The impact of multifunctional genes on "guilt by association" analysis

Many previous studies have shown that by using variants of "guilt-by-association", gene function predictions can be made with very high statistical confidence. In these studies, it is assumed that the "associations" in the data (e.g., protein interaction partners) of a gene are necessary in establishing "guilt". In this paper we show that multifunctionality, rather than association, is a primary driver of gene function prediction. We first show that knowledge of the degree of multifunctionality alone can produce astonishingly strong performance when used as a predictor of gene function. We then demonstrate how multifunctionality is encoded in gene interaction data (such as protein interactions and coexpression networks) and how this can feed forward into gene function prediction algorithms. We find that high-quality gene function predictions can be made using data that possesses no information on which gene interacts with which. By examining a wide range of networks from mouse, human and yeast, as well as multiple prediction methods and evaluation metrics, we provide evidence that this problem is pervasive and does not reflect the failings of any particular algorithm or data type. We propose computational controls that can be used to provide more meaningful control when estimating gene function prediction performance. We suggest that this source of bias due to multifunctionality is important to control for, with widespread implications for the interpretation of genomics studies.     

On the mechanism of midtrimester abortions induced by prostaglandin "impact"

Using Csapo's technique, a single dose of 24.3 +or- 1.1 mg prostaglandin F2alpha (PGF2alpha) had been delivered intraamniotically to 20 sedated pregnant patients (15.9 +or- 0.6 weeks pregnant) in order to provoke a PG impact (PGI), a consequent progesterone (P) withdrawal, and a conversion of the pharmacologically refractory normal pregnant uterus into a reactive organ. The side effects were occasional and acceptable and no further PGF2alpha treatment was needed except in 4 cases (5-10 mg). Only after the Oxytocin test showed that the uterus is becoming reactive, was 50 mU/minute oxytocin infused intravenously to facilitate the evolution of IUP to 93 +or- 3 mmHg and thus promote clinical progress. All the 20 patients aborted both the fetus and the placenta in 16.5 +or- 2.1 hours, but 8 women retained small placental residues to be removed by curettage. The Csapo score was a high 92 +or- 2. As early as 3 hours after PGI, the plasma P levels already decreased significantly. They continued to decline throughout the IAT and reached a 72% withdrawal when the fetus was aborted. 15 patients whose P withdrawal was rapid, aborted before the mean IAT, while those 5 women whose P withdrawal was slow aborted after this time. Thus, the rate of P withdrawal was direct while parity and gestational age indirectly related to the IAT. Studies are in progress to elucidate further the abortifacient action of PGF2alpha and through this knowledge promote predictable therapy.     

The impact of "search precision" in an agent-based tumor model

Several cell surface receptors are overexpressed in malignant brain tumors and reportedly involved in tumor progression and invasion. It is unclear, however, whether such an improvement of cellular signal reception leads to a monotonic increase in the tumor system's average velocity during invasion or whether there is a maximum threshold beyond which the average velocity starts to decelerate. To gain more insight into the systemic effects of such cellular search precision modulations, this study proposes a two-dimensional agent-based model in which the spatio-temporal expansion of malignant brain tumor cells is guided by environmental heterogeneities in mechanical confinement, toxic metabolites and nutrient sources. Here, the spatial field of action is represented by an adaptive grid lattice, which corresponds to the experimental finding that tumor cells are more likely to follow each other along preformed pathways. Another prominent feature is the dual threshold concept for both nutrient level and toxicity, which determine whether cells proliferate, migrate, remain quiescent or die in the next period. The numerical results from varying the key parameters encoding the capability of tumor cells to invade and their ability to proliferate indicate an emergent behavior. Specifically, increasing invasiveness not only leads to an increase in maximum expansion velocity, but also requires a more precise spatial search process, corresponding to an improved cell signal reception, in order to obtain maximum velocity. To increase cellular invasiveness beyond the maximum that can be achieved by exclusively tuning the motility parameter, it requires an additional reduction in the cells' proliferation rate and prompts an even more biased search process. Most interestingly, however, a prominent phase transition suggests that tumor cells do not employ a 100 percent search precision to attain maximum spatial velocity. These findings argue for a selection advantage conferred by limited randomness in processing spatial search and indicate that our computational platform may prove valuable in investigating emergent, multicellular tumor patterns caused by alterations on the molecular level.     

Toxicology and genetic toxicology in the new era of "toxicogenomics": impact of "-omics" technologies.

The unprecedented advances in molecular biology during the last two decades have resulted in a dramatic increase in knowledge about gene structure and function, an immense database of genetic sequence information, and an impressive set of efficient new technologies for monitoring genetic sequences, genetic variation, and global functional gene expression. These advances have led to a new sub-discipline of toxicology: "toxicogenomics". We define toxicogenomics as "the study of the relationship between the structure and activity of the genome (the cellular complement of genes) and the adverse biological effects of exogenous agents". This broad definition encompasses most of the variations in the current usage of this term, and in its broadest sense includes studies of the cellular products controlled by the genome (messenger RNAs, proteins, metabolites, etc.). The new "global" methods of measuring families of cellular molecules, such as RNA, proteins, and intermediary metabolites have been termed "-omic" technologies, based on their ability to characterize all, or most, members of a family of molecules in a single analysis. With these new tools, we can now obtain complete assessments of the functional activity of biochemical pathways, and of the structural genetic (sequence) differences among individuals and species, that were previously unattainable. These powerful new methods of high-throughput and multi-endpoint analysis include gene expression arrays that will soon permit the simultaneous measurement of the expression of all human genes on a single "chip". Likewise, there are powerful new methods for protein analysis (proteomics: the study of the complement of proteins in the cell) and for analysis of cellular small molecules (metabonomics: the study of the cellular metabolites formed and degraded under genetic control). This will likely be extended in the near future to other important classes of biomolecules such as lipids, carbohydrates, etc. These assays provide a general capability for global assessment of many classes of cellular molecules, providing new approaches to assessing functional cellular alterations. These new methods have already facilitated significant advances in our understanding of the molecular responses to cell and tissue damage, and of perturbations in functional cellular systems.As a result of this rapidly changing scientific environment, regulatory and industrial toxicology practice is poised to undergo dramatic change during the next decade. These advances present exciting opportunities for improved methods of identifying and evaluating potential human and environmental toxicants, and of monitoring the effects of exposures to these toxicants. These advances also present distinct challenges. For example, the significance of specific changes and the performance characteristics of new methods must be fully understood to avoid misinterpretation of data that could lead to inappropriate conclusions about the toxicity of a chemical or a mechanism of action. We discuss the likely impact of these advances on the fields of general and genetic toxicology, and risk assessment. We anticipate that these new technologies will (1) lead to new families of biomarkers that permit characterization and efficient monitoring of cellular perturbations, (2) provide an increased understanding of the influence of genetic variation on toxicological outcomes, and (3) allow definition of environmental causes of genetic alterations and their relationship to human disease. The broad application of these new approaches will likely erase the current distinctions among the fields of toxicology, pathology, genetic toxicology, and molecular genetics. Instead, a new integrated approach will likely emerge that involves a comprehensive understanding of genetic control of cellular functions, and of cellular responses to alterations in normal molecular structure and function.     

Effect of the "squat protective response" on impact velocity during backward falls

Risk for injury during a fall depends on the position and velocity of the body segments at the moment of impact. One technique for reducing impact velocity is to absorb energy in the lower extremity muscles during descent, as occurs during squatting or sitting. However, the protective value of this response may depend on the time during descent when the response is initiated. We tested this hypothesis by conducting backward falling experiments with young women (n = 23; aged 21-29 years), who fell onto a soft gymnasium mattress after being suddenly releasing from an inclined position. In trials where subjects were released from a 5 degrees lean, average impact velocities were reduced by 18% when squatting was utilized as opposed to inhibited. Furthermore, increases in the release angle caused an increase in average impact velocity of 8% between lean angles of 2 degrees and 5 degrees, and 7% between lean angles of 5 degrees and 12 degrees. This was due to declines in peak extensor torques and peak flexion rotations, and corresponding reductions in both joint work and potential energy at impact. These results suggest that squatting during descent reduces impact severity, but the effectiveness of the response depends on the stage during descent when it is initiated, diminishing in benefit as the fall progresses and the state of imbalance grows increasingly severe.     

Simulation of impact test for determining "health" of percutaneous bone anchored implants

There is an ongoing requirement for a clinically relevant, noninvasive technique to monitor the integrity of percutaneous implants used for dental restorations, bone-anchored hearing aids, and to retain extra-oral prostheses (ear, eye, nose, etc). Because of the limitations of conventional diagnostic techniques (CT, MRI), mechanical techniques that measure the dynamic response of the implant-abutment system are being developed. This paper documents a finite element analysis that simulates a transient response to mechanical impact testing using contact elements. The detailed model allows for a specific interface between the implant and bone and characterizes potential clinical situations including loss of bone margin height, loss of osseointegration, and development of a soft connective tissue layer at the bone-implant interface. The results also show that the expected difference in interface stiffness between soft connective tissue and osseointegrated bone will cause easily measurable changes in the response of the implant/abutment system. With respect to the loss of bone margin height, changes in the order of 0.2 mm should be detectable, suggesting that this technique is at least as sensitive as radiography. A partial loss of osseointegration, while not being as readily evident as a bone margin loss, would still be detectable for losses as small as 0.5 mm.     

Testing for "snowballing" hybrid incompatibilities in Solanum: impact of ancestral polymorphism and divergence estimates

Two recent high-profile studies offered empirical evidence for a "snowballing" accumulation of postzygotic incompatibilities in Drosophila and Solanum (tomatoes). Here we present a reanalysis of the Solanum data that is motivated by population genetic principles. Specifically, the high levels of intraspecific nucleotide polymorphism in wild tomato species and presumably large effective population size throughout the divergence history of this clade imply that ancestral polymorphism should be taken into account when evaluating sequence divergence between species. Based on our reanalyses of synonymous-site divergence between the four focal Solanum species and a wide range of ancestral polymorphism, we assessed under which conditions the reported accumulation of seed sterility factors supports the snowball effect. Our results highlight the pivotal impact of levels of ancestral polymorphism and alternate divergence values, and they illustrate that robust tests of the snowball effect in Solanum require genome-wide estimates of divergence.     

"In vivo" determination of hip joint separation and the forces generated due to impact loading conditions

Numerous supporting structures assist in the retention of the femoral head within the acetabulum of the normal hip joint including the capsule, labrum, and ligament of the femoral head (LHF). During total hip arthroplasty (THA), the LHF is often disrupted or degenerative and is surgically removed. In addition, a portion of the remaining supporting structures is transected or resected to facilitate surgical exposure. The present study analyzes the effects of LHF absence and surgical dissection in THA patients. Twenty subjects (5 normal hip joints, 10 nonconstrained THA, and 5 constrained THA) were evaluated using fluoroscopy while performing active hip abduction. All THA subjects were considered clinically successful. Fluoroscopic videos of the normal hips were analyzed using digitization, while those with THA were assessed using a computerized interactive model-fitting technique. The distance between the femoral head and acetabulum was measured to determine if femoral head separation occurred. Error analysis revealed measurements to be accurate within 0.75mm. No separation was observed in normal hips or those subjects implanted with constrained THA, while all 10 (100%) with unconstrained THA demonstrated femoral head separation, averaging 3.3mm (range 1.9-5.2mm). This study has shown that separation of the prosthetic femoral head from the acetabular component can occur. The normal hip joint has surrounding capsuloligamentous structures and a ligament attaching the femoral head to the acetabulum. We hypothesize that these soft tissue supports create a passive, resistant force at the hip, preventing femoral head separation. The absence of these supporting structures after THA may allow increased hip joint forces, which may play a role in premature polyethylene wear or prosthetic loosening.     

What research participants want to know about genetic research results: the impact of "genetic exceptionalism"

The disclosure of individual genetic results has generated an ongoing debate about which rules should be followed. We aimed to identify factors related to research participants' preferences about learning the results of genomic studies using their donated tissue samples. We conducted a cross-sectional survey of 279 patients from the United States and Spain who had volunteered to donate a sample for genomic research. Our results show that 48% of research participants would like to be informed about all individual results from future genomic studies using their donated tissue, especially those from the U.S. (71.4%) and those believing that genetic information poses special risks (69.7%). In addition, 16% of research participants considered genetic information to be riskier than other types of personal medical data. In conclusion, our study demonstrates that a high proportion of participants prefer to be informed about their individual results and that there is a higher preference among those research subjects who perceive their genetic information as riskier than other types of personal medical data.     

Defining "adverse environmental impact" and making paragraph 316(b) decisions: a fisheries management approach

The electric utility industry has developed an approach for decisionmaking that includes a definition of Adverse Environmental Impact (AEI) and an implementation process. The definition of AEI is based on lessons from fishery management science and analysis of the statutory term "adverse environmental impact" and is consistent with current natural resource management policy. The industry has proposed a definition focusing on "unacceptable risk to the population"s ability to sustain itself, to support reasonably anticipated commercial or recreational harvests, or to perform its normal ecological function." This definition focuses not on counting individual fish or eggs cropped by the various uses of a water body, but on preserving populations of aquatic organisms and their functions in the aquatic community. The definition recognizes that assessment of AEI should be site-specific and requires both a biological decision and a balancing of diverse societal values. The industry believes that the definition of AEI should be implemented in a process that will maximize the overall societal benefit of the paragraph 316(b) decision by considering the facility"s physical location, design, and operation, as well as the local biology. The approach considers effects on affected fish and shellfish populations and the benefits of any necessary best technology available (BTA) alternatives. This is accomplished through consideration of population impacts, which conversely allows consideration of the benefits of any necessary BTA modifications. This in turn allows selection of BTAs that will protect potentially affected populations in a cost-effective manner. The process also employs risk assessment with stakeholder participation, in accordance with EPA's Guidelines for Ecological Risk Assessment. The information and tools are now available to make informed decisions about site-specific impacts that will ensure protection of aquatic ecosystems and best serve the public interest.     

The impact of impact studies

Summary 1. On January 1, 1970 the National Environmental Protection Act became law in the United States, and has been further strengthened by judicial interpretations. This act requires, among other things, a presentation of information to justify the effect of projects on the environment of both public and private works controlled by the permit process of the federal government, and to suggest alternatives. One of the events which influenced passage of this legislation was the Santa Barbara oil spill of January 1969.2. Insofar as the marine environment is concerned, the most significant activity related to the requirement for impact statements is the study of coastal situations where waste outfalls, atomic power plants or desalination plants may be located. Although many of the studies sponsored by industry have been cursory, the need for critical application of ecological techniques known since the classical studies ofLorenz (1863) and touched upon in brief notes byHerdman (1920) andElmhirst (1932) has become obvious through the public hearing process.3. The impact of impact studies may not only be to raise the standards of environmental studies in the sea, but also to clarify the present somewhat incoherent application by pragmatic ecologists of such debatable theoretical concepts as diversity and community stability.

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L'impact des études d'impact

Extrait Le 1ier janvier 1970 le «National Environmental Policy Act» est devenu une loi aux Etats-Unis, et a été renforcé par des dispositions judiciaires. Cette loi rend obligatoire, entre autres, la présentation d'informations concernant l'effet, sur l'environnement, des travaux publics ou privés projetés et autorisés par le gouvernement fédéral, ainsi que la suggestion de projets alternatifs. Un des évènements qui a influencé l'adoption de cette législation est le rejet de pétrole survenu à Santa Barbara en janvier 1969. Quant à l'environnement marin, la disposition la plus importante relative aux prévisions d'impact concerne l'étude des stations côtières où peuvent être situées des décharges de déchets ou des centrales nucléaires ou de désalination. Quoique beaucoup d'études entreprises par l'industrie aient été superficielles, les enquêtes publiques ont fait apparaître la nécessité d'une application critique des techniques écologiques connues depuis les travaux classiques deLorenz (1863), brièvement évoqués parHerdman (1920) etElmhirst (1932). L'impact des études d'impact pourra non seulement relever le niveau des études sur l'environnement marin, mais aussi clarifier l'application actuellement assez incohérente, par des écologistes pragmatiques, de concepts théoriques aussi contestables que ceux de la diversité ou stabilité des communités.

     

Study protocol of the YOU CALL - WE CALL TRIAL: impact of a multimodal support intervention after a "mild" stroke

Background

More than 60% of new strokes each year are "mild" in severity and this proportion is expected to rise in the years to come. Within our current health care system those with "mild" stroke are typically discharged home within days, without further referral to health or rehabilitation services other than advice to see their family physician. Those with mild stroke often have limited access to support from health professionals with stroke-specific knowledge who would typically provide critical information on topics such as secondary stroke prevention, community reintegration, medication counselling and problem solving with regard to specific concerns that arise. Isolation and lack of knowledge may lead to a worsening of health problems including stroke recurrence and unnecessary and costly health care utilization. The purpose of this study is to assess the effectiveness, for individuals who experience a first "mild" stroke, of a sustainable, low cost, multimodal support intervention (comprising information, education and telephone support) - "WE CALL" compared to a passive intervention (providing the name and phone number of a resource person available if they feel the need to) - "YOU CALL", on two primary outcomes: unplanned-use of health services for negative events and quality of life.

Method/Design

We will recruit 384 adults who meet inclusion criteria for a first mild stroke across six Canadian sites. Baseline measures will be taken within the first month after stroke onset. Participants will be stratified according to comorbidity level and randomised to one of two groups: YOU CALL or WE CALL. Both interventions will be offered over a six months period. Primary outcomes include unplanned use of heath services for negative event (frequency calendar) and quality of life (EQ-5D and Quality of Life Index). Secondary outcomes include participation level (LIFE-H), depression (Beck Depression Inventory II) and use of health services for health promotion or prevention (frequency calendar). Blind assessors will gather data at mid-intervention, end of intervention and one year follow up.

Discussion

If effective, this multimodal intervention could be delivered in both urban and rural environments. For example, existing infrastructure such as regional stroke centers and existing secondary stroke prevention clinics, make this intervention, if effective, deliverable and sustainable.

Trial Registration

ISRCTN95662526     

The efficacy and acceptability of the "prostaglandin impact" in inducing complete abortion during the second week after the missed menstrual period

Clinical research was undertaken using PGF2a (prostaglandin) to induce abortion in 22 pregnant women at 12 +/- 1 days following their missed menstrual period. The PG was administered in a 5 mg single intrauterine dose through the cervix for a 10-minute period. The PG administration caused increased uterine contraction within 20 minutes and raised intrauterine pressure which was sustained for 2 hours. During the initiation of the intrauterine pressure, bleeding started and progesterone and estradiol levels decreased and continued to do so. In those patients who had been sedated, side effects were minimal. At 24 hours following the PG administration, progesterone had been withdrawn at a rate of 44%, bleeding was continuing, and cervical dilatation was at approximately 1 cm. Complete abortion was achieved in 20 out of the 22 women. It is believed that the abortion was effected through the action of endogenous PG, due to the withdrawal effect on progesterone of the exogenously-administered PG.