The National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC): results from phase I and scientific opportunities in phase II.
Genetically triggered thoracic aortic conditions (GenTACs) represent an important problem for patients and their families. Accordingly, the National Heart, Lung, and Blood Institute established the first phase of its national GenTAC Registry in 2006. Between 2007 and 2010, 6 enrolling centers established the GenTAC I Registry consisting of 2,046 patients (Marfan syndrome 576 [28.2%], bicuspid aortic valve disease 504 [24.6%], aneurysm or dissection age <50 years 369 [18%], and others). Biologic samples for DNA analyses (white blood cells or saliva) are available in 97%, and stored plasma is available in 60% of enrollees. Initial scientific inquiry using the GenTAC Registry has included validation studies of genetic causes for aortic syndromes, potential usefulness of transforming growth factor beta (TGFB) blood levels in Marfan subjects, and current surgical approaches to ascending aortic conditions. The second phase of GenTAC will allow biannual follow-up of GenTAC I enrollees for up to 9 years, enrollment of an additional 1,500 subjects, further integration of imaging findings with clinical and genetic data through utilization of an imaging core laboratory, important validation of phenotype-genotype correlations through a phenotyping core laboratory, and integration of a scientific advisory committee to help define the full range and depth of the Registry's scientific capabilities. The registry resources are available to the external scientific community through an application process accessible at https://gentac.rti.org.


Production of Bright Greenish Yellow Fluorescence in Figs Infected by Aspergillus Species in California Orchards.
The relationship of bright greenish yellow fluorescence (BGYF) of dried figs under longwave UV light to colonization by Aspergillus fungi was determined. BGYF in naturally infected figs was associated with decay by only four fungal species: the aflatoxin-producing species Aspergillus flavus (both L and S strains) and A. parasiticus, and the aflatoxin nonproducers A. tamarii and A. alliaceus. BGYF was more likely to be visible internally (after cutting open the fig) than externally. For all four species associated with BGYF, some infected figs did not show BGYF. The absence of fluorescence is probably not associated with the fungal strain or isolate involved, since isolating Aspergillus spp. from nonfluorescent figs followed by inoculating other figs with these isolates resulted in BGYF. Many of the nonfluorescent figs had small fungal colonies (<7 mm in diameter), even though some figs with large colonies were also nonfluorescent. The additional colonization of figs by other fungi did not affect the occurrence of BGYF in figs colonized by fungi in Aspergillus section Flavi. Figs infected with A. flavus or A. parasiticus and showing no BGYF were occasionally contaminated with aflatoxin, while other figs showing BGYF and infected with A. flavus or A. tamarii had no aflatoxins. Although not as promising as originally hoped, BGYF might be of use to remove aflatoxin-contaminated figs for certain specific situations in California.


Effects of prescribed fire and post-fire rainfall on mercury mobilization and subsequent contamination assessment in a legacy mine site in Victoria, Australia.
Prescribed fire conducted in fire-prone areas is a cost-effective choice for forest management, but it also affects many of the physicochemical and bio-geological properties of the forest soil, in a similar manner to wild fires. The aim of this study is to investigate the nature of the mercury mobilization after a prescribed fire and the subsequent temporal changes in concentration. A prescribed fire was conducted in a legacy mine site in Central Victoria, Australia, in late August 2015 and soil sample collection and analyses were carried out two days before and two days after the fire, followed by collection at the end of each season and after an intense rainfall event in September 2016. Results revealed the occurrence of mercury volatilization (8.3-97%) during the fire, and the mercury concentration displayed a significant difference (p < 0.05) before and immediately after the fire. Integrated assessment with number of pollution indices has shown that the study site is extremely contaminated with mercury during all the sampling events, and this poses a serious ecological risk due to the health impacts of mercury on human and ecosystems. In times of climate fluctuation with concomitant increase in forest fire (including prescribed fire), and subsequent precipitation and runoff, the potential for an increased amount of mercury being mobilized is of heighted significance. Therefore, it is recommended that prescribed fire should be cautiously considered as a forest management strategy in any mercury affected landscapes.


Seafood Consumption, Omega-3 Fatty Acids Intake, and Life-Time Prevalence of Depression in the PREDIMED-Plus Trial.
The aim of this analysis was to ascertain the type of relationship between fish and seafood consumption, omega-3 polyunsaturated fatty acids (ω-3 PUFA) intake, and depression prevalence. Cross-sectional analyses of the PREDIMED-Plus trial. Fish and seafood consumption and ω-3 PUFA intake were assessed through a validated food-frequency questionnaire. Self-reported life-time medical diagnosis of depression or use of antidepressants was considered as outcome. Depressive symptoms were collected by the Beck Depression Inventory-II. Logistic regression models were used to estimate the association between seafood products and ω-3 PUFA consumption and depression. Multiple linear regression models were fitted to assess the association between fish and long-chain (LC) ω-3 PUFA intake and depressive symptoms. Out of 6587 participants, there were 1367 cases of depression. Total seafood consumption was not associated with depression. The odds ratios (ORs) (95% confidence intervals (CIs)) for the 2nd, 3rd, and 4th quintiles of consumption of fatty fish were 0.77 (0.63⁻0.94), 0.71 (0.58⁻0.87), and 0.78 (0.64⁻0.96), respectively, and p for trend = 0.759. Moderate intake of total LC ω-3 PUFA (approximately 0.5⁻1 g/day) was significantly associated with a lower prevalence of depression. In our study, moderate fish and LC ω-3 PUFA intake, but not high intake, was associated with lower odds of depression suggesting a U-shaped relationship.


Is medical therapy still the optimal treatment strategy for patients with acute type B aortic dissections?
The optimal treatment of patients with acute type B dissections continues to be debated. A 36-year clinical experience of medical and surgical treatments in 189 patients was retrospectively analyzed (multivariable Cox proportional hazards model) with respect to three outcome end points: all deaths, freedom from reoperation, and freedom from late aortic complications or death. Propensity score analysis identified 2 quintiles (quintiles I and II, consisting of 142 comparable patients) for further comparison of the effects of surgical versus medical treatment. Shock (hazard ratio 14.5, 95% confidence interval 4.7-44.5, P <.001) and visceral ischemia (hazard ratio 10.9, 95% confidence interval 3.9-30.3, P <.001) largely predominated as determinants of death, along with 6 other risk factors (arch involvement, rupture, stroke, previous sternotomy, and coronary or lung disease), which roughly doubled the hazard of death. Female sex was a significant but weaker predictor of death. Renal dysfunction, year of presentation, age, and mode of therapy (medical vs surgical) had no important bearing on overall survival. The actuarial survival estimates for all patients were 71%, 60%, 35%, and 17% at 1, 5, 10, and 15 years, respectively, and were similar for the medical and surgical patients. Reoperation and late aortic complications were predicted by the presence of Marfan syndrome. For the propensity-matched patients in quintiles I and II, survival, freedom from reoperation, and freedom from aortic complications were almost identical in the medically treated and surgical subsets. The prognosis for patients with acute type B aortic dissection is bleak and determined primarily by dissection-related and patient-specific risk factors, which do not appear to be readily modifiable.


Attenuation of myocardial apoptosis by alpha-lipoic acid through suppression of mitochondrial oxidative stress to reduce diabetic cardiomyopathy.
Cardiac failure is a leading cause of the mortality of diabetic patients. In part this is due to a specific cardiomyopathy, referred to as diabetic cardiomyopathy. Oxidative stress is widely considered to be one of the major factors underlying the pathogenesis of the disease. This study aimed to test whether the antioxidant alpha-lipoic acid (alpha-LA) could attenuate mitochondrion-dependent myocardial apoptosis through suppression of mitochondrial oxidative stress to reduce diabetic cardiomyopathy. A rat model of diabetes was induced by a single tail intravenous injection of streptozotocin (STZ) 45 mg/kg. Experimental animals were randomly assigned to 3 groups: normal control (NC), diabetes (DM) and DM treated with alpha-LA (alpha-LA). The latter group was administered with alpha-LA (100 mg/kg ip per day), the remainder received the same volume vehicle. At weeks 4, 8, and 12 after the onset of diabetes, cardiac apoptosis was examined by TUNEL assay. Cardiomyopathy was evaluated by assessment of cardiac structure and function. Oxidative damage was evaluated by the content of malondialdehyde (MDA), reduced glutathione (GSH) and the activity of manganese superoxide diamutase (Mn-SOD) in the myocardial mitochondria. Expression of caspase-9 and caspase-3 proteins was determined by immunohistochemistry and mitochondrial cytochrome c release was detected by Western blotting. At 4, 8, and 12 weeks after the onset of diabetes, significant reductions in TUNEL-positive cells, caspase-9,-3 expression, and mitochondrial cytochrome c release were observed in the alpha-LA group compared to the DM group. In the DM group, the content of MDA in the myocardial mitochondria was significantly increased, and there was a decrease in both the mitochondrial GSH content and the activities of Mn-SOD. They were significantly improved by alpha-LA treatment. HE staining displayed structural abnormalities in diabetic hearts, while alpha-LA reversed this structural derangement. The index of cardiac function (+/-dp/dtmax) in the diabetes group was aggravated progressively from 4 weeks to 12 weeks, but alpha-LA delayed deterioration of cardiac function (P < 0.05). Our findings indicate that the antioxidant alpha-LA can effectively attenuate mitochondria-dependent cardiac apoptosis and exert a protective role against the development of diabetic cardiomyopathy. The ability of alpha-LA to suppress mitochondrial oxidative damage is concomitant with an enhancement of Mn-SOD activity and an increase in the GSH content of myocardial mitochondria.


Interplay of Chemical and Electronic Structure on the Single-Molecule Level in 2D Polymerization.
Single layers of covalently linked organic materials in the form of two-dimensional (2D) polymers constitute structures complementary to inorganic 2D materials. The electronic properties of 2D polymers may be manipulated through a deliberate choice of the organic precursors. Here we address the changes in electronic structure-from precursor molecule to oligomer-by scanning tunneling spectroscopy and ultraviolet photoelectron spectroscopy. For this purpose, we introduce the polymerization reaction of 1,3,5-tris(4-carboxyphenyl)benzene via decarboxylation on Cu(111), which is thoroughly characterized by scanning tunneling microscopy, X-ray photoelectron spectroscopy, and density functional theory calculations. We present a comprehensive study of a contamination-free on-surface coupling scheme and study how dehydrogenation, decarboxylation, and polymerization affect the electronic structure on the molecular level.


Current Approaches and Trends in Graduate Public Health Informatics Education in the United States: Four Case Studies from the Field.
Background:Public Health Informatics (PHI) has taken on new importance in recent years as health and well-being face a number of challenges, including environmental disasters, emerging infectious diseases, such as Zika, Ebola and SARS-CoV-2, the growing impact of the Influenza virus, the opioid epidemic, and social determinants of health. Understanding the relationship between climate change and the health of populations adds further complexity to global health issues. Objectives: To describe four examples of curricula that exist in U.S. based graduate-level public and population health informatics training programs. Methods: Biomedical informatics educators are challenged to provide learners with relevant, interesting, and meaningful educational experiences in working with and learning from the many data sources that comprise the domain of PHI. Programs at four institutions were reviewed to examine common teaching practices that stimulate learners to explore the field of public health informatics. Results: Four case studies represent a range of pedagogical approaches to meeting the requirements of three established accreditation/certification agencies relevant to PHI education. Despite their differences, each program achieved the established learning objectives along with a substantive record of student learning achievements. Conclusion: The overarching goal of empowering learners to serve an active and dynamic role in enhancing preventive measures, informing policy, improving personal health behaviors, and clarifying issues such as quality, cost of care, and the social determinants of health, are essential components of PHI education and training, and must receive additional consideration now and in the future by educators, policy makers, administrators, and government officials.


Treatment of T1b glottic SCC: laser vs. radiation--a Canadian multicenter study.
To assess the oncological and functional outcomes of T1b squamous cell carcinoma (SCC) of the glottic larynx treated with laser in comparison with radiation. A Canadian multicenter cohort study. Three tertiary referral centers for head and neck cancer- Dalhousie University in Halifax, Nova Scotia, Western University in London, Ontario and the University of Manitoba, Winnipeg. Patients with T1b glottic SCC who underwent transoral laser resection or radiation as the primary modality of treatment. Oncological outcomes were evaluated using local control, laryngeal preservation, disease free survival and disease specific survival. Voice outcomes were assessed using the Voice Handicap Index-10 (VHI-10). 63 patients met study criteria. 21 were treated with laser and 42 with radiation. Oncologic outcomes at 2 years for laser and radiation demonstrated local control of 95% and 85.9%; laryngeal preservation of 100% and 85.9%; disease free survival of 88.7% and 85.9% and overall survival of 94.1% and 94.8% respectively. VHI-10 data was available for 23/63 patients. During the last follow up visit VHI-10 ranged from 0 to 11 (median 6) in the laser group and 0 to 34 (median 7) in the radiation group. T1b SCC of the glottis can be effectively treated with transoral laser microsurgery with oncological outcomes that are at least equivalent to radiation. For patients with VHI scores, voice quality was similar between the two groups. To our knowledge this is the first study directly comparing the oncologic and voice outcomes with laser and radiation for the treatment of glottic cancer involving the anterior commissure.


Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture.
To examine the effects of methylcobalamin on glutamate-induced neurotoxicity in the cultured retinal neurons. Primary cultures obtained from the fetal rat retina (gestation days 16 to 19) were used for the experiment. The neurotoxicity was assessed quantitatively using the trypan blue exclusion method. Glutamate neurotoxicity was prevented by chronic exposure to methylcobalamin and S-adenosylmethionine (SAM), which is formed in the metabolic pathway of methylcobalamin. Chronic exposure to methylcobalamin and SAM also inhibited the neurotoxicity induced by sodium nitroprusside that release nitric oxide. By contrast, acute exposure to methylcobalamin did not protect retinal neurons against glutamate neurotoxicity. Chronic administration of methylcobalamin protects cultured retinal neurons against N-methyl-D-aspartate-receptor-mediated glutamate neurotoxicity, probably by altering the membrane properties through SAM-mediated methylation.


Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease.
The promise of Alzheimer's disease biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging measure in Alzheimer's disease and thus represents the most rational target for an initial effort at standardization. The authors of this position paper propose a path toward this goal. The steps include the following: (1) Establish and empower an oversight board to manage and assess the effort, (2) adopt the standardized definition of anatomic hippocampal boundaries on magnetic resonance imaging arising from the European Alzheimer's Disease Centers-Alzheimer's Disease Neuroimaging Initiative hippocampal harmonization effort as a reference standard, (3) establish a scientifically appropriate, publicly available reference standard data set based on manual delineation of the hippocampus in an appropriate sample of subjects (Alzheimer's Disease Neuroimaging Initiative), and (4) define minimum technical and prognostic performance metrics for validation of new measurement techniques using the reference standard data set as a benchmark. Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent was to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry was envisioned as a template that could be applied to other imaging biomarkers.


Nutrient intake of Head Start children: home vs. school.
To determine mean intake of energy and protein, total fat, saturated fat, percent energy from total and saturated fat, cholesterol, carbohydrate, calcium, iron, zinc, folate, vitamins A, C, E, B-6 and B-12, thiamin, niacin, riboflavin, magnesium, sodium and fiber of preschool Head Start children at school and away from school. Twenty-four-hour food intakes for 358 Head Start children were obtained by observing food intake at school and acquiring intake recalls from parents or guardians specifying food their children consumed for the balance of the day. After determining group estimates of energy and nutrient intake, mean intake was compared to standard nutrient recommendations for the entire 24-hour day, i.e., for the time the children were in school and for the remaining hours away from school ("home" intake). The 358 Head Start children attended school either half-day (2- to 3-hour AM and PM sessions) or all-day (5 to 6 hours). Differences in nutrient intake among class times were analyzed using one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test. Differences with a p-value <0.05 (two-tailed) were considered to be statistically significant. Total energy, protein, calcium, iron, zinc, vitamins A, C, E, B6, and B12, thiamin, niacin, riboflavin as well as folate and magnesium were compared to the Recommended Dietary Allowances for the 4- to 6-year-old age group. Other standards that were used for comparisons included the National Cholesterol Education Program (fat, saturated fat and cholesterol), the 1989 National Research Council's Diet and Health Report (carbohydrate and sodium) and the recommendation for fiber proposed by the American Health Foundation. At school, half-day children consumed up to 25% of the daily recommendation for energy and nutrients, while all-day children achieved at least a third of the recommended intakes. When intakes at home and school were combined, all three groups of children (AM, PM and all-day) exceeded dietary recommendations for protein, vitamins and minerals. Energy intake remained below 100% of the recommendation, while intake of total fat, saturated fat and cholesterol exceeded recommendations. Further research is required to explore energy needs and determine nutritional status and nutrient needs of minority and low-income preschool children. Strategies are required to increase nutrient density, but not fat density, of meals and snacks served to children who attend day care for part of the day. Finally, school meals and nutrition education programs such as Team Nutrition should broaden their base to include healthful eating habits for all school children, including the very youngest children in preschool programs.


Single subject research strategies in occupational therapy, part 1.
This paper is designed to orient occupational therapists to the use of single subject methodology as a viable mode of clinical research. The role of single subject designs in today's scientific world is explored through an historical perspective, and major strengths and weaknesses are discussed. Basic methodological concepts and research designs are presented to provide a foundation for therapists interested in documenting intervention results. Finally, some of the problems inherent in transferring single subject strategies to occupational therapy are presented.


ALDH1A3 loss of function causes bilateral anophthalmia/microphthalmia and hypoplasia of the optic nerve and optic chiasm.
The major active retinoid, all-trans retinoic acid, has long been recognized as critical for the development of several organs, including the eye. Mutations in STRA6, the gene encoding the cellular receptor for vitamin A, in patients with Matthew-Wood syndrome and anophthalmia/microphthalmia (A/M), have previously demonstrated the importance of retinol metabolism in human eye disease. We used homozygosity mapping combined with next-generation sequencing to interrogate patients with anophthalmia and microphthalmia for new causative genes. We used whole-exome and whole-genome sequencing to study a family with two affected brothers with bilateral A/M and a simplex case with bilateral anophthalmia and hypoplasia of the optic nerve and optic chiasm. Analysis of novel sequence variants revealed homozygosity for two nonsense mutations in ALDH1A3, c.568A>G, predicting p.Lys190*, in the familial cases, and c.1165A>T, predicting p.Lys389*, in the simplex case. Both mutations predict nonsense-mediated decay and complete loss of function. We performed antisense morpholino (MO) studies in Danio rerio to characterize the developmental effects of loss of Aldh1a3 function. MO-injected larvae showed a significant reduction in eye size, and aberrant axonal projections to the tectum were noted. We conclude that ALDH1A3 loss of function causes anophthalmia and aberrant eye development in humans and in animal model systems.


An update of the WCRF/AICR systematic literature review and meta-analysis on dietary and anthropometric factors and esophageal cancer risk.
In the 2007 World Cancer Research Fund/American Institute for Cancer Research Second Expert Report, the expert panel judged that there was strong evidence that alcoholic drinks and body fatness increased esophageal cancer risk, whereas fruits and vegetables probably decreased its risk. The judgments were mainly based on case-control studies. As part of the Continuous Update Project, we updated the scientific evidence accumulated from cohort studies in this topic. We updated the Continuous Update Project database up to 10 January 2017 by searching in PubMed and conducted dose-response meta-analyses to estimate summary relative risks (RRs) and 95% confidence intervals (CIs) using random effects model. A total of 57 cohort studies were included in 13 meta-analyses. Esophageal adenocarcinoma risk was inversely related to vegetable intake (RR per 100 g/day: 0.89, 95% CI: 0.80-0.99, n = 3) and directly associated with body mass index (RR per 5 kg/m2: 1.47, 95% CI: 1.34-1.61, n = 9). For esophageal squamous cell carcinoma, inverse associations were observed with fruit intake (RR for 100 g/day increment: 0.84, 95% CI: 0.75-0.94, n = 3) and body mass index (RR for 5 kg/m2 increment: 0.64, 95% CI: 0.56-0.73, n = 8), and direct associations with intakes of processed meats (RR for 50 g/day increment: 1.59, 95% CI: 1.11-2.28, n = 3), processed and red meats (RR for 100 g/day increment: 1.37, 95% CI: 1.04-1.82, n = 3) and alcohol (RR for 10 g/day increment: 1.25, 95% CI: 1.12-1.41, n = 6). Evidence from cohort studies suggested a protective role of vegetables and body weight control in esophageal adenocarcinomas development. For squamous cell carcinomas, higher intakes of red and processed meats and alcohol may increase the risk, whereas fruits intake may play a protective role.


Sensory neuron and substance P involvement in symptoms of a zymosan-induced rat model of acute bowel inflammation.
Intestinal inflammation is a painful syndrome with multiple symptoms, including chronic pain. This study examined the possible role of sensory neurons and substance P in symptoms of an animal model of acute intestinal inflammation. The model was induced by injecting ethanol and zymosan into the colon of anesthetized male rats. Three hours later, sections of the colon were stained with hematoxylin and eosin. To determine the role of substance P, 5 mg/kg of the neurokinin-1 receptor (NK-1r) antagonist, CP-96,345, or 300 microg/kg of an antisense oligonucleotide targeted at NK-1r mRNA was administered. Spinal cord sections were examined for internalization of NK-1r, as an indicator of substance P release. Sections of colon revealed infiltration of inflammatory cells following ethanol and zymosan treatment. Plasma extravasation in rats given ethanol and zymosan was significantly greater than in controls given saline only (P<0.0001) or saline and ethanol (P<0.001). In ethanol- and zymosan-treated rats given CP-96,345, plasma extravasation was significantly less than in rats given ethanol and zymosan without the antagonist (P<0.0001). Administration of the antisense oligonucleotide also resulted in lower levels of plasma extravasation compared with controls (P<0.01). Internalization of the NK-1r was observed in neurons of lamina I in the T13-L2 and L6-S2 regions of the spinal cord, as well as in sympathetic preganglionic neurons at the L1 level. This internalization was observed in the absence of any other stimulus besides the inflammation itself. This study implicates substance P and its receptor, the NK-1r, in acute inflammation of the colon.


Functions of base selection step in human DNA polymerase alpha.
Recent studies have revealed that the base selection step of DNA polymerases (pol) plays a role in prevention of DNA replication errors. We investigated whether base selection is required for the DNA replication fidelity of pol alpha and genomic stability in human cells. We introduced an Leu864 to Phe substitution (L864F) into human pol alpha and performed an in vitro LacZ alpha forward mutation assay. Our results showed that the overall mutation rate was increased by 180-fold as compared to that of the wild-type. Furthermore, steady state kinetics analyses consistently showed that L864F pol alpha had a decreased discrimination ability between correct and incorrect nucleotide incorporation, as well as between matched and mismatched primer termini. L864F pol alpha also exhibited increased translesion activity over the abasic, etheno-A, O(4)-methyl-T, and O(6)-methyl-G sites. In addition, our steady state kinetics analyses supported the finding of increased translesion activity of L864F pol alpha over O(6)-methyl-G. We also established stable clones transfected with pola1L864F utilizing the human cancer cell line HCT116. Using the HPRT gene as a reporter, the spontaneous mutation rate of pola1L864F cells was determined to be 2.4-fold greater than that of wild-type cells. Mutation assays were also carried out using cells transiently transfected with the wild-type or pola1L864F, and increased mutant frequencies were observed in pola1L864F cells under both spontaneous and methyl methanesulfonate-induced conditions. Together, our results indicate that the base selection step in human pol alpha functions to prevent DNA replication errors and maintain genomic integrity in HCT116 cells.


Commuting by public transit and physical activity: where you live, where you work, and how you get there.
Most public transit users walk to and from transit. We analyzed the relationship between transit commuting and objectively measured physical activity. Adults aged 20 to 65 working outside the home (n = 1237) were randomly selected from neighborhoods in Seattle and Baltimore regions. Neighborhoods had high or low median income and high or low mean walkability. Mean daily minutes of accelerometer-measured moderate-intensity physical activity (MPA) were regressed on frequency of commuting by transit and neighborhood walkability, adjusting for demographic factors and enjoyment of physical activity. Interaction terms and stratification were used to assess moderating effect of walkability on the relation between transit commuting and MPA. Associations between transit commuting and self-reported days walked to destinations near home and work were assessed using Chi Square tests. Regardless of neighborhood walkability, those commuting by transit accumulated more MPA (approximately 5 to 10 minutes) and walked more to services and destinations near home and near the workplace than transit nonusers. Enjoyment of physical activity was not associated with more transit commute, nor did it confound the relationships between MPA and commuting. Investments in infrastructure and service to promote commuting by transit could contribute to increased physical activity and improved health.


The Need for Head Space: Brachycephaly and Cerebrospinal Fluid Disorders.
Brachycephalic dogs remain popular, despite the knowledge that this head conformation is associated with health problems, including airway compromise, ocular disorders, neurological disease, and other co-morbidities. There is increasing evidence that brachycephaly disrupts cerebrospinal fluid movement and absorption, predisposing ventriculomegaly, hydrocephalus, quadrigeminal cistern expansion, Chiari-like malformation, and syringomyelia. In this review, we focus on cerebrospinal fluid physiology and how this is impacted by brachycephaly, airorhynchy, and associated craniosynostosis.


In vivo assay of the ethanol-induced embryonic hair cell loss and the protective role of the retinoic and folic acid in zebrafish larvae (Danio rerio).
In reference to the auditory manifestation of fetal alcohol syndrome, previous work has preferentially focused on the deviant neural development of the auditory system. Changes in the sensory hair cell, the ultimate sensory organ, were not well understood. In this study, we carried out an in vivo assessment of the embryonic hair cell changes on the lateral line of zebrafish upon exposure to various ethanol concentrations (0.25%, 0.5%, 0.75%, and 1.0%). A significant decrease in the hair cell count was confirmed as the ethanol concentration increased. Long-term observation (up to 240 hours post-fertilization [hpf]) suggested an irreversible hair cell loss with little chance of a simple delayed development. For an underlying biological process, a significant increase of hair cell apoptosis and a significant decrease of cytoplasmic mitochondria were confirmed as the ethanol concentration increased. Co-treatment with retinoic (0.1 nM) or folic (0.1 mM) acid with the same concentrations of ethanol resulted in significant increases in the remaining hair cells, compared to the ethanol-only treatment group, for every ethanol concentration. The retinoic acid provided more effective protection over folic acid, resulting in no significant changes in hair cell counts for every ethanol concentration (except 1.0%), compared with that of the negative control (without chemical treatment). Hair cell counts in every ethanol concentration were significantly lower than those in negative controls without chemical treatment after folic acid co-treatment. In conclusion, gestational ethanol exposure causes developmental sensory hair cell loss. Potential underlying mechanisms include retinoic or folic acid deficiency, and mitochondrial damage with subsequent hair cell apoptosis. Hair cell loss could possibly be prevented by administering either retinoic or folic acid, with retinoic acid supplementation as the preferred treatment.


Characterization of cytoskeleton features and maturation status of cultured human iPSC-derived cardiomyocytes.
Recent innovations in stem cell technologies and the availability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have opened new possibilities for studies and drug testing on human cardiomyocytes in vitro. Still, there are concerns about the precise nature of such 'reprogrammed' cells. We have performed an investigation using immunocytochemistry and confocal microscopy on several cellular features using commercially available hiPSC-CMs. For some selected developmentally regulated or cardiac chamber-specific proteins, we have compared the results from hiPSC-derived cardiomyocytes with freshly isolated, ventricular cardiomyocytes from adult rats. The results show that all typical cardiac proteins are expressed in these hiPSC-CMs. Furthermore, intercalated disc-like structures, calcium cycling proteins, and myofibrils are present. However, some of these proteins are only known from early developmental stages of the ventricular myocardium or the diseased adult heart. A heterogeneous expression pattern in the cell population was noted for some muscle proteins, such as for myosin light chains, or incomplete organization in sarcomeres, such as for telethonin. These observations indicate that hiPSC-CMs can be considered genuine human cardiomyocytes of an early developmental state. The here described marker proteins of maturation may become instrumental in future studies attempting the improvement of cardiomyocyte in vitro models.


A matter of time: rapid motor memory stabilization in childhood.
Are children better than adults in acquiring new skills ('how-to' knowledge) because of a difference in skill memory consolidation? Here we tested the proposal that, as opposed to adults, children's memories for newly acquired skills are immune to interference by subsequent experience. The establishment of long-term memory for a trained movement sequence in adults requires a phase of memory consolidation. This results in substantial delayed, 'offline', performance gains, which nevertheless remain susceptible to interference by subsequent competing motor experience for several hours after training, unless sleep is afforded in the interval. Here we compared the gains attained overnight (delayed gains) by 9-year-olds and adults after training on a novel finger-to-thumb movement sequence, with and without subsequent interference by repeating a different movement sequence. Our results show that, in 9-year-olds, but not in adults, an interval of 15 min. between the training session and interfering experience sufficed to ensure the expression of delayed, consolidation phase, gains. Nevertheless, in the 9-year-olds, as well as in adults, the gains attained with no interference were significantly larger. Altogether, our results show that while the behavioral expressions of childhood and adult consolidation processes are similar, procedural memory stabilizes, in the waking state, at a much faster rate in children. We propose that, in children, rapid stabilization is a mechanism whereby the constraints on consolidating new experiences into long-term procedural memory are relaxed at the cost of selectivity.


Comparison of isoflurane and sevoflurane for anesthesia in beaver.
We compared the hemodynamic and respiratory effects, recovery time, and cost of two gas inhalants (isoflurane and sevoflurane) for anesthetic induction and maintenance of beaver (Castor canadensis) during surgery to implant radio transmitters in the peritoneal cavity. Heart rate, respiratory rate, relative hemoglobin saturation with oxygen (SpO2), and body temperature were measured every 5 min for the first 45 min, and arterial blood gas was measured once, 25 min into the anesthetic procedure. Induction for either agent was smooth and rapid. Heart rate and respiratory rate both decreased during the procedure though neither was lower than baseline values reported in the literature for beaver. Relative hemoglobin saturation with oxygen, body temperature, and blood gas variables did not differ between each anesthetic regime. Both inhalants caused slight respiratory acidosis. Recovery time from anesthesia was highly variable (1-178 min) but did not differ statistically between drugs. Sevoflurane costs ($22.30/60 min) were much higher than isoflurane costs ($3.50/60 min). We recommend isoflurane or sevoflurane for anesthetic induction and maintenance of beaver because of the lack of physiologic differences.


The role of laminin-5 and its receptors in mammary epithelial cell branching morphogenesis.
In vivo, normal mammary epithelial cells utilize hemidesmosome attachment devices to adhere to stroma. However, analyses of a potential role for hemidesmosomes and their components in mammary epithelial tissue morphogenesis have never been attempted. MCF-10A cells are a spontaneously immortalized line derived from mammary epithelium and possess a number of characteristics of normal mammary epithelial cells including expression of hemidesmosomal associated proteins such as the two bullous pemphigoid antigens, alpha 6 beta 4 integrin and its ligand laminin-5. More importantly, MCF-10A cells readily assemble mature hemidesmosomes when plated onto uncoated substrates. When maintained on matrigel, like their normal breast epithelial cell counterparts, MCF-10A cells undergo a branching morphogenesis and assemble hemidesmosomes at sites of cell-matrigel interaction. Function blocking antibodies specific for human laminin-5 and the alpha subunits of its two known receptors (alpha 3 beta 1 and alpha 6 beta 4 integrin) not only inhibit hemidesmosome assembly by MCF-10A cells but also impede branching morphogenesis induced by matrigel. Our results imply that the hemidesmosome, in particular those subunits comprising its laminin-5/integrin 'backbone', play an important role in morphogenetic events. We discuss these results in light of recent evidence that hemidesmosomes are sites involved in signal transduction.


Magnesium and calcium overaccumulate in the leaves of a schengen3 mutant of Brassica rapa.
Magnesium (Mg) and calcium (Ca) are essential mineral nutrients poorly supplied in many human food systems. In grazing livestock, Mg and Ca deficiencies are costly welfare issues. Here, we report a Brassica rapa loss-of-function schengen3 (sgn3) mutant, braA.sgn3.a-1, which accumulates twice as much Mg and a third more Ca in its leaves. We mapped braA.sgn3.a to a single recessive locus using a forward ionomic screen of chemically mutagenized lines with subsequent backcrossing and linked-read sequencing of second back-crossed, second filial generation (BC2F2) segregants. Confocal imaging revealed a disrupted root endodermal diffusion barrier, consistent with SGN3 encoding a receptor-like kinase required for normal formation of Casparian strips, as reported in thale cress (Arabidopsis thaliana). Analysis of the spatial distribution of elements showed elevated extracellular Mg concentrations in leaves of braA.sgn3.a-1, hypothesized to result from preferential export of excessive Mg from cells to ensure suitable cellular concentrations. This work confirms a conserved role of SGN3 in controlling nutrient homeostasis in B. rapa, and reveals mechanisms by which plants are able to deal with perturbed shoot element concentrations resulting from a "leaky" root endodermal barrier. Characterization of variation in leaf Mg and Ca accumulation across a mutagenized population of B. rapa shows promise for using such populations in breeding programs to increase edible concentrations of essential human and animal nutrients.


Zebrafish earns its stripes for in vivo ASC speck dynamics.
Assembly of the ASC speck is critical for signaling by the inflammasome. In this issue, Kuri et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201703103) use live microscopy to track fluorescently tagged endogenous ASC in the zebrafish, describing the molecular domains driving ASC speck assembly and identifying a key role for macrophages in ASC speck removal in vivo.


The ubiquitin-like modifier FAT10 interacts with HDAC6 and localizes to aggresomes under proteasome inhibition.
During misfolded-protein stress, the cytoplasmic protein histone deacetylase 6 (HDAC6) functions as a linker between the dynein motor and polyubiquitin to mediate the transport of polyubiquitylated cargo to the aggresome. Here, we identify a new binding partner of HDAC6, the ubiquitin-like modifier FAT10 (also known as UBD), which is cytokine-inducible and - similar to ubiquitin - serves as a signal for proteasomal degradation. In vivo, the two proteins only interacted under conditions of proteasome impairment. The binding of HDAC6 to FAT10 was mediated by two separate domains: the C-terminal ubiquitin-binding zinc-finger (BUZ domain) of HDAC6 and its first catalytic domain, even though catalytic activity of HDAC6 was not required for this interaction. Both endogenous and ectopically expressed FAT10 as well as the model conjugate FAT10-GFP localized to the aggresome in a microtubule-dependent manner. Furthermore, FAT10-containing as well as ubiquitin-containing aggresomes were reduced in both size and number in HDAC6-deficient fibroblasts. We conclude that, if FAT10 fails to subject its target proteins to proteasomal degradation, an alternative route is taken to ensure their sequestration and possibly also their subsequent removal by transporting them to the aggresome via the association with HDAC6.


An Analysis of Language as a Barrier to Receiving Influenza Vaccinations among an Elderly Hispanic Population in the United States.
Background. The Hispanic population in the United States is growing, and disparities in the receipt of healthcare services as a result of limited English proficiency have been demonstrated. We set out to determine if Spanish language preference was a barrier to receiving influenza vaccinations among Hispanic persons 65 years and older in the USA. Methods. Differences in the receipt of vaccinations by language preference were tested with both Chi-square analyses and adjusted logistic regression analyses. Results. Findings suggest that elderly Hispanic persons, 65 years of age and older, who prefer to communicate in Spanish instead of English, are significantly less likely to have received influenza vaccinations when compared to their Hispanic counterparts who prefer to communicate in English. Conclusions. Influenza infections can more often be fatal in older persons and may disparately affect minority populations such as Hispanic persons. Therefore, understanding barriers to the receipt of effective preventive health measures is necessary.


Analysis of the N-terminal region of the 47-kilodalton integral membrane lipoprotein of Treponema pallidum.
The 47-kDa lipoprotein is an abundant integral membrane protein and dominant immunogen of Treponema pallidum subsp. pallidum. Previous DNA sequencing of the 47-kDa-lipoprotein gene did not reveal consensus features representative of other bacterial lipoprotein genes; this prompted further analyses with emphasis on elucidation of the N terminus of the molecule. To assist in localizing start signals for the protein, the transcription initiation site for the 47-kDa-antigen gene was determined. RNA isolated from both T. pallidum and recombinant Escherichia coli expressing the 47-kDa antigen was used as a template in reverse transcriptase primer extension. Upon analysis of cDNA products, transcription initiation was localized to one nucleotide in T. pallidum and to two adjacent nucleotides in E. coli. When various primers were used in DNA sequencing reactions for these analyses, a previously undetected nucleotide (G) was found in the purported 5' untranslated region; this altered the upstream reading frame to reveal plausible sites for ribosome binding (GGAGG), translation initiation (GTG start codon), and signal peptidase II processing (Val-Val-Gly-Cys). Discounting acylation, the molecular weight of the mature polypeptide is 45,756 (approximately 46,600 with acylation). To derive nonacylated 47-kDa antigen for further structure-function studies, the 47-kDa-antigen gene was subcloned without acylation signals as a genetic construct encoding a glutathione S-transferase fusion protein; following cleavage with thrombin, the nonacylated 47-kDa protein was hydrophilic rather than amphiphilic but retained its antigenicity when tested against 116 human serum samples from patients with various stages of syphilis.


Single-incision sling operations for urinary incontinence in women.
Urinary incontinence has been shown to affect up to 50% of women. Studies in the United States have shown that up to 80% of these women have an element of stress urinary incontinence. Colposuspension and now mid-urethral slings have been shown to be effective in treating patients with stress incontinence. However, associated adverse events include bladder and bowel injury, groin pain and haematoma formation. This has led to the development of third-generation single-incision slings, also referred to as mini-slings.It should be noted that TVT-Secur (Gynecare, Bridgewater, NJ, USA) is one type of single-incision sling; it has been withdrawn from the market because of poor results. However, it is one of the most widely studied single-incision slings and was used in several of the trials included in this review. Despite its withdrawal from clinical use, it was decided that data pertaining to this sling should be included in the first iteration of this review, so that level 1a data are available in the literature to confirm its lack of efficacy. To assess the effectiveness of mini-sling procedures in women with urodynamic clinical stress or mixed urinary incontinence in terms of improved continence status, quality of life or adverse events. We searched the Cochrane Incontinence Group Specialised Trials Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE in process; we handsearched journals and conference proceedings (searched 6 February 2013) and searched ClinicalTrials.gov (searched 20 September 2012), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (searched 20 September 2012) and the reference lists of relevant articles. Randomised or quasi-randomised controlled trials in women with urodynamic stress incontinence, symptoms of stress incontinence or stress-predominant mixed urinary incontinence, in which at least one trial arm involves one of the new single-incision slings. The definition of a single-incision sling is "a sling that does not involve either a retropubic or transobturator passage of the tape or trocar and involves only a single vaginal incision (i.e. no exit wounds in the groin or lower abdomen)." Three review authors assessed the methodological quality of potentially eligible trials and independently extracted data from the individual trials. We identified 31 trials involving 3290 women. Some methodological flaws were observed in some trials; a summary of these is given in the 'Risk of bias in included studies' section.No studies compared single-incision slings versus no treatment, conservative treatment, colposuspension, laparoscopic procedures or traditional sub-urethral slings. Also no data on the comparison of single-incision slings versus retropubic mid-urethral slings (top-down approach) were available, but the review authors believe this did not affect the overall comparison versus retropubic mid-urethral slings.The types of single-incision slings included in this review were TVT-Secur (Gynecare), MiniArc (American Medical Systems, Minnetonka, MN, USA), Ajust (C.R. Bard, Inc.,Covington, GA, USA), Needleless (Mayumana Healthcare, Lisse, The Netherlands), Ophira (Promedon, Cordoba, Argentina), Tissue Fixation System (TFS PTY Ltd, Sydney, Australia) and CureMesh (D.Med. Co., Inc., Seoul, Korea).Women were more likely to remain incontinent after surgery with single-incision slings than with retropubic slings such as tension-free vaginal tape (TVT(TM)) (121/292, 41% vs 72/281, 26%; risk ratio (RR) 2.08, 95% confidence interval (CI) 1.04 to 4.14). Duration of the operation was slightly shorter for single-incision slings but with higher risk of de novo urgency (RR 2.39, 95% CI 1.25 to 4.56). Four of five studies in the comparison included TVT-Secur as the single-incision sling.Single-incision slings resulted in higher incontinence rates compared with inside-out transobturator slings (30% vs 11%; RR 2.55, 95% CI 1.93 to 3.36). The adverse event profile was significantly worse, specifically consisting of higher risks of vaginal mesh exposure (RR 3.75, 95% CI 1.42 to 9.86), bladder/urethral erosion (RR 17.79, 95% CI 1.06 to 298.88) and operative blood loss (mean difference 18.79, 95% CI 3.70 to 33.88). Postoperative pain was less common with single-incision slings (RR 0.29, 95% CI 0.20 to 0.43), and rates of long-term pain or discomfort were marginally lower, but the clinical significance of these differences is questionable. Most of these findings were derived from the trials involving TVT-Secur: Excluding the other trials showed that high risk of incontinence was principally associated with use of this device (RR 2.65, 95% CI 1.98 to 3.54). It has been withdrawn from clinical use.Evidence was insufficient to reveal a difference in incontinence rates with other single-incision slings compared with inside-out or outside-in transobturator slings. Duration of the operation was marginally shorter for single-incision slings compared with transobturator slings, but only by approximately two minutes and with significant heterogeneity in the comparison. Risks of postoperative and long-term groin/thigh pain were slightly lower with single-incision slings, but overall evidence was insufficient to suggest a significant difference in the adverse event profile for single-incision slings compared with transobturator slings. Evidence was also insufficient to permit a meaningful sensitivity analysis of the other single-incision slings compared with transobturator slings, as all confidence intervals were wide. The only significant differences were observed in rates of postoperative and long-term pain, and in duration of the operation, which marginally favoured single-incision slings.Overall results show that TVT-Secur is considerably inferior to retropubic and inside-out transobturator slings, but additional evidence is required to allow any reasonable comparison of other single-incision slings versus transobturator slings.When one single-incision sling was compared with another, evidence was insufficient to suggest a significant difference between any of the slings in any of the comparisons made. TVT-Secur is inferior to standard mid-urethral slings for the treatment of women with stress incontinence and has already been withdrawn from clinical use. Not enough evidence has been found on other single-incision slings compared with retropubic or transobturator slings to allow reliable comparisons. Additional adequately powered and high-quality trials with longer-term follow-up are required. Trials should clearly describe the fixation mechanism of these single-incisions slings: It is apparent that, although clubbed together as a single group, a significant difference in fixation mechanisms may influence outcomes.


Biomarkers of hypercoagulability and inflammation in primary hyperparathyroidism.
Severe primary hyperparathyroidism (PHP) has been associated with increased cardiovascular morbidity. Hypertension, dyslipidemia and impaired glucose metabolism were demonstrated in severe PHP, with improvement after surgery in these variables. Such an association in mild PHP is not known. The study was conducted to determine biomarkers of hypercoagulability and inflammation for cardiovascular disease in patients with primary hyperparathyroidism. Patients (n=35) without CVD were evaluated. Patients were subdivided into two groups, severe (n=15) and mild (n=20) hyperparathyroidism, based on disease severity and whether they had indications for surgery. Results were compared with those obtained in 25, age and weight matched controls. Participants were examined in the hospital endocrine clinic and had measurement of fasting blood levels of calcium, phosphate, alkaline phosphatase, PTH, C-reactive protein, Serum IL-6, D-dimers, Fibrinogen, plasminogen activator inhibitor 1 [PAI-1], and white blood cells (WBC) count. PAI-1 was significantly higher in symptomatic patients (41.4 g/L +/-20) vs. controls (32.5 g/L +/-13.0); (p=0.009). Levels of fibrinogen, d-dimers, IL-6, CRP and leukocytes were similar in patients and controls. Across all subjects PAI-1 was significantly correlated with PTH levels (f=8.44;p=0.005). Patients with severe primary hyperparathyroidism have increased risk for cardiovascular disease, mainly due to the effect of PTH and also the duration and severity of disease. Elevated PAI-1 levels may imply that hypercoagulability may be involved in the pathogenesis of CVD in these patients.


Pomegranate and licorice juices modulate metformin pharmacokinetics in rats.
Food or drinks may significantly alter the pharmacokinetics and pharmacodynamics of drugs which may lead to adverse events. A drug such as metformin is widely used to regulate plasma glucose level and pomegranate and licorice have been identified to help in type-2 diabetes management. However, the interactions of the latter on metformin pharmacokinetics were not studied. Therefore, we aimed here to study the impact of pomegranate and licorice on metformin pharmacokinetics in rats. Juices were given to rats for two days and half an hour before metformin (20 mg/kg) oral administration. Blood samples, then, were collected at different time intervals, processed and analyzed using validated reliable HPLC method. Plasma profile and pharmacokinetic parameters were calculated for each group. Pre-administration of pomegranate significantly reduced metformin maximum plasma concentration from 1410 to 1031 ng/ml. On the other hand, pre-administration of licorice significantly delayed metformin reaching its maximum plasma concentration. In conclusion, pre-administration of pomegranate may potentially reduce efficacy of metformin while licorice might delay metformin action. Thus, both juices should be cautiously administrated with metformin, the mainstay drug for type-2 diabetes mellitus management.


Supporting Diverse Challenges of Ageing with Digital Enhanced Living Solutions.
By the 2050, it is estimated that the proportion of people over the age of 80 will have risen from 3.9% to 9.1% of population of Organisation for Economic Cooperation and Development countries. A large proportion of these people will need significant help to manage various chronic illnesses, including dementia, heart disease, diabetes, limited physical movement and many others. Current approaches typically focus on acute episodes of illness and are not well designed to provide adequately for daily living care support. In our rapidly ageing society, a critical need exists for effective, affordable, scalable and safe in-home and in-residential care solutions leveraging a range of current and emerging sensor, interaction and integration technologies. Key aims are to support the ageing to live longer in their own homes; make daily challenges associated with ageing less limiting through use of technology supports; better support carers - both professional and family - in providing monitoring, proactive intervention, and community connectedness; enable in-home and in-residential care organisations to scale their support services and better use their workforces; and ultimately provide better quality of life. Deakin University researchers have been investigating a range of emerging technologies and platforms to realise this vision, which we in broad terms coin Digital Enhanced Living, in the ageing space but also supporting those with anxiety and depression, sleep disorders, various chronic diseases, recovery from injury, and various predictive analytics. A Smart Home solution, carried out in conjunction with a local start-up, has produced and trialled a novel sensor, interaction, and AI-based technology. Virtual Reality (VR) solutions have been used to support carers in the set-up of dementia-friendly homes, in conjunction with Alzheimers Australia. Activity and nutrition solutions, including the use of conversational agents, have been used to build dialogue to engage and change behaviour. Predictive analytics, in conjunction with major hospitals, have been applied to large medical datasets to better support professionals making judgements around discharge outcomes. A set of lessons have been learned from the design, deployment and trialing of these diverse solutions and new development approaches have been crafted to address the challenges faced. In particular, we found that there is a need to consider user emotional expectations as first-class citizens and create methodologies that consider the user needs during the creation of the software solutions. We find that quality and emotional aspects have to be engineered into the solution, rather than added after a technical solution is deployed.


Direct heteroarylation polymerization: guidelines for defect-free conjugated polymers.
Direct (hetero)arylation polymerization (DHAP) has emerged as a valuable and atom-economical alternative to traditional cross-coupling methods for the synthesis of low-cost and efficient conjugated polymers for organic electronics. However, when applied to the synthesis of certain (hetero)arene-based materials, a lack of C-H bond selectivity has been observed. To prevent such undesirable side-reactions, we report the design and synthesis of new, bulky, phosphine-based ligands that significantly enhance selectivity of the DHAP process for both halogenated and non-halogenated electron-rich and electron-deficient thiophene-based comonomers. To better understand the selectivity issues, density functional theory (DFT) calculations have been performed on various halogenated and non-halogenated electron-rich and electron-deficient thiophene-based comonomers. Calculations showed that the presence of bromine atoms decreases the energy of activation (Ea) of the adjacent C-H bonds, allowing undesirable β-defects for some brominated aromatic units. Both calculations and the new ligands should lead to the rational design of monomers and methods for the preparation of defect-free conjugated polymers from DHAP.


An individualized longitudinal approach to monitoring the dynamics of growth and fitness development in adolescent athletes.
This study evaluated the development of anthropometric and fitness characteristics of 3 individual adolescent junior rugby league players and compared their characteristics with a cross-sectional population matched by age and skill level. Cross-sectional anthropometric and fitness assessments were conducted on 1,172 players selected to the Rugby Football League's talent development program (i.e., the Player Performance Pathway) between 2005 and 2008. Three players of differing relative age, maturational status, and playing position were measured and tracked once per year on 3 occasions (Under 13s, 14s, 15s age categories) and compared against the cross-sectional population. Results demonstrated that the later maturing players increased height (player 1 = 9.2%; player 2 = 7.8%) and a number of fitness characteristics (e.g., 60-m speed-player 1 = -14.9%; player 2 = -9.9%) more than the earlier maturing player (player 3-Height = 2.0%, 60-m sprint = -0.7%) over the 2-year period. The variation in the development of anthropometric and fitness characteristics between the 3 players highlights the importance of longitudinally monitoring individual characteristics during adolescence to assess the dynamic changes in growth, maturation, and fitness. Findings showcase the limitations of short-term performance assessments at one-off time points within annual-age categories, instead of advocating individual development and progression tracking without deselection. Coaches should consider using an individual approach, comparing data with population averages, to assist in the prescription of appropriate training and lifestyle interventions to aid the development of junior athletes.


Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers.
Few studies have investigated the effect of dietary polyphenols on the complex human gut microbiota, and they focused mainly on single polyphenol molecules and select bacterial populations. The objective was to evaluate the effect of a moderate intake of red wine polyphenols on select gut microbial groups implicated in host health benefits. Ten healthy male volunteers underwent a randomized, crossover, controlled intervention study. After a washout period, all of the subjects received red wine, the equivalent amount of de-alcoholized red wine, or gin for 20 d each. Total fecal DNA was submitted to polymerase chain reaction(PCR)-denaturing gradient gel electrophoresis and real-time quantitative PCR to monitor and quantify changes in fecal microbiota. Several biochemical markers were measured. The dominant bacterial composition did not remain constant over the different intake periods. Compared with baseline, the daily consumption of red wine polyphenol for 4 wk significantly increased the number of Enterococcus, Prevotella, Bacteroides, Bifidobacterium, Bacteroides uniformis, Eggerthella lenta, and Blautia coccoides-Eubacterium rectale groups (P < 0.05). In parallel, systolic and diastolic blood pressures and triglyceride, total cholesterol, HDL cholesterol, and C-reactive protein concentrations decreased significantly (P < 0.05). Moreover, changes in cholesterol and C-reactive protein concentrations were linked to changes in the bifidobacteria number. This study showed that red wine consumption can significantly modulate the growth of select gut microbiota in humans, which suggests possible prebiotic benefits associated with the inclusion of red wine polyphenols in the diet. This trial was registered at controlled-trials.com as ISRCTN88720134.


Cooperation, quorum sensing, and evolution of virulence in Staphylococcus aureus.
The virulence and fitness in vivo of the major human pathogen Staphylococcus aureus are associated with a cell-to-cell signaling mechanism known as quorum sensing (QS). QS coordinates the production of virulence factors via the production and sensing of autoinducing peptide (AIP) signal molecules by the agr locus. Here we show, in a wax moth larva virulence model, that (i) QS in S. aureus is a cooperative social trait that provides a benefit to the local population of cells, (ii) agr mutants, which do not produce or respond to QS signal, are able to exploit the benefits provided by the QS of others ("cheat"), allowing them to increase in frequency when in mixed populations with cooperators, (iii) these social interactions between cells determine virulence, with the host mortality rate being negatively correlated to the percentage of agr mutants ("cheats") in a population, and (iv) a higher within-host relatedness (lower strain diversity) selects for QS and hence higher virulence. Our results provide an explanation for why agr mutants show reduced virulence in animal models but can be isolated from infections of humans. More generally, by providing the first evidence that QS is a cooperative social behavior in a Gram-positive bacterium, our results suggest convergent, and potentially widespread, evolution for signaling to coordinate cooperation in bacteria.


Roundtable discussion: what is the future role of the private sector in health?
The role for the private sector in health remains subject to much debate, especially within the context of achieving universal health coverage.This roundtable discussion offers diverse perspectives from a range of stakeholders--a health funder, a representative from an implementing organization, a national-level policy-maker, and an expert working in a large multi-national company--on what the future may hold for the private sector in health. The first perspective comes from a health funder, who argues that the discussion about the future role of the private sector has been bogged down in language. He argues for a 'both/and' approach rather than an 'either/or' when it comes to talking about health service provision in low- and middle-income countries.The second perspective is offered by an implementer of health insurance in sub-Saharan Africa. The piece examines the comparative roles of public sector actors, private sector actors and funding agencies, suggesting that they must work together to mobilize domestic resources to fund and deliver health services in the longer term.Thirdly, a special advisor working in the federal government of Nigeria considers the situation in that country. He notes that the private sector plays a significant role in funding and delivering health services there, and that the government must engage the private sector or forever be left behind.Finally, a representative from a multi-national pharmaceutical corporation gives an overview of global shifts that are creating opportunities for the private sector in health markets. Overall, the roundtable discussants agree that the private sector will play an important role in future health systems. But we must agree a common language, work together, and identify key issues and gaps that might be more effectively filled by the private sector.


Perivascular adipose tissue as a source of therapeutic targets and clinical biomarkers.
Obesity is a modifiable cardiovascular risk factor, but adipose tissue (AT) depots in humans are anatomically, histologically, and functionally heterogeneous. For example, visceral AT is a pro-atherogenic secretory AT depot, while subcutaneous AT represents a more classical energy storage depot. Perivascular adipose tissue (PVAT) regulates vascular biology via paracrine cross-talk signals. In this position paper, the state-of-the-art knowledge of various AT depots is reviewed providing a consensus definition of PVAT around the coronary arteries, as the AT surrounding the artery up to a distance from its outer wall equal to the luminal diameter of the artery. Special focus is given to the interactions between PVAT and the vascular wall that render PVAT a potential therapeutic target in cardiovascular diseases. This Clinical Consensus Statement also discusses the role of PVAT as a clinically relevant source of diagnostic and prognostic biomarkers of vascular function, which may guide precision medicine in atherosclerosis, hypertension, heart failure, and other cardiovascular diseases. In this article, its role as a 'biosensor' of vascular inflammation is highlighted with description of recent imaging technologies that visualize PVAT in clinical practice, allowing non-invasive quantification of coronary inflammation and the related residual cardiovascular inflammatory risk, guiding deployment of therapeutic interventions. Finally, the current and future clinical applicability of artificial intelligence and machine learning technologies is reviewed that integrate PVAT information into prognostic models to provide clinically meaningful information in primary and secondary prevention.


Second malignancies in young children with primary brain tumors following treatment with prolonged postoperative chemotherapy and delayed irradiation: a Pediatric Oncology Group study.
Between 1986 and 1990, the Pediatric Oncology Group conducted a study in which 198 children younger than 3 years of age with malignant brain tumors were treated with prolonged postoperative chemotherapy in an effort to delay irradiation and reduce long-term neurotoxicity. Children younger than 2 years of age received 24 months of chemotherapy followed by irradiation, and those between 2 and 3 years of age received 12 months of chemotherapy plus irradiation. Chemotherapy was given in 28-day cycles (AAB, AAB), with cycle A = vincristine (0.065 mg/kg) intravenously on days 1 and 8 and cyclophosphamide (65 mg/kg) intravenously on day 1, and cycle B = cisplatinum (4 mg/kg) intravenously on day 1 and etoposide (6.5 mg/kg) intravenously on days 3 and 4. Five of the 198 children developed second malignancies, with a cumulative risk at 8 years of 11.3% (95% confidence interval [CI], 0-39%). Four of the five second malignancies occurred in children younger than 2 years of age at diagnosis, with a cumulative risk at 8 years of 18.9% (CI, 0-70%). Initial diagnoses were choroid plexus carcinoma (2 children), ependymoma (1 child), desmoplastic infantile ganglioglioma (2 children), and medulloblastoma (1 child). Duration from diagnosis of initial tumor to second malignancy was 33, 35, 57, 66, and 92 months. Three children younger than 2 years of age developed lymphoproliferative disease, that is, myelodysplastic syndrome (2 children), both with monosomy 7 deletions, and acute myelogenous leukemia (1 child), after 24 to 26 cycles of chemotherapy, including 8 cycles of etoposide. Two of 3 received craniospinal irradiation (2,560/3,840 cGy) and (3,520/5,320 cGy). Time to second malignancy was 7 years 8 months, 4 years 9 months, and 2 years 9 months. Two children developed solid tumors, at 5 years 6 months and 2 years 11 months, respectively, after initiation of treatment. A sarcoma developed after 26 cycles of chemotherapy and no irradiation, and a meningioma developed after 12 cycles of chemotherapy and local craniospinal irradiation. Potential causative factors for this high rate of secondary malignancies include prolonged use of alkylating agents and etoposide with or without irradiation.


Invasion genetics from eDNA and thousands of larvae: A targeted metabarcoding assay that distinguishes species and population variation of zebra and quagga mussels.
Identifying species and population genetic compositions of biological invasions at early life stages and/or from environmental (e)DNA using targeted high-throughput sequencing (HTS) metabarcode assays offers powerful and cost-effective means for early detection, analysis of spread patterns, and evaluating population changes. The present study develops, tests, and applies this method with a targeted sequence assay designed to simultaneously identify and distinguish between the closely related invasive Eurasian zebra and quagga mussels (Dreissena polymorpha and D. rostriformis) and their relatives and discern their respective population genetic patterns. Invasions of these dreissenid mussel species have markedly changed freshwater ecosystems throughout North America and Europe, exerting severe ecological and economic damage. Their planktonic early life stages (eggs and larvae) are morphologically indistinguishable, yet each species exerts differential ecological effects, with the quagga often outcompeting the zebra mussel as adults. Our targeted assay analyzes genetic variation from a diagnostic sequence region of the mitochondrial (mt)DNA cytochrome oxidase I (COI) gene, to assess temporal and spatial inter- and intra-specific genetic variability. The assay facilitates analysis of environmental (e)DNA from water, early life stages from thousands of individuals, and simultaneous analysis of 50-100 tagged field-collected samples. Experiments evaluated its accuracy and performance using: (a) mock laboratory communities containing known DNA quantities per taxon, (b) aquaria with mixed-species/haplotype compositions of adults, and (c) field-collected water and plankton versus traditional sampling of adult communities. Results delineated species compositions, relative abundances, and population-level diversity differences among ecosystems, habitats, time series, and life stages from two allopatric concurrent invasions in the Great Lakes (Lake Erie) and the Hudson River, which had separate founding histories. Findings demonstrate application of this targeted assay and our approach to accurately and simultaneously discern species- and population-level differences across spatial and temporal scales, facilitating early detection and ecological understanding of biological invasions.


Model of coupled transient changes of Rac, Rho, adhesions and stress fibers alignment in endothelial cells responding to shear stress.
Interactions of cell adhesions, Rho GTPases and actin in the endothelial cells' response to external forces are complex and not fully understood, but a qualitative understanding of the mechanosensory response begins to emerge. Here, we formulate a mathematical model of the coupled dynamics of cell adhesions, small GTPases Rac and Rho and actin stress fibers guiding a directional reorganization of the actin cytoskeleton. The model is based on the assumptions that the interconnected cytoskeleton transfers the shear force to the adhesion sites, which in turn transduce the force into a chemical signal that activates integrins at the basal surface of the cell. Subsequently, activated and ligated integrins signal and transiently de-activate Rho, causing the disassembly of actin stress fibers and inhibiting the maturation of focal complexes into focal contacts. Focal complexes and ligated integrins activate Rac, which in turn enhances focal complex assembly. When Rho activity recovers, stress fibers re-assemble and promote the maturation of focal complexes into focal contacts. Merging stress fibers self-align, while the elevated level of Rac activity at the downstream edge of the cell is translated into an alignment of the cells and the newly forming stress fibers in the flow direction. Numerical solutions of the model equations predict transient changes in Rac and Rho that compare well with published experimental results. We report quantitative data on early alignment of the stress fibers and its dependence on cell shape that agrees with the model.


Anterior pituitary hormone deficiency in subjects with total and partial primary empty sella: do all cases need endocrinological evaluation?
To compare anterior pituitary functions between subjects with total and partial primary empty sella (PES) and to assess whether all cases with PES need endocrinological evaluation. Eighty-one subjects with PES (34 total and 47 partial) were included in the study. Basal anterior pituitary and its target hormones were assessed and those with low insulin like growth factor-1 and/or low basal cortisol levels underwent insulin tolerance test (ITT). 67.4% of the subjects with total and 14.9% of those with partial PES had different degrees of hypopituitarism. However, the frequency of hypopituitarism was significantly higher in cases with total PES. The odds ratio (OR) and 95% confidence interval (CI) of secondary hypothyroidism, secondary adrenal, growth hormone and gonadotropin deficiency in subjects with total compared to those with partial PES were as follows: OR = 20.0, 95% CI 4.16 - 95.9, OR = 2.4, 95% CI 1.34 - 5.7, OR = 15.3, 95% CI 4.48 - 52.6 and OR = 10.6, 95% CI 3.37 - 33.5, respectively. A substantial number of subjects with PES, particularly those with total PES, have pituitary hormone deficiency, so regardless of the type of PES, all subjects must be promptly and carefully evaluated for anterior pituitary hormone deficiency.


Nephrectomy versus renal repair after trauma to the kidney: preserve or sacrifice?
The objective of this retrospective study (1992-2003) is to evaluate the effect of nephrectomy in postoperative renal dysfunction. NEPHRECTOMY patients had their kidneys removed and REPAIR patients repaired or only partially resected. All patients were matched 1:1 with controls according to age, Injury Severity Score, Abdominal Abbreviated Injury Score, and mechanism of injury. Outcomes measured were renal dysfunction (serum creatinine > 2 mg/dl for > 2 consecutive days), renal dialysis, length of hospital stay, and mortality. Of 214 patients, 149 were NEPHRECTOMY and 65 REPAIR. Compared to their controls, NEPHRECTOMY and REPAIR patients had a higher rate of renal dysfunction. However, the rate was not different between NEPHRECTOMY and REPAIR. Multivariate analysis found no independent effect of the choice of operation in the development of renal dysfunction. No differences were found in the remaining outcomes measured. We conclude that although renal injury is associated with postoperative renal dysfunction, the type of operation is not. Nephrectomy can be offered when necessary without concerns about increasing the likelihood of postoperative renal failure.


EVALUATION OF CARDIORESPIRATORY, BLOOD GAS, AND LACTATE VALUES DURING EXTENDED IMMOBILIZATION OF WHITE RHINOCEROS (CERATOTHERIUM SIMUM).
Ten white rhinoceros (Ceratotherium simum) were immobilized for a total of 13 procedures in holding facilities in Kruger National Park using etorphine, azaperone, and hyaluronidase to assess the effect of extended immobilization on serial cardiorespiratory, blood gas, and lactate values. Butorphanol was administered intravenously following initial blood collection and physiologic assessment (t=0). Respiratory and cardiovascular parameters, body temperature, and arterial blood gases were monitored at 10-min intervals for a total of 100 min. Initial parameters at the time of recumbency revealed severe hypoxemia, hypercapnia, tachycardia, an increased alveolar-arterial (A-a) gradient, and mildly elevated lactate levels. At 10 min and 20 min, there were significant (P<0.05) changes in the following physiologic parameters: heart rate decreased [96 and 80 beats/min, respectively, vs. 120 beats/min], arterial partial pressure of oxygen (PaO2) increased [48 and 45 mm Hg, respectively vs. 30 mm Hg], arterial hemoglobin oxygen saturation increased [79% and 74%, respectively, vs. 47%], A-a gradient decreased [29.13 and 30.00 mm Hg, respectively, vs. 49.19 mm Hg], and respiratory rate decreased [5 and 5 breaths/min vs. 7 breaths/min]. Blood lactate levels also decreased from 2.54 mM/L to 1.50 and 0.89 mM/L, respectively. Despite initial improvements in blood oxygen levels at t=10 and 20 min, the rhinoceros remained severely hypoxemic for the remainder of the procedure (median PaO2=50.5 mm Hg, 95% confidence interval, 43.8-58.1). Median values for respiratory rate (5 breaths/min) and arterial partial pressure of carbon dioxide (PaCO2; 68.5 mm Hg) did not change significantly for the remaining 80 min. Median lactate, base excess, bicarbonate, and pH values improved between 20 and 100 min despite the persistent hypercapnia, indicating that the animals adequately compensated for respiratory and lactic acidosis. White rhinoceros were immobilized for 100 min with no negative effects, a desirable outcome if procedures require extended chemical immobilization without oxygen supplementation.


Crystallization of calcium oxalates is controlled by molecular hydrophilicity and specific polyanion-crystal interactions.
To gain more insight into protein structure-function relationships that govern ectopic biomineralization processes in kidney stone formation, we have studied the ability of urinary proteins (Tamm-Horsfall protein, osteopontin (OPN), prothrombin fragment 1 (PTF1), bikunin, lysozyme, albumin, fetuin-A), and model compounds (a bikunin fragment, recombinant-, milk-, bone osteopontin, poly-L-aspartic acid (poly asp), poly-L-glutamic acid (poly glu)) in modulating precipitation reactions of kidney stone-related calcium oxalate mono- and dihydrates (COM, COD). Combining scanning confocal microscopy and fluorescence imaging, we determined the crystal faces of COM with which these polypeptides interact; using scanning electron microscopy, we characterized their effects on crystal habits and precipitated volumes. Our findings demonstrate that polypeptide adsorption to COM crystals is dictated first by the polypeptide's affinity for the crystal followed by its preference for a crystal face: basic and relatively hydrophobic macromolecules show no adsorption, while acidic and more hydrophilic polypeptides adsorb either nonspecifically to all faces of COM or preferentially to {100}/{121} edges and {100} faces. However, investigating calcium oxalates grown in the presence of these polypeptides showed that some acidic proteins that adsorb to crystals do not affect crystallization, even if present in excess of physiological concentrations. These proteins (albumin, bikunin, PTF1, recombinant OPN) have estimated total hydrophilicities from 200 to 850 kJ/mol and net negative charges from -9 to -35, perhaps representing a "window" in which proteins adsorb and coat urinary crystals (support of excretion) without affecting crystallization. Strongest effects on crystallization were observed for polypeptides that are either highly hydrophilic (>950 kJ/mol) and highly carboxylated (poly asp, poly glu), or else highly hydrophilic and highly phosphorylated (native OPN isoforms), suggesting that highly hydrophilic proteins strongly affect precipitation processes in the urinary tract. Therefore, the level of hydrophilicity and net charge is a critical factor in the ability of polypeptides to affect crystallization and to regulate biomineralization processes.


Sex- and tissue-specific functions of Drosophila doublesex transcription factor target genes.
Primary sex-determination "switches" evolve rapidly, but Doublesex (DSX)-related transcription factors (DMRTs) act downstream of these switches to control sexual development in most animal species. Drosophila dsx encodes female- and male-specific isoforms (DSX(F) and DSX(M)), but little is known about how dsx controls sexual development, whether DSX(F) and DSX(M) bind different targets, or how DSX proteins direct different outcomes in diverse tissues. We undertook genome-wide analyses to identify DSX targets using in vivo occupancy, binding site prediction, and evolutionary conservation. We find that DSX(F) and DSX(M) bind thousands of the same targets in multiple tissues in both sexes, yet these targets have sex- and tissue-specific functions. Interestingly, DSX targets show considerable overlap with targets identified for mouse DMRT1. DSX targets include transcription factors and signaling pathway components providing for direct and indirect regulation of sex-biased expression.


Patients with Gastric Antral Vascular Ectasia (GAVE) Are at a Higher Risk of Gastrointestinal Bleeding in the Absence of Cirrhosis.
Gastric antral vascular ectasia (GAVE) is commonly found in patients with cirrhosis, but it is also associated with other diseases in the absence of cirrhosis. Whether GAVE confers a different severity of gastrointestinal (GI) bleeding between patients with and without cirrhosis remains unknown. We aim to examine whether there is a difference in clinically significant GI bleeding due to GAVE in patients with or without cirrhosis. This is a retrospective case-control study of patients who were diagnosed with GAVE between January 2000 and June 2014. Patients were categorized into cirrhosis and noncirrhosis groups, and those with an additional GI bleeding source were excluded. Univariate comparisons and multivariable models were constructed using logistic regression. In total, 110 patients diagnosed with GAVE on esophagogastroduodenoscopy (EGD) were included in our analysis; 84 patients had cirrhosis (76.4%) and 26 (23.6%) did not. Active GI bleeding was more prevalent in patients without cirrhosis (63.4% vs. 32.1%, p=0.003) despite similar indications for EGD, and endoscopic treatment with argon plasma coagulation (APC) was required more often in this group, approaching statistical significance (27% vs. 10.7%, p=0.056). There was no difference in bleeding severity, as evidenced by similar re-bleeding rates, surgery, or death attributed to uncontrolled bleeding. The strongest independent risk factor for GI bleeding was the absence of cirrhosis (odds ratio (OR): 5.151 (95% confidence interval (CI): 1.08-24.48, p=0.039). Patients with GAVE in the absence of cirrhosis are at higher risk for active GI bleeding and require more frequent endoscopic treatment than similar patients with cirrhosis. It may be worthwhile to treat GAVE in this population even in the absence of active bleeding.


Species diversity can drive speciation.
A fundamental question in evolutionary ecology and conservation biology is: why do some areas contain greater species diversity than others? Island biogeographic theory has identified the roles of immigration and extinction in relation to area size and proximity to source areas, and the role of speciation is also recognized as an important factor. However, one as yet unexplored possibility is that species diversity itself might help to promote speciation, and indeed the central tenets of island biogeographic theory support such a prediction. Here we use data for plants and arthropods of the volcanic archipelagos of the Canary and Hawaiian Islands to address whether there is a positive relationship between species diversity and rate of diversification. Our index of diversification for each island is the proportion of species that are endemic, and we test our prediction that this increases with increasing species number. We show that even after controlling for several important physical features of islands, diversification is strongly related to species number.


Expression in aneuploid Drosophila S2 cells.
Extensive departures from balanced gene dose in aneuploids are highly deleterious. However, we know very little about the relationship between gene copy number and expression in aneuploid cells. We determined copy number and transcript abundance (expression) genome-wide in Drosophila S2 cells by DNA-Seq and RNA-Seq. We found that S2 cells are aneuploid for >43 Mb of the genome, primarily in the range of one to five copies, and show a male genotype ( approximately two X chromosomes and four sets of autosomes, or 2X;4A). Both X chromosomes and autosomes showed expression dosage compensation. X chromosome expression was elevated in a fixed-fold manner regardless of actual gene dose. In engineering terms, the system "anticipates" the perturbation caused by X dose, rather than responding to an error caused by the perturbation. This feed-forward regulation resulted in precise dosage compensation only when X dose was half of the autosome dose. Insufficient compensation occurred at lower X chromosome dose and excessive expression occurred at higher doses. RNAi knockdown of the Male Specific Lethal complex abolished feed-forward regulation. Both autosome and X chromosome genes show Male Specific Lethal-independent compensation that fits a first order dose-response curve. Our data indicate that expression dosage compensation dampens the effect of altered DNA copy number genome-wide. For the X chromosome, compensation includes fixed and dose-dependent components.


A single burr hole approach for direct transverse sinus cannulation for the treatment of a dural arteriovenous fistula.
A 55-year-old woman with a symptomatic Borden II/Cognard IIa+b transverse sinus dural arteriovenous fistula underwent an attempted percutaneous transvenous embolization which was ultimately not possible given the fistula anatomy. She then underwent a partial percutaneous transarterial embolization but the fistula recurred. Given the failed percutaneous interventions, the patient underwent a combined open surgical/transvenous embolization using neuronavigation and a single burr hole craniectomy. She has remained symptom free for 3 months. This case report illustrates the feasibility of combining minimally invasive open surgical access to allow for direct venous cannulation for endovascular embolization of a dural arteriovenous fistula when traditional percutaneous methods are not an option.


Identification of the Candida albicans Cap1p regulon.
Cap1p, a transcription factor of the basic region leucine zipper family, regulates the oxidative stress response (OSR) in Candida albicans. Alteration of its C-terminal cysteine-rich domain (CRD) results in Cap1p nuclear retention and transcriptional activation. To better understand the function of Cap1p in C. albicans, we used genome-wide location profiling (chromatin immunoprecipitation-on-chip) to identify its transcriptional targets in vivo. A triple-hemagglutinin (HA(3)) epitope was introduced at the C terminus of wild-type Cap1p (Cap1p-HA(3)) or hyperactive Cap1p with an altered CRD (Cap1p-CSE-HA(3)). Location profiling using whole-genome oligonucleotide tiling microarrays identified 89 targets bound by Cap1p-HA(3) or Cap1p-CSE-HA(3) (the binding ratio was at least twofold; P < or = 0.01). Strikingly, Cap1p binding was detected not only at the promoter region of its target genes but also at their 3' ends and within their open reading frames, suggesting that Cap1p may associate with the transcriptional or chromatin remodeling machinery to exert its activity. Overrepresented functional groups of the Cap1p targets (P < or = 0.02) included 11 genes involved in the OSR (CAP1, GLR1, TRX1, SOD1, CAT1, and others), 13 genes involved in response to drugs (PDR16, MDR1, FLU1, YCF1, FCR1, and others), 4 genes involved in phospholipid transport (PDR16, GIT1, RTA2, and orf19.932), and 3 genes involved in the regulation of nitrogen utilization (GST3, orf19.2693, and orf19.3121), suggesting that Cap1p has other cellular functions in addition to the OSR. Bioinformatic analyses of the bound sequences suggest that Cap1p recognizes the DNA motif 5'-MTKASTMA. Finally, transcriptome analyses showed that increased expression generally accompanies Cap1p binding at its targets, indicating that Cap1p functions as a transcriptional activator.


The use of statins after a cardiac intervention is associated with reduced risk of subsequent depression: proof of concept for the inflammatory and oxidative hypotheses of depression?
Depression is associated with immune activation as well as oxidative stress. Statins have in vitro and in vivo antiinflammatory and antioxidative properties. We prospectively investigated whether the use of statins was associated with a reduced risk of development of depression in individuals who have had a cardiac event or intervention. Participants were recruited between May 2005 and March 2006 from the Geelong Hospital, Geelong, Australia, a tertiary hospital in regional Australia that serves a catchment area shown to be representative of the broader Australian community. Patients who were hospitalized for angioplasty, myocardial infarction, or coronary artery bypass graft surgery (N = 193) were followed up prospectively for 9 months to assess development of depression. Depression data were collected 3 months postdischarge (T1) by structured clinical interview (using the Mini International Neuropsychiatric Interview, version 5) and 9 months postdischarge (T2) by self-report (using the Hospital Anxiety and Depression Scale). Major depressive disorder, minor depression, and dysthymia were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Data on statins were collected from medical records. The association between statin therapy and depression was tested using both linear and logistic regression models controlling for clinical, psychological, and demographic confounders. At discharge, 157 participants (81.3%) were receiving statin therapy. Adjusting for possible confounders, taking statins at discharge had a protective effect on depression at T1, reducing the likelihood of dysthymia, minor depression, or major depression by 69% (95% CI, 0.097-0.972; P = .045). At the T2 end point, statin therapy again had a protective effect and was associated with a 79% reduction in the likelihood of depression (95% CI, 0.052-0.876; P = .032). The linear regression model to predict depression at T2 was significantly different from zero (F(11,180) = 8.686, P < .001) and explained 36.3% of the variance in depression. The use of statins was associated with significant reduction in the risk of depression in individuals who have had a cardiac event. This supports the role of oxidative and inflammatory processes in depression and opens the door to rational and novel pathophysiologically based therapies distinct from conventional antidepressants.


SCOWLP: a web-based database for detailed characterization and visualization of protein interfaces.
Currently there is a strong need for methods that help to obtain an accurate description of protein interfaces in order to be able to understand the principles that govern molecular recognition and protein function. Many of the recent efforts to computationally identify and characterize protein networks extract protein interaction information at atomic resolution from the PDB. However, they pay none or little attention to small protein ligands and solvent. They are key components and mediators of protein interactions and fundamental for a complete description of protein interfaces. Interactome profiling requires the development of computational tools to extract and analyze protein-protein, protein-ligand and detailed solvent interaction information from the PDB in an automatic and comparative fashion. Adding this information to the existing one on protein-protein interactions will allow us to better understand protein interaction networks and protein function. SCOWLP (Structural Characterization Of Water, Ligands and Proteins) is a user-friendly and publicly accessible web-based relational database for detailed characterization and visualization of the PDB protein interfaces. The SCOWLP database includes proteins, peptidic-ligands and interface water molecules as descriptors of protein interfaces. It contains currently 74,907 protein interfaces and 2,093,976 residue-residue interactions formed by 60,664 structural units (protein domains and peptidic-ligands) and their interacting solvent. The SCOWLP web-server allows detailed structural analysis and comparisons of protein interfaces at atomic level by text query of PDB codes and/or by navigating a SCOP-based tree. It includes a visualization tool to interactively display the interfaces and label interacting residues and interface solvent by atomic physicochemical properties. SCOWLP is automatically updated with every SCOP release. SCOWLP enriches substantially the description of protein interfaces by adding detailed interface information of peptidic-ligands and solvent to the existing protein-protein interaction databases. SCOWLP may be of interest to many structural bioinformaticians. It provides a platform for automatic global mapping of protein interfaces at atomic level, representing a useful tool for classification of protein interfaces, protein binding comparative studies, reconstruction of protein complexes and understanding protein networks. The web-server with the database and its additional summary tables used for our analysis are available at http://www.scowlp.org.


Evaluation of Different Restoration Combinations Used in the Reattachment of Fractured Teeth: A Finite Element Analysis.
The purpose of this study was to test different restoration combinations used for constructing fractured endodontically treated incisors by reattaching their fractured fragments. Seven types of 3-D FEM mathematical root canal-filled models were generated, simulating cases of (OB) reattaching fractured fragments; (CrPL) reattaching fractured fragments + ceramic palatinal laminate; (CmPL) reattaching fractured fragments + composite palatinal laminate; (CM) reattaching fractured fragments + coronal 1/3 of the root was filled using core material; (BP) reattaching fractured fragments + glass fiber post; (CP) composite resin restoration + glass fiber post; and (OC) composite resin restoration. A 100-N static oblique force was applied to the simulated teeth with 135° on the node at 2 mm above the cingulum to analyze the stress distribution at the tooth. For enamel tissue, the highest stress values were observed in model BP, and the lowest stress values were observed in model CmPL. For dentine tissue, the highest stress concentrations were observed around the fracture line for all models. Reattachment of fractured fragments by bonding may be preferred as a restoration option for endodontically treated incisors; also, palatinal laminate decreases the stress values at tooth tissues, especially at the enamel and the fracture line.


Genomic stability and tumorigenesis.
Cancer research needs to explain the observed incidence of cancer. Many factors determine this process, including: the number of susceptible cells in the tissue of origin; the number of normal cell divisions through which susceptible cells pass in normal development and turnover; the number of cell divisions during tumorigenesis; the selective advantage which tumour cells have acquired; the ease of detection of a cancer; the number of mutations which are required for malignancy; the possible stepwise nature of tumorigenesis; the value of the normal mutation rate; the presence of extrinsic factors such as mutagens or growth promoters; the presence and strength of genomic instability, a phenomenon which has received a great deal of attention. We know very little about most of the factors and their influence in humans. We cannot, therefore, readily answer the question as to whether or not the observed incidence of cancer is what we would expect. Specifically, it is not yet possible to assess whether or not genomic instability is a prerequisite for carcinogenesis. Mathematical models, which assess the importance of genomic instability in tumorigenesis can be helpful, but require interpretation in the context of our overall ignorance. Experimental data have shown genomic instability in some cancers, but we do not yet know whether or not hypermutation initiates and drives tumorigenesis.