The Alzheimer's disease-associated gene TREML2 modulates inflammation by regulating microglia polarization and NLRP3 inflammasome activation

Triggering receptor expressed on myeloid cells-like 2(TREML2)is a newly identified susceptibility gene for Alzheimer's disease(AD).It encodes a microglial inflammation-associated receptor.To date,the potential role of mic roglial TREML2 in neuroinflammation in the context of AD remains unclear.In this study,APP/PS1 mice were used to investigate the dynamic changes of TREML2 levels in brain during AD progression.In addition,lipopolysaccharide(LPS)stimulation of primary microglia as well as a lentivirus-mediated TREML2 overexpression and knockdown were employed to explore the role of TREML2 in neuroinflammation in the context of AD.Our res ults show that TREML2 levels gradually increased in the brains of AP P/PS1 mice during disease progression.LPS stimulation of primary microglia led to the release of inflammato ry cytokines including interleukin-1β,inte rleukin-6,and tumor necrosis factor-a in the culture medium.The LPS-induced mic roglial release of inflammatory cytokines was enhanced by TREML2 overexpression and was attenuated by TREML2 knoc kdown.LPS increased the levels of mic roglial M1-type polarization marker inducible nitric oxide synthase.This effect was enhanced by TREML2 overexpression and ameliorated by TREML2 knockdown.Furthermore,the levels of microglial M2-type polarization markers CD206 and ARG1 in the primary microglia were reduced by TREML2 overexpression and elevated by TREML2 knockdown.LPS stimulation increased the levels of NLRP3 in primary microglia.The LPS-induced increase in NLRP3 was further elevated by TREML2 overexpression and alleviated by TREML2 knockdown.In summary,this study provides the first evidence that TREML2 modulates inflammation by regulating microglial polarization and NLRP3 inflammasome activation.These findings reveal the mechanisms by which TREML2 regulates microglial inflammation and suggest that TREML2 inhibition may represent a novel therapeutic strategy for AD.

Lamotrigine protects against cognitive deficits,synapse and nerve cell damage,and hallmark neuropathologies in a mouse model of Alzheimer’s disease

Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.

Co(OH)_(2)层对负载型Pt纳米晶在催化氨硼烷水解产氢中的提升作用

氨硼烷催化水解脱氢是一种很有前途的产氢和储氢方式.为此,需要开发新型催化剂以降低贵金属的使用量而同时保持其高活性和稳定性.本文利用过渡金属Co(OH)_(2)层来调整Pt基金属催化剂的组成,构建系列不同Pt/Co比的Pt-Co(OH)_(2)/SiO_(2)催化剂,对氨硼烷水解的氢生成速率呈现火山型曲线.当Pt:Co摩尔比为1:11时,催化剂的性能最佳,其转换频率值829 molH_(2)·molpt-1.min-1,优于大多数报道的Pt基催化剂,表观活化能从61.6 kJ/mol降低到31.2 kJ/mol.活性增强的原因在于Pt-Co(OH)_(2)界面上发生从Co(OH)_(2)向Pt的电荷转移,使Pt表面富电子,有利于H_(2)O分子中O-H键的氧化断裂,降低反应能垒,从而显著提高其催化活性和循环稳定性.

A new peptide,VD11,promotes structural and functional recovery after spinal cord injury

The regenerative capacity of the central nervous system is very limited and few effective treatments are currently available for spinal cord injury.It is therefore a priority to develop new drugs that can promote structural and functional recovery after spinal cord injury.Previous studies have shown that peptides can promote substantial repair and regeneration of injured tissue.While amphibians have a pronounced ability to regenerate the spinal cord,few studies have investigated the effect of amphibian spinal cord-derived peptides on spinal cord injury.Here we report for the first time the successful identification and isolation of a new polypeptide,VD11(amino acid sequence:VDELWPPWLPC),from the spinal cord of an endemic Chinese amphibian(Odorrana schmackeri).In vitro experiments showed that VD11 promoted the secretion of nerve growth factor and brain-derived neurotrophic factor in BV2 cells stimulated with lipopolysaccharide,as well as the proliferation and synaptic elongation of PC12 cells subjected to hypoxia.In vivo experiments showed that intravertebral injection of VD11 markedly promoted recovery of motor function in rats with spinal cord injury,alleviated pathological damage,and promoted axonal regeneration.Furthermore,RNA sequencing and western blotting showed that VD11 may affect spinal cord injury through activation of the AMPK and AKT signaling pathways.In summary,we discovered a novel amphibian-derived peptide that promotes structural and functional recovery after spinal cord injury.

High pressure EIGA preparation and 3D printing capability of Ti-6Al-4V powder

Ti-6 Al-4 V alloy powder was processed by electrode induction melting gas atomization(EIGA)at high gas pressure(5.5-7.0 MPa).The effects of atomizing gas pressure on the powder characteristics and the microstructure,along with the mechanical properties of the as-fabricated block by laser melting deposition(LMD),were investigated.The results indicate that the diameters of powders are distributed in a wide range of sizes from 1 to 400μm,and the median powder size(d50)decreases with increasing gas pressure.The powders with a size fraction of 100-150μm obtained at gas pressures of 6.0 and 6.5 MPa have better flowability.The oxygen content is consistent with the change trend of gas pressure within a low range of 0.06%-0.20%.Specimens fabricated by LMD are mainly composed ofα+βgrains with a fine lamellar Widmanstatten structures and have the ultimate tensile strength(UTS)and yield strength of approximately 1100 and 1000 MPa,respectively.Furthermore,the atomized powders have a favorable 3 D printing capability,and the mechanical properties of Ti-6 Al-4 V alloys manufactured by LMD typically exceed those of their cast or wrought counterparts.

Prognostic role of the ABO blood types in Chinese patients with curatively resected non-small cell lung cancer:a retrospective analysis of 1601 cases at a single cancer center

Background:A positive association between the ABO blood types and survival has been suggested in several malignancies.The aim of this study was to assess the role of the ABO blood types in predicting the prognosis of Chinese patients with curatively resected non-small cell lung cancer(NSCLC).Methods:We retrospectively analyzed 1601 consecutive Chinese patients who underwent curative surgery for NSCLC between January 1,2005 and December 31,2009.The relationship between the ABO blood types and survival was investigated.In addition,univariate and multivariate analyses were performed.Results:Group 1(patients with the blood type O or B) had significantly prolonged overall survival(OS) compared with group 2(patients with the blood type A or AB),with a median OS of 74.9 months versus 61.5 months[hazard ratio(HR) 0.83;95%confidence interval(CI) 0.72-0.96;P = 0.015].Additionally,group 1 had significantly longer disease-free survival(DFS;HR 0.86;95%CI 0.76-0.98;P = 0.022) and locoregional relapse-free survival(LRFS;HR 0.79;95%CI 0.64-0.98;P = 0.024) than group 2.The association was not significantly modified by other risk factors for NSCLC,including smoking status,pathologic tumor-node-metastasis stage,pT category,pN category,and chemotherapy.Conclusions:There is an association between the ABO blood types and the survival of Chinese patients with resected NSCLC.Patients with the blood type O or B had significantly prolonged OS,DFS,and LRFS compared with those with the blood type A or AB.

Abnormal lipid synthesis as a therapeutic target for cancer stem cells

Cancer stem cells(CSCs)comprise a subpopulation of cancer cells with stem cell properties,which exhibit the characteristics of high tumorigenicity,self-renewal,and tumor initiation and are associated with the occurrence,metastasis,therapy resistance,and relapse of cancer.Compared with differentiated cells,CSCs have unique metabolic characteristics,and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells.It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism.In this review,we demonstrate that lipid anabolism alterations promote the survival of CSCs,including de novo lipogenesis,lipid desaturation,and cholesterol synthesis.In addition,we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival,the signal transduction pathways involved,and the application prospect of lipid synthesis reprogramming in CSC therapy.It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs.Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.

Insight into band alignment of Zn(O,S)/CZTSe solar cell by simulation

Cd-free kesterite structured solar cells are currently attracting attention because they are environmentally friendly. It is reported that Zn(O,S) can be used as a buffer layer in these solar cells. However, the band alignment is not clear and the carrier concentration of Zn(O,S) layer is low. In this study, the band alignment of the Zn(O,S)/Cu_2 ZnSnSe_4 p–n junction solar cell and the effect of In_2 S_3/Zn(O,S) double buffer layer are studied by numerically simulation with wxAMPS software.By optimizing the band gap structure between Zn(O,S) buffer layer and Cu_2 ZnSnSe_4 absorber layer and enhancing the carrier concentration of Zn(O,S) layer, the device efficiency can be improved greatly. The value of CBO is in a range of 0 eV–0.4 eV for S/(S + O)= 0.6–0.8 in Zn(O,S). The In_2 S_3 is mainly used to increase the carrier concentration when it is used as a buffer layer together with Zn(O,S).

Perioperative nursing of a newborn with Beckwith-Wiedemann syndrome

Objective:To explore the perioperative nursing of a newborn with Beckwith-Wiedemann syndrome.Methods:We observed the blood glucose of the child and prevent infection of omphalocele before transpor tation and before the operation;after the operation,we performed airway nursing,blood glucose monitoring,urination observation,and tumor marker monitoring;finally,at the time of discharge from the hospital,we provided health education.Results:After a series of perioperative nursing measures,the child was discharged smoothly from hospital 34 d after operation.Conclusions:Beckwith-Wiedemann syndrome is a rare congenital malformation.Timely and accurate observation and evaluation of the child during perioperative period and targeted nursing measures can effectively reduce or avoid the occurrence of postoperative complications.

Residual circulating tumor DNA after adjuvant chemotherapy effectively predicts recurrence of stage II-III gastric cancer

Background Circulating tumor DNA(ctDNA)is a promising biomarker for predicting relapse in multiple solid cancers.However,the predictive value of ctDNA for disease recurrence remains indefinite in locoregional gastric cancer(GC).Here,we aimed to evaluate the predictive value of ctDNA in this context.Methods From 2016 to 2019,100 patients with stage II/III resectable GC were recruited in this prospective cohort study(NCT02887612).Primary tumors were collected during surgical resection,and plasma samples were collected perioperatively and within 3 months after adjuvant chemotherapy(ACT).Somatic variants were captured via a targeted sequencing panel of 425 cancer-related genes.The plasma was defined as ctDNA-positive only if one or more variants detected in the plasma were presented in at least 2%of the primary tumors.Results Compared with ctDNA-negative patients,patients with positive postoperative ctDNA had moderately higher risk of recurrence[hazard ratio(HR)=2.74,95%confidence interval(CI)=1.37–5.48;P=0.003],while patients with positive post-ACT ctDNA showed remarkably higher risk(HR=14.99,95%CI=3.08-72.96;P<0.001).Multivariate analyses indicated that both postoperative and post-ACT ctDNA positivity were independent predictors of recurrence-free survival(RFS).Moreover,post-ACT ctDNA achieved better predictive performance(sensitivity,77.8%;specificity,90.6%)than both postoperative ctDNA and serial cancer antigen.A comprehensive model incorporating ctDNA for recurrence risk prediction showed a higher C-index(0.78;95%CI=0.71–0.84)than the model without ctDNA(0.71;95%CI=0.64–0.79;P=0.009).Conclusions Residual ctDNA after ACT effectively predicts high recurrence risk in stage II/III GC,and the combination of tissue-based and circulating tumor features could achieve better risk prediction.

基于“芳香亲核取代-重排”机理检测生物活性分子的荧光探针

生物硫醇包括谷胱甘肽(GSH)、半胱氨酸(Cys)和同型半胱氨酸(Hcy),在生理过程中扮演着不同的重要角色,其分布和浓度的异常变化常与多种疾病的病理过程息息相关.由于生物硫醇结构和反应活性的相似性,对它们的选择性检测极具挑战.近年来,“芳香亲核取代-重排”机理发展成为生物硫醇选择性检测的通用策略,并扩展到其他生物活性分子的检测.本文根据探针荧光团和检测物的不同进行分类,综述了基于“芳香亲核取代-重排”机理的荧光探针的设计、合成与应用进展.

Rationale and study design for one-stop assessment of renal artery stenosis and renal microvascular perfusion with contrast-enhanced ultrasound for patients with suspected renovascular hypertension

Background:Renal artery stenosis (RAS) is always associated with abnormalities in renal microvascular perfusion (RMP).However,few imaging methods can simultaneously evaluate the degree of luminal stenosis and RMP.Thus,this study will aim to evaluate the feasibility of using contrast-enhanced ultrasound (CEUS) for assessing both RAS and RMP to achieve a one-stop assessment of patients with suspected renovascular hypertension. Methods:This will be a single-center diagnostic study with a sample size of 440.Patients with chronic kidney disease (CKD) and suspected of having resistant hypertension will be eligible.Patients with Stages 1–3 CKD will undergo CEUS and computed tomography (CT) angiography (CTA).Values obtained by CEUS and CTA for diagnosing low-grade (lumen reduced by <60%) and high-grade (lumen reduced by ≥60%) RAS will be compared.Moreover,all patients will also undergo radionuclide imaging.The diagnostic value for RAS will be assessed by the receiver operating characteristic curve,including the accuracy,sensitivity,specificity,positive predictive values,negative predictive values,and area under the ROC.Pearson correlation analysis will be performed to assess the association between CEUS findings for RMP and glomerular filtration rate measured by a radionuclide imaging method. Conclusion:The data gathered from this study will be used to evaluate the feasibility of expanding clinical applications of CEUS for evaluation of patients with suspected renovascular hypertension.

弛豫量热技术研究固体材料低温比热性质

比热是物质最基础的热力学性质,通过测量并研究物质低温比热不仅可以计算得到熵、焓、吉布斯自由能等热力学函数,还可以获得有关物质物理性质、能量、结构及相变的信息,为相关热力学问题的探索与研究提供重要依据。低温比热测量一般有绝热量热、交流量热和弛豫量热三种技术;其中弛豫量热因测试样品用量少、测量温区低、测量准确度高、操作方便、有商品化仪器可得等优点,已成为近些年来发展最快、应用最广泛的低温比热测量技术。为了使研究者们更全面地了解这种量热技术,本文详细介绍了弛豫量热技术的测量原理、发展历程以及测量技术的研究进展,并结合当前热门研究领域,简要概述了国内外学者利用弛豫量热技术测量材料低温比热并研究相关热力学性质的最新工作进展。

A Unified Approach Toward Simulating Constant and Varying Amplitude Fatigue Failure Effects of Metals with Fast and Efficient Algorithms

A new finite strain elastoplastic J2-flow model is established with an explicit formulation of work-hardening and softening effects up to eventual failure,in which both a new flow rule free of yielding and an asymptotically vanishing stress limit are incorporated.The novelties of this new model are as follows:(i)Fatigue failure effects under repeated loading conditions with either constant or varying amplitudes are automatically characterized as inherent response features;(ii)neither additional damage-like variables nor failure criteria need to be involved;and(iii)both high-and low-cycle fatigue effects may be simultaneously treated.A fast and efficient algorithm of high accuracy is proposed for directly simulating high-and medium-high-cycle fatigue failure effects under repeated loading conditions.Toward this goal,a direct and explicit relationship between the fatigue life and the stress amplitude is obtained by means of explicit and direct procedures of integrating the coupled elastoplastic rate equations for any given number of loading-unloading cycles with varying stress amplitudes.Numerical examples suggest that the new algorithm is much more fast and efficient than usual tedious and very time-consuming integration procedures.

An immunopathogenic perspective of interleukin-1 signaling

Interleukin-1(IL-1),referred to as two distinct proteins,IL-1αand IL-1β,was first described almost 50 years ago.1 IL-1αand IL-1βrepresent immediate early innate cytokines critically involved in alarming and activating the host defense system.2 Therefore,any impairment of IL-1 signaling pathways often leads to devastating outcomes,such as autoimmunity and autoinflammation,dysmetabolism,cardiovascular disorders,and cancer.2 Many advances in targeting IL-1 in immune therapies have been achieved;for example,the IL-1-blocking agents anakinra(IL-1 receptor antagonist,IL-1Ra),canakinumab(anti-IL-1βmAb),and MABp1(anti-IL-1αmAb)have been approved for clinical use or are being evaluated.2 Remarkably,the CANTOS study,which included over 10,000 patients,showed that blocking IL-1βnot only reduced atherosclerosis-related cardiovascular mortality but was also effective in inflammatory diseases related to lung cancer,arthrosis,and gout.3.

Changes of Damage Associated Molecular Patterns in COVID-19 Patients

Background:The development of severe coronavirus disease 2019(COVID-19)is associated with systemic hyperinflammation,which drives multi-organ failure and death.Disease deterioration tends to occur when the virus is receding;however,whether other factors besides viral products are involved in the inflammatory cascade remains unclear.Methods:Twenty-eight COVID-19 patients with laboratory-confirmed SARS-CoV-2 infection hospitalized at the Fifth Medical Center of Chinese PLA General Hospital from January 23 to February 20,2020 and nine healthy donors during the same period were recruited in the study.COVID-19 patients were grouped as mild,moderate,severe based on disease severity.Plasma damage-associated molecular patterns(DAMPs),including high mobility group box 1(HMGB1),calprotectin(S100A8/A9),surfactant protein A(SP-A),cold-inducible RNA-binding protein(CIRBP),and Histone H4 were detected by ELISA assay,and analyzed in combination with clinical data.Plasma cytokines,chemokines and lymphocytes were determined by flow cytometry.Results:Plasma levels of HMGB1(38292.3±4564.4 vs.32686.3±3678.1,P=0.002),S100A8/A9(1490.8±819.3 vs.742.2±300.8,P=0.015),and SP-A(6713.6±1708.7 vs.5296.3±1240.4,P=0.048)were increased in COVID-19 patients compared to healthy donors,while CIRBP(57.4±30.7 vs.111.9±55.2,P=0.004)levels decreased.Five DAMPs did not vary among mild,moderate,and severe patients.Moreover,SP-A levels correlated positively with inflammatory cytokines and negatively with time elapsed after symptom onset,whereas CIRBP showed an opposite pattern.Conclusions:These findings suggest SP-A may involve in the inflammation of COVID-19,while CIRBP likely plays a protective role.Therefore,DAMPs represent a potential target in the prevention or treatment of COVID-19.

Systematic Discovery and Pathway Analyses of Metabolic Disturbance in COVID-19

Background:The ongoing global coronavirus disease 2019(COVID-19)pandemic is posing a serious public health threat to nations worldwide.Understanding the pathogenesis of the disease and host immune responses will facilitate the discovery of therapeutic targets and better management of infected patients.Metabolomics technology can provide an unbiased tool to explore metabolic perturbation.Methods:Twenty-six healthy controls and 50 COVID-19 patients with mild,moderate,and severe symptoms in the Fifth Medical Center of PLA General Hospital from January 22 to February 16,2020 were recruited into the study.Fasting blood samples were collected and subject to metabolomics analysis by liquid chromatography–mass spectrometry.Metabolite abundance was measured by peak area and was log-transformed before statistical analysis.The principal component analysis,different expression analysis,and metabolic pathway analysis were performed using R package.Co-regulated metabolites and their associations with clinical indices were identified by the weighted correlation network analysis and Spearman correlation coefficients.The potential metabolite biomarkers were analyzed using a random forest model.Results:We uncovered over 100 metabolites that were associated with COVID-19 disease and many of them correlated with disease severity.Sets of highly correlated metabolites were identified and their correlations with clinical indices were presented.Further analyses linked the differential metabolites with biochemical reactions,metabolic pathways,and biomedical MeSH terms,offering contextual insights into disease pathogenesis and host responses.Finally,a panel of metabolites was discovered to be able to discriminate COVID-19 patients from healthy controls,and also another list for mild against more severe cases.Our findings showed that in COVID-19 patients,citrate cycle,sphingosine 1-phosphate in sphingolipid metabolism,and steroid hormone biosynthesis were downregulated,while purine metabolism and tryptophan metabolism were disturbed.Conclusion:This study discovered key metabolites as well as their related biological and medical concepts pertaining to COVID-19 pathogenesis and host immune response,which will facilitate the selection of potential biomarkers for prognosis and discovery of therapeutic targets.