Thermotolerance and heat acclimation may share a common mechanism in humans

Thermotolerance and heat acclimation are key adaptation processes that have been hitherto viewed as separate phenomena. Here, we provide evidence that these processes may share a common basis, as both may potentially be governed by the heat shock response. We evaluated the effects of a heat shock response-inhibitor (quercetin; 2,000 mg/day) on established markers of thermotolerance [gastrointestinal barrier permeability, plasma TNF-α, IL-6, and IL-10 concentrations, and leukocyte heat shock protein 70 (HSP70) content]. Heat acclimation reduced body temperatures, heart rate, and physiological strain during exercise/heat stress) in male subjects (n = 8) completing a 7-day heat acclimation protocol. These same subjects completed an identical protocol under placebo supplementation (placebo). Gastrointestinal barrier permeability and TNF-α were increased on the 1st day of exercise/heat stress in quercetin; no differences in these variables were reported in placebo. Exercise HSP70 responses were increased, and plasma cytokines (IL-6, IL-10) were decreased on the 7th day of heat acclimation in placebo; with concomitant reductions in exercise body temperatures, heart rate, and physiological strain. In contrast, gastrointestinal barrier permeability remained elevated, HSP70 was not increased, and IL-6, IL-10, and exercise body temperatures were not reduced on the 7th day of heat acclimation in quercetin. While exercise heart rate and physiological strain were reduced in quercetin, this occurred later in exercise than with placebo. Consistent with the concept that thermotolerance and heat acclimation are related through the heat shock response, repeated exercise/heat stress increases cytoprotective HSP70 and reduces circulating cytokines, contributing to reductions in cellular and systemic markers of heat strain. Exercising under a heat shock response-inhibitor prevents both cellular and systemic heat adaptations.     

Globin-coupled sensors and protoglobins share a common signaling mechanism

The globin-coupled sensors (GCSs) and protoglobins (Pgbs) form one lineage of the globin superfamily. The GCSs are multidomain sensory proteins involved in aerotaxis or gene regulation, while the Pgbs are single-domain globins of yet unknown function. We postulate that the GCSs and Pgbs share a common signaling mechanism to modulate diverse physiological functions. To elucidate the signaling properties of individual globin domains, we constructed and expressed chimeric receptors in Escherichia coli. We demonstrate that all the chimeric receptors reversibly bind oxygen in vitro and trigger aerotactic responses in vivo. Thus, oxygen binding to the globin domains of diverse GCSs and Pgbs form a common signaling state that can trigger aerotactic responses.     

Protein farnesyltransferase and geranylgeranyltransferase share a common alpha subunit

Mammalian farnesyltransferase, which attaches a 15 carbon isoprenoid, farnesyl, to a cysteine in p21ras proteins, contains two subunits, alpha and beta. The beta subunit is known to bind p21ras proteins. We show here that the alpha subunit is shared with another prenyltransferase that attaches 20 carbon geranylgeranyl to Ras-related proteins. Farnesyltransferase and geranylgeranyltransferase have similar molecular weights on gel filtration, but are separated by ion exchange chromatography. Both enzymes are precipitated and immunoblotted by multiple antibodies directed against the alpha subunit of farnesyltransferase. The two transferases have different specificities for the protein acceptor; farnesyltransferase prefers methionine or serine at the COOH-terminus and geranylgeranyltransferase prefers leucine. The current data indicate that both prenyltransferases are heterodimers that share a common alpha subunit with different beta subunits.     

RNase MRP and RNase P share a common substrate.

RNase MRP is a site-specific ribonucleoprotein endoribonuclease that processes RNA from the mammalian mitochondrial displacement loop containing region. RNase P is a site-specific ribonucleoprotein endoribonuclease that processes pre-tRNAs to generate their mature 5'-ends. A similar structure for the RNase P and RNase MRP RNAs and a common cleavage mechanism for RNase MRP and RNase P enzymes have been proposed. Experiments with protein synthesis antibiotics have shown that both RNase MRP and RNase P are inhibited by puromycin. We also show that E. coli RNase P cleaves the RNase MRP substrate, mouse mitochondrial primer RNA, exactly at a site that is cleaved by RNase MRP.     

Vaults and telomerase share a common subunit, TEP1.

Vaults are large cytoplasmic ribonucleoprotein complexes of undetermined function. Mammalian vaults have two high molecular mass proteins of 193 and 240 kDa. We have identified a partial cDNA encoding the 240-kDa vault protein and determined it is identical to the mammalian telomerase-associated component, TEP1. TEP1 is the mammalian homolog of the Tetrahymena p80 telomerase protein and has been shown to interact specifically with mammalian telomerase RNA and the catalytic protein subunit hTERT. We show that while TEP1 is a component of the vault particle, vaults have no detectable telomerase activity. Using a yeast three-hybrid assay we demonstrate that several of the human vRNAs interact in a sequence-specific manner with TEP1. The presence of 16 WD40 repeats in the carboxyl terminus of the TEP1 protein is a convenient number for this protein to serve a structural or organizing role in the vault, a particle with eight-fold symmetry. The sharing of the TEP1 protein between vaults and telomerase suggests that TEP1 may play a common role in some aspect of ribonucleoprotein structure, function, or assembly.     

Mechanosensitive channels of bacteria and archaea share a common ancestral origin

The ubiquity of mechanosensitive (MS) ion channels set off a search for their functional homologues in archaea, the third domain of life. A new MS channel was identified in the archaeon Methanococcus jannaschii by using the TM1 transmembrane domain of the bacterial MS channel of large conductance, MscL, as a genetic probe to search the archaeal genomic database for MS channel homologues. The hypothetical protein MJ0170 (MscMJ) was found to harbor two MscL-like TM1 structural motifs and showed a high degree of se quence and secondary structure conservation with MscS (YggB) homologues. The alignment of sequences of MscL, MscS and MscMJ homologues further revealed that bacterial and archaeal channels form a phylogenetic tree composed of three main branches and share a common ancestral origin. This suggests the evolution of prokaryotic MS channels via gene duplication of a MscL-like progenitor gene followed by divergence, fur ther indicating that the common ancestor of the prokaryotic MS channels most likely resembled MscL. When expressed in E. coli and functionally examined by the patch clamp, the MscMJ protein behaved as a MS channel with a conductance of 270 pS in 200 mM KCl and a cation selectivity (PK/PC]) of approximately 6. The structural and functional homologue of MscMJ, MscMJLR, was identified as a second type of MS channel in M. jannaschii. The channel has a conductance of approximately 2 nS, rectifies with voltage and shares cation selectivity with MscMJ. The stoichiometry of both types of MS channels revealed that the free energy of activation, deltaG0 approximately 7kT, obtained for MscMJ matches the one calculated for MscS, deltaG0 approximately 5kT, whereas the free energy of activation approximately deltaG0 approximately 18kT of MscMJLR resembles more the deltaG0 = 14-19kT reported for MscL. The presence of two types of MS channels discovered in the cell envelope of M. jannaschii indicates that multiplicity of MS channels in prokaryotes is a necessary element for their survival in the habitats frequently challenged by sudden changes in osmolarity. Further functional and phylogenetic study of MS channels from all three domains of the universal phylogenetic tree may help to understand the evolution and common biophysical principles that govern mechanosensory transduction.     

Preferences for very low and very high voice pitch in humans

Manipulations of voice pitch have been shown to alter attractiveness ratings, but whether preferences extend to very low or very high voice pitch is unknown. Here, we manipulated voice pitch in averaged men's and women's voices by 2 Hz intervals to create a range of male and female voices speaking monopthong vowel sounds and spanning a range of frequencies from normal to very low and very high pitch. With these voices, we used the method of constant stimuli to measure preferences for voice. Nineteen university students (ages: 20-25) participated in three experiments. On average, men preferred high-pitched women's voices to low-pitched women's voices across all frequencies tested. On average, women preferred men's voices lowered in pitch, but did not prefer very low men's voices. The results of this study may reflect selection pressures for men's and women's voices, and shed light on a perceptual link between voice pitch and vocal attractiveness.     

The inositol polyphosphate 5-phosphatases and the apurinic/apyrimidinic base excision repair endonucleases share a common mechanism for catalysis

Inositol polyphosphate 5-phosphatases (5-phosphatase) hydrolyze the 5-position phosphate from the inositol ring of phosphatidylinositol-derived signaling molecules; however, the mechanism of catalysis is only partially characterized. These enzymes play critical roles in regulating cell growth, apoptosis, intracellular calcium oscillations, and post-synaptic vesicular trafficking. The UCLA fold recognition server (threader) predicted that the conserved 300-amino acid catalytic domain, common to all 5-phosphatases, adopts the fold of the apurinic/apyrimidinic (AP) base excision repair endonucleases. PSI-BLAST searches of GENPEPT, using the amino acid sequence of AP endonuclease exonuclease III, identified all members of the 5-phosphatase family with highly significant scores. A sequence alignment between exonuclease III and all known 5-phosphatases revealed six highly conserved motifs containing residues that corresponded to the catalytic residues in the AP endonucleases. Mutation of each of these residues to alanine in the mammalian 43-kDa, or yeast Inp52p 5-phosphatase, resulted in complete loss of enzyme activity. We predict the 5-phosphatase enzymes share a similar mechanism of catalysis to the AP endonucleases, consistent with other common functional similarities such as an absolute requirement for magnesium for activity. Based on this analysis, functional roles have been assigned to conserved residues in all 5-phosphatase enzymes.     

Ricin B chain and discoidin I share a common primitive protein fold

The galactoside-binding B chain of the cytotoxic protein ricin is apparently derived from a conservative exon-sized 40-residue peptide which is repeated four times in the molecule. A very similar peptide can also be seen in the amino acid sequence of the slime mold lectin discoidin I, which itself appears to be the product of a gene duplication. There is presently no chemical or structural evidence concerning the function of this peptide region. Nevertheless, the size of this unit, its prominence in the structure of ricin B chain, and its apparent conservation in carbohydrate-binding proteins from widely divergent organisms suggest that it may represent an extremely ancient galactoside-binding exon unit.     

Adaptations in humans for assessing physical strength from the voice

Recent research has shown that humans, like many other animals, have a specialization for assessing fighting ability from visual cues. Because it is probable that the voice contains cues of strength and formidability that are not available visually, we predicted that selection has also equipped humans with the ability to estimate physical strength from the voice. We found that subjects accurately assessed upper-body strength in voices taken from eight samples across four distinct populations and language groups: the Tsimane of Bolivia, Andean herder-horticulturalists and United States and Romanian college students. Regardless of whether raters were told to assess height, weight, strength or fighting ability, they produced similar ratings that tracked upper-body strength independent of height and weight. Male voices were more accurately assessed than female voices, which is consistent with ethnographic data showing a greater tendency among males to engage in violent aggression. Raters extracted information about strength from the voice that was not supplied from visual cues, and were accurate with both familiar and unfamiliar languages. These results provide, to our knowledge, the first direct evidence that both men and women can accurately assess men''s physical strength from the voice, and suggest that estimates of strength are used to assess fighting ability.     

The human and murine influenza-specific B cell repertoires share a common idiotope

We have dissected the human influenza-specific B cell repertoire by performing Epstein-Barr virus (EBV) limiting dilution analysis of lymphocytes obtained from donors before and after immunization with a commercially available influenza vaccine. In addition to an analysis of precursor frequency and light chain diversity, we studied sera and culture supernatants containing human anti-influenza antibodies with a panel of murine monoclonal antibodies specific for idiotopes identified on murine anti-PR8 and anti-X-31 antibodies. An idiotypic specificity present on the X-31-specific murine monoclonal PY206 has previously been shown to be shared by murine antibodies specific for PR8, X-31, and other influenza viruses. We observed little correlation among the following parameters: anti-viral titer, serum idiotope content, precursor frequency and immune status. More interestingly, there was a striking predominance of human influenza-specific antibodies that utilized lambda light chains. In addition, 12 of 26 human anti-influenza monoclonals strongly inhibited the binding of one of the murine anti-idiotopes to the labeled murine antibody, PY206. This is the same idiotope that is shared among murine antiinfluenza antibodies and all six individuals studied contained clones reactive with this anti-idiotope. Seven of these 12 idiotope-positive human antibodies gave partial cross-reactivity in a second anti-idiotypic system. These observations imply that a significant level of homology exists between the binding sites of human and murine influenza-specific antibodies and suggest that idiotypic manipulation of the human immune response to influenza virus may have important therapeutic implications.     

Human and mouse switch-like genes share common transcriptional regulatory mechanisms for bimodality

Background

The increasing number of sequenced prokaryotic genomes contains a wealth of genomic data that needs to be effectively analysed. A set of statistical tools exists for such analysis, but their strengths and weaknesses have not been fully explored. The statistical methods we are concerned with here are mainly used to examine similarities between archaeal and bacterial DNA from different genomes. These methods compare observed genomic frequencies of fixed-sized oligonucleotides with expected values, which can be determined by genomic nucleotide content, smaller oligonucleotide frequencies, or be based on specific statistical distributions. Advantages with these statistical methods include measurements of phylogenetic relationship with relatively small pieces of DNA sampled from almost anywhere within genomes, detection of foreign/conserved DNA, and homology searches. Our aim was to explore the reliability and best suited applications for some popular methods, which include relative oligonucleotide frequencies (ROF), di- to hexanucleotide zero'th order Markov methods (ZOM) and 2.order Markov chain Method (MCM). Tests were performed on distant homology searches with large DNA sequences, detection of foreign/conserved DNA, and plasmid-host similarity comparisons. Additionally, the reliability of the methods was tested by comparing both real and random genomic DNA.

Results

Our findings show that the optimal method is context dependent. ROFs were best suited for distant homology searches, whilst the hexanucleotide ZOM and MCM measures were more reliable measures in terms of phylogeny. The dinucleotide ZOM method produced high correlation values when used to compare real genomes to an artificially constructed random genome with similar %GC, and should therefore be used with care. The tetranucleotide ZOM measure was a good measure to detect horizontally transferred regions, and when used to compare the phylogenetic relationships between plasmids and hosts, significant correlation (R ² = 0.4) was found with genomic GC content and intra-chromosomal homogeneity.

Conclusion

The statistical methods examined are fast, easy to implement, and powerful for a number of different applications involving genomic sequence comparisons. However, none of the measures examined were superior in all tests, and therefore the choice of the statistical method should depend on the task at hand.