Assessing Excited State Energy Gaps with Time-Dependent Density Functional Theory on Ru(II) Complexes

A set of density functionals coming from different rungs on Jacob's ladder are employed to evaluate the electronic excited states of three Ru(II) complexes. While most studies on the performance of density functionals compare the vertical excitation energies, in this work we focus on the energy gaps between the electronic excited states, of the same and different multiplicity. Excited state energy gaps are important for example to determine radiationless transition probabilities. Besides energies, a functional should deliver the correct state character and state ordering. Therefore, wavefunction overlaps are introduced to systematically evaluate the effect of different functionals on the character of the excited states. As a reference, the energies and state characters from multi-state second-order perturbation theory complete active space (MS-CASPT2) are used. In comparison to MS-CASPT2, it is found that while hybrid functionals provide better vertical excitation energies, pure functionals typically give more accurate excited state energy gaps. Pure functionals are also found to reproduce the state character and ordering in closer agreement to MS-CASPT2 than the hybrid functionals

Interplay of BDNF and GDNF in the mature spinal somatosensory system and its potential therapeutic relevance

The growth factors BDNF and GDNF are gaining more and more attention as modulators of synaptic transmission in the mature central nervous system (CNS). The two molecules undergo a regulated secretion in neurons and may be anterogradely transported to terminals where they can positively or negatively modulate fast synaptic transmission. There is today a wide consensus on the role of BDNF as a pro-nociceptive modulator, as the neurotrophin has an important part in the initiation and maintenance of inflammatory, chronic, and/or neuropathic pain at the peripheral and central level. At the spinal level, BDNF intervenes in the regulation of chloride equilibrium potential, decreases the excitatory synaptic drive to inhibitory neurons, with complex changes in GABAergic/glycinergic synaptic transmission, and increases excitatory transmission in the superficial dorsal horn. Differently from BDNF, the role of GDNF still remains to be unraveled in full. This review resumes the current literature on the interplay between BDNF and GDNF in the regulation of nociceptive neurotransmission in the superficial dorsal horn of the spinal cord. We will first discuss the circuitries involved in such a regulation, as well as the reciprocal interactions between the two factors in nociceptive pathways. The development of small molecules specifically targeting BDNF, GDNF and/or downstream effectors is opening new perspectives for investigating these neurotrophic factors as modulators of nociceptive transmission and chronic pain. Therefore, we will finally consider the molecules of (potential) pharmacological relevance for tackling normal and pathological pain

Specific transcriptional programs differentiate ICOS from CD28 costimulatory signaling in human Naïve CD4+ T cells

14 p.-5 fig. This work is dedicated to the memory of our colleague SZ. SZ was an extraordinary person, a great friend, a remarkable scholar and an unfailing mentor for our students. Her passion for life and research will always be an example. We miss her a lot.Costimulatory molecules of the CD28 family play a crucial role in the activation of immune responses in T lymphocytes, complementing and modulating signals originating from the T-cell receptor (TCR) complex. Although distinct functional roles have been demonstrated for each family member, the specific signaling pathways differentiating ICOS- from CD28-mediated costimulation during early T-cell activation are poorly characterized. In the present study, we have performed RNA-Seq-based global transcriptome profiling of anti-CD3-treated naïve CD4+ T cells upon costimulation through either inducible costimulator (ICOS) or CD28, revealing a set of signaling pathways specifically associated with each signal. In particular, we show that CD3/ICOS costimulation plays a major role in pathways related to STAT3 function and osteoarthritis (OA), whereas the CD3/CD28 axis mainly regulates p38 MAPK signaling. Furthermore, we report the activation of distinct immunometabolic pathways, with CD3/ICOS costimulation preferentially targeting glycosaminoglycans (GAGs) and CD3/CD28 regulating mitochondrial respiratory chain and cholesterol biosynthesis. These data suggest that ICOS and CD28 costimulatory signals play distinct roles during the activation of naïve T cells by modulating distinct sets of immunological and immunometabolic genes.This work was supported by Fondazione CARIPLO (2014-0812) to SZ. and by the Associazione Italiana Ricerca sul Cancro (IG 20714 to UD and IG 20240 to SO, AIRC, Milano), and Fondazione Cariplo (2017-0535) to UD. DC acknowledge support by the Italian Ministry of University and Research program “Departments of Excellence 2018-2022”, AGING Project – Department of Translational Medicine, Università del Piemonte Orientale. Fondazione Umberto Veronesi, Milan, Italy supported EB.Peer reviewe

Paclitaxel-Loaded Nanosponges Inhibit Growth and Angiogenesis in Melanoma Cell Models

This study investigated the effects of free paclitaxel (PTX) and PTX-loaded in pyromellitic nanosponges (PTX-PNS) in reducing in vitro and in vivo melanoma cell growth and invasivity, and in inhibiting angiogenesis. To test the response of cells to the two PTX formulations, the cell viability was evaluated by MTT assay in seven continuous cell lines, in primary melanoma cells, both in 2D and 3D cultures, and in human umbilical vein endothelial cells (HUVECs) after exposure to different concentrations of PTX or PTX-PNS. Cell motility was assessed by a scratch assay or Boyden chamber assay, evaluating cell migration in presence or absence of diverse concentrations of PTX or PTX-PNS. The effect of PTX and PTX-PNS on angiogenesis was evaluated as endothelial tube formation assay, a test able to estimate the formation of three-dimensional vessels in vitro. To assess the anticancer effect of PTX and PTX-PNS in in vivo experiments, the two drug formulations were tested in a melanoma mouse model obtained by B16-BL6 cell implantation in C57/BL6 mice. Results obtained were as follows: 1) MTT analysis revealed that cell proliferation was more affected by PTX-PNS than by PTX in all tested cell lines, in both 2D and 3D cultures; 2) the analysis of the cell migration showed that PTX-PNS acted at very lower concentrations than PTX; 3) tube formation assay showed that PTX-PNS were more effective in inhibiting tube formation than free PTX; and 4) in vivo experiments demonstrated that tumor weights, volumes, and growth were significantly reduced by PTX-PNS treatment with respect to PTX; the angiogenesis and the cell proliferation, detected in the tumor samples with CD31 and Ki-67 antibodies, respectively, indicated that, in the PTX-PNS-treated tumors, the tube formation was inhibited, and a low amount of proliferating cells was present. Taken together, our data demonstrated that our new PTX nanoformulation can respond to some important issues related to PTX treatment, lowering the anti-tumor effective doses and increasing the effectiveness in inhibiting melanoma growth in vivo

Enhanced cytotoxic effect of camptothecin nanosponges in anaplastic thyroid cancer cellsin vitroandin vivoon orthotopic xenograft tumors

Anaplastic carcinoma of the thyroid (ATC) is a lethal human malignant cancer with median survival of 6 months. To date, no treatment has substantially changed its course, which makes urgent need for the development of novel drugs or novel formulations for drug delivery. Nanomedicine has enormous potential to improve the accuracy of cancer therapy by enhancing availability and stability, decreasing effective doses and reducing side effects of drugs. Camptothecin (CPT) is an inhibitor of DNA topoisomerase-I with several anticancer properties but has poor solubility and a high degradation rate. Previously, we reported that CPT encapsulated in β-cyclodextrin-nanosponges (CN-CPT) increased solubility, was protected from degradation and inhibited the growth of prostate tumor cells both in vitro and in vivo. The aim of this study was to extend that work by assessing the CN-CPT effectiveness on ATC both in vitro and in vivo. Results showed that CN-CPT significantly inhibited viability, clonogenic capacity and cell-cycle progression of ATC cell lines showing a faster and enhanced effect compared to free CPT. Moreover, CN-CPT inhibited tumor cell adhesion to vascular endothelial cells, migration, secretion of pro-angiogenic factors (IL-8 and VEGF-α), expression of β-PIX, belonging to the Rho family activators, and phosphorylation of the Erk1/2 MAPK. Finally, CN-CPT significantly inhibited the growth, the metastatization and the vascularization of orthotopic ATC xenografts in SCID/beige mice without apparent toxic effects in vivo. This work extends the previous insight showing that β-cyclodextrin-nanosponges are a promising tool for the treatment of ATC

Percorsi a Sud. Geografie e attori nelle strategie regionali del Mezzogiorno

Il lavoro si colloca nel quadro dell’interesse di ricerca che la Fondazione Agnelli è andata esprimendo negli anni sul tema della dimensione regionale, non soltanto come afferente al ritaglio geografico delle regioni italiane, ma soprattutto nella sua accezione di spazio di aggregazione di società ed economie territorialmente integrate.- Indice #4- Premessa, Marco Demarie #8- Introduzione, Lida Viganoni- Prima parte Una lettura geografica delle regioni meridionali #22- Fra il Tirreno e lo Ionio: frammenti d’Euromediterraneo, Pasquale Coppola e Lida Viganoni #24- La dorsale adriatica fra integrazione e frammentazione territoriale, Alessandro Gallo, Armando Montanari, Paola Morelli e Franco Salvatori #78- Sicilia, un’insularità complessa, Vincenzo Guarrasi #104- La Sardegna, ovvero la modernizzazione difficile, Francesco Boggio #128- Seconda parte Mezzogiorno testimoniato. Cento interviste al ceto dirigente locale #158- Campania: oltre l’”effetto Napoli”, Pasquale Coppola e Lida Viganoni #160- Basilicata: il “modello” dei piccoli?, Pasquale Coppola e Lida Viganoni #196- Calabria: dallo stallo a Gioia Tauro, Rosario Sommella #230- Abruzzo: tra Mezzogiorno e Italia “di mezzo”, Franco Salvatori #250- Molise: limiti e potenzialità di una “cerniera”, Alessandro Gallo #278- Puglia: proiettati verso l’esterno, Paola Morelli #300- Sicilia: visioni per un progetto, Vincenzo Guarrasi e Angela Alaimo #322- Sardegna: presi nella corrente?, Francesco Boggio #338- Riferimenti bibliografici #36

A post-trial survey to assess the impact of dissemination of results and unmasking on participants in a 13-year randomised controlled trial on age-related cataract

<p>Abstract</p> <p>Background</p> <p>The Italian-American Clinical Trial of Nutritional Supplements and Age-Related Cataract was designed to assess the impact of a multivitamin-mineral supplement on age-related cataract. Trial results showed evidence of a beneficial effect of the supplement on all types of cataract combined, opposite effects on two of the three types of cataract (beneficial for nuclear opacities and harmful for posterior sub-capsular opacities) and no statistically significant effect on cortical opacities. No treatment recommendations were made. A post-trial survey was conducted on 817 surviving elderly participants to assess their satisfaction, their understanding of treatment assignment to supplement or placebo and the success of masking.</p> <p>Methods</p> <p>Trial results were communicated by letter and the level of satisfaction and of understanding of the results was assessed by a questionnaire. Participants were offered the option of being unmasked: a second questionnaire was administered to this subset to assess their understanding of the randomisation process and the success of masking.</p> <p>Results</p> <p>610 participants (74.7%) responded to the survey:</p> <p>94.6% thought the description of the results was "very clear" or "quite clear", 5.4% "not clear" or "do not know"; 89.8% considered the results "very interesting" or "quite interesting", 10.2% "not interesting" or "do not know"; 60.3% expressed "satisfaction", 17.2% "both satisfaction and concern", 2.6% "concern", 19.9% "indifference" or "do not know".</p> <p>480 participants (78.7%) accepted the offer to be unmasked to their treatment assignment: 395 (82.3%) recalled/understood the possibility of assignment to vitamins or placebo, 85 (17.7%) did not. 68 participants (17.2%) thought they had taken vitamins (79.4% were correct; p = 0.0006), 47 (11.9%) thought they had taken placebo (59.6% were correct; p = 0.46) and 280 (70.9%) declared they did not know.</p> <p>Conclusions</p> <p>The results were made difficult to explain to study participants by the qualitatively different effect of treatment on the two most visually significant types of cataract. Although the study did not lead to a recommendation to use the dietary supplement, the vast majority of participants reported satisfaction after they received the results but almost 20% of the participants expressed some concern. Masking to treatment assignment was successful in the majority of participants.</p

CASPT2 Potential Energy Curves for NO Dissociation in a Ruthenium Nitrosyl Complex

Ruthenium nitrosyl complexes are fascinating photoactive compounds showing complex photoreactivity, such as N&rarr;O linkage photoisomerism and NO photorelease. This dual photochemical behavior has been the subject of many experimental studies in order to optimize these systems for applications as photoswitches or therapeutic agents for NO delivery. However, despite recent experimental and computational studies along this line, the underlying photochemical mechanisms still need to be elucidated for a more efficient design of these systems. Here, we present a theoretical contribution based on the calculations of excited-state potential energy profiles for NO dissociation in the prototype trans-[RuCl(NO)(py)4]2+ complex at the complete active space second-order perturbation theory (CASPT2). The results point to a sequential two-step photon absorption photorelease mechanism coupled to partial photoisomerization to a side-on intermediate, in agreement with previous density functional theory calculations