The ageing mitochondrial genome

The population of elderly individuals has increased significantly over the past century and is predicted to rise even more rapidly in the future. Ageing is a major risk factor for many diseases such as neurodegenerative disease, diabetes and cancer. This highlights the importance of understanding the mechanisms involved in the ageing process. One plausible mechanism for ageing is accumulation of mutations in the mitochondrial genome. In this review, we discuss some of the most convincing data surrounding age-related mtDNA mutations and the evidence that these mutations contribute to the ageing process.     

WISE 2005: altered cerebrovascular autoregulation after 60 day head-down bed rest

We tested the hypothesis that 60 days of head-down bed rest (HDBR) would affect cerebrovascular autoregulation and that this change would be correlated with changes in tolerance to the upright posture. Twenty-four healthy women (32 +/- 4 yrs) participated in a 60-d bed rest study at the MEDES Clinic in Toulouse, France. End tidal CO2 (ETCO2), continuous blood pressure (BP), middle cerebral artery (MCA) velocity and time to presyncope (endpoint) were measured during an orthostatic tolerance test conducted before/after bed rest. Given the large range of change in tolerance even within assigned countermeasure groups, we separated subjects for this analysis on the basis of the change in endpoint (Delta endpoint) pre- to post-bed rest. Autoregulation and CO2 responsiveness were evaluated on a different day from a two-breath test with intermittent hypercapnic exposure. Autoregressive moving average (ARMA) modeled the two confounding inputs, BP and CO2, on cerebrovascular blood flow. The cerebrovascular resistance index (CVRi) was expected to decrease following a decrease in BP at the MCA to assist in maintenance of cerebral blood flow. Subjects with the smallest Delta endpoint after bed rest had a 78% increase in the gain of the BP --> CVRi response. Meanwhile, the groups with greater decline in orthostatic tolerance post-HDBR had no change in the gain of this response. ETCO2 was lower overall following HDBR, decreasing from 41.8 +/- 3.4 to 40.2 +/- 3.0 in supine rest, 37.9 +/- 3.4 to 33.3 +/- 4.0 in early tilt, and 29.5 +/- 4.4 to 27.1 +/- 5.1 at pre-syncope. There was however, higher MCA velocity at any ETCO2 for post- compared to pre-HDBR. In summary, changes in autoregulation were found only in those subjects who had the smallest change from pre- to post-HDBR orthostatic tolerance. The changes may assist in buffering changes in cerebral blood flow during orthostatic hypotension post-HDBR. The reduction in ETCO2 after bed rest might be due to a change in chemoreceptor response to blood CO2, but the cerebrovascular system seems to have completely compensated.     

The two SAMP repeats and their phosphorylation state in Drosophila Adenomatous polyposis coli-2 play mechanistically distinct roles in negatively regulating Wnt signaling

The tumor suppressor Adenomatous polyposis coli (APC) plays a key role in regulating the canonical Wnt signaling pathway as an essential component of the β-catenin destruction complex. C-terminal truncations of APC are strongly implicated in both sporadic and familial forms of colorectal cancer. However, many questions remain as to how these mutations interfere with APC’s tumor suppressor activity. One set of motifs frequently lost in these cancer-associated truncations is the SAMP repeats that mediate interactions between APC and Axin. APC proteins in both vertebrates and Drosophila contain multiple SAMP repeats that lack high sequence conservation outside of the Axin-binding motif. In this study, we tested the functional redundancy between different SAMPs and how these domains are regulated, using Drosophila APC2 and its two SAMP repeats as our model. Consistent with sequence conservation–based predictions, we show that SAMP2 has stronger binding activity to Axin in vitro, but SAMP1 also plays an essential role in the Wnt destruction complex in vivo. In addition, we demonstrate that the phosphorylation of SAMP repeats is a potential mechanism to regulate their activity. Overall our findings support a model in which each SAMP repeat plays a mechanistically distinct role but they cooperate for maximal destruction complex function.     

The development, regulation and use of biopesticides for integrated pest management

Over the past 50 years, crop protection has relied heavily on synthetic chemical pesticides, but their availability is now declining as a result of new legislation and the evolution of resistance in pest populations. Therefore, alternative pest management tactics are needed. Biopesticides are pest management agents based on living micro-organisms or natural products. They have proven potential for pest management and they are being used across the world. However, they are regulated by systems designed originally for chemical pesticides that have created market entry barriers by imposing burdensome costs on the biopesticide industry. There are also significant technical barriers to making biopesticides more effective. In the European Union, a greater emphasis on Integrated Pest Management (IPM) as part of agricultural policy may lead to innovations in the way that biopesticides are regulated. There are also new opportunities for developing biopesticides in IPM by combining ecological science with post-genomics technologies. The new biopesticide products that will result from this research will bring with them new regulatory and economic challenges that must be addressed through joint working between social and natural scientists, policy makers and industry.     

Suppressor of cytokine signalling protein SOCS3 expression is increased at sites of acute and chronic inflammation

Treatment of cells with cytokines and growth factors leads to the synthesis of Suppressor of Cytokine Signalling (SOCS) proteins that act as potent negative regulators of signalling via the Jak/STAT pathway. We used immunohistochemistry to identify cells and pathologies where SOCS3 expression might influence acute and chronic inflammatory responses in human tissues. Epitope and GFP tagged SOCS3 fusion proteins were localised predominantly in the nucleus of transfected cells and a validated anti SOCS3 antiserum revealed the expression of SOCS3 in the nucleus and cytoplasm of macrophages, endothelial and epithelial cells in a wide range of normal tissues in tissue microarrays (n = 31 different tissues). Nuclear SOCS3 was only seen in cells expressing a high level of the protein. Comparative immunostaining of acute, chronically and granulomatously inflamed human tissues revealed higher levels of nuclear and cytoplasmic SOCS3 expression in inflamed than in corresponding normal tissues, particularly in recruited leukocyte populations, but also in epithelia. The staining appeared more intense, suggesting higher expression levels, in areas where inflammation was more acute, consistent with the time course of SOCS3 induction described in vitro. Expression of SOCS3 protein by leucocytes and other cell types in tissue sections could be a useful marker of cells undergoing acute or chronic stimulation by cytokines in vivo.     

A GC-MS metabolic profiling study of plasma samples from mice on low- and high-fat diets

Metabolic profiling of biofluids, based on the quantitative analysis of the concentration profile of their free low molecular mass metabolites, has been playing increasing role employed as a means to gain understanding of the progression of metabolic disorders, including obesity. Chromatographic methods coupled with mass spectrometry have been established as a strategy for metabolic profiling. Among these, GC-MS, targeting mainly the primary metabolism intermediates, offers high sensitivity, good peak resolution and extensive databases. However, the derivatization step required for many involatile metabolites necessitates specific data validation, normalization and analysis protocols to ensure accurate and reproducible performance. In this study, the GC-MS metabolic profiles of plasma samples from mice maintained on 12- or 15-month long low (10 kcal%) or high (60 kcal%) fat diets were obtained. The profiles of the trimethylsilyl(TMS)-methoxime(MeOx) derivatives of the free polar metabolites were acquired through GC-(ion trap)MS, using [U-(13)C]-glucose as the internal standard. After the application of a recently developed data correction and normalization/filtering protocol for GC-MS metabolomic datasets, the profiles of 48 out of the 77 detected metabolites were used in multivariate statistical analysis. Data mining suggested a decrease in the activity of the energy metabolism with age. In addition, the metabolic profiles indicated the presence of subpopulations with different physiology within the high- and low-fat diet mice, which correlated well with the difference in body weight among the animals and current knowledge about hyperglycemic conditions.     

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective

Background

Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events.

Methodology/Principal Findings

Electronic databases and grey literature were searched and records were screened against eligibility criteria. Data extraction and risk of bias assessments were performed in duplicate. Results were synthesised narratively and meta-analyses were conducted where feasible. Heterogeneity was assessed using I² and publication bias was assessed using Begg''s funnel plot and Egger''s regression test. Many of the 209 eligible studies included an unclear or high risk of bias. Meta-analyses showed a significant effect of preventing influenza-like illness (odds ratio [OR] = 0.23; 95% confidence interval [CI] = 0.16–0.34; p<0.001) and laboratory confirmed influenza infection (OR = 0.15; 95% CI = 0.03–0.63; p = 0.01) through vaccinating immunocompromised patie nts compared to placebo or unvaccinated controls. We found no difference in the odds of influenza-like illness compared to vaccinated immunocompetent controls. The pooled odds of seroconversion were lower in vaccinated patients compared to immunocompetent controls for seasonal influenza A(H1N1), A(H3N2) and B. A similar trend was identified for seroprotection. Meta-analyses of seroconversion showed higher odds in vaccinated patients compared to placebo or unvaccinated controls, although this reached significance for influenza B only. Publication bias was not detected and narrative synthesis supported our findings. No consistent evidence of safety concerns was identified.

Conclusions/Significance

Infection prevention and control strategies should recommend vaccinating immunocompromised patients. Potential for bias and confounding and the presence of heterogeneity mean the evidence reviewed is generally weak, although the directions of effects are consistent. Areas for further research are identified.     

The replacement histone H2A.Z in a hyperacetylated form is a feature of active genes in the chicken

The replacement histone H2A.Z is variously reported as being linked to gene expression and preventing the spread of heterochromatin in yeast, or concentrated at heterochromatin in mammals. To resolve this apparent dichotomy, affinity-purified antibodies against the N-terminal region of H2A.Z, in both a triacetylated and non-acetylated state, are used in native chromatin immmuno-precipitation experiments with mononucleosomes from three chicken cell types. The hyperacetylated species concentrates at the 5′ end of active genes, both tissue specific and housekeeping but is absent from inactive genes, while the unacetylated form is absent from both active and inactive genes. A concentration of H2A.Z is also found at insulators under circumstances implying a link to barrier activity but not to enhancer blocking. Although acetylated H2A.Z is widespread throughout the interphase genome, at mitosis its acetylation is erased, the unmodified form remaining. Thus, although H2A.Z may operate as an epigenetic marker for active genes, its N-terminal acetylation does not.     

Diving heart rate development in postnatal harbour seals, Phoca vitulina

Harbour seals, Phoca vitulina, dive from birth, providing a means of mapping the development of the diving response, and so our objective was to investigate the postpartum development of diving bradycardia. The study was conducted May-July 2000 and 2001 in the St. Lawrence River Estuary (48 degrees 41'N, 68 degrees 01'W). Both depth and heart rate (HR) were remotely recorded during 86,931 dives (ages 2-42 d, n = 15) and only depth for an additional 20,300 dives (combined data covered newborn to 60 d, n = 20). The mean dive depth and mean dive durations were conservative during nursing (2.1 +/- 0.1 m and 0.57 +/- 0.01 min, range = 0-30.9 m and 0-5.9 min, respectively). The HR of neonatal pups during submersion was bimodal, but as days passed, the milder of the two diving HRs disappeared from their diving HR record. By 15 d of age, most of the dive time was spent at the lower diving bradycardia rate. Additionally, this study shows that pups are born with the ability to maintain the lower, more fully developed dive bradycardia during focused diving but do not do so during shorter routine dives.