Volcanic rocks were among the most sought-after materials to produce grinding tools in antiquity because lavas lithologies, either mafic or felsic, ensured good wear resistance and grinding capacity ...with respect to many other kinds of rocks. The interest in findings made of vesciculated lavas, referable to parts of querns, mortars, and/or pestles of the Final Bronze Age site of Monte Croce Guardia (Arcevia) lies in the fact that this settlement was built upon limestones belonging to the sedimentary sequence of the Marche-Umbria Apennines (central Italy) and far away from potential raw materials of volcanic rocks. A petrologic study of 23 grinding tool fragments clearly indicates a provenance from the volcanic provinces of central Italy: Latium and Tuscany Regions. Few leucite tephrites (5) and one leucite phonolite lavas have a clear magmatic affinity with the high-K series of the Roman Volcanic Province (Latium) whereas the most abundant volcanic lithotype (17 samples) is represented by shoshonites (K-series) whose thin section texture, modal mineralogy and major-trace elements contents closely match with the shoshonite lavas from the Radicofani volcanic centre in the Tuscan Magmatic Province. At Radicofani (a volcanic neck in the eastern sector of Tuscany) a Final Bronze Age site coeval to that of Arcevia is present and a potential pathway corridor from that site towards Arcevia (air-line distance of ca. 115 km) is dotted with many settlements of the same age. Through analytical algorithms based on the slope and the different human-dependent cost-functions which can be applied to determine non-isotropic accumulated cost surface, least-cost paths and least-cost corridors, the best route from Radicofani to Monte Croce Guardia, approximately 140 km long, was simulated, with a walking time of 25-30 h, possibly using pack animals and wheel chariots. Three thousand years ago the Apennine Mountains did not thus constitute a barrier for human movements. This study also shed light on some other possible patterns of interactions between Final Bronze Age communities of central Italy through the present-day regions of Tuscany, Umbria and Marche, aimed towards the best performance of strategic economic activities at that time such as that of the transformation of cereals, and accompanied to cultural and social reasons.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Laser wakefield accelerators promise to revolutionize many areas of accelerator science. However, one of the greatest challenges to their widespread adoption is the difficulty in control and ...optimization of the accelerator outputs due to coupling between input parameters and the dynamic evolution of the accelerating structure. Here, we use machine learning techniques to automate a 100 MeV-scale accelerator, which optimized its outputs by simultaneously varying up to six parameters including the spectral and spatial phase of the laser and the plasma density and length. Most notably, the model built by the algorithm enabled optimization of the laser evolution that might otherwise have been missed in single-variable scans. Subtle tuning of the laser pulse shape caused an 80% increase in electron beam charge, despite the pulse length changing by just 1%.
KCC2 is a neuron specific K
-Cl
co-transporter that controls neuronal chloride homeostasis, and is critically involved in many neurological diseases including brain trauma, epilepsies, autism and ...schizophrenia. Despite significant accumulating data on the biology and electrophysiological properties of KCC2, structure-function relationships remain poorly understood. Here we used calixarene detergent to solubilize and purify wild-type non-aggregated and homogenous KCC2. Specific binding of inhibitor compound VU0463271 was demonstrated using surface plasmon resonance (SPR). Mass spectrometry revealed glycosylations and phosphorylations as expected from functional KCC2. We show by electron microscopy (EM) that KCC2 exists as monomers and dimers in solution. Monomers are organized into "head" and "core" domains connected by a flexible "linker". Dimers are asymmetrical and display a bent "S-shape" architecture made of four distinct domains and a flexible dimerization interface. Chemical crosslinking in reducing conditions shows that disulfide bridges are involved in KCC2 dimerization. Moreover, we show that adding a tag to the C-terminus is detrimental to KCC2 function. We postulate that the conserved KCC2 C-ter may be at the interface of dimerization. Taken together, our findings highlight the flexible multi-domain structure of KCC2 with variable anchoring points at the dimerization interface and an important C-ter extremity providing the first in-depth functional architecture of KCC2.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Evidence suggests that metastatic colorectal carcinoma (mCRC) has a high level of intratumor heterogeneity. We carried out a quantitative assessment of tumor heterogeneity for KRAS, NRAS, BRAF and ...PIK3CA mutations, in order to assess potential clinical implications.
Tumor samples (n = 182) from the CAPRI-GOIM trial of first-line cetuximab + FOLFIRI in KRAS exon-2 wild-type mCRC patients were assessed by next-generation sequencing that allows quantitative assessment of mutant genes. Mutant allelic frequency was normalized for the neoplastic cell content and, assuming that somatic mutations usually affect one allele, the Heterogeneity Score (HS) was calculated by multiplying by 2 the frequency of mutant alleles in neoplastic cells. Therefore, HS virtually corresponds to the fraction of neoplastic cells carrying a specific mutation.
The KRAS HS ranged between 12 and 260 with mean value of 87.1 and median value of 84.4, suggesting that in most CRC, the majority of neoplastic cells carry mutant KRAS. Similar findings were observed for NRAS (HS range 35.5–146.7; mean 102.8; median 117.1). In contrast, in BRAF (HS range 17.1–120; mean 54.8; median 54.3) and PIK3CA (HS range 14.3–120; mean 59.5; median 47.3) mutant cases, only a fraction of neoplastic cells seem to carry the mutant allele. The response rate was 70% in KRAS mutant patients with an HS <33 (low KRAS; n = 10) and 45.7% in KRAS HS >33 patients (high KRAS; n = 35); median progression-free survival were 7.97 and 8.37 months, respectively. Low-KRAS tumors had a higher frequency of additional mutations in PIK3CA when compared with high-KRAS (6/10 versus 8/35).
KRAS and NRAS mutations are usually present in the majority of neoplastic cells, whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells. Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Biological age (BA) is the hypothetical underlying age of an organism and has been proposed as a more powerful predictor of health than chronological age (CA). The difference between BA and CA (Δage) ...reflects the rate of biological aging, with lower values indicating slowed-down aging. We sought to compare the relationship of four a priori–defined dietary patterns, including a traditional Mediterranean diet (MD) and three non-Mediterranean diets, with biological aging (Δage) among Italian adults. We also examined distinctive nutritional traits of these diets as potential mediators of such associations.
Cross-sectional analysis on a sub-cohort of 4510 subjects (aged ≥35 y; 52.0% women) from the Moli-sani Study (enrolment, 2005–2010). Food intake was recorded by a 188-item semi-quantitative food-frequency questionnaire. A Mediterranean diet score (MDS) was used as exposure and compared with non-Mediterranean dietary patterns, i.e. DASH (Dietary Approaches to Stop Hypertension), Palaeolithic and the Nordic diets. A Deep Neural Network based on 36 blood biomarkers was used to compute BA and the resulting Δage (BA-CA), which was tested as outcome in multivariable linear regressions adjusted for clinical factors, lifestyles and sociodemographic factors.
In a multivariable-adjusted model, 1 standard deviation increase in the MDS was inversely associated with Δage (β = −0.23; 95%CI -0.40, −0.07), and similar findings were observed with the DASH diet (β = −0.17; 95%CI -0.33, −0.01). High dietary polyphenol content explained 29.8% (p = 0.04) and 65.8% (p = 0.02) of these associations, respectively, while other nutritional factors analysed (e.g. dietary fibre) were unlikely to be on the pathway. No significant associations were found with either the Palaeolithic or the Nordic diets.
Increasing adherence to either the traditional MD or the DASH diet was associated with delayed biological aging, possibly through their high polyphenol content.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mesial temporal lobe epilepsy (mTLE) is the most common form of epilepsy, believed to arise in part from compromised GABAergic inhibition. The neuronal specific K+/Cl− co-transporter 2 (KCC2) is a ...critical determinant of the efficacy of GABAergic inhibition and deficits in its activity are observed in mTLE patients and animal models of epilepsy. To test if reductions of KCC2 activity directly contribute to the pathophysiology of mTLE, we locally ablated KCC2 expression in a subset of principal neurons within the adult hippocampus. Deletion of KCC2 resulted in compromised GABAergic inhibition and the development of spontaneous, recurrent generalized seizures. Moreover, local ablation of KCC2 activity resulted in hippocampal sclerosis, a key pathological change seen in mTLE. Collectively, our results demonstrate that local deficits in KCC2 activity within the hippocampus are sufficient to precipitate mTLE.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Design of a multifunctional magnetic bionanosystem has become increasingly important towards advancing the future of clinical medicine. While hollow iron oxide nanoparticles with enhanced surface ...areas allow for more drug molecules to be attached to the particles, their relatively low saturation magnetization (MS) hinders their practicality in medicinal applications such as drug delivery and hyperthermia therapy. We demonstrate that this limitation can be overcome by utilizing 1D magnetic nanotubes that possess both enhanced surface areas and high MS. In this study, highly crystalline, tunable aspect ratio Fe3O4 nanotubes have been successfully synthesized using a hydrothermal method. Magnetic measurements showed a clear Verwey transition (∼120 K) and high MS (∼75 emu/g) at 300 K, confirming the high quality of the synthesized Fe3O4 nanotubes. Calorimetric experiments on randomly dispersed Fe3O4 nanotubes in water with concentration of 1 mg/mL showed a large Specific Absorption Rate (SAR) value of 400 W/g for an AC magnetic field of 800 Oe, which increased to 500 W/g when the nanotubes were aligned parallel to the DC magnetic field and suspended in a 2% agar solution. Our study shows the possibility of using the Fe3O4 nanotubes as a highly effective multifunctional nanoscale tool for targeted hyperthermia and on-demand drug delivery.
•Hydrothermal synthesis of highly crystalline, tunable aspect ratio Fe3O4 nanotubes.•Systematic study of the growth mechanism of the nanotubes.•The presence of Verwey transition and high MS (75 emu/g) at 300 K.•Nanotubes exhibited large SAR value compared to their hollow counterparts.•Dual-purpose applications in hyperthermia and on-demand drug delivery.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Extraction of chia seed oil was performed with supercritical carbon dioxide (SC-CO
2
). To investigate the effects of pressure and temperature on the oil solubility and yield, two isobaric (250 and ...450 bar) and two isothermal (40 and 60 °C) extraction conditions were selected. The global extraction yield of chia oil increased with pressure enhancement, but temperature had a little influence on it. The maximum oil recovery using SC-CO
2
at a mass flow rate of 8 kg/h was 97%, which was obtained at 60 °C, 450 bar for a 138-min extraction. The results showed that solubility changed from 4.8 g oil/kg CO
2
at 60 °C–250 bar to 28.8 g oil/kg CO
2
at 60 °C–450 bar. The final extract obtained by SC-CO
2
under different conditions and Soxhlet extraction contained mainly α-linolenic (64.9–65.6%) and linoleic (19.8–20.3%) acids. SC-CO
2
extraction is an interesting alternative methodology because it is possible to achieve a chia oil yield close to that obtained by conventional extraction with a similar fatty acid composition using an environmentally friendly process.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Methodologies for generating functional neuronal cells directly from human fibroblasts induced neuronal (iN) cells have been recently developed, but the research so far has only focused on technical ...refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies.
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