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Groundwater in the Rania basin, Iraqi Kurdistan region, has been under intensive exploitation in the last two decades, where quantity and quality are both affected. Hence, any attempt to protect the aquifers has become an urgent need. Saruchawa, Qulai Rania, and Qulai Kanimaran are the three large springs, among dozens of others in the area, that are heavily relied on as the sole or main source of water supply. Hydrochemical analysis, the first and most practical step to evaluating the water quality, was carried out through 60 water samples collected from 13 springs and 17 wells in both dry and wet seasons (October 2018 and May 2019). Laboratory results show a high calcium bicarbonate concentration with weak acids’ dominance. Protection zones are delineated for these springs using aquifer susceptibility to contamination and analysis of the recession part of the spring curves. The equivalent relationship between the protection factor (Fp) produced by the Epikarst, protective cover, infiltration condition, and Karst network development mapping method and the groundwater protection zone (S) is considered. Qulai Rania and Kanimaran Springs are mapped to be in S2 (a highly vulnerable area), whereas Saruchawa Spring is located in S1 (very highly vulnerable). Based on the second method results (recession curve analyses), all three selected springs fall under the (D-type) vulnerability category. As a result, the immediate protection zone was going to be surrounded by the inner protection zone, and both are enclosed within the outer protection zone, which covers the remainder of the catchment area.

Understanding which factors influence exchange rate movements is important for understanding economic development, trade patterns, investment decisions, and for designing economic policies. In this study, we allow for monetary, domestic and global financial variables to assess the relevant importance of each of the variables to exchange rate volatility in the case of Turkey. The paper investigates the dynamics of exchange rate volatility of the Turkish lira in a complementary perspective by employing both Generalized autoregressive conditional heteroskedasticity (GARCH) method and Lyapunov exponents over the period from March 1, 2019 to November 11, 2021. Firstly, decomposing the impact of domestic and global financial variables, the results of the GARCH model indicate that the exchange rate volatility is affected by Volatility index (VIX) and Credit default swaps (CDS). This result suggests that the exchange rate shocks experienced are mainly caused by global factors, therefore policymakers should focus on volatility spillovers caused by global financial markets. Secondly, detected positive maximal Lyapunov exponent shows that complexity in foreign exchange markets has been increased, market expectations lead to multiple-equilibria and diverging volatility eventually will generate recurrent spikes in currency value. These complementary findings have important implications for interventions of Central banks and preventing systemic risks, as well as portfolio and risk management. JEL Classification: C32, G14, G15.

INTRODUCTION: Polymorphisms of the Mu opioid receptor (MOR) gene (OPRM1), which encodes for the primary action site of heroin, have also been found to be associated with heroin addiction. The aim of this study was to investigate the relationships between heroin addiction and G36T OPRK1 and A118G OPRM1 receptor gene polymorphisms in a male population in Turkey. METHODS: 102 male patients with heroin use (without any other drug use) and 82 subjects without any history of opioid use were evaluated. The A118G and G36T SNPs on the MOR and Kappa opioid receptors (KOR) genes were assessed via TaqMan 5'-exonuclease allelic discrimination assays. RESULTS: The mean duration of heroin use was 4.6+-1.9 years. The G36T polymorphism and heterozygous genotype were both found to be more frequent in the patient group (OPRK1 gene). In the patient group, 79 (77.5%) patients had wild-type genotype and 23 (22.5%) patients had mutant genotype. In the control group, 76 (92.7 %) subjects had wild-type genotype and 6 (7.3 %) subjects had mutant genotype (p=0.005). Wild type allele frequency was determined to be 0.894 and mutant type allele frequency was 0.105. With regard to the A118G polymorphism, we found that there was no difference between groups in terms of genotype. DISCUSSION AND CONCLUSION: Our findings support a considerable role for OPRK1 in opioid addiction; however, in conflict with most studies, we did not determine a relationship with A118G in Turkish subjects. We suggest that further studies should be conducted to ascertain the clinical implications of opioid gene polymorphisms in Turkey.

The purpose of this study is to examine the relationship between common rationality (as a factor of convergence of employees and managers), collective decision-making (as one of the important methods of participation), and productivity (as an important indicator of organizational success). Structural equation modeling (SEM) is used to investigate the strength of these relationships. After the distribution of 98 questionnaires among organizational experts we used Smart PLS 2.0 to analyze the data. The results show that the indirect relationship between common rationality and productivity through a mediating variable of collective decision-making is stronger than the direct effect of common rationality on productivity. It means that common rationality as a substantial asset for an organization could be used to improve productivity but if managers want to utilize this asset, they should apply it through another mediator which is collective decision-making. Collective decision-making could facilitate the relationship between common rationality and productivity by creating synergy among employees, reducing biases, increasing decision quality, and reaching the optimal decision.

Objective:The coronavirus disease-2019 (COVID-19) pandemic effect diagnosis and treatment of certain conditions, including bladder cancer (BC). This study aimed to evaluate the effects of the COVID-19 pandemic on BC diagnosis and treatment.Materials and Methods:Following the approval of the ethics committee for the study, data of 869 patients who underwent surgery for BC in the 2-year period between March 1, 2019 and February 28, 2021 were analyzed retrospectively. The number of surgeries performed for BC, the time elapsed between symptoms and diagnosis, the treatments performed, and the operative pathologies were compared before and during the COVID-19 pandemic.Results:During the COVID-19 period, there was a decrease in the total number of BC surgeries compared to the pre-COVID-19 period (p=0.004). It was observed that this decrease was due to a decrease in patients newly diagnosed with BC (p=0.001) as well as the decrease in the number of primary transurethral resection for bladder tumor procedures performed. There was no difference in the tumor stages of the patients at diagnosis (p=0.9). Intracavitary Bacillus Calmette-Guérin therapy use in high-risk non-muscle invasive bladder cancers (NMIBC) patients also decreased (p=0.008) during the pandemic period. It was observed that the time between symptom and diagnosis was longer in MIBC than in NIMBC during both periods (p

Objective:Anesthetic agents and applications affect tumor pathophysiology and immunosuppression in the postoperative period. We evaluated the changes made by hypnotic anesthetic agents used during anesthesia on neutrophil/lymphocyte ratio (NLR) in patients undergoing radical prostate surgery and its relationship with short-term morbidity.Materials and Methods:Age of patients who had radical prostatectomy, physical classification of the American Society of Anesthesiology, perioperative blood transfusion, drugs used during general anesthesia (intravenous, opioid, volatile anesthetic), duration of anesthesia, analgesics used in postoperative pain was examined. Preoperative, postoperative day-0 and day-2 NLR results were recorded.Results:The data of 159 patients who underwent radical prostatectomy were assessed. The patients were divided into 2 groups; Group pentotal-sevoflurane/ desflurane (PSD) (n=101) and Group propofol-sevoflurane/desflurane (PrSD) (n=58). There was no difference in terms of preoperative and postoperative 2 day NLR value, but the highest NLR values in the postoperative day 0 was found to be in Group PrSD. Postoperative complications were higher in Group PSD. However, preoperative NLR values of these complications were higher in Group PrSD. Erythrocyte (red blood cell) replacement patients were divided into 2 groups; between 0 and 2 units (n=147) and more than >2 units (n=12), their preoperative NLR ratios were 2.54 (0.7-16.3) and 3.3 (1.8-8.8) respectively. The cut value of NLR for bleeding was set at 1.77.Conclusion:Increased NLR result is associated with immunosuppression and tumorigenesis, and is an easy and inexpensive technique. In prostate cancer, preoperative high NLR (>1.7) may have a predictive value for bleeding, blood transfusion, and postoperative respiratory distress.

Adenomatoid tumours are benign neoplasms of mesothelial origin that most often occur in the epididymis in men and the uterus or fallopian tubes in women. When the stromal smooth muscle component is prominent, the term leiomyoadenomatoid tumour is recommended. To date, only 10 cases of epididymal leiomyoadenomatoid tumour have been reported. In some cases, coagulation necrosis associated with worrisome regenerative changes can occur and leads to an increase in diagnostic pitfalls such as malignant neoplastic processes. Pathologists should be aware of this entity to avoid misdiagnosis. Herein, we present the eleventh case of epididymal leiomyoadenomatoid tumour in a 59-year-old man.

Метою дослідження є вивчення впливу Інтернету на соціальне та культурне становлення людини, як особистості; на її внутрішній світ та поведін­ку. Оцінка впливу інтернет-залежності на окрему особистість та соціальні групи, аналіз її впливу на становлення моральних цінностей та культуру поведінки в суспільстві. Визначення дії надлишку інформації, на девальвацію етичних норм людської цивілізації, що є найнебезпечнішим і непоправним наслідком активного вторгнення Інтернету в усі сфери діяльності людей. Методи дослідження вивчення джерел впливу інформації з інтернет-мережі, як одного із засобів, впливу на формування світосприйняття населення, що є важливим аспектом навчання й морального виховання, та відіграє важливу роль у процесі формування особистості. З Інтернету люди дізнаються про норми поведінки, яка розцінюється в суспільстві як відповідна тій чи іншій соціальній групі. Соціальні мережі, доступність інформації в інтернет так чи інакше формує світогляд людей та їхні цінності. Найбільш відчутний вплив інтернет чинить на молодих людей як найбільш сприйнятливих споживачів інформації. Методи впливу інформації отриманої з інтернету на формування ціннісних, морально-духовних орієнтацій особистості вивчається відносно нещодавно, при цьому багато проблем у даній галузі ще не охоплено. Новизна дослідження особливості впливу інтернету на морально-духовні та соціальні цінності особистості. У статті висвітлюються позитивні та негативні сторони сприйняття інформації через інтернет. Зосереджується увага на розповсюдження різнопланової інформації через соціальні мережі, та спрямування її на різні соціальні та вікові групи. Висновки. В результаті дослідження визначено вплив інтернету на особистість і моральні цінності людини, як масового засобу впливу, основного джерела інформації для більшості населення. Доведено, що на першому плані при цьому виявляється груповий інтерес, а на другому – пізнавальний. Встановлено, що Інтернет здійснює двоякий вплив на особистість: негативний, з одного боку, це анонімність, віртуальне хижацтво, інтернет-залежність, інформаційна небезпека; та позитивний: освітній і корисний досвід. Крім того користувачі здатні до аналізу отриманої інформації, намагаються її «фільтру­вати», що позитивно впливає на логічне мислення, пам’ять, увагу.

Dealing safely with nuclear waste is an imperative for the nuclear industry. Increasingly, robots are being developed to carry out complex tasks such as perceiving, grasping, cutting, and manipulating waste. Radioactive material can be sorted, and either stored safely or disposed of appropriately, entirely through the actions of remotely controlled robots. Radiological characterisation is also critical during the decommissioning of nuclear facilities. It involves the detection and labelling of radiation levels, waste materials, and contaminants, as well as determining other related parameters (e.g., thermal and chemical), with the data visualised as 3D scene models. This paper overviews work by researchers at the QMUL Centre for Advanced Robotics (ARQ), a partner in the UK EPSRC National Centre for Nuclear Robotics (NCNR), a consortium working on the development of radiation-hardened robots fit to handle nuclear waste. Three areas of nuclear-related research are covered here: human–robot interfaces for remote operations, sensor delivery, and intelligent robotic manipulation.

Effective corporate governance is one of the main features of an efficient market economy. This may help the stakeholders gain information, and the right and the ability to efficiently manage the company through the process of governance. This study examines the effect of Corporate Governance Strategic Control on effective Governance of Corporation. The required data for this research has been collected through questionnaires by random sampling from among the corporates which are listed in stock exchange. Based on incidental sampling, 130 corporates were selected and the researcher-developed questionnaires were given to their managers. Meanwhile, structural equations method is applied using Smart PLS software for data analysis. The obtained results indicated that the Corporate Governance Strategic controls are effective on efficient Governance of Corporation. Moreover, internal and external Corporate Governance control as two main dimensions the Corporate Governance Strategic control are proved effective on Corporate Governance.

Studying language in micro, native and local domains is one of the emphasized streams of research in the newest paradigm of strategy research, namely, “strategy as practice”. This critical study seeks to derive the “what” and “why” of the pattern of strategic control model in weight industry of Iran using qualitative research and drawing on social constructivism philosophy. Accordingly, this study uses grounded analysis and induction-based coding approach through Atlas.ti – specific explorative analysis software. The conclusions are emerged from 15 semi-structured field interviews through theoretical sampling and to reach the stage of saturation extract, and at the end of the Dell data control model weighting has been articulating a strategic industry.

The importance of brand equity in current marketing world is clear. a strong brand can be worth more than the usual value for an organization. This issue has an utmost important in the tourism industry. Todays tourism organization are looking for the identification of effective factor for promoting the equity of brand in their customrs mind. Advertising is also one of the issues that today even the most distant parts of the world are familiar with and in affected by it. This article seeks to develop a systematic framework about brand equity and its dimension, Advertising and consumer response with mediator role of knowledge transfer and innovational performance in in Tourism and Travel Agencies in Tehran and trying to broaden the frontiers of knowledge in this area. Data for this study as non-random sampling of customers in the travel and tourism offices in Tehran city by using a questionnaire has been collected. This study, based on aim, is an applicable research, and based on data collection method, it is a descriptive research with Using Smart PLS software. The result of study showed there was a significant positive effect of on consumer response.forthere more it showed that advertising has a positive effect through brand equity and its dimentions on consumer response.

Today make a strong brand is an objective for many organizations like service organizations. Therefore building a brand in the hotel industry is important in this area, but little research has been carried out with experimental approach in this area. This study examines experimentally the relationship among the components of customer-based brand equity Based on Asker’s assumption in order to determining the most important component in brand equity components in hotel industry. This study, based on aim, is an applicable research, and based on data collection method, it is a descriptive research. The using data was gathered by questionnaire from customers of Mashhad five stare hotels by using Non-random sampling methods available collection. Also, considering its data analysis method, it is a structural equation based research. The results indicate that perceived quality is the strongest predictor when determining brand equity and has significant impact on other brand equity components.it is one of the strongest determinant of brand equity.

This paper reports the results of investigations carried out on the effect of varying curing age and water/cement ratio on the modulus of elasticity and modulus of deformability of laterized concrete. The test specimens were made with sieved samples of selected grain size ranges of laterite used as fine aggregates to replace sand in normal concrete. Batching was by weight. Three mix ratios of (1:1½:3), (1:2:4) and (1:3:6) were used. Water/cement ratio of 0.5, 0.6, 0.7 and 0.75 were used for each of the mix ratios. The specimens were tested at curing ages of seven to 28 days. The results showed that there was a corresponding increase in both modulus of elasticity and modulus of deformability of laterized concrete due to increase in curing ages. The mix proportion, compressive strength and water/cement ratio were found to have significant effects on both modulus of elasticity and modulus of deformability of laterized concrete.

Bilişim alanında son yılların gözde konularından biri Kurumsal Uygulama Tümleşimi?dir. Kurumsal Uygulama Tümleşimi basit bir şekilde, bir organizasyonun bilgi işlem ortamını oluşturan farklı sistemler arasında standart köprüler oluşturulması süreci olarak tanımlanabilir. Kurumsal Uygulama Tümleşimi?nin popüler olmasının nedeni, şirket birleşme, satın alma ve evlilikleri olmuştur. Bu tür ilişkiler içinde olan şirketlerde çalışmakta olan benzer sistemlerin bir süre daha çalışması sağlanırken, hedef en kısa vadede şirketler arasındaki uygulama entegrasyon sorununun çözülmesi olmuştur. XML teknolojisi ile hem kurum içindeki hem de kurumlar arasındaki uygulama entegrasyon sorunlarına çözüm bulunabilir.

In recent years the most popular subject in Information System area is Enterprise Application Integration (EAI). It can be defined as a process of forming a standart connection between different systems of an organization?s information system environment. The incorporating, gaining and marriage of corporations are the major reasons of popularity in Enterprise Application Integration. The main purpose is to solve the application integrating problems while similar systems in such corporations continue working together for a more time. With the help of XML technology, it is possible to find solutions to the problems of application integration either within the corporation or between the corporations.

Bilişim alanında son yılların gözde konularından biri Kurumsal Uygulama Tümleşimi?dir. Kurumsal Uygulama Tümleşimi basit bir şekilde, bir organizasyonun bilgi işlem ortamını oluşturan farklı sistemler arasında standart köprüler oluşturulması süreci olarak tanımlanabilir. Kurumsal Uygulama Tümleşimi?nin popüler olmasının nedeni, şirket birleşme, satın alma ve evlilikleri olmuştur. Bu tür ilişkiler içinde olan şirketlerde çalışmakta olan benzer sistemlerin bir süre daha çalışması sağlanırken, hedef en kısa vadede şirketler arasındaki uygulama entegrasyon sorununun çözülmesi olmuştur. XML teknolojisi ile hem kurum içindeki hem de kurumlar arasındaki uygulama entegrasyon sorunlarına çözüm bulunabilir.

Functional approach to Class II div. I cases is a commonly used method, Jasper Jumper which was described in this paper is an alternative to the other functional appliances as being a fixed one. In this pilot study which contains 5 cases we aimed to describe the mechanic and observe the treatment effects on skeletal and dental structures.

Microbial metabolism has been deeply studied over decades and it is considered to be understood to a great extent. Annotated genome sequences of many microbial species have contributed a lot to generating biochemical knowledge on metabolism. However, researchers still discover novel pathways, unforeseen reactions or unexpected metabolites which contradict to the expected canon of biochemical reactions in living organisms. Here, we highlight a few examples of such non-canonical pathways, how they were found, and what their importance in microbial biotechnology may be. The predictive power of metabolic modelling, well-founded on biochemical knowledge and genomic information is discussed in the light of both discovery of yet unknown existing metabolic routes and the prediction of others, new to Nature., (© 2024 The Author(s). Microbial Biotechnology published by John Wiley & Sons Ltd.)

Background: Amidst the escalating carbon dioxide levels resulting from fossil fuel consumption, there is a pressing need for sustainable, bio-based alternatives to underpin future global economies. Single-carbon feedstocks, derived from CO 2 , represent promising substrates for biotechnological applications. Especially, methanol is gaining prominence for bio-production of commodity chemicals., Results: In this study, we show the potential of Komagataella phaffii as a production platform for itaconic acid using methanol as the carbon source. Successful integration of heterologous genes from Aspergillus terreus (cadA, mttA and mfsA) alongside fine-tuning of the mfsA gene expression, led to promising initial itaconic acid titers of 28 g·L -1 after 5 days of fed-batch cultivation. Through the combined efforts of process optimization and strain engineering strategies, we further boosted the itaconic acid production reaching titers of 55 g·L -1 after less than 5 days of methanol feed, while increasing the product yield on methanol from 0.06 g·g -1 to 0.24 g·g -1 ., Conclusion: Our results highlight the potential of K. phaffii as a methanol-based platform organism for sustainable biochemical production., (© 2024. The Author(s).)

Increasing atmospheric carbon dioxide levels, a reduction of arable land area and the dependence of first and second generation biotechnology feedstocks on agricultural products, call for alternative, sustainable feedstock sources for industrial applications. The direct use of CO 2 or conversion of CO 2 into other single carbon (C1) sources have great potential as they might help to reduce carbon emissions and do not compete with agricultural land use. Here we discuss the microbial use of C1 carbon sources, their potential applications in biotechnology, and challenges towards sustainable C1-based industrial biotechnology processes. We focus on methanol, formic acid, methane, syngas, and CO 2 as feedstocks for bioprocesses, their assimilation pathways, current and emerging applications, and limitations of their application. This mini-review is intended as a first introduction for researchers who are new to the field of C1 biotechnology., Competing Interests: D.M. holds shares of FermX GmbH which develops cell factories for sustainable production of food and feed ingredients from C1 substrates. M.B. and O.A. declare no competing interests., (© 2024 The Authors.)

In this article we explore the intersection of science and art through a collaboration between us scientists and the bioartists Anna Dimitriu and Alex May, focusing on the interface of yeast biotechnology and art. The collaboration, originally initiated in 2018, resulted in three major artworks: CULTURE, depicting the evolution of yeast and human societies; FERMENTING FUTURES, illustrating a synthetic autotrophic yeast and its link to lactic acid production; and WOOD SPIRIT-AMBER ACID, inspired by the VIVALDI project targeting CO2 reduction to methanol. We emphasize the reciprocal nature of the collaboration, detailing the scientific insights gained and the impact of artistic perspectives on us as researchers. We also highlight the historical connection between art and science, particularly in the Renaissance periods, and underscore the educational value of integrating art into science not only to support public engagement and science dissemination, but also to widen our own perceptions in our research., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

Synthetic autotrophs can serve as chassis strains for bioproduction from CO 2 as a feedstock to take measures against the climate crisis. Integration of the Calvin-Benson-Bassham (CBB) cycle into the methylotrophic yeast Komagataella phaffii ( Pichia pastoris ) enabled it to use CO 2 as the sole carbon source. The key enzyme in this cycle is ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) catalyzing the carboxylation step. However, this enzyme is error prone to perform an oxygenation reaction leading to the production of toxic 2-phosphoglycolate. Native autotrophs have evolved different recycling pathways for 2-phosphoglycolate. However, for synthetic autotrophs, no information is available for the existence of such pathways. Deletion of CYB2 in the autotrophic K. phaffii strain led to the accumulation of glycolate, an intermediate in phosphoglycolate salvage pathways, suggesting that such a pathway is enabled by native K. phaffii enzymes. 13 C tracer analysis with labeled glycolate indicated that the yeast pathway recycling phosphoglycolate is similar to the plant salvage pathway. This orthogonal yeast pathway may serve as a sensor for RuBisCO oxygenation, and as an engineering target to boost autotrophic growth rates in K. phaffii ., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)

Microbial metabolism offers a wide variety of opportunities to produce chemicals from renewable resources. Employing such processes of industrial biotechnology provides valuable means to fight climate change by replacing fossil feedstocks by renewable substrate to reduce or even revert carbon emission. Several yeast species are well suited chassis organisms for this purpose, illustrated by the fact that the still largest microbial production of a chemical, namely bioethanol is based on yeast. Although production of ethanol and some other chemicals is highly efficient, this is not the case for many desired bulk chemicals. One reason for low efficiency is carbon loss, which decreases the product yield and increases the share of total production costs that is taken by substrate costs. Here we discuss the causes for carbon loss in metabolic processes, approaches to avoid carbon loss, as well as opportunities to incorporate carbon from CO 2 , based on the electron balance of pathways. These aspects of carbon efficiency are illustrated for the production of succinic acid from a diversity of substrates using different pathways., (© 2023 The Authors. Yeast published by John Wiley & Sons Ltd.)

Rising CO 2 emissions have pushed scientists to develop new technologies for a more sustainable bio-based economy. Microbial conversion of CO 2 and CO 2 -derived carbon substrates into valuable compounds can contribute to carbon neutrality and sustainability. Here, we discuss the potential of C1 carbon sources as raw materials to produce energy, materials, and food and feed using microbial cell factories. We provide an overview of potential microbes, natural and synthetic C1 utilization pathways, and compare their metabolic driving forces. Finally, we sketch a future in which C1 substrates replace traditional feedstocks and we evaluate the costs associated with such an endeavor., (© 2023. The Author(s).)

The increase of CO 2 emissions due to human activity is one of the preeminent reasons for the present climate crisis. In addition, considering the increasing demand for renewable resources, the upcycling of CO 2 as a feedstock gains an extensive importance to establish CO 2 -neutral or CO 2 -negative industrial processes independent of agricultural resources. Here we assess whether synthetic autotrophic Komagataella phaffii ( Pichia pastoris ) can be used as a platform for value-added chemicals using CO 2 as a feedstock by integrating the heterologous genes for lactic and itaconic acid synthesis. 13 C labeling experiments proved that the resulting strains are able to produce organic acids via the assimilation of CO 2 as a sole carbon source. Further engineering attempts to prevent the lactic acid consumption increased the titers to 600 mg L -1 , while balancing the expression of key genes and modifying screening conditions led to 2 g L -1 itaconic acid. Bioreactor cultivations suggest that a fine-tuning on CO 2 uptake and oxygen demand of the cells is essential to reach a higher productivity. We believe that through further metabolic and process engineering, the resulting engineered strain can become a promising host for the production of value-added bulk chemicals by microbial assimilation of CO 2 , to support sustainability of industrial bioprocesses.

Yeasts and especially Pichia pastoris (syn Komagataella spp.) are popular microbial expression systems for the production of recombinant proteins. One of the key advantages of yeast host systems is their ability to secrete the recombinant protein into the culture media. However, secretion of some recombinant proteins is less efficient. These proteins include antibody fragments such as Fabs or scFvs. We have recently identified translocation of nascent Fab fragments from the cytosol into the endoplasmic reticulum (ER) as one major bottleneck. Conceptually, this bottleneck requires engineering to increase the flux of recombinant proteins at the translocation step by pushing on the cytosolic side and pulling on the ER side. This engineering strategy is well-known in the field of metabolic engineering. To apply the push-and-pull strategy to recombinant protein secretion, we chose to modulate the cytosolic and ER Hsp70 cycles, which have a key impact on the translocation process. After identifying the relevant candidate factors of the Hsp70 cycles, we combined the push-and-pull factors in a single strain and achieved synergistic effects for antibody fragment secretion. With this concept we were able to successfully engineer strains and improve protein secretion up to 5-fold for different model protein classes. Overall, titers of more than 1.3 g/L Fab and scFv were reached in bioreactor cultivations., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The yeast genus Komagataella currently consists of seven methylotrophic species isolated from tree environments. Well-characterized strains of K. phaffii and K. pastoris are important hosts for biotechnological applications, but the potential of other species from the genus remains largely unexplored. In this study, we characterized 25 natural isolates from all seven described Komagataella species to identify interesting traits and provide a comprehensive overview of the genotypic and phenotypic diversity available within this genus., Results: Growth tests on different carbon sources and in the presence of stressors at two different temperatures allowed us to identify strains with differences in tolerance to high pH, high temperature, and growth on xylose. As Komagataella species are generally not considered xylose-utilizing yeasts, xylose assimilation was characterized in detail. Growth assays, enzyme activity measurements and 13 C labeling confirmed the ability of K. phaffii to utilize D-xylose via the oxidoreductase pathway. In addition, we performed long-read whole-genome sequencing to generate genome assemblies of all Komagataella species type strains and additional K. phaffii and K. pastoris isolates for comparative analysis. All sequenced genomes have a similar size and share 83-99% average sequence identity. Genome structure analysis showed that K. pastoris and K. ulmi share the same rearrangements in difference to K. phaffii, while the genome structure of K. kurtzmanii is similar to K. phaffii. The genomes of the other, more distant species showed a larger number of structural differences. Moreover, we used the newly assembled genomes to identify putative orthologs of important xylose-related genes in the different Komagataella species., Conclusions: By characterizing the phenotypes of 25 natural Komagataella isolates, we could identify strains with improved growth on different relevant carbon sources and stress conditions. Our data on the phenotypic and genotypic diversity will provide the basis for the use of so-far neglected Komagataella strains with interesting characteristics and the elucidation of the genetic determinants of improved growth and stress tolerance for targeted strain improvement., (© 2022. The Author(s).)

The important industrial protein production host Komagataella phaffii (syn Pichia pastoris) is classified as a non-conventional yeast. But what exactly makes K. phaffii non-conventional? In this review, we set out to address the main differences to the 'conventional' yeast Saccharomyces cerevisiae, but also pinpoint differences to other non-conventional yeasts used in biotechnology. Apart from its methylotrophic lifestyle, K. phaffii is a Crabtree-negative yeast species. But even within the methylotrophs, K. phaffii possesses distinct regulatory features such as glycerol-repression of the methanol-utilization pathway or the lack of nitrate assimilation. Rewiring of the transcriptional networks regulating carbon (and nitrogen) source utilization clearly contributes to our understanding of genetic events occurring during evolution of yeast species. The mechanisms of mating-type switching and the triggers of morphogenic phenotypes represent further examples for how K. phaffii is distinguished from the model yeast S. cerevisiae. With respect to heterologous protein production, K. phaffii features high secretory capacity but secretes only low amounts of endogenous proteins. Different to S. cerevisiae, the Golgi apparatus of K. phaffii is stacked like in mammals. While it is tempting to speculate that Golgi architecture is correlated to the high secretion levels or the different N-glycan structures observed in K. phaffii, there is recent evidence against this. We conclude that K. phaffii is a yeast with unique features that has a lot of potential to explore both fundamental research questions and industrial applications., (© The Author(s) 2021. Published by Oxford University Press on behalf of FEMS. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

BioArt is a new discipline where artists employ materials and techniques of modern life sciences and create novel meanings of biology, often involving living organisms such as tissue culture, bacteria and yeasts, which may also be genetically engineered. The authors have engaged in a collaboration to develop 'Fermenting Futures', a project designed to explore the significance of yeast for early human history by enabling baking and brewing, all the way to industrial biotechnology and synthetic biology with their potential contributions to fight the climate change. Research in two of the authors' lab provides the materials and thematic lines for the artists to develop their installations. The two main pieces reflect on fermentation as a metabolic trait of baker's yeast and its enormous transformational power for human society, and on the application of synthetic biology to enable yeast to grow and produce materials from carbon dioxide. The role of BioArt to support public engagement and science dissemination is discussed, highlighting the importance of collaborations of scientists and artists on equal terms, as showcased here., (© The Author(s) 2021. Published by Oxford University Press on behalf of FEMS. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A yeast deletion mutation in the nuclear-encoded gene, AFO1 , which codes for a mitochondrial ribosomal protein, led to slow growth on glucose, the inability to grow on glycerol or ethanol, and loss of mitochondrial DNA and respiration. We noticed that afo1 - yeast readily obtains secondary mutations that suppress aspects of this phenotype, including its growth defect. We characterized and identified a dominant missense suppressor mutation in the ATP3 gene. Comparing isogenic slowly growing rho-zero and rapidly growing suppressed afo1 - strains under carefully controlled fermentation conditions showed that energy charge was not significantly different between strains and was not causal for the observed growth properties. Surprisingly, in a wild-type background, the dominant suppressor allele of ATP3 still allowed respiratory growth but increased the petite frequency. Similarly, a slow-growing respiratory deficient afo1 - strain displayed an about twofold increase in spontaneous frequency of point mutations (comparable to the rho-zero strain) while the suppressed strain showed mutation frequency comparable to the respiratory-competent WT strain. We conclude, that phenotypes that result from afo1 - are mostly explained by rapidly emerging mutations that compensate for the slow growth that typically follows respiratory deficiency., (Copyright © 2020 Li et al.)

Bladder cancer (BC), the most common malignancy of the urinary tract, accounts for 90-95% of all urothelial carcinomas (UCs), while upper urinary tract UC (UUTUC) accounts for only 5-10%. Radical nephroureterectomy with excision of bladder cuff, and radical cystectomy with pelvic lymph node dissection and a urinary diversion (UD) are the gold standard treatments for UUTUC and muscle-invasive bladder cancer (MIBC), respectively. These two treatments can be performed simultaneously when a bilateral or unilateral UUTUC is present with a MIBC, and are called complete urinary tract extirpation (CUTE) and hemi-CUTE, respectively. This complex surgery can help the patient by avoiding multi-staged surgeries, repeated anesthesia, and delay in completion of treatment. Herein, we report the first cases of a hemi-CUTE and CUTE in our department and share our experience with this aggressive and complex surgical treatment.

The Crabtree phenotype defines whether a yeast can perform simultaneous respiration and fermentation under aerobic conditions at high growth rates. It provides Crabtree positive yeasts an evolutionary advantage of consuming glucose faster and producing ethanol to outcompete other microorganisms in sugar rich environments. While a number of genetic events are associated with the emergence of the Crabtree effect, its evolution remains unresolved. Here we show that overexpression of a single Gal4-like transcription factor is sufficient to convert Crabtree-negative Komagataella phaffii (Pichia pastoris) into a Crabtree positive yeast. Upregulation of the glycolytic genes and a significant increase in glucose uptake rate due to the overexpression of the Gal4-like transcription factor leads to an overflow metabolism, triggering both short-term and long-term Crabtree phenotypes. This indicates that a single genetic perturbation leading to overexpression of one gene may have been sufficient as the first molecular event towards respiro-fermentative metabolism in the course of yeast evolution.

The constitutive glyceraldehyde-3-phosphate dehydrogenase promoter (P GAP ), which is one of the benchmark promoters of Pichia pastoris, was analyzed in terms of putative transcription factor binding sites. We constructed a synthetic library with distinct regulatory properties through deletion and duplication of these putative transcription factor binding sites and selected transcription factor (TF) genes were overexpressed or deleted to understand their roles on heterologous protein production. Using enhanced green fluorescent protein, an expression strength in a range between 0.35- and 3.10-fold of the wild-type P GAP was obtained. Another model protein, recombinant human growth hormone was produced under control of selected promoter variants and 1.6- to 2.4-fold higher product titers were reached compared to wild-type P GAP . In addition, a GAL4-like TF was found to be a crucial factor for the regulation of P GAP , and its overexpression enhanced the heterologous protein production considerably (up to 2.2-fold compared to the parental strain). The synthetic P GAP library generated enabled us to investigate the different putative transcription factors which are responsible for the regulation of P GAP under different growth conditions, ergo recombinant protein production under P GAP . Biotechnol. Bioeng. 2017;114: 2319-2327. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

The objectives of this work are the optimization of the codons of xylA gene from Thermus thermophilus to enhance the production of recombinant glucose isomerase (rGI) in P. pastoris and to investigate the effects of feeding strategies on rGI production. Codons of xylA gene from T. thermophilus were optimized, ca. 30 % of the codons were replaced with those with higher frequencies according to the codon usage bias of P. pastoris, codon optimization resulted in a 2.4-fold higher rGI activity. To fine-tune bioreactor performance, fed-batch bioreactor feeding strategies were designed as continuous exponential methanol feeding with pre-calculated feeding rate based on the pre-determined specific growth rate, and fed-batch methanol-stat feeding. Six feeding strategies were designed, as follows: (S1) continuous exponential methanol- and pulse- sorbitol feeding; (S2) continuous exponential methanol- and peptone- feeding; (S3) continuous exponential methanol- and pulse- mannitol feeding; (S4) continuous exponential methanol- and peptone- feeding and pulse-mannitol feeding; (S5) methanol-stat feeding by keeping methanol concentration at 5 g L(-1); and, (S6) methanol-stat feeding by keeping methanol concentration at 5 g L(-1) and pulse-mannitol feeding. The highest cell and rGI activity was attained as 117 g L(-1) at t = 66 h and 32530 U L(-1) at t = 53 h, in strategy-S5. The use of the co-substrate mannitol does not increase the rGI activity in methanol-stat feeding, where 4.1-fold lower rGI activity was obtained in strategy-S6. The overall cell yield on total substrate was determined at t = 53 h as 0.21 g g(-1) in S5 strategy.

Osteoradionecrosis of the hyoid bone is a rare complication of therapeutic irradiation performed for head and neck cancer. In this article, we present a 52-year-old male patient who admitted with severe odynophagia following chemo-radiotherapy administration for tonsil carcinoma. Fluorine-18-fluorodeoxy-glucose positron emission tomography-computed tomography revealed a metabolic activity in hyoid bone. The pathological findings were consistent with fungal infection and hyoid bone necrosis. Hyoid osteoradionecrosis should be kept in mind in patients with intractable dysphagia following irradiation for head and neck tumors.