Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III deacetylase sirtuin family, which plays a key role in cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and autophagy. Here we analyzed the molecular and biological effects of UBCS039, the first synthetic SIRT6 activator. Our data demonstrated that UBCS039 induced a time-dependent activation of autophagy in several human tumor cell lines, as evaluated by increased content of the lipidated form of LC3B by western blot and of autophagosomal puncta by microscopy analysis of GFP-LC3. UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity since the catalytic mutant H133Y failed to activate autophagy. At the molecular level, SIRT6-mediated autophagy was triggered by an increase of ROS levels, which, in turn, resulted in the activation of the AMPK-ULK1-mTOR signaling pathway. Interestingly, antioxidants were able to completely counteract UBCS039-induced autophagy, suggesting that ROS burst had a key role in upstream events leading to autophagy commitment. Finally, sustained activation of SIRT6 resulted in autophagy-related cell death, a process that was markedly attenuated using either a pan caspases inhibitor (zVAD-fmk) or an autophagy inhibitor (CQ). Overall, our results identified UBCS039 as an efficient SIRT6 activator, thereby providing a proof of principle that modulation of the enzyme can influence therapeutic strategy by enhancing autophagy-dependent cell death

Does fishing have an impact on Maltese maerl grounds?

The sedimentary bottoms off the northeastern coast of the Maltese Islands are important inshore fishing grounds. Between depths of 45m and 80m, these bottoms are characterized by accumulations of unattached calcareous rhodophytes, forming maerl beds. The complex structure of these free-living thalli (rhodoliths) introduces heterogeneity to the otherwise homogenous sedimentary bottoms, thus increasing biotic diversity. Maerl deposits may take hundreds of years to accumulate and their development is strongly correlated with the current and sedimentary regimes and with bottom disturbance, making such beds susceptible to anthropogenic disruption. Two fishing techniques in particular used locally may have an impact on maerl bottoms: parit fishing (bottom-set gill-nets) and bottom trawling using an otter trawl. We investigated the effect of the former by experimental fishing on maerl, and that of the latter by studying rhodolith structure, sediment granulometry, and benthic biodiversity of a 20km2 maerl bed, part of which is regularly trawled. Parit fishing may remove the larger rhodoliths but its impact depends greatly on the strength of the bottom current. The trawled site had more abundant rhodoliths and coarser sediments than the non- trawled site, but a lower sediment organic content. Rhodolith morphology was also different at the two sites. Both sites had a high species richness but low abundance and biomass. Differences in species composition were also noted. These results are discussed in relation to the different environmental characteristics of the two sites, including the role of disturbance, but the relative importance of anthropic activities and natural perturbations is not yet clear.peer-reviewe

Suspension of the fiber mode-cleaner launcher and measurement of the high extinction-ratio (10^{-9}) ellipsometer for the Q & A experiment

The Q & A experiment, first proposed and started in 1994, provides a feasible way of exploring the quantum vacuum through the detection of vacuum birefringence effect generated by QED loop diagram and the detection of the polarization rotation effect generated by photon-interacting (pseudo-)scalar particles. Three main parts of the experiment are: (1) Optics System (including associated Electronic System) based on a suspended 3.5-m high finesse Fabry-Perot cavity, (2) Ellipsometer using ultra-high extinction-ratio polarizer and analyzer, and (3) Magnetic Field Modulation System for generating the birefringence and the polarization rotation effect. In 2002, the Q & A experiment achieved the Phase I sensitivity goal. During Phase II, we set (i) to improve the control system of the cavity mirrors for suppressing the relative motion noise, (ii) to enhance the birefringence signal by setting-up a 60-cm long 2.3 T transverse permanent magnet rotatable to 10 rev/s, (iii) to reduce geometrical noise by inserting a polarization-maintaining optical fiber (PM fiber) as a mode cleaner, and (iv) to use ultra-high extinction-ratio (10^{-9}) polarizer and analyzer for ellipsometry. Here we report on (iii) & (iv); specifically, we present the properties of the PM-fiber mode-cleaner, the transfer function of its suspension system, and the result of our measurement of high extinction-ratio polarizer and analyzer.Comment: 8 pages, 6 figures, presented in the 6th Edoardo Amaldi Conference on Gravitational Waves, Okinawa, Japan, June 2005, and accepted by "Journal of Physics: Conference Series". Modifications from version 2 were made based on the referees' comments on figures. Ref. [31] were update

Public attitudes towards alcohol control policies in Scotland and England: Results from a mixed-methods study

The harmful effects of heavy drinking on health have been widely reported, yet public opinion on governmental responsibility for alcohol control remains divided. This study examines UK public attitudes towards alcohol policies, identifies underlying dimensions that inform these, and relationships with perceived effectiveness. A cross-sectional mixed methods study involving a telephone survey of 3477 adult drinkers aged 16-65 and sixteen focus groups with 89 adult drinkers in Scotland and England was conducted between September 2012 and February 2013. Principal components analysis (PCA) was used to reduce twelve policy statements into underlying dimensions. These dimensions were used in linear regression models examining alcohol policy support by demographics, drinking behaviour and perceptions of UK drinking and government responsibility. Findings were supplemented with a thematic analysis of focus group transcripts. A majority of survey respondents supported all alcohol policies, although the level of support varied by type of policy. Greater enforcement of laws on under-age sales and more police patrolling the streets were strongly supported while support for pricing policies and restricting access to alcohol was more divided. PCA identified four main dimensions underlying support on policies: alcohol availability, provision of health information and treatment services, alcohol pricing, and greater law enforcement. Being female, older, a moderate drinker, and holding a belief that government should do more to reduce alcohol harms were associated with higher support on all policy dimensions. Focus group data revealed findings from the survey may have presented an overly positive level of support on all policies due to differences in perceived policy effectiveness. Perceived effectiveness can help inform underlying patterns of policy support and should be considered in conjunction with standard measures of support in future research on alcohol control policies

Physical activity and clustered cardiovascular disease risk factors in young children: a cross-sectional study (the IDEFICS study)

<p>Background The relevance of physical activity (PA) for combating cardiovascular disease (CVD) risk in children has been highlighted, but to date there has been no large-scale study analyzing that association in children aged ≤9 years of age. This study sought to evaluate the associations between objectively-measured PA and clustered CVD risk factors in a large sample of European children, and to provide evidence for gender-specific recommendations of PA.</p> <p>Methods Cross-sectional data from a longitudinal study in 16,224 children aged 2 to 9 were collected. Of these, 3,120 (1,016 between 2 to 6 years, 2,104 between 6 to 9 years) had sufficient data for inclusion in the current analyses. Two different age-specific and gender-specific clustered CVD risk scores associated with PA were determined. First, a CVD risk factor (CRF) continuous score was computed using the following variables: systolic blood pressure (SBP), total triglycerides (TG), total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-c) ratio, homeostasis model assessment of insulin resistance (HOMA-IR), and sum of two skinfolds (score CRFs). Secondly, another CVD risk score was obtained for older children containing the score CRFs + the cardiorespiratory fitness variable (termed score CRFs + fit). Data used in the current analysis were derived from the IDEFICS (‘Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS’) study.</p> <p>Results In boys <6 years, the odds ratios (OR) for CVD risk were elevated in the least active quintile of PA (OR: 2.58) compared with the most active quintile as well as the second quintile for vigorous PA (OR: 2.91). Compared with the most active quintile, older children in the first, second and third quintiles had OR for CVD risk score CRFs + fit ranging from OR 2.69 to 5.40 in boys, and from OR 2.85 to 7.05 in girls.</p> <p>Conclusions PA is important to protect against clustering of CVD risk factors in young children, being more consistent in those older than 6 years. Healthcare professionals should recommend around 60 and 85 min/day of moderate-to-vigorous PA, including 20 min/day of vigorous PA.</p&gt

A serum proteome signature to predict mortality in severe COVID-19 patients.

Here, we recorded serum proteome profiles of 33 severe COVID-19 patients admitted to respiratory and intensive care units because of respiratory failure. We received, for most patients, blood samples just after admission and at two more later time points. With the aim to predict treatment outcome, we focused on serum proteins different in abundance between the group of survivors and non-survivors. We observed that a small panel of about a dozen proteins were significantly different in abundance between these two groups. The four structurally and functionally related type-3 cystatins AHSG, FETUB, histidine-rich glycoprotein, and KNG1 were all more abundant in the survivors. The family of inter-α-trypsin inhibitors, ITIH1, ITIH2, ITIH3, and ITIH4, were all found to be differentially abundant in between survivors and non-survivors, whereby ITIH1 and ITIH2 were more abundant in the survivor group and ITIH3 and ITIH4 more abundant in the non-survivors. ITIH1/ITIH2 and ITIH3/ITIH4 also showed opposite trends in protein abundance during disease progression. We defined an optimal panel of nine proteins for mortality risk assessment. The prediction power of this mortality risk panel was evaluated against two recent COVID-19 serum proteomics studies on independent cohorts measured in other laboratories in different countries and observed to perform very well in predicting mortality also in these cohorts. This panel may not be unique for COVID-19 as some of the proteins in the panel have previously been annotated as mortality markers in aging and in other diseases caused by different pathogens, including bacteria

Ovarian cancer symptom awareness and anticipated delayed presentation in a population sample

Background: While ovarian cancer is recognised as having identifiable early symptoms, understanding of the key determinants of symptom awareness and early presentation is limited. A population-based survey of ovarian cancer awareness and anticipated delayed presentation with symptoms was conducted as part of the International Cancer Benchmarking Partnership (ICBP). Methods: Women aged over 50 years were recruited using random probability sampling (n = 1043). Computer-assisted telephone interviews were used to administer measures including ovarian cancer symptom recognition, anticipated time to presentation with ovarian symptoms, health beliefs (perceived risk, perceived benefits/barriers to early presentation, confidence in symptom detection, ovarian cancer worry), and demographic variables. Logistic regression analysis was used to identify the contribution of independent variables to anticipated presentation (categorised as < 3 weeks or ≥ 3 weeks). Results: The most well-recognised symptoms of ovarian cancer were post-menopausal bleeding (87.4%), and persistent pelvic (79.0%) and abdominal (85.0%) pain. Symptoms associated with eating difficulties and changes in bladder/bowel habits were recognised by less than half the sample. Lower symptom awareness was significantly associated with older age (p ≤ 0.001), being single (p ≤ 0.001), lower education (p ≤ 0.01), and lack of personal experience of ovarian cancer (p ≤ 0.01). The odds of anticipating a delay in time to presentation of ≥ 3 weeks were significantly increased in women educated to degree level (OR = 2.64, 95% CI 1.61 – 4.33, p ≤ 0.001), women who reported more practical barriers (OR = 1.60, 95% CI 1.34 – 1.91, p ≤ 0.001) and more emotional barriers (OR = 1.21, 95% CI 1.06 – 1.40, p ≤ 0.01), and those less confident in symptom detection (OR = 0.56, 95% CI 0.42 – 0.73, p ≤ 0.001), but not in those who reported lower symptom awareness (OR = 0.99, 95% CI 0.91 – 1.07, p = 0.74). Conclusions: Many symptoms of ovarian cancer are not well-recognised by women in the general population. Evidence-based interventions are needed not only to improve public awareness but also to overcome the barriers to recognising and acting on ovarian symptoms, if delays in presentation are to be minimised

Typhoid fever as a cause of opportunistic infection: case report

BACKGROUND: Typhoid fever is a systemic infection caused by the bacterium Salmonella enterica subspecies enterica serotype typhi, which is acquired by ingestion of contaminated food and water. Each year the disease affects at least 16 million persons world-wide, most of whom reside in the developing countries of Southeast Asia and Africa. In Italy the disease is uncommon with a greater number of cases in Southern regions than in Northern ones. CASE PRESENTATION: We report on a 57-year-old Sri-Lankan male affected by typhoid fever, the onset of which was accompanied by oropharyngeal candidiasis. This clinical sign was due to a transient cell-mediated immunity depression (CD4+ cell count was 130 cells/mm(3)) probably caused by Salmonella typhi infection. Human immunodeficiency virus infection was ruled out. Diagnosis of typhoid fever was made by the isolation of Salmonella typhi from two consecutive blood cultures. The patient recovered after a ten days therapy with ciprofloxacin and his CD4+ cell count improved gradually until normalization within 3 weeks. CONCLUSION: Our patient is the first reported case of typhoid fever associated with oropharyngeal candidiasis. This finding suggests a close correlation between Salmonella typhi infection and transitory immunodepression