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1.  Glucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice 
Nature Communications  2014;5:4924.
DNA damage and telomere dysfunction shorten organismal lifespan. Here we show that oral glucose administration at advanced age increases health and lifespan of telomere dysfunctional mice. The study reveals that energy consumption increases in telomere dysfunctional cells resulting in enhanced glucose metabolism both in glycolysis and in the tricarboxylic acid cycle at organismal level. In ageing telomere dysfunctional mice, normal diet provides insufficient amounts of glucose thus leading to impaired energy homeostasis, catabolism, suppression of IGF-1/mTOR signalling, suppression of mitochondrial biogenesis and tissue atrophy. A glucose-enriched diet reverts these defects by activating glycolysis, mitochondrial biogenesis and oxidative glucose metabolism. The beneficial effects of glucose substitution on mitochondrial function and glucose metabolism are blocked by mTOR inhibition but mimicked by IGF-1 application. Together, these results provide the first experimental evidence that telomere dysfunction enhances the requirement of glucose substitution for the maintenance of energy homeostasis and IGF-1/mTOR-dependent mitochondrial biogenesis in ageing tissues.
Shortened telomeres and reduced mitochondrial biogenesis are cellular hallmarks of ageing. Here, Missios et al. show that old mice with telomere dysfunction have an increased energetic demand that cannot be met unless mice are fed a glucose-rich diet, which improves energy metabolism and extends lifespan.
PMCID: PMC4199114  PMID: 25233189
2.  Habitual alcohol consumption associated with reduced semen quality and changes in reproductive hormones; a cross-sectional study among 1221 young Danish men 
BMJ Open  2014;4(9):e005462.
Study associations between three measures of alcohol consumption (recent, typical/habitual, binging), semen quality and serum reproductive hormones.
Cross-sectional population based study.
Setting and participants
1221 young Danish men, aged 18–28 years were recruited when they attended a compulsory medical examination to determine their fitness for military service from 2008 to 2012. Total alcohol consumption: (1) in the week preceding (habitual/typical) the visit (recent alcohol intake), (2) in a typical week and (3) frequency of ‘binge drinking’ (consuming more than 5 units/day)) in the past 30 days was estimated.
Main outcome measures
Semen quality (volume, sperm concentration, total sperm count, and percentages of motile and morphologically normal spermatozoa) and serum concentration of reproductive hormones (follicle-stimulating hormone, luteinising hormone, testosterone, sex hormone binding globulin, oestradiol, free testosterone and inhibin B).
Sperm concentration, total sperm count and percentage of spermatozoa with normal morphology were negatively associated with increasing habitual alcohol intake. This association was observed in men reporting at least 5 units in a typical week but was most pronounced for men with a typical intake of more than 25 units/week. Men with a typical weekly intake above 40 units had a 33% (95% CI 11% to 59%) reduction in sperm concentration compared to men with an intake of 1–5 units/week. A significant increase in serum free testosterone with increasing alcohol consumption the week preceding the visit was found. Binging was not independently associated with semen quality.
Our study suggests that even modest habitual alcohol consumption of more than 5 units per week had adverse effects on semen quality although most pronounced associations were seen in men who consumed more than 25 units per week. Alcohol consumption was also linked to changes in testosterone and SHBG levels. Young men should be advised to avoid habitual alcohol intake.
PMCID: PMC4185337  PMID: 25277121
3.  Urinary Bisphenol A Levels in Young Men: Association with Reproductive Hormones and Semen Quality 
Environmental Health Perspectives  2014;122(5):478-484.
Background: Few human studies have examined bisphenol A (BPA) exposure in relation to semen quality and reproductive hormones in men, and results are divergent.
Objectives: We examined associations between urinary BPA concentration and reproductive hormones, as well as semen quality, in young men from the general population.
Methods: Our study population consisted of 308 young men from the general population. Urinary BPA concentration was measured by isotope dilution TurboFlow-liquid chromatography–tandem mass spectrometry. We used multiple linear regression analysis to estimate associations between BPA concentration and reproductive hormones and semen quality, adjusting for confounding factors.
Results: We found that 98% of the men had detectable urinary levels of BPA. Median (5th–95th percentiles) BPA concentration was 3.25 ng/mL (0.59–14.89 ng/mL). Men with BPA concentrations above the lowest quartile had higher concentrations of serum testosterone, luteinizing hormone (LH), estradiol, and free testosterone compared with the lowest quartile (ptrend ≤ 0.02). Men in the highest quartile of BPA excretion had on average 18% higher total testosterone (95% CI: 8, 28%), 22% higher LH (95% CI: 6, 39%), and 13% higher estradiol (95% CI: 4, 24%) compared with lowest quartile. Men in the highest quartile of BPA also had significantly lower percentage progressive motile spermatozoa compared with men in the lowest quartile (–6.7 percentage points, 95% CI: –11.76, –1.63). BPA was not associated with other semen parameters. Adjusting for dietary patterns did not influence the results.
Conclusions: The pattern of associations between BPA and reproductive hormones could indicate an antiandrogenic or antiestrogenic effect, or both, of BPA on the hypothalamic–pituitary–gonadal hormone feedback system, possibly through a competitive inhibition at the receptor level. However, additional research is needed to confirm our findings and to further test the suggested potential mechanisms.
Citation: Lassen TH, Frederiksen H, Jensen TK, Petersen JH, Joensen UN, Main KM, Skakkebaek NE, Juul A, Jørgensen N, Andersson AM. 2014. Urinary bisphenol A levels in young men: association with reproductive hormones and semen quality. Environ Health Perspect 122:478–484;
PMCID: PMC4014766  PMID: 24786630
4.  Characterization of a Recombinant Adeno-Associated Virus Type 2 Reference Standard Material 
Human Gene Therapy  2010;21(10):1273-1285.
Here, the AAV Reference Standard Working Group presents the results of their international collaboration to produce and characterize a recombinant AAV serotype 2 Reference Standard Material. The purpose of this material is to provide a universal standard for particle titer, vector genome titer, and infectious titer for AAV2 gene transfer vectors.
A recombinant adeno-associated virus serotype 2 Reference Standard Material (rAAV2 RSM) has been produced and characterized with the purpose of providing a reference standard for particle titer, vector genome titer, and infectious titer for AAV2 gene transfer vectors. Production and purification of the reference material were carried out by helper virus–free transient transfection and chromatographic purification. The purified bulk material was vialed, confirmed negative for microbial contamination, and then distributed for characterization along with standard assay protocols and assay reagents to 16 laboratories worldwide. Using statistical transformation and modeling of the raw data, mean titers and confidence intervals were determined for capsid particles ({X}, 9.18 × 1011 particles/ml; 95% confidence interval [CI], 7.89 × 1011 to 1.05 × 1012 particles/ml), vector genomes ({X}, 3.28 × 1010 vector genomes/ml; 95% CI, 2.70 × 1010 to 4.75 × 1010 vector genomes/ml), transducing units ({X}, 5.09 × 108 transducing units/ml; 95% CI, 2.00 × 108 to 9.60 × 108 transducing units/ml), and infectious units ({X}, 4.37 × 109 TCID50 IU/ml; 95% CI, 2.06 × 109 to 9.26 × 109 TCID50 IU/ml). Further analysis confirmed the identity of the reference material as AAV2 and the purity relative to nonvector proteins as greater than 94%. One obvious trend in the quantitative data was the degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This relatively poor degree of interlaboratory precision and accuracy was apparent even though attempts were made to standardize the assays by providing detailed protocols and common reagents. This is the first time that such variation between laboratories has been thoroughly documented and the findings emphasize the need in the field for universal reference standards. The rAAV2 RSM has been deposited with the American Type Culture Collection and is available to the scientific community to calibrate laboratory-specific internal titer standards. Anticipated uses of the rAAV2 RSM are discussed.
PMCID: PMC2957240  PMID: 20486768
5.  The pharmacogenetics and pharmacogenomics knowledge base: accentuating the knowledge 
Nucleic Acids Research  2007;36(Database issue):D913-D918.
PharmGKB is a knowledge base that captures the relationships between drugs, diseases/phenotypes and genes involved in pharmacokinetics (PK) and pharmacodynamics (PD). This information includes literature annotations, primary data sets, PK and PD pathways, and expert-generated summaries of PK/PD relationships between drugs, diseases/phenotypes and genes. PharmGKB's website is designed to effectively disseminate knowledge to meet the needs of our users. PharmGKB currently has literature annotations documenting the relationship of over 500 drugs, 450 diseases and 600 variant genes. In order to meet the needs of whole genome studies, PharmGKB has added new functionalities, including browsing the variant display by chromosome and cytogenetic locations, allowing the user to view variants not located within a gene. We have developed new infrastructure for handling whole genome data, including increased methods for quality control and tools for comparison across other data sources, such as dbSNP, JSNP and HapMap data. PharmGKB has also added functionality to accept, store, display and query high throughput SNP array data. These changes allow us to capture more structured information on phenotypes for better cataloging and comparison of data. PharmGKB is available at
PMCID: PMC2238877  PMID: 18032438
6.  Alcohol and male reproductive health: a cross-sectional study of 8344 healthy men from Europe and the USA 
Human Reproduction (Oxford, England)  2014;29(8):1801-1809.
Is there an association between alcohol intake and semen quality and serum reproductive hormones among healthy men from the USA and Europe?
Moderate alcohol intake is not adversely associated with semen quality in healthy men, whereas it was associated with higher serum testosterone levels.
High alcohol intake has been associated with a wide range of diseases. However, few studies have examined the correlation between alcohol and reproductive function and most have been conducted in selected populations of infertile men or have a small sample size and the results have been contradictory.
A coordinated international cross-sectional study among 8344 healthy men. A total of 1872 fertile men aged 18–45 years (with pregnant partners) from four European cities and four US states, and 6472 young men (most with unknown fertility) aged 18–28 years from the general population in six European countries were recruited.
The men were recruited using standardized protocols. A semen analysis was performed and men completed a questionnaire on health and lifestyle, including their intake of beer, wine and liquor during the week prior to their visit. Semen quality (semen volume, sperm concentration, percentage motile and morphologically normal sperm) and serum reproductive hormones (FSH, LH, testosterone, sex hormone-binding globulin, and inhibin B and free testosterone) were examined.
The participation rate for our populations was 20–30%. We found no consistent association between any semen variable and alcohol consumption, which was low/moderate in this group (median weekly intake 8 units), either for total consumption or consumption by type of alcohol. However, we found a linear association between total alcohol consumption and total or free testosterone in both groups of men. Young and fertile men who consumed >20 units of alcohol per week had, respectively, 24.6 pmol/l (95% confidence interval 16.3–32.9) and 19.7 pmol/l (7.1–32.2) higher free testosterone than men with a weekly intake between 1 and 10 units. Alcohol intake was not significantly associated with serum inhibin B, FSH or LH levels in either group of men. The study is the largest of its kind and has sufficient power to detect changes in semen quality and reproductive hormones.
The participation rate was low, but higher than in most previous semen quality studies. In addition, the study was cross-sectional and the men were asked to recall their alcohol intake in the previous week, which was used as a marker of intake up to 3 months before. If consumption in that week differed from the typical weekly intake and the intake 3 months earlier, misclassification of exposure may have occurred. However, the men were unaware of their semen quality when they responded to the questions about alcohol intake. Furthermore, we cannot exclude that our findings are due to unmeasured confounders, including diet, exercise, stress, occupation and risk-taking behavior.
Our study suggests that moderate alcohol intake is not adversely associated with semen quality in healthy men, whereas it was associated with higher serum testosterone levels which may be due to a changed metabolism of testosterone in the liver. Healthy men may therefore be advised that occasional moderate alcohol intake may not harm their reproductive health; we cannot address the risk of high alcohol consumption of longer duration or binge drinking on semen quality and male reproductive hormones.
All funding sources were non-profitable and sponsors of this study played no role in the study design, in data collection, analysis, or interpretation, or in the writing of the article. The authors have no conflicts of interest.
PMCID: PMC4093992  PMID: 24893607
semen quality; alcohol; reproductive hormones; male fertility
7.  Enzyme Architecture: On the Importance of Being in a Protein Cage 
Substrate binding occludes water from the active sites of enzymes. There is a correlation between the burden to enzymatic catalysis of deprotonation of carbon acids and the substrate immobilization at solvent-occluded active sites for ketosteroid isomerase (KSI - small burden, substrate pKa = 13), triosephosphate isomerase (TIM, substrate pKa ≈ 18) and diaminopimelate epimerase (DAP epimerase, large burden, substrate pKa ≈ 29) catalyzed reaction. KSI binds substrates at a surface cleft, TIM binds substrate at an exposed “cage” formed by closure of flexible loops; and, DAP epimerase binds substrate in a tight cage formed by an “oyster-like” clamping motion of protein domains. Directed evolution of a solvent-occluded active site at a designed protein catalyst of the Kemp elimination reaction is discussed.
PMCID: PMC4149950  PMID: 24699188
8.  Canine Distemper Virus Antigen Detection in External Epithelia of Recently Vaccinated, Sick Dogs by Fluorescence Microscopy Is a Valuable Prognostic Indicator 
Journal of Clinical Microbiology  2014;53(2):687-691.
Currently, there are no reliable predictors of the clinical outcomes of domesticated dogs that have been recently vaccinated against canine distemper virus (CDV) and develop respiratory disease. In this study, vaccinated dogs from Oklahoma City that were showing clinical signs of respiratory disease were evaluated for CDV antigen using a direct fluorescent antibody test (FAT). Clinical outcomes after standard symptomatic therapy for respiratory disease were recorded, and a statistical analysis of the results was performed. We present our study showing that CDV FAT results were predictive of clinical recovery (prognostic indicator, prospects of clinical recovery) among vaccinated dogs showing clinical signs of respiratory disease. Negative CDV FAT results equated to 80% chances of recovery after symptomatic therapy, compared to 55% chances of recovery when the CDV FAT results were positive. Based on the results of this study, we show that veterinarians can make better informed decisions about the clinical outcomes of suspected CDV cases, with 2-h turnaround times, by using the CDV FAT. Thus, antemortem examination with the CDV FAT on external epithelia of recently vaccinated, sick dogs is a clinically useful diagnostic test and valuable prognostic indicator for veterinarians. Application of the CDV FAT to these samples avoids unnecessary euthanasia of dogs with suspected CDV.
PMCID: PMC4298560  PMID: 25428156
9.  Cerebellar Networks in Individuals at Ultra High-Risk of Psychosis: Impact on Postural Sway and Symptom Severity 
Human brain mapping  2014;35(8):4064-4078.
Despite known deficits in postural control in patients with schizophrenia, this domain has not been investigated in youth at ultra high-risk (UHR) for psychosis. This is particularly relevant as postural control implicates dysfunction in the cerebellum-a region implicated in cognitive dysmetria conceptions of schizophrenia but poorly understood in the prodrome. Here, we extended our understanding of movement abnormalities in UHR individuals to include postural control, and have linked these deficits to both symptom severity and cerebello-cortical network connectivity. UHR and healthy control participants completed an instrumentally-based balance task to quantify postural control along with a resting state brain imaging scan to investigate cerebellar networks. We also quantified positive and negative symptom severity with structured clinical interviews. The UHR group showed overall increased postural sway and decreased cerebello-cortical resting state connectivity, relative to controls. The decreased cerebello-cortical connectivity was seen across multiple networks. Postural sway was also correlated with cerebellar connectivity in this population and uniquely positively correlated with the severity of negative symptoms. Finally, symptom severity was also associated with cerebellar connectivity. Together, our results point to a potential deficit in sensory integration as an underlying contributor to the increased postural sway, and provide evidence of cerebellar abnormalities in UHR individuals. These results extend our understanding of the motor abnormalities of UHR individuals beyond striatum-based dyskinesias to include postural control and sensory integration deficits, and implicate the cerebellum as a distinct neural substrate preceding the onset of psychosis. Taken together, our results extend the cognitive dysmetria framework to UHR populations.
PMCID: PMC4107098  PMID: 24464473
postural control; ultra high-risk; cerebellum; psychosis; resting state connectivity; symptom severity
10.  Reducing false positive incidental findings with ensemble genotyping and logistic regression-based variant filtering methods 
Human mutation  2014;35(8):936-944.
As whole genome sequencing (WGS) uncovers variants associated with rare and common diseases, an immediate challenge is to minimize false positive findings due to sequencing and variant calling errors. False positives can be reduced by combining results from orthogonal sequencing methods, but costly. Here we present variant filtering approaches using logistic regression (LR) and ensemble genotyping to minimize false positives without sacrificing sensitivity. We evaluated the methods using paired WGS datasets of an extended family prepared using two sequencing platforms and a validated set of variants in NA12878. Using LR or ensemble genotyping based filtering, false negative rates were significantly reduced by 1.1- to 17.8-fold at the same levels of false discovery rates (5.4% for heterozygous and 4.5% for homozygous SNVs; 30.0% for heterozygous and 18.7% for homozygous insertions; 25.2% for heterozygous and 16.6% for homozygous deletions) compared to the filtering based on genotype quality scores. Moreover, ensemble genotyping excluded > 98% (105,080 of 107,167) of false positives while retaining > 95% (897 of 937) of true positives in de novo mutation (DNM) discovery, and performed better than a consensus method using two sequencing platforms. Our proposed methods were effective in prioritizing phenotype-associated variants, and ensemble genotyping would be essential to minimize false positive DNM candidates.
PMCID: PMC4112476  PMID: 24829188
whole-genome sequencing; ensemble genotyping; logistic regression; false positive; incidental finding; de novo mutation discovery
11.  Prostaglandins regulate nuclear localization of Fascin and its function in nucleolar architecture 
Molecular Biology of the Cell  2015;26(10):1901-1917.
Fascin, a conserved actin-bundling protein, is not only cytoplasmic but also localizes to the nucleus and nuclear periphery in both Drosophila and mammalian cell contexts. In Drosophila, prostaglandin signaling regulates this localization. In addition, Fascin plays a critical role in nucleolar architecture in both Drosophila and mammalian cells.
Fascin, a highly conserved actin-bundling protein, localizes and functions at new cellular sites in both Drosophila and multiple mammalian cell types. During Drosophila follicle development, in addition to being cytoplasmic, Fascin is in the nuclei of the germline-derived nurse cells during stages 10B–12 (S10B–12) and at the nuclear periphery during stage 13 (S13). This localization is specific to Fascin, as other actin-binding proteins, Villin and Profilin, do not exhibit the same subcellular distribution. In addition, localization of fascin1 to the nucleus and nuclear periphery is observed in multiple mammalian cell types. Thus the regulation and function of Fascin at these new cellular locations is likely to be highly conserved. In Drosophila, loss of prostaglandin signaling causes a global reduction in nuclear Fascin and a failure to relocalize to the nuclear periphery. Alterations in nuclear Fascin levels result in defects in nucleolar morphology in both Drosophila follicles and cultured mammalian cells, suggesting that nuclear Fascin plays an important role in nucleolar architecture. Given the numerous roles of Fascin in development and disease, including cancer, our novel finding that Fascin has functions within the nucleus sheds new light on the potential roles of Fascin in these contexts.
PMCID: PMC4436834  PMID: 25808493
12.  Permeation of Dopamine Sulfate through the Blood-Brain Barrier 
PLoS ONE  2015;10(7):e0133904.
Dopamine sulfate (DA-3- and DA-4-S) have been determined in the human brain, but it is unclear whether they are locally formed in the central nervous system (CNS), or transported into the CNS from peripheral sources. In the current study, permeation of the blood-brain barrier (BBB) by DA-S was studied by injecting 13C6-labelled regioisomers of DA-S (13DA-3-S and 13DA-4-S) and dopamine (DA) subcutaneously (s.c.) in anesthetized rats, then analyzing brain microdialysis and plasma samples by UPLC-MS/MS. The results in the microdialysis samples demonstrated that brain concentrations of 13DA-S regioisomers clearly increased after the s.c. injections. The concentration of DA did not change, indicating the permeation of DA-S through an intact BBB. The analysis of plasma samples, however, showed that DA-S only permeates the BBB to a small extent, as the concentrations in plasma were substantially higher than in the microdialysis samples. The results also showed that the concentrations of DA-3-S were around three times higher than the concentrations of DA-4-S in rat brain, as well as in the plasma samples after the s.c. injections, indicating that DA-3-S and DA-4-S permeate the BBB with similar efficiency. The fate of 13DA-S in brain was followed by monitoring 13C6-labelled DA-S hydrolysis products, i.e. 13DA and its common metabolites; however, no 13C6-labelled products were detected. This suggests that DA-S either permeates through the BBB back to the peripheral circulation or is dissociated or metabolized by unexpected mechanisms.
PMCID: PMC4514783  PMID: 26207745
13.  Cancer-associated TERT promoter mutations abrogate telomerase silencing 
eLife  null;4:e07918.
Mutations in the human telomerase reverse transcriptase (TERT) promoter are the most frequent non-coding mutations in cancer, but their molecular mechanism in tumorigenesis has not been established. We used genome editing of human pluripotent stem cells with physiological telomerase expression to elucidate the mechanism by which these mutations contribute to human disease. Surprisingly, telomerase-expressing embryonic stem cells engineered to carry any of the three most frequent TERT promoter mutations showed only a modest increase in TERT transcription with no impact on telomerase activity. However, upon differentiation into somatic cells, which normally silence telomerase, cells with TERT promoter mutations failed to silence TERT expression, resulting in increased telomerase activity and aberrantly long telomeres. Thus, TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by telomere shortening without additional tumor-selected mutations. These data establish that TERT promoter mutations can promote immortalization and tumorigenesis of incipient cancer cells.
eLife digest
The bulk of the DNA in the human genome is divided between 23 pairs of chromosomes. The ends of these chromosomes contain a repetitive stretch of DNA known as a telomere. Every time a cell divides, a portion of the telomere is lost and can be restored by an enzyme called telomerase.
If the telomeres shorten below a critical length, the cell can no longer divide and eventually dies. Thus, long telomeres increase the number of times a cell can divide. In the majority of human cells—with the exception of stem cells—telomerase activity is absent due to the down regulation of the active protein component (called TERT) after birth. Therefore, the telomeres in these cells shorten after each cell division. However, 90% of human cancers have very high TERT activity, which enables them to divide continuously to drive tumor growth.
Genes are sections of DNA that code for proteins and other molecules. The start of a gene contains a region known as the promoter, which controls when and where in the body the gene is active. Cancer cells often contain mutations in the promoter of the gene that encodes TERT. However, it remains poorly understood how these mutations lead to the formation of tumors.
Chiba et al. have now used a technique called genome editing to introduce mutations that are commonly found in cancer cells into the promoter of the gene for TERT in human embryonic stem cells. Unexpectedly, these changes did not increase the activity of the telomerase enzyme in these cells, nor did they increase the length of the telomeres.
Chiba et al. next caused these genetically engineered stem cells to develop into more specialized cell types—such as nerve cells. These ‘differentiated’ cells normally silence the gene that encodes TERT, but the mutations prevented the gene from being silenced. This led to abnormally high levels of telomerase activity and long telomeres. The experiments also showed that TERT activity in these cells was similar to that found in cancer cells that can divide indefinitely.
Cells containing the promoter mutations were then injected into mice. The cells formed a mass of tumors that contained very long telomeres. These results together suggest that cancer-causing mutations in the gene for TERT stop this gene from being properly silenced in more specialized cells, and that this, on its own, can promote the formation of tumors. These findings are likely to underpin future efforts to treat cancers by targeting the expression and activity of the telomerase enzyme.
PMCID: PMC4507476  PMID: 26194807
telomerase TERT; immortalization; cancer mechanism; genome editing; tumor spectrum; CRISPR/CRISPR-associated systems 9 CAS9; human
14.  Genome-wide burden of deleterious coding variants increased in schizophrenia 
Nature Communications  2015;6:7501.
Schizophrenia is a common complex disorder with polygenic inheritance. Here we show that by using an approach that compares the individual loads of rare variants in 1,042 schizophrenia cases and 961 controls, schizophrenia cases carry an increased burden of deleterious mutations. At a genome-wide level, our results implicate non-synonymous, splice site as well as stop-altering single-nucleotide variations occurring at minor allele frequency of ≥0.01% in the population. In an independent replication sample of 5,585 schizophrenia cases and 8,103 controls of European ancestry we confirm an enrichment in cases of the alleles identified in our study. In addition, the genes implicated by the increased burden of rare coding variants highlight the involvement of neurodevelopment in the aetiology of schizophrenia.
Schizophrenia is a complex disorder with high heritability but poorly understood genetics. Here Olde Loohuis et al. compare schizophrenia patients to unaffected individuals and identify an increased individual burden of rare deleterious mutations in patients.
PMCID: PMC4499856  PMID: 26158538
15.  Highly efficient and compatible shampoo for use after hair transplant 
Sensitive or hyperreactive skin is a common condition defined by prickling, burning, pain, and pruritus. Although this skin problem was initially described on the face, the scalp is often affected. A sensitive scalp can react with irritation to harsh surfactants or other additives which are often present in shampoos. For this reason, we developed a new rinse-off hypertolerant shampoo specifically designed for the hypersensitive and problematic scalp.
The shampoo formulation is based on an extremely mild surfactant system and contains bisabolol, an anti-irritant and anti-inflammatory ingredient of chamomile. The shampoo is free of additives such as perfumes, silicones, colorants, parabens, paraffins, and betaine. Since skin can remain in a hyperreactive state after wounding, the status after hair transplantation was chosen as a model system to test the shampoo. Scalp condition and compatibility of each volunteer were analyzed by a plastic surgeon directly after hair transplant and after stitch removal. The plastic surgeons also rated whether they would recommend the further use of the test shampoo. Additionally, volunteers completed a self-assessment questionnaire.
Following hair transplantation, regular use of the shampoo resulted in a significant reduction in the extent of scabbing and erythema. This was confirmed by dermatological scalp examinations performed by the plastic surgeon as well as in volunteers’ self-assessments. The plastic surgeon highly recommended the further use of the test shampoo after hair transplant to all study participants.
Application of the test shampoo demonstrated excellent skin compatibility and product efficacy after hair transplant. The test shampoo significantly reduced the extent of scabs and erythema. Therefore, the shampoo is ideally suited for use after hair transplantation and for the treatment of sensitive scalp. The excellent skin compatibility is because of the mild surfactant system, the calming ingredient bisabolol, and the absence of potentially irritating ingredients.
PMCID: PMC4517519
sensitive; scalp; shampoo; bisabolol; hair transplant
16.  Immortalisation with hTERT Impacts on Sulphated Glycosaminoglycan Secretion and Immunophenotype in a Variable and Cell Specific Manner 
PLoS ONE  2015;10(7):e0133745.
Limited options for the treatment of cartilage damage have driven the development of tissue engineered or cell therapy alternatives reliant on ex vivo cell expansion. The study of chondrogenesis in primary cells is difficult due to progressive cellular aging and senescence. Immortalisation via the reintroduction of the catalytic component of telomerase, hTERT, could allow repeated, longitudinal studies to be performed while bypassing senescent phenotypes.
Three human cell types: bone marrow-derived stromal cells (BMA13), embryonic stem cell-derived (1C6) and chondrocytes (OK3) were transduced with hTERT (BMA13H, 1C6H and OK3H) and proliferation, surface marker expression and tri-lineage differentiation capacity determined. The sulphated glycosaminoglycan (sGAG) content of the monolayer and spent media was quantified in maintenance media (MM) and pro-chondrogenic media (PChM) and normalised to DNA.
hTERT expression was confirmed in transduced cells with proliferation enhancement in 1C6H and OK3H cells but not BMA13H. All cells were negative for leukocyte markers (CD19, CD34, CD45) and CD73 positive. CD14 was expressed at low levels on OK3 and OK3H and HLA-DR on BMA13 (84.8%). CD90 was high for BMA13 (84.9%) and OK3 (97.3%) and moderate for 1C6 (56.7%), expression was reduced in BMA13H (33.7%) and 1C6H (1.6%). CD105 levels varied (BMA13 87.7%, 1C6 8.2%, OK3 43.3%) and underwent reduction in OK3H (25.1%). 1C6 and BMA13 demonstrated osteogenic and adipogenic differentiation but mineralised matrix and lipid accumulation appeared reduced post hTERT transduction. Chondrogenic differentiation resulted in increased monolayer-associated sGAG in all primary cells and 1C6H (p<0.001), and BMA13H (p<0.05). In contrast OK3H demonstrated reduced monolayer-associated sGAG in PChM (p<0.001). Media-associated sGAG accounted for ≥55% (PChM-1C6) and ≥74% (MM-1C6H).
In conclusion, hTERT transduction could, but did not always, prevent senescence and cell phenotype, including differentiation potential, was affected in a variable manner. As such, these cells are not a direct substitute for primary cells in cartilage regeneration research.
PMCID: PMC4510558  PMID: 26196672
17.  Regulatory B cells preferentially accumulate in tumor-draining lymph nodes and promote tumor growth 
Scientific Reports  2015;5:12255.
Our previous studies found that B16-F10 melanoma growth in the rear footpad of immunocompetent mice induces marked B cell accumulation within tumor-draining popliteal lymph nodes (TDLN). This B cell accumulation drives TDLN remodeling that precedes and promotes metastasis, indicating a tumor-promoting role for TDLN B cells. Here we show that phenotypic characterization of lymphocytes in mice bearing B16-F10 melanomas identifies preferential accumulation of T2-MZP B cells in the TDLN. Comparison of non-draining LNs and spleens of tumor-bearing mice with LNs and spleens from naïve mice determined that this pattern of B cell accumulation was restricted to the TDLN. B cell-deficient and immunocompetent mice reconstituted with T2-MZP B cells but not with other B cell subsets displayed accelerated tumor growth, demonstrating that T2-MZP B cells possess regulatory activity in tumor-bearing mice. Unlike splenic regulatory B cells, however, these TDLN B cells did not exhibit increased IL-10 production, nor did they promote Treg generation in the TDLN. These findings demonstrate that tumors initially signal via the lymphatic drainage to stimulate the preferential accumulation of T2-MZP regulatory B cells. This local response may be an early and critical step in generating an immunosuppressive environment to permit tumor growth and metastasis.
PMCID: PMC4507466  PMID: 26193241
18.  Systematic Review of Couple-Based HIV Intervention and Prevention Studies: Advantages, Gaps, and Future Directions 
AIDS and behavior  2014;18(10):1864-1887.
We conducted a systematic review of couple-based HIV biobehavioral (skills-building, VCT, and adherence) and biomedical (ART, circumcision) prevention and intervention studies designed to reduce sexual-and drug-risk behaviors and HIV transmission and acquisition. Of the 11,162 papers identified in the search, 93 peer-reviewed papers met the inclusion criteria and yielded a total of 33 studies conducted globally. Biobehavioral couple-based prevention and intervention studies have been efficacious in reducing sexual- and drug-risk behaviors, increasing access to HIV testing and care, and improving adherence. Biomedical couple-based studies were found to reduce HIV incidence among HIV-negative sex partners and viral load among HIV-positive partners. Despite much progress, couple-based HIV prevention and intervention studies remain limited; a number of methodological gaps exist and studies focusing on MSM, people who inject drugs, and sex workers are scarce.
PMCID: PMC4507500  PMID: 24980246
Systematic review; Couple-based; HIV; Prevention; Intervention
19.  Quantifying the Recruitment Challenges with Couple-Based Interventions for Cancer: Applications to Early Stage Breast Cancer 
Psycho-oncology  2009;18(6):667-673.
Despite mounting evidence supporting the use of psychosocial interventions to promote adaptation to cancer, enrolling participants into these interventions is challenging. This is particularly salient for couple-based interventions, and newer, more targeted recruitment strategies to increase enrollment are needed. However, there have been few published empirical studies focused specifically on recruitment–related variables associated with enrollment into these types of interventions. To better understand how to encourage participation in couple-based psychosocial interventions for cancer, we examined facilitating and impeding factors to enrollment into a couple-based intervention for women with early stage breast cancer.
In this sample of 99 women diagnosed with early stage breast cancer, patient demographic variables and method of approaching eligible patients were examined as predictors of enrollment into a randomized controlled trial comparing Couple-Based Relationship Enhancement with treatment-as-usual.
Results indicated that women were more likely to enroll if they were contacted at home or at a follow-up medical appointment rather than when first diagnosed at a busy multidisciplinary clinic; they were also more likely to enroll the closer they lived to the research facility.
In addition to decreasing participant burden, timing and setting of recruitment efforts may have important implications for enhancing participation rates in couple-based intervention studies for cancer.
PMCID: PMC4506748  PMID: 19061201
cancer; oncology; couples and breast cancer; psychosocial; recruitment
20.  ER network formation and membrane fusion by atlastin1/SPG3A disease variants 
Molecular Biology of the Cell  2015;26(9):1616-1628.
Atlastin catalyzes GTP-dependent membrane fusion to form the ER network. Mutations in atlastin1 cause the disease hereditary spastic paraplegia (HSP), implying that defects in ER membrane fusion cause HSP. Surprisingly, several disease variants are functional in assays for ER network formation and membrane fusion, warranting rethinking of HSP causation by atlastin1 mutations.
At least 38 distinct missense mutations in the neuronal atlastin1/SPG3A GTPase are implicated in an autosomal dominant form of hereditary spastic paraplegia (HSP), a motor-neurological disorder manifested by lower limb weakness and spasticity and length-dependent axonopathy of corticospinal motor neurons. Because the atlastin GTPase is sufficient to catalyze membrane fusion and required to form the ER network, at least in nonneuronal cells, it is logically assumed that defects in ER membrane morphogenesis due to impaired fusion activity are the primary drivers of SPG3A-associated HSP. Here we analyzed a subset of established atlastin1/SPG3A disease variants using cell-based assays for atlastin-mediated ER network formation and biochemical assays for atlastin-catalyzed GTP hydrolysis, dimer formation, and membrane fusion. As anticipated, some variants exhibited clear deficits. Surprisingly however, at least two disease variants, one of which represents that most frequently identified in SPG3A HSP patients, displayed wild-type levels of activity in all assays. The same variants were also capable of co-redistributing ER-localized REEP1, a recently identified function of atlastins that requires its catalytic activity. Taken together, these findings indicate that a deficit in the membrane fusion activity of atlastin1 may be a key contributor, but is not required, for HSP causation.
PMCID: PMC4436774  PMID: 25761634
22.  Tandem Duplications and the Limits of Natural Selection in Drosophila yakuba and Drosophila simulans 
PLoS ONE  2015;10(7):e0132184.
Tandem duplications are an essential source of genetic novelty, and their variation in natural populations is expected to influence adaptive walks. Here, we describe evolutionary impacts of recently-derived, segregating tandem duplications in Drosophila yakuba and Drosophila simulans. We observe an excess of duplicated genes involved in defense against pathogens, insecticide resistance, chorion development, cuticular peptides, and lipases or endopeptidases associated with the accessory glands across both species. The observed agreement is greater than expectations on chance alone, suggesting large amounts of convergence across functional categories. We document evidence of widespread selection on the D. simulans X, suggesting adaptation through duplication is common on the X. Despite the evidence for positive selection, duplicates display an excess of low frequency variants consistent with largely detrimental impacts, limiting the variation that can effectively facilitate adaptation. Standing variation for tandem duplications spans less than 25% of the genome in D. yakuba and D. simulans, indicating that evolution will be strictly limited by mutation, even in organisms with large population sizes. Effective whole gene duplication rates are low at 1.17 × 10−9 per gene per generation in D. yakuba and 6.03 × 10−10 per gene per generation in D. simulans, suggesting long wait times for new mutations on the order of thousands of years for the establishment of sweeps. Hence, in cases where adaptation depends on individual tandem duplications, evolution will be severely limited by mutation. We observe low levels of parallel recruitment of the same duplicated gene in different species, suggesting that the span of standing variation will define evolutionary outcomes in spite of convergence across gene ontologies consistent with rapidly evolving phenotypes.
PMCID: PMC4503668  PMID: 26176952
23.  Differential adhesion determines the organization of synaptic fascicles in the Drosophila visual system 
Current biology : CB  2014;24(12):1304-1313.
Neuronal circuits in worms, flies and mammals are organized so as to minimize wiring length for a functional number of synaptic connections, a phenomenon called wiring optimization. However, the molecular mechanisms that establish optimal wiring during development are unknown. We addressed this question by studying the role of N-cadherin in the development of optimally wired neurite fascicles in the peripheral visual system of Drosophila.
Photoreceptor axons surround the dendrites of two post-synaptic targets, lamina cells, within a concentric fascicle called a cartridge. N-cadherin is expressed at higher levels in lamina cells than in photoreceptors, and all genetic manipulations that invert these relative differences displace lamina cells to the periphery and relocate photoreceptor axon terminals into the center.
Differential expression of a single cadherin is both necessary and sufficient to determine cartridge structure by positioning the most adhesive elements that will make the most synapses at the core, surrounded by less adhesive elements that make fewer synapses. These results suggest a general model by which differential adhesion can be utilized to determine the relative positions of axons and dendrites to establish optimal wiring.
PMCID: PMC4500537  PMID: 24881879
24.  Parenting behavior in families of female adolescents with nonsuicidal self-injury in comparison to a clinical and a nonclinical control group 
Nonsuicidal self-injury (NSSI) is often accompanied by dysfunctional familial relationships. Problems within the family are also frequent triggers for NSSI.
The current study investigated the parenting behavior in families of 45 female adolescents with NSSI disorder, 27 adolescents with other mental disorders (clinical controls, CCs), and 44 adolescents without mental disorders (nonclinical controls, NCs). The adolescents and their parents (92 mothers, 24 fathers) were surveyed using self-report measures. The parenting dimensions warmth and support, psychological control, and behavioral control (demands, rules, and discipline), as well as parental psychopathology and parental satisfaction were assessed.
Adolescents with NSSI disorder reported significantly less maternal warmth and support than NCs (d = .64); this group difference was not evident in mothers’ reports. No group differences emerged regarding adolescent-reported paternal parenting behavior. Mothers of adolescents with NSSI reported higher depression, anxiety, and stress scores than mothers in the NC group and less parental satisfaction than mothers in both control groups (CC and NC).
Given the association between NSSI, low levels of adolescent-reported maternal warmth and support and low levels of mother-reported parental satisfaction, clinical interventions for adolescents with NSSI should focus on improving family communication and interaction.
PMCID: PMC4495632  PMID: 26157478
Nonsuicidal self-injury (NSSI); Parenting behavior; Parent–child interaction; Warmth and support
25.  Non-suicidal self-injury maintenance and cessation among adolescents: a one-year longitudinal investigation of the role of objectified body consciousness, depression and emotion dysregulation 
Using the objectification theory, scholars have theorized the sense of detachment and disregard for the body that results from continued body objectification are believed to put a person at greater risk for non-suicidal self-injury (NSSI), due to a lack of emotional investment in the body. The goal of the current study was to longitudinally investigate the association between body objectification and NSSI among an early adolescent sample. The overall sample consisted of 120 participants (56 % female) who ranged in age from 11 to 13 years of age (M = 12.34, SD = .48). Participants were followed over the course of a 12-month period, and classified into three groups of interest; adolescents who reported maintaining NSSI behaviour over the course of a year (NSSI Maintain group, n = 20), adolescents who reported stopping the behaviour over the course of a year (NSSI Stop group, n = 40), and a comparison group of adolescents who did not report engaging in NSSI (n = 60). Using a 3 (NSSI Maintain, NSSI Stop, and Comparison) X 2 (Gender) X 2 (Time 1 and Time 2) repeated measures multiple analysis of variance (MANOVA), results indicated a significant group by time interaction, showing group differences with respect to body shame and body surveillance over time. Specifically, both NSSI groups reported significantly greater body shame and body surveillance over time than the non-NSSI group. Additionally, the NSSI Maintain group reported significantly greater body surveillance at T2 when compared to the NSSI Stop and non-NSSI group. The NSSI Maintain group also reported significantly more emotion dysregulation difficulties and depressive symptoms at T2 when compared to the NSSI Stop and non-NSSI group. The influence of body objectification as a core intrapersonal risk factor related to the maintenance and cessation of NSSI behaviour is discussed, as are clinical implications considering body objectification as an important variable in prevention and treatment efforts.
PMCID: PMC4495797  PMID: 26157480

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