DNA methylation networks underlying mammalian traits.

Using DNA methylation profiles (n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

Multiomic prioritisation of risk genes for anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a psychiatric disorder associated with marked morbidity. Whilst AN genetic studies could identify novel treatment targets, integration of functional genomics data, including transcriptomics and proteomics, would assist to disentangle correlated signals and reveal causally associated genes. METHODS: We used models of genetically imputed expression and splicing from 14 tissues, leveraging mRNA, protein, and mRNA alternative splicing weights to identify genes, proteins, and transcripts, respectively, associated with AN risk. This was accomplished through transcriptome, proteome, and spliceosome-wide association studies, followed by conditional analysis and finemapping to prioritise candidate causal genes. RESULTS: We uncovered 134 genes for which genetically predicted mRNA expression was associated with AN after multiple-testing correction, as well as four proteins and 16 alternatively spliced transcripts. Conditional analysis of these significantly associated genes on other proximal association signals resulted in 97 genes independently associated with AN. Moreover, probabilistic finemapping further refined these associations and prioritised putative causal genes. The gene WDR6, for which increased genetically predicted mRNA expression was correlated with AN, was strongly supported by both conditional analyses and finemapping. Pathway analysis of genes revealed by finemapping identified the pathway regulation of immune system process (overlapping genes = MST1, TREX1, PRKAR2A, PROS1) as statistically overrepresented. CONCLUSIONS: We leveraged multiomic datasets to genetically prioritise novel risk genes for AN. Multiple-lines of evidence support that WDR6 is associated with AN, whilst other prioritised genes were enriched within immune related pathways, further supporting the role of the immune system in AN.

Big brown bats experience slower epigenetic ageing during hibernation.

Comparative analyses of bats indicate that hibernation is associated with increased longevity among species. However, it is not yet known if hibernation affects biological ageing of individuals. Here, we use DNA methylation (DNAm) as an epigenetic biomarker of ageing to determine the effect of hibernation on the big brown bat, Eptesicus fuscus. First, we compare epigenetic age, as predicted by a multi-species epigenetic clock, between hibernating and non-hibernating animals and find that hibernation is associated with epigenetic age. Second, we identify genomic sites that exhibit hibernation-associated change in DNAm, independent of age, by comparing samples taken from the same individual in hibernating and active seasons. This paired comparison identified over 3000 differentially methylated positions (DMPs) in the genome. Genome-wide association comparisons to tissue-specific functional elements reveals that DMPs with elevated DNAm during winter occur at sites enriched for quiescent chromatin states, whereas DMPs with reduced DNAm during winter occur at sites enriched for transcription enhancers. Furthermore, genes nearest DMPs are involved in regulation of metabolic processes and innate immunity. Finally, significant overlap exists between genes nearest hibernation DMPs and genes nearest previously identified longevity DMPs. Taken together, these results are consistent with hibernation influencing ageing and longevity in bats.

DNA methylation predicts age and provides insight into exceptional longevity of bats.

Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.

Investigation of glycaemic traits in psychiatric disorders using Mendelian randomisation revealed a causal relationship with anorexia nervosa.

Data from observational studies have suggested an involvement of abnormal glycaemic regulation in the pathophysiology of psychiatric illness. This may be an attractive target for clinical intervention as glycaemia can be modulated by both lifestyle factors and pharmacological agents. However, observational studies are inherently confounded, and therefore, causal relationships cannot be reliably established. We employed genetic variants rigorously associated with three glycaemic traits (fasting glucose, fasting insulin, and glycated haemoglobin) as instrumental variables in a two-sample Mendelian randomisation analysis to investigate the causal effect of these measures on the risk for eight psychiatric disorders. A significant protective effect of a natural log transformed pmol/L increase in fasting insulin levels was observed for anorexia nervosa after the application of multiple testing correction (OR = 0.48 [95% CI: 0.33-0.71]-inverse-variance weighted estimate). There was no consistently strong evidence for a causal effect of glycaemic factors on the other seven psychiatric disorders considered. The relationship between fasting insulin and anorexia nervosa was supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between insulin levels and anorexia.

Recurrent evolution of extreme longevity in bats.

Bats live longer than similar-sized mammals, but the number of lineages that have independently evolved extreme longevity has not previously been determined. Here we reconstruct the evolution of size-corrected longevity on a recent molecular phylogeny and find that at least four lineages of bats have lifespans more than fourfold those of similar-sized placental mammals, with the ancestral bat projected to live 2.6 times as long. We then evaluate a series of phylogenetic generalized least-squares models containing up to nine variables hypothesized to influence extrinsic mortality. These analyses reveal that body mass and hibernation predict longevity. Among hibernators, longevity is predicted by the absolute value of the median latitude of the species range and cave use, while cave use and lack of sexual dimorphism predict longevity among non-hibernators. The importance of torpor in extending lifespan is further supported by the one lineage with extreme longevity that does not hibernate but exhibits flexible thermoregulation, the common vampire bat. We propose several potential mechanisms that may enable bats to live so long, and suggest that the ability to tolerate a wide range of body temperatures could be important for surviving viral or other pathogen infections.

Male Scent Gland Signals Mating Status in Greater Spear-Nosed Bats, Phyllostomus hastatus.

Chemical signals are ubiquitous, but often overlooked as potentially important for conveying information relevant for sexual selection. The male greater spear-nosed bat, Phyllostomus hastatus, possesses a sexually dimorphic gland on the chest that produces an odoriferous secretion. Here, we investigate the potential for this glandular secretion to act as a sexually selected olfactory signal by examining gland activity in and out of the mating season and determining if variation in its chemical composition reflects variation in male mating status or attributes of the individual. Based on gas chromatography-mass spectrometry (GC-MS) measurements of samples collected from wild bats roosting in caves in Trinidad, West Indies, we find that males that defend and roost with groups of females (harem holders) have significantly different chemical profiles from males found roosting in all male groups (bachelors). Additionally, profiles differed significantly among individuals. Taken together, these results suggest that this chemical signal has the potential to communicate both mating status and individual identity and thus could be used to mediate interactions among individuals within this harem-based social mating system.

Non-kin cooperation in bats.

Many bats are extremely social. In some cases, individuals remain together for years or even decades and engage in mutually beneficial behaviours among non-related individuals. Here, we summarize ways in which unrelated bats cooperate while roosting, foraging, feeding or caring for offspring. For each situation, we ask if cooperation involves an investment, and if so, what mechanisms might ensure a return. While some cooperative outcomes are likely a by-product of selfish behaviour as they are in many other vertebrates, we explain how cooperative investments can occur in several situations and are particularly evident in food sharing among common vampire bats (Desmodus rotundus) and alloparental care by greater spear-nosed bats (Phyllostomus hastatus). Fieldwork and experiments on vampire bats indicate that sharing blood with non-kin expands the number of possible donors beyond kin and promotes reciprocal help by strengthening long-term social bonds. Similarly, more than 25 years of recapture data and field observations of greater spear-nosed bats reveal multiple cooperative investments occurring within stable groups of non-kin. These studies illustrate how bats can serve as models for understanding how cooperation is regulated in social vertebrates.

Delayed abdominal closure in the management of ruptured abdominal aortic aneurysm.

The objective of this study was to compare initial use of the open abdomen using the vacuum-pack technique followed by delayed abdominal closure with standard primary abdominal closure in the treatment of ruptured abdominal aortic aneurysm (rAAA) repair. A retrospective review identified 122 rAAA cases, which were divided into two management eras: era 1 (primarily closed) and era 2 (47% open abdomen).One hundred three patients were included in this review: 58 in era 1 and 45 in era 2. Evidence of one of three ischemia-reperfusion (IR) criteria, preoperative hypotension, estimated blood loss > or = 6 L, or intraoperative resuscitation with > or = 12 L, predicted mortality. These criteria were also used as surrogate clinical markers for abdominal compartment syndrome. The in-hospital mortality was higher in those with at least one IR criterion: 43% versus 10% (p = .0003). In those with at least one IR criterion, the initial 24-hour mortality was 21% for era 1 versus 0% for era 2 (p = .03), and the 30-day mortality was 40% for era 1 and 32% for era 2 (p = .77).Three IR criteria were identified and were associated with increased mortality. Patients with these risk factors who were treated with delayed abdominal closure had an improved acute survival rate and a trend for improved long-term survival.

A comparison of infusion volumes in the measurement of intra-abdominal pressure.

Bladder pressure measurement through a foley catheter is the current standard in monitoring for intraabdominal hypertension (IAH) and abdominal compartment syndrome (ACS). Accurate pressure transduction requires a continuous fluid column with a small volume of transducing medium at the tip of the catheter. Infusing excessive fluid volume can falsely elevate the measured intra-abdominal pressure (IAP) due to bladder overdistention and can lead to intrinsic muscular contraction. This effect can be seen with volumes as low as 60 mL. Recent expert consensus has recommended 25 mL as the maximal infusion volume; however, 50 mL is the most commonly cited volume of infusion in the literature. The purpose of this analysis was to determine the variance between IAP values using a range of volume infusions between 10 and 60 mL. Eighteen adult, surgical intensive care unit (SICU) patients who were undergoing IAP measurement for IAH or clinically indicated monitoring were enrolled in a prospective, nontreatment study. Intra-abdominal pressure measurements were obtained with stepwise increases of injectate volume from 10 to 60 mL (in 10 mL increments). Bland-Altman analyses and receiver operating characteristic (ROC) curves were used for analysis. After analysis accounting for data correlation within patients, means and standard deviations were generated for differences between 50 mL and 10, 20, 30, 40, and 60 mL bladder infusion volumes. Bland-Altman analyses showed good agreement between measurements and no significant difference in variance (mean < or =1.35 mm Hg) between volume comparisons. The ROC curve generated for each test volume using a diagnostic pressure value for IAH (!12 mm Hg) showed that a value between 11 and 12 mm Hg gave the best combination of sensitivity and specificity for all test volumes. In SICU patients, with a clinical indication for IAP monitoring, bladder infusion volumes between 10 mL and 60 mL provide consistent IAP measurements.

One size does not fit all: current disposable laparoscopic devices do not fit the needs of female laparoscopic surgeons.

INTRODUCTION: An increasing number of women are entering the field of general surgery. Because surgical devices have traditionally been targeted at men, we hypothesized that, due to smaller hand size, female general surgery residents would have significantly more difficulty utilizing the "one size fits all" handles of disposable laparoscopic (lap) devices when compared with male residents. METHODS: General surgery residents were anonymously surveyed at four university general surgery training programs. Participants were asked to describe their use of four disposable lap instruments: the lap stapler, lap Harmonic scalpel (Ethicon, Inc., Somerville, New Jersey), lap LigaSure (Valleylab, Boulder, Colorado), and lap retrieval bag. Data were tabulated and analyzed, comparing male with female residents for each instrument as well as according to glove size. RESULTS: A total of 120 residents were asked to participate with 65 anonymous responses (28 women and 37 men). Women's median glove size was significantly smaller than men's (6.5 vs. 7.5, p<0.0001), whereas the clinical year and number of lap cases were not significantly different. Women reported the following devices more awkward than their male counterparts: lap stapler, lap Harmonic scalpel, and the lap LigaSure. Women were more likely to use two hands and describe these devices as "always awkward." When results were analyzed by glove size independently of gender we found that, with increasing glove size, residents were more likely to describe these devices as easy to use and used these devices with only one hand. CONCLUSIONS: Current disposable lap devices are not designed for individuals with small hands. Women have significantly smaller hands than their male counterparts and have difficulty with the "one size fits all" lap device handles. With the increasing number of women entering general surgery programs, this problem will likely persist until devices are designed for surgeons with small hand sizes.