Biased PN based impact angle constrained guidance using a nonlinear engagement model

Impact angle constrained guidance laws are important in many applications such as guidance of torpedoes, anti-ballistic missiles and reentry vehicles. In this paper, we design a guidance law which is capable of achieving a wide range of impact angles. Biased proportional navigation guidance uses a bias term in addition to the basic PN command to satisfy additional constraints. Angle constrained BPNG (ACBPNG) uses small angle approximations to derive the bias term for impact angle requirement. We design a modified ACBPNG (MACBPNG) where the required bias term is derived in a closed form considering non-linear equations of motion. Simulations are carried out for a wide range of impact angle requirements. We also analyze capturability from different initial positions and also the launch angles possible at each initial position. The performance of the proposed law is compared with an existing law.

Non-singular terminal sliding mode guidance and control with terminal angle constraints for non-maneuvering targets

In this paper guidance laws to intercept stationary and constant velocity targets at a desired impact angle, based on sliding mode control theory, are proposed. The desired impact angle, which is defined in terms of a desired line-of-sight (LOS) angle, is achieved in finite time by selecting the missile's lateral acceleration (latax) to enforce non-singular terminal sliding mode on a switching surface designed using this desired LOS angle and based on non-linear engagement dynamics. Numerical simulation results are presented to validate the proposed guidance laws for different initial engagement geometries and impact angles.

First-in-Class Inhibitors of Sulfur Metabolism with Bactericidal Activity against Non-Replicating M-tuberculosis

Development of effective therapies to eradicate persistent, slowly replicating M. tuberculosis (Mtb) represents a significant challenge to controlling the global TB epidemic. To develop such therapies, it is imperative to translate information from metabolome and proteome adaptations of persistent Mtb into the drug discovery screening platforms. To this end, reductive sulfur metabolism is genetically and pharmacologically implicated in survival, pathogenesis, and redox homeostasis of persistent Mtb. Therefore, inhibitors of this pathway are expected to serve as powerful tools in its preclinical and clinical validation as a therapeutic target for eradicating persisters. Here, we establish a first functional HTS platform for identification of APS reductase (APSR) inhibitors, a critical enzyme in the assimilation of sulfate for the biosynthesis of cysteine and other essential sulfur-containing molecules. Our HTS campaign involving 38?350 compounds led to the discovery of three distinct structural classes of APSR inhibitors. A class of bioactive compounds with known pharmacology displayed potent bactericidal activity in wild-type Mtb as well as MDR and XDR clinical isolates. Top compounds showed markedly diminished potency in a conditional Delta APSR mutant, which could be restored by complementation with Mtb APSR. Furthermore, ITC studies on representative compounds provided evidence for direct engagement of the APSR target. Finally, potent APSR inhibitors significantly decreased the cellular levels of key reduced sulfur-containing metabolites and also induced an oxidative shift in mycothiol redox potential of live Mtb, thus providing functional validation of our screening data. In summary, we have identified first-in-class inhibitors of APSR that can serve as molecular probes in unraveling the links between Mtb persistence, antibiotic tolerance, and sulfate assimilation, in addition to their potential therapeutic value.