Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling.

Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies." However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR.

N-Acetylaspartate and Choline Metabolites in Cortical and Subcortical Regions in Clinical High Risk Relative to Healthy Control Subjects: An Exploratory 7T MRSI Study.

N-acetylaspartate (NAA) and choline (Cho) are two brain metabolites implicated in several key neuronal functions. Abnormalities in these metabolites have been reported in both early course and chronic patients with schizophrenia (SCZ). It is, however, unclear whether NAA and Cho's alterations occur even before the onset of the disorder. Clinical high risk (CHR) individuals are a population uniquely enriched for psychosis and SCZ. In this exploratory study, we utilized 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to examine differences in total NAA (tNAA; NAA + N-acetylaspartylglutamate [NAAG]) and major choline-containing compounds, including glycerophosphorylcholine and phosphorylcholine [tCho], over the creatine (Cre) levels between 26 CHR and 32 healthy control (HC) subjects in the subcortical and cortical regions. While no tCho/Cre differences were found between groups in any of the regions of interest (ROIs), we found that CHR had significantly reduced tNAA/Cre in the right dorsal lateral prefrontal cortex (DLPFC) compared to HC, and that the right DLPFC tNAA/Cre reduction in CHR was negatively associated with their positive symptoms scores. No tNAA/Cre differences were found between CHR and HC in other ROIs. In conclusion, reduced tNAA/Cre in CHR vs. HC may represent a putative molecular biomarker for risk of psychosis and SCZ that is associated with symptom severity.

Aviation Noise Impacts: State of the Science.

Noise is defined as "unwanted sound." Aircraft noise is one, if not the most detrimental environmental effect of aviation. It can cause community annoyance, disrupt sleep, adversely affect academic performance of children, and could increase the risk for cardiovascular disease of people living in the vicinity of airports. In some airports, noise constrains air traffic growth. This consensus paper was prepared by the Impacts of Science Group of the Committee for Aviation Environmental Protection of the International Civil Aviation Organization and summarizes the state of the science of noise effects research in the areas of noise measurement and prediction, community annoyance, children's learning, sleep disturbance, and health. It also briefly discusses civilian supersonic aircraft as a future source of aviation noise.

Personal and situational variables associated with wind turbine noise annoyance.

The possibility that wind turbine noise (WTN) affects human health remains controversial. The current analysis presents results related to WTN annoyance reported by randomly selected participants (606 males, 632 females), aged 18-79, living between 0.25 and 11.22 km from wind turbines. WTN levels reached 46 dB, and for each 5 dB increase in WTN levels, the odds of reporting to be either very or extremely (i.e., highly) annoyed increased by 2.60 [95% confidence interval: (1.92, 3.58), p < 0.0001]. Multiple regression models had R(2)'s up to 58%, with approximately 9% attributed to WTN level. Variables associated with WTN annoyance included, but were not limited to, other wind turbine-related annoyances, personal benefit, noise sensitivity, physical safety concerns, property ownership, and province. Annoyance was related to several reported measures of health and well-being, although these associations were statistically weak (R(2 )< 9%), independent of WTN levels, and not retained in multiple regression models. The role of community tolerance level as a complement and/or an alternative to multiple regression in predicting the prevalence of WTN annoyance is also provided. The analysis suggests that communities are between 11 and 26 dB less tolerant of WTN than of other transportation noise sources.

Auditory and non-auditory effects of noise on health.

Noise is pervasive in everyday life and can cause both auditory and non-auditory health effects. Noise-induced hearing loss remains highly prevalent in occupational settings, and is increasingly caused by social noise exposure (eg, through personal music players). Our understanding of molecular mechanisms involved in noise-induced hair-cell and nerve damage has substantially increased, and preventive and therapeutic drugs will probably become available within 10 years. Evidence of the non-auditory effects of environmental noise exposure on public health is growing. Observational and experimental studies have shown that noise exposure leads to annoyance, disturbs sleep and causes daytime sleepiness, affects patient outcomes and staff performance in hospitals, increases the occurrence of hypertension and cardiovascular disease, and impairs cognitive performance in schoolchildren. In this Review, we stress the importance of adequate noise prevention and mitigation strategies for public health.

ICBEN review of research on the biological effects of noise 2011-2014.

The mandate of the International Commission on Biological Effects of Noise (ICBEN) is to promote a high level of scientific research concerning all aspects of noise-induced effects on human beings and animals. In this review, ICBEN team chairs and co-chairs summarize relevant findings, publications, developments, and policies related to the biological effects of noise, with a focus on the period 2011-2014 and for the following topics: Noise-induced hearing loss; nonauditory effects of noise; effects of noise on performance and behavior; effects of noise on sleep; community response to noise; and interactions with other agents and contextual factors. Occupational settings and transport have been identified as the most prominent sources of noise that affect health. These reviews demonstrate that noise is a prevalent and often underestimated threat for both auditory and nonauditory health and that strategies for the prevention of noise and its associated negative health consequences are needed to promote public health.

Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies.

Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.

Normal eyeblink classical conditioning in patients with fixed dystonia.

Fixed dystonia without evidence of basal ganglia lesions or neurodegeneration typically affects young women following minor peripheral trauma. We use eyeblink classical conditioning (EBCC) to study whether cerebellar functioning is abnormal in patients with fixed dystonia, since this is part of the pathophysiology of primary dystonia. An auditory tone (conditioning stimulus) was paired with a supraorbital nerve stimulus (unconditioned stimulus) with a delay of 400 ms in order to yield conditioned responses. We recruited 11 fixed dystonia patients of whom six used medication and seven age-matched healthy controls. Non-medicated patients with fixed dystonia performed as well as healthy controls, while medicated patients showed fewer conditioned responses. We found an influence of medication and possibly extent of dystonic features and/or co-occurrence of complex regional pain syndrome (CRPS) on EBCC performance. Our study argues against abnormal cerebellar function in non-medicated, fixed dystonia patients without CRPS or spread of symptoms.

Changes in electroencephalographic microstates between evening and morning are associated with overnight sleep slow waves in healthy individuals.

STUDY OBJECTIVES: Microstates are semi-stable voltage topographies that account for most of electroencephalogram (EEG) variance. However, the impact of time of the day and sleep on microstates has not been examined. To address this gap, we assessed whether microstates differed between the evening and morning and whether sleep slow waves correlated with microstate changes in healthy participants. METHODS: Forty-five healthy participants were recruited. Each participant underwent 6 minutes of resting state EEG recordings in the evening and morning, interleaved by sleep EEGs. Evening-to-morning changes in microstate duration, coverage, and occurrence were assessed. Furthermore, correlation between microstate changes and sleep slow-wave activity (SWA) and slow-wave density (SWD) were performed. RESULTS: Two-way ANOVAs with microstate class (A, B, C, and D) and time (evening and morning) revealed significant microstate class × time interaction for duration (F(44) = 5.571, p = 0.002), coverage (F(44) = 6.833, p = 0.001), and occurrence (F(44) = 5.715, p = 0.002). Post hoc comparisons showed significant effects for microstate C duration (padj = 0.048, Cohen's d = -0.389), coverage (padj = 0.002, Cohen's d = -0.580), and occurrence (padj = 0.002, Cohen's d = -0.606). Topographic analyses revealed inverse correlations between SWD, but not SWA, and evening-to-morning changes in microstate C duration (r = -0.51, padj = 0.002), coverage (r = -0.45, padj = 0.006), and occurrence (r = -0.38, padj = 0.033). CONCLUSIONS: Microstate characteristics showed significant evening-to-morning changes associated with, and possibly regulated by, sleep slow waves. These findings suggest that future microstate studies should control for time of day and sleep effects.

Prefrontal oscillatory slowing in early-course schizophrenia is associated with worse cognitive performance and negative symptoms: a TMS-EEG study.

BACKGROUND: Abnormalities in dorsolateral prefrontal cortex (DLPFC) oscillations are neurophysiological signatures of schizophrenia thought to underlie its cognitive deficits. Transcranial magnetic stimulation with electroencephalography (TMS-EEG) provides a measure of cortical oscillations unaffected by sensory relay functionality and/or patients' level of engagement, which are important confounding factors in schizophrenia. Previous TMS-EEG work showed reduced fast, gamma-range oscillations and a slowing of the main DLPFC oscillatory frequency, or natural frequency, in chronic schizophrenia. However, it is unclear whether this DLPFC natural frequency slowing is present in early-course schizophrenia (EC-SCZ) and is associated with symptom severity and cognitive dysfunction. METHODS: We applied TMS-EEG to the left DLPFC in 30 EC-SCZ and 28 healthy control (HC) subjects. Goal-directed working memory performance was assessed using the "AX" Continuous Performance Task (AX-CPT). The EEG frequency with the highest cumulative power at the stimulation site, or natural frequency, was extracted. We also calculated the local Relative Spectral Power (RSP) as the average power in each frequency band divided by the broadband power. RESULTS: Compared to HC, EC-SCZ had reduced DLPFC natural frequency (p=0.0000002, Cohen's d=-2.32) and higher DLPFC beta-range RSP (p=0.0003, Cohen's d=0.77). In EC-SCZ, the DLPFC natural frequency was inversely associated with negative symptoms. Across all participants, the beta-band RSP negatively correlated with the AX-CPT performance. CONCLUSIONS: A DLPFC oscillatory slowing is an early pathophysiological biomarker of schizophrenia that is associated with its symptom severity and cognitive impairments. Future work should assess whether non-invasive neurostimulation can ameliorate prefrontal oscillatory deficits and related clinical functions in EC-SCZ.

Natural Oscillatory Frequency Slowing in the Premotor Cortex of Early-Course Schizophrenia Patients: A TMS-EEG Study.

Despite the heavy burden of schizophrenia, research on biomarkers associated with its early course is still ongoing. Single-pulse Transcranial Magnetic Stimulation coupled with electroencephalography (TMS-EEG) has revealed that the main oscillatory frequency (or "natural frequency") is reduced in several frontal brain areas, including the premotor cortex, of chronic patients with schizophrenia. However, no study has explored the natural frequency at the beginning of illness. Here, we used TMS-EEG to probe the intrinsic oscillatory properties of the left premotor cortex in early-course schizophrenia patients (<2 years from onset) and age/gender-matched healthy comparison subjects (HCs). State-of-the-art real-time monitoring of EEG responses to TMS and noise-masking procedures were employed to ensure data quality. We found that the natural frequency of the premotor cortex was significantly reduced in early-course schizophrenia compared to HCs. No correlation was found between the natural frequency and age, clinical symptom severity, or dose of antipsychotic medications at the time of TMS-EEG. This finding extends to early-course schizophrenia previous evidence in chronic patients and supports the hypothesis of a deficit in frontal cortical synchronization as a core mechanism underlying this disorder. Future work should further explore the putative role of frontal natural frequencies as early pathophysiological biomarkers for schizophrenia.

Comparison of state-of-the-art deep learning architectures for detection of freezing of gait in Parkinson's disease.

Introduction: Freezing of gait (FOG) is one of the most debilitating motor symptoms experienced by patients with Parkinson's disease (PD). FOG detection is possible using acceleration data from wearable sensors, and a convolutional neural network (CNN) is often used to determine the presence of FOG epochs. We compared the performance of a standard CNN for the detection of FOG with two more complex networks, which are well suited for time series data, the MiniRocket and the InceptionTime. Methods: We combined acceleration data of people with PD across four studies. The final data set was split into a training (80%) and hold-out test (20%) set. A fifth study was included as an unseen test set. The data were windowed (2 s) and five-fold cross-validation was applied. The CNN, MiniRocket, and InceptionTime models were evaluated using a receiver operating characteristic (ROC) curve and its area under the curve (AUC). Multiple sensor configurations were evaluated for the best model. The geometric mean was subsequently calculated to select the optimal threshold. The selected model and threshold were evaluated on the hold-out and unseen test set. Results: A total of 70 participants (23.7 h, 9% FOG) were included in this study for training and testing, and in addition, 10 participants provided an unseen test set (2.4 h, 11% FOG). The CNN performed best (AUC = 0.86) in comparison to the InceptionTime (AUC = 0.82) and MiniRocket (AUC = 0.76) models. For the CNN, we found a similar performance for a seven-sensor configuration (lumbar, upper and lower legs and feet; AUC = 0.86), six-sensor configuration (upper and lower legs and feet; AUC = 0.87), and two-sensor configuration (lower legs; AUC = 0.86). The optimal threshold of 0.45 resulted in a sensitivity of 77% and a specificity of 58% for the hold-out set (AUC = 0.72), and a sensitivity of 85% and a specificity of 68% for the unseen test set (AUC = 0.90). Conclusion: We confirmed that deep learning can be used to detect FOG in a large, heterogeneous dataset. The CNN model outperformed more complex networks. This model could be employed in future personalized interventions, with the ultimate goal of using automated FOG detection to trigger real-time cues to alleviate FOG in daily life.

Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy.

BACKGROUND: Nephronophthisis associated ciliopathies (NPHP-AC) comprise a group of autosomal recessive cystic kidney diseases that includes nephronophthisis (NPHP), Senior-Loken syndrome (SLS), Joubert syndrome (JBTS), and Meckel-Gruber syndrome (MKS). To date, causative mutations in NPHP-AC have been described for 18 different genes, rendering mutation analysis tedious and expensive. To overcome the broad genetic locus heterogeneity, a strategy of DNA pooling with consecutive massively parallel resequencing (MPR) was devised. METHODS: In 120 patients with severe NPHP-AC phenotypes, five pools of genomic DNA with 24 patients each were prepared which were used as templates in order to PCR amplify all 376 exons of 18 NPHP-AC genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L, NEK8, TMEM67, INPP5E, TMEM216, AHI1, ARL13B, CC2D2A, TTC21B, MKS1, and XPNPEP3). PCR products were then subjected to MPR on an Illumina Genome-Analyser and mutations were subsequently assigned to their respective mutation carrier via CEL I endonuclease based heteroduplex screening and confirmed by Sanger sequencing. RESULTS: For proof of principle, DNA from patients with known mutations was used and detection of 22 out of 24 different alleles (92% sensitivity) was demonstrated. MPR led to the molecular diagnosis in 30/120 patients (25%) and 54 pathogenic mutations (27 novel) were identified in seven different NPHP-AC genes. Additionally, in 24 patients only single heterozygous variants of unknown significance were found. CONCLUSIONS: The combined approach of DNA pooling followed by MPR strongly facilitates mutation analysis in broadly heterogeneous single gene disorders. The lack of mutations in 75% of patients in this cohort indicates further extensive heterogeneity in NPHP-AC.

Examining First Night Effect on Sleep Parameters with hd-EEG in Healthy Individuals.

Difficulty sleeping in a novel environment is a common phenomenon that is often described as the first night effect (FNE). Previous works have found FNE on sleep architecture and sleep power spectra parameters, especially during non-rapid eye movement (NREM) sleep. However, the impact of FNE on sleep parameters, including local differences in electroencephalographic (EEG) activity across nights, has not been systematically assessed. Here, we performed high-density EEG sleep recordings on 27 healthy individuals on two nights and examined differences in sleep architecture, NREM (stages 2 and 3) EEG power spectra, and NREM power topography across nights. We found higher wakefulness after sleep onset (WASO), reduced sleep efficiency, and less deep NREM sleep (stage 3), along with increased high-frequency NREM EEG power during the first night of sleep, corresponding to small to medium effect sizes (Cohen's d ≤ 0.5). Furthermore, study individuals showed significantly lower slow-wave activity in right frontal/prefrontal regions as well as higher sigma and beta activities in medial and left frontal/prefrontal areas, yielding medium to large effect sizes (Cohen's d ≥ 0.5). Altogether, these findings suggest the FNE is characterized by less efficient, more fragmented, shallower sleep that tends to affect especially certain brain regions. The magnitude and specificity of these effects should be considered when designing sleep studies aiming to compare across night effects.

Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies.

Nephronophthisis (NPHP), an autosomal recessive cystic kidney disease, is the most frequent genetic cause for end-stage renal failure in the first three decades of life. Mutations in 13 genes (NPHP1-NPHP11, AHI1, and CC2D2A) cause NPHP with ubiquitous expression of the corresponding proteins consistent with the multiorgan involvement of NPHP-related diseases. The genotype-phenotype correlation in these ciliopathies can be explained by gene locus heterogeneity, allelism, and the impact of modifier genes. In some NPHP-related ciliopathies, the nature of the recessive mutations determines disease severity. In order to define the genotype-phenotype correlation more clearly, we evaluated a worldwide cohort of 440 patients from 365 families with NPHP-related ciliopathies, in whom both disease-causing alleles were identified. The phenotypes were ranked in the order of severity from degenerative to degenerative/dysplastic to dysplastic. A genotype of two null alleles caused a range of phenotypes, with an increasing order of severity of NPHP1, NPHP3, NPHP4, NPHP5, NPHP2, NPHP10, NPHP6, to AHI1. Only NPHP6 showed allelic influences on the phenotypes; the presence of two null mutations caused dysplastic phenotypes, whereas at least one missense allele rescued it to a milder degenerative phenotype. We also found nine novel mutations in the NPHP genes. Thus, our studies have important implications for genetic counseling and planning of renal replacement therapy.

Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals.

Bardet-Biedl syndrome (BBS) is a rare, primarily autosomal-recessive ciliopathy. The phenotype of this pleiotropic disease includes retinitis pigmentosa, postaxial polydactyly, truncal obesity, learning disabilities, hypogonadism and renal anomalies, among others. To date, mutations in 15 genes (BBS1-BBS14, SDCCAG8) have been described to cause BBS. The broad genetic locus heterogeneity renders mutation screening time-consuming and expensive. We applied a strategy of DNA pooling and subsequent massively parallel resequencing (MPR) to screen individuals affected with BBS from 105 families for mutations in 12 known BBS genes. DNA was pooled in 5 pools of 21 individuals each. All 132 coding exons of BBS1-BBS12 were amplified by conventional PCR. Subsequent MPR was performed on an Illumina Genome Analyzer II™ platform. Following mutation identification, the mutation carrier was assigned by CEL I endonuclease heteroduplex screening and confirmed by Sanger sequencing. In 29 out of 105 individuals (28%), both mutated alleles were identified in 10 different BBS genes. A total of 35 different disease-causing mutations were confirmed, of which 18 mutations were novel. In 12 additional families, a total of 12 different single heterozygous changes of uncertain pathogenicity were found. Thus, DNA pooling combined with MPR offers a valuable strategy for mutation analysis of large patient cohorts, especially in genetically heterogeneous diseases such as BBS.

A comparison between exposure-response relationships for wind turbine annoyance and annoyance due to other noise sources.

Surveys have shown that noise from wind turbines is perceived as annoying by a proportion of residents living in their vicinity, apparently at much lower noise levels than those inducing annoyance due to other environmental sources. The aim of the present study was to derive the exposure-response relationship between wind turbine noise exposure in L(den) and the expected percentage annoyed residents and to compare it to previously established relationships for industrial noise and transportation noise. In addition, the influence of several individual and situational factors was assessed. On the basis of available data from two surveys in Sweden (N=341, N=754) and one survey in the Netherlands (N=725), a relationship was derived for annoyance indoors and for annoyance outdoors at the dwelling. In comparison to other sources of environmental noise, annoyance due to wind turbine noise was found at relatively low noise exposure levels. Furthermore, annoyance was lower among residents who received economical benefit from wind turbines and higher among residents for whom the wind turbine was visible from the dwelling. Age and noise sensitivity had similar effects on annoyance to those found in research on annoyance by other sources.

Trends in aircraft noise annoyance: the role of study and sample characteristics.

Recently, it has been suggested that the annoyance of residents at a given aircraft noise exposure level increases over the years. The objective of the present study was to verify the hypothesized trend and to identify its possible causes. To this end, the large database used to establish earlier exposure-response relationships on aircraft noise was updated with original data from several recent surveys, yielding a database with data from 34 separate airports. Multilevel grouped regression was used to determine the annoyance response per airport, after which meta-regression was used to investigate whether study characteristics could explain the heterogeneity in annoyance response between airports. A significant increase over the years was observed in annoyance at a given level of aircraft noise exposure. Furthermore, the type of annoyance scale, the type of contact, and the response percentage were found to be sources of heterogeneity. Of these, only the scale factor could statistically account for the trend, although other findings rule it out as a satisfactory explanation. No evidence was found for increased self-reported noise sensitivity. The results are of importance to the applicability of current exposure-annoyance relationships for aircraft noise and provide a basis for decisions on whether these need to be updated.

Urban road traffic noise and annoyance: the effect of a quiet façade.

Road traffic noise in urban areas is a major source of annoyance. A quiet façade has been hypothesized to beneficially affect annoyance. However, only a limited number of studies investigated this hypothesis, and further quantification is needed. This study investigates the effect of a relatively quiet façade on the annoyance response. Logistic regression was performed in a large population based study (GLOBE, N~18,000), to study the association between road traffic noise exposure at the most exposed dwelling façade (L(den)) and annoyance in: (1) The subgroup with a relatively quiet façade (large difference in road traffic noise level between most and least exposed façade (Q>10 dB); (2) the subgroup without a relatively quiet façade (Q<10 dB). Questionnaire data were linked to individual exposure assessment based on detailed spatial data (GIS) and standard modeling techniques. Annoyance was less likely (OR(Q) (>10)