Multiple reaction monitoring for the detection of disease-related synaptic proteins

Synaptic dysfunction occurs early in Alzheimer＇s disease （AD） and is acknowledged as a primary pathologic target for treatment. Synaptic degeneration is the pathological feature most strongly correlated with loss of cognitive function ante mortern （Terry et al., 1991）. Synapses are heavily damaged in hippocampal and neocortical regions of AD brain, whereas motor and occipital cortices are relatively spared （Honer et al., 1992）. Despite extensive work, the molecular mechanisms underlying synaptic degeneration are largely unknown.

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.

Characteristics of gut microbiota in representative mice strains:Implications for biological research

Background:Experimental animals are used to study physiological phenomena,pathological mechanisms,and disease prevention.The gut microbiome is known as a potential confounding factor for inconsistent data from preclinical studies.Although many gut microbiome studies have been conducted in recent decades,few have focused on gut microbiota fluctuation among representative mouse strains.Methods:A range of frequently used mouse strains were selected from 34 isolation packages representing disease-related animal(DRA),immunity defect animal(IDA),or gene-editing animal(GEA)from the BALB/c and C57BL/6J backgrounds together with normal mice,and their microbial genomic DNA were isolated from mouse feces to sequence for the exploration of gut microbiota.Results:Mouse background strain,classification,introduced source,introduced year,and reproduction type significantly affected the gut microbiota structure(p<0.001 for all parameters),with background strain contributing the greatest influence(R^(2)=0.237).In normal groups,distinct gut microbiota types existed in different mouse strains.Sixty-four core operational taxonomic units were obtained from normal mice,and 12 belonged to Lactobacillus.Interestingly,the gut microbiota in C57BL/6J was more stable than that in BALB/c mice.Furthermore,the gut microbiota in the IDA,GEA,and DRA groups significantly differed from that in normal groups(p<0.001 for all).Compared with the normal group,there was a significantly higher Chao 1 and Shannon index(p<0.001 for all)in the IDA,GEA,and DRA groups.Markedly changed classes occurred with Firmicutes and Bacteroidetes.The abundances of Helicobacter,Blautia,Enterobacter,Bacillus,Clostridioides,Paenibacillus,and Clostridiales all significantly decreased in the IDA,GEA,and DRA groups,whereas those of Saccharimonas,Rikenella,and Odoribacter all significantly increased.

Perceived health-related stigma among patients with breast cancer

Breast cancer survivors face many challenges(particularly changes in body image) on their road to restoring physical and psychosocial health following diagnosis. Perceived health-related stigma(PHS)refers to the attachment of negative connotations to some types of disease diagnoses. PHS is common among patients with breast cancer and is associated with adverse emotions, attitudes and behaviors. This article summarizes the latest advances and new perspectives on PHS of breast cancer patients and approaches to block this deleterious process. Effects of PHS on patients with breast cancer, in this paper,and measures, predictors and interventions of PHS have been discussed in depth. Future studies should continue to develop more effective instruments that are specialized for measuring PHS of breast cancer patients, explore the predictors of PHS, and discuss effective interventions on the basis of the predictors.

INTS-MFS:A novel method to predict microRNA-disease associations by integrating network topology similarity and microRNA function similarity

Identifying associations between microRNAs(miRNAs)and diseases is very important to understand the occurrence and development of human diseases.However,these existing methods suffer from the following limitation:first,some disease-related miRNAs are obtained from the miRNA functional similarity networks consisting of heterogeneous data sources,i.e.,disease similarity,protein interaction network,gene expression.Second,little approaches infer disease-related miRNAs depending on the network topological features without the functional similarity of miRNAs.In this paper,we develop a novel model of Integrating Network Topology Similarity and MicroRNA Function Similarity(INTS-MFS).The integrated miRNA similarities are calculated based on miRNA functional similarity and network topological characteristics.INTS-MFS obtained AUC of 0.872 based on five-fold cross-validation and was applied to three common human diseases in case studies.As a results,30 out of top 30 predicted Prostatic Neoplasm-related miRNAs were included in the two databases of dbDEMC and PhenomiR2.0.29 out of top 30 predicted Lung Neoplasm-related miRNAs and Breast Neoplasm-related miRNAs were included in dbDEMC,PhenomiR2.0 and experimental reports.Moreover,INTS-MFS found unknown association with hsa-mir-371a in breast cancer and lung cancer,which have not been reported.It provides biologists new clues for diagnosing breast and lung cancer.

哺乳动物TRIM71蛋白RNA结合特性的分子机制研究

TRIM71 is an RNA-binding protein with ubiquitin ligase activity.Numerous functions of mammalian TRIM71,including cell cycle regulation,embryonic stem cell(ESC)self-renewal,and reprogramming of pluripotent stem cells,are related to its RNA-binding property.We previously reported that a long noncoding RNA(lnc RNA)Trincr1 interacts with mouse TRIM71(m TRIM71)to repress FGF/ERK pathway in mouse ESCs(m ESCs).Herein,we identify an RNA motif specifically recognized by m TRIM71 from Trincr1 RNA,and solve the crystal structure of the NHL domain of m TRIM71 complexed with the RNA motif.Similar to the zebrafish TRIM71,m TRIM71 binds to a stem-loop structured RNA fragment of Trincr1,and an adenosine base at the loop region is crucial for the m TRIM71 interaction.We map similar hairpin RNAs preferably bound by TRIM71 in the m RNA UTRs of the cell-cycle related genes regulated by TRIM71.Furthermore,we identify key residues of m TRIM71,conserved among mammalian TRIM71 proteins,required for the RNA-binding property.Single-site mutations of these residues significantly impair the binding of TRIM71 to hairpin RNAs in vitro and to m RNAs of Cdkn1a/p21 and Rbl2/p130 in m ESCs.Furthermore,congenital hydrocephalus(CH)specific mutation of m TRIM71 impair its binding to the RNA targets as well.These results reveal molecular mechanism behind the recognition of RNA by mammalian TRIM71 and provide insights into TRIM71 related diseases.