The frequency of the perfect genotype in a population subject to pleiotropic mutation

We consider a large population of asexual organisms characterised by a number of quantitative traits that are subject to stabilising selection. Mutation is taken to act pleiotropically, with every mutation generally changing all of the traits under selection. We focus on the equilibrium distribution of the population, where mutation and selection are in balance. It has been previously established that the equilibrium distribution of genotypic effects may be anomalous, as it may contain a singular spike--a Dirac delta function--corresponding to a non-zero proportion of the population having exactly optimal genotypic values. In the present work, we present exact results for the case where three traits are under selection. These results give the equilibrium genetic variance of the population, and the proportion of the population that have the optimal genotype. This is achieved for two different spherically symmetric distributions of mutant effects. Additionally, a simple and robust numerical approach is also presented that allows the treatment of some other mutation distributions, where there are an arbitrary number of selected traits.     

A horizon scan of global conservation issues for 2012

Our aim in conducting annual horizon scans is to identify issues that, although currently receiving little attention, may be of increasing importance to the conservation of biological diversity in the future. The 15 issues presented here were identified by a diverse team of 22 experts in horizon scanning, and conservation science and its application. Methods for identifying and refining issues were the same as in two previous annual scans and are widely transferable to other disciplines. The issues highlight potential changes in climate, technology and human behaviour. Examples include warming of the deep sea, increased cultivation of perennial grains, burning of Arctic tundra, and the development of nuclear batteries and hydrokinetic in-stream turbines.     

Systems analysis of primary Sjögren's syndrome pathogenesis in salivary glands identifies shared pathways in human and a mouse model

Bone tissue has an exceptional quality to regenerate to native tissue in response to injury. However, the fracture repair process requires mechanical stability or a viable biological microenvironment or both to ensure successful healing to native tissue. An improved understanding of the molecular and cellular events that occur during bone repair and remodeling has led to the development of biologic agents that can augment the biological microenvironment and enhance bone repair. Orthobiologics, including stem cells, osteoinductive growth factors, osteoconductive matrices, and anabolic agents, are available clinically for accelerating fracture repair and treatment of compromised bone repair situations like delayed unions and nonunions. Preclinical and clinical studies using biologic agents like recombinant bone morphogenetic proteins have demonstrated an efficacy similar or better than that of autologous bone graft in acute fracture healing. A lack of standardized outcome measures for comparison of biologic agents in clinical fracture repair trials, frequent off-label use, and a limited understanding of the biological activity of these agents at the bone repair site have limited their efficacy in clinical applications.     

Thoracic empyema: a 12-year study from a UK tertiary cardiothoracic referral centre

Background

Empyema is an increasingly frequent clinical problem worldwide, and has substantial morbidity and mortality. Our objectives were to identify the clinical, surgical and microbiological features, and management outcomes, of empyema.

Methods

A retrospective observational study over 12 years (1999–2010) was carried out at The Heart Hospital, London, United Kingdom. Patients with empyema were identified by screening the hospital electronic ‘Clinical Data Repository’. Demographics, clinical and microbiological characteristics, underlying risk factors, peri-operative blood tests, treatment and outcomes were identified. Univariable and multivariable statistical analyses were performed.

Results

Patients (n = 406) were predominantly male (74.1%); median age = 53 years (IQR = 37–69). Most empyema were community-acquired (87.4%) and right-sided (57.4%). Microbiological diagnosis was obtained in 229 (56.4%) patients, and included streptococci (16.3%), staphylococci (15.5%), Gram-negative organisms (8.9%), anaerobes (5.7%), pseudomonads (4.4%) and mycobacteria (9.1%); 8.4% were polymicrobial. Most (68%) cases were managed by open thoracotomy and decortication. Video-assisted thoracoscopic surgery (VATS) reduced hospitalisation from 10 to seven days (P = 0.0005). All-cause complication rate was 25.1%, and 28 day mortality 5.7%. Predictors of early mortality included: older age (P = 0.006), major co-morbidity (P = 0.01), malnutrition (P = 0.001), elevated red cell distribution width (RDW, P<0.001) and serum alkaline phosphatase (P = 0.004), and reduced serum albumin (P = 0.01) and haemoglobin (P = 0.04).

Conclusions

Empyema remains an important cause of morbidity and hospital admissions. Microbiological diagnosis was only achieved in just over 50% of cases, and tuberculosis is a notable causative organism. Treatment of empyema with VATS may reduce duration of hospital stay. Raised RDW appears to associate with early mortality.     

Identification of a chemically induced point mutation mediating herbicide tolerance in annual medics (Medicago spp.)

Background and Aims: Sulfonylurea (SU) herbicides are used extensively in cereal–livestockfarming zones as effective and cheap herbicides with usefullevels of residual activity. These residues can persist beyondthe cropping year, severely affecting legumes in general, andannual medics in particular, resulting in reduced dry matterproduction, lower seed yields and decreased nitrogen fixation.A strand medic cultivar, Medicago littoralis ‘Angel’,has been developed via chemical mutagenesis with tolerance toSU soil residues. Identifying the molecular basis of the observedtolerance was the aim of this study. Methods: Two F₂ populations were generated from crosses between ‘Angel’and varieties of intolerant M. truncatula, the male-sterilemutant tap and the cultivar ‘Caliph’. Genetic mappingwith SSR (single sequence repeat) and gene-based markers allowedidentification of the trait-defining gene. Quantitative geneexpression studies showed the activity of the respective alleles. Key Results: Segregation ratios indicated the control of SU-herbicide toleranceby a single dominant gene. SU herbicides inhibit the biosynthesisof the branched-chain amino acids by targeting the acetolactatesynthase enzyme, allowing the choice of a mapping approach usingacetolactate synthase (ALS) gene homologues as candidates. SSR-markeranalysis suggested the ALS-gene homologue on chromosome 3 inM. truncatula. The ALS-gene sequences from ‘Angel’and intolerant genotypes were sequenced. In ‘Angel’,a single point mutation from C to T translating into an aminoacid change from proline to leucine was identified. The polymorphismwas used to develop a diagnostic marker for the tolerance trait.Expression of the mutant ALS allele was confirmed by quantitativeRT-PCR and showed no differences at various seedling stagesand treatments to the corresponding wild-type allele. Conclusions: The identification of the trait-defining gene and the developmentof a diagnostic marker enable efficient introgression of thiseconomically important trait in annual medic improvement programs.     

Reconciling historical processes and population structure in the sooty tern Sterna fuscata

To test the influence of past vicariant events on population genetic structure of the sooty tern Sterna fuscata , we examined sequence variation in the mitochondrial control region of individuals from the Indo-Pacific and Atlantic Oceans. Our analyses indicate a rapid population expansion at a global scale during the last 100 000 years, consistent with global recolonisation during the interstade following the Pleistocene glacial maxima (125 000–175 000 years bp). We estimate islands of the Great Barrier Reef and Coral Sea were colonised no more than 16 000 years ago, most likely in association with the appearance of new breeding habitat following the final Pleistocene glacial retreat (19 000–22 000 years bp). Our results suggest that ice sheets linked to major glacial events not only impact genetic structuring in temperate seabirds, but that sea level changes in the tropics associated with these same events have also significantly impacted contemporary genetic structuring in tropical seabird species.     

Production of Melanocyte‐Specific Antibodies to Human Melanosomal Proteins: Expression Patterns in Normal Human Skin and in Cutaneous Pigmented Lesions

Multiple factors affect skin pigmentation, including those that regulate melanocyte and/or keratinocyte function. Such factors, particularly those that operate at the level of the melanosome, are relatively well characterized in mice, but the expression and function of structural and enzymatic proteins in melanocytes in human skin are not as well known. Some years ago, we generated peptide‐specific antibodies to murine melanosomal proteins that proved to be instrumental in elucidating melanocyte development and differentiation in mice, but cross‐reactivity of those antibodies with the corresponding human proteins often was weak or absent. In an effort to characterize the roles of melanosomal proteins in human skin pigmentation, and to understand the underlying mechanism(s) of abnormal skin pigmentation, we have now generated polyclonal antibodies against the human melanocyte‐specific markers, tyrosinase, tyrosinase‐related protein 1 (TYRP1), Dopachrome tautomerase (DCT) and Pmel17 (SILV, also known as GP100). We used these antibodies to determine the distribution and function of melanosomal proteins in normal human skin (adult and newborn) and in various cutaneous pigmented lesions, such as intradermal nevi, lentigo simplex, solar lentigines and malignant melanomas. We also examined cytokeratin expression in these same samples to assess keratinocyte distribution and function. Immunohistochemical staining reveals distinct patterns of melanocyte distribution and function in normal skin and in various types of cutaneous pigmented lesions. Those differences in the expression patterns of melanocyte markers provide important clues to the roles of melanocytes in normal and in disrupted skin pigmentation.