Vascular contributions to dementia and Alzheimer's disease are increasingly recognized
. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human ...cognitive dysfunction
, including the early clinical stages of Alzheimer's disease
. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease
, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes
, which maintain BBB integrity
. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography
. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ
in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway
in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.
Data-Driven Finite Elasticity Conti, S.; Müller, S.; Ortiz, M.
Archive for rational mechanics and analysis,
07/2020, Letnik:
237, Številka:
1
Journal Article
Recenzirano
We extend to finite elasticity the Data-Driven formulation of geometrically linear elasticity presented in Conti et al. (Arch Ration Mech Anal 229:79–123, 2018). The main focus of this paper concerns ...the formulation of a suitable framework in which the Data-Driven problem of finite elasticity is well-posed in the sense of existence of solutions. We confine attention to deformation gradients
F
∈
L
p
(
Ω
;
R
n
×
n
)
and first Piola-Kirchhoff stresses
P
∈
L
q
(
Ω
;
R
n
×
n
)
, with
(
p
,
q
)
∈
(
1
,
∞
)
and
1
/
p
+
1
/
q
=
1
. We assume that the material behavior is described by means of a material data set containing all the states (
F
,
P
) that can be attained by the material, and develop germane notions of coercivity and closedness of the material data set. Within this framework, we put forth conditions ensuring the existence of solutions. We exhibit specific examples of two- and three-dimensional material data sets that fit the present setting and are compatible with material frame indifference.
Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of ...established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.
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•FMD rejuvenates the immune system and reduces cancer incidence in C57BL/6 mice•FMD promotes hippocampal neurogenesis and improves cognitive performance in mice•FMD causes beneficial changes in risk factors of age-related diseases in humans
Brandhorst et al. develop a fasting mimicking diet (FMD) protocol, which retains the health benefits of prolonged fasting. In mice, FMD improved metabolism and cognitive function, decreased bone loss and cancer incidence, and extended longevity. In humans, three monthly cycles of a 5-day FMD reduced multiple risk factors of aging
This paper presents an optimization procedure that enables the optimal dispatching of distributed generators and storage systems in a medium-voltage islanded microgrid. The network is assumed to be ...supplied by programmable (dispatchable) and nonprogrammable generators (i.e. nondispatchable, such as renewable energy sources-based units). The optimization goal is to minimize the overall microgrid operating cost and the pollutants emission of the programmable generators, assuming that all of the power made available by the renewable generators (photovoltaic and wind systems) is either directly injected into the network or stored in order to be subsequently delivered according to the proposed storage units' management strategy. The optimization is carried out by a niching evolutionary algorithm (NEA) that is able to find multiple optima and the variation of the objective function in their neighborhood. NEAs allow overcoming the performance of standard algorithms used for optimal power-flow calculations in power systems by avoiding falling into local optima. The optimization procedure is performed on a test microgrid and verified by computer simulations. The numerical results show that the solutions can always improve the microgrid performances irrespective of the network operating conditions in all of the considered cases.
Connections of distributed generation (DG) systems to distribution networks are increasing in number, though they may often be associated with the need of costly grid reinforcements or new control ...issues to maintain optimal operation. Appropriate analysis tools are required to check distribution networks operating conditions in the evolving scenario. Load flow (LF) calculations are typically needed to assess the allowed DG penetration level for a given network in order to ensure, for example, that voltage and current limits are not exceeded.
The present paper deals with the solution of the LF problem in distribution networks with photovoltaic (PV) DG. Suitable models for prediction of the active power produced by PV DG units and the power absorbed by the loads are to be used to represent the uncertainty of solar energy availability and loads variation. The proposed models have been incorporated in a radial distribution probabilistic load flow (PLF) program that has been developed by using Monte Carlo techniques. The developed program allows probabilistic predictions of power flows at the various sections of distribution feeders and voltage profiles at all nodes of a network.
After presenting theoretical concepts and software implementation, a practical case is also discussed to show the application of the study in order to assess the maximum PV peak power that can be installed into a distribution network without violating voltage and current constraints. A comparison between Deterministic Load Flow (DLF) and PLF analyses is also performed.
The 87Sr/86Sr, REE and MoU systematics were investigated in Miocene seep carbonates formed on accretionary ridges at the front of the northern Apennine wedge. Here we evaluate fluid sources, seepage ...intensity and redox conditions during carbonate precipitation. Micrite matrix and early calcite cements lining cavities are the main authigenic carbonate phases and show negligible diagenetic alteration. Their AOM-related (anaerobic oxidation of methane) origin is evident from δ13C values ranging from −38.7‰ to −25.7‰. The 87Sr/86Sr ratios in carbonates vary between 0.708659 and 0.709132. Most micrite values fall within the range of Middle Miocene seawater (Langhian, MNN5a biozone), in agreement with the biostratigraphy of the host sediments, thus reflecting precipitation of seep carbonates close to the seafloor. Highly radiogenic 87Sr/86Sr ratios, of early calcite cements and micrite from conduit-rich facies at the base of carbonate bodies, likely derived from the interaction of fluids with detrital clays during the fault-controlled upward migration through the underlying terrigenous turbidite successions. Strong Mo and U enrichments in carbonates, with MoEF and UEF up to 233.5 and 86.6 respectively, coupled with (Mo/U)EF ratios ranging between 0.7 and 9.7, indicate dynamic redox conditions, episodically sulfidic and restricted to porewaters. This interpretation is also supported by enrichments in MREE of micrites and a general absence of negative Ce anomalies. These new data provide an indirect indication of rates and temporal variability of AOM at fossil methane seeps developed on a thrust related anticline and help to constrain the complex interaction between fluid migration pathways, seepage intensity and environmental conditions as observed in modern seep analogues.
•The Corella seep carbonates (northern Apennines) precipitated in equilibrium with Langhian seawater close to the seafloor.•Sr isotope analysis revealed the contribution of a deep fluid source marked by a strongly radiogenic 87Sr/86Sr composition.•A blind fault in the underlying turbidite successions acted as a pathway for CH4-rich fluids migration toward the seafloor.•Mo and U systematics indicate highly dynamic suboxic conditions, episodically sulfidic and restricted to porewater.•Our data confirm the utility of trace metals for paleoenvironmental reconstructions at cold seeps.
Keen interest in the development and utilization of renewable distributed generation (DG) has been currently observed worldwide. The reliability impact of this highly variable energy source is an ...important aspect that needs to be assessed as renewable power penetration becomes increasingly significant. Distribution system adequacy assessment including wind-based and solar DG units during different modes of operation is described in this paper. Monte Carlo simulation (MCS) and analytical technique are used in this work with a novel utilization of the clearness index probability density function (pdf) to model the solar irradiance using MCS. The results show that there is no significant difference between the outcomes of the two proposed techniques; however, MCS requires much longer computational time. The effect of islanding appears in the improvement of the loss of load expectation (LOLE) and loss of energy expectation (LOEE).
Glioma, including anaplastic astrocytoma and glioblastoma multiforme (GBM) are among the most commonly diagnosed malignant adult brain tumors. GBM is a highly invasive and angiogenic tumor, resulting ...in a 12 to 15 months median survival. The treatment of GBM is multimodal and includes surgical resection, followed by adjuvant radio-and chemotherapy. We have previously reported that short-term starvation (STS) enhances the therapeutic index of chemo-treatments by differentially protecting normal cells against and/or sensitizing tumor cells to chemotoxicity.
To test the effect of starvation on glioma cells in vitro, we treated primary mouse glia, murine GL26, rat C6 and human U251, LN229 and A172 glioma cells with Temozolomide in ad lib and STS mimicking conditions. In vivo, mice with subcutaneous or intracranial models of GL26 glioma were starved for 48 hours prior to radio- or chemotherapy and the effects on tumor progression and survival were measured. Starvation-mimicking conditions sensitized murine, rat and human glioma cells, but not primary mixed glia, to chemotherapy. In vivo, starvation for 48 hours, which causes a significant reduction in blood glucose and circulating insulin-like growth factor 1 (IGF-1) levels, sensitized both subcutaneous and intracranial glioma models to radio-and chemotherapy.
Starvation-induced cancer sensitization to radio- or chemotherapy leads to extended survival in the in vivo glioma models tested. These results indicate that fasting and fasting-mimicking interventions could enhance the efficacy of existing cancer treatments against aggressive glioma in patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We consider a partial differential inclusion problem which models stress-free martensitic inclusions in an austenitic matrix, based on the standard geometrically nonlinear elasticity theory. We show ...that for specific parameter choices there exist piecewise affine continuous solutions for the square-to-oblique and the hexagonal-to-oblique phase transitions. This suggests that for specific crystallographic parameters the hysteresis of the phase transformation will be particularly small.
We develop a critical-state model of fused silica plasticity on the basis of data mined from molecular dynamics (MD) calculations. The MD data is suggestive of an irreversible densification ...transition in volumetric compression resulting in permanent, or plastic, densification upon unloading. The MD data also reveals an evolution towards a critical state of constant volume under pressure-shear deformation. The trend towards constant volume is from above, when the glass is overconsolidated, or from below, when it is underconsolidated. We show that these characteristic behaviors are well-captured by a critical state model of plasticity, where the densification law for glass takes the place of the classical consolidation law of granular media and the locus of constant-volume states defines the critical-state line. A salient feature of the critical-state line of fused silica, as identified from the MD data, that renders its yield behavior anomalous is that it is strongly non-convex, owing to the existence of two well-differentiated phases at low and high pressures. We argue that this strong non-convexity of yield explains the patterning that is observed in molecular dynamics calculations of amorphous solids deforming in shear. We employ an explicit and exact rank-2 envelope construction to upscale the microscopic critical-state model to the macroscale. Remarkably, owing to the equilibrium constraint the resulting effective macroscopic behavior is still characterized by a non-convex critical-state line. Despite this lack of convexity, the effective macroscopic model is stable against microstructure formation and defines well-posed boundary-value problems.
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