SIRT1 longevity factor suppresses NF‐κB ‐driven immune responses: regulation of aging via NF‐κB acetylation?

The aging process involves changes in immune regulation, i.e. adaptive immunity declines whereas innate immunity becomes activated. NF-kappaB signaling is the master regulator of the both immune systems. Two recent articles highlight the role of the NF-kappaB system in aging and immune responses. Adler et al showed that the NF-kappaB binding domain is the genetic regulatory motif which is most strongly associated with the aging process. Kwon et al studying HIV-1 infection and subsequent immune deficiency process demonstrated that HIV-1 Tat protein binds to SIRT1 protein, a well-known longevity factor, and inhibits the SIRT1-mediated deacetylation of the p65 component of the NF-kappaB complex. As a consequence, the transactivation efficiency of the NF-kappaB factor was greatly potentiated, leading to the activation of immune system and later to the decline of adaptive immunity. These observations support the scenario where immune responses and aging process can be enforced by the potentiation of NF-kappaB transactivation efficiency. Longevity factors, such as SIRT1 and its activators, might regulate the efficiency of the NF-kappaB signaling, the major outcome of which is inflamm-aging via proinflammatory responses.     

Bundle‐sheath cell regulation of xylem‐mesophyll water transport via aquaporins under drought stress: a target of xylem‐borne ABA?

The hydraulic conductivity of the leaf vascular system (K_leaf) is dynamic and decreases rapidly under drought stress, possibly in response to the stress phytohormone ABA, which increases sharply in the xylem sap (ABA_xyl) during periods of drought. Vascular bundle‐sheath cells (BSCs; a layer of parenchymatous cells tightly enwrapping the entire leaf vasculature) have been hypothesized to control K_leaf via the specific activity of BSC aquaporins (AQPs). We examined this hypothesis and provide evidence for drought‐induced ABA_xyl diminishing BSC osmotic water permeability (P_f) via downregulated activity of their AQPs. ABA fed to the leaf via the xylem (petiole) both decreased K_leaf and led to stomatal closure, replicating the effect of drought. In contrast, smearing ABA on the leaf blade, while also closing stomata, did not decrease K_leaf within 2–3 h of application, demonstrating that K_leaf does not depend entirely on stomatal closure. GFP‐labeled BSCs showed decreased P_f in response to ‘drought’ and ABA treatment, and a reversible decrease with HgCl₂ (an AQP blocker). These P_f responses, absent in mesophyll cells, suggest stress‐regulated AQP activity specific to BSCs, and imply a role for these cells in decreasing K_leaf via a reduction in P_f. Our results support the above hypothesis and highlight the BSCs as hitherto overlooked vasculature sensor compartments, extending throughout the leaf and functioning as ‘stress‐regulated valves’ converting vasculature chemical signals (possibly ABA_xyl) into leaf hydraulic signals.     

The α‐sheet: A missing‐in‐action secondary structure?

The α-sheet has been speculated to play a role as a toxic conformer in amyloid diseases. However, except for relatively short fragments, its detection has remained elusive. Here, we present molecular dynamics simulations that support the existence of the α-sheet as a stable, metastable, or long-lived secondary structure in polyglutamine and, to a lesser extent, in polyasparagine aggregates.     

Can the combination of electrochemical regeneration of NAD+, selectivity of L‐α‐amino‐acid dehydrogenase,and reductive amination of α‐keto‐acid be applied to the inversion of configuration of a L‐α‐amino‐acid?

The inversion of configuration of L‐alanine can be carried out by combining its selective oxidation in the presence of NAD⁺ and L‐alanine dehydrogenase, electrochemical regeneration of the NAD⁺ at a carbon felt anode, and reductive amination of pyruvate, i.e., reduction of its imino derivative at a mercury cathode, the reaction mixture being buffered with concentrated ammonium/ammonia (1.28M / 1.28M). The dehydrogenase exhibits astonishing activity and stability under such extreme conditions of pH and ionic strength. The main drawback of the process is its slowness. At best, the complete inversion of a 10 mM solution of L‐alanine requires 140 h. A careful and detailed quantitative analysis of each of the key steps involved shows that the enzyme catalyzed oxidation is so thermodynamically uphill that it can be driven efficiently to completion only when both the coenzyme regeneration and the pyruvate reduction are very effective. The first condition is easily fulfilled. Under the best conditions, it is the rate of the chemical reaction producing the imine which controls the whole process kinetically. © 1999 John Wiley & Sons, Inc. Biotechnol Bioeng 64: 101–107, 1999.     

Brief communication: Could Kadanuumuu (KSD‐VP‐1/1) and Lucy (AL 288‐1) have walked together comfortably?

The estimated lower limb length (0.761–0.793 m) of the partial skeleton of Australopithecus afarensis from Woranso‐Mille (KSD‐VP‐1/1) is outside the previously known range for Australopithecus and within the range of modern humans. The lower limb length of KSD‐VP‐1/1 is particularly intriguing when juxtaposed against the lower limb length estimate of the other partial skeleton of A. afarensis, AL 288‐1 (0.525 m). A sample of 36 children (age, >7 years, trochanteric height = 0.56–0.765 m) and 16 adults (trochanteric height = 0.77–1.00 m) walked at their self‐selected slow, preferred, and fast walking velocities, while their oxygen consumption was monitored. Lower limb length and velocity were correlated with slow (P < 0.001, r² = 0.44), preferred (P < 0.001, r² = 0.55), and fast (P < 0.001, r² = 0.69) walking velocity. The relationship between optimal velocity and lower limb length was also determined and lower limb length explained 47% of the variability in optimal velocity. The velocity profile for KSD‐VP‐1/1 (slow = 0.73–0.75 m/s, preferred = 1.08–1.11 m/s, and fast = 1.48–1.54 m/s) is 36–44% higher than that of AL 288‐1 (slow = 0.53 m/s, preferred = 0.78 m/s, and fast = 1.07 m/s). The optimal velocity for AL 288‐1 is 1.04 m/s, whereas that for KSD‐VP‐1/1 is 1.29–1.33 m/s. This degree of lower limb length dimorphism suggests that members of a group would have had to compromise their preferences to walk together or to split into subgroups to walk at their optimal velocity. Am J Phys Anthropol, 2012. © 2012 Wiley Periodicals, Inc.     

The male fight‐flight response: A result of SRY regulation of catecholamines?

The SRY gene, which is located on the Y chromosome and directs male development, may promote aggression and other traditionally male behavioural traits, resulting in the fight-or-flight reaction to stress.     

Who Is the King? The α‐Hydroxy‐β‐oxo‐α,β‐enone Moiety or the Catechol B Ring: Relationship between the Structure of Quercetin Derivatives and Their Pro‐Oxidative Abilities

Quercetin and other flavonoids have been reported to exhibit both antioxidant and pro‐oxidant properties. Most studies about the pro‐oxidative ability were conducted in the presence of metal ions, and the essential functional moiety of quercetin responsible for the pro‐oxidative effect is still unclear. In this study, we evaluated the pro‐oxidative abilities in the absence of metal ions of two quercetin derivatives, i.e., quercetin‐3′‐O‐β‐D ‐glucoside ( 1 ) and quercetin‐3‐O‐β‐D ‐glucoside ( 2 ), by assessing DNA cleavage and HO^.‐radical production. The binding mode between these compounds and DNA was studied by fluorescence and viscometric titrations. The results showed that 1 can efficiently induce oxidative damage to plasmid DNA, while 2 shows poor activity. Both 1 and 2 bind to DNA via groove‐binding. These results proved that the α‐hydroxy‐β‐oxo‐α,β‐enone moiety contributes to the pro‐oxidative activity of quercetin.     

Single‐ or multistage regulation in complex life cycles: does it make a difference?

Data on the different stages of complex life cycles are often rather unbalanced, especially those concerning the effects of density. How does this affect our understanding of a species’ population dynamics? Two discrete three‐stage models with overlapping generations and delayed maturation are constructed to address this question. They assume that survival or emigration in any life stage and/or reproduction can be density dependent. A typical pond‐breeding amphibian species with a well‐studied larval stage serves as an example. Numerical results show that the population dynamics resulting from density dependence at a single (e.g. the larval) stage can be decisively and unpredictably modified by density dependence in additional stages. Superposition of density‐dependent processes could thus be one reason for the difficulties in identifying density dependence in the field. Moreover, in a simulated source‐refuge system with habitat‐specific density‐dependent dispersal of juveniles density dependence in multiple stages can stabilize or destabilize the dynamics and produce misleading age structures. From an applied perspective this model shows that excluding multistage regulation prematurely clearly affects our ability to predict consequences of human impacts.     

Passive immunization against oral AIDS virus transmission: An approach to prevent mother‐to‐infant HIV‐1 transmission?

To develop immunoprophylaxis regimens against mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission, we established a simian-human immunodeficiency virus (SHIV) model in neonatal macaques that mimics intrapartum mucosal virus exposure (T.W. Baba, J. Koch, E.S. Mittler et al: AIDS Res Hum Retroviruses 10:351-357, 1994). We protected four neonates from oral SHIV-vpu+ challenge by ante- and postpartum treatment with a synergistic triple combination of immunoglobulin (Ig) G1 human anti-HIV-1 neutralizing monoclonal antibodies (mAbs) (T.W. Baba, V. Liska, R. Hofmann-Lehmann et al: Nature Med 6:200-206, 2000), which recognize the CD4-binding site of Env, a glycosylation-dependent gp120, or a linear gp41 epitope. Two neonates that received only postpartum mAbs were also protected from oral SHIV-vpu+ challenge, indicating that postpartum treatment alone is sufficient. Next, we evaluated a similar mAb combination against SHIV89.6P, which encodes env of primary HIV89.6. One of four mAb-treated neonates was protected from infection and two maintained normal CD4+ T-cell counts. We conclude that the epitopes recognized by the three mAbs are important determinants for achieving protection. Combination immunoprophylaxis with synergistic mAbs seems promising to prevent maternal HIV-1 transmission in humans.     

RNA epigenetics — chemical messages for posttranscriptional gene regulation

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Lipopolysaccharide‐induced increase in signalling in hippocampus is abrogated by IL‐10 – a role for IL‐1β?

Parenterally administered lipopolysaccharide (LPS) increases the concentration of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in the rat hippocampus and evidence suggests that this effect plays a significant role in inhibiting long-term potentiation (LTP). The anti-inflammatory cytokine IL-10, antagonizes certain effects of IL-1beta, so if the effects of LPS are mediated through an increase in IL-1beta, it might be predicted that IL-10 would also abrogate the effect of LPS. Here, we report that IL-10 reversed the inhibitory effect of LPS on LTP and the data couple this with an inhibitory effect on the LPS-induced increase in IL-1beta. LPS treatment increased hippocampal expression of IL-1 receptor Type I protein. Consistent with the LPS-induced increases in IL-1beta concentration and receptor expression, were downstream changes which included enhanced phosphorylation of IRAK and the stress-activated kinases, JNK and p38; these LPS-induced changes were reversed by IL-10, which concurs with the idea that these events are triggered by increased activation of IL-1RI by IL-1beta. We provide evidence which indicates that LPS treatment leads to evidence of cell death and this was reversed in hippocampus prepared from LPS-treated rats which received IL-10. The evidence is therefore consistent with the idea that IL-10 acts to protect neuronal tissue from the detrimental effects induced by LPS.     

A gene for speed? The evolution and function of α‐actinin‐3

The alpha-actinins are an ancient family of actin-binding proteins that play structural and regulatory roles in cytoskeletal organisation and muscle contraction. alpha-actinin-3 is the most-highly specialised of the four mammalian alpha-actinins, with its expression restricted largely to fast glycolytic fibres in skeletal muscle. Intriguingly, a significant proportion ( approximately 18%) of the human population is totally deficient in alpha-actinin-3 due to homozygosity for a premature stop codon polymorphism (R577X) in the ACTN3 gene. Recent work in our laboratory has revealed a strong association between R577X genotype and performance in a variety of athletic endeavours. We are currently exploring the function and evolutionary history of the ACTN3 gene and other alpha-actinin family members. The alpha-actinin family provides a fascinating case study in molecular evolution, illustrating phenomena such as functional redundancy in duplicate genes, the evolution of protein function, and the action of natural selection during recent human evolution.     

Are Normal‐Weight Americans Over‐Fat?

Data from National Health and Nutrition Examination Surveys (NHANES) 1999-2004 have recently shown the percent body fat of American adults. Average American men and women have ~28 and 40% body fat. When categorized by BMI and age, the data also show high percent body fat values, particularly in lower BMI categories. These data should make one reflect on the health status of Americans in all BMI categories and the use of these data for public health recommendations.     

Cloning and functional analysis of chicory root fructan1‐exohydrolase I (1‐FEH I): a vacuolar enzyme derivedfrom a cell‐wall invertase ancestor? Mass fingerprint of the 1‐FEH I enzyme

This paper describes the cloning and functional analysis of chicory (Cichorium intybus L.) fructan 1-exohydrolase I cDNA (1-FEH I). To our knowledge it is the first plant FEH cloned. Full-length cDNA was obtained by a combination of RT-PCR, 5' and 3' RACE using primers based on N-terminal and conserved amino acid sequences. Electrophoretically purified 1-FEH I enzyme was further analyzed by in-gel trypsin digestion followed by matrix-assisted laser desorption ionization and electrospray time-of-flight tandem mass spectrometry. Functionality of the cDNA was demonstrated by heterologous expression in potato tubers. 1-FEH I takes a new, distinct position in the phylogenetic tree of plant glycosyl hydrolases being more homologous to cell-wall invertases (44-53%) than to vacuolar invertases (38-41%) and fructosyl transferases (33-38%). The 1-FEH I enzyme could not be purified from the apoplastic fluid at significantly higher levels than can be explained by cellular leakage. These and other data suggest a vacuolar localization for 1-FEH I. Also, the pI of the enzyme (6.5) is lower than expected from a typical cell-wall invertase. Unlike plant fructosyl transferases that are believed to have evolved from a vacuolar invertase, 1-FEH I might have evolved from a cell-wall invertase-like ancestor gene that later obtained a vacuolar targeting signal. 1-FEH I mRNA quantities increase in the roots throughout autumn, and especially when roots are stored at low temperature.     

Is there safety‐in‐numbers for prey?

The abundance of prey affects the rate of predation, but little consensus exists on whether this enhances or reduces per capita mortality. Studies of aggregating prey in marine habitats generally emphasise that the probability of predation of any individual is the reciprocal of the number of prey within a school. A field experiment tested the alternative hypotheses that predation by predatory fish on schooling prey (1) increased with an increase in the number of prey per school and that this caused (2) survival to be lower in schools with more individuals. The number of prey (juvenile Acanthochromis polyacanthus ) per school was manipulated in replicate treatments with natural densities of large predatory fish (open plots) and treatments without large predatory fish (exclusion cages). Large predatory fish preyed on juveniles in a density-dependent manner and this was the key source of density-dependent mortality in plots open to all predators. There was some suggestion that small predatory fish also prey on juveniles in a density-dependent manner, but this was weak and did not translate into density-dependent mortality of juveniles. It would appear that aggregation of prey may be a successful strategy against predation from some predators, but not always every predator, or all predators in combination.     

Do some deep‐sea,sediment‐dwelling species of harpacticoid copepods have 1000‐km‐scale range sizes?

The range sizes of sediment‐dwelling deep‐sea species are largely unknown. Such knowledge is important because a deep sea composed in large part of species with 100‐km‐scale ranges would be very different from one composed predominantly of species with 1000‐km‐scale ranges. For example, the total species richness would be much greater in the first case than in the second. As a step towards the determination of the distribution of species’ range sizes in the deep sea, we asked whether harpacticoid copepods (Crustacea) on the continental rise in the northeastern Pacific had 1000‐km‐scale range sizes. We chose harpacticoids because they occur widely in deep‐sea sediments and thus are a typical deep‐sea taxon. In addition, they have no pelagic stage in their life history, so they allow a conservative test of hypotheses about species’ range sizes. We used morphology and gene‐sequence data to assign individuals to species. At least 13.3% of the species we studied had 1000‐km‐scale ranges, raising the question of how these species maintain genetic continuity.     

A new paradigm in molecular recognition? specific antibody binding to membrane‐inserted HIV‐1 epitopes

The conserved membrane proximal external region (MPER), adjacent to the transmembrane domain (TMD) of human immunodeficiency virus type-1 (HIV-1) gp41 glycoprotein subunit, is accessible to the broadly neutralizing 4E10 and 2F5 monoclonal antibodies (mAbs) and, therefore, constitutes a potential target for vaccine design. This gp41 domain is postulated to be functional during the Env glycoprotein-mediated fusion reaction by destabilizing the highly rigid viral envelope. To perform this task, the aromatic-rich MPER is believed to insert into the interfacial region of the viral membrane external monolayer, thereby inducing the restructuring of the lipid bilayer required for fusion-pore opening. This model predicts that: (i) 2F5 and 4E10 mAbs are capable of binding epitopes inserted into the membrane interface; (ii) in-membrane binding will result in effective blocking of MPER membrane activity; and (iii) both processes, in-membrane recognition and blocking of membrane activity, can be modulated by altering both the lipid composition and the MPER amino acid sequence. We review here recently reported experimental data consistent with those predictions, and further speculate on their relevance for prospective anti-HIV vaccine development.