Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines.

Chiral amines are commonly used in the pharmaceutical and agrochemical industries1. The strong demand for unnatural chiral amines has driven the development of catalytic asymmetric methods1,2. Although the N-alkylation of aliphatic amines with alkyl halides has been widely adopted for over 100 years, catalyst poisoning and unfettered reactivity have been preventing the development of a catalyst-controlled enantioselective version3-5. Here we report the use of chiral tridentate anionic ligands to enable the copper-catalysed chemoselective and enantioconvergent N-alkylation of aliphatic amines with α-carbonyl alkyl chlorides. This method can directly convert feedstock chemicals, including ammonia and pharmaceutically relevant amines, into unnatural chiral α-amino amides under mild and robust conditions. Excellent enantioselectivity and functional-group tolerance were observed. The power of the method is demonstrated in a number of complex settings, including late-stage functionalization and in the expedited synthesis of diverse amine drug molecules. The current method indicates that multidentate anionic ligands are a general solution for overcoming transition-metal-catalyst poisoning.

Turning Food Protein Waste into Sustainable Technologies.

For each kilogram of food protein wasted, between 15 and 750 kg of CO2 end up in the atmosphere. With this alarming carbon footprint, food protein waste not only contributes to climate change but also significantly impacts other environmental boundaries, such as nitrogen and phosphorus cycles, global freshwater use, change in land composition, chemical pollution, and biodiversity loss. This contrasts sharply with both the high nutritional value of proteins, as well as their unique chemical and physical versatility, which enable their use in new materials and innovative technologies. In this review, we discuss how food protein waste can be efficiently valorized not only by reintroduction into the food chain supply but also as a template for the development of sustainable technologies by allowing it to exit the food-value chain, thus alleviating some of the most urgent global challenges. We showcase three technologies of immediate significance and environmental impact: biodegradable plastics, water purification, and renewable energy. We discuss, by carefully reviewing the current state of the art, how proteins extracted from food waste can be valorized into key players to facilitate these technologies. We furthermore support analysis of the extant literature by original life cycle assessment (LCA) examples run ad hoc on both plant and animal waste proteins in the context of the technologies considered, and against realistic benchmarks, to quantitatively demonstrate their efficacy and potential. We finally conclude the review with an outlook on how such a comprehensive management of food protein waste is anticipated to transform its carbon footprint from positive to negative and, more generally, have a favorable impact on several other important planetary boundaries.

Hundred-Fold Enhancement in the Anomalous Hall Effect Induced by Hydrogenation.

The anomalous Hall effect (AHE) is one of the most fascinating transport properties in condensed matter physics. However, the AHE magnitude, which mainly depends on net spin polarization and band topology, is generally small in oxides and thus limits potential applications. Here, we demonstrate a giant enhancement of AHE in a LaCoO3-induced 5d itinerant ferromagnet SrIrO3 by hydrogenation. The anomalous Hall resistivity and anomalous Hall angle, which are two of the most critical parameters in AHE-based devices, are found to increase to 62.2 µΩ·cm and 3%, respectively, showing an unprecedentedly large enhancement ratio of ∼10000%. Theoretical analysis suggests the key roles of Berry curvature in enhancing AHE. Furthermore, the hydrogenation concomitantly induces the significant elevation of Curie temperature from 75 to 160 K and 40-fold reinforcement of coercivity. Such giant regulation and very large AHE magnitude observed in SrIrO3 could pave the path for 5d oxide devices.

Copper-Catalyzed Enantioconvergent Radical N-Alkylation of Diverse (Hetero)aromatic Amines.

The 3d transition metal-catalyzed enantioconvergent radical cross-coupling provides a powerful tool for chiral molecule synthesis. In the classic mechanism, the bond formation relies on the interaction between nucleophile-sequestered metal complexes and radicals, limiting the nucleophile scope to sterically uncongested ones. The coupling of sterically congested nucleophiles poses a significant challenge due to difficulties in transmetalation, restricting the reaction generality. Here, we describe a probable outer-sphere nucleophilic attack mechanism that circumvents the challenging transmetalation associated with sterically congested nucleophiles. This strategy enables a general copper-catalyzed enantioconvergent radical N-alkylation of aromatic amines with secondary/tertiary alkyl halides and exhibits catalyst-controlled stereoselectivity. It accommodates diverse aromatic amines, especially bulky secondary and primary ones to deliver value-added chiral amines (>110 examples). It is expected to inspire the coupling of more nucleophiles, particularly challenging sterically congested ones, and accelerate reaction generality.

Genetic and prognostic analysis of blastoid and pleomorphic mantle cell lymphoma: a multicenter analysis in China.

Blastoid or pleomorphic mantle cell lymphoma (B/P-MCL) is characterized by high invasiveness and unfavorable outcomes, which is still a challenge for treating MCL. This retrospective study was performed to comprehensively analyze the clinical, genomic characteristics and treatment options of patients with B/PMCL from multicenter in China. Data were obtained from 693 patients with B/PMCL from three centers in China between April 1999 and December 2019. Seventy-four patients with BMCL (n = 43) or PMCL (n = 31) were included in the analysis. The median age of the cohort was 60.0 years with a male-to-female ratio of 2.89:1. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 44.1% and 46.0%, respectively. Mutations of TP53, ATM, NOTCH1, NOTCH2, NSD2, SMARCA4, CREBBP, KMT2D, FAT1, and TRAF2 genes were the most common genetic changes in B/P-MCL. Progression of disease within 12 months (POD12) could independently predict the poor prognosis of patients with blastoid and pleomorphic variants. Patients with POD12 carried a distinct mutation profile (TP53, SMARCA4, NSD2, NOTCH2, KMT2D, PTPRD, CREBBP, and CDKN2A mutations) compared to patients with non-POD12. First-line high-dose cytosine arabinoside exposure obtained survival benefits in these populations, and BTKi combination therapy as the front-line treatment had somewhat improvement in survival with no significant difference in the statistic. In conclusion, B/P-MCL had inferior outcomes and a distinct genomic profile. Patients with POD12 displayed a distinct mutation profile and a poor prognosis. New therapeutic drugs and clinical trials for B/P-MCL need to be further explored.

Effect of ultrasound-guided stellate ganglion block on inflammatory cytokines and postoperative recovery after partial hepatectomy: a randomised clinical trial.

BACKGROUND: Stellate ganglion block (SGB) has been shown to reduce perioperative complications in various surgeries. Because laparoscopic techniques and instruments have advanced during the past two decades, laparoscopic liver resection is being increasingly adopted worldwide. Lesser blood loss, fewer postoperative complications, and shorter postoperative hospital stays are the advantages of laparoscopic liver resection, as compared to conventional open surgery. There is an urgent need for an effective intervention to reduce perioperative complications and accelerate postoperative recovery. This study investigated the effect of ultrasound-guided SGB on enhanced recovery after laparoscopic partial hepatectomy. METHODS: We compared patients who received SGB with 0.5% ropivacaine (group S) with those who received SGB with 0.9% saline (group N). A total of 58 patients with partial hepatectomy were enrolled (30 S) and (28 N). Before induction of anesthesia, SGB was performed with 0.5% ropivacaine in group S and 0.9% saline in group N. MAIN OUTCOME: Comparison of serum inflammatory cytokines concentration at each time point. RESULTS: Main outcome: When comparing IL-6 and IL-10 concentrations among groups, group S showed less variation over time compared to group N. For comparison between groups, the serum IL-6 concentration in group S was lower than that in group N at 6 and 24 h after operation (P < 0.01), and there was a significant linear relationship between serum IL-6 concentration at 24 h after operation and hospitalization situation. CONCLUSIONS: Ultrasound-guided SGB can stabilize perioperative inflammatory cytokines plays a positive role in the enhanced recovery of patients after laparoscopic partial hepatectomy. The serum IL-6 level within 24 h after surgery may be used as a predictor of hospitalization. TRIAL REGISTRATION: The study was registered at the ClinicalTrials.gov (Registration date: 13/09/2021; Trial ID: NCT05042583).

0.75% ropivacaine may be a suitable drug in pregnant women undergoing urgent cesarean delivery during labor analgesia period.

BACKGROUND: 3% chloroprocaine (CP) has been reported as the common local anesthetic used in pregnant women undergoing urgent cesarean delivery during labor analgesia period. However, 0.75% ropivacaine is considered a promising and effective alternative. Therefore, we conducted a randomized controlled trial to compare the effectiveness and safety of 0.75% ropivacaine with 3% chloroprocaine for extended epidural anesthesia in pregnant women. METHODS: We conducted a double-blind, randomized, controlled, single-center study from November 1, 2022, to April 30, 2023. We selected forty-five pregnant women undergoing urgent cesarean delivery during labor analgesia period and randomized them to receive either 0.75% ropivacaine or 3% chloroprocaine in a 1:1 ratio. The primary outcome was the time to loss of cold sensation at the T4 level. RESULTS: There was a significant difference between the two groups in the time to achieve loss of cold sensation (303, 95%CI 255 to 402 S vs. 372, 95%CI 297 to 630 S, p = 0.024). There was no significant difference the degree of motor block (p = 0.185) at the Th4 level. Fewer pregnant women required additional local anesthetics in the ropivacaine group compared to the chloroprocaine group (4.5% VS. 34.8%, p = 0.011). The ropivacaine group had lower intraoperative VAS scores (p = 0.023) and higher patient satisfaction scores (p = 0.040) than the chloroprocaine group. The incidence of intraoperative complications was similar between the two groups, and no serious complications were observed. CONCLUSIONS: Our study found that 0.75% ropivacaine was associated with less intraoperative pain treatment, higher patient satisfaction and reduced the onset time compared to 3% chloroprocaine in pregnant women undergoing urgent cesarean delivery during labor analgesia period. Therefore, 0.75% ropivacaine may be a suitable drug in pregnant women undergoing urgent cesarean delivery during labor analgesia period. CLINICAL TRIAL NUMBER AND REGISTRY URL: The registration number: ChiCTR2200065201; http://www.chictr.org.cn , Principal investigator: MEN, Date of registration: 31/10/2022.

The use of amino acids and their derivates to mitigate against pesticide-induced toxicity.

Exposure to pesticides induces oxidative stress and deleterious effects on various tissues in non-target organisms. Numerous models investigating pesticide exposure have demonstrated metabolic disturbances such as imbalances in amino acid levels within the organism. One potentially effective strategy to mitigate pesticide toxicity involves dietary intervention by supplementing exogenous amino acids and their derivates to augment the body's antioxidant capacity and mitigate pesticide-induced oxidative harm, whose mechanism including bolstering glutathione synthesis, regulating arginine-NO metabolism, mitochondria-related oxidative stress, and the open of ion channels, as well as enhancing intestinal microecology. Enhancing glutathione synthesis through supplementation of substrates N-acetylcysteine and glycine is regarded as a potent mechanism to achieve this. Selection of appropriate amino acids or their derivates for supplementation, and determining an appropriate dosage, are of the utmost importance for effective mitigation of pesticide-induced oxidative harm. More experimentation is required that involves large population samples to validate the efficacy of dietary intervention strategies, as well as to determine the effects of amino acids and their derivates on long-term and low-dose pesticide exposure. This review provides insights to guide future research aimed at preventing and alleviating pesticide toxicity through dietary intervention of amino acids and their derivates.

Umpolung-Enabled Divergent Dearomative Carbonylations.

Although dearomative functionalizations enable the direct conversion of flat aromatics into precious three-dimensional architectures, the case for simple arenes remains largely underdeveloped due to the high aromatic stabilization energy. We herein report a dearomative sequential addition of two nucleophiles to arene π-bonds via umpolung of chromium-arene complexes. This mode enables divergent dearomative carbonylations of benzene derivatives by tolerating various nucleophiles in combination with alcohols or amines under CO-gas-free conditions, thus providing modular access to functionalized esters or amides. The tunable synthesis of 1,3- or 1,4-cyclohexadienes as well as the construction of all-carbon quaternary centers further highlight the versatility of this dearomatization. Diverse late-stage modifications and derivatizations towards synthetically challenging and bioactive molecules reveal the synthetic utility. A possible mechanism was proposed based on control experiments and intermediate tracking.

Selective Construction and Structural Transformation of Homogeneous Linear Metalla[4]catenane and Metalla[2]catenane Assemblies.

Although the synthesis of mechanically interlocked molecules has been extensively researched, selectively constructing homogeneous linear [4]catenanes remains a formidable challenge. Here, we selectively constructed a homogeneous linear metalla[4]catenane in a one-step process through the coordination-driven self-assembly of a bidentate benzothiadiazole derivative ligand and a binuclear half-sandwich rhodium precursor. The formation of metalla[4]catenanes was facilitated by cooperative interactions between strong sandwich-type π-π stacking and non-classical hydrogen bonds between the components. Moreover, by modulating the aromatic substituents on the binuclear precursor, two homogeneous metalla[2]catenanes were obtained. The molecular structures of these metallacatenanes were unambiguously characterized by single-crystal X-ray diffraction analysis. Additionally, reversible structural transformation between metal-catenanes and the corresponding metallarectangles could be achieved by altering their concentration, as confirmed by mass spectrometry and NMR spectroscopy studies.

Copper-Catalyzed Enantioconvergent Radical C(sp3)-N Cross-Coupling of Activated Racemic Alkyl Halides with (Hetero)aromatic Amines under Ambient Conditions.

The enantioconvergent C(sp3)-N cross-coupling of racemic alkyl halides with (hetero)aromatic amines represents an ideal means to afford enantioenriched N-alkyl (hetero)aromatic amines yet has remained unexplored due to the catalyst poisoning specifically for strong-coordinating heteroaromatic amines. Here, we demonstrate a copper-catalyzed enantioconvergent radical C(sp3)-N cross-coupling of activated racemic alkyl halides with (hetero)aromatic amines under ambient conditions. The key to success is the judicious selection of appropriate multidentate anionic ligands through readily fine-tuning both electronic and steric properties for the formation of a stable and rigid chelating Cu complex. Thus, this kind of ligand could not only enhance the reducing capability of a copper catalyst to provide an enantioconvergent radical pathway but also avoid the coordination with other coordinating heteroatoms, thereby overcoming catalyst poisoning and/or chiral ligand displacement. This protocol covers a wide range of coupling partners (89 examples for activated racemic secondary/tertiary alkyl bromides/chlorides and (hetero)aromatic amines) with high functional group compatibility. When allied with follow-up transformations, it provides a highly flexible platform to access synthetically useful enantioenriched amine building blocks.

Transcriptome and metabolome analysis reveals key genes and secondary metabolites of Casuarina equisetifolia ssp. incana in response to drought stress.

Casuarina equisetifolia is drought tolerant, salt tolerant, and able to grow in barren environments. It is often used to reduce wind damage, to prevent sand erosion, and to help establish plant communities in tropical and subtropical coastal zones. To determine the basis for its drought tolerance, we conducted transcriptomic and metabolic analyses of young branchlets under a non-drought treatment (D_0h) and 2-, 12-, and 24-h-long drought treatments (D_2h, D_12h, and D_24h). A total of 5033 and 8159 differentially expressed genes (DEGs) were identified in D_2h/D_0h and D_24h/D_0h. These DEGs were involved in plant hormone signal transduction, jasmonic acid (JA) biosynthesis, flavonoid biosynthesis, and phenylpropanoid biosynthesis. A total of 148 and 168 differentially accumulated metabolites (DAMs) were identified in D_12h/D_0h and D_24h/D_0h, which were mainly amino acids, phenolic acids, and flavonoids. In conclusion, C. equisetifolia responds to drought by regulating plant hormone signal transduction and the biosynthesis of JA, flavonoid, and phenylpropanoid. These results increase the understanding of drought tolerance in C. equisetifolia at both transcriptional and metabolic levels and provide new insights into coastal vegetation reconstruction and management.

The International Cardiac Arrest Research Consortium Electroencephalography Database.

OBJECTIVES: To develop the International Cardiac Arrest Research (I-CARE), a harmonized multicenter clinical and electroencephalography database for acute hypoxic-ischemic brain injury research involving patients with cardiac arrest. DESIGN: Multicenter cohort, partly prospective and partly retrospective. SETTING: Seven academic or teaching hospitals from the United States and Europe. PATIENTS: Individuals 16 years old or older who were comatose after return of spontaneous circulation following a cardiac arrest who had continuous electroencephalography monitoring were included. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Clinical and electroencephalography data were harmonized and stored in a common Waveform Database-compatible format. Automated spike frequency, background continuity, and artifact detection on electroencephalography were calculated with 10-second resolution and summarized hourly. Neurologic outcome was determined at 3-6 months using the best Cerebral Performance Category (CPC) scale. This database includes clinical data and 56,676 hours (3.9 terabytes) of continuous electroencephalography data for 1,020 patients. Most patients died ( n = 603, 59%), 48 (5%) had severe neurologic disability (CPC 3 or 4), and 369 (36%) had good functional recovery (CPC 1-2). There is significant variability in mean electroencephalography recording duration depending on the neurologic outcome (range, 53-102 hr for CPC 1 and CPC 4, respectively). Epileptiform activity averaging 1 Hz or more in frequency for at least 1 hour was seen in 258 patients (25%) (19% for CPC 1-2 and 29% for CPC 3-5). Burst suppression was observed for at least 1 hour in 207 (56%) and 635 (97%) patients with CPC 1-2 and CPC 3-5, respectively. CONCLUSIONS: The I-CARE consortium electroencephalography database provides a comprehensive real-world clinical and electroencephalography dataset for neurophysiology research of comatose patients after cardiac arrest. This dataset covers the spectrum of abnormal electroencephalography patterns after cardiac arrest, including epileptiform patterns and those in the ictal-interictal continuum.

Intermolecular Dearomative 1,2-Amination/Carbonylation via Nucleophilic Addition of Simple Amines to Arene π-Bonds.

The incorporation of the privileged amino functionality is of paramount importance in organic synthesis. In contrast to the well-developed amination methods for alkenes, the dearomative amination of arenes is largely underexplored due to the inherently inert reactivity of arene π-bonds and selectivity challenges. Herein, we report an intermolecular dearomative aminofunctionalization via direct nucleophilic addition of simple amines to chromium-bound arenes. This multicomponent 1,2-amination/carbonylation reaction enables rapid access to complicated alicyclic compounds containing amino and amide functionalities from benzene derivatives under CO-gas-free conditions, which also represents the first application of nitrogen-based nucleophiles in η6 -coordination-induced arene dearomatizations.

Trefoil-Shaped Metal-Organic Cages as Fluorescent Chemosensors for Multiple Detection of Fe3+, Cr2O72-, and Antibiotics.

The construction of metal-organic cages (MOCs) with specific structures and fluorescence sensing properties is of much importance and challenging. Herein, a novel phenanthroline-based metal-organic cage, [Cd3L3·6MeOH·6H2O] (1), was synthesized by metal-directed assembly of the ligand 3,3'-[(1E,1'E)-(1,10-phenanthroline-2,9-diyl)bis(ethene-2,1-diyl)]dibenzoic acid (H2L) and CdI2 using a solvothermal method. According to single-crystal X-ray analysis, cage 1 exhibits a rare trefoil-shaped structure. Meanwhile, the discrete MOCs are further stacked into a 3D porous supramolecular structure through abundant intermolecular C-H···O interactions. Additionally, through exploration of fluorescence sensing on cations, anions, and antibiotics in aqueous solution, the experimental results indicate that cage 1 has excellent fluorescence sensing abilities for Fe3+, Cr2O72-, and nitrofuran and nitroimidazole antibiotics. The sensing ability of 1 remains unaltered for five cycles toward all analytes. The above results suggested that cage 1 can be considered a potential multiple sensor for the detection of Fe3+, Cr2O72-, and some antibiotics.

Effect of different substituents on the fluorescence properties of precursors of synthetic GFP analogues and a polarity-sensitive lipid droplet probe with AIE properties for imaging cells and zebrafish.

The green fluorescent protein (GFP) is a purely natural specialty protein that has been widely used to design synthetic fluorescent probes. In the present work we designed and synthesized a series of fluorescent compounds akin to GFP precursors by a one-step method, and investigated the luminescence properties of the fluorescent compounds by varying the substituents. We presented the first systematic summary of the photophysical data including extinction coefficients and fluorescence quantum yields for this class of fluorescent dyes. We also carried out density functional theory (DFT) calculations for these dyes to investigate the effect of electronic effects due to different substituents. These studied optical properties may provide a reference for later probe design. More interestingly, we have developed a polarity-sensitive lipid droplet probe T-LD with AIE properties on this basis. The probe exhibited not only favorable pH stability and kinetic stability in terms of optical properties, but also solvent discolouration and polarity-sensitive properties, and was able to label intracellular lipid droplets. We successfully applied the probe for intracellular lipid droplet level monitoring and zebrafish imaging.

Dynamic changes of serum miR-105-3p expression and prognostic value evaluation of postoperative thyroid cancer.

Thyroid cancer (TC) originates from thyroid epithelial cells and is one of the common malignant tumors in the endocrine system. The aim of our study was to explore the dynamic changes of serum miR-105-3p expression after TC surgery and its correlation with clinicopathological manifestations, and evaluate its clinical value as a potential biomarker after surgery. A total of 100 TC patients were selected as the research objects. To detect serum miR-105-3p in patients and its correlation with tumor pathological characteristics and the dynamic changes of postoperative serum miR-105-3p in patients to evaluate its prognostic value as a potential biomarker. Serum miR-105-3p increases in patients with well-differentiated TC and lymph node metastasis; Serum miR-105-3p gradually decreases after surgery, and there is a significant difference between 4 days after surgery and before surgery,  serum miR-105-3p level can significantly distinguish between patients with poor prognosis and good prognosis within 2 years after the operation, and it can predict the improvement of the prognosis of TC after surgery. The level of serum miR-105-3p is closely related to tumor differentiation and lymph node metastasis in TC patients. Its level gradually decreases with the passage of time after surgery. It has a good diagnostic value for the prognosis of TC after surgery and is expected to become a TC surgery. Potential biomarkers for post-diagnosis.

Correlation between clinical characteristics and tinnitus severity in tinnitus patients of different sexes: an analytic retrospective study.

PURPOSE: This study aimed to explore whether sex is influences tinnitus severity and whether the risk factors for tinnitus severity are the same in tinnitus patients of different sexes. METHODS: This was a retrospective study of data from 1427 patients complaining of tinnitus in a local hospital otolaryngology clinic from November 2019 to January 2022. All patients were interviewed and assessed by otoscopy, pure-tone audiometry, tinnitus handicap inventory (THI), visual analogue scale (VAS), and tinnitus refinement test. RESULTS: THI values were higher in females than in males (P = 0.00). Types of tinnitus sounds (OR 0.667, P = 0.000) and degree of hearing loss (OR 1.318, P = 0.000) were risk factors for tinnitus severity in males. Types of tinnitus sounds (OR 0.789, P = 0.005), sensation level (OR 1.023, P = 0.037), tinnitus types (OR 1.163, P = 0.041), tinnitus location (OR 1.198, P = 0.026), and the degree of hearing loss (OR 1.303, P = 0.000) were risk factors for tinnitus severity in females. Sex was an influencing factor for tinnitus severity. There were different risk factors for the tinnitus severity in different sexes. CONCLUSION: The risk factors for tinnitus severity differed according to sex in tinnitus patients, and the risk factors for tinnitus severity were greater in women than in men. These findings add to the literature on sex differences in tinnitus and suggest that medical and psychological screening of affected individuals and customized tinnitus treatment for each individual with tinnitus are needed. TRIAL REGISTRATION NUMBER/DATE OF REGISTRATION: ChiCTR2200057958, 2022/3/24 (retrospectively registered trials).

Development of an audiological assessment and diagnostic model for high occupational noise exposure.

PURPOSE: To explore the diagnostic auditory indicators of high noise exposure and combine them into a diagnostic model of high noise exposure and possible development of hidden hearing loss (HHL). METHODS: We recruited 101 young adult subjects and divided them according to noise exposure history into high-risk and low-risk groups. All subjects completed demographic characteristic collection (including age, noise exposure, self-reported hearing status, and headset use) and related hearing examination. RESULTS: The 8 kHz (P = 0.039) and 10 kHz (P = 0.005) distortion product otoacoustic emission amplitudes (DPOAE) (DPs) in the high-risk group were lower than those in the low-risk group. The amplitudes of the summating potential (SP) (P = 0.017) and action potential (AP) (P = 0.012) of the electrocochleography (ECochG) in the high-risk group were smaller than those in the low-risk group. The auditory brainstem response (ABR) wave III amplitude in the high-risk group was higher than that in the low-risk group. When SNR = - 7.5 dB (P = 0.030) and - 5 dB (P = 0.000), the high-risk group had a lower speech discrimination score than that of the low-risk group. The 10 kHz DPOAE DP, ABR wave III amplitude and speech discrimination score under noise with SNR = - 5 dB were combined to construct a combination diagnostic indicator. The area under the ROC curve was 0.804 (95% CI 0.713-0.876), the sensitivity was 80.39%, and the specificity was 68.00%. CONCLUSIONS: We expect that high noise exposure can be detected early with this combined diagnostic indicator to prevent HHL or sensorineural hearing loss (SNHL). TRIAL REGISTRATION NUMBER/DATE OF REGISTRATION: ChiCTR2200057989, 2022/3/25.

Insulin reduces pyroptosis-induced inflammation by PDHA1 dephosphorylation-mediated NLRP3 activation during myocardial ischemia-reperfusion injury.

BACKGROUND: Previous studies proved that pyrin domain-containing protein 3 (NLRP3)-induced pyroptosis plays an important role in Myocardial ischemia-reperfusion injury (MIRI). Insulin can inhibit the activation of NLRP3 inflammasome, although the exact mechanism remains unclear. The aim of this study was to determine whether insulin reduces NLRP3-induced pyroptosis by regulating pyruvate dehydrogenase E1alpha subunit (PDHA1) dephosphorylation during MIRI. METHODS: Rat hearts were subject to 30 min global ischemia followed by 60 min reperfusion, with or without 0.5 IU/L insulin. Myocardial ischemia-reperfusion injury was evaluated by measuring myocardial enzymes release, Cardiac hemodynamics, pathological changes, infarct size, and apoptosis rate. Cardiac aerobic glycolysis was evaluated by measuring ATP, lactic acid content, and pyruvate dehydrogenase complex (PDHc) activity in myocardial tissue. Recombinant adenoviral vectors for PDHA1 knockdown were constructed. Pyroptosis-related proteins were measured by Western blotting analysis, immunohistochemistry staining, and ELISA assay, respectively. RESULTS: It was found that insulin significantly reduced the area of myocardial infarction, apoptosis rate, and improved cardiac hemodynamics, pathological changes, energy metabolism. Insulin inhibits pyroptosis-induced inflammation during MIRI. Subsequently, Adeno-associated virus was used to knock down cardiac PDHA1 expression. Knockdown PDHA1 not only promoted the expression of NLRP3 but also blocked the inhibitory effect of insulin on NLRP3-mediated pyroptosis in MIRI. CONCLUSIONS: Results suggest that insulin protects against MIRI by regulating PDHA1 dephosphorylation, its mechanism is not only to improve myocardial energy metabolism but also to reduce the NLRP3-induced pyroptosis.