T cells in aging mice: genetic, developmental, and biochemical analyses

A combination of approaches – gene mapping, biomarker analysis, and studies of signal transduction – has helped to clarify the mechanisms of age-related change in mouse immune status and the implications of immune aging for late-life disease. Mapping studies have documented multiple quantitative trait loci (QTL) that influence the levels of age-sensitive T-cell subsets. Some of these QTL have effects that are demonstrable in young-adult mice (8 months of age) and others demonstrable only in middle-aged mice (18 months). Biomarker studies show that T-cell subset levels measured at 8 or 18 months are significant predictors of lifespan for mice dying of lymphoma, fibrosarcoma, mammary adenocarcinoma, or all causes combined. Mice whose immune systems resemble that of young animals, i.e. with low levels of CD4 + and CD8 + memory T cells and relatively high levels of CD4 + T cells, tend to outlive their siblings with the opposite subset pattern. Biochemical analyses show that T cells from aged mice show defects in the activation process within a few minutes of encountering a stimulus and that the defects precede the recognition by the T-cell receptor of agonist peptides on the antigen-presenting cell. Defective assembly of cytoskeletal fibers and hyperglycosylation of T-cell surface glycoproteins contribute to the immunodeficiency state, and indeed treatment with a sialylglycoprotein endopeptidase can restore full function to CD4 + T cells from aged donors in vitro .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75195/1/j.0105-2896.2005.00254.x.pd

Social deprivation and prognostic benefits of cardiac surgery: observational study of 44 902 patients from five hospitals over 10 years

Objective To assess the effects of social deprivation on survival after cardiac surgery and to examine the influence of potentially modifiable risk factors

Distinct but overlapping roles of LRRTM1 and LRRTM2 in developing and mature hippocampal circuits

LRRTMs are postsynaptic cell adhesion proteins that have region-restricted expression in the brain. To determine their role in the molecular organization of synapses in vivo, we studied synapse development and plasticity in hippocampal neuronal circuits in mice lacking both Lrrtm1 and Lrrtm2. We found that LRRTM1 and LRRTM2 regulate the density and morphological integrity of excitatory synapses on CA1 pyramidal neurons in the developing brain but are not essential for these roles in the mature circuit. Further, they are required for long-term-potentiation in the CA3-CA1 pathway and the dentate gyrus, and for enduring fear memory in both the developing and mature brain. Our data show that LRRTM1 and LRRTM2 regulate synapse development and function in a cell-type and developmental-stage-specific manner, and thereby contribute to the fine-tuning of hippocampal circuit connectivity and plasticity

Factorization of Correlation Functions and the Replica Limit of the Toda Lattice Equation

Exact microscopic spectral correlation functions are derived by means of the replica limit of the Toda lattice equation. We consider both Hermitian and non-Hermitian theories in the Wigner-Dyson universality class (class A) and in the chiral universality class (class AIII). In the Hermitian case we rederive two-point correlation functions for class A and class AIII as well as several one-point correlation functions in class AIII. In the non-Hermitian case the spectral density of non-Hermitian complex random matrices in the weak non-Hermiticity limit is obtained directly from the replica limit of the Toda lattice equation. In the case of class A, this result describes the spectral density of a disordered system in a constant imaginary vector potential (the Hatano-Nelson model) which is known from earlier work. New results are obtained for the spectral density in the weak non-Hermiticity limit of a quenched chiral random matrix model at nonzero chemical potential. These results apply to the ergodic or $\epsilon$ domain of quenched QCD at nonzero chemical potential. The spectral density obtained is different from the result derived by Akemann for a closely related model, which is given by the leading order asymptotic expansion of our result. In all cases, the replica limit of the Toda lattice equation explains the factorization of spectral one- and two-point functions into a product of a bosonic (noncompact integral) and a fermionic (compact integral) partition function. We conclude that the fermionic, the bosonic and the supersymmetric partition functions are all part of a single integrable hierarchy. This is the reason that it is possible to obtain the supersymmetric partition function, and its derivatives, from the replica limit of the Toda lattice equation.Comment: 29 pages, 2 figures. Clarifying comments added in sec 3.2.3 and a few typos corrected. Version to appear in Nucl. Phys.

Factors associated with quality of life and mood in adults with strabismus

Background/Aims To explore the factors associated with the mood and quality of life (QoL) of patients with strabismus due to undergo realignment surgery. Methods A cross-sectional study was undertaken with adult patients. Along with demographic, clinical and psychosocial process variables, the Hospital Anxiety and Depression Scale and AS-20 QoL measures were administered. Regression models were used to identify the factors associated with QoL and mood. Results Of the 220 participants, 11% were experiencing clinical levels of depression, and 24% clinical anxiety. This is in line with other forms of facial disfigurement but higher than other chronic diseases. Although mood and QoL were associated with age and diplopia, it was beliefs and cognitions which were more consistently associated with well-being. This included feelings of social anxiety and avoidance, a belief that strabismus has negative consequences, poor understanding of strabismus, social support, fear of negative evaluation and the perceived visibility of their condition. Conclusions Psychosocial rather than clinical characteristics were identified as determinants of wellbeing in this population. It is important for clinicians planning surgery to be aware of these factors which could influence outcomes. Longitudinal studies need to be conducted to explore the direction of causality before interventions to improve well-being are developed and evaluated

Reverberation Mapping Measurements of Black Hole Masses in Six Local Seyfert Galaxies

We present the final results from a high sampling rate, multi-month, spectrophotometric reverberation mapping campaign undertaken to obtain either new or improved Hbeta reverberation lag measurements for several relatively low-luminosity AGNs. We have reliably measured thetime delay between variations in the continuum and Hbeta emission line in six local Seyfert 1 galaxies. These measurements are used to calculate the mass of the supermassive black hole at the center of each of these AGNs. We place our results in context to the most current calibration of the broad-line region (BLR) R-L relationship, where our results remove outliers and reduce the scatter at the low-luminosity end of this relationship. We also present velocity-resolved Hbeta time delay measurements for our complete sample, though the clearest velocity-resolved kinematic signatures have already been published.Comment: 52 pages (AASTeX: 29 pages of text, 8 tables, 7 figures), accepted for publication in the Astrophysical Journa

Effects Of Length, Complexity, And Grammatical Correctness On Stuttering In Spanish-Speaking Preschool Children

Purpose: To explore the effects of utterance length, syntactic complexity, and grammatical correctness on stuttering in the spontaneous speech of young, monolingual Spanish-speaking children. Method: Spontaneous speech samples of 11 monolingual Spanish-speaking children who stuttered, ages 35 to 70 months, were examined. Mean number of syllables, total number of clauses, utterance complexity (i.e., containing no clauses, simple clauses, or subordinate and/or conjoined clauses), and grammatical correctness (i.e., the presence or absence of morphological and syntactical errors) in stuttered and fluent utterances were compared. Results: Findings revealed that stuttered utterances in Spanish tended to be longer and more often grammatically incorrect, and contain more clauses, including more subordinate and/or conjoined clauses. However, when controlling for the interrelatedness of syllable number and clause number and complexity, only utterance length and grammatical incorrectness were significant predictors of stuttering in the spontaneous speech of these Spanish-speaking children. Use of complex utterances did not appear to contribute to the prediction of stuttering when controlling for utterance length. Conclusions: Results from the present study were consistent with many earlier reports of English-speaking children. Both length and grammatical factors appear to affect stuttering in Spanish-speaking children. Grammatical errors, however, served as the greatest predictor of stuttering.Communication Sciences and Disorder

Methods to study splicing from high-throughput RNA Sequencing data

The development of novel high-throughput sequencing (HTS) methods for RNA (RNA-Seq) has provided a very powerful mean to study splicing under multiple conditions at unprecedented depth. However, the complexity of the information to be analyzed has turned this into a challenging task. In the last few years, a plethora of tools have been developed, allowing researchers to process RNA-Seq data to study the expression of isoforms and splicing events, and their relative changes under different conditions. We provide an overview of the methods available to study splicing from short RNA-Seq data. We group the methods according to the different questions they address: 1) Assignment of the sequencing reads to their likely gene of origin. This is addressed by methods that map reads to the genome and/or to the available gene annotations. 2) Recovering the sequence of splicing events and isoforms. This is addressed by transcript reconstruction and de novo assembly methods. 3) Quantification of events and isoforms. Either after reconstructing transcripts or using an annotation, many methods estimate the expression level or the relative usage of isoforms and/or events. 4) Providing an isoform or event view of differential splicing or expression. These include methods that compare relative event/isoform abundance or isoform expression across two or more conditions. 5) Visualizing splicing regulation. Various tools facilitate the visualization of the RNA-Seq data in the context of alternative splicing. In this review, we do not describe the specific mathematical models behind each method. Our aim is rather to provide an overview that could serve as an entry point for users who need to decide on a suitable tool for a specific analysis. We also attempt to propose a classification of the tools according to the operations they do, to facilitate the comparison and choice of methods.Comment: 31 pages, 1 figure, 9 tables. Small corrections adde

Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future

The proper development and coordination of the hypothalamic-pituitary-gonadal (HPG) axis are essential for normal reproductive competence. The key factor that regulates the function of the HPG axis is gonadotrophin-releasing hormone (GnRH). Timely release of GnRH is critical for the onset of puberty and subsequent sexual maturation. Misregulation in this system can result in delayed or absent puberty and infertility. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are genetic disorders that are rooted in a GnRH deficiency but often accompanied by a variety of non-reproductive phenotypes such as the loss of the sense of smell and defects of the skeleton, eye, ear, kidney, and heart. Recent progress in DNA sequencing technology has produced a wealth of information regarding the genetic makeup of CHH and KS patients and revealed the resilient yet complex nature of the human reproductive neuroendocrine system. Further research on the molecular basis of the disease and the diverse signal pathways involved will aid in improving the diagnosis, treatment, and management of CHH and KS patients as well as in developing more precise genetic screening and counseling regime