Efficient Supply Chain Contracting with Loss-averse Players in Presence of Multiple Plausible Breaches

The legal literature distinguishes between the liquidated damage and the penalty clauses in contracts, and holds that penalties designed for the prevention of breach are excessive compared to the liquidated damages. In an efficient supply chain contract, the penalty must satisfy the participation and incentive compatibility constraints of the signatories. Considering loss-averse players, we have calculated optimal penalties in a supply chain contract and compared those with the liquidated damages. Two possible breaches are considered – a breach in quality of the delivery and a breach in the process. In the absence of any penalty, a process breach reduces the supplier’s delivery risk and cost of delivery. Determining the parametric conditions for efficient contracts, numerically we show the effects of various variables on the zone of efficient contract. We show that the optimal penalties need not be excessive compared to the liquidated damages

A GENERALIZED CODE FOR COMPUTING CYCLIC REDUNDANCY CHECK

This paper focuses on developing a generalized CRC code where the user can vary the size of the generator polynomial [1] such as 9 bits (CRC-8), 17 bits (CRC-16), 33 bits (CRC-32), 65 bits (CRC-64). The working of the code has been shown taking an example and the resulting simulations obtained are shown

All-Atom Molecular Dynamics Simulations Indicated the Involvement of a Conserved Polar Signaling Channel in the Activation Mechanism of the Type I Cannabinoid Receptor

The type I cannabinoid G protein-coupled receptor (CB1, GPCR) is an intensely investigated pharmacological target, owing to its involvement in numerous physiological functions as well as pathological processes such as cancers, neurodegenerative diseases, metabolic disorders and neuropathic pain. In order to develop modern medications that exert their effects through binding to the CB1 receptor, it is essential to understand the structural mechanism of activation of this protein. The pool of atomic resolution experimental structures of GPCRs has been expanding rapidly in the past decade, providing invaluable information about the function of these receptors. According to the current state of the art, the activity of GPCRs involves structurally distinct, dynamically interconverting functional states and the activation is controlled by a cascade of interconnecting conformational switches in the transmembrane domain. A current challenge is to uncover how different functional states are activated and what specific ligand properties are responsible for the selectivity towards those different functional states. Our recent studies of the mu-opioid and beta(2)-adrenergic receptors (MOP and beta(2)AR, respectively) revealed that the orthosteric binding pockets and the intracellular surfaces of these receptors are connected through a channel of highly conserved polar amino acids whose dynamic motions are in high correlation in the agonist- and G protein-bound active states. This and independent literature data led us to hypothesize that, in addition to consecutive conformational transitions, a shift of macroscopic polarization takes place in the transmembrane domain, which is furnished by the rearrangement of polar species through their concerted movements. Here, we examined the CB1 receptor signaling complexes utilizing microsecond scale, all-atom molecular dynamics (MD) simulations in order to see if our previous assumptions could be applied to the CB1 receptor too. Apart from the identification of the previously proposed general features of the activation mechanism, several specific properties of the CB1 have been indicated that could possibly be associated with the signaling profile of this receptor

Universal Properties and Specificities of the beta(2)-Adrenergic Receptor-G(s) Protein Complex Activation Mechanism Revealed by All-Atom Molecular Dynamics Simulations

G protein-coupled receptors (GPCRs) are transmembrane proteins of high pharmacological relevance. It has been proposed that their activity is linked to structurally distinct, dynamically interconverting functional states and the process of activation relies on an interconnecting network of conformational switches in the transmembrane domain. However, it is yet to be uncovered how ligands with different extents of functional effect exert their actions. According to our recent hypothesis, based on indirect observations and the literature data, the transmission of the external stimulus to the intracellular surface is accompanied by the shift of macroscopic polarization in the transmembrane domain, furnished by concerted movements of highly conserved polar motifs and the rearrangement of polar species. In this follow-up study, we have examined the beta(2)-adrenergic receptor (beta(2)AR) to see if our hypothesis drawn from an extensive study of the mu-opioid receptor (MOP) is fundamental and directly transferable to other class A GPCRs. We have found that there are some general similarities between the two receptors, in agreement with previous studies, and there are some receptor-specific differences that could be associated with different signaling pathways

Mobility enhancement in CVD-grown monolayer MoS2 via patterned substrate induced non-uniform straining

The extraordinary mechanical properties of 2D TMDCs make them ideal candidates for investigating strain-induced control of various physical properties. Here we explore the role of non-uniform strain in modulating optical, electronic and transport properties of semiconducting, chemical vapour deposited monolayer MoS2, on periodically nanostructured substrates. A combination of spatially resolved spectroscopic and electronic properties explore and quantify the differential strain distribution and carrier density on a monolayer, as it conformally drapes over the periodic nanostructures. The observed accumulation in electron density at the strained regions is supported by theoretical calculations which form the likely basis for the ensuing 60x increase in field effect mobility in strained samples. Though spatially non-uniform, the pattern induced strain is shown to be readily controlled by changing the periodicity of the nanostructures thus providing a robust yet useful macroscopic control on strain and mobility in these systems

Correlated Motions of Conserved Polar Motifs Lay out a Plausible Mechanism of G Protein-Coupled Receptor Activation

Recent advancements in the field of experimental structural biology have provided high-resolution structures of active and inactive state G protein-coupled receptors (GPCRs), a highly important pharmaceutical target family, but the process of transition between these states is poorly understood. According to the current theory, GPCRs exist in structurally distinct, dynamically interconverting functional states of which populations are shifted upon binding of ligands and intracellular signaling proteins. However, explanation of the activation mechanism, on an entirely structural basis, gets complicated when multiple activation pathways and active receptor states are considered. Our unbiased, atomistic molecular dynamics simulations of the μ opioid receptor (MOP) revealed that transmission of external stimulus to the intracellular surface of the receptor is accompanied by subtle, concerted movements of highly conserved polar amino acid side chains along the 7th transmembrane helix. This may entail the rearrangement of polar species and the shift of macroscopic polarization in the transmembrane domain, triggered by agonist binding. Based on our observations and numerous independent indications, we suggest amending the widely accepted theory that the initiation event of GPCR activation is the shift of macroscopic polarization between the ortho- and allosteric binding pockets and the intracellular G protein-binding interface

Diagnostic and therapeutic approaches to optic disc pit maculopathy in children

Background: Optic disc pit (ODP) is a rare congenital defect of the optic disc that can lead to maculopathy and gradual visual impairment. This review summarizes our current knowledge on the diagnostic and therapeutic approaches to ODP maculopathy (ODP-M) in children. Methods: A thorough literature search was performed using the PubMed/MEDLINE database from 1960 to 2020. An additional search was conducted using Google Scholar for completeness. Results: ODP-M is characterized by the accumulation of subretinal and/or intraretinal fluid. The exact pathogenetic mechanisms are not fully understood, and the origin of the fluid remains unknown. Although ODP-M is more likely to occur during the third or fourth decade of life, cases of children with serous retinal detachment have been recorded. Early diagnosis of ODP-M and prompt, appropriate management are crucial, particularly in patients of amblyogenic age. In adults, ODP-M may resolve spontaneously, but most cases require surgical intervention to prevent permanent loss of vision. However, the fact that ODP-M may spontaneously resolve in children cannot be ignored. Various surgical methods have been described, including pars plana vitrectomy (PPV) combined with various techniques, including laser photocoagulation, intravitreal gas injection, and macular buckling. Conclusions: PPV remains the mainstay surgical approach for ODP-M. However, ODP-M may differ between children and adults. Children constitute a unique population of patients that require a different and probably more tailor-made approach. Detailed clinical examination, combined with a thorough analysis of retinal imaging, may improve our understanding of the background and pathophysiology of the disease and eventually provide us with new insights into the management of ODP-M in the pediatric population. How to cite this article: Kalogeropoulos D, Asproudis I,  Ch’ng SW, Mitra A, Sharma A, Katsikatsos K, Asproudis C, Kalogeropoulos C. Diagnostic and therapeutic approaches to optic disc pit maculopathy in children. Med Hypothesis Discov Innov Optom.2021 Spring; 2(1): 24-35. DOI: https://doi.org/10.51329/mehdioptometry12

Intravitreal Fluocinolone Acetonide (ILUVIEN) Implant for the Treatment of Refractory Cystoid Macular Oedema After Retinal Detachment Repair

Cystoid macular oedema (CMO) is one of the most frequent postoperative macular complications to cause partial visual recovery after successful retinal detachment (RD) repair. Refractory CMO is difficult to treat and many strategies have been employed with varying degrees of success. We report for the first time the use of ILUVIEN implant to treat refractory CMO after successful RD repair. A 65-year-old female presented with right eye full-thickness macular hole and underwent pars plana vitrectomy, internal limiting membrane peeling and cryotherapy with gas tamponade with 12% C3F8. She subsequently developed right eye macula-on RD and proliferative vitreoretinopathy and required multiple procedures for successful retinal reattachment. Later, she developed CMO that responded to intravitreal triamcinolone injections and intravitreal dexamethasone 0.7-mg implants but recurrence of CMO continued to be a problem. After receiving ILUVIEN intravitreal implant, her visual acuity improved and CMO resolved without recurrence for 13 months. Refractory CMO after RD repair is difficult to treat and in a quarter of cases will not improve without treatment. Our case shows that a single ILUVIEN implant maintained anatomical dry fovea and improved vision. This also demonstrates that ILUVIEN is an effective management strategy to reduce the need for repeated treatments

The C-terminal Domain (CTD) of Human DNA GlycosylaseNEIL1 Is Required for Forming BERosome Repair Complex with DNA Replication Proteins at the Replicating Genome: DOMINANT NEGATIVE FUNCTION OF THE CTD

The human DNA glycosylase NEIL1 was recently demonstrated to initiate prereplicative base excision repair (BER) of oxidized bases in the replicating genome, thus preventing mutagenic replication. A significant fraction of NEIL1 in cells is present in large cellular complexes containing DNA replication and other repair proteins, as shown by gel filtration. However, how the interaction of NEIL1 affects its recruitment to the replication site for prereplicative repair was not investigated. Here, we show that NEIL1 binarily interacts with the proliferating cell nuclear antigen clamp loader replication factor C, DNA polymerase δ, and DNA ligase I in the absence of DNA via its non-conserved C-terminal domain (CTD); replication factor C interaction results in ~8-fold stimulation of NEIL1 activity. Disruption of NEIL1 interactions within the BERosome complex, as observed for a NEIL1 deletion mutant (N311) lacking the CTD, not only inhibits complete BER in vitro but also prevents its chromatin association and reduced recruitment at replication foci in S phase cells. This suggests that the interaction of NEIL1 with replication and other BER proteins is required for efficient repair of the replicating genome. Consistently, the CTD polypeptide acts as a dominant negative inhibitor during in vitro repair, and its ectopic expression sensitizes human cells to reactive oxygen species. We conclude that multiple interactions among BER proteins lead to large complexes, which are critical for efficient BER in mammalian cells, and the CTD interaction could be targeted for enhancing drug/radiation sensitivity of tumor cells

Effect of deprivation and ethnicity on primary macula-on retinal detachment repair success rate and clinical outcomes:A study of 568 patients

Purpose Socio-economic deprivation and ethnic variation have been frequently linked to poorer health outcomes. We collected a large series of primary macula-on rhegmatogenous retinal detachment (RRD) cases and analysed the effect of socio-economic deprivation and ethnicity on both six-month retinal re-detachment rate and visual outcomes. Materials and methods Retrospective consecutive case series of 568 patients attending Birmingham and Midlands Eye Centre from January 2017–2020. Multiple Indices of Deprivation (IMD) deciles were used for deprivation status and split to two groups: IMD-A (Decile 1–5) and IMD-B (Decile 6–10). The two largest subgroups of ethnicities were compared, White and South Asians (SA). Results We report an overall retinal re-detachment rate of 8.5%. IMD-A re-detached significantly more than IMD-B (11.2% vs 6.0% respectively, p = 0.034). No statistical significance was found between White and SA re-detachment rate (9.1% and 5.6% respectively, p = 0.604). SA median age significantly lower at 49 years (IQR: 37–61) compared to White patients at 57 years (IQR: 50–65) (p = Conclusion We demonstrated an increased retinal re-detachment rate in our more deprived patients according to IMD and a younger cohort of SA compared to White ethnicity. Further prospective studies are required to demonstrate the link between socio-economic deprivation and surgical success