Mesowear Analysis of the Tapirus Pplkensis Population From the Gray Fossil Site, Tennessee, USA

Various methods exist for measuring and analyzing dental wear patterns in mam-mals, and these patterns have been extensively studied in ungulates. Mesowear has proven useful as a method to compare large numbers of individuals, particularly fossil individuals, observe trends through time or between groups, and estimate paleoenvi-ronmental conditions. Levels of attrition (tooth-on-tooth wear) and abrasion (tooth-on-food wear) can be readily compared by observing the shape of the cusp and relative crown height of the tooth. This study uses a modified method of mesowear analysis, examining actual cusp angles of the population of Tapirus polkensis from the Gray Fossil Site, a densely canopied, hickory and oak dominated forest located in Gray, Tennes-see. Crown height and cusp angle were measured for 38 specimens arranged into eruption series from young juveniles to old adults. Results found a strong correlation between eruption series and cusp angle with a steady increase in mean angle as the individuals increase in age. A strong correlation between cusp angle and crown height was also found. Overall, the population showed relatively low wear rates, as would be expected of a forest-dwelling browser. As a mesowear analysis across all age groups for a population has not been conducted before, this study could be useful for measuring relative wear rates at different life stages and could be applied across other com-munities

Topical Rapamycin Therapy to Alleviate the Cutaneous Manifestations of Tuberous Sclerosis Complex

Background and Objectives: Facial angiofibromas are disfiguring facial lesions, present in up to 80% of patients with tuberous sclerosis complex. Recent elucidation of the complex cell signaling pathways that are disrupted in tuberous sclerosis indicates that rapamycin may be successful in alleviating the appearance of these lesions. The objectives of the current study were to evaluate the safety of topically applied rapamycin in patients with tuberous sclerosis complex and to determine its potential effectiveness in treatment of facial angiofibromas. Patients and Methods: The study was a prospective, randomized, double-blind, placebo-controlled study performed at the University of Texas Health Science Center at Houston. Study subjects were recruited from the patient populations at the University of Texas Tuberous Sclerosis Center of Excellence. All subjects were over the age of 13 years and had a diagnosis of tuberous sclerosis complex. Subjects were excluded if they were using any form of rapamycin or if they were pregnant. Study subjects applied the study product to their facial angiofibromas nightly for a duration of 6 months. The investigational product contained one of three doses of rapamycin compounded with Skincerity®: (i) no rapamycin; (ii) 1 mg of rapamycin per 30 cc (0.003%); or (iii) 5 mg of rapamycin per 30 cc (0.015%). Plasma rapamycin concentrations were measured monthly to test for systemic absorption. Complete blood counts were performed monthly to test for anemia, neutropenia, or thrombocytopenia. Upon completion of the trial, subjects were asked if the formulation had improved the appearance of their facial angiofibromas. Results: Twenty-three subjects completed the study. There was no detectable systemic absorption of rapamycin (all blood concentrations were <1.0 ng/mL). There were no significant changes in white blood cell, red blood cell, or platelet counts. Seventy-three percent of subjects in the treatment arms versus 38% of subjects in the placebo arm reported a subjective improvement in the appearance of their facial angiofibromas. Conclusion: The application of low-dose topical rapamycin (0.003–0.015%) to the face can safely decrease the appearance of facial angiofibromas in patients with tuberous sclerosis complex

Association of blood pressure variability and neurocognition in children with chronic kidney disease

Children with chronic kidney disease (CKD) and hypertension have increased blood pressure variability (BPV). Increased BPV has been associated with lower neurocognitive test scores in adults. Children with CKD are at risk for decreased neurocognitive function. Our objective was to determine if children with CKD and increased BPV had worse performance on neurocognitive testing compared with children with CKD and lower BPV

Sleep Disordered Breathing as Measured by SRBD-PSQ and Neurocognition in Children With Hypertension

Cognitive test performance is decreased in hypertensive adults and children, a finding postulated to represent early target-organ damage to the brain. Hypertensive children are often obese, a comorbidity associated with sleep disordered breathing (SDB), itself associated with cognitive problems; potentially confounding the relation between hypertension (HTN) and neurocognition. Our objective was to determine the association between SDB as measured by a scale and questionnaire score and neurocognition among participants enrolled in an ongoing multicenter study of cognition in children with HTN

Re-Evaluation of Sinocastor (Rodentia: Castoridae) with Implications on the Origin of Modern Beavers

The extant beaver, Castor, has played an important role shaping landscapes and ecosystems in Eurasia and North America, yet the origins and early evolution of this lineage remain poorly understood. Here we use a geometric morphometric approach to help re-evaluate the phylogenetic affinities of a fossil skull from the Late Miocene of China. This specimen was originally considered Sinocastor, and later transferred to Castor. The aim of this study was to determine whether this form is an early member of Castor, or if it represents a lineage outside of Castor. The specimen was compared to 38 specimens of modern Castor (both C. canadensis and C. fiber) as well as fossil specimens of C. fiber (Pleistocene), C. californicus (Pliocene) and the early castorids Steneofiber eseri (early Miocene). The results show that the specimen falls outside the Castor morphospace and that compared to Castor, Sinocastor possesses a: 1) narrower post-orbital constriction, 2) anteroposteriorly shortened basioccipital depression, 3) shortened incisive foramen, 4) more posteriorly located palatine foramen, 5) longer rostrum, and 6) longer braincase. Also the specimen shows a much shallower basiocciptal depression than what is seen in living Castor, as well as prominently rooted molars. We conclude that Sinocastor is a valid genus. Given the prevalence of apparently primitive traits, Sinocastor might be a near relative of the lineage that gave rise to Castor, implying a possible Asiatic origin for Castor

Computational Modeling and Analysis of Insulin Induced Eukaryotic Translation Initiation

Insulin, the primary hormone regulating the level of glucose in the bloodstream, modulates a variety of cellular and enzymatic processes in normal and diseased cells. Insulin signals are processed by a complex network of biochemical interactions which ultimately induce gene expression programs or other processes such as translation initiation. Surprisingly, despite the wealth of literature on insulin signaling, the relative importance of the components linking insulin with translation initiation remains unclear. We addressed this question by developing and interrogating a family of mathematical models of insulin induced translation initiation. The insulin network was modeled using mass-action kinetics within an ordinary differential equation (ODE) framework. A family of model parameters was estimated, starting from an initial best fit parameter set, using 24 experimental data sets taken from literature. The residual between model simulations and each of the experimental constraints were simultaneously minimized using multiobjective optimization. Interrogation of the model population, using sensitivity and robustness analysis, identified an insulin-dependent switch that controlled translation initiation. Our analysis suggested that without insulin, a balance between the pro-initiation activity of the GTP-binding protein Rheb and anti-initiation activity of PTEN controlled basal initiation. On the other hand, in the presence of insulin a combination of PI3K and Rheb activity controlled inducible initiation, where PI3K was only critical in the presence of insulin. Other well known regulatory mechanisms governing insulin action, for example IRS-1 negative feedback, modulated the relative importance of PI3K and Rheb but did not fundamentally change the signal flow

Depressive Symptoms in Children with Chronic Kidney Disease

To assess depression in children with chronic kidney disease (CKD) and to determine associations with patient characteristics, intellectual and educational levels, and health related quality of life (HRQoL)

Six RNA Viruses and Forty-One Hosts: Viral Small RNAs and Modulation of Small RNA Repertoires in Vertebrate and Invertebrate Systems

We have used multiplexed high-throughput sequencing to characterize changes in small RNA populations that occur during viral infection in animal cells. Small RNA-based mechanisms such as RNA interference (RNAi) have been shown in plant and invertebrate systems to play a key role in host responses to viral infection. Although homologs of the key RNAi effector pathways are present in mammalian cells, and can launch an RNAi-mediated degradation of experimentally targeted mRNAs, any role for such responses in mammalian host-virus interactions remains to be characterized. Six different viruses were examined in 41 experimentally susceptible and resistant host systems. We identified virus-derived small RNAs (vsRNAs) from all six viruses, with total abundance varying from “vanishingly rare” (less than 0.1% of cellular small RNA) to highly abundant (comparable to abundant micro-RNAs “miRNAs”). In addition to the appearance of vsRNAs during infection, we saw a number of specific changes in host miRNA profiles. For several infection models investigated in more detail, the RNAi and Interferon pathways modulated the abundance of vsRNAs. We also found evidence for populations of vsRNAs that exist as duplexed siRNAs with zero to three nucleotide 3′ overhangs. Using populations of cells carrying a Hepatitis C replicon, we observed strand-selective loading of siRNAs onto Argonaute complexes. These experiments define vsRNAs as one possible component of the interplay between animal viruses and their hosts

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders