Magnetic Ground States of the Rare-Earth Tripod Kagome Lattice Mg_{2}RE_{3}Sb_{3}O_{14} (RE=Gd,Dy,Er).

We present the structural and magnetic properties of a new compound family, Mg_{2}RE_{3}Sb_{3}O_{14} (RE=Gd,Dy,Er), with a hitherto unstudied frustrating lattice, the "tripod kagome" structure. Susceptibility (ac, dc) and specific heat exhibit features that are understood within a simple Luttinger-Tisza-type theory. For RE=Gd, we found long-ranged order (LRO) at 1.65 K, which is consistent with a 120° structure, demonstrating the importance of diople interactions for this 2D Heisenberg system. For RE=Dy, LRO at 0.37 K is related to the "kagome spin ice" physics for a 2D system. This result shows that the tripod kagome structure accelerates the transition to LRO predicted for the related pyrochlore systems. For RE=Er, two transitions, at 80 mK and 2.1 K are observed, suggesting the importance of quantum fluctuations for this putative XY system.

Detecting somatic mosaicism: considerations and clinical implications.

Human disease is rarely a matter of all or nothing; variable expressivity is generally observed. Part of this variability is explained by somatic mosaicism, which can arise by a myriad of genetic alterations. These can take place at any stage of development, possibly leading to unusual features visible at birth, but can also occur later in life, conceivably leading to cancer. Previously, detection of somatic mosaicism was extremely challenging, as many gold standard tests lacked the necessary resolution. However, with the advances in high-throughput sequencing, mosaicism is being detected more frequently and at lower levels. This raises the issue of normal variation within each individual vs mosaicism leading to disease, and how to distinguish between the two. In this article, we will define somatic mosaicism with a brief overview of its main mechanisms in concrete clinical examples, discuss the impact of next-generation sequencing technologies in its detection, and expand on the clinical implications associated with a discovery of somatic mosaicism in the clinic.

Impact of systematic dynamic maneuvers during computed tomography scan on the T classification of head and neck cancers.

OBJECTIVES: To evaluate the impact of systematic dynamic maneuvers during CT scan on the T-staging of head and neck cancer (HNC). MATERIALS AND METHODS: CT scans from the initial workup of 443 consecutive patients treated for HNC in our institution were retrospectively analyzed. CT scans were performed in both expert centers (comprehensive cancer center and university hospital) and non-expert centers. We noted whether dynamic maneuvers (DM) were performed, in 3 categories, namely: DM not done (DMND), done and inadequate (DMDI), done and adequate (DMDA). In the group with DMDA, T-stage was evaluated without and with DM. Interobserver agreement for T staging was assessed after independent double reading of CT scans with and without DM by two radiologists in a random sample. RESULTS: Among the 443 CT scans, DMND was observed in 36.3%, DMDI in 9.3% and DMDA in 54.4%. DMDA were significantly more frequent in expert than in non-expert centers (93.4 vs 6.6%, p < 0.001). In CT scans with DMDA, analysis of the 141 scans rated as T1, T2, T3, or T4 without DM showed agreement of 88.7% with scans with DM, corresponding to a reclassification rate of 11.3% (kappa = 0.85, 95%CI [0.78;0.92]). Among lesions initially classed as Tx without DM (N = 100), the reclassification rate was 76% including DM. CONCLUSION: The performance of systematic DM integrated into CT protocols is useful to reclassify the T stage in HNC and is essential in case of lesions initially classified as Tx without DM. DM should be performed routinely in expert and nonexpert centers.

Evidence for undoped Weyl semimetal charge transport in Y2Ir2O7.

Weyl fermions scattering from a random Coulomb potential are predicted to exhibit resistivity versus temperature [Formula: see text] in a single particle model. Here we show that, in closed-environment-grown polycrystalline samples of Y2Ir2O7, [Formula: see text] over four orders of magnitude in [Formula: see text]. While the measured prefactor, [Formula: see text], is obtained from the model using reasonable materials parameters, the [Formula: see text] behavior extends far beyond the model's range of applicability. In particular, the behavior extends into the low-temperature, high-resistivity region where the Ioffe-Regel parameter, [Formula: see text]. Strong on-site Coulomb correlations, instrumental for predicting a Weyl semimetal state in Y2Ir2O7, are the possible origin of such 'bad' Weyl semimetal behavior.

Imaging appearance and prevalence of the anteromedial meniscofemoral ligament: A potential pitfall to anterior cruciate ligament analysis on MRI.

PURPOSE: To describe the aspect of the anteromedial meniscofemoral ligament on MRI and to assess its prevalence. METHOD: One thousand five hundred sixty knee MRI studies were retrospectively evaluated for the presence of an anteromedial meniscofemoral ligament. In addition to these studies, nine full MRI studies from our department's image archive were also analysed. The anteromedial meniscofemoral ligament length, thickness, and angle with respect to the tibial plateau were evaluated independently by two radiologists. For comparison purposes, the anterior cruciate ligament was assessed in the same manner. RESULTS: There was a 0.77% prevalence of the anteromedial meniscofemoral ligament in the study population. Compared to the anterior cruciate ligament, the anteromedial meniscofemoral ligament was 80.6%-83.8% thinner according to both observers (P =  0.0002), with a mean thickness of 1.53 ±â€¯0.47 mm and 1.80 ±â€¯0.66 mm determined by observers 1 and 2, respectively. The anteromedial meniscofemoral ligament angles were 15%-17.7% lower than the anterior cruciate ligament angles (P <  0.003). Interobserver reproducibility was considered excellent for the length and angle measurements (ICCs varying from 0.85-0.97) and good for the thickness measurements (ICCs 0.66-0.77). CONCLUSIONS: The anteromedial meniscofemoral ligament is a rare structure that can be differentiated from the anterior cruciate ligament based on morphologic criteria.

Multiple signals regulate GAL transcription in yeast.

Gal4p activates transcription of the Saccharomyces GAL genes in response to galactose and is phosphorylated during interaction with the RNA polymerase II (Pol II) holoenzyme. One phosphorylation at S699 is necessary for full GAL induction and is mediated by Srb10p/CDK8 of the RNA Pol II holoenzyme mediator subcomplex. Gal4p S699 phosphorylation is necessary for sensitive response to inducer, and its requirement for GAL induction can be abrogated by high concentrations of galactose in strains expressing wild-type GAL2 and GAL3. Gal4p S699 phosphorylation occurs independently of Gal3p and is responsible for the long-term adaptation response observed in gal3 yeast. SRB10 and GAL3 are shown to represent parallel mechanisms for GAL gene induction. These results demonstrate that Gal4p activity is controlled by two independent signals: one that acts through Gal3p-galactose and a second that is mediated by the holoenzyme-associated cyclin-dependent kinase Srb10p. Since Srb10p is regulated independently of galactose, our results suggest a function for CDK8 in coordinating responses to specific inducers with the environment through the phosphorylation of gene-specific activators.

RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist.

The 5-HT2C receptor is one of three closely related receptor subtypes in the 5-HT2 receptor family. 5-HT2A and 5-HT2B selective antagonists have been described. However, no 5-HT2C selective antagonists have yet been disclosed. As part of an effort to further explore the function of 5-HT2C receptors, we have developed a selective 5-HT2C receptor antagonist, RS-102221 (a benzenesulfonamide of 8-[5-(5-amino-2,4-dimethoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione). This compound exhibited nanomolar affinity for human (pKi = 8.4) and rat (pKi = 8.5) 5-HT2C receptors. The compound also demonstrated nearly 100-fold selectivity for the 5-HT2C receptor as compared to the 5-HT2A and 5-HT2B receptors. RS-102221 acted as an antagonist in a cell-based microphysiometry functional assay (pA2 = 8.1) and had no detectable intrinsic efficacy. Consistent with its action as a 5-HT2C receptor antagonist, daily dosing with RS-102221 (2 mg/kg intraperitoneal) increased food-intake and weight-gain in rats. Surprisingly, RS-102221 failed to reverse the hypolocomotion induced by the 5-HT2 receptor agonist 1-(3-chlorophenyl)piperazine (m-CPP). It is concluded that RS-102221 is the first selective, high affinity 5-HT2C receptor antagonist to be described.

Differential psychostimulant-induced activation of neural circuits in dopamine transporter knockout and wild type mice.

Dopamine (DA) is a neurotransmitter that has been implicated in a wide variety of psychiatric disorders that include attention deficit-hyperactivity disorder (ADHD), schizophrenia, and drug abuse. Recently, we have been working with a mouse in which the gene for the DA transporter (DAT) has been disrupted. This mouse is hyperactive in the open field, displays an inability to inhibit ongoing behaviors, and is deficient on learning and memory tasks. Psychostimulants such as amphetamine and methylphenidate attenuate the hyperlocomotion of the mutants, but stimulate activity of the wild type (WT) controls. The objective of the present study is to examine the neural basis for the differential responses to psychostimulants in these mice. WT and DAT knockout (KO) animals were given vehicle or methylphenidate, amphetamine, or cocaine and brain sections were immunostained for Fos. In WT mice, methylphenidate induced Fos-like immunoreactivity (Fos-LI) in the mesostriatal and mesolimbocortical DA pathways that included the anterior olfactory nucleus, frontal association cortex, orbitofrontal cortex, cingulate cortex, caudate-putamen, globus pallidus, claustrum, lateral septum, nucleus accumbens, basolateral and central nuclei of the amygdala, bed nucleus of stria terminalis, subthalamic nucleus, substantia nigra, ventral tegmental area, and dorsal raphe. Additional areas of activation included the granular dentate gyrus, Edinger-Westphal nucleus, and periaqueductal gray. While the mutants showed little response in most of these same areas, the anterior olfactory nucleus, caudal caudate-putamen, lateral septum, basolateral and central nuclei of the amygdala, and bed nucleus of stria terminalis were activated. Amphetamine and cocaine produced similar changes to that for methylphenidate, except these psychostimulants also induced Fos-LI in the nucleus accumbens of the KO animals. Since the DAT gene is disrupted in the KO mouse, these findings suggest that dopaminergic mechanisms may mediate the WT responses, whereas non-dopaminergic systems predominate in the mutant. In the mutants, it appears that limbic areas and non-dopaminergic transmitter systems within these brain regions may mediate responses to psychostimulants. Inasmuch as the KO mouse may represent a useful animal model for ADHD and because psychostimulants such as cocaine are reinforcing to these animals, our results may provide some useful insights into the neural mechanisms-other than DA-that may contribute to the symptoms of ADHD and/or drug abuse in human patients.

Structure and function of the ovine type 1 corticotropin releasing factor receptor (CRF1) and a carboxyl-terminal variant.

Corticotropin releasing factor (CRF) is the major neuropeptide regulating the hypothalamo-pituitary-adrenocortical axis in most species. A pituitary receptor for CRF (designated CRF1) belonging to the seven-transmembrane helix, G-protein-coupled receptor superfamily has been cloned for human, rat, mouse and xenopus. Since ovine CRF shares only 84% identity to human/rat CRF (h/rCRF) we postulated that the sheep pituitary CRF1 receptor may have similarly diverged from the rodent and human CRF1. We report the molecular cloning of an ovine pituitary cDNA containing a 1245 bp open reading frame encoding a 415 amino acid sheep CRF1 receptor 78, 86, 94, and 95% homologous to xenopus, chicken, rat, mouse, and human CRF1, respectively. The divergence in primary structure between the sheep CRF1 and the other mammalian CRF1s is primarily localized to the extracellular amino terminal domain of the receptor (18 of 22 divergent residues, ovine vs human CRF1). A variant of the oCRF1 was also isolated (oCRF1var) with 133 bp deleted from nucleotide (nt) 1080 to nt 1213 of the open reading frame (ORF) resulting in a new ORF of 1176 nt predicting a 392 residue CRF1 variant receptor. The 133 bp deletion would cause a frame-shift at residue 358 within the carboxyl-third of the seventh transmembrane domain (TM7) resulting in a shortened cytoplasmic tail with a new amino acid sequence from residue 358 to 392. Scatchard analysis of saturation curves using membrane prepared from Cos 7 cells transfected with oCRF1 or oCRF1var indicated that both wild-type and variant receptors were expressed similarly (number of CRF binding sites) and both bound oCRF with high affinity [oCRF1 (Kd): 2.5 + 1.6 nM; oCRF1var: 5.1 + 2.3 nM]. The non-hydrolyzable GTP analogue (GTPgammaS) lowered the affinity of both wild-type and variant oCRF1 receptors to a similar extent (oCRF1: 18.2 nM; oCRF1var: 22.4 nM). Both wild-type and variant oCRF1 receptors exhibited approximately 10-fold greater selectivity for oCRF and sauvagine compared to h/rCRF or alpha-helical [9-41]oCRF. CRF effectively stimulated the accumulation of cAMP (EC50 = 51 pM) in Cos 7 cells transiently transfected with wild-type but not variant oCRF1 receptor. In Cos 7 cells transfected with oCRF1var, cAMP accumulation was only observed at the highest concentration of oCRF utilized (100 nM). Basal (unstimulated) levels of cAMP in Cos 7 cells transfected with oCRF1var (in the presence of 2 mM IBMX) were approximately 50% lower than for the wild-type oCRF1. Differences in cAMP accumulation could not be attributed to differences in receptor number since total binding sites in the transfected cells were not different between wild-type or variant oCRF1 receptors. Agonist-induced receptor internalization, determined as the percent of total [125I] Tyr0-oCRF bound located in the acid-resistant fraction of transfected Cos 7 cells, increased with time (0-60 min at 37 degrees C) for both wild-type and variant oCRF1. Wild-type CRF1 internalized approximately 2-fold greater percent of total [125I] Tyr0-oCRF bound compared to the variant receptor. In summary, an ovine CRF1 and a CRF1 cytoplasmic tail receptor variant displaying high affinity binding to oCRF as well as selectivity for oCRF vs h/rCRF, were cloned from an adult sheep pituitary cDNA library. GTPgammaS studies indicate that both variant and wild-type receptors couple efficiently to Galphas however, only the wild-type oCRF1 is capable of stimulating cAMP production at physiological levels of CRF. Agonist-induced internalization of the ovine CRF1var is also reduced compared to the wild-type CRF1 receptor. We suggest that the oCRF1var interacts efficiently with Galphas but is unable (post-hormonal binding) to effectively stimulate G-protein activation of adenylate cyclase, indicating that the cytoplasmic tail of the CRF1 can modulate receptor function related to signal transduction. (ABSTRACT TRUNCATED)