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<p dir="ltr">In this study, we presented the discovery of the first-in-class covalent inhibitor specific to Src homology 2 domain containing phosphatase 1 (SHP1), an overlooked cancer immunotherapy target. Through high-throughput screening, we identified a chloroacetamide fragment highly selective for SHP1. This fragment was subsequently refined to yield M029, a covalent inhibitor characterized by low-micromolar potency, heightened selectivity, enhanced stability, and improved bioavailability. Notably, M029 targets a cryptic, non-conserved cysteine residue on SHP1, thereby illuminating novel avenues for future drug development focused on SHP1. This presented study also marked the first characterization of SHP1 pharmacology inhibition <i>in vivo</i> using M029 as a tool compound. Consistent to previous genetic studies, SHP1 inhibition was observed to markedly bolster anti-tumor efficacy, primarily through the activation of CD8+ T cells and NK cells, coupled with a reduction in T cell exhaustion. While no synergistic effects were noted in conjunction with anti-PD-1 treatment, M029 as a standalone therapy showcased more favorable responses compared to anti-PD-1 therapy alone, underscoring its potential for clinical application.</p><p dir="ltr">Meanwhile, we also demonstrated the effects of targeting both protein tyrosine phosphatase 1B (PTP1B), and T cell protein tyrosine phosphatase (TC-PTP) using proteolysis targeting chimeras (PROTACs). PROTACs are heterobifunctional small molecules comprising a targeted protein ligand, an E3 ligase ligand, and a linker. By recruiting an E3 ligase to the targeted proteins, PROTACs leverages the cell's ubiquitin-proteasome machinery to achieve selective target protein degradation. In contrast to traditional occupancy-based inhibitors, event-driven PROTACs show improved efficacy by promoting target protein degradation in a catalytic mode of action and greater selectivity through the obligatory formation of the target-PROTAC-E3 ternary complex, which is essential for efficient target degradation. Through optimizing the previously reported PROTAC DU-14, we acquired a cereblon (CRBN)-based PTP1B/TC-PTP dual targeting PROTAC X1 of higher bioavailability than DU-14. X1 showed enhanced efficacy than DU-14 in multiple cell lines and manifested anti-cancer efficacy <i>in vivo</i>. Additionally, employing X1 as a tool compound, we validated the anti-cancer potential of PTP1B/TC-PTP degradation in STAT3 dependent malignancies, such as non-Hodgkin’s lymphomas. Treatments with X1 or DU-14 effectively induced tumor cell apoptosis, whereas the dual inhibitor ABBV-CLS-484 failed to produce comparable outcomes.</p>

The efficiency of wastewater treatment systems is commonly measured by the reductions of parameters such as biological oxygen demand (BOD), chemical oxygen demand (COD) and total suspended solids (TSS) and/or reductions in levels of selected macro compounds (e.g. long-chained hydrocarbons and inorganic compounds). Less attention has generally been paid to micropollutants with high potential toxic effects, such as polycyclic aromatic compounds (PACs), including unsubstituted and alkylated polycyclic aromatic hydrocarbons (PAHs) and dibenzothiophenes, polychlorinated biphenyls (PCBs), human pharmaceuticals and by-products formed during the treatment process. These organic micropollutants occur in wastewaters at trace and ultra-trace levels, therefore their detection requires advanced, costly analyses and large sample volumes. Furthermore, concentrations of micropollutants can fluctuate widely both diurnally and between days. Thus, in order to understand the fate of micropollutants in wastewaters there is a need to develop sampling techniques that allow representative samples to be readily collected. In the work underlying this thesis two types of diffusive passive samplers, semipermeable membrane devices (SPMDs) and polar organic chemical integrative samplers (POCISs), were used to monitor non-polar and polar organic micropollutants in wastewaters subjected to various treatment processes. The pollutants sequestered in these samplers represent micropollutants in the dissolved phase that are available for aquatic organisms. Further, since they collect pollutants in an integrative manner, i.e. they sample continuously during the selected exposure time (usually approx. one to ca. three weeks), the results provide time-weighted average (TWA) concentrations. In addition, the effects of various environmental factors on the uptake of analyzed micropollutants in POCISs and SPMDs were investigated using laboratory calibration and in situ calibration with performance reference compounds (PRCs). The results confirm that SPMDs are good sampling tools for investigating the efficacy of wastewater treatment processes for removing non-polar PACs and PCBs, and the effects of varying the process settings. In addition, analyses of process streams in municipal sewage treatment plants demonstrated that conventional sewage treatment processes are not optimized for removing dissolved four-ringed PAHs, some of the five-ringed PAHs, and tri- to hexa-chlorinated biphenyls. The removal of bioavailable PACs was enhanced by adding sorbents with high sorption capacities to the sludge used in the activated sludge treatment step, and a biologically activated carbon system was designed that robustly removed bioavailable PACs, with removal efficiencies of 96.9-99.7 percent across the tested ranges of five varied process parameters. In situ SPMD calibration data acquired show that uptake of PACs, described by SPMD sampling rates (Rs), were four to eight times higher than published laboratory calibrated Rs values, mainly due to strong (bio)fouling and turbulence effects. In addition, the laboratory calibration study demonstrated that temperature affects the POCIS uptake of pharmaceuticals. The uptake of four pharmaceuticals was higher, by 10-56 percent, at 18 °C compared to 5 °C. For two of the pharmaceuticals our data indicate that the uptake was lower by 18-25 percent at 18 °C. Our results also indicate that uptake of the studied pharmaceuticals was in the linear phase throughout the 35 day exposure period at both temperatures. Finally, calibration studies enabled aqueous concentrations of micropollutants to be more accurately estimated from amounts collected in the passive samplers.

The conventional Mini and Large scale Unmanned Aerial Vehicle systems span anywhere from approximately 12 inches to 12 feet; endowing them with larger propulsion systems, batteries/fuel-tanks, which in turn provide ample power reserves for long-endurance flights, powerful actuators, on-board avionics, wireless telemetry etc. The limitations thus imposed become apparent when shifting to Micro Aerial Vehicles (MAVs) and trying to equip them with equal or near-equal flight endurance, processing, sensing and communication capabilities, as their larger scale cousins. The conventional MAV as outlined by The Defense Advanced Research Projects Agency (DARPA) is a vehicle that can have a maximum dimension of 6 inches and weighs no more than 100 grams. Under these tight constraints, the footprint, weight and power reserves available to on-board avionics and actuators is drastically reduced; the flight time and payload capability of MAVs take a massive plummet in keeping with these stringent size constraints. However, the demand for micro flying robots is increasing rapidly. The applications that have emerged over the years for MAVs include search&rescue operations for trapped victims in natural disaster succumbed urban areas; search&reconnaissance in biological, radiation, natural disaster/hazard succumbed/prone areas; patrolling&securing home/office/building premises/urban areas. VTOL capable rotary and fixed wing flying vehicles do not scale down to micro sized levels, owing to the severe loss in aerodynamic efficiency associated with low Reynolds number physics on conventional airfoils; whereas, present state of the art in flapping wing designs lack in one or more of the minimum qualities required from an MAV: Appreciable flight time, appreciable payload capacity for on-board sensors/telemetry and 6DoF hovering/VTOL performance. This PhD. work is directed towards overcoming these limitations. Firstly, this PhD thesis presents the advent of a novel Quad-Wing MAV configuration (called the QV). The Four-Wing configuration is capable of performing all 6DoF flight maneuvers including VTOL. The thesis presents the design, conception, simulation study and finally hardware design/development of the MAV. Secondly, this PhD thesis proves and demonstrates significant improvement in on-board Energy-Harvesting resulting in increased flight times and payload capacities of the order of even 200%-400% and more. Thirdly, this PhD thesis defines a new actuation principle called, Fixed Frequency, Variable Amplitude (FiFVA). It is demonstrated that by the use of passive elastic members on wing joints, a further significant increase in energy efficiency and consequently reduction in input power requirements is observed. An actuation efficiency increase of over 100% in many cases is possible. The natural evolution of actuation development led to invention of two novel actuation systems to illustrate the FiFVA actuation principle and consequently show energy savings and flapping efficiency improvement. Lastly, but not in the least, the PhD thesis presents supplementary work in the design, development of two novel Micro Architecture and Control (MARC) avionics platforms (autopilots) for the application of demonstrating flight control and communication capability on-board the Four-Wing Flapping prototype. The design of a novel passive feathering mechanism aimed to improve lift/thrust performance of flapping motion is also presented.

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<p> </p> <p>Infectious diseases caused by bacteria, fungi, and plasmodium parasites are a huge global health problem which ultimately leads to millions of deaths annually. The emergence of strains that exhibit resistance to nearly every class of antimicrobial agents, and the inability to keep up with these resistance trends has brought to the fore the need for new therapeutic agents (antibacterial, antifungal, and antimalarial) with novel scaffolds and functionalities capable of targeting microbial resistance. A novel class of compounds featuring an aryl isonitrile moiety has been discovered that exhibits potent inhibitory activity against several clinically relevant strains of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). Synthesis, structure-activity relationship (SAR) studies, and biological investigations have led to lead molecules that exhibit anti-MRSA inhibitory activity as low as 1 – 2 µM. The most potent compounds have also been shown to have low toxicity against mammalian cells and exhibit <i>in vivo</i> efficacy in MRSA skin and thigh infection mouse models.</p> <p>The novel aryl isonitriles have also been evaluated for antifungal activity. This study examines the SAR of aryl isonitrile compounds and showed the isonitriles as compounds that exhibit broad spectrum antifungal activity against species of <i>Candida</i> and <i>Cryptococcus</i>. The most potent derivatives are capable of inhibiting growth of these pathogens at concentrations as low as 0.5 µM. Notably, the most active compounds exhibit excellent safety profile and are non-toxic to mammalian cells up to 256 µM.</p> <p>Beyond the antibacterial and antifungal activities, structure-antimalarial relationship analysis of over 40 novel aryl isonitrile compounds has established the importance of the isonitrile functionality as an important moiety for antimalarial activity. Of the many isonitrile compounds exhibiting potent antimalarial activity, two have emerged as leads with activity comparable to that of Artemisinin. The SAR details presented in this study will prove essential for the development new aryl isonitrile analogues to advance them to the next step in the antimalarial drug discovery process.</p> <p>17-nor-Excelsinidine, a zwitterion monoterpene indole alkaloid isolated from <i>Alstonia scholaris</i> is a subject of synthetic scrutiny. This is primarily due to its intriguing chemical structure which includes a bridged bicyclic ammonium moiety, and its anti-adenovirus and anti-HSV activity. Herein we describe a six-step total synthesis of (±)-17-nor-Excelsinidine from tryptamine. Key to the success of this synthesis is the use of palladium-catalyzed carbonylative heck lactamization methodology which built the 6, 7-membered ring lactam in one step. The resulting pentacyclic product, beyond facilitating the easy access to (±)-17-nor-Excelsinidine, could also serve as a precursor to other related indole alkaloids.</p> <br> <p> </p> <p></p>