Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to ...lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. Herein, we review recent progress with respect to Aβ- and tau-associated mechanisms, and discuss glial dysfunction in AD with emphasis on neuronal and glial receptors that mediate Aβ-induced toxicity. We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. Although we have gained much towards understanding various aspects underlying this devastating neurodegenerative disorder, greater commitment towards research in molecular mechanism, diagnostics and treatment will be needed in future AD research.
Recurrent chromosomal aberrations have led to the discovery of oncogenes or tumour suppressors involved in carcinogenesis. Here we characterized an oncogenic long intergenic non-coding RNA in the ...frequent DNA-gain regions in hepatocellular carcinoma (HCC), LINC01138 (long intergenic non-coding RNA located on 1q21.2). The LINC01138 locus is frequently amplified in HCC; the LINC01138 transcript is stabilized by insulin like growth factor-2 mRNA-binding proteins 1/3 (IGF2BP1/IGF2BP3) and is associated with the malignant features and poor outcomes of HCC patients. LINC01138 acts as an oncogenic driver that promotes cell proliferation, tumorigenicity, tumour invasion and metastasis by physically interacting with arginine methyltransferase 5 (PRMT5) and enhancing its protein stability by blocking ubiquitin/proteasome-dependent degradation in HCC. The discovery of LINC01138, a promising prognostic indicator, provides insight into the molecular pathogenesis of HCC, and the LINC01138/PRMT5 axis is an ideal therapeutic target for HCC treatment.
Understanding soybean (Glycine max) domestication and improvement at a genetic level is important to inform future efforts to further improve a crop that provides the world's main source of oilseed. ...We detect 230 selective sweeps and 162 selected copy number variants by analysis of 302 resequenced wild, landrace and improved soybean accessions at >11× depth. A genome-wide association study using these new sequences reveals associations between 10 selected regions and 9 domestication or improvement traits, and identifies 13 previously uncharacterized loci for agronomic traits including oil content, plant height and pubescence form. Combined with previous quantitative trait loci (QTL) information, we find that, of the 230 selected regions, 96 correlate with reported oil QTLs and 21 contain fatty acid biosynthesis genes. Moreover, we observe that some traits and loci are associated with geographical regions, which shows that soybean populations are structured geographically. This study provides resources for genomics-enabled improvements in soybean breeding.
Sustained activation of glycolytic metabolism would lead to low efficiency of ATP production and compromise of microglial immune functions 9. Since the energy metabolism is required for Aβ ...phagocytosis and clearance, the low efficiency of ATP production due to glycolytic metabolism would impair the phagocytic function of microglia and result in Aβ accumulation. In summary, this study highlights a crosstalk between lactate metabolism and histone lactylation in microglia, and reveals how this lactate-derived epigenetic modification exacerbates microglial dysfunction and neuroinflammation in the development and progression of AD. ...targeting lactate metabolism disorder may represent a novel strategy for AD intervention (Fig. 1). Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer's disease.
Variants of TREM2 are associated with Alzheimer’s disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human ...TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models.
•Elevating TREM2 gene dosage altered microglial morphology and interaction with Aβ•Increasing TREM2 gene dosage reprograms microglial responsivity in AD mouse brains•Transcriptomic profiling identified three groups of TREM2 gene-dosage-dependent genes•Extra TREM2 gene dosage ameliorates neuropathology and memory deficits in AD mice
Augmenting TREM2 gene dosage in AD mouse models leads to reduced amyloid burden and neuropathology and improved memory performance. Gene expression profiling reveals a reprogrammed disease-associated microglial response that may underlie the phenotypic improvement in AD models.
Long noncoding RNAs (lncRNA) participate in carcinogenesis and tumor progression in lung cancer. Here, we report the identification of a lncRNA signature associated with metastasis of non-small cell ...lung cancer (NSCLC). In particular, elevated expression of LINC00963 (MetaLnc9) in human NSCLC specimens correlated with poor prognosis, promoted migration and invasion of NSCLC cells
, and enhanced lung metastasis formation
Mechanistic investigations showed that MetaLnc9 interacted with the glycolytic kinase PGK1 and prevented its ubiquitination in NSCLC cells, leading to activation of the oncogenic AKT/mTOR signaling pathway. MetaLnc9 also interacted with P54nrb/NonO (NONO) to help mediate the activity of CRTC, a coactivator for the transcription factor CREB, reinforcing a positive feedback loop for metastasis. Taken together, our results establish MetaLnc9 as a driver of metastasis and a candidate therapeutic target for treating advanced NSCLC.
.
Abstract
Changes in atmospheric CO
2
concentration have played a central role in algal and plant adaptation and evolution. The commercially important red algal genus,
Pyropia
(Bangiales) appears to ...have responded to inorganic carbon (C
i
) availability by evolving alternating heteromorphic generations that occupy distinct habitats. The leafy gametophyte inhabits the intertidal zone that undergoes frequent emersion, whereas the sporophyte conchocelis bores into mollusk shells. Here, we analyze a high-quality genome assembly of
Pyropia yezoensis
to elucidate the interplay between C
i
availability and life cycle evolution. We find horizontal gene transfers from bacteria and expansion of gene families (e.g. carbonic anhydrase, anti-oxidative related genes), many of which show gametophyte-specific expression or significant up-regulation in gametophyte in response to dehydration. In conchocelis, the release of HCO
3
-
from shell promoted by carbonic anhydrase provides a source of C
i
. This hypothesis is supported by the incorporation of
13
C isotope by conchocelis when co-cultured with
13
C-labeled CaCO
3
.
Triggering receptor expressed on myeloid cells 2 (TREM2) plays crucial roles in Alzheimer's disease (AD) by regulating microglia migration toward, and phagocytosis of oligomeric amyloid-β (oAβ) and ...amyloid plaques. Studies in rodent models of AD have shown that mice with increased TREM2 expression have reduced amyloid pathology. Here, we identified a TREM2 agonist monoclonal Ab (Ab18) by panning a phage-displayed single-chain variable fragment Ab library. By engineering the bivalent immunoglobulin G1 (IgG1) to tetra-variable domain immunoglobulin (TVD-Ig), we further increased the TREM2 activation by 100-fold. Stronger TREM2 activation led to enhanced microglia phagocytosis of the oAβ-lipid complex, migration toward oAβ, and improved microglia survival in vitro. Mechanistic studies showed increased TREM2 clustering on microglia by the tetravalent Ab18 TVD-Ig without altering microglial TREM2 amount. An engineered bispecific Ab targeting TREM2 and transferrin receptor (TfR; Ab18 TVD-Ig/αTfR) improved Ab brain entry by more than 10-fold with a broad brain parenchyma distribution. Weekly treatment of 5XFAD mice (a model of AD) with Ab18 TVD-Ig/αTfR showed a considerable reduction of amyloid burden with increased microglia migration to and phagocytosis of amyloid plaques, improved synaptic and neuronal marker intensity, improved cognitive functions, reduced endogenous tau hyperphosphorylation, and decreased phosphorylated neurofilament H immunostaining. This study demonstrated the feasibility of engineering multivalent TREM2 agonistic Ab coupled with TfR-mediated brain delivery to enhance microglia functions and reduce amyloid pathology in vitro and in vivo. This Ab engineering approach enables the development of effective TREM2-targeting therapies for AD.
Drawing from the S-O-R perspective, this paper proposes a theoretical model explicating the mechanism whereby social media usage functions on customers' engagement in cross-cultural social commerce ...by employing a mixed-method approach including SEM and fsQCA analysis technique. Analysis of the data collected from 135 countries' 2058 international students indicates that social media usage, either for information or socializing purpose, exerts positive effects on international customers' engagement in social commerce through the conduit of cultural identity change, and social support positively moderates the relationships between two dimensions of social media usage and cultural identity change. The analysis of fsQCA further augmented the robust results reached from SEM and identified four types of configurations that trigger customers' engagement in cross-border social commerce. Research implications and limitations are also discussed.
Abstract
Cholesterol is an essential structural component of membranes that contributes to membrane integrity and fluidity. Cholesterol homeostasis plays a critical role in the maintenance of ...cellular activities. Recently, increasing evidence has indicated that cholesterol is a major determinant by modulating cell signaling events governing the hallmarks of cancer. Numerous studies have shown the functional significance of cholesterol metabolism in tumorigenesis, cancer progression and metastasis through its regulatory effects on the immune response, ferroptosis, autophagy, cell stemness, and the DNA damage response. Here, we summarize recent literature describing cholesterol metabolism in cancer cells, including the cholesterol metabolism pathways and the mutual regulatory mechanisms involved in cancer progression and cholesterol metabolism. We also discuss various drugs targeting cholesterol metabolism to suggest new strategies for cancer treatment.
PDF
