Work fluctuations of self-propelled particles in the phase separated state

We study the large deviations of the distribution P(W_\tau) of the work associated with the propulsion of individual active brownian particles in a time interval \tau, in the region of the phase diagram where macroscopic phase separation takes place. P(W_\tau) is characterised by two peaks, associated to particles in the gaseous and in the clusterised phases, and two separate non-convex branches. Accordingly, the generating function of W_\tau cumulants displays a double singularity. We discuss the origin of such non-convex branches in terms of the peculiar dynamics of the system phases, and the relation between the observation time \tau and the typical persistence times of the particles in the two phases.Comment: 7 pages, 5 figure

Transient Overload Characteristics of PM-Assisted Synchronous Reluctance Machines, Including Sensorless Control Feasibility

Synchronous reluctance machines are a highefficiency alternative to induction motors for variable-speed applications. To mitigate the well-known downside of their lower power factor, permanent-magnet-assisted topologies, in which either rare-earth or ferrite magnets are inserted into the rotor in suitable quantities, are often adopted. The design and optimization procedures for PM-assisted topologies have been thoroughly discussed in the related literature. This paper compares synchronous reluctance machines assisted with NdFeB and ferrite magnets, focusing on torque overload capability and feasibility of saliency-based position estimation algorithms. Three prototypes were realized and tested. They all have the stator of a commercial induction motor and the same customdesigned synchronous reluctance rotor laminations. Of the three prototypes, one is a pure synchronous reluctance motor, and the other two have NdFeB and ferrite magnets, respectively; both are designed to give the same torque at rated current. Results from simulations and experiments are presented comparing the transient overload capability of the three machines, in terms of torque capability and de-magnetization limit. A dynamic thermal model of the machines was developed within this scope. Moreover, the feasibility of saliency-based sensorless methods was investigated and is presented here for the three machines, both at high- and low-current loads. The results of the paper suggest that the ferrite-assisted solution is the best candidate for replacing induction motors in variable-speed applications, for its optimal tradeoff between performance and cost

Quantification of the starling population, estimation and mapping of the damage to olive crops in the apulia region

The presence of wildlife in areas with a high concentration of farming activities can create a conflict between conservation objectives and productive purposes. Near Brindisi (Apulia, S-E Italy), a substantial amount of cash compensation claims for damages reported by local farmers and attributed to starlings (Sturnus vulgaris) has been registered. The aim of this study was to quantify the starling population wintering in the Apulia region, in order to assess the potential damage to crop production caused by this species. Our analysis was conducted over three years and included three main activities: a study of starling abundance and movements, the identification of areas and crops affected by damages, and a determination of the damage to the agricultural system in terms of quantity and concentration (heatmap). The study showed a loss of expected production that was coherent with the eating capacity of starlings wintering in the region. This means a loss, in terms of gross profitable production, of around 550,000 euros concentrated in a few narrow areas close to the roosts. Results on species behavior, damage quantification, and mapping are useful elements aimed to activate trade-off measures to preserve production and protection objectives, and to allow policymakers to address enforcement interventions and to establish parameters for financial compensation

miR-23b/SP1/c-myc forms a feed-forward loop supporting multiple myeloma cell growth

Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3'UTR and significantly reduced Sp1-driven nuclear factor-kappa B activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR-23b. Thus MYC-dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed-forward loop with critical growth and survival role in myeloma

Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells' vulnerability to DNA-damaging agents.

Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia (AML), and thus represents a potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD <sup>+</sup> -dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity in different tumor cells. Here, we demonstrate that also CD34 <sup>+</sup> blasts from AML patients show ongoing DNA damage and SIRT6 overexpression. Indeed, we identified a poor-prognostic subset of patients, with widespread instability, which relies on SIRT6 to compensate for DNA-replication stress. As a result, SIRT6 depletion compromises the ability of leukemia cells to repair DNA double-strand breaks that, in turn, increases their sensitivity to daunorubicin and Ara-C, both in vitro and in vivo In contrast, low SIRT6 levels observed in normal CD34 <sup>+</sup> hematopoietic progenitors explain their weaker sensitivity to genotoxic stress. Intriguingly, we have identified DNA-PKcs and CtIP deacetylation as crucial for SIRT6-mediated DNA repair. Together, our data suggest that inactivation of SIRT6 in leukemia cells leads to disruption of DNA-repair mechanisms, genomic instability and aggressive AML. This synthetic lethal approach, enhancing DNA damage while concomitantly blocking repair responses, provides the rationale for the clinical evaluation of SIRT6 modulators in the treatment of leukemia

Synergistic Interactions between HDAC and Sirtuin Inhibitors in Human Leukemia Cells

Aberrant histone deacetylase (HDAC) activity is frequent in human leukemias. However, while classical, NAD+-independent HDACs are an established therapeutic target, the relevance of NAD+-dependent HDACs (sirtuins) in leukemia treatment remains unclear. Here, we assessed the antileukemic activity of sirtuin inhibitors and of the NAD+-lowering drug FK866, alone and in combination with traditional HDAC inhibitors. Primary leukemia cells, leukemia cell lines, healthy leukocytes and hematopoietic progenitors were treated with sirtuin inhibitors (sirtinol, cambinol, EX527) and with FK866, with or without addition of the HDAC inhibitors valproic acid, sodium butyrate, and vorinostat. Cell death was quantified by propidium iodide cell staining and subsequent flow-cytometry. Apoptosis induction was monitored by cell staining with FITC-Annexin-V/propidium iodide or with TMRE followed by flow-cytometric analysis, and by measuring caspase3/7 activity. Intracellular Bax was detected by flow-cytometry and western blotting. Cellular NAD+ levels were measured by enzymatic cycling assays. Bax was overexpressed by retroviral transduction. Bax and SIRT1 were silenced by RNA-interference. Sirtuin inhibitors and FK866 synergistically enhanced HDAC inhibitor activity in leukemia cells, but not in healthy leukocytes and hematopoietic progenitors. In leukemia cells, HDAC inhibitors were found to induce upregulation of Bax, a pro-apoptotic Bcl2 family-member whose translocation to mitochondria is normally prevented by SIRT1. As a result, leukemia cells become sensitized to sirtuin inhibitor-induced apoptosis. In conclusion, NAD+-independent HDACs and sirtuins cooperate in leukemia cells to avoid apoptosis. Combining sirtuin with HDAC inhibitors results in synergistic antileukemic activity that could be therapeutically exploited