A challenge in clinical genomics is to predict whether copy number variation (CNV) affecting a gene or multiple genes will manifest as disease. Increasing recognition of gene dosage effects in ...neurodevelopmental disorders prompted us to develop a computational approach based on critical-exon (highly expressed in brain, highly conserved) examination for potential etiologic effects. Using a large CNV dataset, our updated analyses revealed significant (P < 1.64 × 10(-15)) enrichment of critical-exons within rare CNVs in cases compared to controls. Separately, we used a weighted gene co-expression network analysis (WGCNA) to construct an unbiased protein module from prenatal and adult tissues and found it significantly enriched for critical exons in prenatal (P < 1.15 × 10(-50), OR = 2.11) and adult (P < 6.03 × 10(-18), OR = 1.55) tissues. WGCNA yielded 1,206 proteins for which we prioritized the corresponding genes as likely to have a role in neurodevelopmental disorders. We compared the gene lists obtained from critical-exon and WGCNA analysis and found 438 candidate genes associated with CNVs annotated as pathogenic, or as variants of uncertain significance (VOUS), from among 10,619 developmental delay cases. We identified genes containing CNVs previously considered to be VOUS to be new candidate genes for neurodevelopmental disorders (GIT1, MVB12B and PPP1R9A) demonstrating the utility of this strategy to index the clinical effects of CNVs.
Human SCO1 and SCO2 are paralogous genes that code for metallochaperone proteins with essential, but poorly understood, roles in copper delivery to cytochrome c oxidase (COX). Mutations in these ...genes produce tissue-specific COX deficiencies associated with distinct clinical phenotypes, although both are ubiquitously expressed. To investigate the molecular function of the SCO proteins, we characterized the mitochondrial copper delivery pathway in SCO1 and SCO2 patient backgrounds. Immunoblot analysis of patient cell lines showed reduced levels of the mutant proteins, resulting in a defect in COX assembly, and the appearance of a common assembly intermediate. Overexpression of the metallochaperone COX17 rescued the COX deficiency in SCO2 patient cells but not in SCO1 patient cells. Overexpression of either wild-type SCO protein in the reciprocal patient background resulted in a dominant-negative phenotype, suggesting a physical interaction between SCO1 and SCO2. Chimeric proteins, constructed from the C-terminal copper-binding and N-terminal matrix domains of the two SCO proteins failed to complement the COX deficiency in either patient background, but mapped the dominant-negative phenotype in the SCO2 background to the N-terminal domain of SCO1, the most divergent part of the two SCO proteins. Our results demonstrate that the human SCO proteins have non-overlapping, cooperative functions in mitochondrial copper delivery. Size exclusion chromatography suggests that both the proteins function as homodimers. We propose a model in which COX17 delivers copper to SCO2, which in turn transfers it directly to the CuA site at an early stage of COX assembly in a reaction that is facilitated by SCO1.
Methodological study using correlational methods.
To determine the intratester and intertester reliability and concurrent validity of the figure-of-eight method of measuring hand size in patients ...with hand pathology.
Measuring edema is an important component of the physical examination of patients with conditions affecting the hand. The figure-of-eight method of measuring hand size has been suggested as an alternative to volumetry. The reliability and concurrent validity of the figure-of-eight method has been established in individuals without hand pathology, but not in patients with conditions involving the hand.
Participants were 24 patients with conditions affecting the hand, 9 with bilateral involvement. Two testers performed 3 figure-of-eight measurements of hand size each. A third tester performed 2 volumetric measurements. Intraclass correlation coefficient (ICC3,1) was used to determine intratester reliability of both measurement procedures. ICC2,3 was used to examine intertester reliability of the figure-of-eight method. Pearson product moment correlation coefficients examining the association between the 2 methods were used to establish concurrent validity of the figure-of-eight technique.
Intratester ICCs for figure-of-eight and volumetric methods were 0.98 to 0.99. The intertester ICC for the figure-of-eight method was 0.99. Pearson correlation coefficients examining the relationship between the 2 methods were 0.92 to 0.94.
The figure-of-eight method is a reliable and valid measure of hand size in individuals with conditions affecting the hand.
The attractors of bimanual rhythmic coordination are given as the solutions of a motion equation in relative phase. How are those attractors affected by cognitive activity? In 3 experiments, ...participants (N = 10 in Experiments 1 and 2; N = 5 in Experiment 3) were required to produce in-phase or antiphase coordination while they either did or did not perform an information-reduction task. The average absolute deviation from in-phase (0°) and antiphase (180°) satisfying a particular parameterization of the motion equation was amplified by cognitive activity. That amplification of absolute phase shift was the same for both in-phase and antiphase coordination. Furthermore, the amplification (in degrees) increased linearly with the magnitude of cognitive activity (in bits). Cognitive activity had limited influence on the variability of relative phase and did not affect its average signed deviation. Collectively, the results suggest that cognitive activity produces a shift in the attractors of bimanual coordination dynamics that is directionally nonspecific and is independent of movement speed, detuning, and the in-phase-antiphase distinction.
Lumbar traction is commonly used to treat patients with back pain. Typically, clinicians rely on expert opinion in making decisions about when and how to implement lumbar traction. The purpose of ...this paper was to review current knowledge of lumbar traction and to identify what, if any, empirical evidence supports the expert opinions. This review found that whereas the mechanical effects of lumbar traction are well substantiated, the results of studies examining clinical effectiveness are conflicting. The failure to conclusively demonstrate the clinical benefit of lumbar traction may be related to the varied diagnostic categories and treatment techniques employed in the studies. Of the 10 types of lumbar traction described in the literature, static and intermittent mechanical traction are the two most commonly used. Indications, contraindications, and treatment techniques for these two types of traction are discussed. Based on the findings of this review, further study is needed to determine optimal treatment duration, frequency, and mode of administering lumbar traction. Also, classification systems to identify patients most likely to benefit from traction need to be developed and validated.
Two AAA proteases, each with its catalytic site at the opposite membrane surface, mediate the ATP-dependent degradation of mitochondrial inner membrane proteins. We demonstrate here that a model ...substrate polypeptide containing hydrophilic domains at both sides of the membrane can be completely degraded by either of the AAA proteases, if solvent-exposed domains are in an unfolded state. A short protein tail protruding from the membrane surface is sufficient to allow the proteolytic attack of an AAA protease that facilitates domain unfolding at the opposite side. Our results provide a rationale for the membrane arrangement of AAA proteases in mitochondria and demonstrate that degradation of membrane proteins by AAA proteases involves an active extraction of transmembrane segments and transport of solvent-exposed domains across the membrane.
70% partial hepatectomy (PH) in the rat causes a release, into the cytosolic fraction, of mitochondrial matrix proteins, namely the mitochondrial isoform of aspartate aminotransferase (mAAT) and ...malate dehydrogenase (MDH), during the first 24 h after PH, when no growth of the residual liver is observed. After this time interval, the weight of the liver starts to increase and the normal weight is reached at 96 h after PH. This proliferative phase is characterized by a progressive recovery of the normal levels of intramitochondrial activities of mAAT and MDH. Mitochondria isolated at 24 h after PH show a membrane permeabilization to sucrose accompanied by a release of matrix enzymes; both are blocked by cyclosporin A. These results suggest an alteration of mitochondrial membrane integrity, during the prereplicative phase of liver regeneration, with the occurrence of an increased permeability that allows the passage into the cytosol of matrix enzymes.
To describe a new method for measuring lateral neck flexion range of motion (ROM), document the reliability of the method and present estimates of normal.
One hundred thirty-five subjects ranging in ...age from 14-95 yr. Two physical therapists with 13 and 2 yr of experience, respectively, served as testers.
Measurement of active lateral neck flexion ROM using a universal goniometer modified by the placement of a portion of a small paper clip through the axis. The goniometer arms were aligned with the subject's nose, and the free-swinging paper clip (pendulum) was used as a marker. The more experienced therapist measured lateral flexion of 100 subjects to establish intratester reliability and estimates of normal. Both therapists measured 35 subjects to determine intertester reliability.
Degrees of lateral neck flexion.
Intraclass correlation coefficients for intratester reliability exceeded 0.90. Coefficients for intertester reliability were 0.86 and 0.65. ROM decreased with increasing age.
The modified goniometer is inexpensive, easy to use and can yield high intratester reliability and satisfactory intertester reliability. The estimates of normal provide preliminary values with which a patient's lateral neck flexion ROM can be compared.
James Cyriax's approach to diagnosis and treatment of soft tissue disorders is frequently used by orthopaedic and sport physical therapists. The reliability of using Cyriax's system to determine ...diagnostic categories, however, has not been established. The purpose of this study was to examine the intertherapist reliability of assessments made using Cyriax's shoulder evaluation. Twenty-one cases of painful shoulder were evaluated independently by two experienced physical therapists. Therapists used a checklist to indicate their assessment of each case by selecting a specific shoulder lesion or by indicating that the case did not fit the Cyriax model. Cohen's kappa statistic was used to measure intertherapist agreement. Therapists classified 19 of the 21 cases into the same diagnostic category for a percent agreement of 90.5%. The kappa value was .875, indicating "almost perfect" agreement. Both therapists classified the same four cases of painful shoulder as not fitting the Cyriax model of soft tissue examination. The results of this study show that the Cyriax evaluation can be a highly reliable schema for assessing patients with shoulder pain.
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