Protein tyrosine phosphatases (PTPs) are essential signaling enzymes that, together with protein tyrosine kinases, regulate tyrosine phosphorylation inside the cell. Proper level of tyrosine ...phosphorylation is important for a diverse array of cellular processes, such as proliferation, metabolism, motility, and survival. Aberrant tyrosine phosphorylation, resulting from alteration of PTP expression, misregulation, and mutation, has been linked to the etiology of many human ailments including cancer, diabetes/obesity, autoimmune disorders, and infectious diseases. However, despite the fact that PTPs have been garnering attention as compelling drug targets, they remain a largely underexploited resource for therapeutic intervention. Indeed, PTPs have been widely dismissed as "undruggable", due to concerns that (1) the highly conserved active site (i.e., pTyr-binding pocket) makes it difficult to achieve inhibitor selectivity among closely related family members, and (2) the positive-charged active site prefers negatively charged molecules, which usually lack cell permeability. To address the issue of selectivity, we advanced a novel paradigm for the acquisition of highly potent and selective PTP inhibitors through generation of bivalent ligands that interact with both PTP active site and adjacent unique peripheral pockets. To overcome the bioavailability issue, we have identified nonhydrolyzable pTyr mimetics that are sufficiently polar to bind the PTP active site, yet still capable of efficiently penetrating cell membranes. We show that these pTyr mimetics interact in the desired inhibitory fashion with the PTP active site and tethering them to appropriate molecular fragments to engage less conserved interactions outside of PTP active site can increase PTP inhibitor potency and selectivity. We demonstrate through three pTyr mimetics fragment-based approaches that it is completely feasible to obtain highly potent and selective PTP inhibitors with robust in vivo efficacy in animal models of oncology, diabetes/obesity, autoimmune disorders, and tuberculosis. We hope that these results will help dispel concerns about the druggability of PTPs and entice further effort in fostering a PTP-based drug discovery enterprise. Well-characterized, potent, selective and bioactive inhibitors are essential tools for functional interrogation of PTPs in disease biology and target validation. They will also play a critical role in illuminating the druggability of PTPs and provide the groundwork for new therapies for the treatment of human diseases.
Triggered by the growing needs of developing semiconductor devices at ever‐decreasing scales, strain engineering of 2D materials has recently seen a surge of interest. The goal of this principle is ...to exploit mechanical strain to tune the electronic and photonic performance of 2D materials and to ultimately achieve high‐performance 2D‐material‐based devices. Although strain engineering has been well studied for traditional semiconductor materials and is now routinely used in their manufacturing, recent experiments on strain engineering of 2D materials have shown new opportunities for fundamental physics and exciting applications, along with new challenges, due to the atomic nature of 2D materials. Here, recent advances in the application of mechanical strain into 2D materials are reviewed. These developments are categorized by the deformation modes of the 2D material–substrate system: in‐plane mode and out‐of‐plane mode. Recent state‐of‐the‐art characterization of the interface mechanics for these 2D material–substrate systems is also summarized. These advances highlight how the strain or strain‐coupled applications of 2D materials rely on the interfacial properties, essentially shear and adhesion, and finally offer direct guidelines for deterministic design of mechanical strains into 2D materials for ultrathin semiconductor applications.
The strain engineering of 2D materials is particularly exciting, because an individual sheet can survive remarkably large mechanical strain and its atomic thinness allows mechanical deformations like a piece of paper. These exceptional circumstances create opportunities for the study of new fundamental physics and applications of 2D materials emerging at the large strain level.
5G Key Technologies for Smart Railways Ai, Bo; Molisch, Andreas F.; Rupp, Markus ...
Proceedings of the IEEE,
06/2020, Volume:
108, Issue:
6
Journal Article
Peer reviewed
Open access
Railway communications has attracted significant attention from both academia and industries due to the booming development of railways, especially high-speed railways (HSRs). To be in line with the ...vision of future smart rail communications, the rail transport industry needs to develop innovative communication network architectures and key technologies that ensure high-quality transmissions for both passengers and railway operations and control systems. Under high mobility and with safety, eco-friendliness, comfort, transparency, predictability, and reliability. Fifth-generation (5G) technologies could be a promising solution to dealing with the design challenges on high reliability and high throughput for HSR communications. Based on our in-depth analysis of smart rail traffic services and communication scenarios, we propose a network slicing architecture for a 5G-based HSR system. With a ray tracing-based analysis of radio wave propagation characteristics and channel models for millimeter wave (mmWave) bands in railway scenarios, we draw important conclusions with regard to appropriate operating frequency bands for HSRs. mymargin Specifically, we have identified significant 5G-based key technologies for HSRs, such as spatial modulation, fast channel estimation, cell-free massive multiple-input-multiple-output (MIMO), mmWave, efficient beamforming, wireless backhaul, ultrareliable low latency communications, and enhanced handover strategies. Based on these technologies, we have developed a complete framework of 5G technologies for smart railways and pointed out exciting future research directions.
Protein tyrosine phosphorylation is a key regulatory process in virtually all aspects of cellular functions. Dysregulation of protein tyrosine phosphorylation is a major cause of human diseases, such ...as cancers, diabetes, autoimmune disorders, and neurological diseases. Indeed, protein tyrosine phosphorylation-mediated signaling events offer ample therapeutic targets, and drug discovery efforts to date have brought over two dozen kinase inhibitors to the clinic. Accordingly, protein tyrosine phosphatases （PTPs） are considered next-generation drug targets. For instance, PTPIB is a well-known targets of type 2 diabetes and obesity, and recent studies indicate that it is also a promising target for breast cancer. SHP2 is a bona-fide oncoprotein, mutations of which cause juvenile myelomonocytic leukemia, acute myeloid leukemia, and solid tumors. In addition, LYP is strongly associated with type I diabetes and many other autoimmune diseases. This review summarizes recent findings on several highly recognized PTP family drug targets, including PTPIB, Src homology phosphotyrosyl phosphatase 2 （SHP2）, lymphoid-specific tyrosine phosphatase （LYP）, CD45, Fas associated phosphatase-1 （FAP-1）, striatal enriched tyrosine phosphatases （STEP）, mitogen-activated protein kinase/dual-specificity phosphatase 1 （MKP-1）, phosphatases of regenerating liver-1 （PRL）, low molecular weight PTPs （LMWPTP）, and CDC25. Given that there are over 100 family members, we hope this review will serve as a road map for innovative drug discovery targeting PTPs.
Protein tyrosine phosphatases (PTP) are exciting and novel targets for cancer drug discovery that work in concert with protein tyrosine kinases (PTK) in controlling cellular homeostasis. Given the ...activating role that some PTKs play in initiating growth factor-mediated cellular processes, PTPs are usually perceived as the negative regulators of these events and therefore tumor suppressive in nature. However, mounting evidence indicate that PTPs do not always antagonize the activity of PTKs in regulating tyrosine phosphorylation, but can also play dominant roles in the initiation and progression of signaling cascades that regulate cell functions. It follows, therefore, that PTP malfunction can actively contribute to a host of human disorders, in particular, cancer, metabolic syndromes, and autoimmune diseases. The Src homology domain containing phosphatase 2 (SHP2) and the three-membered family of phosphatases of regenerating liver (PRL) are infamously oncogenic members of the PTP superfamily. Both are established regulators of major cancer pathways such as Ras/ERK1/2, Src, JAK/STAT, JNK, NF-κB, and PTEN/PI3K/AKT. Furthermore, upregulation, mutation, or other dysregulation of these PTPs has been positively correlated with cancer initiation and progression. This review will provide topical coverage of target validation and drug discovery efforts made in targeting these oncogenic PTPs as compelling candidates for cancer therapy.
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The MYB proteins comprise one of the largest families of transcription factors (TFs) in plants. Although several MYB genes have been characterized to play roles in secondary metabolism, the MYB ...family has not yet been identified in apple. In this study, 229 apple MYB genes were identified through a genome-wide analysis and divided into 45 subgroups. A computational analysis was conducted using the apple genomic database to yield a complete overview of the MYB family, including the intron-exon organizations, the sequence features of the MYB DNA-binding domains, the carboxy-terminal motifs, and the chromosomal locations. Subsequently, the expression of 18 MYB genes, including 12 were chosen from stress-related subgroups, while another 6 ones from other subgroups, in response to various abiotic stresses was examined. It was found that several of these MYB genes, particularly MdoMYB121, were induced by multiple stresses. The MdoMYB121 was then further functionally characterized. Its predicted protein was found to be localized in the nucleus. A transgenic analysis indicated that the overexpression of the MdoMYB121 gene remarkably enhanced the tolerance to high salinity, drought, and cold stresses in transgenic tomato and apple plants. Our results indicate that the MYB genes are highly conserved in plant species and that MdoMYB121 can be used as a target gene in genetic engineering approaches to improve the tolerance of plants to multiple abiotic stresses.
Although CRISPR-Cas9/Cpf1 have been employed as powerful genome engineering tools, heterologous CRISPR-Cas9/Cpf1 are often difficult to introduce into bacteria and archaea due to their severe ...toxicity. Since most prokaryotes harbor native CRISPR-Cas systems, genome engineering can be achieved by harnessing these endogenous immune systems. Here, we report the exploitation of Type I-B CRISPR-Cas of Clostridium tyrobutyricum for genome engineering. In silico CRISPR array analysis and plasmid interference assay revealed that TCA or TCG at the 5′-end of the protospacer was the functional protospacer adjacent motif (PAM) for CRISPR targeting. With a lactose inducible promoter for CRISPR array expression, we significantly decreased the toxicity of CRISPR-Cas and enhanced the transformation efficiency, and successfully deleted spo0A with an editing efficiency of 100%. We further evaluated effects of the spacer length on genome editing efficiency. Interestingly, spacers ≤ 20 nt led to unsuccessful transformation consistently, likely due to severe off-target effects; while a spacer of 30–38 nt is most appropriate to ensure successful transformation and high genome editing efficiency. Moreover, multiplex genome editing for the deletion of spo0A and pyrF was achieved in a single transformation, with an editing efficiency of up to 100%. Finally, with the integration of the alcohol dehydrogenase gene (adhE1 or adhE2) to replace cat1 (the key gene responsible for butyrate production and previously could not be deleted), two mutants were created for n-butanol production, with the butanol titer reached historically record high of 26.2 g/L in a batch fermentation. Altogether, our results demonstrated the easy programmability and high efficiency of endogenous CRISPR-Cas. The developed protocol herein has a broader applicability to other prokaryotes containing endogenous CRISPR-Cas systems. C. tyrobutyricum could be employed as an excellent platform to be engineered for biofuel and biochemical production using the CRISPR-Cas based genome engineering toolkit.
•The native Type I-B CRISPR-Cas of C. tyrobutyricum was harnessed for genome editing.•Off-target effects were revealed, and appropriate spacer length was suggested.•Single and multiplex genome editing were achieved with efficiencies of up to 100%.•Carbon flow was redirected to butanol by replacement of cat1 gene with adhE1/adhE2.•High level butanol (26.2 g/L) was obtained in batch fermentation at low temperature.
Melatonin (N‐acetyl‐5‐methoxytryptamine) is an important biological hormone in many abiotic stress responses and developmental processes. In this study, the protective roles of melatonin were ...investigated by measuring the antioxidant defense system and photosynthetic characteristics in maize under salt stress. The results indicated that NaCl treatment led to the decrease in plant growth, chlorophyll contents and photochemical activity of photosystem II (PSII). However, the levels of reactive oxygen species increased significantly under salt stress. Meanwhile, we found that application of exogenous melatonin alleviated reactive oxygen species burst and protected the photosynthetic activity in maize seedlings under salt stress through the activation of antioxidant enzymes. In addition, 100 μM melatonin‐treated plants showed high photosynthetic efficiency and salinity. Immunoblotting analysis of PSII proteins showed that melatonin application alleviated the decline of 34 kDa PSII reaction center protein (D1) and the increase of PSII subunit S protein. Taken together, our study promotes more comprehensive understanding in the protective effects of exogenous melatonin in maize under salt stress, and it may be involved in activation of antioxidant enzymes and regulation of PSII proteins.
Protein tyrosine phosphatases (PTPs) are an important class of enzymes that regulate protein tyrosine phosphorylation levels of a large variety of proteins in cells. Anomalies in protein tyrosine ...phosphorylation have been associated with the development of numerous human diseases, leading to a heightened interest in PTPs as promising targets for drug development. However, therapeutic targeting of PTPs has faced skepticism about their druggability. Besides the conventional small molecule inhibitors, proteolysis-targeting chimera (PROTAC) technology offers an alternative approach to target PTPs. PROTAC molecules utilize the ubiquitin-proteasome system to degrade specific proteins and have unique advantages compared with inhibitors: 1) PROTACs are highly efficient and can work at much lower concentrations than that expected based on their biophysical binding affinity; 2) PROTACs may achieve higher selectivity for the targeted protein than that dictated by their binding affinity alone; and 3) PROTACs may engage any region of the target protein in addition to the functional site. This review focuses on the latest advancement in the development of targeted PTP degraders and deliberates on the obstacles and prospective paths of harnessing this technology for therapeutic targeting of the PTPs.
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