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Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally through eIF3-mediated translation. Elevated expression of H3/H4 in intestinal enterocytes in Drosophila alters chromatin organisation, induces intestinal autophagy through transcriptional regulation, and prevents age-related decline in the intestine. Importantly, it also mediates rapamycin-induced longevity and intestinal health. Histones H3/H4 regulate expression of an autophagy cargo adaptor Bchs (WDFY3 in mammals), increased expression of which in enterocytes mediates increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and Wdfy3 transcription, and alters chromatin organisation in the small intestine, suggesting that the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.

The licensed drug rapamycin has potential to be repurposed for geroprotection. A key challenge is to avoid adverse side effects from continuous dosing. Here we show that geroprotective effects of chronic rapamycin treatment can be obtained with a brief pulse of the drug in early adulthood in female Drosophila and mice. In Drosophila , a brief, early rapamycin treatment of adults extended lifespan and attenuated age-related decline in the intestine to the same degree as lifelong dosing. Lasting memory of earlier treatment was mediated by elevated autophagy in intestinal enterocytes, accompanied by increased levels of intestinal LManV and lysozyme. Brief elevation of autophagy in early adulthood itself induced a long-term increase in autophagy. In mice, a 3-month, early treatment also induced a memory effect, with maintenance similar to chronic treatment, of lysozyme distribution, Man2B1 level in intestinal crypts, Paneth cell architecture and gut barrier function, even 6 months after rapamycin was withdrawn.

Dietary restriction (DR) during adulthood can greatly extend lifespan and improve metabolic health in diverse species. However, whether DR in mammals is still effective when applied for the first time at old age remains elusive. Here, we report results of a late-life DR-switch experiment using 800 mice. Female mice aged 24 months were switched from an ad libitum (AL) diet to DR or vice versa. Strikingly, the switch from DR to AL acutely increases mortality, whereas the switch from AL to DR causes only a weak and gradual increase in survival, suggesting the body has a memory of earlier nutrition. RNA sequencing in liver and brown and white adipose tissue (BAT and WAT, respectively) demonstrates a largely refractory transcriptional and metabolic response in fat tissue to DR after an AL diet, particularly in WAT, and a proinflammatory signature in aged preadipocytes, which is prevented by chronic DR feeding. Our results provide evidence for a ‘nutritional memory’ as a limiting factor for DR-induced longevity and metabolic remodelling of WAT in mammals. Dietary restriction (DR) late in life does not improve survival and has little benefit in metabolic health in mice. The absence of a DR gene-expression signature in fat tissue suggests that a ‘nutritional memory’ interferes with the benefits of DR.

Introduction/Background*Operating on patients with a significantly raised body mass index (BMI) represents a significant challenge to the surgical and the anaesthetic team. Hysterectomy for early-stage uterine cancer is usually performed via laparoscopy.We aimed to evaluate whether a two consultant ‘buddy operating’ approach improves on intra-operative and post-operative outcomes in patients undergoing total laparoscopic hysterectomy (TLH) for endometrial cancer who are morbidly obese.MethodologyA prospectively selected cohort of 25 patients with a BMI 47-70 undergoing TLH was divided into two groups according to whether the first assistant to the Gynae-Oncology consultant was a registrar (ST3-7), or a consultant (‘buddy operating’). Anaesthetic time, operating time, intraoperative estimated blood loss (EBL), requirement for high dependency unit (HDU) bed and length of stay (LOS) were compared in the two groups.Result(s)*Average ‘buddy’ operating time was significantly shorter compared to the registrar-assistant group (01:31h vs 01:59h respectively; p<0.001); a similar trend was seen with the average total anaesthetic time (02:48h vs 03:23h respectively; p<0.001). EBL was less in the ‘buddy operating’ group (39 mls) vs registrar-assistant group (169 mls; p<0.001). Post-operatively, LOS was shorter in the ‘buddy operating’ group as compared to the registrar-assistant, though not significantly so (1.13 vs 1.59 days; p=0.109). 2 of the total patients (8%) required a one-night stay in HDU for observation due to their co-morbidities, both in the registrar-assistant group. Mean BMI, age, ASA and comorbidities were similar in the two groups.Conclusion*In patients with a significantly raised BMI, TLHs by two consultants vs consultant and registrar are associated with better intra and post-operative outcomes, including reduced overall anaesthetic time, operating time, and EBL. There is an association with a reduced length of overall hospital stay, though this was not significant.

•Study is first report of outcomes for advanced ovarian cancer in Wales, and in UK since publication of recent RCT’s.•Study corroborates recent trial evidence of similar outcomes for primary versus interval debulking surgery in advanced primary ovarian cancer.•“Intent-to-treat” analysis provides good evidence for counselling patients on expectations in “real-world” setting, outside clinical trials. This study represents the first reported outcomes for patients with advanced ovarian cancer (AOC) in South-West Wales undergoing treatment with primary debulking surgery or primary chemotherapy respectively. This is a retrospective study of consecutive, unselected patients with advanced ovarian, fallopian tube or primary peritoneal cancer (FIGO III/IV) presenting to a regional cancer centre between October 2007 and October 2014. Patients were identified from Welsh Cancer Services records and relevant data was extracted from electronic National Health Service (NHS) databases. Main outcome measures were median overall survival (OS), progression free survival (PFS) and perioperative adverse events. Hazard ratio estimation was carried out with Cox Regression analysis and survival determined by Kaplan-Meier plots. Of 220 women with AOC, 32.3% underwent primary debulking surgery (PDS) and 67.7% primary chemotherapy and interval debulking (PCT-IDS). Patients were often elderly (median age 67 years) with a poor performance status (26.5% PS >1). Complete cytoreduction (0cm residual) was achieved in 32.4% of patients in the PDS group and in 50.0% of patients undergoing IDS. Median OS for all patients was 21.9 months (PDS: 27.0 and PCT-IDS: 19.2 months; p >0.05) and median PFS was 13.1 months (PDS: 14.3 months and PCT-IDS: 13.0 months; p >0.05). Median overall and progression free survival for patients achieving complete cytoreduction were 48.0 and 23.2 months respectively in the PDS group and 35.4 months and 18.6 months in the IDS group (p >0.05). This retrospective study of an unselected, consecutive cohort of women with AOC in South West Wales shows comparable survival outcomes with recently published trials, despite the relatively advanced age and poor performance status of our patient cohort. Over the seven-year study period, our data also demonstrated a non-significant trend towards improved survival following primary surgery in patients who achieved maximal cytoreduction. Our future aim therefore is to examine and develop the role of extended surgery in these patients.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12–15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN -elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN -elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.

A general solution for data processing of large numbers of micrometer- or submicrometer-particle mass spectra in aerosol analysis is described. The method is based on immediate evaluation of bipolar laser desorption ionization mass spectra acquired in an on-line (impact-free) time-of-flight instrument. The goal of the procedure is a characterization of the particle population under investigation in terms of chemical composition of particle classes, particle distributions, size distributions, and time courses, rather than an investigation of each individual particle. After automatic peak analysis of each newly acquired bipolar mass spectrum, the mass spectral information is statistically evaluated by a fuzzy clustering algorithm, providing for an immediate attribution of the particle to predefined particle classes. The particle distributions over these classes can be monitored as a function of time and particle size range. Definition of the particle classes as used for on-line evaluation is performed in an earlier step, either by manual approach, or by selection from a particle class database, or, as in most cases, by fuzzy clustering of a set of particle mass spectra from the population (the aerosol) under investigation. Definition of the particle classes is depending only on the distinguishability of the spectra patterns of different particles. It is not necessary for the clustering approach to fully “understand” the mass spectra. The range of possible applications of the method is therefore very broad. Particles dominated by inorganic components, as typically observed in aerosol chemistry for example, can be investigated the same way as organic particles (e.g., from smoke or automobile exhaust) or even biological particles such as bacteria, yeast, or pollen. The data processing method has been successfully applied in several fields of stationary applications and will be employed in mobile instruments for large scale field studies in atmospheric chemistry, engine combustion research, and the characterization of house dust.

Beliefs that the risks from a COVID-19 vaccine outweigh the risks from getting COVID-19 and concerns that the vaccine development process was rushed and lacking rigor have been identified as important drivers of hesitancy and refusal to get a COVID-19 vaccine. We tested whether messages designed to address these beliefs and concerns might promote intentions to get a COVID-19 vaccine. We conducted an online survey fielded between March 8-23, 2021 with US Veteran (n = 688) and non-Veteran (n = 387) respondents. In a between-subjects experiment, respondents were randomly assigned to a control group (with no message) or to read one of two intervention messages: 1. a fact-box styled message comparing the risks of getting COVID-19 compared to the vaccine, and 2. a timeline styled message describing the development process of the COVID-19 mRNA vaccines. Most respondents (60%) wanted a COVID-19 vaccine. However, 17% expressed hesitancy and 23% did not want to get a COVID-19 vaccine. The fact-box styled message and the timeline message did not significantly improve vaccination intentions, F(2,358) = 0.86, p = .425, [Formula: see text] = .005, or reduce the time respondents wanted to wait before getting vaccinated, F(2,306) = 0.79, p = .453, [Formula: see text] = .005, compared to no messages. In this experimental study, we did not find that providing messages about vaccine risks and the development process had an impact on respondents' vaccine intentions. Further research is needed to identify how to effectively address concerns about the risks associated with COVID-19 vaccines and the development process and to understand additional factors that influence vaccine intentions.

Improving community resiliency to wildfire is a challenging problem in the face of ongoing development in fire-prone regions. Evacuation and shelter-in-place are the primary options for reducing wildfire casualties, but it can be difficult to determine which option offers the most protection in urgent scenarios. Although guidelines and policies have been proposed to inform this decision, a formal approach to evaluating protective options would help advance protective-action theory. We present an optimization model based on the premise that protecting a community can be viewed as assigning threatened households to one of three actions: evacuation, shelter-in-refuge, or shelter-in-home. While evacuation generally offers the highest level of life protection, it can place residents at greater risk when little time is available. This leads to complex trade-offs involving expected fire intensity, available time, and the quality and accessibility of in-place shelter. An application of the model is presented to illustrate a range of issues that can arise across scenarios.

This paper addresses the problem of resource allocation for distributed real-time periodic tasks, operating in environments that undergo unpredictable changes and that defy the specification of meaningful worst-case execution times. These tasks are supplied by input data originating from various environmental workload sources. Rather than using worst-case execution times (WCETs) to describe the CPU usage of the tasks, we assume here that execution profiles are given to describe the running time of the tasks in terms of the size of the input data of each workload source. The objective of resource allocation is to produce an initial allocation that is robust against fluctuations in the environmental parameters. We try to maximize the input size (workload) that can be handled by the system, and hence to delay possible (costly) reallocations as long as possible. We present an approximation algorithm based on first-fit and binary search that we call FFBS. As we show here, the first-fit algorithm produces solutions that are often close to optimal. In particular, we show analytically that FFBS is guaranteed to produce a solution that is at least 41% of optimal, asymptotically, under certain reasonable restrictions on the running times of tasks in the system. Moreover, we show that if at most 12% of the system utilization is consumed by input independent tasks (e.g., constant time tasks), then FFBS is guaranteed to produce a solution that is at least 33% of optimal, asymptotically. Moreover, we present simulations to compare FFBS approximation algorithm with a set of standard (local search) heuristics such as hill-climbing, simulated annealing, and random search. The results suggest that FFBS, in combination with other local improvement strategies, may be a reasonable approach for resource allocation in dynamic real-time systems.