Maize-infecting viruses are known to inflict significant agronomic yield loss throughout the world annually. Identification of known or novel causal agents of disease prior to outbreak is imperative ...to preserve food security via future crop protection efforts. Toward this goal, a large-scale metagenomic approach utilizing high throughput sequencing (HTS) was employed to identify novel viruses with the potential to contribute to yield loss of graminaceous species, particularly maize, in North America. Here we present four novel viruses discovered by HTS and individually validated by Sanger sequencing. Three of these viruses are RNA viruses belonging to either the Betaflexiviridae or Tombusviridae families. Additionally, a novel DNA virus belonging to the Geminiviridae family was discovered, the first Mastrevirus identified in North American maize. Metagenomic studies of crop and crop-related species such as this may be useful for the identification and surveillance of known and novel viral pathogens of crops. Monitoring related species may prove useful in identifying viruses capable of infecting crops due to overlapping insect vectors and viral host-range to protect food security.
Evidence shows that females have increased supra-threshold peripheral auditory processing compared to males. This is indicated by larger auditory brainstem responses (ABR) wave I amplitude, which ...measures afferent spiral ganglion neuron (SGN)-auditory nerve synchrony. However, the underlying molecular mechanisms of this sex difference are mostly unknown. We sought to elucidate sex differences in ABR wave I amplitude by examining molecular markers known to affect synaptic transmission kinetics. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate fast excitatory transmission in mature SGN afferent synapses. Each AMPAR channel is a tetramer composed of GluA2, 3, and 4 subunits (
, and
genes), and those lacking GluA2 subunits have larger currents, are calcium-permeable, and have faster gating kinetics. Moreover, alternatively spliced
and
isoforms of each AMPAR subunit affect channel kinetics, having faster kinetics those AMPARs containing
and
isoforms. We hypothesized that SGNs of females have more fast-gating AMPAR subunit mRNA than males, which could contribute to more temporally precise synaptic transmission and increased SGN synchrony. Our data show that the index of
relative to
transcripts on SGN was higher in females than males (females: 48%; males: 43%), suggesting that females have more SGNs with higher
mRNA relative to
. Analysis of the relative abundance of the
and
alternatively spliced isoforms showed that females have a 2-fold increase in fast-gating
mRNA, while males have more slow-gating (2.5-fold) of the
. We propose that
may in part mediate greater SGN synchrony in females.
Females of multiple vertebrate species, including fish and mammals, have been reported to have enhanced sound-evoked synchrony of afferents in the auditory nerve. However, the underlying molecular mediators of this physiologic sex difference are unknown. Elucidating potential molecular mechanisms related to sex differences in auditory processing is important for maintaining healthy ears and developing potential treatments for hearing loss in both sexes. This study found that females have a 2-fold increase in
mRNA, a fast-gating AMPA-type glutamate receptor subunit. This difference may contribute to greater neural synchrony in the auditory nerve of female mice compared to males, and this sex difference may be conserved in all vertebrates.
Translational efficiency change is an important mechanism for regulating protein synthesis. Experiments with paired ribosome profiling (Ribo-seq) and mRNA-sequencing (RNA-seq) allow the study of ...translational efficiency by simultaneously quantifying the abundances of total transcripts and those that are being actively translated. Existing methods for Ribo-seq data analysis either ignore the pairing structure in the experimental design or treat the paired samples as fixed effects instead of random effects. To address these issues, we propose a hierarchical Bayesian generalized linear mixed effects model which incorporates a random effect for the paired samples according to the experimental design. We provide an analytical software tool, "riboVI," that uses a novel variational Bayesian algorithm to fit our model in an efficient way. Simulation studies demonstrate that "riboVI" outperforms existing methods in terms of both ranking differentially translated genes and controlling false discovery rate. We also analyzed data from a real ribosome profiling experiment, which provided new biological insight into virus-host interactions by revealing changes in hormone signaling and regulation of signal transduction not detected by other Ribo-seq data analysis tools.
Myostatin, a negative regulator of muscle growth, is considered a potential therapeutic agent for individuals suffering from various muscle wasting and strength declining diseases because inhibiting ...Mstn signaling leads to muscular hypertrophy. In this study we investigate the interaction between myostatin and the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis in muscle function and strength. To this end, we measured hind limb grip strength and myostatin levels in two mouse models of GH gene manipulation; GH receptor knockout (
mice which have reduced GH/IGF-1 action, and bovine GH transgenic (bGH) mice which have excess GH/IGF-1 action. We found that specific muscle force was significantly reduced in bGH mice, and significantly increased in
mice, compared to their respective littermate wild type controls. The expression of the mature form of myostatin was significantly increased in bGH mice, and unchanged in
mice. In the bGH mice, the high levels of mature myostatin were accompanied by increase body weight and lean mass, consistent with other published results indicating that the IGF-1 signaling pathway is dominant over that of Mstn. Our results also suggest that in these mouse models there is an inverse relationship between muscle strength and levels of myostatin and GH, since constitutive overexpression of GH resulted in elevated levels of mature myostatin in muscle, accompanied by a reduction in strength. By contrast, in the
mice with reduced levels of IGF-1, mature myostatin levels were unchanged and muscle strength was increased.
•Recognizing sleep health as a modifiable risk factor is vital to CV health.•There is emerging evidence linking CSA with AF.•CSA may be a marker of abnormal autonomic function and cardiac ...function.•Invasive and expensive therapies may be used in moderate to severe CSA.•PNS is a promising new therapy for CSA to restore normal breathing patterns.
Precipitating factors and chronic diseases associated with atrial fibrillation (AF) are detailed in the literature. Emerging evidence over the last several decades suggests a potential causal relationship between central sleep apnea (CSA) and AF. Mechanisms including apnea-induced hypoxia with intermittent arousal, fluctuating levels of carbon dioxide, enhanced sympathetic/neurohormonal activation and oxidative stress causing inflammation have been implicated as etiologic causes of AF within this subpopulation. CSA affects the efficacy of pharmacologic and catheter-based antiarrhythmic treatments, which is why treating CSA prior to these interventions may lead to lower rates of AF. Subsequently, a reduction in the AF burden with transvenous phrenic nerve stimulation (TPNS) has become a topic of interest. The present review describes the relationship between these conditions, pathophysiologic mechanisms implicating the role of CSA in development of AF, and emerging therapeutic interventions.
Intellectual disability is the most common developmental disorder caused by chromosomal aberrations as well as single-nucleotide variants (SNVs) and small insertions/deletions (indels). Here we ...report identification of a novel, probably pathogenic mutation in the WHSC1 gene in a patient case with phenotype overlapping the features of Wolf-Hirschhorn syndrome. Deletions involving WHSC1 (Wolf-Hirschhorn syndrome candidate 1 gene) were described earlier in patients with Wolf-Hirschhorn syndrome. However, to our knowledge, single-point mutations in WHSC1 associated with any intellectual deficiency syndromes have not been reported. Using whole exome sequencing, we found a de novo nonsense mutation in WHSC1 (c.3412C>T, p.Arg1138Ter, NM_001042424.2) in patient with syndromic intellectual disability. This finding is challenging regarding a possible causative role of WHSC1 in intellectual disability syndromes, specifically Wolf-Hirschhorn syndrome. From the clinical standpoint, our finding suggests that next-generation sequencing along with chromosome microarray analysis (CMA) might be useful in genetic testing for patients with intellectual disability and dysmorphic features.
As a negative regulator of muscle size, myostatin (Mstn) impacts the force-production capabilities of skeletal muscles. In the masticatory system, measures of temporalis-stimulated bite forces in ...constitutive myostatin KOs suggest an absolute, but not relative, increase in jaw-muscle force. Here, we assess the phenotypic and physiologic impact of postnatal myostatin inhibition on bite mechanics using an inducible conditional KO mouse in which myostatin is inhibited with doxycycline (DOX). Given the increased control over the timing of gene inactivation in this model, it may be more clinically-relevant for developing interventions for age-associated changes in the musculoskeletal system. DOX was administered for 12 weeks starting at age 4 months, during which time food intake was monitored. Sex, age and strain-matched controls were given the same food without DOX. Bite forces were recorded just prior to euthanasia after which muscle and skeletal data were collected. Food intake did not differ between control or DOX animals within each sex. DOX males were significantly larger and had significantly larger masseters than controls, but DOX and control females did not differ. Although there was a tendency towards higher absolute bite forces in DOX animals, this was not significant, and bite forces normalized to masseter mass did not differ. Mechanical advantage for incisor biting increased in the DOX group due to longer masseter moment arms, likely due to a more anteriorly-placed masseter insertion. Despite only a moderate increase in bite force in DOX males and none in DOX females, the increase in masseter mass in males indicates a potentially positive impact on jaw muscles. Our data suggest a sexual dimorphism in the role of mstn, and as such investigations into the sex-specific outcomes is warranted.
Abstract
Mouse models are often used to validate novel interventions prior to human testing, although biological differences between mice and humans limit the translatability of outcomes. A common ...assumption in animal research is that maximal physical performance will be present at a young age, and that differences in task performance between young and old can be attributed to the aging process. However, this may not be true for all physical function tasks, and leaving out intermediate time points could drastically alter data interpretation. Here, we document age-related changes in forelimb and hindlimb grip strength, balance and coordination, and body composition in mice (n = 43) collected at multiple time points between 4 and 24 months of age. Maximal forelimb grip strength was recorded at 4 months of age, but maximal hindlimb grip strength was recorded at 15 months of age. Balance performance was stable from 4 to 15 months of age, declining significantly at 18 months. Both lean and fat mass peaked at 18 months before declining steadily. We conclude that the inclusion of intermediate time points is essential for the accurate evaluation of physical function status in mice, particularly in the context of translating intervention outcomes into strategies to be tested in humans.
Teleost fishes have evolved a number of sound-producing mechanisms, including vibrations of the swim bladder. In addition to sound production, the swim bladder also aids in sound reception. While the ...production and reception of sound by the swim bladder has been described separately in fishes, the extent to which it operates for both in a single species is unknown. Here, using morphological, electrophysiological and modelling approaches, we show that the swim bladder of male plainfin midshipman fish (
) exhibits reproductive state-dependent changes in morphology and function for sound production and reception. Non-reproductive males possess rostral 'horn-like' swim bladder extensions that enhance low-frequency (less than 800 Hz) sound pressure sensitivity by decreasing the distance between the swim bladder and inner ear, thus enabling pressure-induced swim bladder vibrations to be transduced to the inner ear. By contrast, reproductive males display enlarged swim bladder sonic muscles that enable the production of advertisement calls but also alter swim bladder morphology and increase the swim bladder to inner ear distance, effectively reducing sound pressure sensitivity. Taken together, we show that the swim bladder exhibits a seasonal functional plasticity that allows it to effectively mediate both the production and reception of sound in a vocal teleost fish.
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