Comb-assisted cavity ring-down spectroscopy of a buffer-gas-cooled molecular beam

We demonstrate continuous-wave cavity ring-down spectroscopy of a partially hydrodynamic molecular beam emerging from a buffer-gas-cooling source. Specifically, the (ν1 + ν3) vibrational overtone band of acetylene (C2H2) around 1.5 μm is accessed using a narrow-linewidth diode laser stabilized against a GPS-disciplined rubidium clock via an optical frequency comb synthesizer. As an example, the absolute frequency of the R(1) component is measured with a fractional accuracy of ∼1 × 10(-9). Our approach represents the first step towards the extension of more sophisticated cavity-enhanced interrogation schemes, including saturated absorption cavity ring-down or two-photon excitation, to buffer-gas-cooled molecular beams

Experimental observation of optical frequency combs in doubly resonant second harmonic generation

Continuously-driven microresonators, whose nonlinear response is dominated by the third-order Kerr nonlinearity, have proven to be valid alternatives to comb sources based on femtosecond mode-locked lasers [1]. More recenlty, the direct generation of optical frequency combs (OFCs) entirely through quadratic interactions has also been demonstrated in singly resonant cavity second harmonic generation (SHG) and in cw pumped nearly degenerate optical parametric oscillation [2,3]. Interestingly, theoretical studies on doubly resonant cavity SHG predicted the emergence of OFCs with a much lower threshold with respect to the singly resonant configurations, as well as rich nonlinear dynamics [4]

Role of TGFβ1/Smads pathway in the pathogenesis of intestinal fibrosis in Crohn’s disease

Inflammatory bowel diseases (IBD) are characterized by an intestinal fibrosis that may lead to stenosis and obstruction (Burke et al., 2007) and by disfuntions of gastrointestinal (GI) motility associated with altered functions of enteric nerves, interstitial cells of Cajal or smooth muscle (Vetuschi et al., 2006). In experimental model TGFβ1/ Smad3 signalling plays a major role in tissue fibrogenesis (Latella et al, 2009). Aim of this study was to evaluate the potential role of the TGFβ1/Smads pathway in intestinal fibrosis and to explore the possible mechanisms by which fibrogenesis induces alterations of GI motility in patients affected by CD. Evaluation of TGFβ1, CTGF, collagen I-III, Smad3/7, PDGF, C-Kit, α-SMA, and a neuronal cocktail expression and a morphometrical analysis were performed in human CD terminal ileum samples; human smooth muscle cells (HSMC) were cultured for morphofuncional and mRNA expression (RT-PCR). Histo-morphometrical evaluation of stenotic fragments showed a significantly increase of a) both intestinal fibrosis and inflammation; b) mucosa, submucosa and muscle layer thickness and c) expression of TGFβ1, CTGF, collagen I-III, Smad3, PDGF, C-Kit and α-SMA staining. HSMC obtained from stenotic tracts showed an increase of PDGF-β and collagen I-III types mRNA and an inhibition in contractile response to acetylcholine compared to pre-stenotic tracts. These data support the hypothesis that TGFβ1/Smads pathway play a central role in development and differentiation of intestinal mesenchymal cells in sustaining intestinal fibrosis in CD and could be responsible for alteration of GI motility

Protective effects of lemon nanovesicles: evidence of the Nrf2/HO-1 pathway contribution from in vitro hepatocytes and in vivo high-fat diet-fed rats

The cross-talk between plant-derived nanovesicles (PDNVs) and mammalian cells has been explored by several investigations, underlining the capability of these natural nanovesicles to regulate several molecular pathways. Additionally, PDNVs possess biological proprieties that make them applicable against pathological conditions, such as hepatic diseases. In this study we explored the antioxidant properties of lemon-derived nanovesicles, isolated at laboratory (LNVs) and industrial scale (iLNVs) in human healthy hepatocytes (THLE-2) and in metabolic syndrome induced by a high-fat diet (HFD) in the rat. Our findings demonstrate that in THLE-2 cells, LNVs and iLNVs decrease ROS production and upregulate the expression of antioxidant mediators, Nrf2 and HO-1. Furthermore, the in vivo assessment reveals that the oral administration of iLNVs improves glucose tolerance and lipid dysmetabolism, ameliorates biometric parameters and systemic redox homeostasis, and upregulates Nrf2/HO-1 signaling in HFD rat liver. Consequently, we believe LNVs/iLNVs might be a promising approach for managing hepatic and dysmetabolic disorders

Therapeutic potential of MEK inhibition in acute myelogenous leukemia: rationale for "vertical" and "lateral" combination strategies

: In hematological malignancies, constitutive activation of the RAF/MEK/ERK pathway is frequently observed, conveys a poor prognosis, and constitutes a promising target for therapeutic intervention. Here, we investigated the molecular and functional effects of pharmacological MEK inhibition in cell line models of acute myeloid leukemia (AML) and freshly isolated primary AML samples. The small-molecule, ATP-non-competitive, MEK inhibitor PD0325901 markedly inhibited ERK phosphorylation and growth of several AML cell lines and approximately 70 % of primary AML samples. Growth inhibition was due to G(1)-phase arrest and induction of apoptosis. Transformation by constitutively active upstream pathway elements (HRAS, RAF-1, and MEK) rendered FDC-P1 cells exquisitely prone to PD0325901-induced apoptosis. Gene and protein expression profiling revealed a selective effect of PD0325901 on ERK phosphorylation and compensatory upregulation of the RAF/MEK and AKT/p70( S6K ) kinase modules, potentially mediating resistance to drug-induced growth inhibition. Consequently, in appropriate cellular contexts, both "vertical" (i.e., inhibition of RAF and MEK along the MAPK pathway) and "lateral" (i.e., simultaneous inhibition of the MEK/ERK and mTOR pathways) combination strategies may result in synergistic anti-leukemic effects. Overall, MEK inhibition exerts potent growth inhibitory and proapoptotic activity in preclinical models of AML, particularly in combination with other pathway inhibitors. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective targeted strategies for the treatment of AML

Brain connectivity changes in autosomal recessive Parkinson Disease: a model for the sporadic form

Biallelic genetic mutations in the Park2 and PINK1 genes are frequent causes of autosomal recessive PD. Carriers of single heterozygous mutations may manifest subtle signs of disease, thus providing a unique model of preclinical PD. One emerging hypothesis suggests that non-motor symptom of PD, such as cognitive impairment may be due to a distributed functional disruption of various neuronal circuits. Using resting-state functional MRI (RS-fMRI), we tested the hypothesis that abnormal connectivity within and between brain networks may account for the patients' cognitive status. Eight homozygous and 12 heterozygous carriers of either PINK1 or Park2 mutation and 22 healthy controls underwent RS-fMRI and cognitive assessment. RS-fMRI data underwent independent component analysis to identify five networks of interest: default-mode network, salience network, executive network, right and left fronto-parietal networks. Functional connectivity within and between each network was assessed and compared between groups. All mutation carriers were cognitively impaired, with the homozygous group reporting a more prominent impairment in visuo-spatial working memory. Changes in functional connectivity were evident within all networks between homozygous carriers and controls. Also heterozygotes reported areas of reduced connectivity when compared to controls within two networks. Additionally, increased inter-network connectivity was observed in both groups of mutation carriers, which correlated with their spatial working memory performance, and could thus be interpreted as compensatory. We conclude that both homozygous and heterozygous carriers exhibit pathophysiological changes unveiled by RS-fMRI, which can account for the presence/severity of cognitive symptom