On the Relevance of Natural Stimuli for the Study of Brainstem Correlates: The Example of Consonance Perception

Some combinations of musical tones sound pleasing to Western listeners, and are termed consonant, while others sound discordant, and are termed dissonant. The perceptual phenomenon of consonance has been traced to the acoustic property of harmonicity. It has been repeatedly shown that neural correlates of consonance can be found as early as the auditory brainstem as reflected in the harmonicity of the scalp-recorded frequency-following response (FFR). “Neural Pitch Salience” (NPS) measured from FFRs—essentially a time-domain equivalent of the classic pattern recognition models of pitch—has been found to correlate with behavioral judgments of consonance for synthetic stimuli. Following the idea that the auditory system has evolved to process behaviorally relevant natural sounds, and in order to test the generalizability of this finding made with synthetic tones, we recorded FFRs for consonant and dissonant intervals composed of synthetic and natural stimuli. We found that NPS correlated with behavioral judgments of consonance and dissonance for synthetic but not for naturalistic sounds. These results suggest that while some form of harmonicity can be computed from the auditory brainstem response, the general percept of consonance and dissonance is not captured by this measure. It might either be represented in the brainstem in a different code (such as place code) or arise at higher levels of the auditory pathway. Our findings further illustrate the importance of using natural sounds, as a complementary tool to fully-controlled synthetic sounds, when probing auditory perception.     

A single proline substitution is critical for the thermostabilization of Clostridium beijerinckii alcohol dehydrogenase

Analysis of the three-dimensional structures of three closely related mesophilic, thermophilic, and hyperthermophilic alcohol dehydrogenases (ADHs) from the respective microorganisms Clostridium beijerinckii (CbADH), Entamoeba histolytica (EhADH1), and Thermoanaerobacter brockii (TbADH) suggested that a unique, strategically located proline residue (Pro100) might be crucial for maintaining the thermal stability of EhADH1. To determine whether proline substitution at this position in TbADH and CbADH would affect thermal stability, we used site-directed mutagenesis to replace the complementary residues in both enzymes with proline. The results showed that replacing Gln100 with proline significantly enhanced the thermal stability of the mesophilic ADH: DeltaT(1/2) (60 min) = + 8 degrees C (temperature of 50% inactivation after incubation for 60 min), DeltaT(1/2) (CD) = +11.5 degrees C (temperature at which 50% of the original CD signal at 218 nm is lost upon heating between 30 degrees and 98 degrees C). A His100 --> Pro substitution in the thermophilic TbADH had no effect on its thermostability. An analysis of the three-dimensional structure of the crystallized thermostable mutant Q100P-CbADH suggested that the proline residue at position 100 stabilized the enzyme by reinforcing hydrophobic interactions and by reducing the flexibility of a loop at this strategic region.     

Defining the biological bases of individual differences in musicality

Advances in molecular technologies make it possible to pinpoint genomic factors associated with complex human traits. For cognition and behaviour, identification of underlying genes provides new entry points for deciphering the key neurobiological pathways. In the past decade, the search for genetic correlates of musicality has gained traction. Reports have documented familial clustering for different extremes of ability, including amusia and absolute pitch (AP), with twin studies demonstrating high heritability for some music-related skills, such as pitch perception. Certain chromosomal regions have been linked to AP and musical aptitude, while individual candidate genes have been investigated in relation to aptitude and creativity. Most recently, researchers in this field started performing genome-wide association scans. Thus far, studies have been hampered by relatively small sample sizes and limitations in defining components of musicality, including an emphasis on skills that can only be assessed in trained musicians. With opportunities to administer standardized aptitude tests online, systematic large-scale assessment of musical abilities is now feasible, an important step towards high-powered genome-wide screens. Here, we offer a synthesis of existing literatures and outline concrete suggestions for the development of comprehensive operational tools for the analysis of musical phenotypes.     

Human immunodeficiency virus (HIV)-specific gamma interferon secretion directed against all expressed HIV genes: relationship to rate of CD4 decline

Immune responses to human immunodeficiency virus (HIV) are detected at all stages of infection and are believed to be responsible for controlling viremia. This study seeks to determine whether gamma interferon (IFN-gamma)-secreting HIV-specific T-cell responses influence disease progression as defined by the rate of CD4 decline. The study population consisted of 31 subjects naive to antiretroviral therapy. All were monitored clinically for a median of 24 months after the time they were tested for HIV-specific responses. The rate of CD4+-T-cell loss was calculated for all participants from monthly CD4 counts. Within this population, 17 subjects were classified as typical progressors, 6 subjects were classified as fast progressors, and 8 subjects were classified as slow progressors. Peripheral blood mononuclear cells were screened for HIV-specific IFN-gamma responses to all expressed HIV genes. Among the detected immune responses, 48% of the recognized peptides were encoded by Gag and 19% were encoded by Nef gene products. Neither the breadth nor the magnitude of HIV-specific responses correlated with the viral load or rate of CD4 decline. The breadth and magnitude of HIV-specific responses did not differ significantly among typical, fast, and slow progressors. These results support the conclusion that although diverse HIV-specific IFN-gamma-secreting responses are mounted during the asymptomatic phase, these responses do not seem to modulate disease progression rates.     

Productive replication and evolution of HIV-1 in ferret cells

A rodent or other small animal model for HIV-1 has not been forthcoming, with the principal obstacles being species-specific restriction mechanisms and deficits in HIV-1 dependency factors. Some Carnivorans may harbor comparatively fewer impediments. For example, in contrast to mice, the domestic cat genome encodes essential nonreceptor HIV-1 dependency factors. All Feliformia species and at least one Caniformia species also lack a major lentiviral restriction mechanism (TRIM5α/TRIMCyp proteins). Here we investigated cells from two species in another carnivore family, the Mustelidae, for permissiveness to the HIV-1 life cycle. Mustela putorius furo (domesticated ferret) primary cells and cell lines did not restrict HIV-1, feline immunodeficiency virus (FIV), equine infectious anemia virus (EIAV), or N-tropic murine leukemia virus (MLV) postentry and supported late HIV-1 life cycle steps comparably to human cells. The ferret TRIM5α gene exon 8, which encodes the B30.2 domain, was found to be pseudogenized. Strikingly, ferret (but not mink) cells engineered to express human HIV-1 entry receptors supported productive spreading replication, amplification, and serial passage of wild-type HIV-1. Nevertheless, produced virions had relatively reduced infectivity and the virus accrued G→A hypermutations, consistent with APOBEC3 protein pressure. Ferret cell-passaged HIV-1 also evolved amino acid changes in the capsid cyclophilin A binding loop. We conclude that the genome of this carnivore can provide essential nonreceptor HIV-1 dependency factors and that ferret APOBEC3 proteins with activity against HIV-1 are likely. Even so, unlike in cat cells, HIV-1 can replicate in ferret cells without vif substitution. The virus evolves in this novel nonprimate cell adaptive landscape. We suggest that further characterization of HIV-1 adaptation in ferret cells and delineation of Mustelidae restriction factor repertoires are warranted, with a view to the potential for an HIV-1 animal model.     

Zinc supplementation increases bone alkaline phosphatase in healthy men.

Zinc takes part in the metabolism of bone as a constituent of the matrix and as an activator of several metallo-enzymes. Animal in vitro and in vivo studies strongly suggest that zinc supplementation could stimulate bone formation and inhibit bone resorption but data in humans remain rare. The biological effects of 50 mg zinc given orally as gluconate in 20 healthy male volunteers were investigated in a 12 weeks double-blind placebo-controlled randomized trial. To investigate bone turnover, total alkaline phosphatases activity (ALP), bone specific alkaline phosphatase activity (BAPE) and BAP mass (BAP-M) concentration were measured as parameters of bone formation while urine calcium and C-terminal collagen peptide were determined as parameters of bone resorption. Samples were obtained in fasting subjects at baseline and after 6 and 12 weeks. In zinc treated subjects, a significant increase was observed at least after 12 weeks in total ALP (p < 0.01), BAP-M (p < 0.05) and BAP-E (p < 0.02). These parameters did not significantly change in the placebo group. Urine zinc/creatinine ratio significantly increased after 6 (p < 0.03) and 12 weeks (p < 0.04) in the zinc-treated group and was significantly different from the placebo group (p < 0.002). There was no significant effect of zinc supplementation on parameters of bone resorption. In conclusion, zinc supplementation at supraphysiological doses increased parameters of bone formation in healthy men while parameters of bone resorption remained unchanged.     

Circadian Rhythms in 6-Sulphatoxymelatonin and Nocturnal Sleep in Blind Children

This article describes the relationship between melatonin secretion and sleep quality and subjective complaints about sleep in totally blind children. Eleven boarding-school children (mean age 15.2 years) participated. The major urinary melatonin metabolite 6-sulphatoxymelatonin (aMT6s) was measured five times a day for 48 h. Sleep-wake cycles were recorded by continuous actigraphic recordings during the same time period. Results showed that delayed secretory peaks in aMT6s were significantly associated with disturbed nocturnal sleep and with complaints about morning fatigue.     

Biosynthesis of extracellular low-molecular-mass papain and trypsin inhibitors by Streptomyces sp. 22: effect of cultural conditions

The production of extracellular inhibitors of papain and trypsin by Streptomyces sp. 22 was studied under different cultural conditions including complex and defined media, temperatures ranging from 18 °C to 37 °C and a variety of sole carbon and nitrogen sources. In complex nutritionally rich medium, maximal specific growth rates were obtained at 37 °C, whereas the highest specific production rates for both papain and trypsin inhibitors were registered at 18 °C. Studies on the effect of different carbon and nitrogen sources in defined media underline the importance of the nitrogen source as a strong regulator of the biosynthesis of both inhibitors. Enhanced formation of the inhibitory compounds occurred in the presence of casein. The dynamics of the formation of both inhibitors in defined media showed close association with growth. However, a partial separation of production phases for papain and trypsin inhibitors was observed in complex medium. The results imply differences in the regulation of biosynthesis of the two inhibitors.