Evolutionary perspectives on human height variation

Human height is a highly variable trait, both within and between populations, has a high heritability, and influences the manner in which people behave and are treated in society. Although we know much about human height, this information has rarely been brought together in a comprehensive, systematic fashion. Here, we present a synthetic review of the literature on human height from an explicit evolutionary perspective, addressing its phylogenetic history, development, and environmental and genetic influences on growth and stature. In addition to presenting evidence to suggest the past action of natural selection on human height, we also assess the evidence that natural and sexual selection continues to act on height in contemporary populations. Although there is clear evidence to suggest that selection acts on height, mainly through life‐history processes but perhaps also directly, it is also apparent that methodological factors reduce the confidence with which such inferences can be drawn, and there remain surprising gaps in our knowledge. The inability to draw firm conclusions about the adaptiveness of such a highly visible and easily measured trait suggests we should show an appropriate degree of caution when dealing with other human traits in evolutionary perspective.     

Using evolutionary information and ancestral sequences to understand the sequence-function relationship in GLP-1 agonists

Glucagon-like peptide-1 (GLP-1) is an incretin hormone with therapeutic potential for type 2 diabetes. A variety of GLP-1 sequences are known from amphibian species, and some of these have been tested here and found to be able to bind and activate the human GLP-1 receptor. While little difference was observed for the in vitro potency for the human GLP-1 receptor, larger differences were found in the enzymatic stability of these peptides. Two peptides showed increased enzymatic stability, and they group together phylogenetically, though they originate from Amphibia and Reptilia. We have used ancestral sequence reconstruction to analyze the evolution of these GLP-1 molecules, including the synthesis of new peptides. We find that the increased stability could not be observed in the resurrected peptides from the common ancestor of frogs, even though they maintain the ability to activate the human GLP-1 receptor. Another method, using residue mapping on evolutionary branches yielded peptides that had maintained potency towards the receptor and also showed increased stability. This represents a new approach using evolutionary data in protein engineering.     

The Liang Bua faunal remains: a 95 k.yr. sequence from Flores, East Indonesia

Excavations at Liang Bua, a limestone cave on the island of Flores, East Indonesia, have yielded a well-dated archaeological and faunal sequence spanning the last 95 k.yr., major climatic fluctuations, and two human species - H. floresiensis from 95 to 17 k.yr.¹, and modern humans from 11 k.yr. to the present. The faunal assemblage comprises well-preserved mammal, bird, reptile and mollusc remains, including examples of island gigantism in small mammals and the dwarfing of large taxa. Together with evidence from Early-Middle Pleistocene sites in the Soa Basin, it confirms the long-term isolation, impoverishment, and phylogenetic continuity of the Flores faunal community. The accumulation of Stegodon and Komodo dragon remains at the site in the Pleistocene is attributed to Homo floresiensis, while predatory birds, including an extinct species of owl, were largely responsible for the accumulation of the small vertebrates. The disappearance from the sequence of the two large-bodied, endemic mammals, Stegodon florensis insularis and Homo floresiensis, was associated with a volcanic eruption at 17 ka and precedes the earliest evidence for modern humans, who initiated use of mollusc and shell working, and began to introduce a range of exotic animals to the island. Faunal introductions during the Holocene included the Sulawesi warty pig (Sus celebensis) at about 7 ka, followed by the Eurasian pig (Sus scrofa), Long-tailed macaque, Javanese porcupine, and Masked palm civet at about 4 ka, and cattle, deer, and horse - possibly by the Portuguese within historic times. The Holocene sequence at the site also documents local faunal extinctions - a result of accelerating human population growth, habitat loss, and over-exploitation.     

Ruminococcus bromii is a keystone species for the degradation of resistant starch in the human colon

The release of energy from particulate substrates such as dietary fiber and resistant starch (RS) in the human colon may depend on the presence of specialist primary degraders (or ‘keystone species'') within the microbial community. We have explored the roles of four dominant amylolytic bacteria found in the human colon in the degradation and utilization of resistant starches. Eubacterium rectale and Bacteroides thetaiotaomicron showed limited ability to utilize RS2- and RS3-resistant starches by comparison with Bifidobacterium adolescentis and Ruminococcus bromii. In co-culture, however, R. bromii proved unique in stimulating RS2 and RS3 utilization by the other three bacterial species, even in a medium that does not permit growth of R. bromii itself. Having previously demonstrated low RS3 fermentation in vivo in two individuals with undetectable populations of R. bromii-related bacteria, we show here that supplementation of mixed fecal bacteria from one of these volunteers with R. bromii, but not with the other three species, greatly enhanced the extent of RS3 fermentation in vitro. This argues strongly that R. bromii has a pivotal role in fermentation of RS3 in the human large intestine, and that variation in the occurrence of this species and its close relatives may be a primary cause of variable energy recovery from this important component of the diet. This work also indicates that R. bromii possesses an exceptional ability to colonize and degrade starch particles when compared with previously studied amylolytic bacteria from the human colon.     

Assignment of 1H, 13C and 15N resonances of the reduced human IgG1 CH3 domain

Here we report the NMR resonance assignments for the reduced form of human IgG1 C_H3 domain, a 26 kDa dimer in solution (residues 341–447). The assignments have been deposited in the BioMagResBank with a BMRB accession number of 15204.     

Platelets do not express the oxidized or reduced forms of tissue factor

Background

Expression of tissue factor (TF) antigen and activity in platelets is controversial and dependent upon the laboratory and reagents used. Two forms of TF were described: an oxidized functional form and a reduced nonfunctional form that is converted to the active form through the formation of an allosteric disulfide. This study tests the hypothesis that the discrepancies regarding platelet TF expression are due to differential expression of the two forms.

Methods

Specific reagents that recognize both oxidized and reduced TF were used in flow cytometry of unactivated and activated platelets and western blotting of whole platelet lysates. TF-dependent activity measurements were used to confirm the results.

Results

Western blotting analyses of placental TF demonstrated that, in contrast to anti-TF#5, which is directed against the oxidized form of TF, a sheep anti-human TF polyclonal antibody recognizes both the reduced and oxidized forms. Flow cytometric analyses demonstrated that the sheep antibody did not react with the surface of unactivated platelets or platelets activated with thrombin receptor agonist peptide, PAR-1. This observation was confirmed using biotinylated active site-blocked factor (F)VIIa: no binding was observed. Likewise, neither form of TF was detected by western blotting of whole platelet lysates with sheep anti-hTF. Consistent with these observations, no FXa or FIXa generation by FVIIa was detected at the surface of these platelets. Similarly, no TF-related activity was observed in whole blood using thromboelastography.

Conclusion and significance

Platelets from healthy donors do not express either oxidized (functional) or reduced (nonfunctional) forms of TF.     

The human episome HALF1: Structure of its genomic counterpart

A human episomal sequence (HALF1) has been identified by its ability to restore expression of hepatic functions when used to transfect a rat dedifferentiated cell line. The genomic equivalent of this human episome (gHALF1) and its flanking sequences were analyzed. HALF1 itself does not present the characteristics of a transposable element but half of its sequence corresponds to retroposons, including Alu and L1 repeats and a processed pseudogene, known to transposevia RNA intermediates. The structural characteristics of these different kinds of retroposons and their origin and evolution were analyzed.     

Application of Fluorescence Microscopy to Measure Apoptosis in Jurkat T Cells After Treatment with a New Investigational Anticancer Agent (N.C.1213)

1. Apoptosis as the mechanism of cell death induced by a new cytotoxic and anticancer agent (N.C.1213) was investigated by morphological and biochemical criteria in human Jurkat T leukemia cells.2. The effect of N.C.1213 on the survival of Jurkat T, LV-50, H-9, and Molt-3 cells was measured. Jurkat T cells exhibited the highest response, with less than 10% of the cells remaining viable after exposure to 10 M N.C.1213 for a 24 hr period. All other cell cultures were also affected but to a lesser extent.3. With the use of a fluorescence microscope, several morphological features characteristic of apoptosis such as condensed chromatin and apoptotic bodies were indemnified in Jurkat T cells after exposure to N.C.1213 and melphalan. The results indicated that melphalan was more cytotoxic than N.C.1213 as shown by the dye exclusion test. However, N.C.1213 showed a greater apoptotic index than melphalan. The IC₅₀ of N.C.1213 in Jurkat T cells was determined to be 3.5 M 4. A DNA ladder (fragmentation of DNA into multimers of approximately 200 base pairs), which is one characteristic feature of apoptosis, was not detected when Jurkat T cells were exposed to N.C.1213. Hence it is probable that the key morphological events in apoptosis observed in the present experimental conditions precede the internucleosomalcleavage of DNA.     

Production of reactive oxygen species by monocyte-derived macrophages from blood of healthy donors and patients with ischemic heart disease

Production of reactive oxygen species (ROS) by macrophages derived from blood monocytes of healthy donors (MP_N) and patients with ischemic heart disease (IHD) (MP_IHD) before, during, and after their incubation with low-density lipoprotein (LDL) isolated from blood plasma of healthy donors (LDL_N) and patients with a high cholesterol level (LDL_H) was investigated by the method of luminol-dependent (spontaneous) and stimulated chemiluminescence (CL) using opsonized zymosan (OZ) or phorbol-12-myristate-13-acetate (PMA) as the CL stimulators. It was shown that proper, luminol-dependent, and zymosan-or PMA-stimulated chemiluminescence of MP_IHD was 1.4-, 1.8-, 2.7-, and 1.6-fold higher than the same types of chemiluminescence of MP_N, respectively, (p<0.05–0.01). Although the effect of OZ on MP_N and MP_IHD was more potent than that of PMA (by 4.3- and 3.2-fold, respectively), but it appeared in 2.5–3.0 times slower than that of PMA. LDL_N and LDL_H incubated with MP_N for the first 15 and 60 min caused the 1.4- and 2.5-increase of the luminol-dependent CL of MP_N; the same treatment of MP_IHD did not influence ROS production by these cells. Repeated increase in the OZ-stimulated CL of MP_N was also observed after preincubation for 15–180 min with LDL_N and LDL_H followed by LDL removal, subsequent MP_N washing and addition of Hanks solution and OZ; the repeated increase in OZ-stimulated CL of MP_N was only observed after incubation with LDL_H than with LDL_N. No increase of CL was observed in experiments with MP_IHD. Thus, more intensive chemiluminescence of macrophages obtained from blood of patients with IHD suggests their in vivo stimulation. LDL_N and LDL_H may cause both primary and secondary (after preincubation) stimulating effect on CL of MP_N but not of MP_IHD. Thus, the analysis of macrophage chemiluminescence is a sensitive test for evaluation the degree of macrophage stimulation; it may be effectively used for monitoring of effectiveness of medical treatment of patients.