Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the ...cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB. Variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses. Importantly, sTREM2 delivered to the hippocampi of both wild-type and
-knockout mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia. Collectively, these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival. This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.
TREM2 is an innate immune receptor specifically expressed in microglia. Coding variations in TREM2 have been reported to increase the risk for Alzheimer's disease (AD) and other neurodegenerative ...diseases. While multiple studies support a role for TREM2 in microglial recruitment to amyloid plaques, the chemoattractant factor modulating TREM2-dependent microglial responses has not been defined.
Potential binding of oligomeric amyloid-β 1-42 (oAβ
) to TREM2 was tested by complementary approaches including solid phase binding, surface plasmon resonance and immunoprecipitation assays. The ability of oAβ
to activate TREM2 signaling pathways was examined by analyzing the phosphorylation of Syk and Akt in primary microglia as well as TREM2-mediated signaling in a reporter cell system. Lastly, the functional outcome of oAβ
-TREM2 interaction was tested by examining impacts on microglial migration in vitro and clustering around oAβ
-bearing brain areas in vivo.
We found that oAβ
bound to TREM2 with high affinity and activated TREM2-dependent signaling pathway. Neither monomeric nor scrambled Aβ bound to TREM2 supporting a specific interaction between oAβ and TREM2. The disease-associated mutations of TREM2 reduced its binding affinity to oAβ
. Furthermore, we identified several positively charged amino acids within residues 31-91 of TREM2 that were crucial for its interaction with oAβ
. Importantly, oAβ
promoted microglial migration in vitro and clustering in vivo in a TREM2-dependent manner.
Our data establish a critical link between oAβ
, a major pathological component of AD, and TREM2, a strong genetic risk factor for AD expressed in microglia, and suggest that such interaction contributes to the pathogenic events in AD by modulating microglial responses.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Detection of chromosome copy number variation (CNV) plays an important role in the diagnosis of patients with unexplained clinical symptoms and for the identification of chromosome disease syndromes ...in the established fetus. In current clinical practice, karyotyping, in conjunction with array-based methods, is the gold standard for detection of CNV. To increase accessibility and reduce patient costs for diagnostic CNV tests, we speculated that next-generation sequencing methods could provide a similar degree of sensitivity and specificity as commercial arrays. CNV in patient samples was assessed on a medium-density single nucleotide polymorphism array and by low-coverage massively parallel CNV sequencing (CNV-seq), with mate pair sequencing used to confirm selected CNV deletion breakpoints. A total of 10 ng of input DNA was sufficient for accurate CNV-seq diagnosis, although 50 ng was optimal. Validation studies of samples with small CNVs showed that CNV-seq was specific and reproducible, suggesting that CNV-seq may have a potential genome resolution of approximately 0.1 Mb. In a blinded study of 72 samples with known gross and submicroscopic CNVs originally detected by single nucleotide polymorphism array, there was high diagnostic concordance with CNV-seq. We conclude that CNV-seq is a viable alternative to arrays for the diagnosis of chromosome disease syndromes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
As the penetration of renewable distributed generation (RDG) continues to grow, the stochastic and intermittent nature of its output imposes significant challenges on distribution networks (DNs), ...such as source–load mismatch and voltage fluctuations, which seriously affects the safety and reliability of the system. Thus, this paper presents a stochastic optimal allocation method for a battery energy storage system (BESS) in the DN, with the consideration of annual load growth, BESS degradation, and DN operation, aiming to minimize the overall cost of DNs and harvest more renewable energy. Based on the rainflow-counting concept, BESS degradation is efficiently modeled and linearized to improve solvability. Additionally, to address the uncertainties of RDG outputs and loads, a stochastic optimization (SO) method is adopted. Furthermore, considering that a large number of integer variables of the BESS allocation model may cause a heavy computational burden, a feasibility pump-based solution algorithm is introduced to accelerate the solving speed. Finally, the effectiveness of the proposed BESS allocation method and the solution algorithm is verified on a 33-bus DN system through comparative analyses, showing high efficiency and performance.
Copy number variation (CNV) is of great significance in human evolution and disorders. Through tracing the parent-of-origin of de novo pathogenic CNVs, we are expected to investigate the relative ...contributions of germline genomic stability on reproductive health. In our study, short tandem repeat (STR) and single nucleotide polymorphism (SNP) were used to determine the parent-of-origin of 87 de novo pathogenic CNVs found in unrelated patients with intellectual disability (ID), developmental delay (DD) and multiple congenital anomalies (MCA). The results shown that there was a significant difference on the distribution of the parent-of-origin for different CNVs types (Chi-square test, p = 4.914 × 10
). An apparently paternal bias existed in deletion CNVs and a maternal bias in duplication CNVs, indicating that the relative contribution of paternal germline variations is greater than that of maternal to the origin of deletions, and vice versa to the origin of duplications. By analyzing the sequences flanking the breakpoints, we also confirmed that non-allelic homologous recombination (NAHR) served as the major mechanism for the formation of recurrent CNVs whereas non-SDs-based mechanisms played a part in generating rare non-recurrent CNVs and might relate to the paternal germline bias in deletion CNVs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The traditional distribution network is prone to widespread power outages and difficult to restore promptly in the event of external grid faults. With the integration of distributed photovoltaic ...generation (PV), the distribution network can be divided into multiple microgrids internally. During external grid faults, it is common to use distributed energy resources within microgrids to supply power to affected loads. Additionally, due to the susceptibility of distributed energy resources to weather and environmental factors, the use of energy storage for auxiliary regulation can enhance the supply reliability of the microgrid cluster. This study aims to give priority to restoring critical loads and models for island partitioning based on the distribution network's characteristics. A heuristic algorithm based on hill climbing strategy is used to solve the islanding model. The reliability of power supply to loads within the island is used as the objective function, and the optimization of power restoration strategies during island operation is achieved through energy storage devices and load regulation. The power restoration optimization method's simulation results prove its effectiveness in enhancing island operation stability, ensuring microgrid power supply reliability.
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