Inference of Evolutionary Forces Acting on Human Biological Pathways.

Because natural selection is likely to act on multiple genes underlying a given phenotypic trait, we study here the potential effect of ongoing and past selection on the genetic diversity of human biological pathways. We first show that genes included in gene sets are generally under stronger selective constraints than other genes and that their evolutionary response is correlated. We then introduce a new procedure to detect selection at the pathway level based on a decomposition of the classical McDonald-Kreitman test extended to multiple genes. This new test, called 2DNS, detects outlier gene sets and takes into account past demographic effects and evolutionary constraints specific to gene sets. Selective forces acting on gene sets can be easily identified by a mere visual inspection of the position of the gene sets relative to their two-dimensional null distribution. We thus find several outlier gene sets that show signals of positive, balancing, or purifying selection but also others showing an ancient relaxation of selective constraints. The principle of the 2DNS test can also be applied to other genomic contrasts. For instance, the comparison of patterns of polymorphisms private to African and non-African populations reveals that most pathways show a higher proportion of nonsynonymous mutations in non-Africans than in Africans, potentially due to different demographic histories and selective pressures.

Chronological order of appearance of extraintestinal manifestations relative to the time of IBD diagnosis in the Swiss Inflammatory Bowel Disease Cohort

BACKGROUND: Data evaluating the chronological order of appearance of extraintestinal manifestations (EIMs) relative to the time of inflammatory bowel disease (IBD) diagnosis is currently lacking. We aimed to assess the type, frequency, and chronological order of appearance of EIMs in patients with IBD. METHODS: Data from the Swiss Inflammatory Bowel Disease Cohort Study were analyzed. RESULTS: The data on 1249 patients were analyzed (49.8% female, median age: 40 [interquartile range, 30-51 yr], 735 [58.8%] with Crohn's disease, 483 [38.7%] with ulcerative colitis, and 31 [2.5%] with indeterminate colitis). A total of 366 patients presented with EIMs (29.3%). Of those, 63.4% presented with 1, 26.5% with 2, 4.9% with 3, 2.5% with 4, and 2.7% with 5 EIMs during their lifetime. Patients presented with the following diseases as first EIMs: peripheral arthritis 70.0%, aphthous stomatitis 21.6%, axial arthropathy/ankylosing spondylitis 16.4%, uveitis 13.7%, erythema nodosum 12.6%, primary sclerosing cholangitis 6.6%, pyoderma gangrenosum 4.9%, and psoriasis 2.7%. In 25.8% of cases, patients presented with their first EIM before IBD was diagnosed (median time 5 mo before IBD diagnosis: range, 0-25 mo), and in 74.2% of cases, the first EIM manifested itself after IBD diagnosis (median: 92 mo; range, 29-183 mo). CONCLUSIONS: In one quarter of patients with IBD, EIMs appeared before the time of IBD diagnosis. Occurrence of EIMs should prompt physicians to look for potential underlying IBD.

Broken colinearity of the amphioxus Hox cluster.

Background In most eumetazoans studied so far, Hox genes determine the identity of structures along the main body axis. They are usually linked in genomic clusters and, in the case of the vertebrate embryo, are expressed with spatial and temporal colinearity. Outside vertebrates, temporal colinearity has been reported in the cephalochordate amphioxus (the least derived living relative of the chordate ancestor) but only for anterior and central genes, namely Hox1 to Hox4 and Hox6. However, most of the Hox gene expression patterns in amphioxus have not been reported. To gain global insights into the evolution of Hox clusters in chordates, we investigated a more extended expression profile of amphioxus Hox genes. Results Here we report an extended expression profile of the European amphioxus Branchiostoma lanceolatum Hox genes and describe that all Hox genes, except Hox13, are expressed during development. Interestingly, we report the breaking of both spatial and temporal colinearity for at least Hox6 and Hox14, which thus have escaped from the classical Hox code concept. We show a previously unidentified Hox6 expression pattern and a faint expression for posterior Hox genes in structures such as the posterior mesoderm, notochord, and hindgut. Unexpectedly, we found that amphioxus Hox14 had the most divergent expression pattern. This gene is expressed in the anterior cerebral vesicle and pharyngeal endoderm. Amphioxus Hox14 expression represents the first report of Hox gene expression in the most anterior part of the central nervous system. Nevertheless, despite these divergent expression patterns, amphioxus Hox6 and Hox14 seem to be still regulated by retinoic acid. Conclusions Escape from colinearity by Hox genes is not unusual in either vertebrates or amphioxus and we suggest that those genes escaping from it are probably associated with the patterning of lineage-specific morphological traits, requiring the loss of those developmental constraints that kept them colinear.

Life-time growth patterns of pumpkinseed Lepomis gibbosus introduced to Europe, relative to North American populations

The pumpkinseed Lepomis gibbosus, an omnivorous, nest guarding North American sunfish, was introduced into European waters about 100 years ago. To assess growth performance following introduction, we reviewed the available data for North American and European populations of pumpkinseed and compared the back-calculated age-specific growth for juveniles (standard length, SL, at age two) and adults (age two to five increment) as well as adult body size (SL at age five), von Bertalanffy growth model parameters and the index of growth (in length) performance (φ′). For continental comparisons of growth trajectory, mean growth curves for North American and Europe were calculated with the von Bertalanffy model using pooled data sets for each continent. Juvenile growth rate did not differ between European and North American pumpkinseed, but mean adult body size and adult growth rate were both significantly greater in North American than European populations. Adult body size decreased with increasing latitude (ANOVA) in North American populations, but this was not observed with adult growth rate. In contrast, adult body size tended to increase with latitude in European populations. Adult body size correlated significantly with φ′. The von Bertalanffy model described the overall growth patterns of North American and European populations reasonably well, but on the individual population level, length asymptotes were unrealistic (estimates that were > 20 % of the mean back-calculated size for the oldest age class) for a third of European populations and 80% of the North American populations. In contrast to North American pumpkinseed populations, somatic growth in European populations appears to be compromised by limited, but adequate, food resources, probably due to strong intraspecific interactions. This appears to be especially acute in adults, having potential ramifications for life span and reproductive allocation

'And the best essay is...' : Extended contact and cross-group friendships at school

We conducted one experimental intervention based on extended contact principles aimed at fostering the formation of cross-group friendships within educational settings. Italian school children took part in a school competition for the best essay on personal experiences of cross-group friendships with immigrants, to be written in small groups. This manipulation was intended to favour the exchange of personal positive cross-group experiences, thus capitalizing on the benefits of extended contact. In the control condition, participants wrote an essay on friendship, without reference to cross-group relations. Results revealed that children who took part in the intervention reported a higher number of outgroup friends 3 months later. This indirect effect was sequentially mediated by pro-contact ingroup and outgroup norms and by outgroup contact behavioural intentions. This study provides experimental evidence that interventions based on extended contact can foster cross-group friendship formation. Theoretical and practical implications of the findings are discussed.

Exploring the relative DNA contribution of first and second object's users on mock touch DNA mixtures

Contact stains recovered at break-in crime scenes are frequently characterized by mixtures of DNA from several persons. Broad knowledge on the relative contribution of DNA left behind by different users overtime is of paramount importance. Such information might help crime investigators to robustly evaluate the possibility of detecting a specific (or known) individual's DNA profile based on the type and history of an object. To address this issue, a contact stain simulation-based protocol was designed. Fourteen volunteers either acting as first or second object's users were recruited. The first user was required to regularly handle/wear 9 different items during an 8-10-day period, whilst the second user for 5, 30 and 120 min, in three independent simulation sessions producing a total of 231 stains. Subsequently, the relative DNA profile contribution of each individual pair was investigated. Preliminary results showed a progressive increase of the percentage contribution of the second user compared to the first. Interestingly, the second user generally became the major DNA contributor when most objects were handled/worn for 120 min, Furthermore, the observation of unexpected additional alleles will then prompt the investigation of indirect DNA transfer events.

Nitric oxide and ethylnitrosourea: relative mutagenicity in the p53 tumor suppressor and hypoxanthine-phosphoribosyltransferase genes.

Nitric oxide (NO) is a cellular messenger which is mutagenic in bacteria and human TK6 cells and induces deamination of 5-methylcytosine (5meC) residues in vitro. The aims of this study were: (i) to investigate whether NO induces 5meC deamination in codon 248 of the p53 gene in cultured human bronchial epithelial cells (BEAS-2B); and (ii) to compare NO mutagenicity to that of ethylnitrosourea (ENU), a strong mutagen. Two approaches were used: (i) a novel genotypic assay, using RFLP/PCR technology on purified exon VII sequence of the p53 gene; and (ii) a phenotypic (HPRT) mutation assay using 6-thioguanine selection. BEAS-2B cells were either exposed to 4 mM DEA/NO (Et2N[N2O2]Na, an agent that spontaneously releases NO into the medium) or transfected with the inducible nitric oxide synthase (iNOS) gene. The genotypic mutation assay, which has a sensitivity of 1 x 10(-6), showed that 4 mM ENU induces detectable numbers of G --> A transitions in codon 248 of p53 while 5-methylcytosine deamination was not detected in either iNOS-transfected cells or cells exposed to 4 mM DEA/NO. Moreover, ENU was dose-responsively mutagenic in the phenotypic HPRT assay, reaching mutation frequencies of 24 and 96 times that of untreated control cells at ENU concentrations of 4 and 8 mM respectively; by contrast, 4 mM DEA/NO induced no detectable mutations in this assay, nor were any observed in cells transfected with murine iNOS. We conclude that if NO is at all promutagenic in these cells, it is significantly less so than the ethylating mutagen, ENU.

Extended Endoscopic Endonasal Approaches for Cerebral Aneurysms: Anatomical, Virtual Reality and Morphometric Study

Introduction. The purpose of the present contribution is to perform a detailed anatomic and virtual reality three-dimensional stereoscopic study in order to test the effectiveness of the extended endoscopic endonasal approaches for selected anterior and posterior circulation aneurysms. Methods. The study was divided in two main steps: (1) simulation step, using a dedicated Virtual Reality System (Dextroscope, Volume Interactions); (2) dissection step, in which the feasibility to reach specific vascular territory via the nose was verified in the anatomical laboratory. Results. Good visualization and proximal and distal vascular control of the main midline anterior and posterior circulation territory were achieved during the simulation step as well as in the dissection step (anterior communicating complex, internal carotid, ophthalmic, superior hypophyseal, posterior cerebral and posterior communicating, basilar, superior cerebellar, anterior inferior cerebellar, vertebral, and posterior inferior cerebellar arteries). Conclusion. The present contribution is intended as strictly anatomic study in which we highlighted some specific anterior and posterior circulation aneurysms that can be reached via the nose. For clinical applications of these approaches, some relevant complications, mainly related to the endonasal route, such as proximal and distal vascular control, major arterial bleeding, postoperative cerebrospinal fluid leak, and olfactory disturbances must be considered

Measurement of the relative rate of prompt χ c0, χ c1 and χ c2 production at TeV

Prompt production of charmonium χ c0, χ c1 and χ c2 mesons is studied using proton-proton collisions at the LHC at a centre-of-mass energy of TeX TeV. The χ c mesons are identified through their decay to J/ψγ, with J/ψ → μ + μ − using photons that converted in the detector. A data sample, corresponding to an integrated luminosity of 1.0 fb−1 collected by the LHCb detector, is used to measure the relative prompt production rate of χ c1 and χ c2 in the rapidity range 2.0 < y < 4.5 as a function of the J/ψ transverse momentum from 3 to 20 GeV/c. First evidence for χ c0 meson production at a high-energy hadron collider is also presented.

Transabdominal-pelvic-perineal (TAPP) anterolateral thigh flap: A new reconstructive technique for complex defects following extended abdominoperineal resection.

BACKGROUND: Abdominoperineal resection (APR) following radiotherapy is associated with a high rate of perineal wound complications. The anterolateral thigh (ALT) flap, combined with the vastus lateralis (VL) muscle, can cover complex perineal and pelvic anteroposterior defects. This is used for the first time transabdominally through the pelvis and the perineum (TAPP) in the infero-posterior directions; this technique has been described and illustrated in this study. METHODS: Among over 90 patients who underwent perineal reconstruction between May 2004 and June 2011, six patients presented high-grade tumours invading perineum, pelvis and sacrum, thereby resulting in a continuous anteroposterior defect. ALT + VL TAPP reconstructions were performed after extended APR and, subsequently, sacrectomy. Patients were examined retrospectively to determine demographics, operative time, complications (general and flap-related), time to complete healing and length of hospital stay. Long-term flap coverage, flap volume stability and functional and aesthetic outcomes were assessed. RESULTS: Mean operating time of the reconstruction was 290 min. No deaths occurred. One patient presented partial flap necrosis. Another patient presented a novel wound dehiscence after flap healing, due to secondary skin dissemination of the primary tumour. Following volumetric flap analysis on serial post-operative CT scans, no significant flap atrophy was observed. All flaps fully covered the defects. No late complications such as fistulas or perineal hernias occurred. Donor-site recovery was uneventful with no functional deficits. CONCLUSIONS: The use of the ALT + VL flap transabdominally is an innovative method to reconstruct exceptionally complex perineal and pelvic defects extending up to the lower back. This flap guarantees superior bulk, obliterating all pelvic dead space, with the fascia lata (FL) supporting the pelvic floor.

On the relative abundance of autopolyploids and allopolyploids.

The prevalence of autopolyploids in angiosperms has long been a subject of debate. Meurountzing (1936) and Darlington (1937) conclude d that autopolyploids were common and important evolutionary entities. However, Clausen et al. (1945) and Stebbins (1947) subsequently considered them rare, in part because the criteria upon which interpretations of autopolyploidy were rendered were not rigorous. This position was reiterated by Grant (1981) decades later, although evidence was mounting that autopolyploid taxa might be important in natural populations (Lewis, 1980). As cytological and genetic data have accumulated, it has become increasingly apparent that the latter view is likely to be correct (Soltis et al., 2004b, 2007, 2010). However, it still appears that the majority of polyploids are allopolyploids (Parisod et al., 2010; Soltis et al., 2010), even though Ramsey & Schemske (1998, p. 467) conclude that 'the rate of autopolyploid formation may often be higher than the rate of allopol yploid formation.' In this letter we survey the literature to assess whether allopolyploids are indeed the prevailing cytotype in nature. Using our new estimates for the incidence of autopolyploidy and allopolyploidy, we discuss some of the evolutionary dynamics that may be driving their frequencies in nature. Finally, we suggest avenues for future research on polyploidy that build on our results and other recent progress in the field.

Teollisten palveluiden tarjoajien ja asiakkaan välisen yhteistyösuhteen kehittäminen

Työssä tutkitaan asennetun laitekannan kunnossapitopalveluun perustuvan yritysten välisen yhteistyösuhteen kehittämisen edellytyksiä. Tutkimus pohjautuu teollisten palveluiden, yritysten välisten yhteistyösuhteiden ja palveluiden kehittämisen osatekijöiden ja menestystekijöiden teoreettiseen tarkasteluun, sekä kohdeyrityksille suoritetun kvalitatiivisen haastattelututkimuksen tulosten analysointiin teoreettisen viitekehyksen valossa. Tavoitteena on muodostaa ehjä ja hallittava kokonaisuus monialaisen ongelmakentän kriittisistä osatekijöistä, sekä niiden keskinäisistä kausaliteeteista. Yritysten välisen yhteistyön lähtökohtana on, että kaikki yhteistyön osapuolet saavuttavat toiminnalla hyötyjä omasta näkökulmastaan tarkasteltuna. Yhteistyösuhteen kehittäminen ja yhteisen arvon toteutuminen edellyttää näin ollen, että tarjottavan palvelukokonaisuuden sisältämät potentiaaliset hyödyt ja toisaalta myös niitä vastaavat riskit ymmärretään sekä palveluntarjoajan että asiakkaan organisaatiossa. Yhteistyösuhteen kehittäminen edellyttää edelleen myös, että suhteen kehittymistä ja saavutettavia hyötyjä pystytään mittaamaan relevanttien mittareiden avulla. Tutkimuksessa keskitytään hyötypotentiaalin selvittämisen edellytyksiin, sekä hyötyjen viestimisen haasteisiin molempia osapuolia palvelevasta objektiivisesta näkökulmasta. Haastattelututkimuksessa havaittujen ongelmakohtien pohjalta eritellään kehityskohteita ja ratkaisuehdotuksia päätöksenteon tueksi sekä laajojen palvelukokonaisuuksien ja niihin liittyvän ongelmakentän hahmottamisen ja hallinnan helpottamiseksi.

[TESTI] unicode Extended-B

Kalajuttůja, Hattǔja

Genetic Basis and Diagnostics of Extended-Spectrum Beta-Lactamases among Enterobacteriaceae in Finland

Since the introduction of antibiotic agents, the amount and prevalence of Beta-lactam resistant enterobacteria has become an increasing problem. Many enterobacteria are opportunistic pathogens that easily acquire resistance mechanisms and genes, which make the situation menacing. These bacteria have acquired resistance and can hydrolyse extended spectrum cephalosporins and penicillins by producing enzymes called extended-spectrum Beta-lactamases (ESBLs). ESBL-producing bacteria are most commonly found in the gastro-intestinal tract of colonised patients. These resistant strains can be found in both health-care associated and community-acquired isolates. The detection and treatment of infections caused by bacteria producing ESBLs are problematic. This study investigated the genetic basis of extended-spectrum Beta-lactamases in Enterobacteriaceae, especially in Escherichia coli and Klebsiella pneumoniae isolates. A total of 994 Finnish Enterobacteriaceae strains, collected at 26 hospital laboratories, during 2000 and 2007 were analysed. For the genetic basis studies, PCR, sequencing and pyrosequencing methods were optimised. In addition, international standard methods, the agar dilution and disk diffusion methods were performed for the resistance studies, and the susceptibility of these strains was tested for antimicrobial agents that are used for treating patients. The genetic analysis showed that bla_CTX-M was the most prevalent gene among the E. coli isolates, while blaS_HV-12 was the most common Beta-lactamase gene in K. pneumoniae. The susceptibility testing results showed that about 60% of the strains were multidrug resistant. The prevalence of ESBL-producing isolates in Finland has been increasing since 2000. However, the situation in Finland is still much better than in many other European countries.