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Alcohol Use Disorder (AUD) is a chronic relapsing disorder affecting an estimated 283 million individuals worldwide, with substantial health and economic consequences. Peroxisome proliferator-activated receptors (PPARs), particularly PPAR-α and PPAR-γ, have shown promise in preclinical studies as potential therapeutic targets for AUD. In this human laboratory study, we aimed to translate preclinical findings on the PPAR-α agonist fenofibrate to a human population with current AUD. We hypothesized that, relative to placebo, fenofibrate at the highest FDA-approved dose of 145 mg/d would attenuate responsiveness to in vivo alcohol cues in the lab and reduce drinking under natural conditions. However, the results did not show significant differences in craving and alcohol consumption between the fenofibrate and placebo groups. Reverse translational studies in rodent models confirmed the lack of fenofibrate effect at human-equivalent doses. These findings suggest that inadequate translation of drug dose from rodents to humans may account for the lack of fenofibrate effects on alcohol craving and consumption in humans with AUD. The results highlight the need for new brain-penetrant PPAR-α agonists to adequately test the therapeutic potential of PPAR-α agonists for AUD, and the importance of reverse translational approaches and selection of human-equivalent doses in drug development.

Human operators often experience large fluctuations in cognitive workload over seconds timescales that can lead to sub-optimal performance, ranging from overload to neglect. Adaptive automation could potentially address this issue, but to do so it needs to be aware of real-time changes in operators' spare cognitive capacity, so it can provide help in times of peak demand and take advantage of troughs to elicit operator engagement. However, it is unclear whether rapid changes in task demands are reflected in similarly rapid fluctuations in spare capacity, and if so what aspects of responses to those demands are predictive of the current level of spare capacity. We used the ISO standard detection response task (DRT) to measure cognitive workload approximately every 4 s in a demanding task requiring monitoring and refueling of a fleet of simulated unmanned aerial vehicles (UAVs). We showed that the DRT provided a valid measure that can detect differences in workload due to changes in the number of UAVs. We used cross-validation to assess whether measures related to task performance immediately preceding the DRT could predict detection performance as a proxy for cognitive workload. Although the simple occurrence of task events had weak predictive ability, composite measures that tapped operators' situational awareness with respect to fuel levels were much more effective. We conclude that cognitive workload does vary rapidly as a function of recent task events, and that real-time predictive models of operators' cognitive workload provide a potential avenue for automation to adapt without an ongoing need for intrusive workload measurements.

Environmental factors can promote phenotypic variation through alterations in the epigenome and facilitate adaptation of an organism to the environment. Although hydrogen sulfide is toxic to most organisms, the fish Poecilia mexicana has adapted to survive in environments with high levels that exceed toxicity thresholds by orders of magnitude. Epigenetic changes in response to this environmental stressor were examined by assessing DNA methylation alterations in red blood cells, which are nucleated in fish. Males and females were sampled from sulfidic and nonsulfidic natural environments; individuals were also propagated for two generations in a nonsulfidic laboratory environment. We compared epimutations between the sexes as well as field and laboratory populations. For both the wild-caught (F0) and the laboratory-reared (F2) fish, comparing the sulfidic and nonsulfidic populations revealed evidence for significant differential DNA methylation regions (DMRs). More importantly, there was over 80% overlap in DMRs across generations, suggesting that the DMRs have stable generational inheritance in the absence of the sulfidic environment. This is an example of epigenetic generational stability after the removal of an environmental stressor. The DMR-associated genes were related to sulfur toxicity and metabolic processes. These findings suggest that adaptation of P. mexicana to sulfidic environments in southern Mexico may, in part, be promoted through epigenetic DNA methylation alterations that become stable and are inherited by subsequent generations independent of the environment.

Human operators often experience large fluctuations in cognitive workload over seconds timescales that can lead to sub-optimal performance, ranging from overload to neglect. Adaptive automation could potentially address this issue, but to do so it needs to be aware of real-time changes in operators' spare cognitive capacity, so it can provide help in times of peak demand and take advantage of troughs to elicit operator engagement. However, it is unclear whether rapid changes in task demands are reflected in similarly rapid fluctuations in spare capacity, and if so what aspects of responses to those demands are predictive of the current level of spare capacity. We used the ISO standard detection response task (DRT) to measure cognitive workload approximately every 4 s in a demanding task requiring monitoring and refueling of a fleet of simulated unmanned aerial vehicles (UAVs). We showed that the DRT provided a valid measure that can detect differences in workload due to changes in the number of UAVs. We used cross-validation to assess whether measures related to task performance immediately preceding the DRT could predict detection performance as a proxy for cognitive workload. Although the simple occurrence of task events had weak predictive ability, composite measures that tapped operators' situational awareness with respect to fuel levels were much more effective. We conclude that cognitive workload does vary rapidly as a function of recent task events, and that real-time predictive models of operators' cognitive workload provide a potential avenue for automation to adapt without an ongoing need for intrusive workload measurements.

Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing (i.e., FDA approved for psoriasis, low incidence of adverse events, excellent safety profile) and tested it using multiple animal strains and models, as well as in a human phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models of stress- facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non-treatment-seeking individuals with AUD in a double-blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity., Introduction Alcohol use disorder (AUD) is a complex psychiatric disease with far reaching impacts on society, including more than 95,000 associated deaths annually in the United States and a net [...]

The number of students with learning disabilities (LD) attending postsecondary institutions has increased steadily over the past two decades. Many of these students have language-based learning difficulties that create barriers to success in foreign language (FL) courses. Many institutions have responded by providing these students with exemptions or alternative courses. Although exemptions and alternatives are needed by some students with severe language difficulties, the literature is increasingly indicating that many of these students can successfully complete FL curricula. This is especially true when accommodations and specialized teaching methodologies are implemented in sections of FL courses designed specifically to meet the needs of students with LD. The purpose of this article is to describe FL course accommodations supported by existing literature and field-based experiences. The article also highlights the benefits of successful FL experiences for student with LD. (Contains 2 tables and 2 figures.)

Sex determination in animals and fungi is regulated by specific sex-determining genes. The Aspergillus nidulans mating type gene matA and the human SRY (Sex-Determining Region Y) encode proteins containing a single HMG (high-mobility group) domain. Analysis of the amino-acid sequence of MatA and SRY transcription factors revealed significant structural similarity. The human SRY protein is able to functionally replace MatA and drives the sexual cycle in the fungus A. nidulans. Functional studies indicate that SRY drives early fruiting body development, and hybrid MatA protein carrying the SRY HMG box is fully capable of driving both early and late stages of sexual development, including gametogenesis. Our data suggest that SRY and MatA are both structurally and functionally related and conserved in regulating sexual processes. The fundamental mechanisms driving evolution of the genetic pathways underlying sex determination, sex chromosomes and sexual reproduction in eukaryotes appear similar.

The number of students with documented learning disabilities (LD) enrolled in postsecondary settings has increased steadily over the past 20 years. Providing "reasonable" accommodations significantly increases the probability of success for these students. The present study investigated the willingness of postsecondary instructors to provide accommodations and alternative courses. Results indicated that instructor willingness to provide accommodations and their support of course alternatives varied as a function of school affiliation (e.g., education, mathematics and science, etc.), rank, and specific accommodation requested. Based on the results of this study and previous literature, programmatic suggestions are provided for facilitating the provision of academic adjustments to student with LD in postsecondary settings. (Contains 1 table and 8 figures.)

The purpose of this study was to identify variables that facilitate the academic success of college students with learning disabilities. Twenty recent college graduates with documented learning disabilities were interviewed using a semi-structured format. An analysis of the transcripts of the interviews revealed eight common themes, many of which were consistent with previous research. The themes included (a) the importance of knowledge of one's disability and concomitant accommodations; (b) limited explanation of results of pyschoeducational evaluations; (c) a dearth of information relating to disability law; (d) the importance of self-advocacy; (e) the significance of accommodations and course alternatives; (f) the importance of support systems; (g) the recognition of the need to persevere under challenging circumstances; and (h) the positive effects of goal-setting. Implications of these results are discussed in relation to characteristics of educational programming that facilitate success among students with specific learning disabilities in postsecondary settings. (Contains 2 tables.)

Although male infertility is currently diagnosed when abnormal sperm parameters are found, the poor predictive ability of sperm parameters on natural fecundity and medically assisted reproduction outcome poses the need for improved diagnostic techniques for male infertility. The accumulating evidence about the role played by the sperm epigenome in modulation of the early phases of embryonic development has led researchers to focus on the epigenetic mechanisms within the sperm epigenome to find new molecular markers of male infertility. Indeed, sperm epigenome abnormalities could explain some cases of unexplained male infertility in men showing normal sperm parameters and were found to be associated with poor embryo development in IVF cycles. The present mini-review summarizes the current knowledge about this interesting topic, starting from a description of the epigenetic mechanisms of gene expression regulation (i.e. DNA methylation, histone modifications, and non-coding RNAs' activity). We also discuss possible mechanisms by which environmental factors might cause epigenetic changes in the human germline and affect embryonic development, as well as subsequent generations' phenotypes. Studies demonstrating sperm epigenome abnormalities in men with male infertility are reviewed, with particular emphasis on those with the more severe form of spermatogenic dysfunction. Observations demonstrate that the diagnostic and prognostic efficacy of sperm epigenome evaluation will help facilitate the management of men with male factor infertility. [ABSTRACT FROM AUTHOR]