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Let-7c, an intronic microRNA (miRNA) embedded in the long non-coding gene LINC00478, can act as a tumor suppressor by targeting oncogenes. Previous studies indicated that in acute promyelocytic leukemia (APL), a subtype of acute myelogenous leukemia (AML) bearing the leukemia promoting PML/RARα fusion protein, let-7c expression seems to be controlled by the host gene promoter, in which canonical Retinoic Acid Responsive Elements (RAREs) are bound by PML/RARα in an all transretinoic acid (ATRA)–sensitive manner. Here, let-7c transcriptional regulation was further investigated and a novel intronic promoter upstream of the pre-miRNA was identified. This new promoter has transcriptional activity strongly indicating that at least two promoters need to be considered for let-7c transcription: the distal host gene and the proximal intronic promoter. Therefore, epigenetic modifying enzymes and histone acetylation and methylation status were analyzed on both let-7c promoters. It was demonstrated that ATRA treatment leads to let-7c upregulation inducing a more open chromatin conformation of the host gene promoter, with an enrichment of epigenetic marks that correlate with a more active transcriptional state. Conversely, the epigenetic marks on the intronic promoter are not significantly affected by ATRA treatment. Interestingly, in solid tumors such as prostate and lung adenocarcinoma it was found that both host and intronic promoters are functional. These data suggest that while the host gene promoter may control let-7c expression in AML, in a nonleukemic tumor context instead the intronic promoter contributes or preferentially regulates let-7c transcription.Implications: Alternative promoter usage represents a regulatory mechanism of let-7c expression in different tissues. Mol Cancer Res; 12(6); 878–89. ©2014 AACR.

PDF file - 725KB, S2. Expression of the primary transcript of miR-99a and miR-125b in cell lines from different solid tumors. S3. UCSC track.

PDF file - 1470KB, Sequences.

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Muscular dystrophies (MDs) are a group of genetic diseases characterized by progressive muscle wasting associated to oxidative stress and persistent inflammation. It is essential to deepen our knowledge on the mechanism connecting these two processes because current treatments for MDs have limited efficacy and/or are associated with side effects. Here, we identified the alarmin high-mobility group box 1 (HMGB1) as a functional link between oxidative stress and inflammation in MDs. The oxidation of HMGB1 cysteines switches its extracellular activities from the orchestration of tissue regeneration to the exacerbation of inflammation. Extracellular HMGB1 is present at high amount and undergoes oxidation in patients with MDs and in mouse models of Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy 3 (LGMDR3) compared to controls. Genetic ablation of HMGB1 in muscles of DMD mice leads to an amelioration of the dystrophic phenotype as evidenced by the reduced inflammation and muscle degeneration, indicating that HMGB1 oxidation is a detrimental process in MDs. Pharmacological treatment with an engineered nonoxidizable variant of HMGB1, called 3S, improves functional performance, muscle regeneration, and satellite cell engraftment in dystrophic mice while reducing inflammation and fibrosis. Overall, our data demonstrate that the balance between HMGB1 redox isoforms dictates whether skeletal muscle is in an inflamed or regenerating state, and that the nonoxidizable form of HMGB1 is a possible therapeutic approach to counteract the progression of the dystrophic phenotype. Rebalancing the HMGB1 redox isoforms may also be a therapeutic strategy for other disorders characterized by chronic oxidative stress and inflammation.

The seismic events which have hit the central part of Italy from 24 august 2016 and the consequent strong earthquakes in October and November 2016 and January 2017, have created extended losses in four regions: Lazio, Marche, Umbria and Abruzzo. These losses have been in terms of life and property. The elevated level of material destruction has also interested a large part of Italian Cultural Heritage, both as regards the monumental building and the movable goods. In fact, Italy is reach of many artistic goods which are not only allocated into Museums. The extended damage on older buildings such a Churches, which are not designed to resist earthquakes, is caused by different factors due overall to the construction techniques dissimilarity and the large variation of their construction typology. Still today Churches are the place where some of the most important artistical works are kept: paintings, frescos, statues, altars and other many sacred objects. During the emergency phase, a big recognition work has been carried out by the Civil Protection Department, as well as by all the Institutions which have been part of the recognition phase after earthquakes, collecting a database through the “Schede AeDES” which has been successively digitalized by the “Ministero per i beni e le attivita culturali e per il Turismo ” (MiBACT), able to gives for each building, the level of damage and the related real situation of intervention. The churches affected by the earthquake have been almost 3000 in the four regions. After the previous assessment on the field of their level of damage and of the related reconstruction’s costs estimation carried out by expert volunteers technicians, on September 2017 the Italian Government have issued a funding plan for the reconstruction of the first 100 churches, chosen on the basis of the intervention’s relevance. Moreover, many interventions of artistic goods rescue are made place thanks to the Fire Fighters, and successively by the MiBACT technicians. In fact, from the 2009 earthquake management experience, it was possible to face the scenario that struck Italy in the latest serious event in 2016. Thanks to the activation of a series of operations, it was possible to recover the huge historical and artistic Italian heritage constituted by many damaged movable goods. After the last seismic events, the technicians of special Units of the Ministry of cultural Heritage and Activities and Tourism (MiBACT), has carried out a survey to map the damage of both historical buildings and movable artistic goods. From this survey, a damage scenario has emerged involving about 20.000 historical artistic assets and movable archaeologists, over 4500 linear meters of archival assets and 10000 volumes of books assets. When possible, the artistic goods are moved from the Churches, catalogued and hospitalized into specific warehouses. The recovery of movable goods, promptly activated by the MiBACT, has involved their removal from the damaged buildings and their subsequent placement in warehouses, even temporary, specially equipped and set up. These storages, managed by MiBACT, are able to guarantee the first activities of intervention for the stabilization of the artworks. In other cases, when was not possible to move the artistic works, a temporary structure has been built for the protection of the goods (such as frescos).

Trabectedin (ET743) and lurbinectedin (PM01183) limit the production of inflammatory cytokines that are elevated during cancer cachexia. Mice carrying C26 colon adenocarcinoma display cachexia (i.e., premature death and body wasting with muscle, fat and cardiac tissue depletion), high levels of inflammatory cytokines and subsequent splenomegaly. We tested whether such drugs protected these mice from cachexia. Ten-week-old mice were inoculated with C26 cells and three days later randomized to receive intravenously vehicle or 0.05 mg/kg ET743 or 0.07 mg/kg PM01183, three times a week for three weeks. ET743 or PM01183 extended the lifespan of C26-mice by 30% or 85%, respectively, without affecting tumor growth or food intake. Within 13 days from C26 implant, both drugs did not protect fat, muscle and heart from cachexia. Since PM01183 extended the animal survival more than ET743, we analyzed PM01183 further. In tibialis anterior of C26-mice, but not in atrophying myotubes, PM01183 restrained the NF-&kappa, B/PAX7/myogenin axis, possibly reducing the pro-inflammatory milieu, and failed to limit the C/EBP&beta, /atrogin-1 axis. Inflammation-mediated splenomegaly of C26-mice was inhibited by PM01183 for as long as the treatment lasted, without reducing IL-6, M-CSF or IL-1&beta, in plasma. ET743 and PM01183 extend the survival of C26-bearing mice unchanging tumor growth or cachexia but possibly restrain muscle-related inflammation and C26-induced splenomegaly.

In 2014, after unprecedented destruction and suffering in Gaza, international donors pledged $3.5bn and a change in approach. Six months later, reconstruction and recovery have barely begun, there has been no accountability for violations of international law, and Gaza remains cut off from the West Bank., This AIDA briefing paper outlines an achievable course of action to address the root causes of the recurrent conflict and put international engagement with Gaza back on the right course.

[EN] This paper shows the restoration work carried out on the mudbrick structures uncovered at the Iron Age (c. 1300-300 BC) site of Salūt, in central Oman. In the region, traditional earthen architecture represented the key building technique until modern times. The traditional concept of constant upkeep is arguably the only way of efficiently preserving ancient structures. However, different mud plaster compositions were tested which could provide a better aspect and a lower static load on the structures. The work strategy was meant to be sustainable from an economic, ecological, and sociological point of view, as it also aimed at documenting and hopefully reviving the traditional earthen architecture currently endangered by the disinterest of younger generations., [ES] Este artículo describe la restauración de las estructuras de adobe descubiertas en el sitio de Salūt, en el centro de Omán, que datan de la Edad del Hierro (c. 1300-300 a. C.). En esta región, la arquitectura tradicional de tierra ha representado la técnica de construcción clave hasta tiempos modernos. El concepto tradicional de mantenimiento continuo es la única forma de preservar eficazmente las estructuras antiguas. Por otra parte, se experimentó con revocos de barro de diversa composición que pudieran conferir un mejor aspecto y una menor carga estática en las estructuras. La estrategia de trabajo pretendía ser sostenible y se fijaba como objetivo documentar y tratar de revivir la arquitectura tradicional de tierra, actualmente en peligro por el desinterés de las generaciones más jóvenes.

Inflammation and tissue regeneration follow tissue damage, but little is known about how these processes are coordinated. Tirone et al. show that alternative redox forms of high mobility group box 1 (HMGB1), the “alarmin” signal released by damaged cells, trigger inflammation or tissue repair after injury by interacting with distinct receptors and that a nonoxidizable HMGB1 mutant promotes regeneration without exacerbating inflammation., Inflammation and tissue regeneration follow tissue damage, but little is known about how these processes are coordinated. High Mobility Group Box 1 (HMGB1) is a nuclear protein that, when released on injury, triggers inflammation. We previously showed that HMGB1 with reduced cysteines is a chemoattractant, whereas a disulfide bond makes it a proinflammatory cytokine. Here we report that fully reduced HMGB1 orchestrates muscle and liver regeneration via CXCR4, whereas disulfide HMGB1 and its receptors TLR4/MD-2 and RAGE (receptor for advanced glycation end products) are not involved. Injection of HMGB1 accelerates tissue repair by acting on resident muscle stem cells, hepatocytes, and infiltrating cells. The nonoxidizable HMGB1 mutant 3S, in which serines replace cysteines, promotes muscle and liver regeneration more efficiently than the wild-type protein and without exacerbating inflammation by selectively interacting with CXCR4. Overall, our results show that the reduced form of HMGB1 coordinates tissue regeneration and suggest that 3S may be used to safely accelerate healing after injury in diverse clinical contexts.

Nuclear positioning within cells is important for multiple cellular processes in development and regeneration. The most intriguing example of nuclear positioning occurs during skeletal muscle differentiation. Muscle fibers (myofibers) are multinucleated cells formed by the fusion of muscle precursor cells (myoblasts) derived from muscle stem cells (satellite cells) that undergo proliferation and differentiation. Correct nuclear positioning within myofibers is required for the proper muscle regeneration and function. The common procedure to assess myoblast differentiation and myofiber formation relies on fixed cells analyzed by immunofluorescence, which impedes the study of nuclear movement and cell behavior over time. Here, we describe a method for the analysis of myoblast differentiation and myofiber formation by live cell imaging. We provide a software for automated nuclear tracking to obtain a high-throughput quantitative characterization of nuclear dynamics and myoblast behavior (i.e., the trajectory) during differentiation and fusion.

Additional file 11: Figure S5. ZEB2 expression in TNM stages, correlation with RFS and CMS in stage 2 CRC patients. ZEB2 transcript levels in the indicated number of CRC patients across all TNM stages. One-way ANOVA resulted in non-significant differences between stages. Outliers are depicted as crosses. n = 1079.

Background Quiescent/slow cycling cells have been identified in several tumors and correlated with therapy resistance. However, the features of chemoresistant populations and the molecular factors linking quiescence to chemoresistance are largely unknown. Methods A population of chemoresistant quiescent/slow cycling cells was isolated through PKH26 staining (which allows to separate cells on the basis of their proliferation rate) from colorectal cancer (CRC) xenografts and subjected to global gene expression and pathway activation analyses. Factors expressed by the quiescent/slow cycling population were analyzed through lentiviral overexpression approaches for their ability to induce a dormant chemoresistant state both in vitro and in mouse xenografts. The correlation between quiescence-associated factors, CRC consensus molecular subtype and cancer prognosis was analyzed in large patient datasets. Results Untreated colorectal tumors contain a population of quiescent/slow cycling cells with stem cell features (quiescent cancer stem cells, QCSCs) characterized by a predetermined mesenchymal-like chemoresistant phenotype. QCSCs expressed increased levels of ZEB2, a transcription factor involved in stem cell plasticity and epithelial-mesenchymal transition (EMT), and of antiapototic factors pCRAF and pASK1. ZEB2 overexpression upregulated pCRAF/pASK1 levels resulting in increased chemoresistance, enrichment of cells with stemness/EMT traits and proliferative slowdown of tumor xenografts. In parallel, chemotherapy treatment of tumor xenografts induced the prevalence of QCSCs with a stemness/EMT phenotype and activation of the ZEB2/pCRAF/pASK1 axis, resulting in a chemotherapy-unresponsive state. In CRC patients, increased ZEB2 levels correlated with worse relapse-free survival and were strongly associated to the consensus molecular subtype 4 (CMS4) characterized by dismal prognosis, decreased proliferative rates and upregulation of EMT genes. Conclusions These results show that chemotherapy-naive tumors contain a cell population characterized by a coordinated program of chemoresistance, quiescence, stemness and EMT. Such population becomes prevalent upon drug treatment and is responsible for chemotherapy resistance, thus representing a key target for more effective therapeutic approaches.

The exclusive reaction $\ensuremath{\gamma}p\ensuremath{\rightarrow}p{\ensuremath{\pi}}^{+}{\ensuremath{\pi}}^{\ensuremath{-}}$ was studied in the photon energy range 3.0--3.8 GeV and the momentum transfer range $0.4l\ensuremath{-}tl1.0\text{ }\text{ }{\mathrm{GeV}}^{2}$. Data were collected with the CLAS detector at the Thomas Jefferson National Accelerator Facility. In this kinematic range, the integrated luminosity was about $20\text{ }\text{ }{\mathrm{pb}}^{\ensuremath{-}1}$. The reaction was isolated by detecting the ${\ensuremath{\pi}}^{+}$ and proton in CLAS, and reconstructing the ${\ensuremath{\pi}}^{\ensuremath{-}}$ via the missing-mass technique. Moments of the di-pion decay angular distributions were derived from the experimental data. Differential cross sections for the $S$, $P$, and $D$-waves, in the ${M}_{{\ensuremath{\pi}}^{+}{\ensuremath{\pi}}^{\ensuremath{-}}}$ mass range 0.4--1.4 GeV, were derived performing a partial wave expansion of the extracted moments. Beside the dominant contribution of the $\ensuremath{\rho}(770)$ meson in the $P$-wave, evidence for the ${f}_{0}(980)$ and the ${f}_{2}(1270)$ mesons was found in the $S$ and $D$-waves, respectively. The differential production cross sections $d\ensuremath{\sigma}/dt$ for individual waves in the mass range of the above-mentioned mesons were extracted. This is the first time the ${f}_{0}(980)$ has been measured in a photoproduction experiment.

In the last few years, non-coding RNAs (ncRNAs) have been a hot topic in cancer research. Many ncRNAs were found to regulate the apoptotic process and to play a role in tumor cell resistance to treatment. The apoptotic program is on the frontline as self-defense from cancer onset, and evasion of apoptosis has been classified as one of the hallmarks of cancer responsible for therapy failure. The B-cell lymphoma 2 (BCL-2) family members are key players in the regulation of apoptosis and mediate the activation of the mitochondrial death machinery in response to radiation, chemotherapeutic agents and many targeted therapeutics. The balance between the pro-survival and the pro-apoptotic BCL-2 proteins is strictly controlled by ncRNAs. Here, we highlight the most common mechanisms exerted by microRNAs, long non-coding RNAs and circular RNAs on the main mediators of the intrinsic apoptotic cascade with particular focus on their significance in cancer biology.

High Mobility Group Box 1 protein was discovered as a nuclear protein, but it has a "second life" outside the cell where it acts as a damage-associated molecular pattern. HMGB1 is passively released or actively secreted in a number of diseases, including trauma, chronic inflammatory disorders, autoimmune diseases and cancer. Extracellular HMGB1 triggers and sustains the inflammatory response by inducing cytokine release and by recruiting leucocytes. These characteristics make extracellular HMGB1 a key molecular target in multiple diseases. A number of strategies have been used to prevent HMGB1 release or to inhibit its activities. Current pharmacological strategies include antibodies, peptides, decoy receptors and small molecules. Noteworthy, salicylic acid, a metabolite of aspirin, has been recently found to inhibit HMGB1. HMGB1 undergoes extensive post-translational modifications, in particular acetylation and oxidation, which modulate its functions. Notably, high levels of serum HMGB1, in particular of the hyper-acetylated and disulfide isoforms, are sensitive disease biomarkers and are associated with different disease stages. In the future, the development of isoform-specific HMGB1 inhibitors may potentiate and fine-tune the pharmacological control of inflammation. We review here the current therapeutic strategies targeting HMGB1, in particular the emerging and relatively unexplored small molecules-based approach.

We present the results of our final analysis of the full data set of g1p(Q2), the spin structure function of the proton, collected using CLAS at Jefferson Laboratory in 2000–2001. Polarized electrons with energies of 1.6, 2.5, 4.2, and 5.7 GeV were scattered from proton targets (NH315 dynamically polarized along the beam direction) and detected with CLAS. From the measured double spin asymmetries, we extracted virtual photon asymmetries A1p and A2p and spin structure functions g1p and g2p over a wide kinematic range (0.05 GeV2

We present the results of our final analysis of the full data set of gp1(Q2), the spin structure function of the proton, collected using CLAS at Jefferson Laboratory in 2000–2001. Polarized electrons with energies of 1.6, 2.5, 4.2, and 5.7 GeV were scattered from proton targets (15NH3 dynamically polarized along the beam direction) and detected with CLAS. From the measured double spin asymmetries, we extracted virtual photon asymmetries Ap1 and Ap2 and spin structure functions gp1 and gp2 over a wide kinematic range (0.05 GeV2

We present the results of our final analysis of the full data set of g_1^p(Q^2), the spin structure function of the proton, collected using CLAS at Jefferson Lab in 2000-2001. Polarized electrons with energies of 1.6, 2.5, 4.2 and 5.7 GeV were scattered from proton targets (15^NH_3 dynamically polarized along the beam direction) and detected with CLAS. From the measured double spin asymmetries, we extracted virtual photon asymmetries A_1^p and A_2^p and spin structure functions g_1^p and g_2^p over a wide kinematic range (0.05 GeV^2 < Q^2 < 5 GeV^2 and 1.08 GeV < W < 3 GeV), and calculated moments of g_1^p. We compare our final results with various theoretical models and expectations, as well as with parameterizations of the world data. Our data, with their precision and dense kinematic coverage, are able to constrain fits of polarized parton distributions, test pQCD predictions for quark polarizations at large x, offer a better understanding of quark-hadron duality, and provide more precise values of higher-twist matrix elements in the framework of the Operator Product Expansion., Comment: 38 pages, 40 figures

Let-7c, an intronic microRNA (miRNA) embedded in the long non-coding gene LINC00478, can act as a tumor suppressor by targeting oncogenes. Previous studies indicated that in acute promyelocytic leukemia (APL), a subtype of acute myelogenous leukemia (AML) bearing the leukemia promoting PML/RARα fusion protein, let-7c expression seems to be controlled by the host gene promoter, in which canonical Retinoic Acid Responsive Elements (RAREs) are bound by PML/RARα in an all transretinoic acid (ATRA)–sensitive manner. Here, let-7c transcriptional regulation was further investigated and a novel intronic promoter upstream of the pre-miRNA was identified. This new promoter has transcriptional activity strongly indicating that at least two promoters need to be considered for let-7c transcription: the distal host gene and the proximal intronic promoter. Therefore, epigenetic modifying enzymes and histone acetylation and methylation status were analyzed on both let-7c promoters. It was demonstrated that ATRA treatment leads to let-7c upregulation inducing a more open chromatin conformation of the host gene promoter, with an enrichment of epigenetic marks that correlate with a more active transcriptional state. Conversely, the epigenetic marks on the intronic promoter are not significantly affected by ATRA treatment. Interestingly, in solid tumors such as prostate and lung adenocarcinoma it was found that both host and intronic promoters are functional. These data suggest that while the host gene promoter may control let-7c expression in AML, in a nonleukemic tumor context instead the intronic promoter contributes or preferentially regulates let-7c transcription. Implications: Alternative promoter usage represents a regulatory mechanism of let-7c expression in different tissues. Mol Cancer Res; 12(6); 878–89. ©2014 AACR.

Beam-target double spin asymmetries and target single-spin asymmetries in exclusive $\pi^+$ and $\pi^-$ electroproduction were obtained from scattering of 1.6 to 5.7 GeV longitudinally polarized electrons from longitudinally polarized protons (for $\pi^+$) and deuterons (for $\pi^-$) using the CEBAF Large Acceptance Spectrometer (CLAS) at Jefferson Lab. The kinematic range covered is $1.1 1.5$ GeV. Very large target-spin asymmetries are observed for $W>1.6$ GeV. When combined with cross section measurements, the present results will provide powerful constraints on nucleon resonance amplitudes at moderate and large values of $Q^2$, for resonances with masses as high as 2.3 GeV.