Canagliflozin Mitigates Diabetic Cardiomyopathy through Enhanced PINK1-Parkin Mitophagy.

Diabetic cardiomyopathy (DCM) is a major determinant of mortality in diabetic populations, and the potential strategies are insufficient. Canagliflozin has emerged as a potential cardioprotective agent in diabetes, yet its underlying molecular mechanisms remain unclear. We employed a high-glucose challenge (60 mM for 48 h) in vitro to rat cardiomyocytes (H9C2), with or without canagliflozin treatment (20 µM). In vivo, male C57BL/6J mice were subjected to streptozotocin and a high-fat diet to induce diabetes, followed by canagliflozin administration (10, 30 mg·kg-1·d-1) for 12 weeks. Proteomics and echocardiography were used to assess the heart. Histopathological alterations were assessed by the use of Oil Red O and Masson's trichrome staining. Additionally, mitochondrial morphology and mitophagy were analyzed through biochemical and imaging techniques. A proteomic analysis highlighted alterations in mitochondrial and autophagy-related proteins after the treatment with canagliflozin. Diabetic conditions impaired mitochondrial respiration and ATP production, alongside decreasing the related expression of the PINK1-Parkin pathway. High-glucose conditions also reduced PGC-1α-TFAM signaling, which is responsible for mitochondrial biogenesis. Canagliflozin significantly alleviated cardiac dysfunction and improved mitochondrial function both in vitro and in vivo. Specifically, canagliflozin suppressed mitochondrial oxidative stress, enhancing ATP levels and sustaining mitochondrial respiratory capacity. It activated PINK1-Parkin-dependent mitophagy and improved mitochondrial function via increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Notably, PINK1 knockdown negated the beneficial effects of canagliflozin on mitochondrial integrity, underscoring the critical role of PINK1 in mediating these protective effects. Canagliflozin fosters PINK1-Parkin mitophagy and mitochondrial function, highlighting its potential as an effective treatment for DCM.

The impact of intraoperative hypotension on postoperative acute kidney injury, mortality and length of stay following off-pump coronary artery bypass grafting surgery: a single-center retrospective cohort study.

BACKGROUND: Off-pump coronary artery bypass grafting (OPCABG) presents distinct hemodynamic characteristics, yet the relationship between intraoperative hypotension and short-term adverse outcomes remains clear. Our study aims to investigate association between intraoperative hypotension and postoperative acute kidney injury (AKI), mortality and length of stay in OPCABG patients. METHODS: Retrospective data of 494 patients underwent OPCABG from January 2016 to July 2023 were collected. We analyzed the relationship between intraoperative various hypotension absolute values (MAP > 75, 65 < MAP ≤ 75, 55 < MAP ≤ 65, MAP ≤ 55 mmHg) and postoperative AKI, mortality and length of stay. Logistic regression assessed the impacts of exposure variable on AKI and postoperative mortality. Linear regression was used to analyze risk factors on the length of intensive care unit stay (ICU) and hospital stay. RESULTS: The incidence of AKI was 31.8%, with in-hospital and 30-day mortality at 2.8% and 3.5%, respectively. Maintaining a MAP greater than or equal 65 mmHg [odds ratio (OR) 0.408; p = 0.008] and 75 mmHg (OR 0.479; p = 0.024) was significantly associated with a decrease risk of AKI compared to MAP less than 55 mmHg for at least 10 min. Prolonged hospital stays were linked to low MAP, while in-hospital mortality and 30-day mortality were not linked to IOH but exhibited correlation with a history of myocardial infarction. AKI showed correlation with length of ICU stay. CONCLUSIONS: MAP > 65 mmHg emerges as a significant independent protective factor for AKI in OPCABG and IOH is related to length of hospital stay. Proactive intervention targeting intraoperative hypotension may provide a potential opportunity to reduce postoperative renal injury and hospital stay. TRIAL REGISTRATION: ChiCTR2400082518. Registered 31 March 2024. https://www.chictr.org.cn/bin/project/edit?pid=225349 .

Effects of ultrasound-guided serratus plane block combined with general anesthesia on postoperative early quality of recovery and analgesia in patients undergoing transapical transcatheter aortic valve implantation surgery: study protocol for a randomized controlled trial.

BACKGROUND: Compared to traditional thoracotomy, transapical transcatheter aortic valve implantation (TAVI) surgery offers reduced trauma and faster recovery, fostering the adoption of enhanced recovery after surgery (ERAS) protocols in cardiac surgery. Despite these advancements, postoperative pain management has received insufficient attention. The potential effects of multi-mode analgesia, including ultrasound-guided serratus anterior plane block (SAPB), on postoperative pain and early quality of recovery have not been widely studied, lacking comprehensive prospective evidence. Therefore, this study aims to investigate the impact of SAPB combined with general anesthesia on early recovery quality and analgesic efficacy in transapical TAVI patients. METHODS: This prospective, randomized controlled study will enroll 70 patients undergoing transapical TAVI, randomly allocated to either the SAPB group or the control group. The primary outcome, assessed using Quality of Recovery-40 (QOR-40) scale, focuses on the quality of recovery at 24 h and 48 h postoperatively. Secondary outcomes include the visual analog scale (VAS) pain scores at rest and during coughing at 6 h, 12 h, 24 h, and 48 h after surgery, frequency of patient-controlled analgesia (PCA) utilization at 24 h and 48 h, opioid consumption at 24 h and 48 h, time and frequency of rescue analgesia and severe pain at 24 h and 48 h, incidence of nausea and vomiting at 48 h after surgery, and dosage of antiemetic drugs. DISCUSSION: The purpose of our study is to evaluate the effects of ultrasound-guided SAPB combined with general anesthesia on postoperative early quality of recovery and analgesia in transapical TAVI patients. The results obtained may provide valuable insight for the implementation of multi-mode analgesia and enhanced ERAS in this specific patient population. TRIAL REGISTRATION: China Clinical Trial Register ChiCTR2300068584. Registered on 24 February 2023.

Semantic effects on the perception of emotional prosody in native and non-native Chinese speakers.

While previous research has found an in-group advantage (IGA) favouring native speakers in emotional prosody perception over non-native speakers, the effects of semantics on emotional prosody perception remain unclear. This study investigated the effects of semantics on emotional prosody perception in Chinese words and sentences for native and non-native Chinese speakers. The critical manipulation was the congruence of prosodic (positive, negative) and semantic (positive, negative, and neutral) valence. Participants listened to a series of audio clips and judged whether the emotional prosody was positive or negative for each utterance. The results revealed an IGA effect: native speakers perceived emotional prosody more accurately and quickly than non-native speakers in Chinese words and sentences. Furthermore, a semantic congruence effect was observed in Chinese words, where both native and non-native speakers recognised emotional prosody more accurately in the semantic-prosody congruent condition than in the incongruent condition. However, in Chinese sentences, this congruence effect was only present for non-native speakers. Additionally, the IGA effect and semantic congruence effect on emotional prosody perception were influenced by prosody valence. These findings illuminate the role of semantics in emotional prosody perception, highlighting perceptual differences between native and non-native Chinese speakers.

Probing structural superlubricity of two-dimensional water transport with atomic resolution.

Low-dimensional water transport can be drastically enhanced under atomic-scale confinement. However, its microscopic origin is still under debate. In this work, we directly imaged the atomic structure and transport of two-dimensional water islands on graphene and hexagonal boron nitride surfaces using qPlus-based atomic force microscopy. The lattice of the water island was incommensurate with the graphene surface but commensurate with the boron nitride surface owing to different surface electrostatics. The area-normalized static friction on the graphene diminished as the island area was increased by a power of ~-0.58, suggesting superlubricity behavior. By contrast, the friction on the boron nitride appeared insensitive to the area. Molecular dynamic simulations further showed that the friction coefficient of the water islands on the graphene could reduce to <0.01.

Pt─O Bond Accelerated Cu0/Cu+ Activity for Boosting Low-Energy Bipolar Hydrogen Production.

To address the imperative challenge of producing hydrogen in a low-energy consumption electrocatalytic system, this study emphasizes the utilization of thermodynamically favorable biomass oxidation for achieving energy-efficient hydrogen generation. This research integrates ultralow PtO2-loaded flower-like nanosheets (denoted as PtO2@Cu2O/Cu FNs) with Cu0/Cu+ pairs and Pt─O bonds, thereby yielding substantial enhancement in both hydrogen evolution reaction (HER, -0.042 VRHE at 10 mA cm-2) and furfural oxidation reaction (FFOR, 0.09 VRHE at 10 mA cm-2). As validated by DFT calculations, the dual built-in electric field (BIEF) is elucidated as the driving force behind the enhanced activities, in which Pt─O bonds expedite the HER, while Cu+/Cu0 promotes low-potential FFOR. By coupling the FFOR and HER together, the resulting bipolar-hydrogen production system requires a low power input (0.5072 kWh per m3) for producing H2. The system can generate bipolar hydrogen and high value-added furoic acid, significantly enhancing hydrogen production efficiency and concurrently mitigating energy consumption.

Pyroptosis and mitochondrial function participated in miR-654-3p-protected against myocardial infarction.

Myocardial infarction (MI) is one of the leading causes of heart failure with highly complicated pathogeneses. miR-654-3p has been recognized as a pivotal regulator of controlling cell survival. However, the function of miR-654-3p in cardiomyocytes and MI has yet to be reported. This study aimed to identify the role of miR-654-3p in the regulation of myocardial infarction. To understand the contribution of miR-654-3p on heart function, we generated cardiac-specific knockdown and overexpression mice using AAV9 technology in MI injury. Mechanically, we combined cellular and molecular techniques, pharmaceutical treatment, RNA sequencing, and functional testing to elucidate the potential pathological mechanisms. We identified that mice subjected to MI decreased the expression of miR-654-3p in the border and infarcted area. Mice lacking miR-654-3p in the heart showed some inflammation infiltration and myocardial fibrosis, resulting in a mild cardiac injury. Furthermore, we found a deficiency of miR-654-3p in cardiomyocytes resulted in pyroptotic cell death but not other programmed cell death. Intriguingly, miR-654-3p deficiency aggravated MI-induced cardiac dysfunction, accompanied by higher myocardial fibrosis and cardiac enzymes and augmented pyroptosis activation. Cardiac elevating miR-654-3p prevented myocardial fibrosis and inflammation infiltration and decreased pyroptosis profile, thereby attenuating MI-induced cardiac damage. Using RNA sequence and molecular biological approaches, we found overexpression of miR-654-3p in the heart promoted the metabolic ability of the cardiomyocytes by promoting mitochondrial metabolism and mitochondrial respiration function. Our finding identified the character of miR-654-3p in protecting against MI damage by mediating pyroptosis and mitochondrial metabolism. These findings provide a new mechanism for miR-654-3p involvement in the pathogenesis of MI and reveal novel therapeutic targets. miR-654-3p expression was decreased after MI. Mice lacking miR-654-3p in the heart showed some inflammation infiltration and myocardial fibrosis, resulting in a mild cardiac injury. The deficiency of miR-654-3p in cardiomyocytes resulted in pyroptotic cell death. miR-654-3p deficiency aggravated MI-induced cardiac dysfunction, accompanied by higher myocardial fibrosis and cardiac enzymes and augmented pyroptosis activation. Overexpression of miR-654-3p prevented myocardial fibrosis and inflammation infiltration and decreased pyroptosis profile, thereby attenuating MI-induced cardiac damage. Overexpression of miR-654-3p in the heart promoted the metabolic ability of the cardiomyocytes by promoting mitochondrial metabolism and mitochondrial respiration function.

Enhanced Biosynthesis of d-Allulose from a d-Xylose-Methanol Mixture and Its Self-Inductive Detoxification by Using Antisense RNAs in Escherichia coli.

d-Allulose, a C-3 epimer of d-fructose, has great market potential in food, healthcare, and medicine due to its excellent biochemical and physiological properties. Microbial fermentation for d-allulose production is being developed, which contributes to cost savings and environmental protection. A novel metabolic pathway for the biosynthesis of d-allulose from a d-xylose-methanol mixture has shown potential for industrial application. In this study, an artificial antisense RNA (asRNA) was introduced into engineered Escherichia coli to diminish the flow of pentose phosphate (PP) pathway, while the UDP-glucose-4-epimerase (GalE) was knocked out to prevent the synthesis of byproducts. As a result, the d-allulose yield on d-xylose was increased by 35.1%. Then, we designed a d-xylose-sensitive translation control system to regulate the expression of the formaldehyde detoxification operon (FrmRAB), achieving self-inductive detoxification by cells. Finally, fed-batch fermentation was carried out to improve the productivity of the cell factory. The d-allulose titer reached 98.6 mM, with a yield of 0.615 mM/mM on d-xylose and a productivity of 0.969 mM/h.

Impact of rural location on receipt of standard of care treatment and survival for locally advanced bladder cancer in Louisiana.

OBJECTIVE: We aim to determine the effect of region of residence (urban vs. rural) on the odds of receiving standard of care treatment for locally advanced BCa in Louisiana and its impact on survival outcomes. METHODS: Using the Louisiana Tumor Registry, we identified American Joint Committee on Cancer (AJCC) stage II or III, BCa diagnoses in Louisiana residents between 2010 and 2020. Treatment received was classified as standard or non-standard of care according to American Urological Association (AUA) guidelines and location of residence was determined using Rural Urban Commuting Area-Tract-level 2010 (RUCA). Multivariable logistic regression analyses and multivariate cox proportional hazard analyses were performed. RESULTS: Of 983 eligible patients, 85.6% (841/983) lived in urban areas. Overall, only 37.5% received standard-of-care (SOC) for the definitive management of locally advanced bladder cancer. Individuals living in rural areas (OR 0.53, 95% CI: 0.31-0.91, p = 0.02) were less likely to receive standard of care treatment. Both rural residence and receipt of non-standard of care therapy were associated with an increased risk of bladder cancer-specific (adj HR 1.53, 95% CI: 1.09-2.14, p = 0.01 and adj HR: 1.85, 95% CI: 1.43-2.39, <0.0001) and overall mortality (adj HR: 1.28, 95% CI: 1.01-1.61, p = 0.04 and adj HR: 1.73 95% CI: 1.44-2.07, p < 0.0001). CONCLUSIONS: Most patients with locally advanced bladder cancer in Louisiana do not receive SOC therapy. Individuals living in rural locations are more likely to receive non-standard of care therapy than individuals in urban areas. Nonstandard of care treatment and rural residence are both associated with worse survival outcomes for Louisiana residents with locally advanced bladder cancer.

[Effect of UVRAG Gene on Ferroptosis Induced by Sorafenib in K562 Cells].

OBJECTIVE: To explore the effect of UV radiation resistance-associated gene (UVRAG) on ferroptosis induced by sorafenib in leukemia K562 cells. METHODS: K562 cells were treated with 0, 0.625, 1.25, 2.5, 5, 10, and 20 µmol/L sorafenib for 24 or 48 hours, and the cell viability was detected by CCK-8 assay. Flow cytometry technology was used to detect the changes of reactive oxygen species (ROS) in K562 cells treated with 0, 5, and 10 µmol/L sorafenib for 24 hours. Western blot was used to detect the protein expression of GPX4 in K562 cells treated with 0, 5, and 10 µmol/L sorafenib and pretreatment with ferroptosis inhibitor. A recombinant lentiviral vector was used to construct UVRAG overexpression cell line in K562 cells. qPCR and Western blot were used to verify UVRAG gene overexpression, and Western blot detected the effect of UVRAG on the protein expression of GPX4 and HMGB1 after treatment with sorafenib. RESULTS: Different concentrations of sorafenib could significantly inhibit the proliferation of K562 cells, and the cell viability gradually decreased with the increase of concentration (r 24 h=-0.9841, r 48 h=-0.9970). The level of ROS was increased (When the concentration was 10 µmol/L, P <0.001), while the expression of GPX4 protein was decreased in the process of 0, 5, 10 µmol/L sorafenib-induced K562 cell death (P <0.05), and the decrease in GPX4 protein could be partially reversed by pretreatment with ferroptosis inhibitor (P <0.05). Compared with NC group and NC-Sorafenib group, the expression of GPX4 protein was significantly decreased (both P <0.05), while HMGB1 protein was significantly increased (both P <0.05). CONCLUSION: Sorafenib can induce ferroptosis in K562 cells, and this process can be promoted by UVRAG.

A Dual-Targeting, Multi-Faceted Biocompatible Nanodrug Optimizes the Microenvironment to Ameliorate Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a highly lethal cardiovascular disease that currently lacks effective pharmacological treatment given the complex pathophysiology of the disease. Here, single-cell RNA-sequencing data from patients with AAA and a mouse model are analyzed, which reveals pivotal pathological changes, including the M1-like polarization of macrophages and the loss of contractile function in smooth muscle cells (SMCs). Both cell types express the integrin αvß3, allowing for their dual targeting with a single rationally designed molecule. To this end, a biocompatible nanodrug, which is termed EVMS@R-HNC, that consists of the multifunctional drug everolimus (EVMS) encapsulated by the hepatitis B virus core protein modifies to contain the RGD sequence to specifically bind to integrin αvß3 is designed. Both in vitro and in vivo results show that EVMS@R-HNC can target macrophages as well as SMCs. Upon binding of the nanodrug, the EVMS is released intracellularly where it exhibits multiple functions, including inhibiting M1 macrophage polarization, thereby suppressing the self-propagating inflammatory cascade and immune microenvironment imbalance, while preserving the normal contractile function of SMCs. Collectively, these results suggest that EVMS@R-HNC presents a highly promising therapeutic approach for the management of AAA.

Superdiffusive Rotation of Interfacial Water on Noble Metal Surface.

Interfacial water on a metal surface acts as an active layer through the reorientation of water, thereby facilitating the energy transfer and chemical reaction across the metal surface in various physicochemical and industrial processes. However, how this active interfacial water collectively behaves on flat noble metal substrates remains largely unknown due to the experimental limitation in capturing librational vibrational motion of interfacial water and prohibitive computational costs at the first-principles level. Herein, by implementing a machine-learning approach to train neural network potentials, we enable performing advanced molecular dynamics simulations with ab initio accuracy at a nanosecond scale to map the distinct rotational motion of water molecules on a metal surface at room temperature. The vibrational density of states of the interfacial water with two-layer profiles reveals that the rotation and vibration of water within the strong adsorption layer on the metal surface behave as if the water molecules in the bulk ice, wherein the O-H stretching frequency is well consistent with the experimental results. Unexpectedly, the water molecules within the adjacent weak adsorption layer exhibit superdiffusive rotation, contrary to the conventional diffusive rotation of bulk water, while the vibrational motion maintains the characteristic of bulk water. The mechanism underlying this abnormal superdiffusive rotation is attributed to the translation-rotation decoupling of water, in which the translation is restrained by the strong hydrogen bonding within the bilayer interfacial water, whereas the rotation is accelerated freely by the asymmetric water environment. This superdiffusive rotation dynamics may elucidate the experimentally observed large fluctuation of the potential of zero charge on Pt and thereby the conventional Helmholtz layer model revised by including the contribution of interfacial water orientation. The surprising superdiffusive rotation of vicinal water next to noble metals will shed new light on the physicochemical processes and the activity of water molecules near metal electrodes or catalysts.

Two-dimensional ice-like water adlayers on a mica surface with and without a graphene coating under ambient conditions.

Water tends to wet all hydrophilic surfaces under ambient conditions, and the first water adlayers on solids are important for a broad range of physicochemical phenomena and technological processes, including corrosion, wetting, lubrication, anti-icing, catalysis, and electrochemistry. Unfortunately, challenges in characterizing the first water adlayer in the laboratory have hampered molecular-level understanding of the contact water structure. Herein, we present the first ab initio molecular dynamics simulation evidence of a previously unreported ice-like adlayer structure (named as Ice-AL-II) on a prototype mica surface under ambient conditions. Calculation showed that the newly identified Ice-AL-II structure is more stable than the widely recognized ice-adlayer structure on mica surfaces (named as Ice-AL-I). Ice-AL-II exhibited a face-centered corner-cut tetragon (or a face-centered irregular pentagon) pattern of a hydrogen-bonded network. The center of the corner-cut tetragon was occupied by either a K+ cation or a water molecule with two H atoms pinned by the mica (100) via double hydrogen bonds. Our simulation also suggested that bilayer Ice-AL-II favors AA stacking rather than AB stacking. Interestingly, when a graphene sheet was coated on top of the ice-like adlayer, the stability of Ice-AL-II was further enhanced. In contrast, due to its strongly puckered structure, the Ice-AL-I structure could be crushed into a near-Ice-AL-II structure by the graphene coating. Ice-AL-II is thus proposed as a promising candidate for the ice-like structure on a mica surface detected by scanning polarization force microscopy and by atomic force microscopy between a graphene coating and a mica surface.

Highly Efficient and Scalable p-i-n Perovskite Solar Cells Enabled by Poly-metallocene Interfaces.

Inverted p-i-n perovskite solar cells (PSCs) are easy to process but need improved interface characteristics with reduced energy loss to prevent efficiency drops when increasing the active photovoltaic area. Here, we report a series of poly ferrocenyl molecules that can modulate the perovskite surface enabling the construction of small- and large-area PSCs. We found that the perovskite-ferrocenyl interaction forms a hybrid complex with enhanced surface coordination strength and activated electronic states, leading to lower interfacial nonradiative recombination and charge transport resistance losses. The resulting PSCs achieve an enhanced efficiency of up to 26.08% for small-area devices and 24.51% for large-area devices (1.0208 cm2). Moreover, the large-area PSCs maintain >92% of the initial efficiency after 2000 h of continuous operation at the maximum power point under 1-sun illumination and 65 °C.

Highly Dispersed Ni Atoms and O3 Promote Room-Temperature Catalytic Oxidation.

Transition metal oxides are promising catalysts for catalytic oxidation reactions but are hampered by low room-temperature activities. Such low activities are normally caused by sparse reactive sites and insufficient capacity for molecular oxygen (O2) activation. Here, we present a dual-stimulation strategy to tackle these two issues. Specifically, we import highly dispersed nickel (Ni) atoms onto MnO2 to enrich its oxygen vacancies (reactive sites). Then, we use molecular ozone (O3) with a lower activation energy as an oxidant instead of molecular O2. With such dual stimulations, the constructed O3-Ni/MnO2 catalytic system shows boosted room-temperature activity for toluene oxidation with a toluene conversion of up to 98%, compared with the O3-MnO2 (Ni-free) system with only 50% conversion and the inactive O2-Ni/MnO2 (O3-free) system. This leap realizes efficient room-temperature catalytic oxidation of transition metal oxides, which is constantly pursued but has always been difficult to truly achieve.

A general descriptor for single-atom catalysts decorated with axial ligand.

Decoration of an axial coordination ligand (ACL) on the active metal site is a highly effective and versatile strategy to tune activity of single-atom catalysts (SACs). However, the regulation mechanism of ACLs on SACs is still incompletely known. Herein, we investigate diversified combinations of ACL-SACs, including all 3d-5d transition metals and ten prototype ACLs. We identify that ACLs can weaken the adsorption capability of the metal atom (M) by raising the bonding energy levels of the M-O bond while enhancing dispersity of the d orbital of M. Through examination of various local configurations and intrinsic parameters of ACL-SACs, a general structure descriptor σ is constructed to quantify the structure-activity relationship of ACL-SACs which solely based on a few key intrinsic features. Importantly, we also identified the axial ligand descriptor σACL, as a part of σ, which can serve as a potential descriptor to determine the rate-limiting steps (RLS) of ACL-SACs in experiment. And we predicted several ACL-SACs, namely, CrN4-, FeN4-, CoN4-, RuN4-, RhN4-, OsN4-, IrN4- and PtN4-ACLs, that entail markedly higher activities than the benchmark catalysts of Pt and IrO2, thereby supporting that the general descriptor σ can provide a simple and cost-effective method to assess efficient electrocatalysts.

First report of Botrytis cinerea causing grey mold on Corydalis yanhusuo in Panan, China.

Yanhusuo (Corydalis yanhusuo (Y. H. Chou & Chun C. Hsu) W. T. Wang ex Z.Y. Su & C.Y. Wu), a perennial herbaceous plant of the Papaveraceae family and genus Corydalis, is also known as Yuanhu and used as medicine by its tuberous roots. It is mainly planted in Zhejiang, Jiangsu and Anhui provinces of China, with the best quality produced in Panan County of Zhejiang province. Yanhusuo has the effects of promoting blood circulation, invigorating the flow of qi and relieving pain, and is widely used in Chinese traditional medicines. In surveys carried out in summer of 2020-2023, grey mold disease was found occurred on C. yanhusuo in Panan County. This disease begins at April, and lasts to July, with incidence of 20% to 70%. The diseased plants showed a large number of gray mold layers adhere to the leaves. When the disease infects from the leaf tips, it form V-shaped lesions; when the leaves are severely infected, the entire leaves die, shrink, curl, and have a large number of gray mold layers on the surface. To identify the causal agent of this leaf disease, diseased leaves were collected from Yanhusuo field at Panan County of Zhejiang province in China since 2020, and tissues at the junction of the healthy and diseased areas were cut off, disinfected with 75% ethanol for 30 seconds, rinsed with sterile water for 3 times for 1 minute each time, air-dried under sterile conditions, and then were inoculated in PDA medium and cultured in a 25℃ incubator. After 2-3 days, picked the edge hyphae of the fungi that grew on the PDA plate and cultured them on a new PDA plate. After 5 days, picked the single spore and inoculated on a new PDA plate for continuous cultivation until pure culture strains were obtained. Thirty strains were isolated from 30 samples that collected from 3 Yanhusuo fields in Panan County. One of the thirty purified strains was named "YH8" for further identification. When cultured on PDA medium, mycelia were initially whitish and turned gray with age. The hyphae accumulate into clusters, and no sclerotia are produced during the cultivation. The conidiophores are slender, septate. The base of the conidiophore is enlarged or slightly enlarged. The conidiophore often has branches and produces a large number of conidia, which are similar to grape clusters. The conidia are monosporous, ovoid, and colorless, 6.08 µm-12.76 µm×8.42 µm-19.34 µm, with an average size of 9.55 µm×14.50 µm. To further identify the species, YH8 genomic DNA was extracted, and the internal transcribed spacer (ITS), heat shock protein (HSP60), and glyceraldehyde-3-phosphate dehydrogenase (G3PDH) genes were amplified with the primers ITS1/4 (White et al. 1990), HSP60-F/HSP60-R, and G3PDH-F/G3PDH-R (Staats et al. 2005), respectively. A multilocus phylogenetic tree was constructed with the ITS, HSP60, and G3PDH reference sequences, and the sequences of PCR amplicons (Genbank number: PP388281, PP376066 and PP376067) were 100% (518 bp out of 518 bp), 99% (994 bp out of 995 bp) and 100% (880 bp out of 880 bp) identical to the Botrytis cinerea strain 5-3, respectively, and the grouping of strain YH8 was supported by 99% bootstrap value. To fulfill the Koch's postulates, spore suspension (approximately 103 CFU/mL) of YH8 was sprayed onto leaves of 3-week Yanhusuo seedlings, and sterile water was sprayed as negative control, 15 seedlings for each treatment, and the experiments was repeated for times. The seedlings were incubated in a growth chamber under 28℃ and 80% humidity. Seven days after inoculation, leaves of noninoculated controls were green and healthy, while the seedlings inoculated with spore suspension of YH8 showed lesions and molds, which were same with field symptoms. The causal pathogen was then reisolated from the lesions, and the gained pathogen showed same colony and spore morphology with YH8, which suggested the confirmation of Koch's postulates. Based on the morphological characteristics and molecular identification, the strain YH8 was identified as B. cinerea. To our knowledge, this is the first report of B. cinerea causing gray mold on the Corydalis yanhusuo in China. This report will provide guide to growers and local technicians for diagnostic and controlling grey mold disease of Yanhusuo.

Mixed response to the first-line treatment of KRAS G12C inhibitor, sotorasib, in non-small cell lung cancer: A brief report.

Key Clinical Message: One Kirsten Ras (KRAS) G12C mutated non-small cell lung cancer (NSCLC) patient had improved poor performance status and obtained mixed response with the first-line KRAS-targeted treatment of sotorasib. After disease progression, partial response was achieved with chemotherapy plus immunotherapy. KRAS G12C mutated immunoenvironment in NSCLC may favor the immunotherapy. Abstract: KRAS is one of the most commonly mutated genes, which used to be untargetable. The phase II CodeBreak 100 trial revealed 6.8-month median progress-free survival (PFS) and 12.5-month overall survival (OS) in previously treated KRAS G12C-mutant NSCLC patients treated with KRAS inhibitor, sotorasib. The specimens of the brain, lymph node (LN), and blood from the patient were analyzed by next-generation sequencing. Hematoxylin and eosin staining and immunohistochemistry were performed for pathological characterization. Computed tomography (CT) and magnetic resonance imaging (MRI) scan were used for treatment response evaluation. The patient was diagnosed in a bad Eastern Cooperative Oncology Group performance status (ECOG-PS) with metastatic KRAS G12C-mutated lung adenocarcinoma who had achieved mixed response to sotorasib as the first-line treatment. Although 5-month PFS of the treatment with sotorasib was not surprising, the patient achieved significantly improved ECOG-PS score from 4 to 1. Subsequently, partial response (PR) was achieved with the treatment of pemetrexed plus pembrolizumab. This case highlights superior efficacy of first-line treatment with sotorasib for the advance untreated KRAS G12C-mutant patients. The high efficacy of the treatment with chemotherapy plus immunotherapy revealed that immunoenvironment of KRAS G12C-mutated patient may favor the immunotherapy.

Formation of compounds with diverse polyelectrolyte morphologies and nonlinear ion conductance in a two-dimensional nanofluidic channel.

Aqueous electrolytes subjected to angstrom-scale confinement have recently attracted increasing interest because of their distinctive structural and transport properties, as well as their promising applicability in bioinspired nanofluidic iontronics and ion batteries. Here, we performed microsecond-scale molecular dynamics simulations, which provided evidence of nonlinear ionic conductance under an external lateral electric field due to the self-assembly of cations and anions with diverse polyelectrolyte morphologies (e.g., extremely large ion clusters) in aqueous solutions within angstrom-scale slits. Specifically, we found that the cations and anions of Li2SO4 and CaSO4 formed chain-like polyelectrolyte structures, whereas those of Na2SO4 and MgSO4 predominantly formed a monolayer of hydrated salt. Additionally, the cations and anions of K2SO4 assembled into a hexagonal anhydrous ionic crystal. These ion-dependent diverse polyelectrolyte morphologies stemmed from the enhanced Coulomb interactions, weakened hydration and steric constraints within the angstrom-scale slits. More importantly, once the monolayer hydrated salt or ionic crystal structure was formed, the field-induced ion current exhibited an intriguing gating effect at a low field strength. This abnormal ion transport was attributed to the concerted movement of cations and anions within the solid polyelectrolytes, leading to the suppression of ion currents. When the electric field exceeded a critical strength, however, the ion current surged rapidly due to the dissolution of many cations and anions within a few nanoseconds in the aqueous solution.