Training-induced criticality in martensites

We propose an explanation for the self-organization towards criticality observed in martensites during the cyclic process known as `training'. The scale-free behavior originates from the interplay between the reversible phase transformation and the concurrent activity of lattice defects. The basis of the model is a continuous dynamical system on a rugged energy landscape, which in the quasi-static limit reduces to a sandpile automaton. We reproduce all the principal observations in thermally driven martensites, including power-law statistics, hysteresis shakedown, asymmetric signal shapes, and correlated disorder.Comment: 5 pages, 4 figure

Social cognition in multiple sclerosis: a 3-year follow-up {MRI} and behavioral study

Social cognition (SC) has become a topic of widespread interest in the last decade. SC deficits were described in multiple sclerosis (MS) patients, in association with amygdala lesions, even in those without formal cognitive impairment. In this 3-year follow-up study, we aimed at longitudinally investigating the evolution of SC deficits and amygdala damage in a group of cognitive-normal MS patients, and the association between SC and psychological well-being. After 3 years (T3) from the baseline examination (T0), 26 relapsing-remitting MS patients (RRMS) were retested with a neuropsychological battery and SC tasks (theory of mind, facial emotion recognition, empathy). A SC composite score (SCcomp) was calculated for each patient. Emotional state, fatigue, and quality of life (QoL) were also evaluated. RRMS patients at T3 underwent a 3T-MRI as performed at T0, from which were calculated both volume and cortical lesion volume (CLV) of the amygdalae. Compared to T0, at T3 all RRMS patients were still cognitive-normal and remained stable in their global SC impaired performance. At T0, SCcomp correlated with amygdala CLV (p = 0.002) while, at T3, was more associated with amygdala volume (p = 0.035) rather than amygdala CLV (p = 0.043). SCcomp change T3-T0 correlated with global emotional state (p = 0.043), depression (p = 0.046), anxiety (p = 0.034), fatigue (p = 0.025), and QoL-social functioning (p = 0.033). We showed the longitudinal stability of SC deficits in cognitive-normal RRMS patients, mirroring the amygdala structural damage and the psychological well-being. These results highlight that SC exerts a key role in M

Homogenization in magnetic-shape-memory polymer composites

Magnetic-shape-memory materials (e.g. specific NiMnGa alloys) react with a large change of shape to the presence of an external magnetic field. As an alternative for the difficult to manifacture single crystal of these alloys we study composite materials in which small magnetic-shape-memory particles are embedded in a polymer matrix. The macroscopic properties of the composite depend strongly on the geometry of the microstructure and on the characteristics of the particles and the polymer. We present a variational model based on micromagnetism and elasticity, and derive via homogenization an effective macroscopic model under the assumption that the microstructure is periodic. We then study numerically the resulting cell problem, and discuss the effect of the microstructure on the macroscopic material behavior. Our results may be used to optimize the shape of the particles and the microstructure.Comment: 17 pages, 4 figure

Heterogeneity of Cortical Lesion Susceptibility Mapping in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Quantitative susceptibility mapping has been used to characterize iron and myelin content in the deep gray matter of patients with multiple sclerosis. Our aim was to characterize the susceptibility mapping of cortical lesions in patients with MS and compare it with neuropathologic observations. MATERIALS AND METHODS: The pattern of microglial activation was studied in postmortem brain tissues from 16 patients with secondary-progressive MS and 5 age-matched controls. Thirty-six patients with MS underwent 3T MR imaging, including 3D double inversion recovery and 3D-echo-planar SWI. RESULTS: Neuropathologic analysis revealed the presence of an intense band of microglia activation close to the pial membrane in subpial cortical lesions or to the WM border of leukocortical cortical lesions. The quantitative susceptibility mapping analysis revealed 131 cortical lesions classified as hyperintense; 33, as isointense; and 84, as hypointense. Quantitative susceptibility mapping hyperintensity edge found in the proximity of the pial surface or at the white matter/gray matter interface in some of the quantitative susceptibility mapping–hyperintense cortical lesions accurately mirrors the microglia activation observed in the neuropathology analysis. CONCLUSIONS: Cortical lesion susceptibility maps are highly heterogeneous, even at individual levels. Quantitative susceptibility mapping hyperintensity edge found in proximity to the pial surface might be due to the subpial gradient of microglial activation

CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis

INTRODUCTION AND METHODS: In order to verify whether parvalbumin (PVALB), a protein specifically expressed by GABAergic interneurons, could be a MS-specific marker of grey matter neurodegeneration, we performed neuropathology/molecular analysis of PVALB expression in motor cortex of 40 post-mortem progressive MS cases, with/without meningeal inflammation, and 10 control cases, in combination with cerebrospinal fluid (CSF) assessment. Analysis of CSF PVALB and neurofilaments (Nf-L) levels combined with physical/cognitive/3TMRI assessment was performed in 110 naïve MS patients and in 32 controls at time of diagnosis. RESULTS: PVALB gene expression was downregulated in MS (fold change = 3.7 ± 1.2, P < 0.001 compared to controls) reflecting the significant reduction of PVALB+ cell density in cortical lesions, to a greater extent in MS patients with high meningeal inflammation (51.8, P < 0.001). Likewise, post-mortem CSF-PVALB levels were higher in MS compared to controls (fold change = 196 ± 36, P < 0.001) and correlated with decreased PVALB+ cell density (r = -0.64, P < 0.001) and increased MHC-II+ microglia density (r = 0.74, P < 0.01), as well as with early age of onset (r = -0.69, P < 0.05), shorter time to wheelchair (r = -0.49, P < 0.05) and early age of death (r = -0.65, P < 0.01). Increased CSF-PVALB levels were detected in MS patients at diagnosis compared to controls (P = 0.002). Significant correlation was found between CSF-PVALB levels and cortical lesion number on MRI (R = 0.28, P = 0.006) and global cortical thickness (R = -0.46, P < 0.001), better than Nf-L levels. CSF-PVALB levels increased in MS patients with severe cognitive impairment (mean ± SEM:25.2 ± 7.5 ng/mL) compared to both cognitively normal (10.9 ± 2.4, P = 0.049) and mild cognitive impaired (10.1 ± 2.9, P = 0.024) patients. CONCLUSIONS: CSF-PVALB levels reflect loss of cortical interneurons in MS patients with more severe disease course and might represent an early, new MS-specific biomarker of cortical neurodegeneration, atrophy, and cognitive decline

A Mouse to Human Search for Plasma Proteome Changes Associated with Pancreatic Tumor Development

Background: The complexity and heterogeneity of the human plasma proteome have presented significant challenges in the identification of protein changes associated with tumor development. Refined genetically engineered mouse (GEM) models of human cancer have been shown to faithfully recapitulate the molecular, biological, and clinical features of human disease. Here, we sought to exploit the merits of a well-characterized GEM model of pancreatic cancer to determine whether proteomics technologies allow identification of protein changes associated with tumor development and whether such changes are relevant to human pancreatic cancer. Methods and Findings: Plasma was sampled from mice at early and advanced stages of tumor development and from matched controls. Using a proteomic approach based on extensive protein fractionation, we confidently identified 1,442 proteins that were distributed across seven orders of magnitude of abundance in plasma. Analysis of proteins chosen on the basis of increased levels in plasma from tumor-bearing mice and corroborating protein or RNA expression in tissue documented concordance in the blood from 30 newly diagnosed patients with pancreatic cancer relative to 30 control specimens. A panel of five proteins selected on the basis of their increased level at an early stage of tumor development in the mouse was tested in a blinded study in 26 humans from the CARET (Carotene and Retinol Efficacy Trial) cohort. The panel discriminated pancreatic cancer cases from matched controls in blood specimens obtained between 7 and 13 mo prior to the development of symptoms and clinical diagnosis of pancreatic cancer. Conclusions: Our findings indicate that GEM models of cancer, in combination with in-depth proteomic analysis, provide a useful strategy to identify candidate markers applicable to human cancer with potential utility for early detection

Inflammatory intrathecal profiles and cortical damage in multiple sclerosis

OBJECTIVE: Grey matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in Multiple Sclerosis (MS), but can these changes be identified in the patient early in the disease course? METHODS: To identify possible biomarkers linking meningeal inflammation, GM damage and disease severity, gene and protein expression were analysed in meninges and CSF from 27 post-mortem secondary progressive MS (SPMS) and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T-MRI were performed at diagnosis in two independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. RESULTS: Increased expression of pro-inflammatory cytokines (IFNγ, TNF, IL2 and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, IL10) was detected in the meninges and CSF of post-mortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar pro-inflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8 and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2 and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. INTERPRETATION: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at time of the diagnosis and of death. These results suggest a role for detailed CSF analysis combined with MRI, as a prognostic marker for more aggressive MS. This article is protected by copyright. All rights reserved

ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression

Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3FAX-Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics