Search

Rui Zhou,* Tao Xu,* XiaoHong Liu, YuanShou Chen, DeYing Kong, Hong Tian, Mingxia Yue, Dujuan Huang, Junwei Zeng Department of Physiology, Zunyi Medical College, Zunyi, People’s Republic of China *These authors contributed equally to this work Objective: The dorsal horn P2Y13 receptor is involved in the development of pain behavior induced by peripheral nerve injury. It is unclear whether the expression of proinflammatory cytokines interleukin (IL)-1β and IL-6 at the spinal dorsal horn are influenced after the activation of P2Y13 receptor in rats with diabetic neuropathic pain (DNP). Methods: A rat model of type 1 DNP was induced by intraperitoneal injection of streptozotocin (STZ). We examined the expression of P2Y13 receptor, Iba-1, IL-1β, IL-6, JAK2, STAT3, pTyr1336, and pTyr1472 NR2B in rat spinal dorsal horn. Results: Compared with normal rats, STZ-diabetic rats displayed obvious mechanical allodynia and the increased expression of P2Y13 receptor, Iba-1, IL-1β, and IL-6 in the dorsal spinal cord that was continued for 6 weeks in DNP rats. The data obtained indicated that, in DNP rats, administration of MRS2211 significantly attenuated mechanical allodynia. Compared with DNP rats, after MRS2211 treatment, expression of the P2Y13 receptor, Iba-1, IL-1β, and IL-6 were reduced 4 weeks after the STZ injection. However, MRS2211 treatment did not attenuate the expression of the P2Y13 receptor, Iba-1, IL-1β, and IL-6 at 6 weeks after the STZ injection. MRS2211 suppressed JAK2 and STAT3 expression in the early stage, but not in the later stage. Moreover, pTyr1336 NR2B was significantly decreased, whereas pTyr1472 NR2B was unaffected in the dorsal spinal cord of MRS2211-treated DNP rats. Conclusion: Intrathecal MRS2211 produces an anti-nociceptive effect in early-stage DNP. A possible mechanism involved in MRS2211-induced analgesia is that blocking the P2Y13 receptor downregulates levels of IL-1β and IL-6, which subsequently inhibit the activation of the JAK2/STAT3 signaling pathway. Furthermore, blocking the activation of the P2Y13 receptor can decrease NR2B-containing NMDAR phosphorylation in dorsal spinal cord neurons, thereby attenuating central sensitization in STZ-induced DNP rats.Keywords: diabetic neuropathic pain, dorsal horn, P2Y13 receptor

The search continues for nickel oxide-based materials with electronic properties similar to cuprate high-temperature superconductors1-10. The recent discovery of superconductivity in the doped infinite-layer nickelate NdNiO2 (refs. 11,12) has strengthened these efforts. Here, we use X-ray spectroscopy and density functional theory to show that the electronic structure of LaNiO2 and NdNiO2, while similar to the cuprates, includes significant distinctions. Unlike cuprates, the rare-earth spacer layer in the infinite-layer nickelate supports a weakly interacting three-dimensional 5d metallic state, which hybridizes with a quasi-two-dimensional, strongly correlated state with [Formula: see text] symmetry in the NiO2 layers. Thus, the infinite-layer nickelate can be regarded as a sibling of the rare-earth intermetallics13-15, which are well known for heavy fermion behaviour, where the NiO2 correlated layers play an analogous role to the 4f states in rare-earth heavy fermion compounds. This Kondo- or Anderson-lattice-like 'oxide-intermetallic' replaces the Mott insulator as the reference state from which superconductivity emerges upon doping.

Competing Interests: Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none.

X-ray circular dichroism, arising from the contrast in X-ray absorption between opposite photon helicities, serves as a spectroscopic tool to measure the magnetization of ferromagnetic materials and identify the handedness of chiral crystals. Antiferromagnets with crystallographic chirality typically lack X-ray magnetic circular dichroism because of time-reversal symmetry, yet exhibit weak X-ray natural circular dichroism. Here, the observation of giant natural circular dichroism in the Ni L 3 -edge X-ray absorption of Ni 3 TeO 6 is reported, a polar and chiral antiferromagnet with effective time-reversal symmetry. To unravel this intriguing phenomenon, a phenomenological model is proposed that classifies the movement of photons in a chiral crystal within the same symmetry class as that of a magnetic field. The coupling of X-ray polarization with the induced magnetization yields giant X-ray natural circular dichroism, revealing typical ferromagnetic behaviors allowed by the symmetry in an antiferromagnet, i.e., the altermagnetism of Ni 3 TeO 6 . The findings provide evidence for the interplay between magnetism and crystal chirality in natural optical activity. Additionally, the first example of a new class of magnetic materials exhibiting circular dichroism is established with time-reversal symmetry., (© 2024 National Synchrotron Radiation Research Center (NSRRC). Advanced Materials published by Wiley‐VCH GmbH.)

Polarons-fermionic charge carriers bearing a strong companion lattice deformation-exhibit a natural tendency for self-localization due to the recursive interaction between electrons and the lattice. While polarons are ubiquitous in insulators, how they evolve in transitions to metallic and superconducting states in quantum materials remains an open question. Here, we use resonant inelastic x-ray scattering to track the electron-lattice coupling in the colossal magneto-resistive bi-layer manganite La_{1.2}Sr_{1.8}Mn_{2}O_{7} across its metal-to-insulator transition. The response in the insulating high-temperature state features harmonic emissions of a dispersionless oxygen phonon at small energy transfer. Upon cooling into the metallic state, we observe a drastic redistribution of spectral weight from the region of these harmonic emissions to a broad high energy continuum. In concert with theoretical calculations, we show that this evolution implies a shift in electron-lattice coupling from static to dynamic lattice distortions that leads to a distinct polaronic ground state in the low temperature metallic phase-a dynamic polaron liquid.

In Alzheimer's disease (AD), microglia are involved in synaptic pruning and mediate synapse loss. LINGO-1 is a negative regulator of nerve growth, and whether antagonizing LINGO-1 can attenuate synaptic pruning by microglia and rescue dendritic spines in the hippocampus in AD is still unclear. On this basis, the anti-LINGO-1 antibody, which binds to LINGO-1 protein and antagonizes the effects of LINGO-1, was administered to 10-month-old APP/PS1 transgenic mice for 2 months. The Morris water maze test, immunohistochemical and stereological methods, immunofluorescence and 3D reconstruction were used. Compared to wild-type mice, APP/PS1 transgenic mice had worse performance on behavioral tests, fewer dendritic spines but more microglia in the hippocampus. Meanwhile, the microglia in APP/PS1 transgenic mice had more branches of medium length (4-6 µm) and a cell body area with greater variability. Moreover, APP/PS1 transgenic mice had more postsynaptic termini colocalized with microglia in the hippocampus than wild-type mice. The anti-LINGO-1 antibody significantly reversed these changes in AD, indicating that the anti-LINGO-1 antibody can improve hippocampus-dependent learning and memory abilities and effectively rescue dendritic spines in the hippocampus of AD mice and that microglia might participate in this progression in AD. These results provide a scientific basis for further studying the mechanism of the anti-LINGO-1 antibody in AD and help to elucidate the role of LINGO-1 in the treatment of AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Helicobacter pylori , a dominant member of the gastric microbiota was associated with various gastrointestinal diseases and presents a significant challenge due to increasing antibiotic resistance. This study identifies H. pylori 's phospholipase A (PldA) as a critical factor in modulating host macrophage responses, facilitating H. pylori 's evasion of the immune system and persistence. PldA alters membrane lipids through reversible acylation and deacylation, affecting their structure and function. We found that PldA incorporates lysophosphatidylethanolamine into macrophage membranes, disrupting their bilayer structure and impairing TNFR1-mediated p38-MK2 signaling. This disruption results in reduced macrophage autophagy and elevated RIP1-dependent apoptosis, thereby enhancing H. pylori survival, a mechanism also observed in multidrug-resistant strains. Pharmacological inhibition of PldA significantly decreases H. pylori viability and increases macrophage survival. In vivo studies corroborate PldA's essential role in H. pylori persistence and immune cell recruitment. Our findings position PldA as a pivotal element in H. pylori pathogenesis through TNFR1-mediated membrane modulation, offering a promising therapeutic target to counteract bacterial resistance.

Objectives: Luteolin is a flavone that provides defense against myocardial ischemia/reperfusion (I/R) injury. However, this compound is subjected to methylation mediated by catechol-O-methyltransferase (COMT), thus influencing its pharmacological effect. To synthesize a new flavone from luteolin that avoids COMT-catalyzed methylation and find out the protective mechanism of LUA in myocardial I/R injury., Materials and Methods: Luteolin and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) were used to synthesize the new flavone known as LUAAPH-1 (LUA). Then, the myocardial ischemia/reperfusion injury cell model was established using H9c2 cells to detect the effect in myocardial ischemia/reperfusion regulation and to identify the underlying mechanism., Results: Pretreatment with LUA (20 μmol/l) substantially increased cell viability while reducing cell apoptosis rate and caspase-3 expression induced by I/R, and the protective effect of LUA on cell viability was stronger than diosmetin, which is the major methylated metabolite of luteolin. In addition, intracellular reactive oxygen species (ROS) production and calcium accumulation were both inhibited by LUA. Furthermore, we identified that LUA markedly relieved the promotive effects of I/R stimulation upon JNK and p38 phosphorylation., Conclusion: LUT pretreatment conveys significant cardioprotective effects after myocardial I/R injury, and JNK and p38 MAPK signaling pathway may be involved., Competing Interests: It has been declared that the authors do not have any financial conflicts of interest.

The extremely overdoped cuprates are generally considered to be Fermi liquid metals without exotic orders, whereas the underdoped cuprates harbor intertwined states. Contrary to this conventional wisdom, using Cu L_{3}-edge and O K-edge resonant x-ray scattering, we reveal a charge order (CO) correlation in overdoped La_{2-x}Sr_{x}CuO_{4} (0.35≤x≤0.6) beyond the superconducting dome. This CO has a periodicity of ∼6 lattice units with correlation lengths of ∼20 lattice units. It shows similar in-plane momentum and polarization dependence and dispersive excitations as the CO of underdoped cuprates, but its maximum intensity differs along the c direction and persists up to 300 K. This CO correlation cannot be explained by the Fermi surface instability and its origin remains to be understood. Our results suggest that CO is prevailing in the overdoped metallic regime and requires a reassessment of the picture of overdoped cuprates as weakly correlated Fermi liquids.

Doxorubicin (DOX) is a potent chemotherapeutic drug for various cancers. Yet, the cardiotoxic side effects limit its application in clinical uses, in which ferroptosis serves as a crucial pathological mechanism in DOX-induced cardiotoxicity (DIC). A reduction of Na+/K + ATPase (NKA) activity is closely associated with DIC progression. However, whether abnormal NKA function was involved in DOX-induced cardiotoxicity and ferroptosis remains unknown. Here, we aim to decipher the cellular and molecular mechanisms of dysfunctional NKA in DOX-induced ferroptosis and investigate NKA as a potential therapeutic target for DIC. A decrease activity of NKA further aggravated DOX-triggered cardiac dysfunction and ferroptosis in NKAα1 haploinsufficiency mice. In contrast, antibodies against the DR-region of NKAα-subunit (DR-Ab) attenuated the cardiac dysfunction and ferroptosis induced by DOX. Mechanistically, NKAα1 interacted with SLC7A11 to form a novel protein complex, which was directly implicated in the disease progression of DIC. Furthermore, the therapeutic effect of DR-Ab on DIC was mediated by reducing ferroptosis by promoting the association of NKAα1/SLC7A11 complex and maintaining the stability of SLC7A11 on the cell surface. These results indicate that antibodies targeting the DR-region of NKA may serve as a novel therapeutic strategy to alleviate DOX-induced cardiotoxicity., Competing Interests: Declaration of competing interest The authors have no conflicts to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The medial prefrontal cortex (mPFC), one of the most vulnerable brain regions in Alzheimer's disease (AD), plays a critical role in cognition. Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein-1 (LINGO-1) negatively affects nerve growth in the central nervous system; however, its role in the pathological damage to the mPFC remains to be studied in AD. In this study, an anti-LINGO-1 antibody was administered to 10-month-old APP/PS1 mice, and behavioral tests, stereological methods, immunohistochemistry and immunofluorescence were used to answer this question. Our results revealed that LINGO-1 was highly expressed in the neurons of the mPFC of AD mice, and the anti-LINGO-1 antibody improved prefrontal cortex-related function and reduced the protein level of LINGO-1, atrophy of the volume, Aβ deposition and massive losses of synapses and neurons in the mPFC of AD mice. Antagonizing LINGO-1 could effectively alleviate the pathological damage in the mPFC of AD mice, which might be an important structural basis for improving prefrontal cortex-related function. Abnormal expression of LINGO-1 in the mPFC may be one of the key targets of AD, and the effect initiated by the anti-LINGO-1 antibody may provide an important basis in the search for drugs for the prevention and treatment of AD., Competing Interests: Conflict of interest The authors declare no competing financial interests., (Copyright © 2023 Elsevier Ltd and Japan Neuroscience Society. All rights reserved.)

RNA interference (RNAi) treatment has been proven to be an important therapeutic approach in cancer based on downregulation of target-oncogenes, but its clinical efficacy still needs further investigation. LMP1 is usually presented by Epstein-Barr virus (EBV)-positive tumor cells like EBV-associated nasopharyngeal carcinoma (NPC) and acts as an oncogene in tumorigenesis. However, the mechanism of LMP1 as a proto-oncogene in nasopharyngeal carcinoma is still unclear. Two sequence-specific shRNAs 1 and 2 were designed to target the different nucleotide loci of EBV latent antigen LMP1 gene and a series of in vivo and in vitro experiments were performed to investigate the therapeutic effect of sequence-specific shRNAs targeting LMP1 and its related molecular mechanisms in EBV-positive NPC. LMP1-shRNA2 generated a truncated LMP1 mRNA and protein, whereas LMP1-shRNA1 completely blocked LMP1 mRNA and protein expression. Both LMP1-shRNAs inhibited the proliferation and migration of NPC cells overexpressing LMP1 (NPC-LMP1) as well as the NPC-associated myeloid-derived suppressor cell (MDSC) expansion in vitro. However, LMP1-shRNA2 maintained the immunogenicity of NPC-LMP1 cells, which provoked MHC-class I-dependent T cell recognition. LMP1-shRNAs inhibited tumor growth in nude mice but did not reach statistical significance compared to control groups, while the LDH nanoparticle loaded LMP1-shRNAs and the antigen-specific T cells induced by NPC-LMP1 cells treated with LMP1-shRNA2 significantly reduced tumor growth in vivo. LMP1-RNAi-based anti-tumor therapy could be a new hope for the clinical efficacy of RNAi treatment of tumors like NPC.

Purpose: To explore the effectiveness of the model based on non-negative matrix factorization (NMF), analyze the tumor microenvironment and immune microenvironment for evaluating the prognosis of lung adenocarcinoma, establish a risk model, and screen independent prognostic factors., Methods: Downloading the transcription data files and clinical information files of lung adenocarcinoma from TCGA database and GO database, the R software was used to establish the NMF cluster model, and then the survival analysis between groups, tumor microenvironment analysis, and immune microenvironment analysis was performed according to the NMF cluster result. R software was used to construct prognostic models and calculate risk scores. Survival analysis was used to compare survival differences between different risk score groups., Results: Two ICD subgroups were established according to the NMF model. The survival of the ICD low-expression subgroup was better than that of the ICD high-expression subgroup. Univariate COX analysis screened out HSP90AA1, IL1, and NT5E as prognostic genes, and the prognostic model established on this basis has clinical guiding significance., Conclusion: The model based on NMF has the prognostic ability for lung adenocarcinoma, and the prognostic model of ICD-related genes has a certain guiding significance for survival., Competing Interests: The authors declare no competing interests., (©2023TheAuthors.PublishedbyElsevierLtd.)

Background: Cervical cancer (CC) is nearly always caused by persistent human papillomavirus (HPV) infection. It is the most common cancer among women living with HIV (WLWH) and is the leading cause of cancer-related death in women in East Africa, with 10,241 new cases reported in Tanzania in 2020. In 2019, the World Health Organization (WHO) presented a global strategy for the elimination of CC as a public health problem, proposing targets to meet by 2030 for HPV vaccine coverage (90% of all 15-year-old girls), CC screening (70% of all women once at 35 and again at 45 years of age) and treatment delivery, to be scaled at national and subnational levels with a context-sensitive approach. This study aims to evaluate the upscaling of screening and treatment services at a rural referral hospital in Tanzania in order to address the second and third WHO targets., Methods: This is an implementation study with a before-and-after design performed at St. Francis Referral Hospital (SFRH) in Ifakara (south-central Tanzania). CC screening and treatment services are integrated within the local HIV Care and Treatment Center (CTC). The standard of care, consisting of visualization of the cervix with acetic acid (VIA) and cryotherapy has been up-scaled with self-sampled HPV testing and also involved the introduction of mobile colposcopy, thermal ablation and loop electrosurgical excision procedure (LEEP). Participants are WLWH aged 18 to 65 years. Outcome measures included the percentage of women screened, HPV prevalence and genotype, and adherence to screening, treatment and follow-up plan. Additionally, we will explore the performance of novel diagnostic tests (QG-MPH®, Prevo-Check® and PT Monitor®), which share the features of being manageable and inexpensive, and thus a potential tool for effective triage in HPV high-prevalence cohorts., Discussion: The study will provide relevant information about HPV prevalence and persistence, as well as reproductive and lifestyle indicators in a CC high-risk cohort of WLWH and about upscaling screening and treatment services at the level of a rural referral hospital in Tanzania. Furthermore, it will provide exploratory data on novel assays., Trial Registration: ClinicalTrials.gov Identifier: NCT05256862, date of registration 25/02/2022. Retrospectively registered., (© 2023. The Author(s).)

The immune regulator galectin-9 (Gal-9) is commonly involved in the regulation of cell proliferation, but with various impacts depending on the cell type. Here, we revealed that Gal-9 expression was persistently increased in Epstein-Barr virus (EBV)-infected primary B cells from the stage of early infection to the stage of mature lymphoblastoid cell lines (LCLs). This sustained upregulation paralleled that of gene sets related to cell proliferation, such as oxidative phosphorylation, cell cycle activation, and DNA replication. Knocking down or blocking Gal-9 expression obstructed the establishment of latent infection and outgrowth of EBV-infected B cells, while exogenous Gal-9 protein promoted EBV acute and latent infection and outgrowth of EBV-infected B cells at the early infection stage. Mechanically, stimulator of interferon gene (STING) activation or signal transducer and activator of transcription 3 (STAT3) inhibition impeded the outgrowth of EBV-infected B cells and promotion of Gal-9-induced lymphoblastoid cell line (LCL) transformation. Accordingly, Gal-9 expression was upregulated by forced EBV nuclear antigen 1 (EBNA1) expression in 293T cells in vitro . Clinical data showed that Gal-9 expression in B-cell lymphomas (BCLs) correlated positively with EBNA1 and disease stage. Targeting Gal-9 slowed LCL tumor growth and metastasis in xenografted immunodeficient mice. These findings highlight an oncogenic role of Gal-9 in EBV-associated BCLs, indicating that Gal-9 boosts the transformation of EBV-infected B cells. IMPORTANCE The cross talk between Epstein-Barr virus (EBV) and the host cell transcriptome assumes important roles in the oncogenesis of EBV-associated malignancies. Here, we first observed that endogenous Gal-9 expression was persistently increased along with an overturned V-type change in antivirus signaling during the immortalization of EBV-transformed B cells. Upregulation of Gal-9 promoted the outgrowth and latent infection of EBV-infected B cells, which was linked to B-cell-origin tumors by suppressing STING signaling and subsequently promoting STAT3 phosphorylation. EBV nuclear antigen EBNA1 induced Gal-9 expression and formed a positive feedback loop with Gal-9 in EBV-infected B cells. Tumor Gal-9 levels were positively correlated with disease stage and EBNA1 expression in patients with B-cell lymphomas (BCLs). Targeting Gal-9 slowed the growth and metastases of LCL tumors in immunodeficient mice. Altogether, our findings indicate that Gal-9 is involved in the lymphomagenesis of EBV-positive BCLs through cross talk with EBNA1 and STING signals.

Electron quasiparticles play a crucial role in simplifying the description of many-body physics in solids with surprising success. Conventional Landau's Fermi-liquid and quasiparticle theories for high-temperature superconducting cuprates have, however, received skepticism from various angles. A path-breaking framework of electron fractionalization has been established to replace the Fermi-liquid theory for systems that show the fractional quantum Hall effect and the Mott insulating phenomena; whether it captures the essential physics of the pseudogap and superconducting phases of cuprates is still an open issue. Here, we show that excitonic excitation of optimally doped Bi 2 Sr 2 CaCu 2 O 8+δ with energy far above the superconducting-gap energy scale, about 1 eV or even higher, is unusually enhanced by the onset of superconductivity. Our finding proves the involvement of such high-energy excitons in superconductivity. Therefore, the observed enhancement in the spectral weight of excitons imposes a crucial constraint on theories for the pseudogap and superconducting mechanisms. A simple two-component fermion model which embodies electron fractionalization in the pseudogap state provides a possible mechanism of this enhancement, pointing toward a novel route for understanding the electronic structure of superconducting cuprates., (© 2022. The Author(s).)

Background: Microvascular invasion (MVI) is a histological factor that is closely related to the early recurrence of hepatocellular carcinoma (HCC) after resection. To investigate whether a noninvasive risk score system based on MVI status can be established to estimate early recurrence of HCC after resection., Methods: Between January 2018 to March 2021, a total of 108 patients with surgically treated single HCC was retrospectively included in our study. Fifty-one patients were pathologically confirmed with MVI and 57 patients were absent of MVI. Univariate and multivariate logistic regression analysis of preoperative laboratory and magnetic resonance imaging (MRI) features were used to screen noninvasive risk factors in association with MVI in HCC. Risk scores based on the odds ratio (OR) values of MVI-related risk factors were calculated to estimate the early recurrence after resection of HCC., Results: In multivariate logistic regression analysis, tumor size > 2 cm (P = 0.024, OR 3.05, 95% CI 1.19-11.13), Prothrombin induced by vitamin K absence-II > 32 mAU/ml (P = 0.001, OR 4.13, 95% CI 1.23-11.38), irregular tumor margin (P = 0.018, OR 3.10, 95% CI 1.16-8.31) and apparent diffusion coefficient value < 1007 × 10 - 3 mm 2 /s (P = 0.035, OR 2.27, 95% CI 1.14-7.71) were independent risk factors correlated to MVI in HCC. Risk scores of patients were calculated and were then categorized into high or low-risk levels. In multivariate cox survival analysis, only high-risk score of MVI was the independent risk factor of early recurrence (P = 0.009, OR 2.11, 95% CI 1.20-3.69), with a sensitivity and specificity of 0.52, 0.88, respectively., Conclusion: A risk score system based on MVI status can help stratify patients in high-risk of early recurrence after resection of HCC., (© 2022. The Author(s).)

The incineration of municipal solid waste has been important in waste management, but it raises another environmental issue concerning residue treatment. This study describes an innovative use of naturally aged incineration bottom ash (AIBA) as an alternative substrate for horizontal subsurface flow (HSSF) constructed wetlands (CW). Although experimental results from a period lasting for 396 days only revealed slightly higher removal ratios in HSSF with AIBA (HSSF-E) than in HSSF-traditional pebble beds (HSSF-C), increasing from 67% to 76% for BOD, 44%-51% for TKN, 47%-54% for NH 3 -N, and 44%-52% for TN. The data indicate that the use of AIBA in HSSF CW can achieves a certain removal efficiency of BOD and nitrogen species. Interestingly, the total phosphorus removal rates also increased significantly from 20% in HSSF-C to 36% in HSSF-E. These observations on the use of AIBA in HSSF CW confirmed that AIBA is a suitable alternative for use as a substrate for HSSF CWs and identified an additional way to reuse incineration bottom ash. Design criteria for a CW using AIBA as a partial substrate is proposed to improve the pollutant removal performance of HSSF CWs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

High power 1.5 µm band fiber lasers are of great importance for many practical applications. Generally, the technical targets including high average output power, narrow linewidth, temporally suppressed intensity dynamics, high spectral purity, single transverse mode lasing, and excellent robustness are the major concerns when constructing a high-performance laser source. Here, we demonstrate the highest output power of a wavelength tunable 1.5 µm band random fiber laser based on the active fiber gain mechanism to the best of our knowledge. A master oscillator power-amplifier (MOPA) configuration is employed to greatly boost the output power to 20 watt-level with a single transverse mode lasing and the same linewidth as the seed, benefiting from the spectral broadening free feature when employing the random fiber laser as the seed. This work not only enriches the progress of random fiber laser, but also provides an attractive alternative in realizing high performance lasing light source at 1.5 µm band.

We present the cobalt 2p3d resonant inelastic X-ray scattering (RIXS) spectra of Co 3 O 4 . Guided by multiplet simulation, the excited states at 0.5 and 1.3 eV can be identified as the 4 T 2 excited state of the tetrahedral Co 2+ and the 3 T 2 g excited state of the octahedral Co 3+ , respectively. The ground states of Co 2+ and Co 3+ sites are determined to be high-spin 4 A 2 ( T d ) and low-spin 1 A 1 g ( O h ), respectively. It indicates that the high-spin Co 2+ is the magnetically active site in Co 3 O 4 . Additionally, the ligand-to-metal charge transfer analysis shows strong orbital hybridization between the cobalt and oxygen ions at the Co 3+ site, while the hybridization is weak at the Co 2+ site., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Recent clinical trials have revealed that the chimeric peptide hormones simultaneously activating glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) demonstrate superior efficacy in glycemic control and body weight reduction, better than those activating the GLP-1R alone. However, the linear peptide-based GLP-1R/GIPR dual agonists are susceptible to proteolytic cleavage by common digestive enzymes present in the gastrointestinal tract and thus not suitable for oral administration. Here, we report the design and synthesis of biaryl-stapled peptides, with and without fatty diacid attachment, that showed potent GLP-1R/GIPR dual agonist activities. Compared to a linear peptide dual agonist and semaglutide, the biaryl-stapled peptides displayed drastically improved proteolytic stability against the common digestive enzymes. Furthermore, two stapled peptides showed excellent efficacy in an oral glucose tolerance test in mice, owing to their potent receptor activity in vitro and good pharmacokinetics exposure upon subcutaneous injection. By exploring a more comprehensive set of biaryl staplers, we expect that this stapling method could facilitate the design of the stapled peptide-based dual agonists suitable for oral administration.

Organic-inorganic hybrid metal halides have recently attracted attention in the global research field for their bright light emission, tunable photoluminescence wavelength, and convenient synthesis method. This study reports the detailed properties of (C 10 H 16 N) 2 MnBr 4 , which emits bright green light with a high photoluminescence quantum yield. Results of powder X-ray diffraction, photoluminescence, thermogravimetric analysis, and Raman spectra show the phase transition of (C 10 H 16 N) 2 MnBr 4 at 430 K. This phase transition was identified as the solid to liquid state of (C 10 H 16 N) 2 MnBr 4 . Moreover, the pressure- and temperature-induced relationship between structural and optical properties in (C 10 H 16 N) 2 MnBr 4 can be identified. This investigation provides deep insights into the luminescent properties of metal halide crystals and promotes further research.

Luteolin is a common dietary flavone possessing potent anti-inflammatory activities. However, when administrated in vivo, luteolin becomes methylated by catechol-O-methyltransferases (COMT) owing to the catechol ring in the chemical structure, which largely diminishes its anti-inflammatory effect. In this study, we made a modification on luteolin, named LUA, which was generated by the chemical reaction between luteolin and 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). Without a catechol ring in the chemical structure, this new flavone could escape from the COMT-catalyzed methylation, thus affording the potential to exert its functions in the original form when administrated in the organism. Moreover, an LPS-stimulated RAW cell model was applied to detect the anti-inflammatory properties. LUA showed much more superior inhibitory effect on LPS-induced production of NO than diosmetin (a major methylated form of luteolin) and significantly suppressed upregulation of iNOS and COX-2 in macrophages. LUA treatment dramatically reduced LPS-stimulated reactive oxygen species (ROS) and mRNA levels of pro-inflammatory mediators such as IL-1β, IL-6, IL-8 and IFN-β. Furthermore, LUA significantly reduced the phosphorylation of JNK and p38 without affecting that of ERK. LUA also inhibited the activation of NF-κB through suppression of p65 phosphorylation and nuclear translocation.

Objective: To investigate the clinical efficacy of coenzyme Q10 (CoQ10) plus trimetazidine (TMZ) in treating acute viral myocarditis (AVMC) and the combination's influence on the oxidative stress markers and the patients' quality of life (QoL)., Methods: This retrospective analysis enrolled 156 patients with AVMC admitted to the Department of Cardiology of the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine between February 2018 and February 2019. Based on the treatment method each patient was administered, the patients were classified into a control group (n=72, CoQ10 therapy) and a combination group (n=84, CoQ10+TMZ therapy). The clinical effectiveness was observed in the two groups two weeks after the treatment, and the changes in the patients' serum inflammatory factor levels, oxidative stress indexes, myocardial enzyme levels, and cardiac function were compared., Results: The combination group had a far superior total effective rate than the control group (90.5% vs. 77.8%, P<0.05). After the treatment, the serum inflammatory factor levels, including tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and C-reactive protein (CRP), decreased in both groups, and the index levels in the combination group were significantly better than they were in the control group (P<0.05). The oxidative stress indicators, such as superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO), improved more significantly in the combination group compared to the control group (P<0.05). The myocardial zymogram creatine kinase (CK), cardiac troponin (cTnI), creatine kinase isoenzyme MB (CK-MB), and lactate dehydrogenase (LDH) levels were reduced in the two groups, with lower levels in the combination group. The left ventricular systolic function and the patients' QoL were better in the combination group compared with the control group (P<0.05)., Conclusions: CoQ10 plus TMZ yields a favorable clinical effectiveness in the treatment of AVMC, and it can effectively promote cardiac function recovery, alleviate oxidative stress and inflammatory reactions, and bolster patients' QoL., Competing Interests: None., (AJTR Copyright © 2021.)

In view of the negative regulatory effect of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) on neurons, an antibody against LINGO-1 (anti-LINGO-1 antibody) was herein administered to 10-month-old APP/PS1 transgenic Alzheimer's disease (AD) mice for 2 months as an experimental intervention. Behavioral, stereology, immunohistochemistry and immunofluorescence analyses revealed that the anti-LINGO-1 antibody significantly improved the cognitive abilities, promoted adult hippocampal neurogenesis (AHN), decreased the amyloid beta (Aβ) deposition, enlarged the hippocampal volume, and increased the numbers of total neurons and GABAergic interneurons, including GABAergic and CCK-GABAergic interneurons rich in cannabinoid type 1 receptor (CB1R), in the hippocampus of AD mice. In contrast, this intervention significantly reduced the number of GABAergic interneurons expressing LINGO-1 and CB1R in the hippocampus of AD mice. More importantly, we also found a negative correlation between LINGO-1 and CB1R on GABAergic interneurons in the hippocampus of AD mice, while the anti-LINGO-1 antibody reversed this relationship. These results indicated that LINGO-1 plays an important role in the process of hippocampal neuron loss in AD mice and that antagonizing LINGO-1 can effectively prevent hippocampal neuron loss and promote AHN. The improvement in cognitive abilities may be attributed to the improvement in AHN, and in the numbers of GABAergic interneurons and CCK-GABAergic interneurons rich in CB1Rs in the hippocampus of AD mice induced by the anti-LINGO-1 antibody. Collectively, the double target effect (LINGO-1 and CB1R) initiated by the anti-LINGO-1 antibody may provide an important basis for the study of drugs for the prevention and treatment of AD in the future., (Copyright © 2021. Published by Elsevier Inc.)

Background: Natural disasters are believed to be associated with cardiovascular disease. This study aimed to explore the changes in mortality due to ischemic heart disease (IHD) and their associations with natural disasters at the global level., Methods: Country-specific data on the impact of natural disasters, rates of mortality due to IHD and years of life lost (YLL) and socioeconomic variables were obtained for 193 countries for the period from 1990 to 2017. An ecological trend study was conducted to estimate the changes in the IHD mortality and YLL rates and their associations with natural disasters (occurrence, casualties and total damage). Correlation analyses and multivariate linear regression were used., Results: Significant changes were found in the IHD mortality and YLL rates and the occurrence of disasters between the two equal periods (1990 to 2003 and 2004 to 2017) (p<0.001). The bivariate Pearson correlation test revealed that the trend in the occurrence of natural disasters was positively correlated with trends in the IHD mortality and YLL rates among females and all individuals (p<0.05) and was marginally correlated among males. Multiple linear regression revealed an independent association between the occurrence of natural disasters and the IHD mortality rate among males, females and all individuals (standardized coefficients = 0.163, 0.357 and 0.241, p<0.05), and similar associations were found for the YLL rate (standardized coefficients = 0.194, 0.233 and 0.189, p<0.05)., Conclusions: Our study demonstrated significant changes in the IHD mortality and YLL rates at the global level and their independent associations with natural disasters. Both males and females were vulnerable to natural disasters. These results provide evidence that can be used to support policy making and resource allocation when responding to disasters and developing strategies to reduce the burden of IHD., Competing Interests: The authors have declared that no competing interests exist.

Background: In non-pregnant adults, the incidence of invasive Group B Streptococcus (GBS) disease is continuously increasing. Elderly and immunocompromised persons are at increased risk of infection. GBS commonly colonizes the vaginal tract, though data on colonization in the elderly are scarce. It is unknown whether the prevalence of GBS colonization is increasing in parallel to the observed rise of invasive infection. We conducted a three-year (2017-2019) prospective observational cross-sectional study in two teaching hospitals in Switzerland to determine the rate of GBS vaginal colonization in women over 60 years and i) to compare the proportions of known risk factors associated with invasive GBS diseases in colonized versus non-colonized women and ii) to evaluate the presence of GBS clusters with specific phenotypic and genotypic patterns in this population., Methods: GBS screening was performed by using vaginal swabs collected during routine examination from women willing to participate in the study and to complete a questionnaire for risk factors. Isolates were characterized for antibiotic resistance profile, serotype and sequence type (ST)., Results: The GBS positivity rate in the elderly was 17% (44/255 positive samples), and similar to the one previously reported in pregnant women (around 20%). We could not find any association between participants' characteristics, previously published risk factors and GBS colonization. All strains were susceptible to penicillin, 22% (8/36) were not susceptible to erythromycin, 14% (5/36) were not susceptible to clindamycin and 8% (3/36) showed inducible clindamycin resistance. Both M and L phenotypes were each detected in one isolate. The most prevalent serotypes were III (33%, 12/36) and V (31%, 11/36). ST1 and ST19 accounted for 11% of isolates each (4/36); ST175 for 8% (3/36); and ST23, ST249 and ST297 for 6% each (2/36). Significantly higher rates of resistance to macrolides and clindamycin were associated with the ST1 genetic background of ST1., Conclusions: Our findings indicate a similar colonization rate for pregnant and elderly women., Trial Registration: Current Controlled Trial ISRCTN15468519 ; 06/01/2017.

We report on the development of a high-resolution and highly efficient beamline for soft X-ray resonant inelastic X-ray scattering (RIXS) located at the Taiwan Photon Source. This beamline adopts an optical design that uses an active grating monochromator (AGM) and an active grating spectrometer (AGS) to implement the energy compensation principle of grating dispersion. Active gratings are utilized to diminish defocus, coma and higher-order aberrations, as well as to decrease the slope errors caused by thermal deformation and optical polishing. The AGS is mounted on a rotatable granite platform to enable momentum-resolved RIXS measurements with scattering angles over a wide range. Several high-precision instruments developed in-house for this beamline are described briefly. The best energy resolution obtained from this AGM-AGS beamline was 12.4 meV at 530 eV, achieving a resolving power of 4.2 × 10 4 , while the bandwidth of the incident soft X-rays was kept at 0.5 eV. To demonstrate the scientific impact of high-resolution RIXS, we present an example of momentum-resolved RIXS measurements on a high-temperature superconducting cuprate, i.e. La 2-x Sr x CuO 4 . The measurements reveal the A 1g buckling phonons in superconducting cuprates, opening a new opportunity to investigate the coupling between these phonons and charge-density waves., (open access.)

Several studies suggest that organochlorine exposure can affect male reproductive functions, causing poor semen quality, endocrine disruption, or dysregulation of thyroid hormones. This study uses multiple linear regression (MLR) models to analyze the correlation between male reproductive functions and polychlorinated biphenyl (PCBs) congeners or p,p'-DDE levels in serum, semen, and indoor dust samples. Multiple comparisons were all adjusted using the false discovery rate (FDR). The results revealed that the PCB congener levels in seminal plasma were significantly associated with the quality parameters of human semen (i.e., sperm count, morphology, and motility) and thyroid hormones after adjusting for covariates, e.g., associations of the sperm concentration with levels of CB105 (β = -0.323, 95% CI: -0.561, -0.085, p = 0.009), CB44 (β = 0.585, 95% CI: 0.290, 0.880, p < 0.001), and CB66 (β = -0.435, 95% CI: -0.728, -0.143, p = 0.004) in the seminal plasma were observed. Correlations between serum pollutants levels and the semen quality, reproductive hormones, or thyroid hormones were also observed. Moreover, our results demonstrate that the quantification of PCBs in seminal plasma can better describe male reproductive disorders than that in serum or dust. Organochlorine exposure measured in serum or dust, especially in seminal plasma, was associated with semen quality, as well as reproductive and thyroid hormones, thus suggesting that the impacts of persistent pollutants on male reproductive health require further investigation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The disinfection efficiencies of two chemical disinfectants, chlorine dioxide and weak acid hypochlorous water (WAHW), were examined in the soiled room and dishwashing room of a hospital infectious disease ward in Taiwan. The investigations were conducted in two seasons, namely winter and summer, in order to examine the correlation between the bioaerosol concentration and the environmental factors. In addition, a single-daily disinfection mode (SM) and a twice-daily disinfection mode (TM) were applied in this study. The results showed that the bacteria and fungi colony counts were strongly correlated with the temperature. Both disinfectants reduced the bacteria and fungi concentrations in the considered rooms. However, of the two disinfectants, the ClO 2 showed a stronger disinfection effect than the WAHW. It means that when using ClO 2 as the disinfectant, the disinfection efficiency of the TM treatment mode is significantly better than that of the SM treatment mode. But, when using WAHW as the disinfectant, no significant difference is found between the disinfection efficiencies of the two methods. Overall, the results showed that the application of ClO 2 twice daily provided the most effective means of satisfying the Taiwan EPA guidelines for the indoor air quality of hospital medical wards., (© Springer Nature B.V. 2020.)

Mounting evidences indicate that autophagy is an essential homeostatic mechanism to maintain the global cardiac structure function. Sophocarpine (SOP), a major bioactive compound derived from the natural plant Sophora flavescens . However, the role of SOP in cardiac hypertrophy remain to be fully elucidated. In the present study, we tested the hypothesis that SOP protects against Ang II-induced cardiac hypertrophy by mediating the regulation of autophagy. The results demonstrated that SOP attenuated the Ang II-induced cardiac hypertrophy, as assessed by measurements of echocardiography parameters, the ratios of heart weight/body weight and left ventricle weight/body weight, histopathological staining, cross-sectional cardiomyocyte area, and the expression levels of cardiac hypertrophic markers. The anti-hypertrophic effect of SOP was mediated by activating autophagy-related pathway, as revealed by reversal of the increased autophagy marker protein expression. These findings reveal a novel mechanism of SOP attenuating cardiac hypertrophy via activating autophagy-related signaling pathways.

Myocardial fibrosis (MFs) is a crucial pathological process that results in cardiac failure in the development of multiple cardiovascular diseases. Puerarin could reportedly be used to treat a variety of cardiovascular diseases. However, the exact mechanism of puerarin on MFs was not clear enough. The separated primary cardiac fibroblasts (CFs) were induced by lipopolysaccharide (LPS) and treated with puerarin. The levels of TNF-α, IL-6, HMGB1, PARP-1, α-SMA, collagen-1, collagen-3, NF-κB pathways were examined by ELISA, immunofluorescence, RT-qPCR, western blot and immunohistochemistry assays. In addition, MFs rats' model was established using transverse aortic constriction (TAC), and the degree of fibrosis was certified by masson staining. We successfully separated primary CFs, and certified that LPS induction could upregulate the levels of PARP-1, HMGB1, inflammatory cytokines and fibrosis-related proteins (α-SMA, collagen-1 and collagen-3). In addition, we proved that puerarin could weaken MFs, and PARP-1 and HMGB1 expressions, which were induced by LPS in primary CFs. In terms of mechanism, HMGB1 expression could be promoted by PARP-1, and PARP-1 could attenuate the therapeutic effect of puerarin on LPS-induced MFs. Besides, PARP-1-HMGB1-NF-κB pathway was related to the protective effect of puerarin on MFs. In vivo, we also verified the protective efficacy of puerarin on MFs induced by TAC, and puerarin also regulated HMGB1-mediated TLR4-NF-κB signaling pathway. We demonstrated that puerarin could ameliorate MFs by downregulating PARP-1 to inhibit HMGB1-mediated TLR4-NF-κB signaling pathway in LPS-induced primary CFs and TAC-induced MFs rats' model.

Cardiovascular diseases are recognized to be a major cause of people morbidity and mortality. A host of stress signals contribute to the pathogenesis of cardiovascular disorders. Deficiency of hydrogen sulfide (H 2 S) or nitric oxide (NO) coordinately plays essential roles in the development of cardiovascular diseases. Recent studies have shown that interaction between the two gaseostransmitters, H 2 S and NO, may give rise to nitroxyl (HNO), one-electron-reduced product of NO. HNO is found to exhibit a variety of biological and pharmacological properties including positive inotropy and cardiovascular protective effects, etc. In this review, recent progresses regarding HNO generation, detection, biochemical and pharmacological functions are discussed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

T cell exhaustion is an obstacle to immunotherapy for solid tumors. An understanding of the mechanism by which T cells develop this phenotype in solid tumors is needed. Here, hypoxia, a feature of the tumor microenvironment, causes T cell exhaustion (T Exh ) by inducing a mitochondrial defect. Upon exposure to hypoxia, activated T cells with a T Exh phenotype are characterized by mitochondrial fragmentation, decreased ATP production, and decreased mitochondrial oxidative phosphorylation activity. The T Exh phenotype is correlated with the downregulation of the mitochondrial fusion protein mitofusin 1 (MFN1) and upregulation of miR-24. Overexpression of miR-24 alters the transcription of many metabolism-related genes including its target genes MYC and fibroblast growth factor 11 ( FGF11 ). Downregulation of MYC and FGF11 induces T Exh differentiation, reduced ATP production and a loss of the mitochondrial mass in T cell receptor (TCR)-stimulated T cells. In addition, we determined that MYC regulates the transcription of FGF11 and MFN1 . In nasopharyngeal carcinoma (NPC) tissues, the T cells exhibit an increased frequency of exhaustion and loss of mitochondrial mass. In addition, inhibition of miR-24 signaling decreases NPC xenograft growth in nude mice. Our findings reveal a mechanism for T cell exhaustion in the tumor environment and provide potential strategies that target mitochondrial metabolism for cancer immunotherapy., (Copyright © 2020 Liu, Yang, Huang, Ni, Zhang, Zhang, He, Gu, Chen, Mai, Chen, Zhang, Gao and Li.)