Serotype-independent pneumococcal vaccines

Streptococcus pneumoniae remains an important cause of disease with high mortality and morbidity, especially in children and in the elderly. The widespread use of the polysaccharide conjugate vaccines in some countries has led to a significant decrease in invasive disease caused by vaccine serotypes, but an increase in disease caused by non-vaccine serotypes has impacted on the overall efficacy of these vaccines on pneumococcal disease. The obvious solution to overcome such shortcomings would be the development of new formulations that provide serotype-independent immunity. This review focuses on the most promising approaches, including protein antigens, whole cell pneumococcal vaccines, and recombinant bacteria expressing pneumococcal antigens. The protective capacity of these vaccine candidates against the different stages of pneumococcal infection, including colonization, mucosal disease, and invasive disease in animal models is reviewed. Some of the human trials that have already been performed or that are currently ongoing are presented. Finally, the feasibility and the possible shortcomings of these candidates in relation to an ideal vaccine against pneumococcal infections are discussed.     

Large-scale in vivo flux analysis shows rigidity and suboptimal performance of Bacillus subtilis metabolism

Qualitative theoretical approaches such as graph theory and stoichiometric analyses are beginning to uncover the architecture and systemic functions of complex metabolic reaction networks. At present, however, only a few, largely unproven quantitative concepts propose functional design principles of the global flux distribution. As operational units of function, molecular fluxes determine the systemic cell phenotype by linking genes, proteins and metabolites to higher-level biological functions. In sharp contrast to other 'omics' analyses, 'fluxome' analysis remained tedious. By large-scale quantification of in vivo flux responses, we identified a robust flux distribution in 137 null mutants of Bacillus subtilis. On its preferred substrate, B. subtilis has suboptimal metabolism because regulators of developmental programs maintain a 'standby' mode that invests substantial resources in anticipation of changing environmental conditions at the expense of optimal growth. Network rigidity and robustness are probably universal functional design principles, whereas the standby mode may be more specific.     

Nicotinic acetylcholine receptors in attention circuitry: the role of layer VI neurons of prefrontal cortex

Cholinergic modulation of prefrontal cortex is essential for attention. In essence, it focuses the mind on relevant, transient stimuli in support of goal-directed behavior. The excitation of prefrontal layer VI neurons through nicotinic acetylcholine receptors optimizes local and top-down control of attention. Layer VI of prefrontal cortex is the origin of a dense feedback projection to the thalamus and is one of only a handful of brain regions that express the α5 nicotinic receptor subunit, encoded by the gene chrna5. This accessory nicotinic receptor subunit alters the properties of high-affinity nicotinic receptors in layer VI pyramidal neurons in both development and adulthood. Studies investigating the consequences of genetic deletion of α5, as well as other disruptions to nicotinic receptors, find attention deficits together with altered cholinergic excitation of layer VI neurons and aberrant neuronal morphology. Nicotinic receptors in prefrontal layer VI neurons play an essential role in focusing attention under challenging circumstances. In this regard, they do not act in isolation, but rather in concert with cholinergic receptors in other parts of prefrontal circuitry. This review urges an intensification of focus on the cellular mechanisms and plasticity of prefrontal attention circuitry. Disruptions in attention are one of the greatest contributing factors to disease burden in psychiatric and neurological disorders, and enhancing attention may require different approaches in the normal and disordered prefrontal cortex.     

Fanconi anemia is associated with a defect in the BRCA2 partner PALB2

The Fanconi anemia and BRCA networks are considered interconnected, as BRCA2 gene defects have been discovered in individuals with Fanconi anemia subtype D1. Here we show that a defect in the BRCA2-interacting protein PALB2 is associated with Fanconi anemia in an individual with a new subtype. PALB2-deficient cells showed hypersensitivity to cross-linking agents and lacked chromatin-bound BRCA2; these defects were corrected upon ectopic expression of PALB2 or by spontaneous reversion.     

BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous ciliopathy. Although nine BBS genes have been cloned, they explain only 40-50% of the total mutational load. Here we report a major new BBS locus, BBS10, that encodes a previously unknown, rapidly evolving vertebrate-specific chaperonin-like protein. We found BBS10 to be mutated in about 20% of an unselected cohort of families of various ethnic origins, including some families with mutations in other BBS genes, consistent with oligogenic inheritance. In zebrafish, mild suppression of bbs10 exacerbated the phenotypes of other bbs morphants.     

Recuperation of nitrogen cycling in Amazonian forests following agricultural abandonment

Phosphorus (P) is generally considered the most common limiting nutrient for productivity of mature tropical lowland forests growing on highly weathered soils. It is often assumed that P limitation also applies to young tropical forests, but nitrogen (N) losses during land-use change may alter the stoichiometric balance of nutrient cycling processes. In the Amazon basin, about 16% of the original forest area has been cleared, and about 30-50% of cleared land is estimated now to be in some stage of secondary forest succession following agricultural abandonment. Here we use forest age chronosequences to demonstrate that young successional forests growing after agricultural abandonment on highly weathered lowland tropical soils exhibit conservative N-cycling properties much like those of N-limited forests on younger soils in temperate latitudes. As secondary succession progresses, N-cycling properties recover and the dominance of a conservative P cycle typical of mature lowland tropical forests re-emerges. These successional shifts in N:P cycling ratios with forest age provide a mechanistic explanation for initially lower and then gradually increasing soil emissions of the greenhouse gas nitrous oxide (N(2)O). The patterns of N and P cycling during secondary forest succession, demonstrated here over decadal timescales, are similar to N- and P-cycling patterns during primary succession as soils age over thousands and millions of years, thus revealing that N availability in terrestrial ecosystems is ephemeral and can be disrupted by either natural or anthropogenic disturbances at several timescales.     

Sequence variant on 8q24 confers susceptibility to urinary bladder cancer

We conducted a genome-wide SNP association study on 1,803 urinary bladder cancer (UBC) cases and 34,336 controls from Iceland and The Netherlands and follow up studies in seven additional case-control groups (2,165 cases and 3,800 controls). The strongest association was observed with allele T of rs9642880 on chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR) = 1.22; P = 9.34 x 10(-12)). Approximately 20% of individuals of European ancestry are homozygous for rs9642880[T], and their estimated risk of developing UBC is 1.49 times that of noncarriers. No association was observed between UBC and the four 8q24 variants previously associated with prostate, colorectal and breast cancers, nor did rs9642880 associate with any of these three cancers. A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 x 10(-7)).     

Modelling conservation in the Amazon basin

Expansion of the cattle and soy industries in the Amazon basin has increased deforestation rates and will soon push all-weather highways into the region's core. In the face of this growing pressure, a comprehensive conservation strategy for the Amazon basin should protect its watersheds, the full range of species and ecosystem diversity, and the stability of regional climates. Here we report that protected areas in the Amazon basin--the central feature of prevailing conservation approaches--are an important but insufficient component of this strategy, based on policy-sensitive simulations of future deforestation. By 2050, current trends in agricultural expansion will eliminate a total of 40% of Amazon forests, including at least two-thirds of the forest cover of six major watersheds and 12 ecoregions, releasing 32 +/- 8 Pg of carbon to the atmosphere. One-quarter of the 382 mammalian species examined will lose more than 40% of the forest within their Amazon ranges. Although an expanded and enforced network of protected areas could avoid as much as one-third of this projected forest loss, conservation on private lands is also essential. Expanding market pressures for sound land management and prevention of forest clearing on lands unsuitable for agriculture are critical ingredients of a strategy for comprehensive conservation.