Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway.
Drug resistance represents a major challenge for treating patients with colon cancer. Accumulating evidence suggests that Insulin-like growth factor (IGF)-associated signaling promotes colon tumorigenesis and cancer stemness. Therefore, the identification of agents, which can disrupt cancer stemness signaling, may provide improved therapeutic efficacy. Mimicking the tumor microenvironment, we treated colon cancer cells with exogenous IGF1. The increased stemness of IGF1-cultured cells was determined by ALDH1 activity, side-population, tumor sphere formation assays. Destruxin B (DB) was evaluated for its anti-tumorigenic and stemness properties using cellular viability, colony-formation tests. The mimic and inhibitor of miR-214 were used to treat colon cancer cells to show its functional association to DB treatment. In vivo mouse models were used to evaluate DB's ability to suppress colon tumor-initiating ability and growth inhibitory function. IGF1-cultured colon cancer cells showed a significant increase in 5-FU resistance and enhanced stemness properties, including an increased percentage of ALDH1+, side-population cells, tumor sphere generation in vitro, and increased tumor initiation in vivo. In support, using public databases showed that increased IGF1 expression was significantly associated with a poorer prognosis in patients with colon cancer. DB, a hexadepsipeptide mycotoxin, was able to suppress colon tumorigenic phenotypes, including colony and sphere formation. The sequential treatment of DB, followed by 5-FU, synergistically inhibited the viability of colon cancer cells. In vivo studies showed that DB suppressed the tumorigenesis by 5-FU resistant colon cells, and in a greater degree when combined with 5-FU. Mechanistically, DB treatment was associated with decreased the mammalian target of rapamycin (mTOR) and β-catenin expression and an increased miR-214 level. We provided evidence of DB as a potential therapeutic agent for overcoming 5-FU resistance induced by IGF1, and suppressing cancer stem-like properties in association with miR-214 regulation. Further investigation is warranted for its translation to clinical application.


Men's judgments of women's facial attractiveness from two- and three-dimensional images are similar.
Although most research on human facial attractiveness has used front-facing two-dimensional (2D) images, our primary visual experience with faces is in three dimensions. Because face coding in the human visual system is viewpoint-specific, faces may be processed differently from different angles. Thus, results from perceptual studies using front-facing 2D facial images may not be generalizable to other viewpoints. We used rotating three-dimensional (3D) images of women's faces to test whether men's attractiveness ratings of women's faces from 2D and 3D images differed. We found a significant positive correlation between men's judgments of women's facial attractiveness from 2D and 3D images (r = 0.707), suggesting that attractiveness judgments from 2D images are valid and provide similar information about women's attractiveness as do 3D images. We also found that women's faces were rated significantly more attractive in 3D images than in 2D images. Our study verifies a novel method using 3D facial images, which may be important for future research on viewpoint-specific social perception. This method may also be valuable for the accurate measurement and assessment of facial characteristics such as averageness, identity, attractiveness, and emotional expression.


Heritability of macular pigment: a twin study.
Several studies have reported higher levels of macular pigment (MP) in association with reduced risk for age-related macular degeneration (ARMD), a disease to which there is a genetic predisposition. A classic twin study was performed to determine the heritability of MP in the healthy eye. One hundred fifty twin pairs (76 monozygotic [MZ] and 74 dizygotic [DZ]), aged 18 to 50 years, participated. MP optical density was measured psychophysically with heterochromatic flicker photometry (HFP) and also with an imaging method involving fundus autofluorescence (AF). The covariance of MP within MZ and DZ twin pairs was compared, and genetic modeling techniques were used to determine the relative contributions of genes and environment to the variation in MP. The mean MP optical density, measured using HFP, was 0.43 +/- 0.21. Using AF, the mean MP optical density, measured at 1 degrees eccentricity, was 0.28 +/- 0.11. MP optical densities correlated more highly in MZ twins than in DZ twins, according to both HFP (MZ: 0.65; DZ: 0.24) and AF (MZ: 0.83; DZ: 0.50). A model combining additive genetic and unique environmental effects provided the best fit and resulted in MP heritability estimates of 0.67 (95% CI, 0.52-0.77) and 0.85 (95% CI, 0.78-0.90) for HFP and AF readings, respectively. This classic twin study demonstrates that genetic background is an important determinant of MP optical density, reflected in heritability estimates of 0.67 and 0.85 for HFP and AF measures, respectively.


Diagnostic prevalence rates from early to mid-adolescence among indigenous adolescents: first results from a longitudinal study.
Investigate change in prevalence rates for mental and substance abuse disorders between early and mid-adolescence among a cohort of indigenous adolescents. The data are from a lagged, sequential study of 651 indigenous adolescents from a single culture in the northern Midwest United States and Canada. At waves 1 (ages 10-12 years) and 4 (ages 13-15 years), one adult caretaker and one tribally enrolled adolescent completed a computer-assisted personal interview that included Diagnostic Interview Schedule for Children-Revised assessment for 11 diagnoses. Multivariate analyses investigate effects of wave 1 adolescent diagnosis and wave 1 biological mother diagnosis (University of Michigan Composite International Diagnostic Interview) on wave 4 diagnostic outcomes. The findings show a increase in prevalence rates for substance abuse disorders and conduct disorders between ages 10 and 12 years and 13 and 15 years among indigenous adolescents, with these disorders affecting more than one fourth of the children. The rate of lifetime conduct disorder is about twice that expected in general population studies (23.4% versus 5%-10%), and the rate of lifetime substance abuse disorder (27.2%) is three times that reported in the 2004 National Survey on Drug Use and Health (9.4%) for individuals 12 years or older. Prevalence rates for any single mental or substance use disorder (44.8 lifetime) for the 13- to 15-year-olds are similar to the lifetime prevalence rates reported in the National Comorbidity Survey-Replication (46.4%) for individuals 18 years and older. A mental health crisis exists on the indigenous reservations and reserves that participated in this study. Current service systems are overwhelmed and unable to meet the demands placed upon them.


Associations with rhizosphere bacteria can confer an adaptive advantage to plants.
Host-associated microbiomes influence host health. However, it is unclear whether genotypic variations in host organisms influence the microbiome in ways that have adaptive consequences for the host. Here, we show that wild accessions of Arabidopsis thaliana differ in their ability to associate with the root-associated bacterium Pseudomonas fluorescens, with consequences for plant fitness. In a screen of 196 naturally occurring Arabidopsis accessions we identified lines that actively suppress Pseudomonas growth under gnotobiotic conditions. We planted accessions that support disparate levels of fluorescent Pseudomonads in natural soils; 16S ribosomal RNA sequencing revealed that accession-specific differences in the microbial communities were largely limited to a subset of Pseudomonadaceae species. These accession-specific differences in Pseudomonas growth resulted in enhanced or impaired fitness that depended on the host's ability to support Pseudomonas growth, the specific Pseudomonas strains present in the soil and the nature of the stress. We suggest that small host-mediated changes in a microbiome can have large effects on host health.


Transcatheter mitral valve repair for functional mitral regurgitation using the Cardioband system: 1 year outcomes.
The Cardioband™ (Edwards Lifesciences) is a transcatheter implant designed to reduce mitral annulus size and mitral regurgitation (MR) severity. We report the 1-year outcomes of consecutive patients who underwent the Cardioband procedure between 2013 and 2016. Sixty patients with moderate or severe secondary MR (72 ± 7 years, 60% ischaemic origin) on guideline-recommended medical therapy were treated and analyzed at 11 European institutions. There were two in-hospital deaths (none device-related), one stroke, two coronary artery complications, and one tamponade. Anchor disengagement, observed in 10 patients (all but one in the first half of the population), resulted in device inefficacy in five patients and led to device modification half way through the study to mitigate this issue. Technical, device, and procedural successes, assessed based on Mitral Valve Academic Research Consortium (MVARC) criteria, were 97% (58/60), 72% (43/60), and 68% (41/60), respectively. At 1-year, overall survival, survival free of readmission for heart failure, and survival free of reintervention (performed in seven patients) were 87%, 66%, and 78%, respectively. In the overall population, MR grade at 12 months was moderate or less 61% and moderate or less in 95% of the 39 patients who underwent a transthoracic echocardiography at 1-year [but worsened by at least one grade in 11 patients (22%)]. Functional status (79% vs. 14% in New York Heart Association Class I/II), quality of life (-19 points on the Minnesota Living with Heart Failure Questionnaire score), and exercise capacity (+58 m by 6MWT) improved significantly (all P < 0.01). In this multicentre trial, the Cardioband mitral system demonstrated reasonable performance and safety. At 1 year, most patients had moderate or less MR and experienced significant functional improvements. A randomized controlled trial is underway to demonstrate the impact of Cardioband in patients on guideline-directed medical therapy.


Colorectal disorders: A dietary management perspective.
Dietary lifestyle is relevant for prevention and treatment of various colorectal conditions. Colorectal disorders have significant morbidity and mortality in a western-style community, particularly irritable bowel syndrome (IBS), colorectal cancer, haemorrhoids, constipation and diverticular disease. This review addresses how bowel health can be maintained, what foods and dietary lifestyles are associated with risk for disease and what foods are of real value in management. Bowel health is that state where the individual is satisfied with defaecation, the diet does not create undue risk for disease and lumenal contents maintain an intact and functional mucosa. Bowel health depends on a healthy dietary lifestyle, but in particular on an adequate intake of non-digestable dietary polysaccharide. Diet influences biology in part by altering the lumenal environment. Effects such as high butyrate levels, lowered pH, a predominance of 'healthy'over 'unhealthy' bacteria, rapid intestinal transit, high faecal bulk, a non-leaky epithelial barrier, adsorption of dietary carcinogens by fibre, low bile salt concentrations, reduced generation of toxic bile salts or protein derivatives and provision of certain bioactive substances are seen as beneficial. Diet influences future risk for colorectal cancer (vegetables, animal fats, polysaccharides amongst others) and for diverticular disease (fibre). Adequate fibre and resistant starch can improve constipation and anorectal conditions such as fissure and haemorrhoids. The role of diet in managing patients with IBS is complex. Fibre may worsen symptoms in severe cases of IBS, diverticular disease and inflammatory bowel disease. Certain carbohydrates of limited digestibility/absorbability, such as lactose, fructose and sorbitol, can precipitate IBS symptoms. Low fat, high fibre diets may reduce recurrence of colorectal adenomas. Diet has a significant role to play in colorectal disorders.


Expression of recombinant Plasmodium falciparum subtilisin-like protease-1 in insect cells. Characterization, comparison with the parasite protease, and homology modeling.
Serine proteases play crucial roles in erythrocyte invasion by merozoites of the malaria parasite. Plasmodium falciparum subtilisin-like protease-1 (PfSUB-1) is synthesized during maturation of the intraerythrocytic parasite and accumulates in a set of merozoite secretory organelles, suggesting that it may play a role in host cell invasion or post-invasion events. We describe the production, purification, and characterization of recombinant PfSUB-1 and comparison with the authentic protease detectable in parasite extracts. The recombinant protease requires high levels of calcium for optimum activity and has an alkaline pH optimum. Using a series of decapeptide and protein substrates, PfSUB-1 was found to have a relaxed substrate specificity with regard to the P1 position but is unable to efficiently cleave substrates with a P1 leucine residue. Similarly, replacement of a P4 valine with alanine severely reduced cleavage efficiency, whereas its replacement with lysine abolished cleavage. In all respects investigated, the recombinant protease was indistinguishable from parasite-derived enzyme. Three-dimensional homology modeling of the PfSUB-1 catalytic domain based on an alignment with closely related bacterial subtilisins and an orthologue from the rodent malaria Plasmodium yoelii suggests that the protease has at least three potential calcium ion-binding sites, three intramolecular disulfide bridges, and a single free cysteine within the enzyme S1 pocket. A predicted highly polar S1 pocket and a hydrophobic S4 subsite are in broad agreement with the experimentally determined substrate specificity.


Consensus recommendations for immunosuppressive treatment of dogs with glomerular disease based on established pathology.
The purpose of this report was to provide consensus recommendations for the use of immunosuppressive therapy in dogs with active glomerular diseases. Recommendations were developed based on comprehensive review of relevant literature on immunosuppressive therapy of glomerular disease in dogs and humans, contemporary expert opinion, and anecdotal experience in dogs with glomerular disease treated with immunosuppression. Recommendations were subsequently validated by a formal consensus methodology. The Study Group recommends empirical application of immunosuppressive therapy for dogs with severe, persistent, or progressive glomerular disease in which there is evidence of an active immune-mediated pathogenesis on kidney biopsy and no identified contraindication to immunosuppressive therapy. The most compelling evidence supporting active immune-mediated mechanisms includes electron-dense deposits identified with transmission electron microscopic examination and unequivocal immunofluorescent staining in the glomeruli. For diseases associated with profound proteinuria, attendant hypoalbuminemia, nephrotic syndrome, or rapidly progressive azotemia, single drug or combination therapy consisting of rapidly acting immunosuppressive drugs is recommended. The Study Group recommends mycophenolate alone or in combination with prednisolone. To minimize the adverse effects, glucocorticoids should not be used as a sole treatment, and when used concurrently with mycophenolate, glucocorticoids should be tapered as quickly as possible. For stable or slowly progressive glomerular diseases, the Study Group recommends mycophenolate or chlorambucil alone or in combination with azathioprine on alternating days. Therapeutic effectiveness should be assessed serially by changes in proteinuria, renal function, and serum albumin concentration. In the absence of overt adverse effects, at least 8 weeks of the rapidly acting nonsteroidal drug therapy and 8-12 weeks of slowly acting drug therapy should be provided before altering or abandoning an immunosuppressive trial.


Sympathoadrenal responses to bronchoconstriction in asthma: an invasive and kinetic study of plasma catecholamines.
1. Bronchoconstriction does not seem to be a stimulus for sympathoadrenal activation, as judged by venous plasma concentrations of noradrenaline, adrenaline or neuropeptide Y-like immunoreactivity. However, venous measurements have methodological drawbacks. In the present study arterial and mixed venous (pulmonary arterial) levels of these variables were determined before and after histamine-induced bronchoconstriction in non-medicated asthmatic subjects. In addition, noradrenaline kinetics in plasma (isotope dilution) and the pulmonary overflows of noradrenaline and neuropeptide Y-like immunoreactivity were determined. 2. Histamine inhalation induced bronchoconstriction; forced expiratory volume in ls decreased by 38.7% +/- 4.1% (SE) and arterial PO2 by 3.0 +/- 0.9 kPa. This acute bronchoconstriction induced significant elevations of arterial and mixed venous plasma noradrenaline from < or = 1.18 nmol/l to > or = 1.40 nmol/l. The clearance of NA from plasma increased marginally. Thus, the arterial plasma NA response was due to increased spillover of noradrenaline to plasma (from 1.80 +/- 0.18 to 2.52 +/- 0.36 mmol min-1/m2 at maximal bronchoconstriction, with a subsequent further increase). There were no elevations of adrenaline or neuropeptide Y-like immunoreactivity in arterial plasma. 3. No sympathetic activation could be demonstrated in the lungs (pulmonary noradrenaline or neuropeptide Y-like immunoreactivity overflow), and no alterations in pulmonary vascular resistance or cardiac output were observed. Neither arterial nor mixed venous plasma concentrations of adrenaline were influenced by bronchoconstriction. 4. Acute bronchoconstriction thus leads to peripheral sympathetic activation (possibly due to the increased work of breathing) which does not involve the lungs.(ABSTRACT TRUNCATED AT 250 WORDS)


Emerging souvenirs-clinical presentation of the returning traveller with imported arbovirus infections in Europe.
Arboviruses are an emerging group of viruses that are causing increasing health concerns globally, including in Europe. Clinical presentation usually consists of a nonspecific febrile illness that may be accompanied by rash, arthralgia and arthritis, with or without neurological or haemorrhagic syndromes. The range of differential diagnoses of other infectious and noninfectious aetiologies is broad, presenting a challenge for physicians. While knowledge of the geographical distribution of pathogens and the current epidemiological situation, incubation periods, exposure risk factors and vaccination history can help guide the diagnostic approach, the nonspecific and variable clinical presentation can delay final diagnosis. This narrative review aims to summarize the main clinical and laboratory-based findings of the three most common imported arboviruses in Europe. Evidence is extracted from published literature and clinical expertise of European arbovirus experts. We present three cases that highlight similarities and differences between some of the most common travel-related arboviruses imported to Europe. These include a patient with chikungunya virus infection presenting in Greece, a case of dengue fever in Turkey and a travel-related case of Zika virus infection in Romania. Early diagnosis of travel-imported cases is important to reduce the risk of localized outbreaks of tropical arboviruses such as dengue and chikungunya and the risk of local transmission from body fluids or vertical transmission. Given the global relevance of arboviruses and the continuous risk of (re)emerging arbovirus events, clinicians should be aware of the clinical syndromes of arbovirus fevers and the potential pitfalls in diagnosis.


H+/e- stoichiometry for NADH dehydrogenase I and dimethyl sulfoxide reductase in anaerobically grown Escherichia coli cells.
Anaerobically grown Escherichia coli cells were shown to acidify the reaction medium in response to oxygen or dimethyl sulfoxide (DMSO) pulses, with the H+/e- stoichiometry being close to 2.5 and 1.5, respectively. In the presence of the NADH dehydrogenase I (NDH-I) inhibitor 8-methyl-N-vanillyl-6-nonenamide (capsaicin) or in mutants lacking NDH-I, this ratio decreased to 1 for O2 and to 0 for DMSO. These data suggest that (i) the H+/e- stoichiometry for E. coli NDH-I is at least 1.5 and (ii) the DMSO reductase does not generate a proton motive force.


CRISPR-Cas Systems and the Paradox of Self-Targeting Spacers.
CRISPR-Cas immune systems in bacteria and archaea record prior infections as spacers within each system's CRISPR arrays. Spacers are normally derived from invasive genetic material and direct the immune system to complementary targets as part of future infections. However, not all spacers appear to be derived from foreign genetic material and instead can originate from the host genome. Their presence poses a paradox, as self-targeting spacers would be expected to induce an autoimmune response and cell death. In this review, we discuss the known frequency of self-targeting spacers in natural CRISPR-Cas systems, how these spacers can be incorporated into CRISPR arrays, and how the host can evade lethal attack. We also discuss how self-targeting spacers can become the basis for alternative functions performed by CRISPR-Cas systems that extend beyond adaptive immunity. Overall, the acquisition of genome-targeting spacers poses a substantial risk but can aid in the host's evolution and potentially lead to or support new functionalities.


Continuous-wave singly-resonant optical parametric oscillator with resonant wave coupling.
We report major enhancements in the overall performance of continuous-wave singly-resonant optical parametric oscillators (cw SROs) through finite output coupling of the resonant wave. Using a cw SRO based on MgO:sPPLT pumped at 532 nm, we demonstrate improvements of 1.08 W in total output power, 10% in total extraction efficiency, and a 130-nm extension in the useful tuning range, while maintaining pump depletions of 70%, idler output powers of 2.59 W, and a minimal increase in oscillation threshold of 24%. The output-coupled cw SRO can deliver a total power of up to 3.6 W at 40% extraction efficiency across 848-1427 nm. The single-frequency resonant wave also exhibits a higher spectral purity than the non-resonant output.


Binding of the terminal mannosyl units of lipoarabinomannan from a virulent strain of Mycobacterium tuberculosis to human macrophages.
Recent studies from this laboratory have demonstrated that macrophage phagocytosis of virulent strains (Erdman and H37Rv), but not the attenuated H37Ra strain of Mycobacterium tuberculosis, is mediated by phagocyte mannose receptors (MR) in addition to complement receptors (CR1 and the leukocyte integrins CR3 and CR4). Lipoarabinomannan (LAM) is a major surface lipoglycan of M. tuberculosis. LAM from the Erdman strain (Man-LAM) contains mannose oligosaccharides at the terminal portions of the molecule. This study investigated the ability of ManLAM to serve as a microbial ligand in adherence to human monocyte-derived macrophages (MDM). Polystyrene microspheres were coated with known amounts of purified ManLAM, LAM without the terminal mannosyl units from an avirulent mycobacterium (AraLAM), lipomannan (LM), or buffer and incubated with MDM monolayers in the absence of serum. The presence of LAM on microspheres was confirmed by indirect immunofluorescence studies. Microspheres coated with ManLAM demonstrated a more than threefold increase in adherence to MDM when compared with microspheres coated with AraLAM, LM, or buffer and the low levels of adherence of microspheres in the latter three groups were comparable. Compared with control monolayers, selective down-modulation of MDM MR on a mannan substrate abrogated the enhanced adherence of microspheres mediated by ManLAM. Adherence of microspheres coated with AraLAM, LM, or buffer was not influenced by MR modulation. To confirm the importance of the terminal mannosyl units of ManLAM in the enhanced adherence of ManLAM microspheres to MDM, these units were selectively removed by exomannosidase treatment. The structure of LAM products before and after enzyme treatment was confirmed by high performance anion exchange chromatography with pulsed amperometric detection. Removal of the terminal mannosyl units abolished the capacity of ManLAM to mediate enhanced adherence of microspheres to MDM. Finally, preincubation of Erdman M. tuberculosis with CS-40, a mAb directed against LAM, resulted in a consistent inhibition of adherence of the bacteria to MDM (up to 49% inhibition), confirming a role for ManLAM on intact bacteria in adherence to MDM. Thus, we provide evidence for a novel receptor-ligand pathway in phagocytosis of M. tuberculosis that consists of MR on macrophages and mannosyl units at the terminal end of ManLAM, a major microbial surface lipoglycan.


An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.
Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.


Patterns of pulmonary structural remodeling after experimental paraquat toxicity. The morphogenesis of intraalveolar fibrosis.
For a study of the evolution of interstitial and intraalveolar fibrosis, ultrastructural and immunohistochemical observations were made of the lungs of 16 cynomolgous monkeys given 1 or 2 injections of 10 mg/kg of paraquat and sacrificed 2 days to 8 weeks later. At 2-3 days, alveolar epithelial cells were denuded in many areas, and fibronectin was conspicuous in alveolar spaces. At 1 week, fibroblasts and inflammatory cells were migrating through gaps in the denuded epithelial basement membranes; Type II cells were regenerating in some areas. At 3-4 weeks, alveoli developing intraalveolar fibrosis contained many myofibroblasts, collagen fibrils, and small elastic fibers; fibrotic alveolar walls were lined by metaplastic squamous cells and bronchiolar epithelial cells. Spiraling collagen fibrils were found in interstitium but not in alveolar spaces, which suggests that they were formed from breakdown of collagen. Newly formed intraalveolar collagen was mainly Type I. At 8 weeks, intraalveolar fibrosis had led to extensive remodeling, with new glandlike alveoli lined by Type II cells; alveoli without intraalveolar fibrosis had more normal architecture. Thus, intraalveolar fibrosis in paraquattreated lung is mediated by intraalveolar migration of interstitial cells, through gaps in the epithelial basement membranes, after epithelial injury. This is followed by connective tissue synthesis on the luminal side of the epithelial basement membrane, by differentiation of interstitial cells into myofibroblasts and smooth-muscle cells, by incorporation of areas of intraalveolar fibrosis into the interstitium, and by coalescence of alveolar walls. Intraalveolar fibrosis is more important than interstitial fibrosis in the structural remodeling that occurs in paraquattreated lung, because it results in obliteration of alveoli, coalescence of alveolar walls, and loss of functional alveolar-capillary units.


Heterogeneity and Delayed Activation as Hallmarks of Self-Organization and Criticality in Excitable Tissue.
Self-organized critical dynamics is assumed to be an attractive mode of functioning for several real-life systems and entails an emergent activity in which the extent of observables follows a power-law distribution. The hallmarks of criticality have recently been observed in a plethora of biological systems, including beta cell populations within pancreatic islets of Langerhans. In the present study, we systematically explored the mechanisms that drive the critical and supercritical behavior in networks of coupled beta cells under different circumstances by means of experimental and computational approaches. Experimentally, we employed high-speed functional multicellular calcium imaging of fluorescently labeled acute mouse pancreas tissue slices to record calcium signals in a large number of beta cells simultaneously, and with a high spatiotemporal resolution. Our experimental results revealed that the cellular responses to stimulation with glucose are biphasic and glucose-dependent. Under physiological as well as under supraphysiological levels of stimulation, an initial activation phase was followed by a supercritical plateau phase with a high number of global intercellular calcium waves. However, the activation phase displayed fingerprints of critical behavior under lower stimulation levels, with a progressive recruitment of cells and a power-law distribution of calcium wave sizes. On the other hand, the activation phase provoked by pathophysiologically high glucose concentrations, differed considerably and was more rapid, less continuous, and supercritical. To gain a deeper insight into the experimentally observed complex dynamical patterns, we built up a phenomenological model of coupled excitable cells and explored empirically the model's necessities that ensured a good overlap between computational and experimental results. It turned out that such a good agreement between experimental and computational findings was attained when both heterogeneous and stimulus-dependent time lags, variability in excitability levels, as well as a heterogeneous cell-cell coupling were included into the model. Most importantly, since our phenomenological approach involved only a few parameters, it naturally lends itself not only for determining key mechanisms of self-organized criticality at the tissue level, but also points out various features for comprehensive and realistic modeling of different excitable systems in nature.


Is the time from HIV seroconversion a determinant of the risk of AIDS after adjustment for updated CD4 cell counts?
To evaluate the effect of time from seroconversion to a given CD4 cell count on progression to AIDS after that count after adjusting for updated CD4 cell counts. Using pooled data from 19 seroconverter cohorts, we examined the association between the time from a CD4 <500 cells/mm 3, (<350, <200) to the first AIDS-defining event and time from seroconversion to that CD4 threshold. We adjusted for age, gender, exposure category, and HIV test interval in Cox models stratified by cohort. We estimated the residual effect of time from seroconversion, adjusting for updated CD4 cell counts. A cause-specific competing-risks model was then used to evaluate this residual effect on progression to each AIDS-defining disease. Analyses were censored on December 31, 1995. Of 3825, 3006, and 1804 individuals reaching CD4 thresholds of 500, 350, and 200, respectively, 1274, 1192, and 985, respectively, developed AIDS. We found a significant effect of time from seroconversion on the risk of AIDS even after adjusting for updated CD4 counts. For individuals reaching a CD4 threshold of 350 cells/mm 3, a 1-year increase from seroconversion was associated with an increase in risk of AIDS of 6% (3%-9%) ( p =.01). This effect appeared to be nonlinear. In the first 4 years, a 1-year increase from seroconversion was associated with an 11% increase in the risk of AIDS, but there was no apparent increase in risk after 4 years. The residual effect of time from seroconversion was significantly heterogeneous ( p =.002), with respect to the risk of individual AIDS-defining diseases. Findings were similar for CD4 thresholds of 500 and 200 cells/mm 3, respectively. We found a small, statistically significant, residual effect of time from seroconversion on the risk of AIDS. In practical terms, when considering an infected individual's risk of AIDS from a given CD4 cell count, there is little to be gained from knowing the time of seroconversion. However, this effect differs significantly among specific AIDS-defining diseases.


Charge transfer in the living matrix.
The living matrix is defined as the continuous molecular fabric of the organism, consisting of fascia, the other connective tissues, extracellular matrices, integrins, cytoskeletons, nuclear matrices and DNA. The extracellular, cellular and nuclear biopolymers or ground substances constitute a body-wide reservoir of charge that can maintain electrical homeostasis and "inflammatory preparedness" throughout the organism. Recent research has emphasized the significance of charge transfer in relation to the scavenging or neutralization of free radicals delivered to sites of injury during and after the oxidative burst. Evidence comes from studies of the role of electrons in mitigating the consequences of inflammation when living systems are connected to the earth (earthing). The phenomenon helps explain how bodywork and movement therapies can facilitate the resolution of acute or chronic injuries, and how patients with inflammatory conditions may "deplete" a therapist during hands-on treatments. It is suggested that barefoot contact with the earth as well as hands-on and hands-off therapies facilitate healing by stimulating the migration of charges into sites of acute or chronic inflammation. One hypothesis to explain the effects of earthing is that charges from the ground substance reservoir prevent "collateral damage" to healthy tissues in the vicinity of an injury. A second hypothesis is that earthing allows electrons to replenish charge in the ground substance reservoirs, making electrons available throughout the body.


The Ratiometric Transcript Signature MX2/GPR183 Is Consistently Associated With RTS,S-Mediated Protection Against Controlled Human Malaria Infection.
The RTS,S/AS01 vaccine provides partial protection against Plasmodium falciparum infection but determinants of protection and/or disease are unclear. Previously, anti-circumsporozoite protein (CSP) antibody titers and blood RNA signatures were associated with RTS,S/AS01 efficacy against controlled human malaria infection (CHMI). By analyzing host blood transcriptomes from five RTS,S vaccination CHMI studies, we demonstrate that the transcript ratio MX2/GPR183, measured 1 day after third immunization, discriminates protected from non-protected individuals. This ratiometric signature provides information that is complementary to anti-CSP titer levels for identifying RTS,S/AS01 immunized people who developed protective immunity and suggests a role for interferon and oxysterol signaling in the RTS,S mode of action.


The relation between language and arithmetic in bilinguals: insights from different stages of language acquisition.
Solving arithmetic problems is a cognitive task that heavily relies on language processing. One might thus wonder whether this language-reliance leads to qualitative differences (e.g., greater difficulties, error types, etc.) in arithmetic for bilingual individuals who frequently have to solve arithmetic problems in more than one language. The present study investigated how proficiency in two languages interacts with arithmetic problem solving throughout language acquisition in adolescents and young adults. Additionally, we examined whether the number word structure that is specific to a given language plays a role in number processing over and above bilingual proficiency. We addressed these issues in a German-French educational bilingual setting, where there is a progressive transition from German to French as teaching language. Importantly, German and French number naming structures differ clearly, as two-digit number names follow a unit-ten order in German, but a ten-unit order in French. We implemented a transversal developmental design in which bilingual pupils from grades 7, 8, 10, 11, and young adults were asked to solve simple and complex additions in both languages. The results confirmed that language proficiency is crucial especially for complex addition computation. Simple additions in contrast can be retrieved equally well in both languages after extended language practice. Additional analyses revealed that over and above language proficiency, language-specific number word structures (e.g., unit-ten vs. ten-unit) also induced significant modulations of bilinguals' arithmetic performances. Taken together, these findings support the view of a strong relation between language and arithmetic in bilinguals.


Progesterone suppression of glutamic acid decarboxylase (GAD67) mRNA levels in the preoptic area: correlation to the luteinizing hormone surge.
The progesterone-induced LH surge in the estrogen-primed rat is thought to be mediated through interneurons since LHRH neurons reportedly lack steroid receptors. Along these lines, glutamate and gamma-aminobutyric acid (GABA) neurons are considered to be two of the major interneurons in the hypothalamus involved in the control of LHRH and LH secretion. Glutamate is a major excitatory amino acid neurotransmitter while GABA is a major inhibitory amino acid neurotransmitter in the control of LH secretion. Glutamate is converted in the brain to GABA by the rate-limiting enzyme glutamic acid decarboxylase (GAD). Regulation of GAD by steroid hormones would therefore appear to be a logical mechanism for the control of LHRH and LH secretion based on the changes in glutamate and GABA production which would result from such regulation. Therefore, the purpose of the present study was to determine whether the steroid hormone, progesterone, regulates the GAD enzyme in the hypothalamus at a time when it induces an LH surge. To accomplish this aim, northern and dot blot analysis were used to measure GAD65 and GAD67 mRNA levels in the preoptic area (POA) and medial basal hypothalamus (MBH) in ovariectomized (OVX) immature rats, OVX rats primed with 2 mu g of estradiol (E2) for 2 days, and OVX rats primed with 2 mu g of E2 for 2 days and administered progesterone (1 mg/kg, 09.00 h) to induce an LH surge. The results of the study show that GAD67 mRNA levels were suppressed by progesterone in the POA at 12.00 h (at the start of the surge) (24.4% suppression vs. E2 only; p <0.01) in the first experiment. This suppression was confirmed in a second experiment as progesterone suppressed GAD67 mRNA levels in the POA at 12.00 h (31.8% vs. E2 only; p <0.05) and also at 14.00 h (40% vs. E2 only; p <0.05) which correlates to the peak of the LH surge. The changes in GAD67 by progesterone were restricted to the POA, as GAD67 mRNA levels in the MBH were unaffected by the steroid treatment. Furthermore, the effect of progesterone on POA GAD67 mRNA levels was specific as it was blocked by prior treatment with the antiprogestin, RU486 (400 mu g). In the MBH, both GAD67 and GAD65 mRNA levels were increased by estradiol treatment at 16.00 h and this increase was prevented by progesterone administration in the presence of estrogen priming. In conclusion, these studies demonstrate that the mRNA for the key enzyme responsible for the conversion of the major excitatory amino acid neurotransmitter in the hypothalamus (glutamate) to the major inhibitory amino acid neurotransmitter (GABA), is regulated by the steroid hormone progesterone. Progesterone suppression of GAD67 mRNA levels in the POA, where LHRH neurons reside, and at a time immediately preceding and during the LH surge, could provide a mechanism for greater stimulation of LHRH neurons through enhanced excitatory glutamate production concomitant with deceased inhibitory GABA production in the POA.


Correlating locations in ipsilateral breast tomosynthesis views using an analytical hemispherical compression model.
To improve cancer detection in mammography, breast examinations usually consist of two views per breast. In order to combine information from both views, corresponding regions in the views need to be matched. In 3D digital breast tomosynthesis (DBT), this may be a difficult and time-consuming task for radiologists, because many slices have to be inspected individually. For multiview computer-aided detection (CAD) systems, matching corresponding regions is an essential step that needs to be automated. In this study, we developed an automatic method to quickly estimate corresponding locations in ipsilateral tomosynthesis views by applying a spatial transformation. First we match a model of a compressed breast to the tomosynthesis view containing a point of interest. Then we estimate the location of the corresponding point in the ipsilateral view by assuming that this model was decompressed, rotated and compressed again. In this study, we use a relatively simple, elastically deformable sphere model to obtain an analytical solution for the transformation in a given DBT case. We investigate three different methods to match the compression model to the data by using automatic segmentation of the pectoral muscle, breast tissue and nipple. For validation, we annotated 208 landmarks in both views of a total of 146 imaged breasts of 109 different patients and applied our method to each location. The best results are obtained by using the centre of gravity of the breast to define the central axis of the model, around which the breast is assumed to rotate between views. Results show a median 3D distance between the actual location and the estimated location of 14.6 mm, a good starting point for a registration method or a feature-based local search method to link suspicious regions in a multiview CAD system. Approximately half of the estimated locations are at most one slice away from the actual location, which makes the method useful as a mammographic workstation tool for radiologists to interactively find corresponding locations in ipsilateral tomosynthesis views.


Dynamic glenohumeral stability provided by the rotator cuff muscles in the mid-range and end-range of motion. A study in cadavera.
Both static and dynamic factors are responsible for glenohumeral joint stability. We hypothesized that dynamic factors could potentially operate throughout the entire range of glenohumeral motion, although capsuloligamentous restraints (a static factor) have been thought to be primarily responsible for stability in the end-range of motion. The purpose of this study was to quantitatively compare the dynamic glenohumeral joint stability in the end-range of motion (the position of anterior instability) with that in the mid-range by investigating the force components generated by the rotator cuff muscles. Ten fresh-frozen shoulders from human cadavera were obtained, and all soft tissues except the rotator cuff were removed. The glenohumeral capsule was resected after the rotator cuff muscles had been released from the scapula. A specially designed frame positioned the humerus in 60 degrees of abduction and 45 degrees of extension with respect to the scapula. The compressive and shear components on the glenoid were measured before and after a constant force was applied individually to each muscle with the humerus in five different positions (from neutral to 90 degrees of external rotation). The dynamic stability index, a new biomechanical parameter reflecting these force components and the concavity-compression mechanism, was calculated. The higher the dynamic stability index, the greater the dynamic glenohumeral stability. In the mid-range of motion, the supraspinatus and subscapularis provided higher dynamic stability indices than did the other muscles (p < 0.05). On the other hand, when the position of anterior instability was simulated in the end-range of motion, the subscapularis, infraspinatus, and teres minor provided significantly higher dynamic stability indices than did the supraspinatus (p < 0.005). The rotator cuff provided substantial anterior dynamic stability to the glenohumeral joint in the end-range of motion as well as in the mid-range. A glenohumeral joint with a lax capsule and ligaments might be stabilized dynamically in the end-range of motion if the glenoid concavity is maintained and the function of the external and internal rotators, which are efficient stabilizers in this position, is enhanced.


Four-component united-atom model of bitumen.
We propose a four-component united-atom molecular model of bitumen. The model includes realistic chemical constituents and introduces a coarse graining level that suppresses the highest frequency modes. Molecular dynamics simulations of the model are carried out using graphic-processor-units based software in time spans in order of microseconds, which enables the study of slow relaxation processes characterizing bitumen. This paper also presents results of the model dynamics as expressed through the mean-square displacement, the stress autocorrelation function, and rotational relaxation. The diffusivity of the individual molecules changes little as a function of temperature and reveals distinct dynamical time scales. Different time scales are also observed for the rotational relaxation. The stress autocorrelation function features a slow non-exponential decay for all temperatures studied. From the stress autocorrelation function, the shear viscosity and shear modulus are evaluated, showing a viscous response at frequencies below 100 MHz. The model predictions of viscosity and diffusivities are compared to experimental data, giving reasonable agreement. The model shows that the asphaltene, resin, and resinous oil tend to form nano-aggregates. The characteristic dynamical relaxation time of these aggregates is larger than that of the homogeneously distributed parts of the system, leading to strong dynamical heterogeneity.


Graphics processing unit parallel accelerated solution of the discrete ordinates for photon transport in biological tissues.
As a widely used numerical solution for the radiation transport equation (RTE), the discrete ordinates can predict the propagation of photons through biological tissues more accurately relative to the diffusion equation. The discrete ordinates reduce the RTE to a serial of differential equations that can be solved by source iteration (SI). However, the tremendous time consumption of SI, which is partly caused by the expensive computation of each SI step, limits its applications. In this paper, we present a graphics processing unit (GPU) parallel accelerated SI method for discrete ordinates. Utilizing the calculation independence on the levels of the discrete ordinate equation and spatial element, the proposed method reduces the time cost of each SI step by parallel calculation. The photon reflection at the boundary was calculated based on the results of the last SI step to ensure the calculation independence on the level of the discrete ordinate equation. An element sweeping strategy was proposed to detect the calculation independence on the level of the spatial element. A GPU parallel frame called the compute unified device architecture was employed to carry out the parallel computation. The simulation experiments, which were carried out with a cylindrical phantom and numerical mouse, indicated that the time cost of each SI step can be reduced up to a factor of 228 by the proposed method with a GTX 260 graphics card.


Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b.
The aim of this study was to evaluate the long-term sustainability of response in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B treated with pegylated interferon (PEG-IFN) alpha-2b alone or in combination with lamivudine. All 266 patients enrolled in the HBV99-01 study were offered participation in a long-term follow-up (LTFU) study. Patients were treated with PEG-IFN alpha-2b (100 mug/wk) alone or in combination with lamivudine (100 mg/day) for 52 weeks. Initial response was defined as HBeAg negativity at 26 weeks posttreatment. For the LTFU study, patients had one additional visit after the initial study (mean interval, 3.0 +/- 0.8 years). Of 266 patients enrolled in the initial study, 172 (65%) participated in the LTFU study. At LTFU, HBeAg and hepatitis B surface antigen (HBsAg) negativity were observed in 37% and 11% of 172 patients, respectively. Sixty-four patients were classified as initial responders and 108 as nonresponders. Among the initial responders, sustained HBeAg negativity and HBsAg loss were observed in 81% and 30%, respectively. Significantly higher rates of HBeAg negativity were observed in genotype A-infected initial responders compared with those with genotype non-A (96% vs 76%; P = .06) as well as HBsAg loss (58% vs 11%; P < .001). HBeAg loss after treatment with PEG-IFN alpha-2b alone or in combination with lamivudine is sustained in the majority of patients and is associated with a high likelihood of HBsAg loss, particularly in genotype A-infected patients. Therefore, PEG-IFN alpha-2b remains an important treatment option in this era of nucleos(t)ide analogue therapy.


Community Unemployment and Disaster-Related Stressors Shape Risk for Posttraumatic Stress in the Longer-Term Aftermath of Hurricane Sandy.
Persons living in communities with limited resources are at heightened risk of posttraumatic stress (PTS) after disasters, especially if they were highly exposed. The support deterrence desistence model and the conservation of resources theory suggest that this risk might increase in the longer-term aftermath of disasters. In the present study, we aimed to test this hypothesis. Two population-based samples of New York City residents in communities affected by Hurricane Sandy were surveyed at either 13-16 months (Time 1; n = 421) or 25-28 months (Time 2; n = 420) postdisaster. Participants reported on their exposure to disaster-related stressors and PTS. The percentage of residents who were unemployed in participants' census tracts was collected from the 2008-2012 American Community Survey. Multilevel models found that disaster-related stressors were more strongly associated with PTS for participants living in communities with high unemployment, but only at Time 2 (Est. = .58, SE = .21, p = .006). Mapping of community unemployment and disaster-related stressors suggested that communities in southern Brooklyn and Queens, and northeastern Staten Island were at particularly high risk for PTS at Time 2. The results suggest the need for ongoing support to economically disadvantaged communities in which residents have endured disaster-related stressors.


Extracellular Caspase-8 Dependent Apoptosis on HeLa Cancer Cells and MRC-5 Normal Cells by ICD-85 (Venom Derived Peptides).
Our previous studies revealed an inhibitory effect of ICD-85 (venom derived peptides) on MDA-MB231 and HL-60 cell lines, through induction of apoptosis. The purpose of this study was to investigate apoptosis-induced mechanism on HeLa and MRC-5 cells by ICD-85 through activation of caspase-8. Cell viability, cytosolic enzyme Lactate Dehydrogenase (LDH) and cell morphology were assessed under unexposed and ICD-85 exposed conditions.Caspase-8 activity was assayed by caspase-8 colorimetric assay Kit. The results show that Inhibitory Concentration 50% (IC50) value of ICD-85 for HeLa cells at 24 h was estimated and found to be 25.32±2.15 µg/mL. Furthermore, treatment of HeLa cells with ICD-85 at concentrations of 1.6×10 and 2.6×10 µg/mL did not significantly increase LDH release. Morphological changes in HeLa cells on treatment with ICD-85 compared with untreated HeLa cells consistent with an apoptotic mechanism of cell death, such as cell shrinkage which finally results in the generation of apoptotic bodies. However, when MRC-5 cells were exposed to ICD-85, no significant changes in cell morphology and LDH were observed at concentrations below 2.6×10µg/ml. Also, the apoptosis-induction mechanism by ICD-85 on HeLa cells was found through activation of caspase-8 and the activity of caspase-8 in HeLa cells was 1.5 folds more than its activity on MRC-5 cells. Therefore, the apoptosis-induced mechanisms by ICD-85 are through activation of caspase-8 and concerning the least cytotoxic effect on MRC-5 cells, ICD-85 may be used as anticancer compound to inhibit growth of cancer cells.


EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing's sarcoma.
More than 90% of Ewing's sarcomas (ES) contain a fusion of the EWS and FLI1 genes, due to the t(11;22)(q24;q12) translocation. At the molecular level, the EWS-FLI1 rearrangements show great diversity. Specifically, many different combinations of exons from EWS and FLI1 encode in-frame fusion transcripts and result in differences in the length and composition of the chimeric protein, which functions as an oncogenic aberrant transcription factor. In the most common fusion type (type 1), EWS exon 7 is linked in frame with exon 6 of FLI1. As the fundamental pathogenetic lesion in ES, the molecular heterogeneity of these fusion transcripts may have functional and clinical significance. We performed a clinical and pathologic analysis of 112 patients with ES in which EWS-FLI1 fusion transcripts were identified by reverse-transcriptase polymerase chain reaction (RT-PCR). Adequate treatment and follow-up data were available in 99 patients treated with curative intent. Median follow-up in these 99 patients was 26 months (range, 1 to 140 months). Univariate and multivariate survival analyses were performed that included other prognostic factors, such as age, tumor location, size, and stage. Among the 99 patients suitable for survival analysis, the tumors in 64 patients contained the type 1 fusion and in 35 patients contained less common fusion types. Stage at presentation was localized in 74 patients and metastatic in 25. Metastases (relative risk [RR] = 2.6; P = .008), and type 1 EWS-FLI1 fusion (RR = 0.37; P = .014) were, respectively, independent negative and positive prognostic factors for overall survival by multivariate analysis. Among 74 patients with localized tumors, the type 1 EWS-FLI1 fusion was also a significant positive predictor of overall survival (RR = 0.32; P = .034) by multivariate analysis. EWS-FLI1 fusion type appears to be prognostically relevant in ES, independent of tumor site, stage, and size. Further studies are needed to clarify the biologic basis of this phenomenon.


DNA damage in nasal and brain tissues of canines exposed to air pollutants is associated with evidence of chronic brain inflammation and neurodegeneration.
Acute, subchronic, or chronic exposures to particulate matter (PM) and pollutant gases affect people in urban areas and those exposed to fires, disasters, and wars. Respiratory tract inflammation, production of mediators of inflammation capable of reaching the brain, systemic circulation of PM, and disruption of the nasal respiratory and olfactory barriers are likely in these populations. DNA damage is crucial in aging and in age-associated diseases such as Alzheimer's disease. We evaluated apurinic/apyrimidinic (AP) sites in nasal and brain genomic DNA, and explored by immunohistochemistry the expression of nuclear factor NFkappaB p65, inducible nitric oxide synthase (iNOS), cyclo-oxygenase 2 (COX2), metallothionein I and II, apolipoprotein E, amyloid precursor protein (APP), and beta-amyloid(1-42) in healthy dogs naturally exposed to urban pollution in Mexico City. Nickel (Ni) and vanadium (V) were measured by inductively coupled plasma mass spectrometry (ICP-MS). Forty mongrel dogs, ages 7 days-10 years were studied (14 controls from Tlaxcala and 26 exposed to urban pollution in South West Metropolitan Mexico City (SWMMC)). Nasal respiratory and olfactory epithelium were found to be early pollutant targets. Olfactory bulb and hippocampal AP sites were significantly higher in exposed than in control age matched animals. Ni and V were present in a gradient from olfactory mucosa > olfactory bulb > frontal cortex. Exposed dogs had (a) nuclear neuronal NFkappaB p65, (b) endothelial, glial and neuronal iNOS, (c) endothelial and glial COX2, (d) ApoE in neuronal, glial and vascular cells, and (e) APP and beta amyloid(1-42) in neurons, diffuse plaques (the earliest at age 11 months), and in subarachnoid blood vessels. Increased AP sites and the inflammatory and stress protein brain responses were early and significant in dogs exposed to urban pollution. Oil combustion PM-associated metals Ni and V were detected in the brain. There was an acceleration of Alzheimer's-type pathology in dogs chronically exposed to air pollutants. Respiratory tract inflammation and deteriorating olfactory and respiratory barriers may play a role in the observed neuropathology. These data suggest that Alzheimer's disease may be the sequela of air pollutant exposures and the resulting systemic inflammation.


Shared electrophysiology mechanisms of body ownership and motor imagery.
Although we feel, see, and experience our hands as our own (body or hand ownership), recent research has shown that illusory hand ownership can be induced for fake or virtual hands and may be useful for neuroprosthetics and brain-computer interfaces. Despite the vast amount of behavioral data on illusory hand ownership, neuroimaging studies are rare, in particular electrophysiological studies. Thus, while the neural systems underlying hand ownership are relatively well described, the spectral signatures of body ownership as measured by electroencephalography (EEG) remain elusive. Here we induced illusory hand ownership in an automated, computer-controlled manner using virtual reality while recording 64-channel EEG and found that illusory hand ownership is reflected by a body-specific modulation in the mu-band over fronto-parietal cortex. In a second experiment in the same subjects, we then show that mu as well as beta-band activity in highly similar fronto-parietal regions was also modulated during a motor imagery task often used in paradigms employing non-invasive brain-computer interface technology. These data provide insights into the electrophysiological brain mechanisms of illusory hand ownership and their strongly overlapping mechanisms with motor imagery in fronto-parietal cortex. They also highlight the potential of combining high-resolution EEG with virtual reality setups and automatized stimulation protocols for systematic, reproducible stimulus presentation in cognitive neuroscience, and may inform the design of non-invasive brain-computer interfaces.


Role of lung injury in the pathogenesis of hyaline membrane disease in premature baboons.
To test the hypothesis that hyaline membrane disease (HMD) has a multifactorial etiology in which barotrauma plays a major role, we compared the immediate institution of high-frequency oscillatory ventilation (HFOV; 15 Hz, n = 5) with positive-pressure ventilation with positive end-expiratory pressure (PPV; n = 7) in premature baboons (140-days gestation) with HMD. Measurements of ventilation settings and physiological parameters were obtained and arterial-to-alveolar O2 (PaO2-to-PAO2) ratio and oxygenation index [(PaO2/PAO2)-to-mean airway pressure ratio (IO2)] were calculated. At death (24 h), static pressure-volume (PV) curves were performed, and phospholipids (PL) and platelet-activating factor (PAF) were measured in lung lavage fluid. Morphological inflation patterns were analyzed using a panel of standards. By design, mean airway pressure was initially higher (19 vs. 13 cmH2O) in the HFOV animals. PaO2-to-PAO2 ratio and IO2 progressively deteriorated in the PPV animals and then stabilized at significantly lower levels than with HFOV. PV curves from HFOV animals had significant increases in lung volume at maximum distending pressure, deflation volume at 10 cmH2O, and hysteresis area compared with PPV, which showed no hysteresis. Seven of seven PPV and only one of five HFOV animals had morphological findings of HMD. PL amount and composition in both groups were consistent with immaturity, even though the quantity was significantly greater in the PPV group. PAF was present (greater than or equal to 0.10 pmol) in six of seven PPV and in the only HFOV animal with HMD. We conclude that HFOV protected PL-deficient premature baboons from changes in gas exchange, lung mechanics, and morphology typical of HMD in this model.(ABSTRACT TRUNCATED AT 250 WORDS)


Epifluorescence intravital microscopy of murine corneal dendritic cells.
Purpose. Dendritic cells (DCs) are antigen-presenting cells vital for initiating immune responses. In this study the authors examined the in vivo migratory capability of resident corneal DCs to various stimuli. Methods. The authors used mice expressing enhanced yellow fluorescent protein (eYFP) under control of the CD11c promoter to visualize corneal DCs. To assess the distribution and mobility of DCs, normal corneas were imaged in vivo and ex vivo with fluorescence microscopy. Intravital microscopy was used to examine the responses of resident central and peripheral corneal DCs to silver nitrate injury, lipopolysaccharide, microspheres, and tumor necrosis factor (TNF-alpha). In some experiments, TNF-alpha injection was used to first induce centripetal migration of DCs to the central cornea, which was subsequently reinjected with microspheres. Results. In normal corneas, DCs were sparsely distributed centrally and were denser in the periphery, with epithelial-level DCs extending into the epithelium. Videomicroscopy showed that though cell processes were in continuous movement, cells generally did not migrate. Within the first 6 hours after stimulation, neither central nor peripheral corneal DCs exhibited significant lateral migration, but central corneal DCs assumed extreme morphologic changes. An increased number of DCs in the TNF-alpha-stimulated central cornea were responsive to subsequent microsphere injection by adopting a migratory behavior, but not with increased speed. Conclusions. In vivo imaging reveals minimal lateral migration of corneal DCs after various stimuli. In contrast, DCs within the central cornea after initial TNF-alpha injection are more likely to respond to a secondary insult with lateral migration.


Blood, bulbs, and bunodonts: on evolutionary ecology and the diets of Ardipithecus, Australopithecus, and early Homo.
Beginning with Darwin, some have argued that predation on other vertebrates dates to the earliest stages of hominid evolution, and can explain many uniquely human anatomical and behavioral characters. Other recent workers have focused instead on scavenging, or particular plant foods. Foraging theory suggests that inclusion of any food is influenced by its profitability and distribution within the consumer's habitat. The morphology and likely cognitive abilities of Ardipithecus, Australopithecus, and early Homo suggest that while hunting and scavenging occurred, their profitability generally would have been considerably lower than in extant primates and/or modern human hunter-gatherers. On the other hand, early hominid diet modelers should not focus solely on plant foods, as this overlooks standard functional interpretations of the early hominid dentition, their remarkable demographic success, and the wide range of available food types within their likely day ranges. Any dietary model focusing too narrowly on any one food type or foraging strategy must be viewed with caution. We argue that early hominid diet can best be elucidated by consideration of their entire habitat-specific resource base, and by quantifying the potential profitability and abundance of likely available foods.


Maturation of bacteriophage T4 lagging strand fragments depends on interaction of T4 RNase H with T4 32 protein rather than the T4 gene 45 clamp.
In the bacteriophage T4 DNA replication system, T4 RNase H removes the RNA primers and some adjacent DNA before the lagging strand fragments are ligated. This 5'-nuclease has strong structural and functional similarity to the FEN1 nuclease family. We have shown previously that T4 32 protein binds DNA behind the nuclease and increases its processivity. Here we show that T4 RNase H with a C-terminal deletion (residues 278-305) retains its exonuclease activity but is no longer affected by 32 protein. T4 gene 45 replication clamp stimulates T4 RNase H on nicked or gapped substrates, where it can be loaded behind the nuclease, but does not increase its processivity. An N-terminal deletion (residues 2-10) of a conserved clamp interaction motif eliminates stimulation by the clamp. In the crystal structure of T4 RNase H, the binding sites for the clamp at the N terminus and for 32 protein at the C terminus are located close together, away from the catalytic site of the enzyme. By using mutant T4 RNase H with deletions in the binding site for either the clamp or 32 protein, we show that it is the interaction of T4 RNase H with 32 protein, rather than the clamp, that most affects the maturation of lagging strand fragments in the T4 replication system in vitro and T4 phage production in vivo.


Neurotrophin 3 upregulates proliferation and collagen production in human aortic valve interstitial cells: a potential role in aortic valve sclerosis.
Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly. Diseased aortic valves are characterized by sclerosis (fibrosis) and nodular calcification. Sclerosis, an early pathological change, is caused by aortic valve interstitial cell (AVIC) proliferation and overproduction of extracellular matrix (ECM) proteins. However, the mechanism of aortic valve sclerosis remains unclear. Recently, we observed that diseased human aortic valves overexpress growth factor neurotrophin 3 (NT3). In the present study, we tested the hypothesis that NT3 is a profibrogenic factor to human AVICs. AVICs isolated from normal human aortic valves were cultured in M199 growth medium and treated with recombinant human NT3 (0.10 µg/ml). An exposure to NT3 induced AVIC proliferation, upregulated the production of collagen and matrix metalloproteinase (MMP), and augmented collagen deposition. These changes were abolished by inhibition of the Trk receptors. NT3 induced Akt phosphorylation and increased cyclin D1 protein levels in a Trk receptor-dependent fashion. Inhibition of Akt abrogated the effect of NT3 on cyclin D1 production. Furthermore, inhibition of either Akt or cyclin D1 suppressed NT3-induced cellular proliferation and MMP-9 and collagen production, as well as collagen deposition. Thus, NT3 upregulates cellular proliferation, ECM protein production, and collagen deposition in human AVICs. It exerts these effects through the Trk-Akt-cyclin D1 cascade. NT3 is a profibrogenic mediator in human aortic valve, and overproduction of NT3 by aortic valve tissue may contribute to the mechanism of valvular sclerosis.


Re-polarization of nuclear spins using selective SABRE-INEPT.
A method is proposed for significant improvement of NMR pulse sequences used in high-field SABRE (Signal Amplification By Reversible Exchange) experiments. SABRE makes use of spin order transfer from parahydrogen (pH2, the H2 molecule in its singlet spin state) to a substrate in a transient organometallic Ir-based complex. The technique proposed here utilizes "re-polarization", i.e., multiple application of an NMR pulse sequence used for spin order transfer. During re-polarization only the form of the substrate, which is bound to the complex, is excited by selective NMR pulses and the resulting polarization is transferred to the free substrate via chemical exchange. Owing to the fact that (i) only a small fraction of the substrate molecules is in the bound form and (ii) spin relaxation of the free substrate is slow, the re-polarization scheme provides greatly improved NMR signal enhancement, ε. For instance, when pyridine is used as a substrate, single use of the SABRE-INEPT sequence provides ε≈260 for 15N nuclei, whereas SABRE-INEPT with re-polarization yields ε>2000. We anticipate that the proposed method is useful for achieving maximal NMR enhancement with spin hyperpolarization techniques.


Preterm Glycosuria - New Data from a Continuous Glucose Monitoring System.
Careful control of glucose homeostasis is essential for infants with very low birth weight (VLBW). In clinical practice, blood and urine glucose levels are monitored; however, their correlation has not been fully investigated in VLBW infants. To evaluate the correlation between interstitial fluid glucose concentration (ISFG), glycosuria, and urine output among VLBW infants through continuous glucose monitoring (CGM). A prospective, single-center, open cohort study enrolled 74 VLBW infants with a mean birth weight of 1,066 g. CGM (Guardian Real-Time CGM®; Medtronic, Northridge, CA, USA) was used to measure glucose. The urine output was calculated using 4-hour intervals. Reagent strips were used for semiquantitative measurement of glycosuria. The CGM delivered 102,334 glucose measurements. 2,684 urine samples were checked for glycosuria, of which 92.06% remained negative. Corresponding glycemia in samples without glycosuria remained normoglycemic (median 103 mg/dL; 10-90th percentile 80-144 mg/dL). The median glucose concentrations for samples in ascending glycosuria categories 1+, 2+, 3+, and 4+ were 152, 181, 214, and 222 mg/dL, respectively. A moderate correlation between ISFG and urine output was found for categories ≥1+ (rs = 0.56; 95% confidence interval 0.42-0.68; p < 0.001). The urine output was significantly lower when glycosuria was absent (p < 0.05). Polyuria was observed only in glycosuria 4+ (median urine output 9.9; interquartile range 7.4-12.2 mL/kg/h). The renal glucose threshold in VLBW infants is between 150 and 180 mg/dL. A negative result for glycosuria is a reliable screening test to exclude hyperglycemia. Occurrence of glycosuria ≥1+ is an indication to test blood glucose.


The Influence of External Focus Instruction Characteristics on Children's Motor Performance.
Research has demonstrated that verbal instructions directing attention externally (i.e., toward the effect of the movement) significantly enhance motor skill performance, and this effect is enhanced when the distance of the external focus relative to the body is increased. However, few studies have investigated this distance-of-focus effect in children. The present study aimed to examine the effect of increasing the distance of an external focus on children's motor performance in 2 experiments. In Experiment 1, children performed standing long jumps under 3 instructional conditions (control, internal attentional focus, and external attentional focus). In Experiment 2, children performed standing long jumps under 4 instructional conditions (control, internal, proximal external attentional focus, and distal external attentional focus). In Experiment 1, results revealed a statistically significant jump distance advantage for the external focus condition. In Experiment 2, a statistically significant jump distance advantage for the distal external focus condition was found. However, instructional and task characteristics beyond distance of focus may have been influential. External focus instructions benefit children's jump performance, but specifically when they are supported by a concrete movement goal reflecting relevant performance criteria. These findings highlight the importance of examining the content of instructions and relevant task characteristics provided to children beyond attentional focus to consider their motivational characteristics.


Position effects in ectopic and allelic mitotic recombination in Saccharomyces cerevisiae.
We have examined the role that genomic location plays in mitotic intragenic recombination. Mutant alleles of the LEU2 gene were inserted at five locations in the yeast genome. Diploid and haploid strains containing various combinations of these inserts were used to examine both allelic recombination (between sequences at the same position on parental homologs) and ectopic recombination (between sequences at nonallelic locations). Chromosomal location had little effect on mitotic allelic recombination. The rate of recombination to LEU2 at five different loci varied less than threefold. This finding contrasts with previous observations of strong position effects in meiosis; frequencies of meiotic recombination at the same five loci differ by about a factor of forty. Mitotic recombination between dispersed copies of leu2 displayed strong position effects. Copies of leu2 located approximately 20 kb apart on the same chromosome recombined at rates 6-13-fold higher than those observed for allelic copies of leu2. leu2 sequences located on nonhomologous chromosomes or at distant loci on the same chromosome recombined at rates similar to those observed for allelic copies. We suggest that, during mitosis, parental homologs interact with each other no more frequently than do nonhomologous chromosomes.


Retention in care and viral suppression in differentiated service delivery models for HIV treatment delivery in sub-Saharan Africa: a rapid systematic review.
Differentiated service delivery (DSD) models for antiretroviral treatment (ART) for HIV are being scaled up in the expectation that they will better meet the needs of patients, improve the quality and efficiency of treatment delivery and reduce costs while maintaining at least equivalent clinical outcomes. We reviewed the recent literature on DSD models to describe what is known about clinical outcomes. We conducted a rapid systematic review of peer-reviewed publications in PubMed, Embase and the Web of Science and major international conference abstracts that reported outcomes of DSD models for the provision of ART in sub-Saharan Africa from January 1, 2016 to September 12, 2019. Sources reporting standard clinical HIV treatment metrics, primarily retention in care and viral load suppression, were reviewed and categorized by DSD model and source quality assessed. Twenty-nine papers and abstracts describing 37 DSD models and reporting 52 discrete outcomes met search inclusion criteria. Of the 37 models, 7 (19%) were facility-based individual models, 12 (32%) out-of-facility-based individual models, 5 (14%) client-led groups and 13 (35%) healthcare worker-led groups. Retention was reported for 29 (78%) of the models and viral suppression for 22 (59%). Where a comparison with conventional care was provided, retention in most DSD models was within 5% of that for conventional care; where no comparison was provided, retention generally exceeded 80% (range 47% to 100%). For viral suppression, all those with a comparison to conventional care reported a small increase in suppression in the DSD model; reported suppression exceeded 90% (range 77% to 98%) in 11/21 models. Analysis was limited by the extensive heterogeneity of study designs, outcomes, models and populations. Most sources did not provide comparisons with conventional care, and metrics for assessing outcomes varied widely and were in many cases poorly defined. Existing evidence on the clinical outcomes of DSD models for HIV treatment in sub-Saharan Africa is limited in both quantity and quality but suggests that retention in care and viral suppression are roughly equivalent to those in conventional models of care.


Pph13 and orthodenticle define a dual regulatory pathway for photoreceptor cell morphogenesis and function.
The function and integrity of photoreceptor cells are dependent upon the creation and maintenance of specialized apical structures: membrane discs/outer segments in vertebrates and rhabdomeres in insects. We performed a molecular and morphological comparison of Drosophila Pph13 and orthodenticle (otd) mutants to investigate the transcriptional network controlling the late stages of rhabdomeric photoreceptor cell development and function. Although Otd and Pph13 have been implicated in rhabdomere morphogenesis, we demonstrate that it is necessary to remove both factors to completely eliminate rhabdomere formation. Rhabdomere absence is not the result of degeneration or a failure of initiation, but rather the inability of the apical membrane to transform and elaborate into a rhabdomere. Transcriptional profiling revealed that Pph13 plays an integral role in promoting rhabdomeric photoreceptor cell function. Pph13 regulates Rh2 and Rh6, and other phototransduction genes, demonstrating that Pph13 and Otd control a distinct subset of Rhodopsin-encoding genes in adult visual systems. Bioinformatic, DNA binding and transcriptional reporter assays showed that Pph13 can bind and activate transcription via a perfect Pax6 homeodomain palindromic binding site and the Rhodopsin core sequence I (RCSI) found upstream of Drosophila Rhodopsin genes. In vivo studies indicate that Pph13 is necessary and sufficient to mediate the expression of a multimerized RCSI reporter, a marker of photoreceptor cell specificity previously suggested to be regulated by Pax6. Our studies define a key transcriptional regulatory pathway that is necessary for late Drosophila photoreceptor development and will serve as a basis for better understanding rhabdomeric photoreceptor cell development and function.


In Vitro Antitumor Effects of AHR Ligands Aminoflavone (AFP 464) and Benzothiazole (5F 203) in Human Renal Carcinoma Cells.
We investigated activity and mechanism of action of two AhR ligand antitumor agents, AFP 464 and 5F 203 on human renal cancer cells, specifically examining their effects on cell cycle progression, apoptosis, and migration. TK-10, SN12C, Caki-1, and ACHN human renal cancer cell lines were treated with AFP 464 and 5F 203. We evaluated cytotoxicity by MTS assays, cell cycle arrest, and apoptosis by flow cytometry and corroborated a mechanism of action involving AhR signal transduction activation. Changes in migration properties by wound healing assays were investigated: 5F 203-sensitive cells show decreased migration after treatment, therefore, we measured c-Met phosphorylation by Western blot in these cells. A 5F 203 induced a decrease in cell viability which was more marked than AFP 464. This cytotoxicity was reduced after treatment with the AhR inhibitor α-NF for both compounds indicating AhR signaling activation plays a role in the mechanism of action. A 5F 203 is sequestered by TK-10 cells and induces CYP1A1 expression; 5F 203 potently inhibited migration of TK-10, Caki-1, and SN12C cells, and inhibited c-Met receptor phosphorylation in TK-10 cells. AhR ligand antitumor agents AFP 464 and 5F 203 represent potential new candidates for the treatment of renal cancer. A 5F 203 only inhibited migration of sensitive cells and c-Met receptor phosphorylation in TK-10 cells. c-Met receptor signal transduction is important in migration and metastasis. Therefore, we consider that 5F 203 offers potential for the treatment of metastatic renal carcinoma. J. Cell. Biochem. 118: 4526-4535, 2017. © 2017 Wiley Periodicals, Inc.


Dame Maud McCarthy (1859-1949): Matron-in-Chief, British Expeditionary Forces France and Flanders, First World War.
Emma Maud McCarthy was one of the most decorated nurses of the First World War. Born in Sydney in 1859, she trained as a nurse at The London Hospital in England. She was one of the first nurses to go to the South African War and in 1914 was one of the first members of Queen Alexandra's Imperial Nursing Service. Maud McCarthy went to France as Matron-in-Chief of British, Colonial and US nursing services until the end of hostilities in 1918. After the First World War she became Matron-in-Chief of the Territorial Army Nursing Service and retired five years later. She was appointed Dame Grand Cross in 1918 and earned awards from Britain, France, Belgium and America. Her influence on nursing was profound. One of the first senior nurses to recognise the impact of war on minds, she set up separate units for men who had self-harmed and she pioneered nurse anaesthetists in the British Armed Forces. Dame Maud McCarthy was an administrator par excellence whose determination to provide the best conditions possible for both her nurses and the men for whom they cared made possible the highest standards of nursing care in the First World War.


Denatured proteins and early folding intermediates simulated in a reduced conformational space.
Conformations of globular proteins in the denatured state were studied using a high-resolution lattice model of proteins and Monte Carlo dynamics. The model assumes a united-atom and high-coordination lattice representation of the polypeptide conformational space. The force field of the model mimics the short-range protein-like conformational stiffness, hydrophobic interactions of the side chains and the main-chain hydrogen bonds. Two types of approximations for the short-range interactions were compared: simple statistical potentials and knowledge-based protein-specific potentials derived from the sequence-structure compatibility of short fragments of protein chains. Model proteins in the denatured state are relatively compact, although the majority of the sampled conformations are globally different from the native fold. At the same time short protein fragments are mostly native-like. Thus, the denatured state of the model proteins has several features of the molten globule state observed experimentally. Statistical potentials induce native-like conformational propensities in the denatured state, especially for the fragments located in the core of folded proteins. Knowledge-based protein-specific potentials increase only slightly the level of similarity to the native conformations, in spite of their qualitatively higher specificity in the native structures. For a few cases, where fairly accurate experimental data exist, the simulation results are in semiquantitative agreement with the physical picture revealed by the experiments. This shows that the model studied in this work could be used efficiently in computational studies of protein dynamics in the denatured state, and consequently for studies of protein folding pathways, i.e. not only for the modeling of folded structures, as it was shown in previous studies. The results of the present studies also provide a new insight into the explanation of the Levinthal's paradox.


Use of albumin as a risk factor for hospital mortality among burn patients in Brazil: non-concurrent cohort study.
among burn patients, it is common to use colloidal substances under the justification that it is necessary to correct the oncotic pressure of the plasma, thereby reducing the edema in the burnt area and the hypotension. The aim here was to assess the risk of hospital mortality, comparing the use of albumin and crystalloid solutions for these patients. non-concurrent historical cohort study at Faculdade de Medicina de Marília; within the Postgraduate program on Internal and Therapeutic Medicine, Universidade Federal de São Paulo; and at the Brazilian Cochrane Center. burn patients hospitalized between 2000 and 2001, with registration in the Hospital Information System, who received albumin, were compared with those who received other types of volume replacement. The primary outcome was the hospital mortality rate. The data were collected from files within the Datasus software. 39,684 patients were included: 24,116 patients with moderate burns and 15,566 patients with major burns. Among the men treated with albumin, the odds ratio for the risk of death was 20.58 (95% confidence interval, CI: 11.28-37.54) for moderate burns and 6.24 (CI 5.22-7.45) for major burns. Among the women, this risk was 40.97 for moderate burns (CI 21.71-77.30) and 7.35 for major burns (CI 5.99-9.01). The strength of the association between the use of albumin and the risk of death was maintained for the other characteristics studied, with statistical significance. the use of albumin among patients with moderate and major burns was associated with considerably increased mortality.


Cox25 teams up with Mss51, Ssc1, and Cox14 to regulate mitochondrial cytochrome c oxidase subunit 1 expression and assembly in Saccharomyces cerevisiae.
In the yeast Saccharomyces cerevisiae, mitochondrial cytochrome c oxidase (COX) biogenesis is translationally regulated. Mss51, a specific COX1 mRNA translational activator and Cox1 chaperone, drives the regulatory mechanism. During translation and post-translationally, newly synthesized Cox1 physically interacts with a complex of proteins involving Ssc1, Mss51, and Cox14, which eventually hand over Cox1 to the assembly pathway. This step is probably catalyzed by assembly chaperones such as Shy1 in a process coupled to the release of Ssc1-Mss51 from the complex. Impaired COX assembly results in the trapping of Mss51 in the complex, thus limiting its availability for COX1 mRNA translation. An exception is a null mutation in COX14 that does not affect Cox1 synthesis because the Mss51 trapping complexes become unstable, and Mss51 is readily available for translation. Here we present evidence showing that Cox25 is a new essential COX assembly factor that plays some roles similar to Cox14. A null mutation in COX25 by itself or in combination with other COX mutations does not affect Cox1 synthesis. Cox25 is an inner mitochondrial membrane intrinsic protein with a hydrophilic C terminus protruding into the matrix. Cox25 is an essential component of the complexes containing newly synthesized Cox1, Ssc1, Mss51, and Cox14. In addition, Cox25 is also found to interact with Shy1 and Cox5 in a complex that does not contain Mss51. These results suggest that once Ssc1-Mss51 are released from the Cox1 stabilization complex, Cox25 continues to interact with Cox14 and Cox1 to facilitate the formation of multisubunit COX assembly intermediates.


High prevalence rate of Entamoeba histolytica asymptomatic infection in a rural Mexican community.
The frequency of Entamoeba histolytica and Entamoeba dispar infection was analyzed in a rural community in the state of Morelos, Mexico, using polymerase chain reaction (PCR). Sociodemographic variables as risk factors for the infection were assessed. Results highlighted the number of individuals with intestinal parasites (43.1%) in the community, indicating extensive fecalism. A high frequency of E. histolytica asymptomatic infection, higher than E. dispar infection (13.8% versus 9.6%), was detected by PCR. Anti-amebic antibody levels (IgG) in serum and saliva (IgA) samples were not associated with E. histolytica intestinal infection. These findings suggest a predominant distribution of E. histolytica strains of low invasive potential in this community.


Defining acceptable levels for ecological indicators: an approach for considering social values.
Ecological indicators can facilitate an adaptive management approach, but only if acceptable levels for those indicators have been defined so that the data collected can be interpreted. Because acceptable levels are an expression of the desired state of the ecosystem, the process of establishing acceptable levels should incorporate not just ecological understanding but also societal values. The goal of this research was to explore an approach for defining acceptable levels of ecological indicators that explicitly considers social perspectives and values. We used a set of eight indicators that were related to issues of concern in the Lake Champlain Basin. Our approach was based on normative theory. Using a stakeholder survey, we measured respondent normative evaluations of varying levels of our indicators. Aggregated social norm curves were used to determine the level at which indicator values shifted from acceptable to unacceptable conditions. For seven of the eight indicators, clear preferences were interpretable from these norm curves. For example, closures of public beaches because of bacterial contamination and days of intense algae bloom went from acceptable to unacceptable at 7-10 days in a summer season. Survey respondents also indicated that the number of fish caught from Lake Champlain that could be safely consumed each month was unacceptably low and the number of streams draining into the lake that were impaired by storm water was unacceptably high. If indicators that translate ecological conditions into social consequences are carefully selected, we believe the normative approach has considerable merit for defining acceptable levels of valued ecological system components.


Dilated ureters, renal dysplasia, and chronic renal failure in an African elephant (Loxodonta africana).
An ultrasonographic reproductive health examination of a 26-yr-old female African elephant (Loxodonta africana) revealed bilateral ureteral wall thickening and dilatation. On ultrasonographic examination, the bladder and both ureters were normal near the trigone; however, the cranial-most aspect of each ureter was dilated and thickened for a length of 30-50 cm. The same month, elevated blood creatinine (3.0 mg/dl), and urine protein-creatinine ratio (4.0) were observed. Chronic renal failure was diagnosed based on these abnormalities, and the persistent ureteral dilatation was seen on subsequent ultrasound examinations. Complete blood cell counts, serum chemistries, and urinalyses remained relatively unchanged until 24 mo after diagnosis, at which time azotemia, hypophosphatemia, and hypercalcemia (including elevated ionized calcium) developed. Hydronephrosis of both kidneys and prominent sacculation of the left ureter were noted on ultrasonographic examination. Lethargy, ventral edema, and oral mucosal ulceration acutely developed 30 mo after diagnosis. Although blood urea nitrogen remained elevated, creatinine, total calcium, and ionized calcium returned to within reference ranges at that time. Due to rapid clinical decline and grave prognosis, humane euthanasia was elected. Bilateral ureteral dilatation, dysplasia of the right kidney, and chronic nephritis of the left kidney were identified postmortem.


Prognosis for patients with hepatocellular carcinoma (HCC) with bile duct tumor thrombus (BDTT) after surgical treatment.
Hepatocellular carcinoma (HCC) with bile duct tumor thrombus (BDTT) is rarely seen in clinical practice, and its treatment strategies and prognosis are still a subject of debate. To ascertain the characteristics of and prognosis for HCC with BDTT, 49 patients with HCC with BDTT were studied out of 763 consecutive patients with HCC who underwent surgical treatment from July 2004 to May 2018. The clinical characteristics of and prognosis for those 49 patients were reviewed and analyzed retrospectively. Of the 49 patients, 25 underwent radical resection, 7 underwent thrombectomy through a choledochotomy, and 17 underwent palliative internal and external bile duct drainage. Results indicated that patients who underwent a radical resection had a better prognosis than patients in the other two groups, with a median survival of 19 months vs. 8 months and 3 months (p < 0.001). Moreover, the preoperative bilirubin level (p = 0.025), intraoperative blood loss (p = 0.006), tumor size (p = 0.005), and the presence of portal and hepatic vein tumor thrombi (p = 0.021) were significant prognostic factors associated with long-term survival for patients who underwent radical resection in this study. Radical resection should be performed with adequate preoperative preparation for patients with HCC with BDTT in whom surgery is not contraindicated.


Discriminative learning of receptive fields from responses to non-Gaussian stimulus ensembles.
Analysis of sensory neurons' processing characteristics requires simultaneous measurement of presented stimuli and concurrent spike responses. The functional transformation from high-dimensional stimulus space to the binary space of spike and non-spike responses is commonly described with linear-nonlinear models, whose linear filter component describes the neuron's receptive field. From a machine learning perspective, this corresponds to the binary classification problem of discriminating spike-eliciting from non-spike-eliciting stimulus examples. The classification-based receptive field (CbRF) estimation method proposed here adapts a linear large-margin classifier to optimally predict experimental stimulus-response data and subsequently interprets learned classifier weights as the neuron's receptive field filter. Computational learning theory provides a theoretical framework for learning from data and guarantees optimality in the sense that the risk of erroneously assigning a spike-eliciting stimulus example to the non-spike class (and vice versa) is minimized. Efficacy of the CbRF method is validated with simulations and for auditory spectro-temporal receptive field (STRF) estimation from experimental recordings in the auditory midbrain of Mongolian gerbils. Acoustic stimulation is performed with frequency-modulated tone complexes that mimic properties of natural stimuli, specifically non-Gaussian amplitude distribution and higher-order correlations. Results demonstrate that the proposed approach successfully identifies correct underlying STRFs, even in cases where second-order methods based on the spike-triggered average (STA) do not. Applied to small data samples, the method is shown to converge on smaller amounts of experimental recordings and with lower estimation variance than the generalized linear model and recent information theoretic methods. Thus, CbRF estimation may prove useful for investigation of neuronal processes in response to natural stimuli and in settings where rapid adaptation is induced by experimental design.


A triad of subunits from the Gal11/tail domain of Srb mediator is an in vivo target of transcriptional activator Gcn4p.
The Srb mediator is an important transcriptional coactivator for Gcn4p in the yeast Saccharomyces cerevisiae. We show that three subunits of the Gal11/tail domain of mediator, Gal11p, Pgd1p, and Med2p, and the head domain subunit Srb2p make overlapping contributions to the interaction of mediator with recombinant Gcn4p in vitro. Each of these proteins, along with the tail subunit Sin4p, also contributes to the recruitment of mediator by Gcn4p to target promoters in vivo. We found that Gal11p, Med2p, and Pgd1p reside in a stable subcomplex in sin4Delta cells that interacts with Gcn4p in vitro and that is recruited independently of the rest of mediator by Gcn4p in vivo. Thus, the Gal11p/Med2p/Pgd1p triad is both necessary for recruitment of intact mediator and appears to be sufficient for recruitment by Gcn4p as a free subcomplex. The med2Delta mutation impairs the recruitment of TATA binding protein (TBP) and RNA polymerase II to the promoter and the induction of transcription at ARG1, demonstrating the importance of the tail domain for activation by Gcn4p in vivo. Even though the Gal11p/Med2p/Pgd1p triad is the only portion of Srb mediator recruited efficiently to the promoter in the sin4Delta strain, this mutant shows high-level TBP recruitment and wild-type transcriptional induction at ARG1. Hence, the Gal11p/Med2p/Pgd1p triad may contribute to TBP recruitment independently of the rest of mediator.


Computation of likelihood ratios in fingerprint identification for configurations of three minutiae.
Recent challenges to fingerprint evidence have brought forward the need for peer-reviewed scientific publications to support the evidential value assessment of fingerprint. This paper proposes some research directions to gather statistical knowledge of the within-source and between-sources variability of configurations of three minutiae on fingermarks and fingerprints. This paper proposes the use of the likelihood ratio (LR) approach to assess the value of fingerprint evidence. The model explores the statistical contribution of configurations of three minutiae using Tippett plots and related measures to assess the quality of the system. Features vectors used for statistical analysis have been obtained following a preprocessing step based on Gabor filtering and image processing to extract minutia position, type, and direction. Spatial relationships have been coded using Delaunay triangulation. The metric, used to assess similarity between two feature vectors is based on an Euclidean distance measure. The within-source variability has been estimated using a sample of 216 fingerprints from four fingers (two donors). Between-sources variability takes advantage of a database of 818 ulnar loops from randomly selected males. The results show that the data-driven approach adopted here is robust. The magnitude of LRs obtained under the prosecution and defense propositions stresses upon the major evidential contribution that small portions of fingermark, containing three minutiae, can provide regardless of its position on the general pattern.