Alcohol's impact on telomere length, a proposed marker of biological aging, is unclear. We performed the largest observational study to date (in n = 245,354 UK Biobank participants) and compared ...findings with Mendelian randomization (MR) estimates. Two-sample MR used data from 472,174 participants in a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption (n = 941,280) and alcohol use disorder (AUD) (n = 57,564 cases). Non-linear MR employed UK Biobank individual data. MR analyses suggested a causal relationship between alcohol traits, more strongly for AUD, and telomere length. Higher genetically-predicted AUD (inverse variance-weighted (IVW) β = -0.06, 95% confidence interval (CI): -0.10 to -0.02, p = 0.001) was associated with shorter telomere length. There was a weaker association with genetically-predicted alcoholic drinks weekly (IVW β = -0.07, CI: -0.14 to -0.01, p = 0.03). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings indicate that alcohol consumption may shorten telomere length. There are implications for age-related diseases.
The intricate shaping of the facial skeleton is essential for function of the vertebrate jaw and middle ear. While much has been learned about the signaling pathways and transcription factors that ...control facial patterning, the downstream cellular mechanisms dictating skeletal shapes have remained unclear. Here we present genetic evidence in zebrafish that three major signaling pathways - Jagged-Notch, Endothelin1 (Edn1), and Bmp - regulate the pattern of facial cartilage and bone formation by controlling the timing of cartilage differentiation along the dorsoventral axis of the pharyngeal arches. A genomic analysis of purified facial skeletal precursors in mutant and overexpression embryos revealed a core set of differentiation genes that were commonly repressed by Jagged-Notch and induced by Edn1. Further analysis of the pre-cartilage condensation gene barx1, as well as in vivo imaging of cartilage differentiation, revealed that cartilage forms first in regions of high Edn1 and low Jagged-Notch activity. Consistent with a role of Jagged-Notch signaling in restricting cartilage differentiation, loss of Notch pathway components resulted in expanded barx1 expression in the dorsal arches, with mutation of barx1 rescuing some aspects of dorsal skeletal patterning in jag1b mutants. We also identified prrx1a and prrx1b as negative Edn1 and positive Bmp targets that function in parallel to Jagged-Notch signaling to restrict the formation of dorsal barx1+ pre-cartilage condensations. Simultaneous loss of jag1b and prrx1a/b better rescued lower facial defects of edn1 mutants than loss of either pathway alone, showing that combined overactivation of Jagged-Notch and Bmp/Prrx1 pathways contribute to the absence of cartilage differentiation in the edn1 mutant lower face. These findings support a model in which Notch-mediated restriction of cartilage differentiation, particularly in the second pharyngeal arch, helps to establish a distinct skeletal pattern in the upper face.
The capability of electronic cigarette devices (e-cigs) to deliver nicotine is key to their potential to replace combustible cigarettes. We compared nicotine delivery and subjective effects ...associated with the use of two classes of e-cigarettes and cigarettes.
14 e-cigarette users were instructed to vape their own e-cigarette device every 20 seconds for 10 minutes while blood was drawn at 1, 2, 4, 6, 8, 10,12, and 15 minutes after initiating vaping. Users rated withdrawal symptoms and side effects before and after vaping. E-cigarette devices were classified as first-generation (same size as cigarette, no activation button) or advanced (larger than cigarette with an activation button). Separately, 10 cigarette smokers completed a similar protocol. Fisher's Exact Test and two-sided t-tests were used as appropriate to determine differences in outcomes between first-generation e-cigarette users, advanced e-cigarette users, and smokers.
Compared to first-generation devices, advanced devices were associated with greater serum nicotine Cmax (ng/ml) (11.5 v. 2.8, p = 0.0231) and greater nicotine boost (ng/ml) (10.8 v. 1.8, p = 0.0177). Overall, e-cigarettes users experienced a significant reduction in withdrawal and craving, although there were no significant differences between users of first-generation and advanced devices. Comparing e-cigarettes overall to cigarettes, cigarettes were associated with greater Cmax (25.9 v. 9.0, p = 0.0043) and greater nicotine boost (21.0 v. 8.2, p = 0.0128).
Advanced e-cigarettes delivered significantly more nicotine than first-generation devices but less than combustible cigarettes. Overall, e-cigarette use was associated with a reduction in withdrawal and craving with no reported side effects. The wide variation in nicotine absorption from different e-cigarette devices should be considered in studies of e-cigarettes for smoking cessation.
Abstract Investigations using quadrupeds have suggested that the motor programs used for slope walking differ from that used for level walking. This idea has not yet been explored in humans. The aim ...of this study was to use electromyographic (EMG) signals obtained during level and slope walking to complement previously published joint angle and joint moment data in elucidating such control strategies. Nine healthy volunteers walked on an instrumented ramp at each of five grades (−39%, −15%, 0%, +15%, +39%). EMG activity was recorded unilaterally from eight lower limb muscles (gluteus maximus (GM), rectus femoris (RF), vastus medialis (VM), biceps femoris (BF), semimembranosus (SM), soleus (Sol), medial gastrocnemius (MG), and tibialis anterior (TA)). The burst onset, duration, and mean activity were calculated for each burst in every trial. The burst characteristics were then averaged within each grade and subject and submitted to repeated measures ANOVAs to assess the effect of grade ( α =0.05, a priori). Power production increased during upslope walking, as did the mean activity and burst durations of most muscles. In this case, the changes in muscle activity patterns were not predictable based on the changes in joint moments because of the activation of biarticular muscles as antagonists. During downslope walking power absorption increased, as did knee extensor activity (mean and duration) and the duration of the ankle plantarflexor activity. The changes in muscle activity during this task were directly related to the changes in joint moments. Collectively these data suggest that the nervous system uses different control strategies to successfully locomote on slopes, and that joint power requirements are an important factor in determining these control strategies.
Catechol-O-methyltransferase (COMT) has been shown to be critical for prefrontal dopamine flux, prefrontal cortex-dependent cognition and activation. Several potentially functional variants in the ...gene have been identified, but considerable controversy exists regarding the contribution of individual alleles and haplotypes to risk for schizophrenia, partly because clinical phenotypes are ill-defined and preclinical studies are limited by lack of adequate models. Here, we propose a neuroimaging approach to overcome these limitations by characterizing the functional impact of ambiguous haplotypes on a neural system-level intermediate phenotype in humans. Studying 126 healthy control subjects during a working-memory paradigm, we find that a previously described risk variant in a functional Val158Met (rs4680) polymorphism interacts with a P2 promoter region SNP (rs2097603) and an SNP in the 3' region (rs165599) in predicting inefficient prefrontal working memory response. We report evidence that the nonlinear response of prefrontal neurons to dopaminergic stimulation is a neural mechanism underlying these nonadditive genetic effects. This work provides an in vivo approach to functional validation in brain of the biological impact of complex genetic variations within a gene that may be critical for its clinical association.
Chronic wasting disease (CWD) is an infectious transmissible spongiform encephalopathy of cervids associated with the presence of a misfolded prion protein (PrPCWD). Progression of PrPCWD ...distribution has been described using immunohistochemistry and histologic changes in a single section of brain stem at the level of the obex resulting in scores from 0 (early) to 10 (terminal) in elk with naturally occurring CWD. Here we describe the spread and distribution of PrPCWD in peripheral tissues and spinal cord in 16 wild and 17 farmed Rocky Mountain elk (Cervus elaphus nelsoni) with naturally occurring CWD and correlate these findings with obex scores. Spinal cord and approximately 110 peripheral tissues were collected, processed, stained with hematoxylin and eosin, and immunolabeled with the anti-prion protein monoclonal antibody F99/97.6.1. The medial retropharyngeal and tracheobronchial lymph nodes were the first tissues to accumulate PrPCWD, followed by other lymphoid tissues, myenteric plexus, spinal cord, and finally tissues outside of the lymphatic and neural systems. However, the only significant histological lesion observed was mild spongiform encephalopathy in the dorsal column of the lower spinal cord in elk with an obex score of ≥9. Initial exposure to CWD prions may be through the respiratory system and spread appears to occur primarily via the autonomic nervous system. Therefore, we suggest using obex scores as a proxy for stage of disease progression and verifying with key peripheral tissues.
In this study, we sought to identify sensory circuitry responsible for motor deficits or compensatory adaptations after peripheral nerve cut and repair. Self-reinnervation of the ankle extensor ...muscles abolishes the stretch reflex and increases ankle yielding during downslope walking, but it remains unknown whether this finding generalizes to other muscle groups and whether muscles become completely deafferented. In decerebrate cats at least 19 wk after nerve cut and repair, we examined the influence of quadriceps (Q) muscles' self-reinnervation on autogenic length feedback, as well as intermuscular length and force feedback, among the primary extensor muscles in the cat hindlimb. Effects of gastrocnemius and soleus self-reinnervation on intermuscular circuitry were also evaluated. We found that autogenic length feedback was lost after Q self-reinnervation, indicating that loss of the stretch reflex appears to be a generalizable consequence of muscle self-reinnervation. However, intermuscular force and length feedback, evoked from self-reinnervated muscles, was preserved in most of the interactions evaluated with similar relative inhibitory or excitatory magnitudes. These data indicate that intermuscular spinal reflex circuitry has the ability to regain functional connectivity, but the restoration is not absolute. Explanations for the recovery of intermuscular feedback are discussed, based on identified mechanisms responsible for lost autogenic length feedback. Functional implications, due to permanent loss of autogenic length feedback and potential for compensatory adaptations from preserved intermuscular feedback, are discussed.
Neuromechanics seeks to understand how muscles, sense organs, motor pattern generators, and brain interact to produce coordinated movement, not only in complex terrain but also when confronted with ...unexpected perturbations. Applications of neuromechanics include ameliorating human health problems (including prosthesis design and restoration of movement following brain or spinal cord injury), as well as the design, actuation and control of mobile robots. In animals, coordinated movement emerges from the interplay among descending output from the central nervous system, sensory input from body and environment, muscle dynamics, and the emergent dynamics of the whole animal. The inevitable coupling between neural information processing and the emergent mechanical behavior of animals is a central theme of neuromechanics. Fundamentally, motor control involves a series of transformations of information, from brain and spinal cord to muscles to body, and back to brain. The control problem revolves around the specific transfer functions that describe each transformation. The transfer functions depend on the rules of organization and operation that determine the dynamic behavior of each subsystem (i.e., central processing, force generation, emergent dynamics, and sensory processing). In this review, we (1) consider the contributions of muscles, (2) sensory processing, and (3) central networks to motor control, (4) provide examples to illustrate the interplay among brain, muscles, sense organs and the environment in the control of movement, and (5) describe advances in both robotics and neuromechanics that have emerged from application of biological principles in robotic design. Taken together, these studies demonstrate that (1) intrinsic properties of muscle contribute to dynamic stability and control of movement, particularly immediately after perturbations; (2) proprioceptive feedback reinforces these intrinsic self-stabilizing properties of muscle; (3) control systems must contend with inevitable time delays that can simplify or complicate control; and (4) like most animals under a variety of circumstances, some robots use a trial and error process to tune central feedforward control to emergent body dynamics.
We performed a whole-transcriptome correlation analysis, followed by the pathway enrichment and testing of innate immune response pathway analyses to evaluate the hypothesis that transcriptional ...activity can predict cortical gray matter thickness (GMT) variability during normal cerebral aging.
Transcriptome and GMT data were available for 379 individuals (age range=28–85) community-dwelling members of large extended Mexican American families. Collection of transcriptome data preceded that of neuroimaging data by 17years. Genome-wide gene transcriptome data consisted of 20,413 heritable lymphocytes-based transcripts. GMT measurements were performed from high-resolution (isotropic 800μm) T1-weighted MRI. Transcriptome-wide and pathway enrichment analysis was used to classify genes correlated with GMT. Transcripts for sixty genes from seven innate immune pathways were tested as specific predictors of GMT variability.
Transcripts for eight genes (IGFBP3, LRRN3, CRIP2, SCD, IDS, TCF4, GATA3, and HN1) passed the transcriptome-wide significance threshold. Four orthogonal factors extracted from this set predicted 31.9% of the variability in the whole-brain and between 23.4 and 35% of regional GMT measurements. Pathway enrichment analysis identified six functional categories including cellular proliferation, aggregation, differentiation, viral infection, and metabolism. The integrin signaling pathway was significantly (p<10−6) enriched with GMT. Finally, three innate immune pathways (complement signaling, toll-receptors and scavenger and immunoglobulins) were significantly associated with GMT.
Expression activity for the genes that regulate cellular proliferation, adhesion, differentiation and inflammation can explain a significant proportion of individual variability in cortical GMT. Our findings suggest that normal cerebral aging is the product of a progressive decline in regenerative capacity and increased neuroinflammation.
•Transcriptome activity predicted gray matter thickness in aging.•Transcriptome-wide association and enrichment analyses were used.•Cellular proliferation and differentiation led to higher cerebral integrity.•Upregulation of neuroinflammation led to lower cerebral integrity.
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