Of sad and wished-for years: Elizabeth Barrett Browning's lifelong illness

The Victorian poet Elizabeth Barrett Browning suffered for most of her life from an illness that her physicians were never able to diagnose, and that Barrett Browning scholars and others have tried to diagnose since her death in 1861. Many suggestions have been offered, but none has been convincing. By happenstance, my daughter was reading the correspondence of Elizabeth and Robert Browning not long ago, and she recognized the symptoms described as those of the rare muscle-weakening disorder she herself has, hypokalemic periodic paralysis (HKPP). The evidence from Barrett Browning's letters and the diary she kept when she was 25 strongly suggest she too had HKPP.     

Identification, replication, and fine-mapping of Loci associated with adult height in individuals of african ancestry

Adult height is a classic polygenic trait of high heritability (h ² ∼0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ∼10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10⁻¹² and 2p14-rs4315565, P = 1.2×10⁻⁸). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10⁻⁴ for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits.     

Effects of phosphorus-mobilizing bacteria on tomato growth and soil microbial activity

Aims

The aim of our study was to clarify whether inoculating a soil with Pseudomonas sp. RU47 (RU47) bacteria would stimulate the enzymatic cleavage of organic P compounds in the rhizosphere and bulk soil, promoting plant growth. Adding either viable or heat treated RU47 cells made it possible to separate direct from indirect effects of the inoculum on P cycling in soil and plants.

Methods

We performed a rhizobox experiment in the greenhouse with tomato plants (Solanum lycopersicum) under low P soil conditions. Three inoculation treatments were conducted, using unselectively grown soil bacteria (bacterial mix), heat treated (HT-RU47) and viable RU47 (RU47) cells, and one not inoculated, optimally P-fertilized treatment. We verified plant growth, nutrient availability, enzyme activities and microbial community structure in soil.

Results

A plant growth promotion effect with improved P uptake was observed in both RU47 treatments. Inoculations of RU47 cells increased microbial phosphatase activity (PA) in the rhizosphere.

Conclusions

Plant growth promotion by RU47 cells is primarily associated with increased microbial PA in soil, while promotion of indigenous Pseudomonads as well as phytohormonal effects appear to be the dominant mechanisms when adding HT-RU47 cells. Thus, using RU47 offers a promising approach for more efficient P fertilization in agriculture.

     

The Sub-Cellular Localization of WRAP53 Has Prognostic Impact in Breast Cancer

WRAP53 protein controls intracellular trafficking of DNA repair proteins, the telomerase enzyme, and splicing factors. Functional loss of the protein has been linked to carcinogenesis, premature aging and neurodegeneration. The aim of this study was to investigate the prognostic significance of WRAP53 protein expression in breast cancer. A tissue microarray was constructed from primary breast tumors and immunostained by a polyclonal WRAP53 antibody to assess the protein expression pattern. Two different patient cohorts with long term follow-up were studied; a test- and a validation set of 154 and 668 breast tumor samples respectively. Breast cancer patients with tumor cells lacking the expression of WRAP53 in the nucleus had a significantly poorer outcome compared to patients with tumor cells expressing this protein in the nuclei (HR = 1.95, 95%CI = 1.09–3.51, p = 0.025). Nuclear localization of WRAP53 was further shown to be an independent marker of prognosis in multivariate analysis (HR = 2.57, 95%CI = 1.27–5.19, p = 0.008), and also significantly associated with better outcome in patients with TP53 mutation. Here we show that the sub-cellular localization of the WRAP53 protein has a significant impact on breast cancer survival, and thus has a potential as a clinical marker in diagnostics and treatment.     

Acorn mast drives long-term dynamics of rodent and songbird populations

Resource pulses can have cascading effects on the dynamics of multiple trophic levels. Acorn mast is a pulsed resource in oak-dominated forests that has significant direct effects on acorn predators and indirect effects on their predators, prey, and pathogens. We evaluated changes in acorn mast, rodent abundance, raptor abundance, and reproductive success of a ground-nesting songbird over a 24-year period (1980–2004) in the southern Appalachian Mountains in an effort to determine the relationships among the four trophic levels. In particular, we examined the following: acorn mast from red oaks (Quercus rubra) and white oaks (Q. alba), abundance of white-footed mice (Peromyscus leucopus) and deer mice (P. maniculatus), population estimates of seven raptor species from three feeding guilds, and nest failure and number of juveniles of dark-eyed juncos (Junco hyemalis). Finally, we recorded seasonal temperature and precipitation to determine the effects of weather on each trophic level. We found that weather patterns had delayed effects of up to 3 years on these trophic interactions. Variation in acorn mast, the keystone resource in this community, was explained by weather conditions as far back as 2 years before the mast event. Acorn mast, in turn, was a strongly positive predictor of rodent abundance the following year, whereas spring and summer temperature and raptor abundance negatively affected rodent abundance. Dark-eyed junco nests were more likely to fail in years in which there were more rodents and raptors. Nest failure rate was a strong predictor of the number of juvenile juncos caught at the end of the summer. Our results improve our understanding of the complex ecological interactions in oak-dominated forests by illustrating the importance of abiotic and biotic factors at different trophic levels. Ethan D. Clotfelter and Amy B. Pedersen contributed equally to the writing of this paper.     

Aip1 and cofilin promote rapid turnover of yeast actin patches and cables: a coordinated mechanism for severing and capping filaments

Rapid turnover of actin structures is required for dynamic remodeling of the cytoskeleton and cell morphogenesis, but the mechanisms driving actin disassembly are poorly defined. Cofilin plays a central role in promoting actin turnover by severing/depolymerizing filaments. Here, we analyze the in vivo function of a ubiquitous actin-interacting protein, Aip1, suggested to work with cofilin. We provide the first demonstration that Aip1 promotes actin turnover in living cells. Further, we reveal an unanticipated role for Aip1 and cofilin in promoting rapid turnover of yeast actin cables, dynamic structures that are decorated and stabilized by tropomyosin. Through systematic mutagenesis of Aip1 surfaces, we identify two well-separated F-actin-binding sites, one of which contributes to actin filament binding and disassembly specifically in the presence of cofilin. We also observe a close correlation between mutations disrupting capping of severed filaments in vitro and reducing rates of actin turnover in vivo. We propose a model for balanced regulation of actin cable turnover, in which Aip1 and cofilin function together to "prune" tropomyosin-decorated cables along their lengths. Consistent with this model, deletion of AIP1 rescues the temperature-sensitive growth and loss of actin cable defects of tpm1Delta mutants.     

Global Analysis of Apicomplexan Protein S‐Acyl Transferases Reveals an Enzyme Essential for Invasion

The advent of techniques to study palmitoylation on a whole proteome scale has revealed that it is an important reversible modification that plays a role in regulating multiple biological processes. Palmitoylation can control the affinity of a protein for lipid membranes, which allows it to impact protein trafficking, stability, folding, signalling and interactions. The publication of the palmitome of the schizont stage of Plasmodium falciparum implicated a role for palmitoylation in host cell invasion, protein export and organelle biogenesis. However, nothing is known so far about the repertoire of protein S‐acyl transferases (PATs) that catalyse this modification in Apicomplexa. We undertook a comprehensive analysis of the repertoire of Asp‐His‐His‐Cys cysteine‐rich domain (DHHC‐CRD) PAT family in Toxoplasma gondii and Plasmodium berghei by assessing their localization and essentiality. Unlike functional redundancies reported in other eukaryotes, some apicomplexan‐specific DHHCs are essential for parasite growth, and several are targeted to organelles unique to this phylum. Of particular interest is DHHC7, which localizes to rhoptry organelles in all parasites tested, including the major human pathogen P. falciparum. TgDHHC7 interferes with the localization of the rhoptry palmitoylated protein TgARO and affects the apical positioning of the rhoptry organelles. This PAT has a major impact on T. gondii host cell invasion, but not on the parasite's ability to egress.     

Behavioral and transcriptome alterations in male and female mice with postnatal deletion of TrkB in dorsal striatal medium spiny neurons

Background

The high affinity tyrosine kinase receptor, TrkB, is the primary receptor for brain derived neurotrophic factor (BDNF) and plays an important role in development, maintenance and plasticity of the striatal output medium size spiny neuron. The striatal BDNF/TrkB system is thereby implicated in many physiologic and pathophysiologic processes, the latter including mood disorders, addiction, and Huntington’s disease. We crossed a mouse harboring a transgene directing cre-recombinase expression primarily to postnatal, dorsal striatal medium spiny neurons, to a mouse containing a floxed TrkB allele (fB) mouse designed for deletion of TrkB to determine its role in the adult striatum.

Results

We found that there were sexually dimorphic alterations in behaviors in response to stressful situations and drugs of abuse. Significant sex and/or genotype differences were found in the forced swim test of depression-like behaviors, anxiety-like behaviors on the elevated plus maze, and cocaine conditioned reward. Microarray analysis of dorsal striatum revealed significant dysregulation in individual and groups of genes that may contribute to the observed behavioral responses and in some cases, represent previously unidentified downstream targets of TrkB.

Conclusions

The data point to a set of behaviors and changes in gene expression following postnatal deletion of TrkB in the dorsal striatum distinct from those in other brain regions.

     

Sandfly Fever Sicilian Virus-Leishmania major co-infection modulates innate inflammatory response favoring myeloid cell infections and skin hyperinflammation

BackgroundThe leishmaniases are a group of sandfly-transmitted diseases caused by species of the protozoan parasite, Leishmania. With an annual incidence of 1 million cases, 1 billion people living in Leishmania-endemic regions, and nearly 30,000 deaths each year, leishmaniasis is a major global public health concern. While phlebotomine sandflies are well-known as vectors of Leishmania, they are also the vectors of various phleboviruses, including Sandfly Fever Sicilian Virus (SFSV).Cutaneous leishmaniasis (CL), caused by Leishmania major (L. major), among other species, results in development of skin lesions on the infected host. Importantly, there exists much variation in the clinical manifestation between individuals. We propose that phleboviruses, vectored by and found in the same sandfly guts as Leishmania, may be a factor in determining CL severity. It was reported by our group that Leishmania exosomes are released into the gut of the sandfly vector and co-inoculated during blood meals, where they exacerbate CL skin lesions. We hypothesized that, when taking a blood meal, the sandfly vector infects the host with Leishmania parasites and exosomes as well as phleboviruses, and that this viral co-infection results in a modulation of leishmaniasis.Methodology/Principal findingsIn vitro, we observed modulation by SFSV in MAP kinase signaling as well as in the IRF3 pathway that resulted in a pro-inflammatory phenotype. Additionally, we found that SFSV and L. major co-infection resulted in an exacerbation of leishmaniasis in vivo, and by using endosomal (Toll-like receptor) TLR3, and MAVS knock-out mice, deduced that SFSV’s hyperinflammatory effect was TLR3- and MAVS-dependent. Critically, we observed that L. major and SFSV co-infected C57BL/6 mice demonstrated significantly higher parasite burden than mice solely infected with L. major. Furthermore, viral presence increased leukocyte influx in vivo. This influx was accompanied by elevated total extracellular vesicle numbers. Interestingly, L. major displayed higher infectiveness with coincident phleboviral infection compared to L. major infection alone.Conclusion/SignificanceOverall our work represents novel findings that contribute towards understanding the causal mechanisms governing cutaneous leishmaniasis pathology. Better comprehension of the potential role of viral co-infection could lead to treatment regimens with enhanced effectiveness.