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The electron-rich five-membered aromatic aza-heterocyclic imidazole, which contains two nitrogen atoms, is an important functional fragment widely present in a large number of biomolecules and medicinal drugs; its unique structure is beneficial to easily bind with various inorganic or organic ions and molecules through noncovalent interactions to form a variety of supramolecular complexes with broad medicinal potential, which is being paid an increasing amount of attention regarding more and more contributions to imidazole-based supramolecular complexes for possible medicinal application. This work gives systematical and comprehensive insights into medicinal research on imidazole-based supramolecular complexes, including anticancer, antibacterial, antifungal, antiparasitic, antidiabetic, antihypertensive, and anti-inflammatory aspects as well as ion receptors, imaging agents, and pathologic probes. The new trend of the foreseeable research in the near future toward imidazole-based supramolecular medicinal chemistry is also prospected. It is hoped that this work provides beneficial help for the rational design of imidazole-based drug molecules and supramolecular medicinal agents and more effective diagnostic agents and pathological probes.

We systematically investigate the mass spectrum and two-body open-charm strong decays of charmonium states in a coupled-channel model where the 3 P 0 quark-antiquark pair creation mechanism is employed. The results of masses, mass shifts, proportions of the c c ¯ component, and open-charm decay widths are provided. The S - D wave mixing angles and di-electric decay widths for vector mesons are also presented. Based on our results, we find that the ψ ( 3770 ) , ψ ( 4040 ) , ψ ( 4160 ) , ψ ( 4360 ) , and ψ ( 4415 ) can be assigned as the 1 3 D 1 -, 3 3 S 1 -, 2 3 D 1 -, 4 3 S 1 -, and 3 3 D 1 -dominated charmonium states, respectively. The ψ 3 ( 3842 ) is a good candidate of the ψ 3 ( 1 D ) charmonium state. The calculated mass and strong decay width of χ c 1 ( 2 P ) with significant continuum contribution ( ∼ 57%) favor the charmonium interpretation for the mysterious χ c 1 ( 3872 ) . When considering the large uncertainty in the observed decay width, the possibility to assign the χ c 0 ( 3860 ) as the χ c 0 ( 2 P ) charmonium state cannot be ruled out. One may describe well the properties of χ c 2 ( 3930 ) with the χ c 2 ( 2 P ) charmonium. The predictions on properties of other c c ¯ states can be tested by future experiments.

Water scarcity mitigation in regional agricultural systems contributes to water use efficiency improvement. Blue (WSIblue), green (WSIgreen) and grey (WSIgrey) water scarcity indices were proposed to describe various water stresses in detail and further determine the type of regional water scarcity. WSIblue and WSIgreen reveal resource-based water scarcities, and WSIgrey characterizes environment-based water shortages. Provincial water scarcity indices of China from 2000–2014 were calculated and analyzed in the current paper. The results indicated that the national WSI, WSIgrey, WSIblue and WSIgreen values are 0.84, 0.16, 0.39 and 0.89, respectively. China is facing a high water stress, manifested as a resource-based water shortage. Northwest and Northeast China experience a severe water quantity scarcity with high WSIblue and WSIgreen values, and the central and eastern regions exhibit a high WSIgrey value. Eastern China faces both serious resource-based and environmental water shortages. The constructed blue, green and grey water scarcity indices compensate for the inability of the existing index to determine the type of water shortage and indicate the reason for water scarcity. They also provide a targeted guiding significance for the formulation of effective measures to improve agricultural water resource management and alleviate regional water scarcity.

Accretion of matter onto black holes (BHs) is a prevalent phenomenon in the cosmos, resulting in consequential changes to both the mass and irreducible mass of the BH. These alterations significantly impact the rotational energy reservoir harbored within. This study investigates the relationship between the increase in a BH’s irreducible mass and the augmentation of its total mass due to the infall of matter (test particles) from the innermost stable circular orbit (ISCO) of a Kerr BH. Interestingly, the ratio of total mass growth to irreducible mass growth proves to be a non-monotonic function concerning the dimensionless spin parameter. It initially rises with spin, culminating near an extreme BH ( ), before declining. At the extreme BH position, the ratio is , indicating that accretion along the ISCO leads to the ultimate stabilization of the BH as an extreme one. Conversely, massless particles falling along unstable circular orbits exhibit a continuous increasing ratio of total mass growth to irreducible mass growth with respect to the dimensionless spin parameter.

Skin microcirculation provides essential insights in clinical practice. However, the specific characteristics and distribution patterns of dermal microarterioles and microvenules remain insufficiently explored. This study aimed to analyze their structural differences and distribution in the human forehead skin using an innovative intravascular dual perfusion technique combined with immunofluorescence staining to distinguish microvessel types within the dermis. Using two post-mortem cadaver specimens, lead oxide-gelatin perfusion was applied to label microarterioles, and latex was used for microvenules. Tissue sections underwent hematoxylin and eosin and immunofluorescence staining, with cluster of differentiation 31 (CD31) serving as a general vascular marker and monocarboxylate transporter 1 (MCT1) as a venule-specific marker. The analysis revealed significant structural differences between dermal layers: vessels in the deep dermis had larger diameters and thicker walls than those in the superficial layer, while microvessel density was higher in the superficial dermis. These findings demonstrate distinct patterns and significant differences in microvessel distribution between the superficial and deep dermal layers, reflecting their layer-specific functional demands. Furthermore, MCT1 was identified as a specific marker for microvenules, and a novel method combining CD31 and MCT1 immunofluorescent staining was introduced to differentiate dermal microarterioles from microvenules. These results offer valuable implications for surgical planning, skin grafting, and diagnostics related to microcirculation.

Berberine (BBR), a widely recognized traditional Chinese medicine, has attracted considerable attention for its promising anti‐inflammatory effects. The activation of nuclear factor erythroid 2‐related factor 2 (Nrf2) effectively safeguards against organ damage stemming from sepsis‐induced oxidative stress and inflammatory responses. This study examined the potential of BBR in alleviating sepsis‐induced acute gastric injury, with a particular focus on elucidating whether its mechanism of action involves the activation of the Nrf2 signaling pathway. Following intraperitoneal injection of BBR, mice were subjected to the cecal ligation and puncture (CLP) method to induce sepsis. In vitro experiments involved pre‐treating the normal gastric epithelial cells (GES‐1) with BBR, followed by treatment with lipopolysaccharide (LPS). Functional assays were then performed to assess cell proliferation and apoptosis. To validate the role of Nrf2 in pyroptosis and inflammation, siRNA targeting Nrf2 (si‐Nrf2) was transfected into LPS‐treated GES‐1 cells. Additionally, mice were administered the Nrf2 inhibitor ML385 to confirm the protective effects of BBR in vivo. BBR displayed a dose‐dependent effect in mitigating gastric tissue damage, suppressing the release of inflammatory cytokines, and reducing the expression of NLRP3, ASC, and GSDMD‐N. In vitro, BBR fostered GES‐1 cell proliferation, hindered apoptosis, and suppressed the levels of TNF‐α, IL‐18, IL‐1β, NLRP3, ASC, and GSDMD‐N. Further analysis revealed that knocking down Nrf2 reversed BBR's inhibitory effect on pyroptosis in LPS‐treated GES‐1 cells. Through binding to Keap1, BBR efficiently prevented the ubiquitination and degradation of Nrf2, ultimately promoting its nuclear translocation. In vivo experiments confirmed that ML385 reversed the protective effect of BBR on pyroptosis and inflammation. Our research reveals that BBR interacts with Keap1 to activate the Keap1/Nrf2 signaling pathway in gastric epithelial cells, thereby suppressing pyroptosis and inflammation in sepsis‐induced acute gastric injury.

The positive-strand RNA ( + RNA) viruses extensively remodel cellular endomembranes to facilitate viral replication, with coronaviruses forming a specialized viral replication organelle (RO) known as double-membrane vesicles (DMVs). These DMVs serve as platforms for viral replication and shield viral RNA from host immune recognition. However, the biogenesis, structural organization, and physiological properties of DMVs remain poorly understood. In this study, we demonstrate that the coronavirus non-structural protein 6 (nsp6) anchors DMVs to lipid droplets (LDs), hijacks the endoplasmic reticulum (ER)-associated protein degradation (ERAD) machinery to degrade PLIN2, and redirects fatty acids (FAs) from LDs to DMVs, thereby supplying lipids for DMV growth. Furthermore, nsp6 anchors ERAD-derived vesicles to DMVs, directly refurnishing membrane components for DMV expansion. Disruption of lipolysis or ERAD impairs DMV formation and inhibits coronaviral replication. We further validated the antiviral effects of ERAD inhibition in female mice in vivo. Our findings elucidate the mechanisms and functional significance of virus-induced organelle remodeling and DMV biogenesis. Given the conservation of viral ROs across +RNA viruses, these structures represent a promising and attractive target for the development of broad-spectrum antiviral therapies. Here the authors show how coronaviruses use host lipid metabolism and ER-associated degradation pathways to form double-membrane vesicles (DMVs) essential for RNA replication, demonstrating that the viral protein nsp6 tethers DMVs to lipid droplets and recruits ERAD-derived vesicles to enable membrane expansion and efficient replication.

Deletions of chromosome 22q13.3 cause Phelan–McDermid syndrome (PMDS), a neurodevelopmental disorder associated with autism; here induced pluripotent stem cells from PMDS patients with autism are used to produce neurons, they are shown to have reduced SHANK3 expression and a defect in excitatory synaptic transmission which can be restored either by increasing SHANK3 or with insulin-like growth factor 1. The nature of Phelan–McDermid syndrome Deletions of chromosome 22q13.3 cause Phelan–McDermid syndrome (PMDS), a neurodevelopmental disorder associated with autism. Ricardo Dolmetsch and colleagues generated induced pluripotent stem (iPS) cells from PMDS patients with autism and used them to produce neurons. PMDS neurons have reduced expression of the SHANK3 gene, which encodes a protein found in a structure known as the postsynaptic density, and a defect in excitatory synaptic transmission that can be restored either by increasing SHANK3 or with insulin-like growth factor 1. These findings add to the picture of synaptic deficits observed in autism spectrum disorders, and point to potential mechanisms for restoring them. Phelan–McDermid syndrome (PMDS) is a complex neurodevelopmental disorder characterized by global developmental delay, severely impaired speech, intellectual disability, and an increased risk of autism spectrum disorders (ASDs) 1 . PMDS is caused by heterozygous deletions of chromosome 22q13.3. Among the genes in the deleted region is SHANK3 , which encodes a protein in the postsynaptic density (PSD) 2 , 3 . Rare mutations in SHANK3 have been associated with idiopathic ASDs 4 , 5 , 6 , 7 , non-syndromic intellectual disability 8 , and schizophrenia 9 . Although SHANK3 is considered to be the most likely candidate gene for the neurological abnormalities in PMDS patients 10 , the cellular and molecular phenotypes associated with this syndrome in human neurons are unknown. We generated induced pluripotent stem (iPS) cells from individuals with PMDS and autism and used them to produce functional neurons. We show that PMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission. Excitatory synaptic transmission in PMDS neurons can be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor 1 (IGF1). IGF1 treatment promotes formation of mature excitatory synapses that lack SHANK3 but contain PSD95 and N -methyl- d -aspartate (NMDA) receptors with fast deactivation kinetics. Our findings provide direct evidence for a disruption in the ratio of cellular excitation and inhibition in PMDS neurons, and point to a molecular pathway that can be recruited to restore it.

BackgroundIn order that the general public is not vulnerable to hackers, security bug reports need to be handled by small groups of engineers before being widely discussed. But learning how to distinguish the security bug reports from other bug reports is challenging since they may occur rarely. Data mining methods that can find such scarce targets require extensive optimization effort.GoalThe goal of this research is to aid practitioners as they struggle to optimize methods that try to distinguish between rare security bug reports and other bug reports.MethodOur proposed method, called SWIFT, is a dual optimizer that optimizes both learner and pre-processor options. Since this is a large space of options, SWIFT uses a technique called ðoe--dominance that learns how to avoid operations that do not significantly improve performance.ResultWhen compared to recent state-of-the-art results (from FARSEC which is published in TSE’18), we find that the SWIFT’s dual optimization of both pre-processor and learner is more useful than optimizing each of them individually. For example, in a study of security bug reports from the Chromium dataset, the median recalls of FARSEC and SWIFT were 15.7% and 77.4%, respectively. For another example, in experiments with data from the Ambari project, the median recalls improved from 21.5% to 85.7% (FARSEC to SWIFT).ConclusionOverall, our approach can quickly optimize models that achieve better recalls than the prior state-of-the-art. These increases in recall are associated with moderate increases in false positive rates (from 8% to 24%, median). For future work, these results suggest that dual optimization is both practical and useful.

The mechanisms of inflammation in bone and joint tissue are complex and involve long non-coding RNAs (lncRNAs), which play an important role in this process. The aim of the present study was to screen out differentially expressed genes in human osteoblasts stimulated by inflammation, and to further explore the mechanisms underlying inflammatory responses and the functional activity of human osteoblasts through bioinformatics methods and in vitro experiments. For this purpose, MG63 cells were stimulated with various concentrations of lipopolysaccharide (LPS) for different periods of time to construct an optimal inflammatory model and RNA sequencing was then performed on these cells. The levels of nuclear enriched abundant transcript 1 (NEAT1), various inflammatory factors, Nod-like receptor protein 3 (NLRP3) protein and osteogenesis-related proteins, as well as the levels of cell apoptosis- and cell cycle-related markers were measured in MG63 cells stimulated with LPS, transfected with NEAT1 overexpression plasmid and treated with bexarotene by western blot analysis, RT-qPCR, immunofluorescence, FISH, TEM and flow cytometry. There were 427 differentially expressed genes in the LPS-stimulated MG63 cells, in which NEAT1 was significantly downregulated. LPS upregulated the expression of inflammatory cytokines and NLRP3, inhibited the expression of autophagy-related and osteogenesis-related proteins, promoted apoptosis and altered the cell cycle, which was partially inhibited by NEAT1 overexpression and promoted by bexarotene. LPS stimulated inflammation in the MG63 cells and inhibited the retinoid X receptor (RXR)-α to downregulate the expression of NEAT1 and decrease levels of autophagy, which promoted the activation of NLRP3 and the release of inflammatory factors, and impaired the functional activity of osteoblasts, thus promoting the development of inflammation.