R-Roscovitine (Seliciclib) prevents DNA damage-induced cyclin A1 upregulation and hinders non-homologous end-joining (NHEJ) DNA repair

<p>Abstract</p> <p>Background</p> <p>CDK-inhibitors can diminish transcriptional levels of cell cycle-related cyclins through the inhibition of E2F family members and CDK7 and 9. Cyclin A1, an E2F-independent cyclin, is strongly upregulated under genotoxic conditions and functionally was shown to increase NHEJ activity. Cyclin A1 outcompetes with cyclin A2 for CDK2 binding, possibly redirecting its activity towards DNA repair. To see if we could therapeutically block this switch, we analyzed the effects of the CDK-inhibitor <it>R</it>-Roscovitine on the expression levels of cyclin A1 under genotoxic stress and observed subsequent DNA damage and repair mechanisms.</p> <p>Results</p> <p>We found that <it>R</it>-Roscovitine alone was unable to alter cyclin A1 transcriptional levels, however it was able to reduce protein expression through a proteosome-dependent mechanism. When combined with DNA damaging agents, <it>R</it>-Roscovitine was able to prevent the DNA damage-induced upregulation of cyclin A1 on a transcriptional and post-transcriptional level. This, moreover resulted in a significant decrease in non-homologous end-joining (NHEJ) paired with an increase in DNA DSBs and overall DNA damage over time. Furthermore, microarray analysis demonstrated that <it>R</it>-Roscovitine affected DNA repair mechanisms in a more global fashion.</p> <p>Conclusions</p> <p>Our data reveal a new mechanism of action for <it>R</it>-Roscovitine on DNA repair through the inhibition of the molecular switch between cyclin A family members under genotoxic conditions resulting in reduced NHEJ capability.</p

La tecnica resinazione del pino laricio (Pinus nigra laricio (Poir.) Maire) in Sicilia: un progetto per la sua rivalutazione nell’ottica di una gestione sostenibile delle foreste mediterranee

In accordo con le moderne esigenze di sostenibilità e multifunzitonalità, è oggi utile prendere in considerazitone la possibilità di riattivare processi legati ad antichi usi del bosco, la cui memtoria rischia di essere persa per sempre insieme alle tradizioni e ai costumi di comunità nate e sviluppatesi proprio grazie a tali attività. Partendo da tali presupposti, si è condotto uno studio sulla attività di resinazione condotta in Sicilia, a carico del pino laricio, nella pineta di Linguaglossa ricadente nel comune omonimo (prtovincia di Catania) sino agli anni ‘50 del secolo scorso in Sicilia. L’indagine ha inoltre avuto lo scopo di vagliare l’opportunità di ripristinare l’attività resinazione nel comune di Linguaglossa a fronte di un rinnovato interesse per questo prodotto ma prendendo in considerazione aspetti che tengano conto tanto della conservazione della pineta quanto della valorizzazione dei servizi ecosistemici come la prevenzione da incendi nonché la conservazione di valori storici e culturali. Sono state recuperate informazioni storiche riguardo le tecniche di resinazione utilizzate durante le diverse campagne resinifere condotte nel passato e, in particolar modo, ci si è concentrati sulla ricerca di informazioni storiografiche risalenti all’ultimo periodo di resinazione (prima metà del secolo scorso). La valutazione di un eventuale ripristino della resinazione in Sicilia non ha ptotuto prescindere dall’analisi della situazione europea e mondiale riguardo alla produzione di resina evidenziando difficoltà legate sopratutto alla limitata competizione del prodotto europeo. Tali difficoltà vengonto confermate dalla stessa ditta che operò a Linguaglossa, la ditta Lombardi, che ancora opera nel settore e che ha rappresentato un punto di riferimento fondamentale per la attività di resinazione nel territorio italiano. Le atuali tendenze e le previsitoni future del mercato evidenziano, tuttavia, una maggiore predisposizione del consumatore nei riguardi di prodotti derivati da risorse naturali rinnovabili e a chilometro zero. Come appare evidente dalle recenti esperienze condotte in diversi paesi europei, la resina europea presenta caratteri del tutto favorevoli al suo rilancio

Delirium and Psychiatric Sequelae Associated to SARS-CoV-2 in Asymptomatic Patients With Psychiatric History and Mild Cognitive Impairment as Risk Factors: Three Case Reports

Human coronaviruses have neuroinvasive and neurotropic abilities that might explain psychiatric outcomes in affected patients. We hypothesized that delirium might be the sole clinical manifestation or even the prodrome of a psychiatric episode consistent with the mental history of a few infected patients with a preexisting diagnosed cognitive impairment. We examined three patients with preexisting mild cognitive impairment and delirium at admission for suspected SARS-CoV-2 infection. We diagnosed delirium using DSM-5 and Confusion Assessment Method (CAM) and measured consciousness level by the Glasgow Coma Scale. All the patients had no history of fever, respiratory complications, anosmia or ageusia, meningitis, and negative cerebrospinal fluid analysis for SARS-CoV-2. Our first patient had no psychiatric history, the second reported only a depressive episode, and the third had a history of bipolar disorder dated back to 40 years before. In the first patient, delirium resolved 2 days following the admission. The other two patients recovered in 4 and 14 days, and delirium appeared as the prodrome of a new psychiatric episode resembling past events. Clinicians should monitor the possibility that SARS-CoV-2 presence in the brain might clinically manifest in the form of delirium and acute psychiatric sequelae, even without other systemic symptoms. Psychiatric history and preexisting mild cognitive impairment are to be considered as predisposing factors for COVID-19 sequelae in delirium patients

On the Formation and Accumulation of Solid Carbon Particles in High-Enthalpy Flows Mimicking Re-Entry in the Titan Atmosphere

The problem relating to the formation of solid particles enabled by hypersonic re-entry in methane-containing atmospheres (such as that of Titan) has been tackled in the framework of a combined experimental-numerical approach implemented via a three-level analysis hierarchy. First experimental tests have been conducted using a wind tunnel driven by an industrial arc-heated facility operating with nitrogen as working gas (the SPES, i.e., the Small Planetary Entry Simulator). The formation of solid phases as a result of the complex chemical reactions established in such conditions has been detected and quantitatively measured with high accuracy. In a second stage of the study, insights into the related formation process have been obtained by using multispecies models relying on the NASA CEA code and the Direct Simulation Monte Carlo (DSMC) method. Through this approach the range of flow enthalpies in which carbonaceous deposits can be formed has been identified, obtaining good agreement with the experimental findings. Finally, the deposited substance has been analyzed by means of a set of complementary diagnostic techniques, i.e., SEM, spectroscopy (Raman, FTIR, UV-visible absorption and fluorescence), GC-MS and TGA. It has been found that carbon produced by the interaction of the simulated Titan atmosphere with a solid probe at very high temperatures can be separated into two chemically different fractions, which also include "tholins"

Morphology of the optic nerve head in glaucomatous eyes with visual field defects in superior or inferior hemifield

To evaluate the morphology of optic nerve head (ONH) and border tissue (BT) of Elschnig in glaucomatous eyes with visual field defects in superior or inferior hemifield

Sexually-transmitted infections: what is the true prevalence? A cross-sectional online survey of men who have sex with men in the Veneto Region of Italy

IntroductionRates of sexually-transmitted infections (STIs) remain high among men who have sex with men (MSM), posing serious public health concerns. The MSM population is recognized as a vulnerable, high-risk group due to barriers to preventive healthcare services and homophobic stigma.MethodsA cross-sectional online survey was conducted using a questionnaire based on European Man-for-Man  Internet Survey 2010 (EMIS 2010) and European Centre for Disease Prevention and Control (ECDC) core indicators specific for behavioral risks. MSM were reached between June and August 2017, using Facebook and dating apps. Descriptive statistics and multivariate logistic regression were used to analyze the data.ResultsA total of 324 respondents were analyzed: 49.7% had seen a doctor specifically for STIs;  and 54.6% reported having experienced at least one STI, the most common being gonorrhea and HPV. Ten respondents reported having HIV infection, and 70% of them were co-infected with other STIs. A more consistent use of condoms and larger numbers of sexual partners were significantly associated with a lower and higher risk of STI, respectively. Only 2.5% of respondents reporting no STIs had been vaccinated to prevent HPV infection.ConclusionComprehensive STI prevention strategies are needed to improve sexual health among MSM. Such strategies should include  implementing programs to improve awareness about routine screening, and promote a consistent use of condoms by MSM

Delirium and Cognitive Impairment as Predisposing Factors of {COVID}-19 Infection in Neuropsychiatric Patients: A Narrative Review

SARS-CoV-2 neuroinvasive and neurotropic abilities may underlie delirium onset and neuropsychiatric outcomes. Only a limited number of studies have addressed the potential effect of SARS-CoV-2 infection on mental health so far. Most studies mainly reported the acute onset of mixed neuropsychiatric conditions in patients infected with SARS-CoV-2, characterized by agitated behavior, altered level of consciousness, and disorganized thinking, regardless of psychological or socioeconomic triggering factors. The present narrative review aims to analyze and discuss the mechanisms underlying the neuroinvasive/neurotropic properties of SARS-CoV-2 and the subsequent mental complications. Delirium appeared as a clinical manifestation of SARS-CoV-2 brain infection in some patients, without systemic or multiple organ failure symptoms. A small number of studies demonstrated that neuropsychiatric symptoms associated with COVID-19, initially presenting as a confused state, may subsequently evolve in a way that is consistent with the patients’ neuropsychiatric history. A literature analysis on this topic prevalently showed case reports and case series of patients presenting delirium or delirium-like symptoms as the main outburst of COVID-19, plus a cognitive impairment, from mild to severe, which pre-existed or was demonstrated during the acute phase or after infection. Dementia appeared as one of the most frequent predisposing factors to SARS-CoV-2 infection complicated with delirium. Instead, contrasting data emerged on the potential link between COVID-19 and delirium in patients with cognitive impairment and without a neuropsychiatric history. Therefore, clinicians should contemplate the possibility that COVID-19 appears as delirium followed by a psychiatric exacerbation, even without other systemic symptoms. In addition, cognitive impairment might act as a predisposing factor for COVID-19 in patients with delirium

Reduced intracranial volume in Fabry Disease: Evidence of abnormal neurodevelopment?

Introduction: Lysosomal storage disorders (LSD) are often characterized by abnormal brain development, reflected by a reduction of intracranial volume (ICV). The aim of our study was to perform a volumetric analysis of intracranial tissues in Fabry Disease (FD), investigating possible reductions of ICV as a potential expression of abnormal brain development in this condition. Materials and Methods: Forty-two FD patients (15males,mean age 43.3±13.0 years) were enrolled along with 38 healthy controls (HC) of comparable age and sex. Volumetric MRI data were segmented using SPM12 to obtain intracranial tissue volumes, from which ICV values were derived. Results: Mean ICV of FD patients was 8.1% smaller compared to the control group (p<5·10−5). Unlike what typically happens in neurodegenerative disorders, no significant differences emerged when comparing between the two groups the fractional volumes of gray matter, white matter and CSF (i.e., normalized by ICV), consistent with a harmonious volumetric reduction of intracranial structures. Discussion: The present results suggest that in FD patients an abnormality of brain development is present, expanding the current knowledge about central nervous system involvement in FD, further emphasizing the importance of an early diagnosis

Dietary restriction: could it be considered as speed bump on tumor progression road?

Dietary restrictions, including fasting (or long-term starvation), calorie restriction (CR), and short-term starvation (STS), are considered a strong rationale that may protect against various diseases, including age-related diseases and cancer. Among dietary approaches, STS, in which food is not consumed during designed fasting periods but is typically not restricted during designated feeding periods, seems to be more suitable, because other dietary regimens involving prolonged fasting periods could worsen the health conditions of cancer patients, being they already naturally prone to weight loss. Until now, the limited amount of available data does not point to a single gene, pathway, or molecular mechanism underlying the benefits to the different dietary approaches. It is well known that the healthy effect is mediated in part by the reduction of nutrient-related pathways. The calorie restriction and starvation (long- and short-term) also suppress the inflammatory response reducing the expression, for example, of IL-10 and TNF-α, mitigating pro-inflammatory gene expression and increasing anti-inflammatory gene expression. The dietary restriction may regulate both genes involved in cellular proliferation and factors associated to apoptosis in normal and cancer cells. Finally, dietary restriction is an important tool that may influence the response to chemotherapy in preclinical models. However, further data are needed to correlate dietary approaches with chemotherapeutic treatments in human models. The aim of this review is to discuss the effects of various dietary approaches on the cancer progression and therapy response, mainly in preclinical models, describing some signaling pathways involved in these processes