Protein-ligand docking: current status and future challenges

Understanding the ruling principles whereby protein receptors recognize, interact, and associate with molecular substrates and inhibitors is of paramount importance in drug discovery efforts. Protein-ligand docking aims to predict and rank the structure(s) arising from the association between a given ligand and a target protein of known 3D structure. Despite the breathtaking advances in the field over the last decades and the widespread application of docking methods, several downsides still exist. In particular, protein flexibility-a critical aspect for a thorough understanding of the principles that guide ligand binding in proteins-is a major hurdle in current protein-ligand docking efforts that needs to be more efficiently accounted for. In this review the key concepts of protein-ligand docking methods are outlined, with major emphasis being given to the general strengths and weaknesses that presently characterize this methodology. Despite the size of the field, the principal types of search algorithms and scoring functions are reviewed and the most popular docking tools are briefly depicted. Recent advances that aim to address some of the traditional limitations associated with molecular docking are also described. A selection of hand-picked examples is used to illustrate these features.     

Electrophysiology and glaucoma: current status and future challenges

Visual electrophysiology allows non-invasive monitoring of the function of most processing stages along the visual pathway. Here, we consider which of the available methods provides the most information concerning glaucomatous optic nerve disease. The multifocal electroretinogram (ERG), although often employed, is less affected in glaucoma than two direct measurements of retinal ganglion cell function, namely the pattern ERG (PERG) and the photopic negative response (PhNR) of the ERG. For the PERG, longitudinal studies have been reported, suggesting that this method can be used for the early detection of glaucoma; for the PhNR, no longitudinal study is available as yet. The multifocal PERG can spatially resolve ganglion cell function but its glaucomatous reduction is typically panretinal, even with only local field changes and so, its topographic resolution is of no advantage in glaucoma. The multifocal visual evoked potential promises objective perimetry and shows sensitivity and specificity comparable with standard automated perimetry but has not been established as a routine tool to date.     

Prokaryote diversity and taxonomy: current status and future challenges

The prokaryotes are by far the most abundant organisms inhabiting planet Earth. They are also by far the most diverse, both metabolically and phylogenetically; they encompass the Bacteria and the Archaea, two out of the three major divisions of living organisms. The current prokaryote species classification is based on a combination of genomic and phenotypic properties. The recommended cut-off value of 70% DNA-DNA similarity to delineate species signifies an extremely broad species definition for the prokaryotes compared with the higher eukaryotes. The number of validly named species of prokaryotes is currently slightly more than 6200. However, on the basis of small-subunit rDNA characterization of whole communities and other approaches, the more exact number of species present can be inferred to be at least two orders of magnitude larger. Classic culturing methods based on colony formation on agar are generally unsatisfactory for the recovery of bacteria from the environment. Many of the most abundant prokaryotes in nature have not yet been brought into culture. Some of these may thrive by means of as yet unknown modes of energy generation. Several novel methods have recently enabled the isolation of some interesting organisms of environmental significance. A better coverage of the prokaryote diversity on Earth depends on such innovative approaches, combined with appropriate funding.     

Mammary gland stem cells: current status and future challenges

Distinct subsets of cells, including cells with stem cell-like properties, have been proposed to exist in normal human breast epithelium and breast carcinomas. The cellular origins of epithelial cells contributing to gland development, tissue homeostasis and cancer are, however, still poorly understood. The mouse is a widely used model of mammary gland development, both directly by studying the mouse mammary epithelial cells themselves and indirectly, by studying development, morphogenesis, differentiation and carcinogenesis of xenotransplanted human breast epithelium in vivo. While in early studies, human or mouse epithelium was implanted as fragments into the mouse gland, more recent technical progress has allowed the self-renewal capacity and differentiation potential of distinct cell populations or even individual cells to be interrogated. Here, we review and discuss similarities and differences between mouse and human gland development with particular emphasis on the identity and localization of stem cells, and the influence of the surrounding microenvironment. It is concluded that while recent advances in the field have contributed immense insight into how the normal mammary gland develops and is maintained, significant discrepancies exist between the mouse and human gland which should be taken into consideration in current and future models of mammary stem cell biology.     

Molecular structure of low density lipoprotein: current status and future challenges

This review highlights recent advances in structural studies on low density lipoprotein (LDL) with particular emphasis on the apolipoprotein moiety of LDL, apolipoprotein B100 (apoB100). Various molecular aspects of LDL are outlined and obstacles to structure determination are addressed. In this context, the prevailing conceptions of the molecular assembly of LDL and how the synergy of complementary biochemical, biophysical and molecular simulation approaches has lead to the current structural model of LDL are discussed. Evidence is presented that structural heterogeneity and the intrinsic dynamics of LDL are key determinants of the functionality of LDL in both health and disease. Some key research directions, remaining open questions and rapidly emerging new concepts for medical applications of LDL, are furthermore outlined. The article concludes by providing an outlook concerning promising future strategies for the clarification of the molecular details of LDL, in particular of apoB100, combining recent advances in molecular modeling with developments of novel experimental techniques. Although new insights into the molecular organization of LDL are forthcoming, many open questions remain unanswered. The major challenge of the next decade will certainly be the elucidation of the molecular structural and dynamic features of apoB100.     

Alien fish species in Indian inland wetlands: current status and future challenges

Although wetlands are well-recognized for their biological, ecological, cultural, hydrological, recreational, socio-economic and educational values, still they are facing severe anthropogenic pressure in the form of habitat destruction, pollution, overexploitation of resources and the invasion of alien species. India is bestowed with several natural and man-made wetlands which support rich aquatic biodiversity with high degree of endemism, especially fish diversity. Zoological Survey of India reported that, inland wetlands alone support 1027 species of fishes with more biological, nutritional and economic values. However, for the past three centuries Indian wetlands are witnessing continuous introduction of exotic fishes. According to available reports, 31 aquaculture species, 600 ornamental varieties and 2 species of larvicidal fish have been introduced. Surfacing reports confirmed that among the introduced fishes nearly 55 fish species established a sustainable reproductive population in several inland wetlands (i.e. wild) including in the biodiversity hotspots. Among the 55 the National Biodiversity Authority of India has declared 14 species as invasive. Though, there are no comprehensive studies available in India about the impacts of invasive alien species on its ecosystem and food security. In addition, researchers are of the opinion that the ongoing climate change, river linking projects, Genetically Improved Farmed Tilapia (GIFT) project and ornamental trade will exacerbate the invasive issues in future. India is thus in a position to develop new robust policy and research guidelines on the exotic species issues. Cooperation among different stakeholders and common public is the need of the hour, else India will lose its unique aquatic diversity and also face huge socio-economic problems.

     

The Rare Disease Bank of Japan: establishment,current status and future challenges

Research on rare diseases cannot be performed without appropriate samples from patients with such diseases. Due to the limited number of such patients, securing biosamples of sufficient quality for extensive research is a challenge and represents an important barrier to the advancement of research on rare diseases. To tackle this problem, the Rare Disease Bank (RDB) was established in 2009 at the National Institute of Biomedical Innovation (NIBIO; currently, the National Institutes of Biomedical Innovation, Health and Nutrition in Japan). Since then, the RDB has focused on three objectives: (1) emphasizing the importance of collecting biosamples from patients with rare diseases, together with appropriate clinical information, from various medical facilities nationwide; (2) maintaining strict high-quality sample management standards; and (3) sharing biosamples with research scientists across Japan for the advancement of research on rare diseases. As of August 2017, the bank has collected 4147 biosamples from patients with rare diseases, including DNA, serum, plasma, and cell samples from various university hospitals and other medical institutions across the country, and provided various research institutions with 13,686 biosample aliquots from 2850 cases. In addition, the management committee has successfully established a bank system that provides high-quality biosamples together with the results of human leukocyte antigen analysis. It is anticipated that the RDB, through the collection and sharing of biosamples with the medical research community, will enhance the understanding, prevention, and treatment of rare diseases in Japan and the world at large.     

Targeted protein degradation: current and future challenges

Traditional approaches in the development of small-molecule drugs typically aim to inhibit the biochemical activity of functional protein domains. In contrast, targeted protein degradation aims to reduce overall levels of disease-relevant proteins. Mechanistically, this can be achieved via chemical ligands that induce molecular proximity between an E3 ubiquitin ligase and a protein of interest, leading to ubiquitination and degradation of the protein of interest. This paradigm-shifting pharmacology promises to address several limitations inherent to conventional inhibitor design. Most notably, targeted protein degradation has the potential not only to expand the druggable proteome beyond the reach of traditional competitive inhibitors but also to develop therapeutic strategies of unmatched selectivity. This review briefly summarizes key challenges that remain to be addressed to deliver on these promises and to realize the full therapeutic potential of pharmacologic modulation of protein degradation pathways.     

Monitoring and adaptive resistance management in Australia for Bt-cotton: current status and future challenges

In the mid-1990 s the Australian Cotton industry adopted an insect-resistant variety of cotton (Ingard) which expresses the Bt toxin Cry1Ac that is specific to a group of insects including the target Helicoverpa armigera. A conservative resistance management plan (RMP), that restricted the area planted to Ingard, was implemented to preserve the efficacy of Cry1Ac until two-gene transgenic cotton was available. In 2004/05 Bollgard II replaced Ingard as the transgenic cotton available in Australia. It improves on Ingard by incorporating an additional insecticidal protein (Cry2Ab). If an appropriate refuge is grown, there is no restriction on the area planted to Bollgard II. In 2004/05 and 2005/06 the Bollgard II acreage represented approximately 80 of the total area planted to cotton in Australia. The sensitivity of field-collected populations of H. armigera to Bt products was assayed before and subsequent to the widespread deployment of Ingard cotton. In 2002 screens against Cry2Ab were developed in preparation for replacement of Ingard with Bollgard II. There have been no reported field failures of Bollgard II due to resistance. However, while alleles that confer resistance to H. armigera in the field are rare for Cry1Ac, they are surprisingly common for Cry2Ab. We present an overview of the current approach adopted in Australia to monitor and adaptively manage resistance to Bt-cotton in field populations of H. armigera and discuss the implications of our findings to date. We also highlight future challenges for resistance management in Australia, many of which extend to other Bt-crop and pest systems.     

嗜盐古菌分类学研究进展

嗜盐古菌是一类需要高盐维持生长的古菌。到目前为止,已发现的嗜盐古菌都属于古菌域的广古菌门,主要包括:嗜盐甲烷古菌类群、嗜盐古菌纲的全部成员以及尚不能培养的纳米嗜盐古菌类群。嗜盐古菌是盐环境的土著类群,驱动着盐环境生态系统的生物地球化学循环。作为极端微生物,嗜盐古菌在理论研究和应用领域具有重要的研究价值。本文从嗜盐古菌分类学地位的变迁、分类学方法、分类学研究现状及我国的嗜盐古菌分类学研究等方面综述了嗜盐古菌分类学的最新研究进展。     

Energy crops: current status and future prospects

Energy crops currently contribute a relatively small proportion to the total energy produced from biomass each year, but the proportion is set to grow over the next few decades. This paper reviews the current status of energy crops and their conversion technologies, assesses their potential to contribute to global energy demand and climate mitigation over the next few decades, and examines the future prospects. Previous estimates have suggested a technical potential for energy crops of～400 EJ yr^?1 by 2050. In a new analysis based on energy crop areas for each of the IPCC SRES scenarios in 2025 (as projected by the IMAGE 2.2 integrated assessment model), more conservative dry matter and energy yield estimates and an assessment of the impact on non‐CO₂ greenhouse gases were used to estimate the realistically achievable potential for energy crops by 2025 to be between 2 and 22 EJ yr^?1, which will offset～100–2070 Mt CO₂‐eq. yr^?1. These results suggest that additional production of energy crops alone is not sufficient to reduce emissions to meet a 550 μmol mol^?1 atmospheric CO₂ stabilization trajectory, but is sufficient to form an important component in a portfolio of climate mitigation measures, as well as to provide a significant sustainable energy resource to displace fossil fuel resources. Realizing the potential of energy crops will necessitate optimizing the dry matter and energy yield of these crops per area of land through the latest biotechnological routes, with or without the need for genetic modification. In future, the co‐benefits of bioenergy production will need to be optimized and methods will need to be developed to extract and refine high‐value products from the feedstock before it is used for energy production.     

Anthrax countermeasures: current status and future needs

The U.S. government does not yet have the range of medical countermeasures needed to protect its citizens from anthrax and other potential bioweapons. In the event of an anthrax attack, treatment interventions in addition to antibiotics would be needed so that very ill patients can be treated and clean-up crews can be better protected, especially if an engineered strain is used. This article describes specific anthrax countermeasures that are in development, barriers to development, and potential mechanisms the government could use to accelerate the movement of these countermeasures through the pipeline. A key challenge will be to encourage the transition of promising leads from basic research to the product development stage, when they may qualify for BioShield funds.     

Cacao biotechnology: current status and future prospects

Theobroma cacao—The Food of the Gods, provides the raw material for the multibillion dollar chocolate industry and is also the main source of income for about 6 million smallholders around the world. Additionally, cocoa beans have a number of other nonfood uses in the pharmaceutical and cosmetic industries. Specifically, the potential health benefits of cocoa have received increasing attention as it is rich in polyphenols, particularly flavonoids. At present, the demand for cocoa and cocoa‐based products in Asia is growing particularly rapidly and chocolate manufacturers are increasing investment in this region. However, in many Asian countries, cocoa production is hampered due to many reasons including technological, political and socio‐economic issues. This review provides an overview of the present status of global cocoa production and recent advances in biotechnological applications for cacao improvement, with special emphasis on genetics/genomics, in vitro embryogenesis and genetic transformation. In addition, in order to obtain an insight into the latest innovations in the commercial sector, a survey was conducted on granted patents relating to T. cacao biotechnology.