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  • A state-of-the-art review on nitrous oxide control from waste treatment and industrial sources
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-03-20
    Osvaldo D. Frutos, Guillermo Quijano, Aitor Aizpuru, Raúl Muñoz

    This review aims at holistically analyzing the environmental problems associated with nitrous oxide (N2O) emissions by evaluating the most important sources of N2O and its environmental impacts. Emissions from wastewater treatment processes and the industrial production of nitric and adipic acid represent nowadays the most important anthropogenic point sources of N2O. Therefore, state-of-the-art strategies to mitigate the generation and release to the atmosphere of this greenhouse and O3-depleting gas in the waste treatment and industrial sectors are also reviewed. An updated review of the end-of-the-pipe technologies for N2O abatement, both in the waste treatment and industrial sectors, is herein presented and critically discussed for the first time. Despite the consistent efforts recently conducted in the development of cost-efficient and eco-friendly N2O abatement technologies, physical/chemical technologies still constitute the most popular treatments for the control of industrial N2O emissions at commercial scale. The recent advances achieved on biological N2O abatement based on heterotrophic denitrification have opened new opportunities for the development of eco-friendly alternatives for the treatment of N2O emissions. Finally, the main limitations and challenges faced by these novel N2O abatement biotechnologies are identified in order to pave the way for market implementation.

  • Advances in kinome research of parasitic worms - implications for fundamental research and applied biotechnological outcomes
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-03-19
    Andreas J. Stroehlein, Neil D. Young, Robin B. Gasser

    Protein kinases are enzymes that play essential roles in the regulation of many cellular processes. Despite expansions in the fields of genomics, transcriptomics and bioinformatics, there is limited information on the kinase complements (kinomes) of most eukaryotic organisms, including parasitic worms that cause serious diseases of humans and animals. The biological uniqueness of these worms and the draft status of their genomes pose challenges for the identification and classification of protein kinases using established tools. In this article, we provide an account of kinase biology, the roles of kinases in diseases and their importance as drug targets, and drug discovery efforts in key socioeconomically important parasitic worms. In this context, we summarise methods and resources commonly used for the curation, identification, classification and functional annotation of protein kinase sequences from draft genomes; review recent advances made in the characterisation of the worm kinomes; and discuss the implications of these advances for investigating kinase signalling and developing small-molecule inhibitors as new anti-parasitic drugs.

  • Stem cells: their source, potency and use in regenerative therapies with focus on adipose-derived stem cells – a review
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-03-18
    Lucie Bacakova, Jana Zarubova, Martina Travnickova, Jana Musilkova, Julia Pajorova, Petr Slepicka, Nikola Slepickova Kasalkova, Vaclav Svorcik, Zdenka Kolska, Hooman Motarjemi, Martin Molitor

    Stem cells can be defined as units of biological organization that are responsible for the development and the regeneration of organ and tissue systems. They are able to renew their populations and to differentiate into multiple cell lineages. Therefore, these cells have great potential in advanced tissue engineering and cell therapies. When seeded on synthetic or nature-derived scaffolds in vitro, stem cells can be differentiated towards the desired phenotype by an appropriate composition, by an appropriate architecture, and by appropriate physicochemical and mechanical properties of the scaffolds, particularly if the scaffold properties are combined with a suitable composition of cell culture media, and with suitable mechanical, electrical or magnetic stimulation. For cell therapy, stem cells can be injected directly into damaged tissues and organs in vivo. Since the regenerative effect of stem cells is based mainly on the autocrine production of growth factors, immunomodulators and other bioactive molecules stored in extracellular vesicles, these structures can be isolated and used instead of cells for a novel therapeutic approach called “stem cell-based cell-free therapy”. There are four main sources of stem cells, i.e. embryonic tissues, fetal tissues, adult tissues and differentiated somatic cells after they have been genetically reprogrammed, which are referred to as induced pluripotent stem cells (iPSCs). Although adult stem cells have lower potency than the other three stem cell types, i.e. they are capable of differentiating into only a limited quantity of specific cell types, these cells are able to overcome the ethical and legal issues accompanying the application of embryonic and fetal stem cells and the mutational effects associated with iPSCs. Moreover, adult stem cells can be used in autogenous form. These cells are present in practically all tissues in the organism. However, adipose tissue seems to be the most advantageous tissue from which to isolate them, because of its abundancy, its subcutaneous location, and the need for less invasive techniques. Adipose tissue-derived stem cells (ASCs) are therefore considered highly promising in present-day regenerative medicine.

  • Investigations into the cancer stem cell niche using in-vitro 3-D tumor models and microfluidics
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-03-17
    M. Sreepadmanabh, Bhushan J. Toley

    The concept of Cancer Stem Cells (CSCs) and the CSC Niche/Tumor Microenvironment (TME) as the central driving force behind tumor progression and maintenance has garnered much attention in recent years. Concomitantly, the widespread adoption of 3D tissue models, organotypic co-cultures, and the revolutionary microfluidic technology has resulted in a plethora of ground-breaking fundamental discoveries and has enabled investigations which were previously unfeasible. A large number of existing review papers concern themselves with either a broad look at the TME and CSC Niche, or on the studies undertaken on a particular niche component alone. In this article, we attempt to bring out a harmonic, expansive look at the concept of CSCs, the TME, and the various advancements in answering key biological queries enabled by these emerging new technologies. Our primary goal is to present a fundamental understanding of CSCs, as well as the CSC niche, and elucidate note-worthy examples of investigations being carried out with regard to each of the major TME components, along with our insights into the potential for further research. We hope that this serves as an impetus to new, as well as existing researchers in this area, to gain fresh perspectives on the CSC niche, as well as provide them with a glimpse at the kind of progress being made using 3D tumor models and microfluidic devices.

  • Circulating tumor cell isolation, culture, and downstream molecular analysis
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-03-17
    Sandhya Sharma, Rachel Zhuang, Marisa Long, Mirjana Pavlovic, Yunqing Kang, Azhar Ilyas, Waseem Asghar

    Circulating tumor cells (CTCs) are a major contributor of cancer metastases and hold a promising prognostic significance in cancer detection. Performing functional and molecular characterization of CTCs provides in-depth knowledge about this lethal disease. Researchers are making efforts to design devices and develop assays for enumeration of CTCs with a high capture and detection efficiency from whole blood of cancer patients. The existing and on-going research on CTC isolation methods has revealed cell characteristics which are helpful in cancer monitoring and designing of targeted cancer treatments. In this review paper, a brief summary of existing CTC isolation methods is presented. We also discuss methods of detaching CTC from functionalized surfaces (functional assays/devices) and their further use for ex-vivo culturing that aid in studies regarding molecular properties that encourage metastatic seeding. In the clinical applications section, we discuss a number of cases that CTCs can play a key role for monitoring metastases, drug treatment response, and heterogeneity profiling regarding biomarkers and gene expression studies that bring treatment design further towards personalized medicine.

  • Biofiltration of volatile organic compounds using fungi and its conceptual and mathematical modeling
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-03-17
    Alberto Vergara-Fernández, Sergio Revah, Patricio Moreno-Casas, Felipe Scott

    Volatile organic compounds (VOCs) are ubiquitous contaminants that can be found both in outdoor and indoor air, posing risks to human health and the ecosystems. The treatment of air contaminated with VOCs in low concentrations can be effectively performed using biofiltration, especially when VOCs are hydrophilic. However, the performance of biofilters inoculated with bacteria has been found to be low with sparsely water soluble molecules when compared to biofilters where fungi develop. Using conceptual and mathematical models, this review presents an overview of the physical, chemical and biological mechanisms that explain the differences in the performance of fungal and bacterial biofilters. Moreover, future research needs are proposed, with an emphasis on integrated models describing the biological and chemical reactions with the mass transfer using high-resolution descriptions of the packing material.

  • Bio-recycling of metals: Recycling of technical products using biological applications
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-03-16
    Katrin Pollmann, Sabine Kutschke, Sabine Matys, Johannes Raff, Gregor Hlawacek, Franziska L. Lederer

    The increasing demand of different essential metals as a consequence of the development of new technologies, especially in the so called “low carbon technologies” require the development of innovative technologies that enable an economic and environmentally friendly metal recovery from primary and secondary resources. There is serious concern that the demand of some critical elements might exceed the present supply within a few years, thus necessitating the development of novel strategies and technologies to meet the requirements of industry and society. Besides an improvement of exploitation and processing of ores, the more urgent issue of recycling of strategic metals has to be enforced. However, current recycling rates are very low due to the increasing complexity of products and the low content of certain critical elements, thus hindering an economic metal recovery. On the other hand, increasing environmental consciousness as well as limitations of classical methods require innovative recycling methodologies in order to enable a circular economy. Modern biotechnologies can contribute to solve some of the problems related to metal recycling. These approaches use natural properties of organisms, bio-compounds, and biomolecules to interact with minerals, materials, metals, or metal ions such as surface attachment, mineral dissolution, transformation, and metal complexation. Further, modern genetic approaches, e.g. realized by synthetic biology, enable the smart design of new chemicals. The article presents some recent developments in the fields of bioleaching, biosorption, bioreduction, and bioflotation, and their use for metal recovery from different waste materials. Currently only few of these developments are commercialized. Major limitations are high costs in comparison to conventional methods and low element selectivity. The article discusses future trends to overcome these barriers. Especially interdisciplinary approaches, the combination of different technologies, the inclusion of modern genetic methods, as well as the consideration of existing, yet unexplored natural resources will push innovations in these fields.

  • Diversity and assembly patterns of activated sludge microbial communities: A review
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-03-15
    Yu Xia, Xianghua Wen, Bing Zhang, Yunfeng Yang

    Understanding diversity and assembly patterns of microbial communities in activated sludge (AS) is pivotal for addressing fundamental ecological questions and wastewater treatment engineering. Recent applications of molecular methods especially next generation sequencing (NGS) have led to the explosion of information about AS community diversity, including the identification of uncultured taxa, and characterization of low-abundance but environmentally important populations such as antibiotic resistant bacteria and pathogens. Those progresses have facilitated the leverage of ecological theories in describing AS community assembly. The lognormal species abundance curve has been applied to estimate AS microbial richness. Taxa-area and taxa-time relationships (TAR and TTR) have been observed for AS microbial communities. Core AS microbial communities have been identified. Meanwhile, the roles of both deterministic and stochastic processes in shaping AS community structures have been examined. Nonetheless, it remains challenging to define tempo-spatial scales for reliable identification of community turnover, and find tight links between AS microbial structure and wastewater treatment plant (WWTP) functions. To solve those issues, we expect that future research will focus on identifying active functional populations in AS using omics- methods integrated with stable-isotope probing (SIP) with the development of bioinformatics tools. Developing mathematic models to understand AS community structures and utilize information on AS community to predict the performance of WWTPs will also be vital for advancing knowledge of AS microbial ecology and environmental engineering.

  • Natural products as modulators of the nuclear receptors and metabolic sensors LXR, FXR and RXR
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-03-13
    Verena Hiebl, Angela Ladurner, Simone Latkolik, Verena M. Dirsch

    Nuclear receptors (NRs) represent attractive targets for the treatment of metabolic syndrome-related diseases. In addition, natural products are an interesting pool of potential ligands since they have been refined under evolutionary pressure to interact with proteins or other biological targets. This review aims to briefly summarize current basic knowledge regarding the liver X (LXR) and farnesoid X receptors (FXR) that form permissive heterodimers with retinoid X receptors (RXR). Natural product-based ligands for these receptors are summarized and the potential of LXR, FXR and RXR as targets in precision medicine is discussed.

  • Microfluidic devices for sample preparation and rapid detection of foodborne pathogens
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-03-10
    Krishna Kant, Mohammad-Ali Shahbazi, Vivek Priy Dave, Tien Anh Ngo, Vinayaka Aaydha Chidambara, Quyen Than Linh, Dang Duong Bang, Anders Wolff

    Rapid detection of foodborne pathogens at an early stage is imperative for preventing the outbreak of foodborne diseases, known as serious threats to human health. Conventional bacterial culturing methods for foodborne pathogen detection are time consuming, laborious, and with poor pathogen diagnosis competences. This has prompted researchers to call the current status of detection approaches into question and leverage new technologies for superior pathogen sensing outcomes. Novel strategies mainly rely on incorporating all the steps from sample preparation to detection in miniaturized devices for online monitoring of pathogens with high accuracy and sensitivity in a time-saving and cost effective manner. Lab on chip is a blooming area in diagnosis, which exploits different mechanical and biological techniques to detect very low concentrations of pathogens in food samples. This is achieved through streamlining the sample handling and concentrating procedures, which will subsequently reduce human errors and enhance the accuracy of the sensing methods. Integration of sample preparation techniques into these devices can effectively minimize the impact of complex food matrix on pathogen diagnosis and improve the limit of detections. Integration of pathogen capturing bio-receptors on microfluidic devices is a crucial step, which can facilitate recognition abilities in harsh chemical and physical conditions, offering a great commercial benefit to the food-manufacturing sector. This article reviews recent advances in current state-of-the-art of sample preparation and concentration from food matrices with focus on bacterial capturing methods and sensing technologies, along with their advantages and limitations when integrated into microfluidic devices for online rapid detection of pathogens in foods and food production line.

  • Effects of shear stress on microalgae – A review
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-03-07
    Chinchin Wang, Christopher Q. Lan

    Cultivation of microalgae requires consideration of shear stress, which is generated by operations such as mixing, circulation, aeration and pumping that are designed to facilitate mass and heat transfer as well as light distribution in cultures. Excessive shear stress can cause increased cell mortality, decreased growth rate and cell viability, or even cell lysis. This review examines the sources of shear stress in different cultivation systems, shear stress tolerance of different microalgal species and the physiological factors and environmental conditions that may affect shear sensitivity, and potential approaches to mitigate the detrimental effects of shear stress. In general, green algae have the greatest tolerance to shear stress, followed by cyanobacteria, haptophytes, red algae, and diatoms, with dinoflagellates comprising the most shear-sensitive species. The shear-sensitivity of microalgae is determined primarily by cell wall strength, cell morphology and the presence of flagella. Turbulence, eddy size, and viscosity are the most prominent parameters affecting shear stress to microalgal cells during cultivation.

  • Translational models of tumor angiogenesis: A nexus of in silico and in vitro models
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-03-05
    Shirin Soleimani, Milad Shamsi, Mehran Akbarpour Ghazani, Hassan Pezeshgi Modarres, Karolina Papera Valente, Mohsen Saghafian, Mehdi Mohammadi Ashani, Mohsen Akbari, Amir Sanati-Nezhad

    Emerging evidence shows that endothelial cells are not only the building blocks of vascular networks that enable oxygen and nutrient delivery throughout a tissue but also serve as a rich resource of angiocrine factors. Endothelial cells play key roles in determining cancer progression and response to anti-cancer drugs. Furthermore, the endothelium-specific deposition of extracellular matrix is a key modulator of the availability of angiocrine factors to both stromal and cancer cells. Considering tumor vascular network as a decisive factor in cancer pathogenesis and treatment response, these networks need to be an inseparable component of cancer models. Both computational and in vitro experimental models have been extensively developed to model tumor-endothelium interactions. While informative, they have been developed in different communities and do not yet represent a comprehensive platform. In this review, we overview the necessity of incorporating vascular networks for both in vitro and in silico cancer models and discuss recent progresses and challenges of in vitro experimental microfluidic cancer vasculature-on-chip systems and their in silico counterparts. We further highlight how these two approaches can merge together with the aim of presenting a predictive combinatorial platform for studying cancer pathogenesis and testing the efficacy of single or multi-drug therapeutics for cancer treatment.

  • Paradigm shift – Metabolic transformation of docosahexaenoic and eicosapentaenoic acids to bioactives exemplify the promise of fatty acid drug discovery
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-28
    Ganesh V. Halade, Laurence M. Black, Mahendra Kumar Verma

    Fatty acid drug discovery (FADD) is defined as the identification of novel, specialized bioactive mediators that are derived from fatty acids and have precise pharmacological/therapeutic potential. A number of reports indicate that dietary intake of omega-3 fatty acids and limited intake of omega-6 promotes overall health benefits. In 1929, Burr and Burr indicated the significant role of essential fatty acids for survival and functional health of many organs. In reference to specific dietary benefits of differential omega-3 fatty acids, docosahexaenoic and eicosapentaenoic acids (DHA and EPA) are transformed to monohydroxy, dihydroxy, trihydroxy, and other complex mediators during infection, injury, and exercise to resolve inflammation. The presented FADD approach describes the metabolic transformation of DHA and EPA in response to injury, infection, and exercise to govern uncontrolled inflammation. Metabolic transformation of DHA and EPA into a number of pro-resolving molecules exemplifies a novel, inexpensive approach compared to traditional, expensive drug discovery. DHA and EPA have been recommended for prevention of cardiovascular disease since 1970. Therefore, the FADD approach is relevant to cardiovascular disease and resolution of inflammation in many injury models. Future research demands identification of novel action targets, receptors for biomolecules, mechanism(s), and drug-interactions with resolvins in order to maintain homeostasis.

  • Molecular aspects of sucrose transport and its metabolism to starch during seed development in wheat: A comprehensive review
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-28
    Rohit Kumar, Shalini Mukherjee, Belay T. Ayele

    Wheat is one of the most important crops globally, and its grain is mainly used for human food, accounting for 20% of the total dietary calories. It is also used as animal feed and as a raw material for a variety of non-food and non-feed industrial products such as a feedstock for the production of bioethanol. Starch is the major constituent of a wheat grain, as a result, it is considered as a critical determinant of wheat yield and quality. The amount and composition of starch deposited in wheat grains is controlled primarily by sucrose transport from source tissues to the grain and its conversion to starch. Therefore, elucidation of the molecular mechanisms regulating these physiological processes provides important opportunities to improve wheat starch yield and quality through biotechnological approaches. This review comprehensively discusses the current understanding of the molecular aspects of sucrose transport and sucrose-to-starch metabolism in wheat grains. It also highlights the advances and prospects of starch biotechnology in wheat.

  • Bacterial components as naturally inspired nano-carriers for drug/gene delivery and immunization: Set the bugs to work?
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-28
    Fatemeh Farjadian, Mohsen Moghoofei, Soroush Mirkiani, Amir Ghasemi, Navid Rabiee, Shima Hadifar, Ali Beyzavi, Mahdi Karimi, Michael R. Hamblin

    Drug delivery is a rapidly growing area of research motivated by the nanotechnology revolution, the ideal of personalized medicine, and the desire to reduce the side effects of toxic anti-cancer drugs. Amongst a bewildering array of different nanostructures and nanocarriers, those examples that are fundamentally bio-inspired and derived from natural sources are particularly preferred. Delivery of vaccines is also an active area of research in this field. Bacterial cells and their components that have been used for drug delivery, include the crystalline cell-surface layer known as “S-layer”, bacterial ghosts, bacterial outer membrane vesicles, and bacterial products or derivatives (e.g. spores, polymers, and magnetic nanoparticles). Considering the origin of these components from potentially pathogenic microorganisms, it is not surprising that they have been applied for vaccines and immunization. The present review critically summarizes their applications focusing on their advantages for delivery of drugs, genes, and vaccines.

  • Metabolic regulation in solventogenic clostridia: regulators, mechanisms and engineering
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-22
    Yunpeng Yang, Xiaoqun Nie, Yuqian Jiang, Chen Yang, Yang Gu, Weihong Jiang

    Solventogenic clostridia, a group of important industrial microorganisms, have exceptional substrate and product diversity, capable of producing a series of two-carbon and even long-chain chemicals and fuels by using various substrates, including sugars, cellulose and hemicellulose, and C1 gases. For the sake of in-depth understanding and engineering these anaerobic microorganisms for broader applications, studies on metabolic regulation of solventogenic clostridia had been extensively carried out during the past ten years, based on the rapid development of various genetic tools. To date, a number of regulators that are essential for cell physiological and metabolic processes have been identified in clostridia, and the relevant mechanisms have also been dissected, providing a wealth of valuable information for metabolic engineering. Here, we reviewed the latest research progress on the metabolic regulation for chemical production and carbohydrate utilization in solventogenic clostridia, by focusing on three typical Clostridium species, the saccharolytic C. acetobutylicum and C. beijerinckii, as well as the gas-fermenting C. ljungdahlii. On this basis, future directions in the study and remodeling of clostridial regulation systems, were proposed for effective modification of these industrially important anaerobes.

  • The functional genomic studies of resveratrol in respect to its anti-cancer effects
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-22
    Lukasz Huminieck, Jarosław Horbańczuk

    Resveratrol has anti-cancer effects in vitro, and hypothetical chemopreventive effects in vivo. Effects are pleiotropic, mediated by changes in expression of many genes and epigenetic reprogramming. Thus, they are well suited for functional genomic studies. We carried out systematic review of such studies (reflecting also on technological progress). Differentially expressed genes commonly linked to resveratrol treatment were linked to cell cycle, proliferation, and apoptosis. However, it is unclear if these are primary and specific targets of resveratrol. We conclude by discussing areas where additional functional genomic studies are desirable, including experiments that better model in vivo effects of dietary intake.

  • Improved genomic resources and new bioinformatic workflow for the carcinogenic parasite Clonorchis sinensis: Biotechnological implications
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-15
    Daxi Wang, Pasi K. Korhonen, Robin B. Gasser, Neil D. Young

    Clonorchis sinensis (family Opisthorchiidae) is an important foodborne parasite that has a major socioeconomic impact on ~35 million people predominantly in China, Vietnam, Korea and the Russian Far East. In humans, infection with C. sinensis causes clonorchiasis, a complex hepatobiliary disease that can induce cholangiocarcinoma (CCA), a malignant cancer of the bile ducts. Central to understanding the epidemiology of this disease is knowledge of genetic variation within and among populations of this parasite. Although most published molecular studies seem to suggest that C. sinensis represents a single species, evidence of karyotypic variation within C. sinensis and cryptic species within a related opisthorchiid fluke (Opisthorchis viverrini) emphasise the importance of studying and comparing the genes and genomes of geographically distinct isolates of C. sinensis. Recently, we sequenced, assembled and characterised a draft nuclear genome of a C. sinensis isolate from Korea and compared it with a published draft genome of a Chinese isolate of this species using a bioinformatic workflow established for comparing draft genome assemblies and their gene annotations. We identified that 50.6% and 52.1% of the Korean and Chinese C. sinensis genomic scaffolds were syntenic, respectively. Within aligned syntenic blocks, the genomes had a high level of nucleotide identity (99.1%) and encoded 15 variable proteins likely to be involved in diverse biological processes. Here, we review current technical challenges of using draft genome assemblies to undertake comparative genomic analyses to quantify genetic variation between isolates of the same species. Using a workflow that overcomes these challenges, we report on a high-quality draft genome for C. sinensis from Korea and comparative genomic analyses, as a basis for future investigations of the genetic structures of C. sinensis populations, and discuss the biotechnological implications of these explorations.

  • Old and new glycopeptide antibiotics: From product to gene and back in the post-genomic era
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-15
    Giorgia Letizia Marcone, Elisa Binda, Francesca Berini, Flavia Marinelli

    Glycopeptide antibiotics are drugs of last resort for treating severe infections caused by multi-drug resistant Gram-positive pathogens. First-generation glycopeptides (vancomycin and teicoplanin) are produced by soil-dwelling actinomycetes. Second-generation glycopeptides (dalbavancin, oritavancin, and telavancin) are semi-synthetic derivatives of the progenitor natural products. Herein, we cover past and present biotechnological approaches for searching for and producing old and new glycopeptide antibiotics. We review the strategies adopted to increase microbial production (from classical strain improvement to rational genetic engineering), and the recent progress in genome mining, chemoenzymatic derivatization, and combinatorial biosynthesis for expanding glycopeptide chemical diversity and tackling the never-ceasing evolution of antibiotic resistance.

  • Natural products as inhibitors of prostaglandin E2 and pro-inflammatory 5-lipoxygenase-derived lipid mediator biosynthesis
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-15
    Andreas Koeberle, Oliver Werz

    Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostanoid formation and represent prevalent therapeutics for treatment of inflammatory disorders. However, NSAIDs are afflicted with severe side effects, which might be circumvented by more selective suppression of pro-inflammatory eicosanoid biosynthesis. This concept led to dual inhibitors of microsomal prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase that are crucial enzymes in the biosynthesis of pro-inflammatory prostaglandin E2 and leukotrienes. The potential of their dual inhibition in light of superior efficacy and safety is discussed. Focus is placed on natural products, for which direct inhibition of mPGES-1 and leukotriene biosynthesis has been confirmed.

  • Chemical genetics in tumor lipogenesis
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-13
    Simone Braig

    Since cancer cells depend on de novo lipogenesis for energy supply, highly active membrane biosynthesis and signaling, enhanced fatty acid synthesis is a crucial characteristic of cancer cells. Hence, targeting lipogenic enzymes and signaling cascades is a very promising approach in developing innovative therapeutic agents for the fight against cancer. This review summarizes main aspects of altered fatty acid synthesis in cancer cells and emphasizes the power of chemical genetic approaches in identifying and analyzing novel anti-cancer drug candidates interfering with lipid metabolism.

  • Marine algal carbohydrates as carbon sources for the production of biochemicals and biomaterials
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-09
    M.T. Cesário, M.M.R. da Fonseca, M.M. Marques, M.C.M.D. de Almeida

    The high content of lipids in microalgae (>60% w/w in some species) and of carbohydrates in seaweed (up to 75%) have promoted intensive research towards valorisation of algal components for the production of biofuels. However, the exploitation of the carbohydrate fraction to produce a range of chemicals and chemical intermediates with established markets is still limited. These include organic acids (e.g. succinic and lactic acid), alcohols other than bioethanol (e.g. butanol), and biomaterials (e.g. polyhydroxyalkanoates). This review highlights current and potential applications of the marine algal carbohydrate fractions as major C-source for microbial production of biomaterials and building blocks.

  • Intracellular drug delivery: Potential usefulness of engineered Shiga toxin subunit B for targeted cancer therapy
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-09
    Vera Luginbuehl, Nicolas Meier, Karin Kovar, Jack Rohrer

    A treasure trove of intracellular cancer drug targets remains hidden behind cell membranes. However, engineered pathogen-derived toxins such as Shiga toxins can deliver small or macromolecular drugs to specific intracellular organelles. After binding to ganglioglobotriaosylceramide (Gb3, CD77), the non-toxic subunit B (StxB) of the Shiga-holotoxin is endocytosed and delivers its payload by a unique retrograde trafficking pathway via the endoplasmic reticulum to the cytosol. This review provides an overview of biomedical applications of StxB-based drug delivery systems in targeted cancer diagnosis and therapy. Biotechnological production of the Stx-material is discussed from the perspective of developing efficacious and safe therapeutics.

  • Enabling personalized implant and controllable biosystem development through 3D printing
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-09
    Neerajha Nagarajan, Agnes Dupret-Bories, Erdem Karabulut, Pinar Zorlutuna, Nihal Engin Vrana

    The impact of additive manufacturing in our lives has been increasing constantly. One of the frontiers in this change is the medical devices. 3D printing technologies not only enable the personalization of implantable devices with respect to patient-specific anatomy, pathology and biomechanical properties but they also provide new opportunities in related areas such as surgical education, minimally invasive diagnosis, medical research and disease models. In this review, we cover the recent clinical applications of 3D printing with a particular focus on implantable devices. The current technical bottlenecks in 3D printing in view of the needs in clinical applications are explained and recent advances to overcome these challenges are presented. 3D printing with cells (bioprinting); an exciting subfield of 3D printing, is covered in the context of tissue engineering and regenerative medicine and current developments in bioinks are discussed. Also emerging applications of bioprinting beyond health, such as biorobotics and soft robotics, are introduced. As the technical challenges related to printing rate, precision and cost are steadily being solved, it can be envisioned that 3D printers will become common on-site instruments in medical practice with the possibility of custom-made, on-demand implants and, eventually, tissue engineered organs with active parts developed with biorobotics techniques.

  • Growth media in anaerobic fermentative processes: The underestimated potential of thermophilic fermentation and anaerobic digestion
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-09-01
    A.T.W.M. Hendriks, J.B. van Lier, M.K. de Kreuk

    Fermentation and anaerobic digestion of organic waste and wastewater is broadly studied and applied. Despite widely available results and data for these processes, comparison of the generated results in literature is difficult. Not only due to the used variety of process conditions, but also because of the many different growth media that are used. Composition of growth media can influence biogas production (rates) and lead to process instability during anaerobic digestion. To be able to compare results of the different studies reported, and to ensure nutrient limitation is not influencing observations ascribed to process dynamics and/or reaction kinetics, a standard protocol for creating a defined growth medium for anaerobic digestion and mixed culture fermentation is proposed. This paper explains the role(s) of the different macro- and micronutrients, as well as the choices for a growth medium formulation strategy. In addition, the differences in nutrient requirements between mesophilic and thermophilic systems are discussed as well as the importance of specific trace metals regarding specific conversion routes and the possible supplementary requirement of vitamins. The paper will also give some insight into the bio-availability and toxicity of trace metals. A remarkable finding is that mesophilic and thermophilic enzymes are quite comparable at their optimum temperatures. This has consequences for the trace metal requirements of thermophiles under certain conditions. Under non-limiting conditions, the trace metal requirement of thermophilic systems is about 3 times higher than for mesophilic systems.

  • Amino acids production focusing on fermentation technologies – A review
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-09-06
    Martina D'Este, Merlin Alvarado-Morales, Irini Angelidaki

    Amino acids are attractive and promising biochemicals with market capacity requirements constantly increasing. Their applicability ranges from animal feed additives, flavour enhancers and ingredients in cosmetic to specialty nutrients in pharmaceutical and medical fields. This review gives an overview of the processes applied for amino acids production and points out the main advantages and disadvantages of each. Due to the advances made in the genetic engineering techniques, the biotechnological processes, and in particular the fermentation with the aid of strains such as Corynebacterium glutamicum or Escherichia coli, play a significant role in the industrial production of amino acids. Despite the numerous advantages of the fermentative amino acids production, the process still needs significant improvements leading to increased productivity and reduction of the production costs. Although the production processes of amino acids have been extensively investigated in previous studies, a comprehensive overview of the developments in bioprocess technology has not been reported yet. This review states the importance of the fermentation process for industrial amino acids production, underlining the strengths and the weaknesses of the process. Moreover, the potential of innovative approaches utilizing macro and microalgae or bacteria are presented.

  • Taxonomy, ecology and biotechnological applications of thraustochytrids: A review
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-09-11
    Loris Fossier Marchan, Kim J. Lee Chang, Peter D. Nichols, Wilfrid J. Mitchell, Jane L. Polglase, Tony Gutierrez

    Thraustochytrids were first discovered in 1934, and since the 1960's they have been increasingly studied for their beneficial and deleterious effects. This review aims to provide an enhanced understanding of these protists with a particular emphasis on their taxonomy, ecology and biotechnology applications. Over the years, thraustochytrid taxonomy has improved with the development of modern molecular techniques and new biochemical markers, resulting in the isolation and description of new strains. In the present work, the taxonomic history of thraustochytrids is reviewed, while providing an up-to-date classification of these organisms. It also describes the various biomarkers that may be taken into consideration to support taxonomic characterization of the thraustochytrids, together with a review of traditional and modern techniques for their isolation and molecular identification. The originality of this review lies in linking taxonomy and ecology of the thraustochytrids and their biotechnological applications as producers of docosahexaenoic acid (DHA), carotenoids, exopolysaccharides and other compounds of interest. The paper provides a summary of these aspects while also highlighting some of the most important recent studies in this field, which include the diversity of polyunsaturated fatty acid metabolism in thraustochytrids, some novel strategies for biomass production and recovery of compounds of interest. Furthermore, a detailed overview is provided of the direct and current applications of thraustochytrid-derived compounds in the food, fuel, cosmetic, pharmaceutical, and aquaculture industries and of some of the commercial products available. This review is intended to be a source of information and references on the thraustochytrids for both experts and those who are new to this field.

  • Zika virus structural biology and progress in vaccine development
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-09-12
    Hsiao-Han Lin, Bak-Sau Yip, Li-Min Huang, Suh-Chin Wu

    The growing number of zika virus (ZIKV) infections plus a 20-fold increase in neonatal microcephaly in newborns in Brazil have raised alarms in many countries regarding the threat to pregnant women. Instances of microcephaly and central nervous system malformations continue to increase in ZIKV outbreak regions. ZIKV is a small enveloped positive-strand RNA virus belonging to the Flavivirus genus of the Flaviviridae family. High-resolution ZIKV structures recently identified by cryo-electron microscopy indicate that the overall ZIKV structure is similar to those of other flaviviruses. With its compact surface, ZIKV is more thermally stable than the dengue virus (DENV). ZIKV E proteins have a characteristic “herringbone” structure with a single glycosylation site. The ZIKV E protein, the major protein involved in receptor binding and fusion, is formed as a head-to-tail dimer on the surfaces of viral particles. The E monomer consists of three distinct domains: DI, DII, and DIII. The finger-like DII contains a fusion loop (FL) that is inserted into the host cell endosomal membrane during pH-dependent conformational changes that drive fusion. Quaternary E:E dimer epitopes located at the interaction site of prM and E dimers can be further divided into two dimer epitopes. To date, more than 50 ZIKV vaccine candidates are now in various stages of research and development. Candidate ZIKV vaccines that are currently in phase I/II clinical trials include inactivated whole viruses, recombinant measles viral vector-based vaccines, DNA and mRNA vaccines, and a mosquito salivary peptide vaccine. Stabilized forms of ZIKV E:E dimer proteins have been successfully obtained either by introducing additional inter-subunit disulfide bond(s) in DII or via the direct assembly of E:E dimer proteins by immobilization with monomeric E proteins. The VLP-based approach is another alternative method for presenting native E:E dimer antigens among the vaccine components. Several forms of ZIKV VLPs have been reported featuring the co-expression of the prM-E, prM-E-NS1, C-prM-E, and NS2B/NS3 viral genes in human cells. To minimize the effect of the cross-reactive ADE-facilitating antibodies between ZIKV and DENV, several novel mutations have been reported either in or near the FL of DII or DIII to dampen the production of cross-reactive antibodies. Future ZIKV vaccine design efforts should be focused on eliciting improved neutralizing antibodies with a reduced level of cross-reactivity to confer sterilizing immunity.

  • Heterotrophic cultivation of microalgae for pigment production: A review
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-09-22
    Jianjun Hu, Dillirani Nagarajan, Quanguo Zhang, Jo-Shu Chang, Duu-Jong Lee

    Pigments (mainly carotenoids) are important nutraceuticals known for their potent anti-oxidant activities and have been used extensively as high end health supplements. Microalgae are the most promising sources of natural carotenoids and are devoid of the toxic effects associated with synthetic derivatives. Compared to photoautotrophic cultivation, heterotrophic cultivation of microalgae in well-controlled bioreactors for pigments production has attracted much attention for commercial applications due to overcoming the difficulties associated with the supply of CO2 and light, as well as avoiding the contamination problems and land requirements in open autotrophic culture systems. In this review, the heterotrophic metabolic potential of microalgae and their uses in pigment production are comprehensively described. Strategies to enhance pigment production under heterotrophic conditions are critically discussed and the challenges faced in heterotrophic pigment production with possible alternative solutions are presented.

  • Silk fibroin/hydroxyapatite composites for bone tissue engineering
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-10-07
    Mehdi Farokhi, Fatemeh Mottaghitalab, Saeed Samani, Mohammad Ali Shokrgozar, Subhas C. Kundu, Rui L. Reis, Yousef Fatahi, David L. Kaplan

    Silk fibroin (SF) is a natural fibrous polymer with strong potential for many biomedical applications. SF has attracted interest in the field of bone tissue engineering due to its extraordinary characteristics in terms of elasticity, flexibility, biocompatibility and biodegradability. However, low osteogenic capacity has limited applications for SF in the orthopedic arena unless suitably functionalized. Hydroxyapatite (HAp) is a well-established bioceramic with biocompatibility and appropriate for constructing orthopedic and dental substitutes. However, HAp ceramics tend to be brittle which can restrict applications in the repair of load-bearing tissues such as bones. Therefore, blending SF and HAp combines the useful properties of both materials as bone constructs for tissue engineering, the subject of this review.

  • Recent advances in polysaccharide bio-based flocculants
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-10-07
    Hossein Salehizadeh, Ning Yan, Ramin Farnood

    Natural polysaccharides, derived from biomass feedstocks, marine resources, and microorganisms, have been attracting considerable attention as benign and environmentally friendly substitutes for synthetic polymeric products. Besides many other applications, these biopolymers are rapidly emerging as viable alternatives to harmful synthetic flocculating agents for the removal of contaminants from water and wastewater. In recent years, a great deal of effort has been devoted to improve the production and performance of polysaccharide bio-based flocculants. In this review, current trends in preparation and chemical modification of polysaccharide bio-based flocculants and their flocculation performance are discussed. Aspects including mechanisms of flocculation, biosynthesis, classification, purification and characterization, chemical modification, the effect of physicochemical factors on flocculating activity, and recent applications of polysaccharide bio-based flocculants are summarized and presented.

  • Improved strategies for electrochemical 1,4-NAD(P)H2 regeneration: A new era of bioreactors for industrial biocatalysis
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-10-10
    Clifford S. Morrison, William B. Armiger, David R. Dodds, Jonathan S. Dordick, Mattheos A.G. Koffas

    Industrial enzymatic reactions requiring 1,4-NAD(P)H2 to perform redox transformations often require convoluted coupled enzyme regeneration systems to regenerate 1,4-NAD(P)H2 from NAD(P) and recycle the cofactor for as many turnovers as possible. Renewed interest in recycling the cofactor via electrochemical means is motivated by the low cost of performing electrochemical reactions, easy monitoring of the reaction progress, and straightforward product recovery. However, electrochemical cofactor regeneration methods invariably produce adventitious reduced cofactor side products which result in unproductive loss of input NAD(P). We review various literature strategies for mitigating adventitious product formation by electrochemical cofactor regeneration systems, and offer insight as to how a successful electrochemical bioreactor system could be constructed to engineer efficient 1,4-NAD(P)H2-dependent enzyme reactions of interest to the industrial biocatalysis community.

  • Next generation organoids for biomedical research and applications
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-10-19
    Yan-Ru Lou, Alan W. Leung

    Organoids are in vitro cultures of miniature fetal or adult organ-like structures. Their potentials for use in tissue and organ replacement, disease modeling, toxicology studies, and drug discovery are tremendous. Currently, major challenges facing human organoid technology include (i) improving the range of cellular heterogeneity for a particular organoid system, (ii) mimicking the native micro- and matrix-environment encountered by cells within organoids, and (iii) developing robust protocols for the in vitro maturation of organoids that remain mostly fetal-like in cultures. To tackle these challenges, we advocate the principle of reverse engineering that replicates the inner workings of in vivo systems with the goal of achieving functionality and maturation of the resulting organoid structures with the input of minimal intrinsic (cellular) and environmental (matrix and niche) constituents. Here, we present an overview of organoid technology development in several systems that employ cell materials derived from fetal and adult tissues and pluripotent stem cell cultures. We focus on key studies that exploit the self-organizing property of embryonic progenitors and the role of designer matrices and cell-free scaffolds in assisting organoid formation. We further explore the relationship between adult stem cells, niche factors, and other current developments that aim to enhance robust organoid maturation. From these works, we propose a standardized pipeline for the development of future protocols that would help generate more physiologically relevant human organoids for various biomedical applications.

  • Potential and limitations of Klebsiella pneumoniae as a microbial cell factory utilizing glycerol as the carbon source
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-10-19
    Vinod Kumar, Sunghoon Park

    Klebsiella pneumoniae is a Gram-negative facultative anaerobe that metabolizes glycerol efficiently under both aerobic and anaerobic conditions. This microbe is considered an outstanding biocatalyst for transforming glycerol into a variety of value-added products. Crude glycerol is a cheap carbon source and can be converted by K. pneumoniae into useful compounds such as lactic acid, 3-hydroxypropionic acid, ethanol, 1,3-propanediol, 2,3-butanediol, and succinic acid. This review summarizes glycerol metabolism in K. pneumoniae and its potential as a microbial cell factory for the production of commercially important acids and alcohols. Although many challenges remain, K. pneumoniae is a promising workhorse when glycerol is used as the carbon source.

  • Amino acid misincorporation in recombinant proteins
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-10-26
    H. Edward Wong, Chung-Jr Huang, Zhongqi Zhang

    Proteins provide the molecular basis for cellular structure, catalytic activity, signal transduction, and molecular transport in biological systems. Recombinant protein expression is widely used to prepare and manufacture novel proteins that serve as the foundation of many biopharmaceutical products. However, protein translation bioprocesses are inherently prone to low-level errors. These sequence variants caused by amino acid misincorporation have been observed in both native and recombinant proteins. Protein sequence variants impact product quality, and their presence can be exacerbated through cellular stress, overexpression, and nutrient starvation. Therefore, the cell line selection process, which is used in the biopharmaceutical industry, is not only directed towards maximizing productivity, but also focuses on selecting clones which yield low sequence variant levels, thereby proactively avoiding potentially inauspicious patient safety and efficacy outcomes. Here, we summarize a number of hallmark studies aimed at understanding the mechanisms of amino acid misincorporation, as well as exacerbating factors, and mitigation strategies. We also describe key advances in analytical technologies in the identification and quantification of sequence variants, and some practical considerations when using LC-MS/MS for detecting sequence variants.

  • Engineering strategies for enhanced production of protein and bio-products in Pichia pastoris: A review
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-11-10
    Zhiliang Yang, Zisheng Zhang

    Pichia pastoris has been recognized as one of the most industrially important hosts for heterologous protein production. Despite its high protein productivity, the optimization of P. pastoris cultivation is still imperative due to strain- and product-specific challenges such as promoter strength, methanol utilization type and oxygen demand. To address the issues, strategies involving genetic and process engineering have been employed. Optimization of codon usage and gene dosage, as well as engineering of promoters, protein secretion pathways and methanol metabolic pathways have proved beneficial to innate protein expression levels. Large-scale production of proteins via high cell density fermentation additionally relies on the optimization of process parameters including methanol feed rate, induction temperature and specific growth rate. Recent progress related to the enhanced production of proteins in P. pastoris via various genetic engineering and cultivation strategies are reviewed. Insight into the regulation of the P. pastoris alcohol oxidase 1 (AOX1) promoter and the development of methanol-free systems are highlighted. Novel cultivation strategies such as mixed substrate feeding are discussed. Recent advances regarding substrate and product monitoring techniques are also summarized. Application of P. pastoris to the production of biodiesel and other value-added products via metabolic engineering are also reviewed. P. pastoris is becoming an indispensable platform through the use of these combined engineering strategies.

  • Biotechnological potential of novel glycoside hydrolase family 70 enzymes synthesizing α-glucans from starch and sucrose
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-11-10
    Joana Gangoiti, Tjaard Pijning, Lubbert Dijkhuizen

    Transglucosidases belonging to the glycoside hydrolase (GH) family 70 are promising enzymatic tools for the synthesis of α-glucans with defined structures from renewable sucrose and starch substrates. Depending on the GH70 enzyme specificity, α-glucans with different structures and physicochemical properties are produced, which have found diverse (potential) commercial applications, e.g. in food, health and as biomaterials. Originally, the GH70 family was established only for glucansucrase enzymes of lactic acid bacteria that catalyze the synthesis of α-glucan polymers from sucrose. In recent years, we have identified 3 novel subfamilies of GH70 enzymes (designated GtfB, GtfC and GtfD), inactive on sucrose but converting starch/maltodextrin substrates into novel α-glucans. These novel starch-acting enzymes considerably enlarge the panel of α-glucans that can be produced. They also represent very interesting evolutionary intermediates between sucrose-acting GH70 glucansucrases and starch-acting GH13 α-amylases. Here we provide an overview of the repertoire of GH70 enzymes currently available with focus on these novel starch-acting GH70 enzymes and their biotechnological potential. Moreover, we discuss key developments in the understanding of structure-function relationships of GH70 enzymes in the light of available three-dimensional structures, and the protein engineering strategies that were recently applied to expand their natural product specificities.

  • αvβ3 and α5β1 integrin-specific ligands: From tumor angiogenesis inhibitors to vascularization promoters in regenerative medicine?
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-11-15
    Luís A. Rocha, David A. Learmonth, Rui A. Sousa, António J. Salgado

    Integrins are cell adhesion receptors predominantly important during normal and tumor angiogenesis. A sequence present on several extracellular matrix proteins composed of Arg-Gly-Asp (RGD) has attracted attention due to its role in cell adhesion mediated by integrins. The development of ligands that can bind to integrins involved in tumor angiogenesis and brake disease progression has resulted in new investigational drug entities reaching the clinical trial phase in humans. The use of integrin-specific ligands can be useful for the vascularization of regenerative medicine constructs, which remains a major limitation for translation into clinical practice. In order to enhance vascularization, immobilization of integrin-specific RGD peptidomimetics within constructs is a recommended approach, due to their high specificity and selectivity towards certain desired integrins. This review endeavours to address the potential of peptidomimetic-coated biomaterials as vascular network promoters for regenerative medicine purposes. Clinical studies involving molecules tracking active integrins in cancer angiogenesis and reasons for their failure are also addressed.

  • Recent advances in reconstructing microbial secondary metabolites biosynthesis in Aspergillus spp.
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-05
    Yi He, Bin Wang, Wanping Chen, Russell J. Cox, Jingren He, Fusheng Chen

    High throughput genome sequencing has revealed a multitude of potential secondary metabolites biosynthetic pathways that remain cryptic. Pathway reconstruction coupled with genetic engineering via heterologous expression enables discovery of novel compounds, elucidation of biosynthetic pathways, and optimization of product yields. Apart from Escherichia coli and yeast, fungi, especially Aspergillus spp., are well known and efficient heterologous hosts. This review summarizes recent advances in heterologous expression of microbial secondary metabolite biosynthesis in Aspergillus spp. We also discuss the technological challenges and successes in regard to heterologous host selection and DNA assembly behind the reconstruction of microbial secondary metabolite biosynthesis.

  • Plants as sources of natural and recombinant anti-cancer agents
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-03
    J.F. Buyel

    Herbal remedies were the first medicines used by humans due to the many pharmacologically active secondary metabolites produced by plants. Some of these metabolites inhibit cell division and can therefore be used for the treatment of cancer, e.g. the mitostatic drug paclitaxel (Taxol). The ability of plants to produce medicines targeting cancer has expanded due to the advent of genetic engineering, particularly in recent years because of the development of gene editing systems such as the CRISPR/Cas9 platform. These technologies allow the introduction of genetic modifications that facilitate the accumulation of native pharmaceutically-active substances, and even the production heterologous recombinant proteins, including human antibodies, lectins and vaccine candidates. Here we discuss the anti-cancer agents that are produced by plants naturally or following genetic modification, and the potential of these products to supply modern healthcare systems. Special emphasis will be put on proteinaceous anti-cancer agents, which can exhibit an improved selectivity and reduced side effects compared to small molecule-based drugs.

  • Biogas upgrading and utilization: Current status and perspectives
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-03
    Irini Angelidaki, Laura Treu, Panagiotis Tsapekos, Gang Luo, Stefano Campanaro, Henrik Wenzel, Panagiotis G. Kougias

    Biogas production is an established sustainable process for simultaneous generation of renewable energy and treatment of organic wastes. The increasing interest of utilizing biogas as substitute to natural gas or its exploitation as transport fuel opened new avenues in the development of biogas upgrading techniques. The present work is a critical review that summarizes state-of-the-art technologies for biogas upgrading and enhancement with particular attention to the emerging biological methanation processes. The review includes comprehensive description of the main principles of various biogas upgrading methodologies, scientific and technical outcomes related to their biomethanation efficiency, challenges that have to be addressed for further development and incentives and feasibility of the upgrading concepts.

  • In vivo therapeutic applications of cell spheroids
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-03
    Chin Siang Ong, Xun Zhou, Jingnan Han, Chen Yu Huang, Andrew Nashed, Shipra Khatri, Gunnar Mattson, Takuma Fukunishi, Huaitao Zhang, Narutoshi Hibino

    Spheroids are increasingly being employed to answer a wide range of clinical and biomedical inquiries ranging from pharmacology to disease pathophysiology, with the ultimate goal of using spheroids for tissue engineering and regeneration. When compared to traditional two-dimensional cell culture, spheroids have the advantage of better replicating the 3D extracellular microenvironment and its associated growth factors and signaling cascades. As knowledge about the preparation and maintenance of spheroids has improved, there has been a plethora of translational experiments investigating in vivo implantation of spheroids into various animal models studying tissue regeneration. We review methods for spheroid delivery and how they have been utilized in tissue engineering experiments. We break down efforts in this field by organ systems, discussing applications of spheroids to various animal models of disease processes and their potential clinical implications. These breakthroughs have been made possible by advancements in spheroid formation, in vivo delivery and assessment. There is unexplored potential and room for further research and development in spheroid-based tissue engineering approaches. Regenerative medicine and other clinical applications ensure this exciting area of research remains relevant for patient care.

  • Biological activities of (−)-epicatechin and (−)-epicatechin-containing foods: Focus on cardiovascular and neuropsychological health
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-02
    Iveta Bernatova

    Recent studies have suggested that certain (−)-epicatechin-containing foods have a blood pressure-lowering capacity. The mechanisms underlying (−)-epicatechin action may help prevent oxidative damage and endothelial dysfunction, which have both been associated with hypertension and certain brain disorders. Moreover, (−)-epicatechin has been shown to modify metabolic profile, blood's rheological properties, and to cross the blood-brain barrier. Thus, (−)-epicatechin causes multiple actions that may provide unique synergy beneficial for cardiovascular and neuropsychological health. This review summarises the current knowledge on the biological actions of (−)-epicatechin, related to cardiovascular and brain functions, which may play a remarkable role in human health and longevity.

  • Bacterial type III secretion system as a protein delivery tool for a broad range of biomedical applications
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-02
    Fang Bai, Zhenpeng Li, Akihiro Umezawa, Naohiro Terada, Shouguang Jin

    A protein delivery tool based on bacterial type III secretion system (T3SS) has been broadly applied in biomedical researches. In this review, we summarize various applications of the T3SS-mediate protein delivery which enables translocation of proteins directly into mammalian cells without protein purification. Some of the remarkable advancements include delivery of antigens for therapeutic vaccines, nucleases for genome editing, transcription factors for cellular reprogramming and stem cells differentiation, and signaling molecules for post-translational proteomics studies. With continued improvement of the T3SS-mediated protein delivery tools, even wider application of the technology is anticipated.

  • High hydrostatic pressure in cancer immunotherapy and biomedicine
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-01
    Irena Adkins, Nada Hradilova, Ondrej Palata, Lenka Sadilkova, Lenka Palova-Jelinkova, Radek Spisek

    High hydrostatic pressure (HHP) has been known to affect biological systems for >100 years. In this review, we describe the technology of HHP and its effect macromolecules and physiology of eukaryotic cells. We discuss the use of HHP in cancer immunotherapy to kill tumor cells for generation of whole cell and dendritic cell-based vaccines. We further summarize the current use and perspectives of HHP application in biomedicine, specifically in orthopedic surgery and for the viral, microbial and protozoan inactivation to develop vaccines against infectious diseases.

  • RNA interference technology to improve the baculovirus-insect cell expression system
    Biotechnol. Adv. (IF 10.597) Pub Date : 2018-02-01
    Cuitlahuac Chavez-Pena, Amine A. Kamen

    The baculovirus expression vector system (BEVS) is a popular manufacturing platform for the production of recombinant proteins, antiviral vaccines, gene therapy vectors, and biopesticides. Besides its successful applications in the industrial sector, the system has also played a significant role within the academic community given its extensive use in the production of hard-to-express eukaryotic multiprotein complexes for structural characterization for example. However, as other expression platforms, BEVS has to be continually improved to overcome its limitation and adapt to the constant demand for manufacturing processes that provide recombinant products with improved quality at higher yields and lower production cost. RNA interference, or RNAi, is a relatively recent technology that has revolutionized how scientist study gene function. Originally introduced as a tool to study biological and disease-related processes it has recently been applied to improve the yield and quality of recombinant proteins produced in several expression systems. In this review, we provide a comprehensive summary of the impact that RNAi-mediated silencing of cellular or viral genes in the BEVS has on the production of recombinant products. We also propose a critical analysis of several aspects of the methodologies described in the literature for the use of RNAi technology in the BEVS with the intent to provide the reader with eventually useful guidance for designing experiments.

  • New strategies and approaches for engineering biosynthetic gene clusters of microbial natural products
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-03-16
    Lei Li, Weihong Jiang, Yinhua Lu

    With the rapidly growing number of sequenced microbial (meta)genomes, enormous cryptic natural product (NP) biosynthetic gene clusters (BGCs) have been identified, which are regarded as a rich reservoir for novel drug discovery. A series of powerful tools for engineering BGCs has accelerated the discovery and development of pharmaceutically active NPs. Here, we describe recent advances in the strategies for BGCs manipulation, which are driven by emerging technologies, including efficient DNA recombination systems, versatile CRISPR/Cas9 genome editing tools and diverse DNA assembly methods. We further discuss how these approaches could be used for genome mining studies and industrial strain improvement.

  • Enabling tools for high-throughput detection of metabolites: Metabolic engineering and directed evolution applications
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-07-16
    Jyun-Liang Lin, James M. Wagner, Hal S. Alper

    Within the Design-Build-Test Cycle for strain engineering, rapid product detection and selection strategies remain challenging and limit overall throughput. Here we summarize a wide variety of modalities that transduce chemical concentrations into easily measured absorbance, luminescence, and fluorescence signals. Specifically, we cover protein-based biosensors (including transcription factors), nucleic acid-based biosensors, coupled enzyme reactions, bioorthogonal chemistry, and fluorescent and chromogenic dyes and substrates as modalities for detection. We focus on the use of these methods for strain engineering and enzyme discovery and conclude with remarks on the current and future state of biosensor development for application in the metabolic engineering field.

  • Learning from quantitative data to understand central carbon metabolism
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-09-18
    Fumio Matsuda, Yoshihiro Toya, Hiroshi Shimizu

    Quantitative analysis of metabolism has been used to identify driver reactions occurring during cancer development and bottleneck reactions in the metabolic engineering of microorganisms. In this review, we compare the advantages and disadvantages of various metabolic analysis methods. We emphasize that metabolic flux analysis based on material balance is a critical method for quantitative investigations into cell metabolism. The absolute determination of metabolite concentration appears to be essential for evaluating the thermodynamic state of metabolism. Obtaining a precise read-out of regulatory mechanisms from the snapshot data remains challenging due to our insufficient knowledge of the control of metabolism.

  • Formulation, construction and analysis of kinetic models of metabolism: A review of modelling frameworks
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-09-13
    Pedro A. Saa, Lars K. Nielsen

    Kinetic models are critical to predict the dynamic behaviour of metabolic networks. Mechanistic kinetic models for large networks remain uncommon due to the difficulty of fitting their parameters. Recent modelling frameworks promise new ways to overcome this obstacle while retaining predictive capabilities. In this review, we present an overview of the relevant mathematical frameworks for kinetic formulation, construction and analysis. Starting with kinetic formalisms, we next review statistical methods for parameter inference, as well as recent computational frameworks applied to the construction and analysis of kinetic models. Finally, we discuss opportunities and limitations hindering the development of larger kinetic reconstructions.

  • Metabolic engineering for the microbial production of marine bioactive compounds
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-03-06
    Xiangzhao Mao, Zhen Liu, Jianan Sun, Sang Yup Lee

    Many marine bioactive compounds have medicinal and nutritional values. These bioactive compounds have been prepared using solvent-based extraction from marine bio-resources or chemical synthesis, which are costly, inefficient with low yields, and environmentally unfriendly. Recent advances in metabolic engineering allowed to some extent more efficient production of these compounds, showing promises to meet the increasing demand of marine natural bioactive compounds. In this paper, we review the strategies and statuses of metabolic engineering applied to microbial production of marine natural bioactive compounds including terpenoids and their derivatives, omega-3 polyunsaturated fatty acids, and marine natural drugs, and provide perspectives.

  • Chassis and key enzymes engineering for monoterpenes production
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-09-06
    Lu Zhang, Wen-Hai Xiao, Ying Wang, Ming-Dong Yao, Guo-Zhen Jiang, Bo-Xuan Zeng, Ruo-Si Zhang, Ying-Jin Yuan

    Microbial production of monoterpenes is often limited by their cytotoxicity and in vivo conversion. Therefore, alleviating cytotoxicity and reducing conversion by chassis engineering are highly desirable. On the other hand, engineering key enzymes is also critical for improving monoterpenes production through facilitating the biosynthesis process. Here we critically review recent advances in cytotoxicity alleviation, reducing in vivo conversion, selecting geranyl diphosphate synthase and engineering monoterpene synthases. These achievements would lead to the development of superior chassis with improved tolerance to cytotoxicity and rationally tailored metabolites profiles to improve titer, yield and productivity for the production of monoterpenes by microbial cells.

  • Cofactor engineering for more efficient production of chemicals and biofuels
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-09-20
    Meng Wang, Biqiang Chen, Yunming Fang, Tianwei Tan

    Cofactors are involved in numerous intracellular reactions and critically influence redox balance and cellular metabolism. Cofactor engineering can support and promote the biocatalysis process, even help driving thermodynamically unfavorable reactions forwards. To achieve efficient production of chemicals and biofuels, cofactor engineering strategies such as altering cofactor supply or modifying reactants' cofactor preference have been developed to maintain redox balance. This review focuses primarily on the effects of cofactor engineering on carbon and energy metabolism. Coupling carbon metabolism with cofactor engineering can promote large-scale production, and even offer possibilities for producing new products or converting new materials.

  • Current advances of succinate biosynthesis in metabolically engineered Escherichia coli
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-09-20
    Li-Wen Zhu, Ya-Jie Tang

    As an important intermediate feedstock, succinate is termed as one of the 12 bio-based platform chemicals. To improve its fermentative production, various strategies have been developed, but challenges are still ahead for succinate biosynthesis to be cost-competitive. In this article, strategies for succinate production through metabolic engineering of Escherichia coli are critically reviewed, with a focus on engineering by-product formation and CO2 fixation, substrate utilization, reducing power balance, metabolic evolution and transcriptional regulation, which provide insights for the current state of succinate production and perspectives for further research for more efficient and economical production of bio-based succinate.

  • Current advances on fermentative biobutanol production using third generation feedstock
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-06-01
    Yue Wang, Shih-Hsin Ho, Hong-Wei Yen, Dillirani Nagarajan, Nan-Qi Ren, Shuangfei Li, Zhangli Hu, Duu-Jong Lee, Akihiko Kondo, Jo-Shu Chang

    Biobutanol is gaining more attention as a potential alternative to ethanol, and the demand for fermentative biobutanol production has renewed interest. The main challenge faced in biobutanol production is the availability of feedstock. Using conventional agricultural biomass as feedstock is controversial and less efficient, while microalgae, the third generation feedstock, are considered promising feedstock for biobutanol production due to their high growth rate and high carbohydrates content. This review is primarily focused on biobutanol production by using carbohydrate-rich microalgal feedstock. Key technologies and challenges involved in producing butanol from microalgae are discussed in detail and future directions are also presented.

  • Harnessing CRISPR/Cas systems for programmable transcriptional and post-transcriptional regulation
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-11-29
    Ahmed Mahas, C. Neal Stewart, Magdy M. Mahfouz

    Genome editing has enabled broad advances and novel approaches in studies of gene function and structure; now, emerging methods aim to precisely engineer post-transcriptional processes. Developing precise, efficient molecular tools to alter the transcriptome holds great promise for biotechnology and synthetic biology applications. Different approaches have been employed for targeted degradation of RNA species in eukaryotes, but they lack programmability and versatility, thereby limiting their utility for diverse applications. The CRISPR/Cas9 system has been harnessed for genome editing in many eukaryotic species and, using a catalytically inactive Cas9 variant, the CRISPR/dCas9 system has been repurposed for transcriptional regulation. Recent studies have used other CRISPR/Cas systems for targeted RNA degradation and RNA-based manipulations. For example, Cas13a, a Type VI-A endonuclease, has been identified as an RNA-guided RNA ribonuclease and used for manipulation of RNA. Here, we discuss different modalities for targeted RNA interference with an emphasis on the potential applications of CRISPR/Cas systems as programmable transcriptional regulators for broad uses, including functional biology, biotechnology, and synthetic biology applications.

  • Hot spots for the protein engineering of Baeyer-Villiger monooxygenases
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-11-22
    Kathleen Balke, Andy Beier, Uwe T. Bornscheuer

    Baeyer-Villiger monooxygenases (BVMOs) are versatile biocatalysts for the conversion of ketones to lactones or esters while also being able to efficiently oxidize sulfides to sulfoxides. However, there are limitations for the application of BVMOs in synthesis. In this review we provide an overview of the protein engineering studies aiming at optimizing different properties of BVMOs. We describe hot spots in the active sites of certain BVMOs that have been successfully targeted for changing the substrate scope, as well as the possibility to influence this property by allosteric effects. The identified hot spots in the active sites for controlling enantio- and regioselectivity are shown to be transferable to other BVMOs and we describe concepts to influence heteroatom oxidation, improve protein stability and change the cofactor dependency of BVMOs. Summarizing all these different studies enabled the identification of BVMO- or property-dependent as well as universal hot spots.

  • Stability of aerobic granules during long-term bioreactor operation
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-11-20
    Rita D.G. Franca, Helena M. Pinheiro, Mark C.M. van Loosdrecht, Nídia D. Lourenço

    Aerobic granular sludge technology has been extensively studied over the past 20 years and is regarded as the upcoming new standard for biological treatment of domestic and industrial wastewaters. Aerobic granules (AG) are dense, compact, self-immobilized microbial aggregates that allow better sludge-water separation and thereby higher biomass concentrations in the bioreactor than conventional activated sludge aggregates. This brings potential practical advantages in terms of investment cost, energy consumption and footprint. Yet, despite the relevant advances regarding the process of AG formation, instability of AG during long-term operation is still seen as a major barrier for a broad practical application of this technology. This paper presents an up-to-date review of the literature focusing on AG stability, aiming to contribute to the identification of key factors for promoting long-term stability of AG and to a better understanding of the underlying mechanisms. Operational conditions leading to AG disintegration are described, including high organic loads, particulate substrates in the influent, toxic feed components, aerobic feeding and too short famine periods. These operational and influent wastewater composition conditions were shown to influence the micro-environment of AG, consequently affecting their stability. Granule stability is generally favored by the presence of a dense core, with microbial growth throughout the AG depth being a crucial intrinsic factor determining its structural integrity. Accordingly, possible practical solutions to improve granule long-term stability are described, namely through the promotion of minimal substrate concentration gradients and control of microbial growth rates within AG, including anaerobic, plug-flow feeding and specific sludge removal strategies.

  • Bioremediation 3.0: Engineering pollutant-removing bacteria in the times of systemic biology
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-08-05
    Pavel Dvořák, Pablo I. Nikel, Jiří Damborský, Víctor de Lorenzo

    Elimination or mitigation of the toxic effects of chemical waste released to the environment by industrial and urban activities relies largely on the catalytic activities of microorganisms—specifically bacteria. Given their capacity to evolve rapidly, they have the biochemical power to tackle a large number of molecules mobilized from their geological repositories through human action (e.g., hydrocarbons, heavy metals) or generated through chemical synthesis (e.g., xenobiotic compounds). Whereas naturally occurring microbes already have considerable ability to remove many environmental pollutants with no external intervention, the onset of genetic engineering in the 1980s allowed the possibility of rational design of bacteria to catabolize specific compounds, which could eventually be released into the environment as bioremediation agents. The complexity of this endeavour and the lack of fundamental knowledge nonetheless led to the virtual abandonment of such a recombinant DNA-based bioremediation only a decade later. In a twist of events, the last few years have witnessed the emergence of new systemic fields (including systems and synthetic biology, and metabolic engineering) that allow revisiting the same environmental pollution challenges through fresh and far more powerful approaches. The focus on contaminated sites and chemicals has been broadened by the phenomenal problems of anthropogenic emissions of greenhouse gases and the accumulation of plastic waste on a global scale. In this article, we analyze how contemporary systemic biology is helping to take the design of bioremediation agents back to the core of environmental biotechnology. We inspect a number of recent strategies for catabolic pathway construction and optimization and we bring them together by proposing an engineering workflow.

  • Covalent and non-covalent chemical engineering of actin for biotechnological applications
    Biotechnol. Adv. (IF 10.597) Pub Date : 2017-08-19
    Saroj Kumar, Alf Mansson

    The cytoskeletal filaments are self-assembled protein polymers with 8–25 nm diameters and up to several tens of micrometres length. They have a range of pivotal roles in eukaryotic cells, including transportation of intracellular cargoes (primarily microtubules with dynein and kinesin motors) and cell motility (primarily actin and myosin) where muscle contraction is one example. For two decades, the cytoskeletal filaments and their associated motor systems have been explored for nanotechnological applications including miniaturized sensor systems and lab-on-a-chip devices. Several developments have also revolved around possible exploitation of the filaments alone without their motor partners. Efforts to use the cytoskeletal filaments for applications often require chemical or genetic engineering of the filaments such as specific conjugation with fluorophores, antibodies, oligonucleotides or various macromolecular complexes e.g. nanoparticles. Similar conjugation methods are also instrumental for a range of fundamental biophysical studies. Here we review methods for non-covalent and covalent chemical modifications of actin filaments with focus on critical advantages and challenges of different methods as well as critical steps in the conjugation procedures. We also review potential uses of the engineered actin filaments in nanotechnological applications and in some key fundamental studies of actin and myosin function. Finally, we consider possible future lines of investigation that may be addressed by applying chemical conjugation of actin in new ways.

Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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