Search

Two structurally-unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951, with antiviral activity in cell culture against monkeypox virus (MPXV) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity, reasonable pharmacokinetics, and non-toxicity in mice at active concentrations. Anti-tumor properties of each compound were validated in mouse xenografts against A549 human lung cancer. The targets of these compounds are unconventional: each binds to a different transient, energy-dependent multi-protein complex containing the protein KAP-1(TRIM28), an allosteric modulator known to broadly regulate mechanisms underlying viral and nonviral disease states including cancer. Treatment with these compounds alters the target multi-protein complexes in a manner consistent with allosteric modulation as their mechanism of action. These compounds appear to remove a block, crucial for cancer survival and progression, on the homeostatic linkage of uncontrolled cellular proliferation to apoptosis. These compounds may provide starting points for development of next-generation non-toxic, cancer therapeutics.

Antiviral compounds displaying several remarkable features have been identified by a uniquely enabling drug screen and advanced through validation in two animal models, and in human primary bronchial epithelial cells grown to an air-liquid interface (ALI) and infected with SARS-CoV-2 (Brazil). Activity is observed in the nanomolar range in mammalian cells in vitro against the six viral families causing most human respiratory viral disease, irrespective of strain, including SARS-CoV-2 delta variant. A substantial barrier to development of viral resistance is demonstrated for influenza (FLUV). The drug target is an allosteric site on a novel host multi-protein complex (MPC) formed transiently, in an energy-dependent fashion, and composed of proteins implicated in viral lifecycles and innate immunity. The composition of this host MPC is modified in viral family-specific ways by FLUV and CoV, and substantially restored to the uninfected state with drug treatment. SQSTM1/p62, a key regulator of the autophagy pathway of innate immunity is i) found in the target MPC from uninfected cells, ii) lost upon infection, and iii) restored by drug treatment of infected cells, as assessed by drug resin affinity chromatography. A small subset of 14-3-3 is identified as the host protein to which the drug is bound. Advanced compounds with good oral bioavailability, half-life, lung exposure, and safety are approaching criteria for a Target Product Profile. We propose these novel drug targets to comprise a previously unappreciated molecular basis for homeostasis that is modified by viruses to facilitate their propagation and is restored by treatment with the therapeutic compounds presented. This discovery has transformative implications for treating respiratory viral-related disease, applicable to everything from COVID-19, seasonal influenza, common ‘winter viruses’ (respiratory syncytial virus, parainfluenza virus, rhinovirus, etc.), emerging respiratory viruses, and prevention of virus-induced asthma/COPD exacerbations. Treating respiratory viral disease with these host-targeted pan-respiratory viral family active compounds early, upon onset of symptoms of viral upper respiratory infection, irrespective of cause, should protect against progression to lower respiratory tract or systemic infection, the hallmarks of serious illness.

In order to further grasp the overhead rules of transmission line de-icing, this thesis designed and developed a newly transmission line icing apparatus, which can acquire the needed ice thickness covered upon a certain transmission line in laboratory. Combined with the walk-in temperature and humidity box, the temperature tester, current generator and other equipment, enhance the technology research capacity of overhead lines ice-melting. And the software can simulate the overlying ice temperature and cloud distribution changes with time, verify the line ice-melting rules. The method can be easily extended to other types of wires, and has certain application value.

In this paper, we compared the device architecture, electrical performance between bulk planar, SegFET, UTBB-SOI and FinFET MOSFETs based on TCAD simulation and we also listed the key fabrication process difference between bulk planar and FinFET devices. Results show that FinFET has best short channel effect (SCE) immunity due to its double gate structure. Hence, FinFET device demonstrates best DC performance, which includes Ion/Ioff, Sub-threshold Swing and DIBL. Analyses also show FinFET has best AC performance: smallest delay and dynamic power consumption. Besides some 20nm technology node’s processes, some brand new processes, such as Fin formation, low-k spacer, poly and HK/MG CMP, SiC/SiGe in-situ doping with Ti-silicide and SAC local interconnects, need to be introduced into the FinFET process flow as a necessary cost of achieving the superior performance.

High-k last and metal gate last process becomes the main stream in 20nm and beyond technology. In high-k last process, the thermal dummy gate oxide (DGO) must be removed before the growth of interfacial layer (IL). In conventional process, to avoid the plasma damage to the device, wet etch is the most popular process to remove DGO. Because the etch rate of ILD(inter layer dielectric) oxide and CESL(CT etch stop layer) layers is much higher than thermal oxide, during the removal of DGO, serious ILD and CESL loss is observed, which will induce many of following process issues, such as high-k/metal residue, gate height variation, work function shift, etc. In this paper, multi-methods are studied to reduce the loss of ILD and CESL layer. The study mainly includes improvements on film quality and optimization of removal process. Finally, the selectivity of ILD oxide and CESL to thermal dummy gate oxide can reach ~1:1.

With the characteristic dimension scaling down of CMOS device, the gate leakage increases significantly and the device gets low reliability performance. Then EOT (Equivalent Oxide Thickness) should be decreased, and more performance would be gained with leakage and reliability sacrifice by an optimized dielectric interfacial layer and high-k material. In this paper, the methods to form IL are the key point of EOT scaling down with gate leakage sacrifice and post replacement metal gate (RMG) treatment lead to work function improvement with hysteresis reduction beyond 20nm node of CMOS devices. Based on data analysis we want to get some optimized conditions to make this layer an enhancement in the research of HKMG logic product process development.

For 20/16nm HK-last and MG-last process, Dummy poly is removed by Wet process. This paper studies the factors impacting the dummy poly removal process, and presents some models to explain the impacting factors. Implant process is one of main factors influencing dummy poly removal capability because the differences of implant ions and doping amount into dummy poly induce difference of poly removal rate by wet process. We also study poly surface single clean, multiple clean and thermal process. Based on the model, we plan N-type doping poly and P-type doping poly with different ion doping amounts on blank wafer and 20nm structure wafers to evaluate dummy poly removal. We find dummy poly removal rate is different between N-type doping poly and P-type doping poly, and receive different dummy poly removal trend by ion amount on N-type doping poly and P-type doping poly. The model can help to improve dummy poly removal process control.

Steel storage rack structures have always been the mainly used type of those cold-formed thin-walled steel elements. Recently, it becomes more important to study its stability and bearing capacity. This paper selects a typical type of rack column-channel column and performs lots of analyzing work about overall buckling, local buckling and distortional buckling of perforated columns with different openings by using the finite element method.

We present an unconventional approach to antiviral drug discovery, which is used to identify potent small molecules against rabies virus. First, we conceptualized viral capsid assembly as occurring via a host-catalyzed biochemical pathway, in contrast to the classical view of capsid formation by self-assembly. This suggested opportunities for antiviral intervention by targeting previously unappreciated catalytic host proteins, which were pursued. Second, we hypothesized these host proteins to be components of heterogeneous, labile, and dynamic multi-subunit assembly machines, not easily isolated by specific target protein-focused methods. This suggested the need to identify active compounds before knowing the precise protein target. A cell-free translation-based small molecule screen was established to recreate the hypothesized interactions involving newly synthesized capsid proteins as host assembly machine substrates. Hits from the screen were validated by efficacy against infectious rabies virus in mammalian cell culture. Used as affinity ligands, advanced analogs were shown to bind a set of proteins that effectively reconstituted drug sensitivity in the cell-free screen and included a small but discrete subfraction of cellular ATP-binding cassette family E1 (ABCE1), a host protein previously found essential for HIV capsid formation. Taken together, these studies advance an alternate view of capsid formation (as a host-catalyzed biochemical pathway), a different paradigm for drug discovery (whole pathway screening without knowledge of the target), and suggest the existence of labile assembly machines that can be rendered accessible as next-generation drug targets by the means described.

This paper presents a reactive power optimization method considering seasonal load changing based on a two-year project. Data of lines, transformers and seasonal load were taken into account to create a simulation model. By taking the moment when the load is maximum in each season, flow of the distribution network was calculated. The calculation results were closer to the actual measurement results. Based on Genetic algorithm, four reactive compensation plan along with seasons were got. The paper got a best project Considerating the line losses, Voltage qualification rate and bus voltage Security. The best reactive power optimization result can significantly reduce the distribution network losses and improve voltage qualification rate.