Using the 3D Facial Norms Database to investigate craniofacial sexual dimorphism in healthy children, adolescents, and adults

Background: Although craniofacial sex differences have been extensively studied in humans, relatively little is known about when various dimorphic features manifest during postnatal life. Using cross-sectional data derived from the 3D Facial Norms data repository, we tested for sexual dimorphism of craniofacial soft-tissue morphology at different ages. Methods: One thousand five hundred fifty-five individuals, pre-screened for craniofacial conditions, between 3 and 25 years of age were placed in to one of six age-defined categories: early childhood, late childhood, puberty, adolescence, young adult, and adult. At each age group, sex differences were tested by ANCOVA for 29 traditional soft-tissue anthropometric measurements collected from 3D facial scans. Additionally, sex differences in shape were tested using a geometric morphometric analysis of 24 3D facial landmarks. Results: Significant (p < 0.05) sex differences were observed in every age group for measurements covering multiple aspects of the craniofacial complex. The magnitude of the dimorphism generally increased with age, with large spikes in the nasal, cranial, and facial measurements observed after puberty. Significant facial shape differences (p < 0.05) were also seen at each age, with some dimorphic features already present in young children (eye fissure inclination) and others emerging only after puberty (mandibular position). Conclusions: Several craniofacial soft-tissue sex differences were already present in the youngest age group studied, indicating that these differences emerged prior to 3 years of age. The results paint a complex and heterogeneous picture, with different groups of traits exhibiting distinct patterns of dimorphism during ontogeny. The definitive adult male and female facial shape was present following puberty, but arose from numerous distinct changes taking place at earlier stages

Extending Epigenesis: From Phenotypic Plasticity to the Bio-Cultural Feedback

The paper aims at proposing an extended notion of epigenesis acknowledging an actual causal import to the phenotypic dimension for the evolutionary diversification of life forms. Section 1 offers introductory remarks on the issue of epigenesis contrasting it with ancient and modern preformationist views. In Section 2 we propose to intend epigenesis as a process of phenotypic formation and diversification a) dependent on environmental influences, b) independent of changes in the genomic nucleotide sequence, and c) occurring during the whole life span. Then, Section 3 focuses on phenotypic plasticity and offers an overview of basic properties (like robustness, modularity and degeneracy) that allows biological systems to be evolvable – i.e. to have the potentiality of producing phenotypic variation. Successively (Section 4), the emphasis is put on environmentally-induced modification in the regulation of gene expression giving rise to phenotypic variation and diversification. After some brief considerations on the debated issue of epigenetic inheritance (Section 5), the issue of culture (kept in the background of the preceding sections) is considered. The key point is that, in the case of humans and of the evolutionary history of the genus Homo at least, the environment is also, importantly, the cultural environment. Thus, Section 6 argues that a bio-cultural feedback should be acknowledged in the “epigenic” processes leading to phenotypic diversification and innovation in Homo evolution. Finally, Section 7 introduces the notion of “cultural neural reuse”, which refers to phenotypic/neural modifications induced by specific features of the cultural environment that are effective in human cultural evolution without involving genetic changes. Therefore, cultural neural reuse may be regarded as a key instance of the bio-cultural feedback and ultimately of the extended notion of epigenesis proposed in this work

Influence of the Temperature and the Genotype of the HSP90AA1 Gene over Sperm Chromatin Stability in Manchega Rams

The present study addresses the effect of heat stress on males' reproduction ability. For that, we have evaluated the sperm DNA fragmentation (DFI) by SCSA of ejaculates incubated at 37°C during 0, 24 and 48 hours after its collection, as a way to mimic the temperature circumstances to which spermatozoa will be subject to in the ewe uterus. The effects of temperature and temperature-humidity index (THI) from day 60 prior collection to the date of semen collection on DFI were examined. To better understand the causes determining the sensitivity of spermatozoa to heat, this study was conducted in 60 males with alternative genotypes for the SNP G/C−660 of the HSP90AA1 promoter, which encode for the Hsp90α protein. The Hsp90α protein predominates in the brain and testis, and its role in spermatogenesis has been described in several species. Ridge regression analyses showed that days 29 to 35 and 7 to 14 before sperm collection (bsc) were the most critical regarding the effect of heat stress over DFI values. Mixed model analyses revealed that DFI increases over a threshold of 30°C for maximum temperature and 22 for THI at days 29 to 35 and 7 to 14 bsc only in animals carrying the GG−660 genotype. The period 29–35 bsc coincide with the meiosis I process for which the effect of the Hsp90α has been described in mice. The period 7–14 bsc may correspond with later stages of the meiosis II and early stages of epididymal maturation in which the replacement of histones by protamines occurs. Because of GG−660 genotype has been associated to lower levels of HSP90AA1 expression, suboptimal amounts of HSP90AA1 mRNA in GG−660 animals under heat stress conditions make spermatozoa DNA more susceptible to be fragmented. Thus, selecting against the GG−660 genotype could decrease the DNA fragmentation and spermatozoa thermal susceptibility in the heat season, and its putative subsequent fertility gainsPublishe

Balancing repair and tolerance of DNA damage caused by alkylating agents

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity

A framework for the first‑person internal sensation of visual perception in mammals and a comparable circuitry for olfactory perception in Drosophila

Perception is a first-person internal sensation induced within the nervous system at the time of arrival of sensory stimuli from objects in the environment. Lack of access to the first-person properties has limited viewing perception as an emergent property and it is currently being studied using third-person observed findings from various levels. One feasible approach to understand its mechanism is to build a hypothesis for the specific conditions and required circuit features of the nodal points where the mechanistic operation of perception take place for one type of sensation in one species and to verify it for the presence of comparable circuit properties for perceiving a different sensation in a different species. The present work explains visual perception in mammalian nervous system from a first-person frame of reference and provides explanations for the homogeneity of perception of visual stimuli above flicker fusion frequency, the perception of objects at locations different from their actual position, the smooth pursuit and saccadic eye movements, the perception of object borders, and perception of pressure phosphenes. Using results from temporal resolution studies and the known details of visual cortical circuitry, explanations are provided for (a) the perception of rapidly changing visual stimuli, (b) how the perception of objects occurs in the correct orientation even though, according to the third-person view, activity from the visual stimulus reaches the cortices in an inverted manner and (c) the functional significance of well-conserved columnar organization of the visual cortex. A comparable circuitry detected in a different nervous system in a remote species-the olfactory circuitry of the fruit fly Drosophila melanogaster-provides an opportunity to explore circuit functions using genetic manipulations, which, along with high-resolution microscopic techniques and lipid membrane interaction studies, will be able to verify the structure-function details of the presented mechanism of perception

New Pharmacological Agents to Aid Smoking Cessation and Tobacco Harm Reduction: What has been Investigated and What is in the Pipeline?

A wide range of support is available to help smokers to quit and aid attempts at harm reduction, including three first-line smoking cessation medications: nicotine replacement therapy, varenicline and bupropion. Despite the efficacy of these, there is a continual need to diversify the range of medications so that the needs of tobacco users are met. This paper compares the first-line smoking cessation medications to: 1) two variants of these existing products: new galenic formulations of varenicline and novel nicotine delivery devices; and 2) twenty-four alternative products: cytisine (novel outside of central and eastern Europe), nortriptyline, other tricyclic antidepressants, electronic cigarettes, clonidine (an anxiolytic), other anxiolytics (e.g. buspirone), selective 5-hydroxytryptamine (5-HT) reuptake inhibitors, supplements (e.g. St John’s wort), silver acetate, nicobrevin, modafinil, venlafaxine, monoamine oxidase inhibitors (MAOI), opioid antagonist, nicotinic acetylcholine receptors (nAChR) antagonists, glucose tablets, selective cannabinoid type 1 receptor antagonists, nicotine vaccines, drugs that affect gamma-aminobutyric acid (GABA) transmission, drugs that affect N-methyl-D-aspartate receptors (NMDA), dopamine agonists (e.g. levodopa), pioglitazone (Actos; OMS405), noradrenaline reuptake inhibitors, and the weight management drug lorcaserin. Six criteria are used: relative efficacy, relative safety, relative cost, relative use (overall impact of effective medication use), relative scope (ability to serve new groups of patients), and relative ease of use (ESCUSE). Many of these products are in the early stages of clinical trials, however, cytisine looks most promising in having established efficacy and safety and being of low cost. Electronic cigarettes have become very popular, appear to be efficacious and are safer than smoking, but issues of continued dependence and possible harms need to be considered

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Understanding patient acceptance and refusal of HIV testing in the emergency department

<p>ABSTRACT</p> <p>Background</p> <p>Despite high rates of patient satisfaction with emergency department (ED) HIV testing, acceptance varies widely. It is thought that patients who decline may be at higher risk for HIV infection, thus we sought to better understand patient acceptance and refusal of ED HIV testing.</p> <p>Methods</p> <p>In-depth interviews with fifty ED patients (28 accepters and 22 decliners of HIV testing) in three ED HIV testing programs that serve vulnerable urban populations in northern California.</p> <p>Results</p> <p>Many factors influenced the decision to accept ED HIV testing, including curiosity, reassurance of negative status, convenience, and opportunity. Similarly, a number of factors influenced the decision to decline HIV testing, including having been tested recently, the perception of being at low risk for HIV infection due to monogamy, abstinence or condom use, and wanting to focus on the medical reason for the ED visit. Both accepters and decliners viewed ED HIV testing favorably and nearly all participants felt comfortable with the testing experience, including the absence of counseling. While many participants who declined an ED HIV test had logical reasons, some participants also made clear that they would prefer not to know their HIV status rather than face psychosocial consequences such as loss of trust in a relationship or disclosure of status in hospital or public health records.</p> <p>Conclusions</p> <p>Testing for HIV in the ED as for any other health problem reduces barriers to testing for some but not all patients. Patients who decline ED HIV testing may have rational reasons, but there are some patients who avoid HIV testing because of psychosocial ramifications. While ED HIV testing is generally acceptable, more targeted approaches to testing are necessary for this subgroup.</p

The unfolded protein response and its relevance to connective tissue diseases

The unfolded protein response (UPR) has evolved to counter the stresses that occur in the endoplasmic reticulum (ER) as a result of misfolded proteins. This sophisticated quality control system attempts to restore homeostasis through the action of a number of different pathways that are coordinated in the first instance by the ER stress-senor proteins IRE1, ATF6 and PERK. However, prolonged ER-stress-related UPR can have detrimental effects on cell function and, in the longer term, may induce apoptosis. Connective tissue cells such as fibroblasts, osteoblasts and chondrocytes synthesise and secrete large quantities of proteins and mutations in many of these gene products give rise to heritable disorders of connective tissues. Until recently, these mutant gene products were thought to exert their effect through the assembly of a defective extracellular matrix that ultimately disrupted tissue structure and function. However, it is now becoming clear that ER stress and UPR, because of the expression of a mutant gene product, is not only a feature of, but may be a key mediator in the initiation and progression of a whole range of different connective tissue diseases. This review focuses on ER stress and the UPR that characterises an increasing number of connective tissue diseases and highlights novel therapeutic opportunities that may arise

Composite transcriptome assembly of RNA-seq data in a sheep model for delayed bone healing

<p>Abstract</p> <p>Background</p> <p>The sheep is an important model organism for many types of medically relevant research, but molecular genetic experiments in the sheep have been limited by the lack of knowledge about ovine gene sequences.</p> <p>Results</p> <p>Prior to our study, mRNA sequences for only 1,556 partial or complete ovine genes were publicly available. Therefore, we developed a composite <it>de novo </it>transcriptome assembly method for next-generation sequence data to combine known ovine mRNA and EST sequences, mRNA sequences from mouse and cow, and sequences assembled <it>de novo </it>from short read RNA-Seq data into a composite reference transcriptome, and identified transcripts from over 12 thousand previously undescribed ovine genes. Gene expression analysis based on these data revealed substantially different expression profiles in standard versus delayed bone healing in an ovine tibial osteotomy model. Hundreds of transcripts were differentially expressed between standard and delayed healing and between the time points of the standard and delayed healing groups. We used the sheep sequences to design quantitative RT-PCR assays with which we validated the differential expression of 26 genes that had been identified by RNA-seq analysis. A number of clusters of characteristic expression profiles could be identified, some of which showed striking differences between the standard and delayed healing groups. Gene Ontology (GO) analysis showed that the differentially expressed genes were enriched in terms including <it>extracellular matrix</it>, <it>cartilage development</it>, <it>contractile fiber</it>, and <it>chemokine activity</it>.</p> <p>Conclusions</p> <p>Our results provide a first atlas of gene expression profiles and differentially expressed genes in standard and delayed bone healing in a large-animal model and provide a number of clues as to the shifts in gene expression that underlie delayed bone healing. In the course of our study, we identified transcripts of 13,987 ovine genes, including 12,431 genes for which no sequence information was previously available. This information will provide a basis for future molecular research involving the sheep as a model organism.</p