Effect of formant frequency spacing on perceived gender in pre-pubertal children's voices

<div><p>Background</p><p>It is usually possible to identify the sex of a pre-pubertal child from their voice, despite the absence of sex differences in fundamental frequency at these ages. While it has been suggested that the overall spacing between formants (formant frequency spacing - ΔF) is a key component of the expression and perception of sex in children's voices, the effect of its continuous variation on sex and gender attribution has not yet been investigated.</p><p>Methodology/Principal findings</p><p>In the present study we manipulated voice ΔF of eight year olds (two boys and two girls) along continua covering the observed variation of this parameter in pre-pubertal voices, and assessed the effect of this variation on adult ratings of speakers' sex and gender in two separate experiments. In the first experiment (sex identification) adults were asked to categorise the voice as either male or female. The resulting identification function exhibited a gradual slope from male to female voice categories. In the second experiment (gender rating), adults rated the voices on a continuum from “masculine boy” to “feminine girl”, gradually decreasing their masculinity ratings as ΔF increased.</p><p>Conclusions/Significance</p><p>These results indicate that the role of ΔF in voice gender perception, which has been reported in adult voices, extends to pre-pubertal children's voices: variation in ΔF not only affects the perceived sex, but also the perceived masculinity or femininity of the speaker. We discuss the implications of these observations for the expression and perception of gender in children's voices given the absence of anatomical dimorphism in overall vocal tract length before puberty.</p></div

eIF2α Kinases Regulate Development through the BzpR Transcription Factor in Dictyostelium discoideum

A major mechanism of translational regulation in response to a variety of stresses is mediated by phosphorylation of eIF2α to reduce delivery of initiator tRNAs to scanning ribosomes. For some mRNAs, often encoding a bZIP transcription factor, eIF2α phosphorylation leads to enhanced translation due to delayed reinitiation at upstream open reading frames. Dictyostelium cells possess at least three eIF2α kinases that regulate various portions of the starvation-induced developmental program. Cells possessing an eIF2α that cannot be phosphorylated (BS167) show abnormalities in growth and development. We sought to identify a bZIP protein in Dictyostelium whose production is controlled by the eIF2α regulatory system.Cells disrupted in the bzpR gene had similar developmental defects as BS167 cells, including small entities, stalk defects, and reduced spore viability. β-galactosidase production was used to examine translation from mRNA containing the bzpR 5' UTR. While protein production was readily apparent and regulated temporally and spatially in wild type cells, essentially no β-galactosidase was produced in developing BS167 cells even though the lacZ mRNA levels were the same as those in wild type cells. Also, no protein production was observed in strains lacking IfkA or IfkB eIF2α kinases. GFP fusions, with appropriate internal controls, were used to directly demonstrate that the bzpR 5' UTR, possessing 7 uORFs, suppressed translation by 12 fold. Suppression occurred even when all but one uORF was deleted, and translational suppression was removed when the ATG of the single uORF was mutated.The findings indicate that BzpR regulates aspects of the development program in Dictyostelium, serving as a downstream effector of eIF2α phosphorylation. Its production is temporally and spatially regulated by eIF2α phosphorylation by IfkA and IfkB and through the use of uORFs within the bzpR 5' UTR

A comparative sequence analysis reveals a common GBD/FH3-FH1-FH2-DAD architecture in formins from Dictyostelium, fungi and metazoa

BACKGROUND: Formins are multidomain proteins defined by a conserved FH2 (formin homology 2) domain with actin nucleation activity preceded by a proline-rich FH1 (formin homology 1) domain. Formins act as profilin-modulated processive actin nucleators conserved throughout a wide range of eukaryotes. RESULTS: We present a detailed sequence analysis of the 10 formins (ForA to J) identified in the genome of the social amoeba Dictyostelium discoideum. With the exception of ForI and ForC all other formins conform to the domain structure GBD/FH3-FH1-FH2-DAD, where DAD is the Diaphanous autoinhibition domain and GBD/FH3 is the Rho GTPase-binding domain/formin homology 3 domain that we propose to represent a single domain. ForC lacks a FH1 domain, ForI lacks recognizable GBD/FH3 and DAD domains and ForA, E and J have additional unique domains. To establish the relationship between formins of Dictyostelium and other organisms we constructed a phylogenetic tree based on the alignment of FH2 domains. Real-time PCR was used to study the expression pattern of formin genes. Expression of forC, D, I and J increased during transition to multi-cellular stages, while the rest of genes displayed less marked developmental variations. During sexual development, expression of forH and forI displayed a significant increase in fusion competent cells. CONCLUSION: Our analysis allows some preliminary insight into the functionality of Dictyostelium formins: all isoforms might display actin nucleation activity and, with the exception of ForI, might also be susceptible to autoinhibition and to regulation by Rho GTPases. The architecture GBD/FH3-FH1-FH2-DAD appears common to almost all Dictyostelium, fungal and metazoan formins, for which we propose the denomination of conventional formins, and implies a common regulatory mechanism

The relationships between workaholism and symptoms of psychiatric disorders: a large-scale cross-sectional study

Despite the many number of studies examining workaholism, large-scale studies have been lacking. The present study utilized an open web-based cross-sectional survey assessing symptoms of psychiatric disorders and workaholism among 16,426 workers (Mage = 37.3 years, SD = 11.4, range = 16–75 years). Participants were administered the Adult ADHD Self-Report Scale, the Obsession-Compulsive Inventory-Revised, the Hospital Anxiety and Depression Scale, and the Bergen Work Addiction Scale, along with additional questions examining demographic and work-related variables. Correlations between workaholism and all psychiatric disorder symptoms were positive and significant. Workaholism comprised the dependent variable in a three-step linear multiple hierarchical regression analysis. Basic demographics (age, gender, relationship status, and education) explained 1.2% of the variance in workaholism, whereas work demographics (work status, position, sector, and annual income) explained an additional 5.4% of the variance. Age (inversely) and managerial positions (positively) were of most importance. The psychiatric symptoms (ADHD, OCD, anxiety, and depression) explained 17.0% of the variance. ADHD and anxiety contributed considerably. The prevalence rate of workaholism status was 7.8% of the present sample. In an adjusted logistic regression analysis, all psychiatric symptoms were positively associated with being a workaholic. The independent variables explained between 6.1% and 14.4% in total of the variance in workaholism cases. Although most effect sizes were relatively small, the study’s findings expand our understanding of possible psychiatric predictors of workaholism, and particularly shed new insight into the reality of adult ADHD in work life. The study’s implications, strengths, and shortcomings are also discussed

The influence of socioeconomic environment on the effectiveness of alcohol prevention among European students: a cluster randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Although social environments may influence alcohol-related behaviours in youth, the relationship between neighbourhood socioeconomic context and effectiveness of school-based prevention against underage drinking has been insufficiently investigated. We study whether the social environment affects the impact of a new school-based prevention programme on alcohol use among European students.</p> <p>Methods</p> <p>During the school year 2004-2005, 7079 students 12-14 years of age from 143 schools in nine European centres participated in this cluster randomised controlled trial. Schools were randomly assigned to either control or a 12-session standardised curriculum based on the comprehensive social influence model. Randomisation was blocked within socioeconomic levels of the school environment. Alcohol use and alcohol-related problem behaviours were investigated through a self-completed anonymous questionnaire at baseline and 18 months thereafter. Data were analysed using multilevel models, separately by socioeconomic level.</p> <p>Results</p> <p>At baseline, adolescents in schools of low socioeconomic level were more likely to report problem drinking than other students. Participation in the programme was associated in this group with a decreased odds of reporting episodes of drunkenness (OR = 0.60, 95% CI = 0.44-0.83), intention to get drunk (OR = 0.60, 95% CI = 0.45-0.79), and marginally alcohol-related problem behaviours (OR = 0.70, 95% CI = 0.46-1.06). No significant programme's effects emerged for students in schools of medium or high socioeconomic level. Effects on frequency of alcohol consumption were also stronger among students in disadvantaged schools, although the estimates did not attain statistical significance in any subgroup.</p> <p>Conclusions</p> <p>It is plausible that comprehensive social influence programmes have a more favourable effect on problematic drinking among students in underprivileged social environments.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN18092805">ISRCTN18092805</a></p

Cucurbitacin I Inhibits Cell Motility by Indirectly Interfering with Actin Dynamics

Cucurbitacins are plant natural products that inhibit activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway by an unknown mechanism. They are also known to cause changes in the organization of the actin cytoskeleton. actin depolymerization experiments, cucurbitacin I had no effect on the rate of actin filament disassembly at the nanomolar concentrations that inhibit cell migration. At elevated concentrations, the depolymerization rate was also unaffected, although there was a delay in the initiation of depolymerization. Therefore, cucurbitacin I targets some factor involved in cellular actin dynamics other than actin itself. Two candidate proteins that play roles in actin depolymerization are the actin-severing proteins cofilin and gelsolin. Cucurbitacin I possesses electrophilic reactivity that may lead to chemical modification of its target protein, as suggested by structure-activity relationship data. However, mass spectrometry revealed no evidence for modification of purified cofilin or gelsolin by cucurbitacin I.Cucurbitacin I results in accumulation of actin filaments in cells by a unique indirect mechanism. Furthermore, the proximal target of cucurbitacin I relevant to cell migration is unlikely to be the same one involved in activation of the JAK2/STAT3 pathway

In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of β-amyloid plaques associated with Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease, known to be associated with the gradual loss of memory, is characterized by low concentration of acetylcholine in the hippocampus and cortex part of the brain. Inhibition of acetylcholinesterase has successfully been used as a drug target to treat Alzheimer's disease but drug resistance shown by butyrylcholinesterase remains a matter of concern in treating Alzheimer's disease. Apart from the many other reasons for Alzheimer's disease, its association with the genesis of fibrils by β-amyloid plaques is closely related to the increased activity of butyrylcholinesterase. Although few data are available on the inhibition of butyrylcholinesterase, studies have shown that that butyrylcholinesterase is a genetically validated drug target and its selective inhibition reduces the formation of β-amyloid plaques.</p> <p>Rationale</p> <p>We previously reported the inhibition of cholinesterases by 2,3-dihydro-1, 5-benzothiazepines, and considered this class of compounds as promising inhibitors for the cure of Alzheimer's disease. One compound from the same series, when substituted with a hydroxy group at C-3 in ring A and 2-thienyl moiety as ring B, showed greater activity against butyrylcholinesterase than to acetylcholinesterase. To provide insight into the binding mode of this compound (Compound A), molecular docking in combination with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases.</p> <p>Conclusion</p> <p>Molecular docking studies revealed that the potential of Compound A to inhibit cholinesterases was attributable to the cumulative effects of strong hydrogen bonds, cationic-π, π-π interactions and hydrophobic interactions. A comparison of the docking results of Compound A against both cholinesterases showed that amino acid residues in different sub-sites were engaged to stabilize the docked complex. The relatively high affinity of Compound A for butyrylcholinesterase was due to the additional hydrophobic interaction between the 2-thiophene moiety of Compound A and Ile69. The involvement of one catalytic triad residue (His438) of butyrylcholinesterase with the 3'-hydroxy group on ring A increases the selectivity of Compound A. C-C bond rotation around ring A also stabilizes and enhances the interaction of Compound A with butyrylcholinesterase. Furthermore, the classical network of hydrogen bonding interactions as formed by the catalytic triad of butyrylcholinesterase is disturbed by Compound A. This study may open a new avenue for structure-based drug design for Alzheimer's disease by considering the 3D-pharmacophoric features of the complex responsible for discriminating these two closely-related cholinesterases.</p

Development and evaluation of an intervention providing insight into the tobacco industry to prevent smoking uptake: a mixed-methods study

Background Smokers who start smoking at an early age are less likely to quit and more likely to die from their habit. Evidence from the US Truth® campaign suggests that interventions focusing on tobacco industry practices and ethics may be effective in preventing smoking uptake. Objectives In an exploratory study, to develop, pilot and provide preliminary evidence of the acceptability and effectiveness of Operation Smoke Storm, a school-based intervention based on the premise of the Truth® campaign, to prevent smoking uptake. Design Mixed-methods, non-randomised controlled study. Component 1 was delivered to Year 7 students, and student focus groups and teacher interviews were conducted to refine the lessons and to develop components 2 and 3. The revised Year 7 lessons and accompanying family booklet were delivered to new Year 7 students 1 year later in one school only; Year 8 students in both schools received the booster session. Setting and participants Students in Years 7–8 (aged 11–13 years) in two UK schools. Intervention A three-component intervention comprising (1) three 50-minute classroom-based sessions in Year 7 in which students acted as secret agents to uncover industry practices through videos, quizzes, discussions and presentations; (2) an accompanying family booklet containing activities designed to stimulate discussions about smoking between parents and students; and (3) a 1-hour interactive classroom-based booster session for Year 8 students, in which students learnt about tobacco marketing strategies from the perspectives of an industry executive, a marketing company and a health campaigner. Main outcome measures Odds ratios to compare the self-reported prevalence of ever smoking and susceptibility to smoking in Year 8 students after the delivery of the booster session in study schools compared with students in local control schools. Qualitative data on acceptability of the intervention. Results The combined prevalence of ever smoking and susceptibility increased from 18.2% in Year 7 to 33.8% in Year 8. After adjusting for confounders there was no significant difference in the odds of a Year 8 student in an intervention school being an ever smoker or susceptible never smoker compared with controls [adjusted odds ratio (aOR) 1.28, 95% confidence interval (CI) 0.83 to 1.97; p = 0.263] and no significant difference in the odds of ever smoking (aOR 0.82, 95% CI 0.42 to 1.58; p = 0.549). Students mostly enjoyed the intervention and acquired new knowledge that appeared to strengthen their aversion to smoking. Teachers liked the ‘off-the-shelf’ nature of the resource, although they highlighted differences by academic ability in the extent to which students understood the messages being presented. Use of the family component was low but it was received positively by those parents who did engage with it. Limitations Logistical difficulties meant that students’ responses in Year 7 and Year 8 could not be linked; however, baseline smoking behaviours differed little between intervention and control schools, and analyses were adjusted for confounders measured at follow-up. Conclusions Operation Smoke Storm is an acceptable resource for delivering smoking-prevention education but it does not appear to have reduced smoking and susceptibility. Future work The lack of a strong signal for potential effectiveness, considered alongside logistical difficulties in recruiting and working with schools, suggests that a fully powered cluster randomised trial of the intervention is not warranted

DAAM is required for thin filament formation and Sarcomerogenesis during muscle development in Drosophila.

During muscle development, myosin and actin containing filaments assemble into the highly organized sarcomeric structure critical for muscle function. Although sarcomerogenesis clearly involves the de novo formation of actin filaments, this process remained poorly understood. Here we show that mouse and Drosophila members of the DAAM formin family are sarcomere-associated actin assembly factors enriched at the Z-disc and M-band. Analysis of dDAAM mutants revealed a pivotal role in myofibrillogenesis of larval somatic muscles, indirect flight muscles and the heart. We found that loss of dDAAM function results in multiple defects in sarcomere development including thin and thick filament disorganization, Z-disc and M-band formation, and a near complete absence of the myofibrillar lattice. Collectively, our data suggest that dDAAM is required for the initial assembly of thin filaments, and subsequently it promotes filament elongation by assembling short actin polymers that anneal to the pointed end of the growing filaments, and by antagonizing the capping protein Tropomodulin

Elevated levels of β-catenin and fibronectin in three-dimensional collagen cultures of Dupuytren's disease cells are regulated by tension in vitro

BACKGROUND: Dupuytren's contracture or disease (DD) is a fibro-proliferative disease of the hand that results in the development of scar-like, collagen-rich disease cords within specific palmar fascia bands. Although the molecular pathology of DD is unknown, recent evidence suggests that β-catenin may play a role. In this study, collagen matrix cultures of primary disease fibroblasts show enhanced contraction and isometric tension-dependent changes in β-catenin and fibronectin levels. METHODS: Western blots of β-catenin and fibronectin levels were determined for control and disease primary cell cultures grown within stressed- and attached-collagen matrices. Collagen contraction was quantified, and immunocytochemistry analysis of filamentous actin performed. RESULTS: Disease cells exhibited enhanced collagen contraction activity compared to control cells. Alterations in isometric tension of collagen matrices triggered dramatic changes in β-catenin and fibronectin levels, including a transient increase in β-catenin levels within disease cells, while fibronectin levels steadily decreased to levels below those seen in normal cell cultures. In contrast, both fibronectin and β-catenin levels increased in attached collagen-matrix cultures of disease cells, while control cultures showed only increases in fibronectin levels. Immunocytochemistry analysis also revealed extensive filamentous actin networks in disease cells, and enhanced attachment and spreading of disease cell in collagen matrices. CONCLUSION: Three-dimensional collagen matrix cultures of primary disease cell lines are more contractile and express a more extensive filamentous actin network than patient-matched control cultures. The elevated levels of β-catenin and Fn seen in collagen matrix cultures of disease fibroblasts can be regulated by changes in isometric tension