On a Low-Frequency and Contrast Stabilized Full-Wave Volume Integral Equation Solver for Lossy Media

In this article, we present a new regularized electric flux volume integral equation (D-VIE) for modeling high-contrast conductive dielectric objects in a broad frequency range. This new formulation is particularly suitable for modeling biological tissues at low frequencies, as it is required by brain epileptogenic area imaging, but also at higher ones, as it is required by several applications, including, but not limited to, deep brain stimulation (DBS). When modeling inhomogeneous objects with high complex permittivities at low frequencies, the traditional D-VIE is ill-conditioned and suffers from numerical instabilities that result in slower convergence and less accurate solutions. In this work, we address these shortcomings by leveraging a new set of volume quasi-Helmholtz projectors. Their scaling by the material permittivity matrix allows for the rebalancing of the equation when applied to inhomogeneous scatterers and, thereby, makes the proposed method accurate and stable even for high complex permittivity objects until arbitrarily low frequencies. Numerical results, canonical and realistic, corroborate the theory and confirm the stability and the accuracy of this new method both in the quasi-static regime and at higher frequencies

Coda wave attenuation tomography in Northern Morocco

In this study we focused on seismic attenuation (1/ Q) tomography in Northern Morocco. For this purpose, two different models are employed: The Single Backscattering model hypothesis of Aki and Chouet (1975) to calculate values of Coda Q (Q) and the Back-projection technique of Xie and Mitchell (1990) to estimate lateral variation in Q via a tomographic inversion. For this investigation, the Coda Q method is applied to a number of 94 local earthquakes with a magnitude between Ml=0.7 and Ml=4. The digital seismograms of these earthquakes were recorded during the year 2008 by both local temporary and permanent broadband seismic station network deployed in Northern of Morocco. The Q quality factor values have been computed at central frequencies 0.75, 1.5, 3, 6 and 12 Hz. The lapse time windows are restricted to 30s in order to sample the earth's crust only. The Q results indicate that strong frequency dependence follow a power law for the entire area. The preliminary results of seismic Coda Q attenuation tomography shows a dependence at each frequency band, between seismic attenuation and the geology structure units in the study area, especially in the region of Al Hoceima and the eastern part of the Rif which are characterized by high attenuation values due to active faults area, while low attenuation values are seen in the west and the south of the Rif in high frequencies.Peer Reviewe

Hypothalamic ERK Mediates the Anorectic and Thermogenic Sympathetic Effects of Leptin

OBJECTIVE—Leptin is an adipocyte hormone that plays a major role in energy balance. Leptin receptors in the hypothalamus are known to signal via distinct mechanisms, including signal transducer and activator of transcription-3 (STAT3) and phosphoinositol-3 kinase (PI 3-kinase). Here, we tested the hypothesis that extracellular signal–regulated kinase (ERK) is mediating leptin action in the hypothalamus

Neuronal Modulation of Brown Adipose Activity Through Perturbation of White Adipocyte Lipogenesis [preprint]

White adipose tissue (WAT) secretes factors to communicate with other metabolic organs to maintain energy homeostasis. We previously reported that perturbation of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) causes expansion of sympathetic neurons within white adipose tissue (WAT) and the appearance of beige adipocytes. Here we report evidence that white adipocyte DNL activity is also coupled to neuronal regulation and thermogenesis in brown adipose tissue (BAT). Induced deletion of FASN in all adipocytes in mature mice (iAdFASNKO) enhanced sympathetic innervation and neuronal activity as well as UCP1 expression in both WAT and BAT. In contrast, selective ablation of FASN in brown adipocytes of mice (iUCP1FASNKO) failed to modulate sympathetic innervation and the thermogenic program in BAT. Surprisingly, DNL in brown adipocytes was also dispensable in maintaining euthermia when UCP1FASNKO mice were cold-exposed. These results indicate that DNL in white adipocytes influences long distance signaling to BAT, which can modify BAT sympathetic innervation and expression of genes involved in thermogenesis

On the Fast Direct Solution of a Preconditioned Electromagnetic Integral Equation

This work presents a fast direct solver strategy for electromagnetic integral equations in the high-frequency regime. The new scheme relies on a suitably preconditioned combined field formulation and results in a single skeleton form plus identity equation. This is obtained after a regularization of the elliptic spectrum through the extraction of a suitably chosen equivalent circulant problem. The inverse of the system matrix is then obtained by leveraging the Woodbury matrix identity, the low-rank representation of the extracted part of the operator, and fast circulant algebra yielding a scheme with a favorable complexity and suitable for the solution of multiple right-hand sides. Theoretical considerations are accompanied by numerical results both of which are confirming and showing the practical relevance of the newly developed scheme

Cervix carcinoma is associated with an up-regulation and nuclear localization of the dual-specificity protein phosphatase VHR

BACKGROUND: The 21-kDa Vaccinia virus VH1-related (VHR) dual-specific protein phosphatase (encoded by the DUSP3 gene) plays a critical role in cell cycle progression and is itself regulated during the cell cycle. We have previously demonstrated using RNA interference that cells lacking VHR arrest in the G1 and G2 phases of the cell cycle and show signs of beginning of cell senescence. METHODS: In this report, we evaluated successfully the expression levels of VHR protein in 62 hysterectomy or conization specimens showing the various (pre) neoplastic cervical epithelial lesions and 35 additional cases of hysterectomy performed for non-cervical pathologies, from patients under 50 years of age. We used a tissue microarray and IHC technique to evaluate the expression of the VHR phosphatase. Immunofluorescence staining under confocal microscopy, Western blotting and RT-PCR methods were used to investigate the localization and expression levels of VHR. RESULTS: We report that VHR is upregulated in (pre) neoplastic lesions (squamous intraepithelial lesions; SILs) of the uterine cervix mainly in high grade SIL (H-SIL) compared to normal exocervix. In the invasive cancer, VHR is also highly expressed with nuclear localization in the majority of cells compared to normal tissue where VHR is always in the cytoplasm. We also report that this phosphatase is highly expressed in several cervix cancer cell lines such as HeLa, SiHa, CaSki, C33 and HT3 compared to primary keratinocytes. The immunofluorescence technique under confocal microscopy shows that VHR has a cytoplasmic localization in primary keratinocytes, while it localizes in both cytoplasm and nucleus of the cancer cell lines investigated. We report that the up-regulation of this phosphatase is mainly due to its post-translational stabilization in the cancer cell lines compared to primary keratinocytes rather than increases in the transcription of DUSP3 locus. CONCLUSION: These results together suggest that VHR can be considered as a new marker for cancer progression in cervix carcinoma and potential new target for anticancer therapy

UFMylation of MRE11 is essential for telomere length maintenance and hematopoietic stem cell survival

International audienc

Plasma and CSF concentrations of N-terminal tau fragments associate with in vivo neurofibrillary tangle burden

INTRODUCTION: Fluid biomarkers capable of specifically tracking tau tangle pathology in vivo are greatly needed. METHODS: We measured cerebrospinal fluid (CSF) and plasma concentrations of N-terminal tau fragments (NTA-tau), using a novel immunoassay (NTA) in the TRIAD cohort, consisting of 272 individuals assessed with amyloid beta (Aβ) positron emission tomography (PET), tau PET, magnetic resonance imaging (MRI) and cognitive assessments. RESULTS: CSF and plasma NTA-tau concentrations were specifically increased in cognitively impaired Aβ-positive groups. CSF and plasma NTA-tau concentrations displayed stronger correlations with tau PET than with Aβ PET and MRI, both in global uptake and at the voxel level. Regression models demonstrated that both CSF and plasma NTA-tau are preferentially associated with tau pathology. Moreover, plasma NTA-tau was associated with longitudinal tau PET accumulation across the aging and Alzheimer's disease (AD) spectrum. DISCUSSION: NTA-tau is a biomarker closely associated with in vivo tau deposition in the AD continuum and has potential as a tau tangle biomarker in clinical settings and trials. HIGHLIGHTS: An assay for detecting N-terminal tau fragments (NTA-tau) in plasma and CSF was evaluated. NTA-tau is more closely associated with tau PET than amyloid PET or neurodegeneration. NTA-tau can successfully track in vivo tau deposition across the AD continuum. Plasma NTA-tau increased over time only in cognitively impaired amyloid-β positive individuals

A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases

Cost-effective strategies for identifying amyloid-β (Aβ) positivity in patients with cognitive impairment are urgently needed with recent approvals of anti-Aβ immunotherapies for Alzheimer’s disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow can reduce the number of confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests needed while accurately classifying patients. We evaluated a two-step workflow for determining Aβ-PET status in patients with mild cognitive impairment (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE ε4 status was developed in BioFINDER-1 (area under the curve (AUC) = 89.3%) and validated in BioFINDER-2 (AUC = 94.3%). In step 1, the blood-based model was used to stratify the patients into low, intermediate or high risk of Aβ-PET positivity. In step 2, we assumed referral only of intermediate-risk patients to CSF Aβ42/Aβ40 testing, whereas step 1 alone determined Aβ-status for low- and high-risk groups. Depending on whether lenient, moderate or stringent thresholds were used in step 1, the two-step workflow overall accuracy for detecting Aβ-PET status was 88.2%, 90.5% and 92.0%, respectively, while reducing the number of necessary CSF tests by 85.9%, 72.7% and 61.2%, respectively. In secondary analyses, an adapted version of the BioFINDER-1 model led to successful validation of the two-step workflow with a different plasma p-tau217 immunoassay in patients with cognitive impairment from the TRIAD cohort (n = 84). In conclusion, using a plasma p-tau217-based model for risk stratification of patients with MCI can substantially reduce the need for confirmatory testing while accurately classifying patients, offering a cost-effective strategy to detect AD in memory clinic settings

Mass spectrometric simultaneous quantification of tau species in plasma shows differential associations with amyloid and tau pathologies

Blood phosphorylated tau (p-tau) biomarkers, at differing sites, demonstrate high accuracy to detect Alzheimerʼs disease (AD). However, knowledge on the optimal marker for disease identification across the AD continuum and the link to pathology is limited. This is partly due to heterogeneity in analytical methods. In this study, we employed an immunoprecipitation mass spectrometry method to simultaneously quantify six phosphorylated (p-tau181, p-tau199, p-tau202, p-tau205, p-tau217 and p-tau231) and two non-phosphorylated plasma tau peptides in a total of 214 participants from the Paris Lariboisière and Translational Biomarkers of Aging and Dementia cohorts. Our results indicate that p-tau217, p-tau231 and p-tau205 are the plasma tau forms that best reflect AD-related brain changes, although with distinct emergences along the disease course and correlations with AD features—amyloid and tau. These findings support the differential association of blood p-tau variants with AD pathology, and our method offers a potential tool for disease staging in clinical trials