Investigating vocal plasticity in song sparrows (Melospizia melodia) as a mechanism to avoid masking noise in urban environments

Animals that successfully colonize urban areas must be tolerant of anthropogenic disturbance including noise. Chronic anthropogenic noise may be difficult for animals that use acoustic signals to overcome if it disrupts communication. Most anthropogenic noise is below 1.5 kHz but can spread into higher frequency ranges overlapping with acoustic signals used in animal communication. Songbird species are common urban colonizers that use acoustic signals that are critical for reproductive success. To avoid the masking effects of loud anthropogenic noise, many songbird species that occupy noisy urban areas have been observed to use songs and calls with higher minimum frequencies compared to rural counterparts. Precise mechanisms for the observed frequency shifts are not well understood but can be accomplished through natural selection, cultural selection, and vocal plasticity. In this study, I test whether male song sparrows (Melospiza melodia) can use vocal plasticity to avoid masking noise when exposed to experimental noise. Song sparrows that occupy noisy urban habitats are observed to have songs with an increased minimum frequency when compared to song sparrows in quieter areas. However, it is unclear how urban song sparrows can increase minimum frequency because song sparrows do not naturally use frequency shifting during singing but rather use a repertoire of crystallized songs with fixed frequency characteristics. I tested the response of 46 males on the campus of Western Carolina University with two experimental noise treatments. Noise treatments differ in whether the frequency of the noise overlaps with song sparrow songs (2.5-4.0 kHz, masking) or does not overlap (0.5-1.5 kHz, non-masking). All males were exposed to both treatments but on different days. During trials, I recorded singing before, during, and after each treatment. I used Raven Pro to measure minimum and maximum frequency, frequency bandwidth, and song length for up to 10 songs from each period of the trials and calculated means to use in statistical analysis. I found an increase in minimum frequency for songs during the masking noise but not during non-masking noise. There was no difference in maximum frequency between treatments, thus bandwidth was significantly narrower during the masking treatment. I found no significant difference in how males changed perches, song types, or variants in response to either noise treatment. However, I found that when males switched to a new song type or variant when the noise started, that they switched to a type or variant that significantly increased the minimum frequency during masking noise. My results suggest that male song sparrows use vocal plasticity to immediately avoid the negative effects of masking noise. My results do not rule out the possibility of cultural or natural selection on frequency shifts observed in urban song sparrows. However, vocal plasticity is a flexible strategy that may allow adopters to both increase detectability in masking noise but also minimize the potential negative impacts of frequency adjustments on song function. Future studies should focus on how vocal plasticity in song sparrows impacts detectability and discrimination of song in anthropogenic noise

Aberrant Ca2+ signaling by IP3Rs in adipocytes links inflammation to metabolic dysregulation in obesity.

Chronic metabolic inflammation is a key feature of obesity, insulin resistance, and diabetes. Here, we showed that altered regulation of the Ca2+ channel inositol trisphosphate receptor (IP3R) was an adipocyte-intrinsic event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation induced by cytokine exposure in vitro or by obesity in vivo led to increases in the abundance and activity of IP3Rs and in the phosphorylation of the Ca2+-dependent kinase CaMKII in adipocytes in a manner dependent on the kinase JNK. In mice, adipocyte-specific loss of IP3R1/2 protected against adipose tissue inflammation and insulin resistance, despite the mice exhibiting substantial diet-induced weight gain. Thus, this work suggests that increased IP3R activity is a key link between obesity, inflammation, and insulin resistance. These data also suggest that approaches to target IP3R-mediated Ca2+ homeostasis in adipocytes may offer new therapeutic opportunities against metabolic diseases, especially because GWAS studies also implicate this locus in human obesity

Aberrant Ca2+ homeostasis in adipocytes links inflammation to metabolic dysregulation in obesity [preprint]

Chronic metabolic inflammation is a key feature of obesity, insulin resistance and diabetes, although the initiation and propagation mechanisms of metaflammation are not fully established, particularly in the adipose tissue. Here we show that in adipocytes, altered regulation of the Ca2+ channel inositol triphosphate receptor (IP3Rs) is a key, adipocyte-intrinsic, event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation, either induced by cytokine exposure in vitro or by obesity in vivo lead to increased expression and activity of IP3Rs in adipocytes in a JNK-dependent manner. This results in increased cytosolic Ca2+ and impaired insulin action. In mice, adipocyte-specific loss of IP3R1/2 protected against adipose tissue inflammation and insulin resistance despite significant diet-induced weight gain. Thus, this work reveals that IP3R over-activation and the resulting increase in cytosolic Ca2+ is a key link between obesity, inflammation and insulin resistance, and suggests that approaches to target adipocyte Ca2+ homeostasis may offer new therapeutic opportunities against metabolic diseases, especially since GWAS studies also implicate this locus in human obesity

Uncoupling of Metabolic Health from Longevity through Genetic Alteration of Adipose Tissue Lipid-Binding Proteins

Deterioration of metabolic health is a hallmark of aging and generally assumed to be detrimental to longevity. Exposure to a high-calorie diet impairs metabolism and accelerates aging; conversely, calorie restriction (CR) prevents age-related metabolic diseases and extends lifespan. However, it is unclear whether preservation of metabolic health is sufficient to extend lifespan. We utilized a genetic mouse model lacking Fabp4/5 that confers protection against metabolic diseases and shares molecular and lipidomic features with CR to address this question. Fabp-deficient mice exhibit extended metabolic healthspan, with protection against insulin resistance and glucose intolerance, inflammation, deterioration of adipose tissue integrity, and fatty liver disease. Surprisingly, however, Fabp-deficient mice did not exhibit any extension of lifespan. These data indicate that extension of metabolic healthspan in the absence of CR can be uncoupled from lifespan, indicating the potential for independent drivers of these pathways, at least in laboratory mice

A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid utilization

Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or utilization. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding1,2 and is repressed by Rev-erbα/β and an HDAC3-containing complex3–5 during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes6–8, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARδ-dependent de novo lipogenic pathway in the liver that modulates fat utilization by muscle via a circulating lipid. The nuclear receptor PPARδ controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARδ activation increases, while hepatocyte-Ppard deletion reduces, muscle fatty acid (FA) uptake. Unbiased metabolite profiling identifies PC(18:0/18:1), or 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine (SOPC), as a serum lipid regulated by diurnal hepatic PPARδ activity. PC(18:0/18:1) reduces postprandial lipid levels and increases FA utilization through muscle PPARα. High fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy utilization in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARδ-PC(18:0/18:1) signaling in metabolic disorders including obesity

Novel role of PKR in inflammasome activation and HMGB1 release

The inflammasome regulates release of caspase activation-dependent cytokines, including IL-1β, IL-18, and high-mobility group box 1 (HMGB1)1-5. During the course of studying HMGB1 release mechanisms, we discovered an important role of double-stranded RNA dependent protein kinase (PKR) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminum, rotenone, live E. coli, anthrax lethal toxin, DNA transfection, and S. Typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1beta, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with multiple inflammasome components, including NLR family pyrin domain-containing 3 (NLRP3), NLR family pyrin domain-containing 1 (NLRP1), NLR family CARD domain-containing protein 4 (NLRC4), Absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell free system with recombinant NLRP3, ASC and pro-casapse-1 reconstitutes inflammasome activity. These results reveal a critical role of PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation

Parallel but not equivalent: Challenges and solutions for repeated assessment of cognition over time

OBJECTIVE: Analyses of individual differences in change may be unintentionally biased when versions of a neuropsychological test used at different follow-ups are not of equivalent difficulty. This study's objective was to compare mean, linear, and equipercentile equating methods and demonstrate their utility in longitudinal research. STUDY DESIGN AND SETTING: The Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE, N = 1,401) study is a longitudinal randomized trial of cognitive training. The Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 819) is an observational cohort study. Nonequivalent alternate versions of the Auditory Verbal Learning Test (AVLT) were administered in both studies. RESULTS: Using visual displays, raw and mean-equated AVLT scores in both studies showed obvious nonlinear trajectories in reference groups that should show minimal change and poor equivalence over time (ps ≤ .001), and raw scores demonstrated poor fits in models of within-person change (root mean square errors of approximation, RMSEAs > 0.12). Linear and equipercentile equating produced more similar means in reference groups (ps ≥ .09) and performed better in growth models (RMSEAs < 0.05). CONCLUSION: Equipercentile equating is the preferred equating method because it accommodates tests more difficult than a reference test at different percentiles of performance and performs well in models of within-person trajectory. The method has broad applications in both clinical and research settings to enhance the ability to use nonequivalent test forms

Deficiency of FcεR1 increases body weight gain but improves glucose tolerance in diet-induced obese mice

Prior studies demonstrated increased plasma immunoglobulin E (IgE) in diabetic patients, but the direct participation of IgE in diabetes or obesity remains unknown. This study found that plasma IgE levels correlated inversely with body weight, body mass index, and body fat mass among a population of randomly selected obese women. IgE receptor FcεR1-deficient (Fcer1a–/–) mice and diet-induced obesity (DIO) mice demonstrated that FcεR1 deficiency in DIO mice increased food intake, reduced energy expenditure, and increased body weight gain, but improved glucose tolerance and glucose-induced insulin secretion. White adipose tissue (WAT) from Fcer1a–/– mice showed increased expression of phospho-AKT, C/EBPα, PPARγ, Glut4, and Bcl-2, but reduced UCP1 and phospho-JNK expression, tissue macrophage accumulation, and apoptosis, suggesting that IgE reduces adipogenesis and glucose uptake, but induces energy expenditure, adipocyte apoptosis, and WAT inflammation. In 3T3-L1 cells, IgE inhibited the expression of C/EBPα and PPARγ, and preadipocyte adipogenesis, and induced adipocyte apoptosis. IgE reduced 3T3-L1 cell expression of Glut4, phospho-AKT, and glucose uptake, which concurred with improved glucose tolerance in Fcer1a–/– mice. This study established two novel pathways of IgE in reducing body weight gain in DIO mice by suppressing adipogenesis and inducing adipocyte apoptosis, while worsening glucose tolerance by reducing Glut4 expression, glucose uptake, and insulin secretion

Novel role of PKR in inflammasome activation and HMGB1 release

The inflammasome regulates release of caspase activation-dependent cytokines, including IL-1β, IL-18, and high-mobility group box 1 (HMGB1)1-5. During the course of studying HMGB1 release mechanisms, we discovered an important role of double-stranded RNA dependent protein kinase (PKR) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminum, rotenone, live E. coli, anthrax lethal toxin, DNA transfection, and S. Typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1beta, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with multiple inflammasome components, including NLR family pyrin domain-containing 3 (NLRP3), NLR family pyrin domain-containing 1 (NLRP1), NLR family CARD domain-containing protein 4 (NLRC4), Absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell free system with recombinant NLRP3, ASC and pro-casapse-1 reconstitutes inflammasome activity. These results reveal a critical role of PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation

Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events.

The emergence of multidrug-resistant (MDR) typhoid is a major global health threat affecting many countries where the disease is endemic. Here whole-genome sequence analysis of 1,832 Salmonella enterica serovar Typhi (S. Typhi) identifies a single dominant MDR lineage, H58, that has emerged and spread throughout Asia and Africa over the last 30 years. Our analysis identifies numerous transmissions of H58, including multiple transfers from Asia to Africa and an ongoing, unrecognized MDR epidemic within Africa itself. Notably, our analysis indicates that H58 lineages are displacing antibiotic-sensitive isolates, transforming the global population structure of this pathogen. H58 isolates can harbor a complex MDR element residing either on transmissible IncHI1 plasmids or within multiple chromosomal integration sites. We also identify new mutations that define the H58 lineage. This phylogeographical analysis provides a framework to facilitate global management of MDR typhoid and is applicable to similar MDR lineages emerging in other bacterial species