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Mesoscale eddies help regulate ocean energy cascades. Eddies deformation influences barotropic instability, which represents kinetic energy transfer between scales; however, the barotropic instability structure has not been well studied. We investigated an intra‐thermocline eddy (ITE) and developed a novel anisotropic method to examine the horizontal barotropic instability. The development of the ITE was monitored using a state‐of‐the‐art autonomous underwater vehicle from May to July. The ITE became trapped in June and moved eastward in July. Based on anisotropic theory, the barotropic instability was separated into isotropic and anisotropic productions. The anisotropy contained information regarding shape and mean flow feedback of the eddy. Barotropic instability was the main source for ITE eastward propagation and was dominated by anisotropic production. Following a shape and anisotropy change, the ITE gained the mean‐flow kinetic energy by the anisotropy shear production in June and by the anisotropy stretch production when moving eastward in July. Plain Language Summary: Mesoscale eddies play vital roles in ocean circulation and are important in energy cascades between large‐scale ocean circulation and dissipate scales. The barotropic instability could induce kinetic energy transition between scales, however, the underlying mechanism has not been well studied. We developed a novel method to decompose the horizontal barotropic instability into isotropic production and anisotropic production. The development of a mesoscale eddy was monitored continuously using a state‐of‐the‐art autonomous underwater vehicle. This mesoscale eddy became stationary in June and began to move eastward in July. In the observation case, the barotropic instability mainly controlled the eddy kinetic energy budget and is dominated by anisotropic production, indicating the contribution of the mean‐flow strain. We found that, the mesoscale eddy gained the mean‐flow kinetic energy via the anisotropy shear production when it was stationary, while via anisotropy stretch production when it moved eastward. Key Points: For 3 months, a state‐of‐the‐art AUV monitored the development of an intra‐thermocline eddy (ITE) in terms of vertical transectsNovel anisotropy analysis was developed and revealed interactions between eddy anisotropy and mean‐flow strain in barotropic instabilityThe anisotropic partitioning of the ITE at different stages helped gain kinetic energy from the mean flow [ABSTRACT FROM AUTHOR]

Porous magnesium alloy foams have gained tremendous interest from scientists because of their super lightweight, unique mechanical and physical properties. Despite numerous studies suggesting these advanced materials for structural and functional applications, their manufacturing processes remain poorly understood. In this paper, the porous Mg‐9 wt. %Al‐1 wt. % Zn alloy foam was prepared through the reactive sintering principle (i. e. the element metal powder reaction principle) by using the powder metallurgical method that is combined with a pore‐making agent. The chemical and phase compositions of the cell wall microstructure were investigated by X‐ray diffraction and scanning electron microscope equipped with energy dispersive spectrometer. The compressive properties of the foams were evaluated by quasi‐static compression testing. The results of the analysis reveal that low‐temperature sintering can produce qualitative magnesium alloy foams with good mechanical properties by taking advantage of the intermetallic/or intermediate compounds which are formed in the cell wall through metal elements powder diffusion and reaction. Particularly, the foam samples sintered at 380 °C for 12 h gave the best compressive properties owing to the alloy intermetallic contents and the relative density of the foams. [ABSTRACT FROM AUTHOR]

Global warming results in high temperature stress (HTS), which presents severe challenges worldwide for modern agricultural production and will have significant impacts on the yield and quality of crops.Accumulation of photosynthetic products, activity of enzymes involved in sucrose–starch metabolism, phytohormone levels and metabolic profiling using LC‐MS were analysed in the flag leaves and/or developing grains subjected to HTS during the grain‐filling stage of an indica rice.HTS induced significant yield loss and reduced the grain quality, with lower amylose content. HTS reduced photosynthetic product accumulation in flag leaves and reduced starch accumulation in developing grains, compared to growth under normal temperatures. The activity of enzymes related to sucrose–starch metabolism were dis‐regulated in developing grains grown under high temperature (HT). Moreover, phytohormone homeostasis in flag leaves and developing grains was also dramatically disturbed by HT. Metabolic profiling detected many metabolites with remarkably different relative fold abundances at different time points in the developing grain at HT versus normal temperatures, these metabolites were enriched in several HTS response pathways.The change in phytohormone ratio and auxin level might be associated with the reduction in photosynthetic products and their translocation, and ultimately with reduced starch accumulation in the developing grain. The detected metabolites might have different roles in response to the HTS in developing grain at different development stages. These results provide a theoretical reference and basis for future rice production towards higher quality and yield when grown under HTS. [ABSTRACT FROM AUTHOR]

Background and purpose: This study was to investigate the prevalence and cardiovascular risk factors (CRFs) of asymptomatic intracranial atherosclerotic stenosis (aICAS) amongst middle‐aged and older adults living in rural communities in China. Methods: This population‐based study included 2019 subjects (aged ≥40 years, 52.3% women) who were free of stroke and living in rural communities in China. From October 2017 to May 2018, data on demographics, CRFs and health conditions were collected through face‐to‐face interviews, physical examination and laboratory tests. Asymptomatic ICAS was detected through a two‐phase procedure: a screening phase with transcranial Doppler ultrasound, followed by a diagnostic phase with magnetic resonance angiography examination. Multivariable logistic regression models were used to analyse CRFs associated with aICAS. Results: Of the 2019 participants, aICAS was detected in 153 persons. The overall prevalence of aICAS was 7.6%, and the prevalence of moderate‐to‐severe aICAS was 5.0%. The multi‐adjusted odds ratio (95% confidence interval) of aICAS associated with CRFs was 2.40 (1.56–3.69) for hypertension, 1.91 (1.32–2.76) for high hypersensitive C‐reactive protein, 1.68 (1.14–2.49) for diabetes and 1.61 (1.08–2.41) for overweight or obesity. When these four CRFs were aggregated, compared with participants without any of these factors, the multi‐adjusted odds ratios (95% confidence interval) of aICAS for persons concurrently having one, two and three or more of these factors were 1.14 (0.52–2.48), 2.91 (1.42–5.99) and 5.51 (2.64–11.50), respectively (P for linear trend <0.001). Conclusions: Asymptomatic ICAS is common amongst rural‐dwelling middle‐aged and older Chinese people. Hypertension, diabetes, overweight or obesity and high hypersensitive C‐reactive protein, especially when coexisting, are strongly associated with aICAS. [ABSTRACT FROM AUTHOR]

Objective: The identification of post‐traumatic stress disorder (PTSD) among natural disaster survivors is remarkably challenging, and there are no reliable objective signatures that can be used to assist clinical diagnosis and optimize treatment. The current study aimed to establish a neurobiological signature of PTSD from the connectivity of large‐scale brain networks and clarify the brain network mechanisms of PTSD. Methods: We examined fifty‐seven unmedicated survivors with chronic PTSD and 59 matched trauma‐exposed healthy controls (TEHCs) using resting‐state functional magnetic resonance imaging (rs‐fMRI). We extracted the node‐to‐network connectivity and obtained a feature vector with a dimensionality of 864 (108 nodes × 8 networks) to represent each subject's functional connectivity (FC) profile. Multivariate pattern analysis with a relevance vector machine was then used to distinguish PTSD patients from TEHCs. Results: We achieved a promising diagnostic accuracy of 89.2% in distinguishing PTSD patients from TEHCs. The most heavily weighted connections for PTSD classification were among the default mode network (DMN), visual network (VIS), somatomotor network, limbic network, and dorsal attention network (DAN). The strength of the anticorrelation of FC between the ventral medial prefrontal cortex (vMPFC) in DMN and the VIS and DAN was associated with the severity of PTSD. Conclusions: This study achieved relatively high accuracy in classifying PTSD patients vs. TEHCs at the individual level. This performance demonstrates that rs‐fMRI‐derived multivariate classification based on large‐scale brain networks can provide potential signatures both to facilitate clinical diagnosis and to clarify the underlying brain network mechanisms of PTSD caused by natural disasters. [ABSTRACT FROM AUTHOR]

Summary: Virus‐like particles encapsulating HBV‐RNA represent a serum biomarker for assessing viral replication activity in clinical practice. However, baseline levels of serum HBV‐RNA and their associations with viral replicative intermediates and liver disease in phases of chronic hepatitis B remain unknown. In this cross‐sectional study, 102 patients were categorized into immune‐tolerant (IT), HBeAg‐positive immune active (HBeAg+IA), inactive carrier (IC) and HBeAg‐negative immune active (HBeAg‐IA) phases. HBV‐RNA in serum samples and in 66 paired liver biopsies were quantified and correlated with serum ALT levels, histopathological scores and the levels of other viral replicative intermediates. Mean levels of serum HBV‐RNA differed among phases, with the highest levels among IT (6.78 ± 0.83 log10 copies mL−1) patients, followed by HBeAg+IA (5.73 ± 1.16 log10 copies mL−1), HBeAg‐IA (4.52 ± 1.25 log10 copies mL−1) and IC (2.96 ± 0.40 log10 copies mL−1) patients. Serum HBV‐RNA levels correlated with HBV DNA in all phases, although correlations with other viral replicative intermediates weakened or disappeared when cases were stratified into phases. Distinct compositions of viral products were found among phases: the ratio of HBsAg to serum HBV‐RNA was highest in IC patients, while the ratio of serum HBV‐RNA to intrahepatic HBV‐RNA and the ratio of intrahepatic HBV‐DNA to intrahepatic HBV‐RNA were significantly higher in IT patients. In conclusion, baseline levels of HBV‐RNA and the composition of viral replicative intermediates differ significantly across the natural course of chronic HBV infection. These findings shed light on the nature of viral replication and pathogenesis of disease among different phases of chronic HBV infection. [ABSTRACT FROM AUTHOR]

Background and purpose: The possible association between carotid stenosis and cognitive impairment in the Chinese population has been rarely investigated. The association between the severity of carotid stenosis and cognitive impairment amongst older Chinese people living in a rural area was assessed. Methods: This cross-sectional study included 1375 participants (age =60 years) from the Confucius Hometown Aging Project in Shandong. In 2010-2011, data were collected through interviews and clinical examinations. Carotid stenosis was assessed using ultrasonography. Cognitive impairment was defined according to the education-specific cutoff scores of the Mini-Mental State Examination. Data were analyzed using multinomial logistic models. Results: The overall prevalence was 7.0% for moderate carotid stenosis, 2.0% for severe stenosis and 6.0% for cognitive impairment. The multi-adjusted odds ratio of cognitive impairment was 1.43 (95% confidence interval 0.63- 3.22) for moderate carotid stenosis and 3.75 (1.24-11.40) for severe carotid stenosis (Ptrend = 0.023). Similar results were obtained in people without a history of cerebrovascular disease. Conclusions: Severe carotid stenosis, even asymptomatic, is associated with cognitive impairment independent of atherosclerotic risk factors and disorders amongst older Chinese people. [ABSTRACT FROM AUTHOR]

Background and purpose White matter hyperintensities ( WMHs) and brain atrophy frequently coexist in older people. However, it is unclear whether the association between these two brain lesions is dependent on the aging process, a vascular mechanism or genetic susceptibility. It was therefore investigated whether the association between load of WMHs and brain atrophy measures is related to age, vascular risk factors ( VRFs) or the APOE-ε4 allele. Methods This population-based study included 492 participants (age ≥60 years, 59.6% women) free of dementia and stroke. Data on demographics, VRFs and APOE genotypes were collected through interviews, clinical examination and laboratory tests. WMHs on magnetic resonance images were assessed using manual visual rating and automatic volumetric segmentation. Hippocampal and ventricular volumes were manually delineated, whereas total gray matter ( GM) volume was measured by automatic segmentation. Data were analyzed with multivariate linear regression models. Results More global WMHs, assessed using either a visual rating scale or a volumetric approach, were significantly associated with lower GM volume and higher ventricular volume; the associations remained significant after adjusting for age, VRFs and the APOE-ε4 allele. In contrast, the association between global WMHs and hippocampal volume was no longer significant after adjusting for age, whereas adjustment for VRFs and APOE-ε4 had no influential effect. Conclusion The association of global WMHs with lower GM volume and higher ventricular volume is independent of age, VRFs and APOE-ε4 allele, suggesting that the process of cerebral microvascular disease and neurodegeneration are associated independently of the normal aging process, vascular mechanisms or genetic susceptibility. [ABSTRACT FROM AUTHOR]

To consider the contribution of snowmelt in flood forecast, this paper presents an integrated model, which combines a rigorous snow model with a distributed run-off model, based on unstructured triangular meshes. Using precipitation, air temperature and wind speed as input data, the integrated model can continuously estimate temporal-spatial variation of both snow depth and amount of snowmelt and subsequently forecast river flow caused by snowmelt. The result of a long-term simulation of past floods showed a good match with observations. It is evinced that consideration of snowmelt in a flood forecast can help avoid incorrect prediction. This includes overestimation in the snow accumulation season and/or underestimation in the snowmelt season caused by using precipitation directly as the input data of the run-off model. A real-time flood forecasting system has been established for the Hii River basin, Japan, by using the model. This system now operates uninterruptedly to make a forecast 6 h ahead, with an interval of 10 min. [ABSTRACT FROM AUTHOR]

Background and purpose: Vascular risk factors (VRFs) are known to cause cerebral microvascular disease, but evidence supporting an effect of VRFs on regional brain atrophy is mixed. We investigate whether an aggregation of VRFs is associated with volume of hippocampus and entorhinal cortex in elderly people living in the community. Methods: This cross-sectional study consists of 523 participants (age ≥60 years, 59.3% women) of the SNAC-K Study in central Stockholm, Sweden, who were free of clinical stroke and cognitive impairment. We collected data on VRFs through interviews, clinical examination and inpatient register system. Hippocampal and entorhinal cortex volume was manually measured on magnetic resonance images. Data were analysed with general linear regression models controlling for demographics and total intracranial volume. Results: In men, high total cholesterol and diabetes were significantly or marginally associated with smaller hippocampus and entorhinal cortex; when current smoking, binge alcohol drinking, high cholesterol and diabetes were aggregated, an increasing number of VRFs were significantly associated with decreasing volume of hippocampus and entorhinal cortex ( P for linear trend <0.01). In women, none of individual VRFs or their aggregation was significantly associated with the volume of these brain regions, except former smoking that was significantly associated with a larger volume of these regions. Conclusions: Aggregation of VRFs is associated with reduced hippocampal and entorhinal cortex volume in apparently healthy elderly men, but not in women. This implies that in men, the medial temporal lobe is vulnerable to cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

In this paper we report a chemical method named coordination reaction method to synthesize ZnO nanowire arreys. ZnO nanowires with the diameter about 80nm were successfully fabricated in the channels of the porous anodic alumina (PAA) template by the above coordination reaction method. The microstructures of ZnO/PAA assembly were characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X-ray diffraction (XRD). The results showed that the ZnO nanowires can be uniformly assembled into the nanochannels of PAA template. The growth mechanism of ZnO nanowires and the conditions of the coordination reaction are discussed. Photoluminescence (PL) measurement shows that the ZnO/PAA assembly system has a blue emission band caused by the various defects of ZnO. (© 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [ABSTRACT FROM AUTHOR]

Background Tumours release angiogenic factors such as vascular endothelium growth factor (VEGF), which induces growth of a capillary network around the tumour. Elevated concentrations of VEGF have been reported in human mammary gland tumours. Methods To evaluate the expression of VEGF-C mRNA in canine mammary tissue, 38 mammary gland tumours (including 15 benign and 23 malignant mammary tumours), and 4 normal mammary glands were investigated by real-time reverse transcriptase quantitative polymerase chain reaction. Results VEGF-C expression in the malignant mammary tumours was much higher than in the benign mammary tumours or normal mammary tissue (P < 0.001). The expression of VEGF-C in tumours with lymph node metastasis was much higher than in those without (P < 0.01). Conclusion The level of expression of VEGF-C did not correlate with tumour size or the patient's age, but was significantly higher in malignant mammary tumours and related to lymph node metastasis, making it a candidate marker for predicting metastasis of canine mammary cancer. [ABSTRACT FROM AUTHOR]

A novel construction of microwave switchable lowpass filter based on electromagnetic bandgap (EBG) and cadmium sulfide (CdS) thin film is proposed. Linearly tapered slot-array EBG structure is well known for its exceptional stopband ability and compact physical size. When the illumination-sensitive CdS thin film is deposited on the perforations of the EBG structure, the stopband phenomenon induced by tapered slot-array can be controlled by optical means. Innovative “conductive islands” were introduced to reside in the center of each perforation in order to enhance the optical switching. It has been demonstrated in both simulation and experimental measurement that the transmission coefficient is switched from 31.3 to 5.6 dB at 13 GHz when the gap width between the conductive island and the perforation is 30 μm. As the gap width decreases, the insertion loss can be reduced. Simulation result indicates that the insertion loss can be improved to around 1 dB at 13 GHz when the gap width is decreased to 5 μm. © 2007 Wiley Periodicals, Inc. Microwave Opt Technol Lett 49: 2238–2242, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.22665 [ABSTRACT FROM AUTHOR]

A new design of wideband microwave bandpass filter based on intercoupled split-ring resonator is proposed. The split-ring resonator structure is well-know for its unique resonance feature that exhibit a negative permeability. By implementing the split-ring resonator directly on a microstrip transmission line, a bandpass filter with a large fractional bandwidth has been achieved. The novel periodic intercoupled split-ring resonator bandpass filter is compatible with microwave planar technology and the passband region is controllable. The filter design has been validated and demonstrated in both simulations and experimental measurements. A bandpass filter with a fractional bandwidth of 50% at a center frequency of 14 GHz was achieved with a maximum insertion loss of 0.75 dB in the passband region. Meanwhile, the fractional bandwidth has been demonstrated to be controllable and this was reduced to 37% by sacrificing the periodicity of the intercoupled split-ring resonator structure. Therefore, the flexible characteristics and the simple implementation method may render the proposed filter to be very useful in many frequency-selective and oscillation-suppression applications. © 2007 Wiley Periodicals, Inc. Microwave Opt Technol Lett 49: 1809–1813, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.22588 [ABSTRACT FROM AUTHOR]

Electromagnetic bandgap structures are well known for their stopband features and can be applied at microwave frequencies. In this work, a wide stopband electromagnetic band-gap (EBG) structure design based on 2D tapered slot array is presented. Each tapered slot length is designed to provide stopband at a specific frequency to maximize the attenuation level. The tapered slot array is positioned in the ground plane of a microstrip transmission line structure. Thus, the overall 9-slot nonlinearly tapered array produces a wide stopband from 9.3 to 20 GHz with attenuation better than 25 dB, which is observed in both simulation and actual measurements. The nonlinearly tapered EBG structure can be applied as an efficient lowpass filter. © 2006 Wiley Periodicals, Inc. Microwave Opt Technol Lett 49: 31–34, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.22038 [ABSTRACT FROM AUTHOR]

This open-label, randomized, crossover study was conducted to demonstrate bioequivalence for telithromycin administered as crushed or whole tablets. Single 800-mg telithromycin doses (2x400-mg tablets) were administered as crushed tablets mixed in 240 mL nutritional supplement drink followed by 120 mL water or as whole tablets swallowed with 240 mL water. Plasma telithromycin concentrations were measured by liquid chromatography/mass spectrometry; pharmacokinetic parameters were determined using noncompartmental methods. Average bioequivalence criteria were applied. Thirty-two subjects received telithromycin by both methods. The 90% confidence intervals for the geometric mean ratios of maximum plasma concentration and area under the plasma concentration-time curve to 24 hours were within the 0.80 to 1.25 range. Median tmax was 3.00 hours for both treatments. Both methods of administration were well tolerated. Crushing telithromycin tablets and administering them with a nutritional supplement drink is bioequivalent to ingesting whole tablets and could be a viable method of administration for patients unable to swallow tablets whole. [ABSTRACT FROM AUTHOR]

Photonic band-gap (PBG) structures are utilized in microwave components as filters to suppress unwanted signals. In this work, rectangular perforations were created in the ground plane of a microstrip line to construct a PBG structure. A gold-coated alumina substrate was utilized to switch or tune the bandstop characteristics of this structure. It was demonstrated that the bandstop characteristics were switched off from -35 to -1 dB at 16 GHz. Tuning of the bandstop edge with a shift of 1.5 GHz was also shown. © 2004 Wiley Periodicals, Inc. Microwave Opt Technol Lett 43: 334–337, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.20462 [ABSTRACT FROM AUTHOR]

The analysis of the APTL has been completed by using a new, general recurrence matrix technique based on the method of lines. This new technique has laid the foundations for the analysis of the new type of planar structures. Numerical results for three complicated structures show that the developed CA D software is accurate, practical. and general. [ABSTRACT FROM AUTHOR]

Presents a response by the authors to the comments on their article "The Recurrence Matrix Technique for the Arbitrary Millimeter-Wave and Microvawe Planar Transmission Lines," in the November 1991 issue. Overview of the article; Conclusion of the article.

Seven novel MhcMamu-DQB1 alleles were observed in a population of rhesus macaques of Chinese origin. [ABSTRACT FROM AUTHOR]

Chronic infections, including Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), can induce host immune exhaustion. However, the key checkpoint molecules involved in this process and the underlying regulatory mechanisms remain largely undefined, which impede the application of checkpoint-based immunotherapy in infectious diseases. Here, through adopting time-of-flight mass cytometry and transcriptional profiling to systematically analyze natural killer (NK) cell surface receptors, we identify leukocyte immunoglobulin like receptor B1 (LILRB1) as a critical checkpoint receptor that defines a TB-associated cell subset (LILRB1 + NK cells) and drives NK cell exhaustion in TB. Mechanistically, Mtb-infected macrophages display high expression of human leukocyte antigen-G (HLA-G), which upregulates and activates LILRB1 on NK cells to impair their functions by inhibiting mitogen-activated protein kinase (MAPK) signaling via tyrosine phosphatases SHP1/2. Furthermore, LILRB1 blockade restores NK cell-dependent anti-Mtb immunity in immuno-humanized mice. Thus, LILRB1-HLA-G axis constitutes a NK cell immune checkpoint in TB and serves as a promising immunotherapy target., (© 2024. The Author(s).)

Aims: Parkinson's disease (PD) patients experience improvement in motor symptoms after deep brain stimulation (DBS) and before initiating stimulation. This is called the microlesion effect. However, the mechanism remains unclear. The study aims to comprehensively explore the changes in functional connectivity (FC) patterns in movement-related brain regions in PD patients during the microlesion phase through seed-based FC analysis., Methods: The study collected the resting functional magnetic resonance imaging data of 49 PD patients before and after DBS surgery (off stimulation). The cortical and subcortical areas related to motor function were selected for seed-based FC analysis. Meanwhile, their relationship with the motor scale was investigated., Results: The motor-related brain regions were selected as the seed point, and we observed various FC declines within the motor network brain regions. These declines were primarily in the left middle temporal gyrus, bilateral middle frontal gyrus, right supplementary motor area, left precentral gyrus, left postcentral gyrus, left inferior frontal gyrus, and right superior frontal gyrus after DBS., Conclusion: The movement-related network was extensively reorganized during the microlesion period. The study provided new information on enhancing motor function from the network level post-DBS., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: The study aimed to investigate the change of amyloid precursor protein (APP) processing and amyloid β (Aβ) metabolites in linking periodontitis to Alzheimer's disease (AD)., Background: Aβ is one of the main pathological features of AD, and few studies have discussed changes in its expression in peripheral tissues or analyzed the relationship between the peripheral imbalance of Aβ production and clearance., Methods: A murine model of periodontitis was established by oral infection with Porphyromonas gingivalis (P. gingivalis). Micro-computed tomography (Micro-CT) was used to observe the destruction of the alveolar bone. Nested quantitative polymerase chain reaction (qPCR) was used to measure small quantities of P.gingivalis DNA in different tissues. Behavioral experiments were performed to measure cognitive function in the mice. The mRNA levels of TNF-α, IL-6, IL-8, RANKL, OPG, APP695, APP751, APP770, and BACE1 in the gingival tissues or cortex were detected by RT-PCR. The levels of Aβ1-40 and Aβ1-42 in gingival crevicular fluid (GCF) and plasma were tested by ELISA., Results: P. gingivalis oral infection was found to cause alveolar bone resorption and impaired learning and memory. P.gingivalis DNA was detected in the gingiva, blood and cortex of the P.gingivalis group by nested qPCR (p < .05). The mRNA expression of TNF-α, IL-6, IL-8, RANKL/OPG, and BACE1 in the gingival tissue was significantly higher than that in the control group (p < .05). Similarly, upregulated mRNA levels of APP695 and APP770 were observed in the gingival tissuses and cortex of the P. gingivalis group (p < .05). The levels of Aβ1-40 and Aβ1-42 in the GCF and plasma of the P. gingivalis group were significantly higher than those in the control group (p < .05)., Conclusion: P. gingivalis can directly invade the brain via hematogenous infection. The invasion of P. gingivalis could trigger an immune response and lead to an imbalance between Aβ production and clearance in peripheral tissues, which may trigger an abnormal Aβ metabolite in the brain, resulting in the occurrence and development of AD., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery require subsequent programming, which is complex and cumbersome. The local field potential (LFP) in the deep brain is associated with motor symptom improvement. The current study aimed to identify LFP biomarkers correlated with improved motor symptoms in PD patients after DBS and verify their guiding role in postoperative programming., Methods: Initially, the study included 36 PD patients undergoing DBS surgery. Temporary external electrical stimulation was performed during electrode implantation, and LFP signals around the electrode contacts were collected before and after stimulation. The stimulating contact at 6 months of programming was regarded as the optimal and effective stimulating contact. The LFP signal of this contact during surgery was analyzed to identify potential LFP biomarkers. Next, we randomly assigned another 30 PD patients who had undergone DBS to physician empirical programming and LFP biomarker-guided programming groups and compared the outcomes., Results: In the first part of the study, LFP signals of electrode contacts changed after electrical stimulation. Electrical stimulation reduced gamma energy and the beta/alpha oscillation ratio. The different programming method groups were compared, indicating the superiority of beta/alpha oscillations ratio-guided programming over physician experience programming for patients' improvement rate (IR) of UPDRS-III. There were no significant differences in the IR of UPDRS-III, post-LED, IR-PDQ39, number of programmings, and the contact change rate between the gamma oscillations-guided programming and empirical programming groups., Conclusion: Overall, the findings reveal that gamma oscillations and the beta/alpha oscillations ratio are potential biomarkers for programming in PD patients after DBS. Instead of relying solely on spike action potential signals from single neurons, LFP biomarkers can provide the appropriate depth for electrode placement., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Predicting Parkinson's disease (PD) can provide patients with targeted therapies. However, disease severity can be roughly evaluated in clinical practice based on the patient's symptoms and signs., Objective: The current study attempted to explore the factors linked with PD severity and construct a predictive model., Method: The PD patients and healthy controls were recruited from our study center while recording their basic demographic information. The serum inflammatory markers levels, such as Cystatin C (Cys C), C-reactive protein (CRP), RANTES (regulated on activation, normal T cell expressed and secreted), Interleukin-10 (IL-10), and Interleukin-6 (IL-6) were determined for all the participants. PD patients were categorized into early and mid-advanced groups based on the Hoehn and Yahr (H-Y) scale and evaluated using PD-related scales. LASSO logistic regression analysis (Model C) helped select variables based on clinical scale evaluations, serum inflammatory factor levels, and transcranial sonography measurements. The optimal harmonious model coefficient λ was determined via 10-fold cross-validation. Moreover, Model C was compared with multivariate (Model A) and stepwise (Model B) logistic regression. The area under the curve (AUC) of a receiver operator characteristic (ROC), brier score, calibration curve, and decision curve analysis (DCA) helped determine the discrimination and calibration of the predictive model, followed by configuring a forest plot and column chart., Results: The study included 113 healthy individuals and 102 PD patients, with 26 early and 76 mid-advanced patients. Univariate analysis of variance screened out statistically significant differences among inflammatory markers Cys C and RANTES. The average Cys C level in the mid-advanced stage was significantly higher than in the early stage (p < 0.001) but not for RANTES (p = 0.740). The LASSO logistic regression model (λ.1se = 0.061) associated with UPDRS-I, UPDRS-II, UPDRS-III, HAMA, PDQ-39, and Cys C as the included independent variables revealed that the Model C discrimination and calibration (AUC = 0.968, Brier = 0.049) were superior to Model A (AUC = 0.926, Brier = 0.079) and Model B (AUC = 0.929, Brier = 0.071) models., Conclusion: The study results show multiple factors are linked with PD assessment. Moreover, the inflammatory marker Cys C and transcranial sonography measurement could objectively predict PD symptom severity, helping doctors monitor PD evolution in patients while targeting interventions., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Cingulin (CGN) is a cytoskeleton-associated protein localized at the apical junctions of epithelial cells. CGN interacts with major cytoskeletal filaments and regulates RhoA activity. However, physiological roles of CGN in development and human diseases are currently unknown. Here, we report a multi-generation family presenting with autosomal dominant non-syndromic hearing loss (ADNSHL) that co-segregates with a CGN heterozygous truncating variant, c.3330delG (p.Leu1110Leufs*17). CGN is normally expressed at the apical cell junctions of the organ of Corti, with enriched localization at hair cell cuticular plates and circumferential belts. In mice, the putative disease-causing mutation results in reduced expression and abnormal subcellular localization of the CGN protein, abolishes its actin polymerization activity, and impairs the normal morphology of hair cell cuticular plates and hair bundles. Hair cell-specific Cgn knockout leads to high-frequency hearing loss. Importantly, Cgn mutation knockin mice display noise-sensitive, progressive hearing loss and outer hair cell degeneration. In summary, we identify CGN c.3330delG as a pathogenic variant for ADNSHL and reveal essential roles of CGN in the maintenance of cochlear hair cell structures and auditory function., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Aims: Protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F) is a serine/threonine phosphatase, and its dysfunction in depression in the hippocampal dentate gyrus has been previously identified. Nevertheless, its role in depression of another critical emotion-controlling brain region, the medial prefrontal cortex (mPFC), remains unclear. We explored the functional relevance of PPM1F in the pathogenesis of depression., Methods: The gene expression levels and colocalization of PPM1F in the mPFC of depressed mice were measured by real-time PCR, western blot and immunohistochemistry. An adeno-associated virus strategy was applied to determine the impact of knockdown or overexpression of PPM1F in the excitatory neurons on depression-related behaviors under basal and stress conditions in both male and female mice. The neuronal excitability, expression of p300 and AMPK phosphorylation levels in the mPFC after knockdown of PPM1F were measured by electrophysiological recordings, real-time PCR and western blot. The depression-related behavior induced by PPM1F knockdown after AMPKα2 knockout or the antidepressant activity of PPM1F overexpression after inhibiting acetylation activity of p300 was evaluated., Results: Our results indicate that the expression levels of PPM1F were largely decreased in the mPFC of mice exposed to chronic unpredictable stress (CUS). Behavioral alterations relevant to depression emerged with short hairpin RNA (shRNA)-mediated genetic knockdown of PPM1F in the mPFC, while overexpression of PPM1F produced antidepressant activity and ameliorated behavioral responses to stress in CUS-exposed mice. Molecularly, PPM1F knockdown decreased the excitability of pyramidal neurons in the mPFC, and restoring this low excitability decreased the depression-related behaviors induced by PPM1F knockdown. PPM1F knockdown reduced the expression of CREB-binding protein (CBP)/E1A-associated protein (p300), a histone acetyltransferase (HAT), and induced hyperphosphorylation of AMPK, resulting in microglial activation and upregulation of proinflammatory cytokines. Conditional knockout of AMPK revealed an antidepressant phenotype, which can also block depression-related behaviors induced by PPM1F knockdown. Furthermore, inhibiting the acetylase activity of p300 abolished the beneficial effects of PPM1F elevation on CUS-induced depressive behaviors., Conclusion: Our findings demonstrate that PPM1F in the mPFC modulates depression-related behavioral responses by regulating the function of p300 via the AMPK signaling pathway., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: In Parkinson's disease (PD), inflammation may lead to the degeneration of dopaminergic (DAergic) neurons. Previous studies showed that inflammatory mediators mainly contributed to this phenomenon. On the other hand, invasive neuromodulation methods such as deep brain stimulation (DBS) have better therapeutic effects for PD. One possibility is that DBS improves PD by influencing inflammation. Therefore, we further explored the mechanisms underlying inflammatory mediators and DBS in the pathogenesis of PD., Methods: We measured serum levels of two inflammatory markers, namely RANTES (regulated on activation, normal T cell expressed and secreted) and tumor necrosis factor-alpha (TNF-α), using Luminex assays in 109 preoperative DBS PD patients, 49 postoperative DBS PD patients, and 113 age- and sex-matched controls. The plasma protein data of the different groups were then statistically analyzed., Results: RANTES (p < 0.001) and TNF-α (p = 0.005) levels differed significantly between the three groups. A strong and significant correlation between RANTES levels and Hoehn-Yahr (H-Y) stage was observed in preoperative PD patients (r s  = 0.567, p < 0.001). Significant correlations between RANTES levels and Unified Parkinson's Disease Rating Scale III (UPDRS III) score (r s1  = 0.644, p = 0.033 and r s2  = 0.620, p = 0.042) were observed in matched patients. No correlation was observed for TNF-α levels., Conclusion: The results of this study indicate that PD patients have a persistent inflammatory profile, possibly via recruitment of activated monocytes, macrophages, and T lymphocytes to the central nervous system (CNS). DBS was shown to have a significant therapeutic effect on PD, which may arise by improving the inflammatory environment of the central nervous system., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Sepsis-induced cardiomyopathy is a decisive factor that plays a critical role in the high mortality of septic patients in the critically ill. Mitochondrial dysfunction occurring during sepsis is a vital contributor to the pathogenesis of myocardial damage. Rosmarinic acid (RA), a natural poly-phenolic compound, has showed cardio-protective and mitochondrial protective effect. The present study was aimed to investigate the effect of RA on sepsis-induced cardiomyopathy. Adult mice were subjected to intraperitoneal injection of saline (control) or lipopolysaccharide (LPS, 5 mg/kg) to mimic sepsis-induced cardiomyopathy. Immediately after LPS challenge, vehicle or RA (100 mg/kg/day) was administrated via gavage. Cardiac function was examined with echocardiographic analyses 12 hours after LPS challenge and cumulative survival of mice was recorded for 8 days. Heart tissues were harvested 12 hours after LPS challenge to perform histological analyses and determine mitochondrial function. We found RA significantly improved cardiac function and survival of LPS-injected mice. Histologically, RA attenuated LPS-mediated cardiomyocyte damage, indicated by decreased cardiomyocyte apoptosis and improved myocardial swollen and disarrangement. Moreover, RA attenuated LPS-mediated myocardial mitochondrial dysfunction, indicated by improved mitochondrial ultrastructure, increased mitochondrial membrane potential (MMP), synthesis of adenosine triphosphate (ATP), markedly decreased reactive oxygen species (ROS) level and alleviated oxidative stress in heart tissues. RA treatment downregulated protein expression of Sirt1 and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and Sirt1 inhibition blocked protective effect of RA on LPS-induced myocardial damage and mitochondrial dysfunction. Collectively, RA attenuates LPS-induced cardiac dysfunction via activating Sirt1/PGC-1α pathway to alleviate mitochondrial impairment. It may be a promising cardio-protective drug to be used for septic patients., (© 2022 John Wiley & Sons Australia, Ltd.)

The breakdown of the blood-brain barrier, which develops early in Alzheimer's disease (AD), contributes to cognitive impairment. Exercise not only reduces the risk factors for AD but also confers direct protection against cognitive decline. However, the exact molecular mechanisms remain elusive, particularly whether exercise can liberate the function of the blood-brain barrier. Here, we demonstrate that long-term exercise promotes the clearance of brain amyloid-β by improving the function of the blood-brain barrier in 5XFAD mice. Significantly, treating primary brain pericytes or endothelial cells with exosomes isolated from the brain of exercised 5XFAD mice improves cell proliferation and upregulates PDGFRβ, ZO-1, and claudin-5. Moreover, exosomes isolated from exercised mice exhibit significant changes in miR-532-5p. Administration or transfection of miR-532-5p to sedentary mice or primary brain pericytes and endothelial cells reproduces the improvement of blood-brain barrier function. Exosomal miR-532-5p targets EPHA4, and accordingly, expression of EphA4 is decreased in exercised mice and miR-532-5p overexpressed mice. A specific siRNA targeting EPHA4 recapitulates the effects on blood-brain barrier-associated cells observed in exercised 5XFAD mice. Overall, our findings suggest that exosomes released by the brain contain a specific miRNA that is altered by exercise and has an impact on blood-brain barrier function in AD., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

As the main loading-bearing tissue of eye, sclera exerts an important role in the pathophysiology of glaucoma. Intraocular pressure (IOP) generates mechanical strain on sclera. Recent studies have demonstrated that sclera, especially the peripapillary sclera, undergoes complicated remodelling under the mechanical strain. However, the mechanisms of the hypertensive scleral remodelling in human eyes remained uncertain. In this study, peripapillary human scleral fibroblasts (ppHSFs) were applied cyclic mechanical strain by Flexcell-5000™ tension system. We found that CXC- ligands and CXCR2 were differentially expressed after strain. Increased cell proliferation and inhibited cell motility were observed when CXCR2 was upregulated under the strain, whereas cell proliferation and motility did not have a significant change when CXCR2 was knocked down. CXCR2 could facilitate cell proliferation ability, modulate the mRNA and protein expressions of type I collagen and matrix metalloproteinase 2 via JAK1/2-STAT3 signalling pathway. In addition, CXCR2 might inhibit cell migration via FAK/MLC 2 pathway. Taken together, CXCR2 regulated protein production and affected cell behaviours of ppHSFs. It might be a potential therapeutic target for the hypertensive scleral remodelling., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The direct binding of human plasminogen (hPg), via its kringle-2 domain (K2 hPg ), to streptococcal M-protein (PAM), largely contributes to the pathogenesis of Pattern D Group A Streptococcus pyogenes (GAS). However, the mechanism of complex formation is unknown. In a system consisting of a Class II PAM from Pattern D GAS isolate NS88.2 (PAM NS88.2 ), with one K2 hPg binding a-repeat in its A-domain, we employed biophysical techniques to analyze the mechanism of the K2 hPg /PAM NS88.2 interaction. We show that apo-PAM NS88.2 is a coiled-coil homodimer (M.Wt. ~80 kDa) at 4°C-25°C, and is monomeric (M.Wt. ~40 kDa) at 37°C, demonstrating a temperature-dependent dissociation of PAM NS88.2 over a narrow temperature range. PAM NS88.2 displayed a single tight binding site for K2 hPg at 4°C, which progressively increased at 25°C through 37°C. We isolated the K2 hPg /PAM NS88.2 complexes at 4°C, 25°C, and 37°C and found molecular weights of ~50 kDa at each temperature, corresponding to a 1:1 (m:m) K2 hPg /PAM NS88.2  monomer complex. hPg activation experiments by streptokinase demonstrated that the hPg/PAM NS88.2  monomer complexes are fully functional. The data show that PAM dimers dissociate into functional monomers at physiological temperatures or when presented with the active hPg module (K2 hPg ) showing that PAM is a functional monomer at 37°C., (© 2021 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Abdominal aortic aneurysm (AAA) is a vascular disease found to have progressive growth in the area of aorta. Rupturing of aorta causes excessive bleeding that leads to health-related issues, which can be fatal sometimes. Therefore, it becomes important to make early diagnosis of AAA and its condition and start immediate treatment. Blood-based biomarker helps to diagnose AAA and to monitor the condition after AAA surgery. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a hormone produced in the heart in small quantities and increased when the heart needs to work harder. NT-proBNP was proved to be strongly linked with AAA incidence. Moreover, quantifying the level of NT-proBNP helps to determine the risk factors on cardiovascular system after the surgery. This work is quantifying the NT-proBNP on interdigitated electrode sensor by using NT-proBNP binding aptamer. The detection limit of NT-proBNP was calculated as 1 pg/mL on a linear regression curve [y = 0.2148x + 0.8849; R² = 0.9049]. The linear range with dose-dependent analysis was from 0.01 until 100 ng/mL. Moreover, the control experiment with complementary aptamer sequence did not show the current signal, specifying the detection of NT-proBNP. This research benefits to identify the heart condition of patient after the removal of AAA., (© 2020 International Union of Biochemistry and Molecular Biology, Inc.)

A substantial percentage of late-life depression patients also have an cognitive impairment, which severely affects the life quality, while the co-occurring mechanisms are still unclear. Physical exercise can ameliorate both depressive behaviors and cognitive dysfunction, but the molecular mechanisms underlying its beneficial effects remain elusive. In this study, we uncover a novel adipose tissue to hippocampus crosstalk mediated by Adiponectin-Notch pathway, with an impact on hippocampal neurogenesis and cognitive function. Adiponectin, an adipocyte-derived hormone, could activate Notch signaling in the hippocampus through upregulating ADAM10 and Notch1, two key molecules in the Notch signaling. Chronic stress inhibits the Adiponectin-Notch pathway and induces impaired hippocampal neurogenesis and cognitive dysfunction, which can be rescued by AdipoRon and running. Inhibition Notch signaling by DAPT mimics the adverse effects of chronic stress on hippocampal neurogenesis and cognitive function. Adiponectin knockout mice display depressive-like behaviors, associated with inhibited Notch signaling, impaired hippocampal neurogenesis and cognitive dysfunction. Physical exercise could activate Adiponectin-Notch pathway, and improve hippocampal neurogenesis and cognitive function, while deleting adiponectin gene or inhibiting Notch signaling blocks its beneficial effects. Together, our data not only suggest that Adiponectin-Notch pathway is involved in the pathogenesis of cognitive dysfunction associated with depression, but also contributes to the therapeutic effect of physical exercise. This work helps to decipher the etiology of cognitive impairment associated with depression and hence will provide a potential innovative therapeutic target for these patients., (© 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Saccharomyces cerevisiae is the preferred source of RNA derivatives, which are widely used as supplements for foods and pharmaceuticals. As the most abundant RNAs, the ribosomal RNAs (rRNAs) transcribed by RNA polymerase I (Pol I) have no 5' caps, thus cannot be translated to proteins. To screen high-nucleic-acid content yeasts more efficiently, a cap-independent protein expression system mediated by Pol I has been designed and established to monitor the regulatory changes of rRNA synthesis by observing the variation in the reporter genes expression. The elements including Pol I-recognized rDNA promoter, the internal ribosome entry site from cricket paralytic virus which can recruit ribosomes internally, reporter genes (URA3 and yEGFP3), oligo-dT and an rDNA terminator were ligated to a yeast episomal plasmid. This system based on the URA3 gene worked well by observing the growth phenotype and did not require the disruption of cap-dependent initiation factors. The fluorescence intensity of strains expressing the yEGFP3 gene increased and drifted after mutagenesis. Combined with flow cytometry, cells with higher GFP level were sorted out. A strain showed 58% improvement in RNA content and exhibited no sequence alteration in the whole expression cassette introduced. This study provides a novel strategy for breeding high-nucleic-acid content yeasts., (© 2020 The Authors. Microbial Biotechnology published by Society for Applied Microbiology and John Wiley & Sons Ltd.)

Background & Aims: Effectiveness of maternal antiviral prophylaxis in mother-to-child transmission of hepatitis B virus (HBV) has been extensively explored in studies where standard immunoprophylaxis is well secured to the newborns. This real-world study aims to test if maternal antiviral prophylaxis can safeguard the newborn when immunoprophylaxis administration was delayed or missed., Methods: Hepatitis B surface antigen-positive pregnant women were categorized into mothers with HBV DNA levels ≥2 × 10 5 IU/mL receiving nucleos(t)ide analogue during the third trimester; mothers with HBV DNA levels ≥2 × 10 5 IU/mL without antiviral treatment; and those with HBV DNA levels <2 × 10 5 IU/mL without antiviral treatment. The immunoprophylaxis procedure was collected and verified by the delivery medical document and logbook of biological product usage. The primary end point was the rate of chronic HBV infection (CHB) in infants., Results: From 2011 to 2017, 251 mother-child pairs were enrolled. Among 187 infants of mothers with HBV DNA levels ≥2 × 10 5 IU/mL, none developed CHB when mothers received antiviral treatment, as compared to 13.0% (10/77) of infants born to untreated mothers (P < .001). None of the infants of mothers with HBV DNA levels <2 × 10 5 IU/mL were infected. Stratified by the time of immunoprophylaxis administration after birth, maternal antiviral prophylaxis predominately benefited infants who failed to receive immunoprophylaxis within 24 hours (100% [6/6] vs 0% [0/2], P = .036) and those who received delayed immunoprophylaxis between 2 and 24 hours (18.8% [3/16] vs 0% [0/32], P = .032)., Conclusions: Antiviral prophylaxis in high viraemic mothers is effective in contingencies of missed or delayed neonatal immunoprophylaxis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background Evidence suggests that enlarged perivascular spaces (PVSs) may represent a marker for cerebral small-vessel disease. We investigated whether vascular risk factors are correlated with visible PVS in older adults. Methods and Results This population-based study included 530 participants (age ≥60 years) who were free from dementia and functional dependence, derived from the Swedish National study on Aging and Care in Kungsholmen (2001-2003). We collected data on demographics, vascular risk factors, and health conditions through interviews, clinical examinations, laboratory tests, and patient registers. Cerebral PVSs and white matter hyperintensities on magnetic resonance images were visually assessed with semiquantitative visual rating scales. Data were analyzed using the general linear regression models. After controlling for demographics and cardiovascular disease, very high blood pressure (≥160/100 mm Hg) was significantly associated with global PVS score (β-coefficient, 1.30; 95% CI, 0.06-2.53) and orthostatic hypotension was associated with PVS score in the basal ganglia (β-coefficient 0.37; 0.03-0.70), but the associations became non-significant when adjusting for white matter hyperintensity load. Orthostatic hypotension was significantly associated with global and lobar PVS scores in carriers but not in noncarriers of the APOE ε4 allele. Global or regional PVS score was not significantly associated with other traditional vascular risk factors such as smoking, diabetes mellitus, physical inactivity, and overweight or obesity. Conclusions This study provides limited evidence supporting a correlation of magnetic resonance imaging-visible PVS with traditional vascular risk factors in older adults. The association of orthostatic hypotension with lobar PVS among APOE ε4 carriers suggests that lobar PVS may be a marker for amyloid-associated small-vessel disease.

Alpinetin, the main active ingredient in the Chinese medicinal herb Alpinia katsumadai Hayata, has been found to have anticancer activity. However, the therapeutic efficacy of signalling cascades modulated by alpinetin remains unknown. Here, we showed that alpinetin provoked mitochondria-associated apoptosis in a dose-dependent manner in breast cancer cells. Mechanistic investigations revealed that alpinetin dampens hypoxia-inducible factor-1α (HIF-1α) signalling due to a lack of NF-κB activation through reduced mitochondrial reactive oxygen species (ROS) production, decreasing HIF-1α transcription. In vivo, we also found alpinetin led to significant tumour regression by inhibiting NF-κB pathway. Overall, our work uncovers a ROS/NF-κB/HIF-1α axis-dependent mechanism underlying the anticancer effects of alpinetin and suggests that alpinetin could act as a novel therapeutic agent against breast cancer., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

In this study, we investigated the role of a long non-coding RNA GAPLINC in angiogenesis using human umbilical vein endothelial cells (HUVEC). We found that hypoxia and hypoxia-inducible factor 1α (HIF-1α) increased the expression of GAPLINC in HUVEC cells. Moreover, GAPLINC overexpression down-regulated miR-211 and up-regulated Bcl2 protein expression. Further rescue experiments confirmed that hypoxia directly increased GAPLINC expression. GAPLINC overexpression also increased cell migration and vessel formation which promoted angiogenesis, and these changes were attributed to the increased expression of vascular endothelial growth factor receptors (VEGFR) and delta-like canonical notch ligand 4 (DLL4) receptors. Finally, we demonstrated that GAPLINC promotes vessel formation and migration by regulating MAPK and NF-kB signalling pathways. Taken together, these findings comprehensively demonstrate that overexpression of GAPLINC increases HUVEC cells angiogenesis under hypoxia condition suggesting that GAPLINC can be a potential target for critical limb ischaemia (CLI) treatment., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

It is well established that cancer cells depend upon aerobic glycolysis to provide the energy they need to survive and proliferate. However, anti-glycolytic agents have yielded few positive results in human patients, in part due to dose-limiting side effects. Here, we discovered the unexpected anti-cancer efficacy of Polydatin (PD) combined with 2-deoxy-D-glucose (2-DG), which is a compound that inhibits glycolysis. We demonstrated in two breast cell lines (MCF-7 and 4T1) that combination treatment with PD and 2-DG induced cell apoptosis and inhibited cell proliferation, migration and invasion. Furthermore, we determined the mechanism of PD in synergy with 2-DG, which decreased the intracellular reactive oxygen (ROS) levels and suppressed the PI3K/AKT pathway. In addition, the combined treatment inhibited the glycolytic phenotype through reducing the expression of HK2. HK2 deletion in breast cancer cells thus improved the anti-cancer activity of 2-DG. The combination treatment also resulted in significant tumour regression in the absence of significant morphologic changes in the heart, liver or kidney in vivo. In summary, our study demonstrates that PD synergised with 2-DG to enhance its anti-cancer efficacy by inhibiting the ROS/PI3K/AKT/HIF-1α/HK2 signalling axis, providing a potential anti-cancer strategy., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Tumour necrotic factor receptor-2 (TNFR2) has been to be cardiac-protective and is expressed in cardiac progenitor cells. Our goal is to define the mechanism for TNFR2-mediated cardiac stem cell activation and differentiation. By employing a protocol of in vitro cardiac stem cell (CSC) differentiation from human inducible pluripotent stem cell (hiPSC), we show that expression of TNFR2 precedes expression of CSC markers followed by expression of mature cardiomyocyte proteins. Activation of TNFR2 by a specific agonist promotes whereas inhibition of TNFR2 by neutralizing antibody diminishes hiPSC-based CSC differentiation. Interestingly, pluripotent cell factor RNA-binding protein Lin28 enhances TNFR2 protein expression in early CSC activation by directly binding to a conserved Lin28-motif within the 3'UTR of Tnfr2 mRNA. Furthermore, inhibition of Lin28 blunts TNFR2 expression and TNFR2-dependent CSC activation and differentiation. Our study demonstrates a critical role of Lin28-TNFR2 axis in CSC activation and survival, providing a novel strategy to enhance stem cell-based therapy for the ischaemic heart diseases., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: The matrine-type alkaloids are bioactive components extracted from Sophora flavescens , which is used in treatment of diabetes mellitus in traditional Chinese medicine. Advanced glycation end products mediate diabetic vascular complications. This study was aimed to investigate the protective effects and molecular mechanisms of matrine-type alkaloids on advanced glycation end products-induced reactive oxygen species-mediated endothelial apoptosis., Methods and Results: Rats aorta and cultured rat aortic endothelial cells were exposed to advanced glycation end products. Matrine-type alkaloids, p38 mitogen-activated protein kinase (MAPK) inhibitor, and small interference RNAs against p38 MAPK kinases MAPK kinase kinase (MKK)3 and MKK6 were administrated. Intracellular reactive oxygen species production, cell apoptosis, phosphorylation of MKKs/p38 MAPK, and expression levels of heme oxygenase/NADPH quinone oxidoreductase were assessed. The nuclear factor erythroid 2-related factor 2 nuclear translocation and the binding activity of nuclear factor erythroid 2-related factor 2 with antioxidant response element were also evaluated. Matrine-type alkaloids suppressed intracellular reactive oxygen species production and inhibited endothelial cell apoptosis in vivo and in vitro by recovering phosphorylation of MKK3/6 and p38 MAPK, nuclear factor erythroid 2-related factor 2 nuclear translocation, and antioxidant response element binding activity, as well as the expression levels of heme oxygenase/NADPH quinone oxidoreductase. p38 MAPK inhibitor treatment impaired the effects of matrine-type alkaloids in vivo and in vitro. MKK3/6 silencing impaired the effects of matrine-type alkaloids in vitro., Conclusions: Matrine-type alkaloids exert endothelial protective effects against advanced glycation end products induced reactive oxygen species-mediated apoptosis by targeting MKK3/6 and enhancing their phosphorylation., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Staphylococcus aureus (S. aureus) causes severe inflammation in various infectious diseases, leading to high mortality. The clinical application of antibiotics has gained a significant curative effect. However, it has led to the emergence of various resistant bacteria. Therefore, in this study, we investigated the protective effect of polydatin (PD), a traditional Chinese medicine extract, on S. aureus lipoteichoic acid (LTA)-induced injury in vitro and in vivo. First, a significant improvement in the pathological conditions of PD in vivo was observed, suggesting that PD had a certain protective effect on LTA-induced injury in a mouse model. To further explore the underlying mechanisms of this protective effect of PD, LTA-induced murine macrophages were used in this study. The results have shown that PD could reduce the NF-κB p65, and IκBα phosphorylation levels increased by LTA, resulting in a decrease in the transcription of pro-inflammatory factors, such as TNF-α, IL-1β and IL-6. However, LTA can not only activate NF-κB through the recognition of TLR2 but also increase the level of intracellular reactive oxygen species (ROS), thereby activating NF-κB signalling. We also detected high levels of ROS that activate caspases 9 and 3 to induce apoptosis. In addition, using a specific NF-κB inhibitor that could attenuate apoptosis, namely NF-κB p65, acted as a pro-apoptotic transcription factor in LTA-induced murine macrophages. However, PD could inhibit the generation of ROS and NF-κB p65 activation, suggesting that PD suppressed LTA-induced injury by attenuating ROS generation and TLR2-NFκB signalling., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)