Alzheimer's disease (AD) is a heterogeneous disease and exhibits diverse clinical presentations and disease progression. Some pathological and anatomical subtypes have been proposed. However, these ...subtypes provide a limited mechanistic understanding for AD. Leveraging gene expression data of 222 AD patients from The Religious Orders Study and Memory and Aging Project (ROSMAP) Study, we identified two AD molecular subtypes (synaptic type and inflammatory type) using consensus non-negative matrix factorization (NMF). Synaptic type is characterized by disrupted synaptic vesicle priming and recycling and synaptic plasticity. Inflammatory type is characterized by disrupted IL2, interferon alpha and gamma pathways. The two AD molecular subtypes were validated using independent data from Gene Expression Omnibus. We further demonstrated that the two molecular subtypes are associated with APOE genotypes, with synaptic type more prevalent in AD patients with E3E4 genotype and inflammatory type more prevalent in AD patients with E3E3 genotype (p = 0.031). In addition, two molecular subtypes are differentially represented in male and female AD, with synaptic type more prevalent in male and inflammatory type in female patients (p = 0.051). Identification of AD molecular subtypes has potential in facilitating disease mechanism understanding, clinical trial design, drug discovery, and precision medicine for AD.
Systems approaches in studying disease relationship have wide applications in biomedical discovery, such as disease mechanism understanding and drug discovery. The FDA Adverse Event Reporting System ...(FAERS) contains rich information about patient diseases, medications, drug adverse events and demographics of 17 million case reports. Here, we explored this data resource to mine disease comorbidity relationships using association rule mining algorithm and constructed a disease comorbidity network.
We constructed a disease comorbidity network with 1059 disease nodes and 12,608 edges using association rule mining of FAERS (14,157 rules). We evaluated the performance of comorbidity mining from FAERS using known disease comorbidities of multiple sclerosis (MS), psoriasis and obesity that represent rare, moderate and common disease respectively. Comorbidities of MS, obesity and psoriasis obtained from our network achieved precisions of 58.6%, 73.7%, 56.2% and recalls 87.5%, 69.2% and 72.7% separately. We performed comparative analysis of the disease comorbidity network with disease semantic network, disease genetic network and disease treatment network. We showed that (1) disease comorbidity clusters exhibit significantly higher semantic similarity than random network (0.18 vs 0.10); (2) disease comorbidity clusters share significantly more genes (0.46 vs 0.06); and (3) disease comorbidity clusters share significantly more drugs (0.64 vs 0.17). Finally, we demonstrated that the disease comorbidity network has potential in uncovering novel disease relationships using asthma as a case study.
Our study presented the first comprehensive attempt to build a disease comorbidity network from FDA Adverse Event Reporting System. This network shows well correlated with disease semantic similarity, disease genetics and disease treatment, which has great potential in disease genetics prediction and drug discovery.
Combined deficiency of factor V (FV) and FVIII (F5F8D) is an autosomal recessive bleeding disorder characterized by simultaneous decreases of both coagulation factors. This review summarizes recent ...reports on the clinical presentations, treatments, and molecular mechanism of F5F8D. Genetic studies identified LMAN1 and MCFD2 as causative genes for this disorder, revealing a previously unknown intracellular transport pathway shared by the two important blood coagulation factors. LMAN1 and MCFD2 form a Ca2+-dependent cargo receptor complex that functions in the transport of FV/FVIII from the endoplasmic reticulum (ER) to the Golgi. Disrupting the LMAN1-MCFD2 receptor, complex formation is the primary molecular defect of missense mutations leading to F5F8D. The EF-hand domains of MCFD2 are necessary and sufficient for the interactions with both LMAN1 and FV/FVIII. Similarly, the carbohydrate recognition domain of LMAN1 contains distinct and separable binding sites for both MCFD2 and FV/FVIII. Therefore, FV and FVIII likely carry duel sorting signals that are separately recognized by LMAN1 and MCFD2 and necessary for the efficient ER-to-Golgi transport. FV and FVIII likely bind LMAN1 through the high-mannose N-linked glycans under the higher Ca2+ conditions in the ER and dissociate in the lower Ca2+ environment of the ER-Golgi intermediate compartment.
•Segregation bands could improve the wear resistance of the rail.•Segregation bands severely reduced the rolling contact fatigue of the rail.•Segregation caused inhomogeneous strain and crack ...initiation in the test.•The friction heat caused dynamic recovery of dislocation.
Rolling contact fatigue (RCF) is the main failure mode of wheel-rail system. In this work, the influence of non-uniform microstructure on the rolling contact fatigue performance in bainitic rail steel was investigated. According to the results, an increase in degree of segregation enabled material to improve the wear resistance through the improvement of the local hardness of the rail, but seriously reduced the rolling contact fatigue performance of the rail. The crack propagated along the segregation band, thereby leading to the failure of the specimen. The main cause of fatigue crack initiation was the non-uniform strain distribution under cyclic loading due to different hardness values between the matrix and the segregation region. A large number of dislocations produced by plastic deformation on the surface of the specimen segmented grains into nanocrystals. Meanwhile, it can be seen from the in-situ heating transmission electron microscope (TEM) that the friction heat generated during RCF test was enough to support the occurrence of dynamic recovery.
The abnormal m6A modification caused by m6A modulators is a common feature of various tumors; however, little is known about which m6A modulator plays the most important role in triple-negative ...breast cancer (TNBC). In this study, when analyzing the influence of m6A modulators (
METTL3, METTL14, WTAP, FTO
, and
ALKBH5
) on the prognosis of breast cancer, especially in TNBC using several on-line databases, methyltransferase-like 3 (
METTL3
) was found to have low expression in breast cancer, and was closely associated with short-distance-metastasis-free survival in TNBC. Further investigation showed that knockdown of
METTL3
could enhance the ability of migration, invasion, and adhesion by decreasing m6A level in TNBC cell lines. Collagen type III alpha 1 chain (
COL3A1
) was identified and verified as a target gene of
METTL3
.
METTL3
could down-regulate the expression of
COL3A1
by increasing its m6A methylation, ultimately inhibiting the metastasis of TNBC cells. Finally, with immunohistochemistry staining in breast cancer tissues, it was proved that
METTL3
expression was negatively correlated with
COL3A1
in TNBC, but not in non-TNBC. This study demonstrated the potential mechanism of m6A modification in metastasis and provided potential targets for treatment in TNBC.
In this research work, the synthesis of anion exchanges membranes (AEMs) from brominated poly (2, 6-dimethyl-1, 4-phenylene oxide) (BPPO) and dimethyethanolamine (DMEA) has been investigated for ...electrodialysis (ED) application. Fourier transform infrared spectroscopy was used to confirm the functional groups in the membranes. The morphology of the prepared membranes was investigated by scanning electron microscopy. Physiochemical and electrochemical properties of the prepared membranes were studied in detail. The membranes possess ion exchange capacity of 0.66mmol/g to 1.38mmol/g, water uptake of 11.60% to 48.50%, volume expansion ratio of 8.58% to 20.21%, tensile strength of 32.52MPa to 49.22MPa and transport number of 0.94 to 0.98. These membranes have higher chemical stability in alkaline medium than QPPO membrane (quaternized with trimethylamine) at room temperature. The membranes DMEA-10 and DMEA-15 were selected for NaCl desalination by ED with a lab-scale electrodialysis cell at constant applied voltage. The prepared membranes DMEA-10 and DMEA-15 showed better performance than the commercial anion exchange membranes Neosepta AMX under the identical conditions.
•Anion exchange membranes with dimethyethanolammonium were prepared.•Developed membranes have high desalination performance and suitable for ED.
Epigenetic age acceleration-the difference between an individual's DNA methylation age and chronological age-is associated with many diseases including cancer. This study aims to evaluate epigenetic ...age acceleration as a prognostic biomarker for gliomas. DNA methylation data of gliomas patients (516 low-grade and intermediate-grade gliomas and 140 glioblastoma) were obtained from The Cancer Genome Atlas (TCGA) and patient epigenetic ages were computed using Horvath's age prediction model. We used multivariate linear regression to assess the association of epigenetic age acceleration with tumor molecular subtypes, including Codel, Classic-like, G-CIMP-high, G-CIMP-low, Mesenchymal-like and PA-like. Compared with Codel subtype, epigenetic ages in other molecular subtypes show deceleration after controlling age and race. Age deceleration for Classic-like, G-CIMP-high, G-CIMP-low, Mesenchymal-like and PA-like were 15.42 years (CI: 7.98-22.86, p = 5.38E-05), 25.00 years (CI: 20.79-29.22, p = 4.06E-28), 28.56 years (CI: 14.37-42.74, p = 8.75E-05), 45.34 years (CI: 38.80-51.88, p = 2.15E-36), and 53.58 years (CI: 44.90-62.26, p = 4.81E-30), respectively. Then, Cox proportional hazards regression was used to assess the association of epigenetic age acceleration with patient overall survival. Our results show epigenetic age acceleration is positively associated with patient overall survival (per 10-year age acceleration, HR = 0.89; 95%CI: 0.82-0.97; p = 9.04E-03) in multivariate analysis. When stratified by molecular subtypes, epigenetic age acceleration remains positively associated with patient survival after adjusting age and tumor grade. In conclusion, epigenetic age acceleration is significantly associated with molecular subtypes and patient overall survival in gliomas, indication that epigenetic age acceleration has potential as a quantitative prognostic biomarker for gliomas.
Throughout much of human history, the vast majority of people lived in small communities. However, in the last few centuries, and particularly in recent decades, there has been a dramatic shift. A ...massive migration has moved populations from rural to urban areas. United Nations reports state that over 4.3 billion individuals now inhabit urban regions, which accounts for more than half (55% as of 2017) of the global population. In most high-income nations, including Western Europe, the Americas, Australia, Japan, and the Middle East, over 80% of people live in urban areas. This figure ranges from 50% to 80% in upper-middle-income countries like Eastern Europe, East Asia, North Africa, South Africa, and South America (United Nations, Department of Economic and Social Affairs, Population Division, 2019). The urban population is anticipated to rise across all countries in the coming decades, albeit at different rates. By 2050, the global population is expected to reach approximately 9.8 billion, with about 6.7 billion residing in cities and 3.1 billion in rural areas. Despite this rapid urbanization, only around 1% of the Earth's land is allocated for urban and infrastructure development. While urbanization has spurred socio-economic growth, it has also led to significant challenges such as traffic congestion and air pollution. In China, the swift growth of cities has notably expanded urban areas and extended the commuting times of residents. The “2022 Commuting Monitoring Report of Major Chinese Cities” reveals that in 2022, over 14 million people in 44 major Chinese cities experienced extreme commuting, with upwards of 13% spending over an hour in transit (Baidu Maps, 2023). Beijing recorded the highest rate, where 26% of commuters faced this issue.
Wireless sensing-based human-vehicle recognition (WiHVR) methods have become a hot spot for research due to its non-invasiveness and cost-effective advantages. However, existing WiHVR methods shows ...limited performance and slow execution time on human-vehicle classification task. To address this issue, a lightweight wireless sensing attention-based deep learning model (LW-WADL) is proposed, which consists of a CBAM module and several depthwise separable convolution blocks in series. LW-WADL takes raw channel state information (CSI) as input, and extracts the advanced features of CSI by jointly using depthwise separable convolution and convolutional block attention mechanism (CBAM). Experimental results show that the proposed model achieves 96.26% accuracy on the constructed CSI-based dataset, and the model size is only 5.89% of the state of the art (SOTA) model. The results demonstrate that the proposed model achieves better performance on WiHVR tasks while reducing the model size compared to SOTA model.
Basal-like breast cancer (BLBC) takes up about 10-20% of all breast cancer(BC), what's more, BLBC has the lowest survival rate among all BC subtypes because of lacks of efficient treatment methods. ...We aimed to explore the molecules that can be used as diagnostic maker for BLBC at early stage and provide optimized treatment strategies for BLBC patients in this study.
Apply weighted gene co-expression network analysis (WGCNA) to identify gene modules related to BLBC;The functional enrichment of candidate genes related to BLBC in the red module of Go data package and KEGG analysis;Overlapping cross analysis of URGs and WGCNA to identify candidate genes in each BC subtype;Divide BCBL patients into high-risk and low-risk groups, and analyze the two groups of overall survival (OS) and relapse free survival (RFS);Screening of GEMIN4 dependent cell lines; QRT PCR was used to verify the expression of GEMIN4 transfected with siRNA; CCK8 was used to determine the effect of GEMIN4 on cell viability; Positive cell count detected by BrdU staining;GO and KEGG enrichment analysis of GEMIN4.
The "red module" has the highest correlation with BLBC, with 913 promising candidate genes identified from the red module;913 red module candidate genes related to BLBC participated in multiple GO terms, and KEGG enrichment analysis results mainly enriched in estrogen signaling pathways and pathways in cancer;There are 386 overlapping candidate genes among the 913 "red module" genes identified by 1893 common URG and WGCNA;In BLBC patients, 9 highly expressed genes are associated with OS. Five highly expressed genes are associated with RFS. Kaplan Meier survival analysis suggests that high GEMIN4 expression levels are associated with poor prognosis in BLBC patients;The GEMIN4 gene dependency score in HCC1143 and CAL120 cell lines is negative and low; Si-GEMIN4-1 can significantly reduce the mRNA expression of GEMIN4; Si-GEMIN4 can inhibit cell viability; Si-GEMIN4 can reduce the number of positive cells;GO enrichment analysis showed that GEMIN4 is associated with DNA metabolism processes and adenylate binding; KEGG pathway enrichment analysis shows that GEMIN4 is related to ribosome biogenesis in eukaryotes.
We hypothesized that GEMIN4 may be the potential target for the treatment of BLBC.
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