. After pretreatment with lidocaine, remimazolam was administered to both nostrils using a mucosal atomizer device. The University of Michigan Sedation Score (UMSS) was assessed for sedation 6, 9, 12, 15, and 20 min after intranasal atomization. We used Dixon's up-and-down method, and probit and isotonic regressions to determine the 50% effective dose (ED50) and 95% effective dose (ED95) of intranasal remimazolam for pre-induction sedation. Results: Twenty-nine pediatric patients were included in the final analysis. The ED50 and ED95 of intranasal remimazolam for successful pre-induction sedation, when processed via probit analysis, were 0.65 (95% confidence interval [CI], 0.59-0.71) and 0.78 mg/kg (95% CI, 0.72-1.07), respectively. In contrast, when processed by isotonic regression, they were 0.65 (95% CI: 0.58-0.72 mg/kg) and 0.78 mg/kg (95% CI: 0.69-1.08 mg/kg), respectively. At 6 min after intranasal remimazolam treatment, 81.2% (13/16) of "positive" participants were successfully sedated with a UMSS ≧ 1. All the "positive" participants were successfully sedated within 9 min. Conclusion: Intranasal remimazolam is feasible for preschool children with a short onset time. For successful pre-induction sedation, the ED50 and ED95 of intranasal remimazolam were 0.65 and 0.78 mg/kg, respectively.

S-acylation of YKT61 modulates its unconventional participation in the formation of SNARE complexes in Arabidopsis.

Hetero-tetrameric soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) complexes are critical for vesicle-target membrane fusion within the endomembrane system of eukaryotic cells. SNARE assembly involves four different SNARE motifs, Qa, Qb, Qc, and R, provided by three or four SNARE proteins. YKT6 is an atypical R-SNARE that lacks a transmembrane domain and is involved in multiple vesicle-target membrane fusions. Although YKT6 is evolutionarily conserved and essential, its function and regulation in different phyla seem distinct. Arabidopsis YKT61, the yeast and metazoan YKT6 homolog, is essential for gametophytic development, plays a critical role in sporophytic cells, and mediates multiple vesicle-target membrane fusion. However, its molecular regulation is unclear. We report here that YKT61 is S-acylated. Abolishing its S-acylation by a C195S mutation dissociates YKT61 from endomembrane structures and causes its functional loss. Although interacting with various SNARE proteins, YKT61 functions not as a canonical R-SNARE but coordinates with other R-SNAREs to participates in the formation of SNARE complexes. Phylum-specific molecular regulation of YKT6 may be evolved to allow more efficient SNARE-assembly in different eukaryotic cells.

Functional types of long trichoid sensilla responding to sex pheromone components in Plutella xylostella.

Sex pheromones, which consist of multiple components in specific ratios promote intraspecific sexual communications of insects. Plutella xylostella (L.) is a worldwide pest of cruciferous vegetables, the mating behavior of which is highly dependent on its olfactory system. Long trichoid sensilla on male antennae are the main olfactory sensilla that can sense sex pheromones. However, the underlying mechanisms remain unclear. In this study, 3 sex pheromone components from sex pheromone gland secretions of P. xylostella female adults were identified as Z11-16:Ald, Z11-16:Ac, and Z11-16:OH in a ratio of 9.4 : 100 : 17 using gas chromatography - mass spectrometry and gas chromatography with electroantennographic detection. Electrophysiological responses of 581 and 385 long trichoid sensilla of male adults and female adults, respectively, to the 3 components were measured by single sensillum recording. Hierarchical clustering analysis showed that the long trichoid sensilla were of 6 different types. In the male antennae, 52.32%, 5.51%, and 1.89% of the sensilla responded to Z11-16:Ald, Z11-16:Ac, and Z11-16:OH, which are named as A type, B type, and C type sensilla, respectively; 2.93% named as D type sensilla responded to both Z11-16:Ald and Z11-16:Ac, and 0.34% named as E type sensilla were sensitive to both Z11-16:Ald and Z11-16:OH. In the female antennae, only 7.53% of long trichoid sensilla responded to the sex pheromone components, A type sensilla were 3.64%, B type and C type sensilla were both 0.52%, D type sensilla were 1.30%, and 1.56% of the sensilla responded to all 3 components, which were named as F type sensilla. The responding long trichoid sensilla were located from the base to the terminal of the male antennae and from the base to the middle of the female antennae. The pheromone mixture (Z11-16:Ald : Z11-16:Ac : Z11-16:OH = 9.4 : 100 : 17) had a weakly repellent effect on female adults of P. xylostella. Our results lay the foundation for further studies on sex pheromone communications in P. xylostella.

Spatiotemporally Controlled T-Cell Combination Therapy for Solid Tumor.

Due to multidimensional complexity of solid tumor, development of rational T-cell combinations and corresponding formulations is still challenging. Herein, a triple combination of T cells are developed with Indoleamine 2,3-dioxygenase inhibitors (IDOi) and Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). To maximize synergism, a spatiotemporally controlled T-cell engineering technology to formulate triple drugs into one cell therapeutic, is established. Specifically, a sequentially responsive core-shell nanoparticle (SRN) encapsulating IDOi and CDK4/6i is anchored onto T cells. The yielded SRN-T cells migrated into solid tumor, and achieved a 1st release of IDOi in acidic tumor microenvironment (TME). Released IDOi restored tryptophan supply in TME, which activated effector T cells and inhibited Tregs. Meanwhile, 1st released core is internalized by tumor cells and degraded by glutathione (GSH), to realize a 2nd release of CDK4/6i, which induced up-regulated expression of C-X-C motif chemokine ligand 10 (CXCL10) and C-C motif chemokine ligand 5 (CCL5), and thus significantly increased tumor infiltration of T cells. Together, with an enhanced recruitment and activation, T cells significantly suppressed tumor growth, and prolonged survival of tumor-bearing mice. This study demonstrated rationality and superiority of a tri-drug combination mediated by spatiotemporally controlled cell-engineering technology, which provides a new treatment regimen for solid tumor.