In Situ Mechanical Characterization of the Mixed- Mode Fracture Strength of the Cu/Si Interface for TSV Structures

In situ nanoindentation experiments have been widely adopted to characterize material behaviors of microelectronic devices. This work introduces the latest developments of nanoindentation experiments in the characterization of nonlinear material properties of 3D integrated microelectronic devices using the through-silicon via (TSV) technique. The elastic, plastic, and interfacial fracture behavior of the copper via and matrix via interface were characterized using small-scale specimens prepared with a focused ion beam (FIB) and nanoindentation experiments. A brittle interfacial fracture was found at the Cu/Si interface under mixed-mode loading with a phase angle ranging from 16.7° to 83.7°. The mixed-mode fracture strengths were extracted using the linear elastic fracture mechanics (LEFM) analysis and a fracture criterion was obtained by fitting the extracted data with the power-law function. The vectorial interfacial strength and toughness were found to be independent with the mode-mix

Synthesis and Characterization of Free-Stand Graphene/Silver Nanowire/Graphene Nano Composite as Transparent Conductive Film with Enhanced Stiffness

As-grown graphene via chemical vapor deposition (CVD) has potential defects, cracks, and disordered grain boundaries induced by the synthesis and transfer process. Graphene/silver nanowire/graphene (Gr/AgNW/Gr) sandwich composite has been proposed to overcome these drawbacks significantly as the AgNW network can provide extra connections on graphene layers to enhance the stiffness and electrical conductivity. However, the existing substrate (polyethylene terephthalate (PET), glass, silicon, and so on) for composite production limits its application and mechanics behavior study. In this work, a vacuum annealing method is proposed and validated to synthesize the free-stand Gr/AgNW/Gr nanocomposite film on transmission electron microscopy (TEM) grids. AgNW average spacing, optical transmittance, and electrical conductivity are characterized and correlated with different AgNW concentrations. Atomic force microscope (AFM) indentation on the free-stand composite indicates that the AgNW network can increase the composite film stiffness by approximately 460% with the AgNW concentration higher than 0.6 mg/mL. Raman spectroscopy shows the existence of a graphene layer and the disturbance of the AgNW network. The proposed method provides a robust way to synthesize free-stand Gr/AgNW/Gr nanocomposite and the characterization results can be utilized to optimize the nanocomposite design for future applications

Adhesion of two-dimensional titanium carbides (MXenes) and graphene to silicon

Two-dimensional transition metal carbides (MXenes) have attracted a great interest of the research community as a relatively recently discovered large class of materials with unique electronic and optical properties. Understanding of adhesion between MXenes and various substrates is critically important for MXene device fabrication and performance. We report results of direct atomic force microscopy (AFM) measurements of adhesion of two MXenes (Ti3C2Tx and Ti2CTx) with a SiO2 coated Si spherical tip. The Maugis-Dugdale theory was applied to convert the AFM measured adhesion force to adhesion energy, while taking into account surface roughness. The obtained adhesion energies were compared with those for mono-, bi-, and tri-layer graphene, as well as SiO2 substrates. The average adhesion energies for the MXenes are 0.90 ± 0.03 J m-2 and 0.40 ± 0.02 J m-2 for thicker Ti3C2Tx and thinner Ti2CTx, respectively, which is of the same order of magnitude as that between graphene and silica tip

Synthesis and Characterization of Free-Stand Graphene/Silver Nanowire/Graphene Nano Composite as Transparent Conductive Film with Enhanced Stiffness

As-grown graphene via chemical vapor deposition (CVD) has potential defects, cracks, and disordered grain boundaries induced by the synthesis and transfer process. Graphene/silver nanowire/graphene (Gr/AgNW/Gr) sandwich composite has been proposed to overcome these drawbacks significantly as the AgNW network can provide extra connections on graphene layers to enhance the stiffness and electrical conductivity. However, the existing substrate (polyethylene terephthalate (PET), glass, silicon, and so on) for composite production limits its application and mechanics behavior study. In this work, a vacuum annealing method is proposed and validated to synthesize the free-stand Gr/AgNW/Gr nanocomposite film on transmission electron microscopy (TEM) grids. AgNW average spacing, optical transmittance, and electrical conductivity are characterized and correlated with different AgNW concentrations. Atomic force microscope (AFM) indentation on the free-stand composite indicates that the AgNW network can increase the composite film stiffness by approximately 460% with the AgNW concentration higher than 0.6 mg/mL. Raman spectroscopy shows the existence of a graphene layer and the disturbance of the AgNW network. The proposed method provides a robust way to synthesize free-stand Gr/AgNW/Gr nanocomposite and the characterization results can be utilized to optimize the nanocomposite design for future applications

Propofol affects the biological behavior of ovarian cancer SKOV3 cells via ERK1/2-MMP-2/9 signaling pathway

Purpose: To investigate the effect of propofol on the biological behavior of ovarian cancer SKOV3 cells, and the mechanism of action involved. Methods: SKOV3 cells cultured in vitro were randomly divided into control group, fat emulsion group, low-dose propofol group (LDPG, 25 μmol/L), medium-dose propofol group (MDPG) (50 μmol/L) and high-dose propofol group (HDPG) (100 μmol/L). Apoptosis was determined by flow cytometry, while Transwell assay was used to measure the migration and invasion abilities of the cells. The protein levels of ERK1/2, MMP-2, MMP-9 were assayed with Western blotting. Moreover, the cells were transfected with siERK, and the regulatory effect of propofol on ERK1/2-MMP-2/9 signaling pathway was determined. Results: Apoptosis in HDPG was significantly reduced, relative to MDPG, while migration and invasion were enhanced, relative to MDPG (p < 0.05). Moreover, MMP-2, ERK1/2, and MMP-9 proteins were significantly higher in MDPG and HDPG than in control, fat emulsion and LDPGs (p < 0.05), and were upregulated in HDPGs, relative to MDPG (p < 0.05). In contrast, propofol did not up-regulate these proteins in siRNA-treated cells. Conclusion: Propofol enhances the migration, proliferation, and invasive ability SKOV3 cells, and upregulates the expressions of MMP-2, ERK1/2, and MMP-9 in these cells, via a mechanism related to the activation of ERK1/2-MMP-2/9 signaling route. These properties provide novel leads for the development of new drugs for ovarian cancer Keywords: Propofol, ERK1/2-MMP-2/9 signal route, Ovarian cancer, Biological behavio

Sex modifies APOE ε4 dose effect on brain tau deposition in cognitively impaired individuals

Recent studies in cognitively unimpaired elderly individuals suggest that the APOE ε4 allele exerts a dosage-dependent effect on brain tau deposition. The aim of this study was to investigate sex differences in APOE ε4 gene dosage effects on brain tau deposition in cognitively impaired individuals using quantitative 18F-flortaucipir PET. Preprocessed 18F-flortaucipir tau PET images, T1-weighted structural MRI, demographic information, global cortical amyloid-β burden measured by 18F-florbetapir PET, CSF total tau and phosphorylated tau measurements were obtained from the Alzheimer\u27s Disease Neuroimaging Initiative database. Two hundred and sixty-eight cognitively impaired individuals with 146 APOE ε4 non-carriers and 122 carriers (85 heterozygotes and 37 homozygotes) were included in the study. An iterative reblurred Van Cittert iteration partial volume correction method was applied to all downloaded PET images. Magnetic resonance images were used for PET spatial normalization. Twelve regional standardized uptake value ratios relative to the cerebellum were computed in standard space. APOE ε4 dosage × sex interaction effect on 18F-flortaucipir standardized uptake value ratios was assessed using generalized linear models and sex-stratified analysis. We observed a significant APOE ε4 dosage × sex interaction effect on tau deposition in the lateral temporal, posterior cingulate, medial temporal, inferior temporal, entorhinal cortex, amygdala, parahippocampal gyrus regions after adjusting for age and education level (P \u3c 0.05). The medial temporal, entorhinal cortex, amygdala and parahippocampal gyrus regions retained a significant APOE ε4 dosage × sex interaction effect on tau deposition after adjusting for global cortical amyloid-β (P \u3c 0.05). In sex-stratified analysis, there was no significant difference in tau deposition between female homozygotes and heterozygotes (P \u3e 0.05). In contrast, male homozygotes standardized uptake value ratios were significantly greater than heterozygotes or non-carriers throughout all 12 regions of interest (P \u3c 0.05). Female heterozygotes exhibited significantly increased tau deposition compared to male heterozygotes in the orbitofrontal, posterior cingulate, lateral temporal, inferior temporal, entorhinal cortex, amygdala and parahippocampal gyrus (P \u3c 0.05). Results from voxel-wise analysis were similar to the ones obtained from regions of interest analysis. Our findings indicate that an APOE ε4 dosage effect on brain region-specific tau deposition exists in males, but not females. These results have important clinical implications towards developing sex and genotype-guided therapeutics in Alzheimer\u27s disease and uncovers a potential explanation underlying differential APOE ε4-associated Alzheimer\u27s risk in males and females

Whole Brain Mapping of Long-Range Direct Input to Glutamatergic and GABAergic Neurons in Motor Cortex

Long-range neuronal circuits play an important role in motor and sensory information processing. Determining direct synaptic inputs of excited and inhibited neurons is important for understanding the circuit mechanisms involved in regulating movement. Here, we used the monosynaptic rabies tracing technique, combined with fluorescent micro-optical sectional tomography, to characterize the brain-wide input to the motor cortex (MC). The whole brain dataset showed that the main excited and inhibited neurons in the MC received inputs from similar brain regions with a quantitative difference. With 3D reconstruction we found that the distribution of input neurons, that target the primary and secondary MC, had different patterns. In the cortex, the neurons projecting to the primary MC mainly distributed in the lateral and anterior portion, while those to the secondary MC distributed in the medial and posterior portion. The input neurons in the subcortical areas also showed the topographic shift model, as in the thalamus, the neurons distributed as outer and inner shells while the neurons in the claustrum and amygdala were in the ventral and dorsal part, respectively. These results lay the anatomical foundation to understanding the organized pattern of motor circuits and the functional differences between the primary and secondary MC

Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells.

Chromatin architecture has been implicated in cell type-specific gene regulatory programs, yet how chromatin remodels during development remains to be fully elucidated. Here, by interrogating chromatin reorganization during human pluripotent stem cell (hPSC) differentiation, we discover a role for the primate-specific endogenous retrotransposon human endogenous retrovirus subfamily H (HERV-H) in creating topologically associating domains (TADs) in hPSCs. Deleting these HERV-H elements eliminates their corresponding TAD boundaries and reduces the transcription of upstream genes, while de novo insertion of HERV-H elements can introduce new TAD boundaries. The ability of HERV-H to create TAD boundaries depends on high transcription, as transcriptional repression of HERV-H elements prevents the formation of boundaries. This ability is not limited to hPSCs, as these actively transcribed HERV-H elements and their corresponding TAD boundaries also appear in pluripotent stem cells from other hominids but not in more distantly related species lacking HERV-H elements. Overall, our results provide direct evidence for retrotransposons in actively shaping cell type- and species-specific chromatin architecture

Loss of p53 Attenuates the Contribution of IL-6 Deletion on Suppressed Tumor Progression and Extended Survival in Kras-Driven Murine Lung Cancer

Interleukin-6 (IL-6) is involved in lung cancer tumorigenesis, tumor progression, metastasis, and drug resistance. Previous studies show that blockade of IL-6 signaling can inhibit tumor growth and increase drug sensitivity in mouse models. Clinical trials in non-small cell lung cancer (NSCLC) reveal that IL-6 targeted therapy relieves NSCLC-related anemia and cachexia, although other clinical effects require further study. We crossed IL-6-/- mice with KrasG12D mutant mice, which develop lung tumors after activation of mutant KrasG12D, to investigate whether IL-6 inhibition contributes to tumor progression and survival time in vivo. KrasG12D; IL-6-/- mice exhibited increased tumorigenesis, but slower tumor growth and longer survival, than KrasG12D mice. Further, in order to investigate whether IL-6 deletion contributes to suppression of lung cancer metastasis, we generated KrasG12D; p53flox/flox; IL-6-/- mice, which developed lung cancer with a trend for reduced metastases and longer survival than KrasG12D; p53flox/flox mice. Tumors from KrasG12D; IL-6-/- mice showed increased expression of TNFα and decreased expression of CCL-19, CCL-20 and phosphorylated STAT3 (pSTAT3) than KrasG12D mice; however, these changes were not present between tumors from KrasG12D; p53flox/flox; IL-6-/- and KrasG12D; p53flox/flox mice. Upregulation of pSTAT3 and phosphorylated AKT (pAKT) were observed in KrasG12D tumors with p53 deletion. Taken together, these results indicate that IL-6 deletion accelerates tumorigenesis but delays tumor progression and prolongs survival time in a Kras-driven mouse model of lung cancer. However, these effects can be attenuated by p53 deletion