The complete sequence and comparative analysis of ape sex chromosomes.

Apes possess two sex chromosomes-the male-specific Y chromosome and the X chromosome, which is present in both males and females. The Y chromosome is crucial for male reproduction, with deletions being linked to infertility1. The X chromosome is vital for reproduction and cognition2. Variation in mating patterns and brain function among apes suggests corresponding differences in their sex chromosomes. However, owing to their repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the methodology developed for the telomere-to-telomere (T2T) human genome, we produced gapless assemblies of the X and Y chromosomes for five great apes (bonobo (Pan paniscus), chimpanzee (Pan troglodytes), western lowland gorilla (Gorilla gorilla gorilla), Bornean orangutan (Pongo pygmaeus) and Sumatran orangutan (Pongo abelii)) and a lesser ape (the siamang gibbon (Symphalangus syndactylus)), and untangled the intricacies of their evolution. Compared with the X chromosomes, the ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements-owing to the accumulation of lineage-specific ampliconic regions, palindromes, transposable elements and satellites. Many Y chromosome genes expand in multi-copy families and some evolve under purifying selection. Thus, the Y chromosome exhibits dynamic evolution, whereas the X chromosome is more stable. Mapping short-read sequencing data to these assemblies revealed diversity and selection patterns on sex chromosomes of more than 100 individual great apes. These reference assemblies are expected to inform human evolution and conservation genetics of non-human apes, all of which are endangered species.

New cells added to the preoptic area during sex change in the common clownfish Amphiprion ocellaris.

Sex differences in cell number in the preoptic area of the hypothalamus (POA) are documented across all major vertebrate lineages and contribute to differential regulation of the hypothalamic-pituitary-gonad axis and reproductive behavior between the sexes. Sex-changing fishes provide a unique opportunity to study mechanisms underlying sexual differentiation of the POA. In anemonefish (clownfish), which change sex from male to female, females have approximately twice the number of medium-sized cells in the anterior POA compared to males. This sex difference transitions from male-like to female-like during sex change. However, it is not known how this sex difference in POA cell number is established. This study tests the hypothesis that new cell addition plays a role. We initiated adult male-to-female sex change in 30 anemonefish (Amphiprion ocellaris) and administered BrdU to label new cells added to the POA at regular intervals throughout sex change. Sex-changing fish added more new cells to the anterior POA than non-changing fish, supporting the hypothesis. The observed effects could be accounted for by differences in POA volume, but they are also consistent with a steady trickle of new cells being gradually accumulated in the anterior POA before vitellogenic oocytes develop in the gonads. These results provide insight into the unique characteristics of protandrous sex change in anemonefish relative to other modes of sex change, and support the potential for future research in sex-changing fishes to provide a richer understanding of the mechanisms for sexual differentiation of the brain.

Stable and persistent male-like behavior during male-to-female sex change in the common clownfish Amphiprion ocellaris.

Many fish species exhibit natural sex change as part of their life, providing unique opportunities to study sexually-differentiated social behaviors and their plasticity. Past research has shown that behavioral sex change in the female-to-male (protogynous) direction occurs rapidly and well before gonadal sex change. However, little is known about the timecourse of behavioral sex change in male-to-female (protandrous) sex-changing species, limiting our ability to compare patterns of behavioral sex change across species and identify conserved or divergent underlying mechanisms. Using the protandrous sex changing anemonefish Amphiprion ocellaris, we assessed behavior (aggression and parental care) and hormones (estradiol and 11-ketotestosterone) in fish over six months of sex change, and compared those fish against their non-changing partners as well as control males and females. Contrary to expectations, we found that sex-changing fish displayed behavior that was persistently male-like, and that their behavior did not become progressively female-like as sex change progressed. Hormones shifted to an intermediate profile between males and females and remained stable until gonads changed. These results support a new perspective that the timecourse for protandrous sex change in anemonefish is completely distinct from other well-established models, such that behavioral sex change does not occur until after gonadal sex change is complete, and that sex-changing fish have a stable and unique behavioral and hormonal phenotype that is distinct from a male-typical or female-typical phenotype. The results also identify aspects of sex change that may fundamentally differ between protandrous and protogynous modes, motivating further research into these remarkable examples of phenotypic plasticity.

Predictors of access to healthcare professionals for people with intellectual disability in Ireland.

The Irish National Intellectual Disability Database is updated annually and in 2017 contained records for nearly 22,000 persons aged 15 years and over. Information was extracted on the contacts each person had with one of eight health professionals in the years 2007, 2012 and 2017. Over these years, there was an increase in the number of people in contact with any professional or with four and more professionals. Nevertheless, the people less likely to have contact were those with milder forms of intellectual disability, persons living with family carers or independently and those linked to smaller provider agencies. By contrast, the odds of people with more severe disability in residential settings were up to eight times greater for having contact with four or more different professionals. As demand for healthcare grows due to increased longevity and service models shift to the community, redeployment of existing professional resources will be needed along with a review of the skill mix.

Impact of bisphenol-A and synthetic estradiol on brain, behavior, gonads and sex hormones in a sexually labile coral reef fish.

Endocrine disrupting chemicals, such as bisphenol A (BPA) and ethinylestradiol (EE2), are detected in the marine environment from plastic waste and wastewater effluent. However, their impact on reproduction in sexually labile coral reef fish is unknown. The objective of this study was to determine impacts of environmentally relevant concentrations of BPA and EE2 on behavior, brain gene expression, gonadal histology, sex hormone profile, and plasma vitellogenin (Vtg) levels in the anemonefish, Amphiprion ocellaris. A. ocellaris display post-maturational sex change from male to female in nature. Sexually immature, male fish were paired together and fed twice daily with normal food (control), food containing BPA (100 µg/kg), or EE2 (0.02 µg/kg) (n = 9 pairs/group). Aggression toward an intruder male was measured at 1, 3, and 6 months. Blood was collected at 3 and 6 months to measure estradiol (E2), 11-ketotestosterone (11-KT), and Vtg. At the end of the study, fish were euthanized to assess gonad morphology and to measure expression of known sexually dimorphic genes in the brain. Relative to control, BPA decreased aggression, altered brain transcript levels, increased non-vitellogenic and vitellogenic eggs in the gonad, reduced 11-KT, and increased plasma Vtg. In two BPA-treated pairs, both individuals had vitellogenic eggs, which does not naturally occur. EE2 reduced 11-KT in subordinate individuals and altered expression of one transcript in the brain toward the female profile. Results suggest BPA, and to a lesser extent EE2, pollution in coral reef ecosystems could interfere with normal reproductive physiology and behavior of the iconic sexually labile anemonefish.

People with intellectual disability in Ireland are still dying young.

BACKGROUND: People with intellectual disability die younger than their non-disabled peers. In recent years, greater attention has been paid to closing the gap. However, evidence that this is being achieved is limited by the dearth of longitudinal, national data. METHOD: Over 4,000 decedents identified in the Irish National Intellectual Disability Database from 2001 to 2016 were compared to deaths in the general population based on age and gender profiles using death rates and standardised mortality ratios. A binary logistic regression analysis also identified the characteristics of persons who had a higher risk of dying. RESULTS: Irish people with intellectual disability die younger and have a higher rate of death than their non-disabled peers. Nor has the gap between their mortality and that of the general population closed in recent years. CONCLUSIONS: More concentrated effort is needed in Ireland on promoting equitable access to health services for people with intellectual disability.

Family carers of people with intellectual disabilities in Ireland: Changes over 10 years.

Data were obtained on nearly 20,000 Irish children and adults living in various family care arrangements in 2007, 2012, and 2017. Over 10 years, the percentage increase in adult persons living with family carers was three times higher than the rise in the general population, with people aged 50 years and over having the highest proportional increase. Also a greater number of persons aged 40-49 group continued to live with both parents in 2017 (47%) compared to 2007 (33%). However, there was marked variation across the nine Community Health Organization areas in the proportions of adults living with family carers (from 49% to 62%). In the coming decades, increased provision will be required in both the quantum and type of supports provided to families so as to sustain their caring role but ensuring equity of provision nationally will be a major challenge.

Individual and combined effects of GIP and xenin on differentiation, glucose uptake and lipolysis in 3T3-L1 adipocytes.

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP), released postprandially from K-cells, has established actions on adipocytes and lipid metabolism. In addition, xenin, a related peptide hormone also secreted from K-cells after a meal, has postulated effects on energy regulation and lipid turnover. The current study has probed direct individual and combined effects of GIP and xenin on adipocyte function in 3T3-L1 adipocytes, using enzyme-resistant peptide analogues, (d-Ala2)GIP and xenin-25-Gln, and knockdown (KD) of receptors for both peptides. (d-Ala2)GIP stimulated adipocyte differentiation and lipid accumulation in 3T3-L1 adipocytes over 96 h, with xenin-25-Gln evoking similar effects. Combined treatment significantly countered these individual adipogenic effects. Individual receptor KD impaired lipid accumulation and adipocyte differentiation, with combined receptor KD preventing differentiation. (d-Ala2)GIP and xenin-25-Gln increased glycerol release from 3T3-L1 adipocytes, but this lipolytic effect was significantly less apparent with combined treatment. Key adipogenic and lipolytic genes were upregulated by (d-Ala2)GIP or xenin-25-Gln, but not by dual peptide culture. Similarly, both (d-Ala2)GIP and xenin-25-Gln stimulated insulin-induced glucose uptake in 3T3-L1 adipocytes, but this effect was annulled by dual treatment. In conclusion, GIP and xenin possess direct, comparable, lipogenic and lipolytic actions in 3T3-L1 adipocytes. However, effects on lipid metabolism are significantly diminished by combined administration.

Exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice.

BACKGROUND: Therapeutic benefits of peptide-based drugs is limited by rapid renal elimination. METHODS: Therefore, to prolong the biological action profile of the recently characterized triple-acting hybrid peptide, exendin-4/gastrin/xenin-8-Gln, a fatty acid (C-16) has been covalently attached, creating exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln. Exendin-4/gastrin and liraglutide/gastrin/xenin-8-Gln were also synthesized as direct comparator peptides. RESULTS: All hybrid peptides evoked significant concentration-dependent increases of insulin secretion from isolated murine islets and BRIN-BD11 cells. Following administration of peptides with glucose to mice, all hybrids significantly reduced the overall glycaemic excursion and increased insulin concentrations. In contrast to other treatments, exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln displayed impressive antihyperglycaemic actions even 12 hours after administration, highlighting protracted duration of effects. Exendin-4/gastrin/xenin-8-Gln, exendin-4/gastrin, and exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln were then progressed to a 31-day twice-daily treatment regimen in obese-diabetic ob/ob mice. All treatments decreased nonfasting glucose and HbA1c concentrations, as well as enhancing circulating and pancreatic insulin levels. Exendin-4/gastrin and exendin-4/gastrin/xenin-8-Gln also decreased food intake. Glucose tolerance was improved by all treatments, but only exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln augmented glucose-induced insulin secretion. Interestingly, treatment regimens that included a xenin component induced clear advantages on the metabolic response to glucose-dependent insulinotropic polypeptide (GIP) and the glucose-lowering actions of insulin. CONCLUSION: This study emphasizes the therapeutic promise of long-acting, multi-targeting hybrid gut peptides for type 2 diabetes.

Ultraviolet light and melanoma.

Melanoma is a clinically heterogeneous disease, and current strategies for treatment of the primary tumour are based on pathological criteria alone. In the recent past, several DNA-sequencing and RNA-sequencing studies of primary and advanced melanoma samples have identified unique relationships between somatic mutations, genomic aberrations, and the genetic fingerprint of ultraviolet radiation (UVR). The recurrent patterns of genomic alterations reveal different disease pathways, drug targets and mechanisms limiting drug response. Here, we examine the known associations between the molecular categories of melanoma and the multidimensional UVR damage. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Emerging therapeutic potential for xenin and related peptides in obesity and diabetes.

Xenin-25 is a 25-amino acid peptide hormone co-secreted from the same enteroendocrine K-cell as the incretin peptide glucose-dependent insulinotropic polypeptide. There is no known specific receptor for xenin-25, but studies suggest that at least some biological actions may be mediated through interaction with the neurotensin receptor. Original investigation into the physiological significance of xenin-25 focussed on effects related to gastrointestinal transit and satiety. However, xenin-25 has been demonstrated in pancreatic islets and recently shown to possess actions in relation to the regulation of insulin and glucagon secretion, as well as promoting beta-cell survival. Accordingly, the beneficial impact of xenin-25, and related analogues, has been assessed in animal models of diabetes-obesity. In addition, studies have demonstrated that metabolically active fragment peptides of xenin-25, particularly xenin-8, possess independent therapeutic promise for diabetes, as well as serving as bioactive components for the generation of multi-acting hybrid peptides with antidiabetic potential. This review focuses on continuing developments with xenin compounds in relation to new therapeutic approaches for diabetes-obesity.

Irish persons with intellectual disability moving from family care to residential accommodation in a period of austerity.

BACKGROUND: Ireland has a growing population of adult persons living with family carers, thereby increasing the demand for residential places. Simultaneously, government policy aimed to reprovision residents living in congregated settings but at a time when funding was curtailed due to the economic crisis. This study examines the movements of people into and among three types of residential options between 2009 and 2014. METHOD: A cohort of 20,163 persons recorded on the National Intellectual Disability Database in 2009 was identified and tracked to the 2014 database. RESULTS: An estimated 200 persons per annum (@1.6% of those living with families) moved from family care although the number of places available nationally fell by 9%. Moreover, transfers of existing residents into vacated places tended to exceed those from families. CONCLUSIONS: More people will have to continue living with their families and for longer if funding for new places remains curtailed.

Perspectives of family members of people with an intellectual disability to a major reconfiguration of living arrangements for people with intellectual disability in Ireland.

AIM: To document the views of family members of people with an intellectual disability regarding implementation of a personalized model of social support in Ireland. METHOD: Forty family members participated in six focus groups. Data were thematically analysed. RESULTS: Family members' preference for particular types of living arrangements were highly reflective of their lived experience. Facilitators to community living included timely information on proposed moves, adequate staffing, suitable properties and locations and consideration of the characteristics of individuals who share a property. Barriers included high support needs, advanced age, a fear of relinquishing current supports, a fear of the sustainability of newer models of residential support and concerns about community opposition. CONCLUSION: The family perspective to reform is characterized by fear and suspicion of the motivation behind these reforms, with cost efficiencies being perceived as a main driver. Greater information is required to empower families to make informed decisions.

Monitoring the prevalence of severe intellectual disability in children across Europe: feasibility of a common database.

AIM: Our aim was to study the feasibility of creating a framework for monitoring and undertaking collaborative research on intellectual disability at the European level, based on existing databases of children with such disability. METHOD: The characteristics of five existing European intellectual disability databases from four countries (Iceland, Latvia, Ireland, and two in France), were discussed on the basis of ideal criteria set by a working group on childhood intellectual disability as part of the Surveillance of Cerebral Palsy in Europe Network (SCPE-NET). Mean prevalence values for severe intellectual disability for the birth years 1990 till 2002 were compared across databases. RESULTS: Methods of case recruitment and diagnosis differed across databases, but classification of intellectual disability and completeness were similar. Severe intellectual disability (IQ<50) prevalence estimates were significantly (p<0.001) different across databases (south-east France: 3.3 out of 1000; south-west France: 3.0 out of 1000; Latvia: 3.9 out of 1000; Ireland: 5.0 out of 1000; and Iceland 5.1 out of 1000). INTERPRETATION: In spite of differences in diagnosis and case inclusion across databases, the construction of a common database for severe intellectual disability was deemed feasible through harmonization of certain criteria, such as age, and through restriction to those with severe intellectual disability.

Early removal of urinary catheter after surgery requiring thoracic epidural: a prospective trial.

OBJECTIVES: To prevent urinary retention, urinary catheters commonly are removed only after thoracic epidural discontinuation after thoracotomy. However, prolonged catheterization increases the risk of infection. The purpose of this study was to determine the rates of urinary retention and catheter-associated infection after early catheter removal. DESIGN: This study described a prospective trial instituting an early urinary catheter removal protocol compared with a historic control group of patients. SETTING: The protocol was instituted at a single, academic thoracic surgery unit. PARTICIPANTS: The study group was comprised of patients undergoing surgery requiring thoracotomy who received an intraoperative epidural for postoperative pain control. INTERVENTIONS: An early urinary catheter removal protocol was instituted prospectively, with all catheters removed on or before postoperative day 2. Urinary retention was determined by bladder ultrasound and treated with recatheterization. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were urinary retention rate, defined as bladder volume>400 mL, and urinary tract infection rate. Results were compared with a retrospective cohort of 210 consecutive patients who underwent surgery before protocol initiation. Among the 101 prospectively enrolled patients, urinary retention rate was higher (26.7% v 12.4%, p = 0.003), while urinary tract infection rate improved moderately (1% v 3.8%, p = 0.280). CONCLUSIONS: Early removal of urinary catheters with thoracic epidurals in place is associated with a high incidence of urinary retention. However, an early catheter removal protocol may play a role in a multifaceted approach to reducing the incidence of catheter-associated urinary tract infections.

Prebrief Time for Immersive Virtual and Augmented Reality Simulation: An Integrative Review.

BACKGROUND: Virtual reality and augmented technology are rapidly advancing and hold the potential to transform nursing education by offering a convenient, efficient, learner-centered way to educate students. A comprehensive and time-oriented prebrief is essential to the process. PURPOSE: This review analyzes the status of scientific exploration regarding the prebrief and time allotments for virtual and augmented reality simulation. METHODS: Whittemore and Knafl's 5-stage method guided this integrative review. The authors searched 6 databases and selected 7 articles based on inclusion criteria. RESULTS: The findings from this review demonstrated objectives, a safe learning environment, orientation, preparation materials, and time in the prebrief; yet, inconsistencies persist in the virtual and augmented reality prebrief. CONCLUSIONS: Defining a comprehensive and consistent prebrief is essential for high-quality simulation. A more standardized process, including time allotments, must be established for virtual and augmented reality.

In vivo detection of DNA secondary structures using permanganate/S1 footprinting with direct adapter ligation and sequencing (PDAL-Seq).

DNA secondary structures are essential elements of the genomic landscape, playing a critical role in regulating various cellular processes. These structures refer to G-quadruplexes, cruciforms, Z-DNA or H-DNA structures, amongst others (collectively called 'non-B DNA'), which DNA molecules can adopt beyond the B conformation. DNA secondary structures have significant biological roles, and their landscape is dynamic and can rearrange due to various factors, including changes in cellular conditions, temperature, and DNA-binding proteins. Understanding this dynamic nature is crucial for unraveling their functions in cellular processes. Detecting DNA secondary structures remains a challenge. Conventional methods, such as gel electrophoresis and chemical probing, have limitations in terms of sensitivity and specificity. Emerging techniques, including next-generation sequencing and single-molecule approaches, offer promise but face challenges since these techniques are mostly limited to only one type of secondary structure. Here we describe an updated version of a technique permanganate/S1 nuclease footprinting, which uses potassium permanganate to trap single-stranded DNA regions as found in many non-B structures, in combination with S1 nuclease digest and adapter ligation to detect genome-wide non-B formation. To overcome technical hurdles, we combined this method with direct adapter ligation and sequencing (PDAL-Seq). Furthermore, we established a user-friendly pipeline available on Galaxy to standardize PDAL-Seq data analysis. This optimized method allows the analysis of many types of DNA secondary structures that form in a living cell and will advance our knowledge of their roles in health and disease.

Methylation profiles at birth linked to early childhood obesity.

Childhood obesity represents a significant global health concern and identifying its risk factors is crucial for developing intervention programs. Many "omics" factors associated with the risk of developing obesity have been identified, including genomic, microbiomic, and epigenomic factors. Here, using a sample of 48 infants, we investigated how the methylation profiles in cord blood and placenta at birth were associated with weight outcomes (specifically, conditional weight gain, body mass index, and weight-for-length ratio) at age six months. We characterized genome-wide DNA methylation profiles using the Illumina Infinium MethylationEpic chip, and incorporated information on child and maternal health, and various environmental factors into the analysis. We used regression analysis to identify genes with methylation profiles most predictive of infant weight outcomes, finding a total of 23 relevant genes in cord blood and 10 in placenta. Notably, in cord blood, the methylation profiles of three genes (PLIN4, UBE2F, and PPP1R16B) were associated with all three weight outcomes, which are also associated with weight outcomes in an independent cohort suggesting a strong relationship with weight trajectories in the first six months after birth. Additionally, we developed a Methylation Risk Score (MRS) that could be used to identify children most at risk for developing childhood obesity. While many of the genes identified by our analysis have been associated with weight-related traits (e.g., glucose metabolism, BMI, or hip-to-waist ratio) in previous genome-wide association and variant studies, our analysis implicated several others, whose involvement in the obesity phenotype should be evaluated in future functional investigations.

Methylation profiles at birth linked to early childhood obesity.

Childhood obesity represents a significant global health concern and identifying risk factors is crucial for developing intervention programs. Many 'omics' factors associated with the risk of developing obesity have been identified, including genomic, microbiomic, and epigenomic factors. Here, using a sample of 48 infants, we investigated how the methylation profiles in cord blood and placenta at birth were associated with weight outcomes (specifically, conditional weight gain, body mass index, and weight-for-length ratio) at age six months. We characterized genome-wide DNA methylation profiles using the Illumina Infinium MethylationEpic chip, and incorporated information on child and maternal health, and various environmental factors into the analysis. We used regression analysis to identify genes with methylation profiles most predictive of infant weight outcomes, finding a total of 23 relevant genes in cord blood and 10 in placenta. Notably, in cord blood, the methylation profiles of three genes (PLIN4, UBE2F, and PPP1R16B) were associated with all three weight outcomes, which are also associated with weight outcomes in an independent cohort suggesting a strong relationship with weight trajectories in the first six months after birth. Additionally, we developed a Methylation Risk Score (MRS) that could be used to identify children most at risk for developing childhood obesity. While many of the genes identified by our analysis have been associated with weight-related traits (e.g., glucose metabolism, BMI, or hip-to-waist ratio) in previous genome-wide association and variant studies, our analysis implicated several others, whose involvement in the obesity phenotype should be evaluated in future functional investigations.