Reference File Research Articles

Small molecule annotation for the Protein Data Bank

The Protein Data Bank (PDB) is the single global repository for three-dimensional structures of biological macromolecules and their complexes, and its more than 100 000 structures contain more than 20 000 distinct ligands or small molecules bound to proteins and nucleic acids. Information about these small molecules and their interactions with proteins and nucleic acids is crucial for our understanding of biochemical processes and vital for structure-based drug design. Small molecules present in a deposited structure may be attached to a polymer or may occur as a separate, non-covalently linked ligand. During curation of a newly deposited structure by wwPDB annotation staff, each molecule is cross-referenced to the PDB Chemical Component Dictionary (CCD). If the molecule is new to the PDB, a dictionary description is created for it. The information about all small molecule components found in the PDB is distributed via the ftp archive as an external reference file. Small molecule annotation in the PDB also includes information about ligand-binding sites and about covalent and other linkages between ligands and macromolecules. During the remediation of the peptide-like antibiotics and inhibitors present in the PDB archive in 2011, it became clear that additional annotation was required for consistent representation of these molecules, which are quite often composed of several sequential subcomponents including modified amino acids and other chemical groups. The connectivity information of the modified amino acids is necessary for correct representation of these biologically interesting molecules. The combined information is made available via a new resource called the Biologically Interesting molecules Reference Dictionary, which is complementary to the CCD and is now routinely used for annotation of peptide-like antibiotics and inhibitors.

Web-based, GPU-accelerated, Monte Carlo simulation and visualization of indirect radiation imaging detector performance.

Monte Carlo simulations play a vital role in the understanding of the fundamental limitations, design, and optimization of existing and emerging medical imaging systems. Efforts in this area have resulted in the development of a wide variety of open-source software packages. One such package, hybridmantis, uses a novel hybrid concept to model indirect scintillator detectors by balancing the computational load using dual CPU and graphics processing unit (GPU) processors, obtaining computational efficiency with reasonable accuracy. In this work, the authors describe two open-source visualization interfaces, webmantis and visualmantis to facilitate the setup of computational experiments via hybridmantis. The visualization tools visualmantis and webmantis enable the user to control simulation properties through a user interface. In the case of webmantis, control via a web browser allows access through mobile devices such as smartphones or tablets. webmantis acts as a server back-end and communicates with an NVIDIA GPU computing cluster that can support multiuser environments where users can execute different experiments in parallel. The output consists of point response and pulse-height spectrum, and optical transport statistics generated by hybridmantis. The users can download the output images and statistics through a zip file for future reference. In addition, webmantis provides a visualization window that displays a few selected optical photon path as they get transported through the detector columns and allows the user to trace the history of the optical photons. The visualization tools visualmantis and webmantis provide features such as on the fly generation of pulse-height spectra and response functions for microcolumnar x-ray imagers while allowing users to save simulation parameters and results from prior experiments. The graphical interfaces simplify the simulation setup and allow the user to go directly from specifying input parameters to receiving visual feedback for the model predictions.

Dual transcriptional profiling of mice and Toxoplasma gondii during acute and chronic infection.

BackgroundThe obligate intracellular parasite Toxoplasma gondii establishes a life-long chronic infection within any warm-blooded host. After ingestion of an encysted parasite, T. gondii disseminates throughout the body as a rapidly replicating form during acute infection. Over time and after stimulation of the host immune response, T. gondii differentiates into a slow growing, cyst form that is the hallmark of chronic infection. Global transcriptome analysis of both host and parasite during the establishment of chronic T. gondii infection has not yet been performed. Here, we conducted a dual RNA-seq analysis of T. gondii and its rodent host to better understand host and parasite responses during acute and chronic infection.ResultsWe obtained nearly one billion paired-end RNA sequences from the forebrains of uninfected, acutely and chronically infected mice, then aligned them to the genomic reference files of both T. gondii and Mus musculus. Gene ontology (GO) analysis of the 100 most highly expressed T. gondii genes showed less than half were shared between acute and chronic infection. The majority of the highly expressed genes common in both acute and chronic infection were involved in transcription and translation, underscoring that parasites in both stages are actively synthesizing proteins. Similarly, most of the T. gondii genes highly expressed during chronic infection were involved in metabolic processes, again highlighting the activity of the cyst stage at 28 days post-infection. Comparative analyses of host genes using uninfected forebrain revealed over twice as many immune regulatory genes were more abundant during chronic infection compared to acute. This demonstrates the influence of parasite development on host gene transcription as well as the influence of the host environment on parasite gene transcription.ConclusionsRNA-seq is a valuable tool to simultaneously analyze host and microbe transcriptomes. Our data shows that T. gondii is metabolically active and synthesizing proteins at 28 days post-infection and that a distinct subset of host genes associated with the immune response are more abundant specifically during chronic infection. These data suggest host and pathogen interplay is still present during chronic infection and provides novel T. gondii targets for future drug and vaccine development.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-806) contains supplementary material, which is available to authorized users.

Discussion of the New Campus of the University Infrastructure File Management

college enrollment in recent years, to accelerate the pace of construction of new university campuses. Build infrastructure during the file that is an important part of college, but also a testament to the new campus construction. So do the new campus construction file management has a very important significance. By analyzing the characteristics of the new campus infrastructure file, Reflections and proposals put forward new campus of the university infrastructure records management, designed to better manage new campus infrastructure file reference.

New approach to the differentiation of marble samples using thermal analysis and chemometrics in order to identify provenance

BackgroundThe possibility of applying a novel chemometric approach which could allow the differentiation of marble samples, all from different quarries located in the Mediterranean basin and frequently used in ancient times for artistic purposes, was investigated. By suggesting tentative or allowing to rule out unlikely attributions, this kind of differentiation could, indeed, be of valuable support to restorers and other professionals in the field of cultural heritage.Experimental data were obtained only using thermal analytical techniques: Thermogravimetry (TG), Derivative Thermogravimetry (DTG) and Differential Thermal Analysis (DTA).ResultsThe extraction of kinetic parameters from the curves obtained using these thermal analytical techniques allowed Activation Energy values to be evaluated together with the logarithm of the Arrhenius pre-exponential factor of the main TG-DTG process.The main data thus obtained after subsequent chemometric evaluation (using Principal Components Analysis) have already proved useful in the identification the original quarry of a small number of archaeological marble finds.ConclusionOne of the most evident advantages of the thermoanalytical – chemometric approach adopted seems to be that it allows the certain identification of an unknown find composed of a marble known to be present among the reference samples considered, that is, contained in the reference file. On the other hand with equal certainty it prevents the occurrence of erroneous or highly uncertain identification if the find being tested does not belong to the reference file considered.

SAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin.

A sequence within the E2 domain of soluble amyloid precursor protein (sAPP) stimulates iron efflux. This activity has been attributed to a ferroxidase activity suggested for this motif. We demonstrate that the stimulation of efflux supported by this peptide and by sAPPα is due to their stabilization of the ferrous iron exporter, ferroportin (Fpn), in the plasma membrane of human brain microvascular endothelial cells (hBMVEC). The peptide does not bind ferric iron explaining why it does not and thermodynamically cannot promote ferrous iron autoxidation. This peptide specifically pulls Fpn down from the plasma membrane of hBMVEC; based on these results, FTP, for ferroportin-targeting peptide, correctly identifies the function of this peptide. The data suggest that in stabilizing Fpn via the targeting due to the FTP sequence, sAPP will increase the flux of iron into the cerebral interstitium. This inference correlates with the observation of significant iron deposition in the amyloid plaques characteristic of Alzheimer's disease.

SNARE and regulatory proteins induce local membrane protrusions to prime docked vesicles for fast calcium‐triggered fusion

Synaptic vesicles fuse with the plasma membrane in response to Ca(2+) influx, thereby releasing neurotransmitters into the synaptic cleft. The protein machinery that mediates this process, consisting of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and regulatory proteins, is well known, but the mechanisms by which these proteins prime synaptic membranes for fusion are debated. In this study, we applied large-scale, automated cryo-electron tomography to image an in vitro system that reconstitutes synaptic fusion. Our findings suggest that upon docking and priming of vesicles for fast Ca(2)(+)-triggered fusion, SNARE proteins act in concert with regulatory proteins to induce a local protrusion in the plasma membrane, directed towards the primed vesicle. The SNAREs and regulatory proteins thereby stabilize the membrane in a high-energy state from which the activation energy for fusion is profoundly reduced, allowing synchronous and instantaneous fusion upon release of the complexin clamp.

Type 1 metabotropic glutamate receptors (m G lu1) trigger the gating of G lu D 2 delta glutamate receptors

The orphan GluD2 receptor belongs to the ionotropic glutamate receptor family but does not bind glutamate. Ligand-gated GluD2 currents have never been evidenced, and whether GluD2 operates as an ion channel has been a long-standing question. Here, we show that GluD2 gating is triggered by type 1 metabotropic glutamate receptors, both in a heterologous expression system and in Purkinje cells. Thus, GluD2 is not only an adhesion molecule at synapses but also works as a channel. This gating mechanism reveals new properties of glutamate receptors that emerge from their interaction and opens unexpected perspectives regarding synaptic transmission and plasticity.

An SVM-based high-quality article classifier for systematic reviews

ObjectiveTo determine whether SVM-based classifiers, which are trained on a combination of inclusion and common exclusion articles, are useful to experts reviewing journal articles for inclusion during new systematic reviews. MethodsTest collections were built using the annotated reference files from 19 procedure and 4 drug systematic reviews. The classifiers were trained by balanced data sets, which were sampled using random sampling. This approach compared two balanced data sets, one with a combination of included and commonly excluded articles and one with a combination of included and excluded articles. AUCs were used as evaluation metrics. ResultsThe AUCs of the classifiers, which were trained on the balanced data set with included and commonly excluded articles, were significantly higher than those of the classifiers, which were trained on the balanced data set with included and excluded articles. ConclusionAutomatic, high-quality article classifiers using machine learning could reduce the workload of experts performing systematic reviews when topic-specific data are scarce. In particular, when used as training data, a combination of included and commonly excluded articles is more helpful than a combination of included and excluded articles.

Disciplining the Vernacular: Fair Use, YouTube, and Remixer Agency

Disciplining the Vernacular: Fair Use, YouTube, and Remixer Agency

Age and Sex Patterns of Drug Prescribing in a Defined American Population

ObjectiveTo describe the age and sex patterns of drug prescribing in Olmsted County, Minnesota. Patients and MethodsPopulation-based drug prescription records for the Olmsted County population in 2009 were obtained using the Rochester Epidemiology Project medical records linkage system (n=142,377). Drug prescriptions were classified using RxNorm codes and were grouped using the National Drug File–Reference Terminology. ResultsOverall, 68.1% of the population (n=96,953) received a prescription from at least 1 drug group, 51.6% (n=73,501) received prescriptions from 2 or more groups, and 21.2% (n=30,218) received prescriptions from 5 or more groups. The most commonly prescribed drug groups in the entire population were penicillins and β-lactam antimicrobials (17%; n=23,734), antidepressants (13%; n=18,028), opioid analgesics (12%; n=16,954), antilipemic agents (11%; n=16,082), and vaccines/toxoids (11%; n=15,918). However, prescribing patterns differed by age and sex. Vaccines/toxoids, penicillins and β-lactam antimicrobials, and antiasthmatic drugs were most commonly prescribed in persons younger than 19 years. Antidepressants and opioid analgesics were most commonly prescribed in young and middle-aged adults. Cardiovascular drugs were most commonly prescribed in older adults. Women received more prescriptions than men for several drug groups, in particular for antidepressants. For several drug groups, use increased with advancing age. ConclusionThis study provides valuable baseline information for future studies of drug utilization and drug-related outcomes in this population.

안드로이드 기반 서비스 라이브러리의 동적 재구성

Android 모바일 플랫폼은 플랫폼에 설치된 모든 어플리케이션들의 클래스(class) 파일들을 복사하여 하나의 디렉터리에 보관하고, 해당 디렉터리에서 메모리 맵 파일(memory-mapped file) 방식으로 참조함으로써 서비스 라이브러리를 플랫폼에 추가하기 위해서는 플랫폼의 바이너리(binary) 이미지를 반드시 새롭게 생성하여 플랫폼을 교체해야만 한다. 또한, 이러한 메모리 맵 파일 방식의 참조는 어플리케이션이 참조하는 라이브러리가 중복될 경우 해당 디렉터리에서도 중복되어 포함되므로 디바이스의 저장 공간 낭비를 불러오게 된다. 따라서, Android 모바일 플랫폼상에서 동작하는 각 어플리케이션들의 서비스 라이브러리를 공유 라이브러리 형태로 관리하며, 플랫폼의 버전 관리 및 기능 추가 및 변경을 실시간 및 동적으로 지원할 수 있는 Android 플랫폼용 동적 재구성 기법이 필요하다. 본 논문에서는 Android 모바일 플랫폼을 대상으로 하여, 동적으로 서비스 라이브러리를 추가할 수 있는 플랫폼 동적 재구성 기법을 제안한다. Android mobile platform copy the class files of all applications installed in android platform and keep them into one directory. But to add the service library into a platform, Android must generate a new binary image of platform and replace the platform because android refer the libraries using the memory-mapped file method in a directory. And this memory-mapped file reference method waste the storage space of mobile device because that directory include the duplicated libraries if the libraries refered by application are duplicated, Therefore a dynamic reconfiguration method on android mobile platform is needed to manage the service libraries of application executed on android platform and support the version management and function addition/modification. In this paper, we propose the platform dynamic reconfiguration method to add dynmically the service libraries on android platform.

Disambiguation of PharmGKB drug–disease relations with NDF-RT and SPL

PharmGKB is a leading resource of high quality pharmacogenomics data that provides information about how genetic variations modulate an individual’s response to drugs. PharmGKB contains information about genetic variations, pharmacokinetic and pharmacodynamic pathways, and the effect of variations on drug-related phenotypes. These relationships are represented using very general terms, however, and the precise semantic relationships among drugs, and diseases are not often captured. In this paper we develop a protocol to detect and disambiguate general clinical associations between drugs and diseases using more precise annotation terms from other data sources. PharmGKB provides very detailed clinical associations between genetic variants and drug response, including genotype-specific drug dosing guidelines, and this procedure will armGKB. The availability of more detailed data will help investigators to conduct more precise queries, such as finding particular diseases caused or treated by a specific drug.We first mapped drugs extracted from PharmGKB drug–disease relationships to those in the National Drug File Reference Terminology (NDF-RT) and to Structured Product Labels (SPLs). Specifically, we retrieved drug and disease role relationships describing and defining concepts according to their relationships with other concepts from NDF-RT. We also used the NCBO (National Center for Biomedical Ontology) annotator to annotate disease terms from the free text extracted from five SPL sections (indication, contraindication, ADE, precaution, and warning). Finally, we used the detailed drug and disease relationship information from NDF-RT and the SPLs to annotate and disambiguate the more general PharmGKB drug and disease associations.

CASMI—The Small Molecule Identification Process from a Birmingham Perspective

The Critical Assessment of Small Molecule Identification (CASMI) contest was developed to provide a systematic comparative evaluation of strategies applied for the annotation and identification of small molecules. The authors participated in eleven challenges in both category 1 (to deduce a molecular formula) and category 2 (to deduce a molecular structure) related to high resolution LC-MS data. For category 1 challenges, the PUTMEDID_LCMS workflows provided the correct molecular formula in nine challenges; the two incorrect submissions were related to a larger mass error in experimental data than expected or the absence of the correct molecular formula in a reference file applied in the PUTMEDID_LCMS workflows. For category 2 challenges, MetFrag was applied to construct in silico fragmentation data and compare with experimentally-derived MS/MS data. The submissions for three challenges were correct, and for eight challenges, the submissions were not correct; some submissions showed similarity to the correct structures, while others showed no similarity. The low number of correct submissions for category 2 was a result of applying the assumption that all chemicals were derived from biological samples and highlights the importance of knowing the origin of biological or chemical samples studied and the metabolites expected to be present to define the correct chemical space to search in annotation processes.

Central Sterile Services: The Critical Link between Manufacturer and Surgeon

It is at the time of use that a medical device must perform exactly as it was designed and intended. It is the role of Central Sterile Services (CSS) to assure this objective. To accomplish this challenging task, CSS needs the support and expertise of device manufacturers.Often, as devices are introduced into a hospital, the manufacturer's representative instructs nurses and physicians on how to use the device. Unfortunately, the CSS staff may be overlooked entirely, which can lead to errors. Processing errors undermine patient care and can erode clinical satisfaction with the device. It is important to understand that the manufacturer's representative may be knowledgeable in the use of the device, but lack reprocessing knowledge.CSS plays a major role in device use. This is especially true for devices undergoing sterilization. Before the device is packaged, the CSS technician is the last one to handle it. Once the device is packaged, it is sterilized. When it is opened, it is intended to be used directly on a patient; there is no room for error. The device must be sterile and fully functional.To help ensure that a device is prepared exactly as intended, manufacturers should include CSS staff in device introduction and training. It is incumbent upon the manufacturer to consult the CSS manger when introducing new devices into the healthcare facility. This helps to ensure that the proper resources—such as staffing, time, equipment, and packaging—are available. Training CSS staff is every bit as important as training the direct caregivers. For best results, the initial training should take place with a manufacturer's representative. The training must be based on the manufacturer's “instructions for use” (IFU) and a standard CSS processes. Therefore, the representative must be fully educated on all facets of device processing that are stated in the IFU. It's essential that all CSS processes—including cleaning, quality assurance, assembly, disinfection or packaging requirements, and sterilization modalities—are addressed, starting when the device arrives in the decontamination room.Healthcare facilities must have current IFU on file for reference. Having additional training resources further helps in consistent accurate preparation of the device. Training material that CSS staff often find effective include training booklets, wall charts, and videos. Many manufacturers have their IFU, along with instructional videos, posted on their website. In addition, some manufacturers of complex devices have “train the trainer” programs or specialists trained for the reprocessing function. Periodic training programs might be needed to clear up any misunderstandings and ensure everyone understands proper procedures.The bottom line: Even though CSS professionals are not present in the delivery of patient care, they—along with nurses, physicians, or radiology technicians—are crucial members of the patient-care delivery team. To help assure that a device functions exactly as it was designed, the manufacturer must team up with CSS to provide the necessary training and support. After all, the CSS technician is the last person to handle a sterile device before it is presented to a surgeon and used on a patient.

The interplay between RPGR, PDEδ and Arl2/3 regulate the ciliary targeting of farnesylated cargo

Defects in primary cilia result in human diseases known as ciliopathies. The retinitis pigmentosa GTPase regulator (RPGR), mutated in the most severe form of the eye disease, is located at the transition zone of the ciliary organelle. The RPGR-interacting partner PDEδ is involved in trafficking of farnesylated ciliary cargo, but the significance of this interaction is unknown. The crystal structure of the propeller domain of RPGR shows the location of patient mutations and how they perturb the structure. The RPGR·PDEδ complex structure shows PDEδ on a highly conserved surface patch of RPGR. Biochemical experiments and structural considerations show that RPGR can bind with high affinity to cargo-loaded PDEδ and exposes the Arl2/Arl3-binding site on PDEδ. On the basis of these results, we propose a model where RPGR is acting as a scaffold protein recruiting cargo-loaded PDEδ and Arl3 to release lipidated cargo into cilia.

Comparison of the values of measured hydratation of sporting youths with normative values

Backround: When measuring body composition, we monitor the fractionalization of body weight and the share of the individual elements in its aggregate value. The total body water (TBW) is a very important element in addition to the share of body fat (BF), muscle mass and bone minerals. Water is the largest element of the body weight and its sufficient amount (organism hydration) is a condition for maintaining the physiological functions of the person and thus has an immediate effect on the health of the individual. Objective: The aim of the study is to check the standard values of the percentage share of the representation of the total body water in the total body weight in different age groups of sporting youths using the tetrapolar bio-impedance Tanita 418 MA scale. Methods: The research group included a total of 532 individuals (332 men and 200 women) at the age from 12 to 17 years. They were individuals with regular physical activity and without any health problems. The measurement was carried out using the tetrapolar bio-impedance TANITA 418 MA scale. The confidence interval at the reliability level of .99 was used to define the range of the standard values of the percentage share of the total body water representation. The normalization index Ni was used to compare the mean values of the total body water representation with the reference file. Results: The mean values of the TBW representation in boys ranged from 61.75 to 64.34% and in girls from 55.51 to 58.69%, always in relation to the age. The value of the upper bound of (95%) the confidence interval of the Tanita 418 MA device software did not exceed the lower bound of the standard (65%) in any of the monitored files. Conclusions: The results showed significant gender differences in the total body water representation that, however, the standard of the used device does not respect. The standard values are set high which was also confirmed by the comparison of our results with other studies that used the same method of measurement.

Feature Based Retention Time Alignment for Improved HDX MS Analysis

An algorithm for retention time alignment of mass shifted hydrogen-deuterium exchange (HDX) data based on an iterative distance minimization procedure is described. The algorithm performs pairwise comparisons in an iterative fashion between a list of features from a reference file and a file to be time aligned to calculate a retention time mapping function. Features are characterized by their charge, retention time and mass of the monoisotopic peak. The algorithm is able to align datasets with mass shifted features, which is a prerequisite for aligning hydrogen-deuterium exchange mass spectrometry datasets. Confidence assignments from the fully automated processing of a commercial HDX software package are shown to benefit significantly from retention time alignment prior to extraction of deuterium incorporation values.

Lessons learned from developing a drug evidence base to support pharmacovigilance.

This work identified challenges associated with extraction and representation of medication-related information from publicly available electronic sources. We gained direct observational experience through creating and evaluating the Drug Evidence Base (DEB), a repository of drug indications and adverse effects (ADEs), and supplemented this through literature review. We extracted DEB content from the National Drug File Reference Terminology, from aggregated MEDLINE co-occurrence data, and from the National Library of Medicine's DailyMed. To understand better the similarities, differences and problems with the content of DEB and the SIDER Side Effect Resource, and Vanderbilt's MEDI Indication Resource, we carried out statistical evaluations and human expert reviews. While DEB, SIDER, and MEDI often agreed on medication indications and side effects, cross-system shortcomings limit their current utility. The drug information resources we evaluated frequently employed multiple, disparate vaguely related UMLS concepts to represent a single specific clinical drug indication or adverse effect. Thus, evaluations comparing drug-indication and drug-ADE coverage for such resources will encounter substantial numbers of false negative and false positive matches. Furthermore, our review found that many indication and ADE relationships are too complex - logically and temporally - to represent within existing systems. To enhance applicability and utility, future drug information systems deriving indications and ADEs from public resources must represent clinical concepts uniformly and as precisely as possible. Future systems must also better represent the inherent complexity of indications and ADEs.

MicroRNA‐independent recruitment of Argonaute 1 to nanos mRNA through the Smaug RNA‐binding protein

Argonaute (Ago) proteins are typically recruited to target messenger RNAs via an associated small RNA such as a microRNA (miRNA). Here, we describe a new mechanism of Ago recruitment through the Drosophila Smaug RNA-binding protein. We show that Smaug interacts with the Ago1 protein, and that Ago1 interacts with and is required for the translational repression of the Smaug target, nanos mRNA. The Ago1/nanos mRNA interaction does not require a miRNA, but it does require Smaug. Taken together, our data suggest a model whereby Smaug directly recruits Ago1 to nanos mRNA in a miRNA-independent manner, thereby repressing translation.