Inverter design with positive feedback field-effect transistors

As the physical size of semiconductor devices continues to be aggressively scaled down, feedback field-effect transistors (FBFET) with a positive feedback mechanism among a few promising steep switching devices have received attention as next-generation switching devices. Conventional FBFETs have been studied to explore their device performance. However, this has been restricted to the case of single FBFET; basic circuit designs with FBFETs have not been investigated extensively. In this work, we propose an inverter circuit design with silicon-on-insulator (SOI) FBFETs; we verified this inverter design with mixed-mode technology computer-aided design simulation. The basic principles and mechanisms for designing FBFET inverter circuits are explained because their configuration is different from conventional inverters. In addition, the device parameters necessary to optimize circuit construction are introduced for logic device applications.

PI3K/AKT Pathway Promotes Keloid Fibroblasts Proliferation by Enhancing Glycolysis Under Hypoxia

Background Keloids are disfiguring fibro-proliferative disorders characterized by glucose metabolism reprogramming, namely elevated glycolysis and compromised oxidative phosphorylation. Our previous study demonstrated altered glucose metabolism and enhanced phosphorylation of the PI3K/AKT pathway in keloid fibroblasts (KFb) under hypoxic conditions. However, whether the PI3K/AKT pathway influences KFb cell function by regulating glucose metabolism under hypoxic conditions remains unclear. Results Our findings revealed that when the PI3K/AKT pathway was inactivated with LY294002 under hypoxia, the protein expression of glycolytic enzymes GLUT1, HK2, PFKFB3, PGK1, ENO1, PKM2, and LDHA decreased under hypoxia, while the amount of mitochondria and mitochondrial membrane potential (MMP) increased, and mitochondrial ultrastructure in KFb remained unchanged. The key parameters of extracellular acidification rate (ECAR) markedly diminished, and those of oxygen consumption rate (OCR) significantly increased after inhibition of the PI3K/AKT pathway. When the PI3K/AKT pathway was suppressed, the levels of ROS and mitochondrial ROS were significantly increased. Meanwhile, cell proliferation, migration, and invasion were inhibited, and apoptosis was increased when the PI3K/AKT pathway was blocked. Additionally, cell proliferation was compromised when KFb were treated with both SC79 (an activator of the PI3K/AKT pathway) and 2-DG (an inhibitor of glycolysis), compared to the SC79 group. Moreover, a positive feedback mechanism was demonstrated in the PI3K/AKT pathway and HIF-1α. Conclusions Our data collectively demonstrated that the PI3K/AKT pathway promotes proliferation and inhibits apoptosis in KFb under hypoxia by regulating glycolysis, indicating that the PI3K/AKT signaling pathway could be a therapeutic target for keloids.

A growth model for water distribution networks with loops

Water distribution networks (WDNs) expand their service areas over time. These growth dynamics are poorly understood. One facet of WDNs is that they have loops in general, and closing loops may be a functionally important process for enhancing their robustness and efficiency. We propose a growth model for WDNs that generates networks with loops and is applicable to networks with multiple water sources. We apply the proposed model to four empirical WDNs to show that it produces networks whose structure is similar to that of the empirical WDNs. The comparison between the empirical and modelled WDNs suggests that the empirical WDNs may realize a reasonable balance between cost, efficiency and robustness in terms of the network structure. We also study the design of pipe diameters based on a biological positive feedback mechanism. Specifically, we apply a model inspired by Physarum polycephalum to find moderate positive correlations between the empirical and modelled pipe diameters. The difference between the empirical and modelled pipe diameters suggests that we may be able to improve the performance of WDNs by following organizing principles of biological flow networks.

Ccq1–Raf2 interaction mediates CLRC recruitment to establish heterochromatin at telomeres

Telomeres, highly ordered DNA-protein complexes at eukaryotic linear chromosome ends, are specialized heterochromatin loci conserved among eukaryotes. In Schizosaccharomyces pombe, the shelterin complex is important for subtelomeric heterochromatin establishment. Despite shelterin has been demonstrated to mediate the recruitment of the Snf2/histone deacetylase–containing repressor complex (SHREC) and the Clr4 methyltransferase complex (CLRC) to telomeres, the mechanism involved in telomeric heterochromatin assembly remains elusive due to the multiple functions of the shelterin complex. Here, we found that CLRC plays a dominant role in heterochromatin establishment at telomeres. In addition, we identified a series of amino acids in the shelterin subunit Ccq1 that are important for the specific interaction between Ccq1 and the CLRC subunit Raf2. Finally, we demonstrated that the Ccq1–Raf2 interaction is essential for the recruitment of CLRC to telomeres, that contributes to histone H3 lysine 9 methylation, nucleosome stability and the shelterin-chromatin association, promoting a positive feedback mechanism for the nucleation and spreading of heterochromatin at subtelomeres. Together, our findings provide a mechanistic understanding of subtelomeric heterochromatin assembly by shelterin-dependent CLRC recruitment to chromosomal ends.

Robust designation of meiotic crossover sites by CDK-2 through phosphorylation of the MutSγ complex

SUMMARYCrossover formation is essential for proper segregation of homologous chromosomes during meiosis. Here we show that C. elegans Cyclin-dependent kinase 2 (CDK-2) forms a complex with cyclin-like protein COSA-1 and supports crossover formation by promoting conversion of meiotic double-strand breaks (DSBs) into crossover-specific recombination intermediates. Further, we identify MutSγ component MSH-5 as a CDK-2 phosphorylation target. MSH-5 has a disordered C-terminal tail that contains 13 potential CDK phosphosites and is required to concentrate crossover-promoting proteins at recombination sites. Phosphorylation of the MSH-5 tail appears dispensable in a wild- type background, but when MutSγ activity is partially compromised, crossover formation and retention of CDK-2/COSA-1 at recombination sites are exquisitely sensitive to phosphosite loss. Our data support a model in which robustness of crossover designation reflects a positive feedback mechanism involving CDK-2-mediated phosphorylation and scaffold-like properties of the MSH-5 C-terminal tail, features that combine to promote full recruitment and activity of crossover-promoting complexes.

Roles of vertical distributions of atmospheric transient eddy dynamical forcing and diabatic heating in midlatitude unstable air–sea interaction

Atmospheric transient eddy dynamical forcing (TEDF)-driven midlatitude unstable air–sea interaction has recently been recognized as a crucial positive feedback for the maintenance of the extratropical decadal variabilities. Our recent theoretical work (Chen et al., Clim Dyn 10.1007/s00382-020-05405-0, 2020) has characterized such an interaction through building an analytical midlatitude barotropic atmospheric model coupled to a simplified upper oceanic model. This study extends the analytical model to including a two-layer quasi-geostrophic baroclinic atmospheric model and then identifies the roles of vertical distributions of atmospheric TEDF and diabatic heating in midlatitude unstable air–sea interaction. It is found that midlatitude air–sea coupling with more realistic vertical profiles of atmospheric TEDF and diabatic heating destabilizes oceanic Rossby wave modes over the entire range of zonal wavelengths, in which the most unstable coupled mode features an equivalent barotropic atmospheric low (high) pressure over a cold (warm) oceanic surface. Spatial structure and period of the most unstable mode are more consistent with the observation than those from in previous model. Although either TEDF or diabatic heating alone can lead to a destabilized coupled mode, the former makes a dominant contribution to the instability. The increase of low-layer TEDF stimulates the instability more effectively if the TEDF in upper layer is larger than in lower layer, while the TEDF in either high or low layers can individually cause the instability. The surface heating always destabilizes the air–sea interaction, while the mid-level heating always decays the coupled mode. The results of this study further confirm the TEDF-driven positive feedback mechanism in midlatitude air–sea interaction proposed by recent observational and numerical experiment studies.

Using Artificial Seagrass for Promoting Positive Feedback Mechanisms in Seagrass Restoration

Worldwide, seagrass meadows are under threat. Consequently, there is a strong need for seagrass restoration to guarantee the provision of related ecosystem services such as nutrient cycling, carbon sequestration and habitat provision. Seagrass often grows in vast meadows in which the presence of seagrass itself leads to a reduction of hydrodynamic energy. By modifying the environment, seagrass thus serves as foundation species and ecosystem engineer improving habitat quality for itself and other species as well as positively affecting its own fitness. On the downside, this positive feedback mechanism can render natural recovery of vanished and destroyed seagrass meadows impossible. An innovative approach to promote positive feedback mechanisms in seagrass restoration is to create an artificial seagrass (ASG) that mimics the facilitation function of natural seagrass. ASG could provide a window of opportunity with respect to suitable hydrodynamic and light conditions as well as sediment stabilization to allow natural seagrass to re-establish. Here, we give an overview of challenges and open questions for the application of ASG to promote seagrass restoration based on experimental studies and restoration trials and we propose a general approach for the design of an ASG produced from biodegradable materials. Considering positive feedback mechanisms is crucial to support restoration attempts. ASG provides promising benefits when habitat conditions are too harsh for seagrass meadows to re-establish themselves.

Successful IL-12 cancer immunotherapy requires NK cell-derived CCL5 for anti-tumor DC-T cell crosstalk

Targeting T cells for cancer immunotherapy commonly fails to generate lasting tumor control. Harnessing additional orchestrators of the immune response against tumors may enhance and broaden clinical benefit. Here, we demonstrate that therapeutic targeting of the IFNγ-IL-12 pathway relies on the amplification of anti-tumoral DC-T cell crosstalk by NK cells. Utilizing an engineered adenoviral platform for paracrine delivery into the tumor microenvironment, we show that IL-12 enhances functional DC-CD8 T cell interactions to generate profound anti-tumor immunity. This effect depends on the abundance of intra-tumoral NK cells and specifically their capacity to produce the DC chemoattractant CCL5. Failure to respond to IL-12 and other IFNγ-inducing therapies such as immune checkpoint blockade can be overcome by intra-tumoral therapeutic delivery of CCL5 resulting in the recruitment of cDC1s. Our findings reveal novel mechanistic insights how to enhance T cell-NK cell-DC crosstalks, enforcing a tumor-eliminating positive feedback mechanism to promote anti-tumor immunity and overcome resistance.