Patterned monolayers of nitronyl nitroxide radicals

We report here the results of the preliminary characterization of the monolayer obtained both by self-assembling and microcontact printing of a di-alkyl sulfide nitronyl nitroxide derivative, 11-decyl sulfanyl-undecanyl nitronyl nitroxide of which we describe the synthesis. The sulfide unit has been introduced in order to allow the grafting of the molecule to the gold surface as well as to improve the stability of the organic radical with respect to different grafting agents like thiols, whereas the two long alkyl chains have been introduced to enhance the packing order of the molecules in a self assembled monolayer structure. X-band ESR was used to demonstrate the persistence of the paramagnetic character of the radical in the self-assembled monolayers, and to study its relatively large mobility. The microcontact printed monolayer was characterized by AFM, suggesting a non-negligible mobility of the molecules on the surfaces and a strong tilting of the molecules on the surface

The effect of timing and composition of gestational weight gain in obese pregnant women on infant birth weight: A prospective cohort study.

Introduction: CK2 is a protein kinase implicated in several essential cellular processes, over-expressed in cancer and described to regulate insulin signaling cascade. Recently CK2 has been described to negatively regulate thermogenesis (Shinoda K et al, 2015, Cell Metabolism) and to inhibit insulin release (Rossi M et al, 2015, PNAS). Nevertheless, the role of CK2 in adipose tissue (AT) and its involvement in human obesity development and therapy has been poorly investigated. Methods: Our multi-disciplinary team performed biochemical analysis of signaling pathways by WB and in vitro kinase activity assays, and glucose handling studies using glucose uptake assay and IF in adipocyte cultures and glucose and insulin tolerance test in mice. Moreover we quantify CK2 expression/activity in human AT specimens of 27 obese patients, clinically characterized, in 12 obese patients underwent relevant weight loss and 11 normal-weight controls. Results: We proved that CK2 amount and activity were not influenced by insulin stimulation and that CK2 activity was efficiently inhibited by specific inhibitors, structurally unrelated. We worked with CX-4945, a CK2 inhibitor currently used in cancer clinical trials, using the minimal concentration (2.5 \u192 dM) and pre-treatment time (1hr) able to efficiently inhibit CK2 activity, avoiding any cytotoxic effect. Pharmacological inhibition of CK2 did not significantly affect in vitro adipogenic differentiation or expression profiling of mature adipocytes. Conversely, we showed that in human and murine adipocytes CK2-inhibition decreases the insulin-induced glucose uptake by counteracting Akt-signaling and GLUT4-translocation to the plasma membrane. We compared CK2 expression and activity in different mouse tissues highlighted that white skeletal muscle fibres and liver contained the highest quantity of this kinase. CK2 was expressed more in brown AT than in white AT depots. We show that CK2 promotes insulin-signaling in mouse AT, liver and skeletal muscle and that in vivo acute treatment with CX-4945 impairs glucose- tolerance in mice. Studies in tissues of ob/ob and db/db mice highlights an up-regulation of CK2 expression and activity only in WAT. CK2 hyper-activation is strongly evident also in SAT and VAT of obese patients and weight loss obtained by bariatric surgery or hypocaloric diet reverts CK2 up-regulation to normal level. Conclusion: We show that CK2 is involved in insulin sensitivity, glucose handling and remodeling of WAT. Moreover we identify CK2 hyper-activation as a hallmark of human obesity, suggesting a new potential therapeutic target for metabolic diseases

Relationship Between Baseline Prostate-specific Antigen on Cancer Detection and Prostate Cancer Death:Long-term Follow-up from the European Randomized Study of Screening for Prostate Cancer

Background: The European Association of Urology guidelines recommend a risk-based strategy for prostate cancer screening based on the first prostate-specific antigen (PSA) level and age. Objective: To analyze the impact of the first PSA level on prostate cancer (PCa) detection and PCa-specific mortality (PCSM) in a population-based screening trial (repeat screening every 2–4 yr). Design, setting, and participants: We evaluated 25 589 men aged 55–59 yr, 16 898 men aged 60–64 yr, and 12 936 men aged 65–69 yr who attended at least one screening visit in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial (screening arm: repeat PSA testing every 2–4 yr and biopsy in cases with elevated PSA; control arm: no active screening offered) during 16-yr follow-up (FU). Outcome measurements and statistical analysis: We assessed the actuarial probability for any PCa and for clinically significant (cs)PCa (Gleason ≥7). Cox proportional-hazards regression was performed to assess whether the association between baseline PSA and PCSM was comparable for all age groups. A Lorenz curve was computed to assess the association between baseline PSA and PCSM for men aged 60–61 yr. Results and limitations: The overall actuarial probability at 16 yr ranged from 12% to 16% for any PCa and from 3.7% to 5.7% for csPCa across the age groups. The actuarial probability of csPCa at 16 yr ranged from 1.2–1.5% for men with PSA &lt;1.0 ng/ml to 13.3–13.8% for men with PSA ≥3.0 ng/ml. The association between baseline PSA and PCSM differed marginally among the three age groups. A Lorenz curve for men aged 60–61 yr showed that 92% of lethal PCa cases occurred among those with PSA above the median (1.21 ng/ml). In addition, for men initially screened at age 60–61 yr with baseline PSA &lt;2 ng/ml, further continuation of screening is unlikely to be beneficial after the age of 68–70 yr if PSA is still &lt;2 ng/ml. No case of PCSM emerged in the subsequent 8 yr (up to age 76–78 yr). A limitation is that these results may not be generalizable to an opportunistic screening setting or to contemporary clinical practice. Conclusions: In all age groups, baseline PSA can guide decisions on the repeat screening interval. Baseline PSA of &lt;1.0 ng/ml for men aged 55–69 yr is a strong indicator to delay or stop further screening. Patient summary: In prostate cancer screening, the patient's baseline PSA (prostate-specific antigen) level can be used to guide decisions on when to repeat screening. The PSA test when used according to current knowledge is valuable in helping to reduce the burden of prostate cancer.</p

The Legionella effector WipB is a translocated Ser/Thr phosphatase that targets the host lysosomal nutrient sensing machinery

Legionella pneumophila infects human alveolar macrophages and is responsible for Legionnaire’s disease, a severe form of pneumonia. L. pneumophila encodes more than 300 putative effectors, which are translocated into the host cell via the Dot/Icm type IV secretion system. These effectors highjack the host’s cellular processes to allow bacterial intracellular growth and replication. Here we adopted a multidisciplinary approach to investigate WipB, a Dot/Icm effector of unknown function. The crystal structure of the N-terminal domain at 1.7 Å resolution comprising residues 25 to 344 revealed that WipB harbours a Ser/Thr phosphatase domain related to the eukaryotic phospho-protein phosphatase (PPP) family. The C-terminal domain (residues 365–524) is sufficient to pilot the effector to acidified LAMP1-positive lysosomal compartments, where WipB interacts with the v-ATPase and the associated LAMTOR1 phosphoprotein, key components of the lysosomal nutrient sensing (LYNUS) apparatus that controls the mammalian target of rapamycin (mTORC1) kinase complex at the lysosomal surface. We propose that WipB is a lysosome-targeted phosphatase that modulates cellular nutrient sensing and the control of energy metabolism during Legionella infection

Molecular targets for the protodynamic action of cis-urocanic acid in human bladder carcinoma cells

<p>Abstract</p> <p>Background</p> <p>cis-urocanic acid (cis-UCA) is an endogenous amino acid metabolite capable of transporting protons from the mildly acidic extracellular medium into the cell cytosol. The resulting intracellular acidification suppresses many cellular activities. The current study was aimed at characterizing the molecular mechanisms underlying cis-UCA-mediated cytotoxicity in cultured cancer cells.</p> <p>Methods</p> <p>5367 bladder carcinoma cells were left untreated or treated with cis-UCA. Cell death was assessed by measuring caspase-3 activity, mitochondrial membrane polarization, formation and release of cytoplasmic histone-associated DNA fragments, and cellular permeabilization. Cell viability and metabolic activity were monitored by colorimetric assays. Nuclear labelling was used to quantify the effects of cis-UCA on cell cycle. The activity of the ERK and JNK signalling pathways was studied by immunoblotting with specific antibodies. Phosphatase activity in cis-UCA-treated cells was determined by assay kits measuring absorbance resulting from the dephosphorylation of an artificial substrate. All statistical analyses were performed using the two-way Student's t-test (p < 0.05).</p> <p>Results</p> <p>Here we report that treatment of the 5637 human bladder carcinoma cells with 2% cis-UCA induces both apoptotic and necrotic cell death. In addition, metabolic activity of the 5637 cells is rapidly impaired, and the cells arrest in cell cycle in response to cis-UCA. Importantly, we show that cis-UCA promotes the ERK and JNK signalling pathways by efficiently inhibiting the activity of serine/threonine and tyrosine phosphatases.</p> <p>Conclusions</p> <p>Our studies elucidate how cis-UCA modulates several cellular processes, thereby inhibiting the proliferation and survival of bladder carcinoma cells. These anti-cancer effects make cis-UCA a potential candidate for the treatment of non-muscle invasive bladder carcinoma.</p

Estimate of overdiagnosis of breast cancer due to mammography after adjustment for lead time. A service screening study in Italy

INTRODUCTION: Excess of incidence rates is the expected consequence of service screening. The aim of this paper is to estimate the quota attributable to overdiagnosis in the breast cancer screening programmes in Northern and Central Italy. METHODS: All patients with breast cancer diagnosed between 50 and 74 years who were resident in screening areas in the six years before and five years after the start of the screening programme were included. We calculated a corrected-for-lead-time number of observed cases for each calendar year. The number of observed incident cases was reduced by the number of screen-detected cases in that year and incremented by the estimated number of screen-detected cases that would have arisen clinically in that year. RESULTS: In total we included 13,519 and 13,999 breast cancer cases diagnosed in the pre-screening and screening years, respectively. In total, the excess ratio of observed to predicted in situ and invasive cases was 36.2%. After correction for lead time the excess ratio was 4.6% (95% confidence interval 2 to 7%) and for invasive cases only it was 3.2% (95% confidence interval 1 to 6%). CONCLUSION: The remaining excess of cancers after individual correction for lead time was lower than 5%

Switches, Excitable Responses and Oscillations in the Ring1B/Bmi1 Ubiquitination System

In an active, self-ubiquitinated state, the Ring1B ligase monoubiquitinates histone H2A playing a critical role in Polycomb-mediated gene silencing. Following ubiquitination by external ligases, Ring1B is targeted for proteosomal degradation. Using biochemical data and computational modeling, we show that the Ring1B ligase can exhibit abrupt switches, overshoot transitions and self-perpetuating oscillations between its distinct ubiquitination and activity states. These different Ring1B states display canonical or multiply branched, atypical polyubiquitin chains and involve association with the Polycomb-group protein Bmi1. Bistable switches and oscillations may lead to all-or-none histone H2A monoubiquitination rates and result in discrete periods of gene (in)activity. Switches, overshoots and oscillations in Ring1B catalytic activity and proteosomal degradation are controlled by the abundances of Bmi1 and Ring1B, and the activities and abundances of external ligases and deubiquitinases, such as E6-AP and USP7

Circular economy inspired imaginaries for sustainable innovations

In this chapter, Narayan and Tidström draw on the concept of imaginaries to show how Circular Economy (CE) can facilitate values that enable sustainable innovation. Innovation is key for sustainability, however, understanding and implementing sustainable innovation is challenging, and identifying the kind of actions that could direct sustainable innovations is important. The findings of this study indicate that CE-inspired imaginaries enable collaboration and by relating such imaginaries to common and shared social and cultural values, intermediaries could motivate actors into taking actions that contribute to sustainable innovation.fi=vertaisarvioitu|en=peerReviewed