The role of ncRNA regulatory mechanisms in diseases-case on gestational diabetes.

Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not have the potential to encode proteins. Meanwhile, they can occupy a significant portion of the human genome and participate in gene expression regulation through various mechanisms. Gestational diabetes mellitus (GDM) is a pathologic condition of carbohydrate intolerance that begins or is first detected during pregnancy, making it one of the most common pregnancy complications. Although the exact pathogenesis of GDM remains unclear, several recent studies have shown that ncRNAs play a crucial regulatory role in GDM. Herein, we present a comprehensive review on the multiple mechanisms of ncRNAs in GDM along with their potential role as biomarkers. In addition, we investigate the contribution of deep learning-based models in discovering disease-specific ncRNA biomarkers and elucidate the underlying mechanisms of ncRNA. This might assist community-wide efforts to obtain insights into the regulatory mechanisms of ncRNAs in disease and guide a novel approach for early diagnosis and treatment of disease.

Ghrelin alleviates intestinal ischemia-reperfusion injury by activating the GHSR-1α/Sirt1/FOXO1 pathway.

Ischemia-reperfusion (IR) injury is primarily characterized by the restoration of blood flow perfusion and oxygen supply to ischemic tissue and organs, but it paradoxically leads to tissue injury aggravation. IR injury is a challenging pathophysiological process that is difficult to avoid clinically and frequently occurs during organ transplantation, surgery, shock resuscitation, and other processes. The major causes of IR injury include increased levels of free radicals, calcium overload, oxidative stress, and excessive inflammatory response. Ghrelin is a newly discovered brain-intestinal peptide with anti-inflammatory and antiapoptotic effects that improve blood supply. The role and mechanism of ghrelin in intestinal ischemia-reperfusion (IIR) injury remain unclear. We hypothesized that ghrelin could attenuate IIR-induced oxidative stress and apoptosis. To investigate this, we established IIR by using a non-invasive arterial clip to clamp the root of the superior mesenteric artery (SMA) in mice. Ghrelin was injected intraperitoneally at a dose of 50 µg/kg 20 min before IIR surgery, and [D-Lys3]-GHRP-6 was injected intraperitoneally at a dose of 12 nmol/kg 20 min before ghrelin injection. We mimicked the IIR process with hypoxia-reoxygenation (HR) in Caco-2 cells, which are similar to intestinal epithelial cells in structure and biochemistry. Our results showed that ghrelin inhibited IIR/HR-induced oxidative stress and apoptosis by activating GHSR-1α. Moreover, it was found that ghrelin activated the GHSR-1α/Sirt1/FOXO1 signaling pathway. We further inhibited Sirt1 and found that Sirt1 was critical for ghrelin-mediated mitigation of IIR/HR injury. Overall, our data suggest that pretreatment with ghrelin reduces oxidative stress and apoptosis to attenuate IIR/HR injury by binding with GHSR-1α to further activate Sirt1.

iRice-MS: An integrated XGBoost model for detecting multitype post-translational modification sites in rice.

Post-translational modification (PTM) refers to the covalent and enzymatic modification of proteins after protein biosynthesis, which orchestrates a variety of biological processes. Detecting PTM sites in proteome scale is one of the key steps to in-depth understanding their regulation mechanisms. In this study, we presented an integrated method based on eXtreme Gradient Boosting (XGBoost), called iRice-MS, to identify 2-hydroxyisobutyrylation, crotonylation, malonylation, ubiquitination, succinylation and acetylation in rice. For each PTM-specific model, we adopted eight feature encoding schemes, including sequence-based features, physicochemical property-based features and spatial mapping information-based features. The optimal feature set was identified from each encoding, and their respective models were established. Extensive experimental results show that iRice-MS always display excellent performance on 5-fold cross-validation and independent dataset test. In addition, our novel approach provides the superiority to other existing tools in terms of AUC value. Based on the proposed model, a web server named iRice-MS was established and is freely accessible at http://lin-group.cn/server/iRice-MS.

CST3 alleviates retinal vascular leakage by regulating the Rap1 signaling pathway.

Retinal vascular leakage is a major event in several retinal diseases, including diabetic retinopathy (DR). In a previous study, we demonstrated that the aqueous humor concentration of Cystatin C (CST3), a physiological inhibitor of cysteine protease, is negatively correlated with the severity of diabetic macular edema. However, its function in the retina has not been clearly elucidated. In this study, we found a significant decrease in the aqueous humor concentration of CST3 with DR progression. Furthermore, we found that CST3 was expressed in retinal endothelial cells and that its expression was significantly downregulated in high glucose-treated human retinal microvascular endothelial cells (HRMECs) and the retinal vessels of oxygen-induced retinopathy (OIR) mice. Silencing CST3 expression resulted in decreased HRMEC migration and tubule formation ability. Exogenous addition of the CST3 protein significantly improved HRMEC migration and tubular formation. In-vivo experiments demonstrated that CST3 silencing induced retinal vascular leakage in WT mice, while its intravitreal injection significantly reduced retinal leakage in OIR mice. Mechanistically, CST3 promoted the expression of the downstream adhesion molecules, claudin5, VE-cadherin, and ZO-1, in retinal vascular cells by regulating the Rap1 signaling pathway. Therefore, this study revealed a novel mechanism by which CST3 improves retinal vascular function and provided evidence that it is a potential therapeutic target for retinal vascular leakage.

Bouncing Dynamics of Drops' Successive Off-Center Impact.

Bouncing dynamics of a trailing drop off-center impacting a leading drop with varying time intervals and Weber numbers are investigated experimentally. Whether the trailing drop impacts during the spreading or receding process of the leading drop is determined by the time interval. For a short time interval of 0.15 ≤ Δt* ≤ 0.66, the trailing drop impacts during the spreading of the leading drop, and the drops completely coalesce and rebound; for a large time interval of 0.66 < Δt* ≤ 2.21, the trailing drop impacts during the receding process, and the drops partially coalesce and rebound. Whether the trailing drop directly impacts the surface or the liquid film of the leading drop is determined by the Weber number. The trailing drop impacts the surface directly at moderate Weber numbers of 16.22 ≤ We ≤ 45.42, while it impacts the liquid film at large Weber numbers of 45.42 < We ≤ 64.88. Intriguingly, when the trailing drop impacts the surface directly or the receding liquid film, the contact time increases linearly with the time interval but independent of the Weber number; when the trailing drop impacts the spreading liquid film, the contact time suddenly increases, showing that the force of the liquid film of the leading drop inhibits the receding of the trailing drop. Finally, a theoretical model of the contact time for the drops is established, which is suitable for different impact scenarios of the successive off-center impact. This study provides a quantitative relationship to calculate the contact time of drops successively impacting a superhydrophobic surface, facilitating the design of anti-icing surfaces.

Redox Relay-Induced C-S Radical Cross-Coupling Strategy: Application in Nontraditional Site-Selective Thiocyanation of Quinoxalinones.

Oxidative cross-coupling is a powerful strategy to form C-heteroatom bonds. However, oxidative cross-coupling for constructing C-S bond is still a challenge due to sulfur overoxidation and poisoning transition-metal catalysts. Now, electrochemical redox relay using sulfur radicals formed in situ from inorganic sulfur source offers a solution to this problem. Herein, electrochemical redox relay-induced C-S radical cross-coupling of quinoxalinones and ammonium thiocyanate with bromine anion as mediator is presented. The electrochemical redox relay comprised initially the formation of sulfur radical via indirect electrochemical oxidation, simultaneous electrochemical reduction of the imine bond, electro-oxidation-triggered radical coupling involving dearomatization-rearomatization, and the reformation of the imine bond through anodic oxidation. Applying this strategy, various quinoxalinones bearing multifarious electron-deficient/-rich substituents at different positions were well compatible with moderate to excellent yields and good steric hindrance compatibility under constant current conditions in an undivided cell without transition-metal catalysts and additional redox reagents. Synthetic applications of this methodology were demonstrated through gram-scale preparation and follow-up transformation. Notably, such a unique strategy may offer new opportunities for the development of new quinoxalinone-core leads.

Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis.

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

Targeting Cartilage miR-195/497 Cluster for Osteoarthritis Treatment Regulates the Circadian Clock.

INTRODUCTION: Osteoarthritis (OA) is the most prevalent and debilitating joint disease without an effective therapeutic option. Multiple risk factors for OA have been identified, including abnormal chondrocyte miRNA secretion and circadian rhythms disruption, both of which have been found to cause progressive damage and loss of articular cartilage. Environmental disruption of circadian rhythms in mice predisposes animals to cartilage injury and OA. METHODS: The role of miR-195/497 cluster during OA progression was verified by mouse OA model with intra-articular injection of Agomir and Antagomir. We performed micro-CT analysis, Osteoarthritis Research Society International scores, and histological analysis in mouse knee joints. RNA sequencing was performed on the mouse cartilage cell line to explore the molecular mechanism of the miR-195/497 cluster and proteins in signaling pathway were evaluated using Western blot. Senescence-associated phenotypes were detected by Western blot, senescence ß-galactosidase staining, and immunofluorescence. RESULTS: This study demonstrated that miR-195/497-5p expression is disrupted in OA with senescent chondrocytes. In addition, miR-195/497-5p influenced the circadian rhythm of mice chondrocytes by modulating the expression of the Per2 protein, resulting in the gradual degradation of articular cartilage. We found that the miR-195/497 cluster targets DUSP3 expression. The deletion of the miR-195/497 cluster increased the level of DUSP3 expression and decreased the levels of phosphorylated ERK 1/2 and CREB. Per2 transcription is upregulated by stimulating CREB and ERK 1/2 phosphorylation. CONCLUSION: Our findings identify a regulatory mechanism connecting chondrocyte miR-195/497-5p to cartilage maintenance and repair and imply that circadian rhythm disturbances affected by miR-195/497-5p are risk factors for age-related joint diseases such as OA.

Hydroxycitric Acid Alleviated Lung Ischemia-Reperfusion Injury by Inhibiting Oxidative Stress and Ferroptosis through the Hif-1α Pathway.

Lung ischemia-reperfusion injury (LIRI) is a prevalent occurrence in various pulmonary diseases and surgical procedures, including lung resections and transplantation. LIRI can result in systemic hypoxemia and multi-organ failure. Hydroxycitric acid (HCA), the primary acid present in the peel of Garcinia cambogia, exhibits anti-inflammatory, antioxidant, and anticancer properties. However, the effects of HCA on LIRI remain unknown. To investigate the impact of HCA on LIRI in mice, the mice were randomly divided into four groups: the control group, the I/R model group, and the I/R + low- or high-dose HCA groups. Human umbilical vein endothelial cells (HUVECs) were subjected to hypoxia for 12 h followed by reoxygenation for 6 h to simulate in vitro LIRI. The results demonstrated that administration of HCA effectively attenuated lung injury, inflammation, and edema induced by ischemia reperfusion. Moreover, HCA treatment significantly reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels while decreasing iron content and increasing superoxide dismutase (SOD) levels after ischemia-reperfusion insult. Mechanistically, HCA administration significantly inhibited Hif-1α and HO-1 upregulation both in vivo and in vitro. We found that HCA could also alleviate endothelial barrier damage in H/R-induced HUVECs in a concentration-dependent manner. In addition, overexpression of Hif-1α counteracted HCA-mediated inhibition of H/R-induced endothelial cell ferroptosis. In summary, these results indicate that HCA alleviated LIRI by inhibiting oxidative stress and ferroptosis through the Hif-1α pathway.

Metal-free sulfonylation of quinoxalinones to access 2-sulfonyl-oxylated quinoxalines via oxidative O-S cross coupling.

The C2 sulfonylation of quinoxalinones via a metal-free oxidative S-O cross-coupling strategy for synthesizing 2-sulfonyloxylated quinoxalines is established. It effectively solved the long-standing problems in the C2 transformation of quinoxalinones via a metal-free oxidative O-S coupling strategy. Compared with the traditional C2 transformed quinoxalinones-C2 chlorination method, this protocol is mild, facile, and environmentally friendly and exhibits good atomic economy and excellent functional group tolerance. Moreover, the utility of this methodology and the sulfonyloxyl handles was demonstrated through the synthesis of 2-substituted quinoxaline-based bioactive molecules.

Electrochemical Oxidation Induced Selective C-C Bond Cleavage.

Selective C-C bond cleavage under mild conditions can serve as a valuable tool for organic syntheses and macromolecular degradation. However, the conventional chemical methods have largely involved the use of noble transition-metal catalysts as well as the stoichiometric and perhaps environmentally unfriendly oxidants, compromising the overall sustainable nature of C-C transformation chemistry. In this regard, electrochemical C-C bond cleavage has been identified as a sustainable and scalable strategy that employs electricity to replace byproduct-generating chemical reagents. To date, the progress made in this area has mainly relied on Kolbe electrolysis and related processes. Encouragingly, more and more examples of the cleavage of C-C bonds via other maneuvers have recently been developed. This review provides an overview on the most recent and significant developments in electrochemically oxidative selective C-C bond cleavage, with an emphasis on both synthetic outcomes and reaction mechanisms, and it showcases the innate advantages and exciting potentials of electrochemical synthesis.

Noble-Metal Nanoframes and Their Catalytic Applications.

Noble-metal nanoframes consisting of interconnected, ultrathin ridges have received considerable attention in the field of heterogeneous catalysis. The enthusiasm arises from the high utilization efficiency of atoms for significantly reducing the material loading while enhancing the catalytic performance. In this review article, we offer a comprehensive assessment of research endeavors in the design and rational synthesis of noble-metal nanoframes for applications in catalysis. We start with a brief introduction to the unique characteristics of nanoframes, followed by a discussion of the synthetic strategies and their controls in terms of structure and composition. We then present case studies to elucidate mechanistic details behind the synthesis of mono-, bi-, and multimetallic nanoframes, as well as heterostructured and hybrid systems. We discuss their performance in electrocatalysis, thermal catalysis, and photocatalysis. Finally, we highlight recent progress in addressing the structural and compositional stability issues of nanoframes for the assurance of robustness in catalytic applications.

Deep-4mCW2V: A sequence-based predictor to identify N4-methylcytosine sites in Escherichia coli.

N4-methylcytosine (4mC) is a type of DNA modification which could regulate several biological progressions such as transcription regulation, replication and gene expressions. Precisely recognizing 4mC sites in genomic sequences can provide specific knowledge about their genetic roles. This study aimed to develop a deep learning-based model to predict 4mC sites in the Escherichia coli. In the model, DNA sequences were encoded by word embedding technique 'word2vec'. The obtained features were inputted into 1-D convolutional neural network (CNN) to discriminate 4mC sites from non-4mC sites in Escherichia coli genome. The examination on independent dataset showed that our model could yield the overall accuracy of 0.861, which was about 4.3% higher than the existing model. To provide convenience to scholars, we provided the data and source code of the model which can be freely download from https://github.com/linDing-groups/Deep-4mCW2V.

Isolated unilateral oculomotor palsy caused by pure midbrain infarction: a case report.

Purpose: Multiple etiologies may cause oculomotor nerve palsies. Identification of different etiologies is very important for subsequent treatment. Midbrain infarction is a rare cause of oculomotor nerve palsy. Materials and methods: We herein present a case of isolated unilateral oculomotor paresis caused by pure midbrain infarction. Results: Her pupillary sphincter and inferior rectus muscles were selectively spared. The symptoms were completely relieved after two months of antiplatelet therapy. We proposed that fibers from Edinger-Westphal nucleus and inferior rectus nucleus do not course through the paramedian area of the midbrain. Conclusions: Our report adds to the understanding of fascicles arrangement in the midbrain.

Newest perspectives of glycopeptide antibiotics: biosynthetic cascades, novel derivatives, and new appealing antimicrobial applications.

Glycopeptide antibiotics (GPAs) are a family of non-ribosomal peptide natural products with polypeptide skeleton characteristics, which are considered the last resort for treating severe infections caused by multidrug-resistant Gram-positive pathogens. Over the past few years, an increasing prevalence of Gram-positive resistant strain "superbugs" has emerged. Therefore, more efforts are needed to study and modify the GPAs to overcome the challenge of superbugs. In this mini-review, we provide an overview of the complex biosynthetic gene clusters (BGCs), the ingenious crosslinking and tailoring modifications, the new GPA derivatives, the discoveries of new natural GPAs, and the new applications of GPAs in antivirus and anti-Gram-negative bacteria. With the development and interdisciplinary integration of synthetic biology, next-generation sequencing (NGS), and artificial intelligence (AI), more GPAs with new chemical structures and action mechanisms will constantly be emerging.

Divergent and Selective Light Alkene Cross-Coupling.

Light olefins are abundantly manufactured in the petroleum industry and thus represent ideal starting materials for modern chemical synthesis. Selective and divergent transformations of feedstock light olefins to value-added chemicals are highly sought-after but remain challenging. Herein we report an exceptionally regioselective carbonickelation of light alkenes followed by in situ trapping with three types of nucleophiles, namely a reductant, base, or Grignard reagent. This protocol enables efficient 1,2-hydrofunctionalization, dicarbofunctionalization, and branched-selective Heck-type cross-coupling of light alkenes with aryl and alkenyl reagents to streamline access to diverse alkyl arenes and complex alkenes. Harnessing bulky N-heterocyclic carbene ligands with acenaphthyl backbones for nickel catalysts is crucial to attain high reactivity and selectivity. This strategy provides a rare, modular, and divergent platform for upgrading feedstock alkenes and is expected to find broad applications in medicinal chemistry and industrial processes.

Enantioselective Ni/N-Heterocyclic Carbene-Catalyzed Redox-Economical Coupling of Aldehydes, Alkynes, and Enones for Rapid Construction of Acyclic All-Carbon Quaternary Stereocenters.

Acyclic quaternary carbon stereocenters exist widely in natural products and bioactive molecules, but their enantioselective construction remains a prominent challenge. In particular, multicomponent enantioselective couplings of simple precursors to acyclic all-carbon quaternary stereocenters are very rare. We describe herein an N-heterocyclic carbene (NHC)-Ni catalyzed redox-economical three-component reaction of aldehydes, alkynes, and enones that proceeds in a highly chemo-, regio-, and enantioselective manner. A wide variety of valuable acyclic α-quaternary chiral ketones were synthesized in a single step with 100% atom economy. This reaction proceeds through the formation of a transient cyclic enolate followed by an aldol reaction/ring-opening sequence. The strategy is expected to inspire new and efficient approaches to generate other acyclic quaternary stereocenters.

Enantio- and Regioselective Ni-Catalyzed para-C-H Alkylation of Pyridines with Styrenes via Intermolecular Hydroarylation.

Direct asymmetric functionalization of the pyridyl C-H bond represents a longstanding challenge in organic chemistry. We herein describe the first enantioselective para-C-H activation of pyridines through the use of a Ni-Al bimetallic catalyst system and N-heterocyclic carbene (NHC) ligand for intermolecular hydroarylation of styrenes. The reaction procceds in high to excellent enantioselectivities (up to 98.5:1.5 er) and high site-selectivities for both styrene and pyridine components (up to >98:2). Consequently, a broad range of enantioenriched 1,1-diarylalkanes containing pyridine moieties could be prepared in a single step with 100% atom economy. Computational studies supported a mechanism involving a ligand-to-ligand H-transfer (LLHT) and reductive elimination sequence, with LLHT being the rate- and enantioselectivity-determining step. DFT studies indicate that the π-π stacking interaction between the NHC aryl fragment and trans-styrenes is critical for high reactivity and enantiocontrol.

HOCl-Activated Reactive Organic Selenium Delivery Platform for Alleviation of Inflammation.

Selenium plays an important role in the biological system and can be used to treat various types of diseases. However, the current selenium delivery systems face the problems of low activity of released Se-containing compounds or nonspecific toxicity of reactive organic selenium donors in living systems. In response to these problems, we constructed a reactive organic selenium delivery platform by the activation of HOCl. Compared with prodrugs without activation capability, the hypochloroselenoite derivatives released from the present platform after activation displayed higher reactivity and could react with various nucleophiles to participate in specific life processes. Taking the selected compound (DHU-Se1) as an example, we found that it could alleviate the process of inflammation by blocking the polarization of macrophages from M0 to M1. Therefore, the development of this system is of great significance for expanding the application of selenium-containing compounds and treating related diseases.

Caspofungin at sub-inhibitory concentration promotes the formation of Candida albicans persister cells.

AIMS: Low caspofungin exposure is frequently encountered in patients with invasive candidiasis caused by Candida albicans. This study aimed to investigate the effects of caspofungin on C. albicans at sub-inhibitory concentrations. METHODS AND RESULTS: First, a comparative transcriptomics analysis was performed on C. albicans receiving caspofungin at sub-minimum inhibitory concentrations (sub-MICs). The results showed that caspofungin significantly changed the mRNA expression profile in DAY185, with DE-mRNAs enriched in the functions of cell wall biosynthesis, metabolism, etc. Subsequently, cellular fitness, cell aggregation, energy metabolism activity and the proportion of persister cells of C. albicans were quantitatively and/or qualitatively assessed after sub-MIC caspofungin exposure. No significant changes in cell fitness and aggregation formation were observed during treatment of C. albicans with sub-MIC caspofungin. In C. albicans aggregation treated with sub-MIC caspofungin, we observed a decrease in respiratory metabolism and an increase in persister cells; this effect was more pronounced in als1ΔΔ than in DAY185. CONCLUSIONS: Pre-exposure to sub-MIC caspofungin suppresses C. albicans respiratory metabolism and promotes persister cell development. SIGNIFICANCE AND IMPACT OF THE STUDY: Caspofungin should be used with caution in patients with C. albicans infections, as anti-infection therapy may fail due to persister cells.