Genetic analysis of self-associating immunoglobulin G rheumatoid factors from two rheumatoid synovia implicates an antigen-driven response.

Although much has been learned about the molecular basis of immunoglobulin M (IgM) rheumatoid factors (RFs) in healthy individuals and in patients with mixed cryoglobulinemia and rheumatoid arthritis, little is known about the genetic origins of the potentially pathogenic IgG RFs in the inflamed rheumatoid synovia of patients. Recently, we generated from unmanipulated synovium B cells several hybridomas that secreted self-associating IgG RFs. To delineate the genetic origins of such potentially pathogenic RFs, we adapted the anchored polymerase chain reaction to rapidly clone and characterize the expressed Ig V genes for the L1 and the D1 IgG RFs. Then, we identified the germline counterparts of the expressed L1 IgG RF V genes. The results showed that the L1 heavy chain was encoded by a Vh gene that is expressed preferentially during early ontogenic development, and that is probably located within 240 kb upstream of the Jh locus. The overlap between this RF Vh gene and the restricted fetal antibody repertoire is reminiscent of the natural antibody-associated Vh genes, and suggests that at least part of the "potential pathogenic" IgG RFs in rheumatoid synovium may derive from the "physiological" natural antibody repertoire in a normal immune system. Indeed, the corresponding germline Vh gene for L1 encodes the heavy chain of an IgM RF found in a 19-wk-old fetal spleen. Furthermore, the comparisons of the expressed RF V genes and their germline counterparts reveal that the L1 heavy and light chain variable regions had, respectively, 16 and 7 somatic mutations, which resulted in eight and four amino acid changes. Strikingly, all eight mutations in the complementarity determining regions of the V gene-encoded regions were replacement changes, while only 6 of 11 mutations in the framework regions caused amino acid changes. Combined with L1's high binding affinity toward the Fc fragment, these results suggest strongly that the L1 IgG RF must have been driven by the Fc antigen

Popular matchings with two-sided preferences and one-sided ties

We are given a bipartite graph $G = (A \cup B, E)$ where each vertex has a preference list ranking its neighbors: in particular, every $a \in A$ ranks its neighbors in a strict order of preference, whereas the preference lists of $b \in B$ may contain ties. A matching $M$ is popular if there is no matching $M'$ such that the number of vertices that prefer $M'$ to $M$ exceeds the number of vertices that prefer $M$ to~$M'$. We show that the problem of deciding whether $G$ admits a popular matching or not is NP-hard. This is the case even when every $b \in B$ either has a strict preference list or puts all its neighbors into a single tie. In contrast, we show that the problem becomes polynomially solvable in the case when each $b \in B$ puts all its neighbors into a single tie. That is, all neighbors of $b$ are tied in $b$'s list and $b$ desires to be matched to any of them. Our main result is an $O(n^2)$ algorithm (where $n = |A \cup B|$) for the popular matching problem in this model. Note that this model is quite different from the model where vertices in $B$ have no preferences and do not care whether they are matched or not.Comment: A shortened version of this paper has appeared at ICALP 201

Between-days intra-rater reliability with a hand held myotonometer to quantify muscle tone in the acute stroke population

A myotonometer can objectively quantify changes in muscle tone. The between-days intra-rater reliability in a ward setting for the acute stroke population remains unknown. This study aimed to investigate the device’s between-days intra-rater reliability when used in a ward setting for acute stroke participants. Muscle tone of biceps brachii, brachioradialis, rectus femoris, and tibialis anterior was recorded in the ward at bedside by one physiotherapist on two consecutive days. This study included participants who were within 1 month of their first stroke occurrence. Participants who were medically unstable or who suffered from brain stem injury were excluded. Reliability was assessed by the intraclass correlation coefficient (ICC), standard error of measurement (SEM), smallest real difference (SRD), and the Bland-Altman limits of agreement. The results indicated excellent between-days intra-rater reliability (ICC > 0.75). SEM and SRD show small differences between measurements. The Bland-Altman analysis indicated a tendency of overestimation of the rectus femoris. MyotonPRO demonstrated acceptable reliability when used in a ward setting in those patients with acute stroke. However, results should be interpreted with caution, due to the limitations of the study and the varying level of consistency observed between different muscles

Decoder Hardware Architecture for HEVC

This chapter provides an overview of the design challenges faced in the implementation of hardware HEVC decoders. These challenges can be attributed to the larger and diverse coding block sizes and transform sizes, the larger interpolation filter for motion compensation, the increased number of steps in intra prediction and the introduction of a new in-loop filter. Several solutions to address these implementation challenges are discussed. As a reference, results for an HEVC decoder test chip are also presented.Texas Instruments Incorporate

Age effect on retina and optic disc normal values

Purpose: To investigate retinal thickness and optic disc parameters by the Retinal Thickness Analyzer (RTA) glaucoma program in older normal subjects and to determine any age effect. Methods: Subjects over 40 years of age without any prior history of eye diseases were recruited. Only subjects completely normal on clinical ophthalmologic examination and on visual field testing by Humphrey Field Analyzer (HFA) using the SITA 24-2 program were included. A total of 74 eyes from 74 subjects with even age distribution over the decades were enrolled and underwent topographic measurements of the posterior pole and of the optic disc by RTA. The `glaucoma full' program in software version 4.11B was applied. Results: Mean patient age was 59.9 +/- 10.3 years with a range from 40 to 80 years. The only parameter intraocular pressure (IOP) correlated with was retinal posterior pole asymmetry (r=0.27, p=0.02). IOP itself increased significantly with age (r=0.341, p=0.003). Mean defect and pattern standard deviation of the HFA did not correlate with any of the retinal or optic disc measurements. Increasing age correlated significantly with some of the morphologic measurements of the RTA: decreasing perifoveal minimum thickness (r=-0.258, p=0.026), increased cup-to-disc area ratio (r=0.302, p=0.016) and increased cup area (r=0.338 p=0.007). Conclusions: An age effect exists for some of the retina and optic disc measurements obtained by the RTA. Copyright (C) 2005 S. Karger AG, Basel

Phase Structure and Compactness

In order to study the influence of compactness on low-energy properties, we compare the phase structures of the compact and non-compact two-dimensional multi-frequency sine-Gordon models. It is shown that the high-energy scaling of the compact and non-compact models coincides, but their low-energy behaviors differ. The critical frequency $\beta^2 = 8\pi$ at which the sine-Gordon model undergoes a topological phase transition is found to be unaffected by the compactness of the field since it is determined by high-energy scaling laws. However, the compact two-frequency sine-Gordon model has first and second order phase transitions determined by the low-energy scaling: we show that these are absent in the non-compact model.Comment: 21 pages, 5 figures, minor changes, final version, accepted for publication in JHE

Quantitative trait loci conferring grain mineral nutrient concentrations in durum wheat 3 wild emmer wheat RIL population

Mineral nutrient malnutrition, and particularly deficiency in zinc and iron, afflicts over 3 billion people worldwide. Wild emmer wheat, Triticum turgidum ssp. dicoccoides, genepool harbors a rich allelic repertoire for mineral nutrients in the grain. The genetic and physiological basis of grain protein, micronutrients (zinc, iron, copper and manganese) and macronutrients (calcium, magnesium, potassium, phosphorus and sulfur) concentration was studied in tetraploid wheat population of 152 recombinant inbred lines (RILs), derived from a cross between durum wheat (cv. Langdon) and wild emmer (accession G18-16). Wide genetic variation was found among the RILs for all grain minerals, with considerable transgressive effect. A total of 82 QTLs were mapped for 10 minerals with LOD score range of 3.2–16.7. Most QTLs were in favor of the wild allele (50 QTLs). Fourteen pairs of QTLs for the same trait were mapped to seemingly homoeologous positions, reflecting synteny between the A and B genomes. Significant positive correlation was found between grain protein concentration (GPC), Zn, Fe and Cu, which was supported by significant overlap between the respective QTLs, suggesting common physiological and/or genetic factors controlling the concentrations of these mineral nutrients. Few genomic regions (chromosomes 2A, 5A, 6B and 7A) were found to harbor clusters of QTLs for GPC and other nutrients. These identified QTLs may facilitate the use of wild alleles for improving grain nutritional quality of elite wheat cultivars, especially in terms of protein, Zn and Fe

Multi-level evidence of an allelic hierarchy of USH2A variants in hearing, auditory processing and speech/language outcomes.

Language development builds upon a complex network of interacting subservient systems. It therefore follows that variations in, and subclinical disruptions of, these systems may have secondary effects on emergent language. In this paper, we consider the relationship between genetic variants, hearing, auditory processing and language development. We employ whole genome sequencing in a discovery family to target association and gene x environment interaction analyses in two large population cohorts; the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK10K. These investigations indicate that USH2A variants are associated with altered low-frequency sound perception which, in turn, increases the risk of developmental language disorder. We further show that Ush2a heterozygote mice have low-level hearing impairments, persistent higher-order acoustic processing deficits and altered vocalizations. These findings provide new insights into the complexity of genetic mechanisms serving language development and disorders and the relationships between developmental auditory and neural systems

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care