Product Family Research Articles

Anticancer action of naturally occurring emodin for the controlling of cervical cancer.

One of the major causes of death on the globe is cancer. The fourth most frequent malignancy in women worldwide is cervical cancer. Several cancer patients are remaining incurable due to the emergence of medication resistance, despite notable advances in cancer research over the previous few decades. The importance of natural sources as possible therapeutic candidates may be significant. Anthraquinones are one of the many chemical families of natural products, and they stand out for their wide range of structural variations, notable biological activity, and low toxicity. A natural substance called emodin, an anthraquinone derivative, is present in the roots and rhizomes of several plants. This substance has demonstrated antineoplastic, anti-inflammatory, antiangiogenic, and antiproliferative properties. It is also capable of preventing cancer spread and can reverse cancer cells' multidrug resistance. Emodin, a broad-spectrum inhibitor of cancer cells, have anticancer properties in many different types of biological pathways. These molecular mechanisms in cancer cells include the suppression of cell growth and proliferation, deterioration of the cell cycle arrest, the start of apoptosis, antimetastasis, and antiangiogenic impact. Therefore, the aim of the present review summarised the antiproliferative and anticarcinogenic qualities of cervical cancer of emodin.

Streamlined Strategy for Scalable and Enantioselective Total Syntheses of the Eburnane Alkaloids.

A general, concise, and efficient strategy for the enantioselective synthesis of the eburnane alkaloid family of natural products is disclosed. Specifically, 13 members of the natural product family were prepared from commercially available and inexpensive starting materials. The brevity and modularity of the route are largely on account of a two-phase synthesis logic and a key catalytic enantioconvergent cross-coupling to establish the C20 stereogenic center. The strategies described here are expected to facilitate in-depth biological studies and provide access to new anticancer eburnane analogues.

A Ferric-Superoxide Intermediate Initiates P450-Catalyzed Cyclic Dipeptide Dimerization.

The cytochrome P450 (CYP) AspB is involved in the biosynthesis of the diketopiperazine (DKP) aspergilazine A. Tryptophan-linked dimeric DKP alkaloids are a large family of natural products that are found in numerous species and exhibit broad and often potent bioactivity. The proposed mechanisms for C-N bond formation by AspB, and similar C-C bond formations by related CYPs, have invoked the use of a ferryl-intermediate as an oxidant to promote substrate dimerization. Here, the parallel application of steady-state and transient kinetic approaches reveals a very different mechanism that involves a ferric-superoxide species as a primary oxidant to initiate DKP-assembly. Single turnover kinetic isotope effects and a substrate analog suggest the probable nature and site for abstraction. The direct observation of CYP-superoxide reactivity rationalizes the atypical outcome of AspB and reveals a new reaction manifold in heme enzymes.

Discovery of Tetronate-Containing Kongjuemycins from a Coral-Associated Actinomycete and Elucidation of Their Biosynthetic Origin.

Tetronate antibiotics make up a growing family of natural products with a wide variety of biological activities. Herein, we report four new tetronates kongjuemycins (KJMs, 5-8) from a coral-associated actinomycete Pseudonocardia kongjuensis SCSIO 11457, and the identification and characterization of the KJM biosynthetic gene cluster (kjm) by heterologous expression, comparative genomic analysis, isotope labeling, and gene knockout studies. The biosynthesis of KJMs is demonstrated to harness diverse precursors from primary metabolism for building secondary metabolites.

Engineered biosynthesis through the adenylation domains from nonribosomal peptide synthetases.

Nonribosomal peptide synthetases, consisting of multiple catalytic domains, are involved in the biosynthesis of an important family of bioactive natural products in a coordinated manner. Among the functional domains, adenylation domains are specifically responsible for recognizing carboxylic acid building blocks and synthesizing aminoacyl adenylates. Given their critical roles in the biosynthesis of the growing peptide, A-domains are also referred to as the "gatekeeper". In this review, very recent developments in the A-domains from NRPSs are reviewed to expand the fundamental knowledge of the A domain, including knowledge on the structures, functions, and molecular interactions. Several recent examples were also discussed to highlight the great .potential of A-domain engineering. This study should provide a framework for the combinatorial biosynthesis or synthetic biology-driven microbial production of novel nonribosomal peptides.

Sowing Agroecology in Rio Doce through a Technical Assistance and Rural Outreach Program in a Territory Affected by the Biggest Environmental Disaster in Brazilian History

Abstract The work of an Agroecological Technical Assistance and Rural Outreach program (ATER, in its acronym in Portuguese) is a profound process of communication between technical specialists in agricultural production and farming families, specialists in their practice and their social context. The ATER program of the “Sowing Agroecology in Rio Doce” project works with 138 families whose farming activity was hampered by the rupture of the Fundão Mining Tailings Dam (Brazil), considered the greatest environmental disaster in Brazilian history. The work seeks to train family farmers for the agroecological transition, aiming at building production systems that operate in an economically viable, environmentally correct, socially fair, and culturally diverse way. The project takes place in three dimensions: animal, where the welfare and health of animals are worked on, and in the development of more autonomous systems regarding the use of inputs and medicines; natural goods, where it operates in agricultural production, water resources, and environmental conservation of the properties, aiming at the production free of pesticides and industrialized inputs; and culture, through understanding the social reality of families, valuing cultural manifestations and traditions, aiming to strengthen the social cohesion of communities and encourage cooperation between families, and seeking to create short marketing circuits, work groups, and collective purchases of inputs. In this way, the process takes place from the One Health perspective, as it seeks to integrate human, animal, and environmental health. This approach has contributed to increasing production and family autonomy, bringing economic viability, food security, and environmental conservation to the region. Information © The Authors 2023

: Software product lines extraction driven by language server protocol

Software product lines (SPL) describe highly-variable software systems as a family of similar products that differ in terms of the features they provide. The promise of SPL engineering is to enable massive software reuse by allowing software features to be reused across a variety of different products made for several customers. However, there are some disadvantages in the extraction of SPLs from standard applications. Most notably, approaches to the development of SPLs are not supported by the base language and use a syntax and composition techniques that require a deep understanding of the tools being used. Therefore, the same features cannot be used in a different application and developers must face a steep learning curve when developing SPLs for the first time or when switching from one approach to a different one. Ultimately, this problem is due to a lack of standards in the area of SPL engineering and in the way SPLs are extracted from variability-unaware applications. In this work, we present a framework based on LSP and dubbed ▪ that aims at standardizing such a process by decoupling the refactoring operations made by the user from the effect they have on the source code. This way, the server for a specific SPL development approach can be used across several development environments that provide clients with customized refactoring options. Conversely, the developers can use the same client to refactor SPLs made according to different approaches without needing to learn the syntax of each approach. To showcase the applicability of the approach, we present an evaluation performed by refactoring four SPLs according to two different approaches: the results show that a minimal implementation of the ▪ client and server applications can be used to reduce the effort of extracting an SPL up to the 93% and that it can greatly reduce or even completely hide the implementation details from the developer, depending on the chosen approach.

Lewis Acid-Promoted [2 + 2] Cycloadditions of Allenes and Ketenes: Versatile Methods for Natural Product Synthesis.

ConspectusCycloaddition reactions are an effective method to quickly build molecular complexity. As predicted by the Woodward-Hoffmann rules, concerted cycloadditions with alkenes allow for the constructions of all possible stereoisomers of product by use of either the Z or E geometry. While this feature of cycloadditions is widely used in, for example, [4 + 2] cycloadditions, translation to [2 + 2] cycloadditions is challenging because of the often stepwise and therefore stereoconvergent nature of these processes. Over the past decade, our lab has explored Lewis acid-promoted [2 + 2] cycloadditions of electron-deficient allenes or ketenes with alkenes. The concerted, asynchronous cycloadditions allow for the synthesis of various cyclobutanes with control of stereochemistry.Our lab developed the first examples of Lewis acid-promoted ketene-alkene [2 + 2] cycloadditions. Compared with traditional thermal conditions, Lewis acid-promoted conditions have several advantages, such as increased reactivity, increased yield, improved diastereoselectivity, and, for certain cases, inverse diastereoselectivity. Detailed mechanistic studies revealed that the diastereoselectivity was controlled by the size of the substituent and the barrier of a deconjugation event. However, these reactions required the use of stoichiometric amounts of EtAlCl2 because of the product inhibition, which led us to investigate catalytic enantioselective [2 + 2] cycloadditions of allenoates with alkenes. Through the use of chiral oxazaborolidines, a broad range of cyclobutanes can be prepared with the control of enantioselectivity. Mechanistic experiments, including 2D-labled alkenes and Hammett analysis, illuminate likely transition state models for the cycloadditions. Additional studies led to the development of Lewis acid-catalyzed intramolecular stereoselective [2 + 2] cycloadditions of chiral allenic ketones/esters with alkenes.The methods we developed have been instrumental in the synthesis of several families of natural products. Specifically, one key lactone motif in (±)-gracilioether F was constructed by a ketene-alkene [2 + 2] cycloaddition and subsequent regioselective Baeyer-Villiger oxidation sequence. Enantioselective allenoate-alkene [2 + 2] cycloadditions allowed for the synthesis of (-)-hebelophyllene E. Another attempt of applying this method in the synthesis of (+)-[5]-ladderanoic acid failed to deliver the desired cyclobutane because of an unexpected rearrangement. The key cyclobutane was later assembled by a stepwise carboboration/Zweifel olefination process. Finally, the stereoselective [2 + 2] cycloadditions of allenic ketones and alkenes was applied in the syntheses of (-)-[3]-ladderanol, (+)-hippolide J, and (-)-cajanusine.

Spinning switches on a wreath product

We classify an algebraic phenomenon on several families of wreath products that can be seen as coming from a generalization of a puzzle about switches on the corners of a spinning table. Such puzzles have been written about and generalized since they were first popularized by Martin Gardner in 1979. In this paper, we build upon a paper of Bar Yehuda, Etzion, and Moran, a paper of Ehrenborg and Skinner, and a paper of Rabinovich to provide perhaps the fullest generalization yet, modeling both the switches and the spinning table as arbitrary finite groups combined via a wreath product. We classify large families of wreath products depending on whether or not they correspond to a solvable puzzle, completely classifying the puzzle in the case when the switches behave like abelian groups, constructing winning strategies for all wreath products that are p-groups, and providing novel examples for other puzzles where the switches behave like nonabelian groups, including the puzzle consisting of two interchangeable copies of the monster group M. Lastly, we provide a number of open questions and conjectures, and provide other suggestions of how to generalize some of these ideas further.

Multi-objective reinforcement learning-based framework for solving selective maintenance problems in reconfigurable cyber-physical manufacturing systems

ABSTRACT Unlike mass production manufacturing systems, where configurations are rarely changed after the initial design, reconfigurable cyber-physical systems (RCPMS) self-change their structures throughout missions and thus self-adjust production in response to demand requirements. Accordingly, such a paradigm requires enhancing selective maintenance strategy to optimise scheduling maintenance actions, selecting configuration layouts for capacity and product family changes, and achieving maintenance cost reduction and reliability maximisation. This paper is the first to propose a robust model for a selective maintenance problem with imperfect repairs in the RCPMS context. The model also integrates uncertainties originating from the imperfect observations of components' health status. The model's objectives are to maximise the expected reliability and minimise the variance and maintenance cost under maintenance resource constraints. Moreover, we propose a new deep reinforcement learning framework for solving the resulting multi-objective and combinatorial optimisation problem. In addition, we use decision values to enhance the scalarisation process by permitting the priorities of specific objectives to be adjusted after the learning process. Furthermore, we employ Analytical Hierarchy Process to adjust the static priorities with respect to the objective functions and the actual learning context. Finally, broad experiments are conducted to highlight the performance of the proposed model and resolution framework.

Remodeling Isoprene Pyrophosphate Metabolism for Promoting Terpenoids Bioproduction

Terpenoids are the largest family of natural products. They are made from the building block isoprene pyrophosphate (IPP), and their bioproduction using engineered cell factories has received a great deal of attention. To date, the insufficient metabolic supply of IPP remains a great challenge for the efficient synthesis of terpenoids. In this work, we discover that the imbalanced metabolic flux distribution between the central metabolism and the IPP supply hinders IPP accumulation in Bacillus subtilis (B. subtilis). Therefore, we remodel the IPP metabolism using a series of genetically encoded two-input-multi-output (TIMO) circuits that are responsive to pyruvate or/and malonyl-CoA, resulting in an IPP pool that is significantly increased by up to four-fold. As a proof-of-concept validation, we design an IPP metabolism remodeling strategy to improve the production of three valuable terpenoids, including menaquinone-7 (MK-7, 4.1-fold), lycopene (9-fold), and β-carotene (0.9-fold). In particular, the titer of MK-7 in a 50-L bioreactor reached 1549.6 mg∙L−1, representing the highest titer reported so far. Thus, we propose a TIMO genetic circuits-assisted IPP metabolism remodeling framework that can be generally used for the synergistic fine-tuning of complicated metabolic modules to achieve the efficient bioproduction of terpenoids.

Healthy Family Life: A Sine Qua Non For Sustainable Development

This study aims to raise awareness of the importance of enhancing family life and strengthening the family unit for the sustainable development of African society. When the family, the most significant social unit, is threatened, sustainable growth cannot be achieved. The central theme of this study is the importance of a healthy family life as a contributor to societal development. Parents in the society are now downplaying family values and ethics, which is considered as one of the main problems contributing to a number of troubles that are emerging in the society. This study demonstrates that poor parental involvement is one of the social elements that foster unhealthy family structures, which has serious negative effects on sustainable development. The paper x-rayed the passion that people now have for work in order to satisfy human wants and the neglects for home fronts thereby creating large gap in building virtues and moral life of their family members. In order to have a balanced and healthy society, that is free of stress, full of maximum productivity and conducive family living, it is crucial that work ethics and family life be given the desired attention in the society. This research demonstrates how important it is for parents to raise morally sound, well-educated children, which highlights the importance of striking a healthy balance between job and home life. The paper therefore conclude that every home should endeavour to uphold the sanctity of family life in order for the society to have sustainable development.

Targeted Discovery of Cryptic Enediyne Natural Products via FRET-Coupled High-Throughput Elicitor Screening.

Enediyne antibiotics are a striking family of DNA-cleaving natural products with high degrees of cytotoxicity and structural complexity. Microbial genome sequences, which have recently accumulated, point to an untapped trove of "cryptic" enediynes. Most of the cognate biosynthetic gene clusters (BGCs) are sparingly expressed under standard growth conditions, making it difficult to characterize their products. Herein, we report a fluorescence-based DNA cleavage assay coupled with high-throughput elicitor screening for the rapid, targeted discovery of cryptic enediyne metabolites. We applied the approach to Streptomyces clavuligerus, which harbors two such BGCs with unknown products, identified steroids as effective elicitors, and characterized 10 cryptic enediyne-derived natural products, termed clavulynes A-J with unusual carbonate and terminal olefin functionalities, with one of these congeners matching the recently reported jejucarboside. Our results contribute to the growing repertoire of enediynes and provide a blueprint for identifying additional ones in the future.

Mathematical models for the formation and evaluation of manufacturing cells in a textile company: A case study

Purpose: Use mathematical models of Mixed Integer Linear Programming oriented to cellular distribution and aggregate production planning in order to obtain the appropriate product family for each manufacturing cell and from this, minimize production and material handling costs through the allocation of production resources.Design/methodology/approach: This article develops two mathematical models in LINGO 18.0 software, performing the computational calculation to obtain the best efficiency in cell formation at minimum production cost.Findings: The mathematical model oriented to the formation of manufacturing cells allows a grouping of products and machines with 82.5% group efficiency. By reallocating machines to each cell and redistributing facilities, the cost of material handling is reduced by 35.1%, and the distance traveled in product manufacturing is reduced by 26.6%. The mathematical model of aggregated planning provides information on production resource requirements such as personnel, machinery, distances traveled, as well as the cost generated by the need to outsource part of the production, inventory maintenance and overtime work.Research limitations/implications: It is necessary to clearly define the capacity variables. The model does not take into account the cost of mobilizing machines and readjusting facilities.Practical implications: The case study company can adequately plan production and efficiently manage its resources.Social implications: The study can be applied to other textile SMEs.Originality/value: The aggregate production planning model requires the assignment of the mathematical model of manufacturing cell formation in order to calculate the resource requirements needed to meet a demand.

Evaluating the circularity and multi-lifecycle green profit of product family design

As sustainability and circularity are emerging as the new normal for business, manufacturers have attempted to apply recovery strategies such as reuse, remanufacturing, and recycling to product family design to generate higher profits and mitigate the environmental impact. Compared to single-product design, product family design involves developing sharing decisions in which components and operations are common across product variants. However, existing approaches have not clearly explained the multi-lifecycle effects of sharing decisions. This paper proposes an evaluation model that quantifies the multi-lifecycle economic profit and environmental impact of a product family design. A bi-objective optimization model with economic and environmental objectives is developed to assess the effects of sharing over multiple lifecycles. The evaluation results provide a broader understanding of the multi-lifecycle effect of component and operation sharing and the trade-off between economic profit and environmental impact. This study considers a smartphone family design case to validate the proposed model.

Phytoestrogens and Amenorrhea in Athletes

Plants contain several different families of natural products. Phytoestrogens are one such compound that is found in variety of plant foods. On the basis of the chemical structure, phytoestrogens are classified into four major categories such as flavonoids, isoflavonoids, lignans, and stilbenes. Structurally phytoestrogens are very much similar to 17 β-estradiol, so they have a tendency to exhibit estrogen-like activity, which has increased the interest of researchers to use it as a hormone replacement therapy. Nowadays, special attention is given to various isoflavonoids including genistein, diadzens, coumestrol, equol, and several prenylated flavonoids mainly, 8-prenylnaringein and stilbene resveratrol. Menstrual changes and bone density may be favorably influenced by phytoestrogens. These compounds have not only been observed to mimic the role of estrogen in humans but have also shown to exhibit effects and action in both similar and divergent manner as of the hormone. The eventual action of phytoestrogen in specific cells is determined by several factors such as the relative levels of estrogen receptors both α and β and the varied number and types of coactivators and corepressors presently existing in the cell. An increase in the consumption of herbal and natural nutritional supplements with ergogenic goals with particular regard to ecdysteroids, phytosterols, and vegetal sterols has been observed in past among the athletes which call for the need to assess the knowledge of athletes and physically active individuals about the plant-based nutritional supplements as well as its associations with amenorrhea in female athletes, their health profile, and reproductive life.

Joint optimization of low-carbon product family configuration and smart production line selection

To meet the requirements of small batch orders and rapid production, many enterprises began to use robots, artificial intelligence, cloud computing, and other new technologies to construct smart production lines, which are high-flexible and capable of autonomously diagnosing their health and autonomously designing continuous improvement projects. In this study, a joint optimization model is established for concurrently determining the optimal product family configuration and the optimal construction plan for a smart production line. Greenhouse gas emissions are considered in the joint optimization model to realize the low-carbon design concept. A quantum evolutionary algorithm and a genetic algorithm are developed to solve the established optimization model. A case study of the electronic dictionary product family is provided to illustrate the proposed method. The numeric experiments show that the proposed model can reap more profit from a systematic perspective compared with the traditional two-stage approach, and the proposed quantum evolutionary algorithm has a good performance in solving the joint optimization problem.

A METHOD TO CAPTURE AND SHARE PRODUCTION REQUIREMENTS SUPPORTING A COLLABORATIVE PRODUCTION PREPARATION PROCESS

AbstractThe production preparation process (3P) enables collaboration between design and production engineers during product development but its efficiency is limited by the abundance of documentation of manufacturing constraints and capabilities. Empirical studies showed that use of production requirements can increase the efficiency of 3P, however, the support for production engineers to capture and share production requirements is scarce. A method to support production engineers in identifying, defining, structuring and sharing production requirements and collaborating with design engineers is presented. The method has three major parts - focus areas and requirement categories, a worksheet for production requirements capturing and prioritization, and a workflow for using the worksheet. The method was developed in collaboration with practitioners and contributes to the existing knowledge by providing production engineers with a structured way of working with production requirements. Evaluation of the method in the case company showed its usability when developing product variants and that additional work is needed to support the development of new product families and assembly lines.

INCORPORATING FIELD EFFECTS INTO THE DESIGN OF MODULAR PRODUCT FAMILIES

AbstractWith advancing digitalization, new technologies with more and more digital components make it necessary to integrate new components into current and future products. Sensors and actuators, such as motors, emit electromagnetic and thermal fields that can greatly affect product performance. Recent work has considered fields at the functional level using functional structures and at the system level using DSM. In this paper, the effects of fields on product architecture are investigated at the component level. Using an appropriate visualization, the impact of fields on the product structure is considered. Architectural guidelines are then used to develop suitable product structures. The methodological approach is then applied to a product family of vacuum cleaner robots. The overlaid field information helps to gain deeper insights into the product architecture. The approach is useful for representing alternative structures. The new mapping of functional and structural relationships by moving module boundaries against fields can help promote architectural innovation.

Optimal product aggregation for sales and operations planning in mass customisation context

Sales and operations planning (S&OP) is a multi-actor tactical planning process that balances aggregate demand and capacities to deliver realistic production plans. The way demand is aggregated into product families (PFs) is crucial for the alignment sought by S&OP. The issue of gathering individual products into PFs is particularly challenging in the mass customisation (MC) context where products are depicted through combinations of attributes derived from a set of features. This paper introduces the aggregation scheme concept that refers to the subset of features used to constitute PFs. Several aggregation schemes may be considered with different performances from the perspective of the actors involved in the S&OP. A multi-objective model is designed to identify efficient aggregation schemes considering both sales and operations expectations. The model is implemented on numerical instances from automotive industry. The results highlight the existence of more efficient and balanced aggregation schemes than those currently used.