Emerging frontiers in virtual drug discovery: From quantum mechanical methods to deep learning approaches

Virtual screening-based approaches to discover initial hit and lead compounds have the potential to reduce both the cost and time of early drug discovery stages, as well as to find inhibitors for even challenging target sites such as protein–protein interfaces. Here in this review, we provide an overview of the progress that has been made in virtual screening methodology and technology on multiple fronts in recent years. The advent of ultra-large virtual screens, in which hundreds of millions to billions of compounds are screened, has proven to be a powerful approach to discover highly potent hit compounds. However, these developments are just the tip of the iceberg, with new technologies and methods emerging to propel the field forward. Examples include novel machine-learning approaches, which can reduce the computational costs of virtual screening dramatically, while progress in quantum-mechanical approaches can increase the accuracy of predictions of various small molecule properties.     

Recent developments in chromatographic purification of biopharmaceuticals

Over the last several decades, researchers have time and again proposed use of non-chromatographic methods for processing of biotherapeutic products. However, chromatography continues to be the backbone of downstream processing, particularly at process scale. There are many reasons for this, critical ones being the unparalleled scalability, robustness, and selectivity that process chromatography offers over its peers. It is no surprise then that process chromatography has been a topic of major developments in resin matrix, ligand chemistry, modalities, high throughput process development, process modelling, and approaches for control. In this review, we attempt to summarize major developments in the above-mentioned areas. Greater significance has been given to advancements in the last 5 years (2013–2017).     

Animal cognition: 1900-2000

During the 20th century there has been considerable progress in the study of animal cognition, based on essential ideas that were developed earlier. These essential ideas include the metaphors of the animal, the questions, the sources of hypotheses, and the types of explanations. The progress cannot be generally characterized as continuous improvement, cyclic changes, or discrete steps, but the quality of the empirical results has increased substantially since the first experiments in the field. Improvements in research methods have been primarily responsible for this progress. These have included improvements in animal husbandry, stimulus control, apparatus design, the measurement of behavior, experimental procedures, and data analysis. In the last third of the century the computer has led to major improvements in all stages of the research process in animal cognition. Although they have greatly improved the quality of the empirical results, they have not led to a general theory of animal cognition. In the near future the available research methods are likely to lead to further progress in the developments of quantitative theories of animal cognition.     

Vaccines against Tuberculosis: Where Are We and Where Do We Need to Go?

In this review we discuss recent progress in the development, testing, and clinical evaluation of new vaccines against tuberculosis (TB). Over the last 20 years, tremendous progress has been made in TB vaccine research and development: from a pipeline virtually empty of new TB candidate vaccines in the early 1990s, to an era in which a dozen novel TB vaccine candidates have been and are being evaluated in human clinical trials. In addition, innovative approaches are being pursued to further improve existing vaccines, as well as discover new ones. Thus, there is good reason for optimism in the field of TB vaccines that it will be possible to develop better vaccines than BCG, which is still the only vaccine available against TB.     

NMR methodology for the study of nucleic acids.

During the past few years, NMR methodology for the study of nucleic acids has benefited from new developments that greatly improved state-of-the-art technology for the precise determination of three-dimensional structures. Substantial progress has been made in designing experimental protocols for the measurement of residual dipolar couplings, in sensitivity optimization of triple-resonance experiments and in detection of hydrogen bonds and in developing computational methods for structure refinement using NMR restraints.     

Proteome-scale analysis of biochemical activity

During the last 10 years, there has been a large increase in the number of genome sequences available for study, altering the way that the biology of organisms is studied. In particular, scientific attention has increasingly focused on the proteome, and specifically on the role of all the proteins encoded by the genome. We focus here on several aspects of this problem. We describe several technologies in widespread use to clone genes on a genome-wide scale, and to express and purify the proteins encoded by these genes. We also describe a number of methods that have been developed to analyze various biochemical properties of the proteins, with attention to the methodology and the limitations of the approaches, followed by a look at possible developments in the next decade.     

Advances in microbial delignification

Microbial delignification is a new field of applied research. The progress will therefore run parallel to the development of new basic knowledge on the physiological demands of white-rot fungi to degrade lignin and on new knowledge on enzyme mechanisms involved in lignin degradation.In the last few years both basic and applied research on microbial conversion of lignocellulosic materials have vastly expanded. In certain areas, such as microbial delignification, considerable progress has recently been made. Basidiospores from Sporotrichum pulverulentum and some CEL(-) mutants have been obtained. Crossing of mycelium from single basidiospore cultures of wild-type and CEL(-) mutants will eventually give rise to much better CEL(-) mutants than those which have been used in the past. An understanding of which enzymes are the most important for lignin degradation to take place is also beginning to develop. This review discusses present knowledge and future possibilities in this field.     

钝头蛇属Pareas（蛇亚目：钝头蛇科）系统分类研究进展

钝头蛇属（Pareas）蛇类形态高度保守,种间形态差异微弱。以分子系统学方法为中心的整合分类方法的应用,为本类群分类难题的解决作出了重要贡献,近8年有9个新种得以描述,其中,仅在近3年就增加了7个新种,并有6个同物异名被恢复。本文依据最新研究成果,对近期钝头蛇属蛇类系统分类研究成果进行了综述,并斟酌中文种名,整理了物种名录,并编制了分类检索表。截止目前,钝头蛇属共有26种,其中在我国有分布的18种,中国特有种9种。同时,对研究中存在的问题进行了探讨,并对下一步工作提出了建议：本属物种多样性估计过低、标本采集覆盖范围不足、证据使用不甚全面,大范围密集采样以及系统发育基因组学方法的应用有助于本类群系统关系的最终解决。     

Recent advances in drug design methods: Where will they lead?

Drug design methods have made significant new advances over the last ten years, mainly in the areas of molecular modelling. In more recent times important developments in theory have led to a different type of modelling becoming possible, the so-called de novo or automated design algorithms. In this new method the programs perform much of the chemist's thinking, in finding appropriately sized chemical groups to fit into a target site. However this is a combinatoric problem which has no general analytical solution; it is ripe for optimization. Other advances, such as combinatorial chemical synthesis and screening, will dramatically influence the search for new lead structures for target sites, which at present are poorly understood. Already these methods are being applied to peptide libraries. Peptides do not make good drug compounds because of their poor bioavailability; further, their flexibility reduces their affinity. In some cases peptide backbones can be removed and replaced with rigid non-peptide scaffolds.     

Metal‐Air Batteries: Metal–Air Batteries with High Energy Density: Li–Air versus Zn–Air (Adv. Energy Mater. 1/2011)

In the past decade, there have been exciting developments in the field of lithium ion batteries as energy storage devices, resulting in the application of lithium ion batteries in areas ranging from small portable electric devices to large power systems such as hybrid electric vehicles. However, the maximum energy density of current lithium ion batteries having topatactic chemistry is not sufficient to meet the demands of new markets in such areas as electric vehicles. Therefore, new electrochemical systems with higher energy densities are being sought, and metal‐air batteries with conversion chemistry are considered a promising candidate. More recently, promising electrochemical performance has driven much research interest in Li‐air and Zn‐air batteries. This review provides an overview of the fundamentals and recent progress in the area of Li‐air and Zn‐air batteries, with the aim of providing a better understanding of the new electrochemical systems.     

Metal–Air Batteries with High Energy Density: Li–Air versus Zn–Air

In the past decade, there have been exciting developments in the field of lithium ion batteries as energy storage devices, resulting in the application of lithium ion batteries in areas ranging from small portable electric devices to large power systems such as hybrid electric vehicles. However, the maximum energy density of current lithium ion batteries having topatactic chemistry is not sufficient to meet the demands of new markets in such areas as electric vehicles. Therefore, new electrochemical systems with higher energy densities are being sought, and metal‐air batteries with conversion chemistry are considered a promising candidate. More recently, promising electrochemical performance has driven much research interest in Li‐air and Zn‐air batteries. This review provides an overview of the fundamentals and recent progress in the area of Li‐air and Zn‐air batteries, with the aim of providing a better understanding of the new electrochemical systems.     

Transducers,sensors, and instrumentation in clinical biomechanics

Successful measurements in any field are dependent on the availability of appropriate transducer materials and the associated instrumentation. In recent years there has been a most welcome advance in both these areas. If we consider first the transducer developments that have recently taken place, these have much to do with the discovery and application of new materials such as electroactive polymers, fibre optic devices and many others. Instrumentation has largely benefitted from the microelectronics revolution. Our ability to process and ultimately display data has improved to a remarkable extent. Indeed, the designer of instrumentation is under enormous pressure to convert the data into the digital domain as early as possible simply because the resulting instrument will usually be easier to design and construct, more accurate, more reliable, smaller and possibly more important still, cheaper. This paper reviews some of these developments, gives a number of examples of applications in the clinical biomechanics area and makes some predictions for future developments.     

Gold nanoparticles and bioconjugation: a pathway for proteomic applications

In the last few years gold nanoparticles (AuNPs) became extremely interesting materials due to their enhanced optical, chemical and electrical properties. With the intention of taking advantage of those properties, the use of AuNPs has spread into a wide variety of areas such as physics, chemistry, biology, industry and medicine. More interestingly, their ability to form robust conjugates with biomolecules has given proteomics a new tool to improve aspects where the current methods to study proteins and their interactions in living cells cannot achieve the success required. In this review we present some of the current methods for AuNPs synthesis, the tailoring of their surface with ligands to improve stability and strategies to conjugate with biomolecules. Lastly, we also discuss their application in proteomic methods and recent developments in clinical diagnosis.     

Deconstructing death in paleodemography

In 1992 in this Journal (Konigsberg and Frankenberg [1992] Am. J. Phys. Anthropol. 89:235-256), we wrote about the use of maximum likelihood methods for the "estimation of age structure in anthropological demography." More specifically, we presented a particular method (the "iterated age-length key") from the fisheries literature and suggested that the method could be used in human and primate demography and paleodemography as well. In our paper (section titled "Some Future Directions"), we spelled out two broad areas that we expected to see develop over the ensuing years. First, we felt that the use of explicit likelihood methods would open up interest in basic estimation issues, such as the calculation of standard errors for demographic estimates and the formulation of tests for whether samples differed in their demographic structure. Second, we felt that the time was ripe for hazards analyses that would incorporate the uncertainty in estimation that follows from using age "indicators" rather than known ages. While some of these developments have occurred during the last decade, few have been reported in the American Journal of Physical Anthropology. In this paper we resolve some issues from our 1992 paper, and attempt to redress this deficit in the literature by reviewing some recent developments in paleodemography over the past decade.     

Protein sequence comparison and fold recognition: progress and good-practice benchmarking

Protein sequence comparison methods have grown increasingly sensitive during the last decade and can often identify distantly related proteins sharing a common ancestor some 3 billion years ago. Although cellular function is not conserved so long, molecular functions and structures of protein domains often are. In combination with a domain-centered approach to function and structure prediction, modern remote homology detection methods have a great and largely underexploited potential for elucidating protein functions and evolution. Advances during the last few years include nonlinear scoring functions combining various sequence features, the use of sequence context information, and powerful new software packages. Since progress depends on realistically assessing new and existing methods and published benchmarks are often hard to compare, we propose 10 rules of good-practice benchmarking.     

Flow cytometry in radiation research: past, present and future

Flow cytometry is an invaluable technique in research and clinical laboratories. The technique has been applied extensively to many areas of radiation research at both the experimental and clinical level. In the past few years, there has been a significant increase in the capabilities of modern flow cytometers to undertake multicolor analysis in a user-friendly manner. The developments in cytometric technology are being matched by the rapid development of new reagents, new fluorochromes and new platforms such as bead arrays. These developments are facilitating many new applications in both basic and clinical research that have relevance for many fields of biology, including radiation research. This review provides a historical overview of the application of flow cytometry to radiobiology and an update on how technology and reagents have changed and cites examples of new applications relevant to radiation researchers. In addition, some entirely new flow instrumentation is currently under development that has significant potential for applications in radiation research.     

Protein folding: from the levinthal paradox to structure prediction.

This article is a personal perspective on the developments in the field of protein folding over approximately the last 40 years. In addition to its historical aspects, the article presents a view of the principles of protein folding with particular emphasis on the relationship of these principles to the problem of protein structure prediction. It is argued that despite much that is new, the essential elements of our current understanding of protein folding were anticipated by researchers many years ago. These elements include the recognition of the central importance of the polypeptide backbone as a determinant of protein conformation, hierarchical protein folding, and multiple folding pathways. Important areas of progress include a detailed characterization of the folding pathways of a number of proteins and a fundamental understanding of the physical chemical forces that determine protein stability. Despite these developments, fold prediction algorithms still encounter difficulties in identifying the correct fold for a given sequence. This may be due to the possibility that the free energy differences between at least a few alternate conformations of many proteins are not large. Significant progress in protein structure prediction has been due primarily to the explosive growth of sequence and structural databases. However, further progress is likely to depend in part on the ability to combine information available from databases with principles and algorithms derived from physical chemical studies of protein folding. An approach to the integration of the two areas is outlined with specific reference to the PrISM program that is a fully integrated sequence/structural-analysis/fold-recognition/homology model building software system.     

Proteome-Scale Analysis of Biochemical Activity

ABSTRACT

During the last 10 years, there has been a large increase in the number of genome sequences available for study, altering the way that the biology of organisms is studied. In particular, scientific attention has increasingly focused on the proteome, and specifically on the role of all the proteins encoded by the genome. We focus here on several aspects of this problem. We describe several technologies in widespread use to clone genes on a genome-wide scale, and to express and purify the proteins encoded by these genes. We also describe a number of methods that have been developed to analyze various biochemical properties of the proteins, with attention to the methodology and the limitations of the approaches, followed by a look at possible developments in the next decade.     

A look to future directions in gene therapy research for monogenic diseases

The concept of gene therapy has long appealed to biomedical researchers and clinicians because it promised to treat certain diseases at their origins. In the last several years, there have been several trials in which patients have benefited from gene therapy protocols. This progress, however, has revealed important problems, including the problem of insertional oncogenesis. In this review, which focuses on monogenic diseases, we discuss the problem of insertional oncogenesis and identify areas for future research, such as developing more quantitative assays for risk and efficacy, and ways of minimizing the genotoxic effects of gene therapy protocols, which will be important if gene therapy is to fulfill its conceptual promise.