Genome-Wide Identification, Expression Analysis under Abiotic Stress and Co-Expression Analysis of MATE Gene Family in Torreya grandis.

The multidrug and toxin efflux (MATE) family participates in numerous biological processes and plays important roles in abiotic stress responses. However, information about the MATE family genes in Torreya grandis remains unclear. In this study, our genome-wide investigation identified ninety MATE genes in Torreya grandis, which were divided into five evolutionary clades. TgMATE family members are located on eleven chromosomes, and a total of thirty TgMATEs exist in tandem duplication. The promoter analysis showed that most TgMATEs contain the cis-regulatory elements associated with stress and hormonal responses. In addition, we discovered that most TgMATE genes responded to abiotic stresses (aluminum, drought, high temperatures, and low temperatures). Weighted correlation network analysis showed that 147 candidate transcription factor genes regulated the expression of 14 TgMATE genes, and it was verified through a double-luciferase assay. Overall, our findings offer valuable information for the characterization of the TgMATE gene mechanism in responding to abiotic stress and exhibit promising prospects for the stress tolerance breeding of Torreya grandis.

IFNα-induced BST2+ tumor-associated macrophages facilitate immunosuppression and tumor growth in pancreatic cancer by ERK-CXCL7 signaling.

Pancreatic ductal adenocarcinoma (PDAC) features an immunosuppressive tumor microenvironment (TME) that resists immunotherapy. Tumor-associated macrophages, abundant in the TME, modulate T cell responses. Bone marrow stromal antigen 2-positive (BST2+) macrophages increase in KrasG12D/+; Trp53R172H/+; Pdx1-Cre mouse models during PDAC progression. However, their role in PDAC remains elusive. Our findings reveal a negative correlation between BST2+ macrophage levels and PDAC patient prognosis. Moreover, an increased ratio of exhausted CD8+ T cells is observed in tumors with up-regulated BST2+ macrophages. Mechanistically, BST2+ macrophages secrete CXCL7 through the ERK pathway and bind with CXCR2 to activate the AKT/mTOR pathway, promoting CD8+ T cell exhaustion. The combined blockade of CXCL7 and programmed death-ligand 1 successfully decelerates tumor growth. Additionally, cGAS-STING pathway activation in macrophages induces interferon (IFN)α synthesis leading to BST2 overexpression in the PDAC TME. This study provides insights into IFNα-induced BST2+ macrophages driving an immune-suppressive TME through ERK-CXCL7 signaling to regulate CD8+ T cell exhaustion in PDAC.

Preserving frozen stallion sperm on dry ice using polymers that modulate ice crystalization kinetics.

Cryopreserved semen is routinely shipped in liquid nitrogen. Dry ice could serve as an alternative coolant, however, frozen storage above liquid nitrogen temperatures (LN2, -196 °C) may negatively affect shelf-life and cryosurvival. In this study, we determined critical temperatures for storage of cryopreserved stallion sperm. We evaluated: (i) effects of cooling samples to different subzero temperatures (-10 °C to -80 °C) prior to storing in LN2, (ii) stability at different storage temperatures (i.e., in LN2, dry ice, -80 °C and -20 °C freezers, 5 °C refrigerator), and (iii) sperm cryosurvival during storage on dry ice (i.e., when kept below -70 °C and during warming). Furthermore, (iv) we analyzed if addition of synthetic polymers (PVP-40, Ficoll-70) modulates ice crystallization kinetics and improves stability of cryopreserved specimens. Sperm motility and membrane intactness were taken as measures of cryosurvival, and an artificial insemination trial was performed to confirm fertilizing capacity. We found that adding PVP-40 or Ficoll-70 to formulations containing glycerol reduced ice crystal sizes and growth during annealing. Post-thaw sperm viability data indicated that samples need to be cooled below -40 °C before they can be safely plunged and stored in LN2. No negative effects of relocating specimens from dry ice to LN2 and vice versa became apparent. However, sample warming above -50 °C during transport in dry ice should be avoided to ensure preservation of viability and fertility. Moreover, addition of PVP-40 or Ficoll-70 was found to increase sperm cryosurvival, especially under non-ideal storage conditions where ice recrystallization may occur.

Optimizing the aldosterone-to-renin ratio cut-off for screening primary aldosteronism based on cardiovascular risk: a collaborative study.

OBJECTIVES: Aldosterone-to-renin ratio (ARR) based screening is the first step in the diagnosis of primary aldosteronism (PA). However, the guideline-recommended ARR cutoff covers a wide range, from the equivalent of 1.3 to 4.9 ng·dl-1/mIU∙l-1. We aimed to optimize the ARR cutoff for PA screening based on the risk of cardiovascular diseases (CVD). METHODS: Longitudinally, we included hypertensive participants from the Framingham Offspring Study (FOS) who attended the sixth examination cycle and followed up until 2014. At baseline (1995-1998), we used circulating concentrations of aldosterone and renin to calculate ARR (unit: ng·dl-1/mIU∙l-1) among 1,433 subjects who were free of CVD. We used spline regression to calculate the ARR threshold based on the incident CVD. We used cross-sectional data from the Chongqing Primary Aldosteronism Study (CONPASS) to explore whether the ARR cutoff selected from FOS is applicable to PA screening. RESULTS: In FOS, CVD risk increased with an increasing ARR until a peak of ARR 1.0, followed by a plateau in CVD risk (hazard ratio 1.49, 95%CI 1.19-1.86). In CONPASS, when compared to essential hypertension with ARR < 1.0, PA with ARR ≥ 1.0 carried a higher CVD risk (odds ratio 2.24, 95%CI 1.41-3.55), while essential hypertension with ARR ≥ 1.0 had an unchanged CVD risk (1.02, 0.62-1.68). Setting ARR cutoff at 2.4 ~ 4.9, 10% ~30% of PA subjects would be unrecognized although they carried a 2.45 ~ 2.58-fold higher CVD risk than essential hypertension. CONCLUSIONS: The CVD risk-based optimal ARR cutoff is 1.0 ng·dl-1/mIU∙l-1 for PA screening. The current guideline-recommended ARR cutoff may miss patients with PA and high CVD risk. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03224312).

Mechanochemical Release of Fluorophores from a "Flex-activated" Mechanophore.

Optical force probes that can release force-dependent and visualized signals with minimal changes in the polymer main chains under mechanical load are highly sought after but currently limited. In this study, we introduce a flex-activated mechanophore (FA) based on the Diels-Alder adduct of anthracene and dimethyl acetylenedicarboxylatea that exhibits turn-on mechanofluorescence. We demonstrate that when FA is incorporated into polymer networks or in its crystalline state, it can release fluorescent anthracenes through a retro-Diels-Alder mechanochemical reaction under compression or hydrostatic high pressure, respectively. The flex-activated mechanism of FA is successfully confirmed. Furthermore, we systematically modulate the force delivered to the mechanophore by varying the crosslinking density of the networks and the applied macroscopic pressures. This modulation leads to incremental increases in mechanophore activation, successive release of anthracenes, and quantitative enhancement of fluorescence intensity. The exceptional potential of FA as a sensitive force probe in different bulk states is highlighted, benefiting from its unique flex-activated mode with highly emissive fluorophore releasing. Overall, this report enriches our understanding of the structures and functions of flex-activated mechanophores and polymeric materials.

Phosphoproteomics Reveals the Wolframin-Calcium Axis as an Important Pathogenic Signaling Node in Primary Aldosteronism.

BACKGROUND: Aldosterone-producing adenoma (APA) is a benign adrenal tumor with autonomous aldosterone production which causes hypertension and excess cardiovascular risk. Protein phosphorylation regulates aldosterone secretion from adrenal cortical cells, but how signaling networks are remodeled in APA remains unknown. METHODS: We performed an integrated proteomic and phosphoproteomic profiling of 15 APA and 10 matched nonfunctioning adrenocortical tumors (NFAT) based on the 4-dimensional label-free technique. We further validated our main findings in enlarged APA samples, mice, and adrenocortical cell line. RESULTS: The proteomic and phosphoproteomic profiling of APA and NFAT quantified 5989 proteins and 9011 phosphopeptides. We highlighted differentially expressed and phosphorylated proteins which modulated aldosterone synthesis and secretion from APA. As intracellular calcium is the central signal for aldosterone synthesis, our integrated calcium signaling network implicated wolframin in the control of calcium influx and CYP11B2 (aldosterone synthase) activation in APA (ratio of wolframin expression in APA to NFAT: 6.411, P<0.001). Among 97 APA cases for validation, a higher expression level of wolframin was associated with a higher plasma aldosterone concentration postcaptopril challenge test and a higher systolic blood pressure. In vitro, the secretion of aldosterone was enhanced by wolframin overexpression, while aldosterone secretion in response to potassium or angiotensin II was inhibited by the knockdown of wolframin. Further in vivo and in vitro data demonstrated the wolframin-calcium axis as an important regulator of CYP11B2 expression and aldosterone production. CONCLUSIONS: Wolframin is a regulatory protein in aldosterone hypersecretion. Remodeled calcium transportation and mitochondrial function are involved in wolframin-related aldosterone secretion.

Accuracy of Gallium-68 Pentixafor Positron Emission Tomography-Computed Tomography for Subtyping Diagnosis of Primary Aldosteronism.

Importance: Adrenal vein sampling (AVS) is the recommended procedure for subtyping primary aldosteronism (PA) as unilateral PA (UPA) or bilateral PA (BPA), with different treatment needed for each: adrenalectomy for UPA and medication for BPA. However, AVS is invasive and technically difficult, and how to subtype PA noninvasively is currently a great challenge. Objective: To evaluate the accuracy of gallium-68 pentixafor positron emission tomography-computed tomography (PET-CT) in subtyping PA using AVS as a reference standard. Design, Setting, and Participants: This diagnostic study was conducted at a tertiary hospital in China among patients diagnosed with PA. Enrollment was started in November 2021, with follow-up ending in May 2022. Exposures: : Patients were recruited to undergo gallium-68 pentixafor PET-CT and AVS. Main Outcomes and Measures: Maximum standardized uptake value (SUVmax) of each adrenal gland during PET-CT was measured to calculate the lateralization index of SUVmax. Area under the receiver operating characteristic curve (AUROC), specificity, and sensitivity were used to analyze the accuracy of the lateralization index based on SUVmax for subtyping PA. Results: Among 100 patients with PA who completed the study (47 female [47.0%] and 53 male [53.0%]; median [IQR] age, 49 [38-56] years), 43 individuals had UPA and 57 individuals had BPA. Aldosterone-cortisol ratio (Spearman ρ = 0.26; P < .001) in adrenal veins was positively correlated with SUVmax of adrenal glands at 10 minutes during PET-CT. Using lateralization index based on SUVmax at 10 minutes to identify UPA, the AUROC was 0.90 (95% CI, 0.83-0.97). A cutoff value for lateralization index based on SUVmax at 10 minutes set at 1.65 conferred a specificity of 1.00 (95% CI, 0.94-1.00) and sensitivity of 0.77 (95% CI, 0.61-0.88). The diagnostic concordance rate of PET-CT and AVS was 90 patients (90.0%) compared with 54 patients (54.0%) between traditional CT and AVS. Conclusions and Relevance: This study found good diagnostic accuracy of gallium-68 pentixafor PET-CT in differentiating UPA from BPA. These findings suggest that gallium-68 pentixafor PET-CT may be used to avoid invasive AVS in some patients with PA.

Analysis of pathogen distribution and antimicrobial resistance at infected sites in plastic surgery.

OBJECTIVE: By analyzing the distribution and drug resistance of common pathogen in different sites in plastic surgery to provide reference for clinicians to choose the best antibacterial treatment plan. METHODS: Pathogens of postoperative infection in plastic surgery from January 2011 to December 2021 were retrospectively analyzed to determine the species and quantity, and to access the trend of each pathogen's detection rate. The antibiotic sensitivity and distribution characteristics of common pathogens were studied in conjunction with the site of infection. RESULTS: A total of 1709 bacterial strains were detected, including 1244 gram-positive bacterial strains and 465 gram-negative bacterial strains. The main pathogen of perineum was Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa), while Staphylococcus aureus (S. aureus) was the most common pathogen in the other infected sites. The detection rate of methicillin-resistant S. aureus (MRSA) and methicillin-resistant coagulase-negative staphylococcus (MRCNS) was on the rise from 2011 to 2021. No S. aureus and coagulase-negative staphylococcus (CoNS) strains were resistant to vancomycin. The sensitive rate of S. aureus from all parts and CoNS from all sites except lower limbs and mandible was higher than 80% to linezolid. The resistance rate of S. aureus and CoNS in all parts to penicillin, clindamycin, and erythromycin was high. The susceptibility rate of CoNS in lower mandible was high to gentamicin. CONCLUSIONS: Staphylococcus aureus was the primary pathogen of gram-positive bacteria in all site of plastic surgery except perineum, followed by CoNS. The distribution and drug resistance of pathogen in different infection sites were different. We should formulate more accurate and reasonable antibacterial programs according to drug resistance results of various parts to reduce the emergence of resistant strains and effectively prevent and control infection.

Phenylalanine Ammonia Lyase GmPAL1.1 Promotes Seed Vigor under High-Temperature and -Humidity Stress and Enhances Seed Germination under Salt and Drought Stress in Transgenic Arabidopsis.

Seed vigor is an important agronomic attribute, essentially associated with crop yield. High-temperature and humidity (HTH) stress directly affects seed development of plants, resulting in the decrease of seed vigor. Therefore, it is particularly important to discover HTH-tolerant genes related to seed vigor. Phenylalanine ammonia lyase (PAL, EC 4.3.1.24) is the first rate-limiting enzyme in the phenylpropanoid biosynthesis pathway and a key enzyme involved in plant growth and development and environmental adaptation. However, the biological function of PAL in seed vigor remains unknown. Here, GmPAL1.1 was cloned from soybean, and its protein was located in the cytoplasm and cell membrane. GmPAL1.1 was significantly induced by HTH stress in developing seeds. The overexpression of GmPAL1.1 in Arabidopsis (OE) accumulated lower level of ROS in the developing seeds and in the leaves than the WT at the physiological maturity stage under HTH stress, and the activities of SOD, POD, and CAT and flavonoid contents were significantly increased, while MDA production was markedly reduced in the leaves of the OE lines than in those of the WT. The germination rate and viability of mature seeds of the OE lines harvested after HTH stress were higher than those of the WT. Compared to the control, the overexpression of GmPAL1.1 in Arabidopsis enhanced the tolerance to salt and drought stresses during germination. Our results suggested the overexpression of GmPAL1.1 in Arabidopsis promoted seed vigor at the physiological maturation period under HTH stress and increased the seeds' tolerance to salt and drought during germination.

Development and validation of model for sparing adrenal venous sampling in diagnosing unilateral primary aldosteronism.

CONTEXT: Current guidelines recommend adrenal venous sampling (AVS) to identify unilateral primary aldosteronism (UPA) before offering adrenalectomy. However, AVS is costly and technically challenging, limiting its use to expert centres. OBJECTIVE: To establish a model to predict UPA, and therefore, bypass the need for AVS prior to surgery. DESIGN AND SETTING: The model was developed in a Chinese cohort and validated in an Australian cohort. Previously published prediction models of UPA were also tested. PARTICIPANTS: primary aldosteronism patients with a definite subtyping diagnosis based on AVS and/or surgery. MAIN OUTCOME MEASURE: Diagnostic value of the model. RESULTS: In the development cohort (268 UPA and 88 bilateral primary aldosteronism), combinations of different levels of low serum potassium (≤3.0 or 3.5 mmol/l), high PAC (≥15-30 ng/dl), low PRC (≤2.5-10 µIU/ml) and presence of unilateral nodule on adrenal CT (>8-15 mm in diameter) showed specificity of 1.00 and sensitivity of 0.16-0.52. The model of serum potassium 3.5 mmol/l or less, PAC at least 20 ng/dl, PRC 5 µIU/ml or less plus a unilateral nodule at least 10 mm had the highest sensitivity of 0.52 (0.45-0.58) and specificity of 1.00 (0.96-1.00). In the validation cohort (84 UPA and 117 bilateral primary aldosteronism), the sensitivity and specificity of the model were 0.13 (0.07-0.22) and 1.00 (0.97-1.00), respectively. Ten previous models were tested, and only one had a specificity of 1.00 in our cohorts but with a very low sensitivity [0.07 (0.04-0.10) and 0.01 (0.00-0.06) in our development and validation cohorts, respectively]. CONCLUSION: A combination of high PAC, low PRC, low serum potassium and unilateral adrenal nodule could accurately determine primary aldosteronism subtype in 13-52% of patients with UPA and obviate the need for AVS before surgery.

EnSite NavX mapping system guided implantation of a dual-chamber permanent pacemaker in a 41-year-old pregnant woman with a 4-year follow-up.

BACKGROUND: X-ray fluoroscopy has been the primary cardiac imaging modality in permanent pacemaker implantation (PPI) operations, but it inevitably results in radiation exposure for both operators and patients. Fluoroscopy is considered a contraindication, especially in certain circumstances, such as gestation, during which the fetus is most sensitive to radiation exposure. Therefore, measures to avoid radiation exposure are necessary, and a more safe and feasible approach is needed for this procedure. Since the EnSite NavX mapping system (ENMS) can create the required geometric contours of those relevant cardiac structures and chambers, it can be used as an alternative to X-ray fluoroscopy in PPI. In addition, because the displacement of atrial leads is a common complication of PPI, lead displacement may occur more readily without fluoroscopic guidance. Therefore, reliable measures are required to prevent leads from displacement. CASE INTRODUCTION: A 41-year-old woman at the 15th week of gestation was referred to our department with recurrent episodes of syncope and amaurosis fugax for 2 years. Holter monitoring showed sinus rhythm, Mobitz Type II atrioventricular block and high-grade atrioventricular block with ventricular arrest up to 4945 ms. A dual-chamber PPI was performed successfully for the patient under the guidance of the ENMS instead of fluoroscopy. Displacement of atrial lead was effectively avoided by bending the top of atrial lead before implantation and making it a U-shape during operation, which left space for possible subsequent external pulling stress. CONCLUSIONS: For PPI, ENMS is a feasible and reliable alternative to traditional X-ray fluoroscopy, especially when performing operations on pregnant patients. By bending the top of the active-fixation atrial lead into a U-shape during operation, the displacement of atrial lead may be avoided.

Polymer mechanochemistry for the release of small cargoes.

The field of force-induced release of small cargoes within polymeric materials has experienced rapid growth over the past decade, not only including achieving diversified functional materials that report force, trigger degradation, activate drugs and release catalysts, but also involving investigations on the interesting force-coupled reactivity of mechanophores, such as ferrocenes. In this highlight article, we review the recent progress on polymer mechanochemistry that releases small cargoes, including small molecules and metal ions. Since mechanophores play a key role in force-responsive materials, we introduce the progress by discussing different types of mechanophores and their mechanochemical reactions for the release of acids, gases, fluorophores, drugs, iron ions, and so on. At the end, we provide our perspectives on the remaining challenges and future targets in this growing field.

Fabrication and Decryption of a Microarray of Digital Dithiosuccinimide Oligomers.

Digital polymers with precisely arranged binary units provide an important option for information storage. This is especially true if the digital polymers are assembled in a device, as it would be of great benefit for data writing and reading in practice. Herein, inspired by the DNA microarray technique, the programmable information storing and reading on a mass spectrometry target plate is proposed. First, an array of 4-bit sequence-coded dithiosuccinimide oligomers is efficiently built through sequential thiol-maleimide Michael couplings with good sequence readability by tandem mass spectrometry (MS/MS). Then, toward engineering microarrays for information storage, a programmed robotic arm is specifically designed for precisely loading sequence-coded oligomers onto the target plate, and a decoding software is developed for efficient readout of the data from MS/MS sequencing. Notably, short sequence-coded oligomer chains can be used to write long strings of information, and extra error-correction codes are not required as usual due to the inherent concomitant fragmentation signals. Not only text but also bitimages can be automatically stored and decoded with excellent accuracy. This work provides a promising platform of digital polymers for programmable information storing and reading.

Structural break-aware pairs trading strategy using deep reinforcement learning.

Pairs trading is an effective statistical arbitrage strategy considering the spread of paired stocks in a stable cointegration relationship. Nevertheless, rapid market changes may break the relationship (namely structural break), which further leads to tremendous loss in intraday trading. In this paper, we design a two-phase pairs trading strategy optimization framework, namely structural break-aware pairs trading strategy (SAPT), by leveraging machine learning techniques. Phase one is a hybrid model extracting frequency- and time-domain features to detect structural breaks. Phase two optimizes pairs trading strategy by sensing important risks, including structural breaks and market-closing risks, with a novel reinforcement learning model. In addition, the transaction cost is factored in a cost-aware objective to avoid significant reduction of profitability. Through large-scale experiments in real Taiwan stock market datasets, SAPT outperforms the state-of-the-art strategies by at least 456% and 934% in terms of profit and Sortino ratio, respectively.

Migraine and Ischemic Stroke: A Mendelian Randomization Study.

INTRODUCTION: Previous epidemiological studies have found an increased risk for ischemic stroke in patients with migraine; however, the evidence for a causal relationship between migraine and ischemic stroke is scarce. This study aims to explore the potential causal relationship between migraine and ischemic stroke and its subtypes [including large artery stroke (LAS), small vessel stroke (SVS), and cardioembolic stroke (CES)]. METHODS: We used data on genetic variants associated with migraine identified from a genome-wide association study (GWAS) meta-analysis among 889,018 European ancestries. Summary data for ischemic stroke and its subtypes were obtained from the MEGASTROKE consortium including up to 438,847 participants. We performed two-sample Mendelian randomization (MR) analyses using the inverse-variance-weighted method as the primary approach. The MR-Egger, weighted median, simple median, simple mode, and weighted mode methods were also conducted as sensitivity analyses to determine the robustness of our results. RESULTS: We failed to detect statistically significant associations between migraine and ischemic stroke (OR, 0.935; 95% CI 0.851-1.027; P = 0.159) and its subtypes (LAS: OR, 0.818; 95% CI 0.692-0.967; P = 0.018) (SVS: OR, 0.935; 95% CI 0.781-1.119; P = 0.460) (CES: OR, 1.015; 95% CI 0.867-1.189; P = 0.850). The results were consistent with the sensitivity analyses. CONCLUSIONS: By conducting a series of causal inference approaches, this study supports no causal effect of migraine on ischemic stroke and its subtypes.

Heightened Cardiovascular Risk in Hypertension Associated With Renin-Independent Aldosteronism Versus Renin-Dependent Aldosteronism: A Collaborative Study.

Background While both renin-dependent and renin-independent aldosterone secretion contribute to aldosteronism, their relative associations with cardiovascular disease (CVD) risk has not been investigated. Methods and Results A total of 2909 participants from the FOS (Framingham Offspring Study) with baseline, serum aldosterone concentration, and plasma renin concentration who attended the sixth examination cycle and were followed up until 2014 and who were free of CVD were included. We further recruited 2612 hypertensive participants from the CONPASS (Chongqing Primary Aldosteronism Study). Captopril challenge test was performed to confirm renin-dependent or -independent aldosteronism in CONPASS. Among 1433 hypertensive subjects of FOS, when compared with those with serum aldosterone concentration <10 ng dL-1 (normal aldosterone), participants who had serum aldosterone concentration ≥10 ng dL-1 and plasma renin concentration ≤15 mIU L-1 (identified as renin-independent aldosteronism) showed a higher risk of CVD (hazard ratio, 1.40 [95% CI, 1.08-1.82]), while those who had serum aldosterone concentration ≥10 ng dL-1 and plasma renin concentration >15 mIU L-1 (identified as renin-dependent aldosteronism) showed an unchanged CVD risk. In CONPASS, renin-independent aldosteronism carried a significantly higher risk of CVD than normal aldosterone (odds ratio, 2.57 [95% CI, 1.13-5.86]), while the CVD risk remained unchanged in renin-dependent aldosteronism. Elevation of the urinary potassium-to-sodium excretion ratio, reflective of mineralocorticoid receptor activity, was only observed in participants with renin-independent aldosteronism. Conclusions Among patients with hypertension, renin-independent aldosteronism is more closely associated with CVD risk than renin-dependent aldosteronism.

Group-2 Innate Lymphoid Cells Promote HCC Progression Through CXCL2-Neutrophil-Induced Immunosuppression.

BACKGROUND AND AIMS: Due to their inherent characteristics, the function of group-2 innate lymphoid cells (ILC2s) varies in a context-dependent manner. ILC2s are involved in certain liver diseases; however, their involvement in HCC is unknown. In the present study, we assessed the role of an HCC-derived ILC2 population in tumor progression. APPROACH AND RESULTS: Through FACS and single-cell RNA sequencing, we discovered that ILC2s were highly enriched in human HCC and correlated significantly with tumor recurrence and worse progression-free survival as well as overall survival in patients. Mass cytometry identified a subset of HCC-derived ILC2s that had lost the expression of killer cell lectin-like receptor subfamily G, member 1 (KLRG1). Distinct from their circulating counterparts, these hepatic ILC2s highly expressed CD69 and an array of tissue resident-related genes. Furthermore, reduction of E-cadherin in tumor cells caused the loss of KLRG1 expression in ILC2s, leading to their increased proliferation and subsequent accumulation in HCC sites. The KLRG1- ILC2 subset showed elevated production of chemotaxis factors, including C-X-C motif chemokine (C-X-C motif) ligand (CXCL)-2 and CXCL8, which in turn recruited neutrophils to form an immunosuppressive microenvironment, leading to tumor progression. Accordingly, restoring KLRG1 in ILC2s, inhibiting CXCL2 in ILC2s, or depleting neutrophils inhibited tumor progression in a murine HCC model. CONCLUSIONS: We identified HCC-associated ILC2s as an immune regulatory cell type that promotes tumor development, suggesting that targeting these ILC2s might lead to new treatments for HCC.

Mechanochemical Release of N-Heterocyclic Carbenes from Flex-Activated Mechanophores.

We have discovered a new flex-activated mechanophore that releases an N-heterocyclic carbene (NHC) under mechanical load. The mechanophore design is based upon NHC-carbodiimide (NHC-CDI) adducts and demonstrates an important first step toward flex-activated designs capable of further downstream reactivities. Since the flex-activation is non-destructive to the main polymer chains, the material can be subjected to multiple compression cycles to achieve iterative increases in the activation percentage of mechanophores. Two different NHC structures were demonstrated, signifying the potential modularity of the mechanophore design.

Dynamic versus static ultra-widefield fluorescein angiography in eyes with diabetic retinopathy: a pilot prospective cross-sectional study.

AIM: To analyze differences in ultra-widefield fluorescein angiography (UWFA) findings between dynamic and static images of eyes with diabetic retinopathy (DR). METHODS: This cross-sectional study included 28 eyes of 28 patients with DR undergoing UWFA. A series of UWFA images acquired from each patient were converted into a time-lapse video and used as a dynamic image. A single, clear, arteriovenous phase image was chosen as a static image. Non-perfusion index (NPI) and its correlation with vascular abnormalities in different zones were compared between dynamic and static UWFA imaging. RESULTS: NPI appeared to increase from the center to the far-periphery in both groups. Dynamic NPI was lower in the total retinal area (0.26 vs 0.29, P=0.009) and far-periphery (0.33 vs 0.36, adjusted P=0.042), which was contrary to the static NPI. Far-peripheral NPI was associated with intraretinal microvascular abnormality in the posterior area in both groups. CONCLUSION: Time-lapse dynamic UWFA imaging is a useful modality to differentially diagnose hypofluorescence in the most peripheral region. This modality could provide a reliable method for NPI measurement.

The AKT-independent MET-V-ATPase-MTOR axis suppresses liver cancer vaccination.

Despite recent progress in hepatitis treatment, there have been no significant advances in the development of liver cancer vaccines in recent years. In this study, we investigated the regulatory effect and potential mechanism of hepatocyte growth factor receptor (MET, also known as HGFR) on tumor vaccinations for liver cancer in mice. Herein, we demonstrate that MET expression is significantly associated with the immunogenicity of liver cancer in mice and humans, and that MET depletion dramatically enhances the protective efficacy of chemotherapy-based anti-liver cancer vaccination. Mechanistically, MET repressed liver cancer immunogenicity independent of the traditional PI3K-AKT cascade, and MET interacted with vacuolar ATP synthase (V-ATPase) and mediated the activation of mammalian target of rapamycin (MTOR), thus suppressing liver cancer immunogenicity. The efficacy of chemotherapy-based liver cancer vaccination was markedly enhanced by targeting the MET-V-ATPase-MTOR axis, highlighting a translational strategy for identifying MET-associated drug candidates for cancer prevention.