Cadmium hyperaccumulation leads to an increase of glutathione rather than phytochelatins in the cadmium hyperaccumulator Sedum alfredii.
Sedum alfredii has been reported to be a cadmium (Cd) hyperaccumulator. Phytochelatins (PCs) and other thiol (SH)-containing compounds have been proposed to play an important role in the detoxification and tolerance of some heavy metals, but it is not clear whether PCs are responsible for Cd hyperaccumulation and tolerance in S. alfredii. In this study, two geographically isolated populations of S. alfredii were studied: one population grew on an old Pb/Zn mine site, while the other on a non-mine site. The mine population of this species exhibited a stronger heavy metal tolerance than in the other population. Root-to-shoot transport of Cd was higher in population located at the mine site than at the non-mine site. Considerable amounts of Cd were accumulated in leaves and stems of mine plants, while most Cd was distributed in roots of non-mine plants. Non-protein SH in plant tissues of two populations were further investigated by a HPLC pre-column derivatization system. Upon exposure to Cd, no PCs were detected in all tissues of mine population, while an appreciable amount of glutathione (GSH) was observed in the descending order of stem>root>leaf. The concentrations of GSH consistently increased with the increase of exogenous Cd concentrations and time. On the contrary, Cd exposure strongly induced the production of PCs (mainly PC(2) and PC(3)) and GSH in plant tissues of non-mine population, and the concentrations of GSH showed an initial drop over the duration of 7-d exposure. The present results provided strong evidence that PCs are not involved in Cd transport, hyperaccumulation and tolerance in mine population of S. alfredii.


Role of functionally dominant species in varying environmental regimes: evidence for the performance-enhancing effect of biodiversity.
Theory suggests that biodiversity can act as a buffer against disturbances and environmental variability via two major mechanisms: Firstly, a stabilising effect by decreasing the temporal variance in ecosystem functioning due to compensatory processes; and secondly, a performance enhancing effect by raising the level of community response through the selection of better performing species. Empirical evidence for the stabilizing effect of biodiversity is readily available, whereas experimental confirmation of the performance-enhancing effect of biodiversity is sparse. Here, we test the effect of different environmental regimes (constant versus fluctuating temperature) on bacterial biodiversity-ecosystem functioning relations. We show that positive effects of species richness on ecosystem functioning are enhanced by stronger temperature fluctuations due to the increased performance of individual species. Our results provide evidence for the performance enhancing effect and suggest that selection towards functionally dominant species is likely to benefit the maintenance of ecosystem functioning under more variable conditions.


EGCG, a green tea catechin, attenuates the progression of heart failure induced by the heart/muscle-specific deletion of MnSOD in mice.
Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme affected in heart/muscle-specific MnSOD-deficient mice (H/M-SOD2-/-), which develop progressive congestive heart failure and exhibit pathology typical of dilated cardiomyopathy. In this study we investigated the beneficial effects of epigallocatechin gallate (EGCG) on the cardiac remodeling and telomere biology in H/M-SOD2-/- mice. H/M-SOD2-/- mice were divided into three groups: those receiving normal drinking water (KO), a low dose of EGCG (L: 10mg/L), and a high dose of EGCG (H: 100mg/L) beginning at eight weeks of age and lasting for eight weeks. The mice in the KO group exhibited significantly dilated cardiac remodeling with reduced contractility, which was prevented by the administration of EGCG. Although the mortality of KO mice was about 50% at 16 weeks of age, the mice that received EGCG had a high survival rate. The cardiac dilatation with reduced cardiac contraction in KO mice was prevented by EGCG treatment. The levels of myocardial oxidative stress and free fatty acids were lower in the group treated with EGCG compared with the KO group. The increased expression of nitric oxide synthase 2, nitrotyrosine, fatty acid synthase, Toll-like receptor 4, and Sirt1 in the KO mice were prevented by EGCG treatment. The shortening of the telomere length, decreased telomerase activity in KO mice were also prevented by EGCG. H/M-SOD2-/- mice receiving EGCG have a lower mortality rate and exhibit less inflammation and a better preserved cardiac function and telomere biology.


The role of surgical intervention in lung cancer with carcinomatous pleuritis.
Patients with non-small cell lung cancer (NSCLC) associated with carcinomatous pleuritis are currently classified as having stage IV disease per the 7th edition of the tumor-node-metastasis (TNM) system, which means that the disease is deemed incurable. In fact, the 5-year survival rate of these patients was only 2% in a large global cohort collected by the International Association for the Study of Lung Cancer. However, patients with carcinomatous pleuritis have heterogeneous conditions. Some have minimal pleural effusion, which is first detected at thoracotomy; some have numerous pleural nodules without any effusion; and others have massive effusion and nodules with symptoms. Several investigators have reported the contribution of surgical intervention to favorable outcomes of patients with carcinomatous pleuritis first detected at thoracotomy. These reports show a relatively higher 5-year survival rate of 15% to 37%. The extrapleural pneumonectomy (EPP) is a radical surgical procedure that is commonly employed in the treatment of malignant pleural mesothelioma. Two authors reported that they have successfully performed EPPs for the treatment of patients with carcinomatous pleuritis. Their 5-year survival rates were estimated to be 22% and 61%, a significantly improved outcome. Although the development of chemotherapeutic agents, including molecular targeted drugs, might have the potential to prolong the survival of patients with advanced lung cancer, surgical interventions including EPP might have a role in improving the survival of patients with carcinomatous pleuritis of minimal disease and those without massive effusion or numerous pleural nodules.


Electrostatics, Hydrogen Bonding, and Molecular Structure at Polycation and Peptide:Lipid Membrane Interfaces.
Polycation and peptide-modified surfaces represent opportunities for developing potentially novel biocidal materials in a growing effort to combat bacterial resistance to traditional bactericides. It is well-known that the positive charge of these compounds is crucial to their function in biofouling prevention and as antimicrobials; however, methods for quantifying the number of positive charges on surface-bound polycations and peptides are necessary to predict, control, and optimize the design and therefore the utility of these compounds. This Spotlight on Applications reports on such an approach that combines second harmonic generation (SHG) spectroscopy, quartz crystal microbalance with dissipation monitoring (QCM-D), and atomistic simulations to obtain mechanistic insight into polycation-membrane interactions using supported lipid bilayers (SLBs) as our model system. We find that at high surface coverage, the large polycations we surveyed feature a considerably smaller percentage of ionization when compared to the smaller polycations and peptides. At these high charge densities, we suspect a pKa shift of the charged groups to lower charge-charge repulsion as well as the formation of a looplike conformation such that less monomeric units form contact-ion pairs with the bilayer. Our sum frequency generation (SFG) spectroscopy results complement our understanding of the polycation-membrane interaction. At a high density of the polycation poly(allylamine hydrochloride) (PAH), second-order spectral line shapes are consistent with the expulsion of interfacial water molecules possibly due to contact-ion pair formation between PAH and the lipid bilayer. This finding could be essential for understanding the underlying first steps of cell lysis and penetration by polycations and should be explored further.


Increased carotid and brachial intima-media thickness is related to diffuse coronary involvement rather than focal lesions.
We evaluated whether an increased carotid intima-media thickness (cIMT) and brachial artery IMT (bIMT) are related to diffuse coronary involvement rather than focal lesions. Patients (n = 88) with at least 1 significant lesion of the main epicardial coronary arteries (≥50%) were included in the present study. We used a novel score based on length and mean narrowing of all lesions in order to predict diffuse coronary involvement. Both cIMT and bIMT were higher in patients with long coronary lesion than focal lesion (P < .001). The patients with long coronary lesion had a higher rate of total coronary involvement than patients with focal lesion (P < .001). The cIMT had a higher correlation with total atherosclerotic burden in the coronary vasculature (r = .495, P < .001) and the longest lesion length (r = .489, P < .001) than cardiovascular risk factor score (r = .453, P < .001 and r = .324, P = .012, respectively). These findings may be valuable for clarifying the prognostic value of IMT measurements.


Effect of emodin on chondrocyte viability in an in vitro model of osteoarthritis.
Emodin is an anthraquinone isolated from the Chinese herb Radix et Rhizoma Rhei and has been used to treat various diseases for centuries. The aim of the present study was to investigate the effect of emodin on the inflammatory mediators in rat chondrocytes. In the present study, chondrocytes were isolated from rats, cultured and harvested when they reached generation P3. Cells were treated with different doses of emodin (10, 20, and 30 µg/ml) followed by interleukin 1β (IL-1β, 10 ng/ml). Control cells were either untreated or treated with IL-1β alone. An enzyme-linked immunosorbent assay was used to measure levels of nitric oxide (NO) and prostaglandin E2 (PGE2). Reverse transcription-quantitative polymerase chain was performed to measure levels of matrix metallopeptidase (MMP)-3 and -13 mRNA. The expression of MMP-3, MMP-13, extracellular-signal regulatory kinase (ERK)1/2, phosphorylated ERK1/2 and β-catenin proteins were detected by western-blot analysis. The results demonstrated that treatment with emodin treatment reduced the cytotoxicity of IL-1β and inhibited the expression of NO and PGE2 in rat chondrocytes. Furthermore, emodin inhibited the expression of MMP3 and MMP13, and the phosphorylation of various proteins involved in the ERK and Wnt/β-catenin pathway. Therefore, emodin is able to promote the proliferation of chondrocytes by inhibiting the ERK and Wnt/β-catenin pathway and downregulating the expression of a series of inflammatory mediators in chondrocytes.


Disrupted neural synchronization in toddlers with autism.
Autism is often described as a disorder of neural synchronization. However, it is unknown how early in development synchronization abnormalities emerge and whether they are related to the development of early autistic behavioral symptoms. Here, we show that disrupted synchronization is evident in the spontaneous cortical activity of naturally sleeping toddlers with autism, but not in toddlers with language delay or typical development. Toddlers with autism exhibited significantly weaker interhemispheric synchronization (i.e., weak "functional connectivity" across the two hemispheres) in putative language areas. The strength of synchronization was positively correlated with verbal ability and negatively correlated with autism severity, and it enabled identification of the majority of autistic toddlers (72%) with high accuracy (84%). Disrupted cortical synchronization, therefore, appears to be a notable characteristic of autism neurophysiology that is evident at very early stages of autism development.


Crayfish immunity - Recent findings.
Freshwater crayfish is an important commodity as well as a successful model for studies on crustacean immunity. Due to the ease with which they are kept and the available methods for hemocyte separation and culture they have proven to be very useful. Here, recent progress regarding pattern recognition, immune effector production and antiviral mechanisms are discussed. Several cases of functional resemblance between vertebrate complement and the crayfish immune reactions are highlighted.


Assessing Measurement Properties of a Simplified Chinese Version of Sleep Condition Indicator (SCI-SC) in Community Residents.
The study aimed to assess the measurement properties of a simplified Chinese version of the Sleep Condition Indicator (SCI-SC) in the community. A psychometric evaluation through an observational cross-sectional survey design was conducted. Community residents (N = 751) in Hangzhou, China completed the SCI-SC and the simplified Chinese version of the Sleep Quality Questionnaire (SQQ) in July 2021. Data were randomly split into a development sample (N = 375) for model development by exploratory factor analysis (EFA) and a holdout sample (N = 376) for validation by confirmatory factor analysis (CFA). Multi-group CFA (MGCFA) was used to assess configural, metric, scalar, and strict measurement invariance across gender, age, marital status, body mass index (BMI), napping habits, generic exercise, hobby, and administered survey. Moreover, statistical analyses were performed to determine the reliability (alpha and omega) and construct validity of the instrument. Both factor analyses showed a stable solution with two dimensions of Sleep Pattern and Sleep-Related Impact. Good structural validity, robust internal consistency, and construct validity with the SQQ were demonstrated. There was evidence of strict invariance across gender, BMI, napping habits, generic exercise, hobby, and administered survey subgroups, but only metric and scalar invariances were established across age and marital status groups, respectively. The SCI-SC demonstrated promising psychometric properties, with high SQQ concordance and consistent structure of the original version. The SCI-SC can be used by sleep researchers as well as healthcare professionals in various contexts in detecting risks for insomnia disorder in the community.


Prevalence and characteristics of women with induced abortion--Favela México 70, São Vicente-São Paulo.
In Brazil, abortion is among the leading causes of maternal mortality. Research has shown that abortion is practiced clandestinely by women of all social classes, but has unequal consequences depending on social inclusion, producing risks to poor women. Although the issue has been widely explored in the past 20 years, there is a lack of data about low-income women. Thus, the present study aims to estimate the prevalence of women with induced abortion. Women from a population-based household survey in low-income sectors of São Vicente, São Paulo were recruited. Women of childbearing age from 15 to 49 years were eligible. The evaluation of the prevalence ratios for women with induced abortion was performed by using generalized linear models, with Poisson log-link function and robust variance to approximate the binomial. The most frequent variables that influenced reporting of abortion were: "always accept this practice" (95% CI 2.98-11.02), followed by "not having a child born alive" (95% CI 1.35-19.78), having "two to five live births" (95% CI 1.42-14.40), "having 'six or more live births" (95% CI 1.35-19.78), "age at interview" (95% CI 1.01-1.07) and "income" < R$ 484.97' (95% CI 1.04-2.96). A widespread campaign about the practice of abortion, which can raise awareness among women in favor of the cause, especially among those in low-income strata is necessary to prevent unnecessary deaths.


Haplotype-Phased Synthetic Long Reads from Short-Read Sequencing.
Next-generation DNA sequencing has revolutionized the study of biology. However, the short read lengths of the dominant instruments complicate assembly of complex genomes and haplotype phasing of mixtures of similar sequences. Here we demonstrate a method to reconstruct the sequences of individual nucleic acid molecules up to 11.6 kilobases in length from short (150-bp) reads. We show that our method can construct 99.97%-accurate synthetic reads from bacterial, plant, and animal genomic samples, full-length mRNA sequences from human cancer cell lines, and individual HIV env gene variants from a mixture. The preparation of multiple samples can be multiplexed into a single tube, further reducing effort and cost relative to competing approaches. Our approach generates sequencing libraries in three days from less than one microgram of DNA in a single-tube format without custom equipment or specialized expertise.


White matter and subcortical gray matter lesion volume changes and late-life depression outcome: a 4-year magnetic resonance imaging study.
Cross-sectional studies have shown that late-onset depression is associated with larger deep white matter lesions (WMLs) and subcortical gray matter lesions (GMLs). In a longitudinal analysis, we examined changes in deep WMLs and subcortical GMLs in older depressed and nondepressed subjects over a 4-year period. Brain magnetic resonance imaging (MRI) scans were obtained on 164 depressed and 126 healthy subjects aged 60 years or older at baseline, and 2 and 4 years after recruitment. WMLs and GMLs were measured using a semiautomated technique. We used repeated-measures analysis of covariance to determine cross-sectional lesion volume differences, whether lesion volume changes differed between patients and controls, and the effect of lesion volume changes on outcome in late-life depression. Mean volumes of lesions for the depressive group were 6.51, 8.18 and 7.75 cm2 for WMLs and 0.23, 0.30 and 0.34 cm2 for GMLs at baseline, 2-year and 4-year follow-up, respectively. Mean volumes of lesions for the control group were 4.83, 6.22 and 6.45 cm2 for WMLs and 0.17, 0.25 and 0.23 cm2 for GMLs at baseline, 2-year and 4-year follow-up, respectively. Cross-sectional between-group mean lesion volumes were significantly different for each measure. However, the pattern of WML and GML volume changes over time was not significantly different between groups. Treatment outcome was associated with changes in total and white matter lesion volume over time. Lesion volume progression is associated with aging and the pathological condition of late-life depression. The mechanisms that produce these progressive lesion changes remain unclear. Treatments aimed at arresting lesion progression may play a role in the management of late-life depression.


External validation of clinical severity scores to guide referral of paediatric acute respiratory infections in resource-limited primary care settings.
Accurate and reliable guidelines for referral of children from resource-limited primary care settings are lacking. We identified three practicable paediatric severity scores (the Liverpool quick Sequential Organ Failure Assessment (LqSOFA), the quick Pediatric Logistic Organ Dysfunction-2, and the modified Systemic Inflammatory Response Syndrome) and externally validated their performance in young children presenting with acute respiratory infections (ARIs) to a primary care clinic located within a refugee camp on the Thailand-Myanmar border. This secondary analysis of data from a longitudinal birth cohort study consisted of 3010 ARI presentations in children aged ≤ 24 months. The primary outcome was receipt of supplemental oxygen. We externally validated the discrimination, calibration, and net-benefit of the scores, and quantified gains in performance that might be expected if they were deployed as simple clinical prediction models, and updated to include nutritional status and respiratory distress. 104/3,010 (3.5%) presentations met the primary outcome. The LqSOFA score demonstrated the best discrimination (AUC 0.84; 95% CI 0.79-0.89) and achieved a sensitivity and specificity > 0.80. Converting the scores into clinical prediction models improved performance, resulting in ~ 20% fewer unnecessary referrals and ~ 30-50% fewer children incorrectly managed in the community. The LqSOFA score is a promising triage tool for young children presenting with ARIs in resource-limited primary care settings. Where feasible, deploying the score as a simple clinical prediction model might enable more accurate and nuanced risk stratification, increasing applicability across a wider range of contexts.


Beyond the Levant: first evidence of a pre-pottery Neolithic incursion into the Nefud Desert, Saudi Arabia.
Pre-Pottery Neolithic assemblages are best known from the fertile areas of the Mediterranean Levant. The archaeological site of Jebel Qattar 101 (JQ-101), at Jubbah in the southern part of the Nefud Desert of northern Saudi Arabia, contains a large collection of stone tools, adjacent to an Early Holocene palaeolake. The stone tool assemblage contains lithic types, including El-Khiam and Helwan projectile points, which are similar to those recorded in Pre-Pottery Neolithic A and Pre-Pottery Neolithic B assemblages in the Fertile Crescent. Jebel Qattar lies ∼500 kilometres outside the previously identified geographic range of Pre-Pottery Neolithic cultures. Technological analysis of the typologically diagnostic Jebel Qattar 101 projectile points indicates a unique strategy to manufacture the final forms, thereby raising the possibility of either direct migration of Levantine groups or the acculturation of mobile communities in Arabia. The discovery of the Early Holocene site of Jebel Qattar suggests that our view of the geographic distribution and character of Pre-Pottery Neolithic cultures may be in need of revision.


Little White Lies: Pericarp Color Provides Insights into the Origins and Evolution of Southeast Asian Weedy Rice.
Weedy rice is a conspecific form of cultivated rice (Oryza sativa L.) that infests rice fields and results in severe crop losses. Weed strains in different world regions appear to have originated multiple times from different domesticated and/or wild rice progenitors. In the case of Malaysian weedy rice, a multiple-origin model has been proposed based on neutral markers and analyses of domestication genes for hull color and seed shattering. Here, we examined variation in pericarp (bran) color and its molecular basis to address how this trait evolved in Malaysian weeds and its possible role in weed adaptation. Functional alleles of the Rc gene confer proanthocyanidin pigmentation of the pericarp, a trait found in most wild and weedy Oryzas and associated with seed dormancy; nonfunctional rc alleles were strongly favored during rice domestication, and most cultivated varieties have nonpigmented pericarps. Phenotypic characterizations of 52 Malaysian weeds revealed that most strains are characterized by the pigmented pericarp; however, some weeds have white pericarps, suggesting close relationships to cultivated rice. Phylogenetic analyses indicate that the Rc haplotypes present in Malaysian weeds likely have at least three distinct origins: wild O. rufipogon, white-pericarp cultivated rice, and red-pericarp cultivated rice. These diverse origins contribute to high Rc nucleotide diversity in the Malaysian weeds. Comparison of Rc allelic distributions with other rice domestication genes suggests that functional Rc alleles may confer particular fitness benefits in weedy rice populations, for example, by conferring seed dormancy. This may promote functional Rc introgression from local wild Oryza populations.


Premature ovarian failure: a critical condition in the reproductive potential with various genetic causes.
Premature ovarian failure (POF) is identified as a heterogeneous disorder leading to amenorrhea and ovarian failure before the age of 40 years. The first known symptom of the disease is having irregular menstrual periods. The phenotype appearance of POF depends significantly on the variations in hormones. Low levels of gonadal hormones (estrogens and inhibins) and increased level of gonadotropins [luteinizing hormone (LH) and Follicle stimulating hormone (FSH)] (hypergonadotropic amenorrhea) are well documented as causes of POF. There is an association between the failure of germ cell development and complete ovarian failure, and consistently decreased number of germ cells is more likely associated with partial ovarian failure resulting in secondary amenorrhea. A literature review on recent findings about POF and its association with genomic alterations in terms of genes and chromosomes. POF is a complex heterogeneous disorder. Some of POF cases are carriers of a single gene mutation inherited in an autosomal or X-linked manner while a number of patients suffer from a chromosome abnormality like Turner syndrome in mosaic form and manifest secondary amenorrhea associated with ovarian dysgenesis. Among many of the known involved genes in POF development, several are prove to be positively associated to the disease development in different populations. While there is a promising association between X chromosome anomalies and specific gene mutations with POF, genome-wide analysis could prove a powerful tool for identifying the most important candidate genes that influence POF manifestation.


Imaging genetics of cognitive functions: Focus on episodic memory.
Human cognitive functions are highly variable across individuals and are both genetically and environmentally influenced. Recent behavioral genetics studies have identified several common genetic polymorphisms, which are related to individual differences in memory performance. In addition, imaging genetics studies are starting to explore the neural correlates of genetic differences in memory functions on the level of brain circuits. In this review we will describe how functional magnetic resonance imaging (fMRI) can be used to validate and extend findings of behavioral genetics studies of episodic memory and give examples of recent advances in this new and exciting research field. In addition, we will present advantages and problems related to the different sensitivity of behavioral- vs. imaging genetics studies and discuss possible methodological approaches for an appropriate evaluation and integration of the results. Although the field of imaging genetics of episodic memory is still young, it already became clear that imaging methods have a large potential to enhance our understanding of the neural mechanisms that underlie genetic differences in memory.


Invasive Fungal Infections in Patients with Hematological Malignancies: Emergence of Resistant Pathogens and New Antifungal Therapies.
Invasive fungal infections caused by drug-resistant organisms are an emerging threat to heavily immunosuppressed patients with hematological malignancies. Modern early antifungal treatment strategies, such as prophylaxis and empirical and preemptive therapy, result in long-term exposure to antifungal agents, which is a major driving force for the development of resistance. The extended use of central venous catheters, the nonlinear pharmacokinetics of certain antifungal agents, neutropenia, other forms of intense immunosuppression, and drug toxicities are other contributing factors. The widespread use of agricultural and industrial fungicides with similar chemical structures and mechanisms of action has resulted in the development of environmental reservoirs for some drug-resistant fungi, especially azole-resistant Aspergillus species, which have been reported from four continents. The majority of resistant strains have the mutation TR34/L98H, a finding suggesting that the source of resistance is the environment. The global emergence of new fungal pathogens with inherent resistance, such as Candida auris, is a new public health threat. The most common mechanism of antifungal drug resistance is the induction of efflux pumps, which decrease intracellular drug concentrations. Overexpression, depletion, and alteration of the drug target are other mechanisms of resistance. Mutations in the ERG11 gene alter the protein structure of C-demethylase, reducing the efficacy of antifungal triazoles. Candida species become echinocandin-resistant by mutations in FKS genes. A shift in the epidemiology of Candida towards resistant non-albicans Candida spp. has emerged among patients with hematological malignancies. There is no definite association between antifungal resistance, as defined by elevated minimum inhibitory concentrations, and clinical outcomes in this population. Detection of genes or mutations conferring resistance with the use of molecular methods may offer better predictive values in certain cases. Treatment options for resistant fungal infections are limited and new drugs with novel mechanisms of actions are needed. Prevention of resistance through antifungal stewardship programs is of paramount importance.


Multidrug-resistant Proteus mirabilis bloodstream infections: risk factors and outcomes.
Our aims were to identify (i) risk factors associated with the acquisition of multidrug-resistant (MDR, to 3 or more classes of antimicrobials) Proteus mirabilis isolates responsible for bloodstream infections (BSIs) and (ii) the impact on mortality of such infections. Risk factors for acquiring MDR P. mirabilis BSIs were investigated in a case-case-control study; those associated with mortality were assessed by comparing survivors and nonsurvivors in a cohort study. The population consisted of 99 adult inpatients with P. mirabilis BSIs identified by our laboratory over an 11-year period (1999 to 2009), 36 (33.3%) of which were caused by MDR strains, and the overall 21-day mortality rate was 30.3%. Acquisition of an MDR strain was independently associated with admission from a long-term care facility (odds ratio [OR], 9.78; 95% confidence interval [CI], 1.94 to 49.16), previous therapy with fluoroquinolones (OR, 5.52; 95% CI, 1.30 to 23.43) or oxyimino-cephalosporins (OR, 4.72; 95% CI, 1.31 to 16.99), urinary catheterization (OR, 3.89; 95% CI, 1.50 to 10.09), and previous hospitalization (OR, 2.68; 95% CI, 10.4 to 6.89). Patients with MDR P. mirabilis BSIs received inadequate initial antimicrobial therapy (IIAT, i.e., treatment with drugs to which the isolate displayed in vitro resistance) more frequently than those with non-MDR infections; they also had increased mortality and (for survivors) longer post-BSI-onset hospital stays. In multivariate regression analysis, 21-day mortality was associated with septic shock at BSI onset (OR, 12.97; 95% CI, 32.2 to 52.23), P. mirabilis isolates that were MDR (OR, 6.62; 95% CI, 16.4 to 26.68), and IIAT (OR, 9.85; 95% CI, 26.7 to 36.25), the only modifiable risk factor of the 3. These findings can potentially improve clinicians' ability to identify P. mirabilis BSIs likely to be MDR, thereby reducing the risk of IIAT--a major risk factor for mortality in these cases--and facilitating the prompt implementation of appropriate infection control measures.


CD40Ig treatment results in allograft acceptance mediated by CD8CD45RC T cells, IFN-gamma, and indoleamine 2,3-dioxygenase.
Treatment with CD40Ig results in indefinite allograft survival in a complete MHC-mismatched heart allograft model in the rat. Here we show that serial second, third, and fourth adoptive transfers of total splenocytes from CD40Ig-treated recipients into secondary recipients led to indefinite donor-specific allograft acceptance. Purification of splenocyte subpopulations from CD40Ig-treated recipients demonstrated that only the adoptively transferred CD8(+)CD45RC(low) subset resulted in donor-specific long-term survival, whereas CD8(+)CD45RC(low) T cells from naive animals did not. Accepted grafts displayed increased indoleamine 2,3-dioxygenase (IDO) expression restricted in the graft to ECs. Coculture of donor ECs with CD8(+)CD45RC(low) T cells purified from CD40Ig-treated animals resulted in donor-specific IDO expression dependent on IFN-gamma. Neutralization of IFN-gamma or IDO triggered acute allograft rejection in both CD40Ig-treated and adoptively transferred recipients. This study demonstrates for what we believe to be the first time that interference in CD40-CD40 ligand (CD40-CD40L) interactions induces allospecific CD8(+) Tregs that maintain allograft survival. CD8(+)CD45RC(low) T cells act through IFN-gamma production, which in turn induces IDO expression by graft ECs. Thus, donor alloantigen-specific CD8(+) Tregs may promote local graft immune privilege through IDO expression.


Workspaces that move people.
Few companies measure whether the design of their workspaces helps or hurts performance, but they should. The authors have collected data that capture individuals' interactions, communications, and location information. They've learned that face-to-face interactions are by far the most important activity in an office; creating chance encounters between knowledge workers, both inside and outside the organization, improves performance. The Norwegian telecom company Telenor was ahead of its time in 2003, when it incorporated "hot desking" (no assigned seats) and spaces that could easily be reconfigured for different tasks and evolving teams. The CEO credits the design of the offices with helping Telenor shift from a state-run monopoly to a competitive multinational carrier with 150 million subscribers. In another example, data collected at one pharmaceuticals company showed that when a salesperson increased interactions with coworkers on other teams by 10%, his or her sales increased by 10%. To get the sales staff running into colleagues from other departments, management shifted from one coffee machine for every six employees to one for every 120 and created a new large cafeteria for everyone. Sales rose by 20%, or $200 million, afterjust one quarter, quickly justifying the capital investment in the redesign.


Climate services for health: predicting the evolution of the 2016 dengue season in Machala, Ecuador.
El Niño and its effect on local meteorological conditions potentially influences interannual variability in dengue transmission in southern coastal Ecuador. El Oro province is a key dengue surveillance site, due to the high burden of dengue, seasonal transmission, co-circulation of all four dengue serotypes, and the recent introduction of chikungunya and Zika. In this study, we used climate forecasts to predict the evolution of the 2016 dengue season in the city of Machala, following one of the strongest El Niño events on record. We incorporated precipitation, minimum temperature, and Niño3·4 index forecasts in a Bayesian hierarchical mixed model to predict dengue incidence. The model was initiated on Jan 1, 2016, producing monthly dengue forecasts until November, 2016. We accounted for misreporting of dengue due to the introduction of chikungunya in 2015, by using active surveillance data to correct reported dengue case data from passive surveillance records. We then evaluated the forecast retrospectively with available epidemiological information. The predictions correctly forecast an early peak in dengue incidence in March, 2016, with a 90% chance of exceeding the mean dengue incidence for the previous 5 years. Accounting for the proportion of chikungunya cases that had been incorrectly recorded as dengue in 2015 improved the prediction of the magnitude of dengue incidence in 2016. This dengue prediction framework, which uses seasonal climate and El Niño forecasts, allows a prediction to be made at the start of the year for the entire dengue season. Combining active surveillance data with routine dengue reports improved not only model fit and performance, but also the accuracy of benchmark estimates based on historical seasonal averages. This study advances the state-of-the-art of climate services for the health sector, by showing the potential value of incorporating climate information in the public health decision-making process in Ecuador. European Union FP7, Royal Society, and National Science Foundation.


Traceability of animal protein byproducts in ruminants by multivariate analysis of isotope ratio mass spectrometry to prevent transmission of prion diseases.
Ruminant feed containing animal byproduct proteins (ABPs) is prohibited in many countries due to its risk of transmitting prion diseases (PD). In most cases the entire herd is sacrificed, which causes great harm to the producer countries by preventing their exportation of ruminant derived-products. We used stable isotope ratio mass spectrometry (IRMS) of carbon (13C/12C) and nitrogen (15N/14N) to trace the animal protein in the blood of 15 buffaloes (Bubalus bubalis) divided into three experimental groups: 1 - received only vegetable protein (VP) during 117 days; 2 - received animal and vegetable protein (AVP); and 3 - received animal and vegetable protein with animal protein subsequently removed (AVPR). Groups 2 and 3 received diets containing 13.7% bovine meat and bone meal (MBM) added to a vegetable diet (from days 21-117 in the AVP group and until day 47 in the AVPR group, when MBM was removed). On the 36th day, differences were detectable in the feeding profile (p <0.01) among the three experimental groups, which remained for a further 49 days (85th day). The AVPR group showed isotopic rate reversibility on the 110th day by presenting values similar to those in the control group (VP) (p> 0.05), indicating that it took 63 days to eliminate MBM in this group. Total atoms exchange (> 95%) of 13C and 15N was observed through incorporation of the diet into the AVP and AVPR groups. IRMS is an accurate and sensitive technique for tracing the feeding profile of ruminants through blood analysis, thus enabling investigation of ABP use.


Changing face of hepatic encephalopathy: role of inflammation and oxidative stress.
The face of hepatic encephalopathy (HE) is changing. This review explores how this neurocognitive disorder, which is associated with both acute and chronic liver injury, has grown to become a dynamic syndrome that spans a spectrum of neuropsychological impairment, from normal performance to coma. The central role of ammonia in the pathogenesis of HE remains incontrovertible. However, over the past 10 years, the HE community has begun to characterise the key roles of inflammation, infection, and oxidative/nitrosative stress in modulating the pathophysiological effects of ammonia on the astrocyte. This review explores the current thoughts and evidence base in this area and discusses the potential role of existing and novel therapies that might abrogate the oxidative and nitrosative stresses inflicted on the brain in patients with, or at risk of developing, HE.


Acute-phase serum amyloid A protein and its implication in the development of type 2 diabetes in the KORA S4/F4 study.
We sought to investigate whether elevated levels of acute-phase serum amyloid A (A-SAA) protein precede the onset of type 2 diabetes independently of other risk factors, including parameters of glucose metabolism. Within the population-based Cooperative Health Research in the Region of Augsburg (KORA) S4 study, we measured A-SAA concentrations in 836 initially nondiabetic subjects (55-74 years of age) without clinically overt inflammation who participated in a 7-year follow-up examination including an oral glucose tolerance test. A-SAA concentrations were significantly associated with incident type 2 diabetes (odds ratio [OR] for a one-SD increase of A-SAA adjusted for age and sex = 1.28 [95% CI 1.08-1.53], P = 0.005), particularly in younger subjects (P value for interaction = 0.047). The association attenuated when adjusting for parameters of glucose metabolism (fasting glucose, fasting insulin, HbA1c, and 2-h glucose; OR 1.16 [0.95-1.42], P = 0.15). Similar analyses for high-sensitive C-reactive protein (hs-CRP) yielded the following ORs: 1.39 (1.10-1.68, P = 0.0006) and 1.13 (0.88-1.45, P = 0.34), respectively. In contrast, A-SAA concentrations were significantly associated with 2-h glucose levels at follow-up even after adjustment for parameters of glucose metabolism (P = 0.008, n = 803). Our findings indicate similarly strong prospective associations with type 2 diabetes for A-SAA and hs-CRP and suggest a potential causal link via postchallenge hyperglycemia.


Spin-orbit-coupled Bose-Einstein condensates.
Spin-orbit (SO) coupling--the interaction between a quantum particle's spin and its momentum--is ubiquitous in physical systems. In condensed matter systems, SO coupling is crucial for the spin-Hall effect and topological insulators; it contributes to the electronic properties of materials such as GaAs, and is important for spintronic devices. Quantum many-body systems of ultracold atoms can be precisely controlled experimentally, and would therefore seem to provide an ideal platform on which to study SO coupling. Although an atom's intrinsic SO coupling affects its electronic structure, it does not lead to coupling between the spin and the centre-of-mass motion of the atom. Here, we engineer SO coupling (with equal Rashba and Dresselhaus strengths) in a neutral atomic Bose-Einstein condensate by dressing two atomic spin states with a pair of lasers. Such coupling has not been realized previously for ultracold atomic gases, or indeed any bosonic system. Furthermore, in the presence of the laser coupling, the interactions between the two dressed atomic spin states are modified, driving a quantum phase transition from a spatially spin-mixed state (lasers off) to a phase-separated state (above a critical laser intensity). We develop a many-body theory that provides quantitative agreement with the observed location of the transition. The engineered SO coupling--equally applicable for bosons and fermions--sets the stage for the realization of topological insulators in fermionic neutral atom systems.


Improving Population Health Management Strategies: Identifying Patients Who Are More Likely to Be Users of Avoidable Costly Care and Those More Likely to Develop a New Chronic Disease.
To explore using the Patient Activation Measure (PAM) for identifying patients more likely to have ambulatory care-sensitive (ACS) utilization and future increases in chronic disease. Secondary data are extracted from the electronic health record of a large accountable care organization. This is a retrospective cohort design. The key predictor variable, PAM score, is measured in 2011, and is used to predict outcomes in 2012-2014. Outcomes include ACS utilization and the likelihood of a new chronic disease. Our sample of 98,142 adult patients was drawn from primary care clinic users. To be included, patients had to have a PAM score in 2011 and at least one clinic visit in each of the three subsequent years. PAM level is a significant predictor of ACS utilization. Less activated patients had significantly higher odds of ACS utilization compared to those with high PAM scores. Similarly, patients with low PAM scores were more likely to have a new chronic disease diagnosis over each of the years of observation. Assessing patient activation may help to identify patients who could benefit from greater support. Such an approach may help ACOs reach population health management goals.


Ecological time lags and the journey towards conservation success.
Global conservation targets to reverse biodiversity declines and halt species extinctions are not being met despite decades of conservation action. However, a lack of measurable change in biodiversity indicators towards these targets is not necessarily a sign that conservation has failed; instead, temporal lags in species' responses to conservation action could be masking our ability to observe progress towards conservation success. Here we present our perspective on the influence of ecological time lags on the assessment of conservation success and review the principles of time lags and their ecological drivers. We illustrate how a number of conceptual species may respond to change in a theoretical landscape and evaluate how these responses might influence our interpretation of conservation success. We then investigate a time lag in a real biodiversity indicator using empirical data and explore alternative approaches to understand the mechanisms that drive time lags. Our proposal for setting and evaluating conservation targets is to use milestones, or interim targets linked to specific ecological mechanisms at key points in time, to assess whether conservation actions are likely to be working. Accounting for ecological time lags in biodiversity targets and indicators will greatly improve the way that we evaluate conservation successes.


Cannabis use during pregnancy and postpartum.
To help obstetric care providers, including family physicians, nurse practitioners, midwives, and obstetricians, educate patients on the risks of cannabis use in pregnancy and postpartum and its relationship to nausea and vomiting in pregnancy. The Ovid MEDLINE database was searched using the MeSH terms pregnancy, cannabis, lactation, and cannabinoid hyperemesis in various combinations. The relevant articles were reviewed and further sources were found within the references of these articles. In utero exposure to cannabis has been associated with long-term neurodevelopmental outcomes that persist into young adulthood. Cannabis should not be used to treat nausea and vomiting in pregnancy and its chronic use might lead to the development of cannabinoid hyperemesis syndrome. There is no known safe level of cannabis use during pregnancy or lactation. Pregnant women should be counseled regarding the risks of in utero exposure and encouraged to abstain from use in pregnancy and while breastfeeding.


Improved prognosis for older adolescents with acute lymphoblastic leukemia.
The prognosis for older adolescents and young adults with acute lymphoblastic leukemia (ALL) has been historically much worse than that for younger patients. We reviewed the outcome of older adolescents (age 15 to 18 years) treated in four consecutive Total Therapy studies to determine if recent improved treatment extended to this high-risk group. Between 1991 and 2007, 963 pediatric patients, including 89 older adolescents, were enrolled on Total Therapy studies XIIIA, XIIIB, XIV, and XV. In the first three studies, treatment selection was based on presenting clinical features and leukemic cell genetics. In study XV, the level of residual disease was used to guide treatment, which featured intensive methotrexate, glucocorticoid, vincristine, and asparaginase, as well as early triple intrathecal therapy for higher-risk ALL. The 89 older adolescents were significantly more likely to have T-cell ALL, the t(4;11)(MLL-AF4), and detectable minimal residual disease during or at the end of remission induction; they were less likely to have the t(12;21)(ETV6-RUNX1) compared with younger patients. In the first three studies, the 44 older adolescents had significantly poorer event-free survival and overall survival than the 403 younger patients. This gap in prognosis was abolished in study XV: event-free survival rates at 5 years were 86.4% ± 5.2% (standard error) for the 45 older adolescents and 87.4% ± 1.7% for the 453 younger patients; overall survival rates were 87.9% ± 5.1% versus 94.1% ± 1.2%, respectively. Most older adolescents with ALL can be cured with risk-adjusted intensive chemotherapy without stem-cell transplantation.


Genome profiling of ERBB2-amplified breast cancers.
Around 20% of breast cancers (BC) show ERBB2 gene amplification and overexpression of the ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs, genomically and biologically heterogeneous, may help understand their behavior and design new therapeutic strategies. We defined the high resolution genome and gene expression profiles of 54 ERBB2-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. Expression of ERBB2, phosphorylated ERBB2, EGFR, IGF1R and FOXA1 proteins was assessed by immunohistochemistry to evaluate the functional ERBB2 status and identify co-expressions. First, we identified the ERBB2-C17orf37-GRB7 genomic segment as the minimal common 17q12-q21 amplicon, and CRKRS and IKZF3 as the most frequent centromeric and telomeric amplicon borders, respectively. Second, GISTIC analysis identified 17 other genome regions affected by copy number aberration (CNA) (amplifications, gains, losses). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in ERBB2-amplified BCs. The genomic profiles of estrogen receptor-positive (ER+) and negative (ER-) ERBB2-amplified BCs were different. The WNT/β-catenin signaling pathway was involved in ER- ERBB2-amplified BCs, and PVT1 and TRPS1 were candidate oncogenes associated with ER+ ERBB2-amplified BCs. The size of the ERBB2 amplicon was different in inflammatory (IBC) and non-inflammatory BCs. ERBB2-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. IHC results showed (i) a linear relationship between ERBB2 gene amplification and its gene and protein expressions with a good correlation between ERBB2 expression and phosphorylation status; (ii) a potential signaling cross-talk between EGFR or IGF1R and ERBB2, which could influence response of ERBB2-positive BCs to inhibitors. FOXA1 was frequently coexpressed with ERBB2 but its expression did not impact on the outcome of patients with ERBB2-amplified tumors. We have shown that ER+ and ER- ERBB2-amplified BCs are different, distinguished ERBB2 amplicons in IBC and non-IBC, and identified genomic features that may be useful in the design of alternative therapeutical strategies.


Gene gun intradermal DNA immunization followed by boosting with modified vaccinia virus Ankara: enhanced CD8+ T cell immunogenicity and protective efficacy in the influenza and malaria models.
In influenza and malaria, CD8+ T cells play an important role in protective immunity in mice. An immunization strategy consisting of DNA priming followed by boosting with recombinant modified vaccinia virus Ankara (MVA) induces complete protection, associated with high levels of CD8+ T cells, against Plasmodium berghei sporozoite challenge in mice. Intradermal delivery of DNA with a gene gun requires smaller amounts of DNA than intramuscular injection, in order to induce similar levels of immune responses. The present study compares both routes for the induction of specific CD8+ T cell responses and protection using different prime-boost immunization regimes in the influenza and the malaria models. In the DNA/MVA regime, equally high CD8+ T cell responses and levels of protection are achieved using ten times less DNA when delivered with a gene gun compared to intramuscular injection.


Dynamic nuclear polarization of nucleic acid with endogenously bound manganese.
We report the direct dynamic nuclear polarization (DNP) of (13)C nuclei of a uniformly [(13)C,(15)N]-labeled, paramagnetic full-length hammerhead ribozyme (HHRz) complex with Mn(2+) where the enhanced polarization is fully provided by the endogenously bound metal ion and no exogenous polarizing agent is added. A (13)C enhancement factor of ε = 8 was observed by intra-complex DNP at 9.4 T. In contrast, "conventional" indirect and direct DNP experiments were performed using AMUPol as polarizing agent where we obtained a (1)H enhancement factor of ε ≈ 250. Comparison with the diamagnetic (Mg(2+)) HHRz complex shows that the presence of Mn(2+) only marginally influences the (DNP-enhanced) NMR properties of the RNA. Furthermore two-dimensional correlation spectra ((15)N-(13)C and (13)C-(13)C) reveal structural inhomogeneity in the frozen, amorphous state indicating the coexistence of several conformational states. These demonstrations of intra-complex DNP using an endogenous metal ion as well as DNP-enhanced MAS NMR of RNA in general yield important information for the development of new methods in structural biology.


Statistical basis for predicting technological progress.
Forecasting technological progress is of great interest to engineers, policy makers, and private investors. Several models have been proposed for predicting technological improvement, but how well do these models perform? An early hypothesis made by Theodore Wright in 1936 is that cost decreases as a power law of cumulative production. An alternative hypothesis is Moore's law, which can be generalized to say that technologies improve exponentially with time. Other alternatives were proposed by Goddard, Sinclair et al., and Nordhaus. These hypotheses have not previously been rigorously tested. Using a new database on the cost and production of 62 different technologies, which is the most expansive of its kind, we test the ability of six different postulated laws to predict future costs. Our approach involves hindcasting and developing a statistical model to rank the performance of the postulated laws. Wright's law produces the best forecasts, but Moore's law is not far behind. We discover a previously unobserved regularity that production tends to increase exponentially. A combination of an exponential decrease in cost and an exponential increase in production would make Moore's law and Wright's law indistinguishable, as originally pointed out by Sahal. We show for the first time that these regularities are observed in data to such a degree that the performance of these two laws is nearly the same. Our results show that technological progress is forecastable, with the square root of the logarithmic error growing linearly with the forecasting horizon at a typical rate of 2.5% per year. These results have implications for theories of technological change, and assessments of candidate technologies and policies for climate change mitigation.


Progesterone signalling in breast cancer: a neglected hormone coming into the limelight.
Understanding the biology of the breast and how ovarian hormones impinge on it is key to rational new approaches in breast cancer prevention and therapy. Because of the success of selective oestrogen receptor modulators (SERMs), such as tamoxifen, and aromatase inhibitors in breast cancer treatment, oestrogens have long received the most attention. Early progesterone receptor (PR) antagonists, however, were dismissed because of severe side effects, but awareness is now increasing that progesterone is an important hormone in breast cancer. Oestrogen receptor-α (ERα) signalling and PR signalling have distinct roles in normal mammary gland biology in mice; both ERα and PR delegate many of their biological functions to distinct paracrine mediators. If the findings in the mouse model translate to humans, new preventive and therapeutic perspectives might open up.


Advanced scripting for the automated profiling of two-dimensional gas chromatography-time-of-flight mass spectrometry data from combustion aerosol.
Multidimensional gas chromatography is an appropriate tool for the non-targeted and comprehensive characterisation of complex samples generated from combustion processes. Particulate matter (PM) emission is composed of a large number of compounds, including condensed semi-volatile organic compounds (SVOCs). However, the complex amount of information gained from such comprehensive techniques is associated with difficult and time-consuming data analysis. Because of this obstacle, two-dimensional gas chromatography still receives relatively little use in aerosol science [1-4]. To remedy this problem, advanced scripting algorithms based on knowledge-based rules (KBRs) were developed in-house and applied to GCxGC-TOFMS data. Previously reported KBRs and newer findings were considered for the development of these algorithms. The novelty of the presented advanced scripting tools is a notably selective search criterion for data screening, which is primarily based on fragmentation patterns and the presence of specific fragments. Combined with "classical" approaches based on retention times, a fast, accurate and automated data evaluation method was developed, which was evaluated qualitatively and quantitatively for type 1 and type 2 errors. The method's applicability was further tested for PM filter samples obtained from ship fuel combustion. Major substance classes, including polycyclic aromatic hydrocarbons (PAH), alkanes, benzenes, esters and ethers, can be targeted. This approach allows the classification of approximately 75% of the peaks of interest within real PM samples. Various conditions of combustion, such as fuel composition and engine load, could be clearly characterised and differentiated.


Impact of perioperative myocardial infarction on angiographic and clinical outcomes following coronary artery bypass grafting (from PRoject of Ex-vivo Vein graft ENgineering via Transfection [PREVENT] IV).
Myocardial infarction (MI) after coronary artery bypass grafting (CABG) is associated with significant morbidity and mortality. Frequency, management, mechanisms, and angiographic and clinical outcomes associated with perioperative MI remain poorly understood. PREVENT IV was a multicenter, randomized, placebo-controlled trial of edifoligide in 3,014 patients undergoing CABG. Angiographic and 2-year clinical follow-up were complete for 1,920 and 2,956 patients, respectively. Perioperative MI was defined as creatinine kinase-MB increase >or=10 times the upper limit of normal or >or=5 times the upper limit of normal with new 30-ms Q waves within 24 hours of surgery. Baseline characteristics, in-hospital management, and angiographic and clinical outcomes of patients with and without perioperative MI were compared. Perioperative MI occurred in 294 patients (9.8%). Patients with perioperative MI had longer surgery (250 vs 230 minutes; p <0.001), more on-pump surgery (83% vs 78%; p = 0.048), and worse target-artery quality (p <0.001). Patients with perioperative MI more frequently underwent angiography within 30 days of enrollment (1.7% vs 0.6%; p = 0.021). One-year angiographic vein graft failure occurred in 62.4% of patients with and 43.8% of patients without perioperative MI (p <0.001). Two-year composite clinical outcome (death, MI, or revascularization) was worse in patients with perioperative MI before (19.4% vs 15.2%; p = 0.039) and after (hazard ratio 1.33, 95% confidence interval 1.00 to 1.76, p = 0.046) adjusting for differences in significant predictors. In conclusion, perioperative MI was relatively common, was associated with worse outcomes, and mechanisms other than vein graft failure accounted for a substantial proportion of these MIs. Further research is needed into the prevention and treatment of perioperative MI in patients undergoing CABG.


Release of toxic elements in fishpond sediments under dynamic redox conditions: Assessing the potential environmental risk for a safe management of fisheries systems and degraded waterlogged sediments.
Waterlogged soils and sediments contaminated with potentially toxic elements (PTEs) constitute a complicated case of degraded areas; their management requires understanding of the dynamic redox-driven PTE mobilization. Such studies about PTE redox-induced dynamics in fishpond sediments are still scarce, but of great importance concerning environmental and human health risk. We studied the redox potential (EH)-induced impacts on the solubility of As, Co, Cu, Mo, Ni, Se, V, and Zn in the sediments of a fish farm in the Nile Delta, Egypt, using an automated apparatus of biogeochemical microcosm. We assessed the fate of elements as affected by the EH-induced changes in pH, Fe, Mn, SO42-, Cl-, and the dissolved aliphatic (DOC) and aromatic (DAC) organic carbon. Sediment redox ranged from -480 mV to +264 mV. Flooding the sediments caused a significant decrease in pH from 8.2 to 5.7. Dissolved concentrations of As, Co, Ni, Se, and Zn, as well as DOC, Fe, and Mn increased under the reducing acidic conditions. The release of As, Co, Ni, Se, and Zn could be attributed to the decrease of EH and the subsequent decrease of pH, as well as to the increase of DOC, and/or the dissolution of Fe-Mn oxides caused by redox reactions. Dissolved concentrations of Cu, Mo, and V increased under oxic conditions and were significantly positive correlated with EH, pH, DAC, and SO42-. This enhancement might be caused by the EH-dependent increase of pH under oxic conditions (particularly for Mo and V), which also led to DAC increase. Sulfide oxidation and the release of the associated elements may have also had a contribution, particularly in the release of Cu. Therefore, the release dynamics of dissolved Cu, Mo, and V in the sediments were controlled, to a certain extent, by the changes of EH/pH, DAC, and sulfur chemistry. We conclude that the biogeochemical differences in the behaviour of the studied elements under variable redox regimes substantially affected the fishponds via possible enhancement of PTE mobilization. Our work shows that the potential environmental risks related to PTE mobilization and fish food security should be taken into consideration for the management of degraded aquaculture systems and waterlogged soils and sediments.


Hyperglycemic pseudohypoxia and diabetic complications.
Vasodilation and increased blood flow are characteristic early vascular responses to acute hyperglycemia and tissue hypoxia. In hypoxic tissues these vascular changes are linked to metabolic imbalances associated with impaired oxidation of NADH to NAD+ and the resulting increased ratio of NADH/NAD+. In hyperglycemic tissues these vascular changes also are linked to an increased ratio of NADH/NAD+, in this case because of an increased rate of reduction of NAD+ to NADH. Several lines of evidence support the likelihood that the increased cytosolic ratio of free NADH/NAD+ caused by hyperglycemia, referred to as pseudohypoxia because tissue partial pressure oxygen is normal, is a characteristic feature of poorly controlled diabetes that mimics the effects of true hypoxia on vascular and neural function and plays an important role in the pathogenesis of diabetic complications. These effects of hypoxia and hyperglycemia-induced pseudohypoxia on vascular and neural function are mediated by a branching cascade of imbalances in lipid metabolism, increased production of superoxide anion, and possibly increased nitric oxide formation.


Aspergillus peritonitis in peritoneal dialysis patients: A systematic review.
Fungal peritonitis in patients undergoing peritoneal dialysis (PD) is very difficult to treat and is associated with significant morbidity and mortality. Among fungal pathogens, Aspergillus peritonitis presents a higher mortality rate when compared to Candida peritonitis and its identification as well as appropriate treatment remains a challenge for the physicians. We critical reviewed all published cases in literature of Aspergillus peritonitis in PD patients. The results showed that a total of 55 cases (51% males) of Aspergillus peritonitis in PD patients were reported from 1968 to 2019. Mean patient age was 49.54±19.63years and mean PD duration prior to fungal infection was 33.31±32.45months. Aspergillus fumigatus was isolated in 17/55 patients, Aspergillus niger in 15, Aspergillus terreus in 9, unidentified Aspergillus spp. in 6, Aspergillus flavus in 4, whereas sporadic cases of other Aspergillus spp. were reported. As far as predisposing factors are concerned, 75% of patients suffered from prior bacterial peritonitis receiving antimicrobial therapy. Initial antifungal treatment was intravenous and/or intraperitoneal administration of amphotericin B formulations monotherapy in 47.2% of patients or in combination with fluconazole in 13.2%, or with itraconazole in 13.2%, or with caspofungin in 3.8%, or with ketoconazole or with 5-FC in 1.9%, each. Peritoneal catheter removal was performed in 85.5% of cases. Mortality rate was 38.2%, while 81.8% of the survived patients switched to hemodialysis. Conclusively, Aspergillus peritonitis diagnosis can be difficult, due to unspecific symptoms. Early treatment with appropriate antifungal agents can be determinant for patient prognosis. Despite appropriate treatment, reported mortality remains high.


Cesarean section rate differences by migration indicators.
To answer the question: are there differences in cesarean section rates among childbearing women in Canada according to selected migration indicators? Secondary analyses of 3,500 low-risk women who had given birth between January 2003 and April 2004 in one of ten hospitals in the major Canadian migrant-receiving cities (Montreal, Toronto, Vancouver) were conducted. Women were categorized as non-refugee immigrant, asylum seeker, refugee, or Canadian-born and by source country world region. Stratified analyses were performed. Cesarean section rates differed by migration status for women from two source regions: South East and Central Asia (non-refugee immigrants 26.0 %, asylum seekers 28.6 %, refugees 56.7 %, p = 0.001) and Latin America (non-refugee immigrants 37.7 %, asylum seekers 25.6 %, refugees 10.5 %, p = 0.05). Of these, low-risk refugee women who had migrated to Canada from South East and Central Asia experienced excess cesarean sections, while refugees from Latin America experienced fewer, compared to Canadian-born (25.4 %, 95 % CI 23.8-27.3). Cesarean section rates of African women were consistently high (31-33 %) irrespective of their migration status but were not statistically different from Canadian-born women. Although it did not reach statistical significance, risk for cesarean sections also differed by time since migration (≤2 years 29.8 %, >2 years 47.2 %). Migration status, source region, and time since migration are informative migration indicators for cesarean section risk.


Assessing the impact of population stratification on genetic association studies.
Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and case-cohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies.


Differences in synthesis and absorption of cholesterol of two effective lipid-lowering therapies.
Effective statin therapy is associated with a marked reduction of cardiovascular events. However, the explanation for full benefits obtained for LDL cholesterol targets by combined lipid-lowering therapy is controversial. Our study compared the effects of two equally effective lipid-lowering strategies on markers of cholesterol synthesis and absorption. A prospective, open label, randomized, parallel design study, with blinded endpoints, included 116 subjects. We compared the effects of a 12-week treatment with 40 mg rosuvastatin or the combination of 40 mg simvastatin/10 mg ezetimibe on markers of cholesterol absorption (campesterol and β-sitosterol), synthesis (desmosterol), and their ratios to cholesterol. Both therapies similarly decreased total and LDL cholesterol, triglycerides and apolipoprotein B, and increased apolipoprotein A1 (P < 0.05 vs baseline for all). Simvastatin/ezetimibe increased plasma desmosterol (P = 0.012 vs baseline), and decreased campesterol and β-sitosterol (P < 0.0001 vs baseline for both), with higher desmosterol (P = 0.007) and lower campesterol and β-sitosterol compared to rosuvastatin, (P < 0.0001, for both). In addition, rosuvastatin increased the ratios of these markers to cholesterol (P < 0.002 vs baseline for all), whereas simvastatin/ezetimibe significantly decreased the campesterol/cholesterol ratio (P = 0.008 vs baseline) and tripled the desmosterol/cholesterol ratio (P < 0.0001 vs baseline). The campesterol/cholesterol and β-sitosterol/cholesterol ratios were lower, whereas the desmosterol/cholesterol ratio was higher in patients receiving simvastatin/ezetimibe (P < 0.0001 vs rosuvastatin, for all). Pronounced differences in markers of cholesterol absorption and synthesis were observed between two equally effective lipid-lowering strategies.


An epidemiological review of gastrointestinal outbreaks associated with Clostridium perfringens, North East of England, 2012-2014.
An anecdotal increase in C. perfringens outbreaks was observed in the North East of England during 2012-2014. We describe findings of investigations in order to further understanding of the epidemiology of these outbreaks and inform control measures. All culture-positive (>105 c.f.u./g) outbreaks reported to the North East Health Protection Team from 1 January 2012 to 31 December 2014 were included. Epidemiological (attack rate, symptom profile and positive associations with a suspected vehicle of infection), environmental (deficiencies in food preparation or hygiene practices and suspected vehicle of infection) and microbiological investigations are described. Forty-six outbreaks were included (83% reported from care homes). Enterotoxin (cpe) gene-bearer C. perfringens were detected by PCR in 20/46 (43%) and enterotoxin (by ELISA) and/or enterotoxigenic faecal/food isolates with indistinguishable molecular profiles in 12/46 (26%) outbreaks. Concerns about temperature control of foods were documented in 20/46 (43%) outbreaks. A suspected vehicle of infection was documented in 21/46 (46%) of outbreaks (meat-containing vehicle in 20/21). In 15/21 (71%) identification of the suspected vehicle was based on descriptive evidence alone, in 5/21 (24%) with supporting evidence from an epidemiological study and in 2/21 (10%) with supporting microbiological evidence. C. perfringens-associated illness is preventable and although identification of foodborne outbreaks is challenging, a risk mitigation approach should be taken, particularly in vulnerable populations such as care homes for the elderly.


Erectile dysfunction and risk of clinical cardiovascular events: a meta-analysis of seven cohort studies.
For many years, erectile dysfunction (ED) has been considered as a complication of cardiovascular disease (CVD) or regarded as a late consequence of generalized arterial disease. However, a growing body of evidence suggests that ED is an early manifestation of atherosclerosis and a precursor to systemic vascular disease. We conducted a meta-analysis to evaluate the association between ED and the risk of CVD events. Relevant studies published between January 1966 and September 2009 were identified by searching Medline, Embase, and The Cochrane Library. Studies were selected using a prior defined criteria. The strength of the relationship between ED and CVD events was assessed by adjusted relative risks (RRs). The adjusted RRs of CVD events. A total of 45,558 participants from seven cohort studies (eight full-text articles) were identified in this meta-analysis. The studies provided adjusted RRs estimates for ED subjects comparing with health subjects, leading to a pooled adjusted RR of 1.47 (95% confidence interval [CI], 1.29-1.66, P < 0.001; P for heterogeneity = 0.152; I(2) = 36.2%) for CVD events. The risks of CVD, all-cause mortality and myocardial infarction were 1.41 (95% CI, 1.22-1.64 P < 0.001), 1.23 (95% CI, 1.02-1.48; P = 0.034), and 1.43 (95% CI, 1.10-1.85 P = 0.007), respectively. The overall adjusted RR decreased significant from 1.63 (<7 years) to 1.37 (≥ 7 years) along with the elongation of follow-up. There is evidence of an increased risk of CVD events for patients with ED. Patients who are discovered to have ED are supposed to be thoroughly assessed for cardiovascular risk and occult systemic vascular disease.


Clonal and parallel evolution of primary lung cancers and their metastases revealed by molecular dissection of cancer cells.
Several models of cancer progression, including clonal evolution, parallel evolution, and same-gene models, have been proposed to date. The purpose of this study is to investigate the authenticity of these models by comparison of accumulated genetic alterations between primary and corresponding metastatic lung cancers. A whole-genome allelic imbalance scanning using a high-resolution single nucleotide polymorphism array and mutational analysis of the p53, EGFR, and KRAS genes were done on eight sets of primary and metastatic lung cancers. Based on the genotype data, the natural history of each case was deduced, and candidate metastasis suppressor loci were determined. Five to 20 chromosomal regions showed allelic imbalance in each tumor. Accumulated genetic alterations were similar between primary and corresponding metastatic tumors, and the majority(>67%) of genetic alterations detected in metastatic tumors was also detected in the corresponding primary tumors. On the other hand, in seven of the eight cases, there were genetic alterations accumulated only in metastatic tumors. Among these alterations, allelic imbalances at chromosome 11p15 and 11p11-p13 regions were the most frequent ones (4 of 8, 50%). Likewise, four cases showed genetic alterations detected only in primary tumors. The natural history of each case indicated that the process of metastasis varies among cases, and that all three models are applicable to lung cancer progression. According to the clonal and parallel evolution models, it is possible that a metastasis suppressor gene(s) for lung cancer is present on chromosome 11p.


Correlated genetic effects on reproduction define a domestication syndrome in a forest tree.
Compared to natural selection, domestication implies a dramatic change in traits linked to fitness. A number of traits conferring fitness in the wild might be detrimental under domestication, and domesticated species typically differ from their ancestors in a set of traits known as the domestication syndrome. Specifically, trade-offs between growth and reproduction are well established across the tree of life. According to allocation theory, selection for growth rate is expected to indirectly alter life-history reproductive traits, diverting resources from reproduction to growth. Here we tested this hypothesis by examining the genetic change and correlated responses of reproductive traits as a result of selection for timber yield in the tree Pinus pinaster. Phenotypic selection was carried out in a natural population, and progenies from selected trees were compared with those of control trees in a common garden experiment. According to expectations, we detected a genetic change in important life-history traits due to selection. Specifically, threshold sizes for reproduction were much higher and reproductive investment relative to size significantly lower in the selected progenies just after a single artificial selection event. Our study helps to define the domestication syndrome in exploited forest trees and shows that changes affecting developmental pathways are relevant in domestication processes of long-lived plants.


Neuronal connectivity in major depressive disorder: a systematic review.
The causes of major depressive disorder (MDD), as one of the most common psychiatric disorders, still remain unclear. Neuroimaging has substantially contributed to understanding the putative neuronal mechanisms underlying depressed mood and motivational as well as cognitive impairments in depressed individuals. In particular, analyses addressing changes in interregional connectivity seem to be a promising approach to capture the effects of MDD at a systems level. However, a plethora of different, sometimes contradicting results have been published so far, making general conclusions difficult. Here we provide a systematic overview about connectivity studies published in the field over the last decade considering different methodological as well as clinical issues. A systematic review was conducted extracting neuronal connectivity results from studies published between 2002 and 2015. The findings were summarized in tables and were graphically visualized. The review supports and summarizes the notion of an altered frontolimbic mood regulation circuitry in MDD patients, but also stresses the heterogeneity of the findings. The brain regions that are most consistently affected across studies are the orbitomedial prefrontal cortex, anterior cingulate cortex, amygdala, hippocampus, cerebellum and the basal ganglia. The results on connectivity in MDD are very heterogeneous, partly due to different methods and study designs, but also due to the temporal dynamics of connectivity. While connectivity research is an important step toward a complex systems approach to brain functioning, future research should focus on the dynamics of functional and effective connectivity.


Anti-inflammatory effects of progesterone in lipopolysaccharide-stimulated BV-2 microglia.
Female sex is associated with improved outcome in experimental brain injury models, such as traumatic brain injury, ischemic stroke, and intracerebral hemorrhage. This implies female gonadal steroids may be neuroprotective. A mechanism for this may involve modulation of post-injury neuroinflammation. As the resident immunomodulatory cells in central nervous system, microglia are activated during acute brain injury and produce inflammatory mediators which contribute to secondary injury including proinflammatory cytokines, and nitric oxide (NO) and prostaglandin E2 (PGE2), mediated by inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. We hypothesized that female gonadal steroids reduce microglia mediated neuroinflammation. In this study, the progesterone's effects on tumor necrosis factor alpha (TNF-α), iNOS, and COX-2 expression were investigated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. Further, investigation included nuclear factor kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways. LPS (30 ng/ml) upregulated TNF-α, iNOS, and COX-2 protein expression in BV-2 cells. Progesterone pretreatment attenuated LPS-stimulated TNF-α, iNOS, and COX-2 expression in a dose-dependent fashion. Progesterone suppressed LPS-induced NF-κB activation by decreasing inhibitory κBα and NF-κB p65 phosphorylation and p65 nuclear translocation. Progesterone decreased LPS-mediated phosphorylation of p38, c-Jun N-terminal kinase and extracellular regulated kinase MAPKs. These progesterone effects were inhibited by its antagonist mifepristone. In conclusion, progesterone exhibits pleiotropic anti-inflammatory effects in LPS-stimulated BV-2 microglia by down-regulating proinflammatory mediators corresponding to suppression of NF-κB and MAPK activation. This suggests progesterone may be used as a potential neurotherapeutic to treat inflammatory components of acute brain injury.


Calcium entry into voltage-clamped presynaptic terminals of squid.
Voltage-clamp measurements of Ca current and Arsenazo III measurements of intracellular Ca concentration were used to assess Ca ion entry into voltage-clamped presynaptic terminals of squid 'giant' synapses. Depolarization of voltage-clamped terminals filled with Arsenazo III produced absorbance changes consistent with intracellular accumulation of Ca ions. These intracellular Ca transients had a bell-shaped dependence on presynaptic potential and were maximal at approximately -10 mV. Arsenazo III signals recorded from the proximal portion of voltage-clamped presynaptic terminals had a dependence on command potential which was shifted relative to signals recorded from other presynaptic regions. Micro-electrode measurements of presynaptic membrane potential showed that during voltage-clamp depolarizations the proximal region was less depolarized than the rest of the presynaptic terminal. This indicates that voltage-clamped presynaptic terminals may be poorly controlled at their proximal region due to current flow into the adjacent axon. This poor control can cause heterogeneous Ca entry into the presynaptic terminal and thus heterogeneous release of transmitter along the terminal. Application of Ca ions from an extracellular pipette positioned near the distal end of the presynaptic terminal was used to restrict Ca entry to this well-controlled region. Local Ca application decreased the contribution of release from the poorly controlled proximal region to synaptic transfer curves. Presynaptic Ca currents were derived by correcting membrane currents for leakage and capacitive currents and other currents measured in the absence of Ca application. Ca currents measured in this way activated along a sigmoidal time course and did not inactivate for depolarizations as long as 25 ms. Peak Ca currents occurred at approximately -10 mV and inward Ca currents had an apparent 'reversal potential' near +60 mV. Ca channel activation, assessed with tail current measurements, was half-maximal at -13 mV and maximal at +20 mV. Simultaneous measurements of presynaptic Ca currents and Arsenazo III transients revealed a quantitative correspondence between Ca current integrals and Arsenazo III signal amplitude. This suggests that both methods provide reliable measures of Ca ion entry into presynaptic terminals under these conditions.


The role of an internal nasal dilator in athletes.
The nasal valve area has the minimal cross-sectional area of the upper airways. Nasal dilators have been found able to improve sport performance in athletes. The aim of this study was to investigate whether the use an internal nasal dilator may be able to affect respiratory pattern in a group of athletes. The use of internal nasal dilator induced a significant reduction of fatigue perception (p=0.000) and was optimally accepted. In conclusion, the present study demonstrates that Nas-air® is an internal nasal dilator able to reduce the fatigue perception and is preferred to external nasal dilator.


Risks versus benefits of different types of long-acting injectable antipsychotics.
Since their introduction into clinical practice in the early 1960s, long-acting depot antipsychotics have been widely used as maintenance therapy for patients with schizophrenia. The improved pharmacokinetics of injectable long-acting antipsychotic therapies have provided more reliable drug delivery and reduced differences in peak and trough plasma levels of the drug. Studies that have compared short-acting oral antipsychotics with long-acting injectable antipsychotics, although imperfect, support injectable antipsychotics as having real benefit over oral antipsychotics on patient outcome owing largely to improved adherence. If patients forget or refuse to take their prescribed oral medications, weeks or months may go by before they experience an exacerbation; the effects of nonadherence become apparent too late to preempt the problem. On the other hand, if a patient fails to show up for an injection, the problem of nonadherence can be immediately addressed. When injectable medication is combined with an active psychosocial treatment program that will respond assertively to nonadherence, relapse rates may be reduced. By preventing or delaying relapse, consistent treatment can improve the patient's quality of life and lead to an overall reduction in the cost of care.


The Different Expression Patterns of HSP22, a Late Embryogenesis Abundant-like Protein, in Hypertrophic H9C2 Cells Induced by NaCl and Angiotensin II.
High-NaCl diet is a contributing factor for cardiac hypertrophy. The role of HSP22 as a protective protein during cardiac hypertrophy due to hypernatremia is unclear. Accordingly, this study aimed to establish a cellular hypernatremic H9C2 model and to compare the expression of HSP22 in Ca2+ homeostasis between a high-NaCl and angiotensin II-induced hypertrophic cellular H9C2 model. Real-time PCR was performed to compare the mRNA expression. Flow cytometry and confocal microscopy were used to analyze the cells. The addition of 30 mM NaCl for 48 h was the most effective condition for the induction of hypertrophic H9C2 cells (termed the in vitro hypernatremic model). Cardiac cellular hypertrophy was induced with 30 mM NaCl and 1 µM angiotensin II for 48 h, without causing abnormal morphological changes or cytotoxicity of the culture conditions. HSP22 contains a similar domain to that found in the consensus sequences of the late embryogenesis abundant protein group 3 from Artemia. The expression of HSP22 gradually decreased in the in vitro hypernatremic model. In contrast to the in vitro hypernatremic model, HSP22 increased after exposure to angiotensin II for 48 h. Intracellular Ca2+ decreased in the angiotensin II model and further decreased in the in vitro hypernatremic model. Impaired intracellular Ca2+ homeostasis was more evident in the in vitro hypernatremic model. The results showed that NaCl significantly decreased HSP22. Decreased HSP22, due to the hypernatremic condition, affected the Ca2+ homeostasis in the H9C2 cells. Therefore, hypernatremia induces cellular hypertrophy via impaired Ca2+ homeostasis. The additional mechanisms of HSP22 need to be explored further.


Adenophostin A and analogues modified at the adenine moiety: synthesis, conformational analysis and biological activity.
The synthesis of adenophostin A (2) and two analogues [etheno adenophostin (4) and 8-bromo adenophostin (5)] modified at the adenine moiety, is reported. A combination of NMR analysis and molecular modelling was used to compare their structures in solution and determined that they all adopt very similar conformations. The analogues were tested for their ability to mobilise Ca(2+) from DT40 cells expressing recombinant Type 1 rat Ins(1,4,5)P(3)R which reveals etheno adenophostin as a high affinity fluorescent probe of the Ins(1,4,5)P(3)R. 8-Bromo adenophostin was only slightly less potent. The biological results support our current hypothesis regarding the binding mode of adenophostin A at the Ins(1,4,5)P(3)R, i. e. that a cation-pi interaction between the base moiety and Arg 504 of the receptor in combination with H-bonding may be responsible for the high potency of adenophostin A relative to Ins(1,4,5)P(3).


What is an attractive body? Using an interactive 3D program to create the ideal body for you and your partner.
What is the ideal body size and shape that we want for ourselves and our partners? What are the important physical features in this ideal? And do both genders agree on what is an attractive body? To answer these questions we used a 3D interactive software system which allows our participants to produce a photorealistic, virtual male or female body. Forty female and forty male heterosexual Caucasian observers (females mean age 19.10 years, s.d. 1.01; 40 males mean age 19.84, s.d. 1.66) set their own ideal size and shape, and the size and shape of their ideal partner using the DAZ studio image manipulation programme. In this programme the shape and size of a 3D body can be altered along 94 independent dimensions, allowing each participant to create the exact size and shape of the body they want. The volume (and thus the weight assuming a standard density) and the circumference of the bust, waist and hips of these 3D models can then be measured. The ideal female body set by women (BMI = 18.9, WHR = 0.70, WCR = 0.67) was very similar to the ideal partner set by men, particularly in their BMI (BMI = 18.8, WHR = 0.73, WCR = 0.69). This was a lower BMI than the actual BMI of 39 of the 40 women. The ideal male body set by the men (BMI = 25.9, WHR = 0.87, WCR = 0.74) was very similar to the ideal partner set by the women (BMI = 24.5, WHR = 0.86, WCR = 0.77). This was a lower BMI than the actual BMI of roughly half of the men and a higher BMI than the other half. The results suggest a consistent preference for an ideal male and female body size and shape across both genders. The results also suggest that both BMI and torso shape are important components for the creation of the ideal body.


Quantification and evaluation of the role of antielastin autoantibodies in the emphysematous lung.
Chronic obstructive pulmonary disease (COPD) may be an autoimmune disease. Smoking causes an imbalance of proteases and antiproteases in the lung resulting in the generation of elastin peptides that can potentially act as autoantigens. Similar to COPD, Z alpha-1 antitrypsin deficiency (Z-A1ATD) and cystic fibrosis (CF) are associated with impaired pulmonary antiprotease defences leading to unopposed protease activity. Here, we show that there is a trend towards higher bronchoalveolar lavage fluid (BALF) antielastin antibody levels in COPD and Z-A1ATD and significantly lower levels in CF compared to control BALF; the lower levels in CF are due to the degradation of these antibodies by neutrophil elastase. We also provide evidence that these autoantibodies have the potential to induce T cell proliferation in the emphysematous lung. This study highlights that antielastin antibodies are tissue specific, can be detected at elevated levels in COPD and Z-A1ATD BALF despite their being no differences in their levels in plasma compared to controls, and suggests a therapeutic role for agents targeting these autoantibodies in the lungs.


Changes in human skeletal muscle ultrastructure and force production after acute resistance exercise.
Muscle ultrastructure and contractile properties were examined before and after a single bout of resistance exercise (8 sets of 8 repetitions at 80% of 1 repetition maximum). Eight untrained males performed the concentric (Con) phase of arm-curl exercise with one arm and the eccentric (Ecc) phase with the other arm. Needle biopsies were obtained from biceps brachii before exercise (Base), immediately postexercise from each arm (post-Con and post-Ecc), and 48 h postexercise from each arm (48 h-Con and 48 h-Ecc). Electron microscopy was used to quantify the presence of disrupted fibers in each sample. Analysis of variance revealed a greater (P < or = 0.05) proportion of disrupted fibers in post-Con, post-Ecc, 48 h-Con, and 48 h-Ecc samples compared with Base. Significantly more fibers were disrupted in post-Ecc (82%) and 48 h-Ecc (80%) samples compared with post-Con (33%) and 48 h-Con (37%), respectively. Voluntary and evoked strength measurements recovered to Base values within 24 h in the Con arm but remained depressed (P < or = 0.05) for 72-96 h in the Ecc arm. These data indicate that both the raising and lowering phases of weightlifting produced myofibrillar disruption, with the greatest disruption occurring during the lowering phase.


A differentially methylated region within the gene Kcnq1 functions as an imprinted promoter and silencer.
The imprinted gene cluster on mouse distal chromosome 7 contains a differentially methylated CpG island that maps within the Kcnq1 gene that has been shown to be required for the imprinting of multiple genes. To evaluate models for how this imprinting control region (ICR) regulates imprinting, we have characterized it structurally and functionally. We show that the region contains a promoter for a paternally expressed anti-sense transcript, Kcnq1ot1, and we define the extent of the minimal promoter. We describe three paternal-specific nuclease hypersensitive sites immediately upstream from the start site and show that they are required for full promoter activity. The expression of Kcnq1ot1 during pre- and postnatal development is compared to that of other imprinted genes in its vicinity, Cdnkn1c and Kcnq1. The lack of coordination in their expression tends to rule out an enhancer competition model for the action of the ICR in imprinting control. Using a stable transfection assay we show that the region contains a position-independent and orientation-independent silencer. We propose, on the basis of these findings, that the Kcnq1 ICR functions as a silencer on the paternal chromosome to effect the repression of neighboring genes.


Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811.
Cyclosporin A (CsA) shows cytoprotective properties in many cellular and in vivo models that may depend on interference of the interaction of cyclophilin A with calcineurin or of cyclophilin D with the mitochondrial permeability transition (PT) pore. The nonimmunosuppressive cyclosporin derivative N-methyl-4-valine-cyclosporin (PKF220-384) inhibits the mitochondrial permeability transition (MPT) like CsA but without calcineurin inactivation. PKF220-384 has been used to discriminate between PT pore- and calcineurin mediated effects but is no longer available. Here, we evaluated the effects of another nonimmunosuppressive cyclosporin derivative, N-methyl-4-isoleucine-cyclosporin (NIM811) on the MPT. Using two newly developed microtiter plate assays, one measuring mitochondrial swelling from absorbance and the other measuring mitochondrial membrane potential from changes in safranin fluorescence, we show that NIM811 blocks the MPT induced by calcium and inorganic phosphate, alone or in combination with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the complex I inhibitor rotenone, and the prooxidant t-butylhydroperoxide. NIM811 was equipotent to CsA and half as potent as PKF220-384. Additionally, we show that NIM811 blocks cell killing and prevents in situ mitochondrial inner membrane permeabilization and depolarization during tumor necrosis factor-alpha-induced apoptosis to cultured rat hepatocytes. NIM811 inhibition of apoptosis was equipotent with CsA except at higher concentrations: CsA lost efficacy but NIM 811 did not. We conclude that NIM811 is a useful alternative to PKF220-384 to investigate the role of the mitochondrial permeability transition in apoptotic and necrotic cell death.


Decomposition of diverse litter mixtures in streams.
In view of growing interest in understanding how biodiversity affects ecosystem functioning, we investigated effects of riparian plant diversity on litter decomposition in forest streams. Leaf litter from 10 deciduous tree species was collected during natural leaf fall at two locations (Massif Central in France and Carpathians in Romania) and exposed in the field in litter bags. There were 35 species combinations, with species richness ranging 1-10. Nonadditive effects on the decomposition of mixed-species litter were minor, although a small synergistic effect was observed in the Massif Central stream where observed litter mass remaining was significantly lower overall than expected from data on single-species litter. In addition, variability in litter mass remaining decreased with litter diversity at both locations. Mean nitrogen concentration of single- and mixed-species litters (0.68-4.47% of litter ash-free dry mass) accounted for a large part of the variation in litter mass loss across species combinations. For a given species or mixture, litter mass loss was also consistently faster in the Massif Central than in the Carpathians, and the similarity in general stream characteristics, other than temperature, suggests that this effect was largely due to differences in thermal regimes. These results support the notion that decomposition of litter mixtures is primarily driven by litter quality and environmental factors, rather than by species richness per se. However, the observed consistent decrease in variability of decomposition rate with increasing plant species richness indicates that conservation of riparian tree diversity is important even when decomposition rates are not greatly influenced by litter mixing.


Altered chromosomal positioning, compaction, and gene expression with a lamin A/C gene mutation.
Lamins A and C, encoded by the LMNA gene, are filamentous proteins that form the core scaffold of the nuclear lamina. Dominant LMNA gene mutations cause multiple human diseases including cardiac and skeletal myopathies. The nuclear lamina is thought to regulate gene expression by its direct interaction with chromatin. LMNA gene mutations may mediate disease by disrupting normal gene expression. To investigate the hypothesis that mutant lamin A/C changes the lamina's ability to interact with chromatin, we studied gene misexpression resulting from the cardiomyopathic LMNA E161K mutation and correlated this with changes in chromosome positioning. We identified clusters of misexpressed genes and examined the nuclear positioning of two such genomic clusters, each harboring genes relevant to striated muscle disease including LMO7 and MBNL2. Both gene clusters were found to be more centrally positioned in LMNA-mutant nuclei. Additionally, these loci were less compacted. In LMNA mutant heart and fibroblasts, we found that chromosome 13 had a disproportionately high fraction of misexpressed genes. Using three-dimensional fluorescence in situ hybridization we found that the entire territory of chromosome 13 was displaced towards the center of the nucleus in LMNA mutant fibroblasts. Additional cardiomyopathic LMNA gene mutations were also shown to have abnormal positioning of chromosome 13, although in the opposite direction. These data support a model in which LMNA mutations perturb the intranuclear positioning and compaction of chromosomal domains and provide a mechanism by which gene expression may be altered.