Cholesterol impairment contributes to neuroserpin aggregation

Intraneural accumulation of misfolded proteins is a common feature of several neurodegenerative pathologies including Alzheimer's and Parkinson's diseases, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). FENIB is a rare disease due to a point mutation in neuroserpin which accelerates protein aggregation in the endoplasmic reticulum (ER). Here we show that cholesterol depletion induced either by prolonged exposure to statins or by inhibiting the sterol regulatory binding-element protein (SREBP) pathway also enhances aggregation of neuroserpin proteins. These findings can be explained considering a computational model of protein aggregation under non-equilibrium conditions, where a decrease in the rate of protein clearance improves aggregation. Decreasing cholesterol in cell membranes affects their biophysical properties, including their ability to form the vesicles needed for protein clearance, as we illustrate by a simple mathematical model. Taken together, these results suggest that cholesterol reduction induces neuroserpin aggregation, even in absence of specific neuroserpin mutations. The new mechanism we uncover could be relevant also for other neurodegenerative diseases associated with protein aggregation.Comment: 7 figure

The three-body recombination of a condensed Bose gas near a Feshbach resonance

In this paper, we study the three-body recombination rate of a homogeneous dilute Bose gas with a Feshbach resonance at zero temperature. The ground state and excitations of this system are obtained. The three-body recombination in the ground state is due to the break-up of an atom pair in the quantum depletion and the formation of a molecule by an atom from the broken pair and an atom from the condensate. The rate of this process is in good agreement with the experiment on $^{23}$Na in a wide range of magnetic fields.Comment: 10 pages, 2 figures, to be published in Phys. Rev.

Nuove prospettive nel monitoraggio biologico degli elementi metallici: l'esempio del cromo esavalente

L’industria galvanica è un settore importante su tutto il territorio nazionale, poiché i processi che la caratterizzano riguardano un gran numero di fabbricazioni industriali ed artigianali. Nella cromatura galvanica esiste un rischio chimico specifico dovuto all’esposizione a composti contenenti Cromo esavalente [Cr(VI)]. Il condensato dell’aria espirata (CAE) è stato usato per studiare l’esposizione acuta e a lungo termine a Cr(VI) in lavoratori addetti alla cromatura a spessore. Cr-CAE correla con specifici biomarcatori di stress ossidativo ed è possibile misurarne anche la frazione non ancora ridotta a Cr(III). Il CAE è quindi un fluido biologico promettente per il monitoraggio della dose assorbita a livello dell’organo bersaglio, della cinetica di riduzione polmonare di Cr(VI) e più in generale dei suoi effetti locali pneumotossici nelle lavorazioni galvaniche, con la possibilità di affiancare la sua raccolta e la sua analisi alle misure tradizionalmente fatte durante il monitoraggio biologico

Switching off malignant mesothelioma : exploiting the hypoxic microenvironment

Malignant mesotheliomas are aggressive, asbestos-related cancers with poor patient prognosis, typically arising in the mesothelial surfaces of tissues in pleural and peritoneal cavity. The relative unspecific symptoms of mesotheliomas, misdiagnoses, and lack of precise targeted therapies call for a more critical assessment of this disease. In the present review, we categorize commonly identified genomic aberrations of mesotheliomas into their canonical pathways and discuss targeting these pathways in the context of tumor hypoxia, a hallmark of cancer known to render solid tumors more resistant to radiation and most chemo-therapy. We then explore the concept that the intrinsic hypoxic microenvironment of mesotheliomas can be Achilles’ heel for targeted, multimodal therapeutic intervention

Anti-CTLA-4 therapy for malignant mesothelioma

Immunotherapy is an emerging therapeutic strategy with a promising clinical outcome in some solid tumors, particularly metastatic melanoma. One approach to immunotherapy is immune checkpoint inhibitors, such as blockage of CTLA-4 and PD-1/PD-L1. This special report aims to describe the state of clinical trials of tremelimumab in patients with unresectable malignant mesothelioma (MM) in particular with regard to the clinical efficacy, safety and tolerability. Criticism and perspective of this treatment are also discussed. Biological and clinical considerations rule out the use of tremelimumab as single agent for MM and, more generally, the use of immune checkpoint inhibitors for MM is still largely questionable and not supported by evidences

Monitoraggio ambientale e biologico dell’esposizione ad idrocarburi mono-aromatici ed a metil tert-butil etere in un gruppo di lavoratori addetti all’erogazione di carburanti

Lo studio è stato condotto per valutare gli indicatori biologici di esposizione a vapori di benzina in lavoratori addetti all’erogazione di carburante tramite un approccio combinato di monitoraggio ambientale e biologico. L’esposizione personale a benzene, toluene, etilbenzene e xilene (BTEX) e l’escrezione urinaria di BTEX, metil tert-butil etere (MTBE-U), degli acidi trans,transmuconico (t,t-MA) ed S-fenilmercapturico (S-PMA) e della cotinina sono stati valutati con tecniche cromatografiche accoppiate alla spettrometria di massa. I livelli di MTBE-U erano influenzati dalla sola esposizione professionale a vapori di benzina, mentre quelli di B-U ed S-PMA dipendevano da abitudine tabagica ed esposizione professionale

Metallic elements in exhaled breath condensate of patients with interstitial lung diseases

Epidemiological data support the hypothesis that environmental and occupational agents play an important role in the development of interstitial lung diseases such as idiopathic interstitial pneumonia (IIPs) and sarcoidosis. The aim of this study was to assess the elemental composition of exhaled breath condensate (EBC) in patients with interstitial lung diseases (ILDs) of unknown etiology and healthy subjects as an indirect evaluation of tissue burden, which could improve our understanding of the role of metals in the pathogenesis of ILDs. EBC was obtained from 33 healthy subjects, 22 patients with sarcoidosis, 15 patients with non-specific interstitial pneumonia (NSIP) and 19 with IIPs. Trace elements and toxic metals in the samples were measured by means of inductively coupled plasma-mass spectrometry. There are only small overall differences in the EBC levels of a number of metallic elements among patients with idiopathic pulmonary fibrosis (IPF), NSIP or sarcoidosis, and no pattern is capable of distinguishing them with a high degree of sensitivity and specificity. However, a pattern of pneumotoxic (Si, Ni) and essential elements (Zn, Se and Cu) with the addition of Co distinguished the patients with ILDs from healthy non-smokers with relatively high degrees of sensitivity (96.4%) and specificity (90.9%). Assessing the elemental composition of EBC in patients with different ILDs seems to provide useful information. The non-invasiveness of the EBC method makes it suitable for patients with pulmonary diseases, although further studies are required to confirm the usefulness of this approach and to better understand the underlying pathophysiological processes

Diagnóstico molecular de huanglongbing dos citros, via qPCR, em mudas de valência sobre Swingle.

O HLB é, sem dúvidas, a grande ameaça da citricultura no país, por ser uma doença severa e destrutiva, com prejuízos no desenvolvimento da planta e na produção de frutos. Os agentes causais da doença são espécies da bactéria Candidatus Liberibacter spp., que se alojam em vasos do floema. Três espécies de Liberibacter estão associadas ao HLB dos citros: Ca. Liberibacter africanus, Ca. L. asiaticus e Ca. L. americanus, sendo as duas últimas de ocorrência no Brasil. A doença pode se propagar através de seu vetor, o psilídeo Diaphorina citri, e/ou por enxertia de tecidos infectados (Bové, 2006). O HLB não provoca a morte das plantas, mas, com o passar dos anos, elas se tornam debilitadas e improdutivas. Pomares inteiros podem ficar inviáveis economicamente dentro de sete a dez anos após o aparecimento da primeira planta sintomática se as medidas de controle não forem tomadas (Gottwald et al., 2007).O período de incubação do HLB depende de vários fatores, variando geralmente de seis a doze meses (Bové, 2006). Diante disso, a inspeção visual do pomar não representa o controle da doença, visto que plantas assintomáticas, porém infectadas, podem permanecer como fontes de inóculo para plantas ainda sadias. Como discutido por Bové (2006) e Gottwald et al. (2007), o conhecimento da proporção de plantas sintomáticas e assintomáticas é importante e deve ser utilizado na decisão da eliminação de pomares inteiros altamente infestados. Assim, a detecção de Ca. Liberibacter sp. precocemente é de extrema importância, pois minimiza, dentro do possível, o impacto financeiro aos citricultores com a erradicação das plantas.Hoje o método mais confiável para o diagnóstico do HLB é o PCR quantitativo em tempo real (qPCR), que amplifica e detecta o DNA bacteriano presente no tecido. O método visual é também utilizado, porém o diagnóstico é impreciso e pode levar a falsos negativos (plantas infectadas e ainda assintomáticas) ou falsos positivos, uma vez que os sintomas da doença podem ser facilmente confundidos com deficiência nutricional.pdf 186

Bronchoalveolar lavage, sputum and exhaled clinically relevant inflammatory markers: values in healthy adults.

11noBronchoalveolar lavage (BAL), induced sputum and exhaled breath markers (exhaled nitric oxide and exhaled breath condensate) can each provide biological insights into the pathogenesis of respiratory disorders. Some of their biomarkers are also employed in the clinical management of patients with various respiratory diseases. In the clinical context, however, defining normal values and cut-off points is crucial. The aim of the present review is to investigate to what extent the issue of defining normal values in healthy adults has been pursued for the biomarkers with clinical value. The current authors reviewed data from literature that specifically addressed the issue of normal values from healthy adults for the four methodologies. Most studies have been performed for BAL (n = 9), sputum (n = 3) and nitric oxide (n = 3). There are no published studies for breath condensate, none of whose markers yet has clinical value. In healthy adult nonsmokers the cut-off points (mean+2sd) for biomarkers with clinical value were as follows. BAL: 16.7% lymphocytes, 2.3% neutrophils and 1.9% eosinophils; sputum: 7.7 x 10(6).mL(-1) total cell count and 2.2% eosinophils; nitric oxide: 20.2 ppb. The methodologies differ concerning the quantity and characteristics of available reference data. Studies focusing on obtaining reference values from healthy individuals are still required, more evidently for the new, noninvasive methodologies.nonemixedBALBI B; PIGNATTI P; CORRADI M; BAIARDI P; BIANCHI L; BRUNETTI G; RADAELI A; MOSCATO G; MUTTI A; SPANEVELLO A; MALERBA MBalbi, B; Pignatti, P; Corradi, M; Baiardi, P; Bianchi, L; Brunetti, G; Radaeli, A; Moscato, G; Mutti, A; Spanevello, Antonio; Malerba, M

Spectroscopic investigation of quantum confinement effects in ion implanted silicon-on-sapphire films

Crystalline Silicon-on-Sapphire (SOS) films were implanted with boron (B$^+$) and phosphorous (P$^+$) ions. Different samples, prepared by varying the ion dose in the range $10^{14}$ to 5 x $10^{15}$ and ion energy in the range 150-350 keV, were investigated by the Raman spectroscopy, photoluminescence (PL) spectroscopy and glancing angle x-ray diffraction (GAXRD). The Raman results from dose dependent B$^+$ implanted samples show red-shifted and asymmetrically broadened Raman line-shape for B$^+$ dose greater than $10^{14}$ ions cm$^{-2}$. The asymmetry and red shift in the Raman line-shape is explained in terms of quantum confinement of phonons in silicon nanostructures formed as a result of ion implantation. PL spectra shows size dependent visible luminescence at $\sim$ 1.9 eV at room temperature, which confirms the presence of silicon nanostructures. Raman studies on P$^+$ implanted samples were also done as a function of ion energy. The Raman results show an amorphous top SOS surface for sample implanted with 150 keV P$^+$ ions of dose 5 x $10^{15}$ ions cm$^{-2}$. The nanostructures are formed when the P$^+$ energy is increased to 350 keV by keeping the ion dose fixed. The GAXRD results show consistency with the Raman results.Comment: 9 Pages, 6 Figures and 1 Table, \LaTex format To appear in SILICON(SPRINGER