The seismic signature of Upper‐Mantle Plumes: application to the Northern East African Rift

Several seismic and numerical studies proposed that below, some hotspots upper‐mantle plumelets rise from a thermal boundary layer below 660 km depth, fed by a deeper plume source. We recently found tomographic evidence of multiple upper‐mantle upwellings, spaced by several 100 km, rising through the transition zone below the northern East African Rift. To better test this interpretation, we run 3‐D numerical simulations of mantle convection for Newtonian and non‐Newtonian rheologies, for both thermal instabilities rising from a lower boundary layer, and the destabilization of a thermal anomaly placed at the base of the box (700–800 km depth). The thermal structures are converted to seismic velocities using a thermodynamic approach. Resolution tests are then conducted for the same P and S data distribution and inversion parameters as our traveltime tomography. The Rayleigh Taylor models predict simultaneous plumelets in different stages of evolution rising from a hot layer located below the transition zone, resulting in seismic structure that looks more complex than the simple vertical cylinders that are often anticipated. From the wide selection of models tested, we find that the destabilization of a 200 °C, 100 km thick thermal anomaly with a non‐Newtonian rheology, most closely matches the magnitude and the spatial and temporal distribution of the anomalies below the rift. Finally, we find that for reasonable upper‐mantle viscosities, the synthetic plume structures are similar in scale and shape to the actual low‐velocity anomalies, providing further support for the existence of upper‐mantle plumelets below the northern East African Rift

Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease.

The CABLES1 cell cycle regulator participates in the adrenal-pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing's disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene

Fabrication Methods for Adaptive Deformable Mirrors

Previously, it was difficult to fabricate deformable mirrors made by piezoelectric actuators. This is because numerous actuators need to be precisely assembled to control the surface shape of the mirror. Two approaches have been developed. Both approaches begin by depositing a stack of piezoelectric films and electrodes over a silicon wafer substrate. In the first approach, the silicon wafer is removed initially by plasmabased reactive ion etching (RIE), and non-plasma dry etching with xenon difluoride (XeF2). In the second approach, the actuator film stack is immersed in a liquid such as deionized water. The adhesion between the actuator film stack and the substrate is relatively weak. Simply by seeping liquid between the film and the substrate, the actuator film stack is gently released from the substrate. The deformable mirror contains multiple piezoelectric membrane layers as well as multiple electrode layers (some are patterned and some are unpatterned). At the piezolectric layer, polyvinylidene fluoride (PVDF), or its co-polymer, poly(vinylidene fluoride trifluoroethylene P(VDF-TrFE) is used. The surface of the mirror is coated with a reflective coating. The actuator film stack is fabricated on silicon, or silicon on insulator (SOI) substrate, by repeatedly spin-coating the PVDF or P(VDFTrFE) solution and patterned metal (electrode) deposition. In the first approach, the actuator film stack is prepared on SOI substrate. Then, the thick silicon (typically 500-micron thick and called handle silicon) of the SOI wafer is etched by a deep reactive ion etching process tool (SF6-based plasma etching). This deep RIE stops at the middle SiO2 layer. The middle SiO2 layer is etched by either HF-based wet etching or dry plasma etch. The thin silicon layer (generally called a device layer) of SOI is removed by XeF2 dry etch. This XeF2 etch is very gentle and extremely selective, so the released mirror membrane is not damaged. It is possible to replace SOI with silicon substrate, but this will require tighter DRIE process control as well as generally longer and less efficient XeF2 etch. In the second approach, the actuator film stack is first constructed on a silicon wafer. It helps to use a polyimide intermediate layer such as Kapton because the adhesion between the polyimide and silicon is generally weak. A mirror mount ring is attached by using adhesive. Then, the assembly is partially submerged in liquid water. The water tends to seep between the actuator film stack and silicon substrate. As a result, the actuator membrane can be gently released from the silicon substrate. The actuator membrane is very flat because it is fixed to the mirror mount prior to the release. Deformable mirrors require extremely good surface optical quality. In the technology described here, the deformable mirror is fabricated on pristine substrates such as prime-grade silicon wafers. The deformable mirror is released by selectively removing the substrate. Therefore, the released deformable mirror surface replicates the optical quality of the underlying pristine substrate

Molecular Anthropology in the genomic era

Molecular Anthropology is a relatively young field of research. In fact, less than 50 years have passed since the symposium ''Classification and Human Evolution'' ( 1962, Burg Wartenstein, Austria), where the term was formally introduced by Emil Zuckerkandl. In this time, Molecular Anthropology has developed both methodologically and theoretically and extended its applications, so covering key aspects of human evolution such as the reconstruction of the history of human populations and peopling processes, the characterization of DNA in extinct humans and the role of adaptive processes in shaping the genetic diversity of our species. In the current scientific panorama, molecular anthropologists have to face a double challenge. As members of the anthropological community, we are strongly committed to the integration of biological findings and other lines of evidence (e.g. linguistic and archaeological), while keeping in line with methodological innovations which are moving the approach from the genetic to the genomic level. In this framework, the meeting "DNA Polymorphisms in Human Populations: Molecular Anthropology in the Genomic Era" ( Rome, December 3-5, 2009) offered an opportunity for discussion among scholars from different disciplines, while paying attention to the impact of recent methodological innovations. Here we present an overview of the meeting and discuss perspectives and prospects of Molecular Anthropology in the genomic era

Entanglement and correlation functions following a local quench: a conformal field theory approach

We show that the dynamics resulting from preparing a one-dimensional quantum system in the ground state of two decoupled parts, then joined together and left to evolve unitarily with a translational invariant Hamiltonian (a local quench), can be described by means of quantum field theory. In the case when the corresponding theory is conformal, we study the evolution of the entanglement entropy for different bi-partitions of the line. We also consider the behavior of one- and two-point correlation functions. All our findings may be explained in terms of a picture, that we believe to be valid more generally, whereby quasiparticles emitted from the joining point at the initial time propagate semiclassically through the system.Comment: 19 pages, 4 figures, v2 typos corrected and refs adde

Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain

Long noncoding RNAs (lncRNAs) have been implicated in numerous cellular processes including brain development. However, the in vivo expression dynamics and molecular pathways regulated by these loci are not well understood. Here, we leveraged a cohort of 13 lncRNA-null mutant mouse models to investigate the spatiotemporal expression of lncRNAs in the developing and adult brain and the transcriptome alterations resulting from the loss of these lncRNA loci. We show that several lncRNAs are differentially expressed both in time and space, with some presenting highly restricted expression in only selected brain regions. We further demonstrate altered regulation of genes for a large variety of cellular pathways and processes upon deletion of the lncRNA loci. Finally, we found that 4 of the 13 lncRNAs significantly affect the expression of several neighboring protein-coding genes in a cis-like manner. By providing insight into the endogenous expression patterns and the transcriptional perturbations caused by deletion of the lncRNA locus in the developing and postnatal mammalian brain, these data provide a resource to facilitate future examination of the specific functional relevance of these genes in neural development, brain function, and disease.National Science Foundation (U.S.) (Postdoctoral Research Fellowship in Biology DBI-0905973

A randomized, phase II study of sequential belimumab and rituximab in primary Sjögren's syndrome

BACKGROUND: Primary Sjögren’s syndrome (pSS) is characterized by B cell hyperactivity and elevated B-lymphocyte stimulator (BLyS). Anti-BLyS treatment (e.g., belimumab) increases peripheral memory B cells; decreases naive, activated, and plasma B cell subsets; and increases stringency on B cell selection during reconstitution. Anti-CD20 therapeutics (e.g., rituximab) bind and deplete CD20-expressing B cells in circulation but are less effective in depleting tissue-resident CD20(+) B cells. Combined, these 2 mechanisms may achieve synergistic effects. METHODS: This 68-week, phase II, double-blind study (GSK study 201842) randomized 86 adult patients with active pSS to 1 of 4 arms: placebo, s.c. belimumab, i.v. rituximab, or sequential belimumab + rituximab. RESULTS: Overall, 60 patients completed treatment and follow-up until week 68. The incidence of adverse events (AEs) and drug-related AEs was similar across groups. Infections/infestations were the most common AEs, and no serious infections of special interest occurred. Near-complete depletion of minor salivary gland CD20(+) B cells and a greater and more sustained depletion of peripheral CD19(+) B cells were observed with belimumab + rituximab versus monotherapies. With belimumab + rituximab, reconstitution of peripheral B cells occurred, but it was delayed compared with rituximab. At week 68, mean (± standard error) total EULAR Sjögren’s syndrome disease activity index scores decreased from 11.0 (1.17) at baseline to 5.0 (1.27) for belimumab + rituximab and 10.4 (1.36) to 8.6 (1.57) for placebo. CONCLUSION: The safety profile of belimumab + rituximab in pSS was consistent with the monotherapies. Belimumab + rituximab induced enhanced salivary gland B cell depletion relative to the monotherapies, potentially leading to improved clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02631538. FUNDING: Funding was provided by GSK

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD

Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1).

OBJECTIVE: To extend the phenotypic description of Charcot-Marie-Tooth disease (CMTX1) and to draw new genotype-phenotype relationships. METHODS: Mutations in GJB1 cause the main X-linked form of CMTX (CMTX1). We report cross-sectional data from 160 patients (from 120 different families, with 89 different mutations) seen at the Inherited Neuropathies Consortium centers. RESULTS: We evaluated 87 males who had a mean age of 41 years (range 10-78 years) and 73 females who had a mean age of 46 years (range 15-84 years). Sensory-motor polyneuropathy affects both sexes, more severely in males than in females, and there was a strong correlation between age and disease burden in males but not in females. Compared with females, males had more severe reduction in motor and sensory neurophysiology parameters. In contrast to females, the radial nerve sensory response in older males tended to be more severely affected compared with younger males. Median and ulnar nerve motor amplitudes were also more severely affected in older males, whereas ulnar nerve motor potentials tended to be more affected in older females. Conversely, there were no statistical differences between the sexes in other features of the disease, such as problems with balance and hand dexterity. CONCLUSIONS: In the absence of a phenotypic correlation with specific GJB1 mutations, sex-specific distinctions and clinically relevant attributes need to be incorporated into the measurements for clinical trials in people with CMTX1. CLINICALTRIALSGOV IDENTIFIER: NCT01193075