Sophoridine exerts anti-arthritic effects on fibroblast-like synoviocytes and collagen-induced arthritis in rats.

The discovery of alternative medicines with fewer adverse effects is urgently needed for rheumatoid arthritis (RA). Sophoridine (SR), the naturally occurring quinolizidine alkaloid isolated from the leguminous sophora species, has been demonstrated to possess a wide range of pharmacological activities. However, the effect of SR on RA remains unknown. In this study, the collagen-induced arthritis (CIA) rat model and tumor necrosis factor alpha (TNFα)-induced fibroblast-like synoviocytes (FLSs) were utilized to investigate the inhibitory effect of SR on RA. The anti-arthritic effect of SR was evaluated using the CIA rat model in vivo and TNFα-stimulated FLSs in vitro. Mechanistically, potential therapeutic targets and pathways of SR in RA were analyzed through drug target databases and disease databases, and validation was carried out through immunofluorescence, immunohistochemistry, and Western blot. The in vivo results revealed that SR treatment effectively ameliorated synovial inflammation and bone erosion in rats with CIA. The in vitro studies showed that SR could significantly suppress the proliferation and migration in TNFα-induced arthritic FLSs. Mechanistically, SR treatment efficiently inhibited the activation of MAPKs (JNK and p38) and NF-κB pathways in TNFα-induced arthritic FLSs. These findings were further substantiated by Immunohistochemistry results in the CIA rat. SR exerts an anti-arthritic effect in CIA rats through inhibition of the pathogenic characteristic of arthritic FLSs via suppressing NF-κB and MAPKs (JNK and p38) signaling pathways. SR may have a great potential for development as a novel therapeutic agent for RA treatment.

NtGCN2 confers cadmium tolerance in Nicotiana tabacum L. by regulating cadmium uptake, efflux, and subcellular distribution.

General control non-derepressible-2 (GCN2) is widely expressed in eukaryotes and responds to biotic and abiotic stressors. However, the precise function and mechanism of action of GCN2 in response to cadmium (Cd) stress in Nicotiana tabacum L. (tobacco) remains unclear. We investigated the role of NtGCN2 in Cd tolerance and explored the mechanism by which NtGCN2 responds to Cd stress in tobacco by exposing NtGCN2 transgenic tobacco lines to different concentrations of CdCl2. NtGCN2 was activated under 50 µmol·L-1 CdCl2 stress and enhanced the Cd tolerance and photosynthetic capacities of tobacco by increasing chlorophyll content and antioxidant capacity by upregulating NtSOD, NtPOD, and NtCAT expression and corresponding enzyme activities and decreasing malondialdehyde and O2·- contents. NtGCN2 enhanced the osmoregulatory capacity of tobacco by elevating proline (Pro) and soluble sugar contents and maintaining low levels of relative conductivity. Finally, NtGCN2 enhanced Cd tolerance in tobacco by reducing Cd uptake and translocation, promoting Cd efflux, and regulating Cd subcellular distribution. In conclusion, NtGCN2 improves the tolerance of tobacco to Cd through a series of mechanisms, namely, increasing antioxidant, photosynthetic, and osmoregulation capacities and regulating Cd uptake, translocation, efflux, and subcellular distribution. This study provides a scientific basis for further exploration of the role of NtGCN2 in plant responses to Cd stress and enhancement of the Cd stress signaling network in tobacco.

CTF-former: A novel simplified multi-task learning strategy for simultaneous multivariate chaotic time series prediction.

Multivariate chaotic time series prediction is a challenging task, especially when multiple variables are predicted simultaneously. For multiple related prediction tasks typically require multiple models, however, multiple models are difficult to keep synchronization, making immediate communication between predicted values challenging. Although multi-task learning can be applied to this problem, the principles of allocation and layout options between shared and specific representations are ambiguous. To address this issue, a novel simplified multi-task learning method was proposed for the precise implementation of simultaneous multiple chaotic time series prediction tasks. The scheme proposed consists of a cross-convolution operator designed to capture variable correlations and sequence correlations, and an attention module proposed to capture the information embedded in the sequence structure. In the attention module, a non-linear transformation was implemented with convolution, and its local receptive field and the global dependency of the attention mechanism achieve complementarity. In addition, an attention weight calculation was devised that takes into account not only the synergy of time and frequency domain features, but also the fusion of series and channel information. Notably the scheme proposed a purely simplified design principle of multi-task learning by reducing the specific network to single neuron. The precision of the proposed solution and its potential for engineering applications were verified with the Lorenz system and power consumption. The mean absolute error of the proposed method was reduced by an average of 82.9% in the Lorenz system and 19.83% in power consumption compared to the Gated Recurrent Unit.

Neuronal CFL1 upregulation in head and neck squamous cell carcinoma enhances tumor-nerve crosstalk and promotes tumor growth.

Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer type, marked by a pronounced nerve density within the tumor microenvironment and a high rate of perineural invasion (PNI). Growing evidence suggests that the nervous system plays a vital role in HNSCC progression. Yet, the mechanisms governing cancer-nerve interactions remain largely elusive. Our research revealed that cofilin-1 (CFL1) is significantly overexpressed in HNSCC and correlates with both PNI and unfavorable prognosis. Utilizing multiplex fluorescent immunohistochemistry, we have localized CFL1 chiefly to the nerves adjacent to tumor sites. Significantly, it is the elevated expression of CFL1 in neuronal structures, rather than in the tumor cells, that aligns with diminished patient survival rates. We observed that HNSCC cells induced the expression of neuronal CFL1 and that the conditional knockout of neuronal CFL1 impedes tumor-nerve interactions. Both Gene Ontology functional enrichment analyses and Gene Set Enrichment Analysis demonstrate that CFL1 expression in HNSCC is associated with specific biological processes, including "RIBOSOME," "PROTEASOME," and "cadherin binding." In summary, HNSCC promotes the expression of CFL1 in nerves, which is essential for cancer-nerve interactions. The neuronal CFL1 is associated with PNI and may be a potential molecular prognostic marker of poor survival in HNSCC.

Inhibitory effects of norcantharidin on titanium particle-induced osteolysis, osteoclast activation and bone resorption via MAPK pathways.

Wear particles generated from the surface of implanted prostheses can lead to peri-implant osteolysis and subsequent aseptic loosening. In the inflammatory environment, extensive formation and activation of osteoclasts are considered the underlying cause of peri-implant osteolysis. Current medications targeting osteoclasts for the treatment of particle-induced bone resorption are not ideal due to significant side effects. Therefore, there is an urgent need to develop more effective drugs with fewer side effects. Norcantharidin (NCTD), a derivative of cantharidin extracted from blister beetles, is currently primarily used for the treatment of solid tumors in clinical settings. However, the potential role of NCTD in treating aseptic loosening of the prosthesis has not been reported. In this study, the in vitro results demonstrated that NCTD could effectively inhibit the formation of osteoclasts and bone resorption induced by the RANKL. Consistently, NCTD strongly inhibited RANKL-induced mRNA and protein levels of c-Fos and NFATc1, concomitant with reduced expression of osteoclast specific genes including TRAP, CTR and CTSK. The in vivo data showed that NCTD exerted significant protective actions against titanium particle-induced inflammation and subsequent osteolysis. The molecular mechanism investigation revealed that NCTD could suppress the activations of RANKL-induced MAPK (p38, ERK). Overall, these findings support the potential use of NCTD for the treatment of aseptic loosening following total joint arthroplasty.

Divergent Synthesis of F- and CF3-Containing N-Fused Heterocycles Enabled by Fragmentation Cycloaddition of ß-CF3-1,3-Enynes with N-Aminopyridiniums Ylides.

The two novel cyclization modes of ß-CF3-1,3-enynes are presented herein for the divergent construction of F- and CF3-containing N-fused heterocycles. Fluorinated pyrazolo[1,5-a]pyridines were afforded from ß-CF3-1,3-enynes with N-aminopyridiniums ylides via detrifluoromethylative [2 + 3] cyclizations, followed by fluorine transfer from a CF3 unit. Whereas reaction with N-aminoisoquinoliniums ylides gave CF3-substituted pyrrolo[2,1-a]isoquinoline by unprecedented fragmentation [3 + 2]-cycloadditions. Additionally, gram-scale experiments and synthetic utility are demonstrated by further derivatization of fluorinated heterocycles.

Frailty and Adverse Outcomes After SARS-CoV-2 Infection in Elderly Patients on Maintenance Hemodialysis: A Cohort Study.

Purpose: Frailty is an important geriatric syndrome associated with aging and adverse events, especially in patients with severe infection. To help guide prognosis for elderly patients undergoing maintenance hemodialysis (MHD) who experience acute infection, this study investigated whether baseline (pre-infection) frailty may be associated with adverse outcomes in elderly patients undergoing MHD who suffer SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. Patients and Methods: Patients (aged ≥60 y) receiving MHD had been assessed for overall frailty and the 5 frailty components based on the Fried Frailty Phenotype scale within 3 months prior to SARS-CoV-2 infection. Results: There were 59 and 98 patients in the frail and non-frail groups, respectively. Three months after SARS-CoV-2 infection, 21 (13.4%) and 45 (28.7%) patients had died or were in hospital. The multivariate COX proportional risk model suggested that the all-cause mortality rate in patients judged overall frail or with low activity was significantly higher compared with that of the non-frail (P = 0.049; 0.003). The multivariate logistic regression analysis showed that hospitalization 3 months after SARS-CoV-2 infection was associated with both overall frailty and low activity (OR 2.276, 95% CI: 1.034-5.010, P = 0.041; OR 2.809, 95% CI: 1.311-6.020, P = 0.008, respectively). Conclusion: Overall frailty and specifically low activity were significantly associated with all-cause mortality and hospitalization in this elderly MHD population after SARS-CoV-2 infection. Early assessment of frailty and effective interventions are recommended to improve the prognosis of patients receiving MHD who are at higher risk of acute infection.

Nonlinear Topological Mechanics in Elliptically Geared Isostatic Metamaterials.

Despite the extensive studies of topological systems, the experimental characterizations of strongly nonlinear topological phases have been lagging. To address this shortcoming, we design and build elliptically geared isostatic metamaterials. Their nonlinear topological transitions can be realized by collective soliton motions, which stem from the transition of nonlinear Berry phase. Endowed by the intrinsic nonlinear topological mechanics, surface polar elasticity and dislocation-bound zero modes can be created or annihilated as the topological polarization reverses orientation. Our approach integrates topological physics with strongly nonlinear mechanics and promises multiphase structures at the micro- and macroscales.

Relationship of Frailty with Kidney Function in Adults More Than 60-Years-Old: Effect of Using Different Formulas to Estimate Glomerular Filtration Rate.

Objective: Determine the relationship of renal function with frailty using different formulas for estimated glomerular filtration rate (eGFR). Methods: Individuals who were 60-years-old or more (n=507) were recruited from August 2020 to June 2021, and the FRAIL scale was used to classify them as non-frail or frail. The three equations used to compute the eGFR were based on serum creatinine (eGFRcr), cystatin C (eGFRcys), or SCr+CysC (eGFRcr-cys). Renal function was classified using eGFR and defined as normal (≥90 mL/min/1.73m2), mild damage (59-89 mL/min/1.73m2), or moderate damage (≤60 mL/min/1.73m2). The relationship of frailty with renal function was analyzed. A subset of participants (n=358) was used to analyze changes in eGFR from 1 January 2012 to 31 December 2021 according to frailty and using the different eGFR equations. Results: There were significant differences between the eGFRcr-cys and eGFRcr values in the frail group (P<0.05), but not the non-frail group; however, the differences between the eGFRcr-cys and eGFRcys values were significant in the frail and non-frail groups (P<0.001). Based on each eGFR equation, the prevalence of frailty increased as eGFR decreased (P<0.001), but there was no significant relationship after adjusting for age or the age-adjusted Charlson co-morbidity index. There were temporal declines in eGFR in all three frailty groups (robust, pre-frail, and frail), especially in the frail group (2.226 mL/min/1.73m2 per year; P<0.001). Conclusion: For older individuals who are frail, the eGFRcr value may not provide accurate estimates of renal function. Frailty is associated with a rapid decline in kidney function.

Adaptive optimization technology of a conformal infrared dome based on the Von Karman surface under hypersonic conditions.

With the advent of the hypersonic era, diverse combat methods of hypersonic precision-guided weapons have been gradually developed. This study focuses on the precise design of a conformal infrared dome to accommodate different working conditions. To achieve this, an adaptive optimization technology for configuring conformal infrared domes is proposed, employing a multi-objective genetic algorithm. The technology enables the dome to dynamically balance its aerodynamic and imaging performance, taking into account the specific characteristics of each working condition. Moreover, it streamlines the design process of the conformal infrared domes. By optimizing the design with von Karman surfaces, we can overcome the limitations associated with the traditional quadric configuration. In order to evaluate its performance, a comparison was made with a conventional ellipsoid dome. The results indicate that, under the same working conditions, the air drag coefficient of the optimized infrared dome is reduced by 34.29% and that the peak signal-to-noise ratio of the distorted image from the infrared detection system is increased by 1.7%. We have demonstrated the effectiveness of the optimization method to balance aerodynamic performance and optical performance. Hopefully, our new method will improve the comprehensive performance of the infrared dome as well as the guidance capability of infrared detection technology.

Dearomative cyclization of pyridines/isoquinolines with cyclopropenones: access to indolizinones and benzo-fused indolizinones.

Dearomatization reactions provide a rapid approach to construct complicated molecules that are difficult to synthesize by traditional methods from simple aromatic compounds. Herein, we report an efficient dearomative [3+2] cycloaddition reaction of 2-alkynyl pyridines with diarylcyclopropenones, leading to the synthesis of densely functionalized indolizinones in moderate to good yields under metal-free conditions. In addition, this strategy can also be employed in dearomative cyclization of isoquinolines to access a variety of benzo-fused indolizinones. Density functional theory (DFT) calculations revealed that an appropriate substituent at the 2-position of pyridine is crucial to the dearomatization process.

Hierarchical deconvolution dehazing method based on transmission map segmentation.

Images captured in fog are often affected by scattering. Due to the absorption and scattering of light by aerosols and water droplets, the image quality will be seriously degraded. The specific manifests are brightness decrease, contrast decrease, image blur, and noise increase. In the single-image dehazing method, the image degradation model is essential. In this paper, an effective image degradation model is proposed, in which the hierarchical deconvolution strategy based on transmission map segmentation can effectively improve the accuracy of image restoration. Specifically, the transmission map is obtained by using the dark channel prior (DCP) method, then the transmission histogram is fitted. The next step is to divide the image region according to the fitting results. Furthermore, to more accurately recover images of complex objects with a large depth of field, different levels of inverse convolution are adopted for different regions. Finally, the sub-images of different regions are fused to get the dehazing image. We tested the proposed method using synthetic fog images and natural fog images respectively. The proposed method is compared with eight advanced image dehazing methods on quantitative rating indexes such as peak signal-to-noise ratio (PSNR), structural similarity (SSIM), image entropy, natural image quality evaluator (NIQE), and blind/referenceless image spatial quality evaluator (BRISQUE). Both subjective and objective evaluations show that the proposed method achieves competitive results.

Peimine suppresses collagen-induced arthritis, activated fibroblast-like synoviocytes and TNFα-induced MAPK pathways.

BACKGROUND AND PURPOSE: Peimine (PM), a main isosterol alkaloid component isolated from the bulbs of traditional Chinese herb Fritillaria cirrhosa D. Don, has been demonstrated to exhibit multiple pharmacological properties, including anti-inflammation, anti-cancer and pain suppression. However, its effect on rheumatoid arthritis (RA) remains unknown. In the present study, we investigated the effect of PM on collagen-induced arthritis (CIA) rats in vivo and its inhibition on destructive behaviors of arthritic fibroblast-like synoviocytes (FLSs) in vitro. METHODS: Arthritis was induced in rats by chicken type II collagen. Arthritis score, radiological evaluation, and histopathological assessment were used to evaluate the therapeutic effects of PM on CIA rats. EdU assay, wound healing assay and real-time PCR were used to examine the inhibitory effect of PM on proliferation, migration, and over-expression of pro-inflammatory cytokines in TNFα-induced arthritic FLSs. TRAP staining and scanning electron microscopy were used to analyze the effect of PM on osteoclastogensis and bone resorption. Western blot was used to reveal PM's molecular mechanism of action on RA. RESULTS: PM significantly suppressed synovitis and bone destruction in CIA rats. In vitro experiments showed that PM treatment significantly inhibited TNFα-induced destructive behaviors of arthritic FLSs, including over-proliferation, migration and over-expression of pro-inflammatory cytokines. Additionally, RANKL-induced osteoclast formation and bone-resorpting function were also inhibited by PM. Further molecular mechanism studies revealed that PM treatment significantly suppressed TNFα-induced activations of MAPKs (ERK, JNK and p38) in arthritic FLSs. CONCLUSION: Our findings provide strong evidence that PM has the potential to be developed as a therapeutic agent for patients with RA.

Recent progress of direct thiocyanation reactions.

Thiocyanates are common in natural products, synthetic drugs and bioactive molecules. Many thiocyanate derivatives show excellent antibacterial, antiparasitic and anticancer activities. Thiocyanation can introduce SCN groups into parent molecules for constructing SCN-containing small organic molecules. Among them, the direct introduction method mainly includes nucleophilic reaction, electrophilic reaction and free radical reaction, which can simply and quickly introduce SCN groups at the target sites to construct thiocyanates, and has broad application prospects. In this review, we summarize the research progress of direct thiocyanation in recent years.

Deconstructive Cycloaromatization Strategy toward N,O-Bidentate Ligands from Indolizines and Cyclopropenones.

The innovative construction of novel N,O-bidentate ligands represents a long-standing challenge for chemists. Here, we report an unprecedented approach for the construction of N,O-bidentate derivatives via the merging of ring deconstruction with cycloaromatization of indolizines and cyclopropenones. Without any catalysts, our method can deliver a series of polyaryl 2-(pyridin-2-yl)phenols in excellent yields. In addition, N,O-bidentate organic BF2 complexes can also be constructed via this one-pot protocol.

Piperlongumine Inhibits Titanium Particles-Induced Osteolysis, Osteoclast Formation, and RANKL-Induced Signaling Pathways.

Wear particle-induced aseptic loosening is the most common complication of total joint arthroplasty (TJA). Excessive osteoclast formation and bone resorptive activation have been considered to be responsible for extensive bone destruction and prosthesis failure. Therefore, identification of anti-osteoclastogenesis agents is a potential therapy strategy for the treatment of aseptic loosening and other osteoclast-related osteolysis diseases. In the present study, we reported, for the first time, that piperlongumine (PL), a key alkaloid compound from Piper longum fruits, could significantly suppress the formation and activation of osteoclasts. Furthermore, PL effectively decreased the mRNA expressions of osteoclastic marker genes such as tartrate-resistant acid phosphatase (TRAP), calcitonin receptor (CTR), and cathepsin K (CTSK). In addition, PL suppressed the receptor activator of nuclear factor-κB ligand (RANKL)-induced activations of MAPKs (ERK, JNK and p38) and NF-κB, which down-regulated the protein expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Using a titanium (Ti) particle-induced calvarial osteolysis model, we demonstrated that PL could ameliorate Ti particle-induced bone loss in vivo. These data provide strong evidence that PL has the potential to treat osteoclast-related diseases including periprosthetic osteolysis (PPO) and aseptic loosening.

Construction of Chiral Cyclic Compounds Enabled by Enantioselective Photocatalysis.

Chiral cyclic molecules are some of the most important compounds in nature, and are widely used in the fields of drugs, materials, synthesis, etc. Enantioselective photocatalysis has become a powerful tool for organic synthesis of chiral cyclic molecules. Herein, this review summarized the research progress in the synthesis of chiral cyclic compounds by photocatalytic cycloaddition reaction in the past 5 years, and expounded the reaction conditions, characters, and corresponding proposed mechanism, hoping to guide and promote the development of this field.

Evaluation of flow field in the anterior segment during irrigation and aspiration in cataract surgery with three-dimensional computational simulation.

INTRODUCTION: To quantitatively analyze the flow field and fluid pressure contour in the anterior segment during the irrigation and aspiration (I/A) procedure by means of computational fluid dynamics (CFD) simulation. METHODS: Four different models were established combining the irrigation sleeve, aspiration cannula, anterior chamber, and capsule to simulate various scenarios during the coaxial I/A procedure. Commercial CFX software was applied to perform the steady-state simulation with the k-ε turbulence model. The inlet boundary condition was a balanced salt solution with a 100 cm height of pressure, and the mass flow rate boundary condition set at 40 cc/min was applied at the outlet. RESULTS: The four models included the I/A tip located in the middle of the pupillary plane, the capsule equator, and the middle of the posterior capsule. The inlet/outlet pressure at the tip of the I/A cannula was almost the same in the four models. Following ejection into the anterior chamber and capsule bag, the streamline speed rapidly decreased. The pressure in the anterior chamber and capsule bag was approximately 60-70 mmHg. The area on the cornea and capsule closer to the initial streamline of the inlet irrigation possessed larger pressure. The differential pressure on the cornea and capsule was greater when the irrigation orifice directly facing the wall. CONCLUSION: The pressure varies at different positions in the anterior segment during the I/A procedure. The study suggests that specific precautions are required when the tip moves closer to the wall and the irrigation orifice is directed toward the opposite wall.

Time-accuracy imaging quality prediction method for an infrared detection system under hypersonic conditions.

The imaging quality of infrared detection systems over time directly affects their ability to track targets accurately. In this study, a prediction scheme for the image quality of infrared detection system under hypersonic conditions based on time accuracy has been developed. Further, based on the time discretization, a calculation model has been established for the prediction scheme to perform numerical simulation. In particular, for verifying the reliability of this prediction method and the associated numerical calculation model, a comparison has been made between the numerical simulation results and the wind tunnel test results. The maximum error of the comparison result is less than 4.5%, and the reliability of the method proposed in this paper has been proved.

Aberration characteristic correlation configuration optimization of a conformal dome based on the von Karman surface.

In this paper, the von Karman surface is used in the configuration design of the infrared conformal dome to improve its aerodynamic performance. The principle of differential geometry is used to study the geometric characteristics of the von Karman dome. Additionally, by using ray tracing, the geometric aberrations and wave aberrations of the von Karman dome are analyzed. Further, considering the geometric characteristics and aberration characteristics, an optimization method for the configuration of the von Karman dome is proposed. To prove the effectiveness of the optimization method, the aberrations introduced by the conformal dome after the configuration optimization and the original von Karman dome are compared. The comparison showed that the geometric aberration of the optimized conformal dome is reduced by 43.68%. The optimization method can significantly correct the aberration introduced by the von Karman dome and improve the guidance capability of infrared detection technology.