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At least 253 records · Page 14Linked to original sources
PubMed2001

Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function.

Loss of fragile X mental retardation protein (FMRP) function causes the fragile X mental retardation syndrome. FMRP harbors three RNA binding domains, associates with polysomes, and is thought to regulate mRNA translation and/or localization, but the RNAs to which it binds are unknown. We have used RNA selection to demonstrate that the FMRP RGG box binds intramolecular G quartets. This data allowed us to identify mRNAs encoding proteins involved in synaptic or developmental neurobiology that harbor FMRP binding elements. The majority of these mRNAs have an altered polysome association in fragile X patient cells. These data demonstrate that G quartets serve as physiologically relevant targets for FMRP and identify mRNAs whose dysregulation may underlie human mental retardation.

Base Sequence↗
PubMed1993

Loss of function of the Drosophila zfh-1 gene results in abnormal development of mesodermally derived tissues.

The Drosophila zfh-1 gene encodes an unusual protein with nine Cys2His2 type zinc-finger motifs and one homeodomain that shows a complex pattern of expression in the embryonic mesoderm and nervous system. To study the function of zfh-1, we generated loss-of-function zfh-1 mutations. Phenotypic analysis of zfh-1 mutant embryos reveals that the gene is not required for the initial segregation of the mesoderm or for the differentiation of mesodermally derived tissues. Rather, loss of zfh-1 function results in various degrees of local errors in cell fate or positioning.

Alleles↗
PubMed1993

Duchenne-Becker muscular dystrophy and the nondystrophic myotonias. Paradigms for loss of function and change of function of gene products.

Recessively inherited disorders can most often be considered loss of function: the patient has only defective copies of the defective gene (homozygous or hemizygous), with little or no functional protein products produced. Dominantly inherited disorders can most often be considered change of function: the patient has both mutant and normal copies of the gene (heterozygous); however, the mutant gene produces an abnormal protein product that causes dysfunction of the cell. Categorization of inherited disorders simply by their inheritance pattern thus affords some predictions concerning the underlying biochemical defect. To illustrate these generalizations, the molecular data on two important human inherited neurologic disorders will be described. X-linked recessive Duchenne/Becker muscular dystrophy has been shown to caused by loss of function of the dystrophin product. Dominantly inherited hyperkalemic periodic paralysis and paramyotonia congenita have been shown to be the result of single amino acid changes of the skeletal muscle voltage-sensitive sodium channel that alter the channel's function in response to environmental or physiologic stimuli (change of function).

Dystrophin↗
PubMed1996

Titrating for antiproteinuric effect: the clue to renoprotection?

Proteinuria may be involved in the final common pathway of progressive renal function loss. If so, intervention treatment that reduces proteinuria might prevent or retard long-term renal function loss. In renal patients and in experimental renal disease the severity of proteinuria is associated with the rate of long-term renal function loss. Several large trials on the prevention of long-term renal function loss by antihypertensive treatment with ACE inhibitors (ACEi), were recently completed in diabetic and in non-diabetic renal disease. In those studies long-term renal function loss could indeed be retarded by ACEi; these ACEi regimens were associated with a more effective reduction of proteinuria than control regimens. In studies with a single treatment regimen (drug treatment or a protein restricted diet) a more effective reduction of proteinuria is associated with a more favourable long-term course of renal function as well. As reduction of proteinuria is mostly associated with a lower blood pressure (BP) the respective contributions of the fall in BP and in proteinuria are hard to dissect. Remarkably, however, the efficacy of the reduction of proteinuria (but not of BP) at onset of antihypertensive treatment is predictive of long-term renal outcome. Albeit consistent with a causal role of proteinuria reduction in renoprotection these data cannot distinguish between proteinuria as a marker or a mediator of renal damage. In view of the consistent association of antiproteinuric efficacy with long-term renal outcome we suggest that it would be worthwhile to attempt to improve long-term renoprotection by a strategy aimed at enhancing antiproteinuric efficacy. This approach is feasible as antiproteinuric efficacy of ACEi can be enhanced in several ways, ie, by dietary sodium and protein restriction and by adding a diuretic or indomethacin. Such a strategy would require that titration for adequate BP control is followed by titration for a maximal antiproteinuric effect. If this treatment strategy would improve long-term renal outcome, it would not only be a step forward in the clinical treatment of chronic renal failure, but it would also provide compelling evidence for a causal role of proteinuria in the progression of renal disease.

Humans↗
PubMed1994

Detection of functional vision loss using the Ishihara plates.

Many techniques have been described for the detection of functional visual loss. We report four cases in which Ishihara pseudo-isochromatic colour plates gave objective evidence of functional vision loss. In all cases the patients were able to read the first test pattern (No. 12), but could not distinguish any of the following pseudo-isochromatic numbers (plates 2-17). However, they experienced no difficulty in tracing the winding lines (plates 18-24), demonstrating that they in fact had normal colour vision.

Adolescent↗
PubMed2006

A discriminative learning framework with pairwise constraints for video object classification.

To deal with the problem of insufficient labeled data in video object classification, one solution is to utilize additional pairwise constraints that indicate the relationship between two examples, i.e., whether these examples belong to the same class or not. In this paper, we propose a discriminative learning approach which can incorporate pairwise constraints into a conventional margin-based learning framework. Different from previous work that usually attempts to learn better distance metrics or estimate the underlying data distribution, the proposed approach can directly model the decision boundary and, thus, require fewer model assumptions. Moreover, the proposed approach can handle both labeled data and pairwise constraints in a unified framework. In this work, we investigate two families of pairwise loss functions, namely, convex and nonconvex pairwise loss functions, and then derive three pairwise learning algorithms by plugging in the hinge loss and the logistic loss functions. The proposed learning algorithms were evaluated using a people identification task on two surveillance video data sets. The experiments demonstrated that the proposed pairwise learning algorithms considerably outperform the baseline classifiers using only labeled data and two other pairwise learning algorithms with the same amount of pairwise constraints.

Algorithms↗
PubMed2000

Autoimmune T cells retard the loss of function in injured rat optic nerves.

We recently demonstrated that autoimmune T cells protect neurons from secondary degeneration after central nervous system (CNS) axotomy in rats. Here we show, using both morphological and electrophysiological analyses, that the neuroprotection is long-lasting and is manifested functionally. After partial crush injury of the rat optic nerve, systemic injection of autoimmune T cells specific to myelin basic protein significantly diminished the loss of retinal ganglion cells and conducting axons, and significantly retarded the loss of the visual response evoked by light stimulation. These results support our challenge to the traditional concept of autoimmunity as always harmful, and suggest that in certain situations T cell autoimmunity may actually be beneficial. It might be possible to employ T cell intervention to slow down functional loss in the injured CNS.

Animals↗
PubMed1976

Pure tone-spondee threshold relationships in functional hearing loss: a hypothesis.

A hypothesis is offered to account for the fact that in functional hearing loss, spondee threshold is frequently significantly lower than the pure-tone average. The hypothesis has three basic components: (1) that patients with functional hearing loss use a loudness criterion in making response decisions to suprathreshold stimuli; (2) that, at suprathreshold levels, pure tones and spondee words appear equally loud at equal sound pressure levels, and (3) that calibration values employed in pure-tone and speech audiometry contribute to the aberrant speech-pure tone relationship. Factors that may confound the speech-pure tone relationship are discussed as are the clinical and research implication of the hypothesis.

Audiometry↗
PubMed2003

Is loss of function of the prion protein the cause of prion disorders?

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases that involve misfolding of the prion protein. Recent studies have provided evidence that normal prion protein might have a physiological function in neuroprotective signaling, suggesting that loss of prion protein activity might contribute to the pathogenesis of prion disease. However, studies using knockout animals do not support the loss-of-function hypothesis and argue that prion neurodegeneration might be associated with a gain of a toxic activity by the misfolded prion protein. Thus, the mechanism of neurodegeneration in spongiform encephalopathies remains enigmatic.

Animals↗
PubMed2001

Loss-of-function mutations reveal that the Drosophila nautilus gene is not essential for embryonic myogenesis or viability.

nautilus (nau), the single Drosophila member of the bHLH-containing myogenic regulatory family of genes, is expressed in a subset of muscle precursors and differentiated fibers. It is capable of inducing muscle-specific transcription as well as myogenic transformation, and plays a role in the differentiation of a subset of muscle precursors into mature muscle fibers. In previous studies, the nau zygotic loss-of-function phenotype was determined using genetic deficiencies in which the gene is deleted. We note that this genetic loss-of-function phenotype differs from the loss-of-function phenotype determined using RNA interference (L. Misquitta and B. M. Paterson, 1999, Proc. Natl. Acad. Sci. USA 96, 1451-1456). The present study re-examines this loss-of-function phenotype using EMS-induced mutations that specifically alter the nau gene, and extends the genetic analysis to include the loss of both maternal and zygotic nau function. In brief, embryos lacking nau both maternally and zygotically are missing a distinct subset of muscle fibers, consistent with its apparent expression in a subset of muscle fibers. The muscle loss is tolerated, however, such that the loss of nau both maternally and zygotically does not result in lethality at any stage of development.

Animals↗
PubMed2002

A role for dystroglycan in epithelial polarization: loss of function in breast tumor cells.

Receptors mediating cell-basement membrane interactions are potent regulators of epithelial architecture and function, and alterations in signals from the basement membrane are implicated in the aberrant behavior of carcinoma cells. In this study, we have investigated the role of the basement membrane receptor dystroglycan (DG) in mammary epithelial cell function, and the significance of loss of DG function in breast tumor cell lines. Nonmalignant mammary epithelial cells express a functional DG. Analysis of multiple breast carcinoma cell lines revealed that DG is expressed in all of the cell lines examined, as evidenced by beta-DG expression, but that alpha-DG is functionally diminished in the majority. High levels of alpha-DG correlated strongly with the ability of cells to polarize in the presence of the basement membrane. Overexpression of the DG cDNA in HMT-3522-T4-2 cells elevated alpha-DG levels and altered responsiveness to the basement membrane; DG overexpression restored the ability of the cells to undergo cytoskeletal changes, to polarize, and to restrict growth in response to basement membrane proteins. Moreover, restoration of DG function to these cells greatly reduced their tumorigenic potential in nude mice. These data point to DG as an important mediator of normal cell responses to the basement membrane, and as a significant variable in carcinoma cells, in which its frequent loss can contribute to aberrant cell behavior.

Basement Membrane↗
PubMed2026

CRISPR/Cas9 loss-of-function screen in a neuronal model of AP-4 deficiency identifies ATG9A trafficking modulators.

Biallelic loss-of-function variants in adaptor protein complex 4 (AP-4) disrupt trafficking of transmembrane proteins at the trans-Golgi network, including autophagy-related protein 9A (ATG9A), leading to childhood-onset hereditary spastic paraplegia (AP-4-HSP). AP-4-HSP is characterized by features of both a neurodevelopmental and a degenerative neurological disease. To investigate the molecular mechanisms underlying AP-4-HSP and identify potential therapeutic targets, we conducted an arrayed CRISPR/Cas9 loss-of-function screen of 8,478 genes, targeting the "druggable genome," in a human neuronal model of AP-4 deficiency. Through this phenotypic screen and subsequent experiments, key modulators of ATG9A trafficking were identified, and complementary pathway analyses provided insights into the regulatory landscape of ATG9A transport. Knockdown of ANPEP and NPM1 enhanced ATG9A availability outside the trans-Golgi network, suggesting that they regulate ATG9A localization. These findings deepen our understanding of ATG9A trafficking in the context of AP-4 deficiency and offer a framework for the development of targeted interventions for AP-4-HSP.

Humans↗
PubMed2004

Computerized kinetic perimetry detects tubular visual fields in patients with functional visual loss.

PURPOSE: To report a novel test that uses computerized kinetic perimetry to detect tubular visual fields in patients with functional visual loss. DESIGN: Observational case series. METHODS: Ten patients who demonstrated generalized visual field constriction on prior examinations underwent testing combining computerized kinetic perimetry with a reversed Galilean telescope, used for optical visual field expansion. RESULTS: Six patients with physiologic visual field constriction demonstrated expansion of their visual fields with the use of the reversed telescope. Four patients with functional visual loss responded to the reversed telescope by demonstrating tubular visual fields, with responses equal to or smaller than their demonstrated visual fields delineated without the telescope. CONCLUSIONS: This test uses a computerized kinetic examination to reduce the subjective nature of tangent screen testing for tubular visual fields and to provide a computerized recording of visual fields. This method is a novel and easy-to-use technique to demonstrate functional visual loss.

Computing Methodologies↗
PubMed1999

Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma.

Loss of tumor suppressors that restrain important oncoproteins such as c-Myc may contribute to malignant progression. Bin1 is an adapter protein with features of a tumor suppressor that was identified through its interaction with and inhibition of the oncogenic properties of c-Myc. In this study, we analyzed the patterns of Bin1 expression in normal melanocytes and melanoma cells at different stages of tumor progression. Evidence is provided that Bin1 function is abrogated in melanoma cells by a mechanism based on aberrant splicing of a tissue-specific exon. Specifically, most melanoma cells inappropriately expressed exon 12A, which is spliced alternately into Bin1 isoforms found in brain but not into isoforms found in melanocytes and many other nonneuronal cells. Exon 12A sequences abolished the ability of Bin1 to inhibit malignant transformation by c-Myc or adenovirus E1A. Similarly, these sequences abolished the ability of Bin1 to induce programmed cell death in melanoma cells that endogenously expressed exon 12A. Our findings suggest that aberrant splicing of Bin1 may contribute to melanoma progression, and they define a mechanism by which the activity of a tumor suppressor can be eliminated in cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Vestibular ocular reflexes in Ménière's disease patients evaluated by passive high frequency head rotation (yaw) and sidewards acceleration.

Despite the fact that vertigo is the most apparent complaint at the onset of Ménière's disease, standard vestibular examination seldom shows vestibular function loss in the early phase. In this study, three relatively advanced diagnostic tests (passive high frequency head shaking, passive head impulse test and sidewards linear acceleration) were applied to trace vestibular function loss in the early phase in 25 patients with possible Ménière's disease (American Academy of Otolaryngology-Head and Neck Surgery 1995 criteria); one test (passive high frequency head shaking) was also conducted in 20 chronic definite Ménière's disease patients. Head movements were induced by a head shaker and whole-body linear translation by a motor-driven linear slit. Eye movements were detected by electro-oculography (head shaking) and the scleral coil technique (impulse test and linear translation). Standard vestibular examination showed no vestibular function loss in the early phase patient group. In contrast, 17 out of 25 patients (68%) showed a phase lag upon head shaking that was 1-2 degrees larger than the 95% confidence interval in healthy subjects; the remaining 8 patients showed a normal phase lag. Gain was normal in all 25 patients. In the chronic patient group, standard vestibular examination was abnormal (calorics) in 16 out of 20 patients (60%) and 18 out of 20 (90%) showed an abnormal phase on passive head shaking. In 11 of the 25 early phase patients (44%), an increased latency was observed in the response to a passive head impulse to one side. The side to which the abnormal latency occurred did not correspond to the documented or reported side of the hearing loss in 2 out of the 11 patients. The amplitude of ocular counter rolling induced by sidewards sinusoidal translation was reduced in 17 out of the 25 early phase Ménière's disease patients, of whom 6 showed a normal head impulse and head shaking test. Our findings indicate that vestibular function loss occurs in Ménière's disease patients within 9 months of the first vertigo attack. Also, the results support the hypothesis that, at least in some patients, function loss in the statolith system might precede function loss in the horizontal canals.

Acceleration↗
PubMed2001

Which HAQ is best? A comparison of the HAQ, MHAQ and RA-HAQ, a difficult 8 item HAQ (DHAQ), and a rescored 20 item HAQ (HAQ20): analyses in 2,491 rheumatoid arthritis patients following leflunomide initiation.

OBJECTIVE: To determine whether the full Health Assessment Questionnaire (HAQ), the shortened modified HAQ (MHAQ), or the new shortened RA-HAQ, developed on the basis of Rasch item response theory (IRT), performs best in terms of distributional characteristics, detection of functional loss, and identification of change in functional status in patients with active rheumatoid arthritis (RA). METHODS: A total of 2,491 clinic patients with RA with active disease from the practices of 519 US rheumatologists were assessed by questionnaire at the time leflunomide was started and at subsequent followup when there had been sufficient time for response. RESULTS: The HAQ scores were almost normally distributed along the 0-3 scale, but 95% of MHAQ and RA-HAQ values were clustered between 0 and 1.5. Normal or minimally abnormal scores (0 or 0.125) were noted in 6.6% of HAQ but in 21-22% of MHAQ/RA-HAQ. Mild functional loss (< or =0.375) was found in 12.7, 39.1, and 36.1% of patients by the HAQ, MHAQ, and RA-HAQ, respectively. This indicates that the MHAQ and RA-HAQ generally fail to identify appropriately the extent of functional loss in RA. The HAQ was significantly better at detecting changes than the MHAQ or RA-HAQ, with relative efficiencies of 1.28 and 1.37 compared to the MHAQ and RA-HAQ, respectively. This results in roughly a 20-26% reduction in sample size requirements. Two additional HAQ were identified that performed better than the HAQ itself, a 20 item HAQ without the use of aids and devices and an 8 item HAQ composed of the most difficult item in each of the 8 HAQ subscale categories. CONCLUSION: The HAQ is better (more efficient) than the MHAQ or RA-HAQ at detecting treatment change, and identifies the extent of functional disability better than the shortened questionnaires. The 3 questionnaires have different means, sensitivities, and distributional properties and cannot be thought of as simply different versions of the same questionnaire. The benefits of the MHAQ and RA-HAQ are that they are short and easier to score. But these benefits come at the price of loss of sensitivity and loss of sensitivity to change. The 20 item HAQ and the difficult 8 item HAQ are intriguing additional choices that are worthy of further study.

Aged↗
PubMed2002

Urinary incontinence and psychological distress in community-dwelling older adults.

OBJECTIVES: To examine the relationship between urinary incontinence (UI) and psychological distress in older adults. We hypothesized that persons with UI associated with condition-specific functional loss would be most likely to report psychological distress. DESIGN: A population-based longitudinal survey. SETTING: Continuing participants in a study of community-dwelling adults who were initially living in East Baltimore in 1981. PARTICIPANTS: Persons aged 50 and older (n=781) at follow-up interviews conducted between 1993 and 1996 for whom complete data were available. MEASUREMENTS: Participants were classified as incontinent if they reported any uncontrolled urine loss within the 12 months preceding the 13-year follow-up interview. Condition-specific functional loss secondary to UI was further assessed based on a series of questions relating directly to participants' inability to engage in certain activities due to their UI. Psychological distress was assessed using the General Health Questionnaire (GHQ) at interviews in 1981 and at the 13-year follow-up. RESULTS: Persons with UI were more likely to experience psychological distress as measured by the GHQ than were persons without UI (unadjusted odds ratio (OR)=1.74, 95% confidence interval (CI)=1.13-2.68). Persons with condition-specific functional loss secondary to UI were substantially more likely to have psychological distress as measured by the GHQ than were persons without UI (unadjusted OR=4.02, 95% CI=1.86-8.70). In multivariate models that controlled for potentially influential characteristics such as age, gender, ethnicity, and chronic medical conditions the association between condition-specific functional loss secondary to UI and psychological distress remained statistically significant. Among people with UI, persons with persistently elevated GHQ scores were much more likely to report condition-specific functional impairment from UI (adjusted OR=6.55, 95% CI=1.94-22.12). CONCLUSION: Individuals with UI, especially when incontinence was associated with condition-specific functional loss, were more likely to have psychological distress than were other older adults. Our findings support a general conceptual model that condition-specific functional impairment mediates the relationship between a chronic medical condition and psychological distress.

Age Factors↗