A T-shaped gate tunneling field effect transistor with negative capacitance, super-steep subthreshold swing.

With the development of semiconductor technology, the size of traditional metal oxide semiconductor field effect transistor devices continues to decrease, but it cannot meet the requirements of high performance and low power consumption. Low power tunneling field effect transistor (TFET) has gradually become the focus of researchers. This paper proposes a novel T-shaped gate TFET based on the silicon with the negative capacitance (NC-TGTFET). On the basis of TGTFET, ferroelectric material (HZO) is used as gate dielectric. The simulation results show that, compared with the traditional TGTFET, the opening order and sensitivity of the two tunneling junctions are different. The influences of thickness and the doping concentration of pocket and ferroelectric material properties on the characteristics of NC-TGTFET is also discussed by Sentaurus simulation tool. Furthermore, the negative capacitance of ferroelectric material makes NC-TGTFET have a very steep subthreshold swing (18.32 mV/dec) at the range of drain current from 1 × 10-15to 1 × 10-7Aµm-1. And the on-state current (Vg= 0.5 V,Vd= 0.5 V) is 1.52 × 10-6Aµm-1.

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1.

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

Metabolite-Mediated Responses of Phyllosphere Microbiota to Rust Infection in Two Malus Species.

Plants recruit beneficial microbes to enhance their ability to fight pathogens. However, the current understanding of microbial recruitment is largely limited to belowground systems (root exudates and the rhizosphere). It remains unclear whether the changes in leaf metabolites induced by infectious pathogens can actively recruit beneficial microbes to mitigate the growth of foliar pathogens. In this study, we integrated microbiome and metabolomic analyses to systematically explore the dynamics of phyllosphere fungal and bacterial communities and key leaf metabolites in two crabapple species (Malus sp. "Flame" and Malus sp. "Kelsey") at six stages following infection with Gymnosporangium yamadae. Our results showed that the phyllosphere microbiome changed during lesion expansion, as highlighted by a reduction in bacterial alpha-diversity and an increase in fungal alpha-diversity; a decreasing and then an increasing complexity of the microbial co-occurrence network was observed in Kelsey and a decreasing complexity occurred in Flame. In addition, nucleotide sugars, diarylheptanoids, and carboxylic acids with aromatic rings were more abundant in early stages of collection, which positively regulated the abundance of bacterial orders Pseudomonadales (in Kelsey), Acidimicrobiales, Bacillales, and Flavobacteriales (in Flame). In addition, metabolites such as flavonoids, lignin precursors, terpenoids, coumarins, and quaternary ammonium salts enriched with the expansion of lesions had a positive regulatory effect on fungal families Rhynchogastremataceae and Golubeviaceae (in Flame) and the bacterial order Actinomycetales (in Kelsey). Our findings highlight that plants may also influence phyllosphere microorganisms by adjusting leaf metabolites in response to biotic stress. IMPORTANCE Our findings demonstrate the response patterns of bacterial and fungal communities in the Malus phyllosphere to rust fungus G. yamadae infection, and they also reveal how the phyllosphere microbiome changes with the expansion of lesions. We identified several metabolites whose relative abundance varied significantly with lesion expansion. Using a framework for assessing the role of leaf metabolites in shaping the phyllosphere microbiome of the two Malus species, we identified several specific metabolites that have profoundly selective effects on the microbial community. In conclusion, our study provides new evidence of the ecological niche of the phyllosphere in supporting the "cry for help" strategy for plants.

Suboptimal activation of protease-activated receptors enhances alpha2beta1 integrin-mediated platelet adhesion to collagen.

Thrombin and fibrillar collagen are potent activators of platelets at sites of vascular injury. Both agonists cause platelet shape change, granule secretion, and aggregation to form the primary hemostatic plug. Human platelets express two thrombin receptors, protease-activated receptors 1 and 4 (PAR1 and PAR4) and two collagen receptors, the alpha(2)beta(1) integrin (alpha(2)beta(1)) and the glycoprotein VI (GPVI)/FcRgamma chain complex. Although these receptors and their signaling mechanisms have been intensely studied, it is not known whether and how these receptors cooperate in the hemostatic function of platelets. This study examined cooperation between the thrombin and collagen receptors in platelet adhesion by utilizing a collagen-related peptide (alpha2-CRP) containing the alpha(2)beta(1)-specific binding motif, GFOGER, in conjunction with PAR-activating peptides. We demonstrate that platelet adhesion to alpha2-CRP is substantially enhanced by suboptimal PAR activation (agonist concentrations that do not stimulate platelet aggregation) using the PAR4 agonist peptide and thrombin. The enhanced adhesion induced by suboptimal PAR4 activation was alpha(2)beta(1)-dependent and GPVI/FcRgamma-independent as revealed in experiments with alpha(2)beta(1)- or FcRgamma-deficient mouse platelets. We further show that suboptimal activation of other platelet G(q)-linked G protein-coupled receptors (GPCRs) produces enhanced platelet adhesion to alpha2-CRP. The enhanced alpha(2)beta(1)-mediated platelet adhesion is controlled by phospholipase C (PLC), but is not dependent on granule secretion, activation of alpha(IIb)beta(3) integrin, or on phosphoinositol-3 kinase (PI3K) activity. In conclusion, we demonstrate a platelet priming mechanism initiated by suboptimal activation of PAR4 or other platelet G(q)-linked GPCRs through a PLC-dependent signaling cascade that promotes enhanced alpha(2)beta(1) binding to collagens containing GFOGER sites.

Driver mutations among never smoking female lung cancer tissues in China identify unique EGFR and KRAS mutation pattern associated with household coal burning.

Lung cancer in never smokers, which has been partially attributed to household solid fuel use (i.e., coal), is etiologically and clinically different from lung cancer attributed to tobacco smoking. To explore the spectrum of driver mutations among lung cancer tissues from never smokers, specifically in a population where high lung cancer rates have been attributed to indoor air pollution from domestic coal use, multiplexed assays were used to detect >40 point mutations, insertions, and deletions (EGFR, KRAS, BRAF, HER2, NRAS, PIK3CA, MEK1, AKT1, and PTEN) among the lung tumors of confirmed never smoking females from Xuanwei, China [32 adenocarcinomas (ADCs), 7 squamous cell carcinomas (SCCs), 1 adenosquamous carcinoma (ADSC)]. EGFR mutations were detected in 35% of tumors. 46% of these involved EGFR exon 18 G719X, while 14% were exon 21 L858R mutations. KRAS mutations, all of which were G12C_34G>T, were observed in 15% of tumors. EGFR and KRAS mutations were mutually exclusive, and no mutations were observed in the other tested genes. Most point mutations were transversions and were also found in tumors from patients who used coal in their homes. Our high mutation frequencies in EGFR exon 18 and KRAS and low mutation frequency in EGFR exon 21 are strikingly divergent from those in other smoking and never smoking populations from Asia. Given that our subjects live in a region where coal is typically burned indoors, our findings provide new insights into the pathogenesis of lung cancer among never smoking females exposed to indoor air pollution from coal.

Characteristics of lung cancers harboring NRAS mutations.

PURPOSE: We sought to determine the frequency and clinical characteristics of patients with lung cancer harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS-mutant lung cancer cells. EXPERIMENTAL DESIGN: We reviewed clinical data from patients whose lung cancers were identified at six institutions or reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) to harbor NRAS mutations. Six NRAS-mutant cell lines were screened for sensitivity against inhibitors of multiple kinases (i.e., EGFR, ALK, MET, IGF-1R, BRAF, PI3K, and MEK). RESULTS: Among 4,562 patients with lung cancers tested, NRAS mutations were present in 30 (0.7%; 95% confidence interval, 0.45%-0.94%); 28 of these had no other driver mutations. 83% had adenocarcinoma histology with no significant differences in gender. While 95% of patients were former or current smokers, smoking-related G:C>T:A transversions were significantly less frequent in NRAS-mutated lung tumors than KRAS-mutant non-small cell lung cancer [NSCLC; NRAS: 13% (4/30), KRAS: 66% (1772/2733), P < 0.00000001]. Five of 6 NRAS-mutant cell lines were sensitive to the MEK inhibitors, selumetinib and trametinib, but not to other inhibitors tested. CONCLUSION: NRAS mutations define a distinct subset of lung cancers (∼1%) with potential sensitivity to MEK inhibitors. Although NRAS mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking.

[Control effects of mowing in combining with planting tree species on Chromolaena odorata in karst region of Guangxi, China].

A field experiment was conducted in 2006-2008 to evaluate the control effects of three mowing frequencies in combining with planting three tree species with three densities on the Chromolaena odorata in southwestern Karst region of Guangxi. In all treatments, the relative coverage, height, density, and aboveground biomass of C. odorata were decreased by 89.7%-99.3%, 41.6% - 81.2%, 61.4% - 83.2% and 91.7% - 97.8%, respectively, and the capitulum number was significantly lesser than that in the control (P<0.05). The control effects on the growth of C. odorata were in the order of mowing frequency > tree species > planting density, and the optimal control mode was mowing twice one year and planting four plants of Delavaya yunnanensis per plot (4 m x 4 m).

Inhibition of DNA replication by berenil of bacterial plasmids containing poly(dA)-poly(dT) sequences. 2D gel analysis of replicative intermediates.

Berenil, an aromatic compound used in veterinary medicine to treat trypanosome infections in livestock, has been shown to interfere with kinetoplast DNA replication. The drug is thought to bind to the minor groove of DNA and form hydrogen bonds between opposite A/T pairs. Studies utilizing Trypanosoma cruzi, revealed that minicircle DNA, which is 60% A-T rich, and also the major component of kinetoplast DNA networks, is one of the targets for berenil. In order to better understand the mode of action of berenil and its effect on DNA replication, we have studied the effect of the drug on pBR322 derived plasmids containing poly(dA)-poly(dT) sequences. The resulting plasmids were pVL26, which contained 240 bp of poly(dA)-poly(dT) inserted at the EcoRV site of pBR322 and pKH47, which contained 100 bp of poly(dA)-poly(dT) inserted at the PvuII site of pBR322. When cultures containing all of these plasmids were exposed to berenil, plasmids pVL26 and pKH47 were found to have significantly lower yields than pBR322, with pKH47 being the most sensitive to berenil. In the present study we show that the poly(dA)-poly(dT) sequences in plasmids pVL26 and pKH47 are not very stably maintained. However, the resulting deletion mutants containing a fraction of the poly(dA)-poly(dT) sequences were still sensitive to berenil. We also analyzed by 2D agarose gel electrophoresis the progression of the replication fork through the homopolymer region in plasmid pVL26d but failed to detect a replication barrier in this region in the presence of berenil.