C176-loaded and phosphatidylserine-modified nanoparticles treat retinal neovascularization by promoting M2 macrophage polarization.

Retinal neovascularization (RNV), a typical pathological manifestation involved in most neovascular diseases, causes retinal detachment, vision loss, and ultimately irreversible blindness. Repeated intravitreal injections of anti-VEGF drugs were developed against RNV, with limitations of incomplete responses and adverse effects. Therefore, a new treatment with a better curative effect and more prolonged dosage is demanding. Here, we induced macrophage polarization to anti-inflammatory M2 phenotype by inhibiting cGAS-STING signaling with an antagonist C176, appreciating the role of cGAS-STING signaling in the retina in pro-inflammatory M1 polarization. C176-loaded and phosphatidylserine-modified dendritic mesoporous silica nanoparticles were constructed and examined by a single intravitreal injection. The biosafe nanoparticles were phagocytosed by retinal macrophages through a phosphatidylserine-mediated "eat me" signal, which persistently release C176 to suppress STING signaling and thereby promote macrophage M2 polarization specifically. A single dosage can effectively alleviate pathological angiogenesis phenotypes in murine oxygen-induced retinopathy models. In conclusion, these C176-loaded nanoparticles with enhanced cell uptake and long-lasting STING inhibition effects might serve as a promising way for treating RNV.

Testing functional anchor groups for the efficient immobilization of molecular catalysts on silver surfaces.

Modifications of complexes by attachment of anchor groups are widely used to control molecule-surface interactions. This is of importance for the fabrication of (catalytically active) hybrid systems, viz. of surface immobilized molecular catalysts. In this study, the complex fac-Re(S-Sbpy)(CO)3Cl (S-Sbpy = 3,3'-disulfide-2,2'-bipyridine), a sulfurated derivative of the prominent Re(bpy)(CO)3Cl class of CO2 reduction catalysts, was deposited onto the clean Ag(001) surface at room temperature. The complex is thermostable upon sublimation as supported by infrared absorption and nuclear magnetic resonance spectroscopy. Its anchoring process has been analyzed using scanning tunneling microscopy (STM) and density functional theory (DFT) calculations. The growth behavior was directly contrasted to the one of the parent complex fac-Re(bpy)(CO)3Cl (bpy = 2,2'-bipyridine). The sulfurated complex nucleates as single molecule at different surface sites and at molecule clusters. In contrast, for the parent complex nucleation only occurs in clusters of several molecules at specifically oriented surface steps. While this shows that surface immobilization of the sulfurated complex is more efficient as compared to the parent, symmetry analysis of the STM topographic data supported by DFT calculations indicates that more than 90% of the complexes adsorb in a geometric configuration very similar to the one of the parent complex.

Bifurcation of Excited-State Population Leads to Anti-Kasha Luminescence in a Disulfide-Decorated Organometallic Rhenium Photosensitizer.

We report a rhenium diimine photosensitizer equipped with a peripheral disulfide unit on one of the bipyridine ligands, [Re(CO)3(bpy)(S-Sbpy4,4)]+ (1+, bpy = 2,2'-bipyridine, S-Sbpy4,4 = [1,2]dithiino[3,4-c:6,5-c']dipyridine), showing anti-Kasha luminescence. Steady-state and ultrafast time-resolved spectroscopies complemented by nonadiabatic dynamics simulations are used to disclose its excited-state dynamics. The calculations show that after intersystem crossing the complex evolves to two different triplet minima: a (S-Sbpy4,4)-ligand-centered excited state (3LC) lying at lower energy and a metal-to-(bpy)-ligand charge transfer (3MLCT) state at higher energy, with relative yields of 90% and 10%, respectively. The 3LC state involves local excitation of the disulfide group into the antibonding σ* orbital, leading to significant elongation of the S-S bond. Intriguingly, it is the higher-lying 3MLCT state, which is assigned to display luminescence with a lifetime of 270 ns: a signature of anti-Kasha behavior. This assignment is consistent with an energy barrier ≥ 0.6 eV or negligible electronic coupling, preventing reaction toward the 3LC state after the population is trapped in the 3MLCT state. This study represents a striking example on how elusive excited-state dynamics of transition-metal photosensitizers can be deciphered by synergistic experiments and state-of-the-art calculations. Disulfide functionalization lays the foundation of a new design strategy toward harnessing excess energy in a system for possible bimolecular electron or energy transfer reactivity.

Neutralization of CX3CL1 Attenuates TGF-ß-Induced Fibroblast Differentiation Through NF-κB Activation and Mitochondrial Dysfunction in Airway Fibrosis.

BACKGROUND: Severe asthma, characterized by inflammation and airway remodeling, involves fibroblast differentiation into myofibroblasts expressing α-SMA. This process leads to the production of fibronectin and connective tissue growth factor (CTGF), driven by factors such as transforming growth factor (TGF)-ß. Furthermore, the persistent presence of myofibroblasts is associated with resistance to apoptosis and mitochondrial dysfunction. The chemokine (C-X3-C motif) ligand 1 (CX3CL1) plays a role in tissue fibrosis. However, it is currently unknown whether neutralization of CX3CL1 decreases TGF-ß-induced fibroblast differentiation and mitochondrial dysfunction in normal human lung fibroblasts (NHLFs). METHODS: CX3CL1/C-X3-C motif chemokine receptor 1 (CX3CR1), CX3CL1 was analyzed by immunofluorescence (IF) or immunohistochemical (IHC) staining of ovalbumin-challenged mice. CX3CL1 release was detected by ELISA. TGF-ß-induced CTGF, fibronectin, and α-SMA expression were evaluated in NHLFs following neutralization of CX3CL1 (TP213) treatment for the indicated times by Western blotting or IF staining. Mitochondrion function was detected by a JC-1 assay and seahorse assay. Cell apoptosis was observed by a terminal uridine nick-end labeling (TUNEL) assay. RESULTS: An increase in CX3CL1 expression was observed in lung tissues from mice with ovalbumin-induced asthma by IF staining. CX3CR1 was increased in the subepithelial layer of the airway by IHC staining. Moreover, CX3CR1 small interfering (si)RNA downregulated TGF-ß-induced CTGF and fibronectin expression in NHLFs. CX3CL1 induced CTGF and fibronectin expression in NHLFs. TGF-ß-induced CX3CL1 secretion from NHLFs. Furthermore, TP213 decreased TGF-ß-induced CTGF, fibronectin, and α-SMA expression in NHLFs. Mitochondrion-related differentially expressed genes (DEGs) were examined after CX3CL1 neutralization in TGF-ß-treated NHLFs. TP213 alleviated TGF-ß-induced mitochondrial dysfunction and apoptosis resistance in NHLFs. CX3CL1 induced p65, IκBα, and IKKα phosphorylation in a time-dependent manner. Furthermore, CX3CL1-induced fibronectin expression and JC-1 monomer were decreased by p65 siRNA. TP213 reduced TGF-ß-induced p65 and α-SMA expression in NHLFs. CONCLUSIONS: These findings suggest that neutralizing CX3CL1 attenuates lung fibroblast activation and mitochondrial dysfunction. Understanding the impacts of CX3CL1 neutralization on fibroblast mitochondrial function could contribute to the development of therapeutic strategies for managing airway remodeling in severe asthma.

Morphology and chemical composition of Taiwan oil millet (Eccoilopus formosanus) epicuticular wax.

MAIN CONCLUSION: Taiwan oil millet has two types of epicuticular wax: platelet wax composed primarily of octacosanol and filament wax constituted essentially by the singular compound of octacosanoic acid. Taiwan oil millet (TOM-Eccoilopus formosanus) is an orphan crop cultivated by the Taiwan indigenous people. It has conspicuous white powder covering its leaf sheath indicating abundant epicuticular waxes, that may contribute to its resilience. Here, we characterized the epicuticular wax secretion in TOM leaf blade and leaf sheath using various microscopy techniques, as well as gas chromatography to determine its composition. Two kinds of waxes, platelet and filaments, were secreted in both the leaf blades and sheaths. The platelet wax is secreted ubiquitously by epidermal cells, whereas the filament wax is secreted by a specific cell called epidermal cork cells. The newly developed filament waxes were markedly re-synthesized by the epidermal cork cells through papillae protrusions on the external periclinal cell wall. Ultrastructural images of cork cell revealed the presence of cortical endoplasmic reticulum (ER) tubules along the periphery of plasma membrane (PM) and ER-PM contact sites (EPCS). The predominant wax component was a C28 primary alcohol in leaf blade, and a C28 free fatty acid in the leaf sheath, pseudopetiole and midrib. The wax morphology present in distinct plant organs corresponds to the specific chemical composition: platelet wax composed of alcohols exists mainly in the leaf blade, whereas filament wax constituted mainly by the singular compound C28 free fatty acids is present abundantly in leaf sheath. Our study clarifies the filament wax composition in relation to a previous study in sorghum. Both platelet and filament waxes comprise a protection barrier for TOM.

USP24-i-101 targeting of USP24 activates autophagy to inhibit drug resistance acquired during cancer therapy.

Drug resistance in cancer therapy is the major reason for poor prognosis. Addressing this clinically unmet issue is important and urgent. In this study, we found that targeting USP24 by the specific USP24 inhibitors, USP24-i and its analogues, dramatically activated autophagy in the interphase and mitotic periods of lung cancer cells by inhibiting E2F4 and TRAF6, respectively. USP24 functional knockout, USP24C1695A, or targeting USP24 by USP24-i-101 inhibited drug resistance and activated autophagy in gefitinib-induced drug-resistant mice with doxycycline-induced EGFRL858R lung cancer, but this effect was abolished after inhibition of autophagy, indicating that targeting USP24-mediated induction of autophagy is required for inhibition of drug resistance. Genomic instability and PD-L1 levels were increased in drug resistant lung cancer cells and were inhibited by USP24-i-101 treatment or knockdown of USP24. In addition, inhibition of autophagy by bafilomycin-A1 significantly abolished the effect of USP24-i-101 on maintaining genomic integrity, decreasing PD-L1 and inhibiting drug resistance acquired in chemotherapy or targeted therapy. In summary, an increase in the expression of USP24 in cancer cells is beneficial for the induction of drug resistance and targeting USP24 by USP24-i-101 optimized from USP24-i inhibits drug resistance acquired during cancer therapy by increasing PD-L1 protein degradation and genomic stability in an autophagy induction-dependent manner.

Recent Advances in Nanomedicine for Ocular Fundus Neovascularization Disease Management.

As an indispensable part of the human sensory system, visual acuity may be impaired and even develop into irreversible blindness due to various ocular pathologies. Among ocular diseases, fundus neovascularization diseases (FNDs) are prominent etiologies of visual impairment worldwide. Intravitreal injection of anti-vascular endothelial growth factor drugs remains the primary therapy but is hurdled by common complications and incomplete potency. To renovate the current therapeutic modalities, nanomedicine emerged as the times required, which is endowed with advanced capabilities, able to fulfill the effective ocular fundus drug delivery and achieve precise drug release control, thus further improving the therapeutic effect. This review provides a comprehensive summary of advances in nanomedicine for FND management from state-of-the-art studies. First, the current therapeutic modalities for FNDs are thoroughly introduced, focusing on the key challenges of ocular fundus drug delivery. Second, nanocarriers are comprehensively reviewed for ocular posterior drug delivery based on the nanostructures: polymer-based nanocarriers, lipid-based nanocarriers, and inorganic nanoparticles. Thirdly, the characteristics of the fundus microenvironment, their pathological changes during FNDs, and corresponding strategies for constructing smart nanocarriers are elaborated. Furthermore, the challenges and prospects of nanomedicine for FND management are thoroughly discussed.

Uncovering Language Disparity of ChatGPT on Retinal Vascular Disease Classification: Cross-Sectional Study.

BACKGROUND: Benefiting from rich knowledge and the exceptional ability to understand text, large language models like ChatGPT have shown great potential in English clinical environments. However, the performance of ChatGPT in non-English clinical settings, as well as its reasoning, have not been explored in depth. OBJECTIVE: This study aimed to evaluate ChatGPT's diagnostic performance and inference abilities for retinal vascular diseases in a non-English clinical environment. METHODS: In this cross-sectional study, we collected 1226 fundus fluorescein angiography reports and corresponding diagnoses written in Chinese and tested ChatGPT with 4 prompting strategies (direct diagnosis or diagnosis with a step-by-step reasoning process and in Chinese or English). RESULTS: Compared with ChatGPT using Chinese prompts for direct diagnosis that achieved an F1-score of 70.47%, ChatGPT using English prompts for direct diagnosis achieved the best diagnostic performance (80.05%), which was inferior to ophthalmologists (89.35%) but close to ophthalmologist interns (82.69%). As for its inference abilities, although ChatGPT can derive a reasoning process with a low error rate (0.4 per report) for both Chinese and English prompts, ophthalmologists identified that the latter brought more reasoning steps with less incompleteness (44.31%), misinformation (1.96%), and hallucinations (0.59%) (all P<.001). Also, analysis of the robustness of ChatGPT with different language prompts indicated significant differences in the recall (P=.03) and F1-score (P=.04) between Chinese and English prompts. In short, when prompted in English, ChatGPT exhibited enhanced diagnostic and inference capabilities for retinal vascular disease classification based on Chinese fundus fluorescein angiography reports. CONCLUSIONS: ChatGPT can serve as a helpful medical assistant to provide diagnosis in non-English clinical environments, but there are still performance gaps, language disparities, and errors compared to professionals, which demonstrate the potential limitations and the need to continually explore more robust large language models in ophthalmology practice.

First-in-Class Dual EZH2-HSP90 Inhibitor Eliciting Striking Antiglioblastoma Activity In Vitro and In Vivo.

Structural analysis of tazemetostat, an FDA-approved EZH2 inhibitor, led us to pinpoint a suitable site for appendage with a pharmacophoric fragment of second-generation HSP90 inhibitors. Resultantly, a magnificent dual EZH2/HSP90 inhibitor was pinpointed that exerted striking cell growth inhibitory efficacy against TMZ-resistant Glioblastoma (GBM) cell lines. Exhaustive explorations of chemical probe 7 led to several revelations such as (i) compound 7 increased apoptosis/necrosis-related gene expression, whereas decreased M phase/kinetochore/spindle-related gene expression as well as CENPs protein expression in Pt3R cells; (ii) dual inhibitor 7 induced cell cycle arrest at the M phase; (iii) compound 7 suppressed reactive oxygen species (ROS) catabolism pathway, causing the death of TMZ-resistant GBM cells; and (iv) compound 7 elicited substantial in vivo anti-GBM efficacy in experimental mice xenografted with TMZ-resistant Pt3R cells. Collectively, the study results confirm the potential of dual EZH2-HSP90 inhibitor 7 as a tractable anti-GBM agent.

Development of a prediction model for emergency medical service witnessed traumatic out-of-hospital cardiac arrest: A multicenter cohort study.

BACKGROUND/PURPOSE: To develop a prediction model for emergency medical technicians (EMTs) to identify trauma patients at high risk of deterioration to emergency medical service (EMS)-witnessed traumatic cardiac arrest (TCA) on the scene or en route. METHODS: We developed a prediction model using the classical cross-validation method from the Pan-Asia Trauma Outcomes Study (PATOS) database from 1 January 2015 to 31 December 2020. Eligible patients aged ≥18 years were transported to the hospital by the EMS. The primary outcome (EMS-witnessed TCA) was defined based on changes in vital signs measured on the scene or en route. We included variables that were immediately measurable as potential predictors when EMTs arrived. An integer point value system was built using multivariable logistic regression. The area under the receiver operating characteristic (AUROC) curve and Hosmer-Lemeshow (HL) test were used to examine discrimination and calibration in the derivation and validation cohorts. RESULTS: In total, 74,844 patients were eligible for database review. The model comprised five prehospital predictors: age <40 years, systolic blood pressure <100 mmHg, respiration rate >20/minute, pulse oximetry <94%, and levels of consciousness to pain or unresponsiveness. The AUROC in the derivation and validation cohorts was 0.767 and 0.782, respectively. The HL test revealed good calibration of the model (p = 0.906). CONCLUSION: We established a prediction model using variables from the PATOS database and measured them immediately after EMS personnel arrived to predict EMS-witnessed TCA. The model allows prehospital medical personnel to focus on high-risk patients and promptly administer optimal treatment.

Identifying TYMP as an Immune Prognostic Marker in Clear Cell Renal Cell Carcinoma.

BACKGROUND: In clear cell renal cell carcinoma (ccRCC), only some patients can benefit from immunotherapy therapy, and it is urgent to find immune-related molecular markers and targets. METHODS: Thymidine phosphorylase (TYMP) expression level and predictive value in pan-cancers were analyzed using TIMER, GEPIA2, and The Human Protein Atlas. We obtained ccRCC tissues to verify the differential expression of TYMP and confirmed the biological function in vitro. Subsequently, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) are used to explore the potential mechanism of TYMP. Finally, TIMER was used to analyze the infiltration levels and prognostic value of different immune cells. RESULTS: TYMP is upregulated in various cancers, including ccRCC, and there is a certain degree of causality between high expression and poor prognosis in ccRCC. It was confirmed that TYMP knockdown could suppress cell aggressiveness, and cause cell death. Differential analysis showed that 55 differential genes were upregulated in the high-expression groups of TYMP. KEGG and GSEA analyses suggested that TYMP was linked to immune cell invasion, fatty acid metabolism, and P53 signaling pathway. Further investigation revealed that the expression level of TYMP linked positively to T-cell follicular helper and Tregs, but negatively with mast cell activation. Finally, a Nomogram was established on the base of expression level of TYMP and the clinical characteristics of ccRCC patients to predict prognosis. CONCLUSIONS: Patient survival is poor and immune cell infiltration is abnormal when TYMP is highly expressed in ccRCC, suggesting that ccRCC patients could benefit from using TYMP as a molecular diagnostic and therapeutic target.

Retinogenesis in a Dish: Bibliometric Analysis and Visualization of Retinal Organoids From 2011 to 2022.

Retinal organoid (RO) is the three-dimensional (3D) retinal culture derived from pluripotent or embryonic stem cells which recapitulates organ functions, which was a revolutionary milestone in stem cell technology. The purpose of this study is to explore the hotspots and future directions on ROs, as well as to better understand the fields of greatest research opportunities. Eligible publications related to RO from 2011 to 2022 were acquired from the Web of Science (WoS) Core Collection database. Bibliometric analysis was performed by using software including VOSviewer, CiteSpace, and ArcGIS. A total of 520 articles were included, and the number of annual publications showed a rapid increase with an average rate of 40.86%. The United States published the most articles (241/520, 46.35%) with highest total citation frequencies (5,344). University College London (UK) contributed the largest publication output (40/520, 7.69%) and received highest total citation frequencies. Investigative Ophthalmology & Visual Science was the most productive journal with 129 articles. Majlinda Lako contributed the most research with 32 articles, while Olivier Goureau has the strongest collaboration work. Research could be subdivided into four keyword clusters: "culture and differentiation," "morphogenesis and modeling," "gene therapy," and "transplantation and visual restoration," and evolution of keywords was identified. Last decade has witnessed the huge progress in the field of RO, which is a young and promising research area with extensive and in-depth studies. More attention should be paid to RO-related models and therapies based on specific retinal diseases, especially inherited retinopathies.

NCI677397 targeting USP24-mediated induction of lipid peroxidation induces ferroptosis in drug-resistant cancer cells.

Cancer represents a profound challenge to healthcare systems and individuals worldwide. The development of multiple drug resistance is a major problem in cancer therapy and can result in progression of the disease. In our previous studies, we developed small-molecule inhibitors targeting ubiquitin-specific peptidase 24 (USP24) to combat drug-resistant lung cancer. Recently, we found that the USP24 inhibitor NCI677397 induced ferroptosis, a type of programmed cell death, in drug-resistant cancer cells by increasing lipid reactive oxygen species (ROS) levels. In the present study, we investigated the molecular mechanisms and found that the targeting of USP24 by NCI677397 increased gene expression of most lipogenesis-related genes, such as acyl-CoA synthetase long-chain family member 4 (ACSL4), and activated autophagy. In addition, the activity of several antioxidant enzymes, such as glutathione peroxidase 4 (GPX4) and dihydrofolate reductase (DHFR), was inhibited by NCI677397 treatment via an increase in protein degradation, thereby inducing lipid ROS production and lipid peroxidation. In summary, we demonstrated that NCI677397 induced a marked increase in lipid ROS levels, subsequently causing lipid peroxidation and leading to the ferroptotic death of drug-resistant cancer cells. Our study provides new insights into the clinical use of USP24 inhibitors as ferroptosis inducers (FINs) to block drug resistance during chemotherapy.

Spontaneous Pneumocephalus: A Case Report with a Literature Review.

BACKGROUND: Pneumocephalus is defined as gas in the intracranial space. Common causes include head trauma, surgery, and diagnostic/therapeutic procedures resulting from the direct disruption of the dura. Spontaneous or nontraumatic pneumocephalus is an uncommon condition, often caused by infection, either due to insidious disruption of the dura or gas-forming pathogens. CASE REPORT: Herein, we report a rare case of spontaneous pneumocephalus associated with meningitis in a patient who received conservative treatment without surgical intervention. Blood culture revealed group A streptococcus. The pneumocephalus subsided gradually with antibiotic treatment, and no neurological deficits remained. A follow-up brain computed tomography scan showed the absence of pneumocephalus, but it showed progressive hydrocephalus. The patient was discharged on the 21st day of hospitalization. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Spontaneous pneumocephalus associated with meningitis is rare. It should always raise the suspicion of meningitis and prompt suitable treatment. Emergency physicians should always be vigilant for this particular possibility on brain computed tomography.

Effect of crew ratio of advanced life support-trained personnel on patients with out-of-hospital cardiac arrest: A systematic review and meta-analysis.

BACKGROUND/PURPOSE: This review aimed to investigate the effect of crew ratios of on-scene advanced life support (ALS)-trained personnel on patients with out-of-hospital cardiac arrest (OHCA). METHODS: We systematically searched PubMed, Ovid EMBASE, and the Cochrane Central Register of Controlled Trials databases from the inception date until September 30, 2022, for eligible studies. Two reviewers independently screened the studies for relevance, extracted data, and quality. We compared the effect of the ratio of on-scene ALS-trained personnel >50 % to those with a ratio ≤50 % among prehospital personnel on the clinical outcomes of OHCA patients. The primary outcome was survival-to-discharge and secondary outcomes were any return of spontaneous circulation (ROSC), sustained ROSC (≥2 h), and favourable neurological outcome at discharge (cerebral performance category scores: 1 or 2). Pooled odds ratios (ORs) were calculated, and the certainty of evidence was assessed. RESULTS: From 10,864 references, we identified four non-randomised studies, including 16,475 patients. Two studies were performed in Japan and two in Taiwan. There were significant differences in survival-to-discharge (OR: 1.24, 95 % confidence interval [CI]: 1.07-1.44, I2: 7 %), any ROSC (OR:1.22, 95 % CI: 1.04-1.43, I2: 74 %) and sustained ROSC (OR: 1.39, 95 % CI: 1.16-1.65, I2: 40 %), but insignificant differences in favourable neurological outcome at discharge. The overall certainty of evidence was rated as very low for all outcomes. CONCLUSION: Prehospital ALS care with a ratio of on-scene ALS-trained personnel >50 % could improve OHCA patient outcomes than crew ratios ≤50 %. Further studies are required to reach a robust conclusion.

Identification and evolution analysis of YUCCA genes of Medicago sativa and Medicago truncatula and their expression profiles under abiotic stress.

The YUCCAs (YUC) are functionally identified flavin-containing monooxidases (FMOs) in plants that act as an important rate-limiting enzyme functioning in the auxin synthesis IPA (indole-3-pyruvic acid) pathway. In this study, 12 MsYUCs and 15 MtYUCs containing characteristic conserved motifs were identified in M. sativa (Medicago sativa L.) and M. truncatula (Medicago truncatula Gaertn.), respectively. Phylogenetic analysis revealed that YUC proteins underwent an evolutionary divergence. Both tandem and segmental duplication events were presented in MsYUC and MtYUC genes. Comparative syntenic maps of M. sativa with M. truncatula, Arabidopsis (Arabidopsis thaliana), or rice (Oryza sativa L.) were constructed to illustrate the evolution relationship of the YUC gene family. A large number of cis-acting elements related to stress response and hormone regulation were revealed in the promoter sequences of MsYUCs. Expression analysis showed that MsYUCs had a tissue-specific, genotype-differential expression and a differential abiotic stress response pattern based on transcriptome data analysis of M. sativa online. In addition, RT-qPCR confirmed that salt stress significantly induced the expression of MsYUC1/MsYUC10 but significantly inhibited MsYUC2/MsYUC3 expression and the expression of MsYUC10/MsYUC11/MsYUC12 was significantly induced by cold treatment. These results could provide valuable information for functional analysis of YUC genes via gene engineering of the auxin synthetic IPA pathway in Medicago.

CdWRKY2 transcription factor modulates salt oversensitivity in bermudagrass [Cynodon dactylon (L.) Pers.].

Common bermudagrass [Cynodon dactylon (L.) Pers.] has higher utilization potential on saline soil due to its high yield potential and excellent stress tolerance. However, key functional genes have not been well studied partly due to its hard transformation. Here, bermudagrass "Wrangler" successfully overexpressing CdWRKY2 exhibited significantly enhanced salt and ABA sensitivity with severe inhibition of shoot and root growth compared to the transgenic negative line. The reduced auxin accumulation and higher ABA sensitivity of the lateral roots (LR) under salt stress were observed in CdWRKY2 overexpression Arabidopsis lines. IAA application could rescue or partially rescue the salt hypersensitivity of root growth inhibition in CdWRKY2-overexpressing Arabidopsis and bermudagrass, respectively. Subsequent experiments in Arabidopsis indicated that CdWRKY2 could directly bind to the promoter region of AtWRKY46 and downregulated its expression to further upregulate the expression of ABA and auxin pathway-related genes. Moreover, CdWRKY2 overexpression in mapk3 background Arabidopsis could partly rescue the salt-inhibited LR growth caused by CdWRKY2 overexpression. These results indicated that CdWRKY2 could negatively regulate LR growth under salt stress via the regulation of ABA signaling and auxin homeostasis, which partly rely on AtMAPK3 function. CdWRKY2 and its homologue genes could also be useful targets for genetic engineering of salinity-tolerance plants.

Deep learning-based semantic segmentation of non-melanocytic skin tumors in whole-slide histopathological images.

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the two most common skin cancer and impose a huge medical burden on society. Histopathological examination based on whole-slide images (WSIs) remains to be the confirmatory diagnostic method for skin tumors. Accurate segmentation of tumor tissue in WSIs by deep-learning (DL) models can reduce the workload of pathologists and help surgeons ensure the complete removal of tumors. To accurately segment the tumor areas in WSIs of BCC, SCC and squamous cell papilloma (SCP, homologous to SCC) with robust models. We established a data set (ZJU-NMSC) containing 151 WSIs of BCC, SCC and SCP in total. Seven models were utilized to segment WSIs, including the state-of-the-art model, models proposed by us and other models. Dice score, intersection over union, accuracy, sensitivity and specificity were used to evaluate and compare the performance of different models. Heatmaps and tumor tissue masks were generated to reflect the results of the segmentation. The processing times of models are also recorded and compared. While the dice score of most models is higher than 0.85, deeplab v3+ has the best performance and the corresponding tumor tissue mask is more consistent with the ground truth tumor areas even with complex and small lobular lesions. This study broadens the use of DL-based segmentation models in WSIs of skin tumors in terms of tumor types and computational approaches. Segmenting tumor areas can simplify the process of histopathological inspection and benefit the diagnosis and following management of the diseases in practice.

Case report: Dysphagia after COVID-19 infection in a stroke patient-Is neurostimulation a potential management?

A 90-year-old man with stroke was weaned from tube feeding 4 months after stroke onset. However, he had a coronavirus disease 2019 (COVID-19) infection after 2 months and suffered from drastically worsened oropharyngeal dysphagia that required a reinsertion of the nasogastric tube. A videofluoroscopic swallowing study revealed poor bolus oral transit, significantly delayed swallowing reflex, reduced pharyngeal movements, and insufficient cough response. Repetitive transcranial magnetic stimulation and neuromuscular electrical stimulation were applied, in addition to conventional swallowing training. The feeding tube was removed after 20 treatment sessions. Clinicians should be aware of the risk of dysphagia after COVID-19 infection in patients with underlying neurological diseases. The management of post-COVID-19 dysphagia has not yet been fully established. Repetitive transcranial electrical stimulation combined with neuromuscular electrical stimulation may be used as an auxiliary intervention in specific cases.