ABSTRACT
Direct wafer bonding is one of the most attractive techniques for next-generation semiconductor devices, and plasma has been playing an indispensable role in the wider adoption of the wafer bonding technique by lowering its process temperature. Although numerous studies on plasma-assisted direct wafer bonding have been reported, there is still a lack of deep investigations focusing on the plasma itself. Other than the plasma surface treatment, the wafer bonding process includes multiple steps such as surface cleaning and annealing that require comprehensive studies to maximize the bonding strengths. In this work, we evaluate the various process steps of Si-SiO2 wafer bonding through case-by-case experimental studies, covering factors including the plasma conditions for surface treatment and secondary factors such as the time intervals between some process steps. The results show that plasma treatment with increasing input power has a trade-off between bonding strengths and interfacial voids, requiring the optimization of the plasma conditions. It is also noticeable that the effects of plasma treatment on wafer bonding can be improved when the plasma-treated wafers are stored in ambient atmosphere before the subsequent process step, which may suggest that wafer exposure to air during the bonding process is advantageous compared to processing entirely in vacuum. The results are expected to allow plasma-assisted direct wafer bonding technology to play a bigger role in the packaging process of semiconductor device manufacturing.
ABSTRACT
BACKGROUND: Prior exposure to stress is a risk factor for developing posttraumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. METHODS: Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacologic manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. RESULTS: Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2C receptor (5-HT2CR) activity during memory consolidation were necessary for stress enhancement of fear memory, but neither process affected fear memory in unstressed mice. Additionally, prior stress increased amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also showed that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. CONCLUSIONS: Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD.
Subject(s)
Fear/physiology , Memory Consolidation/physiology , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Serotonin/metabolism , Stress, Psychological/physiopathology , Amygdala/drug effects , Amygdala/metabolism , Animals , Association Learning/drug effects , Association Learning/physiology , Conditioning, Psychological/drug effects , Conditioning, Psychological/physiology , Disease Models, Animal , Dorsal Raphe Nucleus/metabolism , Electroshock , Fear/drug effects , Male , Memory Consolidation/drug effects , Mice, Inbred C57BL , Mice, Transgenic , Models, Neurological , Models, Psychological , Neurons/drug effects , Neurons/metabolism , Optogenetics , Restraint, Physical , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Serotonin Plasma Membrane Transport Proteins/genetics , Stress Disorders, Post-Traumatic/metabolismABSTRACT
NQO1 gene expression was evaluated by RT-PCR and SNP status by RFLP in matched samples of lung tumors and adjacent normal tissue. NQO1 was found to be overexpressed in lung tumors when compared to matched normal lung tissue. The mean expression in normal lung tissue was 28.26 x 10(-14) ng/microl +/- 44.9 SD and 61.46 x 10(-14) ng/microl +/- 103.2 SD in lung tumors. NQO1 gene expression was higher in the tumor than in the matched normal lung tissue in 27/50 (59%) patients (p=0.014). In the normal samples, 25 (50%) were wild-type, 16 were heterozygotes (32%) and 8 had the SNP (16%). In the matched tumor samples 14 were wild-type (28%), 16 were heterozygous (32%) and 19 (38%) had the SNP (p=0.0043). The genomic NQO1 mutation was associated with survival in a pilot study of stage II/III NSCLC patients. Patients with a homozygous SNP genotype had a significantly shorter survival (median 12 months), than heterozygous or homozygous wild-type patients (median 41 months) (p=0.007), suggesting NQO1 may be important in chemosensitivity as well as the pathogenesis of lung cancer and NQO1 genotyping may be a useful component of pharmacogenetic strategies for the treatment of NSCLC.
