Discovery of new acetylcholinesterase inhibitors for Alzheimer’s disease: virtual screening and in vitro characterisation

For more than two decades, the development of potent acetylcholinesterase (AChE) inhibitors has been an ongoing task to treat dementia associated with Alzheimer’s disease and improve the pharmacokinetic properties of existing drugs. In the present study, we used three docking-based virtual screening approaches to screen both ZINC15 and MolPort databases for synthetic analogs of physostigmine and donepezil, two highly potent AChE inhibitors. We characterised the in vitro inhibitory concentration of 11 compounds, ranging from 14 to 985 μM. The most potent of these compounds, S-I 26, showed a fivefold improved inhibitory concentration in comparison to rivastigmine. Moderate inhibitors carrying novel scaffolds were identified and could be improved for the development of new classes of AChE inhibitors.     

Visualizing biomolecular electrostatics in virtual reality with UnityMol‐APBS

Virtual reality is a powerful tool with the ability to immerse a user within a completely external environment. This immersion is particularly useful when visualizing and analyzing interactions between small organic molecules, molecular inorganic complexes, and biomolecular systems such as redox proteins and enzymes. A common tool used in the biomedical community to analyze such interactions is the Adaptive Poisson‐Boltzmann Solver (APBS) software, which was developed to solve the equations of continuum electrostatics for large biomolecular assemblages. Numerous applications exist for using APBS in the biomedical community including analysis of protein ligand interactions and APBS has enjoyed widespread adoption throughout the biomedical community. Currently, typical use of the full APBS toolset is completed via the command line followed by visualization using a variety of two‐dimensional external molecular visualization software. This process has inherent limitations: visualization of three‐dimensional objects using a two‐dimensional interface masks important information within the depth component. Herein, we have developed a single application, UnityMol‐APBS, that provides a dual experience where users can utilize the full range of the APBS toolset, without the use of a command line interface, by use of a simple graphical user interface (GUI) for either a standard desktop or immersive virtual reality experience.     

Enhanced contrast acoustic‐resolution photoacoustic microscopy using double‐stage delay‐multiply‐and‐sum beamformer for vasculature imaging

In acoustic‐resolution photoacoustic microscopy (AR‐PAM) systems, the lateral resolution in the focal zone of the ultrasound (US) transducer is determined by the numerical aperture (NA) of the transducer. To have a high lateral resolution, a large NA is used. However, the larger the NA, the smaller the depth of focus [DOF]. As a result, the lateral resolution is deteriorated at depths out of the focal region. The synthetic aperture focusing technique (SAFT) along with a beamformer can be used to improve the resolution outside the focal region. In this work, for image formation in AR‐PAM, we propose the double‐stage delay‐multiply‐and‐sum (DS_DMAS) algorithm to be combined with SAFT. The proposed method is evaluated experimentally using hair targets and in vivo vasculature imaging. It is shown that DS_DMAS provides a higher resolution and contrast compared to other methods. For the B‐mode images obtained using the hair phantom, the proposed method reduces the average noise level for all the depths by about 134%, 57% and 23%, compared to the original low‐ resolution, SAFT+DAS and SAFT+DMAS methods, respectively. All the results indicate that the proposed method can be an appropriate algorithm for image formation in AR‐PAM systems.      

Different attentional dysfunctions in eEF2K−/−, IL1RAPL1−/− and SHANK3Δ11−/− mice

A common feature of several psychiatric disorders is the attentional impairment. eEF2K ^?/?, IL1RAPL1 ^?/? and SHANK3Δ11 ^?/? mice were used as animal models consistently linked to changes in synaptic plasticity, learning and memory. All knockout (KO) mice and their corresponding littermates were submitted to the novel object recognition (NOR) and visual object recognition (VOR) tasks. In the NOR, eEF2K^?/? mice exhibited a normal performance in terms of mean discrimination index, while SHANK3Δ11^?/? and IL1RAPL1 ^?/? mice were impaired when a delay of 2 and 24 hours was introduced. Surprisingly, when submitted to VOR, where the two objects were replaced with two shapes delivered from two iPods, all the mutant mice performed worse than those in the NOR. In VOR, the application of motion to different shapes, to increase attention, improved performance in eEF2K ^?/? and IL1RAPL1 ^?/? but not in SHANK3Δ11 ^?/? mice. In SHANK3Δ11 ^?/? mice, attentional deficit was also present even if different motions were applied to the same shapes or when these mice were repeatedly exposed for 5 days to the context. Behavioral analysis showed that eEF2K^?/? and IL1RAPL1 ^?/? mice had a good flexibility tested in the T‐maze. eEF2K^?/? showed normal self‐grooming. On the basis of previous literature data indicating that SHANK3Δ11 ^?/? showed impaired flexibility and reduced sociability, we identified in this genotype the most exhaustive model showing all the core symptoms of autism spectrum disorder including a heavy visual attention deficit. These findings show the importance of VOR to identify mouse models of autism.     

Presence‐only versus presence–absence data in species composition determinant analyses

Aim Studying relationships between species and their physical environment requires species distribution data, ideally based on presence–absence (P–A) data derived from surveys. Such data are limited in their spatial extent. Presence‐only (P‐O) data are considered inappropriate for such analyses. Our aim was to evaluate whether such data may be used when considering a multitude of species over a large spatial extent, in order to analyse the relationships between environmental factors and species composition. Location The study was conducted in virtual space. However, geographic origin of the data used is the contiguous USA. Methods We created distribution maps for 50 virtual species based on actual environmental conditions in the study. Sampling locations were based on true observations from the Global Biodiversity Information Facility. We produced P–A data by selecting ∼1000 random locations and recorded the presence/absence of all species. We produced two P‐O data sets. Full P‐O set was produced by sampling the species in locations of true occurrences of species. Partial P‐O was a subset of full P‐O data set matching the size of the P–A data set. For each data set, we recorded the environmental variables at the same locations. We used CCA to evaluate the amount of variance in species composition explained by each variable. We evaluated the bias in the data set by calculating the deviation of average values of the environmental variables in sampled locations compared to the entire area. Results P–A and P‐O data sets were similar in terms of the amount of variance explained by the different environmental variables. We found sizable environmental and spatial bias in the P‐O data set, compared to the entire study area. Main conclusions Our results suggest that although P‐O data from collections contain bias, the multitude of species, and thus the relatively large amount of information in the data, allow the use of P‐O data for analysing environmental determinants of species composition.     

Advancements in Input‐Output Models and Indicators for Consumption‐Based Accounting

The use of global, multiregional input‐output (MRIO) analysis for consumption‐based (footprint) accounting has expanded significantly over the last decade. Most of the global studies on environmental and social impacts associated with consumption or embodied in international trade would have been impossible without the rapid development of extended MRIO databases. We present an overview of the developments in the field of MRIO analysis, in particular as applied to consumption‐based environmental and social footprints. We first provide a discussion of research published on various global MRIO databases and the differences between them, before focusing on the virtual laboratory computing infrastructure for potentially making MRIO databases more accessible for collaborative research, and also for supporting greater sectoral and regional detail. We discuss work that includes a broader range of extensions, in particular the inclusion of social indicators in consumption‐based accounting. We conclude by discussing the need for the development of detailed nested MRIO tables for investigating linkages between regions of different countries, and the applications of the rapidly growing field of global MRIO analysis for assessing a country's performance toward the United Nations Sustainable Development Goals.     

Technical Note: Virtual reconstruction of KNM‐ER 1813 Homo habilis cranium

A very limiting factor for paleoanthropological studies is the poor state of preservation of the human fossil record, where fragmentation and deformation are considered normal. Although anatomical information can still be gathered from a distorted fossil, such specimens must typically be excluded from advanced morphological and morphometric analyses, thus reducing the fossil sample size and, ultimately, our knowledge of human evolution. In this contribution we provide the first digital reconstruction of the KNM‐ER 1813 Homo habilis cranium. Based on state of‐the‐art three‐dimensional digital modeling and geometric morphometric (GM) methods, the facial portion was aligned to the neurocranium, the overall distortion was removed, and the missing regions were restored. The reconstructed KNM‐ER 1813 allows for an adjustment of the anthropometric measurements gathered on the original fossil. It is suitable for further quantitative studies, such as GM analyses focused on skull morphology or for finite element analysis to explore the mechanics of early Homo feeding behavior and diet. Am J Phys Anthropol 153:154–160, 2014. © 2013 Wiley Periodicals, Inc.     

虚拟生物实验室实例

虚拟生物实验室在生物课程资源中有巨大并且尚未开发的潜力。它对于不同级别学生的学习都是有利的。介绍了虚拟生物实验室的一些实例。并展望了其应用前景。     

The “online brain”: how the Internet may be changing our cognition

The impact of the Internet across multiple aspects of modern society is clear. However, the influence that it may have on our brain structure and functioning remains a central topic of investigation. Here we draw on recent psychological, psychiatric and neuroimaging findings to examine several key hypotheses on how the Internet may be changing our cognition. Specifically, we explore how unique features of the online world may be influencing: a) attentional capacities, as the constantly evolving stream of online information encourages our divided attention across multiple media sources, at the expense of sustained concentration; b) memory processes, as this vast and ubiquitous source of online information begins to shift the way we retrieve, store, and even value knowledge; and c) social cognition, as the ability for online social settings to resemble and evoke real‐world social processes creates a new interplay between the Internet and our social lives, including our self‐concepts and self‐esteem. Overall, the available evidence indicates that the Internet can produce both acute and sustained alterations in each of these areas of cognition, which may be reflected in changes in the brain. However, an emerging priority for future research is to determine the effects of extensive online media usage on cognitive development in youth, and examine how this may differ from cognitive outcomes and brain impact of uses of Internet in the elderly. We conclude by proposing how Internet research could be integrated into broader research settings to study how this unprecedented new facet of society can affect our cognition and the brain across the life course.     

Necessary and sufficient conditions for the asymmetric synthesis of chiral amines using ω‐aminotransferases

The half reactions of ω‐aminotransferase (ω‐AT) from Vibrio fluvialis JS17 (ω‐ATVf) were carried out using purified pyridoxal 5′‐phosphate‐enzyme (PLP‐Enz) and pyridoxamine 5′‐phosphate‐enzyme (PMP‐Enz) complexes to investigate the relative activities of substrates. In the reaction generating PMP‐Enz from PLP‐Enz using L ‐alanine as an amine donor, L ‐alanine showed about 70% of the initial reaction rate of (S)‐α‐methylbenzylamine ((S)‐α‐MBA). However, in the subsequent half reaction recycling PLP‐Enz from PMP‐Enz using acetophenone as an amine acceptor, acetophenone showed nearly negligible reactivity compared to pyruvate. These results indicate that the main bottleneck in the asymmetric synthesis of (S)‐α‐MBA lies not in the amination of PLP by alanine, but in the amination of acetophenone by PMP‐Enz, where conformational restraints of the enzyme structure is likely to be the main reason for limiting the amine group transfer from PMP‐Enz to acetophenone. Based upon those half reaction experiments using the two amino acceptors of different activity, it appears that the relative activities of the two amine donors and the two acceptors involved in the ω‐AT reactions can roughly determine the asymmetric synthesis yield of the target chiral amine compound. Predicted conversion yields of several target chiral amines were calculated and compared with the experimental conversion yields. Approximately, a positive linear correlation (Pearson's correlation coefficient = 0.92) was observed between the calculated values and the experimental conversion yields. To overcome the low (S)‐α‐MBA productivity of ω‐ATVf caused by the possible disadvantageous structural constraints for acetophenone, new ω‐ATs showing higher affinity to benzene ring of acetophenone than ω‐ATVf were computationally screened using comparative modeling and protein‐ligand docking. ω‐ATs from Streptomyces avermitilis MA‐4680 (SAV2612) and Agrobacterium tumefaciens str. C58 (Atu4761) were selected, and the two screened ω‐ATs showed higher asymmetric synthesis reaction rate of (S)‐α‐MBA and lower (S)‐α‐MBA degradation reaction rate than ω‐ATVf. To verify the higher conversion yield of the variants of ω‐ATs, the reaction with 50 mM acetophenone and 50 mM alanine was performed with coupling of lactate dehydrogenase and two‐phase reaction system. SAV2612 and Atu4761 showed 70% and 59% enhanced yield in the synthesis of (S)‐α‐MBA compared to that of ω‐ATVf, respectively. Biotechnol. Bioeng. 2011;108: 253–263. © 2010 Wiley Periodicals, Inc.     

Cognitive Ergonomics in Virtual Environments: Development of an Intuitive and Appropriate Input Device for Navigating in a Virtual Maze

For patients suffering from mild cognitive impairments, the navigation through a virtual maze should be as intuitive and efficient as possible in order to minimize cognitive and physical strain. This paper discusses the appropriateness of interaction devices for being used for easy navigation tasks. Information gained from human centered evaluation was used to develop an intuitive and ergonomic interaction device. Two experiments examined the usability of tracked interaction devices. Usability problems with the devices are discussed. The findings from the experiments were translated into general design guidance, in addition to specific recommendations. A new device was designed on the basis of these recommendations and its usability was evaluated in a second experiment. The results were used to develop a lightweight interaction device for navigation in the virtual maze.     

Technical Note: 3D From Standard Digital Photography of Human Crania—A Preliminary Assessment

This study assessed three‐dimensional (3D) photogrammetry as a tool for capturing and quantifying human skull morphology. While virtual reconstruction with 3D surface scanning technology has become an accepted part of the paleoanthropologist's tool kit, recent advances in 3D photogrammetry make it a potential alternative to dedicated surface scanners. The principal advantages of photogrammetry are more rapid raw data collection, simplicity and portability of setup, and reduced equipment costs. We tested the precision and repeatability of 3D photogrammetry by comparing digital models of human crania reconstructed from conventional, 2D digital photographs to those generated using a 3D surface scanner. Overall, the photogrammetry and scanner meshes showed low degrees of deviation from one another. Surface area estimates derived from photogrammetry models tended to be slightly larger. Landmark configurations generally did not cluster together based upon whether the reconstruction was created with photogrammetry or surface scanning technology. Average deviations of landmark coordinates recorded on photogrammetry models were within the generally allowable range of error in osteometry. Thus, while dependent upon the needs of the particular research project, 3D photogrammetry appears to be a suitable, lower‐cost alternative to 3D imaging and scanning options. Am J Phys Anthropol 154:152–158, 2014. © 2014 Wiley Periodicals, Inc.     

中国主要农产品虚拟要素贸易网络结构特征分析

据虚拟水概念定义虚拟要素,并将其划分为虚拟资源要素和虚拟生态要素两类,选取虚拟资源要素中的耕地要素和虚拟生态要素中的化肥/农药要素为研究对象,定量分析2002—2016年以粮食贸易为载体的虚拟耕地、虚拟化肥/农药要素的贸易量,构建虚拟要素贸易网络,通过复杂网络的研究方法,结果表明:2002—2016年我国主要农产品虚拟耕地、化肥/农药要素的贸易总量呈下降趋势,降幅分别约25.51%、8.01%;虚拟耕地要素网络节点入度较大的为长江中下游、华南、西南地区,出度较大的为黄淮海和东北地区,虚拟化肥/农药要素网络与之相反;地区间节点强度的差异性大,虚拟耕地要素差值最大可达1459.56万hm~2,虚拟化肥/农药要素达61.38万t;二者网络节点度和强度的累积分布均符合幂律分布规律,其尾部的"重尾"现象揭示了节点度和强度的高可变性以及网络结构的脆弱性;虚拟耕地要素的输入区网络同配,输出区网络异配,揭示了地区间耕地要素的流动既呈集聚又有分散的态势,虚拟化肥/农药要素网络节点相关性皆为减函数,网络异配,揭示了虚拟化肥/农药要素在八大区域间联通的状况。网络结构特征分析为研究网络抗毁性特征和网络的优化调控机制奠定基础,为中国粮食贸易格局和粮价制定以及各个地区的农业种植结构调整提供理论依据。     

Exploring the carbohydrate‐binding ability of Canavalia bonariensis lectin in inflammation models

Lectins are a group of proteins of non‐immune origin recognized for their ability to bind reversibly to carbohydrates. Researchers have been intrigued by oligosaccharides and glycoconjugates for their involvement as mediators of complex cellular events and then many biotechnological applications of lectins are based on glycocode decoding and their activities. Here, we report a structural and biological study of a ConA‐like mannose/glucose‐specific lectin from Canavalia bonariensis seeds, CaBo. More specifically, we evaluate the binding of CaBo with α‐methyl‐D‐mannoside (MMA) and mannose‐1,3‐α‐D‐mannose (M13) and the resultant in vivo effects on a rat model of acute inflammation. A virtual screening was also carried out to cover a larger number of possible bindings of CaBo. In silico analysis demonstrated the stability of CaBo interaction with mannose‐type ligands, and the lectin was able to induce acute inflammation in rats with the participation of the carbohydrate recognition domain (CRD) and histamine release. These results confirm the ability of CaBo to interact with hybrid and high‐mannose N‐glycans, supporting the hypothesis that CaBo's biological activity occurs primarily through its interaction with cell surface glycosylated receptors.     

Virtual human hand: model and kinematics

The human hand plays an important role in daily life. It is the interface between the human and the exterior world by positioning, orienting, touching and grasping objects. The human hand has multiple degrees of freedom (DOFs) to enable mobility and dexterity. A virtual human hand model can be inserted into CAD (Computer Aided Design) models to assess the manipulation capabilities in the early design stage to reduce design time and cost. Joystick assessment is one of the important design cases. This study is a first step towards a comprehensive hand simulation tool to simulate the manipulation and grasping of objects. This paper presents a novel 25 DOFs' hand skeletal model based on hand anatomy and hand kinematics: (1) joint range of motion, (2) Denavit–Hartenberg method to define the joint relationship and (3) finger workspace determination. Novelty for this hand model includes arching the palm with the four DOFs added in the carpometacarpal and wrist joints for the ring and small fingers.     

Structure‐guided screening of chemical database to identify NS3‐NS2B inhibitors for effective therapeutic application in dengue infection

Dengue infection is the most common arthropod‐borne disease caused by dengue viruses, predominantly affecting millions of human beings annually. To find out promising chemical entities for therapeutic application in Dengue, in the current research, a multi‐step virtual screening effort was conceived to screen out the entire “screening library” of the Asinex database. Initially, through “Lipinski rule of five” filtration criterion almost 0.6 million compounds were collected and docked with NS3‐NS2B protein. Thereby, the chemical space was reduced to about 3500 compounds through the analysis of binding affinity obtained from molecular docking study in AutoDock Vina. Further, the “Virtual Screening Workflow” (VSW) utility of Schrödinger suite was used, which follows a stepwise multiple docking programs such as ‐ high‐throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) docking, and in postprocessing analysis the MM‐GBSA based free binding energy calculation. Finally, five potent molecules were proposed as potential inhibitors for the dengue NS3‐NS2B protein based on the investigation of molecular interactions map and protein‐ligand fingerprint analyses. Different pharmacokinetics and drug‐likeness parameters were also checked, which favour the potentiality of selected molecules for being drug‐like candidates. The molecular dynamics (MD) simulation analyses of protein‐ligand complexes were explained that NS3‐NS2B bound with proposed molecules quite stable in dynamic states as observed from the root means square deviation (RMSD) and root means square fluctuation (RMSF) parameters. The binding free energy was calculated using MM‐GBSA method from the MD simulation trajectories revealed that all proposed molecules possess such a strong binding affinity towards the dengue NS3‐NS2B protein. Therefore, proposed molecules may be potential chemical components for effective inhibition of dengue NS3‐NS2B protein subjected to experimental validation.     

Buoyancy of some Palaeozoic ammonoids and their hydrostatic properties based on empirical 3D‐models

The interpretation of the function of the ammonoid phragmocone as a buoyancy device is now widely accepted among ammonoid researchers. During the 20^th century, several theoretical models were proposed for the role of the chambered shell (phragmocone); accordingly, the phragmocone had hydrostatic properties, which enabled it to attain neutral buoyancy, presuming it was partially filled with gas. With new three‐dimensional reconstructions of ammonoid shells, we are now able to test these hypothetical models using empirical volume data of actual ammonoid shells. We investigated three Palaeozoic ammonoids (Devonian and Carboniferous), namely Fidelites clariondi, Diallagites lenticulifer and Goniatites multiliratus, to reconstruct their hydrostatic properties, their syn vivo shell orientation and their buoyancy. According to our models, measurements and calculations, these specimens had aperture orientations of 19°, 64° and 125° during their lives. Although none of our results coincide with the aperture orientation of the living Nautilus, they do verify the predictions for shell orientations based on published theoretical models. Our calculations also show that the shorter the body chamber, the poorer was the hydrodynamic stability of the animal. This finding corroborates the results of theoretical models from the 1990s. With these results, which are based on actual specimens, we favour the rejection of hypotheses suggesting a purely benthonic mode of life of ammonoids. Additionally, it is now possible to assess hydrodynamic properties of the shells through ontogeny and phylogeny, leading to insights to validate theoretical modes of life and habitat through the animal's life.