Gonadal development and sex-specific demographics of the shovelnose sturgeon in the Middle Mississippi River

Harvest of the shovelnose sturgeon, Scaphirhynchus platorynchus for caviar has increased. To determine whether populations can withstand increased harvest, detailed information regarding sexual demographics is needed. We describe gender and reproductive development of 306 shovelnose sturgeon from the Middle Mississippi River (River km 0–322) during September 2001 through December 2003. Using dissection and histology, we identified three of the four gonadal stages described previously for male lake sturgeon and all seven stages for females. Males reached maturity at a smaller size than did females. Gonads can be rapidly inspected for sex and stage of development for the shovelnose sturgeon. The sex ratio was not different from 1 : 1. Seven intersexual fish occurred. Female fecundity was positively related to body weight (number of eggs = 30.24 × body weight − 8392; P = 0.013; r² = 0.45) and weakly related to fork length (number of eggs = 146.37 × fork length − 66 176, P = 0.053, r² = 0.23).     

Warming and free-air CO2 enrichment alter demographics in four co-occurring grassland species

Species differ in their responses to global changes such as rising CO(2) and temperature, meaning that global changes are likely to change the structure of plant communities. Such alterations in community composition must be underlain by changes in the population dynamics of component species. Here, the impact of elevated CO(2) (550 micromol mol(-1)) and warming (+2 degrees C) on the population growth of four plant species important in Australian temperate grasslands is reported. Data collected from the Tasmanian free-air CO(2) enrichment (TasFACE) experiment between 2003 and 2006 were analysed using population matrix models. Population growth of Themeda triandra, a perennial C(4) grass, was largely unaffected by either factor but population growth of Austrodanthonia caespitosa, a perennial C(3) grass, was reduced substantially in elevated CO(2) plots. Warming and elevated CO(2) had antagonistic effects on population growth of two invasive weeds, Hypochaeris radicata and Leontodon taraxacoides, with warming causing population decline. Analysis of life cycle stages showed that seed production, seedling emergence and establishment were important factors in the responses of the species to global changes. These results show that the demographic approach is very useful in understanding the variable responses of plants to global changes and in elucidating the life cycle stages that are most responsive.     

A simpler analysis for the measurement of second virial coefficients by self-interaction chromatography

We describe a thermodynamic approach that supports the adoption of a simplified procedure for the determination of protein second virial coefficients (B(2)) by self-interaction chromatography. Its major advantage over the original method is a decrease in the number of parameters to which magnitudes must be assigned for the determination of B(2). Improved correlation of virial coefficients obtained by the chromatographic procedure with those obtained by light scattering is achieved by taking into account the twofold larger magnitudes of the former because of the experimental distinction between free and immobilized protein molecules in self-interaction chromatography.     

Characterization of Streptococcus pneumoniae isolated from children with otitis media

Streptococcus pneumoniae is the main causative agent of acute otitis media in children. Serotype-based vaccines have provided some protection against otitis media, but not as much as anticipated, demonstrating the need for alternative vaccine options. Pneumococcal otitis media isolates were obtained from children 5 years old or younger from hospitals around Mississippi in the prevaccine era (1999-2000). These isolates were compared by capsular typing, pneumococcal surface protein A (PspA) family typing, antibiotic susceptibility, and DNA fingerprinting. Our study shows that there is great genetic variability among pneumococcal clinical isolates of otitis media, except with regard to PspA. Therefore, efforts focused on the development of a PspA-based pneumococcal vaccine would be well placed.     

GSK-3β dysregulation contributes to parkinson's-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

Aberrant posttranslational modifications (PTMs) of proteins, namely phosphorylation, induce abnormalities in the biological properties of recipient proteins, underlying neurological diseases including Parkinson''s disease (PD). Genome-wide studies link genes encoding α-synuclein (α-Syn) and Tau as two of the most important in the genesis of PD. Although several kinases are known to phosphorylate α-Syn and Tau, we focused our analysis on GSK-3β because of its accepted role in phosphorylating Tau and to increasing evidence supporting a strong biophysical relationship between α-Syn and Tau in PD. Therefore, we investigated transgenic mice, which express a point mutant (S9A) of human GSK-3β. GSK-3β-S9A is capable of activation through endogenous natural signaling events, yet is unable to become inactivated through phosphorylation at serine-9. We used behavioral, biochemical, and in vitro analysis to assess the contributions of GSK-3β to both α-Syn and Tau phosphorylation. Behavioral studies revealed progressive age-dependent impairment of motor function, accompanied by loss of tyrosine hydroxylase-positive (TH+ DA-neurons) neurons and dopamine production in the oldest age group. Magnetic resonance imaging revealed deterioration of the substantia nigra in aged mice, a characteristic feature of PD patients. At the molecular level, kinase-active p-GSK-3β-Y216 was seen at all ages throughout the brain, yet elevated levels of p-α-Syn-S129 and p-Tau (S396/404) were found to increase with age exclusively in TH+ DA-neurons of the midbrain. p-GSK-3β-Y216 colocalized with p-Tau and p-α-Syn-S129. In vitro kinase assays showed that recombinant human GSK-3β directly phosphorylated α-Syn at a single site, Ser129, in addition to its known ability to phosphorylate Tau. Moreover, α-Syn and Tau together cooperated with one another to increase the magnitude or rate of phosphorylation of the other by GSK-3β. Together, these data establish a novel upstream role for GSK-3β as one of several kinases associated with PTMs of key proteins known to be causal in PD.After Alzheimer''s disease (AD), Parkinson''s disease (PD) is the second most prevalent neurodegenerative disease, characterized by selective loss of TH+ DA-neurons of substantia nigra (SN) with diminished production of dopamine (DA).¹ Genome-wide studies have identified SNCA and MAPT, genes encoding α-synuclein (α-Syn) and Tau, respectively, as having strong association to the genesis of PD.^{2, 3, 4} Although the precise etiology of PD remains a mystery, SNCA amplifications and mutations directly link α-Syn dysfunction to disease causation,^{5, 6} firmly establishing a role for α-Syn in sporadic and familial PD, respectively. α-Syn can be phosphorylated at several sites,⁷ and the predominance of α-Syn phosphorylated at serine 129 (S129) in Lewy bodies⁸ suggests its phosphorylation status at S129 has an important pathological role. Various PD models have shown that phosphorylation at S219 enhanced α-syn toxicity resulting in accelerated motor abnormalities and loss of DA-neurons.^{9, 10}Fewer studies have examined the role of Tau (or p-Tau) in PD, but interest in the field has grown since completion of several genome-wide association studies. p-Tau has been found to colocalize with α-Syn in tissue from sporadic PD and dementia with Lewy bodies.¹¹ We^{12, 13} and others^14,15 have also identified p-Tau in different brain regions of PD, dementia with Lewy bodies, and AD. High levels of p-Tau have also been observed in vivo in several toxin^{16, 17, 18} and transgenic α-Syn models of PD,^19,20 suggesting that p-Tau may be an important common factor in the neurodegeneration of not only tauopathies but also of synucleinopathies, such as PD.^{21, 22, 23, 24} Most studies to date have focused on the formation and accumulation of Tau and p-Tau in idiopathic PD. Yet several studies have provided evidence that leucine-rich repeat kinase-2 (LRRK2), a kinase, that when mutated is involved in familial forms of PD, can directly interact with, and activate GSK-3β, resulting in increased p-TAU formation.^25,26Among the kinases known to hyperphosphorylate Tau, glycogen synthase kinase-3β (GSK-3β) may be the most important given its ability to phosphorylate Tau at the majority of its serine/threonine sites that cause associated toxicities in AD.^27,28 The importance of GSK-3β is illustrated in that it is embryonically lethal when knocked out in mice. Regulation of GSK-3β is tightly controlled through a series of direct and indirect measures. Direct regulation occurs through autophosphorylation at Tyr216,^29,30 resulting in a kinase-active form, p-GSK-3β-Y216, whereas phosphorylation at Ser9 results in a kinase-inactive state.³¹ The activity of GSK-3β can also be controlled indirectly through binding to inhibitory complexes with other cytoplasmic proteins,^32,33 or through Wnt-mediated sequestration into multivesicular bodies³⁴ resulting in the physical separation of GSK-3β from its cytoplasmic targets. Control of GSK-3β in the normal state is therefore tightly regulated, with its dysregulation and ensuing aberrant phosphorylation of targets being a common occurrence in many diverse diseases. Several studies have shown that GSK-3β is an important mediator in the injury and repair processes of neurons during cross-talk between DA-neurons and reactive astrocytes.^35,36 These studies showed that astrocyte-derived Wnt1 was capable of blocking GSK-3β activation, allowing the nuclear accumulation of β-catenin and subsequent gene expression of β-catenin-dependent targets essential for neuron survival and repair during chemical or metabolic insults. The importance of regulating the active/inactive states of GSK-3β in regard to neuronal stability is further supported through the analysis of conditional (Tet-inducible) transgenic mice expressing a dominant-negative GSK-3β-K85R mutant or expressing the GSK-3β-S9A mutant.^37,38 In these studies, post-natal Tet-regulated expression of either GSK-3β-K85R or GSK-3β-S9A led to neurodegeneration in the cortex, striatum, and hippocampus. What separates our TG PD model from the tet-inducible GSK-3β models is the spatial patterns of transgene expression, which is influenced by the choice of promoters. The Tet-inducible GSK-3β models are expressed using a CAMKII promoter with our human(h) GSK-3β-S9A transgene being expressed under the Thy-1 promoter. CAMKII-driven expression is limited to neurons originating from the forebrain with Thy-1 promoter-driven expression restricted to neurons in all or most brain regions.^39,40 Although promoter choice effecting tissue expression ultimately decides which regions show degeneration, the important message is that both inactive and hyperactive states of GSK-3β reduce neuronal viability.In our past studies in various in vitro and in vivo models of PD and in postmortem PD tissues, we have consistently observed a positive correlation between increased α-Syn and p-Tau levels with increased GSK-3β-Y216 (the kinase-active form of GSK-3β).^{12, 13, 16, 19, 20} In in vitro studies of MPTP-treated SH-SY5Y cells, blockade of GSK-3β with lithium, or with the highly selective non-ATP competitive inhibitor, TDZD-8, prevented the induction of p-GSK-3β-Y216, abolished p-Tau formation, and reversed the accumulation and aggregation of both p-Tau and α-Syn, averting cell death.¹⁶ Other studies using Rotenone or MPTP/MPP+ in chemical PD models, have shown similar results of decreased neuronal viability during treatments accompanied by dose- and time-dependent increases in GSK-3β activation, with decreased cytotoxicity detected when GSK-3β was inhibited or knocked-down through the use of GSK-3β-specific small molecule inhibitors or through RNAi.^41,42 This suggested to us that p-GSK-3β-Y216 may have a contributory role in the pathogenesis of PD. Using a mouse model overexpressing hGSK-3β-S9A under the Thy-1 promoter together with in vitro kinase assays allowed us to discern the role GSK-3β has in the development of PD-like pathology.⁴³ Analysis of our hGSK-3β-S9A mouse model showed here for the first time that upon aging, these mice develop the cardinal features of parkinsonism, manifested as impaired motor behavior, with associated loss of TH+ neurons, reduced DA production, and shrinkage of SN. Invitro kinase assays confirmed that hGSK-3β was capable of phosphorylating α-Syn on Serine 129 together with the known ability to phosphorylate Tau. Remarkably, both α-Syn and Tau influenced the rate and magnitude of phosphorylation of the other by GSK-3β indicating that an intimate physical relationship exist between the trio of PD related proteins. Together, these data shown indicate the importance of GSK-3β activation, in the behavioral and physiological development of PD like pathology in a new mouse model.     

Endemic dengue associated with the co-circulation of multiple viral lineages and localized density-dependent transmission

Dengue is one of the most important infectious diseases of humans and has spread throughout much of the tropical and subtropical world. Despite this widespread dispersal, the determinants of dengue transmission in endemic populations are not well understood, although essential for virus control. To address this issue we performed a phylogeographic analysis of 751 complete genome sequences of dengue 1 virus (DENV-1) sampled from both rural (Dong Thap) and urban (Ho Chi Minh City) populations in southern Viet Nam during the period 2003-2008. We show that DENV-1 in Viet Nam exhibits strong spatial clustering, with likely importation from Cambodia on multiple occasions. Notably, multiple lineages of DENV-1 co-circulated in Ho Chi Minh City. That these lineages emerged at approximately the same time and dispersed over similar spatial regions suggests that they are of broadly equivalent fitness. We also observed an important relationship between the density of the human host population and the dispersion rate of dengue, such that DENV-1 tends to move from urban to rural populations, and that densely populated regions within Ho Chi Minh City act as major transmission foci. Despite these fluid dynamics, the dispersion rates of DENV-1 are relatively low, particularly in Ho Chi Minh City where the virus moves less than an average of 20 km/year. These low rates suggest a major role for mosquito-mediated dispersal, such that DENV-1 does not need to move great distances to infect a new host when there are abundant susceptibles, and imply that control measures should be directed toward the most densely populated urban environments.     

Life course trajectories of systolic blood pressure using longitudinal data from eight UK cohorts

Background

Much of our understanding of the age-related progression of systolic blood pressure (SBP) comes from cross-sectional data, which do not directly capture within-individual change. We estimated life course trajectories of SBP using longitudinal data from seven population-based cohorts and one predominantly white collar occupational cohort, each from the United Kingdom and with data covering different but overlapping age periods.

Methods and Findings

Data are from 30,372 individuals and comprise 102,583 SBP observations spanning from age 7 to 80+y. Multilevel models were fitted to each cohort. Four life course phases were evident in both sexes: a rapid increase in SBP coinciding with peak adolescent growth, a more gentle increase in early adulthood, a midlife acceleration beginning in the fourth decade, and a period of deceleration in late adulthood where increases in SBP slowed and SBP eventually declined. These phases were still present, although at lower levels, after adjusting for increases in body mass index though adulthood. The deceleration and decline in old age was less evident after excluding individuals who had taken antihypertensive medication. Compared to the population-based cohorts, the occupational cohort had a lower mean SBP, a shallower annual increase in midlife, and a later midlife acceleration. The maximum sex difference was found at age 26 (+8.2 mm Hg higher in men, 95% CI: 6.7, 9.8); women then experienced steeper rises and caught up by the seventh decade.

Conclusions

Our investigation shows a general pattern of SBP progression from childhood in the UK, and suggests possible differences in this pattern during adulthood between a general population and an occupational population. Please see later in the article for the Editors'' Summary     

Report from the second cytomegalovirus and immunosenescence workshop

The Second International Workshop on CMV & Immunosenescence was held in Cambridge, UK, 2-4th December, 2010. The presentations covered four separate sessions: cytomegalovirus and T cell phenotypes; T cell memory frequency, inflation and immunosenescence; cytomegalovirus in aging, mortality and disease states; and the immunobiology of cytomegalovirus-specific T cells and effects of the virus on vaccination. This commentary summarizes the major findings of these presentations and references subsequently published work from the presenter laboratory where appropriate and draws together major themes that were subsequently discussed along with new areas of interest that were highlighted by this discussion.