Transcription activator WCC recruits deacetylase HDA3 to control transcription dynamics and bursting in Neurospora.

RNA polymerase II initiates transcription either randomly or in bursts. We examined the light-dependent transcriptional activator White Collar Complex (WCC) of Neurospora to characterize the transcriptional dynamics of the strong vivid (vvd) promoter and the weaker frequency (frq) promoter. We show that WCC is not only an activator but also represses transcription by recruiting histone deacetylase 3 (HDA3). Our data suggest that bursts of frq transcription are governed by a long-lived refractory state established and maintained by WCC and HDA3 at the core promoter, whereas transcription of vvd is determined by WCC binding dynamics at an upstream activating sequence. Thus, in addition to stochastic binding of transcription factors, transcription factor-mediated repression may also influence transcriptional bursting.

Diminuendo al bottom-Clarifying the semantics of music notation by re-modeling.

One of many aspects of musical notation is that of a graphical language which strives to be totally precise, but falls short because it has been defined by historical evolution, cultural construction and de-central ramification. This article applies standard techniques for computer languages to reconstruct a precise model for the syntax and semantics of the historically grown notation systems, taking the conventional way of notating musical dynamics as a simple example. It turns out that no single such model is possible, but a multitude of incompatibles: some have fundamentally different evaluation algorithms, others only slightly different parameter settings. Musical practice is allowed to switch between these models without even noticing their existence, but science may need distinctness. This article constructs and demonstrates an extensible mathematical framework for their precise description and proposes an extensible nomenclature system as a basis for their application and discussion.

Impact of room acoustic parameters on speech and music perception among participants with cochlear implants.

OBJECTIVES: Besides numerous other factors, listening experience with cochlear implants is substantially impaired by room acoustics. Even for persons without hearing impairment, the perception of auditory scenes, for example, concerning speech intelligibility, acoustic quality or audibility, is considerably influenced by room acoustics. For CI users, complex listening environments are usually associated with heavy losses. The aim of the present study was to determine room acoustic criteria that particularly influence speech pleasantness for CI users. DESIGN: Accordingly, speech material of the Oldenburg Sentence Test (Oldenburger Satztest, OLSA) as well as basic music material (major and minor triads) were auralized using the software Auratorium which allows auralization of simulated rooms. The constructed rooms for speech stimuli were based on the standard DIN 18041:2016-03 concerning acoustic quality in rooms, the binding standard referred to by room acoustic consultants in Germany, which also includes specifications for inclusive applications in schools. For the music perception tests, two typical concert halls of different sizes were modelled. The auralized test stimuli were unilaterally presented to 10 CI users via their auxiliary input as well as to 18 participants with typical hearing via headphones (control group). Speech pleasantness was evaluated using modified MUSHRA tests. Concerning music perception, chord discrimination was tested using paired comparisons. RESULTS: A strong preference of small source to listener distances by CI users was found, but no significant preference for room acoustic attenuation which exceeded the recommended for inclusive applications in schools. The analyses of the energy-time-structures suggested that a dense concentration of early reflections makes a beneficial impact on CI listeners' pleasantness ratings. Music materials were distinguished more consistently without any room acoustic impact, while any room acoustic impact led to performance close to chance level. This effect is probably due to spectral smearing effects caused by reverberation. CONCLUSIONS: These results suggest that in terms of pleasantness of speech, for CI-users, source-to-listener distance is the more influential parameter than room attenuation which goes beyond the German standard recommendation. Reflections from which CI users can benefit seem to occur much earlier than those from which NH listeners benefit. Future studies on chord discrimination concerning room acoustics are needed.

Reimmunization increases contraceptive effectiveness of gonadotropin-releasing hormone vaccine (GonaCon-Equine) in free-ranging horses (Equus caballus): Limitations and side effects.

Wildlife and humans are increasingly competing for resources worldwide, and a diverse, innovative, and effective set of management tools is needed. Controlling abundance of wildlife species that are simultaneously protected, abundant, competitive for resources, and in conflict with some stakeholders but beloved by others, is a daunting challenge. Free-ranging horses (Equus caballus) present such a conundrum and managers struggle for effective tools for regulating their abundance. Controlling reproduction of female horses presents a potential alternative. During 2009-2017, we determined the long-term effectiveness of GnRH vaccine (GonaCon-Equine) both as a single immunization and subsequent reimmunization on reproduction and side effects in free-ranging horses. At a scheduled management roundup in 2009, we randomly assigned 57 adult mares to either a GonaCon-Equine treatment group (n = 29) or a saline control group (n = 28). In a second roundup in 2013, we administered a booster vaccination to these same mares. We used annual ground observations to estimate foaling proportions, social behaviors, body condition, and injection site reactions. We found this vaccine to be safe for pregnant females and neonates, with no overt deleterious behavioral side effects during the breeding season. The proportion of treated mares that foaled following a single vaccination was lower than that for control mares for the second (P = 0.03) and third (P = 0.08) post-treatment foaling seasons but was similar (P = 0.67) to untreated mares for the fourth season, demonstrating reversibility of the primary vaccine treatment. After two vaccinations, however, the proportion of females giving birth was lower (P <0.001) than that for control mares for three consecutive years and ranged from 0.0-0.16. The only detectable adverse side effect of vaccination was intramuscular swelling at the vaccination site. Regardless of vaccine treatment (primary/secondary), approximately 62% (34/55) of immunized mares revealed a visible reaction at the vaccine injection site. However, none of these mares displayed any evidence of lameness, altered gait or abnormal range of movement throughout the 8 years they were observed in this study. Our research suggests that practical application of this vaccine in feral horses will require an initial inoculation that may provide only modest suppression of fertility followed by reimmunization that together could result in greater reduction in population growth rates over time.

Frequency Modulation of Transcriptional Bursting Enables Sensitive and Rapid Gene Regulation.

Gene regulation is a complex non-equilibrium process. Here, we show that quantitating the temporal regulation of key gene states (transcriptionally inactive, active, and refractory) provides a parsimonious framework for analyzing gene regulation. Our theory makes two non-intuitive predictions. First, for transcription factors (TFs) that regulate transcription burst frequency, as opposed to amplitude or duration, weak TF binding is sufficient to elicit strong transcriptional responses. Second, refractoriness of a gene after a transcription burst enables rapid responses to stimuli. We validate both predictions experimentally by exploiting the natural, optogenetic-like responsiveness of the Neurospora GATA-type TF White Collar Complex (WCC) to blue light. Further, we demonstrate that differential regulation of WCC target genes is caused by different gene activation rates, not different TF occupancy, and that these rates are tuned by both the core promoter and the distance between TF-binding site and core promoter. In total, our work demonstrates the relevance of a kinetic, non-equilibrium framework for understanding transcriptional regulation.

Transcriptional refractoriness is dependent on core promoter architecture.

Genes are often transcribed in random bursts followed by long periods of inactivity. Here we employ the light-activatable white collar complex (WCC) of Neurospora to study the transcriptional bursting with a population approach. Activation of WCC by a light pulse triggers a synchronized wave of transcription from the frequency promoter followed by an extended period (∼1 h) during which the promoter is refractory towards restimulation. When challenged by a second light pulse, the newly activated WCC binds to refractory promoters and has the potential to recruit RNA polymerase II (Pol II). However, accumulation of Pol II and phosphorylation of its C-terminal domain repeats at serine 5 are impaired. Our results suggest that refractory promoters carry a physical memory of their recent transcription history. Genome-wide analysis of light-induced transcription suggests that refractoriness is rather widespread and a property of promoter architecture.

Peroxiredoxin-2 and STAT3 form a redox relay for H2O2 signaling.

Hydrogen peroxide (H(2)O(2)) acts as a signaling messenger by oxidatively modifying distinct cysteinyl thiols in distinct target proteins. However, it remains unclear how redox-regulated proteins, which often have low intrinsic reactivity towards H(2)O(2) (k(app) ∼1-10 M(-1) s(-1)), can be specifically and efficiently oxidized by H(2)O(2). Moreover, cellular thiol peroxidases, which are highly abundant and efficient H(2)O(2) scavengers, should effectively eliminate virtually all of the H(2)O(2) produced in the cell. Here, we show that the thiol peroxidase peroxiredoxin-2 (Prx2), one of the most H(2)O(2)-reactive proteins in the cell (k(app) ∼10(7)-10(8) M(-1) s(-1)), acts as a H(2)O(2) signal receptor and transmitter in transcription factor redox regulation. Prx2 forms a redox relay with the transcription factor STAT3 in which oxidative equivalents flow from Prx2 to STAT3. The redox relay generates disulfide-linked STAT3 oligomers with attenuated transcriptional activity. Cytokine-induced STAT3 signaling is accompanied by Prx2 and STAT3 oxidation and is modulated by Prx2 expression levels.