Rhythmicity of coastal marine picoeukaryotes, bacteria and archaea despite irregular environmental perturbations.
Seasonality in marine microorganisms has been classically observed in phytoplankton blooms, and more recently studied at the community level in prokaryotes, but rarely investigated at the scale of individual microbial taxa. Here we test if specific marine eukaryotic phytoplankton, bacterial and archaeal taxa display yearly rhythms at a coastal site impacted by irregular environmental perturbations. Our seven-year study in the Bay of Banyuls (North Western Mediterranean Sea) shows that despite some fluctuating environmental conditions, many microbial taxa displayed significant yearly rhythms. The robust rhythmicity was found in both autotrophs (picoeukaryotes and cyanobacteria) and heterotrophic prokaryotes. Sporadic meteorological events and irregular nutrient supplies did, however, trigger the appearance of less common non-rhythmic taxa. Among the environmental parameters that were measured, the main drivers of rhythmicity were temperature and day length. Seasonal autotrophs may thus be setting the pace for rhythmic heterotrophs. Similar environmental niches may be driving seasonality as well. The observed strong association between Micromonas and SAR11, which both need thiamine precursors for growth, could be a first indication that shared nutritional niches may explain some rhythmic patterns of co-occurrence.


Embodiment of evolutionary computation in general agents.
Holland's Adaptation in Natural and Artificial Systems largely dealt with how systems, comprised of many self-interested entities, can and should adapt as a whole. This seminal book led to the last 25 years of work in genetic algorithms (GAs) and related forms of evolutionary computation (EC). In recent years, the expansion of the Internet, other telecommunications technologies, and other large scale networks have led to a world where large numbers of semi-autonomous software entities (i.e., agents) will be interacting in an open, universal system. This development cast the importance of Holland's legacy in a new light. This paper argues that Holland's fundamental arguments, and the years of developments that have followed, have a direct impact on systems of general network agents, regardless of whether they explicitly exploit EC. However, it also argues that the techniques and theories of EC cannot be directly transferred to the world of general agents (rather than EC-specific) without examination of effects that are embodied in general software agents. This paper introduces a framework for EC interchanges between general-purpose software agents. Preliminary results are shown that illustrate the EC effects of asynchronous actions of agents within this framework. Building on this framework, coevolutionary agents that interact in a simulated producer/consumer economy are introduced. Using these preliminary results as illustrations, areas for future investigation of embodied EC software agents are discussed.


Plasmids of Psychrotolerant Polaromonas spp. Isolated From Arctic and Antarctic Glaciers - Diversity and Role in Adaptation to Polar Environments.
Cold-active bacteria of the genus Polaromonas (class Betaproteobacteria) are important components of glacial microbiomes. In this study, extrachromosomal replicons of 26 psychrotolerant Polaromonas strains, isolated from Arctic and Antarctic glaciers, were identified, sequenced, and characterized. The plasmidome of these strains consists of 13 replicons, ranging in size from 3,378 to 101,077 bp. In silico sequence analyses identified the conserved backbones of these plasmids, composed of genes required for plasmid replication, stable maintenance, and conjugal transfer. Host range analysis revealed that all of the identified plasmids are narrow-host-range replicons, only able to replicate in bacteria of closely related genera (Polaromonas and Variovorax) of the Comamonadaceae family. Special attention was paid to the identification of plasmid auxiliary genetic information, which may contribute to the adaptation of bacteria to environmental conditions occurring in glaciers. Detailed analysis revealed the presence of genes encoding proteins potentially involved in (i) protection against reactive oxygen species, ultraviolet radiation, and low temperatures; (ii) transport and metabolism of organic compounds; (iii) transport of metal ions; and (iv) resistance to heavy metals. Some of the plasmids also carry genes required for the molecular assembly of iron-sulfur [Fe-S] clusters. Functional analysis of the predicted heavy metal resistance determinants demonstrated that their activity varies, depending on the host strain. This study provides the first molecular insight into the mobile DNA of Polaromonas spp. inhabiting polar glaciers. It has generated valuable data on the structure and properties of a pool of plasmids and highlighted their role in the biology of psychrotolerant Polaromonas strains and their adaptation to the environmental conditions of Arctic and Antarctic glaciers.


Developmental roles of the Mi-2/NURD-associated protein p66 in Drosophila.
The NURD and Sin3 histone deacetylase complexes are involved in transcriptional repression through global deacetylation of chromatin. Both complexes contain many different components that may control how histone deacetylase complexes are regulated and interact with other transcription factors. In a genetic screen for modifiers of wingless signaling in the Drosophila eye, we isolated mutations in the Drosophila homolog of p66, a protein previously purified as part of the Xenopus NURD/Mi-2 complex. p66 encodes a highly conserved nuclear zinc-finger protein that is required for development and we propose that the p66 protein acts as a regulatory component of the NURD complex. Animals homozygous mutant for p66 display defects during metamorphosis possibly caused by misregulation of ecdysone-regulated expression. Although heterozygosity for p66 enhances a wingless phenotype in the eye, loss-of-function clones in the wing and the eye discs do not have any detectable phenotype, possibly due to redundancy with the Sin3 complex. Overexpression of p66, on the other hand, can repress wingless-dependent phenotypes. Furthermore, p66 expression can repress multiple reporters in a cell culture assay, including a Wnt-responsive TCF reporter construct, implicating the NURD complex in repression of Wnt target genes. By co-immunoprecipitation, p66 associates with dMi-2, a known NURD complex member.


Natural history of pruritus in primary biliary cirrhosis.
The natural history of pruritus in primary biliary cirrhosis (PBC) remains poorly defined. The aim of this investigation was to evaluate outcomes of pruritus in clinical trials for ursodeoxycholic acid (UDCA). In a UDCA-placebo trial begun in 1988 (n = 180), a 55% prevalence rate for pruritus was observed. Serum alkaline phosphatase level and Mayo risk score were independent risk factors for pruritus (P < 0.0001). Among placebo-treated patients (n = 91), the annual risks for development or improvement/resolution of pruritus were 27% and 23%, respectively. For UDCA-treated patients (n = 89), a trend toward improvement in pruritus was observed after 1 year compared to placebo (30% vs. 23%, P = 0.08) but not at 2 or 3 years. In a 3-dose UDCA trial begun in 1995 (n = 155), the overall prevalence of pruritus was significantly lower at 37% when compared to UDCA-placebo participants (P < 0.001). Baseline serum alkaline phosphatase level and Mayo risk score were again independent risk factors for pruritus (P < 0.0001). Among 13 (3.9%) patients with refractory pruritus, symptom resolution (n = 5) or improvement (n = 8) was associated with the use of oral rifampin (300 or 600 mg daily). Two patients treated with rifampin developed biochemical evidence for hepatotoxicity necessitating drug withdrawal. Although less prevalent among recently diagnosed individuals, more than one third of PBC patients develop pruritus. No significant risk reduction in developing pruritus with UDCA therapy was observed compared to placebo-treated patients. The long-term administration of rifampin for refractory pruritus is associated with occasional hepatotoxicity.


Scattering-phase theorem: anomalous diffraction by forward-peaked scattering media.
The scattering-phase theorem states that the values of scattering and reduced scattering coefficients of the bulk random media are proportional to the variance of the phase and the variance of the phase gradient, respectively, of the phase map of light passing through one thin slice of the medium. We report a new derivation of the scattering phase theorem and provide the correct form of the relation between the variance of phase gradient and the reduced scattering coefficient. We show the scattering-phase theorem is the consequence of anomalous diffraction by a thin slice of forward-peaked scattering media. A new set of scattering-phase relations with relaxed requirement on the thickness of the slice are provided. The condition for the scattering-phase theorem to be valid is discussed and illustrated with simulated data. The scattering-phase theorem is then applied to determine the scattering coefficient μs, the reduced scattering coefficient μ's, and the anisotropy factor g for polystyrene sphere and Intralipid-20% suspensions with excellent accuracy from quantitative phase imaging of respective thin slices. The spatially-resolved μs, μ's and g maps obtained via such a scattering-phase relationship may find general applications in the characterization of the optical property of homogeneous and heterogeneous random media.


A look into the nature and causes of human errors in the intensive care unit.
The purpose of this study was to investigate the nature and causes of human errors in the intensive care unit (ICU), adopting approaches proposed by human factors engineering. The basic assumption was that errors occur and follow a pattern that can be uncovered. Concurrent incident study. Medical-surgical ICU of a university hospital. Two types of data were collected: errors reported by physicians and nurses immediately after an error discovery; and activity profiles based on 24-hr records taken by observers with human engineering experience on a sample of patients. During the 4 months of data collection, a total of 554 human errors were reported by the medical staff. Errors were rated for severity and classified according to the body system and type of medical activity involved. There was an average of 178 activities per patient per day and an estimated number of 1.7 errors per patient per day. For the ICU as a whole, a severe or potentially detrimental error occurred on the average twice a day. Physicians and nurses were about equal contributors to the number of errors, although nurses had many more activities per day. A significant number of dangerous human errors occur in the ICU. Many of these errors could be attributed to problems of communication between the physicians and nurses. Applying human factor engineering concepts to the study of the weak points of a specific ICU may help to reduce the number of errors. Errors should not be considered as an incurable disease, but rather as preventable phenomena.


Quasi-experimental evaluation of a nationwide diabetes prevention programme.
Diabetes is a leading cause of morbidity, mortality and cost of illness1,2. Health behaviours, particularly those related to nutrition and physical activity, play a key role in the development of type 2 diabetes mellitus3. Whereas behaviour change programmes (also known as lifestyle interventions or similar) have been found efficacious in controlled clinical trials4,5, there remains controversy about whether targeting health behaviours at the individual level is an effective preventive strategy for type 2 diabetes mellitus6 and doubt among clinicians that lifestyle advice and counselling provided in the routine health system can achieve improvements in health7-9. Here we show that being referred to the largest behaviour change programme for prediabetes globally (the English Diabetes Prevention Programme) is effective in improving key cardiovascular risk factors, including glycated haemoglobin (HbA1c), excess body weight and serum lipid levels. We do so by using a regression discontinuity design10, which uses the eligibility threshold in HbA1c for referral to the behaviour change programme, in electronic health data from about one-fifth of all primary care practices in England. We confirm our main finding, the improvement of HbA1c, using two other quasi-experimental approaches: difference-in-differences analysis exploiting the phased roll-out of the programme and instrumental variable estimation exploiting regional variation in programme coverage. This analysis provides causal, rather than associational, evidence that lifestyle advice and counselling implemented at scale in a national health system can achieve important health improvements.


Hydrolysis by somatic angiotensin-I converting enzyme of basic dipeptides from a cholecystokinin/gastrin and a LH-RH peptide extended at the C-terminus with gly-Arg/Lys-arg, but not from diarginyl insulin.
Endoproteolytic cleavage of protein prohormones often generates intermediates extended at the C-terminus by Arg-Arg or Lys-Arg, the removal of which by a carboxypeptidase (CPE) is normally an important step in the maturation of many peptide hormones. Recent studies in mice that lack CP activity indicate the existence of alternative tissue or plasma enzymes capable of removing C-terminal basic residues from prohormone intermediates. Using inhibitors of angiotensin I-converting enzyme (ACE) and CP, we show that both these enzymes in mouse serum can remove the basic amino acids from the C-terminus of CCK5-GRR and LH-RH-GKR, but only CP is responsible for converting diarginyl insulin to insulin. ACE activity removes C-terminal dipeptides to generate the Gly-extended peptides, whereas CP hydrolysis gives rise to CCK5-GR and LH-RH-GK, both of which are susceptible to the dipeptidyl carboxypeptidase activity of ACE. Somatic ACE has two similar protein domains (the N-domain and the C-domain), each with an active site that can display different substrate specificities. CCK5-GRR is a high-affinity substrate for both the N-domain and C-domain active sites of human sACE (Km of 9.4 microm and 9.0 microm, respectively) with the N-domain showing greater efficiency (kcat : Km ratio of 2.6 in favour of the N-domain). We conclude that somatic forms of ACE should be considered as alternatives to CPs for the removal of basic residues from some Arg/Lys-extended peptides.


The role of thymic immunity and insulitis in the development of streptozocin-induced diabetes in mice.
This article is concerned with the role of thymic immunity in the development of diabetes experimentally induced by multiple injections of subdiabetogenic doses of streptozocin (STZ). Euthymic +/+, +/nu, and athymic nu/nu mice of CD-1 and BALB/cAJcl origin were studied. Daily intraperitoneal (i.p.) injections of 30 mg/kg body wt of STZ for 5 consecutive days in CD-1 +/+ and +/nu mice resulted in hyperglycemia and mononuclear cell infiltrations of islets (insulitis). The CD-1 nu/nu mice developed neither insulitis nor hyperglycemia after the same treatment. In the nu/nu mice, when thymic immunity was restored by thymus grafting, both insulitis and hyperglycemia developed, thus demonstrating that thymic immunity was a prerequisite for the development of insulitis and hyperglycemia. There was a positive correlation among the degrees of thymic immunity, insulitis, and hyperglycemia in CD-1 +/nu, nu/nu with thymus grafts, and nu/nu mice, indicating that thymic immunity may amplify the diabetogenic effect of STZ by eliciting insulitis. In contrast, in BALB/cAJcl mice, a nonsusceptible strain to insulitis, no significant differences in plasma glucose levels were observed between the +/nu and nu/nu or between the nu/nu and thymus-grafted nu/nu mice. Furthermore, no significant difference was found in plasma testosterone levels between the +/nu and nu/nu mice of both CD-1 and BALB/cAJcl origin. In conclusion, our data indicate that thymic immunity enhances the diabetogenic effect of STZ by eliciting insulitis in susceptible mice.


Prevalence and correlates of lifetime suicidal ideation and suicide attempts among Latino subgroups in the United States.
Limited data are available to understand the prevalence and correlates of suicidal behavior among U.S. Latino subgroups. This article compares the prevalence of lifetime suicidal ideation and suicide attempts among major U.S. Latino ethnic subgroups and identifies psycho-sociocultural factors associated with suicidal behaviors. The National Latino and Asian American Study includes Spanish- and English-speaking Mexicans, Puerto Ricans, Cubans, and other Latinos. A total of 2554 interviews were conducted in both English and Spanish by trained interviewers between May 2002 and November 2003. Lifetime psychiatric disorders were measured using the World Health Organization-Composite International Diagnostic Interview. Descriptive statistics and logistic models were used to determine demographic, clinical, cultural, and social correlates of lifetime suicidal ideation and suicide attempts. The lifetime prevalence of suicidal ideation and suicide attempts among Latinos was 10.1% and 4.4%, respectively. Puerto Ricans were more likely to report ideation as compared with other Latino subgroups, but this difference was eliminated after adjustments for demographic, psychiatric, and sociocultural factors. Most lifetime suicide attempts described by Latinos were reported as occurring when they were under the age of 18 years. Any lifetime DSM-IV diagnoses, including dual diagnoses, were associated with an increased risk of lifetime suicidal ideation and suicide attempts among Latinos. In addition, female gender, acculturation (born in the United States and English speaking), and high levels of family conflict were independently and positively correlated with suicide attempts among Latinos, even among those without any psychiatric disorder. These findings reinforce the importance of understanding the process of acculturation, the role of family, and the sociocultural context for suicide risk among Latinos. These should be considered in addition to psychiatric diagnoses and symptoms in Latino suicide research, treatment, and prevention, especially among young individuals.


Cell-mediated immunity to a synthetic gliadin peptide resembling a sequence from adenovirus 12.
Cell-mediated immunity to a synthetic peptide, which has a 12-residue sequence from A-gliadin analogous to part of an early-region protein (Elb) from adenovirus 12, was investigated in patients with coeliac disease, healthy subjects, and disease controls by means of an indirect leucocyte-migration-inhibition assay. Patients with coeliac disease being treated with a gluten-free diet showed a significantly greater response than healthy subjects (p less than 0.001) or patients with inflammatory bowel disease. This cellular immune response was dependent on antigen concentration and was not present in untreated coeliac patients.


Analysis of Metal-Binding Features of the Wild Type and Two Domain-Truncated Mutant Variants of Littorina littorea Metallothionein Reveals Its Cd-Specific Character.
After the resolution of the 3D structure of the Cd₉-aggregate of the Littorina littorea metallothionein (MT), we report here a detailed analysis of the metal binding capabilities of the wild type MT, LlwtMT, and of two truncated mutants lacking either the N-terminal domain, Lltr2MT, or both the N-terminal domain, plus four extra flanking residues (SSVF), Lltr1MT. The recombinant synthesis and in vitro studies of these three proteins revealed that LlwtMT forms unique M₉-LlwtMT complexes with Zn(II) and Cd(II), while yielding a complex mixture of heteronuclear Zn,Cu-LlwtMT species with Cu(I). As expected, the truncated mutants gave rise to unique M₆-LltrMT complexes and Zn,Cu-LltrMT mixtures of lower stoichiometry with respect to LlwtMT, with the SSVF fragment having an influence on their metal binding performance. Our results also revealed a major specificity, and therefore a better metal-coordinating performance of the three proteins for Cd(II) than for Zn(II), although the analysis of the Zn(II)/Cd(II) displacement reaction clearly demonstrates a lack of any type of cooperativity in Cd(II) binding. Contrarily, the analysis of their Cu(I) binding abilities revealed that every LlMT domain is prone to build Cu₄-aggregates, the whole MT working by modules analogously to, as previously described, certain fungal MTs, like those of C. neoformans and T. mesenterica. It is concluded that the Littorina littorea MT is a Cd-specific protein that (beyond its extended binding capacity through an additional Cd-binding domain) confers to Littorina littorea a particular adaptive advantage in its changeable marine habitat.


High-Efficiency Polycrystalline Thin Film Tandem Solar Cells.
A promising way to enhance the efficiency of CIGS solar cells is by combining them with perovskite solar cells in tandem devices. However, so far, such tandem devices had limited efficiency due to challenges in developing NIR-transparent perovskite top cells, which allow photons with energy below the perovskite band gap to be transmitted to the bottom cell. Here, a process for the fabrication of NIR-transparent perovskite solar cells is presented, which enables power conversion efficiencies up to 12.1% combined with an average sub-band gap transmission of 71% for photons with wavelength between 800 and 1000 nm. The combination of a NIR-transparent perovskite top cell with a CIGS bottom cell enabled a tandem device with 19.5% efficiency, which is the highest reported efficiency for a polycrystalline thin film tandem solar cell. Future developments of perovskite/CIGS tandem devices are discussed and prospects for devices with efficiency toward and above 27% are given.


Electrochemistry of Atomically Precise Metal Nanoclusters.
Thiolate-protected metal nanoparticles containing a few to few hundred metal atoms are interesting materials exhibiting unique physicochemical properties. They encompass the bulk-to-molecule transition region, where discrete electronic states emerge and electronic band energetics yield to quantum confinement effects. Recent progresses in the synthesis and characterization of ultrasmall gold nanoparticles have opened up new avenues for the isolation of extremely monodispersed nanoparticles with atomically precision. These nanoparticles are also called nanoclusters to distinguish them from other regular metal nanoparticles with core diameter >2 nm. These nanoclusters are typically identified by their actual molecular formulas; prominent among these are Au25(SR)18, Au38(SR)24, and Au102(SR)44, where SR is organothiolate. A number of single crystal structures of these nanoclusters have been disclosed. Researchers have effectively utilized density functional theory (DFT) calculations to predict their atomic and electronic structures, as well as their physicochemical properties. The atomically precise metal nanoclusters have been the focus of recent studies owing to their novel size-specific electrochemical, optical, and catalytic properties. In this Account, we highlight recent advances in electrochemistry of atomically precise metal nanoclusters and their applications in electrocatalysis and electrochemical sensing. Compared with gold nanoclusters, much less progress has been made in the electrochemical studies of other metal nanoclusters, and thus, we mainly focus on the electrochemistry and electrochemical applications of gold-based nanoclusters. Voltammetry has been extremely powerful in investigating the electronic structure of metal nanoclusters, especially near HOMO and LUMO levels. A sizable opening of HOMO-LUMO gap observed for Au25(SR)18 gradually decreases with increasing nanocluster size, which is in line with the change in the optical gap. Heteroatom-doping has been a powerful strategy to modify the optical and electrochemical properties of metal nanoclusters at the atomic level. While the superatom theory predicts 8-electron configuration for [Au25(SR)18]- and many doped nanoclusters thereof, Pt- and Pd-doped [PtAu24(SR)18]0 and [PdAu24(SR)18]0 nanoclusters show dramatically different electronic structures, as manifested in their optical spectra and voltammograms, suggesting the occurrence of the Jahn-Teller distortion in these doped nanoclusters. Furthermore, metal-doping may alter their surface binding properties, as well as redox potentials. Metal nanoclusters offer great potential for attaining high activity and selectivity in their electrocatalytic applications. The well-defined core-shell structure of a metal nanocluster is of special advantage because the core and shell can be independently engineered to exhibit suitable binding properties and redox potentials. We discuss recent progress made in electrocatalysis based upon metal nanoclusters tailored for water splitting, CO2 conversion, and electrochemical sensing. A well-defined model nanocatalyst is absolutely necessary to reveal the detailed mechanism of electrocatalysis and thereby to lead to the development of a new efficient electrocatalyst. We envision that atomically controlled metal nanoclusters will enable us to systematically optimize the electrochemical and surface properties suitable for electrocatalysis, thus providing a powerful platform for the discovery of finely tuned nanocatalysts.


Molecular characterization of mucinous ovarian tumours supports a stratified treatment approach with HER2 targeting in 19% of carcinomas.
Mucinous ovarian carcinomas (MCs) typically do not respond to current conventional therapy. We have previously demonstrated amplification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas (MCs) and presented anecdotal evidence of response with HER2-targeted treatment in a small series of women with recurrent HER2-amplified (HER2+) MC. Here, we explore HER2 amplification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours (MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry (IHC), FISH, and CISH, and interpreted per ASCO/CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis (p < 0.001). Assessment of HER2 status revealed overexpression/amplification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non-amplified status, and 3+ IHC with amplified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 amplification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 amplification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence (p = 0.019) or death (p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2-overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2-targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the ∼34% of MC cases with neither HER2 amplification nor KRAS mutations.


The effect of marital status on the survival of patients with colorectal neuroendocrine neoplasms: an analysis of the SEER database.
increasing evidence suggests that marital status is associated with tumor prognosis. The prognostic impact of marital status on colorectal neuroendocrine neoplasms has not been studied adequately. This study explored the relationship between marital status and prognosis of colorectal neuroendocrine neoplasms. during 2004-2012, 7,180 colorectal neuroendocrine neoplasm patients were identified from the Surveillance, Epidemiology and End Results database. A primary comparison (married vs unmarried) was performed with a 1:1 propensity matching score. Secondary comparisons were performed individually between three unmarried subgroups (single, divorced/separated, widowed) and the married group. The effect of marital status according to sex and extension of disease was explored. married patients had better survival (overall survival) (p < 0.001) and colorectal neuroendocrine neoplasm cause-specific survival (p = 0.001) rates compared to unmarried patients. Multivariate analysis indicated that marital status was an independent prognostic factor and married patients had a better overall survival (HR = 1.673; 95% CI: 1.446-1.936; p < 0.001) and colorectal neuroendocrine neoplasm cause-specific survival (HR = 1.365; 95% CI: 1.141-1.632; p = 0.001). Subgroup analysis showed that married patients had the best prognosis of cause-specific survival/overall survival and widowed patients had the worst prognosis (log-rank test p < 0.05). Marital status plays a more important role in colorectal neuroendocrine neoplasms patients with localized disease than in those with regional or distant disease. marital status is an independent prognostic factor for survival in colorectal neuroendocrine neoplasms patients. Married patients have a better prognosis with early stage disease. Single, widowed and male patients are regarded as a high-risk population.


Meaningful interpretation of subdiffusive measurements in living cells (crowded environment) by fluorescence fluctuation microscopy.
In living cell or its nucleus, the motions of molecules are complicated due to the large crowding and expected heterogeneity of the intracellular environment. Randomness in cellular systems can be either spatial (anomalous) or temporal (heterogeneous). In order to separate both processes, we introduce anomalous random walks on fractals that represented crowded environments. We report the use of numerical simulation and experimental data of single-molecule detection by fluorescence fluctuation microscopy for detecting resolution limits of different mobile fractions in crowded environment of living cells. We simulate the time scale behavior of diffusion times tau(D)(tau) for one component, e.g. the fast mobile fraction, and a second component, e.g. the slow mobile fraction. The less the anomalous exponent alpha the higher the geometric crowding of the underlying structure of motion that is quantified by the ratio of the Hausdorff dimension and the walk exponent d(f)/d(w) and specific for the type of crowding generator used. The simulated diffusion time decreases for smaller values of alpha # 1 but increases for a larger time scale tau at a given value of alpha # 1. The effect of translational anomalous motion is substantially greater if alpha differs much from 1. An alpha value close to 1 contributes little to the time dependence of subdiffusive motions. Thus, quantitative determination of molecular weights from measured diffusion times and apparent diffusion coefficients, respectively, in temporal auto- and crosscorrelation analyses and from time-dependent fluorescence imaging data are difficult to interpret and biased in crowded environments of living cells and their cellular compartments; anomalous dynamics on different time scales tau must be coupled with the quantitative analysis of how experimental parameters change with predictions from simulated subdiffusive dynamics of molecular motions and mechanistic models. We first demonstrate that the crowding exponent alpha also determines the resolution of differences in diffusion times between two components in addition to photophysical parameters well-known for normal motion in dilute solution. The resolution limit between two different kinds of single molecule species is also analyzed under translational anomalous motion with broken ergodicity. We apply our theoretical predictions of diffusion times and lower limits for the time resolution of two components to fluorescence images in human prostate cancer cells transfected with GFP-Ago2 and GFP-Ago1. In order to mimic heterogeneous behavior in crowded environments of living cells, we need to introduce so-called continuous time random walks (CTRW). CTRWs were originally performed on regular lattice. This purely stochastic molecule behavior leads to subdiffusive motion with broken ergodicity in our simulations. For the first time, we are able to quantitatively differentiate between anomalous motion without broken ergodicity and anomalous motion with broken ergodicity in time-dependent fluorescence microscopy data sets of living cells. Since the experimental conditions to measure a selfsame molecule over an extended period of time, at which biology is taken place, in living cells or even in dilute solution are very restrictive, we need to perform the time average over a subpopulation of different single molecules of the same kind. For time averages over subpopulations of single molecules, the temporal auto- and crosscorrelation functions are first found. Knowing the crowding parameter alpha for the cell type and cellular compartment type, respectively, the heterogeneous parameter gamma can be obtained from the measurements in the presence of the interacting reaction partner, e.g. ligand, with the same alpha value. The product alpha x gamma = gamma is not a simple fitting parameter in the temporal auto- and two-color crosscorrelation functions because it is related to the proper physical models of anomalous (spatial) and heterogeneous (temporal) randomness in cellular systems.We have already derived an analytical solution gamma for in the special case of gamma = 3/2. In the case of two-color crosscorrelation or/and two-color fluorescence imaging (co-localization experiments), the second component is also a two-color species gr, for example a different molecular complex with an additional ligand. Here, we first show that plausible biological mechanisms from FCS/ FCCS and fluorescence imaging in living cells are highly questionable without proper quantitative physical models of subdiffusive motion and temporal randomness. At best, such quantitative FCS/ FCCS and fluorescence imaging data are difficult to interpret under crowding and heterogeneous conditions. It is challenging to translate proper physical models of anomalous (spatial) and heterogeneous (temporal) randomness in living cells and their cellular compartments like the nucleus into biological models of the cell biological process under study testable by single-molecule approaches. Otherwise, quantitative FCS/FCCS and fluorescence imaging measurements in living cells are not well described and cannot be interpreted in a meaningful way.


A unifying model for timing of walking onset in humans and other mammals.
The onset of walking is a fundamental milestone in motor development of humans and other mammals, yet little is known about what factors determine its timing. Hoofed animals start walking within hours after birth, rodents and small carnivores require days or weeks, and nonhuman primates take months and humans approximately a year to achieve this locomotor skill. Here we show that a key to the explanation for these differences is that time to the onset of walking counts from conception and not from birth, indicating that mechanisms underlying motor development constitute a functional continuum from pre- to postnatal life. In a multiple-regression model encompassing 24 species representative of 11 extant orders of placental mammals that habitually walk on the ground, including humans, adult brain mass accounted for 94% of variance in time to walking onset postconception. A dichotomous variable reflecting species differences in functional limb anatomy accounted for another 3.8% of variance. The model predicted the timing of walking onset in humans with high accuracy, showing that this milestone in human motor development occurs no later than expected given the mass of the adult human brain, which in turn reflects the duration of its ontogenetic development. The timing of motor development appears to be highly conserved in mammalian evolution as the ancestors of some of the species in the sample presented here diverged in phylogenesis as long as 100 million years ago. Fundamental patterns of early human life history may therefore have evolved before the evolution of primates.


Quantifying the Brain Predictivity of Artificial Neural Networks With Nonlinear Response Mapping.
Quantifying the similarity between artificial neural networks (ANNs) and their biological counterparts is an important step toward building more brain-like artificial intelligence systems. Recent efforts in this direction use neural predictivity, or the ability to predict the responses of a biological brain given the information in an ANN (such as its internal activations), when both are presented with the same stimulus. We propose a new approach to quantifying neural predictivity by explicitly mapping the activations of an ANN to brain responses with a non-linear function, and measuring the error between the predicted and actual brain responses. Further, we propose to use a neural network to approximate this mapping function by training it on a set of neural recordings. The proposed method was implemented within the TensorFlow framework and evaluated on a suite of 8 state-of-the-art image recognition ANNs. Our experiments suggest that the use of a non-linear mapping function leads to higher neural predictivity. Our findings also reaffirm the observation that the latest advances in classification performance of image recognition ANNs are not matched by improvements in their neural predictivity. Finally, we examine the impact of pruning, a widely used ANN optimization, on neural predictivity, and demonstrate that network sparsity leads to higher neural predictivity.


Transcriptional profiling identifies cyclin D1 as a critical downstream effector of mutant epidermal growth factor receptor signaling.
Activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain determine responsiveness to EGFR tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer (NSCLC). The modulation of transcriptional pathways by mutant EGFR signaling is not fully understood. Previously, we and others identified a single base pair change leading to a threonine to methionine (T790M) amino acid alteration in the ATP-binding pocket of the EGFR as a common mechanism of acquired resistance. The gefitinib-resistant, T790M-mutant H1975 NSCLC cell line undergoes prominent growth arrest and apoptosis when treated with the irreversible EGFR inhibitor, CL-387,785. We did a transcriptional profiling study of mutant EGFR target genes that are differentially expressed in the "resistant" gefitinib-treated and the "sensitive" CL387,785-treated H1975 cells to identify the pivotal transcriptional changes in NSCLC with EGFR-activating mutations. We identified a small subset of early gene changes, including significant reduction of cyclin D1 as a result of EGFR inhibition by CL-387,785 but not by gefitinib. The reduction in cyclin D1 transcription was associated with subsequent suppression of E2F-responsive genes, consistent with proliferation arrest. Furthermore, cyclin D1 expression was higher in EGFR-mutant lung cancer cells compared with cells with wild-type EGFR. EGFR-mutant cells were routinely sensitive to the cyclin-dependent kinase inhibitor flavopiridol, confirming the functional relevance of the cyclin D axis. These studies suggest that cyclin D1 may contribute to the emergence of EGFR-driven tumorigenesis and can be an alternative target of therapy.


Self-propagative replication of Aβ oligomers suggests potential transmissibility in Alzheimer disease.
The aggregation of amyloid-β (Aβ) peptide and its deposition in parts of the brain form the central processes in the etiology of Alzheimer disease (AD). The low-molecular weight oligomers of Aβ aggregates (2 to 30 mers) are known to be the primary neurotoxic agents whose mechanisms of cellular toxicity and synaptic dysfunction have received substantial attention in the recent years. However, how these toxic agents proliferate and induce widespread amyloid deposition throughout the brain, and what mechanism is involved in the amplification and propagation of toxic oligomer species, are far from clear. Emerging evidence based on transgenic mice models indicates a transmissible nature of Aβ aggregates and implicates a prion-like mechanism of oligomer propagation, which manifests as the dissemination and proliferation of Aβ toxicity. Despite accumulating evidence in support of a transmissible nature of Aβ aggregates, a clear, molecular-level understanding of this intriguing mechanism is lacking. Recently, we reported the characterization of unique replicating oligomers of Aβ42 (12-24 mers) in vitro called Large Fatty Acid-derived Oligomers (LFAOs) (Kumar et al., 2012, J. Biol. Chem). In the current report, we establish that LFAOs possess physiological activity by activating NF-κB in human neuroblastoma cells, and determine the experimental parameters that control the efficiency of LFAO replication by self-propagation. These findings constitute the first detailed report on monomer - oligomer lateral propagation reactions that may constitute potential mechanism governing transmissibility among Aβ oligomers. These data support the previous reports on transmissible mechanisms observed in transgenic animal models.


Gel-based proteomics of liver cancer progression in rat.
A significant challenge in proteomics biomarker research is to identify the changes that are of highest diagnostic interest, among the many unspecific aberrations associated with disease burden and inflammation. In the present study liver tissue specimens (n=18) from six experimental stages were collected from the resistant hepatocyte (RH) rat model of liver cancer and analyzed by 2D DIGE. The study included triplicates of regenerating liver, control "sham-operated" liver, three distinct premalignant stages and hepatomas. Out of 81 identified proteins two-thirds were differentially abundant in rat hepatomas compared to control rat liver and, secondly, the majority of proteins were also changed in precursor stages. This underscores the importance of adequate control samples in explorative cancer biomarker research. We confirm several proteomic changes previously identified in human hepatocellular carcinoma (HCC) and we identify novel candidate proteomic aberrations for further analysis in human HCC. In particular, increased levels of HSP70, HSP90, AKR1B1, AKR7A3, GCLM, ANXA5, VDBP, RGN and SULT1E1 were associated specifically with rat hepatomas, or with liver cancer progression in rat. In addition, we examine an integrated gel-based workflow for analysis of protein post-translational modifications (PTMs) and microtubule-association. We highlight differential PTM and localization of HSP60 as an interesting target for further analysis in liver cancer.


PPM1D gene amplification and overexpression in breast cancer: a qRT-PCR and chromogenic in situ hybridization study.
PPM1D (protein phosphatase magnesium-dependent 1δ) maps to the 17q23.2 amplicon and is amplified in ∼8% of breast cancers. The PPM1D gene encodes a serine threonine phosphatase, which is involved in the regulation of several tumour suppressor pathways, including the p53 pathway. Along with others, we have recently shown that PPM1D is one of the drivers of the 17q23.2 amplicon and a promising therapeutic target. Here we investigate whether PPM1D is overexpressed when amplified in breast cancers and the correlations between PPM1D overexpression and amplification with clinicopathological features and survival of breast cancer patients from a cohort of 245 patients with invasive breast cancer treated with therapeutic surgery followed by adjuvant anthracycline-based chemotherapy. mRNA was extracted from representative sections of tumours containing >50% of tumour cells and subjected to TaqMan quantitative real-time PCR using primers for PPM1D and for two housekeeping genes. PPM1D overexpression was defined as the top quartile of expression levels. Chromogenic in situ hybridization with in-house-generated probes for PPM1D was performed. Amplification was defined as >50% of cancer cells with >5 signals per nucleus/large gene clusters. PPM1D overexpression and amplification were found in 25 and 6% of breast cancers, respectively. All cases harbouring PPM1D amplification displayed PPM1D overexpression. PPM1D overexpression was inversely correlated with expression of TOP2A, EGFR and cytokeratins 5/6 and 17. PPM1D amplification was significantly associated with HER2 overexpression, and HER2, TOP2A and CCND1 amplification. No association between PPM1D gene amplification and PPM1D mRNA overexpression with survival was observed. In conclusion, PPM1D is consistently overexpressed when amplified; however, PPM1D overexpression is more pervasive than gene amplification. PPM1D overexpression and amplification are associated with tumours displaying luminal or HER2 phenotypes. Co-amplification of PPM1D and HER2/TOP2A and CCND1 are not random events and may suggest the presence of a 'firestorm' genetic profile.


Dietary Salt Intake and Discretionary Salt Use in Two General Population Samples in Australia: 2011 and 2014.
The limited Australian measures to reduce population sodium intake through national initiatives targeting sodium in the food supply have not been evaluated. The aim was, thus, to assess if there has been a change in salt intake and discretionary salt use between 2011 and 2014 in the state of Victoria, Australia. Adults drawn from a population sample provided 24 h urine collections and reported discretionary salt use in 2011 and 2014. The final sample included 307 subjects who participated in both surveys, 291 who participated in 2011 only, and 135 subjects who participated in 2014 only. Analysis included adjustment for age, gender, metropolitan area, weekend collection and participation in both surveys, where appropriate. In 2011, 598 participants: 53% female, age 57.1(12.0)(SD) years and in 2014, 442 participants: 53% female, age 61.2(10.7) years provided valid urine collections, with no difference in the mean urinary salt excretion between 2011: 7.9 (7.6, 8.2) (95% CI) g/salt/day and 2014: 7.8 (7.5, 8.1) g/salt/day (p = 0.589), and no difference in discretionary salt use: 35% (2011) and 36% (2014) reported adding salt sometimes or often/always at the table (p = 0.76). Those that sometimes or often/always added salt at the table and when cooking had 0.7 (0.7, 0.8) g/salt/day (p = 0.0016) higher salt excretion. There is no indication over this 3-year period that national salt reduction initiatives targeting the food supply have resulted in a population reduction in salt intake. More concerted efforts are required to reduce the salt content of manufactured foods, together with a consumer education campaign targeting the use of discretionary salt.


Behavioral reactivity to emotion challenge is associated with cortisol reactivity and regulation at 7, 15, and 24 months of age.
Emotionally arousing stimuli have been largely unsuccessful in eliciting cortisol responses in young children. Whether or not emotion challenge will elicit a cortisol response, however, may in part be determined by the extent to which the tasks elicit behavioral reactivity and regulation. We examined relations of behavioral reactivity and regulation to emotional arousal in the context of fear and frustration to the cortisol response at 7, 15, and 24 months of age in a low income, rural population based sample of 1,292 families followed longitudinally from birth. At each age, children participated in fear and frustration inducing tasks, and cortisol samples were taken at three time points (before the tasks began, 20 min following peak emotional arousal or after the series of tasks ended, and 40 min after peak arousal or the tasks ended) in order to capture both increases (reactivity) and subsequent decreases (regulation) in the cortisol response. Using multilevel models, we predicted the cortisol response from measures of behavioral reactivity and regulation. At 7 months of age, cortisol reactivity and recovery were related to behavioral reactivity during a frustration-eliciting task and marginally related to behavioral reactivity during a fear-eliciting task. At 15 and 24 months of age, however, cortisol reactivity and recovery were related only to behavioral reactivity during a fear-eliciting task. Results indicate that while behavioral reactivity is predictive of whether or not infants and young children will exhibit a cortisol response to emotionally arousing tasks, behavioral and cortisol reactivity are not necessarily coupled.


Single point mutation in Bin/Amphiphysin/Rvs (BAR) sequence of endophilin impairs dimerization, membrane shaping, and Src homology 3 domain-mediated partnership.
Bin/Amphiphysin/Rvs (BAR) domain-containing proteins are essential players in the dynamics of intracellular compartments. The BAR domain is an evolutionarily conserved dimeric module characterized by a crescent-shaped structure whose intrinsic curvature, flexibility, and ability to assemble into highly ordered oligomers contribute to inducing the curvature of target membranes. Endophilins, diverging into A and B subgroups, are BAR and SH3 domain-containing proteins. They exert activities in membrane dynamic processes such as endocytosis, autophagy, mitochondrial dynamics, and permeabilization during apoptosis. Here, we report on the involvement of the third α-helix of the endophilin A BAR sequence in dimerization and identify leucine 215 as a key residue within a network of hydrophobic interactions stabilizing the entire BAR dimer interface. With the combination of N-terminal truncation retaining the high dimerization capacity of the third α-helices of endophilin A and leucine 215 substitution by aspartate (L215D), we demonstrate the essential role of BAR sequence-mediated dimerization on SH3 domain partnership. In comparison with wild type, full-length endophilin A2 heterodimers with one protomer bearing the L215D substitution exhibit very significant changes in membrane binding and shaping activities as well as a dramatic decrease of SH3 domain partnership. This suggests that subtle changes in the conformation and/or rigidity of the BAR domain impact both the control of membrane curvature and downstream binding to effectors. Finally, we show that expression, in mammalian cells, of endophilin A2 bearing the L215D substitution impairs the endocytic recycling of transferrin receptors.


Toy trains, loaded dice and the origin of life: dimerization on mineral surfaces under periodic drive with Gaussian inputs.
In a major extension of previous work, we model the putative hydrothermal rock pore setting for the origin of life on Earth as a series of coupled continuous flow units (the toy train). Perfusing through this train are reactants that set up thermochemical and pH oscillations, and an activated nucleotide that produces monomer and dimer monophosphates. The dynamical equations that model this system are thermally self-consistent. In an innovative step that breaks some new ground, we build stochasticity of the inputs into the model. The computational results infer various constraints and conditions on, and insights into, chemical evolution and the origin of life and its physical setting: long, interconnected porous structures with longitudinal non-uniformity would have been favourable, and the ubiquitous pH dependences of biology may have been established in the prebiotic era. We demonstrate the important role of Gaussian fluctuations of the inputs in driving polymerization, evolution and diversification. In particular, we find that the probability distribution of the resulting output fluctuations is left-skewed and right-weighted (the loaded dice), which could favour chemical evolution towards a living RNA world. We tentatively name this distribution 'Goldilocks'. These results also vindicate the general approach of constructing and running a simple model to learn important new information about a complex system.


Global research production in glyphosate intoxication from 1978 to 2015: A bibliometric analysis.
Glyphosate (N-phosphonomethylglycine) has been used as a broad-spectrum herbicide that has been widely used in the agricultural industry and also available for home use. The main aim of this study is to present a general overview of glyphosate intoxication-related publications from its introducing since the early 1970s using bibliometric technique. On June 23, 2016, a literature search of the Scopus database was performed. We then extracted and analyzed the data using well-established qualitative and quantitative bibliometric indices: Publication year, affiliation, document type, country name, subject category, journal name, publishing language, and collaboration and citation patterns. We recognized a total of 3735 publications on glyphosate published between 1973 and 2015. There were 875 publications related to glyphosate intoxication in the Scopus database published between 1978 and 2015. Articles (757) comprised 86.5% of the total publications, followed by reviews (41; 4.7%). Most publications were published in English (87.9%), followed by Portuguese (6.6%). The number of publications related to glyphosate intoxication increased from 44 in 1978-1987 up to 152 in 1996-2005 and then quadrupled in 2006-2015. The United States was the leading country with 180 documents representing 20.6%, followed by Brazil (120; 13.7%), Canada (78; 8.9%), Argentina (61; 7.0%), and France (57; 6.5%). The 85.6% of the publications was cited, and the average of citation per document was 17.13 with h-index of 55. Furthermore, the United States achieved the highest h-index of 33. Most of the global international collaborations are made with researchers from the United States, who collaborated with 23 countries/territories in 44 publications. The trends in global glyphosate-related research between 1978 and 2015 were evaluated by a bibliometric technique. Results showed that English was the leading publishing language, and the major publication type was original article. Findings showed that number of research publications related to glyphosate intoxication increased significantly in the last decade. The United States and Brazil are the two most productive countries in research on glyphosate intoxication. This study will be beneficial to policy makers by identifying areas that need greater investment and research funding to target appropriate agriculture sectors so as to improve glyphosate safety in a global setting.


Role of midgut electrogenic K+ pump potential difference in regulating lumen K+ and pH in larval lepidoptera.
Larvae of Manduca sexta were fed on tobacco leaves or synthetic diets with differing potassium content. For all diets tested, midgut lumen K+ activity coefficients were low, and midgut lumen K+ activities, K+ concentrations and pH values were as closely regulated as in blood. The transmidgut electrochemical potential difference for potassium based on activities was lower than had previously been estimated from concentrations, but was dominated by the electrical gradient established by the electrogenic K+ ATPase. Midgut K+ activities and pH profiles were similar, as would be suggested by a model in which the generation of high pH was linked to electrogenic K+ transport.


Fluorescence imaging in colorectal surgery.
Fluorescent imaging is an emerging technological tool that can guide surgeons during surgery by highlighting anatomical structures and pathology, and help with intraoperative decision making. A comprehensive review of published literature was performed using the search terms "fluorescence", "imaging" and "colorectal surgery" in PubMed. Only clinical trials that were published in English were included in this review. Ex vivo and animal studies were excluded. This review demonstrates the use of fluorescence imaging in colorectal surgery in four areas: (1) assessment of tissue perfusion and vasculature; (2) assessment of tumour; (3) lymphatic drainage and (4) identification of the urinary tract. The most commonly used fluorescent dyes are nonspecific, such as indocyanine green and methylene blue, but there is increasing interest in the development of specific fluorescently labelled molecular markers. Fluorescence imaging is a potentially useful tool for colorectal surgery. Early studies on fluorescence imaging have been promising but larger scale randomised controlled trials are warranted to demonstrate the effectiveness and benefits of using fluorescence imaging routinely. The development of molecular dyes that are specific to targets could significantly increase the potential use of fluorescence imaging during surgery.


Nicotine-induced oxidative stress contributes to EMT and stemness during neoplastic transformation through epigenetic modifications in human kidney epithelial cells.
Nicotine is a component of cigarette smoke and mounting evidence suggests toxicity and carcinogenicity of tobacco smoke in kidney. Carcinogenicity of nicotine itself in kidney and the underlying molecular mechanisms are not well-understood. Hence, the objective of this study was to determine the carcinogenic effects of chronic nicotine exposure in Hk-2 human kidney epithelial cells. The effects of nicotine exposure on the expression of genes for cellular reprogramming, redox status, and growth signaling pathways were also evaluated to understand the molecular mechanisms. Results revealed that chronic exposure to nicotine induced growth and neoplastic transformation in HK-2 cells. Increased levels of intracellular reactive oxygen species (ROS), acquired stem cell-like sphere formation, and epithelial-mesenchymal-transition (EMT) changes were observed in nicotine exposed cells. Treatment with antioxidant N-acetyl cysteine (NAC) resulted in abrogation of EMT and stemness in HK-2 cells, indicating the role of nicotine-induced ROS in these morphological changes. The result also suggests that ROS controls the stemness through regulation of AKT pathway during early stages of carcinogenesis. Additionally, the expression of epigenetic regulatory genes was altered in nicotine-exposed cells and the changes were reversed by NAC. The epigenetic therapeutics 5-aza-2'-deoxycytidine and Trichostatin A also abrogated the stemness. This suggests the nicotine-induced oxidative stress caused epigenetic alterations contributing to stemness during neoplastic transformation. To our knowledge, this is the first report showing the ROS-mediated epigenetic modifications as the underlying mechanism for carcinogenicity of nicotine in human kidney epithelial cells. This study further suggests the potential of epigenetic therapeutics for pharmacological intervention in nicotine-induced kidney cancer.


Application of a generalized random effects regression model for cluster-correlated longitudinal data to a school-based smoking prevention trial.
In cluster-randomized trials, groups of subjects (clusters) are assigned to treatments, whereas observations are taken on the individual subjects. Since observations on subjects in the same cluster are typically more similar than observations from different clusters, analyses of such data must take intracluster correlation into account rather than assuming independence among all observations. Random effects models are useful for this purpose. The problem becomes more complicated if, in addition, repeated observations are taken on subjects over time. This introduces intraindividual correlation, which is typical for longitudinal studies. The Waterloo Smoking Prevention Project, study 3 (WSPP3), 1989-1996, is a study giving rise to cluster-correlated longitudinal data, where schools were randomized to either a smoking intervention program or to a control condition. Smoking status was assessed on grade 6 students in these schools, with annual follow-up observations throughout elementary and high school years. The authors illustrate the use of a generalized random effects model for analyzing this type of data. This model obtains appropriate estimates and standard errors for both individual-level covariates and those at the level of the cluster.


The lived experience of patients in protective isolation during their hospital stay for allogeneic haematopoietic stem cell transplantation.
Patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) usually receive hospital care in protective isolation until full neutrophil recovery. Although the aim of protective isolation is to benefit patients' health by preventing risks of infection, it could have severe psychological implications. The aim of this study was to explore the lived experiences of protective isolation in adult patients who had been treated with allogeneic HSCT. A descriptive phenomenological inquiry based on Giorgi's approach was conducted in a university hospital in Italy. Ten patients (7 female and 3 male, age range 28-66), who had undergone allogeneic HSCT to treat a haematological malignancy, were interviewed about their hospital stay in protective isolation. A general meaning structure was identified as being isolated to achieve transformation. The revelatory themes were as follows: (1) the special place for transformation, (2) the experience of embodied transformation, and (3) light and shade from inside and outside. Participants experienced a transformation of themselves, of their relationships with loved ones, and of the environment. Since patients may live the experience of being treated with allogeneic HSCT in protective isolation as a transformation process, health-care providers should monitor the psychosocial implications of the isolation practice.


Efficacy of polymer coating of probiotic beads suspended in pressurized and pasteurized longan juices on the exposure to simulated gastrointestinal environment.
Alginate-coated Lactobacillus acidophilus LA5 or Lactobacillus casei 01 was recoated with either 0.1-0.5% (w/v) alginate or 0.05-0.15% (w/v) poly-L-lysine (PLL) plus 0.2% (w/v) alginate or 5-15% (w/v) gelatin, after which they were determined for survivability in gastric or bile longan juices. The morphology of encapsulated probiotic cells illustrated that recoated beads with 0.5% alginate showed a more compact surface and a greater protective effect than other recoating materials. The recoated beads with 0.5% alginate and 0.05-0.15% PLL plus 0.2% alginate of both strains showed the highest viability in gastric longan juice. In bile longan juice, only 0.5% alginate showed the best protection for both recoated beads. When considering the storage stability, encapsulated L. acidophilus LA5 exhibited a higher viable count than those of the free cells, whereas L. casei 01 showed equivalent viability of both free and double-coated cells. Based on the impact of pressurization or pasteurization, both processed juices gave rise to equivalent survivability of the probiotic cells during storage.


IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function.
Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency associated with an increased susceptibility to herpesvirus infection and hematologic malignancy as well as a deficiency of NK cell function. It is caused by defective WAS protein (WASp). WASp facilitates filamentous actin (F-actin) branching and is required for F-actin accumulation at the NK cell immunological synapse and NK cell cytotoxicity ex vivo. Importantly, the function of WASp-deficient NK cells can be restored in vitro after exposure to IL-2, but the mechanisms underlying this remain unknown. Using a WASp inhibitor as well as cells from patients with WAS, we have defined a direct effect of IL-2 signaling upon F-actin that is independent of WASp function. We found that IL-2 treatment of a patient with WAS enhanced the cytotoxicity of their NK cells and the F-actin content at the immunological synapses formed by their NK cells. IL-2 stimulation of NK cells in vitro activated the WASp homolog WAVE2, which was required for inducing WASp-independent NK cell function, but not for baseline activity. Thus, WAVE2 and WASp define parallel pathways to F-actin reorganization and function in human NK cells; although WAVE2 was not required for NK cell innate function, it was accessible through adaptive immunity via IL-2. These results demonstrate how overlapping cytoskeletal activities can utilize immunologically distinct pathways to achieve synonymous immune function.


Emotional and cognitive experiences during the time of diagnosis and decision-making following a prenatal diagnosis: a qualitative study of males presented with congenital heart defect in the fetus carried by their pregnant partner.
Expectant fathers consider the second-trimester obstetric ultrasound examination as an important step towards parenthood, but are ill prepared for a detection of a fetal anomaly. Inductive research is scarce concerning their experiences and needs for support. Consequently, the aim of this study was to explore the emotional and cognitive experiences, during the time of diagnosis and decision-making, among males presented with congenital heart defect in the fetus carried by their pregnant partner. Twelve expectant fathers were consecutively recruited through two tertiary referral centers for fetal cardiology in Sweden, after they had been presented with a prenatal diagnosis of congenital heart defect in the fetus carried by their pregnant partner. The respondents were interviewed via telephone, and the interviews were analyzed using inductive qualitative content analysis. The respondents experienced an intense emotional shock in connection with detection. However, they set their own needs aside to attend to the supportive needs of their pregnant partner, and stressed the importance of an informed joint decision regarding whether to continue or terminate the pregnancy. When terminating the pregnancy, they experienced a loss of a wanted child, an emotionally intense termination procedure, needs of support neglected by professionals, and worries about the risk of recurrence in future pregnancies. When continuing the pregnancy, they tried to keep a positive attitude about the coming birth, but were simultaneously worried about the postnatal situation. The findings illustrate the importance of inclusive care and adequate follow-up routines for both expectant parents following a prenatal diagnosis. This includes the initial emotional shock, the decisional process, and depending on decision reached, the termination or continuation of the pregnancy. Expectant fathers presented with a fetal anomaly need adequate follow-up routines to address worries about risk of recurrence in future pregnancies and worries about the postnatal situation.


Surgical management of acute type A aortic dissection: branch-first arch replacement with total aortic repair.
Acute type A dissection (ATAAD) remains a morbid condition with reported surgical mortality as high as 25%. We describe our surgical approach to ATAAD and discuss the indications for adjunct techniques such as the frozen elephant trunk or complete aortic repair with endovascular methods. Arch replacement using the "branch-first technique" allows for complete root, ascending aorta, and arch replacement. A long landing zone is created for proximal endografting with a covered stent. Balloon-assisted intimal disruption and bare metal stenting of all residual dissected aorta to the level of the aortic bifurcation is then performed to obliterate the false lumen (FL) and achieve single true lumen (TL) flow. Additional branch vessel stenting is performed as required.


Cassava breeding: opportunities and challenges.
Although cassava is a major food crop, its scientific breeding began only recently compared with other crops. Significant progress has been achieved, particularly in Asia where cassava is used mainly for industrial processes and no major biotic constraints affect its productivity. Cassava breeding faces several limitations that need to be addressed. The heterozygous nature of the crop and parental lines used to generate new segregating progenies makes it difficult to identify parents with good breeding values. Breeding so far has been mainly based on a mass phenotypic recurrent selection. There is very little knowledge on the inheritance of traits of agronomic relevance. Several approaches have been taken to overcome the constraints in the current methodologies for the genetic improvement of cassava. Evaluations at early stages of selection allow for estimates of general combining ability effect or breeding values of parental lines. Inbreeding by sequential self-pollination facilitates the identification of useful recessive traits, either already present in the Manihot gene pool or induced by mutagenesis.


Quality and cost of services for seriously mentally ill individuals in British Columbia and the United States.
To better understand the strengths and weaknesses of systems of services for seriously mentally ill individuals in Canada and the United States, the quality and cost of services in the province of British Columbia (population 3.2 million) were compared with those of services in the 50 states. A survey of selected psychiatric facilities, data from the Canadian Ministry of Health, and information from families and consumers were assessed using methods similar to those used in a 1990 survey that rated services for individuals with serious mental illness in the 50 states. Separate scores were given for hospitals, outpatient and community support services, rehabilitation services, housing, and children's services. British Columbia scored higher than any single state in the United States and more than twice as high as 40 states on the quality of services for seriously mentally ill individuals. Compared with the states, British Columbia ranked ninth in cost of services per capita. When ratings of quality and cost were combined, British Columbia appeared to be delivering services almost twice as good as those in New York State at about half the cost. However, recent trends, such as shortages of inpatient beds and increasing numbers of seriously mentally ill persons among the homeless population, suggest that British Columbia's services may be deteriorating. Probable reasons for the superior services for seriously mentally ill individuals in British Columbia include single-source funding, a strong mandate to treat such individuals, and a comprehensive approach to providing services. The Canadian health system, as implemented in British Columbia, has definite advantages for individuals with serious mental illnesses.


Anthrax toxin protective antigen is activated by a cell surface protease with the sequence specificity and catalytic properties of furin.
Proteolytic cleavage of the protective antigen (PA) protein of anthrax toxin at residues 164-167 is necessary for toxic activity. Cleavage by a cellular protease at this sequence, Arg-Lys-Lys-Arg, normally follows binding of PA to a cell surface receptor. We attempted to identify this protease by determining its sequence specificity and catalytic properties. Semi-random cassette mutagenesis was used to generate mutants with replacements of residues 164-167 by Arg, Lys, Ser, or Asn. Analysis of 19 mutant proteins suggested that lethal factor-dependent toxicity required the sequence Arg-Xaa-Xaa-Arg. Based on these data, three additional mutants were constructed with the sequences Ala-Lys-Lys-Arg, Arg-Lys-Lys-Ala, and Arg-Ala-Ala-Arg. Of these mutant proteins, Arg-Ala-Ala-Arg was toxic, confirming that the cellular protease can recognize the sequence Arg-Xaa-Xaa-Arg. The mutant containing the sequence Ala-Lys-Lys-Arg was also toxic but required > 13 times more protein to produce equivalent toxicity. This sequence specificity is similar to that of the ubiquitous subtilisin-like protease furin, which is involved in processing of precursors of certain receptors and growth factors. Therefore we tested whether a recombinant soluble furin would cleave PA. This furin derivative efficiently cleaved native PA and the Arg-Ala-Ala-Arg mutant but not the nontoxic PA mutants. In addition, previously identified inhibitors of furin blocked cleavage of receptor-bound PA. These data imply that furin is the cellular protease that activates PA, and that nearly all cell types contain at least a small amount of furin exposed on their cell surface.


Molecular divergence with major morphological consequences: development and evolution of organ size and shape.
Understanding the causes of the morphological diversity among organisms is a topic of great interest to evolutionary developmental biologists. Although developmental biologists have had great success in identifying the developmental mechanisms and molecular processes that specify organ size and shape within species, only relatively recently have the molecular tools become available to study how variation in these mechanisms gives rise to the phenotypic differences that are observed among closely related species. In addition to these technological advances, researchers interested in understanding how molecular variation gives rise to phenotypic variation have used three primary strategies to identify the molecular differences underlying species-specific traits: the candidate gene approach, differential gene expression screens, and between-species genetic mapping experiments. In this review, we discuss how these approaches have been successful in identifying the genes and the cellular mechanisms by which they specify variation in one of the most recognizable examples of the evolution of organ size, the adaptive variation in beak morphology among Darwin's finches. We also discuss insect reproductive structures as a model with great potential to advance our understanding of the specification and evolution of organ size and shape differences among species. The results from these two examples, and those from other species, show that species-specific variation in organ size and shape typically evolves via changes in the timing, location, and amount of gene/protein expression that act on tissue growth processes.


Ways of thinking: from crows to children and back again.
This article reviews some of the recent work on the remarkable cognitive capacities of food-caching corvids. The focus will be on their ability to think about other minds and other times, and tool-using tests of physical problem solving. Research on developmental cognition suggests that young children do not pass similar tests until they are at least four years of age in the case of the social cognition experiments, and eight years of age in the case of the tasks that tap into physical cognition. This developmental trajectory seems surprising. Intuitively, one might have thought that the social and planning tasks required more complex forms of cognitive process, namely Mental Time Travel and Theory of Mind. Perhaps the fact that children pass these tasks earlier than the physical problem-solving tasks is a reflection of cultural influences. Future research will hope to identify these cognitive milestones by starting to develop tasks that might go some way towards understanding the mechanisms underlying these abilities in both children and corvids, to explore similarities and differences in their ways of thinking.


Basal body reorientation mediated by a Ca2+-modulated contractile protein.
A rapid, Ca2+-dependent change in the angle between basal bodies (up to 180 degrees) is associated with light-induced reversal of swimming direction (the "photophobic" response) in a number of flagellated green algae. In isolated, detergent-extracted, reactivated flagellar apparatus complexes of Spermatozopsis similis, axonemal beat form conversion to the symmetrical/undulating flagellar pattern and basal body reorientation (from the antiparallel to the parallel configuration) are simultaneously induced at greater than or equal to 10(-7) M Ca2+. Basal body reorientation, however, is independent of flagellar beating since it is induced at greater than or equal to 10(-7) M Ca2+ when flagellar beating is inhibited (i.e., in the presence of 1 microM orthovanadate in reactivation solutions; in the absence of ATP or dithiothreitol in isolation and reactivation solutions), or when axonemes are mechanically removed from flagellar apparatuses. Although frequent axonemal beat form reversals were induced by varying the Ca2+ concentration, antiparallel basal body configuration could not be restored in isolated flagellar apparatuses. Observations of the photophobic response in vivo indicate that even though the flagella resume the asymmetric, breaststroke beat form 1-2 s after photostimulation, antiparallel basal body configuration is not restored until a few minutes later. Using an antibody generated against the 20-kD Ca2+-modulated contractile protein of striated flagellar roots of Tetraselmis striata (Salisbury, J. L., A. Baron, B. Surek, and M. Melkonian, 1984, J. Cell Biol., 99:962-970), we have found the distal connecting fiber of Spermatozopsis similis to be immunoreactive by indirect immunofluorescence and immunogold electron microscopy. Electrophoretic and immunoblot analysis indicates that the antigen of S. similis flagellar apparatuses consists, like the Tetraselmis protein, of two acidic isoforms of 20 kD. We conclude that the distal basal body connecting fiber is a contractile organelle and reorients basal bodies during the photophobic response in certain flagellated green algae.


rSeqDiff: detecting differential isoform expression from RNA-Seq data using hierarchical likelihood ratio test.
High-throughput sequencing of transcriptomes (RNA-Seq) has recently become a powerful tool for the study of gene expression. We present rSeqDiff, an efficient algorithm for the detection of differential expression and differential splicing of genes from RNA-Seq experiments across multiple conditions. Unlike existing approaches which detect differential expression of transcripts, our approach considers three cases for each gene: 1) no differential expression, 2) differential expression without differential splicing and 3) differential splicing. We specify statistical models characterizing each of these three cases and use hierarchical likelihood ratio test for model selection. Simulation studies show that our approach achieves good power for detecting differentially expressed or differentially spliced genes. Comparisons with competing methods on two real RNA-Seq datasets demonstrate that our approach provides accurate estimates of isoform abundances and biological meaningful rankings of differentially spliced genes. The proposed approach is implemented as an R package named rSeqDiff.


Severely Burdened Individuals Do Not Need to Be Excluded From Internet-Based and Mobile-Based Stress Management: Effect Modifiers of Treatment Outcomes From Three Randomized Controlled Trials.
Although internet-based and mobile-based stress management interventions (iSMIs) may be a promising strategy to reach employees suffering from high chronic stress, it remains unknown whether participants with high symptom severity of depression or anxiety also benefit from iSMIs or should be excluded. This study aimed to evaluate the efficacy of iSMIs in subgroups with high symptom severity and to test whether baseline symptom severity moderates treatment outcome. Data from three randomized controlled trials (N=791) were pooled to identify effect modifiers and to evaluate efficacy in subgroups with different levels of initial symptom severity. The outcomes perceived stress (Perceived Stress Scale, PSS), depression severity (Center for Epidemiological Depression Scale, CES-D), and anxiety (Hospital Anxiety and Depression Scale, HADS) symptom severity were assessed at baseline, 7-week postassessment, and 6-month follow-up. Potential moderators were tested in predicting differences in the change of outcome in multiple moderation analyses. Simple slope analyses evaluated efficacy of the iSMI comparing the intervention group with the waitlist control group in subgroups with low, moderate, and severe initial symptomology based on means and SDs of the study population. In addition, subgroups with clinical values of depression (CES-D≥16) and anxiety (HADS≥8) at baseline were explored, and response rates (RRs; 50% symptom reduction) and symptom-free (SF) status (CES-D<16, HADS<8) were reported. Individuals with high stress (PSS≥30), depression (CES-D≥33), anxiety (HADS≥15), and emotional exhaustion (MBI≥5.6) benefited significantly from the intervention with great reductions of stress (dpost=0.86-1.16, dFU=0.93-1.35), depression (dpost=0.69-1.08, dFU=0.91-1.19), and anxiety (dpost=0.79-1.19, dFU=1.06-1.21), and effects were sustained at 6-month follow-up. Symptom severity moderated treatment outcomes, as individuals with higher symptom severity at baseline benefited significantly more from the intervention than individuals with lower symptom severity. Furthermore, 82.9% (656/791) of individuals had clinical depression values at baseline, of which significantly more individuals in the intervention group reached at least 50% symptom reduction or fell under clinical cut-off (RR: 29.2%, 93/318; SF: 39.6%, 126/318) compared with the waitlist control group (RR: 8.0%, 27/338; SF: 18.6%, 63/338) at postassessment. Significantly more individuals with clinical anxiety values at baseline (HADS≥8, 85.3%, 675/791) in the intervention group achieved at least 50% symptom reduction or fell under clinical cut-off (RR: 27.7%, 94/339; SF: 39.8%, 135/339) compared with the WLC (RR: 4.8%, 16/336; SF: 15.5%, 52/336). Highly burdened individuals benefit greatly from iSMIs and therefore should not be excluded from participation. Stress management may be a valid entry point to reach highly burdened individuals who otherwise may not seek treatment. 1) German Clinical Trials Register DRKS00005112; https://www.drks.de/DRKS00005112 (Archived by WebCite at http://www.webcitation.org/6zmIZwvdA); 2) German Clinical Trials Register DRKS00005384; https://www.drks.de/ DRKS00005384 (Archived by WebCite at http://www.webcitation.org/6zmIerdtr); and 3) German Clinical Trials Register DRKS00004749; https://www.drks.de/DRKS00004749 (Archived by WebCite at http://www.webcitation.org/6zmIjDQPx).


Block of potassium channels and facilitation of acetylcholine release at the neuromuscular junction by the venom of the scorpion, Pandinus imperator.
Venom from the scorpion Pandinus imperator potently and selectively blocks voltage-gated K+ channels in bullfrog neurones (Pappone, P. A. and Cahalan, M. D. 1987, J. Neurosci. 7, 3300-3305). Its effects on neuromuscular transmission have now been assessed. Twitch tension studies on chick biventer cervicis preparations showed that the venom (1 microgram/ml and above) significantly augmented responses to nerve but not muscle stimulation; there was little change in postjunctional sensitivity to cholinoceptor agonists or K+-induced depolarization. Electrophysiological studies on mouse triangularis sterni preparations revealed that the venom had no effect on spontaneous transmitter release, but increased evoked transmitter release. Extracellular recordings of nerve terminal action potentials showed that the venom selectively reduced the component of the waveform associated with K+ currents. These results confirm that this venom can selectively block neuronal K+ currents, and they show that this can facilitate the release of acetylcholine at the neuromuscular junction.


Effects of Acid Treatment on Dental Zirconia: An In Vitro Study.
The aim of this study was to evaluate the effects of hydrofluoric (HF) acid, acetic acid, and citric acid treatments on the physical properties and structure of yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) at ambient temperature. In total, 110 bar-shaped zirconia specimens were randomly assigned to 11 groups. The specimens in the control group (C) received no surface treatment, while those in the Cage group were hydrothermally aged at 134°C and 0.2 MPa for 20 h. Ten specimens each were immersed at ambient temperature in 5% and 40% HF acid for 2 h (40HF0), 1 day (5HF1, 40HF1), and 5 days (5HF5, 40HF5), while 10 each were immersed at ambient temperature in 10% acetic acid and 20% citric acid for 7 (AC7, CI7) and 14 days (AC14, CI14). X-ray diffraction (XRD) was used to quantitatively estimate the monoclinic phase. Furthermore, flexural strength, surface roughness, and surface Vickers hardness were measured after treatment. Scanning electron microscopy (SEM) was used to characterize the surface morphology. The Cage group specimens exhibited an increased monoclinic phase and flexural strength. Furthermore, 40% HF acid immersion decreased the flexural strength and surface hardness and deteriorated the surface finish, while 5% HF acid immersion only decreased the surface hardness. All the HF acid-immersed specimens showed an etched surface texture on SEM observations, while the other groups did not. These findings suggest that the treatment of Y-TZP with 40% HF acid at ambient temperature causes potential damage, while treatment with 5% HF acid, acetic acid, and citric acid is safe.


DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling.
The disrupted in schizophrenia 1 (DISC1) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role in the disorder is unknown. Here we report that the gene encoding phosphodiesterase 4B (PDE4B) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The PDEs inactivate adenosine 3',5'-monophosphate (cAMP), a second messenger implicated in learning, memory, and mood. We show that DISC1 interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and an increase in PDE4B activity. We propose a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.


EPR study of mouse tissues in search for adaptive responses to low level whole-body X-irradiation.
Effect of a low dose of whole-body X-irradiation (D1 = 0.075 Gy) of mice on some biochemical changes induced in the spleen and thymus by a subsequent challenge dose (D2 = 1.5 Gy) was studied by electron paramagnetic resonance (EPR). Kunming and SHK mice were used. Concentration of ribonucleotide reductase (RR) in the spleen and thymus of unirradiated Kunming mice was 0.70 and 0.46 microM respectively, and of unirradiated SKH mice--0.37 and 0.21 microM respectively (systematic error 45%). For mice exposed only to the low dose (D1 group), a stimulating effect on RR activity in spleen and thymus was found, while in mice subjected only to the D2 dose (D2 group) activity of the enzyme in the organs decreased considerably 18 h after irradiation. The group of mice irradiated with D1 and D2 doses, given at a 6-h interval (D1 plus D2 group), showed a RR activity in the organs lower than D1 and higher than D2 groups. This finding indicates that there exists an adaptation-like response to a low-dose whole-body irradiation in murine spleen and thymus. This low 'inductive' dose makes the organs' RR less susceptible to inhibition induced by a subsequent challenge dose. Preliminary results showed that the same kind of response is probably a characteristic of the RR content of splenocytes as well as of the rate of thymidine incorporation into splenocytes. 5-Thyml radicals of DNA (TH radicals) induced in whole tissues by gamma-irradiation in vitro at 77 K were also studied. Radiochemical yield of these radicals (4.0 and 5.3 nmol j-1), for spleen and thymus respectively of unirradiated Kunming mice, and 2.3 and 2.6 nmol J-1, for spleen and thymus respectively of unirradiated SHK mice (systematic error 30%), decreased significantly in both organs upon D2 irradiation. This decrease, however, was the consequence of DNA content diminishing upon D2 irradiation rather than change of DNA radiosensitivity: the beta value of TH radicals, i.e. yield of radicals per unit mass of DNA in each organ was equal for the mice from all D1, D1 plus D2, D2 and control groups. The beta values of TH radicals in mouse spleen and thymus were of the same order of magnitude compared with the yield of the single-strand breaks of DNA measured previously in rat organs just after whole-body irradiation, i.e. about 1 x 10(2) (Gy x 10(12) Da)-1.


Ethnic differences in internal medicine referrals and diagnosis in the Netherlands.
As in other Western countries, the number of immigrants in the Netherlands is growing rapidly. In 1980 non-western immigrants constituted about 3% of the population, in 1990 it was 6% and currently it is more than 10%. Nearly half of the migrant population lives in the four major cities. In the municipality of Rotterdam 34% of the inhabitants are migrants. Health policy is based on the ideal that all inhabitants should have equal access to health care and this requires an efficient planning of health care resources, like staff and required time per patient. The aim of this study is to examine ethnic differences in the use of internal medicine outpatient care, specifically to examine ethnic differences in the reason for referral and diagnosis. We conducted a study with an open cohort design. We registered the ethnicity, sex, age, referral reasons, diagnosis and living area of all new patients that visited the internal medicine outpatient clinic of the Erasmus Medical Centre in Rotterdam (Erasmus MC) for one year (March 2002-2003). Additionally, we coded referrals according to the International Classification of Primary Care (ICPC) and categorised diagnosis according to the Diagnosis Treatment Combination (DTC). We analysed data by using Poisson regression and logistic regression. All ethnic minority groups (Surinam, Turkish, Moroccan, Antillean/Aruban and Cape Verdean immigrants) living in Rotterdam municipality, make significantly more use of the outpatient clinic than native Dutch people (relative risk versus native Dutch people was 1.83, 1.97, 1.79, 1.65 and 1.88, respectively). Immigrant patients are more likely to be referred for analysis and treatment of 'gastro-intestinal signs & symptoms' and were less often referred for 'indefinite, general signs'. Ethnic minorities were more frequently diagnosed with 'Liver diseases', and less often with 'Analysis without diagnosis'. The increased use of the outpatient facilities seems to be restricted to first-generation immigrants, and is mainly based on a higher risk of being referred with 'gastro-intestinal signs & symptoms'. These findings demonstrate substantial ethnic differences in the use of the outpatient care facilities. Ethnic differences may decrease in the future when the proportion of first-generation immigrants decreases. The increased use of outpatient health care seems to be related to ethnic background and the generation of the immigrants rather than to socio-economic status. Further study is needed to establish this.


Mechanisms of disease: aquaporin-4 antibodies in neuromyelitis optica.
Neuromyelitis optica (NMO) is a rare CNS inflammatory disorder that predominantly affects the optic nerves and spinal cord. Recent serological findings strongly suggest that NMO is a distinct disease rather than a subtype of multiple sclerosis. In NMO, serum antibodies, collectively known as NMO-IgG, characteristically bind to cerebral microvessels, pia mater and Virchow-Robin spaces. The main target antigen for this immunoreactivity has been identified as aquaporin-4 (AQP4). The antibodies are highly specific for NMO, and they are also found in patients with longitudinally extensive transverse myelitis without optic neuritis, which is thought to be a precursor to NMO in some cases. An antibody-mediated pathogenesis for NMO is supported by several observations, including the characteristics of the AQP4 antibodies, the distinct NMO pathology--which includes IgG and complement deposition and loss of AQP4 from spinal cord lesions--and emerging evidence of the beneficial effects of B-cell depletion and plasma exchange. Many aspects of the pathogenesis, however, remain unclear.


Neural decoding of visual stimuli varies with fluctuations in global network efficiency.
Functional magnetic resonance imaging (fMRI) studies have shown that neural activity fluctuates spontaneously between different states of global synchronization over a timescale of several seconds. Such fluctuations generate transient states of high and low correlation across distributed cortical areas. It has been hypothesized that such fluctuations in global efficiency might alter patterns of activity in local neuronal populations elicited by changes in incoming sensory stimuli. To test this prediction, we used a linear decoder to discriminate patterns of neural activity elicited by face and motion stimuli presented periodically while participants underwent time-resolved fMRI. As predicted, decoding was reliably higher during states of high global efficiency than during states of low efficiency, and this difference was evident across both visual and nonvisual cortical regions. The results indicate that slow fluctuations in global network efficiency are associated with variations in the pattern of activity across widespread cortical regions responsible for representing distinct categories of visual stimulus. More broadly, the findings highlight the importance of understanding the impact of global fluctuations in functional connectivity on specialized, stimulus driven neural processes. Hum Brain Mapp 38:3069-3080, 2017. © 2017 Wiley Periodicals, Inc.


Activated TLR signaling in atherosclerosis among women with lower Framingham risk score: the multi-ethnic study of atherosclerosis.
Atherosclerosis is the leading cause of cardiovascular disease (CVD). Traditional risk factors can be used to identify individuals at high risk for developing CVD and are generally associated with the extent of atherosclerosis; however, substantial numbers of individuals at low or intermediate risk still develop atherosclerosis. A case-control study was performed using microarray gene expression profiling of peripheral blood from 119 healthy women in the Multi-Ethnic Study of Atherosclerosis cohort aged 50 or above. All participants had low (<10%) to intermediate (10% to 20%) predicted Framingham risk; cases (N = 48) had coronary artery calcium (CAC) score >100 and carotid intima-media thickness (IMT) >1.0 mm, whereas controls (N = 71) had CAC<10 and IMT <0.65 mm. We identified two major expression profiles significantly associated with significant atherosclerosis (odds ratio 4.85; P<0.001); among those with Framingham risk score <10%, the odds ratio was 5.30 (P<0.001). Ontology analysis of the gene signature reveals activation of a major innate immune pathway, toll-like receptors and IL-1R signaling, in individuals with significant atherosclerosis. Gene expression profiles of peripheral blood may be a useful tool to identify individuals with significant burden of atherosclerosis, even among those with low predicted risk by clinical factors. Furthermore, our data suggest an intimate connection between atherosclerosis and the innate immune system and inflammation via TLR signaling in lower risk individuals.


Shear thickening in concentrated suspensions: phenomenology, mechanisms and relations to jamming.
Shear thickening is a type of non-Newtonian behavior in which the stress required to shear a fluid increases faster than linearly with shear rate. Many concentrated suspensions of particles exhibit an especially dramatic version, known as Discontinuous Shear Thickening (DST), in which the stress suddenly jumps with increasing shear rate and produces solid-like behavior. The best known example of such counter-intuitive response to applied stresses occurs in mixtures of cornstarch in water. Over the last several years, this shear-induced solid-like behavior together with a variety of other unusual fluid phenomena has generated considerable interest in the physics of densely packed suspensions. In this review, we discuss the common physical properties of systems exhibiting shear thickening, and different mechanisms and models proposed to describe it. We then suggest how these mechanisms may be related and generalized, and propose a general phase diagram for shear thickening systems. We also discuss how recent work has related the physics of shear thickening to that of granular materials and jammed systems. Since DST is described by models that require only simple generic interactions between particles, we outline the broader context of other concentrated many-particle systems such as foams and emulsions, and explain why DST is restricted to the parameter regime of hard-particle suspensions. Finally, we discuss some of the outstanding problems and emerging opportunities.


Methyl mercury exposure at Niigata, Japan: results of neurological examinations of 103 adults.
Large-scale poisonings caused by methyl mercury (MeHg) have occurred in Japan (Minamata in the 1950s and Niigata in the 1960s) and Iraq (in the 1970s). The current WHO neurological risk standard for adult exposure (hair level: 50 μg/g) was based partly on evidence from Niigata which did not consider any cases who were diagnosed later and/or exposed to low level of MeHg (hair mercury level less than 50 μg/g). Early in the Niigata epidemic in June 1965 there were two extensive surveys. From these two surveys, we examined 103 adults with hair mercury measurement who consulted two medical institutions. We compared the prevalence and the distribution of neurological signs related to MeHg poisoning between exposure categories. We found 48 subjects with neurological signs related to MeHg poisoning who had hair mercury concentration less than 50 μg/g. Among the neurological signs, sensory disturbance of the bilateral distal extremities was observed more frequently, followed by disequilibrium, hearing impairment, and ataxia, in groups with hair MeHg concentration both below 50 μg/g and over 50 μg/g. The present study suggests the possibility that exposure to MeHg at levels below the current WHO limits could cause neurologic signs, in particular, sensory disturbance.