Signatures of moiré trions in WSe2/MoSe2 heterobilayers.

Moiré superlattices formed by van der Waals materials can support a wide range of electronic phases, including Mott insulators1-4, superconductors5-10 and generalized Wigner crystals2. When excitons are confined by a moiré superlattice, a new class of exciton emerges, which holds promise for realizing artificial excitonic crystals and quantum optical effects11-16. When such moiré excitons are coupled to charge carriers, correlated states may arise. However, no experimental evidence exists for charge-coupled moiré exciton states, nor have their properties been predicted by theory. Here we report the optical signatures of trions coupled to the moiré potential in tungsten diselenide/molybdenum diselenide heterobilayers. The moiré trions show multiple sharp emission lines with a complex charge-density dependence, in stark contrast to the behaviour of conventional trions. We infer distinct contributions to the trion emission from radiative decay in which the remaining carrier resides in different moiré minibands. Variation of the trion features is observed in different devices and sample areas, indicating high sensitivity to sample inhomogeneity and variability. The observation of these trion features motivates further theoretical and experimental studies of higher-order electron correlation effects in moiré superlattices.

The Polyanionic Drug Suramin Neutralizes Histones and Prevents Endotheliopathy.

Drugs are needed to protect against the neutrophil-derived histones responsible for endothelial injury in acute inflammatory conditions such as trauma and sepsis. Heparin and other polyanions can neutralize histones but challenges with dosing or side effects such as bleeding limit clinical application. In this study, we demonstrate that suramin, a widely available polyanionic drug, completely neutralizes the toxic effects of individual histones, but not citrullinated histones from neutrophil extracellular traps. The sulfate groups on suramin form stable electrostatic interactions with hydrogen bonds in the histone octamer with a dissociation constant of 250 nM. In cultured endothelial cells (Ea.Hy926), histone-induced thrombin generation was significantly decreased by suramin. In isolated murine blood vessels, suramin abolished aberrant endothelial cell calcium signals and rescued impaired endothelial-dependent vasodilation caused by histones. Suramin significantly decreased pulmonary endothelial cell ICAM-1 expression and neutrophil recruitment caused by infusion of sublethal doses of histones in vivo. Suramin also prevented histone-induced lung endothelial cell cytotoxicity in vitro and lung edema, intra-alveolar hemorrhage, and mortality in mice receiving a lethal dose of histones. Protection of vascular endothelial function from histone-induced damage is a novel mechanism of action for suramin with therapeutic implications for conditions characterized by elevated histone levels.

Diagnostic performance of radiomics for predicting osteoporosis in adults: a systematic review and meta-analysis.

This study aimed to assess the diagnostic accuracy of radiomics for predicting osteoporosis and the quality of radiomic studies. The study protocol was prospectively registered on PROSPERO (CRD42023425058). We searched PubMed, EMBASE, Web of Science, and Cochrane Library databases from inception to June 1, 2023, for eligible articles that applied radiomic techniques to diagnosing osteoporosis or abnormal bone mass. Quality and risk of bias of the included studies were evaluated with radiomics quality score (RQS), METhodological RadiomICs Score (METRICS), and Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tools. The data analysis utilized the R program with mada, metafor, and meta packages. Ten retrospective studies with 5926 participants were included in the systematic review and meta-analysis. The overall risk of bias and applicability concerns for each domain of the studies were rated as low, except for one study which was considered to have a high risk of flow and time bias. The mean METRICS score was 70.1% (range 49.6-83.2%). There was moderate heterogeneity across studies and meta-regression identified sources of heterogeneity in the data, including imaging modality, feature selection method, and classifier. The pooled diagnostic odds ratio (DOR) under the bivariate random effects model across the studies was 57.22 (95% CI 27.62-118.52). The pooled sensitivity and specificity were 87% (95% CI 81-92%) and 87% (95% CI 77-93%), respectively. The area under the summary receiver operating characteristic curve (AUC) of the radiomic models was 0.94 (range 0.8 to 0.98). The results supported that the radiomic techniques had good accuracy in diagnosing osteoporosis or abnormal bone mass. The application of radiomics in osteoporosis diagnosis needs to be further confirmed by more prospective studies with rigorous adherence to existing guidelines and multicenter validation.

Arbuscular Mycorrhizal Fungus Alleviates Charged Nanoplastic Stress in Host Plants via Enhanced Defense-Related Gene Expressions and Hyphal Capture.

Contamination of small-sized plastics is recognized as a factor of global change. Nanoplastics (NPs) can readily enter organisms and pose significant ecological risks. Arbuscular mycorrhizal (AM) fungi are the most ubiquitous and impactful plant symbiotic fungi, regulating essential ecological functions. Here, we first found that an AM fungus, Rhizophagus irregularis, increased lettuce shoot biomass by 25-100% when exposed to positively and negatively charged NPs vs control, although it did not increase that grown without NPs. The stress alleviation was attributed to the upregulation of gene expressions involving phytohormone signaling, cell wall metabolism, and oxidant scavenging. Using a root organ-fungus axenic growth system treated with fluorescence-labeled NPs, we subsequently revealed that the hyphae captured NPs and further delivered them to roots. NPs were observed at the hyphal cell walls, membranes, and spore walls. NPs mediated by the hyphae were localized at the root epidermis, cortex, and stele. Hyphal exudates aggregated positively charged NPs, thereby reducing their uptake due to NP aggregate formation (up to 5000 nm). This work demonstrates the critical roles of AM fungus in regulating NP behaviors and provides a potential strategy for NP risk mitigation in terrestrial ecosystems. Consequent NP-induced ecological impacts due to the affected AM fungi require further attention.

PI3Kδ and mTOR dual inhibitors: Design, synthesis and anticancer evaluation of 3-substituted aminomethylquinoline analogues.

Phosphatidylinositide-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) have recently been identified as potential cancer targets. In our work, a new family of quinoline analogues was designed, developed, and evaluated as dual inhibitors of PI3Kδ/mTOR. The preliminary biological activity analysis led to the discovery of the lead compounds 5h and 5e. Compounds 5h and 5e exhibited excellent anti-tumor potency with IC50 of 0.26 µM and 0.34 µM against Ramos cells, respectively. Importantly, based on the enzymatic activity assay results, compounds 5h and 5e were identified as dual inhibitors of PI3Kδ and mTOR, with IC50 values of 0.042 µM and 0.056 µM for PI3Kδ and 0.059 µM and 0.073 µM for mTOR, respectively. Furthermore, these compounds showed superior selectivity for blocking PI3Kδ compared to other PI3K isoforms (α, ß, and γ), supporting the concept of developing inhibitors that specifically target PI3Kδ/mTOR. The most effective compound 5h was chosen for additional biological testing. At a low dose of 0.5 µM, a western blot investigation confirmed the anticancer effects by inhibiting the PAM cascade, which in turn reduced downstream biomarkers pAkt (Ser473), pAkt (Thr308), and pRPS6 (Ser235/236). Furthermore, it increased apoptosis at the early (10.03 times) and late (17.95 times) stages in the Annexin-V assay as compared to the standard. In addition, the expression of p53, caspase-3, caspase-9, and the Bax/BCl-2 ratio were all significantly increased by compound 5h in the ELISA assay. Based on these results, it appears that 5h may activate the intrinsic apoptosis pathway, which in turn triggers cell death. Furthermore, the anticancer effects could be attributed to the inhibition of PI3Kδ/mTOR, as shown by docking interactions. Lastly, it demonstrated improved in vitro metabolic stability and passed the in silico ADMET/drug-likeness test. This profile recommends 5h for future in vivo PK-PD and efficacy investigations in animal cancer models.

Longitudinal patient-reported outcomes after minimally invasive McKeown esophagectomy for patients with esophageal squamous cell carcinoma.

PURPOSE: Surgery for esophageal squamous cell carcinoma (ESCC) is characterized by a poor prognosis and high complication rate, resulting in a heavy symptom burden and poor health-related quality of life (QOL). We evaluated longitudinal patient-reported outcomes (PROs) to analyze the correlations between symptoms and QOL and their changing characteristics during postoperative rehabilitation. METHODS: We investigated patients with ESCC who underwent minimally invasive McKeown esophagectomy at Sichuan Cancer Hospital between April 2019 and December 2019. Longitudinal data of the clinical characteristics and PROs were collected. The MD Anderson Symptom Inventory and European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaires were used to assess symptoms and QOL and compare the trajectories of PROs during the investigation. RESULTS: A total of 244 patients with ESCC were enrolled in this study. Regarding QOL, role and emotional functions returned to baseline at 1 month after surgery, and cognitive and social functions returned to baseline at 3 months after surgery. However, physical function and global QOL did not return to baseline at 1 year after surgery. At 7 days and 1, 3, 6, and 12 months after surgery, the main symptoms of the patients were negatively correlated with physical, role, emotional, cognitive, and social functions and the overall health status (P < 0.05). CONCLUSION: Patients with ESCC experience reduced health-related QOL and persisting symptoms after minimally invasive McKeown esophagectomy, but a recovery trend was observed within 1 month. The long-term QOL after esophagectomy is acceptable.

Progress in the relationship between mechanical ventilation parameters and ventilator-related complications during perioperative anesthesia.

BACKGROUND: Mechanical ventilation, as an important respiratory support, plays an important role in general anesthesia and it is the cornerstone of intraoperative management of surgical patients. Different from spontaneous respiration, intraoperative mechanical ventilation can lead to postoperative lung injury, and its impact on surgical mortality cannot be ignored. Postoperative lung injury increases hospital stay and is related to preoperative conditions, anesthesia time, and intraoperative ventilation settings. METHOD: Through reading literature and research reports, the relationship between perioperative input parameters and output parameters related to mechanical ventilation and ventilator-related complications was reviewed, providing reference for the subsequent setting of input parameters of mechanical ventilation and new ventilation strategies. RESULTS: The parameters of inspiratory pressure rise time and inspiratory time can change the gas distribution, gas flow rate and airway pressure into the lungs, but there are few clinical studies on them. It can be used as a prospective intervention to study the effect of specific protective ventilation strategies on pulmonary complications after perioperative anesthesia. CONCLUSION: There are many factors affecting lung function after perioperative mechanical ventilation. Due to the difference of human body, the ventilation parameters suitable for each patient are different, and the deviation of each ventilation parameter can lead to postoperative pulmonary complications. Inspiratory pressure rise time and inspiratory time will be used as the new ventilation strategy.

Recent advances in early pregnancy loss diagnosis in dairy cows: New approaches.

Early pregnancy loss is a primary cause of low reproductive rates in dairy cows, posing severe economic losses to dairy farming. The accurate diagnosis of dairy cows with early pregnancy loss allows for oestrus synchronization, shortening day open, and increasing the overall conception rate of the herd. Several techniques are available for detecting early pregnancy loss in dairy cows, including rectal ultrasound, circulating blood progesterone, and pregnancy-associated glycoproteins (PAGs). Yet, there is a need to improve on existing techniques and develop novel strategies to identify cows with early pregnancy loss accurately. This manuscript reviews the applications of rectal ultrasound, circulating blood progesterone concentration, and PAGs in the diagnosis of pregnancy loss in dairy cows. The manuscript also discusses the recent progress of new technologies, including colour Doppler ultrasound (CDUS), interferon tau-induced genes (ISGs), and exosomal miRNA in diagnosing pregnancy loss in dairy cows. This study will provide an option for producers to re-breed cows with pregnancy loss, thereby reducing the calving interval and economic costs. Meanwhile, this manuscript might also act as a reference for exploring more economical and precise diagnostic technologies for early pregnancy loss in dairy cows.

Mechanisms of denitrifying granular sludge disintegration and calcium ion-enhanced re-granulation in acidic wastewater treatment.

Granular sludge is an alternative technology for the direct treatment of acidic nitrate-containing wastewater. Rapid remediation of disintegrated granules is essential to achieve efficient nitrogen removal. In this study, denitrifying granules were inactivated and disintegrated when the influent nitrate-nitrogen concentration was elevated from 240 to 360 mg L-1 in acidic wastewater (pH = 4.1) in a sequencing batch reactor. Tightly bound extracellular polymeric substances (TB-EPS) decreased by 60%, and extracellular protein (PN) was the main component of the reduced EPS. The three-dimensional excitation emission matrices (3D-EEM) results confirmed that the PNs that decreased were mainly tryptophan-like, tyrosine-like, and aromatic. This study further confirmed that the decrease in PN was mainly from the destruction of C=O (amide I) and N-H functional groups. Overloading of nitrogen-inhibited denitrifying activity and the destruction and dissolution of TB-EPS by acidic pH were responsible for granule disintegration, with PNs playing a major role in maintaining granule stability. Based on this, new granules with an average particle size of 454.4 µm were formed after calcium chloride addition; EPS nearly doubled during granule formation with PN as the dominant component, accounting for 64.7-78.4% of the EPS. Atomic force microscopy (AFM) revealed that PN-PN adhesion increased by 1.6-4.9 times in the presence of calcium ions, accelerating the re-granulation of disintegrated particles. This study provides new insights into the disintegration and remediation of granular sludge under acidic conditions.

[Comprehensive therapy of traditional Chinese medicine for erectile dysfunction with damp-heat stasis: A clinical observation of 103 cases].

OBJECTIVE: To assess the clinical effect and safety of comprehensive therapy of traditional Chinese medicine (TCM) in the treatment of erectile dysfunction (ED) with damp-heat stasis. METHODS: We selected 108 cases of ED with damp-heat stasis meeting the inclusion criteria and treated with tadalafil (the control group, n = 54) or tadalafil + comprehensive TCM therapy (the trial group, n = 54) in the First Affiliated Hospital of Henan University of Chinese Medicine in the same period. After 8 weeks of treatment, we recorded the patients' scores on IIEF-5, TCM syndrome, erectile quality (EQS), 9-Item Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Scale 7 (GAD-7). At 16 weeks of our study, we collected the efficacy parameters, safety indicators and adverse reactions by telephone follow-up and compared the data obtained between the two groups of patients. RESULTS: Totally, 103 of the patients completed the study, 51 in the control and 52 in the trial group. Compared with the baseline, the IIEF-5 and EQS scores were both markedly increased after 8 weeks of treatment in the trial group (12.35±3.00 vs 18.36±2.82, P< 0.05; 39.5 ï¼»30.25－43ï¼½ vs 67.5 ï¼»54.5－76.75ï¼½, P< 0.05) and the control (11.96±2.79 vs 15.88±3.86, P< 0.05; 38.0 ï¼»29－42ï¼½ vs 56 ï¼»49－64ï¼½, P< 0.05), even more significantly in the former than in the latter (P< 0.05); the TCM syndrome and GAD-7 scores were remarkably decreased in the trial (9.5 ï¼»8－12ï¼½ vs 4.0 ï¼»2.25－5ï¼½, P< 0.05; 5 ï¼»2.25－6.75ï¼½ vs 2.5 ï¼»1－4.75ï¼½, P< 0.05) and the control group (10.0 ï¼»8－12ï¼½ vs 5.0 ï¼»3－6ï¼½, P< 0.05; 5.0 ï¼»3－6ï¼½ vs 4.0 ï¼»2－5ï¼½, P< 0.05), even more significantly in the former than in the latter (P< 0.05), so were the PHQ-9 scores (P< 0.05), but with no statistically significant difference between the two groups (P > 0.05). The IIEF-5 scores of the two groups remained significantly higher than the baseline during the follow-up (P< 0.05), even higher in the trial than in the control group (17.04±2.60 vs 14.16±3.34, P< 0.05). No obvious abnormal safety indicators or adverse events were observed during the study. CONCLUSION: Comprehensive TCM therapy combined with tadalafil is superior to tadalafil alone in the treatment of ED with damp-heat stasis, and has a better long-term efficacy and a higher safety.

Ablation of Plasma Prekallikrein Decreases Low-Density Lipoprotein Cholesterol by Stabilizing Low-Density Lipoprotein Receptor and Protects Against Atherosclerosis.

BACKGROUND: High blood cholesterol accelerates the progression of atherosclerosis, which is an asymptomatic process lasting for decades. Rupture of atherosclerotic plaques induces thrombosis, which results in myocardial infarction or stroke. Lowering cholesterol levels is beneficial for preventing atherosclerotic cardiovascular disease. METHODS: Low-density lipoprotein (LDL) receptor (LDLR) was used as bait to identify its binding proteins in the plasma, and the coagulation factor prekallikrein (PK; encoded by the KLKB1 gene) was revealed. The correlation between serum PK protein content and lipid levels in young Chinese Han people was then analyzed. To investigate the effects of PK ablation on LDLR and lipid levels in vivo, we genetically deleted Klkb1 in hamsters and heterozygous Ldlr knockout mice and knocked down Klkb1 using adeno-associated virus-mediated shRNA in rats. The additive effect of PK and proprotein convertase subtilisin/kexin 9 inhibition also was evaluated. In addition, we applied the anti-PK neutralizing antibody that blocked the PK and LDLR interaction in mice. Mice lacking both PK and apolipoprotein e (Klkb1-/-Apoe-/-) were generated to assess the role of PK in atherosclerosis. RESULTS: PK directly bound LDLR and induced its lysosomal degradation. The serum PK concentrations positively correlated with LDL cholesterol levels in 198 young Chinese Han adults. Genetic depletion of Klkb1 increased hepatic LDLR and decreased circulating cholesterol in multiple rodent models. Inhibition of proprotein convertase subtilisin/kexin 9 with evolocumab further decreased plasma LDL cholesterol levels in Klkb1-deficient hamsters. The anti-PK neutralizing antibody could similarly lower plasma lipids through upregulating hepatic LDLR. Ablation of Klkb1 slowed the progression of atherosclerosis in mice on Apoe-deficient background. CONCLUSIONS: PK regulates circulating cholesterol levels through binding to LDLR and inducing its lysosomal degradation. Ablation of PK stabilizes LDLR, decreases LDL cholesterol, and prevents atherosclerotic plaque development. This study suggests that PK is a promising therapeutic target to treat atherosclerotic cardiovascular disease.

Self-pulsing and dual-mode lasing in a square microcavity semiconductor laser.

Self-pulsing and dual-mode lasing in a square microcavity semiconductor laser are studied experimentally. Self-sustained pulses originating from undamped relaxation oscillation induced by a two-mode interaction are obtained, as the injection current is slightly above the laser threshold. A repetition frequency of 4.4 GHz and a pulse width of 30-40 ps are obtained at a current of 8 mA. The laser switches to continuous-wave operation when the injection current is higher than a certain value, and dual-mode lasing with 30.7 GHz at 16 mA and 10.7 GHz at 27 mA are observed in the lasing spectra. Furthermore, the relative intensity noise spectra are presented to reveal the relationship between the lasing states and the dynamics induced by relaxation oscillation and mode beating.

Generation of High-Density High-Polarization Positrons via Single-Shot Strong Laser-Foil Interaction.

We put forward a novel method for producing ultrarelativistic high-density high-polarization positrons through a single-shot interaction of a strong laser with a tilted solid foil. In our method, the driving laser ionizes the target, and the emitted electrons are accelerated and subsequently generate abundant γ photons via the nonlinear Compton scattering, dominated by the laser. These γ photons then generate polarized positrons via the nonlinear Breit-Wheeler process, dominated by a strong self-generated quasistatic magnetic field B^{S}. We find that placing the foil at an appropriate angle can result in a directional orientation of B^{S}, thereby polarizing positrons. Manipulating the laser polarization direction can control the angle between the γ photon polarization and B^{S}, significantly enhancing the positron polarization degree. Our spin-resolved quantum electrodynamics particle-in-cell simulations demonstrate that employing a laser with a peak intensity of about 10^{23} W/cm^{2} can obtain dense (≳10^{18} cm^{-3}) polarized positrons with an average polarization degree of about 70% and a yield of above 0.1 nC per shot. Moreover, our method is feasible using currently available or upcoming laser facilities and robust with respect to the laser and target parameters. Such high-density high-polarization positrons hold great significance in laboratory astrophysics, high-energy physics, and new physics beyond the standard model.

Metabolic engineering of Escherichia coli for high-level production of violaxanthin.

BACKGROUND: Xanthophylls are a large class of carotenoids that are found in a variety of organisms and play particularly important roles in the light-harvesting and photoprotection processes of plants and algae. Violaxanthin is an important plant-derived xanthophyll with wide potential applications in medicines, foods, and cosmetics because of its antioxidant activity and bright yellow color. To date, however, violaxanthins have not been produced using metabolically engineered microbes on a commercial scale. Metabolic engineering for microbial production of violaxanthin is hindered by inefficient synthesis pathway in the heterologous host. We systematically optimized the carotenoid chassis and improved the functional expression of key enzymes of violaxanthin biosynthesis in Escherichia coli. RESULTS: Co-overexpression of crtY (encoding lycopene ß-cyclase), crtZ (encoding ß-carotene 3-hydroxylase), and ZEP (encoding zeaxanthin epoxidase) had a notable impact on their functions, resulting in the accumulation of intermediate products, specifically lycopene and ß-carotene. A chassis strain that did not accumulate the intermediate was optimized by several approaches. A promoter library was used to optimize the expression of crtY and crtZ. The resulting strain DZ12 produced zeaxanthin without intermediates. The expression of ZEP was further systematically optimized by using DZ12 as the chassis host. By using a low copy number plasmid and a modified dithiol/disulfide system, and by co-expressing a full electron transport chain, we generated a strain producing violaxanthin at about 25.28 ± 3.94 mg/g dry cell weight with decreased byproduct accumulation. CONCLUSION: We developed an efficient metabolically engineered Escherichia coli strain capable of producing a large amount of violaxanthin. This is the first report of a metabolically engineered microbial platform that could be used for the commercial production of violaxanthin.

Recent advances in small-molecule fluorescent probes for studying ferroptosis.

Ferroptosis is an iron-dependent, non-apoptotic form of programmed cell death driven by excessive lipid peroxidation (LPO). Mounting evidence suggests that the unique modality of cell death is involved in the development and progression of several diseases including cancer, cardiovascular diseases (CVDs), neurodegenerative disorders, etc. However, the pathogenesis and signalling pathways of ferroptosis are not fully understood, possibly due to the lack of robust tools for the highly selective and sensitive imaging of ferroptosis analytes in complex living systems. Up to now, various small-molecule fluorescent probes have been applied as promising chemosensors for studying ferroptosis through tracking the biomolecules or microenvironment-related parameters in vitro and in vivo. In this review, we comprehensively reviewed the recent development of small-molecule fluorescent probes for studying ferroptosis, with a focus on the analytes, design strategies and bioimaging applications. We also provided new insights to overcome the major challenges in this emerging field.

The protocol of tagging endogenous proteins with fluorescent tags using CRISPR-Cas9 genome editing.

The currently widely used CRISPR-Cas9 genome editing technology enables the editing of target genes (knock-out or knock-in) with high accuracy and efficiency. Guided by the small guide RNA, the Cas9 nuclease induces a DNA double-strand break at the targeted genomic locus. The DNA double-strand break can be repaired by the homology-directed repair pathway in the presence of a repair template. With the repair template containing the coding sequence of a fluorescent tag, the targeted gene can be inserted with the sequence of a fluorescent tag at the designed position. The genome editing mediated labeling of endogenous proteins with fluorescent tags avoids the potential artifacts caused by gene overexpression and substantially improves the reproductivity of imaging experiments. This protocol focuses on creating mammalian cell lines with endogenous proteins tagged with fluorescent proteins or self-labeling protein tags using CRISPR-Cas9 genome editing.

Brilliant circularly polarized γ-ray sources via single-shot laser plasma interaction.

Circularly polarized (CP) γ-ray sources are versatile for broad applications in nuclear physics, high-energy physics, and astrophysics. The laser-plasma based particle accelerators provide accessibility for much higher flux γ-ray sources than conventional approaches, in which, however, the circular polarization properties of the emitted γ-photons are usually neglected. In this Letter, we show that brilliant CP γ-ray beams can be generated via the combination of laser plasma wakefield acceleration and plasma mirror techniques. In a weakly nonlinear Compton scattering scheme with moderate laser intensities, the helicity of the driving laser can be transferred to the emitted γ-photons, and their average polarization degree can reach ∼61% (20%) with a peak brilliance of ≳1021 photons/(s · mm2 · mrad2 · 0.1% BW) around 1 MeV (100 MeV). Moreover, our proposed method is easily feasible and robust with respect to the laser and plasma parameters.

mGluR5/ERK signaling regulated the phosphorylation and function of glycine receptor α1ins subunit in spinal dorsal horn of mice.

Inhibitory glycinergic transmission in adult spinal cord is primarily mediated by glycine receptors (GlyRs) containing the α1 subunit. Here, we found that α1ins, a longer α1 variant with 8 amino acids inserted into the intracellular large loop (IL) between transmembrane (TM)3 and TM4 domains, was expressed in the dorsal horn of the spinal cord, distributed at inhibitory synapses, and engaged in negative control over nociceptive signal transduction. Activation of metabotropic glutamate receptor 5 (mGluR5) specifically suppressed α1ins-mediated glycinergic transmission and evoked pain sensitization. Extracellular signal-regulated kinase (ERK) was critical for mGluR5 to inhibit α1ins. By binding to a D-docking site created by the 8-amino-acid insert within the TM3-TM4 loop of α1ins, the active ERK catalyzed α1ins phosphorylation at Ser380, which favored α1ins ubiquitination at Lys379 and led to α1ins endocytosis. Disruption of ERK interaction with α1ins blocked Ser380 phosphorylation, potentiated glycinergic synaptic currents, and alleviated inflammatory and neuropathic pain. These data thus unraveled a novel, to our knowledge, mechanism for the activity-dependent regulation of glycinergic neurotransmission.

A comprehensive review of BET-targeting PROTACs for cancer therapy.

Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as an effective strategy for drug discovery, given their unique advantages over target protein inhibition. The bromodomain and extra-terminal (BET) family proteins play a key role in regulating oncogene expression and are considered attractive therapeutic targets for cancer therapy. Considering the therapeutic potential of BET proteins in cancer and the marked attractiveness of PROTACs, BET-targeting PROTACs have been extensively pursued. Recently, BET-targeting PROTACs based on new E3 ligases and novel strategies, such as light-activated, macrocyclic, folate-caged, aptamer-PROTAC conjugation, antibody-coupling, and autophagy-targeting strategies, have emerged. In the present review, we provide a comprehensive summary of advances in BET-targeting PROTACs.

Serum complement C1q level is associated with left ventricular hypertrophy induced by coarctation of the aorta: A retrospective observational study.

BACKGROUND: The complement system plays an important role in the development of left ventricular hypertrophy. Complement C1q is an initial component of the classical complement pathway and is related to many inflammatory diseases. We aimed to determine whether there was an association between serum complement C1q and left ventricular hypertrophy induced by coarctation of the aorta (CoA). METHODS: Based on whether CoA was combined with a large ventricular septal defect (VSD) or patent ductus arteriosus (PDA), the patients were divided into a simple CoA group (n = 15) and a complex CoA group (n = 13). Meanwhile, we selected simple large VSD (n = 14) patients and normal children (n = 28) as the control group. The serum complement C1q level was compared using immunity transmission turbidity among different groups. RESULTS: The preoperative content of C1q in the simple CoA group was significantly lower than that in the complex CoA group and normal group (96.97 ± 20.66 vs. 130.73 ± 35.78, 96.97 ± 20.66 vs. 156.21 ± 29.14, P < 0.05). There was no significant difference in the preoperative content of C1q between the complex CoA group and the large VSD group (P > 0.05). There was a negative correlation between the preoperative complement C1q content and the interventricular septal thickness and left ventricular posterior wall thickness (r = - 0.035, r = - 0.288, P < 0.05). The percentage of postoperative decrease in C1q in children with simple CoA or complex CoA was positively correlated with the time of cardiopulmonary bypass and aortic cross clamp, respectively (r = 0.797, r = 0.622, r = 0.898, r = 0.920, P < 0.05). There was no significant difference in the content of preoperative triglycerides (TG), total cholesterol (TCHO), high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein cholesterol (LDL-C) among the different groups (P > 0.05). In the simple CoA group and complex CoA group, the preoperative complement C1q, TG, TCHO, HDL-C and LDL-C levels were significantly higher than those after the operation (P < 0.05). There was no significant correlation between preoperative complement C1q and TG, TCHO, HDL-C or LDL-C (P > 0.05). CONCLUSIONS: Complement C1q has an inhibitory effect on the formation of left ventricular hypertrophy, which may not be mediated by regulating lipid metabolism. During cardiac surgery, complement C1q may have a protective effect against myocardial injury.