Quality Control Mechanisms Research Articles

HSP90a promotes the resistance to oxaliplatin in HCC through regulating IDH1-induced cell competition

Though burgeoning research manifests that cell competition, an essential selection and quality control mechanism for maintaining tissue or organ growth and homeostasis in multicellular organisms, is closely related to tumorigenesis and development, the mechanism of cell competition associated with tumor drug resistance remains elusive. In the study, we uncovered that oxaliplatin-resistant hepatocellular carcinoma (HCC) cells exhibit a pronounced competitive advantage against their sensitive counterparts, which is related to lipid takeover of resistant cells from sensitive cells. Of note, such lipid takeover is dependent on the existence of isocitrate dehydrogenase 1 (IDH1) in resistant HCC cells. Mechanistically, IDH1 activity is regulated by heat shock protein 90 alpha (HSP90α) through binding with each other, which orchestrates the expressions of lipid metabolic enzymes and lipid accumulation in resistant HCC cells. Our results suggest that HCC cell competition-driven chemoresistance can be regulated by HSP90α/IDH1-mediated lipid metabolism, which may serve as a promising target for overcoming drug resistance in HCC.

MITOCHONDRIAL TURNOVER IS ELEVATED IN RESPONSE TO INTESTINAL INFLAMMATION AND IS AMENABLE TO THERAPUTIC TARGETING VIA UROLITHIN A

Abstract Inflammatory bowel disease (IBD) is a complex, multifactorial set of diseases defined by chronic and relapsing inflammation of the gut. Changes in oxidative stress, inflammation, and metabolism are central to the disease process, linking mitochondrial health to IBD pathogenesis. Mitophagy is a quality-control mechanism that selectively removes dysfunctional mitochondria. Multiple mitophagy pathways co-exist in the intestine, including the canonical PINK1/PARKIN pathway and NIX. We have previously shown that NIX is increased in IBD, removing damaged mitochondria in the epithelium. Whether this translates to a physiologic increase in mitochondrial turnover remains unanswered. We hypothesized that mitophagy within the intestinal epithelium represents a key homeostatic response to inflammation. To study this hypothesis, we employed the use of a novel transgenic mouse expressing the pH-dependent fluorescent protein, mt-Keima, tethered to the mitochondria. Adult mt-Keima mice were subjected to chemically induced colitis (3% DSS) for 7 days to induce intestinal inflammation. In vivo mitophagic flux, measured via live-cell confocal microscopy, was increased nearly 4-fold (n=3, p<0.05) in DSS-treated animals compared to controls. Despite this consistent elevation, NIX expression varied in both human and mouse tissue, suggesting that other mitophagy pathways, like PARKIN, may be involved. Interestingly, activated PARKIN (pSer65-PARKIN) was higher in inflamed tissues of humans and mice as compared to controls, though variation was present. To determine the functional importance of PARKIN, Parkin-/- mice were subjected to a 7-day treatment of 2% DSS. These mice developed a more severe colitis, suggesting that Parkin-mediated mitophagy contributes to the mitochondrial damage response in IBD. These data collectively indicate that mitophagy is elevated in IBD, and both NIX and PARKIN likely work in parallel to respond to the elevated mitophagic demand. Interestingly, both NIX and pSer65-PARKIN expression are co-expressed in human control tissues, while both were generally expressed in inflamed biopsies, and at higher levels. We speculate that the mechanism of mitophagy may not necessarily be important, but that it is elevated in response to intestinal inflammation. To address this aim, we administered a known mitophagy inducer, urolithin A, to mice on a 7-day course of DSS. Urolithin A + DSS-treated mice had elevated NIX and pSer65-PARKIN expression compared to vehicle + DSS controls. This elevation correlated with decreased disease activity and improved O2 mitochondria respiration. We conclude that mitophagy is an imperative homeostatic response to remove superfluously damaged mitochondria in IBD and is amenable to therapeutic intervention. Elevating mitophagic flux might be a potential therapeutic option to help improve disease outcomes in IBD.

Mutation of p53 increases the competitive ability of pluripotent stem cells.

During development, the rate of tissue growth is determined by the relative balance of cell division and cell death. Cell competition is a fitness quality-control mechanism that contributes to this balance by eliminating viable cells that are less fit than their neighbours. The mutations that confer cells with a competitive advantage and the dynamics of the interactions between winner and loser cells are not well understood. Here, we show that embryonic cells lacking the tumour suppressor p53 are 'super-competitors' that eliminate their wild-type neighbours through the direct induction of apoptosis. This elimination is context dependent, as it does not occur when cells are pluripotent and it is triggered by the onset of differentiation. Furthermore, by combining mathematical modelling and cell-based assays we show that the elimination of wild-type cells is not through competition for space or nutrients, but instead is mediated by short-range interactions that are dependent on the local cell neighbourhood. This highlights the importance of the local cell neighbourhood and the competitive interactions within this neighbourhood for the regulation of proliferation during early embryonic development.

IoT-BIM and blockchain integration for enhanced data traceability in offsite manufacturing

The transformation of dynamic supply chains within the realm of offsite manufacturing presents a unique and compelling opportunity to effectively respond to shifts in market demand. However, this paradigm shift also entails novel challenges and prospects for streamlining processes, augmenting efficiency, and ultimately driving success across production workflows and logistical operations. Dynamic supply chains necessitate unimpeded access to high-quality, dependable data to facilitate real-time, data-driven decision-making. Furthermore, owing to their inherently intricate nature, these supply chains are subject to a heightened vulnerability to disruptions and delays, surpassing those encountered in traditional supply chains. Against this backdrop, this paper proposes a framework that synthesises the convergence of the Internet of Things (IoT), Building Information Modelling (BIM), and blockchain technology (BCT) into a cohesive and integrated system, thereby optimising the efficiency and transparency of supply chain management operations. The proposed framework takes cognisance of the challenges inherent in ensuring information traceability, mitigating fragmented information, enhancing interoperability, and fortifying reliability throughout the design, production, and implementation phases of assets within dynamic supply chains operating in the offsite manufacturing domain. To illustrate the efficacy of our proposition, we present a framework that exemplifies the seamless integration of a permissioned, open-source distributed ledger, which forms the bedrock of our support infrastructure for IoT and BIM integration.Through rigorous analysis, we showcase the effectiveness of the developed framework in the form of a designed Supply Chain Management Model (SCMM-PDO), which harmonises the physical, digital, and operational layers within a robust system architecture (BCT.IoT-BIM). The integration of these technologies provides a decentralised solution, reinforcing supply chains with improved security, reliability, and quality control mechanisms, thus enhancing the efficiency of the supply chain network. It is anticipated that this transformative integration will yield substantial improvements in key performance indicators (KPIs) such as operational efficiency, cost reduction, and the cultivation of trust and accountability across supply chain activities.The research proposes an IoT and BIM conceptual framework that simulates the dynamic supply chain operations, facilitating real-time analysis and prediction of supply chain participants' behaviours from resources, processes, and assets. Furthermore, the integration of IoT-BIM (digital twinning) with a blockchain-based system, such as Hyperledger Fabric, engenders a secure and transparent framework for the diligent tracking of assets and information throughout the supply chain. The findings of this study offer an all-encompassing conceptual framework for the secure and transparent tracking of asset information by integrating Blockchain-based technologies with IoT and BIM. This research endeavour thus expands the existing body of knowledge, establishing a foundation for future investigations within this proliferating field.

Sirtuins mediate mitochondrial quality control mechanisms: a novel therapeutic target for osteoporosis.

Mitochondria plays a role in cell differentiation and apoptosis processes. Maintaining mitochondrial function is critical, and this involves various aspects of mitochondrial quality control such as protein homeostasis, biogenesis, dynamics, and mitophagy. Osteoporosis, a metabolic bone disorder, primarily arises from two factors: the dysregulation between lipogenic and osteogenic differentiation of aging bone marrow mesenchymal stem cells, and the imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Mitochondrial quality control has the potential to mitigate or even reverse the effects. Among the Sirtuin family, consisting of seven Sirtuins (SIRT1-7), SIRT1-SIRT6 play a crucial role in maintaining mitochondrial quality control. Additionally, SIRT1, SIRT3, SIRT6, and SIRT7 are directly involved in normal bone development and homeostasis by modulating bone cells. However, the precise mechanism by which these Sirtuins exert their effects remains unclear. This article reviews the impact of various aspects of mitochondrial quality control on osteoporosis, focusing on how SIRT1, SIRT3, and SIRT6 can improve osteoporosis by regulating mitochondrial protein homeostasis, biogenesis, and mitophagy. Furthermore, we provide an overview of the current state of clinical and preclinical drugs that can activate Sirtuins to improve osteoporosis. Specific Sirtuin-activating compounds are effective, but further studies are needed. The findings of this study may offer valuable insights for future research on osteoporosis and the development of clinical prevention and therapeutic target strategies.

Varicella zoster virus glycoprotein E facilitates PINK1/Parkin-mediated mitophagy to evade STING and MAVS-mediated antiviral innate immunity

Viruses have evolved to control mitochondrial quality and content to facilitate viral replication. Mitophagy is a selective autophagy, in which the damaged or unnecessary mitochondria are removed, and thus considered an essential mechanism for mitochondrial quality control. Although mitophagy manipulation by several RNA viruses has recently been reported, the effect of mitophagy regulation by varicella zoster virus (VZV) remains to be fully determined. In this study, we showed that dynamin-related protein-1 (DRP1)-mediated mitochondrial fission and subsequent PINK1/Parkin-dependent mitophagy were triggered during VZV infection, facilitating VZV replication. In addition, VZV glycoprotein E (gE) promoted PINK1/Parkin-mediated mitophagy by interacting with LC3 and upregulating mitochondrial reactive oxygen species. Importantly, VZV gE inhibited MAVS oligomerization and STING translocation to disrupt MAVS- and STING-mediated interferon (IFN) responses, and PINK1/Parkin-mediated mitophagy was required for VZV gE-mediated inhibition of IFN production. Similarly, carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-mediated mitophagy induction led to increased VZV replication but attenuated IFN production in a three-dimensional human skin organ culture model. Our results provide new insights into the immune evasion mechanism of VZV gE via PINK1/Parkin-dependent mitophagy.

The application of mirabilite in traditional Chinese medicine and its chemical constituents, processing methods, pharmacology, toxicology and clinical research.

Purpose: This study reviews the use of mirabilite in traditional Chinese medicine and various preparations by describing its chemical composition, processing methods, pharmacology, toxicology, and clinical research progress. Methods: The applications and processing methods of mirabilite are searched in traditional and modern Chinese medical writings, and the articles on chemical composition, pharmacological effects, toxicology, and clinical studies of mirabilite and its combinations in PubMed and China Knowledge Network are reviewed, sorted, and analyzed. Results: The main chemical component of mirabilite is sodium sulfate decahydrate (Na2SO4·10H2O), followed by small amounts of sodium chloride, magnesium sulfate, calcium sulfate, and other inorganic salts. This study systematically organizes the history of the medicinal use of mirabilite in China for more than 2,000years. This mineral has been used by nine Chinese ethnic groups (Han, Dai, Kazakh, Manchu, Mongolian, Tujia, Wei, Yi, and Tibetan) in a large number of prescription preparations. The Pharmacopoeia of the People's Republic of China (2020 edition) records stated that mirabilite can be used for abdominal distension, abdominal pain, constipation, intestinal carbuncle, external treatment of breast carbuncle, hemorrhoids, and other diseases. The traditional processing methods of mirabilite in China include refining, boiling, sautéing, filtration after hot water blistering, and firing. Since the Ming Dynasty, processing by radish has become the mainstream prepared method of mirabilite. Mirabilite can exhibit anti-inflammatory detumescence effects by inhibiting AMS, LPS, IL-6, IL-10, TNF-α, and NO levels and attenuating the upregulation of TNF-α and NF-κB genes. It can promote cell proliferation and wound healing by increasing the production of cytokines TGFβ1 and VEGF-A and gastrointestinal motility by increasing the release of vasoactive intestinal peptide, substance P, and motilin. It can increase the expression of low-density lipoprotein receptor and AKT phosphorylation in the liver by up-regulating bile acid synthesis genes; reduce TRB3 expression in the liver, FGF15 co-receptor KLB expression, and FGF15 production in the ileum, and JNK signal transduction; and increase the transcription of CYP7A1 to achieve a cholesterol-lowering effect. Mirabilite also has a variety of pharmacological effects, such as regulating intestinal flora, anti-muscle paralysis, anti-colon cancer, promoting water discharge, and analgesic. Only a few toxicological studies on mirabilite are available. External application of mirabilite can cause local skin to be flushed or itchy, and its oral administration is toxic to neuromuscular cells. The sulfur ions of its metabolites can also be toxic to the human body. At present, no pharmacokinetic study has been conducted on mirabilite as a single drug. This mineral has been widely used in the clinical treatment of inflammation, edema, wound healing, digestive system diseases, infusion extravasation, hemorrhoids, skin diseases, breast accumulation, muscle paralysis, intestinal preparation before microscopic examination, and other diseases and symptoms. Conclusion: Mirabilite has good application prospects in traditional Chinese medicine and ethnomedicine. In-depth research on its processing methods, active ingredients, quality control, pharmacokinetics, pharmacological and toxicological mechanisms, and standardized clinical application is needed. This paper provides a reference for the application and research of mirabilite in the future.

Role of autophagy in cancer-associated fibroblast activation, signaling and metabolic reprograming.

Tumors not only consist of cancerous cells, but they also harbor several normal-like cell types and non-cellular components. cancer-associated fibroblasts (CAFs) are one of these cellular components that are found predominantly in the tumor stroma. Autophagy is an intracellular degradation and quality control mechanism, and recent studies provided evidence that autophagy played a critical role in CAF formation, metabolic reprograming and tumor-stroma crosstalk. Therefore, shedding light on the autophagy and its role in CAF biology might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the exploitation of more efficient cancer diagnosis and treatment. Here, we provide an overview about the involvement of autophagy in CAF-related pathways, including transdifferentiation and activation of CAFs, and further discuss the implications of targeting tumor stroma as a treatment option.

Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria

Cellular proteostasis requires transport of polypeptides across membranes. Although defective transport processes trigger cytosolic rescue and quality control mechanisms that clear translocases and membranes from unproductive cargo, proteins that are synthesized within mitochondria are not accessible to these mechanisms. Mitochondrial-encoded proteins are inserted cotranslationally into the inner membrane by the conserved insertase OXA1L. Here, we identify TMEM126A as a OXA1L-interacting protein. TMEM126A associates with mitochondrial ribosomes and translation products. Loss of TMEM126A leads to the destabilization of mitochondrial translation products, triggering an inner membrane quality control process, in which newly synthesized proteins are degraded by the mitochondrial iAAA protease. Our data reveal that TMEM126A cooperates with OXA1L in protein insertion into the membrane. Upon loss of TMEM126A, the cargo-blocked OXA1L insertase complexes undergo proteolytic clearance by the iAAA protease machinery together with its cargo.

VERTICAL INTEGRATION OF CONTRACT FARMING V/S PROCUREMENT FROM TRADERS

The rice export industry in India has traditionally relied on intermediary traders for the procurement of rice from local farmers. However, this study explores the hypothesis that vertical backward integration through contract farming can be a more profitable and sustainable option for rice export companies. The research involves a comprehensive analysis of the economic viability, quality control mechanisms, and supply chain transparency associated with both traditional trader-based procurement and the vertically integrated contract farming model. The study employs qualitative data collection methods. Financial analyses will be conducted to compare the profit margins of companies adopting vertical backward integration versus those relying on traders. Additionally, qualitative assessments will explore the quality assurance mechanisms, supply chain transparency, and long-term sustainability of each model. Preliminary findings should suggest that vertical backward integration offers export companies the advantage of direct control over the cultivation process, enabling them to enforce stringent quality standards. Furthermore, the elimination of intermediaries may result in cost efficiencies, potentially leading to higher profit margins

Game-Theoretic Incentive Mechanism for Collaborative Quality Control in Blockchain-Enhanced Carbon Emissions Verification

Game-Theoretic Incentive Mechanism for Collaborative Quality Control in Blockchain-Enhanced Carbon Emissions Verification

New mode of action of curcumin on prostate cancer cells: Modulation of endoplasmic reticulum-associated degradation mechanism and estrogenic signaling.

Prostate cancer is leading to cancer-related mortality in numerous men each year worldwide. While there are several treatment options, acquired drug resistance mostly limits the success of treatments. Therefore, there is a need for the development of innovative treatments. Curcumin is one of the bioactive polyphenolic ingredients identified in turmeric and has numerous biological activities, such as anti-inflammatory and anticancer. In the present study, we investigated the effect of curcumin on the ER-associated degradation (ERAD) and estrogenic signaling in prostate cancer cells. The antiproliferative effect of curcumin on human androgen-dependent prostate cancer cell lines LNCaP and VCaP was estimated by WST-1 assay. Morphological alterations were investigated with an inverted microscope. We investigated the effect of curcumin on ERAD and estrogen signaling proteins by immunoblotting assay. To evaluate the impact of curcumin on endoplasmic reticulum (ER) protein quality-related, the expression level of 32 genes was analyzed by quantitative reverse transcription polymerase chain reaction. The nuclear translocation of estrogen receptor was examined by nuclear fractionation and immunofluorescence microscopy. We found that curcumin effectively reduced the proliferation rates of LNCaP and VCaP cells. ERAD proteins; Hrd1, gp78, p97/VCP, Ufd1 and Npl4 were strongly induced by curcumin. Also, the steady-state level of polyubiquitin was increased in a dose-dependent manner in both cell lines. Curcumin administration remarkably decreased the protein levels of estrogen receptor-alfa (Erα), whereas estrogen receptor-beta unaffected. Additionally, curcumin strongly restricted the nuclear translocation of Erα. Present data suggest that curcumin may be effectively used in therapeutic approaches associated with the targeting ER protein quality control mechanism and modulation of estrogen signaling in prostate cancer.

A transporter's doom or destiny: SLC6A1 in health and disease, novel molecular targets and emerging therapeutic prospects.

As the first member of the solute carrier 6 (SLC6) protein family, the γ-aminobutyric acid (GABA) transporter 1 (GAT1, SLC6A1), plays a pivotal role in the uptake of GABA from the synaptic cleft into neurons and astrocytes. This process facilitates the subsequent storage of GABA in presynaptic vesicles. The human SLC6A1 gene is highly susceptible to missense mutations, leading to severe clinical outcomes, such as epilepsy, in the afflicted patients. The molecular mechanisms of SLC6A1-associated disorders are discerned to some degree; many SLC6A1 mutations are now known to impair protein folding, and consequently fail to reach the plasma membrane. Inherently, once inside the endoplasmic reticulum (ER), GAT1 abides by a complex cascade of events that enable efficient intracellular trafficking. This involves association with specialized molecular chaperones responsible for steering the protein folding process, oligomerization, sorting through the Golgi apparatus, and ultimately delivery to the cell surface. The entire process is subject to stringent quality control mechanisms at multiple checkpoints. While the majority of the existing loss-of-function SLC6A1 variants interfere with folding and membrane targeting, certain mutants retain abundant surface expression. In either scenario, suppressed GAT1 activity disrupts GABAergic neurotransmission, preceding the disease manifestation in individuals harboring these mutations. The nervous system is enthralling and calls for systematic, groundbreaking research efforts to dissect the precise molecular factors associated with the onset of complex neurological disorders, and uncover additional non-canonical therapeutic targets. Recent research has given hope for some of the misfolded SLC6A1 variants, which can be salvaged by small molecules, i.e., chemical and pharmacological chaperones, acting on multiple upstream targets in the secretory pathway. We here highlight the significance of pharmacochaperoning as a therapeutic strategy for the treatment of SLC6A1-related disorders.

In vivo evidence for homeostatic regulation of ribosomal protein levels in Drosophila.

The ribosome is a molecular machine essential for protein synthesis, which is composed of approximately 80 different ribosomal proteins (Rps). Studies in yeast and cell culture systems have revealed that the intracellular level of Rps is finely regulated by negative feedback mechanisms or ubiquitin-proteasome system, which prevents over- or under-abundance of Rps in the cell. However, in vivo evidence for the homeostatic regulation of intracellular Rp levels has been poor. Here, using Drosophila genetics, we show that intracellular Rp levels are regulated by proteasomal degradation of excess Rps that are not incorporated into the ribosome. By establishing an EGFP-fused Rp gene system that can monitor endogenously expressed Rp levels, we found that endogenously expressed EGFP-RpS20 or -RpL5 is eliminated from the cell when RpS20 or RpL5 is exogenously expressed. Notably, the level of endogenously expressed Hsp83, a housekeeping gene, was not affected by exogenous expression of Hsp83, suggesting that the strict negative regulation of excess protein is specific for intracellular Rps. Further analyses revealed that the maintenance of cellular Rp levels is not regulated at the transcriptional level but by proteasomal degradation of excess free Rps as a protein quality control mechanism. Our observations provide not only the in vivo evidence for the homeostatic regulation of Rp levels but also a novel genetic strategy to study in vivo regulation of intracellular Rp levels and its role in tissue homeostasis via cell competition.Key words: ribosomal protein, proteasomal degradation, Drosophila.

Methods for Monitoring ER-Phagy.

The endoplasmic reticulum (ER) serves as a central hub for protein synthesis, folding, and lipid biosynthesis in eukaryotic cells. Maintaining ER homeostasis is essential for optimal cellular function, and one mechanism that has garnered attention is endoplasmic reticulum-specific autophagy, or ER-phagy. ER-phagy selectively removes specific ER portions, playing a pivotal role in cellular health and adaptation to environmental stressors. ER-phagy can be induced by diverse cellular conditions such as amino acid starvation, disruption of ER quality control mechanisms, and accumulation of misfolded ER protein, highlighting cellular adaptability and the significance of ER-phagy in stress responses. Clinically relevant mutations in ER-phagy receptors are implicated in various diseases, underlining the fundamental importance of ER-phagy in ER homeostasis. Here, we provide comprehensive protocols and general considerations while investigating ER-phagy using three fundamental techniques-Western blotting, immunofluorescence, and flow cytometry-commonly used in ER-phagy detection and quantitation.

Endoplasmic reticulum associated degradation preserves neurons viability by maintaining endoplasmic reticulum homeostasis.

Endoplasmic reticulum-associated degradation (ERAD) is a principal quality-control mechanism responsible for targeting misfolded ER proteins for cytosolic degradation. Evidence suggests that impairment of ERAD contributes to neuron dysfunction and death in neurodegenerative diseases, many of which are characterized by accumulation and aggregation of misfolded proteins. However, the physiological role of ERAD in neurons remains unclear. The Sel1L-Hrd1 complex consisting of the E3 ubiquitin ligase Hrd1 and its adaptor protein Sel1L is the best-characterized ERAD machinery. Herein, we showed that Sel1L deficiency specifically in neurons of adult mice impaired the ERAD activity of the Sel1L-Hrd1 complex and led to disruption of ER homeostasis, ER stress and activation of the unfold protein response (UPR). Adult mice with Sel1L deficiency in neurons exhibited weight loss and severe motor dysfunction, and rapidly succumbed to death. Interestingly, Sel1L deficiency in neurons caused global brain atrophy, particularly cerebellar and hippocampal atrophy, in adult mice. Moreover, we found that cerebellar and hippocampal atrophy in these mice resulted from degeneration of Purkinje neurons and hippocampal neurons, respectively. These findings indicate that ERAD is required for maintaining ER homeostasis and the viability and function of neurons in adults under physiological conditions.

MARKETING TOOLS OF ENTERPRISES OF THE AGRICULTURAL SECTOR OF UKRAINE

The article is devoted to the justification and rationalization of the instrumental content of the marketing activity of domestic enterprises in the agrarian sector. Provisions characterizing the role and importance of agricultural marketing are defined, among which are highlighted: optimization of resource use and management of results; increase in farm income; expansion of markets; growth of the agricultural industry; introduction and distribution of new technologies; job creation; allowance to national income; value creation. It was determined that many factors should be considered in agribusiness when determining the marketing strategy, and the marketing complex as a strategy will positively affect the work of the enterprise. Twelve controllable marketing elements are outlined, which include the following components: product planning, pricing, branding, distribution channels, personal selling, advertising, promotions and promotions, packaging, display, service, delivery, research, and analysis. The difference between consumer and agricultural goods is substantiated, and the specifics of agricultural goods are determined, including the dependence of production on natural and biological factors, seasonality of production, predominance of wholesale sales; the need for processing, short consumption period, lack of ideal substitutes; lack of effective quality control mechanisms; the limited influence of the brand, advertising, after-sales service, fashion and style, emotional factors; low elasticity of demand. Certain aspects of state policy are revealed as an addition to the traditional Ps of the marketing mix for the sale of agricultural products; in particular, it is stated that the agricultural policy should be structured in such a way as to provide support to small farmers through projects of improvement, diversification, and sale of agricultural products.

A Software Quality Model Combining Demand and Delivery Perspectives to Ensure Quality in IT Implementations

In this paper we describe a model which fosters the quality of the artefact within software development projects via defined quality gates. In combination with defined roles these quality gates facilitate communication and transparency regarding the progress within the project and of the software artefact in particular. The motivation for this paper have their origin in identified and confirmed challenges during software development projects which do not follow a defined quality control mechanism. 
 We evaluate the quality model in relation to current software development projects in classical as well as agile environments, one of which we describe in this paper. The project setting includes multiple business departments, business IT, internal delivery IT and external delivery IT departments. It deals with the central procurement platform in the company.

Evaluasi Permasalahan Kekuatan Splicing Benang pada Mesin Winding PT INS dengan Metode Seven Tools

Yarn manufacturing engineering stands as one of the initial phases in the textile industry and holds considerable significance in determining subsequent process qualities. PT INS specializes in producing ring spun yarn, wherein the final stage integrates an automatic yarn quality control mechanism within the winding machine. When the sensor identifies any yarn irregularity, an automatic cutting process initiates. Additionally, the winding machine incorporates a yarn splicing procedure to reconnect separated yarn ends or join yarn during cop changes. Any flaw in this splicing process can lead to a weak yarn splice, evident in the diminished Retained Spliced Strength (RSS), which in turn impacts subsequent weaving and knitting processes. PT INS encountered a yarn splicing issue, evidenced by consistently low RSS values from each spindle on its winding machines. An analysis was conducted employing various tools, including Control Charts, Fishbone Diagrams, Check Sheets, and Pareto Diagrams, to pinpoint the problematic spindle and identify the root cause of the splicing problem. Subsequently, improvement measures were proposed based on the analysis of each contributing factor. These steps aim not only to enhance the splicing process within the winding machine but also to elevate overall yarn quality. Through this approach, PT INS aims to rectify the splicing discrepancies, ultimately ensuring a more robust splicing process within the winding machine and elevating the overall yarn quality.

Degradation of citrate synthase lacking the mitochondrial targeting sequence is inhibited in cells defective in Hsp70/Hsp40 chaperones under heat stress conditions.

Most nucleus-encoded mitochondrial precursor proteins are synthesized in the cytosol and imported into mitochondria in a post-translational manner. In recent years, the quality control mechanisms of nonimported mitochondrial proteins have been intensively studied. In a previous study, we established that in budding yeast a mutant form of citrate synthase 1 (N∆Cit1) that lacks the N-terminal mitochondrial targeting sequence, and therefore mislocalizes to the cytosol is targeted for proteasomal degradation by the SCFUcc1 ubiquitin ligase complex. Here, we show that Hsp70 and Hsp40 chaperones (Ssa1 and Ydj1 in yeast, respectively) are required for N∆Cit1 degradation under heat stress conditions. In the absence of Hsp70 function, a portion of N∆Cit1-GFP formed insoluble aggregates and cytosolic foci. However, the extent of ubiquitination of N∆Cit1 was unaffected, implying that Hsp70/Hsp40 chaperones are involved in the postubiquitination step of N∆Cit1 degradation. Intriguingly, degradation of cytosolic/peroxisomal gluconeogenic citrate synthase (Cit2), an endogenous substrate for SCFUcc1-mediated proteasomal degradation, was not highly dependent on Hsp70 even under heat stress conditions. These results suggest that mitochondrial citrate synthase is thermally vulnerable in the cytosol, where Hsp70/Hsp40 chaperones are required to facilitate its degradation.