Disability in multiple sclerosis (MS) is driven in part by the failure of remyelination and progressive neurodegeneration. Microglia, and specifically triggering receptor expressed on myeloid cells 2 ...(TREM2), a factor highly expressed in microglia, have been shown to play an important role in remyelination. Here, using a focal demyelination model in the brain, we demonstrate that demyelination is persistent in TREM2 knockout mice, lasting more than 6 weeks after lysolecithin injection and resulting in substantial neurodegeneration. We also find that TREM2 knockout mice exhibit an altered glial response following demyelination. TREM2 knockout microglia demonstrate defects in migration and phagocytosis of myelin debris. In addition, human monocyte‐derived macrophages from subjects with a TREM2 mutation prevalent in human disease also show a defect in myelin debris phagocytosis. Together, we highlight the central role of TREM2 signaling in remyelination and neuroprotection. These findings provide insights into how chronic demyelination might lead to axonal damage and could help identify novel neuroprotective therapeutic targets for MS.
Main Points
Focal demyelination in TREM2 KO mice demonstrates remyelination failure and neurodegeneration.
TREM2 KO mice exhibit altered glial response after demyelination.
Human macrophages with TREM2 mutation have defective myelin debris phagocytosis.
Chemotherapy, radiotherapy, targeted therapy, and immunotherapy are established cancer treatment modalities that are widely used due to their demonstrated efficacy against tumors and favorable safety ...profiles or tolerability. Nevertheless, treatment resistance continues to be one of the most pressing unsolved conundrums in cancer treatment. Hypoxia-inducible factors (HIFs) are a family of transcription factors that regulate cellular responses to hypoxia by activating genes involved in various adaptations, including erythropoiesis, glucose metabolism, angiogenesis, cell proliferation, and apoptosis. Despite this critical function, overexpression of HIFs has been observed in numerous cancers, leading to resistance to therapy and disease progression. In recent years, much effort has been poured into developing innovative cancer treatments that target the HIF pathway. Combining HIF inhibitors with current cancer therapies to increase anti-tumor activity and diminish treatment resistance is one strategy for combating therapeutic resistance. This review focuses on how HIF inhibitors could be applied in conjunction with current cancer treatments, including those now being evaluated in clinical trials, to usher in a new era of cancer therapy.
Package-on-Package (PoP) is a popular technology for fabricating chipsets of accelerated processing units. However, the coefficient of thermal expansion mismatch between Si chips and polymer ...substrates induces thermal warpage during the reflow process. As such, the reflow temperature and reliability of solder joints are critical aspects of PoP. Although Sn58Bi is a good candidate for low-temperature processes, its brittleness causes other reliability issues. In this study, an in-situ observation was performed on composite solders (CSs) made of an Sn-3.0Ag-0.5Cu (SAC305) solder and an Sn58Bi solder that were mixed during reflow at temperatures of 170 °C (CS-170), 180 °C (CS-180), and 190 °C (CS-190). The volumes of the mixed-solder regions were in the order of CS-190 > CS-180 > CS-170. A calculated Sn58Bi-SAC305 isoplethal section of the Sn-Ag-Cu-Bi quaternary system was employed to elucidate the melting behavior of CS-190. CS-190 with Sn cyclic twin boundary and Bi phase preferred orientation of 0001 was demonstrated by electron backscatter diffraction. Moreover, Cu/CS-190/Cu joints with a shear strength of 46 MPa were formed. CS-190 can reduce the brittleness of SnBi solder owing to the reduced solid-solution hardening with the decrease in the Bi content. These factors can improve the reliability of PoP technology.
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•An in-situ observation was performed on a composite solder made of SAC305/Sn58Bi.•SAC305/Sn58Bi were completely mixed by 190 °C reflow to form Sn-31.1Bi-1.4Ag-0.2Cu with a melting-like point of 176°C.•Cu/SAC305-Sn58Bi/Cu solder joints were assembled with a shear strength of 44.6 MPa.
Tensor decomposition is critical for compressing data and extracting key features in novel high-dimensional signal processing systems. However, due to the enormous amount of data and the highly ...complicated computations, designing an efficient tensor decomposition processor is very challenging. This paper presents the algorithm and VLSI architecture design of a low-latency and high-throughput tensor decomposition processor. A parallel higher-order orthogonal iteration (P-HOOI) algorithm is proposed where multiple updated matrices are computed concurrently. Thus, a low-latency tensor decomposition is achieved. Furthermore, a novel VLSI architecture is presented so that the efficiency of the component utilization is improved and the hardware complexity is greatly reduced. Therefore, the proposed tensor decomposition processor enhances the processing throughput with minimum employment of hardware components. Performance evaluations based on the post-layout estimations in the ASIC flow and based on the FPGA platform are reported in this paper. Compared with state-of-the-art designs in the literature the proposed tensor decomposition engine greatly enhances the throughput and hardware efficiency.
Abstract
High-entropy alloys (HEAs) are well known for their excellent high-temperature stability, mechanical properties, and promising resistance against oxidation and corrosion. However, their ...low-temperature applications are rarely studied, particularly in electronic packaging. In this study, the interfacial reaction between a Sn-3.0Ag-0.5Cu solder and FeCoNiCrCu
0.5
HEA substrate was investigated. (Cu
0.76
, Ni
0.24
)
6
Sn
5
intermetallic compound was formed the substrate at the interface between the solder and the FeCoNiCrCu
0.5
HEA substrate. The average Sn grain size on the HEA substrate was 246 μm, which was considerably larger than that on a pure Cu substrate. The effect of the substrate on Sn grain size is due to the free energy required for the heterogeneous nucleation of Sn on the FeCoNiCrCu
0.5
substrate.
We have reported a method of fabricating (111)-orientated nanotwinned copper (nt-Cu) by direct current electroplating. X-ray analysis was performed for the samples annealed at 200 to 350 °C for an ...hour. X-ray diffraction indicates that the (200) signal intensity increases while (111) decreases. Abnormal grain growth normally results from transformation of surface energy or strain energy density. The average grain size increased from 3.8 µm for the as-deposited Cu films to 65-70 µm after the annealing at 250 °C for 1 h. For comparison, no significant grain growth behavior was observed by random Cu film after annealing for an hour. This research shows the potential for its broad electric application in interconnects and three-dimensional integrated circuit (3D IC) packaging.
Rice flag leaves are major source organs providing more than half of the nutrition needed for rice seed development. The dynamic metabolic changes in rice flag leaves and the detailed metabolic ...relationship between source and sink organs in rice, however, remain largely unknown. In this study, the metabolic changes of flag leaves in two japonica and two indica rice cultivars were investigated using non-targeted metabolomics approach. Principal component analysis (PCA) revealed that flag leaf metabolomes varied significantly depending on both species and developmental stage. Only a few of the metabolites in flag leaves displayed the same change pattern across the four tested cultivars along the process of seed development. Further association analysis found that levels of 45 metabolites in seeds that are associated with human nutrition and health correlated significantly with their levels in flag leaves. Comparison of metabolomics of flag leaves and seeds revealed that some flavonoids were specific or much higher in flag leaves while some lipid metabolites such as phospholipids were much higher in seeds. This reflected not only the function of the tissue specific metabolism but also the different physiological properties and metabolic adaptive features of these two tissues.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose: Current vaccines for the SARS-CoV-2 virus mainly induce neutralizing antibodies but overlook the T cell responses. This study aims to generate an exosomal vaccine carrying T cell epitope ...peptides of SARS-CoV-2 for the induction of CD8+ T cell response. Methods: Thirty-one peptides presented by HLA-A0201 molecule were conjugated to the DMPE-PEG-NHS molecules, and mixed with DSPE-PEG to form the peptide-PEG-lipid micelles, then fused with exosomes to generate the exosomal vaccine, followed by purification using size-exclusion chromatography and validation by Western blotting, liquid nuclear magnetic resonance (NMR) test and transmission electron microscopy. Furthermore, the exosomal vaccine was mixed with Poly (I:C) adjuvant and subcutaneously administered for three times into the hybrid mice of HLA-A0201/DR1 transgenic mice with wild-type mice. Then, the epitope-specific T cell responses were detected by ex vivo ELISPOT assay and intracellular cytokine staining. Results: The exosomal vaccine was purified from the Peak 2 fraction of FPLC and injected into the hybrid mice for three times. The IFN-γ spot forming units and the frequencies of IFN-γ+/CD8+ T cells were 10– 82-fold and 13– 65-fold, respectively, higher in the exosomal vaccine group compared to the Poly (I:C) control group, without visible organ toxicity. In comparison with the peptides cocktail vaccine generated in our recent work, the exosomal vaccine induced significantly stronger T cell response. Conclusion: Exosomal vaccine loading T cell epitope peptides of SARS-CoV-2 virus was initially generated without pre-modification for both peptides and exosomes, and elicited robust CD8+ T cell response in HLA-A transgenic mice. Graphical Abstract:
Tubular epithelial cells (TECs) exposed to hypoxia incite tubulointerstitial inflammation (TII), while the exact mechanism is unclear. In this study, we identified that hypoxia evoked tubule injury ...as evidenced by tubular hypoxia-inducible factor-1α and kidney injury molecule-1 (KIM-1) expression and that renal small extracellular vesicle (sEV) production was increased with the development of TII after ischemia-reperfusion injury (IRI). Intriguingly, KIM-1-positive tubules were surrounded by macrophages and co-localized with sEVs. In vitro, KIM-1 expression and sEV release were increased in hypoxic TECs and the hypoxia-induced inflammatory response was ameliorated when KIM-1 or Rab27a, a master regulator of sEV secretion, was silenced. Furthermore, KIM-1 was identified to mediate hypoxic TEC-derived sEV (Hypo-sEV) uptake by TECs. Phosphatidylserine (PS), a ligand of KIM-1, was present in Hypo-sEVs as detected by nanoflow cytometry. Correspondingly, the inflammatory response induced by exogenous Hypo-sEVs was attenuated when KIM-1 was knocked down. In vivo, exogenous-applied Hypo-sEVs localized to KIM-1-positive tubules and exacerbated TII in IRI mice. Our study demonstrated that KIM-1 expressed by injured tubules mediated sEV uptake via recognizing PS, which participated in the amplification of tubule inflammation induced by hypoxia, leading to the development of TII in ischemic acute kidney injury.
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The researchers demonstrated that TECs could communicate through KIM-1-mediated sEV uptake, leading to the spread of injury signals and the resultant progression of TII. The study provides a new insight into the mechanism of hypoxia-induced TII and offers a potential therapy target for ischemic kidney disease.
Seed development dedicates to reserve synthesis and accumulation and uncovering its genetic and biochemical mechanisms has been a major research focus. Although proteomic and transcriptomic analyses ...revealed dynamic changes of genes and enzymes involved, the information regarding concomitant metabolic changes is missing. Here we investigated the dynamic metabolic changes along the rice grain development of two japonica and two indica cultivars using non-targeted metabolomics approach, in which we successfully identified 214 metabolites. Statistical analyses revealed both cultivar and developmental stage dependent metabolic changes in rice grains. Generally, the stage specific metabolic kinetics corresponded well to the physiological status of the developing grains, and metabolic changes in developing rice grain are similar to those of dicot Arabidopsis and tomato at reserve accumulation stage but are different from those of dicots at seed desiccation stage. The remarkable difference in metabolite abundances between japonica and indica rice grain was observed at the reserve accumulation stage. Metabolite-metabolite correlation analysis uncovered potential new pathways for several metabolites. Taken together, this study uncovered both conserved and diverse development associated metabolic kinetics of rice grains, which facilitates further study to explore fundamental questions regarding the evolution of seed metabolic capabilities as well as their potential applications in crop improvement.
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