Search

Controlling exciton coupling in DNA templated dye aggregates is achieved by modifying sterics and hydrophobicity of Cy5-R dyes (varying the 5,5′-substituents). We conclude that sterics play the main role in orientation and coupling strength.

While only one enantiomer of chiral biomolecules performs a biological function, access to both enantiomers (or enantiomorphs) proved to be advantageous for technology. Using dye covalent attachment to a DNA Holliday junction (HJ), we created two pairs of dimers of bis(chloroindolenine)squaraine dye that enabled strongly coupled molecular excitons of opposite chirality in solution. The exciton chirality inversion was achieved by interchanging single covalent linkers of unequal length tethering the dyes of each dimer to the HJ core. Dimers in each pair exhibited profound exciton-coupled circular dichroism (CD) couplets of opposite signs. Dimer geometries, modeled by simultaneous fitting absorption and CD spectra, were related in each pair as nonsuperimposable and nearly exact mirror images. The origin of observed exciton chirality inversion was explained in the view of isomerization of the stacked Holliday junction. This study will open new opportunities for creating excitonic DNA-based materials that rely on programmable system chirality.

Background: External contexts, including the social and physical contexts, are independent predictors of momentary physical activity and sedentary behaviors. However, no studies to date have examined how external contexts are related to overall momentary movement behavior compositions using compositional data analysis. Therefore, this study aimed to determine differences in momentary movement behavior compositions between different social and physical contexts in adolescents. Methods: Overall, 119 adolescents (mean age 14.7 y, SD = 1.44) provided details about their momentary physical and social contexts over 4 days using ecological momentary assessment. Sedentary behaviors, light-intensity physical activity, and moderate to vigorous physical activity were assessed using ActiGraph GT3X+ accelerometers. Compositional multivariate multilevel models were estimated to determine if movement behavior compositions differed between contexts. Results: Participants engaged in significantly less sedentary behaviors when outdoors compared with indoors and replaced it with moderate to vigorous physical activity. Participants also engaged in significantly less sedentary behaviors when with friends or friends and family and replaced it with light-intensity physical activity. Conclusion: These results highlight the potential of targeting external contexts to increase physical activity and to reduce sedentary behavior in adolescents’ daily lives. These factors could be targeted in mobile health and just-in-time adaptive interventions to improve young people’s movement behavior compositions.

Little is known about the acute affective response to physical activity in people with depression, which may have implications for acute symptom management and may also be a mechanism that explains the antidepressant effects of physical activity. This study aimed to quantitatively synthesize existing research on the acute affective response to physical activity in people with depression.Five online databases were searched to July 2021 to identify studies that examined pre-post changes in affective states following a bout of moderate-to-vigorous physical activity in people with depression. The affective response to physical activity was synthesized using a random-effects meta-analysis with a robust variance estimator.A total of 18 studies were included in the meta-analysis. Results showed that people with depression experienced a favourable affective response following an acute bout of physical activity (SMD = 0.585, 95% confidence interval = [0.456, 0.714], 95% prediction interval = [-0.079, 1.249]). Moderator analysis indicated this effect was consistent across different types of affective states, exercise conditions, and participant characteristics. Additionally, results were robust to changes in the study protocol and publication bias.Only within-person pre-post changes in affective responses were examined. No comparisons were made with control conditions.Acute bouts of physical activity can significantly improve affective states in people with depression. Future research should examine the effect of physical activity on affective states in non-experimental settings and examine whether the affective response to physical activity is a predictor of the long-term antidepressant effects of physical activity interventions.

STUDY QUESTION Does 12 weeks of high-intensity interval training (HIIT) result in greater improvements in cardio-metabolic and reproductive outcomes compared to standard moderate-intensity continuous training (MICT) in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER HIIT offers greater improvements in aerobic capacity, insulin sensitivity and menstrual cyclicity, and larger reductions in hyperandrogenism compared to MICT. WHAT IS KNOWN ALREADY Exercise training is recognized to improve clinical outcomes in women with PCOS, but little is known about whether HIIT results in greater health outcomes compared to standard MICT. STUDY DESIGN, SIZE, DURATION This was a two-armed randomized clinical trial enrolling a total of 29 overweight women with PCOS between May 2016 and November 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS Women with PCOS aged 18–45 years were randomly assigned to 12 weeks of either MICT (60–75% peak heart rate, N = 14) or HIIT (>90% peak heart rate, N = 15), each completed three times per week. The primary clinical outcomes were aerobic capacity (VO2peak) and insulin sensitivity (euglycaemic–hyperinsulinaemic clamp). Secondary outcomes included hormonal profiles, menstrual cyclicity and body composition. MAIN RESULTS AND THE ROLE OF CHANCE Both HIIT and MICT improved VO2peak (HIIT; Δ 5.8 ± 2.6 ml/kg/min, P LIMITATIONS, REASONS FOR CAUTION This study has a small sample size and the findings of the effect of the exercise interventions are limited to overweight reproductive-aged women, who do not have any co-existing co-morbidities that require medication. WIDER IMPLICATIONS OF THE FINDINGS Exercise, regardless of intensity, has clear health benefits for women with PCOS. HIIT appears to be a more beneficial strategy and should be considered for promoting health and reducing cardio-metabolic risk in overweight women with PCOS. STUDY FUNDING/COMPETING INTEREST(s) This work was supported by a Project Support Grant from the Australian National Health and Medical Research Council (NHMRC) Centre for Research Excellence in PCOS. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER ACTRN12615000242527. TRIAL REGISTRATION DATE 19 February 2015. DATE OF FIRST PATIENT’S ENROLMENT 27 May 2016.

Loci with greater than 2-fold average increase in methylation in relapse samples compared to primary tumours

Supplementary Figure S1 - DNA Methylation Change in Relapse Cancer Cells Relative to Primary Tumours Supplementary Figure S2 - Average Promoter Methylation of Bivalent Genes in Ovarian Tumours Supplementary Figure S3 - Change in DNA Methylation and Gene Expression for Candidate Pathways

Data showing greater than expected overlap of H3K4me3 and H3K27me3 marks in gene promoters and how variable ChIP-seq library complexity impacts upon discovery of bivalent domains

Bivalent chromatin domains containing both active H3K4me3 and repressive H3K27me3 histone marks define gene sets poised for expression or silencing in differentiating embryonic stem (ES) cells. In cancer cells, aberrantly poised genes may facilitate changes in transcriptional states after exposure to anticancer drugs. In this study, we used ChIP-seq to characterize genome-wide positioning of H3K4me3- and H3K27me3-associated chromatin in primary high-grade serous ovarian carcinomas and in normal ovarian surface and fallopian tube tissue. Gene sets with proximal bivalent marks defined in this manner were evaluated subsequently as signatures of systematic change in DNA methylation and gene expression, comparing pairs of tissue samples taken from patients at primary presentation and relapse following chemotherapy. We found that gene sets harboring bivalent chromatin domains at their promoters in tumor tissue, but not normal epithelia, overlapped with Polycomb-repressive complex target genes as well as transcriptionally silenced genes in normal ovarian and tubal stem cells. The bivalently marked genes we identified in tumors before chemotherapy displayed increased promoter CpG methylation and reduced gene expression at relapse after chemotherapy of ovarian cancer. Overall, our results support the hypothesis that preexisting histone modifications at genes in a poised chromatin state may lead to epigenetic silencing during acquired drug resistance.Significance: These results suggest epigenetic targets for intervention to prevent the emergence of cancer drug resistance. Cancer Res; 78(6); 1383–91. ©2018 AACR.

No one builds their lives on remediated weaknesses. No one. Who does a deficits-based approach benefit? Those we serve, or the professional community? Do our current models of practice support flourishing? Our professional biases make it hard for us to see not only how our practice may be getting it wrong today but is also perpetuating systems that prevent us from getting it right tomorrow. A paradigm shift to a strengths-based model that interrogates the educational, research, and practice systems we work in is proposed. It is a shift that we must see, speak, and act on. Our vulnerability and willingness to rethink is our strength, which will meet the changing needs of society. This lecture will draw on literature from positive psychology, disability justice, well-being, and research that centers the voice of self-advocates.

DNA-templated molecular (dye) aggregates are a novel class of materials that have garnered attention in a broad range of areas including light harvesting, sensing, and computing. Using DNA to template dye aggregation is attractive due to the relative ease with which DNA nanostructures can be assembled in solution, the diverse array of nanostructures that can be assembled, and the ability to precisely position dyes to within a few Angstroms of one another. These factors, combined with the programmability of DNA, raise the prospect of designer materials custom tailored for specific applications. Although considerable progress has been made in characterizing the optical properties and associated electronic structures of these materials, less is known about their excited-state dynamics. For example, little is known about how the excited-state lifetime, a parameter essential to many applications, is influenced by structural factors, such as the number of dyes within the aggregate and their spatial arrangement. In this work, we use a combination of transient absorption spectroscopy and global target analysis to measure excited-state lifetimes in a series of DNA-templated cyanine dye aggregates. Specifically, we investigate six distinct dimer, trimer, and tetramer aggregates-based on the ubiquitous cyanine dye Cy5-templated using both duplex and Holliday junction DNA nanostructures. We find that these DNA-templated Cy5 aggregates all exhibit significantly reduced excited-state lifetimes, some by more than 2 orders of magnitude, and observe considerable variation among the lifetimes. We attribute the reduced excited-state lifetimes to enhanced nonradiative decay and proceed to discuss various structural factors, including exciton delocalization, dye separation, and DNA heterogeneity, that may contribute to the observed reduction and variability of excited-state lifetimes. Guided by insights from structural modeling, we find that the reduced lifetimes and enhanced nonradiative decay are most strongly correlated with the distance between the dyes. These results inform potential tradeoffs between dye separation, excitonic coupling strength, and excited-state lifetime that motivate deeper mechanistic understanding, potentially via further dye and dye template design.

BACKGROUND The demand for orthopaedic specialist consultation for patients with osteoarthritis (OA) in public hospitals is large and continues to grow. Lengthy wait times are increasingly affecting patients from low socioeconomic and culturally and linguistically diverse (CALD) backgrounds who are more likely to rely on public health care. OBJECTIVE The aim of this study was to co-design a digital health intervention for patients with OA who are waiting for an orthopaedic specialist consultation at a public health service, which is located in local government areas (LGAs) of identified social and economic disadvantage. METHODS The stakeholders involved in the co-design process included the research team, end-users (patients), clinicians, academic experts, senior hospital staff and a research, design and development agency. The iterative co-design process comprised of several key phases, which included the collation and refinement of evidence-based information by the research team with assistance from academic experts. Structured interviews with 16 clinicians (sex: 10 female and six male) and 11 end-users (mean ± SD, age: 64.3 ± 7.2, sex: seven female and four male) of 1-hour duration were completed to understand the needs of the intervention. Weekly workshops were held with key stakeholders throughout the development. A different cohort of 15 end-users examined the feasibility of the study during a 2-week testing period (age: 61.5 ± 9.7, sex: 12 female and three male). The system usability scale (SUS) was utilized as the primary measure of the feasibility of the intervention. RESULTS Seven content modules were developed which were refined over several iterative rounds. Key themes highlighted in the clinician and end-user interviews were the diverse characteristics of patients, the hierarchical structure with which patients view health practitioners, the importance of delivering information in multiple formats (written, audio and visual) and access to patient-centered information as early as possible in the healthcare journey. All content was translated to Vietnamese, the most widely spoken language following English in the LGAs included in this study. Patients with hip and knee OA from diverse CALD backgrounds tested its feasibility. A mean score of 82.7 ± 16 was recorded for the SUS placing it in the excellent category for usability. CONCLUSIONS Through the co-design process, we developed an evidence-based, holistic and patient-centered digital health intervention. The intervention has been specifically designed to be used by patients from diverse backgrounds, including those with low health, digital and written literacy levels. The effectiveness of the intervention for improving the physical and mental health of patients will be determined by a high-quality randomized controlled trial.

Molecular excitons are useful for applications in light harvesting, organic optoelectronics, and nanoscale computing. Electronic energy transfer (EET) is a process central to the function of devices based on molecular excitons. Achieving EET with a high quantum efficiency is a common obstacle to excitonic devices, often owing to the lack of donor and acceptor molecules that exhibit favorable spectral overlap. EET quantum efficiencies may be substantially improved through the use of heteroaggregates-aggregates of chemically distinct dyes-rather than individual dyes as energy relay units. However, controlling the assembly of heteroaggregates remains a significant challenge. Here, we use DNA Holliday junctions to assemble homo- and heterotetramer aggregates of the prototypical cyanine dyes Cy5 and Cy5.5. In addition to permitting control over the number of dyes within an aggregate, DNA-templated assembly confers control over aggregate composition, i.e., the ratio of constituent Cy5 and Cy5.5 dyes. By varying the ratio of Cy5 and Cy5.5, we show that the most intense absorption feature of the resulting tetramer can be shifted in energy over a range of almost 200 meV (1600 cm

Molecular excitons, which propagate spatially via electronic energy transfer, are central to numerous applications including light harvesting, organic optoelectronics, and nanoscale computing; they may also benefit applications such as photothermal therapy and photoacoustic imaging through the local generation of heat via rapid excited-state quenching. Here we show how to tune between energy transfer and quenching for heterodimers of the same pair of cyanine dyes by altering their spatial configuration on a DNA template. We assemble "transverse" and "adjacent" heterodimers of Cy5 and Cy5.5 using DNA Holliday junctions. We find that the transverse heterodimers exhibit optical properties consistent with excitonically interacting dyes and fluorescence quenching, while the adjacent heterodimers exhibit optical properties consistent with nonexcitonically interacting dyes and disproportionately large Cy5.5 emission, suggestive of energy transfer between dyes. We use transient absorption spectroscopy to show that quenching in the transverse heterodimer occurs via rapid nonradiative decay to the ground state (∼31 ps) and that in the adjacent heterodimer rapid energy transfer from Cy5 to Cy5.5 (∼420 fs) is followed by Cy5.5 excited-state relaxation (∼700 ps). Accessing such drastically different photophysics, which may be tuned on demand for different target applications, highlights the utility of DNA as a template for dye aggregation.

Polycystic ovary syndrome (PCOS) is characterised by a hormonal imbalance affecting the reproductive and metabolic health of reproductive-aged women. Exercise is recommended as a first-line therapy for women with PCOS to improve their overall health; however, women with PCOS are resistant to the metabolic benefits of exercise training. Here, we aimed to gain insight into the mechanisms responsible for such resistance to exercise in PCOS. We employed an in vitro approach with electrical pulse stimulation (EPS) of cultured skeletal muscle cells to explore whether myotubes from women with PCOS have an altered gene expression signature in response to contraction. Following EPS, 4719 genes were differentially expressed (false discovery rate

Exercise can improve mental health; however many tertiary students do not reach recommended levels of weekly engagement. Short-term exercise may be more achievable for tertiary students to engage in to promote mental health, particularly during times of high stress. The current scoping review aimed to provide an overview of controlled trials testing the effect of short-term (single bout and up to 3 weeks) exercise across mental health domains, both at rest and in response to an experimentally manipulated laboratory stress task, in tertiary students. The search was conducted using ‘Evidence Finder,’ a database of published and systematic reviews and controlled trials of interventions in the youth mental health field. A total of 14 trials meet inclusion criteria, six measured mental health symptoms in response to an experimentally manipulated laboratory stress task and the remaining eight measured mental health symptoms. We found that short-term exercise interventions appeared to reduce anxiety like symptoms and anxiety sensitivity and buffered against a drop in mood following an experimentally manipulated laboratory stress task. There was limited available evidence testing the impacts of exercise on depression like symptoms and other mental health mental health domains, suggesting further work is required. Universities should consider implementing methods to increase student knowledge about the relationship between physical exercise and mental health and student access to exercise facilities.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with insulin resistance and impaired energy metabolism in skeletal muscle, the aetiology of which is currently unclear. Here, we mapped the gene expression profile of skeletal muscle from women with PCOS and determined if cultured primary myotubes retain the gene expression signature of PCOS in vivo. Transcriptomic analysis of vastus lateralis biopsies collected from PCOS women showed lower expression of genes associated with mitochondrial function, while the expression of genes associated with the extracellular matrix was higher compared to controls. Altered skeletal muscle mRNA expression of mitochondrial-associated genes in PCOS was associated with lower protein expression of mitochondrial complex II–V, but not complex I, with no difference in mitochondrial DNA content. Transcriptomic analysis of primary myotube cultures established from biopsies did not display any differentially expressed genes between controls and PCOS. Comparison of gene expression profiles in skeletal muscle biopsies and primary myotube cultures showed lower expression of mitochondrial and energy metabolism-related genes in vitro, irrespective of the group. Together, our results show that the altered mitochondrial-associated gene expression in skeletal muscle in PCOS is not preserved in cultured myotubes, indicating that the in vivo extracellular milieu, rather than genetic or epigenetic factors, may drive this alteration. Dysregulation of mitochondrial-associated genes in skeletal muscle by extracellular factors may contribute to the impaired energy metabolism associated with PCOS.

Exciton delocalization plays a prominent role in the photophysics of molecular aggregates, ultimately governing their particular function or application. Deoxyribonucleic acid (DNA) is a compelling scaffold in which to template molecular aggregates and promote exciton delocalization. As individual dye molecules are the basis of exciton delocalization in molecular aggregates, their judicious selection is important. Motivated by their excellent photostability and spectral properties, here, we examine the ability of squaraine dyes to undergo exciton delocalization when aggregated via a DNA Holliday junction (HJ) template. A commercially available indolenine squaraine dye was chosen for the study given its strong structural resemblance to Cy5, a commercially available cyanine dye previously shown to undergo exciton delocalization in DNA HJs. Three types of DNA–dye aggregate configurations—transverse dimer, adjacent dimer, and tetramer—were investigated. Signatures of exciton delocalization were observed in all squaraine–DNA aggregates. Specifically, strong blue shift and Davydov splitting were observed in steady-state absorption spectroscopy and exciton-induced features were evident in circular dichroism (CD) spectroscopy. Strongly suppressed fluorescence emission provided additional, indirect evidence for exciton delocalization in the DNA-templated squaraine dye aggregates. To quantitatively evaluate and directly compare the excitonic Coulombic coupling responsible for exciton delocalization, the strength of excitonic hopping interactions between the dyes was obtained by simultaneously fitting the experimental steady-state absorption and CD spectra via a Holstein-like Hamiltonian, in which, following the theoretical approach of Kühn, Renger, and May, the dominant vibrational mode is explicitly considered. The excitonic hopping strength within indolenine squaraines was found to be comparable to that of the analogous Cy5 DNA-templated aggregate. The squaraine aggregates adopted primarily an H-type (dyes oriented parallel to each other) spatial arrangement. Extracted geometric details of the dye mutual orientation in the aggregates enabled a close comparison of aggregate configurations and the elucidation of the influence of dye angular relationship on excitonic hopping interactions in squaraine aggregates. These results encourage the application of squaraine-based aggregates in next-generation systems driven by molecular excitons.

Aim To describe the quality and completeness of the description and reporting of physical activity and exercise interventions delivered to young people to promote mental health or treat mental illness. Methods We conducted a series of scoping reviews identifying 64 controlled trials of physical activity and exercise interventions delivered to young people. We extracted: intervention characteristics, personnel and delivery format, the intensity, duration, frequency and type of physical activity or exercise. Results There was limited reporting of intervention details across studies; 52% did not provide information to confidently assess intervention intensity, 29% did not state who delivered the intervention, and 44% did not specify the intervention delivery format. Conclusions We recommend that authors adhere to the CONSORT reporting requirements and its intervention reporting extensions, (a) the Template for Intervention Description and Replication, (b) Consensus for Exercise Reporting Template and (c) as part of this, detail the frequency, intensity, time and type of physical activity recommendations and prescriptions. Without this, future trials are unable to replicate and extend previous work to support or disconfirm existing knowledge, leading to research waste and diminishing translation and implementation potential.

Background The optimal choice for mesh fixation in laparoscopic inguinal hernia repair (LIHR) has not been well established. This review compared the effects of glue versus mechanical mesh fixation in LIHR on incidence of chronic postoperative inguinal pain (CPIP) and other secondary outcomes, including acute pain, seroma, haematoma, hernia recurrence and other postoperative complications. Methods A systematic review of English/non-English studies using MEDLINE, the Cochrane Library, OpenGrey, OpenThesis and Web of Science, and searching bibliographies of included studies was completed. Search terms included laparoscopic, hernia, fibrin glue, Tisseel, Tissucol, cyanoacrylate, Glubran and Liquiband. Only RCTs comparing mechanical with glue-based fixation in adult patients (aged over 18 years) that examined CPIP were included. Two authors independently completed risk-of-bias assessment and data extraction against predefined data fields. All pooled analyses were computed using a random-effects model. Results Fifteen RCTs met the inclusion criteria; 2777 hernias among 2109 patients were assessed. The incidence of CPIP was reduced with use of glue-based fixation (risk ratio (RR) 0.36, 95 per cent c.i. 0.19 to 0.69; P = 0.002), with moderate heterogeneity that disappeared with sensitivity analysis (8 d.f.) for patient-blinded studies (RR 0.43, 0.27 to 0.86). Trial sequential analysis provided evidence for a relative risk reduction of at least 25 per cent. The incidence of haeamtoma was reduced by using glue-based fixation (RR 0.29, 0.10 to 0.82; P = 0.02) with no significant effects on seroma formation or hernia recurrence (RR 1.07, 0.46 to 2.47; P = 0.88). Conclusion Glue-based mesh fixation appears to reduce the incidence of CPIP and haematoma after LIHR compared with mechanical fixation, with comparable recurrence rates.

Polycystic ovary syndrome (PCOS) is a common and complex endocrinopathy with reproductive and metabolic manifestations, carrying a major health and economic burden. Exercise training has consistently been found improve clinical outcomes in women with PCOS, but shortfalls with exercise prescription are evident. Research suggests that high intensity intermittent exercise (HIIT) is feasible, well tolerated and enjoyable for people with or at risk of chronic disease and can address many of the shortfalls and barriers to exercise participation. To investigate the effects of high intensity exercise, twenty-four reproductive aged, overweight and obese, previously sedentary women with PCOS were recruited from the community and randomised to complete either 12 weeks of moderate intensity continuous cycling exercise (MOD; 50-60% of maximal heart rate [HRmax]; n=11) or HIIT (90-95% HRmax; n=13). All exercise was supervised by an exercise physiologist and completed 3 times per week on a cycle ergometer. Baseline and post testing measures consisted of peak oxygen consumption (VO2peak) determine by a graded maximal exercise test, insulin sensitivity determined by hyperinsulinaemic-euglycaemic clamp, body composition outcomes and anti-mullerian hormone (AMH). Enjoyment was also measured throughout the intervention using feeling scales. Significant improvements were seen for VO2peak after HIIT with an average increase of 5.6 ± 2.5 mL.kg-1.min-1 (P=0.013) and non-significant increases in the MOD group (3.4 ± 2.1 mL/kg/min; P=0.20). Body composition, fasting insulin and AMH values remained unchanged in both groups. Non-significant improvements in glucose infusion rate (3.3 ± 2.8 mg.lbmkg-1.min-1; P=0.06) and insulin sensitivity index (M-to-I ratio; 3.0 ± 3.8 mg.lbmkg-1.min-1[mU/I]-1 x 100; P=0.17) were found as a result of HIIT compared to no changes after moderate intensity exercise. Importantly, HIIT was also found to be more enjoyable than moderate intensity continuous exercise. The present study is the first to compare current exercise recommendations of moderate and vigorous intensities in women with PCOS. The results of this study provide preliminary validation of HIIT and should be considered for improving cardio-metabolic health in women with PCOS.

Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder affecting metabolic, reproductive and mental health of 8-13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 85% of women with PCOS. This underlying IR has been identified as unique from, but synergistic with, obesity-induced IR (1). Skeletal muscle accounts for up to 85% of whole body insulin-stimulated glucose uptake, however, in PCOS this is reduced about 27% when assessed by hyperinsulinemic euglycemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). Previous work suggested that Transforming Growth Factor Beta (TGFβ) superfamily ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30ng/ml), a novel TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=10) and healthy controls (n=10). AMH negatively affected glucose uptake and insulin signalling increasing p-IRS1 (ser312) in a dose-dependent manner in myotubes from both women with and without PCOS. AMH did not appear to activate the canonical TGFβ/BMP signalling pathway. Conversely, TGFβ1 had an opposite effect in both PCOS and control myotubes cultures, decreasing phosphorylation of IRS1 (ser312) and enhancing glucose uptake via Smad2/3 signalling. In conclusion, these results suggest that AMH may play a role in skeletal muscle IR observed in PCOS, however, further research is required to elucidate its mechanisms of action and broader impact in this syndrome. References: (1) Stepto et al. Hum Reprod 2013 Mar;28(3):777-784. (2) Cassar et al. Hum Reprod 2016 Nov;31(11):2619-2631. (3) Corbould et al., Am J Physiol-Endoc 2005 May;88(5):E1047-54. (4) Stepto et al. J Clin Endocrinol Metab, 2019 Nov 1;104(11):5372-5381. (5) Raja-Khan et al. Reprod Sci 2014 Jan;21(1):20-31.

The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumor evolution is poorly understood. Phenotypic drifts can be transmitted via inheritable transcriptional programs. Cell-type specific transcription is maintained through the activation of epigenetically defined regulatory regions including promoters and enhancers. Here we have annotated the epigenome of 47 primary and metastatic estrogen-receptor (ERα)-positive breast cancer clinical specimens and inferred phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Shared regions contain a unique set of regulatory information including the motif for transcription factor YY1. We identify YY1 as a critical determinant of ERα transcriptional activity promoting tumor growth in most luminal patients. YY1 also contributes to the expression of genes mediating resistance to endocrine treatment. Finally, we used H3K27ac levels at active enhancer elements as a surrogate of intra-tumor phenotypic heterogeneity to track the expansion and contraction of phenotypic subpopulations throughout breast cancer progression. By tracking the clonality of SLC9A3R1-positive cells, a bona fide YY1-ERα-regulated gene, we show that endocrine therapies select for phenotypic clones under-represented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.

Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy affecting metabolic and reproductive health of 8–13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 38–95% of women with PCOS. This underlying IR has been identified as unique from, but synergistic with, obesity-induced IR (1). Skeletal muscle accounts for up to 85% of whole-body insulin-stimulated glucose uptake; however, in PCOS this is reduced by about 27% when assessed by a euglycaemic-hyperinsulinaemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that in vivo environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). A potential environmental mechanism contributing to the development of peripheral IR may be the extracellular matrix remodelling and aberrant transforming growth factor beta (TGFβ) signalling. Previous work demonstrated that TGFβ superfamily ligands are involved in the increased collagen deposition and fibrotic tissue in the ovaries, and suggested that these ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5 ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30 ng/ml), a TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=5) and healthy controls (n=5). TGFβ1 did not have a significant effect on insulin signalling but induced expression of some ECM related genes and proteins, and increased glucose uptake via Smad2/3 signalling in myotubes from both groups. Conversely, AMH did not appear to activate the TGFβ/Smad signalling pathway and had no significant impact on insulin signalling or glucose uptake in any of the groups. In conclusion, these findings suggest that TGFβ1, but not AMH, may play a role in skeletal muscle ECM remodelling/fibrosis and glucose metabolism in PCOS but does not have a direct effect on insulin signalling pathway. Further research is required to elucidate its contribution to the development of in vivo skeletal muscle IR and broader impact in this syndrome. References: (1) Stepto et al., Hum Reprod 2013 Mar;28(3):777–784. (2) Cassar et al., Hum Reprod 2016 Nov;31(11):2619–2631. (3) Corbould et al., Am J Physiol-Endoc 2005 May;88(5):E1047-54. (4) Stepto et al., J Clin Endocrinol Metab, 2019 Nov 1;104(11):5372–5381. (5) Raja-Khan et al., Reprod Sci 2014 Jan;21(1):20–31.

Polycystic ovary syndrome (PCOS) is a common and complex endocrinopathy with significant metabolic and reproductive manifestations, carrying a major health and economic burden. Consistent improvements in clinical outcomes have been reported as a result of exercise training, but shortfalls with exercise prescription are evident. Research suggests that high-intensity intermittent training (HIIT) is feasible, well tolerated and enjoyable for people with or at risk of chronic disease and can address many of the shortfalls and barriers to exercise participation. To investigate the effects of high-intensity exercise on cardio-metabolic health, twenty-four reproductive aged, overweight or obese, sedentary women with PCOS were recruited from the community and randomised to complete either 12 weeks of moderate intensity continuous cycling training (MICT; 60–65% of maximal heart rate [HRmax]; n=11) or HIIT (90–100% HRmax; n=13). All exercise was supervised by an exercise physiologist and completed 3 times per week on a cycle ergometer. Baseline and post-testing measures consisted of peak oxygen consumption (VO2peak) determined by a graded maximal exercise test, body composition by DXA scan and insulin sensitivity determined by euglycaemic-hyperinsulinaemic clamp. Significant improvements in VO2peak were seen after both HIIT (P

Exciton delocalization in dye aggregate systems is a phenomenon that is revealed by spectral features, such as Davydov splitting, J- and H-aggregate behavior, and fluorescence suppression. Using DNA as an architectural template to assemble dye aggregates enables specific control of the aggregate size and dye type, proximal and precise positioning of the dyes within the aggregates, and a method for constructing large, modular two- and three-dimensional arrays. Here, we report on dye aggregates, organized via an immobile Holliday junction DNA template, that exhibit large Davydov splitting of the absorbance spectrum (125 nm, 397.5 meV), J- and H-aggregate behavior, and near-complete suppression of the fluorescence emission (∼97.6% suppression). Because of the unique optical properties of the aggregates, we have demonstrated that our dye aggregate system is a viable candidate as a sensitive absorbance and fluorescence optical reporter. DNA-templated aggregates exhibiting exciton delocalization may find application in optical detection and imaging, light-harvesting, photovoltaics, optical information processing, and quantum computing.

Background/AimThis scoping review examined the breadth and outcomes of controlled trials testing the effect of physical activity and exercise interventions across all mental health outcomes for mental health promotion and indicated prevention studies in young people.MethodsThe literature search was conducted using ‘Evidence Finder’.ResultsThirty publications were included. Available evidence suggested that interventions of varying intensity may lead to a reduction in depression symptoms and that moderate-to-vigorous-intensity and light-intensity interventions may reduce anxiety symptoms. Effects of physical activity/exercise interventions on additional mental health outcomes were also shown; however, the number of studies was small, indicating a limited evidence base. Robust research regarding the effects of physical activity/exercise on mental health promotion and as an indicated prevention strategy in young people is lacking.ConclusionThe available evidence suggests that physical activity/exercise is a promising mental health promotion and early intervention strategy and warrants further investigation.

Background Polycystic ovary syndrome (PCOS) is a reproductive-metabolic condition. Insulin resistance is a hallmark of PCOS and is related to increased hyperandrogenism that drives inherent metabolic, reproductive and psychological features of the syndrome. Insulin resistance in women with PCOS is managed by weight loss, lifestyle interventions (i.e. exercise, diet) and insulin-sensitising medications. This manuscript describes the protocol of our study evaluating the effectiveness of high intensity intermittent training (HIIT) or moderate intensity exercise on cardiometabolic, reproductive and mental health in overweight women with PCOS. Methods/design We will employ a three arm, parallel-group, randomised controlled trial recruiting 60 women diagnosed with PCOS, aged between 18 and 45 years and with a body mass index (BMI) greater than 25 kg/m2. Following screening and baseline testing, women will be randomised by simple randomisation procedure using computer generated sequence allocation to undergo one of two 12-week supervised interventions: either HIIT or moderate intensity exercise (standard supervised exercise), or to standard care [Con] (unsupervised lifestyle advice) at a 1:1:1 allocation ratio. The primary outcome for this trial is to measure the improvements in metabolic health; specifically changes in insulin sensitivity in response to different exercise intensities. Baseline and post-intervention testing include anthropometric measurements, cardiorespiratory fitness testing, reproductive hormone profiles (anti-müllerian hormone and steroid profiles), metabolic health, health-related quality of life and mental health questionnaires and objective and subjective lifestyle monitoring. Reporting of the study will follow the CONSORT statement. Discussion This trial aims to demonstrate the comparative efficacy and maintenance of different exercise intensities to advance the understanding of PCOS management and provide insight into the optimal exercise intensity for improved cardiometabolic outcomes. Secondary outcomes will include the impact of different exercise protocols on reproductive hormone profiles, mental health and health-related quality of life. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12615000242527. Registered on 17 March 2015. Electronic supplementary material The online version of this article (10.1186/s13063-019-3313-8) contains supplementary material, which is available to authorized users.

This abstract was withdrawn by the authors.

This abstract was withdrawn by the authors.

Lumbar hernias can be superior (Grynfelt) and inferior (Petit). Inferior lumbar hernias are extremely rare and, therefore, are associated with diagnostic difficulty. We present a case of a primary spontaneous inferior lumbar hernia in a 79-year-old woman that was initially diagnosed as a large lipoma on ultrasound. The first operation was abandoned and an open mesh repair was conducted. Lumbar hernias can be primary acquired (55%), secondary acquired (25%) or congenital (20%). Cross-sectional imaging by CT or MRI appears to be the gold standard in diagnosis as ultrasound may lead to misdiagnosis. Strangulation, incarceration and obstruction are recognised complications, requiring prompt surgical intervention. There are currently no guidelines for surgical managements, although laparoscopic surgery may give the best results. In view of the scarcity of published cases, we aim to add to the literature to raise the index of suspicion and to promote prompt surgical management of lumbar hernias.