Comparative modular analysis of gene expression in vertebrate organs.

ABSTRACT: BACKGROUND: The degree of conservation of gene expression between homologous organs largely remains an open question. Several recent studies reported some evidence in favor of such conservation. Most studies compute organs' similarity across all orthologous genes, whereas the expression level of many genes are not informative about organ specificity. RESULTS: Here, we use a modularization algorithm to overcome this limitation through the identification of inter-species co-modules of organs and genes. We identify such co-modules using mouse and human microarray expression data. They are functionally coherent both in terms of genes and of organs from both organisms. We show that a large proportion of genes belonging to the same co-module are orthologous between mouse and human. Moreover, their zebrafish orthologs also tend to be expressed in the corresponding homologous organs. Notable exceptions to the general pattern of conservation are the testis and the olfactory bulb. Interestingly, some co-modules consist of single organs, while others combine several functionally related organs. For instance, amygdala, cerebral cortex, hypothalamus and spinal cord form a clearly discernible unit of expression, both in mouse and human. CONCLUSIONS: Our study provides a new framework for comparative analysis which will be applicable also to other sets of large-scale phenotypic data collected across different species.

Comparative modular analysis of gene expression in vertebrate development

The focus of my PhD research was the concept of modularity. In the last 15 years, modularity has become a classic term in different fields of biology. On the conceptual level, a module is a set of interacting elements that remain mostly independent from the elements outside of the module. I used modular analysis techniques to study gene expression evolution in vertebrates. In particular, I identified ``natural'' modules of gene expression in mouse and human, and I showed that expression of organ-specific and system-specific genes tends to be conserved between such distance vertebrates as mammals and fishes. Also with a modular approach, I studied patterns of developmental constraints on transcriptome evolution. I showed that none of the two commonly accepted models of the evolution of embryonic development (``evo-devo'') are exclusively valid. In particular, I found that the conservation of the sequences of regulatory regions is highest during mid-development of zebrafish, and thus it supports the ``hourglass model''. In contrast, events of gene duplication and new gene introduction are most rare in early development, which supports the ``early conservation model''. In addition to the biological insights on transcriptome evolution, I have also discussed in detail the advantages of modular approaches in large-scale data analysis. Moreover, I re-analyzed several studies (published in high-ranking journals), and showed that their conclusions do not hold out under a detailed analysis. This demonstrates that complex analysis of high-throughput data requires a co-operation between biologists, bioinformaticians, and statisticians.

FM127: Systemic metal ion levels in patients with modular neck total hip arthroplasties: a prospective cohort study

There is increasing evidence that modular neck stems are prone to corrosion-related complications. Recent studies showed elevated metal ions levels and occasional pseudotumor formation in patients with such implants. The purpose of this study was to compare systemic metal-ion levels in patients after primary THA with modular neck stems to those of patients after non-modular implants. To our knowledge, this is the first cohort study including a control group, THA without CoCr heads and dry-assembled neck-stem connections. Methods: 50 patients after THA at a minimum follow-up of 1 year have been selected for the study. Patients with multiple prosthesis or other implants have been deselected. All received a cementless SPS stem from Symbios (Ti6Al4V). 40 patients have the modular neck (CoCr) version and 10 a monobloc version. All bearings were either ceramic-ceramic or ceramic-polyethylene to minimize other sources of CoCr ion release. In the modular group, the neck was chosen pre-operatively based on a 3D planning, allowing for a dry assembly of the stem and neck on the back table before implantation. A plasma system coupled to mass spectrometry was used for a complete elementary quantification in blood and serum separately. Clinical outcome was measured using the Oxford Hip Score. Results : Complete data sets of 29 patients (24 in the modular neck-group (10male, mean age 63y, 35-84y) and 5 in the monobloc-group (3 male, 69 y, 51-83y) are available to date. Mean Co blood levels were .95 ug/L (.14-12.4) in the modular group vs .27 ug/L (.10-.73) in the monobloc group (p=.2). Respective values for Cr were significantly higher in the modular group (.99 g/L; range .75-1.21) compared to those in the monobloc group (.74 g/L ;.62-.86; p=.001). No significant difference was found when comparing serum levels. 5/24 patients had Co levels above 1 g/L (12/24 for Cr), which is by some considered as a relevant elevation. The maximum Co level was measured in an asymptomatic patient. The Oxford Hip Scores were similar in both groups. Conclusion: Cr levels were significantly elevated in the modular neck group compared to those in the monobloc group. 1/24 patients with a modular prosthesis exhibited Co levels, which are beyond the threshold accepted even for metal-on-metal bearing couples. These results have contributed to our decision to abandon the use of modular neck stems. Routine follow-up including annual measurements of systemic CoCr concentrations should be considered.

Unification of multi-species vertebrate anatomy ontologies for comparative biology in Uberon.

BACKGROUND: Elucidating disease and developmental dysfunction requires understanding variation in phenotype. Single-species model organism anatomy ontologies (ssAOs) have been established to represent this variation. Multi-species anatomy ontologies (msAOs; vertebrate skeletal, vertebrate homologous, teleost, amphibian AOs) have been developed to represent 'natural' phenotypic variation across species. Our aim has been to integrate ssAOs and msAOs for various purposes, including establishing links between phenotypic variation and candidate genes. RESULTS: Previously, msAOs contained a mixture of unique and overlapping content. This hampered integration and coordination due to the need to maintain cross-references or inter-ontology equivalence axioms to the ssAOs, or to perform large-scale obsolescence and modular import. Here we present the unification of anatomy ontologies into Uberon, a single ontology resource that enables interoperability among disparate data and research groups. As a consequence, independent development of TAO, VSAO, AAO, and vHOG has been discontinued. CONCLUSIONS: The newly broadened Uberon ontology is a unified cross-taxon resource for metazoans (animals) that has been substantially expanded to include a broad diversity of vertebrate anatomical structures, permitting reasoning across anatomical variation in extinct and extant taxa. Uberon is a core resource that supports single- and cross-species queries for candidate genes using annotations for phenotypes from the systematics, biodiversity, medical, and model organism communities, while also providing entities for logical definitions in the Cell and Gene Ontologies. THE ONTOLOGY RELEASE FILES ASSOCIATED WITH THE ONTOLOGY MERGE DESCRIBED IN THIS MANUSCRIPT ARE AVAILABLE AT: http://purl.obolibrary.org/obo/uberon/releases/2013-02-21/ CURRENT ONTOLOGY RELEASE FILES ARE AVAILABLE ALWAYS AVAILABLE AT: http://purl.obolibrary.org/obo/uberon/releases/

Adverse tissue reaction to corrosion at the neck-stem junction after modular primary total hip arthroplasty.

Complications related to the neck-stem junction of modular stems used for total hip arthroplasty (THA) are generating increasing concern. A 74-year-old male had increasing pain and a cutaneous reaction around the scar 1 year after THA with a modular neck-stem. Imaging revealed osteolysis of the calcar and a pseudo-tumour adjacent to the neck-stem junction. Serum cobalt levels were elevated. Revision surgery to exchange the stem and liner and to resect the pseudo-tumour was performed. Analysis of the stem by scanning electron microscopy and by energy dispersive X-ray and white light interferometry showed fretting corrosion at the neck-stem junction contrasting with minimal changes at the head-neck junction. Thus, despite dry assembly of the neck and stem on the back table at primary THA, full neck-stem contact was not achieved, and the resulting micromotion at the interface led to fretting corrosion. This case highlights the mechanism of fretting corrosion at the neck-stem interface responsible for adverse local tissue reactions. Clinical and radiological follow-up is mandatory in patients with dual-modular stems.

Expert clinical reasoning and pain assessment in mechanically ventilated patients: A descriptive study.

BACKGROUND: Pain assessment in mechanically ventilated patients is challenging, because nurses need to decode pain behaviour, interpret pain scores, and make appropriate decisions. This clinical reasoning process is inherent to advanced nursing practice, but is poorly understood. A better understanding of this process could contribute to improved pain assessment and management. OBJECTIVE: This study aimed to describe the indicators that influence expert nurses' clinical reasoning when assessing pain in critically ill nonverbal patients. METHODS: This descriptive observational study was conducted in the adult intensive care unit (ICU) of a tertiary referral hospital in Western Switzerland. A purposive sample of expert nurses, caring for nonverbal ventilated patients who received sedation and analgesia, were invited to participate in the study. Data were collected in "real life" using recorded think-aloud combined with direct non-participant observation and brief interviews. Data were analysed using deductive and inductive content analyses using a theoretical framework related to clinical reasoning and pain. RESULTS: Seven expert nurses with an average of 7.85 (±3.1) years of critical care experience participated in the study. The patients had respiratory distress (n=2), cardiac arrest (n=2), sub-arachnoid bleeding (n=1), and multi-trauma (n=2). A total of 1344 quotes in five categories were identified. Patients' physiological stability was the principal indicator for making decision in relation to pain management. Results also showed that it is a permanent challenge for nurses to discriminate situations requiring sedation from situations requiring analgesia. Expert nurses mainly used working knowledge and patterns to anticipate and prevent pain. CONCLUSIONS: Patient's clinical condition is important for making decision about pain in critically ill nonverbal patients. The concept of pain cannot be assessed in isolation and its assessment should take the patient's clinical stability and sedation into account. Further research is warranted to confirm these results.

A modular tethering complex for endosomal recycling.

How proteins migrate through the interconnected organelles of the endolysosomal system is poorly understood. A piece of the puzzle has been added with the identification of a complex of tethering factors that functions in the recycling of proteins towards the cell surface.

Population Variation and Genetic Control of Modular Chromatin Architecture in Humans.

Chromatin state variation at gene regulatory elements is abundant across individuals, yet we understand little about the genetic basis of this variability. Here, we profiled several histone modifications, the transcription factor (TF) PU.1, RNA polymerase II, and gene expression in lymphoblastoid cell lines from 47 whole-genome sequenced individuals. We observed that distinct cis-regulatory elements exhibit coordinated chromatin variation across individuals in the form of variable chromatin modules (VCMs) at sub-Mb scale. VCMs were associated with thousands of genes and preferentially cluster within chromosomal contact domains. We mapped strong proximal and weak, yet more ubiquitous, distal-acting chromatin quantitative trait loci (cQTL) that frequently explain this variation. cQTLs were associated with molecular activity at clusters of cis-regulatory elements and mapped preferentially within TF-bound regions. We propose that local, sequence-independent chromatin variation emerges as a result of genetic perturbations in cooperative interactions between cis-regulatory elements that are located within the same genomic domain.

Are we modular lying cues detectors ? The answer is "yes sometimes"

We quickly form first impressions about newly encountered people guiding our subsequent behaviour (approach, avoidance). Such instant judgments might be innate and automatic, being performed unconsciously and independently to other cognitive processes. Lying detection might be subject to such a modular process. Unfortunately, numerous studies highlighted problems with lying detection paradigms such as high error rates and learning effects. Additionally, humans should be motivated doing both detecting others' lies and dis- guising own lies. Disguising own lies might even be more challenging than detecting other people's lies. Thus, when trying to disguise cheating behaviour, liars might display a mixture of disguising (fake) trust cues and uncontrolled lying cues making the interpretation of the expression difficult (perceivers are guessing). In two consecutive online studies, we tested whether seeing an increasing amount (range 0-4) of lying cues (LC) and non-lying cues (NLC) on a standard face results in enhanced guessing behaviour (studies 1 and 2) and that enhanced guessing is accompanied by slower responding (study 2). Results showed that pronounced guessing and slowest responding occurred for faces with an intermediate number and not with the highest number of LC and NLC. In particular, LC were more impor- tant than NLC to uncertain lying decisions. Thus, only a few LC may interfere with automatic processing of lying detection (irrespective of NLC), probably because too little lying cue information is yet available.

Digital evidence, 'absence' of data and ambiguous patterns of reasoning

In this paper we discuss the use of digital data by the Swiss Federal Criminal Court in a recent case of attempted homicide. We use this case to examine drawbacks for the defense when the presentation of scientific evidence is partial, especially when the only perspective mentioned is that of the prosecution. We tackle this discussion at two distinct levels. First, we pursue an essentially non-technical presentation of the topic by drawing parallels between the court's summing up of the case and flawed patterns of reasoning commonly seen in other forensic disciplines, such as DNA and particle traces (e.g., gunshot residues). Then, we propose a formal analysis of the case, using elements of probability and graphical probability models, to justify our main claim that the partial presentation of digital evidence poses a risk to the administration of justice in that it keeps vital information from the defense. We will argue that such practice constitutes a violation of general principles of forensic interpretation as established by forensic science literature and current recommendations by forensic science interest groups (e.g., the European Network of Forensic Science Institutes). Finally, we posit that argument construction and analysis using formal methods can help replace digital evidence appropriately into context and thus support a sound evaluation of the evidence.