Novel Approach to Cardiovascular Outcome Prediction in Haemodialysis Patients.
Cardiovascular mortality is high in haemodialysis (HD) patients. Arterial stiffness and global longitudinal strain (GLS) are important non-atheromatous cardiovascular risk predictors. No study has encompassed both parameters in a combined model for prediction of outcomes in HD patients. This is important because left ventricular (LV) dysfunction can result from fibrotic remodelling secondary to increased arterial stiffness. Two hundred and nineteen HD patients had pulse wave velocity (PWV) and echocardiography (including GLS) assessments. Patients were followed-up until death, transplantation or November 16, 2015, whichever happened first. Pearson's correlation coefficient was used to determine factors associated with PWV and GLS. A multivariable Cox regression model investigated factors associated with all-cause, cardiac death and events. One hundred and ninety eight HD patients had full datasets (median age 64.2, 68.7% males) with a mean LV ejection fraction (LVEF) of 61.7 ± 10.1% and GLS -13.5 ± 3.3%; 51% had LV hypertrophy. Forty eight deaths (15 cardiac) and 44 major cardiac events occurred during a median follow-up of 27.6 (25th-75th percentile, 17.3-32.7) months. In separate survival models, PWV and GLS were independently associated with all-cause mortality; however, in a combined model, LV mass indexed to height2.7 (LVMI/HT2.7; adjusted hazard ratio (HR) 1.02, 95% CI 1.00-1.04) and PWV (adjusted HR 1.23, 95% CI 1.03-1.47) were significant. PWV was neither associated with cardiac death nor associated with related cardiac events. However, GLS was associated with cardiac death (adjusted HR 1.24, 95% CI 1.00-1.54) and cardiac events (adjusted HR 1.13, 95% CI 1.03-1.25). PWV and LVMI/HT2.7 were superior to GLS in prediction of all-cause mortality. However, GLS was associated with cardiac death and events even when accounting for LVEF and LVMI/HT2.7.


DNATwist: a Web-based tool for teaching middle and high school students about pharmacogenomics.
DNATwist is a Web-based learning tool (available at http://www.dnatwist.org) that explains pharmacogenomics concepts to middle- and high-school students. Its features include (i) a focus on drug responses of interest to teenagers (e.g., alcohol intolerance), (ii) reusable graphical interfaces that reduce extension costs, and (iii) explanations of molecular and cellular drug responses. In testing, students found the tool and topic understandable and engaging. The tool is being modified for use at the Tech Museum of Innovation in California.


HLA-specific memory B-cell detection in kidney transplantation: Insights and future challenges.
Humoral alloimmunity mediated by anti-human leucocyte antigen (HLA) antibodies is a major challenge in kidney transplantation and impairs the longevity of the transplanted organ. The immunological risk of an individual patient is currently mainly assessed by detection of HLA antibodies in the serum, which are produced by long-lived bone marrow-residing plasma cells. However, humoral alloimmunity is complex, and alloreactive memory B cells constitute an additional factor in the interplay of immune cells. These recirculating "silent" cells are responsible for the immunological recall response by differentiating into antibody-producing cells upon antigen re-encounter. Historically, due to the lack of appropriate and routinely applicable assays to determine the presence and HLA specificity of alloreactive memory B cells, their contribution to the humoral alloimmune response has clinically often been suspected but could not be determined. In this review, we give an overview of recent advances in techniques to detect alloreactive memory B cells and discuss their strengths and limitations. Furthermore, we summarize experiences with these techniques in alloimmunized individuals and transplant recipients, thereby emphasizing unmet needs to be addressed in future studies.


Assessment of Esophageal Adenocarcinoma Risk Using Somatic Chromosome Alterations in Longitudinal Samples in Barrett's Esophagus.
Cancers detected at a late stage are often refractory to treatments and ultimately lethal. Early detection can significantly increase survival probability, but attempts to reduce mortality by early detection have frequently increased overdiagnosis of indolent conditions that do not progress over a lifetime. Study designs that incorporate biomarker trajectories in time and space are needed to distinguish patients who progress to an early cancer from those who follow an indolent course. Esophageal adenocarcinoma is characterized by evolution of punctuated and catastrophic somatic chromosomal alterations and high levels of overall mutations but few recurrently mutated genes aside from TP53. Endoscopic surveillance of Barrett's esophagus for early cancer detection provides an opportunity for assessment of alterations for cancer risk in patients who progress to esophageal adenocarcinoma compared with nonprogressors. We investigated 1,272 longitudinally collected esophageal biopsies in a 248 Barrett's patient case-cohort study with 20,425 person-months of follow-up, including 79 who progressed to early-stage esophageal adenocarcinoma. Cancer progression risk was assessed for total chromosomal alterations, diversity, and chromosomal region-specific alterations measured with single-nucleotide polymorphism arrays in biopsies obtained over esophageal space and time. A model using 29 chromosomal features was developed for cancer risk prediction (area under receiver operator curve, 0.94). The model prediction performance was robust in two independent esophageal adenocarcinoma sets and outperformed TP53 mutation, flow cytometric DNA content, and histopathologic diagnosis of dysplasia. This study offers a strategy to reduce overdiagnosis in Barrett's esophagus and improve early detection of esophageal adenocarcinoma and potentially other cancers characterized by punctuated and catastrophic chromosomal evolution.


Consequences of bottle-feeding to the oral facial development of initially breastfed children.
To identify and assess the possible consequences of bottle-feeding on the oral facial development of children who were breastfed up to at least six months of age. Two hundred and two children (4 years of age) enrolled in an early health attention program participated in the study. The sample was divided into two groups: G1 (children who used only a cup to drink) and G2 (those who used a bottle). Lip closure was observed in 82% of the children in G1 and in 65% of those in G2 (p = 0.0065). The tongue coming to rest in the maxillary arch was found in 73% of the children in G1 and in 47% of those in G2 (p = 0.0001). Nasal breathing was observed in 69% of G1 and in 37% of G2 (p = 0.0001). The maxilla was shown to be normal in 90% of G1 and in 78% of G2 (p = 0.0206). Use of the bottle, even among breastfed children interferes negatively with oral facial development.


Epimorphic regeneration in mice is p53-independent.
The process of regeneration is most readily studied in species of sponge, hydra, planarian and salamander (i.e., newt and axolotl). The closure of MRL mouse ear pinna through-and-through holes provides a mammalian model of unusual wound healing/regeneration in which a blastema-like structure closes the ear hole and cartilage and hair follicles are replaced. Recent studies, based on a broad level of DNA damage and a cell cycle pattern of G₂/M "arrest," showed that p21(Cip1/Waf1) was missing from the MRL mouse ear and that a p21-null mouse could close its ear holes. Given the p53/p21 axis of control of DNA damage, cell cycle arrest, apoptosis and senescence, we tested the role of p53 in the ear hole regenerative response. Using backcross mice, we found that loss of p53 in MRL mice did not show reduced healing. Furthermore, cross sections of MRL. p53(-/-) mouse ears at 6 weeks post-injury showed an increased level of adipocytes and chondrocytes in the region of healing whereas MRL or p21(-/-) mice showed chondrogenesis alone in this same region, though at later time points. In addition, we also investigated other cell cycle-related mutant mice to determine how p21 was being regulated. We demonstrate that p16 and Gadd45 null mice show little healing capacity. Interestingly, a partial healing phenotype in mice with a dual Tgfβ/Rag2 knockout mutation was seen. These data demonstrate an independence of p53 signaling for mouse appendage regeneration and suggest that the role of p21 in this process is possibly through the abrogation of the Tgfβ/Smad pathway.


Triatoma dimidiata infestation in Chagas disease endemic regions of Guatemala: comparison of random and targeted cross-sectional surveys.
Guatemala is presently engaged in the Central America Initiative to interrupt Chagas disease transmission by reducing intradomiciliary prevalence of Triatoma dimidiata, using targeted cross-sectional surveys to direct control measures to villages exceeding the 5% control threshold. The use of targeted surveys to guide disease control programs has not been evaluated. Here, we compare the findings from the targeted surveys to concurrent random cross-sectional surveys in two primary foci of Chagas disease transmission in central and southeastern Guatemala. Survey prevalences of T. dimidiata intradomiciliary infestation by village and region were compared. Univariate logistic regression was used to assess the use of risk factors to target surveys and to evaluate indicators associated with village level intradomiciliary prevalences >5% by survey and region. Multivariate logistic regression models were developed to assess the ability of random and targeted surveys to target villages with intradomiciliary prevalence exceeding the control threshold within each region. Regional prevalences did not vary by survey; however, village prevalences were significantly greater in random surveys in central (13.0% versus 8.7%) and southeastern (22.7% versus 6.9%) Guatemala. The number of significant risk factors detected did not vary by survey in central Guatemala but differed considerably in the southeast with a greater number of significant risk factors in the random survey (e.g. land surface temperature, relative humidity, cropland, grassland, tile flooring, and stick and mud and palm and straw walls). Differences in the direction of risk factor associations were observed between regions in both survey types. The overall discriminative capacity was significantly greater in the random surveys in central and southeastern Guatemala, with an area under the receiver-operator curve (AUC) of 0.84 in the random surveys and approximately 0.64 in the targeted surveys in both regions. Sensitivity did not differ between surveys, but the positive predictive value was significantly greater in the random surveys. Surprisingly, targeted surveys were not more effective at determining T. dimidiata prevalence or at directing control to high risk villages in comparison to random surveys. We recommend that random surveys should be selected over targeted surveys whenever possible, particularly when the focus is on directing disease control and elimination and when risk factor association has not been evaluated for all regions under investigation.


Visual similarity in short-term recall for where and when.
Two experiments examined the effects of visual similarity on short-term recall for where and when in the visual spatial domain. A series of squares of similar or dissimilar colours were serially presented at various locations on the screen. At recall, all coloured squares were simultaneously presented in a random order at the bottom of the screen, and the locations used for presentation were indicated by white squares. Participants were asked to place the colours at their appropriate location in their presentation order. Performance for location (where) and order (when) was assessed separately. Results revealed that similarity severely hinders both memory for what was where and memory for what was when, under quiet and articulatory suppression conditions. These results provide further evidence that similarity has a major impact on processing relational information in memory.


Etiology of preeclampsia: an update.
Preeclampsia still ranks as one of obstetrics major problems. Clinicians typically encounter preeclampsia as maternal disease with variable degrees of fetal involvement. More and more the unique immunogenetic maternal - paternal relationship is appreciated, and as such also the specific 'genetic conflict' that is characteristic of haemochorial placentation. Factors influencing the unique maternal-fetal (paternal) interaction probably include the length and type of sexual relationship, the maternal (decidual natural killer cells) acceptation of the invading cytotrophoblast (paternal HLA-C), and seminal levels of transforming growth factor-b and probably other cytokines. The magnitude of the maternal response would be determined by factors including a maternal set of genes determining her characteristic inflammatory responsiveness, age, quality of her endothelium, obesity/insulin resistance and probably a whole series of susceptibility genes amongst which the thrombophilias received a lot of attention in recent years.


Energy-Efficient Wireless Sensor Networks for Precision Agriculture: A Review.
Wireless sensor networks (WSNs) can be used in agriculture to provide farmers with a large amount of information. Precision agriculture (PA) is a management strategy that employs information technology to improve quality and production. Utilizing wireless sensor technologies and management tools can lead to a highly effective, green agriculture. Based on PA management, the same routine to a crop regardless of site environments can be avoided. From several perspectives, field management can improve PA, including the provision of adequate nutrients for crops and the wastage of pesticides for the effective control of weeds, pests, and diseases. This review outlines the recent applications of WSNs in agriculture research as well as classifies and compares various wireless communication protocols, the taxonomy of energy-efficient and energy harvesting techniques for WSNs that can be used in agricultural monitoring systems, and comparison between early research works on agriculture-based WSNs. The challenges and limitations of WSNs in the agricultural domain are explored, and several power reduction and agricultural management techniques for long-term monitoring are highlighted. These approaches may also increase the number of opportunities for processing Internet of Things (IoT) data.


Molecular characterization of two proteins involved in the excision of the conjugative transposon Tn1545: homologies with other site-specific recombinases.
Excision is probably the initial and rate-limiting step of the movements of conjugative transposons of Gram-positive bacteria such as Tn916 and Tn1545. We have shown, by molecular cloning and DNA sequencing, that a 2058 bp Sau3A right-junction fragment of transposon Tn1545 specifies two gene products that are involved in the excision of the element. The DNA sequence of these genes, designated orf1 and orf2, has been determined and the corresponding proteins, ORF1 and ORF2, have been identified in a bacterial cell-free coupled transcription-translation system. These proteins are freely diffusible since they are able to trans-complement in vivo a deletion derivative of Tn1545 defective for excision. Using an in vivo complementation assay, we have demonstrated that ORF2 alone is able to catalyse excision and that ORF1 strongly stimulates the activity of ORF2. We also found that ORF1 and ORF2 display local homology with, respectively, proteins Xis and Int from lamboid phages, which suggests that these excision systems have a common origin. Based on the functional properties of the integrase of bacteriophage lambda, on the analysis of the nucleotide sequence of the junction fragments and of the target before insertion and after excision, a model is proposed for ORF2-catalysed excision of Tn1545 and related conjugative transposons.


Kidney health for all: Bridging the gap in kidney health education and literacy.
The high burden of kidney disease, global disparities in kidney care, and poor outcomes of kidney failure bring a concomitant growing burden to persons affected, their families, and carers, and the community at large. Health literacy is the degree to which persons and organizations have or equitably enable individuals to have the ability to find, understand, and use information and services to make informed health-related decisions and actions for themselves and others. Rather than viewing health literacy as a patient deficit, improving health literacy largely rests with health care providers communicating and educating effectively in codesigned partnership with those with kidney disease. For kidney policy makers, health literacy provides the imperative to shift organizations to a culture that places the person at the center of health care. The growing capability of and access to technology provides new opportunities to enhance education and awareness of kidney disease for all stakeholders. Advances in telecommunication, including social media platforms, can be leveraged to enhance persons' and providers' education; The World Kidney Day declares 2022 as the year of "Kidney Health for All" to promote global teamwork in advancing strategies in bridging the gap in kidney health education and literacy. Kidney organizations should work toward shifting the patient-deficit health literacy narrative to that of being the responsibility of health care providers and health policy makers. By engaging in and supporting kidney health-centered policy making, community health planning, and health literacy approaches for all, the kidney communities strive to prevent kidney diseases and enable living well with kidney disease.


Metatranscriptome analysis of the microbial fermentation of dietary milk proteins in the murine gut.
Undigestible food ingredients are converted by the microbiota into a large range of metabolites, predominated by short chain fatty acids (SCFA). These microbial metabolites are subsequently available for absorption by the host mucosa and can serve as an energy source. Amino acids fermentation by the microbiota expands the spectrum of fermentation end-products beyond acetate, propionate and butyrate, to include in particular branched-SCFA. Here the long-term effects of high protein-diets on microbial community composition and functionality in mice were analyzed. Determinations of the microbiota composition using phylogenetic microarray (MITChip) technology were complemented with metatranscriptome and SCFA analyses to obtain insight in in situ expression of protein fermentation pathways and the phylogenetic groups involved. High protein diets led to increased luminal concentrations of branched-SCFA, in accordance with protein fermentation in the gut. Bacteria dominantly participating in protein catabolism belonged to the Lachnospiraceae, Erysipelotrichaceae and Clostridiaceae families in both normal- and high- protein diet regimes. This study identifies the microbial groups involved in protein catabolism in the intestine and underpins the value of in situ metatranscriptome analyses as an approach to decipher locally active metabolic networks and pathways as a function of the dietary regime, as well as the phylogeny of the microorganisms executing them.


Assessment of a physical activity program on the medical-hospital costs of a healthcare company.
The protective effect of regular physical activity against risk of development of noncommunicable diseases and reduction of medical-hospital costs are well established in the literature. However, no study investigated the financial impact of workplace physical activity promotion programs in Brazil. To investigate the financial impact of a workplace physical activity promotion program on the medical-hospital costs of a private healthcare company. The average healthcare cost per capita was monitored along one year and compared between employees who performed physical activity with sufficient frequency and the ones who did not adhere to the program. Employees were matched per age, sex and length of work at the company. From 3,744 employees offered participation in the program, only 80 performed physical activity 2 or more times per week. The average medical-hospital cost per capita/year was BRL 2,874.00 (SD=5.259), being BRL 125.00 higher, on average, for the employees who did not adhere to the program. The average medical-hospital cost per capita/year was BRL 1,901.00 lower, on average, for the employees who performed physical activity 3 or more times per week (n=3) compared to the ones who did not (p=0.34). The results of the present study do not allow asserting that the medical-hospital costs of employees who adhered to the program decreased. Longer follow-up and adjustments in the program design are needed to assess its actual impact.


Diffusion weighted image denoising using overcomplete local PCA.
Diffusion Weighted Images (DWI) normally shows a low Signal to Noise Ratio (SNR) due to the presence of noise from the measurement process that complicates and biases the estimation of quantitative diffusion parameters. In this paper, a new denoising methodology is proposed that takes into consideration the multicomponent nature of multi-directional DWI datasets such as those employed in diffusion imaging. This new filter reduces random noise in multicomponent DWI by locally shrinking less significant Principal Components using an overcomplete approach. The proposed method is compared with state-of-the-art methods using synthetic and real clinical MR images, showing improved performance in terms of denoising quality and estimation of diffusion parameters.


Semiparametric accelerated failure time cure rate mixture models with competing risks.
Modern medical treatments have substantially improved survival rates for many chronic diseases and have generated considerable interest in developing cure fraction models for survival data with a non-ignorable cured proportion. Statistical analysis of such data may be further complicated by competing risks that involve multiple types of endpoints. Regression analysis of competing risks is typically undertaken via a proportional hazards model adapted on cause-specific hazard or subdistribution hazard. In this article, we propose an alternative approach that treats competing events as distinct outcomes in a mixture. We consider semiparametric accelerated failure time models for the cause-conditional survival function that are combined through a multinomial logistic model within the cure-mixture modeling framework. The cure-mixture approach to competing risks provides a means to determine the overall effect of a treatment and insights into how this treatment modifies the components of the mixture in the presence of a cure fraction. The regression and nonparametric parameters are estimated by a nonparametric kernel-based maximum likelihood estimation method. Variance estimation is achieved through resampling methods for the kernel-smoothed likelihood function. Simulation studies show that the procedures work well in practical settings. Application to a sarcoma study demonstrates the use of the proposed method for competing risk data with a cure fraction.


Stem cell-based therapies for Duchenne muscular dystrophy.
Muscular dystrophies are a group of genetic muscle disorders that cause progressive muscle weakness and degeneration. Within this group, Duchenne muscular dystrophy (DMD) is the most common and one of the most severe. DMD is an X chromosome linked disease that occurs to 1 in 3500 to 1 in 5000 boys. The cause of DMD is a mutation in the dystrophin gene, whose encoded protein provides both structural support and cell signaling capabilities. So far, there are very limited therapeutic options available and there is no cure for this disease. In this review, we discuss the existing cell therapy research, especially stem cell-based, which utilize myoblasts, satellite cells, bone marrow cells, mesoangioblasts and CD133+ cells. Finally, we focus on human pluripotent stem cells (hPSCs) which hold great potential in treating DMD. hPSCs can be used for autologous transplantation after being specified to a myogenic lineage. Over the last few years, there has been a rapid development of isolation, as well as differentiation, techniques in order to achieve effective transplantation results of myogenic cells specified from hPSCs. In this review, we summarize the current methods of hPSCs myogenic commitment/differentiation, and describe the current status of hPSC-derived myogenic cell transplantation.


Two-year mortality, complications, and healthcare use in children with medicaid following tracheostomy.
To assess patient characteristics associated with adverse outcomes in the first 2 years following tracheostomy, and to report healthcare utilization and cost of caring for these children. Retrospective cohort study. Children (0-16 years) in Medicaid from 10 states undergoing tracheostomy in 2009, identified with International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes and followed through 2011, were selected using the Truven Health Medicaid Marketscan Database (Truven Health Analytics, Inc., Ann Arbor, MI). Patient demographic and clinical characteristics were assessed with likelihood of death and tracheostomy complication using chi-square tests and logistic regression. Healthcare use and spending across the care continuum (hospital, outpatient, community, and home) were reported. A total of 502 children underwent tracheostomy in 2009, with 34.1% eligible for Medicaid because of disability. Median age at tracheostomy was 8 years (interquartile range 1-16 years), and 62.7% had a complex chronic condition. Two-year rates of in-hospital mortality and tracheostomy complication were 8.9% and 38.8%, respectively. In multivariable analysis, the highest likelihood of mortality occurred in children age < 1 year compared with 13+ years (odds ratio [OR] 7.3; 95% confidence interval [CI], 3.2-17.1); the highest likelihood of tracheostomy complication was in children with a complex chronic condition versus those without a complex chronic condition (OR 3.3; 95% CI, 1.1-9.9). Total healthcare spending in the 2 years following tracheostomy was $53.3 million, with hospital, home, and primary care constituting 64.4%, 9.4%, and 0.5% of total spending, respectively. Mortality and morbidity are high, and spending on primary and home care is small following tracheostomy in children with Medicaid. Future studies should assess whether improved outpatient and community care might improve their health outcomes. 4. Laryngoscope, 126:2611-2617, 2016.


Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77 1726) pharmacokinetics in leflunomide-treated patients with rheumatoid arthritis.
Leflunomide is a disease-modifying antirheumatic drug used for the treatment of rheumatoid arthritis (RA). Cytochromes P450, mainly CYP1A2 and CYP2C19, may be involved in the transformation of leflunomide to leflunomide metabolite (A77 1726, 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide). The aim of this study was to investigate whether genetic polymorphisms in CYP1A2 and CYP2C19 influence leflunomide pharmacokinetics, treatment response, and the occurrence of adverse drug reactions (ADRs). The study included 67 patients with RA and 4 patients with polyarthritis resembling RA and psoriasis treated with leflunomide. A77 1726 steady-state plasma concentrations were determined by validated high-performance liquid chromatography with UV detection. A population pharmacokinetic model was developed to estimate the oral clearance (CL/F) and volume of distribution (V/F). A genotyping approach was used to determine C-163A, C-729T, and T-739G in the CYP1A2 gene as well as single nucleotide polymorphisms that characterize CYP2C19*2, *3, *4, and *17 alleles. A large interindividual variability in trough A77 1726 steady-state plasma concentrations was observed (from 1.9 to 156.9 mg/l). A77 1726 CL/F was 71% higher in carriers of the CYP2C19*2 allele compared with noncarriers. The A77 1726 average steady-state plasma concentration was associated with the treatment response. Patients with a greater decrease in C-reactive protein (CRP) had higher average steady-state plasma A77 1726 concentrations: 49.7 +/- 39.0 mg/l in patients with DeltaCRP of more than 8.5 mg/l compared with 24.8 +/- 13.7 mg/l in patients with DeltaCRP of <or=8.5 mg/l (p = 0.015). No association of A77 1726 steady-state plasma concentrations with the occurrence of ADRs was observed. Our results suggest that genetic variability in leflunomide-metabolizing enzymes influences leflunomide metabolite concentrations that are associated with the treatment response but not with leflunomide-induced toxicity.


The microevolution of V1r vomeronasal receptor genes in mice.
Vomeronasal sensitivity is important for detecting intraspecific pheromonal cues as well as environmental odorants and is involved in mating, social interaction, and other daily activities of many vertebrates. Two large families of seven-transmembrane G-protein-coupled receptors, V1rs and V2rs, bind to various ligands to initiate vomeronasal signal transduction. Although the macroevolution of V1r and V2r genes has been well characterized throughout vertebrates, especially mammals, little is known about their microevolutionary patterns, which hampers a clear understanding of the evolutionary forces behind the rapid evolutionary turnover of V1r and V2r genes and the great diversity in receptor repertoire across species. Furthermore, the role of divergent vomeronasal perception in enhancing premating isolation and maintaining species identity has not been evaluated. Here we sequenced 44 V1r genes and 25 presumably neutral noncoding regions in 14 wild-caught mice belonging to Mus musculus and M. domesticus, two closely related species with strong yet incomplete reproductive isolation. We found that nucleotide changes in V1rs are generally under weak purifying selection and that only ∼5% of V1rs may have been subject to positive selection that promotes nonsynonymous substitutions. Consistent with the low functional constraints on V1rs, 18 of the 44 V1rs have null alleles segregating in one or both species. Together, our results demonstrate that, despite occasional actions of positive selection, the evolution of V1rs is in a large part shaped by purifying selection and random drift. These findings have broad implications for understanding the driving forces of rapid gene turnovers that are often observed in the evolution of large gene families.


Body mass index and weight change in men with prostate cancer: progression and mortality.
Body mass index (BMI) is a modifiable lifestyle factor that has been associated with an increased risk of fatal prostate cancer and biochemical recurrence. The main purpose of the present study was to investigate the association between the exposure BMI at the time of a prostate cancer diagnosis and weight change after diagnosis, and the outcomes of prostate cancer progression and mortality in a large cohort study. Data from 4,376 men diagnosed with clinically localized prostate cancer between 1997 and 2002 were analyzed. BMI and weight change were self-reported in 2007. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were estimated in complete-case analysis (n = 3,214) using Cox proportional hazards models. Progression was experienced among 639 (14.6 %) of the study participants, and in total, 450 (10.3 %) deaths of any cause and 134 (3.1 %) prostate cancer-specific deaths were recorded during follow-up. Obese men had a 47 % increased rate of overall mortality compared to normal weight men (HR 1.47, 95 % CI 1.03-2.10). No statistically significant associations were found for BMI and prostate cancer progression or prostate cancer-specific mortality. A weight loss >5 % after diagnosis almost doubled the rate of overall mortality compared to maintaining a stable weight (HR 1.94, 95 % CI 1.41-2.66), while a weight gain >5 % was associated with an almost doubled increased rate of prostate cancer-specific mortality (HR 1.93, 95 % CI 1.18-3.16). Being obese was associated with an increased rate of overall mortality, and gaining weight after a prostate cancer diagnosis was associated with an increased rate of prostate cancer-specific mortality.


Changes of beta-adrenoceptors in the aortic muscle cells of spontaneously hypertensive rats.
The characteristics of [125I]monoiodocyanopindolol (ICYP) binding to beta-adrenoceptors of cultured aortic smooth muscle cells derived from 4-week-old spontaneously hypertensive rats (SHR) and the Wistar-Kyoto normotensive rats (WKY) were examined. During optimization of the binding assays, we found that the specific binding of ICYP by intact cells was masked by a high level of nonspecific ICYP accumulation in intact cells presumably owing to the lipophilic nature of ICYP. Optimal specific ICYP binding requires that the cells be gently lysed with hypotonic dilution followed by a freeze-and-thaw cycle. Under most experimental conditions tested, the total number of ICYP binding sites in WKY aortic muscle cells was considerably and consistently smaller than that in SHR cells. There was no difference in the Kd values for ICYP binding to SHR and WKY cells. However, when ICYP binding was carried out using crude membrane fractions with well-defined plasma membrane content isolated from aortic muscle strips of adult rats, we found no difference in the number of beta-adrenoceptor sites between SHR and WKY. Morphological evidence indicated that cultured SHR aortic muscle cells contained a greater proportion of larger cells with multinuclear features. These results suggest that an increase in the number of beta-adrenoceptor density per cell in SHR may be associated with cellular hypertrophy of aortic smooth muscle cells. We conclude that under cultured conditions, a higher incidence of polyploid smooth muscle cells in the SHR as compared with WKY was expressed earlier than under in vivo conditions. Therefore, the interpretation of results obtained from cultured cell studies in relation to under in vivo conditions should be exercised with caution.


Cytokine and alloantibody networks in long term cardiac allografts in rat recipients treated with rapamycin.
Treatment with rapamycin (RPM) prevents accelerated rejection of (LEW x BN)F1 cardiac allografts in LEW rats presensitized with BN skin grafts. This study analyzed the influence of RPM on cytokine (IL-2, IL-4, IL-10, and IL-12) and alloantibody networks in this model. Accelerated (24-h) rejection was associated with strong expression of intragraft IL-2 and IL-12 (p40) mRNAs, which reached maximal levels 3 to 6 h post-transplantation. IL-4 and IL-10 mRNAs were readily detectable throughout the observation period. RPM therapy abrogated rejection at 24 h and prolonged cardiac allograft survival to about 50 days. This effect was correlated with a profound initial depression of IL-2 mRNA; delayed expression of IL-2 mRNA was detected in well functioning grafts at > 20 days. In RPM-treated hosts, expression of IL-12 (p40) mRNA was low at the early time points (6-24 h), but prominent in long term grafts. The expression of both IL-4 and IL-10 mRNAs was preserved in RPM-conditioned hosts. Immunohistologic analysis of long term allografts revealed an interstitial cellular infiltrate and areas of intimal proliferation within small arteries indicative of early transplant arteriosclerosis. Analysis of cytokine proteins showed dense labeling of mononuclear and some endothelial cells for IL-4 and IL-12 (p70), but not for IL-2 or IFN-gamma alloantibody in the early post-transplant period. However, an increase in circulating and intragraft IgM and, to a lesser extent, IgG, primarily of the IgG2b subclass, was evident in long term recipients. Thus, RPM treatment reduces, but does not completely inhibit, the expression of Th1-type and preserves the expression of Th2-type cytokines. The demonstration of IL-12 in long term allografts after RPM therapy may reflect late activation of macrophages that, coupled with the appearance of IgG2b, may contribute to the chronic rejection of cardiac allografts.


Living-donor kidney transplant from hepatitis B surface antigen-positive donors to hepatitis B antibody-positive recipients without hepatitis B immunoglobulin prophylaxis in an endemic country.
Living-donor kidney transplant from donors who are chronically infected with hepatitis B virus can be considered as a possibility to compensate for insufficiency of organ transplants, particularly in a hepatitis B virus endemic country. In this study, the safety and efficacy were reviewed retrospectively in living-donor kidney transplant from donors who were chronically infected with hepatitis B virus. In the years between 2012 and 2013, we transplanted 4 renal grafts from hepatitis B surface antigen-positive living donors to antihepatitis B antibody-positive recipients. Lamivudine was prescribed for recipients after transplant without hepatitis B immunoglobulin. In 1-year follow-up, there were no abnormal findings in the levels of renal and liver enzymes, and there was no unwanted seroconversion to positive hepatitis B surface antigen. When combined with careful hepatitis B virus-monitoring, renal grafts from hepatitis B surface antigen-positive living donors can be transplanted to hepatitis B antibody-positive recipients, without the need for hepatitis B immunoglobulin prophylaxis, in a hepatitis B virus endemic country.


Female-induced remote regulation of sperm physiology may provide opportunities for gamete-level mate choice.
In sedentary externally fertilizing species, direct interactions between mating partners are limited and prefertilization communication between sexes occurs largely at the gamete level. Certain combinations of eggs and sperm often have higher fertilization success than others, which may be contingent on egg-derived chemical factors that preferentially attract sperm from compatible males. Here, we examine the mechanisms underlying such effects in the marine mussel Mytilus galloprovincialis, where differential sperm attraction has recently been shown to be associated with variation in offspring viability. Specifically, we focus on the sperm surface glycans, an individually unique layer of carbohydrates that moderate self-recognition and other cellular-level interactions. In many species egg-derived factors trigger remarkable changes in the sperm's glycan layer, physiology, and swimming behavior, and thus potentially moderate mate choice at the gamete level. Here, we show that sperm glycan modifications and the strength of acrosome reaction are both dependent on specific male-female interactions (male-female combination). We also find associations between female-induced sperm glycan changes and the Ca2+ influx into sperm--a key regulator of fertilization processes from sperm capacitation to gamete fusion. Together, our results suggest that female-induced remote regulation of sperm physiology may constitute a novel mechanism of gamete-level mate choice.


Metalworking fluid exposure and cancer risk in a retrospective cohort of female autoworkers.
Metalworking fluids (MWFs) have been associated with cancer of several sites, but the risks have been primarily examined in men or in studies that adjusted for gender in analyses. To evaluate whether risks were similar in women, we report cancer mortality risk among 4,825 female autoworkers within the united autoworkers-general motors autoworkers cohort. Standardized mortality rates (SMRs) were calculated based on Michigan death rates (1980-2004). Internal comparisons (1941-2004) were examined using Cox regression for straight, soluble, and synthetic MWFs, and their corresponding oil- and water-based fractions. MWF exposure levels in the female cohort were generally less than two-third the MWF levels in the male cohort. Female autoworkers had an excess of cancer from all sites (SMR, 1.10; 95 % confidence interval (CI), 0.98-1.22) and lung cancer (SMR, 2.08; 95 % CI, 1.71-2.52). Colon cancer risk increased with straight (mineral oil) MWF exposure (exposure > median; hazard ratio = 3.1; 95 % CI, 1.2-8.0). A protective effect was observed for ovarian cancer with the soluble MWFs and water-based MWF metrics. Although bladder, rectal, and laryngeal cancers and malignant melanoma have been associated with straight MWF exposure and pancreatic cancer with synthetic MWF in men, there were too few deaths in this female subcohort to examine exposure-response relations for these sites. Results were null for lung and breast cancer. Our findings support an association between colon cancer and straight MWFs, but we found limited evidence of risk for other tumor sites at the lower exposure levels experienced by the female autoworkers.


Specific binding of telomeric G-quadruplexes by hydrosoluble perylene derivatives inhibits repeat addition processivity of human telomerase.
Telomerase is responsible for the immortal phenotype of cancer cells and telomerase inhibition may specifically target cancer cell proliferation. Ligands able to selectively bind to G-quadruplex telomeric DNA have been considered as telomerase inhibitors but their mechanisms of action have often been deduced from a non-quantitative telomerase activity assay (TRAP assay) that involves a PCR step and that does not provide insight on the mechanism of inhibition. Furthermore, quadruplex ligands have also been shown to exert their effects by affecting association of telomere binding proteins with telomeres. Here, we use quantitative direct telomerase activity assays to evaluate the strength and mechanism of action of hydrosoluble perylene diimides (HPDIs). HPDIs contain a perylene moiety and different numbers of positively charged side chains. Side chain features vary with regard to number and distances of the charges. IC(50) values of HPDIs were in the low micromolar (0.5-5 μM) range depending on the number and features of the side chains. HPDIs having four side chains emerged as the best compounds of this series. Analysis of primer elongation products demonstrated that at low HPDI concentrations, telomerase inhibition involved formation of telomeric G-quadruplex structures, which inhibited further elongation by telomerase. At high HPDI concentrations, telomerase inhibition occurred independently of G-quadruplex formation of the substrate. The mechanism of action of HPDIs and their specific binding to G-quadruplex DNA was supported by PAGE analysis, CD spectroscopy and ESI-MS. Finally, competition Telospot experiments with duplex DNA indicated specific binding of HPDIs to the single-stranded telomeric substrates over double stranded DNA, a result supported by competitive ESI-MS. Altogether, our results indicate that HPDIs act by stabilizing G-quadruplex structures in single-stranded telomeric DNA, which in turn prevents repeat addition processivity of telomerase.


Screening for pain in knee osteoarthritis: which question?
To compare three questions on knee pain with respect to determined prevalence and associations with disability and structural change. Postal survey to 4057 men and women aged 40-79 years. Knee pain was defined by three questions: (A) "Have you ever had pain in or around the knee on most days for at least a month? If so, have you experienced any pain during the last year?" (B) "Have you had pain within the last year in or around the knee that occurred on most days for at least a month?" (C) "Have you had knee pain on most days of the last month?" [American College of Rheumatology (ACR) criteria for knee osteoarthritis]. Disability was assessed with the SF-36 health status questionnaire. Radiographs (AP weight bearing and skyline) were obtained on a proportion (n = 459) and graded for maximum osteophyte in any compartment. Prevalence of knee pain for questions A, B, and C were 28.3%, 25.3%, and 19.3% respectively. Highest rates of disability were observed for question C (71.3% compared with 60.9% for question A). There was no major difference between questions in terms of percentage with > or = grade 1 osteophyte or > or = grade 2 osteophyte. Sensitivity and specificity of each question for > or = grade 1 osteophyte did vary, with question A being most sensitive but least specific (58.7% and 59.1%) and question C most specific (72.7%) but least sensitive (45.4%). Estimates of knee pain and disability are influenced by even minor changes in question content. The ACR criteria question may be a better predictor of disability but is relatively insensitive for use in the community.


Evaluating the prevalence, content and readability of complementary and alternative medicine (CAM) web pages on the internet.
Complementary and alternative medicine (CAM) use is growing rapidly. As CAM is relatively unregulated, it is important to evaluate the type and availability of CAM information. The goal of this study is to deter-mine the prevalence, content and readability of online CAM information based on searches for arthritis, diabetes and fibromyalgia using four common search engines. Fifty-eight of 599 web pages retrieved by a "condition search" (9.6%) were CAM-oriented. Of 216 CAM pages found by the "condition" and "condition + herbs" searches, 78% were authored by commercial organizations, whose pur-pose involved commerce 69% of the time and 52.3% had no references. Although 98% of the CAM information was intended for consumers, the mean read-ability was at grade level 11. We conclude that consumers searching the web for health information are likely to encounter consumer-oriented CAM advertising, which is difficult to read and is not supported by the conventional literature.


Large-scale expansion of human stem and progenitor cells from bone marrow mononuclear cells in continuous perfusion cultures.
There is a growing consensus that clinical practice in the areas of bone marrow (BM) transplantation and gene therapy will rely on the ex vivo expansion of hematopoietic cells. We report here on the development of continuously perfused culture systems (bioreactor systems) that expand human stem and progenitor cells from BM mononuclear cell (MNC) populations obtained without cell enrichment. In three separate experiments, 10 bioreactors were each inoculated with 3 x 10(7) BM MNC from patients undergoing marrow harvest for autologous transplantation. At various times thereafter (between days 6 and 16), duplicate bioreactors were harvested and cells were analyzed. The bioreactors contained three cell populations that were analyzed separately: nonadherent cells; cells that were loosely adherent to the endogenously formed stromal layer; and an adherent cell layer that required trypsinization for removal. Total cell numbers increased continuously to give an overall 10-fold (range, 8- to 11-fold) expansion by day 14. The adherent stromal layer significantly expanded to more than 2 x 10(7) cells, but remained less than 6% of the total cell population. Colony-forming unit-granulocyte-macrophage (CFU-GM) numbers expanded 21-fold (range, 12- to 34-fold) by day 14 and, because this expansion was greater than that for total cells, CFU-GM were enriched by as much as fourfold by day 14. Burst-forming unit-erythroid (BFU-E) numbers peaked earlier than did CFU-GM numbers, with a 12-fold (range, 6- to 18-fold) expansion obtained on day 8. In contrast to CFU-GM, which were predominantly nonadherent, BFU-E were more evenly distributed between the three cell populations. Stem cell activity was measured by the long-term culture-initiating cell (LTC-IC) limiting dilution assay. The number of LTC-IC per reactor consistently increased with time in all cultures, resulting in a 7.5-fold (range, 3.4- to 9.8-fold) expansion. In summary, more than 3 billion cells, containing 12 million CFU-GM, were reproducibly generated from the equivalent of a 10 to 15 ml BM aspirate. These data indicate that small numbers of BM MNC can be readily expanded ex vivo in continuous perfusion cultures, and that such ex vivo expansion may have direct applications in clinical and experimental BM transplantation.


A mathematical model of electrotonic interactions between ventricular myocytes and fibroblasts.
Functional intercellular coupling has been demonstrated among networks of cardiac fibroblasts, as well as between fibroblasts and atrial or ventricular myocytes. In this study, the consequences of these interactions were examined by implementing the ten Tusscher model of the human ventricular action potential, and coupling it to our electrophysiological models for mammalian ventricular fibroblasts. Our simulations reveal significant electrophysiological consequences of coupling between 1 and 4 fibroblasts to a single ventricular myocyte. These include alterations in plateau height and/or action potential duration (APD) and changes in underlying ionic currents. Two series of simulations were carried out. First, fibroblasts were modeled as a spherical cell with a capacitance of 6.3 pF and an ohmic membrane resistance of 10.7 G Omega. When these "passive" fibroblasts were coupled to a myocyte, they caused slight prolongation of APD with no changes in the plateau, threshold for firing, or rate of initial depolarization. In contrast, when the same myocyte-fibroblast complexes were modeled after addition of the time- and voltage-gated K(+) currents that are expressed in fibroblasts, much more pronounced effects were observed: the plateau height of the action potential was reduced and the APD shortened significantly. In addition, each fibroblast exhibited significant electrotonic depolarizations in response to each myocyte action potential and the resting potential of the fibroblasts closely approximated the resting potential of the coupled ventricular myocyte.


Alterations of the Cl-/NaCO3- anion exchanger in erythrocytes of uraemic patients.
We have studied the transport activity of the erythrocyte anion exchanger by measuring the DIDS-sensitive Li+ influx in fresh red blood cells incubated in HCO3- medium. In addition, the amount of erythrocyte band 3 protein was determined by electrophoretic analysis. The study was performed in twenty uraemic patients on chronic haemodialysis (12 males and 8 females, mean age 47.9 years), and in 20 healthy controls (10 males and 10 females, mean age 44.7 years). Mean time on haemodialysis was 63.9 months (range 6-170 months). The DIDS-sensitive Li+ influx was decreased in erythrocytes from uraemic patients as compared to erythrocytes from controls (619.6 +/- 34.1 vs 761.2 +/- 36.6 mumol/l cell x h, P less than 0.01). The content of band 3 protein was decreased in erythrocytes from uraemic patients as compared to erythrocytes from controls (30.01 +/- 0.39 vs 32.12 +/- 0.48%, P less than 0.01). These results indicate that the Cl-/NaCO3- anion exchanger is altered in erythrocytes from uraemic patients in chronic haemodialysis, and suggest that the regulation of ion content may be compromised in the red blood cells of these patients.


Comparison of percent density from raw and processed full-field digital mammography data.
Mammographic density has been established as a strong risk factor for breast cancer, primarily using digitized film mammograms. Full-field digital mammography (FFDM) is replacing film mammography, has different properties than film, and provides both raw and processed clinical display representation images. We evaluated and compared FFDM raw and processed breast density measures and their associations with breast cancer. A case-control study of 180 cases and 180 controls matched by age, postmenopausal hormone use, and screening history was conducted. Mammograms were acquired from a General Electric Senographe 2000D FFDM unit. Percent density (PD) was assessed for each FFDM representation using the operator-assisted Cumulus method. Reproducibility within image type (n = 80) was assessed using Lin's concordance correlation coefficient (rc). Correlation of PD between image representations (n = 360) was evaluated using Pearson's correlation coefficient (r) on the continuous measures and the weighted kappa statistic (κ) for quartiles. Conditional logistic regression was used to estimate odds ratios (ORs) for the PD and breast cancer associations for both image representations with 95% confidence intervals. The area under the receiver operating characteristic curve (AUC) was used to assess the discriminatory accuracy. Percent density from the two representations provided similar intra-reader reproducibility (rc= 0.92 for raw and rc= 0.87 for processed images) and was correlated (r = 0.82 and κ = 0.64). When controlling for body mass index, the associations of quartiles of PD with breast cancer and discriminatory accuracy were similar for the raw (OR: 1.0 (ref.), 2.6 (1.2 to 5.4), 3.1 (1.4 to 6.8), 4.7 (2.1 to 10.6); AUC = 0.63) and processed representations (OR: 1.0 (ref.), 2.2 (1.1 to 4.1), 2.2 (1.1 to 4.4), 3.1 (1.5 to 6.6); AUC = 0.64). Percent density measured with an operator-assisted method from raw and processed FFDM images is reproducible and correlated. Both percent density measures provide similar associations with breast cancer.


Occupational coronary heart disease among bridge and tunnel officers.
Traffic-control officers employed in New York City tunnels prior to 1981 have been at increased risk of mortality from coronary heart disease. In this study, the authors assessed current coronary heart disease prevalence and evaluated associations between coronary heart disease and occupational factors among New York City bridge and tunnel officers. A clinical cardiovascular disease surveillance and cross-sectional occupational epidemiologic study was conducted. The authors used comprehensive evaluations to identify current and prior incidences of coronary heart disease. Occupational risk factors evaluated included job strain, current and historic exposure to carbon monoxide, and occupational physical inactivity. Current carbon monoxide exposure was assessed via workshift changes in carboxyhemoglobin. Coronary heart disease occurred in 29 (5.5%) of the 526 bridge and tunnel officers examined. Risk of coronary heart disease was associated positively with total years each bridge and tunnel officer work had worked in that capacity (odds ratio = 1.64 for each decade of employment, adjusted for nonoccupational coronary heart disease risk factors). Carboxyhemoglobin levels were low in the subjects, and job strain and physical inactivity were very prevalent. Occupational factors contributed to the risk of coronary heart disease in New York City bridge and tunnel officers. The authors were unable to identify the specific factors that led to the increase in risk described.


Synthesis of mucoadhesive thiol-bearing microgels from 2-(acetylthio)ethylacrylate and 2-hydroxyethylmethacrylate: novel drug delivery systems for chemotherapeutic agents to the bladder.
Thiol-bearing microgels have been synthesised from copolymerisation of 2-(acetylthio)ethylacrylate and 2-hydroxyethylmethacrylate, and subsequent deprotection using sodium thiomethoxide. The concentration of thiol groups on these microgels could be tailored by use of different molar ratios of the two monomers. These thiol-bearing microgels were shown to adhere to ex vivo porcine urinary bladder, which was correlated with their level of thiolation. By simply mixing solutions of thiol-bearing microgels and doxorubicin, high levels of drug loading into the microgels could be achieved. Thiol-bearing microgels controlled the release of doxorubicin in a time-dependent manner over several hours. These doxorubicin-loaded thiol-bearing microgels could have application in the treatment of early-stage bladder cancers. The method used represents a new 'bottom-up' approach for the synthesis of novel mucoadhesive microgels.


High frequencies of circulating IFN-gamma-secreting CD8 cytotoxic T cells specific for a novel MHC class I-restricted Mycobacterium tuberculosis epitope in M. tuberculosis-infected subjects without disease.
MHC class I-restricted CD8 cytotoxic T lymphocytes (CTL) are essential for protective immunity to Mycobacterium tuberculosis in animal models but their role in humans remains unclear. We therefore studied subjects who had successfully contained M. tuberculosis infection in vivo, i.e. exposed healthy household contacts and individuals with inactive self-healed pulmonary tuberculosis. Using the ELISPOT assay for IFN-gamma, we screened peptides from ESAT-6, a secreted antigen that is highly specific for M. tuberculosis. We identified a novel nonamer epitope: unstimulated peripheral blood-derived CD8 T cells displayed peptide-specific IFN-gamma release ex vivo while CD8 T cell lines and clones exhibited HLA-A68.02-restricted cytolytic activity and recognized endogenously processed antigen. The frequency of CD8 CTL specific for this single M. tuberculosis epitope, 1/2500 peripheral blood lymphocytes, was equivalent to the combined frequency of all IFN-gamma-secreting purified protein derivative-reactive T cells ex vivo. This highly focused CTL response was maintained in an asymptomatic contact over 2 years and is the most potent antigen-specific antimycobacterial CD8 CTL response hitherto described. Thus, human M. tuberculosis-specific CD8 CTL are not necessarily associated with active disease per se. Rather, our results are consistent with a protective role for these ESAT-6-specific CD8 T cells in the long-term control of M. tuberculosis in vivo in humans.


Efficient factor VIII affinity purification using a small synthetic ligand.
Hemophilia A is currently treated by infusions of the coagulation factor (F) VIII, of which production and purification remain a challenging task. Current purification procedures using immunoaffinity chromatography are cumbersome, expensive, and suffer from the instability of the applied antibody ligands, which elute along with the product and contaminate it. Recently, FVIII was purified using octapeptide ligands, but their use is limited due to the low resistance to proteases. Our goal was to develop and evaluate a novel ligand for FVIII purification, overcoming the drawbacks of current procedures. Peptide ligands were screened for binding of (125)I-plasma-derived-FVIII (pdFVIII) in a microbead assay. A selected ligand-coated Toyopearl resin was then used for pdFVIII purification from cell-conditioned Delbucco's modified Eagle's medium (DMEM) containing fetal bovine serum. The proteolytic stability of ligand was measured by incubating with human serum and proteinase K, and its cytotoxicity towards human OV-MZ-6 cells was assayed. A high-affinity octapeptidic FVIII ligand was modified into the small, highly stable and non-toxic peptidomimetic ligand L4 by rational and combinatorial design without affecting its affinity for FVIII. Using ligand L4-coated Toyopearl resin, pdFVIII was isolated from cell-conditioned medium with high purity and 89% column retention after elution with a mild buffer containing 0.6 m NaCl at pH 6.8. Ligand L4 offers a valuable alternative to antibody-based procedures for laboratory and industrial production. Its synthesis by established solid-phase procedures is straightforward and considerably cheaper than the biotechnological production of antibodies, and safety concerns associated with the use of biological material are overcome.


The human genes for S-adenosylhomocysteine hydrolase and adenosine deaminase are syntenic on chromosome 20.
Human-Chinese hamster cell hybrids and a monoclonal antibody to human S-adenosylhomocysteine hydrolase were used to identify chromosome 20 as the location of the human gene for this enzyme. The gene for adenosine deaminase had previously been mapped to this chromosome. The activity of S-adenosylhomocysteine hydrolase is dependent in vivo on that of adenosine deaminase, since the substrates for the deaminase, adenosine and deoxyadenosine, respectively, inhibit and inactivate S-adenosylhomocysteine hydrolase in genetic or drug-induced adenosine deaminase deficiency. This functional dependence and the likelihood that S-adenosylhomocysteine hydrolase, a eukaryotic enzyme, arose later than adenosine deaminase, which occurs in prokaryotes as well as eukaryotes, suggest that the occurrence of their genes on the same chromosome may have evolutionary significance. In addition, the unusual capacity of S-adenosylhomocysteine hydrolase to form stable complexes with adenosine and its cofactor, nicotinamide adenine dinucleotide, suggest that evolution of its gene may have involved recombination of a portion of the adenosine deaminase gene with an adenine nucleotide domain-coding sequence of another preexisting gene.


Emerging Roles for Ciz1 in Cell Cycle Regulation and as a Driver of Tumorigenesis.
Precise duplication of the genome is a prerequisite for the health and longevity of multicellular organisms. The temporal regulation of origin specification, replication licensing, and firing at replication origins is mediated by the cyclin-dependent kinases. Here the role of Cip1 interacting Zinc finger protein 1 (Ciz1) in regulation of cell cycle progression is discussed. Ciz1 contributes to regulation of the G1/S transition in mammalian cells. Ciz1 contacts the pre-replication complex (pre-RC) through cell division cycle 6 (Cdc6) interactions and aids localization of cyclin A- cyclin-dependent kinase 2 (CDK2) activity to chromatin and the nuclear matrix during initiation of DNA replication. We discuss evidence that Ciz1 serves as a kinase sensor that regulates both initiation of DNA replication and prevention of re-replication. Finally, the emerging role for Ciz1 in cancer biology is discussed. Ciz1 is overexpressed in common tumors and tumor growth is dependent on Ciz1 expression, suggesting that Ciz1 is a driver of tumor growth. We present evidence that Ciz1 may contribute to deregulation of the cell cycle due to its ability to alter the CDK activity thresholds that are permissive for initiation of DNA replication. We propose that Ciz1 may contribute to oncogenesis by induction of DNA replication stress and that Ciz1 may be a multifaceted target in cancer therapy.


CoMFA study of novel phenyl ring-substituted 3alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter.
A series of phenyl ring-substituted analogues of 3alpha-(diphenylmethoxy)tropane (benztropine) has been prepared as novel probes for the dopamine transporter. Cross-validated comparative molecular field analysis (CoMFA) models of the binding domain on the dopamine transporter were constructed using 37 geometry-optimized structures of these compounds and their corresponding binding affinities (K(i) values) for the displacement of [(3)H]WIN 35,428 or potency of [(3)H]dopamine uptake inhibition (IC(50) values) in rat caudate putamen tissue. The most predictive model (q(2) = 0.78) correlated the steric component of CoMFA to the dependent variable of [(3)H]WIN 35,428 binding affinities. A novel series of seven phenyl ring-substituted analogues of 3alpha-(diphenylmethoxy)tropane was prepared, and our best molecular model was used to accurately predict their binding affinities. This study is the first to provide a CoMFA model for this class of dopamine uptake inhibitors. This model represents an advancement in the design of novel dopamine transporter ligands, based on 3alpha-(diphenylmethoxy)tropane, and further substantiates structure-activity relationships that have previously been proposed for this class of compounds. This CoMFA model can now be used to predict the binding affinities of novel 3alpha-(diphenylmethoxy)tropane analogues at the dopamine transporter and will be useful in the design of molecular probes within this class of dopamine uptake inhibitors.


Use of the Magnetic Field for Improving Gyroscopes' Biases Estimation.
An accurate orientation is crucial to a satisfactory position in pedestrian navigation. The orientation estimation, however, is greatly affected by errors like the biases of gyroscopes. In order to minimize the error in the orientation, the biases of gyroscopes must be estimated and subtracted. In the state of the art it has been proposed, but not proved, that the estimation of the biases can be accomplished using magnetic field measurements. The objective of this work is to evaluate the effectiveness of using magnetic field measurements to estimate the biases of medium-cost micro-electromechanical sensors (MEMS) gyroscopes. We carry out the evaluation with experiments that cover both, quasi-error-free turn rate and magnetic measurements and medium-cost MEMS turn rate and magnetic measurements. The impact of different homogeneous magnetic field distributions and magnetically perturbed environments is analyzed. Additionally, the effect of the successful biases subtraction on the orientation and the estimated trajectory is detailed. Our results show that the use of magnetic field measurements is beneficial to the correct biases estimation. Further, we show that different magnetic field distributions affect differently the biases estimation process. Moreover, the biases are likewise correctly estimated under perturbed magnetic fields. However, for indoor and urban scenarios the biases estimation process is very slow.


Influence of ageing and essential amino acids on quantitative patterns of troponin T alternative splicing in human skeletal muscle.
Ageing is associated with a loss of skeletal muscle performance, a condition referred to as sarcopenia. In part, the age-related reduction in performance is due to a selective loss of muscle fiber mass, but mass-independent effects have also been demonstrated. An important mass-independent determinant of muscle performance is the pattern of expression of isoforms of proteins that participate in muscle contraction (e.g., the troponins). In the present study, we tested the hypothesis that ageing impairs alternative splicing of the pre-mRNA encoding fast skeletal muscle troponin T (TNNT3) in human vastus lateralis muscle. Furthermore, we hypothesized that resistance exercise alone or in combination with consumption of essential amino acids would attenuate age-associated effects on TNNT3 alternative splicing. Our results indicate that ageing negatively affects the pattern of TNNT3 alternative splicing in a manner that correlates quantitatively with age-associated reductions in muscle performance. Interestingly, whereas vastus lateralis TNNT3 alternative splicing was unaffected by a bout of resistance exercise 24 h prior to muscle biopsy, ingestion of a mixture of essential amino acids after resistance exercise resulted in a significant shift in the pattern of TNNT3 splice form expression in both age groups to one predicted to promote greater muscle performance. We conclude that essential amino acid supplementation after resistance exercise may provide a means to reduce impairments in skeletal muscle quality during ageing in humans.


DNA diagnostics by surface-bound melt-curve reactions.
Melting-curve procedures track DNA denaturation in real time and so provide an effective way of assessing sequence variants. Dynamic allele-specific hybridization (DASH) is one such method, based on fluorescence, which uses heat to denature a single allele-specific probe away from one strand of a polymerase chain reaction product attached to a solid support. DASH is a proven system for research genotyping, but here we evaluate it for DNA diagnostics under two scenarios. First, for mutation scanning (resequencing), a human genomic sequence of 97 bp was interrogated with 15 probes tiled with 12-base overlaps, providing up to fourfold redundancy per base. This test sequence spanned three high-frequency single nucleotide polymorphisms, all of which were correctly revealed in 16 individuals. Second, to score multiple different mutations in parallel, 18 alterations in the gyrA gene of Salmonella were assessed in 62 strains by using wild-type- and mutation-specific probes. Both experiments were performed in a blinded manner, and all results were confirmed by sequencing. All DNA variants were unambiguously resolved in every sample, with no false-positive or false-negative signals across all of the investigations. In conclusion, DASH performs accurately and robustly when applied to DNA diagnostic challenges, including mutation scoring and mutation scanning.


Inherent high correlation of individual motility enhances population dispersal in a heterotrophic, planktonic protist.
Quantitative linkages between individual organism movements and the resulting population distributions are fundamental to understanding a wide range of ecological processes, including rates of reproduction, consumption, and mortality, as well as the spread of diseases and invasions. Typically, quantitative data are collected on either movement behaviors or population distributions, rarely both. This study combines empirical observations and model simulations to gain a mechanistic understanding and predictive ability of the linkages between both individual movement behaviors and population distributions of a single-celled planktonic herbivore. In the laboratory, microscopic 3D movements and macroscopic population distributions were simultaneously quantified in a 1L tank, using automated video- and image-analysis routines. The vertical velocity component of cell movements was extracted from the empirical data and used to motivate a series of correlated random walk models that predicted population distributions. Validation of the model predictions with empirical data was essential to distinguish amongst a number of theoretically plausible model formulations. All model predictions captured the essence of the population redistribution (mean upward drift) but only models assuming long correlation times (minute), captured the variance in population distribution. Models assuming correlation times of 8 minutes predicted the least deviation from the empirical observations. Autocorrelation analysis of the empirical data failed to identify a de-correlation time in the up to 30-second-long swimming trajectories. These minute-scale estimates are considerably greater than previous estimates of second-scale correlation times. Considerable cell-to-cell variation and behavioral heterogeneity were critical to these results. Strongly correlated random walkers were predicted to have significantly greater dispersal distances and more rapid encounters with remote targets (e.g. resource patches, predators) than weakly correlated random walkers. The tendency to disperse rapidly in the absence of aggregative stimuli has important ramifications for the ecology and biogeography of planktonic organisms that perform this kind of random walk.


Car drivers with dementia: Different complications due to different etiologies?
Older drivers with dementia are an at-risk group for unsafe driving. However, dementia refers to various etiologies and the question is whether dementias of different etiology have similar effects on driving ability. The literature on the effects of dementia of various etiologies on driving ability is reviewed. Studies addressing dementia etiologies and driving were identified through PubMed, PsychINFO, and Google Scholar. Early symptoms and prognoses differ between dementias of different etiology. Therefore, different etiologies may represent different likelihoods with regard to fitness to drive. Moreover, dementia etiologies could indicate the type of driving problems that can be expected to occur. However, there is a great lack of data and knowledge about the effects of almost all etiologies of dementia on driving. One could hypothesize that patients with Alzheimer's disease may well suffer from strategic difficulties such as finding a route, whereas patients with frontotemporal dementia are more inclined to make tactical-level errors because of impaired hazard perception. Patients with other dementia etiologies involving motor symptoms may suffer from problems on the operational level. Still, the effects of various etiologies of dementias on driving have thus far not been studied thoroughly. For the detection of driving difficulties in patients with dementia, structured interviews with patients but also their family members appear crucial. Neuropsychological assessment could support the identification of cognitive impairments. The impact of such impairments on driving could also be investigated in a driving simulator. In a driving simulator, strengths and weaknesses in driving behavior can be observed. With this knowledge, patients can be advised appropriately about their fitness to drive and options for support in driving (e.g., compensation techniques, car adaptations). However, as long as no valid, reliable, and widely accepted test battery is available for the assessment of fitness to drive, costly on-road test rides are inevitable. The development of a fitness-to-drive test battery for patients with dementia could provide an alternative for these on-road test rides, on condition that differences between dementia etiologies are taken into consideration.


Nigella Sativa Oil Protects the Rat Ovary from Oxidative Injury Due to Ischemia-Reperfusion.
BACKGROUND The aim of this study was to evaluate the effects of Nigella sativa (N. sativa) oil (NSO) on ovarian oxidative damage following ischemia-reperfusion injury, using a rat model of ovarian torsion. MATERIAL AND METHODS Forty-eight female albino Wistar rats were divided into six groups: (Group 1) laparotomy only; (Group 2) intraperitoneal NSO (2 ml/kg), 1 hour following laparotomy; (Group 3) 3 hours of ovarian ischemia; (Group 4) 3 hours of ovarian ischemia followed by 3 hours of reperfusion; (Group 5) 3 hours of ovarian ischemia and 2 ml/kg of NSO 1 hour before laparotomy; (Group 6) 3 hours of reperfusion after 3 hours of ovarian ischemia and 2 ml/mg of NSO 1 hour before laparotomy. RESULTS The antioxidant status, ceruloplasmin level, native thiol, total thiol, and disulfide levels of the control group (Group 1) were significantly increased compared with the ovarian ischemia-reperfusion group treated with NSO (Group 6) (p=0.003, p=0.002, p=0.006, p=0.001 and p=0.003, respectively); these levels in the ovarian ischemia group (Group 3) and ischemia-reperfusion group (Group 4) were statistically similar to those of the ovarian ischemia + NSO group (Group 5) and ovarian ischemia-reperfusion + NSO group (Group 6). CONCLUSIONS In this preliminary rat study, administration of NSO shortly after the onset of ovarian ischemia-reperfusion injury, did not significantly reduce levels of markers of oxidative injury. Further studies are required to evaluate the ovarian changes at the tissue level, and to determine the optimum dose of NSO.


Utility of Rapid On-Site Cytologic Evaluation during Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Malignant and Nonmalignant Disease.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an accurate procedure to sample mediastinal tissue. Rapid on-site cytologic evaluation (ROSE) has been advocated to improve the performance of this procedure, but its benefit remains controversial. Our objective is to assess the utility of ROSE for EBUS-TBNA diagnostic accuracy among unselected patients. We prospectively collected data from all consecutive EBUS-TBNA procedures performed between 2008 and 2014. ROSE was introduced since 2011 in our daily practice. The accuracy of EBUS-TBNA with and without ROSE was compared in a univariate and multivariate model accounting for confounding factors. The impact of ROSE was then analyzed according to the etiology and size of the lesions. Among 348 EBUS-TBNA procedures analyzed, 213 were performed with ROSE. The overall accuracy tended to be better with ROSE than without (90.6 vs. 84.4%; p = 0.082). After adjustment in a multivariate model, the benefit of ROSE still did not reach statistical significance (adjusted odds ratio 1.86; 95% confidence interval 0.79-4.41). Similar results were obtained in subgroups of patients with malignant disease or sarcoidosis. The size of the lesion did not influence the impact of ROSE on accuracy. ROSE was associated with a moderate increase in the accuracy of EBUS-TBNA, but the difference was not statistically significant. The same effect of ROSE was observed in malignant and nonmalignant lesions and this effect was not influenced by the lesion's size.


Patient-caregiver concordance in symptom assessment and improvement in outcomes for patients undergoing cancer chemotherapy.
To measure the agreement between cancer patients' and family caregivers' perceptions of the patients' symptom severity, and the association between changes in caregiver accuracy and changes in outcomes. Secondary analysis of baseline and 10-week follow-up data from 142 cancer patient/caregiver dyads. Patient/caregiver agreement about symptom burden was measured for the 8 most prevalent symptoms and overall. Bivariate analyses examined the patient and caregiver characteristics associated with caregivers who were overestimators, underestimators or accurate at baseline. We tested the relationship between change in caregiver accuracy and both caregiver behaviour (e.g. use of information, hours spent caregiving) and patient outcomes (e.g. total symptom severity and frequency). At baseline, caregivers overestimated the severity of 17 out of 18 symptoms; 50% predicted mean symptom severity accurately. Accuracy worsened over time for 51%, stayed the same for 36%, and improved for 13%. While not statistically significant, caregivers whose accuracy improved over time had patients who reported greater declines in: symptom severity, number of symptoms, symptom interference, total symptom frequency and depression. In addition, these caregivers experienced greater reductions in their use of information and hours helping the patient. Caregivers typically over-estimate cancer patients' symptom burden and accuracy does not improve over time. Improving caregiver accuracy may boost the positive effects of cognitive behavioural interventions designed to improve cancer patients' quality of life.


Paediatric tracheostomy: A modified technique and its outcomes, results from a South Indian tertiary care.
To review the key parameters related to the proposed modified pediatric tracheostomy technique with to determine the efficacy, safety and outcomes in a tertiary hospital in south India. Patients and Methods A retrospective chart review of all children aged below 16 years who underwent tracheostomy at a tertiary hospital in south India during the period of August 2014 to August 2016. Data on age, gender, indication for tracheostomy, primary disease condition, duration of intubation, complications and decannulation rate were recorded. Fifty children aged below 16 years underwent tracheostomy between August 2014 and August 2016. The average of the children was 5.35 years. (Range14 days to 14 years). The male female ratio was 1.6:1. In our study prolonged intubation was the most common indication (62%). None of the children had early post-operative complications such as bleeding, pneumothorax, surgical emphysema or accidental decannulation. Peristomal granulations (24%) was the most common complication although none was severe to warrant operative intervention. One child had a lifethreatening tube block requiring cardiopulmonary resuscitation. None of the children had accidental decannulation during the period of the study. Tracheocutaneous fistula was seen in 2 children (4%) and was the only long-term complication. These children required surgical decannulation. There was no clinical evidence of tracheal stenosis or tracheomalacia in any child. Pediatric tracheostomy is challenging for both the surgeon and the care-giver specially in the early post-operative period. Our proposed modified technique addresses these concerns and without any significant complications.


BayesMendel: an R environment for Mendelian risk prediction.
Several important syndromes are caused by deleterious germline mutations of individual genes. In both clinical and research applications it is useful to evaluate the probability that an individual carries an inherited genetic variant of these genes, and to predict the risk of disease for that individual, using information on his/her family history. Mendelian risk prediction models accomplish these goals by integrating Mendelian principles and state-of-the-art statistical models to describe phenotype/genotype relationships. Here we introduce an R library called BayesMendel that allows implementation of Mendelian models in research and counseling settings. BayesMendel is implemented in an object-oriented structure in the language R and distributed freely as an open source library. In its first release, it includes two major cancer syndromes: the breast-ovarian cancer syndrome and the hereditary non-polyposis colorectal cancer syndrome, along with up-to-date estimates of penetrance and prevalence for the corresponding genes. Input genetic parameters can be easily modified by users. BayesMendel can also serve as a generic tool for genetic epidemiologists to flexibly implement their own Mendelian models for novel syndromes and local subpopulations, without reprogramming complex statistical analyses and prediction tools.


Phosphorylation variation during the cell cycle scales with structural propensities of proteins.
Phosphorylation at specific residues can activate a protein, lead to its localization to particular compartments, be a trigger for protein degradation and fulfill many other biological functions. Protein phosphorylation is increasingly being studied at a large scale and in a quantitative manner that includes a temporal dimension. By contrast, structural properties of identified phosphorylation sites have so far been investigated in a static, non-quantitative way. Here we combine for the first time dynamic properties of the phosphoproteome with protein structural features. At six time points of the cell division cycle we investigate how the variation of the amount of phosphorylation correlates with the protein structure in the vicinity of the modified site. We find two distinct phosphorylation site groups: intrinsically disordered regions tend to contain sites with dynamically varying levels, whereas regions with predominantly regular secondary structures retain more constant phosphorylation levels. The two groups show preferences for different amino acids in their kinase recognition motifs - proline and other disorder-associated residues are enriched in the former group and charged residues in the latter. Furthermore, these preferences scale with the degree of disorderedness, from regular to irregular and to disordered structures. Our results suggest that the structural organization of the region in which a phosphorylation site resides may serve as an additional control mechanism. They also imply that phosphorylation sites are associated with different time scales that serve different functional needs.


G protein-coupled signal transduction pathways for interleukin-8.
Interleukin-8 (IL-8) is one of the major mediators of the inflammatory response. The pathways by which IL-8 activates inositide-specific phospholipase C (PLC) were investigated by co-expression of different components of the guanosine triphosphate binding protein (G protein) pathway in COS-7 cells. Two distinct IL-8 receptors reconstituted ligand-dependent activation of endogenous PLC when transfected together with the G protein alpha subunits G alpha 14, G alpha 15, or G alpha 16. However, reconstitution was not observed with cells that overexpressed G alpha q or G alpha 11. Furthermore, IL-8 receptors interacted with endogenous pertussis toxin-sensitive G proteins or with the recombinant G protein Gi to release free beta gamma subunits that could then specifically activate the beta 2 isoform of PLC. These findings suggest that IL-8 acts through signal-transducing pathways that are limited to specific heterotrimeric G proteins and effectors. These may provide suitable targets for the development of anti-inflammatory agents.


Resting potential-dependent regulation of the voltage sensitivity of sodium channel gating in rat skeletal muscle in vivo.
Normal muscle has a resting potential of -85 mV, but in a number of situations there is depolarization of the resting potential that alters excitability. To better understand the effect of resting potential on muscle excitability we attempted to accurately simulate excitability at both normal and depolarized resting potentials. To accurately simulate excitability we found that it was necessary to include a resting potential-dependent shift in the voltage dependence of sodium channel activation and fast inactivation. We recorded sodium currents from muscle fibers in vivo and found that prolonged changes in holding potential cause shifts in the voltage dependence of both activation and fast inactivation of sodium currents. We also found that altering the amplitude of the prepulse or test pulse produced differences in the voltage dependence of activation and inactivation respectively. Since only the Nav1.4 sodium channel isoform is present in significant quantity in adult skeletal muscle, this suggests that either there are multiple states of Nav1.4 that differ in their voltage dependence of gating or there is a distribution in the voltage dependence of gating of Nav1.4. Taken together, our data suggest that changes in resting potential toward more positive potentials favor states of Nav1.4 with depolarized voltage dependence of gating and thus shift voltage dependence of the sodium current. We propose that resting potential-induced shifts in the voltage dependence of sodium channel gating are essential to properly regulate muscle excitability in vivo.


Multi-isotype Glycoproteomic Characterization of Serum Antibody Heavy Chains Reveals Isotype- and Subclass-Specific N-Glycosylation Profiles.
Antibodies are critical glycoproteins that bridge the innate and adaptive immune systems to provide protection against infection. The isotype/subclass of the antibody, the co-translational N-glycosylation on the CH2 domain, and the remodeling of the N-linked glycans during passage through the ER and Golgi are the known variables within the Fc domain that program antibody effector function. Through investigations of monoclonal therapeutics, it has been observed that addition or removal of specific monosaccharide residues from antibody N-glycans can influence the potency of antibodies, highlighting the importance of thoroughly characterizing antibody N-glycosylation. Although IgGs usually have a single N-glycosylation site and are well studied, other antibody isotypes, e.g. IgA and IgM, that are the first responders in certain diseases, have two to five sites/monomer of antibody, and little is known about their N-glycosylation. Here we employ a nLC-MS/MS method using stepped-energy higher energy collisional dissociation to characterize the N-glycan repertoire and site occupancy of circulating serum antibodies. We simultaneously determined the site-specific N-linked glycan repertoire for IgG1, IgG4, IgA1, IgA2, and IgM in individual healthy donors. Compared with IgG1, IgG4 displayed a higher relative abundance of G1S1F and a lower relative abundance of G1FB. IgA1 and IgA2 displayed mostly biantennary N-glycans. IgA2 variants with the either serine (S93) or proline (P93) were detected. In digests of the sera from a subset of donors, we detected an unmodified peptide containing a proline residue at position 93; this substitution would strongly disfavor N-glycosylation at N92. IgM sites N46, N209, and N272 displayed mostly complex glycans, whereas sites N279 and N439 displayed higher relative abundances of high-mannose glycoforms. This multi-isotype approach is a crucial step toward developing a platform to define disease-specific N-glycan signatures for different isotypes to help tune antibodies to induce protection. Data are available via ProteomeXchange with identifier PXD010911.


A universal genomic coordinate translator for comparative genomics.
Genomic duplications constitute major events in the evolution of species, allowing paralogous copies of genes to take on fine-tuned biological roles. Unambiguously identifying the orthology relationship between copies across multiple genomes can be resolved by synteny, i.e. the conserved order of genomic sequences. However, a comprehensive analysis of duplication events and their contributions to evolution would require all-to-all genome alignments, which increases at N2 with the number of available genomes, N. Here, we introduce Kraken, software that omits the all-to-all requirement by recursively traversing a graph of pairwise alignments and dynamically re-computing orthology. Kraken scales linearly with the number of targeted genomes, N, which allows for including large numbers of genomes in analyses. We first evaluated the method on the set of 12 Drosophila genomes, finding that orthologous correspondence computed indirectly through a graph of multiple synteny maps comes at minimal cost in terms of sensitivity, but reduces overall computational runtime by an order of magnitude. We then used the method on three well-annotated mammalian genomes, human, mouse, and rat, and show that up to 93% of protein coding transcripts have unambiguous pairwise orthologous relationships across the genomes. On a nucleotide level, 70 to 83% of exons match exactly at both splice junctions, and up to 97% on at least one junction. We last applied Kraken to an RNA-sequencing dataset from multiple vertebrates and diverse tissues, where we confirmed that brain-specific gene family members, i.e. one-to-many or many-to-many homologs, are more highly correlated across species than single-copy (i.e. one-to-one homologous) genes. Not limited to protein coding genes, Kraken also identifies thousands of newly identified transcribed loci, likely non-coding RNAs that are consistently transcribed in human, chimpanzee and gorilla, and maintain significant correlation of expression levels across species. Kraken is a computational genome coordinate translator that facilitates cross-species comparisons, distinguishes orthologs from paralogs, and does not require costly all-to-all whole genome mappings. Kraken is freely available under LPGL from http://github.com/nedaz/kraken.


Integrated risk and recovery monitoring of ecosystem restorations on contaminated sites.
Ecological restorations of contaminated sites balance the human and ecological risks of residual contamination with the benefits of ecological recovery and the return of lost ecological function and ecosystem services. Risk and recovery are interrelated dynamic conditions, changing as remediation and restoration activities progress through implementation into long-term management and ecosystem maturation. Monitoring restoration progress provides data critical to minimizing residual contaminant risk and uncertainty, while measuring ecological advancement toward recovery goals. Effective monitoring plans are designed concurrently with restoration plan development and implementation and are focused on assessing the effectiveness of activities performed in support of restoration goals for the site. Physical, chemical, and biotic measures characterize progress toward desired structural and functional ecosystem components of the goals. Structural metrics, linked to ecosystem functions and services, inform restoration practitioners of work plan modifications or more substantial adaptive management actions necessary to maintain desired recovery. Monitoring frequency, duration, and scale depend on specific attributes and goals of the restoration project. Often tied to restoration milestones, critical assessment of monitoring metrics ensures attainment of risk minimization and ecosystem recovery. Finally, interpretation and communication of monitoring findings inform and engage regulators, other stakeholders, the scientific community, and the public. Because restoration activities will likely cease before full ecosystem recovery, monitoring endpoints should demonstrate risk reduction and a successional trajectory toward the condition established in the restoration goals. A detailed assessment of the completed project's achievements, as well as unrealized objectives, attained through project monitoring, will determine if contaminant risk has been minimized, if injured resources have recovered, and if ecosystem services have been returned. Such retrospective analysis will allow better planning for future restoration goals and strengthen the evidence base for quantifying injuries and damages at other sites in the future.


Inflammasome-mediated secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids.
Many studies have shown that TLR4- and TLR2-deficient mice are protected from high-fat diet-induced inflammation and insulin resistance, suggesting that saturated fatty acids derived from the high-fat diet activate TLR-mediated proinflammatory signaling pathways and induce insulin resistance. However, evidence that palmitic acid, the major dietary saturated fatty acid, can directly activate TLR has not been demonstrated. In this article, we present multiple lines of evidence showing that palmitic acid directly activates TLR2, a major TLR expressed on human monocytes, by inducing heterodimerization with TLR1 in an NADPH oxidase-dependent manner. Dimerization of TLR2 with TLR1 was inhibited by the n-3 fatty acid docosahexaenoic acid. Activation of TLR2 by palmitic acid leads to expression of pro-IL-1β that is cleaved by caspase-1, which is constitutively present in monocytes, to release mature IL-1β. Our results reveal mechanistic insight about how palmitic acid activates TLR2, upregulates NALP3 expression, and induces inflammasome-mediated IL-1β production in human monocytes, which can trigger enhanced inflammation in peripheral tissues, and suggest that these processes are dynamically modulated by the types of dietary fat we consume.


A direct comparison of errorless and errorful therapy for object name relearning in Alzheimer's disease.
Developing rehabilitation techniques to combat cognitive decline is a key goal of healthcare strategies aimed at promoting increased longevity and better quality of life for individuals with Alzheimer's disease (AD). In AD, problems with episodic memory and word-finding greatly affect everyday life and, as such, these symptoms provide a clear clinical target for therapeutic interventions. Errorless learning (EL) has been proposed as a particularly effective technique for relearning in individuals with memory dysfunction, including AD. However, EL learning has rarely been directly contrasted with other more traditional trial-and-error techniques (errorful learning or EF) in individuals with AD, especially in the context of alleviating word-finding problems. In the current study, we directly contrasted the therapeutic gains of an EL learning paradigm (consisting of reading/repetition of object names) with an EF learning technique (comprised of phonemic/orthographic cueing) in eight mild to moderate AD patients with pronounced anomia. Both techniques were administered concurrently in sessions run twice a week over a five-week period. Therapeutic gains were assessed at one week and five weeks post-intervention using confrontation naming. Our results suggest that, both at the group and individual patient level, EL and EF techniques were equally effective. Correlational analyses of overall therapy gains and background assessments of patient neuropsychology revealed that individuals with better scores on measures of semantic memory, pre-intervention naming, and recognition memory demonstrated larger therapy gains. No individual patient showed a significant advantage for EL over EF learning, however, for patients that showed a numerical advantage in this direction. These results suggest that either EL or EF therapy can be used to alleviate word-finding problems in AD.


A Psycho-Behavioral Perspective on Modelling Obsessive-Compulsive Disorder (OCD) in Animals: The Role of Context.
Obsessive-compulsive disorder is a heterogeneous and debilitating condition, characterized by intrusive thoughts and compulsive repetition. Animal models of OCD are important tools that have the potential to contribute significantly to our understanding of the condition. Although there is consensus that pre-clinical models are valuable in elucidating the underlying neurobiology in psychiatric disorders, the current paper attempts to prompt ideas on how interpretation of animal behavior can be expanded upon to more effectively converge with the human disorder. Successful outcomes in psychopharmacology involve rational design and synthesis of novel compounds and their testing in well-designed animal models. As part of a special journal issue on OCD, this paper will 1) review the psychobehavioral aspects of OCD that are of importance on how the above ideas can be articulated, 2) briefly elaborate on general issues that are important for the development of animal models of OCD, with a particular focus on the role and importance of context, 3) propose why translational progress may often be less than ideal, 4) highlight some of the significant contributions afforded by animal models to advance understanding, and 5) conclude by identifying novel behavioral constructs for future investigations that may contribute to the face, predictive and construct validity of OCD animal models. We base these targets on an integrative approach to face and construct validity, and note that the issue of treatment-resistance in the clinical context should receive attention in current animal models of OCD.


High efficiency solid-state sensitized solar cell-based on submicrometer rutile TiO2 nanorod and CH3NH3PbI3 perovskite sensitizer.
We report a highly efficient solar cell based on a submicrometer (~0.6 μm) rutile TiO2 nanorod sensitized with CH3NH3PbI3 perovskite nanodots. Rutile nanorods were grown hydrothermally and their lengths were varied through the control of the reaction time. Infiltration of spiro-MeOTAD hole transport material into the perovskite-sensitized nanorod films demonstrated photocurrent density of 15.6 mA/cm(2), voltage of 955 mV, and fill factor of 0.63, leading to a power conversion efficiency (PCE) of 9.4% under the simulated AM 1.5G one sun illumination. Photovoltaic performance was significantly dependent on the length of the nanorods, where both photocurrent and voltage decreased with increasing nanorod lengths. A continuous drop of voltage with increasing nanorod length correlated with charge generation efficiency rather than recombination kinetics with impedance spectroscopic characterization displaying similar recombination regardless of the nanorod length.