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Genomics in the Journals Jan 30, 2014

NEW YORK(GenomeWeb News) – The University of Perugia's Agostinho Carvalho and colleagues explored the influence that polymorphisms in a gene called PTX3 — known for its role in mediating immune responses to fungi — might have on an individual's risk of developing invasive aspergillosis infections after hematopoietic stem cell transplantation.

As they reported in the New England Journal of Medicine, the researchers started by genotyping almost two-dozen SNPs in and around the PTX3 gene in 268 individuals slated to receive hematopoietic stem cell transplants as well as their healthy donors. In the two years following these transplants, they saw that a certain homozygous PTX3 haplotype in stem cell donors coincided with an elevated risk of invasive aspergillosis infections in transplant recipients.

Those findings were supported by the team's subsequent analysis using PTX3 SNP profiles from 107 more transplant recipients who developed invasive aspergillosis and another 223 matched controls.

Meanwhile, further follow-up experiments indicated that the elevated infection risk might stem from lower-than-usual PTX3 expression and stability in white blood cells known as neutrophils in those with the homozygous PTX3 haplotype, leading to less efficient immune system attacks on the Aspergillus fumigatus fungus.

"[W]e found that genetic deficiency of PTX3 affects the antifungal function of neutrophils," Carvalho and co-authors wrote. "This deficiency may increase susceptibility to invasive aspergillosis in patients undergoing [hematopoietic stem cell transplantation]."


Researchers from Switzerland, Germany, Japan, and the US characterized previously undescribed bacteria living within Theonella swinhoei, a marine sponge known for occurring in diverse and varied chemotypes — work they described in Nature.

The group used a combination of 16S ribosomal RNA sequencing, metagenomic sequencing, and multiple displacement amplification-assisted single-cell sequencing approaches to assess microbes isolated from samples of a T. swinhoei sponge variant growing off of Japan's East Coast.

The resulting data indicated that that sponge is home to at least two chemically divergent phylotypes of related bacteria containing clusters of genes that can produce a range of bioactive compounds such as peptides and polyketides.

Based on their current characterization of the bugs, the investigators suspect that bacteria from one of the phylotypes in this so-called Entotheonella genus produces a substantial fraction of the 40 or so bioactive natural products associated with the T. swinhoei sponge.

"The pronounced bioactivities and chemical uniqueness of 'Entotheonella' compounds provide significant opportunities for ecological studies and drug discovery," the study's senior author Jörn Piel, a researcher affiliated with ETH Zurich and the University of Bonn, and his colleagues wrote.


American researchers reporting in PLOS One looked at how well an updated model based on patient age and protein biomarkers in the blood could predict outcomes in children with septic shock.

Members of the team initially introduced the "Pediatric Sepsis Biomarker Risk Model," nicknamed PERSEVERE, in a 2012 study. For the current analysis, the group tested the PERSEVERE model's ability to predict mortality in an independent group of 182 children between the ages of 1 and 13-years-old who were treated for septic shock at one of several different intensive care units.

Using blood protein profiles from samples collected over the first day the pediatric patients presented with sepsis, the researchers found that children classified as high-risk using the PERSEVERE model had a 34 percent mortality rate in the following month or so. For children in the low-risk group, mortality was closer to 3 percent.

"Understanding the risk of mortality at an early time point is fundamental for clinical practice and clinical research," first author Hector Wong, director of the Cincinnati Children's Hospital Medical Center's division of critical care medicine, said in a statement. "Without this objective information, we have nothing concrete to help us guide decisions on which patients need the most aggressive treatment."


A Science study suggests that specializations in virulence-related effector protein-coding genes have largely driven the distinct host preferences of the potato blight-causing pathogen Phytophthora infestans and a sister species from the same clade called P. mirabilis, which infects the four o'clock plant, Mirabilis jalapa.

A team from the US, the UK, and Germany turned to comparative genomics to narrow in on 345 genes from P. infestans and P. mirabilis — including more than 80 disease effector genes — that are expressed in their respective host plants and show signs of positive selection in the pathogens.

Through a phylogenetic analysis of sequences similar to those coding for a P. infestans effector protein called EPIC1 (known for inhibiting cystatin-like protease enzymes), the investigators found evidence of host-specific effector adaptations in the potato and four o'clock pathogens.

Their subsequent experiments, which included effector activity assays, immunoprecipitation tests, and targeted mutation studies, supported the notion that the Phytophthora species considered have each undergone adaptations that result in enhanced effector-based inhibition of the protease enzymes found in their preferred plant host.


Researchers from the University of California at San Diego, the Rady Children's Hospital-San Diego, and elsewhere used exome sequencing to define a set of genes contributing to a neurodegenerative condition called hereditary spastic paraplegias, or HSPs, in another Science study.

The team did whole-exome sequencing on 93 individuals from 55 families affected by HSPs, a group of heterogenous conditions marked by a progressive decline in corticospinal motor tract function (including a jump in uncontrollable lower limb movements and stiffness) as individuals age.

When they sorted through protein-coding sequences from individuals with or without HSP, the investigators detected HSP-associated mutations in 18 genes not previously implicated in the degenerative conditions.

After further verifying the role of many of the new candidate genes in HSPs, the team developed a network called the "HSPome" that offered a look at not only the new and known genes contributing to HSPs, but also their shared pathways and interactions with one another.

That network, in turn, made it possible to track down still other apparent contributors to HSPs, as well as some apparent genetic overlap with neurodegenerative conditions such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease.

"Knowing the biological processes underlying neurodegenerative disorders is seminal to driving future scientific studies that aim to uncover the exact mechanisms implicated in common neurodegenerative diseases, and to indicate the path toward development of effective treatments," UCSD neurosciences and pediatrics researcher Joseph Gleeson, the study's senior author, said in a statement.

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