The Popeye domain containing (POPDC) genes encode transmembrane proteins, which are abundantly expressed in striated muscle cells. Hallmarks of the POPDC proteins are the presence of three ...transmembrane domains and the Popeye domain, which makes up a large part of the cytoplasmic portion of the protein and functions as a cAMP-binding domain. Interestingly, despite the prediction of structural similarity between the Popeye domain and other cAMP binding domains, at the protein sequence level they strongly differ from each other suggesting an independent evolutionary origin of POPDC proteins. Loss-of-function experiments in zebrafish and mouse established an important role of POPDC proteins for cardiac conduction and heart rate adaptation after stress. Loss-of function mutations in patients have been associated with limb-girdle muscular dystrophy and AV-block. These data suggest an important role of these proteins in the maintenance of structure and function of striated muscle cells.
Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in ...this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood.
Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Respective downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2-associated death promoter) and Sirtuin1 were identified by transcriptome, protein arrays, and chromatin immunoprecipitation analyses. Overexpression of miR-24 or silencing of its targets significantly impaired angiogenesis in zebrafish embryos. Blocking of endothelial miR-24 limited myocardial infarct size of mice via prevention of endothelial apoptosis and enhancement of vascularity, which led to preserved cardiac function and survival.
Our findings indicate that miR-24 acts as a critical regulator of endothelial cell apoptosis and angiogenesis and is suitable for therapeutic intervention in the setting of ischemic heart disease.
The cardiac autonomic nervous system (CANS) plays a key role for the regulation of cardiac activity with its dysregulation being involved in various heart diseases, such as cardiac arrhythmias. The ...CANS comprises the extrinsic and intrinsic innervation of the heart. The intrinsic cardiac nervous system (ICNS) includes the network of the intracardiac ganglia and interconnecting neurons. The cardiac ganglia contribute to the tight modulation of cardiac electrophysiology, working as a local hub integrating the inputs of the extrinsic innervation and the ICNS. A better understanding of the role of the ICNS for the modulation of the cardiac conduction system will be crucial for targeted therapies of various arrhythmias. We describe the embryonic development, anatomy, and physiology of the ICNS. By correlating the topography of the intracardiac neurons with what is known regarding their biophysical and neurochemical properties, we outline their physiological role in the control of pacemaker activity of the sinoatrial and atrioventricular nodes. We conclude by highlighting cardiac disorders with a putative involvement of the ICNS and outline open questions that need to be addressed in order to better understand the physiology and pathophysiology of the ICNS.
Binaural speech intelligibility of individual listeners under realistic conditions was predicted using a model consisting of a gammatone filter bank, an independent equalization-cancellation (EC) ...process in each frequency band, a gammatone resynthesis, and the speech intelligibility index (SII). Hearing loss was simulated by adding uncorrelated masking noises (according to the pure-tone audiogram) to the ear channels. Speech intelligibility measurements were carried out with 8 normal-hearing and 15 hearing-impaired listeners, collecting speech reception threshold (SRT) data for three different room acoustic conditions (anechoic, office room, cafeteria hall) and eight directions of a single noise source (speech in front). Artificial EC processing errors derived from binaural masking level difference data using pure tones were incorporated into the model. Except for an adjustment of the SII-to-intelligibility mapping function, no model parameter was fitted to the SRT data of this study. The overall correlation coefficient between predicted and observed SRTs was 0.95. The dependence of the SRT of an individual listener on the noise direction and on room acoustics was predicted with a median correlation coefficient of 0.91. The effect of individual hearing impairment was predicted with a median correlation coefficient of 0.95. However, for mild hearing losses the release from masking was overestimated.
An eye-tracking paradigm was developed for use in audiology in order to enable online analysis of the speech comprehension process. This paradigm should be useful in assessing impediments in speech ...processing. In this paradigm, two scenes, a target picture and a competitor picture, were presented simultaneously with an aurally presented sentence that corresponded to the target picture. At the same time, eye fixations were recorded using an eye-tracking device. The effect of linguistic complexity on language processing time was assessed from eye fixation information by systematically varying linguistic complexity. This was achieved with a sentence corpus containing seven German sentence structures. A novel data analysis method computed the average tendency to fixate the target picture as a function of time during sentence processing. This allowed identification of the point in time at which the participant understood the sentence, referred to as the decision moment. Systematic differences in processing time were observed as a function of linguistic complexity. These differences in processing time may be used to assess the efficiency of cognitive processes involved in resolving linguistic complexity. Thus, the proposed method enables a temporal analysis of the speech comprehension process and has potential applications in speech audiology and psychoacoustics.
The Popeye domain-containing (POPDC) gene family, consisting of
(also known as
)
, and
, encodes transmembrane proteins abundantly expressed in striated muscle. POPDC proteins have recently been ...identified as cAMP effector proteins and have been proposed to be part of the protein network involved in cAMP signaling. However, their exact biochemical activity is presently poorly understood. Loss-of-function mutations in animal models causes abnormalities in skeletal muscle regeneration, conduction, and heart rate adaptation after stress. Likewise, patients carrying missense or nonsense mutations in POPDC genes have been associated with cardiac arrhythmias and limb-girdle muscular dystrophy. In this review, we introduce the POPDC protein family, and describe their structure function, and role in cAMP signaling. Furthermore, the pathological phenotypes observed in zebrafish and mouse models and the clinical and molecular pathologies in patients carrying POPDC mutations are described.
The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their ...structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein-protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.
In studies investigating binaural processing in human listeners, relatively long and task-dependent time constants of a binaural window ranging from 10 ms to 250 ms have been observed. Such time ...constants are often thought to reflect “binaural sluggishness.” In this study, the effect of binaural sluggishness on binaural unmasking of speech in stationary speech-shaped noise is investigated in 10 listeners with normal hearing. In order to design a masking signal with temporally varying binaural cues, the interaural phase difference of the noise was modulated sinusoidally with frequencies ranging from 0.25 Hz to 64 Hz. The lowest, that is the best, speech reception thresholds (SRTs) were observed for the lowest modulation frequency. SRTs increased with increasing modulation frequency up to 4 Hz. For higher modulation frequencies, SRTs remained constant in the range of 1 dB to 1.5 dB below the SRT determined in the diotic situation. The outcome of the experiment was simulated using a short-term binaural speech intelligibility model, which combines an equalization–cancellation (EC) model with the speech intelligibility index. This model segments the incoming signal into 23.2-ms time frames in order to predict release from masking in modulated noises. In order to predict the results from this study, the model required a further time constant applied to the EC mechanism representing binaural sluggishness. The best agreement with perceptual data was achieved using a temporal window of 200 ms in the EC mechanism.
The minimum standard deviations achievable for concurrent estimates of thresholds and psychometric function slopes as well as the optimal target values for adaptive procedures are calculated as ...functions of stimulus level and track length on the basis of the binomial theory. The optimum pair of targets for a concurrent estimate is found at the correct response probabilities p1 = 0.19 and p2 = 0.81 for the logistic psychometric function. An adaptive procedure that converges at these optimal targets is introduced and tested with Monte Carlo simulations. The efficiency increases rapidly when each subject's response consists of more than one statistically independent Bernoulli trial. Sentence intelligibility tests provide more than one Bernoulli trial per sentence when each word is scored separately. The number of within-sentence trials can be quantified by the j factor Boothroyd and Nittrouer, J. Acoust. Soc. Am. 84, 101-114 (1988). The adaptive procedure was evaluated with 10 normal-hearing and 11 hearing-impaired listeners using two German sentence tests that differ in j factors. The expected advantage of the sentence test with the higher j factor was not observed, possibly due to training effects. Hence, the number of sentences required for a reliable speech reception threshold (approximately 1 dB standard deviation) concurrently with a slope estimate (approximately 20%-30% relative standard deviation) is at least N = 30 if word scoring for short, meaningful sentences (j approximately 2) is performed.
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