Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To ...overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer's cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.
Glioblastoma multiforme (GBM) is a grade IV astrocytoma and the most common form of malignant brain tumor in adults. GBM remains one of the most fatal and least successfully treated solid tumors: ...current therapies provide a median survival of 12-15 months after diagnosis, due to the high recurrence rate. Glioma Stem Cells (GSCs) are believed to be the real driving force of tumor initiation, progression and relapse. Therefore, better therapeutic strategies GSCs-targeted are needed. Resveratrol is a polyphenolic phytoalexin found in fruits and vegetables displaying pleiotropic health benefits. Many studies have highlighted its chemo-preventive and chemotherapeutic activities in a wide range of solid tumors. In this work, we analyzed the effects of Resveratrol exposure on cell viability, proliferation and motility in seven GSC lines isolated from GBM patients. For the first time in our knowledge, we investigated Resveratrol impact on Wnt signaling pathway in GSCs, evaluating the expression of seven Wnt signaling pathway-related genes and the protein levels of c-Myc and β-catenin. Finally, we analyzed Twist1 and Snail1 protein levels, two pivotal activators of epithelial-mesenchymal transition (EMT) program. Results showed that although response to Resveratrol exposure was highly heterogeneous among GSC lines, generally it was able to inhibit cell proliferation, increase cell mortality, and strongly decrease cell motility, modulating the Wnt signaling pathway and the EMT activators. Treatment with Resveratrol may represent a new interesting therapeutic approach, in order to affect GSCs proliferation and motility, even if further investigations are needed to deeply understand the GSCs heterogeneous response.
Cascina Oremo is a group of buildings conceived by the “Fondazione Cassa di Risparmio di Biella” to accommodate associations that focus on childhood disabilities. It is a multifunctional complex ...converted from an old farmhouse located in Biella. It consists of two different buildings: the multifunctional farmhouse building, created by renovating the existing farmhouse structure, and the pool building, a new building that houses the pool and sports areas. It hosts four different associations, each allocated specific spaces. This case study aims to illustrate the automation and control system choices, particularly highlighting the metering not only for cost allocation in accordance with DLgs 102/14 but also for interfacing with the Building Management System designed to assist the designer in ensuring that the building’s performance adheres to the project specifications over time and improves the overall system efficiency within the Deming cycle perspective. Furthermore, it integrates with Artificial Intelligence and the smart grid. The Building Management System also serves as an enabling platform for informing occupants to achieve a high level of Sustainable and Responsible Investment.
Bone marrow mesenchymal stem cells (BM-MSCs) are multipotent cells that can differentiate into different cell lineages and have emerged as a promising tool for cell-targeted therapies and tissue ...engineering. Their use in a therapeutic context requires large-scale in vitro expansion, increasing the probability of genetic and epigenetic instabilities. Some evidence shows that an organized program of replicative senescence is triggered in human BM-MSCs (hBM-MSCs) on prolonged in vitro expansion that includes alterations in phenotype, differentiation potential, telomere length, proliferation rates, global gene-expression patterns, and DNA methylation profiles.
In this study, we monitored the chromosomal status, the biologic behavior, and the senescence state of hBM-MSCs derived from eight healthy donors at different passages during in vitro propagation. For a more complete picture, the telomere length was also monitored in five of eight donors, whereas the genomic profile was evaluated in three of eight donors by array-comparative genomic hybridization (array-CGH). Finally, an epigenomic profile was delineated and compared between early and late passages, by pooling DNA of hBM-MSCs from four donors.
Our data indicate that long-term culture severely affects the characteristics of hBM-MSCs. All the observed changes (that is, enlarged morphology, decreased number of cell divisions, random loss of genomic regions, telomere shortening) might be regulated by epigenetic modifications. Gene Ontology analysis revealed that specific biologic processes of hBM-MSCs are affected by variations in DNA methylation from early to late passages.
Because we revealed a significant decrease in DNA methylation levels in hBM-MSCs during long-term culture, it is very important to unravel how these modifications can influence the biologic features of hBM-MSCs to keep track of this organized program and also to clarify the conflicting observations on hBM-MSC malignant transformation in the literature.
We present an original strategy for the calculation of direct and inverse photo-emission spectra from first principles.
The main goal is to go beyond the standard Green's function approaches, such as ...the $GW$ method, in order to find a good description not only of the quasiparticles but also of the satellite structures, which are of particular importance in strongly correlated materials.
To this end we use as a key quantity the three-body Green's function, or, more precisely, its hole-hole-electron and electron-electron-hole parts, and we show how the one-body Green's function, and hence the corresponding spectral function, can be retrieved from it.
We show that, contrary to the one-body Green's function, information about satellites is already present in the non-interacting three-body Green's function. Therefore, simple approximations to the three-body self-energy, which is defined by the Dyson equation for the three-body Green's function and which contains many-body effects, can still yield accurate spectral functions. In particular, the self-energy can be chosen to be static which could simplify a self-consistent solution of the Dyson equation.
We give a proof of principle of our strategy by applying it to the Hubbard dimer, for which the exact self-energy is available.
The coefficient of friction (COF) is an important parameter when evaluating brake system performance. It is complex to predict friction due to its dependence on parameters, such as sliding velocity, ...contact pressure, temperature, and friction material mixtures. The aim of this work is to evaluate the macroscopic COF of a disc brake system under specific braking conditions by a meso-scale approach, using a cellular automaton simulation where the friction material mixture is modelled starting from its basic components. The influence of the local components in contact is taken into account. Simulated COF values are in line with the experimental values.
The coefficient of friction (COF) is one of the most important parameters to evaluate the performance of a brake system. To design proper brake systems, it is important to know the COF when ...estimating the brake force and resulting torque. It is challenging to simulate the COF since friction in disc brakes is a complex phenomenon that depends on several parameters such as sliding velocity, contact pressure, materials, and temperatures, etc. There is a lack of studies found in the literature focusing on simulation of the COF for a full brake system based on tribometer material characterization. The aim of this work is therefore to investigate the possibility to use a finite element analysis (FEA) approach combined with a COF
pv
-map to compute the global COF of a disc brake system. The local COF is determined from a
pv
-map for each local sliding velocity and contact pressure determined by the FEA. Knowing the local COF, the braking force of the entire brake system and the global COF can be evaluated. Results obtained by the simulation are compared with dyno bench test of the same brake system to investigate the validity of the simulation approach. Results show that the simulation is perfectly in line with the experimental measurements in terms of in-stop COF development, but slightly higher with a positive offset for every braking.
Copper from vehicles disc brakes is one main contributor of the total copper found in the environment. Therefore, the U.S. Environmental Protection Agency (EPA) and the automotive industries started ...the Copper-Free Brake Initiative. The pad friction material is essentially composed of a binder, fillers, reinforcing fibres and frictional additives. Copper and brass fibres are the most commonly used fibres in brake pads. There is a need to understand how the contact temperature distribution will change if copper-based fibres are changed to steel fibres. The aim of this work is, therefore, to investigate how this change could influence the local contact temperatures. This is done by developing a multi-scale simulation approach which combines cellular automaton, finite element analysis (FEA) and computational fluid dynamics (CFD) approaches with outputs from inertia brake dyno bench tests of Cu-full and Cu-free pads. FEA and thermal-CFD are used to set the pressure and the temperature boundary conditions of the cellular automaton. The outputs of dyno tests are used to calibrate FEA and CFD simulations. The results of the study show lower peaks in contact temperature and a more uniform temperature distribution for the Cu-free pad friction material.
Bruton's tyrosine-kinase (BTK) is a non-receptor tyrosine kinase recently associated with glioma tumorigenesis and a novel prognostic marker for poor survival in patients with glioma. The p65BTK is a ...novel BTK isoform involved in different pathways of drug resistance of solid tumors, thus we aimed to investigate the expression and the putative role of p65BTK in tumors of the central nervous system (CNS). We selected a large cohort of patients with glial tumors (
= 71) and analyzed the expression of p65BTK in different histotypes and correlation with clinical parameters. Sections were stained with glial fibrillary acidic protein (GFAP), p53, epidermal growth factor receptor (EGFR), S100, vimentin, and epithelial membrane antigen (EMA) antibodies. Glioma stem cell (GSC) lines, isolated from glioblastoma multiforme (GBM), were treated with different concentrations of ibrutinib, a specific inhibitor of BTK, in order to evaluate their metabolic activity, mitotic index and mortality. Moreover, an orthotopic xenotransplant of GSC from human GBM was used to evaluate the expression of p65BTK in the brain of immunodeficient mice. p65BTK was expressed in GSC and in gemistocytes in human gliomas at different histological grade. We found a significant correlation between BTK expression and low-grade (LG) tumors (
≤ 0.05) and overall survival (OS) of patients with grade III gliomas (
≤ 0.05), suggestive of worst prognosis. Interestingly, the expression of p65BTK remained restricted exclusively to gemistocytic cells in the xenograft mouse model. Ibrutinib administration significantly reduced metabolic activity and mitotic index and increased mortality in GSC, highlighting the specific role of p65BTK in cell proliferation and survival. In conclusion, our data demonstrated that p65BTK is expressed in glioma tumors, restricted to gemistocytic cells, has a key role in GSC and has a bad prognostic value, thus highlighting the importance of future research for targeted therapy of human gliomas.
Emissions from disc brake wear adversely affect the air quality in cities. Finite Element Analysis (FEA) approachesfocussing on the macroscopic wear of pads and rotors can be found in the literature, ...but none of thesetake the wear and emission dependence of the local contact pressure and sliding speed into account. The aim ofthe present study is to further develop an FEA approach for simulation of macroscopic wear and airborneemission to include the dependences of local contact pressure and sliding speed by implementing wear andemission maps obtained by pin-on-disc tribometer tests. Results from a dyno bench test are compared withsimulated results. The simulated rotor and pads wear, and airborne emissions are in line with the measuredvalues.
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