Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic ...strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed.
Apolipoprotein E (apoE) (299 residues) is a highly helical protein that plays a critical role in cholesterol homeostasis. It comprises a four-helix bundle N-terminal (NT) and a C-terminal (CT) domain ...that can exist in lipid-free and lipid-associated states. In humans, there are two major apoE isoforms, apoE3 and apoE4, which differ in a single residue in the NT domain, with apoE4 strongly increasing risk of Alzheimer's disease (AD) and cardiovascular diseases (CVD). It has been proposed that the CT domain initiates rapid lipid binding, followed by a slower NT domain helix bundle opening and lipid binding to yield discoidal reconstituted high density lipoprotein (rHDL). However, the contribution of the NT domain on the CT domain organization in HDL remains poorly understood. To understand this, we employed Cys-specific cross-linking and spatially-sensitive fluorophores in the NT and CT domains of apoE3 and apoE4, and in isolated CT domain. We noted that the helices in isolated CT domain are oriented parallel to those in the neighboring molecule in rHDL, whereas full length apoE3 and apoE4 adopt either an anti-parallel or hairpin-like organization. It appears that the bulky NT domain determines the spatial organization of its CT domain in rHDL, a finding that has significance for apoE4, which is more susceptible to proteolytic cleavage in AD brains, showing increased accumulation of neurotoxic NT and CT fragments. We envisage that the structural organization of HDL apoE would have profound functional consequences in its ability to regulate cholesterol homeostasis in AD and CVD.
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•ApoE LDL receptor binding domain directs orientation of C-terminal domain in nascent HDL.•ApoE3 and apoE4 adopt anti-parallel or hairpin orientation in nascent HDL.•Isolated apoE C-terminal domain adopts parallel orientation in nascent HDL.•Site specific pyrene labeling and X-linking aid in inferring apoE alignment in HDL.
•The intensity modulation of two intense cyclones by the mesoscale eddies is investigated.•Mesoscale eddies can modulate LHF by ∼20 W m−2 over eddies during cyclone passage.•Knowledge of air-sea ...interaction associated with eddies is necessary for improving intensity forecasts.
The Bay of Bengal, an affluent region for mesoscale oceanic eddies, is also home to devastating tropical cyclones. The intensity modulation of two cyclones, Phailin (2013) and Fani (2019), in the Bay of Bengal by the oceanic eddies is studied. The intensities of both the cyclones rapidly changed after transiting over mesoscale eddies. The surface and subsurface oceanic conditions before and during the passage of the two cyclones were analysed. During Phailin (Fani), the cyclonic (anticyclonic) eddy resulted in significant (weak) sea surface temperature cooling due to the shallow (deep) D26 isotherm. Wind shear estimates revealed that it had no (minor) effect on the weakening (intensification) of Phailin (Fani). The analysis of enthalpy fluxes during the two cyclones has shown that during Phailin (Fani), the latent heat flux supply was reduced (enhanced) by 20 W m−2 (30 W m−2) over the regions of the cyclonic (anticyclonic) eddy due to significant (weak) sea surface temperature cooling. The case study of cyclone interaction with mesoscale oceanic eddies has shown that a thorough understanding of mesoscale eddies is vital for improving the accuracy of the cyclone intensity forecasts.
► MILP optimisation model to reschedule disrupted railway traffic. ► Linear disruption constraints to partition the solution space. ► Rescheduling is dependent on sequencing order of disrupted ...trains. ► Proposed non-standard sequencing procedure. ► It is possible to optimally reschedule small-sized problem instances.
Resolving disruptions, by dispatching and rescheduling conflicting trains is an NP-complete problem. Earlier literature classify railway operations as: (i) tactical scheduling, (ii) operational scheduling, and (iii) rescheduling. We distinguish the three based on operational criticality. Existing optimisation models do not distinguish precisely between scheduling and rescheduling based on constraints modelling; the only difference is in their objective function. Our model is the first of its kind to incorporate disruptions in an MILP model and to include conflicts-resolving constraints in the model itself. The major advantage of such a formulation is that only those trains which are disrupted are rescheduled and other non-conflicting trains retain their original schedules. Our model reschedules disrupted train movements on both directions of a single track layout with an objective to minimise total delay of all trains at their destinations. Using a small sized data it is proved that all possible conflicts out of a disruption are resolved. Apart from achieving optimal resolutions, we infer through experimental verification that a non-standard dispatch ordering is a requisite for global optimality, as cogitated by other authors.
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