3D MHD Simulations of accreting neutron stars: evidence of QPO emission from the surface

3D Magnetohydrodynamic simulations show that when matter accretes onto neutron stars, in particular if the misalignment angle is small, it does not constantly fall at a fixed spot. Instead, the location at which matter reaches the star moves. These moving hot spots can be produced both during stable accretion, where matter falls near the magnetic poles of the star, and unstable accretion, characterized by the presence of several tongues of matter which fall on the star near the equator, due to Rayleigh-Taylor instabilities. Precise modeling with Monte Carlo simulations shows that those movements could be observed as high frequency Quasi Periodic Oscillations. We performed a number of new simulation runs with a much wider set of parameters, focusing on neutron stars with a small misalignment angle. In most cases we observe oscillations whose frequency is correlated with the mass accretion rate $\dot{M}$. Moreover, in some cases double QPOs appear, each of them showing the same correlation with $\dot{M}$.Comment: 2 pages, 1 figure, to appear in the Proceedings of the Bologna x-ray conference 2009, uses aipproc.cls, aip-6s.clo,

Safe drugs to fight mutant protein overload and alpha-1-antitrypsin deficiency

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DYSPHORIA AS A PSYCHIATRIC SYNDROME: A PRELIMINARY STUDY FOR A NEW TRANSNOSOGRAPHIC DIMENSIONAL APPROACH

Background: We currently define dysphoria as a complex and disorganized emotional state with proteiform phenomenology, characterized by a multitude of symptoms. Among them prevail irritability, discontent, interpersonal resentment and surrender. Dysphoria, in line with the most recent Interpersonal Dysphoria Model, could represent a “psychopathological organizer” of the Borderline Personality Disorder. We would like to extend this theoretical concept to other psychiatric disorders in order to consider dysphoria as a possible psychopathological nucleus, a syndrome on its own. This syndromic vision may open up the possibility of new paths both in the differential diagnosis and in the therapeutic approach to the various disorders. Aims: The goal of this paper is to understand if the dimensional spectrum that composes dysphoria differs from the different psychiatric disorders. Specifically, we would like to assess if the phenomenological expression of dysphoria differs in patients with Borderline Personality Disorder (BPD), Mixed State Bipolar Disorder (BDM) and Major Depressive Disorder (MDD) through an observational comparative study. Subjects and methods: In this study, 30 adult patients, males and females between the ages of 18 and 65, were enrolled from the Psychiatric Service of the Santa Maria della Misericordia Hospital in Perugia (PG), Italy, from January 1st to June 30th, 2018. The aim was to form 3 groups each one composed of 10 individuals affected respectively with Borderline Personality Disorder (BPD), with Bipolar Disorder, Mixed State (BPM) and Major Depression Disorder (MDD). After a preliminary assessment to exclude organic and psychiatric comorbidity, we administered them the Neapen Dysphoria Scale – Italian Version (NDS-I), a specific dimensional test for dysphoria. Starting from the dataset, with the aid of the statistical program SPSS 20, we have obtained graphs showing the comparison between disorders groups selected and NDS-I total score and subscales (irritability, discontent, interpersonal resentment, surrender). Finally, a comparison was made, taking two groups at a time, between the means of single groups for total scores and for single subscales considered into the NDS-I test. We made it using the Mann-Whitney U test, a nonparametric test with 2 independent samples, by setting a significance level =0.05. Conclusions: This study, through a transnosographic-dimensional approach, allowed us to explore dysphoria and its expressions in different psychopathological groups, despite analyzing a small sample. Differences between means of values obtained through NDS-I subscales were statistically significant in patients with BPD, BDM and MDD (p<0.05). Among the latter, the group of BPD patients has greater pervasiveness and severity of dysphoria symptoms

Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander's Disease

Alexander's disease (AxD) is a rare, usually relentlessly progressive disorder of astroglial cells in the central nervous system related to mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP). The pathophysiology of AxD is only partially understood. Available data indicate that an excessive GFAP gene expression may play a role. In particular, a "threshold hypothesis" has been reported, suggesting that mutant GFAP representing about 20% of the total cellular GFAP should be sufficient to cause disease. Thus, strategies based on reducing cellular mutant GFAP protein levels and/or activating biological processes involved in the correct protein folding could be effective in counteracting the toxic effect of misfolded GFAP. Considering that clomipramine (CLM), which has been selected by a wide small molecules screening as the greatest inhibitory potential drug against GFAP expression, is contraindicated because of its proconvulsant activity in the infantile form of AxD, which is also characterized by the occurrence of epileptic seizures, two powerful antiepileptic agents, carbamazepine (CBZ) and phenytoin (PHT), which share specific stereochemical features in common with CLM, were taken into consideration in a reliable in vitro model of AxD. In the present work, we document for the first time that CBZ and PHT have a definite inhibitory effect on pathological GFAP cellular expression and folding. Moreover, we confirm previous results of a similar beneficial effect of CLM. In addition, we have demonstrated that CBZ and CLM play a refolding effect on mutant GFAP proteins, likely ascribed at the induction of CRYAB expression, resulting in the decrease of mutant GFAP aggregates formation. As CBZ and PHT are currently approved for use in humans, their documented effects on pathological GFAP cellular expression and folding may indicate a potential therapeutic role as disease-modifying agents of these drugs in the clinical management of AxD, particularly in AxD patients with focal epilepsy with and without secondary generalization

Parental origin and somatic mosaicism of PHOX2B mutations in Congenital Central Hypoventilation Syndrome.

Heterozygous polyalanine repeat expansions of PHOX2B have been associated with Congenital Central Hypoventilation Syndrome, a rare neurocristopathy characterized by absence of adequate control of respiration during sleep. Here we report a PHOX2B mutational screening in 63 CCHS patients, 58 of whom presenting with poly-A expansions or frameshift, missense and nonsense mutations. To assess a somatic or germline occurrence of poly-A length variations, the relative amounts of mutant and wild type alleles have been quantified in 20 selected CCHS patients presenting with an expansion, and in their parents. Somatic mosaicism was shown in four parents, while no mosaic was found among CCHS patients. Moreover, while co-segregation analysis of the PHOX2B poly-A expansions with selected marker alleles in the same 20 CCHS trios has not demonstrated any parent-of-origin effect of the mutations, it has provided further clues to clarify the molecular mechanism underlying the expansion occurrence. Finally, the segregation of PHOX2B poly-A anomalous tracts within family members has allowed us to exclude tendency of polymorphic variations towards expansion. This strengthens the notion that expanded polyalanine tracts, identified as frequent disease-causing mutations also in other human diseases, are mitotically and meiotically stable

PHOX2B-Mediated Regulation of ALK Expression: In Vitro Identification of a Functional Relationship between Two Genes Involved in Neuroblastoma

BACKGROUND: Neuroblastoma (NB) is a severe pediatric tumor originating from neural crest derivatives and accounting for 15% of childhood cancer mortality. The heterogeneous and complex genetic etiology has been confirmed with the identification of mutations in two genes, encoding for the receptor tyrosine kinase Anaplastic Lymphoma Kinase (ALK) and the transcription factor Paired-like Homeobox 2B (PHOX2B), in a limited proportion of NB patients. Interestingly, these two genes are overexpressed in the great majority of primary NB samples and cell lines. These observations led us to test the hypothesis of a regulatory or functional relationship between ALK and PHOX2B underlying NB pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Following this possibility, we first confirmed a striking correlation between the transcription levels of ALK, PHOX2B and its direct target PHOX2A in a panel of NB cell lines. Then, we manipulated their expression in NB cell lines by siRNA-mediated knock-down and forced over-expression of each gene under analysis. Surprisingly, PHOX2B- and PHOX2A-directed siRNAs efficiently downregulated each other as well as ALK gene and, consistently, the enhanced expression of PHOX2B in NB cells yielded an increment of ALK protein. We finally demonstrated that PHOX2B drives ALK gene transcription by directly binding its promoter, which therefore represents a novel PHOX2B target. CONCLUSIONS/SIGNIFICANCE: These findings provide a compelling explanation of the concurrent involvement of these two genes in NB pathogenesis and are going to foster a better understanding of molecular interactions at the base of the disease. Moreover, this work opens new perspectives for NBs refractory to conventional therapies that may benefit from the design of novel therapeutic RNAi-based approaches for multiple gene targets

QPO emission from moving hot spots on the surface of neutron stars: a model

We present recent results of 3D magnetohydrodynamic simulations of neutron stars with small misalignment angles, as regards the features in lightcurves produced by regular movements of the hot spots during accretion onto the star. In particular, we show that the variation of position of the hot spot created by the infalling matter, as observed in 3D simulations, can produce high frequency Quasi Periodic Oscillations with frequencies associated with the inner zone of the disk. Previously reported simulations showed that the usual assumption of a fixed hot spot near the polar region is valid only for misalignment angles relatively large. Otherwise, two phenomena challenge the assumption: one is the presence of Rayleigh-Taylor instabilities at the disk-magnetospheric boundary, which produce tongues of accreting matter that can reach the star almost anywhere between the equator and the polar region; the other one is the motion of the hot spot around the magnetic pole during stable accretion. In this paper we start by showing that both phenomena are capable of producing short-term oscillations in the lightcurves. We then use Monte Carlo techniques to produce model lightcurves based on the features of the movements observed, and we show that the main features of kHz QPOs can be reproduced. Finally, we show the behavior of the frequencies of the moving spots as the mass accretion rate changes, and propose a mechanism for the production of double QPO peaks.Comment: MNRAS accepted on 2009 December 11, 14 pages, 12 figure

COVID-19 teleassistance and teleconsultation: a matched case-control study (MIRATO project, Lombardy, Italy)

BackgroundDuring the COVID-19 pandemic, telemedicine has been recognised as a powerful modality to shorten the length of hospital stay and to free up beds for the sicker patients. Lombardy, and in particular the areas of Bergamo, Brescia, and Milan, was one of the regions in Europe most hit by the COVID-19 pandemic. The primary aim of the MIRATO project was to compare the incidence of severe events (hospital readmissions and mortality) in the first three months after discharge between COVID-19 patients followed by a Home-Based Teleassistance and Teleconsultation (HBTT group) program and those discharged home without Telemedicine support (non-HBTT group).MethodsThe study was designed as a matched case-control study. The non-HBTT patients were matched with the HBTT patients for sex, age, presence of COVID-19 pneumonia and number of comorbidities. After discharge, the HBTT group underwent a telecare nursing and specialist teleconsultation program at home for three months, including monitoring of vital signs and symptoms. Further, in this group we analysed clinical data, patients' satisfaction with the program, and quality of life.ResultsFour hundred twenty-two patients per group were identified for comparison. The median age in both groups was 70 ± 11 years (62% males). One or more comorbidities were present in 86% of the HBTT patients and 89% in the non-HBTT group (p = ns). The total number of severe events was 17 (14 hospitalizations and 3 deaths) in the HBTT group and 40 (26 hospitalizations and 16 deaths) in the non-HBTT group (p = 0.0007). The risk of hospital readmission or death after hospital discharge was significantly lower in HBTT patients (Log-rank Test p = 0.0002). In the HBTT group, during the 3-month follow-up, 5,355 teleassistance contacts (13 ± 4 per patient) were performed. The number of patients with one or more symptoms declined significantly: from 338 (78%) to 183 (45%) (p &lt; 0.00001). Both the physical (ΔPCS12: 5.9 ± 11.4) component and the mental (ΔMCS12: 4.4 ± 12.7) component of SF-12 improved significantly (p &lt; 0.0001). Patient satisfaction with the program was very high in all participants.ConclusionsCompared to usual care, an HBTT program can reduce severe events (hospital admissions/mortality) at 3-months from discharge and improve symptoms and quality of life.Clinical trial registrationwww.ClinicalTrials.gov, NCT04898179

Fraisinib: a calixpyrrole derivative reducing A549 cell-derived NSCLC tumor in vivo acts as a ligand of the glycine-tRNA synthase, a new molecular target in oncology

Background and purpose: Lung cancer is the leading cause of death in both men and women, constituting a major public health problem worldwide. Non-small-cell lung cancer accounts for 85%–90% of all lung cancers. We propose a compound that successfully fights tumor growth in vivo by targeting the enzyme GARS1.Experimental approach: We present an in-depth investigation of the mechanism through which Fraisinib [meso-(p-acetamidophenyl)-calix(4)pyrrole] affects the human lung adenocarcinoma A549 cell line. In a xenografted model of non-small-cell lung cancer, Fraisinib was found to reduce tumor mass volume without affecting the vital parameters or body weight of mice. Through a computational approach, we uncovered that glycyl-tRNA synthetase is its molecular target. Differential proteomics analysis further confirmed that pathways regulated by Fraisinib are consistent with glycyl-tRNA synthetase inhibition.Key results: Fraisinib displays a strong anti-tumoral potential coupled with limited toxicity in mice. Glycyl-tRNA synthetase has been identified and validated as a protein target of this compound. By inhibiting GARS1, Fraisinib modulates different key biological processes involved in tumoral growth, aggressiveness, and invasiveness.Conclusion and implications: The overall results indicate that Fraisinib is a powerful inhibitor of non-small-cell lung cancer growth by exerting its action on the enzyme GARS1 while displaying marginal toxicity in animal models. Together with the proven ability of this compound to cross the blood–brain barrier, we can assess that Fraisinib can kill two birds with one stone: targeting the primary tumor and its metastases “in one shot.” Taken together, we suggest that inhibiting GARS1 expression and/or GARS1 enzymatic activity may be innovative molecular targets for cancer treatment