Test-retest reliability for common tasks in vision science.

Research in perception and attention has typically sought to evaluate cognitive mechanisms according to the average response to a manipulation. Recently, there has been a shift toward appreciating the value of individual differences and the insight gained by exploring the impacts of between-participant variation on human cognition. However, a recent study suggests that many robust, well-established cognitive control tasks suffer from surprisingly low levels of test-retest reliability (Hedge, Powell, & Sumner, 2018b). We tested a large sample of undergraduate students (n = 160) in two sessions (separated by 1-3 weeks) on four commonly used tasks in vision science. We implemented measures that spanned a range of perceptual and attentional processes, including motion coherence (MoCo), useful field of view (UFOV), multiple-object tracking (MOT), and visual working memory (VWM). Intraclass correlations ranged from good to poor, suggesting that some task measures are more suitable for assessing individual differences than others. VWM capacity (intraclass correlation coefficient [ICC] = 0.77), MoCo threshold (ICC = 0.60), UFOV middle accuracy (ICC = 0.60), and UFOV outer accuracy (ICC = 0.74) showed good-to-excellent reliability. Other measures, namely the maximum number of items tracked in MOT (ICC = 0.41) and UFOV number accuracy (ICC = 0.48), showed moderate reliability; the MOT threshold (ICC = 0.36) and UFOV inner accuracy (ICC = 0.30) showed poor reliability. In this paper, we present these results alongside a summary of reliabilities estimated previously for other vision science tasks. We then offer useful recommendations for evaluating test-retest reliability when considering a task for use in evaluating individual differences.

The importance of international collaboration for rare diseases research: a European perspective.

Over the last two decades, important contributions were made at national, European and international levels to foster collaboration into rare diseases research. The European Union (EU) has put much effort into funding rare diseases research, encouraging national funding organizations to collaborate together in the E-Rare program, setting up European Reference Networks for rare diseases and complex conditions, and initiating the International Rare Diseases Research Consortium (IRDiRC) together with the National Institutes of Health in the USA. Co-ordination of the activities of funding agencies, academic researchers, companies, regulatory bodies, and patient advocacy organizations and partnerships with, for example, the European Research Infrastructures maximizes the collective impact of global investments in rare diseases research. This contributes to accelerating progress, for example, in faster diagnosis through enhanced discovery of causative genes, better understanding of natural history of rare diseases through creation of common registries and databases and boosting of innovative therapeutic approaches. Several examples of funded pre-clinical and clinical gene therapy projects show that integration of multinational and multidisciplinary expertize generates new knowledge and can result in multicentre gene therapy trials. International collaboration in rare diseases research is key to improve the life of people living with a rare disease.

Phase separation and the 'coffee-ring' effect in polymer-nanocrystal mixtures.

The coupling between the 'coffee-ring' effect and liquid-liquid phase separation is examined for ternary mixtures of solvent, polymer and semiconductor nanocrystal. Specifically, we study mixtures of toluene, polystyrene (PS) and colloidal silicon nanocrystals (SiNCs) using real-space imaging and spectroscopic techniques to resolve the kinetic morphology of the drying front for varied molecular weight of the PS. Our results demonstrate that the size of the polymer has a significant impact on both phase-separation and drying, and we relate these observations to simulations, measured and predicted binodal curves, and the observed shape of the flow field at the contact line. The results inform a deposition process that reduces the influence of drying instabilities for low-molecular-weight polymers while paving the way for more detailed and generic computational descriptions of drying instabilities in complex fluids.

Identification of the gene responsible for Best macular dystrophy.

Best macular dystrophy (BMD), also known as vitelliform macular dystrophy (VMD2; OMIM 153700), is an autosomal dominant form of macular degeneration characterized by an abnormal accumulation of lipofuscin within and beneath the retinal pigment epithelium cells. In pursuit of the disease gene, we limited the minimum genetic region by recombination breakpoint analysis and mapped to this region a novel retina-specific gene (VMD2). Genetic mapping data, identification of five independent disease-specific mutations and expression studies provide evidence that mutations within the candidate gene are a cause of BMD. The 3' UTR of the candidate gene contains a region of antisense complementarity to the 3' UTR of the ferritin heavy-chain gene (FTH1), indicating the possibility of antisense interaction between VMD2 and FTH1 transcripts.

A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy.

Stargardt-like macular dystrophy (STGD3, MIM 600110) and autosomal dominant macular dystrophy (adMD) are inherited forms of macular degeneration characterized by decreased visual acuity, macular atrophy and extensive fundus flecks. Genetic mapping data suggest that mutations in a single gene may be responsible for both conditions, already known to bear clinical resemblance. Here we limit the minimum genetic region for STGD3 and adMD to a 0.6-cM interval by recombination breakpoint mapping and identify a single 5-bp deletion within the protein-coding region of a new retinal photoreceptor-specific gene, ELOVL4, in all affected members of STGD3 and adMD families. Bioinformatic analysis of ELOVL4 revealed that it has homology to a group of yeast proteins that function in the biosynthesis of very long chain fatty acids. Our results are therefore the first to implicate the biosynthesis of fatty acids in the pathogenesis of inherited macular degeneration.

Receptor for motilin identified in the human gastrointestinal system.

Motilin is a 22-amino acid peptide hormone expressed throughout the gastrointestinal (GI) tract of humans and other species. It affects gastric motility by stimulating interdigestive antrum and duodenal contractions. A heterotrimeric guanosine triphosphate-binding protein (G protein)-coupled receptor for motilin was isolated from human stomach, and its amino acid sequence was found to be 52 percent identical to the human receptor for growth hormone secretagogues. The macrolide antibiotic erythromycin also interacted with the cloned motilin receptor, providing a molecular basis for its effects on the human GI tract. The motilin receptor is expressed in enteric neurons of the human duodenum and colon. Development of motilin receptor agonists and antagonists may be useful in the treatment of multiple disorders of GI motility.

Horner's syndrome from hypothalamic infarction.

We report a case of Horner's syndrome due to ipsilateral posterior hypothalamic infarction, occurring in the absence of other signs of hypothalamic dysfunction. Associated symptoms of contralateral faciobrachial weakness and dysarthria correlated with the extension of the infarct into the posterior limb of the internal capsule seen by magnetic resonance imaging. The likely vascular anatomy of this lesion is discussed.

Expression of Disrupted-In-Schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development.

DISC1 (Disrupted-In-Schizophrenia 1) has been associated with schizophrenia in multiple genetic studies. Studies from our laboratory have shown that Disc1, the mouse ortholog of DISC1, is highly expressed in the dentate gyrus of the hippocampus in the adult mouse brain. Because developmental dysfunction of the hippocampus is thought to play a major role in schizophrenia pathogenesis, and the dentate gyrus is a major locus for adult neurogenesis in the mouse, we investigated Disc1 expression during mouse brain development. Strikingly, Disc1 is strongly expressed in the hippocampus during all stages of hippocampal development, from embryonic day 14 through adulthood. Disc1 mRNA was detected in the dentate gyrus at all stages in which this structure was identifiable, as well as in the cornu ammonis (CA) fields of the hippocampus, the subiculum and adjacent entorhinal cortex, and the developing cerebral neocortex, hypothalamus, and olfactory bulbs, all of which also express Disc1 in the adult mouse brain. In addition, Disc1 mRNA was seen in regions of the developing mouse brain which do not express Disc1 during adulthood, regions including the bed nucleus of the stria terminalis, reticular thalamic nucleus and reuniens thalamic nucleus. These results demonstrate that Disc1 marks the hippocampus from its earliest stages, and suggest that developmental Disc1 dysfunction may lead to defects in hippocampal function that are associated with schizophrenia.

Identification of genes differentially expressed in benign prostatic hyperplasia.

Differences between benign prostatic hyperplasia (BPH) and normal prostate tissue at the level of mRNA expression provide an opportunity to identify candidate genes for this disease. A cDNA subtraction procedure was used to isolate differentially expressed genes in BPH. The subtraction was done by solution hybridization of BPH cDNA against excess normal prostate cDNA. We identified known, EST, and novel genes by sequence and database analysis of the subtracted cDNAs. Several of these cDNAs were used as probes in Northern blotting analysis to confirm over-expression of their corresponding mRNAs in BPH tissues. One highly upregulated sequence of interest shared identity with a known mRNA encoding human NELL2, a protein containing epidermal growth factor-like domains. NELL2 was not previously reported to be expressed in prostate and may code for a novel prostatic growth factor. In situ hybridization analysis of hyperplastic prostate specimens demonstrated that NELL2 mRNA expression is predominantly localized in basal cells of the epithelium. Disease-related changes in the levels of NELL2 may contribute to alterations in epithelial-stromal homeostasis in BPH. (J Histochem Cytochem 49:669-670, 2001)

Expression of the type I diabetes-associated gene LRP5 in macrophages, vitamin A system cells, and the Islets of Langerhans suggests multiple potential roles in diabetes.

LRP5 is a novel member of the low-density lipoprotein receptor family that is genetically associated with Type 1 diabetes. As a start to defining the normal function of LRP5 and to generate testable hypotheses of its potential role in Type 1 diabetes pathogenesis, we carried out an extensive expression analysis of this gene at the mRNA and protein levels in normal human, monkey, and mouse, as well as in non-obese diabetic (NOD) mice at several stages of diabetes development. In all species, expression of LRP5 was found in four functionally important cell types: the distributed mononuclear phagocyte system, the islets of Langerhans, vitamin A-metabolizing cells, and CNS neurons. Given the critical role of macrophages in the onset and progression of islet cell destruction in Type 1 diabetes and the hypothesized role of retinoids as modifiers of diabetes progression, these findings suggest that LRP5 may confer Type 1 diabetes risk by altering the normal functioning of one or more of these regulatory systems. Specifically, given that the LRP5 polymorphisms associated with diabetes are in the promoter region of the gene, alterations in LRP5 expression may be responsible for diabetes susceptibility and therefore may be potential targets for therapeutic intervention. (J Histochem Cytochem 48:1357-1368, 2000)

Psychopathology of pancreatic cancer. A psychobiologic probe.

Reports of characteristic psychiatric symptoms occurring in patients with pancreatic cancer appear regularly in the literature. A review of this literature reveals that symptoms of depression and/or anxiety may appear in approximately 50% of patients with pancreatic cancer before the diagnosis is made. This review proposes that the psychopathology of pancreatic tumors may be linked to tumor-induced changes in neuroendocrine or acid-base systems. Although confirmatory data are lacking, informed speculation centers on the potential role of adrenocorticotropic hormone, parathyroid hormone, thyrotropin-releasing hormone, glucagon, serotonin, insulin, and bicarbonate in the production of depression and/or anxiety in this disease. Elucidation of the pathophysiology of the psychiatric symptoms in patients with pancreatic cancer may provide a marker for early diagnosis of pancreatic neoplasia as well as a probe into the biologic bases of depression and anxiety.

Cellular migration patterns in the developing mouse cerebral cortex.

The migration patterns of embryonic mouse cortical cells were investigated using a replication-incompetent retrovirus vector (BAG). The lateral ventricles of embryonic day 12 mouse embryos were infected with BAG and brains were harvested 2, 3, 4 and 6 days after infection. The location and morphology of all infected cortical cells were recorded from serial sections of entire brains, which were then reconstructed in three dimensions. Examination of the distribution of labelled cells revealed that there were migration patterns characteristic of each medial-lateral domain of the cortex. In the medial and dorsal areas, migration was often radial, although tangential spread increased with survival time, in large part due to ramification of cells in the intermediate zone. In the dorsolateral and lateral areas of the cortex, radial migration was generally not observed. Rather, variable extents of tangential migration occurred, and often resulted in wide separation of cells in the cortical plate. Almost all of the cellular dispersion occurred in the intermediate zone, although a modest degree of dispersion also occurred within the cortical plate itself. Most dispersion occurred in the mediolateral plane, with relatively little dispersion along the anteroposterior axis. Though characteristic migration patterns could be defined, wide variability in the extents of radial migration and tangential separation of cells was seen. The patterns of migration paralleled the distribution of radial glial fibers in all areas, and are most likely a reflection of the role of this network in supporting the migration of cortical neurons. The extent and variability of cellular dispersion supports a lineage-independent mechanism of cortical column ontogenesis.

The alignment of migrating neural cells in relation to the murine neopallial radial glial fiber system.

The direction of neural cell migration in relation to the pattern of alignment of adjacent radial glial fibers has been studied in the developing neopallium of embryonic days 16-18 mouse embryos. The radial glial fibers were stained with RC2, a monoclonal antibody selective for cells of astroglial lineage in the developing murine brain. Migrating neural cells were stained histochemically with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal) following retroviral transduction of the gene encoding beta-galactosidase into proliferating progenitors on E13. The leading processes and, generally, the somata of migrating neurons were found to be aligned in parallel with the radial glial fibers, despite substantial variations in the patterns of alignment of the fiber fascicles. The set of observations is consistent with the hypothesis that neural cell migration is supported by radial glial fibers.

Mapping of hKCa3 to chromosome 1q21 and investigation of linkage of CAG repeat polymorphism to schizophrenia.

CAG trinucleotide polymorphisms in the neuronal small conductance calcium-activated potassium channel gene hKCa3 have been reported to be associated with schizophrenia. Attempts to confirm this finding have met with mixed results. We investigated hKCa3 CAG allele lengths in families from the National Institute of Mental Health (NIMH) Schizophrenia Genetics Initiative, by comparing transmission to discordant siblings and parental transmission to affected offspring. Overall, there was no convincing evidence that hKCa3 CAG lengths differ between schizophrenics and controls. We did, however, observe a trend (P = 0.063) toward over-representation of long (> or = 19) CAG repeats in the shorter of the two hKCa3 alleles in schizophrenics. There was no evidence of excessive parental transmission of long CAG repeat alleles to affected offspring. In addition, we re-mapped hKCa3 and found that it resides on chromosome 1q21, in a region which has been linked to familial hemiplegic migraine, but not to schizophrenia. These data provide no significant support for the association of hKCa3 with schizophrenia.

Vertebrate retinal ganglion cells are selected from competent progenitors by the action of Notch.

The first cells generated during development of the vertebrate retina are the ganglion cells, the projection neurons of the retina. Although they are one of the most intensively studied cell types within the central nervous system, little is known of the mechanisms that determine ganglion cell fate. We demonstrate that ganglion cells are selected from a large group of competent progenitors that comprise the majority of the early embryonic retina and that differentiation within this group is regulated by Notch. Notch activity in vivo was diminished using antisense oligonucleotides or augmented using a retrovirally transduced constitutively active allele of Notch. The number of ganglion cells produced was inversely related to the level of Notch activity. In addition, the Notch ligand Delta inhibited retinal progenitors from differentiating as ganglion cells to the same degree as did activated Notch in an in vitro assay. These results suggest a conserved strategy for neurogenesis in the retina and describe a versatile in vitro and in vivo system with which to examine the action of the Notch pathway in a specific cell fate decision in a vertebrate.

Cell fate determination in the vertebrate retina.

In the vertebrate central nervous system, the retina has been a useful model for studies of cell fate determination. Recent results from studies conducted in vitro and in vivo suggest a model of retinal development in which both the progenitor cells and the environment change over time. The model is based upon the notion that the mitotic cells within the retina change in their response properties, or "competence", during development. These changes presage the ordered appearance of distinct cell types during development and appear to be necessary for the production of the distinct cell types. As the response properties of the cells change, so too do the environmental signals that the cells encounter. Together, intrinsic properties and extrinsic cues direct the choice of cell fate.

The human inward rectifier K(+) channel subunit kir5.1 (KCNJ16) maps to chromosome 17q25 and is expressed in kidney and pancreas.

A novel human Kir5.1 (inward rectifier K+ channel subunit, gene name KCNJ16) was identified through database searches. This human KCNJ16 was mapped to chromosome 17q25. The full-length cDNA was identified and its genomic structure was determined. Tissue distribution studies showed that human KCNJ16 is significantly expressed in human kidney, pancreas and thyroid gland. In situ hybridization revealed expression in convoluted tubule cells of kidney and in the acinar and ductal cells of pancreas. These suggest that human Kir5.1 may be involved in the regulation of fluid and pH balance, thus making it a potential therapeutic target for hypertension, renal failure, or pancreatic disease.

Expression of cysteinyl leukotriene synthetic and signalling proteins in inflammatory cells in active seasonal allergic rhinitis.

BACKGROUND: Cysteinyl leukotrienes (CysLTs) are bioactive lipids that have been shown to contribute to allergic and inflammatory diseases. Eosinophils and mast cells have the capacity to produce large amounts of CysLTs after allergic or non-allergic stimulation. Molecular identification of both the synthetic and signalling proteins in the CysLT pathway allows the investigation of expression of the CysLT enzymes and receptors in active allergic rhinitis. OBJECTIVE: We examined the expression of the proteins involved in the synthesis of CysLTs and the cysteinyl leukotriene-1 (CysLT1) and cysteinyl leukotriene-2 (CysLT2) receptors in inflammatory cells from patients with active seasonal allergic rhinitis. METHODS: Nasal lavage samples were obtained from patients during active seasonal allergic rhinitis. Specific cellular immunocytochemical techniques were used to detect the cysteinyl leukotriene synthetic proteins, namely 5-lipoxygenase (5-LO), 5-lipoxygenase-activating protein (FLAP) and leukotriene C4 synthase (LTC4S). In situ hybridization and immunocytochemical techniques were used to identify the mRNA and proteins for the CysLT1 and CysLT2 receptors. RESULTS: 5-LO, FLAP and LTC4S, and the CysLT1 and CysLT2 receptors were expressed in the majority of eosinophils and in subsets of mast cells and mononuclear cells. 5-LO, FLAP and the CysLT1 receptor, but not LTC4S or the CysLT2 receptor, were expressed in a subset of nasal neutrophils. CONCLUSIONS: Our study demonstrates the presence of CysLT pathway proteins in key allergic and inflammatory cells from the upper airway of patients with active seasonal allergic rhinitis. Our expression data highlight the potential of CysLT-modifying agents to treat both upper and lower airway symptoms in patients suffering from allergic rhinitis and asthma.