Pricing decisions for three-echelon supply chain with advertising and quality effort-dependent fuzzy demand

Simultaneous influence of market power structure, advertising and quality efforts on the optimal pricing decisions and performance of a multi-echelon supply chain under uncertainty have received scant attention in the literature. We focus on this gap by examining a serial decentralised three-echelon supply chain consisting of a supplier, a manufacturer and a retailer. The uncertainty associated with customer demand, marginal production costs and effort costs is expressed as linguistic or fuzzy variables. We analyse centralised supply chain to obtain all benchmark parameters. We investigate four decentralised supply chain cases through fuzzy game theoretic approach. We compare among three Stackelberg games with various supply chain leaderships and a vertical Nash. Our key findings are as follows. First, the manufacturer puts least quality effort while retailer puts least advertising effort when they act as Stackelberg leader in a three-echelon supply chain. Second, supplier's per unit price is governed by the channel leadership in three-echelon supply chain while retail prices are less affected by the leadership. We investigate the impact of fuzzy degree of quality and advertising sensitivity on optimal profit distribution among agents. We present numerical analysis to illustrate the importance of the derived theoretical results and discuss additional managerial insights.     

A Novel Human Neutralizing mAb Recognizes Delta,Gamma and Omicron Variants of SARS-CoV-2 and Can Be Used in Combination with Sotrovimab

The dramatic experience with SARS-CoV-2 has alerted the scientific community to be ready to face new epidemics/pandemics caused by new variants. Among the therapies against the pandemic SARS-CoV-2 virus, monoclonal Antibodies (mAbs) targeting the Spike glycoprotein have represented good drugs to interfere in the Spike/ Angiotensin Converting Enzyme-2 (ACE-2) interaction, preventing virus cell entry and subsequent infection, especially in patients with a defective immune system. We obtained, by an innovative phage display selection strategy, specific binders recognizing different epitopes of Spike. The novel human antibodies specifically bind to Spike-Receptor Binding Domain (RBD) in a nanomolar range and interfere in the interaction of Spike with the ACE-2 receptor. We report here that one of these mAbs, named D3, shows neutralizing activity for virus infection in cell cultures by different SARS-CoV-2 variants and retains the ability to recognize the Omicron-derived recombinant RBD differently from the antibodies Casirivimab or Imdevimab. Since anti-Spike mAbs, used individually, might be unable to block the virus cell entry especially in the case of resistant variants, we investigated the possibility to combine D3 with the antibody in clinical use Sotrovimab, and we found that they recognize distinct epitopes and show additive inhibitory effects on the interaction of Omicron-RBD with ACE-2 receptor. Thus, we propose to exploit these mAbs in combinatorial treatments to enhance their potential for both diagnostic and therapeutic applications in the current and future pandemic waves of coronavirus.     

LYTACs: An Emerging Tool for the Degradation of Non-Cytosolic Proteins

In the last two decades, targeted protein degradation has rapidly gained popularity as a technique to eliminate disease-causing undruggable proteins. Over the years, many tools have been devised to degrade proteins by exploiting natural protein homeostasis machinery available in our body, with LYTACs being the latest to come on board. LYTACs, or lysosome-targeting chimeras, make use of the lysosome degradation pathway by recruiting proteins to lysosome-shuttling receptors located at the cell surface. LYTACs are specifically meant for the degradation of membrane-bound and extracellular proteins, which account for the products of 40 % of all protein-encoding genes. In this highlight, we describe two studies that demonstrate the scope of LYTACs and its advantages over the other protein degradation platforms. In the first study, the LYTAC utilizes the cation-independent mannose-6-phosphate receptor (CI−M6PR), while the second study uses the asialoglycoprotein receptor (ASGPR) which is found only on the surface of liver cells.     

Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool

Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising molecules for interventions for type 2 diabetes. Once weekly dosing brings greater patient compliance and more stable glycemic control. Starting from our previous highly potent compound with a thienoprimidine scaffold, which is unfortunately severely hit by hepatic biotransformation, a lead compound was rapidly generated by drawing on the experience of our previously discovered long-acting compounds with pyrrolopyrimidine scaffold. With the aid of an in silico biotransformation prediction tool, (R)-2-((2-(3-aminopiperidin-1-yl)-4-oxo-6-(pyridin-3-yl)thieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-fluorobenzonitrile was eventually generated and determined to have high potency, a fine pharmacokinetic profile, and a long-acting in vivo efficacy.     

Robust Antiskyrmion Phase in Bulk Tetragonal Mn–Pt(Pd)–Sn Heusler System Probed by Magnetic Entropy Change and AC‐Susceptibility Measurements

Magnetic skyrmions, topologically protected chiral spin textures having potential applications in data storage, are stabilized in certain magnetic materials with broken inversion symmetry. The existence of magnetic antiskyrmions has been recently demonstrated in thin plates of a tetragonal Heusler material with D_2d crystal symmetry. Here, the robust nature of the antiskyrmion phase in bulk tetragonal Mn–Pt(Pd)–Sn compounds by utilizing magnetic entropy change and AC‐susceptibility measurements is shown. It is found that the formation of the antiskyrmion phase is accompanied by a positive magnetic entropy change, which is supported by the concomitant observation of an anomaly in AC‐susceptibility measurements. Supporting these findings, no anomalies are found in AC‐susceptibility and magnetic entropy change measurements for a Mn–Pt(Pd)–Sn compound that is stabilized in the cubic phase by slight changes in chemical composition, thereby showing the robustness of the antiskyrmion phase to the D_2d crystal structure.     

RGO/MgO hybrid nanocomposites with high specific capacitance

A scalable, cost effective synthesis of reduced graphene oxide (RGO)-magnesium oxide (MgO) hybrid nanocomposite (RGOMOHNC) is reported in the present work. The process involves an in-situ sonication method in aqueous medium at room temperature e.g., 30 °C. The as synthesized graphene oxide (GO) and RGOMOHNC powders are characterized by the XRD, FESEM, TEM, FTIR, RS and XPS techniques. The results indicate that in-situ growth of 20–30 nm MgO nanoparticles effectively increases the graphitic nature of the layered RGO microstructure. The experimentally measured cyclic voltammetry (CV) plots show that the specific capacitance of the RGOMOHNC powders is three orders of magnitude higher than that of the GO powders. A mechanism of RGOMOHNC formation has been proposed.     

Mutational studies on conserved histidine residues in the chlorophyll-binding protein CP43 of photosystem II

Two chlorophyll-binding antenna proteins in the photosystem II core, CP43 and CP47, are structurally similar and are thought to have evolved from a common ancestor. Several conserved histidine residues in hydrophobic regions of CP47 have been shown to be important for photosystem II structure, function, and energy transfer. The purpose of this study was to determine whether similarly located histidine residues in CP43 function in a similar way. Three conserved histidine residues in presumed membrane-spanning regions of CP43, His40, His105, and His119, were mutated to glutamine (Q) and tyrosine (Y). The strains H105Q, H119Q, and H119Y were photoautotrophs whereas H40Q, H40Y, and H105Y were obligate photoheterotrophs. The H40Y and H105Y strains lacked detectable amounts of photosystem II reaction centers and hence could not evolve oxygen whereas H40Q retained a significant amount of photosystem II and oxygen evolution capacity. The observation that mutation of histidine residues to tyrosine has more drastic effects than mutation of these residues to glutamine is in agreement with results obtained for CP47 and suggests the involvement of these residues in chlorophyll binding. The drastic functional changes observed upon mutating His40 and His105 of CP43 are similar to those observed when mutating the corresponding histidine residues in CP47, thus suggesting that the similarity between CP43 and CP47 extends to the relative importance of functionally relevant residues. Interestingly, the His40-->Gln mutation in CP43 had significant effects on photosystem II electron transfer in that it affected the thermodynamics of Q(A)- oxidation by Q(B) and increased the charge recombination rate between Q(A)- and donor side components. This indicates that relatively minor changes in CP43 can significantly impact the properties of the photosystem II reaction center. The implications of this finding are discussed.     

Simulation, fabrication and characterization of a novel P-I-N-drainMOSFET structure for hot carrier suppression

A new P-I-N-drain MOSFET structure has been developed with very low (near-intrinsic) doping (10¹⁵-10¹⁶ cm^-3 in our case) in the channel near the source/drain ends. The new structure is more effective in reducing the peak electric field at the channel/drain junction than LDD structures, and hence results in better hot carrier suppression. Also, simulations show that the near-intrinsic region near the drain reduces the transverse electric field and gives rise to higher carrier mobility and drive current. Experimental results show that, with the new structure, the substrate current and oxide charging due to hot-carrier injection are greatly reduced     

An assessment of missed opportunities for immunization in children and pregnant women attending different health facilities of a state hospital

Coronary pacing has been performed to treat bradycardias occurring during percutaneous transluminal coronary angioplasty (PTCA) using an angioplasty guidewire. We describe a case of a 62-year-old man who developed ventricular tachycardia (VT) during PTCA. The tachycardia was successfully terminated by overdrive pacing via an angioplasty guidewire.