ARAX: a graph-based modular reasoning tool for translational biomedicine.

MOTIVATION: With the rapidly growing volume of knowledge and data in biomedical databases, improved methods for knowledge-graph-based computational reasoning are needed in order to answer translational questions. Previous efforts to solve such challenging computational reasoning problems have contributed tools and approaches, but progress has been hindered by the lack of an expressive analysis workflow language for translational reasoning and by the lack of a reasoning engine-supporting that language-that federates semantically integrated knowledge-bases. RESULTS: We introduce ARAX, a new reasoning system for translational biomedicine that provides a web browser user interface and an application programming interface (API). ARAX enables users to encode translational biomedical questions and to integrate knowledge across sources to answer the user's query and facilitate exploration of results. For ARAX, we developed new approaches to query planning, knowledge-gathering, reasoning and result ranking and dynamically integrate knowledge providers for answering biomedical questions. To illustrate ARAX's application and utility in specific disease contexts, we present several use-case examples. AVAILABILITY AND IMPLEMENTATION: The source code and technical documentation for building the ARAX server-side software and its built-in knowledge database are freely available online (https://github.com/RTXteam/RTX). We provide a hosted ARAX service with a web browser interface at arax.rtx.ai and a web API endpoint at arax.rtx.ai/api/arax/v1.3/ui/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

RTX-KG2: a system for building a semantically standardized knowledge graph for translational biomedicine.

BACKGROUND: Biomedical translational science is increasingly using computational reasoning on repositories of structured knowledge (such as UMLS, SemMedDB, ChEMBL, Reactome, DrugBank, and SMPDB in order to facilitate discovery of new therapeutic targets and modalities. The NCATS Biomedical Data Translator project is working to federate autonomous reasoning agents and knowledge providers within a distributed system for answering translational questions. Within that project and the broader field, there is a need for a framework that can efficiently and reproducibly build an integrated, standards-compliant, and comprehensive biomedical knowledge graph that can be downloaded in standard serialized form or queried via a public application programming interface (API). RESULTS: To create a knowledge provider system within the Translator project, we have developed RTX-KG2, an open-source software system for building-and hosting a web API for querying-a biomedical knowledge graph that uses an Extract-Transform-Load approach to integrate 70 knowledge sources (including the aforementioned core six sources) into a knowledge graph with provenance information including (where available) citations. The semantic layer and schema for RTX-KG2 follow the standard Biolink model to maximize interoperability. RTX-KG2 is currently being used by multiple Translator reasoning agents, both in its downloadable form and via its SmartAPI-registered interface. Serializations of RTX-KG2 are available for download in both the pre-canonicalized form and in canonicalized form (in which synonyms are merged). The current canonicalized version (KG2.7.3) of RTX-KG2 contains 6.4M nodes and 39.3M edges with a hierarchy of 77 relationship types from Biolink. CONCLUSION: RTX-KG2 is the first knowledge graph that integrates UMLS, SemMedDB, ChEMBL, DrugBank, Reactome, SMPDB, and 64 additional knowledge sources within a knowledge graph that conforms to the Biolink standard for its semantic layer and schema. RTX-KG2 is publicly available for querying via its API at arax.rtx.ai/api/rtxkg2/v1.2/openapi.json . The code to build RTX-KG2 is publicly available at github:RTXteam/RTX-KG2 .

Vehicle emissions of radical precursors and related species observed in the 2009 SHARP campaign.

UNLABELLED: The 2009 Study of Houston Atmospheric Radical Precursors (SHARP) field campaign had several components that yielded information on the primary vehicular emissions of formaldehyde (HCHO) and nitrous acid (HONO), in addition to many other species. Analysis of HONO measurements at the Moody Tower site in Houston, TX, yielded emission ratios of HONO to the vehicle exhaust tracer species NOx and CO of 14 pptv/ppbv and 2.3 pptv/ppbv, somewhat smaller than recently published results from the Galleria site, although evidence is presented that the Moody Tower values should be upper limits to the true ratios of directly emitted HONO, and are consistent with ratios used in current standard emissions models. Several other Moody Tower emission ratios are presented, in particular a value for HCHO/CO of 2.4 pptv/ppbv. Considering only estimates of random errors, this would be significantly lower than a previous value, though the small sample size and possible systematic differences should be taken into account. Emission factors for CO, NOx, and HCHO, as well as various volatile organic compounds (VOCs), were derived from mobile laboratory measurements both in the Washburn Tunnel and in on-road exhaust plume observations. These two sets of results and others reported in the literature all agree well, and are substantially larger than the CO, NOx, and HCHO emission factors derived from the emission ratios reported from the Galleria site. IMPLICATIONS: Emission factors for the species measured in the various components of the 2009 SHARP campaign in Houston, TX, including HCHO, HONO, CO, CO2, nitrogen oxides, and VOCs, are needed to support regional air quality monitoring. Components of the SHARP campaign measured these species in several different ways, each with their own potential for systematic errors and differences in vehicle fleets sampled. Comparisons between data sets suggest that differences in sampling place and time may result in quite different emission factors, while also showing that different vehicle mixes can yield surprisingly similar emission factors.

Adaptation of a proton transfer reaction mass spectrometer instrument to employ NO+ as reagent ion for the detection of 1,3-butadiene in the ambient atmosphere.

A proton transfer reaction mass spectrometer (PTR-MS) instrument was adapted to employ NO+ as a chemical reagent ion without any hardware changes by switching the reagent ion source gas from water vapor to dry air. Ionization of dry air within the hollow cathode ion source generates a very intense source of NO+ with only a minor impurity of NO2+. The intensities of the primary NO+ reagent ion and the unwanted impurity NO2+ are controllable and dependent on the operational conditions of the hollow cathode ion source. Ion source tuning parameters are described, which maintain an intense source of NO+ while keeping the impurity NO2+ signal to less than 2% of the total reagent ion intensity. This method is applied to the detection of 1,3-butadiene. NO+ reacts efficiently with 1,3-butadiene via a charge exchange reaction to produce only the molecular ion, which is detected at m/z 54. Detection sensitivities of the order of 45 pptv for a 1-s measurement of 1,3-butadiene are demonstrated. We present the first real-time on-line sub parts per billion measurement of 1,3-butadiene in the ambient atmosphere. The only likely interference is from 1,2-butadiene. Concurrent measurements of benzene are provided and suggest that the vehicular emissions are the predominant source of 1,3-butadiene in a suburban Boston area monitoring location.

An analysis of plasma estradiol concentrations during clomiphene citrate-human menopausal gonadotropin stimulation in an in vitro fertilization-embryo transfer program.

We report here a range of plasma estradiol (E2) concentrations suitable for use in an in vitro fertilization (IVF) program. This range was derived from nonparametric analysis of plasma E2 levels using plasma E2 measurements beginning 10 days before the anticipated day of the midcycle LH surge (midpoint), as calculated from each patient's six previous menstrual cycles, during which time the patients all received the same ovarian stimulation regimen. The regimen consisted of 100 mg clomiphene citrate/day for 5 days, beginning 10 days before the anticipated midpoint, plus 150 IU human menopausal gonadotropin, commencing the day after clomiphene. A consecutive series of 102 IVF conception cycles induced in this standardized fashion were analyzed in this study. The 5th-95 percentile envelope of plasma E2 concentrations was derived as a valid clinical indicator of satisfactory folliculogenesis during IVF treatment. Five women had plasma E2 concentrations below the 5th percentile of the E2 range on at least 3 consecutive days of ovarian stimulation, while six women had E2 levels above the 95th percentile of this range on at least 3 consecutive days. This plasma E2 range defined objectively the diagnoses of ovarian hyperstimulation and inadequate stimulation in an IVF program. These criteria should help clinicians in managing ovarian responses during IVF superovulation stimulation treatment.

T helper lymphocyte depression in early human pregnancy.

Peripheral blood lymphocyte subclasses were determined in 60 women with normal pregnancies, 20 from each trimester, and in 20 controls using automated flow cytofluorimetry. The cells were stained with the monoclonal antibodies OKT3, OKT4 and OKT8 to stain total T cells, T helper and T suppressor-cytotoxic lymphocytes, respectively. A polyvalent rabbit anti-human Ig serum was used to stain B lymphocytes. Absolute numbers of T lymphocytes were significantly reduced in both the first and second trimesters. This was due to a significant decrease in T helper lymphocytes and a smaller, statistically not significant, reduction in the number of T suppressor lymphocytes. There was no significant change in lymphocyte subclasses during the third trimester. Total lymphocyte numbers were normal throughout pregnancy.

Relaxin in human pregnancy serum measured with an homologous radioimmunoassay.

This study reports serum levels of relaxin in normal and special-interest pregnancies using an homologous radioimmunoassay for human relaxin. The mean levels in uncomplicated antenatal patients were lower than those reported in studies using heterologous assays, but the trend in serum levels was similar. Serum levels peaked at ten weeks' gestation and decreased progressively to term. Relaxin was detectable in all pregnant subjects assessed at the time of the first missed menses. The mean relaxin levels in patients having in vitro fertilization and embryo transfer who subsequently delivered a single infant were significantly higher than those in normal antenatal patients at an equivalent gestational age. Patients with twin pregnancies after in vitro fertilization and embryo transfer generally had higher levels than patients with single pregnancies. Some pregnant patients who aborted after in vitro fertilization and embryo transfer had declining levels of relaxin before 40 days postlaparoscopy.

A prospective study of prognostic factors in in vitro fertilization and embryo transfer.

Multiple factors influence the outcome of in vitro fertilization and embryo transfer (IVF-ET). This prospective study was designed to assess their relative importance, in order to improve prognostic ability and treatment success. Prior to IVF-ET, couples were divided into "good" (GP) and "poor" (PP) prognosis groups according to female age, semen quality, previous response to stimulation, and embryo quality. The data obtained from 716 consecutive treatment cycles then were evaluated using univariate statistics and logistic regression, a technique designed to assess the relative contribution of significant factors. The pregnancy rate per GP cycle was 14.7%, compared with 5.4% per PP cycle (chi 1(2) = 12.7, P less than 0.001). The most important prognostic factors were female age, the pregnancy rate showing a linear decline after the age of 25, and previous failed fertilization due to abnormal sperm. The rate of pregnancy also declined after 14 or more follicles were aspirated and/or nine oocytes were retrieved. A formula for the probability of pregnancy, derived from the logistic regression, provides patients with a more accurate prognosis before treatment.

Decreased natural killer cell activity in endometriosis patients: relationship to disease pathogenesis.

A number of reports have measured NK cell activity in patients with endometriosis with varied results. Therefore we have examined the NK activity of PBL from 44 gynecological patients undergoing laparoscopy. This analysis has demonstrated a significant reduction in NK activity only in more severe stages of endometriosis (stages III and IV) relative to patients with milder disease and controls. These data indicate that decreased NK activity is unlikely to be a primary etiological factor in the development of endometriosis but may indicate that decreased NK activity is related to the development of the more frequent and/or larger lesions characteristic of severe endometriosis. These data could indicate potential for immunotherapy of patients with advanced endometriosis by the upregulation of NK activity in vivo.

Referral issues in psychotherapy and psychoanalysis.

The authors consider the complex decisions involved in the initial consultation of a person looking for treatment when this person must be referred to a professional colleague. They explore the way decisions are made in the referral processes and the complex practical and transference-countertransference issues that arise at the outset and whenever second opinions are sought during an ongoing psychotherapy. They present four clinical examples in varying detail to emphasize how readily misunderstandings can develop when even experienced consultants are not sufficiently alert to the complex conscious and unconscious motives and messages being expressed in the exchanges. They make recommendations on how to conceptualize and respond to them.

Tearfulness: a psychoanalytic interpretation.

In our view, the tearful feeling state is occasioned by the ego temporarily threatened with being inundated by complex memories and affects. For the moment, the ego cannot provide appropriate satisfying and integrated verbal expression. Words and verbal thinking are delayed. In this brief period, a controlled regression occurs during which the ego relates the current "precipitating experience" to temporally older conflictual experiences in the presence of the current object as a transference object and with a series of relationships so closely connected to that experience that they are interchanged in whole or part by the less selective, regressed, ego operations. The conscious experience may be sadness, gratitude, love, pride, or joy. But beneath these, there is the controlled regression, which interrupts verbal expression while the ego works through the earlier related conflicts,now remembered. The tearful feeling, a step in the direction of overt weeping, primitively expresses the frustration of an early wish for relief from pain, the pain of the imbalance of a complex conflict. The tearful feeling both expresses the wish for relief of pain and, at the same time, interrupts current verbal expression until the needed defense operations reduce the threat of ego disruption by working through old conflicts once again. Our thesis, then, is that within the analytic or psychotherapeutic hour the patient's feeling of tearfulness is a "too much" ego phenomenon that leads to a psychophysiological outlet.

Evaluation of a unique mechanical client lift: efficiency and perspectives of nursing staff.

This study evaluated the acceptability of a mechanical client lift based on the design employed for helicopter rescue lifts. Twenty-three nursing personnel completed questionnaires which explored their preferences, intentions to use the lift, perceptions of helpfulness, and exertion. Sixteen clients in a long term care setting consented to participate. One hundred manual lifts and 100 belt lifts were observed for comparative time and staff measures. The findings suggest that: 1) nursing staff will prefer the belt lift device for changing incontinent briefs; 2) nursing staff will prefer the belt lift device for toileting; 3) nursing staff will prefer the belt lift device to the currently used lift (in cases where either lift is appropriate) for bed/chair transfer; and, 5) the time required to utilize the belt lift as compared to manual lifting methods will not increase significantly.

Short-term variation in near-highway air pollutant gradients on a winter morning.

Quantification of exposure to traffic-related air pollutants near highways is hampered by incomplete knowledge of the scales of temporal variation of pollutant gradients. The goal of this study was to characterize short-term temporal variation of vehicular pollutant gradients within 200-400 m of a major highway (>150 000 vehicles/d). Monitoring was done near Interstate 93 in Somerville (Massachusetts) from 06:00 to 11:00 on 16 January 2008 using a mobile monitoring platform equipped with instruments that measured ultrafine and fine particles (6-1000 nm, particle number concentration (PNC)); particle-phase (>30 nm) [Formula: see text], [Formula: see text], and organic compounds; volatile organic compounds (VOCs); and CO(2), NO, NO(2), and O(3). We observed rapid changes in pollutant gradients due to variations in highway traffic flow rate, wind speed, and surface boundary layer height. Before sunrise and peak traffic flow rates, downwind concentrations of particles, CO(2), NO, and NO(2) were highest within 100-250 m of the highway. After sunrise pollutant levels declined sharply (e.g., PNC and NO were more than halved) and the gradients became less pronounced as wind speed increased and the surface boundary layer rose allowing mixing with cleaner air aloft. The levels of aromatic VOCs and [Formula: see text], [Formula: see text] and organic aerosols were generally low throughout the morning, and their spatial and temporal variations were less pronounced compared to PNC and NO. O(3) levels increased throughout the morning due to mixing with O(3)-enriched air aloft and were generally lowest near the highway reflecting reaction with NO. There was little if any evolution in the size distribution of 6-225 nm particles with distance from the highway. These results suggest that to improve the accuracy of exposure estimates to near-highway pollutants, short-term (e.g., hourly) temporal variations in pollutant gradients must be measured to reflect changes in traffic patterns and local meteorology.

Evolutions of an orientation concerning the nature of the male homosexualities.

None of the adults I have treated have had major disturbances in their sexual identity except for the selection of the sex of the person with whom they express their sexual feelings. Only one lives out a role that is ambisexual. All the men I have seen have been able to relate sexually to women with varying degrees of comfort. Six have had sexual intercourse with women and can function physiologically but without a sense of closeness or satisfaction, and five have been able to achieve climax. Some decided not to stay in their marriages, divorced, and adopted an overtly homosexual lifestyle. Some felt increasing ability to relate to women and decided to marry. Still others resolved current conflicts with their gay partners and felt no need for further therapy. All but one were actively employed and functioning well by external observation in demanding jobs requiring postgraduate college education. In terms of the detailed analytic work, there were no sets of insights that resulted in a major sexual partner reorientation. Those who decided to marry did so when they felt more able to resolve their narcissistic needs and make a relationship with a caring tolerant woman. They maintained their homosexual fantasies though the fantasies were more acceptable and less disruptive. It was not always the partner's penis that determined the sexual interest of these men. More often, it was the contour of the male body, the firmness of the musculature, the masculine bodily movements, the very identity and role of the father in the family. I did not see these foci of interest only as displacements from the genitals but rather as primary erotogenic stimuli. It is the seeking of a narcissistic object, the self in the other. This very orientation may be the innate variable. This position is spelled out in some detail by Leavy (1985). To varying degrees, the families of all these men were experienced as being composed of vigorous, active, articulate, determined, aspiring mothers and rather quiet, removed, passive fathers. The reported presence of this general pattern is impressive though the prominence of these characteristics differed from family to family. I have not postulated that these parental-child relations are causative in the boy's development of a homosexual life. However, they may be crucial if the genetic and/or constitutional factors discussed above are also present.(ABSTRACT TRUNCATED AT 400 WORDS)