Gravitational waves from non-Abelian gauge fields at a tachyonic transition

We compute the gravitational wave spectrum from a tachyonic preheating transition of a Standard Model-like SU(2)-Higgs system. Tachyonic preheating involves exponentially growing IR modes, at scales as large as the horizon. Such a transition at the electroweak scale could be detectable by LISA, if these non-perturbatively large modes translate into non-linear dynamics sourcing gravitational waves. Through large-scale numerical simulations, we find that the spectrum of gravitational waves does not exhibit such IR features. Instead, we find two peaks corresponding to the Higgs and gauge field mass, respectively. We find that the gravitational wave production is reduced when adding non-Abelian gauge fields to a scalar-only theory, but increases when adding Abelian gauge fields. In particular, gauge fields suppress the gravitational wave spectrum in the IR. A tachyonic transition in the early Universe will therefore not be detectable by LISA, even if it involves non-Abelian gauge fields.Peer reviewe

Extent of MGMT promoter methylation modifies the effect of temozolomide on overall survival in patients with glioblastoma: a regional cohort study

BACKGROUND: MGMT methylation in glioblastoma predicts response to temozolomide but dichotomizing methylation status may mask the true prognostic value of quantitative MGMT methylation. This study evaluated whether extent of MGMT methylation interacts with the effect of temozolomide on overall survival. METHODS: We included consecutive glioblastoma patients aged ≥16 years diagnosed (April 2012–May 2020) at a neuro-oncology center. All patients had quantitative MGMT methylation measured using pyrosequencing. Those with MGMT methylated tumors were stratified into high and low methylation groups based on a cut-off using Youden index on 2-year survival. Our accelerated failure time survival models included extent of MGMT methylation, age, postoperative Karnofsky performance score, extent of resection, temozolomide regimen, and radiotherapy. RESULTS: There were 414 patients. Optimal cut-off point using Youden index was 25.9% MGMT methylation. The number of patients in the unmethylated, low and high methylation groups was 223 (53.9%), 81 (19.6%), and 110 (26.6%), respectively. In the adjusted model, high (hazard ratio [HR] 0.60, 95% confidence intervals [CI] 0.46–0.79, P = 0.005) and low (HR 0.67, 95% CI 0.50–0.89, P < 0.001) methylation groups had better survival compared to unmethylated group. There was no evidence for interaction between MGMT methylation and completed temozolomide regimen (interaction term for low methylation P = 0.097; high methylation P = 0.071). This suggests no strong effect of MGMT status on survival in patients completing temozolomide regimen. In patients not completing the temozolomide regimen, higher MGMT methylation predicted better survival (interaction terms P < 0.001). CONCLUSIONS: Quantitative MGMT methylation may provide additional prognostic value. This is important when assessing clinical and research therapies

Are we developing career-readiness skills in science graduates?

BACKGROUND As students transition from university education to employment, they require a range of skills and competencies to ensure future career readiness, including technical expertise, problem-solving abilities, effective communication, social network building, cultural awareness, resilience, and adaptability (Jackson, 2018; Roberts, 2016; Tomlinson, 2017). A number of these attributes are captured within the Threshold Learning Outcomes for Science graduates (Jones et al., 2011). The fluidity of careers also requires a greater emphasis on the development of metacognitive and reflective abilities so that graduates will have the capability, capacity, and confidence to use their personal resources appropriately and flexibly, regardless of environment. However, recent research has suggested that generic skill development is lacking in undergraduate science curricula (Sarkar et al., 2020). The work presented here aimed to understand more about the employability skills viewed as important by academics, students, graduates, and industry whilst also gauging perceived levels of attainment and confidence in those skills. DESIGN AND METHODS The confidence and capability of academics to prepare Science students to be career ready was explored by conducting surveys and community-of-practice style workshops. The perspectives of industry employers, students, and graduates was sought via surveys and focus groups. This information was then used in a co-creation workshop to identify effective ways of providing career pathways and industry connections to students as well as to develop employability skills. RESULTS AND CONCLUSIONS Survey results identified four key employability skills that were deemed important by all groups, but which industry felt were underdeveloped in graduates, and in which students were not confident. These were: working in a team and acknowledging other viewpoints, effective time management, communication to various audiences and making confident decisions. Discussions held in the academic-specific workshop identified key roadblocks to the effective implementation of employability skill development. These were: lack of opportunity/time to integrate skills into existing curricula, engaging students to participate, and assessment of the skills. The co-creation workshop then captured industry and academic insights facilitating the development of potential methodologies to overcome these roadblocks to help in teaching the key skills identified. Outcomes will be used to develop national best-practice guidelines for the integration of employability skill development. This may facilitate changes to the Science curriculum to ensure graduates are career ready. REFERENCES Jackson, D. (2018). Developing graduate career readiness in Australia: Shifting from extra-curricular internships to work-integrated learning. International Journal of Work-Integrated Learning, 19, 23-35. Jones, S., Yates, B., &amp; Kelder, J. (2011). Science Learning and Teaching Academic Standards Statement. Australian Learning &amp; Teaching Council, Sydney. Roberts, S. (2016). Capital limits: Social class, motivations for term-time job searching and the consequences of joblessness among UK university students. Journal of Youth Studies, 20, 1–18. Sarkar, M., Overton, T., Thompson, C. D., &amp; Rayner, G. (2020). Academics’ perspectives of the teaching and development of generic employability skills in science curricula. Higher Education Research &amp; Development, 39(2), 346–361. Tomlinson, M. (2017). Forms of graduate capital and their relationship to graduate employability. Education + Training, 59, 338-352

Future-proofing career readiness in science graduates: where, when and how?

BACKGROUND To ensure future career readiness, students must develop a range of skills and capacities including technical expertise, problem-solving abilities, effective communication, social and professional network building, interpersonal and cultural awareness, resilience, and adaptability (Jackson, 2018; Roberts, 2016; Tomlinson, 2017) as well as develop a well-grounded self-identity (Jackson, 2017). Given that careers are continuously evolving and perpetually fluid (Starr-Glass, 2019), graduates also need to critically perceive, engage, and reflect on their own identity and self-efficacy (Sarkar et al., 2016). However, recent research has shown that there is a lack of generic skill development in undergraduate science curricula (Sarkar et al., 2020) and academics have expressed concerns about their ability to provide reflective practice opportunities for students. This project, funded by the Australian Council of Deans of Science, aims to enhance the confidence and capability of academics to enhance their students career readiness; promote collaborative curriculum development between industry partners, graduates, and students; and develop national best practice guidelines for the enhancement of science graduate employability skills. THE WORKSHOP You are invited to join us for a collaborative and interactive workshop to explore where, when, and how employability skills could be implemented within the Sciences curriculum. We have used insights from students, graduates, industry employers and academics to propose possible best practice guidelines. This workshop will specifically road-test the co-created guidelines while also providing an opportunity for participants to further explore the following aspects: development of generic skills identified as more difficult to teach (such as metacognitive and reflective abilities, resilience and adaptability) enhancing the knowledge of career pathways and connecting with employers scaffolding and integration of work integrated learning activities into the curriculum (both in the workplace and in the classroom). REFERENCES Jackson, D. (2017). Developing pre-professional identity in undergraduates through work-integrated learning. Higher Education, 74, 833–853. Jackson, D. (2018) Developing graduate career readiness in Australia: Shifting from extra-curricular internships to work-integrated learning. International J Work-Integrated Learning, 19, 23-35. Roberts, S. (2016). Capital limits: Social class, motivations for term-time job searching and the consequences of joblessness among UK university students. Journal of Youth Studies, 20, 1–18. https://doi.org/10.1080/13676261.2016.1260697 Sarkar, M., Overton, T., Thompson, C. D., &amp; Rayner, G.  (2016) Graduate employability: View of recent science graduates and employers. International Journal of Innovation in Science and Mathematics Education, 24(3), 31-48. Sarkar, M., Overton, T., Thompson, C. D., &amp; Rayner, G. (2020). Academics’ perspectives of the teaching and development of generic employability skills in science curricula. Higher Education Research &amp; Development, 39(2), 346–361. Starr-Glass D (2019) Doing and being: future graduates, careers and Industry 4.0. On the Horizon, 27, 145–152. Tomlinson M (2017) Forms of graduate capital and their relationship to graduate employability. Education + Training, 59, 338-352

Aortic stenosis post-COVID-19: a mathematical model on waiting lists and mortality

Objectives To provide estimates for how different treatment pathways for the management of severe aortic stenosis (AS) may affect National Health Service (NHS) England waiting list duration and associated mortality. Design We constructed a mathematical model of the excess waiting list and found the closed-form analytic solution to that model. From published data, we calculated estimates for how the strategies listed under Interventions may affect the time to clear the backlog of patients waiting for treatment and the associated waiting list mortality. Setting The NHS in England. Participants Estimated patients with AS in England. Interventions (1) Increasing the capacity for the treatment of severe AS, (2) converting proportions of cases from surgery to transcatheter aortic valve implantation and (3) a combination of these two. Results In a capacitated system, clearing the backlog by returning to pre-COVID-19 capacity is not possible. A conversion rate of 50% would clear the backlog within 666 (533–848) days with 1419 (597–2189) deaths while waiting during this time. A 20% capacity increase would require 535 (434–666) days, with an associated mortality of 1172 (466–1859). A combination of converting 40% cases and increasing capacity by 20% would clear the backlog within a year (343 (281–410) days) with 784 (292–1324) deaths while awaiting treatment. Conclusion A strategy change to the management of severe AS is required to reduce the NHS backlog and waiting list deaths during the post-COVID-19 ‘recovery’ period. However, plausible adaptations will still incur a substantial wait to treatment and many hundreds dying while waiting

Total plasma homocysteine, folate, and vitamin b12 status in healthy Iranian adults: the Tehran homocysteine survey (2003–2004)/a cross – sectional population based study

BACKGROUND: Elevated plasma total homocysteine is an independent risk factor for cardiovascular disease and a sensitive marker of the inadequate vitamin B12 and folate insufficiency. Folate and vitamin B12 have a protective effect on cardiovascular disease. This population based study was conducted to evaluate the plasma total homocysteine, folate, and vitamin B12 in healthy Iranian individuals. METHODS: This study was a part of the Cardiovascular Risk Factors Survey in the Population Lab Region of Tehran University has been designed and conducted based on the methodology of MONICA/WHO Project. A total of 1214 people aged 25–64 years, were recruited and assessed regarding demographic characteristics, homocysteine, folate, and vitamin B12 levels with interview, questionnaires, examination and blood sampling. Blood samples were gathered and analyzed according to standard methods. RESULTS: The variables were assessed in 1214 participants including 428 men (35.3%) and 786 women (64.7%). Age-adjusted prevalence of hyperhomocysteinemia (Hcy≥15 μmol/L) was 73.1% in men and 41.07% in women (P < 0.0001). Geometric mean of plasma homocysteine was 19.02 ± 1.46 μmol/l in men and 14.05 ± 1.45 μmol/l in women (P < 0.004) which increased by ageing. Age-adjusted prevalence of low serum folate level was 98.67% in men and 97.92% in women. Age-adjusted prevalence of low serum vitamin B12 level was 26.32% in men and 27.2% in women. Correlation coefficients (Pearson's r) between log tHcy and serum folate, and vitamin B12 indicated an inverse correlation (r = -0.27, r = -0.19, P < 0.0001, respectively). CONCLUSION: These results revealed that the prevalence of hyperhomocysteinemia, low folate and vitamin B12 levels are considerably higher than other communities. Implementation of preventive interventions such as food fortification with folic acid is necessary

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies

BACKGROUND. Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment

Fragile Genomic Sites Are Associated with Origins of Replication

Genome rearrangements are mediators of evolution and disease. Such rearrangements are frequently bounded by transfer RNAs (tRNAs), transposable elements, and other repeated elements, suggesting a functional role for these elements in creating or repairing breakpoints. Though not well explored, there is evidence that origins of replication also colocalize with breakpoints. To investigate a potential correlation between breakpoints and origins, we analyzed evolutionary breakpoints defined between Saccharomyces cerevisiae and Kluyveromyces waltii and S. cerevisiae and a hypothetical ancestor of both yeasts, as well as breakpoints reported in the experimental literature. We find that origins correlate strongly with both evolutionary breakpoints and those described in the literature. Specifically, we find that origins firing earlier in S phase are more strongly correlated with breakpoints than are later-firing origins. Despite origins being located in genomic regions also bearing tRNAs and Ty elements, the correlation we observe between origins and breakpoints appears to be independent of these genomic features. This study lays the groundwork for understanding the mechanisms by which origins of replication may impact genome architecture and disease

Glucose and Fatty Acids Synergize to Promote B-Cell Apoptosis through Activation of Glycogen Synthase Kinase 3β Independent of JNK Activation

The combination of elevated glucose and free-fatty acids (FFA), prevalent in diabetes, has been suggested to be a major contributor to pancreatic β-cell death. This study examines the synergistic effects of glucose and FFA on β-cell apoptosis and the molecular mechanisms involved. Mouse insulinoma cells and primary islets were treated with palmitate at increasing glucose and effects on apoptosis, endoplasmic reticulum (ER) stress and insulin receptor substrate (IRS) signaling were examined.Increasing glucose (5-25 mM) with palmitate (400 µM) had synergistic effects on apoptosis. Jun NH2-terminal kinase (JNK) activation peaked at the lowest glucose concentration, in contrast to a progressive reduction in IRS2 protein and impairment of insulin receptor substrate signaling. A synergistic effect was observed on activation of ER stress markers, along with recruitment of SREBP1 to the nucleus. These findings were confirmed in primary islets. The above effects associated with an increase in glycogen synthase kinase 3β (Gsk3β) activity and were reversed along with apoptosis by an adenovirus expressing a kinase dead Gsk3β.Glucose in the presence of FFA results in synergistic effects on ER stress, impaired insulin receptor substrate signaling and Gsk3β activation. The data support the importance of controlling both hyperglycemia and hyperlipidemia in the management of Type 2 diabetes, and identify pancreatic islet β-cell Gsk3β as a potential therapeutic target

The roles of vicariance and isolation by distance in shaping biotic diversification across an ancient archipelago: evidence from a Seychelles caecilian amphibian

© 2020 The Authors. Published by BMC. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1186/s12862-020-01673-wBackground Island systems offer excellent opportunities for studying the evolutionary histories of species by virtue of their restricted size and easily identifiable barriers to gene flow. However, most studies investigating evolutionary patterns and processes shaping biotic diversification have focused on more recent (emergent) rather than ancient oceanic archipelagos. Here, we focus on the granitic islands of the Seychelles, which are unusual among island systems because they have been isolated for a long time and are home to a monophyletic radiation of caecilian amphibians that has been separated from its extant sister lineage for ca. 65–62 Ma. We selected the most widespread Seychelles caecilian species, Hypogeophis rostratus, to investigate intraspecific morphological and genetic (mitochondrial and nuclear) variation across the archipelago (782 samples from nine islands) to identify patterns and test processes that shaped their evolutionary history within the Seychelles. Results Overall a signal of strong geographic structuring with distinct northern- and southern-island clusters were identified across all datasets. We suggest that these distinct groups have been isolated for ca. 1.26 Ma years without subsequent migration between them. Populations from the somewhat geographically isolated island of Frégate showed contrasting relationships to other islands based on genetic and morphological data, clustering alternatively with northern-island (genetic) and southern-island (morphological) populations. Conclusions Although variation in H. rostratus across the Seychelles is explained more by isolation-by-distance than by adaptation, the genetic-morphological incongruence for affinities of Frégate H. rostratus might be caused by local adaptation over-riding the signal from their vicariant history. Our findings highlight the need of integrative approaches to investigate fine-scale geographic structuring to uncover underlying diversity and to better understand evolutionary processes on ancient, continental islands.Funding for this research was provided by two grants from the National Science Foundation (BSR 88–17453, BSR 90–24505) [funding for fieldwork and lab work], two grants from the National Geographic Society (Grants 1977: 1633, 1743) [funding for fieldwork], three grants from the University of Michigan Office of the Vice President for Research, and a Research Partnership Award from the University of Michigan to RAN [morphology work]; a joint NHM-UCL IMPACT studentship [to fund STM’s PhD, lab work and fieldwork], Mohamed Bin Zayed Species Conservation Fund [funding for fieldwork] and Systematics Research Fund [funding for fieldwork] to STM; an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant #P20GM103408 to LL [funding for lab work]; a NERC/BBSRC SynTax grant [funding for fieldwork and collaboration], and Darwin Initiative (grant 19–002) [funding for fieldwork, lab work and capacity building] with partners Bristol University, Islands Conservation Society, Seychelles Islands Foundation, Seychelles Ministry of Environment, Seychelles National Parks Authority, Seychelles Natural History Museum, University of Kent, Zoological Society of London to MW, DJG, JJD. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.Published onlin