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Abstract A major driver of neuronal hyperexcitability is dysfunction of K+ channels, including voltage-gated KCNQ2/3 channels. Their hyperpolarized midpoint of activation and slow activation and deactivation kinetics produce a current that regulates membrane potential and impedes repetitive firing. Inherited mutations in KCNQ2 and KCNQ3 are linked to a wide spectrum of neurodevelopmental disorders (NDDs), ranging from benign familial neonatal seizures to severe epileptic encephalopathies and autism spectrum disorders. However, the impact of these variants on the molecular mechanisms underlying KCNQ3 channel function remains poorly understood and existing treatments have significant side effects. Here, we use voltage clamp fluorometry, molecular dynamic simulations, and electrophysiology to investigate NDD-associated variants in KCNQ3 channels. We identified two distinctive mechanisms by which loss– and gain–of function NDD-associated mutations in KCNQ3 affect channel gating: one directly affects S4 movement while the other changes S4-to-pore coupling. MD simulations and electrophysiology revealed that polyunsaturated fatty acids (PUFAs) primarily target the voltage-sensing domain in its activated conformation and form a weaker interaction with the channel’s pore. Consistently, two such compounds yielded partial and complete functional restoration in R227Q- and R236C-containing channels, respectively. Our results reveal the potential of PUFAs to be developed into therapies for diverse KCNQ3-based channelopathies.

The output of renewable energy units and electric vessels， characterized by its uncertainty and impact， pose challenges to the safe and stable operation of shore power supply systems. To address this， an operating strategy for wind-solar-storage hybrid shore power supply systems based on distributionally robust optimization （DRO） is proposed. First， a deterministic operating model of the shore power supply systems is established with the objective of minimizing total costs， without considering the uncertainty of wind-solar power output and impact loads. Building on this model， a two-stage wind-solar-storage hybrid shore power supply system model based on DRO is developed. This model uses a combinatorial approach to describe the uncertainty of wind-solar power output， aiming to reduce the wind and solar power curtailment caused by prediction errors and output fluctuations. Finally， the column-and-constraint generation （C&CG） method is employed to solve the model. Using data from a specific shore power supply system， the proposed strategy is validated to effectively enhance the consumption capacity of wind-solar resources and reduce operational costs.

Objective To evaluate the application of Orem’s Self-Care theory in nursing of patients with ulcerative colitis of colon damp-heat syndrome treated with retention enema of Traditional Chinese Medicine. Methods Eighty-four patients with ulcerative colitis of colon damp-heat syndrome were selected as the study subjects, and were randomly divided into the experimental group (n=42) and the control group(n=42). Patients in both groups were treated with Chinese herbal medicine retention enema and conventional nursing interventions, and patients in the experimental group were given Orem's self-care theory-guided interventions. Clinical symptoms, inflammatory indicators and quality of the two groups of patients were compared. Results After intervention, the UCDAI index of both groups of patients showed a decrease in hematochezia, diarrhea, endoscopic manifestations, and physician evaluated scores compared to those before intervention, with the experimental group being lower than the control group (P＜0. 01). The levels of TNF- α, IL-6 and IL-8 in both two groups had dropped after intervention, and levels of inflammatory index in the experimental group were lower than those in the control group (P＜0. 01). After intervention, the IBDQ scores of intestinal symptoms, systemic symptoms, emotional function, and social function in both groups of patients decreased compared to those before intervention, and IBDQ scores in the experimental group were lower than those in the control group (P＜0. 01). Conclusion Nursing interventions based on the Orem's self-care theory are effective to relieve the clinical symptoms and inflammatory reactions of patients with ulcerative colitis of colon damp-heat syndrome, and improve their quality of life. (目的 探讨Orem自护理论运在中药保留灌肠治疗大肠湿热证溃疡性结肠炎患者中的应用效果。方法 选取2020年2月—2023年2月医院肛肠科住院接受治疗的84例大肠湿热证溃疡性结肠炎患者为研究对象, 采用随机数字表法将其分为研究组和对照组, 各42例。两组患者均采用保留灌肠治疗, 在此基础上, 对照组采用常规护理干预, 研究组在常规护理基础上增加Orem自护理论干预。对比两组患者临床症状、炎性反应指标和生存质量。结果 干预后两组患者溃疡性结肠炎疾病活动指数(UCDAI)中的便血、腹泻、内镜表现、医师评定的评分相较于干预前均有降低, 且研究组低于对照组(P＜0. 01)。干预后两组患者的TNF-α、IL-6、IL-8的水平相较于干预前均有降低, 且研究组低于对照组(P＜0. 01)。干预后两组患者炎症性肠病患者生活质量量表(IBDQ)评分中的肠道症状、全身症状、情感功能及社会功能的评分相较于干预前降低, 且研究组低于对照组(P＜0. 01)。结论 在中药保留灌肠治疗大肠湿热证溃疡性结肠炎患者护理中, 基于Orem自护理论指导护理能够有效改善患者临床症状和炎性反应, 提高患者的生活质量。)

Background: Neonatal resuscitation is stressful for healthcare professionals as measured using the National Aeronautics and Space Administration-Task Load Index (NASA-TLX). Little is known regarding the perceived workload and associated factors among healthcare professionals including medical doctors (MDs) and nurses/midwives who have differences in training and experiences. We aimed to characterize and compare the perceived workload between MDs and nurses/midwives who provided neonatal resuscitation. Methods: In a prospectively designed, cellphone-based surveillance, perceived workload and stress of MDs and nurses/midwives during neonatal resuscitation was evaluated using a modified multi-dimensional NASA-TLX survey in three tertiary Neonatal Intensive Care Units in China. The NASA-TLX data on mental, physical, temporal demand, performance, effort, and frustration were independently rated by participants and collated to a composite score of all dimensions. Demographics of participants and deliveries were also collected for statistical analyses using univariate comparison and multiple linear regression. Results: From 410 valid surveys (187 (46%) MDs; 223 (54%) nurses/midwives), significant differences were noted between MDs and nurses/midwives including working years and dimensional and overall NASA-TLX scores. While MDs had lower overall NASA-TLX scores than nurses, their scores were inversely related with simulation-based training. More team members presence during resuscitation was associated with higher NASA-TLX scores. Other independent factors associated with NASA-TLX scores included gestational age, Apgar score at 1 min, year of practice for MDs and all resuscitation questions asked by nurses/midwives. Conclusions: MDs and nurses/midwives attending deliveries had different perceptions in workload and stress which could be lowered from simulation-based training in neonatal resuscitation.

The STK11 gene mutation is a common genetic alteration in non-small cell lung cancer (NSCLC) and is significantly associated with poor responses to current immunotherapy regimens. Despite its prevalence, there is currently no established standard for front-line treatment in this subtype of NSCLC, underscoring the increasing need for personalized therapeutic strategies. In this report, we present a case of a patient with STK11-mutant NSCLC who was treated with first-line cadonilimab (10mg/kg) in combination with pemetrexed (500mg/m^2) plus carboplatin (AUC=5), resulting in a notable extension of progression-free survival (PFS). This case highlights the potential efficacy and feasibility of combining immunotherapy with chemotherapy in patients with STK11-mutant NSCLC. Additionally, we provide a review of recent advancements in research related to STK11 mutations in lung cancer as reported in the literature.

Abstract Background The aim of this study is to analyze the associations among fat distribution, left ventricular (LV) structure, and function in T2DM patients and further assess the sex differences among them. Methods Two thousand and one hundred seven T2DM patients were enrolled to this study. Patients' height, weight, BMI, visceral fat area (VFA), baPWV, parameters of cardiac structure and function, and clinical biochemical indicators were measured and collected. Results There were significant differences between male and female T2DM patients in age, duration of diabetes, complication ratio of hypertension and dyslipidemia, smoking history, visceral fat, baPWV, and ventricular structure and function (p

Mycoplasma pneumonia (MPS), caused by Mycoplasma hyopneumoniae (Mhp), is a chronic, airborne respiratory disease that poses a significant threat to the global swine industry. The P97 and P46 proteins are major antigens of Mhp, with the R1 region of P97 possessing full adhesive capability. Studies have shown that the main antigenic regions of Mhp P42 and P65 proteins exhibit strong immunogenicity. In this study, we first linked the genes encoding P97R1 and P46 proteins to form the P97R1P65 gene and subsequently constructed three shuttle plasmids: pFBD-P97R1P46, pFBD-P97R1P46-p65, and pFBD-P65-P42. These proteins were expressed using the Bac to Bac system and formulated into subunit vaccines for mouse immunization. Mouse experiments indicated that the P97R1P46 + P65-P42 protein combination elicited higher levels of specific antibodies, IL-2, IL-4, and CD8+ T cells compared to other subunit vaccine groups, a finding further validated in subsequent mouse challenge protection experiments. Therefore, we utilized the MultiBac expression system to co-express P97R1P46, P65, and P42 proteins in the pFastMultibacDual vector for immunization experiments in piglets. The piglet immunization experiments demonstrated that the Mhp subunit vaccine prepared in this study could induce specific antibodies against Mhp, with the combination of P97R1P46, P65, and P42 proteins inducing the highest level of humoral immunity. This study provides valuable insights for the development of Mhp subunit vaccines.

Macrophages are the basic mediators and coordinators of various types of chronic inflammation and play a crucial role in the formation and development of atherosclerosis (AS). In the complex microenvironment of atherosclerotic plaques, macrophages of different sources are exposed to different signal stimuli and thus polarized into various subpopulations. Various types of macrophages with predominantly M1 and M2 phenotypes also play different regulatory roles in the initiation and progression of AS. Lipid-lowering drugs, mainly statins, are widely used in clinical practice, but the adverse reactions are obvious and there is a lack of personalized treatment. Emerging targeted macrophage and Traditional Chinese medicine (TCM)-related therapies can regulate the cellular microenvironment, inhibit the polarization of M1 macrophages, and promote the activation of M2 macrophages, providing new ideas for the prevention and treatment of AS.

Abstract Optical resonators are indispensable tools in optical metrology that usually benefit from an evacuated and highly-isolated environment to achieve peak performance. Even in the more sophisticated design of Fabry-Perot (FP) cavities, the material choice limits the achievable quality factors. For this reason, monolithic resonators are emerging as promising alternative to traditional designs, but their design is still at preliminary stage and far from being optimized. Here, we demonstrate a monolithic FP resonator with 4.5 cm3 volume and 2 × 105 finesse. In the ambient environment, we achieve 18 Hz integrated laser linewidth and 7 × 10−14 frequency stability measured from 0.08 s to 0.3 s averaging time, the highest spectral purity and stability demonstrated to date in the context of monolithic reference resonators. By locking two separate lasers to distinct modes of the same resonator, a 96 GHz microwave signals is generated with phase noise -100 dBc/Hz at 10 kHz frequency offset, achieving orders of magnitude improvement in the approach of photonic heterodyne synthesis. The compact monolithic FP resonator is promising for applications in spectrally-pure, high-frequency microwave photonic references as well as optical clocks and other metrological devices. ©2024. All rights reserved.

Abstract The current clinical application of glaucoma drainage devices is made of non-degradable materials. These non-degradable drainage devices often trigger inflammatory responses and scar proliferation, possibly leading to surgical failure. We developed a biodegradable material hydroxyapatite-coated magnesium (HA-Mg) as a glaucoma drainage device. Twelve New Zealand white rabbits were randomly assigned to three groups: HA-Mg drainage plate group (6 right eyes), trabeculectomy group (6 right eyes), and control group (12 left eyes). Results showed that all HA-Mg drainage plates were completely degraded ~4 months postoperatively. At the 5th month postoperatively, there was no statistical difference in the corneal endothelium density between the HA-Mg drainage plate group and the control group (p = 0.857). The intraocular pressure (IOP) level in the HA-Mg drainage plate implantation group was lower than in the other two groups. The trypan blue dye still drained from the anterior chamber to the subconjunctiva 5 months after HA-Mg drainage plate implantation. HE staining revealed the scleral linear aqueous humor drainage channel and anterior synechia were observed after drainage plate completely degraded, with no obvious infiltration with the inflammatory cells. This study showed the safety and efficacy of HA-Mg glaucoma drainage plate in controlling IOP after implantation into the anterior chamber of rabbit eyes. Graphical abstract We developed a biodegradable material hydroxyapatite-coated magnesium (HA-Mg) as a glaucoma drainage device. This study evaluated the safety and efficacy of HA-Mg glaucoma drainage plate in controlling intraocular pressure after implantation into the anterior chamber of rabbit eyes.

ABSTRACT Classical swine fever virus (CSFV), an obligate intracellular pathogen, hijacks cellular metabolism to evade immune surveillance and facilitate its replication. The precise mechanisms by which CSFV modulates immune metabolism remain largely unknown. Our study reveals that CSFV infection disrupts serine metabolism, which plays a crucial role in antiviral immunity. Notably, we discovered that CSFV infection leads to the deacetylation of PHGDH, a key enzyme in serine metabolism, resulting in autophagic degradation. This deacetylation impairs PHGDH’s enzymatic activity, reduces serine biosynthesis, weakens innate immunity, and promotes viral proliferation. Molecularly, CSFV infection induces the association of HDAC3 with PHGDH, leading to deacetylation at the K364 site. This modification attracts the E3 ubiquitin ligase RNF125, which facilitates the addition of K63-linked ubiquitin chains to PHGDH-K364R. Subsequently, PHGDH is targeted for lysosomal degradation by p62 and NDP52. Furthermore, the deacetylation of PHGDH disrupts its interaction with the NAD+ substrate, destabilizing the PHGDH-NAD complex, impeding the active site, and thereby inhibiting de novo serine synthesis. Additionally, our research indicates that deacetylated PHGDH suppresses the mitochondria-MAVS-IRF3 pathway through its regulatory effect on serine metabolism, leading to decreased IFN-β production and enhanced viral replication. Overall, our findings elucidate the complex interplay between CSFV and serine metabolism, revealing a novel aspect of viral immune evasion through the lens of immune metabolism.IMPORTANCEClassical swine fever (CSF) seriously restricts the healthy development of China’s aquaculture industry, and the unclear pathogenic mechanism and pathogenesis of classical swine fever virus (CSFV) are the main obstacle to CSF prevention, control, and purification. Therefore, it is of great significance to explore the molecular mechanism of CSFV and host interplay, to search for the key signaling pathways and target molecules in the host that regulate the replication of CSFV infection, and to elucidate the mechanism of action of host immune dysfunction and immune escape due to CSFV infection for the development of novel CSFV vaccines and drugs. This study reveals the mechanism of serine metabolizing enzyme post-translational modifications and antiviral signaling proteins in the replication of CSFV and enriches the knowledge of CSFV infection and immune metabolism.

BackgroundSenecavirus A (SVA) is a newly pathogenic virus correlated with the acute death of piglets and vesicular lesions in pigs. The further prevalence of SVA will cause considerable economic damage to the global pig farming industry. Therefore, rapid and accurate diagnostic tools for SVA are crucial for preventing and controlling the disease.MethodsWe designed multiple primer pairs targeting the most conserved region of the SVA 3D gene and selected those with the highest specificity. Nfo-probes were subsequently developed based on the highest specificity primer pairs. Subsequently, the recombinase-assisted amplification (RAA) reaction was completed, and the reaction temperature and duration were optimized. The RAA amplicons were detected using a lateral flow device (LFD). Finally, a rapid and intuitive RAA-LFD assay was established against SVA.ResultsThe SVA RAA-LFD assay can be performed under reaction conditions of 35°C within 17 minutes, with results observable to the naked eye. We then evaluated the performance of this method. It exhibited high specificity and no cross-reaction with the other common swine pathogens. The lowest detectable limits of this method for the plasmid of pMD18-SVA-3D, DNA amplification product, and viral were 3.86×101 copies/µL, 8.76×10-7 ng/µL, and 1×100.25 TCID50/mL, respectively. A total of 44 clinical samples were then tested using the RAA-LFD, PCR, and RT-qPCR methods. The results demonstrated a consistent detection rate between the RAA-LFD and RT-qPCR assays.ConclusionThe SVA RAA-LFD assay developed in our study exhibits excellent specificity, sensitivity, and time-saving attributes, making it ideally suited for utilization in lack-instrumented laboratory and field settings.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by producing remarkable clinical outcomes for patients with various cancer types. However, only a subset of patients benefits from immunotherapeutic interventions due to the primary and acquired resistance to ICIs. Myeloid-derived suppressor cells (MDSCs) play a crucial role in creating an immunosuppressive tumor microenvironment (TME) and contribute to resistance to immunotherapy. V-domain Ig suppressor of T cell activation (VISTA), a negative immune checkpoint protein highly expressed on MDSCs, presents a promising target for overcoming resistance to current ICIs. This article provides an overview of the evidence supporting VISTA's role in regulating MDSCs in shaping the TME, thus offering insights into how to overcome immunotherapy resistance.

In the original publication, there was a mistake in Figure 1B(b,c) as published [...]

This paper proposes a critical clearing time (CCT) estimation method by the domain of attraction (DA) of a state-reduction model of power systems using sum of squares (SOS) programming. By exploiting the property of the Jacobian matrix and the structure of the boundary of the DA, it is found the DA of the state-reduction model and that of the full model of a power system are topological isomorphism. There are one-to-one correspondence relationships between the number of equilibrium points, the type of equilibrium points, and solutions of the two system models. Based on these findings, an expanding interior algorithm is proposed with SOS programming to estimate the DA of the state-reduction model. State trajectories of the full model can be transformed to those of the state-reduction model by orthogonal or equiradius projection. In this way, CCT of a grid fault is estimated with the DA of the state-reduction model. The calculational burden of SOS programming in the DA estimation using the state-reduction model is rather small compared with using the full model. Simulation results show the proposed expanding interior algorithm is able to provide a tight estimation of DA of power systems with higher accuracy and lower time costs.

Recently, the emergence of HP-PRRSV (Highly Pathogenic porcine reproductive and respiratory syndrome virus) and the exacerbation of mixed infections of PRRSV and PCV have resulted in significant economic losses for the Chinese pig industry. This study collected a total of 226 samples suspected of infection with the aforementioned viruses from diverse pig farms in seven urban districts of central and northern Guangdong Province between 2020 and 2022. The positive rates of PRRSV, PCV2, and PCV3 in the samples were 33.2%, 37.6%, and 7.5%, respectively, and there were various mixed-infection scenarios present in the samples. This study successfully isolated multiple strains of PRRSV2 and PCV2 from their positive samples, and obtained the gene sequences of six PCV3 (ORF1 + ORF2) from samples. The associated sequences obtained were subjected to bioinformatic analysis and revealed the following:Predominantly prevalent strains of PRRSV in Guangdong Province include HP-PRRSV and NADC30-like variants, whereas PCV2 is primarily represented by the 2b and 2d subtypes. Specifically, the amino acid variation patterns exhibited by the PRRSV GP5 and NSP2 proteins of the strains sg_2108, qy_2008, and fs_2108 under environmental selective pressure are remarkably similar to the characteristics of Highly Pathogenic PRRSV; thus, it is inferred that they may possess higher virulence. The detected PCV3 strains were predominantly concentrated within the PCV3a-IM branch. All PRRSV strains involved in this study are wild-type-PRRSV (wt-PRRSV), comprising three recombinant strains and seven highly virulent strains. Among these strains, the ORF1a gene exhibited the highest variability in their genomes. Environmental selective pressure may enhance the virulence and immune evasion capabilities of PRRSV and drive mutations in the Cap proteins of PCV2 and PCV3. Conversely, PCV2 and PCV3 strains demonstrated greater stability in genetic evolution. In conclusion, this study enhances the epidemiological data regarding PRRSV, PCV2, and PCV3 in Guangdong Province, China, and is significant for the surveillance, prevention, and active control of these three diseases.

The occurrence of classical swine fever (CSF) poses a significant threat to the global swine industry. Developing an effective and safe vaccine is crucial for preventing and controlling CSF. Here, we constructed self-assembled ferritin nanoparticles fused with the classical swine fever virus (CSFV) E2 protein and a derived B cell epitope (Fe-E2B) using a baculovirus expression system (BVES), demonstrating enhanced immunogenicity. Furthermore, we provide a detailed evaluation of the immunological efficacy of the FeE2B in rabbits. The results showed that robust and sustained antibody responses were detected in rabbits immunized with the Fe-E2B nanoparticle vaccine, comparable to those elicited by commercially available vaccines. Additionally, we demonstrated that the vaccine effectively activated crucial immune factors IFN-γ and IL-4 in vivo, increasing their levels by 1.41-fold and 1.39-fold, respectively. Immunization with Fe-E2B enabled rabbits to avoid viremia and stereotypic fever after CSFV challenge. In conclusion, this study highlights the potential of ferritin nanoparticles as antigen-presenting carriers to induce robust immune responses, proposing a candidate vaccine strategy for the prevention and control of CSF.

Herein, the radiation patterns of single-split ring resonators (SSRRs) and double-split ring resonators (DSRRs) in the vertical direction are tailored by reconfiguring the resonator geometries. To design unequal arm lengths for controlling the floating split angle of the resonators and changing their electromagnetic multipole compositions, vertical metamaterials were fabricated using the metal-stress-driven self-folding method. The simulation results well agree with the experimental transmittance and reflectance results and demonstrate the geometry-dependent angle variation of the far-field radiation. Symmetric SSRRs and DSRRs radiate in the vertical and horizontal directions, respectively. With increasing pad shift, the radiation angle of the asymmetric SSRR completely rotates toward the horizontal direction along the ring plane, but the DSRRs can rotate only from 0° to 45° to the horizontal plane. Furthermore, by decomposing the multipoles into their constituents, we show that the directional scattering performance can be verified by manipulating the horizontal and vertical components of the electric dipoles. This novel combination of SSRRs and DSRRs can effectively and efficiently reconfigure the radiation direction in the infrared (IR) region, paving the way for color routers, metasurfaces, and directive IR emitters in compact optical metadevices.

Background: Fibro-adipogenic progenitors (FAP) are muscle resident mesenchymal stem cells pivotal for regulation of myofiber repair. Experimental results show in addition involvement in a range of other pathological conditions and potential for pharmacological intervention. FAP histopathology in human muscle biopsies is largely unknown, but has potential to inform translational research. Methods: CD10+ FAPs in 32 archival muscle biopsies from 8 groups (normal, dermatomyositis, inclusion body myositis (IBM), anti-synthetase syndrome, immune-mediated necrotizing myopathy (IMNM), denervation, type 2 atrophy, rhabdomyolysis) were visualized by CD10 immunohistochemistry and their histology compared. Groups are compared by semi-quantitative scoring. Results: Histological activation of endomysial CD10+ FAPs includes prominent expansion of a network of cell processes surrounding muscle fibers, as well as endomysial cell clusters evidencing proliferation. Prominence of periarteriolar processes is a notable feature in some pathologies. FAP activation is often associated with fiber degeneration/regeneration, foci of inflammation, and denervation in keeping with experimental results. Type 2 atrophy shows no evidence of FAP activation. Dermatomyositis and anti-synthetase syndrome associated myositis demonstrate diffuse activation. Conclusion: Assessment of CD10+ FAP activation is routinely possible using CD10 immunohistochemistry and demonstrates several patterns in keeping with preclinical results. Prominent expansion of FAP processes surrounding myofibers suggests enhanced interaction between myofiber/basement membranes and FAPs during activation. The presence of diffuse FAP activation in dermatomyositis biopsies unrelated to fiber repair raises the possibility of FAP activation as part of the autoimmune process. Future diagnostic applications, clinical significance and therapeutic potential remain to be elucidated.

Membrane-less organelles (MLOs) formed through liquid-liquid phase separation (LLPS) are associated with numerous important biological functions, but the abnormal phase separation will also dysregulate the physiological processes. Emerging evidence points to the importance of LLPS in human health and diseases. Nevertheless, despite recent advancements, our knowledge of the molecular relationship between LLPS and diseases is frequently incomplete. In this review, we outline our current understanding about how aberrant LLPS affects developmental disorders, tandem repeat disorders, cancers and viral infection. We also examine disease mechanisms driven by aberrant condensates, and highlight potential treatment approaches. This study seeks to expand our understanding of LLPS by providing a valuable new paradigm for understanding phase separation and human disorders, as well as to further translate our current knowledge regarding LLPS into therapeutic discoveries.

As a retrovirus with high recombination and mutation rate， HIV targets CD4+ T lymphocytes， causing damage to the body's immune system and eventually leading to severe immune function defects. Different subtypes of the HIV virus exhibit significant sequence differences in their structural and regulatory genes， and this diversity is closely related to etiology， transmission， diagnosis， drug therapy， disease progression， and vaccine development. As a country with the largest number of HIV subtypes， rapid and accurate typing of the HIV virus holds great significance for China's efforts in disease prevention and control. This study provides a comprehensive reveiw of domestic and international HIV genotyping methods， and summarizes the clinical significance of different subtypes in order to provide reference for further research.

C26H24N2O2, monoclinic, P21/n (no. 14), a = 10.949(6) Å, b = 9.930(5) Å, c = 20.125(13) Å, β = 98.51(3)°, V = 2164(2) Å3, Z = 4, Rgt(F) = 0.0465, wRref(F2) = 0.1260, T = 296(2) K.

ABSTRACT As an essential component of host defense against infection, necroptosis is a novel highly regulated mode of cell death that is mediated by signaling complexes containing receptor-interacting protein kinase 1 (RIPK1) and RIPK3. Lymphocyte depletion and immunosuppression are typical clinical features of pigs infected with classical swine fever virus (CSFV). Here, we provide the first evidence for the involvement of necroptosis in the necrosis of T lymphocytes in the spleen and peripheral blood of pigs infected in vivo with CSFV. However, it is true for some viruses with non-cytopathic effects, including CSFV, to balance host defense against infection. In vitro, the induction of autophagy by CSFV at a later stage of infection clearly restricts necroptosis. Mechanistic studies revealed that CSFV NS4A protein promoted tripartite motif-containing 25 expression, synergistically induced the occurrence of mitophagy, targeted the autophagic degradation of RIPK3 to block the progression of necroptosis occurrence, and achieved persistent viral infection. Interestingly, we found that RIPK3 was able to specifically localize at the outer mitochondrial membrane, and the autophagy receptor NDP52 was most likely involved in the autophagic degradation of RIPK3 during CSFV infection. Our findings provide evidence supporting that the CSFV-induced autophagy pathway plays an important role in counteracting host cell necrosis, enriching our knowledge of pathogens that may subvert and evade necroptosis this host defense, and shedding new light on understanding the mechanisms of T lymphocyte exhaustion and immunosuppression during CSFV infection. IMPORTANCE CSFV infection in pigs causes persistent high fever, hemorrhagic necrotizing multi-organ inflammation, and high mortality, which seriously threatens the global swine industry. Cell death is an essential immune response of the host against pathogen invasion, and lymphopenia is the most typical clinical feature in the acute phase of CSFV infection, which affects the initial host antiviral immunity. As an “old” virus, CSFV has evolved mechanisms to evade host immune response after a long genetic evolution. Here, we show that necroptosis is a limiting host factor for CSFV infection and that CSFV-induced autophagy can subvert this host defense mechanism to promote its sustained replication. Our findings reveal a complex link between necroptosis and autophagy in the process of cell death, provide evidence supporting the important role for CSFV in counteracting host cell necrosis, and enrich our knowledge of pathogens that may subvert and evade this host defense.

CSFV (classical swine fever virus) is currently endemic in developing countries in Asia and has recently re-emerged in Japan. Under the pressure of natural selection pressure, CSFV keeps evolving to maintain its ecological niche in nature. CSFV has evolved mechanisms that induce immune depression, but its pathogenic mechanism is still unclear. In this study, using transcriptomics and metabolomics methods, we found that CSFV infection alters innate host immunity by activating the interferon pathway, inhibiting host inflammation, apoptosis, and remodelling host metabolism in porcine alveolar macrophages. Moreover, we revealed that autophagy could alter innate immunity and metabolism induced by CSFV infection. Enhanced autophagy further inhibited CSFV-induced RIG-I-IRF3 signal transduction axis and JAK-STAT signalling pathway and blocked type I interferon production while reducing autophagy inhibition of the NF-κB signalling pathway and apoptosis in CSFV infection cells. Furthermore, the level of CSFV infection-induced glycolysis and the content of lactate and pyruvate, as well as 3-phosphoglyceraldehyde, a derivative of glycolysis converted to serine, was altered by autophagy. We also found that silencing HK2 (hexokinase 2), the rate-limiting enzyme of glycolytic metabolism, could induce autophagy but reduce the interferon signalling pathway, NF-κB signalling pathway, and inhibition of apoptosis induced by CSFV infection. In addition, inhibited cellular autophagy by silencing ATG5 or using 3-Methyladenine, could backfill the inhibitory effect of silencing HK2 on the cellular interferon signalling pathway, NF-κB signalling pathway, and apoptosis.

Objective To investigate the characteristics of changes in serum degraded monosaccharide levels in children with systemic lupus erythematosus (SLE) and its relationship with the severity of the disease and immune dysfunction. Methods Children firstly diagnosed as SLE and hospitalized in the Affiliated Hospital of Qingdao University from January 2019 to March 2022 were enrolled in the SLE group, healthy childrenwho underwent physical examination at the same period were chosen as the control and matched in a ration of 1∶1 in age and sex with the SLE group. The clinical data of both groups were collected. The serum levels of five kinds of degraded monosaccharides, which were mannose, glucosamine, aminogalactose, N-acetyl glucosamine and galactose, were analyzed in both groups. The correlations between serum levels of degraded monosaccharides and SLE disease activity and immunologic markers were analyzed with Pearson correlation coefficient. Results Totally 45 children with SLE (13 with mild disease activity, 15 with moderate disease activity, and 17 with severe disease activity) and 50 healthy children were enrolled in the experiment. Compared with the control group, the SLE group showed elevated levels of serum mannose, glucosamine, aminogalactose, N-acetyl glucosamine, and galactose (all P < 0.05); and serum levels of mannose, N-acetyl glucosamine, and galactose gradually increased with increasing disease activity (all P < 0.05). There was no significant difference in glucosamine and aminogalactose levels in children with SLE of different disease activity (all P > 0.05). Pearson correlation coefficient showed that serum degraded monosaccharide levels were positively correlated with disease activity indexes and various immunologic markers. Conclusions Serum levels of degraded monosaccharides in children with SLE are elevated and some of which are correlated with disease activity and immune dysfunction.

This study aimed to explore the effects of osteogenic growth peptide C-terminal pentapeptide (G36G), and its analog G48A on bone modeling in rats with ovariectomy-induced osteoporosis. Ovariectomized rats were administered PBS (OVX group), risedronate (RISE group), G36G combined with risedronate (36GRI group), G36G (G36G group), or G48A (G48A group). The sham-operation rats (SHAM group) were administered PBS. Serum osteocalcin and IGF-2 levels in the SHAM, OVX, G36G, G48A, and RISE groups were observably lower than the 36GRI group (P < 0.01) and the bone mineral density of the entire femur, distal metaphysis, and lumbar L1–L4 in the 36GRI group were notably increased (P < 0.05). The bending energy of the 36GRI group was prominently higher than the other groups (P < 0.05). Other features measured in the study that provided significant outcomes was the ratio of femora ash weight/dry weigh, parameters of trabecular bone volume (TBV)/total tissue volume, TBV/sponge bone volume, mean trabecular plate thickness, mean trabecular plate space, bone surface, parameters of sfract(s) and sfract(d), tetracycline-labeled, and osteoid surfaces. Bone loss in ovariectomized rats may be partially inhibited by G36G and G48A. A combination treatment with G36G and risedronate may be an effective intervention for osteoporosis.

The host restriction factor serine incorporator 5 (SERINC5) plays a key role in inhibiting viral activity and has been shown to inhibit classical swine fever virus (CSFV) infection. However, the action of SERINC5 in the interaction between host cells and CSFV remains poorly understood. This study found that SERINC5 represses CSFV-induced autophagy through MAPK1/3-mTOR and AKT-mTOR signalling pathways. Further research showed that SERINC5 promotes apoptosis by repressing autophagy. Likewise, it was demonstrated that SERINC5 interacting proteins IFITM1/2/3 inhibit CSFV replication and regulate autophagy in a lysosomal-associated membrane protein LAMP1-dependent manner. In addition, IFITM1/2/3 interference promotes the NF-κB signalling pathway for potential immunoregulation by inhibiting autophagy. Finally, the functional silencing of IFITM1/2/3 genes was demonstrated to enhance the inhibitory effect of SERINC5 on autophagy. Taken together, These data uncover a novel mechanism through SERINC5 and its interacting proteins IFITM1/2/3, which mediates CSFV replication, and provides new avenues for controlling CSFV.

Two processes of mesoscale convection moving eastward into the Bohai Bay on 12 May and 13 Jul in 2018, which are weakened process and enhanced process respectively, are simulated and analyzed by using the ocean-atmosphere-wave coupling model and dynamic downscaling method. Both processes occur under the control of strong southwesterly at low level and warm tongue near surface, which bring abundant water vapor and heat. The results show that the coupling model can simulate the right trend of the weakened process, but the wrong trend of the enhanced process, and the simulated intensity is overall weak. The simulation effects are improved obviously after the spatial resolution of the model increasing by using dynamic downscaling method twice. Through the comparison of sensitivity experiments, it is indicated that the coupling model has certain advantages in providing better initial and boundary conditions for the dynamic downscaling, which is suitable for the simulation, compared with the general atmospheric WRF model. Through the diagnosis and analysis of the simulation results, it's concluded that before the convection systems entering the sea, the convective available potential energy (CAPE) is large in the Bohai Bay and coastal areas. As the convection systems moving eastward into the sea, the CAPE is gradually consumed, but the supplement of CAPE in the enhanced process is stronger than that in the weakened process. The 0-6 km vertical wind shear condition of the enhanced process is also stronger than that of the weakened process in the Bohai Bay before the convection systems entering the sea, which is another favorable factor for the development of the convection. In the weakened process, the cold pool effect is increasingly stronger with an obvious rear inflow, and there is an obvious wind velocity convergence in the front of the cold pool during the convection systems moving. In the enhanced process, however, the strength of the cold pool is weaker, but the range is larger compared with the weakened process, and there is an obvious wind direction convergence in the front of the cold pool. In the weakened process, the underlying surface of the ocean provide less water vapor and heat energy for the convection region, making the convection difficult to maintain or further develop, while in the enhanced process the sea surface provides mass water vapor and heat energy transfer to the convective region when the convection system moving over the sea.

Fleas represent a group of paramount medical significance, subsisting on blood and acting as vectors for an array of naturally occurring diseases. These pathogens constitute essential elements within the plague biome, exerting deleterious effects on both human and livestock health. In this study, we successfully assembled and sequenced the whole mitochondrial genome of Frontopsylla spadix and Neopsylla specialis using long-range PCR and next-generation sequencing technologies. The mitogenomes of F. spadix and N. specialis both have 37 genes with full lengths of 15,085 bp and 16,820 bp, respectively. The topology of the phylogenetic tree elucidates that species F. spadix is clustered in a branch alongside other members of the family Leptopsyllidae, whereas species N. specialis is a sister taxon to Dorcadia ioffi and Hystrichopsylla weida qinlingensis. It also suggests that Pulicidae form a monophyletic clade, Ctenopthalmidae, Hystrichopsyllidae, Vermipsyllidae form a sister group to Ceratophyllidae/Leptopsyllidae group. The mitochondrial genomes of F. spadix and N. specialis were sequenced for the first time, which will contribute to a more comprehensive phylogenetic analysis of the Siphonaptera order. The foundation for subsequent systematic studies, and molecular biology of fleas was established.

Maturity-onset diabetes of the young type 3 (MODY3) is a specific type of diabetes mellitus with inherited impairment of the islet β cell function due to the mutation in the hepatocyte nuclear factor 1α (HNF1α) gene. It is a rare condition and easily misdiagnosed as T1DM or T2DM. In this study, the clinical features of two unrelated Chinese MODY3 probands were described and analyzed. Next-generation sequencing was performed to identify the mutated genes, and Sanger sequencing was employed to verify the location of the pathogenic variant in the related family members. It was found that proband 1 inherited a start codon mutation c.2T>C (p.Met1?) in exon 1 of the HNF1α gene from his affected mother, and proband 2 inherited a frameshift mutation c.1136_1137del (p.Pro379fs) in exon 6 of the HNF1α gene also from her affected mother. Proband 1 and proband 2 differed in islet dysfunction, complications, and treatments due to their different disease durations and levels of hemoglobin A1c (HbA1c). The findings of this study demonstrate that early identification of MODY and diagnosis through genetic testing are critical for the treatment of the patient.

The safety of high-speed railroads is an important indicator of travelers’ trust, and it is also an important factor in determining whether or not the operation volume can reach the expected goal. Therefore, high-speed railroad companies in Europe, the United States, and Japan have invested heavily in establishing safety monitoring systems in order to avoid the occurrence of disasters and to strengthen the mechanism of crisis response and emergency treatment. High-speed railroad operation may occur in a variety of accidents, different disaster warning, emergency response and rescue, need to have different equipment, contingency measures, and well-trained personnel to deal with. Therefore, the safety standards for high-speed rail systems in advanced countries around the world are much higher than those for traditional train systems. The theories and technologies of disaster prevention and relief have matured both at home and abroad. This study combines the theories and technologies of disaster prevention with GIS, such as monitoring instruments, satellite positioning, remote sensing detection, radio transmission, the Internet, database management, and information management, to provide effective support for decision-making and analysis of commanders, to rapidly assist in crisis management, and to strengthen the mechanism of emergency response.

The J-TEXT capability is enhanced compared to two years ago with several upgrades of its diagnostics and the increase of electron cyclotron resonance heating (ECRH) power to 1 MW. With the application of electron cyclotron wave (ECW), the ECW assisted plasma startup is achieved; the tearing mode is suppressed; the toroidal injection of 300 kW ECW drives around 24 kA current; fast electrons are generated with toroidal injected ECW and the runaway current conversion efficiency increases with ECRH power. The mode coupling between 2/1 and 3/1 modes are extensively studied. The coupled 2/1 and 3/1 modes usually lead to major disruption. Their coupling can be either suppressed or avoided by external resonant magnetic perturbation fields and hence avoids the major disruption. It is also found that the 2/1 threshold of external field is significantly reduced by a pre-excited 3/1 mode, which can be either a locked island or an external kink mode. The disruption control is studied by developing prediction methods capable of cross tokamak application and by new mitigation methods, such as the biased electrode or electromagnetic pellet injector. The high-density operation and related disruptions are studied from various aspects. Approaching the density limit, the collapse of the edge shear layer is observed and such collapse can be prevented by applying edge biasing, leading to an increased density limit. The density limit is also observed to increase, if the plasma is operated in the poloidal divertor configuration or the plasma purity is increased by increasing the pre-filled gas pressure or ECRH power during the start-up phase.

Fabrication of the Mg–9Al–1Zn–0.5Mn alloy with excellent mechanical performance using selective laser melting (SLM) technology is quite difficult owing to the poor weldability and low boiling point. To address these challenges and seek the optimal processing parameters, response surface methodology was systematically utilized to determine the appropriate SLM parameter combinations. Mg–9Al–1Zn–0.5Mn sample with high relative density (99.5 ​± ​0.28%) and favorable mechanical properties (microhardness ​= ​95.6 ​± ​5.28 HV0.1, UTS ​= ​370.2 ​MPa, and At ​= ​10.4%) was achieved using optimized SLM parameters (P ​= ​120 ​W, v ​= ​500 ​mm/s, and h ​= ​45 ​μm). Sample ​is dominated by a random texture and microstructure is primarily constituted by quantities of fine equiaxed grains (α-Mg phase), a small amount of β-Al12Mg17 structures (4.96 ​vol%, including spherical: [21¯1¯0]α// [111]β and long lath-like: [21¯1¯0]α// [11¯5]β or [1¯011]α// [32¯1¯]β), and some short rod-shaped Al8Mn5 nanoparticles. Benefiting from grain boundary strengthening, solid solution strengthening, and precipitation hardening of various nanoparticles (β-Al12Mg17 and Al8Mn5), high-performance Mg–9Al–1Zn–0.5Mn alloy biomedical implants can be fabricated. Precipitation hardening dominates the strengthening mechanism of the SLM Mg–9Al–1Zn–0.5Mn alloy.

Summary: Efficient regeneration requires multiple cell types acting in coordination. To better understand the intercellular networks involved and how they change when regeneration fails, we profile the transcriptome of hematopoietic, stromal, myogenic, and endothelial cells over 14 days following acute muscle damage. We generate a time-resolved computational model of interactions and identify VEGFA-driven endothelial engagement as a key differentiating feature in models of successful and failed regeneration. In addition, the analysis highlights that the majority of secreted signals, including VEGFA, are simultaneously produced by multiple cell types. To test whether the cellular source of a factor determines its function, we delete VEGFA from two cell types residing in close proximity: stromal and myogenic progenitors. By comparing responses to different types of damage, we find that myogenic and stromal VEGFA have distinct functions in regeneration. This suggests that spatial compartmentalization of signaling plays a key role in intercellular communication networks.

Background and purpose: Glioma is the most common and malignant primary brain tumor in the central nervous system (CNS). Glioblastoma is highly malignant and aggressive, and the prognosis of patients with recurrent glioblastoma is very poor. This study aimed to screen the genes related to the recurrent glioblastoma, and analyze the relationship between their expressions, clinicopathological parameters and prognosis in glioma. Methods: By mining the relevant datasets of the primary and recurrent cases of glioblastoma in the GEO database, the differentially expressed gene (DEG) in the samples of primary and recurrent glioblastomas were screened and analyzed. All DEGs analyses were carried out in ontology function and pathway enrichment. Protein-protein interaction (PPI) network was constructed and used for screening Hub gene. Key genes were intersected by PPI network and Venn diagram, and the Gene Expression Profiling Interactive Analysis (GEPIA) and Chinese Glioma Genome Atlas (CGGA) database were analyzed for association of key gene expressions and survival status. Key genes were furtherly analyzed to determine the relationship between their expressions and clinicopathological parameters of glioma. Results: There were 40 DEG screened in the dataset GSE62153, including 34 up-regulated genes and 6 down-regulated genes. There were 19 DEG screened in the dataset GSE58399, including 16 up-regulated genes and 3 down-regulated genes. Go functional analyses showed that the DEG of GSE62153 were mainly involved in 11 physiological processes, such as central nervous system development, myelin sheath, actin binding, central nervous system myelination. The DEG of GSE58399 were mainly enriched in the positive regulation of epithelial cell migration. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment showed that the datasets GSE62153 and GSE58399 were both enriched in histidine metabolism. By using the STRING database, the core of PPI network was constructed with 20 protein molecules. A total of 10 hub genes were screened, including MOBP, OPALIN, ERMN, PLP1, MOG, CLDN11, ASPA, TMEM125, KLK6 and NKX6-2 gene. The key genes for recurrent glioblastoma were ERMN, MOG and MOBP gene. Based on analyses using The Cancer Genome Atlas (TCGA) and CGGA databases, the prognosis of patients with high expressions of ERMN, MOG and MOBP was favorable compared with the low expression group. The expression levels of key genes in glioblastoma were lower compared with the control tissues (P

Endoplasmic reticulum stress (ERS)-mediated autophagy is indispensable for modulation of replication and pathogenesis of numerous mammalian viruses. We have previously shown that classical swine fever virus (CSFV) infection induces ERS-mediated autophagy for maintaining viral replication both in vivo and in vitro, however, the underlying mechanism remains unclarified. Here we found that CSFV infection activates the PERK pathway-dependent complete autophagy to promote viral replication in cultured PK-15 and 3D4/2 cells. Likewise, our results also suggested the essential roles of the IRE1/GRP78-mediated complete autophagy in CSFV replication in vitro. Furthermore, we suggested that CSFV infection induces activation of the PERK and IRE1 pathway for potential immunoregulation via promoting transcription of proinflammatory cytokine (IFN-γ and TNF-α) genes in the CSFV-infected cells. Finally, pharmacological treatment of PERK- or IRE1-pathway regulators, and the corresponding SiRNAs interventions did not affect the viabilities of the cells, excluding the potential interference elicited by altered cell viabilities. Taken together, our results suggest that CSFV infection induces complete autophagy through activation of the PERK and IRE1 pathway to facilitate viral replication in cultured cells, and modulation of proinflammatory cytokines may be a potential mechanism involved in this event. Our findings will open new horizons for molecular mechanisms of sustainable replication and pathogenesis of CSFV, and lay a theoretical foundation for the development of ERS-autophagy-targeting therapeutic strategies for clinical control of CSF.

To investigate the role of microglia in the process of cognitive impairment caused by local ionizing radiation, eighteen male mice from the institute of cancer research (ICR) were randomly divided into a control group (Control) and a head 10 Gy irradiation group (Irradiation, 10 Gy-IR). The head ionization irradiation group underwent X-ray (Siemens linear accelerator) single head irradiation illuminated to an absorbed dose of 10 Gy. Fifty-six days later, the new and old object recognition test and the new and old place recognition test were used to test the cognitive function of the mice; immunohistochemistry was used to detect the mouse hippocampal microglia marke (IBA-1) change; RT-PCR was used to detect changes at the mRNA level of hippocampal M1/M2 microglia markers (CD16, INOS, CD68, CXCL10, Arg1, CD206). The results showed that compared with the control group, the time discrimination index of new things (p

Background: Specific tumor markers have yet to be identified in rectal cancer. This study aims to identify a novel genetic signature in rectal cancer to provide clues for survival and immunotherapy. Methods: DEGs were obtained from two GEO datasets of rectal cancer. By using data from TCGA and GSE133057, two cohorts of rectal cancer were applied to establish and evaluate the signature. A nomogram was constructed for training and validation. We integrated the risk-score with clinicopathological features and assessed its interplay with immune cells and molecules. Finally, our study performed functional annotations, gene-targeted miRNAs, and single-cell analysis. Results: A total of 468 DEGs were identified, and a signature consisting of 5 genes (CLIC5, ENTPD8, PACSIN3, HGD, and GNG7) was selected to calculate the risk-score. The model exhibited high performance in time-dependent ROC and a nomogram. Further results showed that overall survival was significantly worse in the high-risk group. As an independent prognostic factor, the risk-score was associated with vascular invasion. There was a dramatic difference in nonregulatory CD4+ and CD8+ T cells between the high and low-risk groups, and the 5 genes were correlated with immune inhibitors. There was a considerable difference in autophagy, immune, cell cycle, infection, and apoptosis-associated terms and pathways in GO and KEGG. The functional states of differentiation, apoptosis, and quiescence were closely related to the 5-gene signature in single-cell analysis. Conclusion: Our results suggest that the signature could serve as a novel prognostic biomarker in rectal cancer, which might benefit decision-making regarding immunotherapy.

Okun's law is generally interpreted in economic terms. This paper is interpreted from a social perspective through regression and mediating effect models. Okun's law is demonstrated based on data from the World Development Indicators (WDI) dataset. There is indeed a relationship between unemployment and economic growth, with unemployment negatively affecting economic growth after controlling for the two-way causality problem. This result remains robust after replacing the core explanatory variables. This paper interprets the asymmetry of Okun's law from a social perspective, using alcohol consumption as a mediating variable to measure the harm caused by unemployment to the unemployed. Analysis of the data reveals that alcohol consumption mediates between unemployment and economic growth. Unemployment increases alcohol consumption, which causes incurable harm to the unemployed. It reduces the willingness and probability of the unemployed to re-employ and further reduces the potential for economic growth. This is why the economic expansion did not lead to employment growth, revealing the asymmetry of Okun's law. The gender-specific heterogeneity analysis found that the impact of unemployment on economic growth did not vary much by gender.