Expanding the ligandable proteome by paralog hopping with covalent probes.

More than half of the ~20,000 protein-encoding human genes have at least one paralog. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to a subset of paralogous proteins. Here, we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs that lack the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we mutated the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling (ABPP) that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide-N112C-CCNE1 interaction into a NanoBRET-ABPP assay capable of identifying compounds that reversibly inhibit both N112C- and WT-CCNE1:CDK2 complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings thus provide a roadmap for leveraging electrophile-cysteine interactions to extend the ligandability of the proteome beyond covalent chemistry.

A new truck-drone routing problem for parcel delivery by considering energy consumption and altitude.

The high population density in metropolitan areas, high-rise buildings, and changes in people's lifestyles have completely changed the way postal packages are delivered. People no longer go to the ground floor to receive a postal package. In the meantime, the delivery of postal packages through the balconies and windows of the units on the upper floors of the buildings will gradually become inevitable. Hence, a new Vehicle Routing Problem with Drone mathematical model has been developed with the objective of minimizing total delivery time and with the ability to deliver postal packages in the path of drones at different heights. In addition, the drone's energy consumption is computed by taking into account wind speed, the weight of the postal parcel, the weight of the drone's body, and other factors in the drone's path. A two-phase algorithm based on the nearest neighborhood and local search is presented to solve the developed mathematical model in different instances. Several small-sized test problems are designed and solved, and the performance of the heuristic approach is evaluated compared to the outputs of the CPLEX solver. Finally, the proposed model is implemented on a real-world scale to demonstrate the efficacy and applicability of the proposed model as well as the heuristic approach. The results show that the model successfully finds the optimal planning of the delivery routes, especially when we deal with delivery points at different heights.

Combination of pricing and inventory policies for deteriorating products with sustainability considerations.

Economic, environmental, and social criteria are all being taken into consideration simultaneously when determining pricing policies or inventory levels in sustainable production management. The combination of pricing and inventory policies is an important source of leverage for the efficient management of perishable products. This paper, among the first studies, proposes the problem of devising optimal pricing and inventory management decisions simultaneously where the environmental and social criteria are contributed for perishable complementary products replenished and sold by the same company. This study considers two interrelated price-sensitive linear demand functions to consider the possibility of shortage with both budget and warehouse capacity constraints. Another contribution of the proposed model is to consider an upper bound for environmental pollution and a lower bound for job opportunities as the constraints to the model. As a complex optimization model, the challenge of complexity is addressed by a heuristic algorithm for finding an optimal solution. After an extensive analysis using numerical examples, some managerial insights are concluded from the results. One finding from these analyses confirms that the total capacity of the warehouse, the total available budget, carbon emissions, and variable job opportunities have a high impact on the optimal solution to find a balance between sustainability criteria for making pricing and inventory policies.

Interaction of quercetin and 5-fluorouracil: cellular and pharmacokinetic study.

5-fluorouracil (5-FU) is a widely used chemotherapeutic agent, and its uncontrolled blood levels contribute to toxicity. Quercetin, as an important flavonoid, has many biological effects, including anti-tumor and anti-inflammatory features. The current study investigated the synergistic effect between 5-FU and quercetin using HT-29 cell line and fibroblast cells. Rats were assigned to two groups. The 5-FU/quercetin group received intraperitoneal quercetin (10 mg/kg) and the Tween was injected to the control group for 14 consecutive days. On the 15th day, both groups received 50 mg/kg of 5-FU. Upon the final injection, blood samples were obtained at different times. Pharmacokinetic parameters were evaluated using high-performance liquid chromatography (HPLC). The mean (±SD) of maximum plasma concentration (Cmax) of 5-FU in combination therapy group was 3.10 ± 0.18 µg/ml and the area under the curve (AUC) was 153.89 ± 21.36, which increased by 113% and 128% compared to control group, respectively. Quercetin increased anti-tumor activity of 5-FU and enhanced Cmax and AUC of 5-FU. These findings confirm the synergistic effects between quercetin and 5-FU at the usual doses in cancer treatment, which may lead to reduced toxicity.

A bi-level multi-follower optimization model for R&D project portfolio: an application to a pharmaceutical holding company.

The need for a study of project portfolio optimization in pharmaceutical R&D has become all the more urgent with the outbreak of COVID-19. This study examines a new model for optimizing R&D project portfolios under a decentralized decision-making structure in a pharmaceutical holding company. Specifically, two levels of decision makers hierarchically decide on budget allocation and project portfolio selection-scheduling to maximize their profit, and we formulate the problem as a bi-level multi-follower mixed-integer optimization model. At the upper level, the investment company has complete knowledge of the subsidiaries' response, acts first, and decides on the best budget allocation. At the lower level, each subsidiary responds to the allocated budget and decides on its portfolio scheduling. Since the lower level represents several mixed-integer programming problems, solving the resulting bi-level model is challenging. Therefore, we propose an efficient hybrid solution approach based on parametric optimization and convert the bi-level model into a single-level mixed-integer model. To validate it, we solve a case and discuss the optimal strategy of each actor. The experimental results show that the planned project portfolio for each subsidiary of the holding company is drastically affected by the allocated budget and its decisions. Supplementary Information: The online version contains supplementary material available at 10.1007/s10479-022-05052-0.

Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants.

The COVID-19 pandemic continues to be a public health threat with emerging variants of SARS-CoV-2. Nirmatrelvir (PF-07321332) is a reversible, covalent inhibitor targeting the main protease (Mpro) of SARS-CoV-2 and the active protease inhibitor in PAXLOVID (nirmatrelvir tablets and ritonavir tablets). However, the efficacy of nirmatrelvir is underdetermined against evolving SARS-CoV-2 variants. Here, we evaluated the in vitro catalytic activity and potency of nirmatrelvir against the Mpro of prevalent variants of concern (VOCs) or variants of interest (VOIs): Alpha (α, B.1.1.7), Beta (ß, B.1.351), Delta (δ, B1.617.2), Gamma (γ, P.1), Lambda (λ, B.1.1.1.37/C37), Omicron (ο, B.1.1.529), as well as the original Washington or wildtype strain. These VOCs/VOIs carry prevalent mutations at varying frequencies in the Mpro specifically for α, ß, γ (K90R), λ (G15S), and ο (P132H). In vitro biochemical enzymatic assay characterization of the enzyme kinetics of the mutant Mpros demonstrates that they are catalytically comparable to wildtype. We found that nirmatrelvir has similar potency against each mutant Mpro including P132H that is observed in the Omicron variant with a Ki of 0.635 nM as compared to a Ki of 0.933 nM for wildtype. The molecular basis for these observations were provided by solution-phase structural dynamics and structural determination of nirmatrelvir bound to the ο, λ, and ß Mpro at 1.63 to 2.09 Å resolution. These in vitro data suggest that PAXLOVID has the potential to maintain plasma concentrations of nirmatrelvir many-fold times higher than the amount required to stop the SARS-CoV-2 VOC/VOI, including Omicron, from replicating in cells.

A review on femoropopliteal arterial deformation during daily lives and nickel-titanium stent properties.

The increasing number of studies on the behaviour of stent placement in recent decades provides a clear understanding of peripheral artery disease (PAD). The severe mechanical loads (axial tension and compression, bending, radial compression and torsion) deformation of the femoropopliteal artery (FPA) is responsible for the highest failure rate of permanent nickel-titanium (Nitinol) stents. Therefore, the purpose of this article is to review research papers that examined the deformation of the natural load environment of FPA, the properties of Nitinol and mechanical considerations. In conclusion, a better understanding of mechanical behaviour for FPA Nitinol stents contributes to increased mechanical performance and fatigue-life.

Structural basis for Nirmatrelvir in vitro efficacy against the Omicron variant of SARS-CoV-2

The COVID-19 pandemic continues to be a public health threat with emerging variants of SARS-CoV-2. Nirmatrelvir (PF-07321332) is a reversible, covalent inhibitor targeting the main protease (Mpro) of SARS-CoV-2 and the active protease inhibitor in PAXLOVID (nirmatrelvir tablets and ritonavir tablets). We evaluated the in vitro catalytic activity and in vitro potency of nirmatrelvir against the main protease (Mpro) of prevalent variants of concern (VOC) or variants of interest (VOI): Alpha (, B.1.1.7), Beta ({beta}, B.1.351), Delta ({delta}, B1.617.2), Gamma ({gamma}, P.1), Lambda ({lambda}, B.1.1.1.37/C37), Omicron (o, B.1.1.529) as well as the original Washington or wildtype strain. These VOC/VOI carry prevalent mutations at varying frequencies in the Mpro specifically for: , {beta},{gamma} (K90R), {lambda} (G15S) and o (P132H). In vitro biochemical enzymatic assay characterization of the enzyme kinetics of the mutant Mpros demonstrate that they are catalytically comparable to wildtype. Nirmatrelvir has similar potency against each mutant Mpro including P132H that is observed in the Omicron variant with a Ki of 0.635 nM as compared to a Ki of 0.933nM for wildtype. The molecular basis for these observations were provided by solution-phase structural dynamics and structural determination of nirmatrelvir bound to the o, {lambda} and {beta} Mpro at 1.63 - 2.09 [A] resolution. These in vitro data suggest that PAXLOVID has the potential to maintain plasma concentrations of nirmatrelvir many-fold times higher than the amount required to stop the SARS-CoV-2 VOC/VOI, including Omicron, from replicating in cells (1).

Increased personal protective equipment consumption during the COVID-19 pandemic: An emerging concern on the urban waste management and strategies to reduce the environmental impact.

Personal protective equipments (PPEs) are essential protective products for individuals exposed to microorganism, toxic substances, and pathogens. However, the advent of the coronavirus pandemic generated a heavy demand for PPE, which has led to a rapid accumulation of plastic waste related to potentially infectious PPE in the urban waste stream. Mismanagement of these wastes can lead to subsequent environmental problems. This study estimates the daily consumption of facemasks, gloves, and daily medical waste generation during the SARs-CoV-2 pandemic in the selected 33 countries worldwide. The results indicate that China used the highest daily facemasks and gloves among these selected countries, followed by India, the US, Brazil, Indonesia, and Japan. Moreover, India is the first one in medical waste production, followed by the USA, Brazil, the United Kingdom, France, and Spain. The article also provides viable strategies and discusses the pros and cons of strategies to address the unprecedented generation of plastic waste material during the pandemic. This manuscript also encourages scientific communities and policymakers to pay exceptional attention to the pandemic's plastic waste.

A multiobjective model for the green capacitated location-routing problem considering drivers' satisfaction and time window with uncertain demand.

Location-routing problem is a combination of facility location problem and vehicle routing problem. Numerous logistics problems have been extended to investigate greenhouse issues and costs related to the environmental impact of transportation activities. The green capacitated locating-routing problem (LRP) seeks to find the best places to establish facilities and simultaneously design routes to satisfy customers' stochastic demand with minimum total operating costs and total emitted carbon dioxide. In this paper, features that make the problem more practical are: considering time windows for customers and drivers, assuming city traffic congestion to calculate travel time along the edges, and dealing with capacitated warehouses and vehicles. The main novelty of this study is to combine the mentioned features and consider the problem closer to the real-world case uses. A mixed-integer programming model has been developed and scenario production method is used to solve this stochastic model. Since the problem belongs to the class of NP-hard problems, a combination of the progressive hedging algorithm (PHA) and genetic algorithm (GA) is considered to solve large-scale problems. It is the first time, as per our knowledge, that this combination is implemented on a green capacitated location routing problem (G-CLPR) and resulted in satisfactory solutions. Nondominating sorting genetic algorithm II (NSGA-II) and epsilon constraints methods are used to face with the bi-objective problem. Finally, sensitivity analysis is performed on the problem's input parameters and the efficiency of the proposed method is measured. Comparing the results of the proposed solution approach with those of the exact method indicates that the solution approach is computationally efficient in finding promising solutions.

An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19.

The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.

Carbon-efficient closed-loop supply chain network: an integrated modeling approach under uncertainty.

Inspired by a circular economy paradigm, an evolving momentum of policies and legislations aims to close the loop of product lifecycles through improved level of recycling, remanufacturing, and reuse, with the objective of adding value to the economy while not endangering the environment. However, the trade-off between the environmental and economic sustainability of designing business processes is inevitable. To address this trade-off in the supply chain context, competing objectives regarding both cost minimization and reduction in carbon emission should be simultaneously considered and integrated into a comprehensive model. This complexity is however elevated when uncertainty of demand is taken into consideration. In this study, the design of a closed-loop supply chain is investigated where competing objectives of cost and sustainability of supply chain operations are evaluated under demand uncertainty. Augmented Weighted Tchebycheff (AWT) and ε-constraint methods are employed to address the multi-objectivity of the problem while a robust optimization approach is applied to deal with the demand uncertainty. The results confirm that the proposed approach provides efficient solutions for designing a green closed-loop supply chain network.

An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment of COVID-19

AbstractThe worldwide outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become an established global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to counter the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity, and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse- adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency, in a phase I clinical trial in healthy human participants. ClinicalTrials.gov Identifier: NCT04756531 One-Sentence SummaryPF-07321332 is disclosed as a novel, orally active, investigational small-molecule inhibitor of the SARS-CoV-2 main protease, which is being evaluated in clinical trials for the treatment of COVID-19.

Competing Endogenous RNAs (CeRNAs): Novel Network in Neurological Disorders.

Neurological disorders (NDs) comprise a broad range of diseases affecting both central and peripheral nervous systems. These complex multifactorial diseases have a high rate of mortality all over the world, particularly in aged people. Today, new evidence drove our attention to the notable role of noncoding RNAs (ncRNAs) in the progression of NDs. Remarkably, recent studies showed that there are close communication networks among RNA transcripts such as mRNAs, long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and pseudogenes for regulating each other's expression through competing for shared sequences in microRNAs (miRs). This concept is a new area of ongoing research recognized as competing endogenous RNA (ceRNA) hypothesis. CeRNAs are novel regulatory molecules in a wide range of biological stages and pathological contexts. Indeed, the disruption of ceRNA networks (ceRNETs) may affect neural development genes and induce neuropathological changes leading to the development of NDs. Because of this, identifying the correlation of ceRNETs with NDs will open a new window for expanding our knowledge about this field of science, as well as creating novel roads for developing specific diagnostic biomarkers for NDs management. Owing to these unique features, exploring the exact role of ceRNAs is a hot topic in NDs investigations. Hence, in this review, we will summarize the evidence supporting ceRNETs in the regulation of NDs-related gene expression.

Henoch-Schönlein purpura in Saudi Arabia: characteristics and rare vital organ involvement.

Henoch-Schönlein purpura (HSP) is the most common small vessel vasculitis in children with an annual incidence of between 10 and 30 per 100,000. It is an inflammation that affects many organs primarily in the skin, gastrointestinal (GI) tract, musculoskeletal, also vital organs like kidneys and lungs which may lead to chronic kidney disease and pulmonary hemorrhage. In this review, we are showing the characteristics of Saudi patients with HSP and the relation with preceding infections, gender, and seasonal variations in addition to the common and most severe systemic involvements. We found cases that were challenging to diagnose and others with unfortunate fetal complications.

Single stage transoral cordectomy and medialization thyroplasty in early glottic squamous cell carcinoma: A case report

Objective@#To present the case of a 78-year-old man with Glottic SCCa stage I who underwent single stage transoral cordectomy type IV with medialization thyroplasty under general anesthesia. @*Methods@#Design: Case Report. Setting: Tertiary Government Training Hospital. Patient: One. @*Results@#Postoperatively, patient was able to phonate and gave a VHI score of 12 and GRBAS score of 4. He was able to resume oral feeding without any signs of aspiration. Postoperative flexible laryngoscopy showed fully mobile vocal cords with good approximation in the midline. @*Conclusion@# This report suggests that vocal cord medialization via thyroplasty may be performed after cordectomy in a single stage, providing acceptable postoperative voice as well as good swallowing outcome

Sustainable closed-loop supply chain network for an integrated water supply and wastewater collection system under uncertainty.

Today, an increase in the drought and water shortage all around the world is a challengeable threat for different governments and international committees. Water supply chain aims to manage the water consumption and to control the water shortage. Contrary to most of previous studies focused on the forward directions of the water supply chain, this paper also considers the reverse logistics known as a Closed-Loop Supply Chain (CLSC). Hence, an integrated Water Supply and Wastewater Collection System (WSWCS) under uncertainty is proposed. Furthermore, regarding the trend of sustainable development, the environmental dimensions and social benefits of the integrated WSWCS are contributed. To meet the standards of the sustainable development in developing countries, a case study in Iran is applied to a novel multi-objective stochastic optimization model based on triple bottom lines of sustainability. Having already been employed to similar optimization problems, the Social Engineering Optimizer (SEO) has been never applied in this research area. Another innovation of this study is to introduce an improved multi-objective SEO to solve this complicated model. Eventually, with regards to an extensive comparison contributing to the Pareto-based metrics and different sensitivities, some managerial implications are concluded as the main findings.

BOLD and EEG signal variability at rest differently relate to aging in the human brain.

Variability of neural activity is regarded as a crucial feature of healthy brain function, and several neuroimaging approaches have been employed to assess it noninvasively. Studies on the variability of both evoked brain response and spontaneous brain signals have shown remarkable changes with aging but it is unclear if the different measures of brain signal variability - identified with either hemodynamic or electrophysiological methods - reflect the same underlying physiology. In this study, we aimed to explore age differences of spontaneous brain signal variability with two different imaging modalities (EEG, fMRI) in healthy younger (25 â€‹± â€‹3 years, N â€‹= â€‹135) and older (67 â€‹± â€‹4 years, N â€‹= â€‹54) adults. Consistent with the previous studies, we found lower blood oxygenation level dependent (BOLD) variability in the older subjects as well as less signal variability in the amplitude of low-frequency oscillations (1-12 â€‹Hz), measured in source space. These age-related reductions were mostly observed in the areas that overlap with the default mode network. Moreover, age-related increases of variability in the amplitude of beta-band frequency EEG oscillations (15-25 â€‹Hz) were seen predominantly in temporal brain regions. There were significant sex differences in EEG signal variability in various brain regions while no significant sex differences were observed in BOLD signal variability. Bivariate and multivariate correlation analyses revealed no significant associations between EEG- and fMRI-based variability measures. In summary, we show that both BOLD and EEG signal variability reflect aging-related processes but are likely to be dominated by different physiological origins, which relate differentially to age and sex.

ALOX12 gene polymorphisms and serum selenium status in elderly osteoporotic patients.

BACKGROUND: Osteoporosis is a systemic bone disease which leads to a reduction in bone mass. Many studies have shown that up to 80% of bone mineral density (BMD) variations are attributed to genetic factors. Arachidonate 12-lipoxygenase enzyme, encoded by the ALOX12 gene, produces lipid peroxides as reactive oxygen species (ROS), leading to oxidative stress and the development of osteoporosis. Selenium (Se) is incorporated into selenoproteins, which may reduce the risk of osteoporosis. OBJECTIVES: We aimed to investigate the association of 2 ALOX12 single nucleotide polymorphisms (SNPs) and serum Se level with lumbar spine and femoral neck BMD among elderly individuals living in Amirkola, Iran. MATERIAL AND METHODS: The study consisted of 180 individuals aged ≥60 years (90 healthy and 90 osteoporotic patients). We examined the effect of 2 ALOX12 SNPs (rs2292350 and rs9897850), using the polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) on both BMD regions measured by dual energy X-ray absorptiometry (DXA). Serum Se level was measured using an atomic absorption spectrophotometer PGG990 AAS (PG Instruments Ltd., Luterworth, USA). RESULTS: The rs2292350 SNP showed a significant association with femoral neck BMD (p = 0.04). Moreover, in terms of serum Se level, a significant difference was found between the patient group (57.58 ±25.54 µg/L) and the control group (81.09 ±25.58 µg/L) (p < 0.001). In addition, individuals with higher serum Se levels also had higher BMD of the lumbar spine (r2 = 0.392; p < 0.001) and the femoral neck (r2 = 0.478; p < 0.001). CONCLUSIONS: The results suggested that genetic variation in ALOX12 might influence BMD variations in our recruited participants. As for the patients with lower serum Se levels, it was observed that serum Se deficiency was accompanied by some ALOX12 variation, contributing to the development of osteoporosis.