Diosmetin-7-O-ß-D-glucopyranoside from Pogostemonis Herba alleviated SARS-CoV-2-induced pneumonia by reshaping macrophage polarization and limiting viral replication.

ETHNOPHARMACOLOGICAL RELEVANCE: Viral pneumonia is the leading cause of death after SARS-CoV-2 infection. Despite effective at early stage, long-term treatment with glucocorticoids can lead to a variety of adverse effects and limited benefits. The Chinese traditional herb Pogostemonis Herba is the aerial part of Pogostemon Cablin (Blanco) Benth., which has potent antiviral, antibacterial, anti-inflammatory, and anticancer effects. It was used widely for treating various throat and respiratory diseases, including COVID-19, viral infection, cough, allergic asthma, acute lung injury and lung cancer. AIM OF THE STUDY: To investigate the antiviral and anti-inflammatory effects of chemical compounds from Pogostemonis Herba in SARS-CoV-2-infected hACE2-overexpressing mouse macrophage RAW264.7 cells and hACE2 transgenic mice. MATERIALS AND METHODS: The hACE2-overexpressing RAW264.7 cells were exposed with SARS-CoV-2. The cell viability was detected by CCK8 assay and cell apoptotic rate was by flow cytometric assay. The expressions of macrophage M1 phenotype markers (TNF-α and IL-6) and M2 markers (IL-10 and Arg-1) as well as the viral loads were detected by qPCR. The mice were inoculated intranasally with SARS-CoV-2 omicron variant to induce viral pneumonia. The levels of macrophages, neutrophils, and T cells in the lung tissues of infected mice were analyzed by full spectrum flow cytometry. The expressions of key proteins were detected by Western blot assay. RESULTS: Diosmetin-7-O-ß-D-glucopyranoside (DG) presented the strongest anti-SARS-CoV-2 activity. Intervention with DG at the concentrations of 0.625-2.5 µM not only reduced the viral replication, cell apoptosis, and the productions of inflammatory cytokines (IL-6 and TNF-α) in SARS-CoV-2-infected RAW264.7 cells, but also reversed macrophage polarity from M1 to M2 phenotype. Furthermore, treatment with DG (25-100 mg/kg) alleviated acute lung injury, and reduced macrophage infiltration in SARS-COV-2-infected mice. Mechanistically, DG inhibited SARS-COV-2 gene expression and HK3 translation via targeting YTHDF1, resulting in the inactivation of glycolysis-mediated NF-κB pathway. CONCLUSIONS: DG exerted the potent antiviral and anti-inflammatory activities. It reduced pneumonia in SARS-COV-2-infected mice via inhibiting the viral replication and accelerating M2 macrophage polarization via targeting YTHDF1, indicating its potential for COVID-19 treatment.

Prediction of Arteriovenous Access Dysfunction by Mel Spectrogram-based Deep Learning Model.

Background: The early detection of arteriovenous (AV) access dysfunction is crucial for maintaining the patency of vascular access. This study aimed to use deep learning to predict AV access malfunction necessitating further vascular management. Methods: This prospective cohort study enrolled prevalent hemodialysis (HD) patients with an AV fistula or AV graft from a single HD center. Their AV access bruit sounds were recorded weekly using an electronic stethoscope from three different sites (arterial needle site, venous needle site, and the midpoint between the arterial and venous needle sites) before HD sessions. The audio signals were converted to Mel spectrograms using Fourier transformation and utilized to develop deep learning models. Three deep learning models, (1) Convolutional Neural Network (CNN), (2) Convolutional Recurrent Neural Network (CRNN), and (3) Vision Transformers-Gate Recurrent Unit (ViT-GRU), were trained and compared to predict the likelihood of dysfunctional AV access. Results: Total 437 audio recordings were obtained from 84 patients. The CNN model outperformed the other models in the test set, with an F1 score of 0.7037 and area under the receiver operating characteristic curve (AUROC) of 0.7112. The Vit-GRU model had high performance in out-of-fold predictions, with an F1 score of 0.7131 and AUROC of 0.7745, but low generalization ability in the test set, with an F1 score of 0.5225 and AUROC of 0.5977. Conclusions: The CNN model based on Mel spectrograms could predict malfunctioning AV access requiring vascular intervention within 10 days. This approach could serve as a useful screening tool for high-risk AV access.

Biomimetic cell stimulation with a graphene oxide antigen-presenting platform for developing T cell-based therapies.

Chimeric antigen receptor (CAR)-engineered T cells represent a front-line therapy for cancers. However, the current CAR T cell manufacturing protocols do not adequately reproduce immunological synapse formation. Here, in response to this limitation, we have developed a flexible graphene oxide antigen-presenting platform (GO-APP) that anchors antibodies onto graphene oxide. By decorating anti-CD3 (αCD3) and anti-CD28 (αCD28) on graphene oxide (GO-APP3/28), we achieved remarkable T cell proliferation. In vitro interactions between GO-APP3/28 and T cells closely mimic the in vivo immunological synapses between antigen-presenting cells and T cells. This immunological synapse mimicry shows a high capacity for stimulating T cell proliferation while preserving their multifunctionality and high potency. Meanwhile, it enhances CAR gene-engineering efficiency, yielding a more than fivefold increase in CAR T cell production compared with the standard protocol. Notably, GO-APP3/28 stimulated appropriate autocrine interleukin-2 (IL-2) in T cells and overcame the in vitro reliance on external IL-2 supplementation, offering an opportunity to culture T cell-based products independent of IL-2 supplementation.

Synthesis of alkynyl cyclopropa[c]coumarins via propargyl sulfonium salts as C1 synthons.

Herein, we present a novel approach for the preparation of alkynyl cyclopropa[c]coumarin derivatives with medium to good yields utilizing propargyl sulfonium salts as C1 synthons. Compared with Br-, using ClO4- as the counter anion significantly enhances the yield due to its lesser nucleophilic ability. This method features mild reaction conditions and a broad substrate scope with good diastereoselectivity when the substituted R1 group is at the 5-position of the coumarin scaffold.

Effects of online high-definition transcranial direct current stimulation over left dorsolateral prefrontal cortex on predominant negative symptoms and EEG functional connectivity in patients with schizophrenia: a randomized, double-blind, controlled trial.

AIMS: Schizophrenia, a debilitating mental disorder, is characterized by persistent negative symptoms such as avolition and anhedonia. Currently, there are no effective treatments available for these symptoms. Thus, our study aims to assess the efficacy of online high-definition transcranial direct current stimulation (online HD-tDCS) in addressing the negative symptoms of schizophrenia, utilizing a double-blind, randomized, sham-controlled trial design. METHODS: Fifty-nine patients with schizophrenia were randomized to receive either active HD-tDCS or sham stimulation, targeting the left dorsolateral prefrontal cortex. Outcomes were measured by changes in the Positive and Negative Syndrome Scale Factor Score for Negative Symptom (PANSS-FSNS). Exact low-resolution electromagnetic tomography was used to assess the functional connectivity. RESULTS: All 59 participants, including 50.84% females with an average age of 43.36 years, completed the trial. In the intention-to-treat analysis, patients receiving active HD-tDCS showed greater improvement in PANSS-FSNS scores compared to those receiving the sham procedure. The differences were 2.34 (95% confidence interval [CI], 1.28-3.40), 4.28 (95% CI, 2.93-5.62), and 4.91 (95% CI, 3.29-6.52) after the intervention, as well as at 1-week and 1-month follow-ups, respectively. A tingling sensation on the scalp was more common in the active group (63.3%) compared to the sham group (10.3%). Additionally, HD-tDCS was associated with a decrease in delta-band connectivity within the default mode network. CONCLUSIONS: High-definition transcranial direct current stimulation was effective and safe in ameliorating negative symptoms in patients with schizophrenia when combined with online functional targeting.

Urinary Concentrations of Organophosphate Flame-Retardant Metabolites in the US Population.

Importance: Organophosphate flame retardants (OPFRs) are an important group of pollutants associated with endocrine disorders, cancer, and nephrotoxicity. However, temporal trends in OPFR metabolite concentrations remain understudied. Objectives: To examine changes in urinary concentrations of OPFR metabolites among US children, youths, and adults from 2011 to 2020, and to evaluate whether sociodemographic factors were associated with variations in temporal trends. Design, Setting, and Participants: This population-based cross-sectional study used data from 4 US National Health and Nutrition Examination Survey (NHANES) cycles (2011-2012, 2013-2014, 2015-2016, and 2017-2020 [to March 2020 before the COVID-19 pandemic]). The study included children and youths (aged 6-19 years) and adults (aged ≥20 years) with valid urinary concentrations of the following OPFR metabolites: bis(2-chloroethyl) phosphate (BCEtP), bis(1-chloro-2-propyl) phosphate (BCPP), diphenyl phosphate (DPhP), and dibutyl phosphate (DBuP). Data analysis was performed between February and May 2024. Exposures: Calendar year and key sociodemographic subgroups (age, race and ethnicity, sex, educational attainment, and poverty-to-income ratio). Main Outcomes and Measures: The main outcome was urinary concentrations of OPFR metabolites among children, youths, and adults. Survey-weighted linear regression models were applied to estimate trends. Results: The study population of 10 549 NHANES participants included 3154 children and youths (mean [SE] age, 12.5 [0.1] years; 51.2% were male) and 7395 adults (mean [SE] age, 47.8 [0.4] years; 52.0% were women). Among children and youths, mean (95% CI) BCEtP concentrations decreased from 0.68 (0.60-0.77) µg/L in 2011-2012 to 0.41 (0.37-0.45) µg/L in 2017-2020 (P for trend < .001). Among adults, mean (95% CI) BCEtP concentrations decreased from 0.43 (0.37-0.50) µg/L in 2011-2012 to 0.29 (0.27-0.33) µg/L in 2017-2020 (P for trend < .001), and mean BCPP concentrations decreased from 0.15 (0.14-0.17) µg/L to 0.13 (0.12-0.14) µg/L (P for trend = .002). Parent level of educational attainment was associated with concentrations of BCPP and BCEtP among children and youths; however, no significant differences among adults were observed. Conclusions and Relevance: This study identified variations in temporal trends in urinary concentrations of OPFR metabolites among the US population from 2011 to 2020. In addition, substantial disparities in exposure levels persisted among children with different levels of parent educational attainment. These findings suggest that policy makers should consider socioeconomic factors to further reduce OPFR exposure and promote equity, ensuring a safe living environment for all individuals.

Microbial community response to temperature reduction during anaerobic treatment of long chain fatty acids-containing wastewater.

Acclimating mesophilic biomass to low temperatures have been used to start-up psychrophilic anaerobic reactors, but limited microbial information is available during the acclimation. To investigate microbial responses to temperature reductions, duplicate lab-scale anaerobic digestion (AD) reactors were operated for 166 days, with the temperature being reduced from 37°C to 15°C, using synthetic long chain fatty acid (LCFA)-containing wastewater as the feedstock. The acclimated biomass at 15°C exhibited efficient removal of organic matter (total COD>75%, soluble COD>88%, and LCFA>99%). Temperature reductions lead to significant reductions in microbiome diversity. Fermentative bacteria were highly dynamic and functional redundant during temperature reductions. Smithella was the dominant syntrophic bacteria involved in LCFA degradation coupled with Methanothrix and Methanocorpusculum at 15°C. Membrane modifications and compatible cellular solutes production were triggered by temperature reductions as microbial response to cold stress. This study provided molecular insights in microbial acclimation to low temperatures for psychrophilic AD.

Full-length nanopore sequencing of circular RNA landscape in peripheral blood cells following sequential BNT162b2 mRNA vaccination.

Circular RNAs (circRNA) lack 5' or 3' ends; their unique covalently closed structures prevent RNA degradation by exonucleases. These characteristics provide circRNAs with high pharmaceutical stability and biostability relative to current standard-of-care linear mRNAs. CircRNA levels are reportedly associated with certain human diseases, making them novel disease biomarkers and a noncanonical class of therapeutic targets. In this study, the endogenous circRNAs underlying the response to BNT162b2 mRNA vaccination were evaluated. To this end, peripheral blood samples were subjected to full-length sequencing of circRNAs via nanopore sequencing and transcriptome sequencing. Fifteen samples, comprising pre-, first, and second vaccination cohorts, were obtained from five healthcare workers with no history of SARS-CoV-2 infection or previous vaccination. A total of 4706 circRNAs were detected; following full-length sequencing, 4217 novel circRNAs were identified as being specifically expressed during vaccination. These circRNAs were enriched in the binding motifs of stress granule assemblies and SARS-CoV-2 RNA binding proteins, namely poly(A) binding protein cytoplasmic 1 (PABPC1), pumilio RNA binding family member 1 (PUM1), and Y box binding protein 1 (YBX1). Moreover, 489 circRNAs were identified as previously reported miRNA sponges. The differentially expressed circRNAs putatively originated from plasma B cells compared to circRNAs reported in human blood single-cell RNA sequencing datasets. The pre- and post-vaccination differences observed in the circRNA expression landscape in response to the SARS-CoV-2 BNT162b2 mRNA vaccine.

Multimodal Social Sensing for the Spatio-Temporal Evolution and Assessment of Nature Disasters.

Social sensing, using humans as sensors to collect disaster data, has emerged as a timely, cost-effective, and reliable data source. However, research has focused on the textual data. With advances in information technology, multimodal data such as images and videos are now shared on media platforms, aiding in-depth analysis of social sensing systems. This study proposed an analytical framework to extract disaster-related spatiotemporal information from multimodal social media data. Using a pre-trained multimodal neural network and a location entity recognition model, the framework integrates disaster semantics with spatiotemporal information, enhancing situational awareness. A case study of the April 2024 heavy rain event in Guangdong, China, using Weibo data, demonstrates that multimodal content correlates more strongly with rainfall patterns than textual data alone, offering a dynamic perception of disasters. These findings confirm the utility of multimodal social media data and offer a foundation for future research. The proposed framework offers valuable applications for emergency response, disaster relief, risk assessment, and witness discovery, and presents a viable approach for safety risk monitoring and early warning systems.

VesiMCNN: Using pre-trained protein language models and multiple window scanning convolutional neural networks to identify vesicular transport proteins.

Vesicular transport is a critical cellular process responsible for the proper organization and functioning of eukaryotic cells. This mechanism relies on specialized vesicles that shuttle macromolecules, such as proteins, across the cellular landscape, a process pivotal to maintaining cellular homeostasis. Disruptions in vesicular transport have been linked to various disease mechanisms, including cancer and neurodegenerative disorders. In this study, we present vesiMCNN, a novel computational approach that integrates pre-trained protein language models with a multi-window scanning convolutional neural network architecture to accurately identify vesicular transport proteins. To the best of our knowledge, this is the first study to leverage the power of pre-trained language models in combination with the multi-window scanning technique for this task. Our method achieved a Matthews Correlation Coefficient (MCC) of 0.558 and an Area Under the Receiver Operating Characteristic (AUC-ROC) of 0.933, outperforming existing state-of-the-art approaches. Additionally, we have curated a comprehensive benchmark dataset for the study of vesicular transport proteins, which can facilitate further research in this field. The remarkable performance of our model, combined with the comprehensive dataset and novel deep learning model, marks a significant advancement in the field of vesicular transport protein research.

Programmable editing of primary MicroRNA switches stem cell differentiation and improves tissue regeneration.

Programmable RNA editing is harnessed for modifying mRNA. Besides mRNA, miRNA also regulates numerous biological activities, but current RNA editors have yet to be exploited for miRNA manipulation. To engineer primary miRNA (pri-miRNA), the miRNA precursor, we present a customizable editor REPRESS (RNA Editing of Pri-miRNA for Efficient Suppression of miRNA) and characterize critical parameters. The optimized REPRESS is distinct from other mRNA editing tools in design rationale, hence enabling editing of pri-miRNAs that are not editable by other RNA editing systems. We edit various pri-miRNAs in different cells including adipose-derived stem cells (ASCs), hence attenuating mature miRNA levels without disturbing host gene expression. We further develop an improved REPRESS (iREPRESS) that enhances and prolongs pri-miR-21 editing for at least 10 days, with minimal perturbation of transcriptome and miRNAome. iREPRESS reprograms ASCs differentiation, promotes in vitro cartilage formation and augments calvarial bone regeneration in rats, thus implicating its potentials for engineering miRNA and applications such as stem cell reprogramming and tissue regeneration.

Using microfluidic and conventional platforms to evaluate the effects of lanthanides on spheroid formation.

Metastasis contributes to the increased mortality rate of cancer, but the intricate mechanisms remain unclear. Cancer cells from a primary tumor invade nearby tissues and access the lymphatic or circulatory system. If these cells manage to survive and extravasate from the vasculature into distant tissues and ultimately adapt to survive, they will proliferate and facilitate malignant tumor formation. Traditional two-dimensional (2D) cell cultures offer a rapid and convenient method for validating the efficacy of anticancer drugs within a reasonable cost range, but their utility is limited because of tumors' high heterogeneity in vivo and spatial complexities. Three-dimensional (3D) cell cultures that mimic the physiological conditions of cancer cells in vivo have gained considerable interest. In these cultures, cells assemble into spheroids through gravity, magnetic forces, or their low-adhesion to the plates. Although these approaches address some of the limitations of 2D cultures, they often require a considerable amount of time and cost. Therefore, this study aims to enhance the effectiveness of 3D culture techniques by using microfluidic systems to provide a high-throughput and sensitive pipeline for drug screening. Using these systems, we studied the effects of lanthanide elements, which have garnered interest in cancer treatment, on spheroid formation and cell spreading. Our findings suggest that these elements alter the compactness of cell spheroids and decrease cell mobility.

Pancreatic necrosis volume is closely associated with late-onset vascular complications after discharge in necrotizing pancreatitis.

PURPOSE: To explore the incidence, dynamic changes, prognostic factors and prognosis of late-onset vascular complications after discharge in patients with necrotizing pancreatitis (NP), and determine the relationship between the pancreatic necrosis volume (PNV) and late-onset vascular complications. METHODS: This was a retrospective cohort study that included NP patients who did not have any vascular complications during index hospitalization. Computed tomography (CT) examinations were performed, and the PNV was calculated based on the picture archiving and communication system. Multivariate logistic regression analysis was employed to determine the potential prognostic factors for late-onset vascular complications after discharge. RESULTS: A total of 35.6 % (37/104) of the patients had late-onset portal venous system involvement during the one-year follow-up period, including 35 patients with stenosis and 2 patients with occlusion. No venous thrombosis or arterial vascular complications were observed. PNV > 134 cm3 (OR, 7.08, 95 % CI 1.83-27.36; P = 0.005) and pancreatic necrosis involving the body and/or tail of the pancreas (OR, 10.05; 95 % CI, 2.66-38.02; P = 0.001) were prognostic factors for abnormal patency of the portal venous system. The abnormal patency of the portal venous system tended to persist during follow-up, and gastric varices were observed in 32.4 % (12/37) of the patients in the abnormal patency group without any symptoms. CONCLUSIONS: Late-onset vascular complications involving venous stenosis or occlusion were common in NP patients after discharge, approximately one third of whom developed gastric varices. PNV and the location of necrosis were closely associated with the development of these complications.

Indium-Assisted Construction of {SiNb18O54}-Based Aggregates and Their Assembly into Extended Polyoxoniobate Architectures.

In this research, indium ions were introduced into polyoxoniobates (PONbs) reaction systems to facilitate the construction of different {SiNb18O54}-based aggregates, including an {In(en)2{SiNb18O54}2} (en = ethylenediamine) dimer, an {[InO2][In2(en)O3]2{SiNb18O54}3} trimer, and an {[In(en)2][InO2][In7(en)5O9]{SiNb18O54}4} tetramer. Interestingly, these aggregates were further assembled into three uncommon extended PONb architectures in the presence of [Cu(en)2]2+ complexes, namely, H3[Cu(en)2(H2O)][Cu(en)2]6[Cu(en)2]2{[In(en)2][K2{SiNb18O54}(H2O)6]2}·1.5en·16H2O, H9{[Cu(en)2]6{[Cu(en)2]3[Cu(en)2(H2O)][In(H2O)2][In2(en)(H2O)2(OH)]2{SiNb18O54}3}·5en·29H2O, and H14[Cu(en)2]0.5[Cu(en)2(H2O)]{[Cu(en)2]2{[Cu(en)2]3[Cu(en)2(H2O)]5[K(H2O)2][In(H2O)2][In(en)2][In7(OH)9(en)5]{SiNb18O54}4}·7en·39H2O. In addition, all of them have good water vapor adsorption capacities and moderate proton transport capabilities. The above results indicate that introducing suitable heteroatoms to induce the aggregation PONb building blocks and further assembling them into new structures is an effective strategy to enrich the PONbs' structural diversity and develop new functional materials.

Interdependence of Support Wettability -Electrodeposition Rate - Sodium Metal Anode and SEI Microstructure.

This study examines how current collector support chemistry (sodiophilic intermetallic Na2Te vs. sodiophobic baseline Cu) and electrodeposition rate affect microstructure of sodium metal and its solid electrolyte interphase (SEI). Capacity and current (6 mAh cm-2, 0.5-3 mA cm-2) representative of commercially relevant mass loading in anode-free sodium metal battery (AF-SMBs) are analyzed. Synchrotron X-ray nanotomography and grazing-incidence wide-angle X-ray scattering (GIWAXS) are combined with cryogenic focused ion beam (cryo-FIB) microscopy. Highlighted are major differences in film morphology, internal porosity, and crystallographic preferred orientation e.g. (110) vs. (100) and (211) with support and deposition rate. Within the SEI, sodium fluoride (NaF) is more prevalent with Te-Cu versus sodium hydride (NaH) and sodium hydroxide (NaOH) with baseline Cu. Due to competitive grain growth the preferred orientation of sodium crystallites depends on film thickness. Mesoscale modelling delineates the role of SEI (ionic conductivity, morphology) on electrodeposit growth and onset of electrochemical instability.

Using Urine Biomarkers to Differentiate Bladder Dysfunctions in Women with Sensory Bladder Disorders.

Sensory bladder disorders encompass several distinct conditions with overlapping symptoms, which pose diagnostic challenges. This study aimed to evaluate urine biomarkers for differentiating between various sensory bladder disorders, including non-Hunner's interstitial cystitis (NHIC), detrusor overactivity (DO), hypersensitive bladder (HSB), and urodynamically normal women. A retrospective analysis of 191 women who underwent a videourodynamic study (VUDS) was conducted, with some also receiving cystoscopic hydrodistention to confirm the presence of NHIC. Participants were categorized into four groups: DO (n = 51), HSB (n = 29), NHIC (n = 81), and normal controls (n = 30). The urine levels of inflammatory and oxidative stress biomarkers were measured. The DO patients exhibited elevated IP-10 levels, while the HSB patients had decreased TAC and 8-OHdG levels. The NHIC patients showed lower IL-2 and higher TNF-α levels. A TNF-α ≥ 1.05 effectively identified NHIC, with an AUROC of 0.889, a sensitivity of 98.8%, and a specificity of 81.3%. An IP-10 ≥ 6.31 differentiated DO with an AUROC of 0.695, a sensitivity of 56.8%, and a specificity of 72.3%. An 8-OHdG ≤ 14.705 and a TAC ≤ 528.7 identified HSB with AUROCs of 0.754 and 0.844, respectively. The combination of 8-OHdG and TAC provided an AUROC of 0.853 for HSB. These findings suggest that TNF-α, IP-10, TAC, 8-OHdG, and IL-2 are promising non-invasive biomarkers for distinguishing between these conditions, which may improve diagnosis and management.

The relationship between changes in functional connectivity gradients and cognitive-emotional disorders in sudden sensorineural hearing loss.

Sudden sensorineural hearing loss, a prevalent emergency in otolaryngology, is known to potentially precipitate cognitive and emotional disorders in affected individuals. Extensive research has documented the phenomenon of cortical functional reorganization in patients with sudden sensorineural hearing loss. However, the potential link between this neural functional remodelling and cognitive-emotional disorders remains unclear. To investigate this issue, 30 bilateral sudden sensorineural hearing loss patients and 30 healthy adults were recruited for this study. We collected clinical data and resting-state functional magnetic resonance imaging data from the participants. Gradient mapping analysis was employed to calculate the first three gradients for each subject. Subsequently, gradient changes in sudden sensorineural hearing loss patients were compared with healthy controls at global, regional and network levels. Finally, we explored the relationship between gradient values and clinical variables. The results revealed that at the global level, sudden sensorineural hearing loss did not exhibit significant differences in the primary gradient but showed a state of compression in the second and third gradients. At the regional level, sudden sensorineural hearing loss patients exhibited a significant reduction in the primary gradient values in the temporal pole and ventral prefrontal cortex, which were closely related to neuro-scale scores. Regarding the network level, sudden sensorineural hearing loss did not show significant differences in the primary gradient but instead displayed significant changes in the control network and default mode network in the second and third gradients. This study revealed disruptions in the functional hierarchy of sudden sensorineural hearing loss, and the alterations in functional connectivity gradients were closely associated with cognitive and emotional disturbances in patients. These findings provide new evidence for understanding the functional remodelling that occurs in sudden sensorineural hearing loss.

The transcription factor RppA regulates chlorophyll and carotenoid biosynthesis to improve photoprotection in cyanobacteria.

Chlorophyll is an essential photosynthetic pigment but also a strong photosensitizer. Excessive free chlorophyll and its precursors can cause oxidative damage to photosynthetic organisms. Cyanobacteria are the oldest oxygenic photosynthetic organisms and the ancestors of the chloroplast. Owing to their complex habitats, cyanobacteria require precise regulation of chlorophyll synthesis to respond to environmental factors, especially changes in light. Chlorophyll synthase, encoded by chlG, is the enzyme catalyzing the final step of chlorophyll biosynthesis, which is closely related to photosynthesis biogenesis. However, the transcriptional regulation on chlG remains unclear. Here, the transcription factor, regulator of photosynthesis and photopigment-related gene expression A (RppA) was identified to bind to the chlG promoter by screening a yeast one-hybrid library in the cyanobacterium Synechocystis sp. PCC 6803. The rppA knock-out mutant showed a phenotype of slow growth and severe oxidative damage under dark-light transition conditions. The up-regulated transcriptional expression of chlG was significantly higher and more chlorophyll and its precursors accumulated in the rppA knock-out mutant than those in the wild-type strain during the transition from darkness to light, indicating RppA represses the expression of chlG in Synechocystis. Meanwhile, RppA could synchronously promote the transcription of carotenoids biosynthesis-related genes to enhance carotenoids synthesis during the dark-light transition. These results reveal synergistic regulation of chlorophyll and carotenoids biosynthesis in cyanobacteria in response to frequent dark-light transitions, which slows down chlorophyll biosynthesis while promoting carotenoids biosynthesis to avoid oxidative damage caused by excessive reactive oxygen species accumulation.

Gypenoside A-loaded mPEG-PLGA nanoparticles ameliorate high-glucose-induced retinal microvasculopathy by inhibiting ferroptosis.

Diabetic retinopathy (DR) is one of the chronic microvascular complications of type 2 diabetes mellitus (T2DM), which will cause retinal detachment and blindness without ideal therapies. Gypenoside A (GPA) are the main bioactive compound from Gynostemma pentaphyllum, and have various pharmacological effects. However, it suffered from poor bioavailability and potential cardiotoxicity in the clinical application. To overcome those limitations, in this study, nearly spherical nanoparticles (GPA-NP) with a mean particle size of 140.6 ±â€¯22.4 nm were prepared by encapsulating GPA into mPEG-PLGA. This encapsulation efficiency was 84.4 ±â€¯6.9 %, and the drug load was 4.02 %±0.35 %. The results showed that GPA-NP displayed more prolonged GPA release and higher bioavailability in vitro than GPA. GPA-NP obviously reduced the levels of oxidative stress markers and inflammatory cytokines in both retinal tissues of DR mice and high glucose-exposed HRMEC better than GPA alone. Mechanismly, GPA blocked the Nrf2-Keap1 interaction by binding with Kelch domain of Keap1 via alkyl and hydrogen bonds. Therefore, GPA-NP exerted more potent protectivity effects against high glucose-induced retinal microvascular endothelial ferroptosis in vitro and in vivo by activating Nrf2/HO-1/GPX4 pathway. It could be a promising therapeutic agent for preventing DR.