TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein predominantly expressed in microglia within the central nervous system (CNS). TREM2 regulates multiple microglial functions, including lipid metabolism, immune reaction, inflammation, and microglial phagocytosis. Recent studies have found that TREM2 is highly expressed in activated microglia after ischemic stroke. However, the role of TREM2 in the pathologic response after stroke remains unclear. Herein, TREM2-deficient microglia exhibit an impaired phagocytosis rate and cholesteryl ester (CE) accumulation, leading to lipid droplet formation and upregulation of Perilipin-2 (PLIN2) expression after hypoxia. Knockdown of TREM2 results in increased lipid synthesis (PLIN2, SOAT1) and decreased cholesterol clearance and lipid hydrolysis (LIPA, ApoE, ABCA1, NECH1, and NPC2), further impacting microglial phenotypes. In these lipid droplet-rich microglia, the TGF-β1/Smad2/3 signaling pathway is downregulated, driving microglia towards a pro-inflammatory phenotype. Meanwhile, in a neuron-microglia co-culture system under hypoxic conditions, we found that microglia lost their protective effect against neuronal injury and apoptosis when TREM2 was knocked down. Under in vivo conditions, TREM2 knockdown mice express lower TGF-β1 expression levels and a lower number of anti-inflammatory M2 phenotype microglia, resulting in increased cerebral infarct size, exacerbated neuronal apoptosis, and aggravated neuronal impairment. Our work suggests that TREM2 attenuates stroke-induced neuroinflammation by modulating the TGF-β1/Smad2/3 signaling pathway. TREM2 may play a direct role in the regulation of inflammation and also exert an influence on the post-ischemic inflammation and the stroke pathology progression via regulation of lipid metabolism processes. Thus, underscoring the therapeutic potential of TREM2 agonists in ischemic stroke and making TREM2 an attractive new clinical target for the treatment of ischemic stroke and other inflammation-related diseases.National Natural Science Foundation of China ; Science and Technology Commission of Shanghai Municipality ; China Scholarship Counci

A Survey on Temporal Knowledge Graph Completion: Taxonomy, Progress, and Prospects

Temporal characteristics are prominently evident in a substantial volume of knowledge, which underscores the pivotal role of Temporal Knowledge Graphs (TKGs) in both academia and industry. However, TKGs often suffer from incompleteness for three main reasons: the continuous emergence of new knowledge, the weakness of the algorithm for extracting structured information from unstructured data, and the lack of information in the source dataset. Thus, the task of Temporal Knowledge Graph Completion (TKGC) has attracted increasing attention, aiming to predict missing items based on the available information. In this paper, we provide a comprehensive review of TKGC methods and their details. Specifically, this paper mainly consists of three components, namely, 1)Background, which covers the preliminaries of TKGC methods, loss functions required for training, as well as the dataset and evaluation protocol; 2)Interpolation, that estimates and predicts the missing elements or set of elements through the relevant available information. It further categorizes related TKGC methods based on how to process temporal information; 3)Extrapolation, which typically focuses on continuous TKGs and predicts future events, and then classifies all extrapolation methods based on the algorithms they utilize. We further pinpoint the challenges and discuss future research directions of TKGC

Preconditioned extracellular vesicles from hypoxic microglia reduce poststroke AQP4 depolarization, disturbed cerebrospinal fluid flow, astrogliosis, and neuroinflammation

Background: Stroke stimulates reactive astrogliosis, aquaporin 4 (AQP4) depolarization and neuroinflammation. Preconditioned extracellular vesicles (EVs) from microglia exposed to hypoxia, in turn, reduce poststroke brain injury. Nevertheless, the underlying mechanisms of such effects are elusive, especially with regards to inflammation, AQP4 polarization, and cerebrospinal fluid (CSF) flow. Methods: Primary microglia and astrocytes were exposed to oxygen-glucose deprivation (OGD) injury. For analyzing the role of AQP4 expression patterns under hypoxic conditions, a co-culture model of astrocytes and microglia was established. Further studies applied a stroke model, where some mice also received an intracisternal tracer infusion of rhodamine B. As such, these in vivo studies involved the analysis of AQP4 polarization, CSF flow, astrogliosis, and neuroinflammation as well as ischemia-induced brain injury. Results: Preconditioned EVs decreased periinfarct AQP4 depolarization, brain edema, astrogliosis, and inflammation in stroke mice. Likewise, EVs promoted postischemic CSF flow and cerebral blood perfusion, and neurological recovery. Under in vitro conditions, hypoxia stimulated M2 microglia polarization, whereas EVs augmented M2 microglia polarization and repressed M1 microglia polarization even further. In line with this, astrocytes displayed upregulated AQP4 clustering and proinflammatory cytokine levels when exposed to OGD, which was reversed by preconditioned EVs. Reduced AQP4 depolarization due to EVs, however, was not a consequence of unspecific inflammatory regulation, since LPS-induced inflammation in co-culture models of astrocytes and microglia did not result in altered AQP4 expression patterns in astrocytes. Conclusions: These findings show that hypoxic microglia may participate in protecting against stroke-induced brain damage by regulating poststroke inflammation, astrogliosis, AQP4 depolarization, and CSF flow due to EV release

Nudel and FAK as Antagonizing Strength Modulators of Nascent Adhesions through Paxillin

Competition for binding to the cellular protein paxillin by the proteins Nudel and focal adhesion kinase is important for the proper regulation of cell adhesion and migration

Comparative genomics reveals insights into avian genome evolution and adaptation

Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits

Survival analysis of rutting failures in hot in-place recycling maintained asphalt pavements using field data

Reclaimed asphalt pavement (RAP) serves as an eco-friendly alternative to new construction materials. Hot In-Place Recycling (HIR), which involves the complete on-site recycling of RAP, emerges as a sustainable maintenance solution with resource conservation and cost reduction benefits. Numerous laboratory studies have delved into its advantages, focusing on aspects such as the rejuvenation of binding agents and improved resistance to rutting. Despite its performance benefits, research into extending pavement service life via this technology is limited due to a lack of comprehensive maintenance history and performance inspection data, i.e., censored data. To address this, survival analysis, a method commonly used in the medical field to evaluate treatment effectiveness, was applied. Specifically, a multistate survival analysis, incorporating the non-parametric Kaplan-Meier (KM) method, semi-parametric Cox proportional hazards regression model (Cox regression model) and a parametric generalized F model, was conducted. The treatment service life (TSL) was introduced to measure the duration between the completion of one maintenance activity and the occurrence of the next. The analysis of data from the Jiangsu Provincial Maintenance Management System revealed several noteworthy insights. For instance, a 1 mm increase in the initial rutting depth (RD) raised the risk of re-maintenance for HIR-treated segments by a factor of 1.03. Additionally, delaying maintenance by one year resulted in a 27% increase in the risk of re-maintenance, and a 1,000-fold rise in Equivalent Single Axle Load (ESAL) doubled the risk of re-maintenance. The median TSL for HIR-maintained sections, as estimated through the Generalized F model, was approximately 8.87 years, closely aligned with the median TSL of 9 years obtained using the KM method and the Cox regression model. This approach adeptly addresses the crucial challenge of determining the optimal timing and choosing effective maintenance treatments for pavements, a pivotal element of sustainable maintenance management. These findings disrupt the traditional belief that HIR is predominantly cost-effective without delivering significant long-term improvements in pavement performance. Instead, they emphasize the potential of HIR as a sustainable pavement maintenance treatment, advocating for its widespread adoption and implementation in pavement maintenance

Evaluation of Regional Power Grid Investment Capacity Based on Transmission and Distribution Price Reform

The transmission and distribution price reform has changed the profit model of the power grid, and a reasonable assessment of the investment capacity of the regional power grid is critical to the future investment planning of the power grid. To this end, first of all, sort out the key index system of power grid investment capacity for transmission and distribution price reform. Then comprehensively consider the available distribution profit, depreciation and external financing of the power grid, and establish a quantitative model of power grid investment capacity; Finally, the ability to invest in the establishment of quantitative models to measure the ability of a power grid investment companies, investment capacity is calculated after the reform of the electricity transmission and distribution, in order to verify the ability to quantify the investment rationality and effectiveness of the model. Finally, taking three power companies as examples, the feasibility of the model and the rationality of investment capacity evaluation are verified

A laboratory evaluation of factors affecting rutting resistance of asphalt mixtures using wheel tracking test

Rutting is one of the most common distresses in early damage to asphalt pavements. It can raise the risk of ride safety issues, accelerate pavement deterioration, and increase maintenance costs. To investigate the factors that affect the rutting resistance of asphalt mixtures, internal factors (such as aggregate gradation, asphalt content, and layer thickness), external factors (including temperature and traffic loading), and human factors (such as compaction degree) were tested using wheel tracking tests. The test results showed that the rutting resistance of asphalt mixtures can be improved by designing a tightly interlocked aggregate skeleton using the Bailey method's primary control sieve, using an optimal asphalt content, achieving sufficient compaction, maintaining a layer thickness of 2.5–3 times its nominal maximum aggregate size, using an asphalt softening point higher than the pavement temperature, and avoiding overloaded vehicles. In highly rutted areas, it is recommended to use a stone mastic asphalt with a stable aggregate skeleton matrix and styrene-butadiene-styrene modified asphalt with a softening point higher than the highest pavement temperature.</p