Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify ...probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders.
Objectives
To evaluate the associations between sensory impairments and 10‐year risk of cognitive impairment.
Design
The Epidemiology of Hearing Loss Study (EHLS), a longitudinal, population‐based ...study of aging in the Beaver Dam, Wisconsin community. Baseline examinations were conducted in 1993 and follow‐up examinations have been conducted every 5 years.
Setting
General community.
Participants
EHLS members without cognitive impairment at EHLS‐2 (1998–2000). There were 1,884 participants (mean age 66.7) with complete EHLS‐2 sensory data and follow‐up information.
Measurements
Cognitive impairment was defined as a Mini‐Mental State Examination score of <24 or history of dementia or Alzheimer's disease. Hearing impairment was a pure‐tone average of hearing thresholds (0.5, 1, 2, 4 kHz) of >25 dB hearing level in either ear, visual impairment was a Pelli‐Robson contrast sensitivity of <1.55 log units in the better eye, and olfactory impairment was a San Diego Odor Identification Test score of <6.
Results
Hearing, visual, and olfactory impairment were independently associated with cognitive impairment risk (hearing: hazard ratio (HR) = 1.90, 95% confidence interval (CI) = 1.11–3.26; vision: HR = 2.05, 95% CI = 1.24–3.38; olfaction: HR = 3.92, 95% CI = 2.45–6.26)). Nevertheless, 85% of participants with hearing impairment, 81% with visual impairment, and 76% with olfactory impairment did not develop cognitive impairment during follow‐up.
Conclusion
The relationship between sensory impairment and cognitive impairment was not unique to one sensory system, suggesting that sensorineural health may be a marker of brain aging. The development of a combined sensorineurocognitive measure may be useful in uncovering mechanisms of healthy brain aging.
Sensory Impairments and Risk of Mortality in Older Adults Schubert, Carla R; Fischer, Mary E; Pinto, A Alex ...
The journals of gerontology. Series A, Biological sciences and medical sciences,
05/2017, Letnik:
72, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Sensory impairments increase with age and the majority of older people will experience a sensory impairment if they live long enough. However, the relationships of hearing, visual, and olfactory ...impairments with mortality are not well understood.
Epidemiology of Hearing Loss Study participants (n = 2,418) aged 53-97 years (mean = 69 years) were examined in 1998-2000 and hearing, visual acuity, and olfaction were measured. Participants were followed for mortality for up to 17 years (mean = 12.8 years). Cox proportional hazards models were used to assess the association between prevalent sensory impairments and the 15-year cumulative incidence of death.
A total of 1,099 (45.4%) of participants died during the follow-up period. In age- and sex-adjusted Cox models, the risk of mortality was higher among participants with one (hazard ratio HR = 1.40, 95% confidence interval CI = 1.19, 1.64) or two or more (HR = 2.12, 95% CI = 1.74, 2.58) sensory impairments than among participants with no sensory impairments. Olfactory impairment at baseline was significantly associated with mortality (HR = 1.28, 95% CI = 1.07, 1.52) after adjusting for age, sex, sensory comorbidities, cardiovascular risk factors and disease, cognitive impairment, frailty, subclinical atherosclerosis, and inflammatory marker levels (n = 1,745). Hearing and visual impairment were not associated with mortality after adjusting for subclinical atherosclerosis and inflammation.
Olfactory impairment, but not hearing or visual impairment, was associated with an increased risk of mortality. These results suggest that olfactory impairment may be a marker of underlying physiologic processes or pathology that is associated with aging and reduced survival in older adults.
Doublecortin (Dcx) defines a growing family of microtubule (MT)-associated proteins (MAPs) involved in neuronal migration and process outgrowth. We show that Dcx is essential for the function of ...Kif1a, a kinesin-3 motor protein that traffics synaptic vesicles. Neurons lacking Dcx and/or its structurally conserved paralogue, doublecortin-like kinase 1 (Dclk1), show impaired Kif1a-mediated transport of Vamp2, a cargo of Kif1a, with decreased run length. Human disease-associated mutations in Dcx's linker sequence (e.g., W146C, K174E) alter Kif1a/Vamp2 transport by disrupting Dcx/Kif1a interactions without affecting Dcx MT binding. Dcx specifically enhances binding of the ADP-bound Kif1a motor domain to MTs. Cryo-electron microscopy and subnanometer-resolution image reconstruction reveal the kinesin-dependent conformational variability of MT-bound Dcx and suggest a model for MAP-motor crosstalk on MTs. Alteration of kinesin run length by MAPs represents a previously undiscovered mode of control of kinesin transport and provides a mechanism for regulation of MT-based transport by local signals.
► Dcx is required for neuronal transport mediated by the kinesin-3 motor Kif1a ► Dcx increases Kif1a/Vamp2 run length without affecting conventional kinesin ► Dcx enhances the affinity of the ADP-bound Kif1a motor domain for microtubules ► Kif1a microtubule binding requires displacement of the flexible Dcx domain linker
Autophagy is involved with the turnover of intracellular components and the management of stress responses. Genetic studies in mice have shown that suppression of neuronal autophagy can lead to the ...accumulation of protein aggregates and neurodegeneration. However, no study has shown that increasing autophagic gene expression can be beneficial to an aging nervous system. Here we demonstrate that expression of several autophagy genes is reduced in Drosophila neural tissues as a normal part of aging. The age-dependent suppression of autophagy occurs concomitantly with the accumulation of insoluble ubiquitinated proteins (IUP), a marker of neuronal aging and degeneration. Mutations in the Atg8a gene (autophagy-related 8a) result in reduced lifespan, IUP accumulation and increased sensitivity to oxidative stress. In contrast, enhanced Atg8a expression in older fly brains extends the average adult lifespan by 56% and promotes resistance to oxidative stress and the accumulation of ubiquitinated and oxidized proteins. These data indicate that genetic or age-dependent suppression of autophagy is closely associated with the buildup of cellular damage in neurons and a reduced lifespan, while maintaining the expression of a rate-limiting autophagy gene prevents the age-dependent accumulation of damage in neurons and promotes longevity.
Objectives
To determine associations between smoking, adiposity, diabetes mellitus, and other risk factors for cardiovascular disease (CVD) and the 15‐year incidence of hearing impairment (HI).
...Design
A longitudinal population‐based cohort study (1993–95 to 2009–10), the Epidemiology of Hearing Loss Study (EHLS).
Setting
Beaver Dam, Wisconsin.
Participants
Participants in the Beaver Dam Eye Study (1988–90; residents of Beaver Dam, WI, aged 43–84 in 1987–88) were eligible for the EHLS. There were 1,925 participants with normal hearing at baseline.
Measurements
Fifteen‐year cumulative incidence of HI (pure‐tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz greater than 25 decibels hearing level in either ear). Cigarette smoking, exercise, and other factors were ascertained according to questionnaire. Blood pressure, waist circumference, body mass index, and glycosylated hemoglobin were measured.
Results
Follow‐up examinations (≥1) were obtained from 87.2% (n = 1,678; mean baseline age 61). The 15‐year cumulative incidence of HI was 56.8%. Adjusting for age and sex, current smoking (hazard ratio (HR) = 1.31, P = .048), education (<16 years; HR = 1.35, P = .01), waist circumference (HR = 1.08 per 10 cm, P = .02), and poorly controlled diabetes mellitus (HR = 2.03, P = .048) were associated with greater risk of HI. Former smokers and people with better‐controlled diabetes mellitus were not at greater risk.
Conclusion
Smoking, central adiposity, and poorly controlled diabetes mellitus predicted incident HI. These well‐known risk factors for CVD suggest that vascular changes may contribute to HI in aging. Interventions targeting reductions in smoking and adiposity and better glycemic control in people with diabetes mellitus may help prevent or delay the onset of HI.
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Perfluorocarbon-nanoemulsions (PFC-NE) made of PFC and phospholipids (PL) by homogenization are optimal for in vivo-19F labelling of monocytes and subsequently of inflamed tissues in ...magnetic resonance imaging (MRI). Necessary requirements for in vivo use of PFC-NE are sterility, suitable droplet sizes and the absence of immune activating liposomes, which are a typical byproduct of the homogenization process.
To meet these requirements, we developed an aseptic in-vial preparation technique for PFC-NE based on dual centrifugation (DC) by testing different PFC/phospholipid ratios as well as the application of additives. Two different PFC, perfluorooctylbromide (PFOB) and perfluoro-15-crown-5-ether (PFCE), were investigated. Particle sizes were assessed by dynamic light scattering and NE morphology by cryoTEM. DC homogenization was optimal when using an excess of PL (8.7 % (m/m) of utilized PFC, z-ave: 180 nm, pdi: 0.2). A purification approach by centrifugation was implemented to remove liposomes formed from the excess of PL during homogenization. The purification success was proven by phospholipid assay and PFC quantification via density and sound velocity measurements.
DC in combination with a short centrifugation is a fast and reliable way of small-scale aseptic PFC-NE production for 19F MRI passive-targeting experiments of monocytes and inflamed tissues.
Abstract
Although retinal microvessels (RMVs) and brain microvessels (BMVs) are closely related in their developmental and share similar blood-neural barriers, studies have reported markedly ...different responses to stressors such as diabetes. Therefore, we hypothesized that RMVs and BMVs will display substantial differences in gene expression levels even though they are of the same embryological origin. In this study, both RMVs and BMVs were mechanically isolated from rats. Full retinal and brain tissue samples (RT, BT) were collected for comparisons. Total RNA extracted from these four groups were processed on Affymetrix rat 2.0 microarray Chips. The transcriptional profiles of these tissues were then analyzed. In the present paper we looked at differentially expressed genes (DEGs) in RMVs (against RT) and BMVs (against BT) using a rather conservative threshold value of ≥ ± twofold change and a false discovery rate corrected for multiple comparisons (
p
< 0.05). In RMVs a total of 1559 DEGs were found, of which 1004 genes were higher expressed in RMVs than in RT. Moreover, 4244 DEGs between BMVs and BT were identified, of which 1956 genes were ≥ twofold enriched in BMVs. Using these DEGs, we comprehensively analyzed the actual expression levels and highlighted their involvement in critical functional structures in RMVs and BMVs, such as junctional complex, transporters and signaling pathways. Our work provides for the first time the transcriptional profiles of rat RMVs and BMVs. These results may help to understand why retina and brain microvasculature show different susceptibilities to stressors, and they might even provide new insight for pharmacological interventions.
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