As antibody-drug conjugates have become a very important modality for cancer therapy, many site-specific conjugation approaches have been developed for generating homogenous molecules. The selective ...antibody coupling is achieved through antibody engineering by introducing specific amino acid or unnatural amino acid residues, peptides, and glycans. In addition to the use of synthetic cytotoxins, these novel methods have been applied for the conjugation of other payloads, including non-cytotoxic compounds, proteins/peptides, glycans, lipids, and nucleic acids. The non-cytotoxic compounds include polyethylene glycol, antibiotics, protein degraders (PROTAC and LYTAC), immunomodulating agents, enzyme inhibitors and protein ligands. Different small proteins or peptides have been selectively conjugated through unnatural amino acid using click chemistry, engineered C-terminal formylglycine for oxime or click chemistry, or specific ligation or transpeptidation with or without enzymes. Although the antibody protamine peptide fusions have been extensively used for siRNA coupling during early studies, direct conjugations through engineered cysteine or lysine residues have been demonstrated later. These site-specific antibody conjugates containing these payloads other than cytotoxic compounds can be used in proof-of-concept studies and in developing new therapeutics for unmet medical needs.
Antibody-drug conjugates (ADCs) have become a promising class of antitumor agents with four conjugates being approved by regulatory agencies for treating cancer patients. To improve the conventional ...conjugations that are currently applied to generate these heterogeneous products, various site-specific approaches have been developed. These methods couple cytotoxins or chemotherapeutic drugs to specifically defined sites in antibody molecules including cysteine, glutamine, unnatural amino acids, short peptide tags, and glycans. The ADCs produced showed high homogeneity, increased therapeutic index, and strong antitumor activities in vitro and in vivo. Moreover, there are recent trends in using these next generation technologies beyond the cytotoxin-conjugated ADC. These site-specific conjugations have been applied for the generation of many different immunoconjugates including bispecific Fab or small molecule-antibody conjugates, immunosuppressive antibodies, and antibody-antibiotic conjugates. Thus, it is likely that additional technologies and related site-specific conjugates will emerge in the near future, with various chemicals or small molecular weight proteins in addition to cytotoxin for better treatment of many challenging diseases.
N-glycosylation is one of major post-translational modifications in nature, and it is essential for protein structure and function. As hydrophilic moieties of glycoproteins, N-glycans play important ...roles in protein stability. They protect the proteins against proteolytic degradation, aggregation, and thermal denaturation through maintaining optimal conformations. There are extensive evidences showing the involvement of N-glycans in the pharmacodynamics and pharmacokinetics of recombinant therapeutic proteins and antibodies. Highly sialylated complex-type glycans enable the longer serum half-lives of proteins against uptake through hepatic asialoglycoprotein receptor and mannose receptor for degradation in lysosomes. Moreover, the presence of nonhuman glycans results in clearance through pre-existing antibodies from serum and induces IgE-mediated anaphylaxis. N-glycans also facilitate or reduce the adverse immune responses of the proteins through interacting with multiple glycan-binding proteins, including those specific for mannose or mannose 6-phosphate. Due to the glycan impacts, a few therapeutic proteins were glycoengineered to improve the pharmacokinetics and stability. Thus, N-glycosylation should be extensively investigated and optimized for each individual protein for better efficacy and safety.
The noticeable proliferation of Starbucks outlets stands as a testament to the company’s burgeoning success in the market and its exceptional adaptability within the dynamic beverage industry ...landscape. In this paper, we embark on an in-depth exploration of various dimensions within Starbucks’ intricate marketing strategy, encompassing elements such as brand logo, brand loyalty, target consumer demographics, location selection criteria, pricing methodologies, product promotion tactics, and advertising strategies. As Starbucks continues its relentless global expansion, our comprehensive analysis endeavors to illuminate the multifaceted strategies that the company employs to sustain its preeminence in the fiercely competitive coffee market. The study delves into the ways Starbucks has effectively harnessed the power of its iconic brand logo, masterfully cultivated unwavering brand loyalty among its diverse consumer base, astutely catered to the unique preferences of specific target demographics, strategically handpicked prime locations for its outlets, meticulously positioned its pricing strategies, and innovatively deployed product promotion and advertising techniques. By conducting a thorough examination of these diverse facets that constitute the bedrock of Starbucks’ approach, our research seeks to offer invaluable insights into the complex interplay of factors that underlie the brand’s enduring prosperity and its enduring appeal on a global scale. As Starbucks’ influence continues to expand and evolve, our analysis aims to provide a comprehensive understanding of the dynamics that drive its continued success, making it a compelling case study for both academics and industry professionals alike.
The quantification of heating, ventilation, and air condition (HVAC) system flexibility is critical to the operations of both the grid and buildings in demand response (DR) programs. However, the ...flexibility quantification is challenging due to the non-linearity and non-convexity of thermal dynamics associated with HVAC components. This paper proposes a novel HVAC flexibility quantification method based on a semidefinite programming (SDP) formulation. The SDP is reformulated from the non-convex problem of HVAC power optimization, and can be solved efficiently in real-time. The physics-based HVAC model is incorporated to ensure the reliability and accuracy of solutions. The quantification results are organized into an HVAC flexibility table that can provide response strategies on adjusting HVAC setpoints in response to the grid signals received. The developed response strategies minimize occupant discomfort while satisfying grid requirements. A case study of a test building model is carried out to illustrate the flexibility quantification framework and compares the performance of two DR strategies.
Increasing evidence has supported the important role of mesenchymal stem cells (MSCs) in wound healing, however, the underlying mechanism remains unclear. Recently, we have isolated a unique ...population of MSCs from human gingiva (GMSCs) with similar stem cell‐like properties, immunosuppressive, and anti‐inflammatory functions as human bone marrow‐derived MSCs (BMSCs). We describe here the interplay between GMSCs and macrophages and the potential relevance in skin wound healing. When cocultured with GMSCs, macrophages acquired an anti‐inflammatory M2 phenotype characterized by an increased expression of mannose receptor (MR; CD206) and secretory cytokines interleukin (IL)‐10 and IL‐6, a suppressed production of tumor necrosis factor (TNF)‐α, and decreased ability to induce Th‐17 cell expansion. In vivo, we demonstrated that systemically infused GMSCs could home to the wound site in a tight spatial interaction with host macrophages, promoted them toward M2 polarization, and significantly enhanced wound repair. Mechanistically, GMSC treatment mitigated local inflammation mediated by a suppressed infiltration of inflammatory cells and production of IL‐6 and TNF‐α, and an increased expression of IL‐10. The GMSC‐induced suppression of TNF‐α secretion by macrophages appears to correlate with impaired activation of NFκB p50. These findings provide first evidence that GMSCs are capable to elicit M2 polarization of macrophages, which might contribute to a marked acceleration of wound healing. STEM CELLS 2010;28:1856–1868
Abnormal mitochondrial fission participates in the pathogenesis of many diseases. Long non-coding RNAs (lncRNAs) are emerging as new players in gene regulation, but how lncRNAs operate in the ...regulation of mitochondrial network is unclear. Here we report that a lncRNA, named cardiac apoptosis-related lncRNA (CARL), can suppress mitochondrial fission and apoptosis by targeting miR-539 and PHB2. The results show that PHB2 is able to inhibit mitochondrial fission and apoptosis. miR-539 is responsible for the dysfunction of PHB2 and regulates mitochondrial fission and apoptosis by targeting PHB2. Further, we show that CARL can act as an endogenous miR-539 sponge that regulates PHB2 expression, mitochondrial fission and apoptosis. Our present study reveals a model of mitochondrial fission regulation that is composed of CARL, miR-539 and PHB2. Modulation of their levels may provide a new approach for tackling apoptosis and myocardial infarction.
Carbon monoxide (CO) is attracting increasing attention because of its role as a gasotransmitter with cytoprotective and homeostatic properties. Carbon monoxide releasing molecules (CORMs) are ...spatially and temporally controlled CO releasers that exhibit superior and more effective pharmaceutical traits than gaseous CO because of their chemistry and structure. Experimental and preclinical research in animal models has shown the therapeutic potential of inhaled CO and CORMs, and the biological effects of CO and CORMs have also been observed in preclinical trials via the genetic modulation of heme oxygenase-1 (HO-1). In this review, we describe the pharmaceutical use of CO and CORMs, methods of detecting CO release, and developments in CORM design and synthesis. Many valuable clinical CORMs formulated using macromolecules and nanomaterials are also described.
Residential ON/OFF devices, such as thermal-controlled loads and smart appliances, have great potential for providing frequency regulation service in the power grid. These devices can be engaged ...using centralized, distributed, or local control. However, both centralized and distributed controls require significant costs for communication infrastructure, while local controllers may perform poorly due to a lack of coordination. To address the challenges, a stochastic demand-side management controller is proposed. The stochastic controller dynamically adjusts the aggregated response power profile by randomizing the execution of demand response actions using a stochastic filter with no communication required. The system frequency response is analytically proved to be critically damped to the nominal value. Using the stochastic controller on grid-interactive water heaters, test cases are implemented to validate the frequency regulation performance under a power system transient scenario. The proposed controller produces the best system frequency response compared to benchmark controllers.
Commercial buildings spend vast amount of money every year on their electricity consumption. Though optimal scheduling and control of commercial buildings had been widely discussed in the literature, ...coordination of multiple buildings connected to power networks still need further consideration. Privacy issue is a major consideration to building managers, which makes the coordination problem very challenging. This article first provides a convex formulation for the optimal operation of heating, ventilation, and air conditioning systems in commercial buildings. Then, this article proposes the use of the alternating direction method of multiplier to enable privacy-based coordination of multiple commercial buildings in the electric grid. The formulated problem considers the thermal discomfort of the occupants and the building power consumption on the one hand, and the power losses of the power network on the other hand. The algorithm uses minimal amount of exchanged data to avoid any privacy invasion. A case study of multiple commercial buildings is done on an IEEE 15-bus distribution system to verify the proposed problem formulation. The results showed that the algorithm can achieve comparable performance to the centralized case in terms of minimizing the thermal discomfort, power consumption, and power losses.
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