Clinically meaningful improvements in patient-reported outcomes in mitapivat-treated patients with pyruvate kinase deficiency.

Clinically meaningful benefits in the signs, symptoms, and impacts of #PKDeficiency as assessed by disease-specific patient-reported outcome measures were observed in mitapivat-treated adult patients in two phase 3 clinical trials.

Typhoon-induced stormwater drives nutrient dynamics and triggers phytoplankton blooms in Laizhou Bay, China.

In this study, we investigated the hydrological and ecological impacts of heavy rainfall caused by the storm Rumbia and Typhoon Lekima on Laizhou Bay (LZB) through land‒sea synchronous field surveys, online remote sensors, and simulated enclosure experiments. Within two weeks of Rumbia, approximately 9% and 16% of the annual riverine total nitrogen (TN) and total phosphorus (TP) fluxes, respectively, were transported to the LZB and the proportions were 17% and 35%, respectively, for Lekima. The land use on the watersheds increased the rates of land-derived nutrient loading and altered their biogeochemical forms. Consequently, the average concentrations of dissolved inorganic nitrogen (DIN) and phosphorus (DIP) in the LZB increased by 2.6 and 1.0 times post-Rumbia and by 3.5 and 1.3 times post-Lekima, respectively. Relatively lower salinity and temperature, sudden increases in DIN, and strengthened coastal currents stimulated the growth of highly adaptable and small diatoms, resulting in the first diatom blooms. Subsequently, a bloom of Noctiluca scintillans formed.

Huanglian Jiedu decoction inhibits vascular smooth muscle cell-derived foam cell formation by activating autophagy via suppressing P2RY12.

ETHNOPHARMACOLOGICAL RELEVANCE: Huanglian Jiedu Decoction (HLJDD) is a Chinese medicine with a long history of therapeutic application. It is widely used in treating atherosclerosis (AS) in Chinese medicine theory and clinical practice. However, the mechanism of HLJDD in treating AS remains unclear. AIM OF THE STUDY: To investigate the efficacy and mechanism of HLJDD in treating AS. MATERIALS AND METHODS: AS was induced on high-fat diet-fed ApoE-/- mice, with the aorta pathological changes evaluated with lipid content and plaque progression. In vitro, foam cells were induced by subjecting primary mouse aortic vascular smooth muscle cells (VSMCs) to oxLDL incubation. After HLJDD intervention, VSMCs were assessed with lipid stack, apoptosis, oxidative stress, and the expression of foam cell markers. The effects of P2RY12 were tested by adopting clopidogrel hydrogen sulfate (CDL) in vivo and transfecting P2RY12 over-expressive plasmid in vitro. Autophagy was inhibited by Chloroquine or transfecting siRNA targeting ATG7 (siATG7). The mechanism of HLJDD treating atherosclerosis was explored using network pharmacology and validated with molecular docking and co-immunoprecipitation. RESULTS: HLJDD exhibited a dose-dependent reduction in lipid deposition, collagen loss, and necrosis within plaques. It also reversed lipid accumulation and down-regulated the expression of foam cell markers. P2RY12 inhibition alleviated AS, while P2RY12 overexpression enhanced foam cell formation and blocked the therapeutic effects of HLJDD. Network pharmacological analysis suggested that HLJDD might mediate PI3K/AKT signaling pathway-induced autophagy. P2RY12 overexpression also impaired autophagy. Similarly, inhibiting autophagy counteracted the effect of CDL, exacerbated AS in vivo, and promoted foam cell formation in vitro. However, HLJDD treatment mitigated these detrimental effects by suppressing the PI3K/AKT signaling pathway. Immunofluorescence and molecular docking revealed a high affinity between P2RY12 and PIK3CB, while co-immunoprecipitation assays illustrated their interaction. CONCLUSIONS: HLJDD inhibited AS in vivo and foam cell formation in vitro by restoring P2RY12/PI3K/AKT signaling pathway-suppressed autophagy. This study is the first to reveal an interaction between P2RY12 and PI3K3CB.

A promising future of metal-N-heterocyclic carbene complexes in medicinal chemistry: The emerging bioorganometallic antitumor agents.

Metal complexes based on N-heterocyclic carbene (NHC) ligands have emerged as promising broad-spectrum antitumor agents in bioorganometallic medicinal chemistry. In recent decades, studies on cytotoxic metal-NHC complexes have yielded numerous compounds exhibiting superior cytotoxicity compared to cisplatin. Although the molecular mechanisms of these anticancer complexes are not fully understood, some potential targets and modes of action have been identified. However, a comprehensive review of their biological mechanisms is currently absent. In general, apoptosis caused by metal-NHCs is common in tumor cells. They can cause a series of changes after entering cells, such as mitochondrial membrane potential (MMP) variation, reactive oxygen species (ROS) generation, cytochrome c (cyt c) release, endoplasmic reticulum (ER) stress, lysosome damage, and caspase activation, ultimately leading to apoptosis. Therefore, a detailed understanding of the influence of metal-NHCs on cancer cell apoptosis is crucial. In this review, we provide a comprehensive summary of recent advances in metal-NHC complexes that trigger apoptotic cell death via different apoptosis-related targets or signaling pathways, including B-cell lymphoma 2 (Bcl-2 family), p53, cyt c, ER stress, lysosome damage, thioredoxin reductase (TrxR) inhibition, and so forth. We also discuss the challenges, limitations, and future directions of metal-NHC complexes to elucidate their emerging application in medicinal chemistry.

Impact of clinical pathway implementation satisfaction, work engagement, and hospital-patient relationship on quality of care in Chinese nurses.

AIMS: This study aimed to investigate how clinical pathway implementation satisfaction, work engagement, and hospital-patient relationship impact the quality of care that is provided by nurses in public hospitals. BACKGROUND: Clinical pathways are recommended as a form of quality improvement by broader healthcare systems and are widely used in the world. Nurses are the most involved group of healthcare professionals in the implementation of clinical pathways in public hospitals. So, it is important to investigate how their satisfaction with the process affects the quality of care they provide and influencing factors. METHODS: This descriptive cross-sectional study surveyed nurses practicing across seven tertiary public hospitals in Sichuan Province, China, online. The survey consisted of a questionnaire for the general characteristics of the participants and four Chinese maturity scales validated by previous studies: clinical pathway implementation satisfaction scale, work engagement scale, hospital-patient relationship perception scale, and quality of care scale. The bootstrap method was used to test a moderated mediation model using Hayes' PROCESS macro models 4 and 8. We followed STROBE guidelines to prepare the study report. RESULTS: A total of 880 nurses filled out the questionnaires, 821 of which were regarded as valid. Clinical pathway implementation satisfaction had a positive effect on quality of care (B = 0.873, P < 0.001). Work engagement played a mediation role between nurses' clinical pathway implementation satisfaction and the quality of care (effect = 0.080, Boot 95% CI = [0.023, 0.142]). This mediation model was moderated by the hospital-patient relationship (P < 0.01). CONCLUSION: Clinical pathway implementation satisfaction may enhance the quality of care by work engagement of nurses. Moreover, a good hospital-patient relationship can enhance the positive impact of nurses' satisfaction on work engagement and health service quality. IMPLICATIONS FOR NURSING AND NURSING POLICY: Public hospital managers need to pay attention to nurses' evaluation of and perceptions toward clinical pathway implementation and then take corresponding measures to improve their satisfaction to enhance the quality of care. At the same time, the government, society, and hospitals also need to foster good hospital-patient relationships to ensure that nurses have a high level of work engagement that aids in providing high-quality care services.

Memory-electroluminescence for multiple action-potentials combination in bio-inspired afferent nerves.

The development of optoelectronics mimicking the functions of the biological nervous system is important to artificial intelligence. This work demonstrates an optoelectronic, artificial, afferent-nerve strategy based on memory-electroluminescence spikes, which can realize multiple action-potentials combination through a single optical channel. The memory-electroluminescence spikes have diverse morphologies due to their history-dependent characteristics and can be used to encode distributed sensor signals. As the key to successful functioning of the optoelectronic, artificial afferent nerve, a driving mode for light-emitting diodes, namely, the non-carrier injection mode, is proposed, allowing it to drive nanoscale light-emitting diodes to generate a memory-electroluminescence spikes that has multiple sub-peaks. Moreover, multiplexing of the spikes can be obtained by using optical signals with different wavelengths, allowing for a large signal bandwidth, and the multiple action-potentials transmission process in afferent nerves can be demonstrated. Finally, sensor-position recognition with the bio-inspired afferent nerve is developed and shown to have a high recognition accuracy of 98.88%. This work demonstrates a strategy for mimicking biological afferent nerves and offers insights into the construction of artificial perception systems.

Geniposide ameliorates atherosclerosis by restoring lipophagy via suppressing PARP1/PI3K/AKT signaling pathway.

BACKGROUND: Atherosclerosis (AS) is the leading cause of global death, which manifests as arterial lipid stack and plaque formation. Geniposide is an iridoid glycoside extract from Gardenia jasminoides J.Ellis that ameliorates AS by mediating autophagy. However, how Geniposide regulates autophagy and treats AS remains unclear. PURPOSE: To evaluate the efficacy and mechanism of Geniposide in treating AS. STUDY DESIGN AND METHODS: Geniposide was administered to high-fat diet-fed ApoE-/- mice and oxidized low-density lipoprotein-incubated primary vascular smooth muscle cells (VSMCs). AS was evaluated with arterial lipid stack, plaque progression, and collagen loss in the artery. Foam cell formation was detected by lipid accumulation, inflammation, apoptosis, and the expression of foam cell markers. The mechanism of Geniposide in treating AS was assessed using network pharmacology. Lipophagy was measured by lysosomal activity, expression of lipophagy markers, and the co-localization of lipids and lipophagy markers. The effects of lipophagy were blocked using Chloroquine. The role of PARP1 was assessed by Olaparib (a PARP1 inhibitor) intervention and PARP1 overexpression. RESULTS: In vivo, Geniposide reversed high-fat diet-induced hyperlipidemia, plaque progression, and inflammation. In vitro, Geniposide inhibited VSMC-derived foam cell formation by suppressing lipid stack, apoptosis, and the expressions of foam cell markers. Network pharmacological analysis and in vitro validation suggested that Geniposide treated AS by enhancing lipophagy via suppressing the PI3K/AKT signaling pathway. The benefits of Geniposide in alleviating AS were offset by Chloroquine in vivo and in vitro. Inhibiting PARP1 using Olaparib promoted lipophagy and alleviated AS progression, while PARP1 overexpression exacerbated foam cell formation and lipophagy blockage. The above effects of PARP1 were weakened by PI3K inhibitor LY294002. PARP1 also inhibited the combination of the ABCG1 and PLIN1. CONCLUSION: Geniposide alleviated AS by restoring PARP1/PI3K/AKT signaling pathway-suppressed lipophagy. This study is the first to present the lipophagy-inducing effect of Geniposide and the binding of ABCG1 and PLIN1 inhibited by PARP1.

Palladium-catalyzed (Z)-selective allylation of phosphine oxides with vinylethylene carbonates to construct phosphorus allyl alcohols.

Allylphosphine oxide compounds are important building blocks with broad applications in organic synthesis and pharmaceutical science. Herein, we report an unprecedented palladium-catalyzed allylation of phosphine oxides with vinylethylene carbonates, producing various phosphorus allyl alcohols in excellent yields with high Z-selectivity. In addition, gram-scale synthesis and further functional group transformations demonstrate the practical utility of this synthetic method.

Satisfaction with clinical pathway implementation versus job performance of clinicians: empirical evidence on the mediating role of work engagement from public hospitals in Sichuan, China.

BACKGROUND: The job performance of clinicians is a clear indicator of both hospital capacity and the level of hospital service. It plays a crucial role in maintaining the effectiveness and quality of medical care. Clinical pathways are a systematic method of quality improvement successfully recommended by broader healthcare systems. Since clinicians play a key role in implementing clinical pathways in public hospitals, this study aims to investigate the effect of the satisfaction of clinicians in public hospitals with clinical pathway implementation on their job performance. METHODS: A cross-sectional study design was used. Questionnaires were administered online. A total of 794 clinicians completed the questionnaires in seven tertiary public hospitals in Sichuan Province, China, of which 723 were valid for analysis. Questionnaires contained questions on social demographic characteristics, satisfaction with clinical pathway implementation, work engagement, and job performance. Structural Equation Model (SEM) was used to test the hypotheses. RESULTS: The satisfaction of clinicians in public hospitals with clinical pathway implementation was significantly positively correlated with work engagement (r = 0.570, P < 0.01) and job performance (r = 0.522, P < 0.01). A strong indirect effect of clinicians' satisfaction with clinical pathway implementation on job performance mediated by work engagement was observed, and the value of this effect was 0.383 (boot 95%CI [0.323, 0.448]). CONCLUSION: The satisfaction of clinicians in public hospitals with clinical pathway implementation not only directly influences their job performance, but also indirectly affects it through the mediating variable of work engagement. Therefore, managers of public hospitals need to pay close attention to clinicians' evaluation and perception of the clinical pathway implementation. This entails taking adequate measures, such as providing strong organizational support and creating a favorable environment for the clinical pathway implementation. Additionally, focusing on teamwork to increase clinicians' satisfaction can further enhance job performance. Furthermore, managers should give higher priority to increasing employees' work engagement to improve clinicians' job performance.

Silver Nanowire Networks with Moisture-Enhanced Learning Ability.

The human brain possesses a remarkable ability to memorize information with the assistance of a specific external environment. Therefore, mimicking the human brain's environment-enhanced learning abilities in artificial electronic devices is essential but remains a considerable challenge. Here, a network of Ag nanowires with a moisture-enhanced learning ability, which can mimic long-term potentiation (LTP) synaptic plasticity at an ultralow operating voltage as low as 0.01 V, is presented. To realize a moisture-enhanced learning ability and to adjust the aggregations of Ag ions, we introduced a thin polyvinylpyrrolidone (PVP) coating layer with moisture-sensitive properties to the surfaces of the Ag nanowires of Ag ions. That Ag nanowire network was shown to exhibit, in response to the humidity of its operating environment, different learning speeds during the LTP process. In high-humidity environments, the synaptic plasticity was significantly strengthened with a higher learning speed compared with that in relatively low-humidity environments. Based on experimental and simulation results, we attribute this enhancement to the higher electric mobility of the Ag ions in the water-absorbed PVP layer. Finally, we demonstrated by simulation that the moisture-enhanced synaptic plasticity enabled the device to adjust connection weights and delivery modes based on various input patterns. The recognition rate of a handwritten data set reached 94.5% with fewer epochs in a high-humidity environment. This work shows the feasibility of building our electronic device to achieve artificial adaptive learning abilities.

Local injection of platelet-rich plasma offers a new therapeutic option for the treatment of esophagotracheal fistula: a case report.

Esophagotracheal fistula (ETF), one of the most serious complications in the treatment of esophageal cancer, presents a complex management challenge. Early diagnosis and treatment are crucial to alleviate clinical symptoms and improve the quality of life of patients with ETF. The most commonly used method for treating ETF is esophageal stenting. However, because of the variable location and size of the fistula, stent placement alone sometimes fails to completely close the fistula, and complications such as fracture and displacement of the esophageal stent may occur. Therefore, safer and more effective methods for the treatment of ETF are required. In recent years, the application of bioactive factors to promote human tissue repair and wound healing has increased and achieved good therapeutic results. We herein describe a case in which we performed endoscopic injection of platelet-rich plasma directly into the ETF site and achieved a favorable outcome. This case suggests that local injection of platelet-rich plasma is a novel treatment modality for ETF.

Network pharmacology and in vivo evidence of the pharmacological mechanism of geniposide in the treatment of atherosclerosis.

BACKGROUND: Atherosclerosis (AS) is a fundamental pathological state in various cardiovascular diseases. Geniposide, which is the main active component of Gardenia jasminides, is effective against AS. However, the underlying molecular mechanisms remain unclear. Here, we sought to elucidate them. METHODS: The targets of AS and geniposide were collected from online public databases. The potential mechanism of Geniposide in treating AS was predicted by constructing a protein-protein interaction (PPI) network and conducting Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses. Hub proteins and core pathways were verified by molecular docking and in vivo experiments. Moreover, the effect of geniposide on AS was assessed by measuring the atherosclerotic plaque area in the thoracic aorta of mice. ApoE-/- mice were used to establish AS models and randomly divided into different groups. Two different doses of geniposide were administered to the mice. Hematoxylin and eosin (HE) staining was performed to evaluate the effects of geniposide on AS. Oil Red O and Sirius Red staining were used to evaluate plaque stability. The protein expression of key markers involved in the signalling pathways was examined using western blotting and immunofluorescence. RESULTS: A total of 239 active targets, 3418 AS-related disease targets, and 129 overlapping targets were identified. Hub genes were detected, and molecular docking revealed that geniposide strongly interacted with hub proteins (AKT1, VEGFA, CTNNB1, MMP9, and EGFR). Moreover, 109 signalling pathways, including the Rap1 signalling pathway, were identified using enrichment analysis. The results of in vivo experiments demonstrated that geniposide reduced body weight and blood lipid levels, alleviated the formation of atherosclerotic plaques, enhanced plaque stability, and inhibited inflammation, at least partially, by activating the Rap1/PI3K/Akt signalling pathway in ApoE-/- mice. CONCLUSION: Geniposide can alleviate AS and enhance the stability of atherosclerotic plaques by regulating the Rap1/PI3K/Akt signalling pathway.

Induced attack with prescribed consensus trajectory against multiagent systems.

This paper proposes a new induced attack strategy against multiagent systems from the perspective of the attacker. It is noted that the induced attack can drive multiagent systems as a whole to follow a specific trajectory prescribed by the attacker, which cannot be achieved by denial-of-service attacks or deception attacks. Firstly, the induced attack signal is produced by establishing an attack generation exosystem, whose dynamics can be regulated to generate the prescribed consensus trajectory. Then, by the local state information and the induced attack signal among partial agents, a new induced attack protocol is proposed, which consists of the nominal consensus term and the induced attack term. By constructing the projection of the induced attack signal onto the consensus subspace, an explicit expression of the prescribed consensus trajectory is determined, which describes the movement trajectory of the entire multiagent system under the induced attack. Meanwhile, the induced attack design criterion is proposed to determine the dynamics matrix of the attack generation exosystem via the robust H∞ scheme. Finally, the simulation example is performed to illustrate the effectiveness of theoretical results.

Electron Oscillation-Induced Splitting Electroluminescence from Nano-LEDs for Device-Level Encryption.

Data security is a major concern in digital age, which generally relies on algorithm-based mathematical encryption. Recently, encryption techniques based on physical principles are emerging and being developed, leading to the new generation of encryption moving from mathematics to the intersection of mathematics and physics. Here, device-level encryption with ideal security is ingeniously achieved using modulation of the electron-hole radiative recombination in a GaN-light-emitting diode (LED). When a nano-LED is driven in the non-carrier injection mode, the oscillation of confined electrons can split what should be a single light pulse into multiple pulses. The morphology (amplitude, shape, and pulse number) of those history-dependent multiple pulses that act as carriers for transmitted digital information depends highly on the parameters of the driving signals, which makes those signals mathematically uncrackable and can increase the volume and security of transmitted information. Moreover, a hardware and software platform are designed to demonstrate the encrypted data transmission based on the device-level encryption method, enabling recognition of the entire ASCII code table. The device-level encryption based on splitting electroluminescence provides an encryption method during the conversion process of digital signals to optical signals and can improve the security of LED-based communication.

Psychometric validation of the Pyruvate Kinase Deficiency Diary and Pyruvate Kinase Deficiency Impact Assessment in adults in the phase 3 ACTIVATE trial.

BACKGROUND: Pyruvate kinase (PK) deficiency is a rare hereditary disorder characterized by chronic hemolytic anemia and serious sequalae which negatively affect patient quality of life. This study aimed to psychometrically validate the first disease-specific patient-reported outcome (PRO) instruments: the 7-item PK Deficiency Diary (PKDD) and 12-item PK Deficiency Impact Assessment (PKDIA), designed to assess signs, symptoms, and impacts of PK deficiency in patients enrolled in the ACTIVATE global phase 3 study of mitapivat versus placebo (NCT03548220). METHODS: All validation analyses for the PKDD and PKDIA were performed on blinded data, with analyses on item integrity, scoring, reliability, and validity conducted on data from screening and baseline. Completion rates and baseline response distributions were characterized using descriptive statistics. Item response modelling was used to inform a weighted scoring system. Reliability was assessed by internal consistency and test-retest reliability; and validity by convergent and known-groups analyses. RESULTS: Of the 80 adults enrolled, baseline data were available for 77 (96.3%) and 78 (97.5%) patients for the PKDD and PKDIA, respectively. Item responses skewed right, indicating that mean values exceeded median values, especially for items utilizing a 0-10 numeric scale, which were subsequently recoded to a 0-4 scale; 4 items were removed from the PKDIA due to redundancy or low relevance to the trial population. Both the PKDD and PKDIA demonstrated high internal consistency (McDonald's coefficient ω = 0.86 and 0.90, respectively), test-retest reliability (intra-class coefficients of 0.94 and 0.87, respectively), and convergent validity with other PROs (linear correlation coefficients [|r|] between 0.30-0.73 and 0.50-0.82, respectively). CONCLUSIONS: The findings provide evidence of validity and reliability for the PKDD and PKDIA, the first disease-specific PRO measures for PK deficiency, and can therefore increase understanding of, and more accurately capture, the wider impact of PK deficiency on health-related quality of life. Trial registration ClinicalTrials.gov, NCT03548220. Registered June 07, 2018; https://www. CLINICALTRIALS: gov/ct2/show/NCT03548220 .

Pyruvate kinase (PK) deficiency is a rare genetic blood disorder with a wide range of signs and symptoms that may have a negative impact on patients' quality of life. Patient-reported outcome (PRO) instruments are tools that assess how a disease affects a patient from the patient's perspective. These instruments must go through a validation process to make sure they truly capture the patient's experience with their condition or its treatment. This study aimed to validate two new PRO instruments in adult patients enrolled in the ACTIVATE clinical trial (NCT03548220), where patients with PK deficiency received the drug mitapivat or a placebo. These two new PRO instruments are the first to be developed specifically for PK deficiency: the PK Deficiency Diary (PKDD), a daily diary that asks 7 questions to measure the core signs and symptoms of PK deficiency, and the PK Deficiency Impact Assessment (PKDIA), a weekly questionnaire with 12 questions to assess the impact of PK deficiency on a patient's life. The results of this study showed that the PKDD and PKDIA properly and reliably measured the signs, symptoms, and impacts of PK deficiency that they aimed to capture. These findings indicate that the PKDD and PKDIA are the first validated PROs specifically for PK deficiency and can help improve the understanding of the impact of PK deficiency on patients' quality of life.

Base-Promoted Formal (3 + 2) Cycloaddition of α-Halohydroxamates with Electron-Deficient Alkenyl-iminoindolines To Synthesize Spiro-indolinepyrrolidinones.

Construction of pyrrolidinyl-spiroindoles with easily available starting materials has attracted considerable attention from the synthesis community and is in great demand. Here, we describe a base-promoted formal (3 + 2) cycloaddition of α-halohydroxamates with alkenyl-iminoindolines. The present methodology features mild reaction conditions and a broad substrate scope with up to 99% yield and excellent diastereoselectivity. The versatility of this approach is demonstrated through valuable synthetic transformations. Preliminary mechanistic studies shed light on the mechanism of this cycloaddition process.

Direct Acylation of Unactivated Alkyl Halides with Aldehydes through N-Heterocyclic Carbene Organocatalysis.

Catalytic acylation of organohalides with aldehydes is an ideal strategy for the direct synthesis of ketones. However, the utilization of unactivated alkyl halides in such a transformation remains a formidable challenge. In this study, we developed a cross-coupling reaction of aldehydes with unactivated alkyl halides through N-heterocyclic carbene catalysis. With this protocol, various ketones could be rapidly synthesized from readily available starting materials under mild conditions. This organocatalytic system was successfully applied in the late-stage functionalization of pharmaceutical derivatives. Mechanistic investigations suggest a closed-shell nucleophilic substitution mechanism for this reaction.

Gasdermin D-mediated pyroptosis: mechanisms, diseases, and inhibitors.

Gasdermin D (GSDMD)-mediated pyroptosis and downstream inflammation are important self-protection mechanisms against stimuli and infections. Hosts can defend against intracellular bacterial infections by inducing cell pyroptosis, which triggers the clearance of pathogens. However, pyroptosis is a double-edged sword. Numerous studies have revealed the relationship between abnormal GSDMD activation and various inflammatory diseases, including sepsis, coronavirus disease 2019 (COVID-19), neurodegenerative diseases, nonalcoholic steatohepatitis (NASH), inflammatory bowel disease (IBD), and malignant tumors. GSDMD, a key pyroptosis-executing protein, is linked to inflammatory signal transduction, activation of various inflammasomes, and the release of downstream inflammatory cytokines. Thus, inhibiting GSDMD activation is considered an effective strategy for treating related inflammatory diseases. The study of the mechanism of GSDMD activation, the formation of GSDMD membrane pores, and the regulatory strategy of GSDMD-mediated pyroptosis is currently a hot topic. Moreover, studies of the structure of caspase-GSDMD complexes and more in-depth molecular mechanisms provide multiple strategies for the development of GSDMD inhibitors. This review will mainly discuss the structures of GSDMD and GSDMD pores, activation pathways, GSDMD-mediated diseases, and the development of GSDMD inhibitors.

Pressure- and Rate-Dependent Mechanoluminescence with Maximized Efficiency and Tunable Wavelength in ZnS: Mn2+, Eu3.

Mechanoluminescence (ML) has received widespread attention because of potential application in stress sensors and imaging. However, pursuing highly efficient ML remains a challenge due to multifactorial limitations such as pressure and loading rate. Here, we systematically investigate pressure- and rate-dependent ML in Mn2+ and Eu3+ co-doped ZnS in a gigapascal pressure range by using a high-pressure dynamic diamond anvil cell and microsecond time-resolved fluorescent methods and demonstrate the giant tunability in both ML efficiency and wavelength. Compressed from ambient pressure to 11 GPa at different compression rates, ZnS: Mn2+, Eu3+ exhibits a volcano shape in ML emission efficiency with an optimum at ∼3.5 GPa and ∼211.1 GPa/s, at least 1000-fold higher than that measured in the MPa range. The pressure-dependent ML is accompanied with a tunable yellow-to-red emission color change. A combination of high-pressure X-ray diffraction and photoluminescence measurements reveals that the pressure- and rate-dependent ML behavior derives from pressure-induced strengthening of the crystal piezoelectric field and enhanced interaction between the host lattice and doped ions with a significant change of the energy level of the Mn ion. Significantly, the highly efficient ML of ZnS: Mn2+, Eu3+ at the GPa level is reproducible under a compression-decompression process and can be manipulated on a micron scale, implying great potential in mechanical-optical energy conversion and application in dynamic pressure imaging, stress sensors, and multicolor displays.

Highly Stereoselective Synthesis of Bis-C-ferrocenyl Glycosides via Palladium-Catalyzed Directed C-H Glycosylation.

Conjugation of carbohydrates to ferrocene scaffolds is of great value in drug design, given the nontoxic and lipophilic nature of ferrocene. However, the efficient and stereoselective synthesis of C-ferrocenyl glycosides remains a challenge. Herein, we developed a Pd-catalyzed stereoselective C-H glycosylation to provide rapid access to sole bis-C-ferrocenyl glycosides in good to high yields (up to 98% yield) with exclusive stereoselectivity. A diverse range of glycosyl chlorides were well tolerated, including d-mannose, d-glucose, l-xylose, l-rhamnose, d-mannofuranose, and d-ribofuranose. Additionally, a mononuclear PdII intermediate was characterized by X-ray single-crystal diffraction, and might participate in the C-H palladation step.