Source Reconstruction of Atmospheric Releases with Limited Meteorological Observations Using Genetic Algorithms

A genetic algorithm is paired with a Lagrangian puff atmospheric model to reconstruct the source characteristics of an atmospheric release. Observed meteorological and ground concentration measurements from the real-world Dipole Pride controlled release experiment are used to test the methodology. A sensitivity study is performed to quantify the relative contribution of the number and location of sensor measurements by progressively removing them. Additionally, the importance of the meteorological measurements is tested by progressively removing surface observations and vertical profiles. It is shown that the source term reconstruction can occur also with limited meteorological observations. The proposed general methodology can be applied to reconstruct the characteristics of an unknown atmospheric release given limited ground and meteorological observations.     

Viscoelectromechanics modeling of intestine wall hyperelasticity

Elastic-electroactive biological media are sensitive to both mechanical and electric forces. Their active behavior is often associated with the presence of reinforcing fibers and their excitation-contraction coupling is due to the interplay between the passive elastic tissue and the active muscular network. In this paper we focus on the theoretical framework of constitutive equations for viscous electroactive media. The approach is based on the additive decomposition of the Helmholtz free energy accompanied to the multiplicative decomposition of the deformation gradient in elastic, viscous and active parts. We describe a thermodynamically sound scenario that accounts for geometric and material nonlinearities.     

Surface-enhanced Raman scattering study of nano-sized organic carbon particles produced in combustion processes

Surface-enhanced Raman scattering (SERS) has been employed for the first time to characterize nano-sized organic carbon (NOC) particles produced in ordinary combustion processes. Ag-coated glass microparticles, used as SERS substrate, provide a Raman scattering cross section enhancement up to five orders of magnitude, which allows sample investigation at low concentration level. The observed spectral features supply a deeper insight on the chemical properties of the investigated combustion product. In addition, the high sensitivity of the SERS technique might be useful to test and characterize the toxicity of NOC particles.     

The Hedgehog-GLI Pathway Regulates MEK5-ERK5 Expression and Activation in Melanoma Cells

Malignant melanoma is the deadliest skin cancer, with a poor prognosis in advanced stages. We recently showed that the extracellular signal-regulated kinase 5 (ERK5), encoded by the MAPK7 gene, plays a pivotal role in melanoma by regulating cell functions necessary for tumour development, such as proliferation. Hedgehog-GLI signalling is constitutively active in melanoma and is required for proliferation. However, no data are available in literature about a possible interplay between Hedgehog-GLI and ERK5 pathways. Here, we show that hyperactivation of the Hedgehog-GLI pathway by genetic inhibition of the negative regulator Patched 1 increases the amount of ERK5 mRNA and protein. Chromatin immunoprecipitation showed that GLI1, the major downstream effector of Hedgehog-GLI signalling, binds to a functional non-canonical GLI consensus sequence at the MAPK7 promoter. Furthermore, we found that ERK5 is required for Hedgehog-GLI-dependent melanoma cell proliferation, and that the combination of GLI and ERK5 inhibitors is more effective than single treatments in reducing cell viability and colony formation ability in melanoma cells. Together, these findings led to the identification of a novel Hedgehog-GLI-ERK5 axis that regulates melanoma cell growth, and shed light on new functions of ERK5, paving the way for new therapeutic options in melanoma and other neoplasms with active Hedgehog-GLI and ERK5 pathways.     

Selective Inhibition of Helicobacter pylori Carbonic Anhydrases by Carvacrol and Thymol Could Impair Biofilm Production and the Release of Outer Membrane Vesicles

Helicobacter pylori, a Gram-negative neutrophilic pathogen, is the cause of chronic gastritis, peptic ulcers, and gastric cancer in humans. Current therapeutic regimens suffer from an emerging bacterial resistance rate and poor patience compliance. To improve the discovery of compounds targeting bacterial alternative enzymes or essential pathways such as carbonic anhydrases (CAs), we assessed the anti-H. pylori activity of thymol and carvacrol in terms of CA inhibition, isoform selectivity, growth impairment, biofilm production, and release of associated outer membrane vesicles-eDNA. The microbiological results were correlated by the evaluation in vitro of H. pylori CA inhibition, in silico analysis of the structural requirements to display such isoform selectivity, and the assessment of their limited toxicity against three probiotic species with respect to amoxicillin. Carvacrol and thymol could thus be considered as new lead compounds as alternative H. pylori CA inhibitors or to be used in association with current drugs for the management of H. pylori infection and limiting the spread of antibiotic resistance.     

Role of Bevacizumab on Vascular Endothelial Growth Factor in Apolipoprotein E Deficient Mice after Traumatic Brain Injury

Traumatic brain injury (TBI) disrupts the blood–brain barrier (BBB). Vascular endothelial growth factor (VEGF) is believed to play a key role in TBI and to be overexpressed in the absence of apolipoprotein E (ApoE). Bevacizumab, a VEGF inhibitor, demonstrated neuroprotective activity in several models of TBI. However, the effects of bevacizumab on Apo-E deficient mice are not well studied. The present study aimed to evaluate VEGF expression and the effects of bevacizumab on BBB and neuroinflammation in ApoE^−/− mice undergoing TBI. Furthermore, for the first time, this study evaluates the effects of bevacizumab on the long-term consequences of TBI, such as atherosclerosis. The results showed that motor deficits induced by controlled cortical impact (CCI) were accompanied by increased brain edema and VEGF expression. Treatment with bevacizumab significantly improved motor deficits and significantly decreased VEGF levels, as well as brain edema compared to the control group. Furthermore, the results showed that bevacizumab preserves the integrity of the BBB and reduces the neuroinflammation induced by TBI. Regarding the effects of bevacizumab on atherosclerosis, it was observed for the first time that its ability to modulate VEGF in the acute phase of head injury prevents the acceleration of atherosclerosis. Therefore, the present study demonstrates not only the neuroprotective activity of bevacizumab but also its action on the vascular consequences related to TBI.     

Differential Response of Wheat Rhizosphere Bacterial Community to Plant Variety and Fertilization

The taxonomic assemblage and functions of the plant bacterial community are strongly influenced by soil and host plant genotype. Crop breeding, especially after the massive use of nitrogen fertilizers which led to varieties responding better to nitrogen fertilization, has implicitly modified the ability of the plant root to recruit an effective bacterial community. Among the priorities for harnessing the plant bacterial community, plant genotype-by-microbiome interactions are stirring attention. Here, we analyzed the effect of plant variety and fertilization on the rhizosphere bacterial community. In particular, we clarified the presence in the bacterial community of a varietal effect of N and P fertilization treatment. 16S rRNA gene amplicon sequence analysis of rhizospheric soil, collected from four wheat varieties grown under four N-P fertilization regimes, and quantification of functional bacterial genes involved in the nitrogen cycle (nifH; amoA; nirK and nosZ) were performed. Results showed that variety played the most important role and that treatments did not affect either bacterial community diversity or bacterial phyla abundance. Variety-specific response of rhizosphere bacterial community was detected, both in relation to taxa (Nitrospira) and metabolic functions. In particular, the changes related to amino acid and aerobic metabolism and abundance of genes involved in the nitrogen cycle (amoA and nosZ), suggested that plant variety may lead to functional changes in the cycling of the plant-assimilable nitrogen.     

The Lack of STING Impairs the MHC-I Dependent Antigen Presentation and JAK/STAT Signaling in Murine Macrophages

STING is a transmembrane ER resident protein that was initially described as a regulator of innate immune response triggered by viral DNA and later found to be involved in a broader range of immune processes. Here, we assessed its role in the antigen presentation by generating a STING KO macrophage cell line. In the absence of STING, we observed an impaired OVA-derived SIINFEKL peptide presentation together with a decreased level of MHC-I complex on the plasma membrane, likely due to a decreased mRNA expression of β2 m light chain as no relevant alterations of the peptide-loading complex (TAPs) were found. Moreover, JAK-STAT signaling resulted in impaired STING KO cells following OVA and LPS treatments, suggesting a dampened activation of immune response. Our data revealed a new molecular role of STING in immune mechanisms that could elucidate its role in the pathogenesis of autoimmune disorders and cancer.     

A Plasma Circular RNA Profile Differentiates Subjects with Alzheimer’s Disease and Mild Cognitive Impairment from Healthy Controls

The most frequently used biomarkers to support the diagnosis of Alzheimer’s Disease (AD) are Aβ42, total-Tau, and phospho-tau protein levels in CSF. Moreover, magnetic resonance imaging is used to assess hippocampal atrophy, 18F-FDG PET to identify abnormal brain metabolism, and PET imaging for amyloid deposition. These tests are rather complex and invasive and not easily applicable to clinical practice. Circulating non-coding RNAs, which are inherently stable and easy to manage, have been reported as promising biomarkers for central nervous system conditions. Recently, circular RNAs (circRNAs) as a novel class of ncRNAs have gained attention. We carried out a pilot study on five participants with AD and five healthy controls (HC) investigating circRNAs by Arraystar Human Circular RNA Microarray V2.0. Among them, 26 circRNAs were differentially expressed (FC ≥ 1.5, p < 0.05) in participants with AD compared to HC. From a top 10 of differentially expressed circRNAs, a validation study was carried out on four up-regulated (hsa_circRNA_050263, hsa_circRNA_403959, hsa_circRNA_003022, hsa_circRNA_100837) and two down-regulated (hsa_circRNA_102049, hsa_circRNA_102619) circRNAs in a larger population. Moreover, five subjects with mild cognitive impairment (MCI) were investigated. The analysis confirmed the upregulation of hsa_circRNA_050263, hsa_circRNA_403959, and hsa_circRNA_003022 both in subjects with AD and in MCI compared to HCs. We also investigated all microRNAs potentially interacting with the studied circRNAs. The GO enrichment analysis shows they are involved in the development of the nervous system, and in the cellular response to nerve growth factor stimuli, protein phosphorylation, apoptotic processes, and inflammation pathways, all of which are processes related to the pathology of AD.     

From Nature to Synthetic Compounds: Novel 1(N),2,3 Trisubstituted-5-oxopyrrolidines Targeting Multiple Myeloma Cells

The insurgence of drug resistance in treating Multiple Myeloma (MM) still represents a major hamper in finding effective treatments, although over the past decades new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have been discovered. Recently, our research team, within a Nature-Aided Drug Discovery project, isolated from Hibiscus Sabdariffa L. calyces the secondary metabolite called Hib-ester which possesses antiproliferative properties against human multiple myeloma RPMI 8226 cells, reduces migration and cell invasion and inhibits proteasome without neurotoxic effects. In the present study, we explored the chemical spaces of the hit compound Hib-ester. We explored the structure-activity relationships (SAR), and we optimized the scaffold through sequentially modifying Hib-ester subunits. Compound screening was performed based on cytotoxicity against the RPMI 8226 cells to assess the potential efficacy toward human MM. The ability of the most effective molecules to inhibit the proteasome was evaluated and the binding mode of the most promising compounds in the proteasome chymotrypsin binding pocket was deciphered through molecular modeling simulations. Compounds 13 and 14 are more potent than Hib-ester, demonstrating that our strategy was suitable for the identification of a novel chemotype for developing possible drug candidates and hopefully widening the drug armamentarium against MM.