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Polycyclic polyprenylated acylphloroglucinols (PPAPs) comprise a large group of compounds of mostly plant origin. The best-known compound is hyperforin from St. John's wort with its antidepressant, antitumor and antimicrobial properties. The chemical synthesis of PPAP variants allows the generation of compounds with improved activity and compatibility. Here, we studied the antimicrobial activity of two synthetic PPAP-derivatives, the water-insoluble PPAP23 and the water-soluble sodium salt PPAP53. In vitro, both compounds exhibited good activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Both compounds had no adverse effects on Galleria mellonella wax moth larvae. However, they were unable to protect the larvae from infection with S. aureus because components of the larval coelom neutralized the antimicrobial activity; a similar effect was also seen with serum albumin. In silico docking studies with PPAP53 revealed that it binds to the F1 pocket of human serum albumin with a binding energy of −7.5 kcal/mol. In an infection model of septic arthritis, PPAP23 decreased the formation of abscesses and S. aureus load in kidneys; in a mouse skin abscess model, topical treatment with PPAP53 reduced S. aureus counts. Both PPAPs were active against anaerobic Gram-positive gut bacteria such as neurotransmitter-producing Clostridium, Enterococcus or Ruminococcus species. Based on these results, we foresee possible applications in the decolonization of pathogens. [ABSTRACT FROM AUTHOR]

Abstract Background Germline variants affecting the proofreading activity of polymerases epsilon and delta cause a hereditary cancer and adenomatous polyposis syndrome characterized by tumors with a high mutational burden and a specific mutational spectrum. In addition to the implementation of multiple pieces of evidence for the classification of gene variants, POLE and POLD1 variant classification is particularly challenging given that non-disruptive variants affecting the proofreading activity of the corresponding polymerase are the ones associated with cancer. In response to an evident need in the field, we have developed gene-specific variant classification recommendations, based on the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria, for the assessment of non-disruptive variants located in the sequence coding for the exonuclease domain of the polymerases. Methods A training set of 23 variants considered pathogenic or benign was used to define the usability and strength of the ACMG/AMP criteria. Population frequencies, computational predictions, co-segregation data, phenotypic and tumor data, and functional results, among other features, were considered. Results Gene-specific variant classification recommendations for non-disruptive variants located in the exonuclease domain of POLE and POLD1 were defined. The resulting recommendations were applied to 128 exonuclease domain variants reported in the literature and/or public databases. A total of 17 variants were classified as pathogenic or likely pathogenic, and 17 as benign or likely benign. Conclusions Our recommendations, with room for improvement in the coming years as more information become available on carrier families, tumor molecular characteristics and functional assays, are intended to serve the clinical and scientific communities and help improve diagnostic performance, avoiding variant misclassifications.

Background: Accreta, increta and percreta are all examples of morbidly adherent placenta. This new score, the placenta previa with attached placenta [PPAP] score, was developed from ultrasound and magnetic resonance imaging [MRI] data for pregnant women who had both placenta previa and an adhering placenta.Aim of the work: The purpose of this future research was to assess the effectiveness of a novel scoring system for identifying placenta previa with an attached placenta. Patients and Methods: This prospective cohort study included 100 cases. It was conducted at Faculty of Medicine, of Al-Azhar University. The duration of the study was from December 2020 to December 2022. There were also MRI and ultrasound tests performed at this time. Two things go into determining your PPAP score: [1] any prior uterine surgery [including a cesarean section, a surgical abortion, or uterine reconstruction], and [2] the findings of an ultrasound [US] or [MRI].Results: PPAP score in detection of having adherent placenta reported a sensitivity of 88.24% and specificity of 91.57%.Conclusion: PPAP scoring system is effective and reliable system for diagnosis of adherent placenta in females with placenta previa.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) comprise a large group of compounds of mostly plant origin. The best-known compound is hyperforin from St. John’s wort with its antidepressant, antitumor and antimicrobial properties. The chemical synthesis of PPAP variants allows the generation of compounds with improved activity and compatibility. Here, we studied the antimicrobial activity of two synthetic PPAP-derivatives, the water-insoluble PPAP23 and the water-soluble sodium salt PPAP53. In vitro, both compounds exhibited good activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Both compounds had no adverse effects on Galleria mellonella wax moth larvae. However, they were unable to protect the larvae from infection with S. aureus because components of the larval coelom neutralized the antimicrobial activity; a similar effect was also seen with serum albumin. In silico docking studies with PPAP53 revealed that it binds to the F1 pocket of human serum albumin with a binding energy of −7.5 kcal/mol. In an infection model of septic arthritis, PPAP23 decreased the formation of abscesses and S. aureus load in kidneys; in a mouse skin abscess model, topical treatment with PPAP53 reduced S. aureus counts. Both PPAPs were active against anaerobic Gram-positive gut bacteria such as neurotransmitter-producing Clostridium, Enterococcus or Ruminococcus species. Based on these results, we foresee possible applications in the decolonization of pathogens.

Background: Germline variants affecting the proofreading activity of polymerases epsilon and delta cause a hereditary cancer and adenomatous polyposis syndrome characterized by tumors with a high mutational burden and a specific mutational spectrum. In addition to the implementation of multiple pieces of evidence for the classification of gene variants, POLE and POLD1 variant classification is particularly challenging given that non-disruptive variants affecting the proofreading activity of the corresponding polymerase are the ones associated with cancer. In response to an evident need in the field, we have developed gene-specific variant classification recommendations, based on the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria, for the assessment of non-disruptive variants located in the sequence coding for the exonuclease domain of the polymerases. Methods: A training set of 23 variants considered pathogenic or benign was used to define the usability and strength of the ACMG/AMP criteria. Population frequencies, computational predictions, co-segregation data, phenotypic and tumor data, and functional results, among other features, were considered. Results: Gene-specific variant classification recommendations for non-disruptive variants located in the exonuclease domain of POLE and POLD1 were defined. The resulting recommendations were applied to 128 exonuclease domain variants reported in the literature and/or public databases. A total of 17 variants were classified as pathogenic or likely pathogenic, and 17 as benign or likely benign. Conclusions: Our recommendations, with room for improvement in the coming years as more information become available on carrier families, tumor molecular characteristics and functional assays, are intended to serve the clinical and scientific communities and help improve diagnostic performance, avoiding variant misclassifications. [ABSTRACT FROM AUTHOR]

Background: Post-pancreatectomy acute pancreatitis (PPAP) is a recently identified clinical condition characterized by sustained elevated serum amylase levels for at least 48 h post-operatively, consistent radiological findings, and relevant clinical features. The purpose of this study was to determine the frequency of PPAP after DP, to investigate the rate of major complications in patients with sustained or transiently elevated serum amylase activity, and to explore the usability of CT as a prerequisite for the diagnosis of PPAP. Methods: This retrospective single-center observational study included consecutive patients 18 years or older who underwent DP at Karolinska University Hospital between 2008 and 2020. The two serum amylase levels on post-operative days (POD) 1 and 2 were correlated with post-operative major complications by logistic regression analyses. Results: Of the 403 patients who underwent DP, 14% (n = 58) had sustained elevated serum amylase levels according to PPAP criteria, and 31% (n = 126) had transiently elevated serum amylase levels on either POD1 or POD2. Of the patients with sustained elevated levels, 45% (n = 26) developed major complications, but less than 2% (n = 1) showed imaging findings consistent with acute pancreatitis. Of the 126 patients who exhibited only transiently elevated serum amylase on either POD1 or POD2, 38% (n = 48) developed major complications. The frequency of PPAP was 0.25% (n = 1). Conclusion: These findings indicate that PPAP after DP is rare and that computed tomography has limited usability for diagnosing PPAP. The findings also suggest that transiently elevated serum amylase may be an early indicator of acute pancreatitis, especially when peaked. [ABSTRACT FROM AUTHOR]

The cancer syndrome polymerase proofreading-associated polyposis results from germline mutations in the POLE and POLD1 genes. Mutations in the exonuclease domain of these genes are associated with hyper- and ultra-mutated tumors with a predominance of base substitutions resulting from faulty proofreading during DNA replication. When a new variant is identified by gene testing of POLE and POLD1, it is important to verify whether the variant is associated with PPAP or not, to guide genetic counseling of mutation carriers. In 2015, we reported the likely pathogenic (class 4) germline POLE c.1373A > T p.(Tyr458Phe) variant and we have now characterized this variant to verify that it is a class 5 pathogenic variant. For this purpose, we investigated (1) mutator phenotype in tumors from two carriers, (2) mutation frequency in cell-based mutagenesis assays, and (3) structural consequences based on protein modeling. Whole-exome sequencing of two tumors identified an ultra-mutator phenotype with a predominance of base substitutions, the majority of which are C > T. A SupF mutagenesis assay revealed increased mutation frequency in cells overexpressing the variant of interest as well as in isogenic cells encoding the variant. Moreover, exonuclease repair yeast-based assay supported defect in proofreading activity. Lastly, we present a homology model of human POLE to demonstrate structural consequences leading to pathogenic impact of the p.(Tyr458Phe) mutation. The three lines of evidence, taken together with updated co-segregation and previously published data, allow the germline variant POLE c.1373A > T p.(Tyr458Phe) to be reclassified as a class 5 variant. That means the variant is associated with PPAP. [ABSTRACT FROM AUTHOR]

Background : Post-pancreatectomy acute pancreatitis (PPAP) is a newly described clinical entity defined as elevated serum amylase sustained ≥ 48 h postoperatively, radiological findings consistent with acute pancreatitis, and associated clinically relevant features. This study aimed to investigate the incidence of PPAP and the rate of major complications after pancreatoduodenectomy (PD) in patients with only transiently elevated serum amylase. Methods: A retrospective single-center observational study was conducted including consecutive patients ≥ 18 years of age undergoing PD at Karolinska University Hospital, between 2008 and 2020. Serum amylase on postoperative day (POD) 1 and 2 and records from computer tomography were analyzed and correlated with postoperative major complications by logistic regressions. Results: Of some 1078 patients that underwent PD, 284 exhibited sustained elevated serum amylase (according to PPAP criteria) and 183 transiently elevated serum amylase on either POD1 or POD2. Of the patients with sustained elevated levels, 43% (n = 123) developed major complications, but only 6.3% (n = 18) showed findings consistent with acute pancreatitis on imaging. Of the 183 cases that exhibited only transiently elevated serum amylase on either POD1 or POD2, 32% (n = 58) developed major complications. Conclusion: Sustained hyperamylasemia was observed in 26% of patients after PD, and an additional 17% of patients had a transient elevation of serum amylase postoperatively. Acute pancreatitis after PD may be underdiagnosed, partly by overlooking transiently elevated serum amylase and partly by requiring imaging that potentially fails to recognize mild but complication-prone acute pancreatitis. [ABSTRACT FROM AUTHOR]

Garsubellin A is a thirty‐carbon meroterpenoid capable of enhancing the enzyme choline acetyltransferase whose decreased level is associated with the symptoms of Alzheimer's disease. Due to the potentially useful biological activity along with the novel molecular architecture, this plant metabolite has remained a popular synthetic target. Herein we report a full account of our synthetic investigations that have led to the enantioselective total synthesis of garsubellin A, establishing its absolute stereostructure. The protecting group‐free, twelve‐step synthetic route has enabled the syntheses of the natural (−)‐garsubellin A and its unnatural (+)‐antipode. [ABSTRACT FROM AUTHOR]

In order for an automobile company to survive on the market, it is necessary that their products comply with the specifications and requirements of customers. For the realization of specifications, it is necessary to constantly control the production process, as well as certain parameters that depend exclusively on customer requirements. In this paper, an electric motor named Colt is observed and analyzed. Three groups of motors and their heat dissipation to the environment were observed. Due to the construction and the position where the electric motor is installed in the vehicle, the impact of heat dissipation on the environment is extremely important, which is defined by the customer. In addition to enabling adequate data to be obtained, this analysis will allow for the accelerated approval of PPAP samples. [ABSTRACT FROM AUTHOR]

Zymomonas mobilis ZM4 is a gram-negative, facultative anaerobic, natural ethanologenic bacterium used in industrial production of bio-products. For expression of genes, promoters are required. However, most of the promoters reported from Z. mobilis poorly function in Escherichia coli. This makes the process of expression and screening labor-intensive. In the present study, we compared the strengths of two Z. mobilis promoters, P chap and P pap , which drive the expression of chaperonin and phosphatase PAP2 family protein, respectively, with P tac promoter. In E. coli , the P tac promoter was found to be the strongest followed by P pap and P pdc , while in Z. mobilis , P pdc was found to be the strongest and P chap the weakest promoter. Further characterization of the promoters was done by cloning the gfp uv gene which expresses the green fluorescent protein, under their control and measuring the fluorescence of the E. coli transformants. The activity of these promoters was also studied at different pH (pH 5, 7 and 9) and different temperatures (30°C, 37°C and 42°C) in exponential and stationary phases. Both P chap and P pap promoters showed higher activity in stationary phase than in exponential phase. Since the promoters were active at all temperatures and pH studied, they can be used for gene expression in E. coli under desired environmental conditions. • Spacer lengths and −10 and −35 box sequences of P chap and P pap promoters determined. • The promoters' strengths determined by cloning gfp uv gene under their control. • The strong promoter of Zymomonas mobilis , P pdc , found to be a weak promoter in Escherichia coli. • In E. coli , P tac promoter was the strongest followed by P pap and P pdc. [ABSTRACT FROM AUTHOR]

Pathogenic germline exonuclease domain (ED) variants of POLE and POLD1 cause the Mendelian dominant condition polymerase proof-reading associated polyposis (PPAP). We aimed to describe the clinical features of all PPAP patients with probably pathogenic variants. We identified patients with a variants mapping to the EDs of POLE or POLD1 from cancer genetics clinics, a colorectal cancer (CRC) clinical trial, and systematic review of the literature. We used multiple evidence sources to separate ED variants into those with strong evidence of pathogenicity and those of uncertain importance. We performed quantitative analysis of the risk of CRC, colorectal adenomas, endometrial cancer or any cancer in the former group. 132 individuals carried a probably pathogenic ED variant (105 POLE, 27 POLD1). The earliest malignancy was colorectal cancer at 14. The most common tumour types were colorectal, followed by endometrial in POLD1 heterozygotes and duodenal in POLE heterozygotes. POLD1-mutant cases were at a significantly higher risk of endometrial cancer than POLE heterozygotes. Five individuals with a POLE pathogenic variant, but none with a POLD1 pathogenic variant, developed ovarian cancer. Nine patients with POLE pathogenic variants and one with a POLD1 pathogenic variant developed brain tumours. Our data provide important evidence for PPAP management. Colonoscopic surveillance is recommended from age 14 and upper-gastrointestinal surveillance from age 25. The management of other tumour risks remains uncertain, but surveillance should be considered. In the absence of strong genotype–phenotype associations, these recommendations should apply to all PPAP patients. [ABSTRACT FROM AUTHOR]

The automotive industry is one of the main drivers of industrial production and is well known for high-quality criteria. In the past, original equipment manufacturers (OEMs) pushed forward the main processes of new vehicle production. Today, OEM transfers a great deal of high-level engineering tasks to suppliers. As automotive industries are highly automated robot lines, constituting serial production in millions, the smallest error in a delivered product/component causes the downtime for the whole line. In these situations, it is necessary to validate another supplier of the same component, which can last a very long time. This paper presents a quality management model for incoming components in the automotive industry which can recognize possible risks in the early phase of the component prototype development. The model is successfully applied in a company that produces components for OEM, which will be presented in the second part of the paper. [ABSTRACT FROM AUTHOR]

Garsubellin A is a meroterpene capable of enhancing the enzyme choline acetyltransferase whose decreased level is believed to play a central role in the symptoms of Alzheimer's disease. Due to the potentially useful biological activity together with the novel bridged and fused cyclic molecular architecture, garsubellin A has garnered substantial synthetic interest, but its absolute stereostructure has been undetermined. We report here the first enantioselective total synthesis of (+)‐garsubellin A. Our synthesis relies on stereoselective fashioning of a cyclohexanone framework and double conjugate addition of 1,2‐ethanedithiol that promotes aldol cyclization to build the bicyclic [3.3.1] skeleton. The twelve‐step, protecting group‐free synthetic route has enabled the syntheses of both the natural (−)‐garsubellin A and its unnatural (+)‐antipode for biological evaluations. [ABSTRACT FROM AUTHOR]

Today are used a lot of quality tools, essential for the continuous improvement of the quality of products and processes. The use of quality tools and techniques bring benefits to the growth of the industry. The growth of the aerospace industry depends very much on the quality and reliability of the products made. In order to produce high quality products, it is necessary to maintain the highest quality throughout the entire supply chain. With this in mind, the aerospace equipment manufacturers expressly request suppliers to improve product quality by implementing basic aircraft tools - advanced product quality planning (APQP), failure mode and effect analysis (FMEA), statistical process control (SPC), measurement system analysis (MSA) and production part approval process (PPAP) or obtaining ISO/AS certification - which in some cases is an entry level requirement. The standard of the quality management system in the aerospace industry, AS9100, involves the use of the basic tools APQP, FMEA, MSA, PPAP and SPC. At the present, it is important to meet the specific requirements of the clients. In this paper, the importance of implementing advanced product quality planning in the aerospace industry will be addressed and argued in the form of a way of improving the quality management. In the conclusion, the own points of view on the subject will be highlighted, and also which are the benefits of the approach of improving the quality management using these quality tools and techniques. [ABSTRACT FROM AUTHOR]

Germline mutations of the POLE gene are responsible for polymerase proofreading-associated polyposis syndrome (PPAP). These mutations were hypothesised to predispose to extra-gastrointestinal tumours (ovary, endometrium, brain), but this association has not been confirmed so far. We report a family with an autosomal dominant inheritance of PPAP due to a c.1089C>A; p.Asn363Lys mutation in the proofreading exonuclease domain of POLE. Ten patients presenting a history of colorectal tumours and three patients with polyposis are indexed in this family. Three carriers (including siblings and a distant cousin at 30, 45 and 52 respectively) and another member (at 37 not tested) presented glioblastoma. This is the second family reported to carry this mutation. Among the four glioblastomas in the family that we report, both show similar pathology: giant cell glioblastoma. These cases suggest that the c.1089C>A germline POLE mutation may confer an increased risk of brain cancer [incidence 17.4% (4/23) in mutation carriers combining the two families]. More observations are needed to support this hypothesis. It seems that not all mutations of POLE are equally associated with extra-gastrointestinal tumours. Although carriers of a mutation responsible for PPAP should benefit from screening for colorectal and uterine cancer, due to the rapid evolution of glioblastoma the value of neurological follow-up and brain imaging screening remains questionable. Nevertheless, considering the limitations of standard therapy for glioblastoma, mutation status could be useful for targeting therapy. The biological mechanism linking POLE mutation to glioblastoma remains to be determined. [ABSTRACT FROM AUTHOR]

We describe a family in which four siblings exhibited multiple or classic colonic polyposis with or without colorectal carcinoma (CRC). One female developed three primary tumors, including CRC and carcinomas of the ovary and breast. Whole‐exome sequencing of germline DNA from affected and unaffected individuals revealed a novel missense mutation in the exonuclease domain of POLE (c.833C>A; p.Thr278Lys) associated with a highly penetrant, autosomal‐dominant inheritance pattern. Functional studies in yeast and demonstration of a high mutational burden in the available tumors confirmed the pathogenicity of the novel variant. Prominent POLE‐deficient somatic mutational signatures were seen in the CRCs, but in contrast, a mutational signature typical of concomitant tumoral loss of POLE and mismatch‐repair function (POLE‐exo*/MSI) was noted in the breast cancer. The breast cancer also showed distinctive pathological characteristics that reflect the presence of both the germline POLE variant and the secondary somatic MMR alterations. In a family of four siblings with colonic polyposis and colonic and extracolonic tumors, we found a novel variant in POLE gene (c.833C>A; p.Thr278Lys) that we proved to be pathogenic by functional assays in yeast and high mutational burden in tumors. Prominent POLE‐deficient somatic mutational signatures were seen in the CRCs, but a mutational signature typical of concomitant tumoral loss of POLE and mismatch repair function (POLE‐exo*/MSI) was noted in the breast cancer. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to test Production Part Approval Process (PPAP) as a tool to build quality into the new product and processes and ensure that it meets the customer expectations. Research method is qualitative method using so called case-study to study the suitability of PPAP as a tool for quality management by building quality right into the new product and process. The case studies have been made with three different kinds of companies. PPAP is suitable tool for quality management in NPD processes when taking into account many requirements about personnel, processes, documentation etc. The paper has some limitations such as limited sample size. The results are encouraging managers to use PPAP as a tool for managing their company’s product development processes, quality work and supply chain partnerships. The manner in which the stakeholders could use to facilitate a sense of partnerships or co-workers aiming the same goals rather than have a traditional customer-seller relationship was valued in this study.

Colorectal cancer (CRC) is one of the most common forms of cancer worldwide and familial adenomatous polyposis (FAP) accounts for approximately 1% of all CRCs. Adenomatous polyposis syndromes can be divided into; familial adenomatous polyposis (FAP) - classic FAP and attenuated familial adenomatous polyposis (AFAP), MUTYHassociated polyposis (MAP), NTHL1-associated polyposis (NAP) and polymerase proofreading-associated polyposis (PPAP). The polyposis syndromes genetics and clinical manifestation of disease varies and cases with clinical diagnosis of FAP might molecularly show a different diagnosis. This review examines different aspects of the adenomatous polyposis syndromes genetics and clinical manifestation of disease; in addition the genotype-phenotype and modifier alleles of FAP will be discussed. New technology has made it possible to diagnose some of the APC mutation negative patients into their respective syndromes. There still remain many molecularly undiagnosed adenomatous polyposis patients indicating that there remain causative genes to be discovered and with today's technology these are expected to be identified in the near future. The knowledge about the role of modifier alleles in FAP will contribute to improved pre-symptomatic diagnosis and treatment. New novel mutations will continually be discovered in genes already associated with disease and new genes will be discovered that are associated with adenomatous polyposis. The search for modifier alleles in FAP should be made a priority. [ABSTRACT FROM AUTHOR]

The important of strong and healthy banking sector is really needed for economical development continuance in Indonesia which of course begins from districts to central. This condition encourages the parties involved in it to do appraisal on bank financial performance. This research is done to 10 Bank Perkreditan Rakyat in Southeast Sulawesi with the aims for knowing and analyzing the effect of CAR, LDR, BOPO and PPAP on Bank Perkreditan Rakyat financial performace (ROA) in Southeast Sulawesi. This research result shows that the improvement of CAR and BOPO will push the reduction of ROA, meanwhile LDR is not proven able to increase ROA even tended to become the cause of enhancement of ROA. Meanwhile increase of PPAP is proven to boost of ROA.

"Production Part Approval Process", known as "PPAP", is a requirement of ISO/TS 16949 standard in the automotive industry. It is a methodology through which providers are required to demonstrate a proper understanding of all customer requirements and the ability to produce products that meet all the requirements imposed in the stipulated time and in a constant manner. This paper presents the importance of the Control Plan in the product development and staging, this being one of the tools on which PPAP methodology is based. Companies use Control Plans realized using the results from Failure Mode and Effects Analysis (FMEA) to evaluate a process or product for strengths and weaknesses and to prevent problems before they occur. [ABSTRACT FROM AUTHOR]

One of the requirements of the process approach is to identify the methods and evaluation criteria for process measurement. The effectiveness described as the ability to execute scheduled tasks and the objectives may be the measure used to evaluate processes. The article presents a few concepts of efficiency indicators that can be used in assessing the activities carried out within the framework of the implementation of new projects, according to APQP&PPAP guidelines. This paper proposes four concepts of indicators to assess the effectiveness of the above-described process, including index based on the Taguchi loss function. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of an unnatural polyprenylated acylphloroglucinol (PPAP), regioisomeric with nemorosone and clusianone, has been accomplished. The separated enantiomers of this new PPAP, along with those of nemorosone and clusianone, have been screened for activity against HeLa (cervix carcinoma), MIA-PaCa-2 (pancreatic carcinoma), and MCF7 (mamma carcinoma) cancer cell lines. All of the isomers examined gave surprisingly similar results in the screens. [Copyright &y& Elsevier]