Neurologic Outcomes for Adult Spinal Cord Ependymomas Stratified by Tumor Location: A Retrospective Cohort Study and 2-Year Outlook

Determine whether craniocaudal spinal cord tumor location affects long-term neurologic outcomes in adults diagnosed with spinal ependymomas (SE). A retrospective cohort analysis of patients aged ≥ 18 years who underwent surgical resection for SE over a ten-year period was conducted. Tumor location was classified as cervical, thoracic, or lumbar/conus. Primary endpoints were post-operative McCormick Neurologic Scale (MNS) scores at \u3c 3 days, 6 weeks, 1 year, and 2 years. One-way ANOVA was performed to detect significant differences in MNS scores between tumor locations. Twenty-eight patients were identified. The average age was 44.2 ± 15.4 years. Sixteen were male, and 13 were female. There were 10 cervical-predominant SEs, 13 thoracic-predominant SEs, and 5 lumbar/conus-predominant SEs. No significant differences were observed in pre-operative MNS scores between tumor locations (p = 0.73). One-way ANOVA testing demonstrated statistically significant differences in post-operative MNS scores between tumor locations at \u3c 3 days (p = 0.03), 6 weeks (p = 0.009), and 1 year (p = 0.003); however, no significant difference was observed between post-operative MNS scores at 2 years (p = 0.13). The mean MNS score for patients with thoracic SEs were higher at all follow-up time points. Tumors arising in the thoracic SE are associated with worse post-operative neurologic outcomes in comparison to SEs arising in other spinal regions. This is likely multifactorial in etiology, owing to both anatomical differences including spinal cord volume as well as variations in tumor characteristics. No significant differences in 2-year MNS scores were observed, suggesting that patients ultimately recover from neurological insult sustained at the time of surgery

Structural Diversity of Ultralong CDRH3s in Seven Bovine Antibody Heavy Chains

Antigen recognition by mammalian antibodies represents the most diverse setting for protein-protein interactions, because antibody variable regions contain exceptionally diverse variable gene repertoires of DNA sequences containing combinatorial, non-templated junctional mutational diversity. Some animals use additional strategies to achieve structural complexity in the antibody combining site, and one of the most interesting of these is the formation of ultralong heavy chain complementarity determining region 3 loops in cattle. Repertoire sequencing studies of bovine antibody heavy chain variable sequences revealed that bovine antibodies can contain heavy chain complementarity determining region 3 (CDRH3) loops with 60 or more amino acids, with complex structures stabilized by multiple disulfide bonds. It is clear that bovine antibodies can achieve long, peculiarly structured CDR3s, but the range of diversity and complexity of those structures is poorly understood. We determined the atomic resolution structure of seven ultralong bovine CDRH3 loops. The studies, combined with five previous structures, reveal a large diversity of cysteine pairing variations, and highly diverse globular domains

The Cost of Antibiotic Mass Drug Administration for Trachoma Control in a Remote Area of South Sudan

Trachoma is one of a group of so-called “neglected tropical diseases” (NTDs) for which safe and effective treatments are available. The International Trachoma Initiative oversees donation of the antibiotic azithromycin to endemic countries. Delivery of this drug to communities affected by trachoma is the responsibility of national programmes and their implementing partners, and should be conducted as part of a comprehensive control strategy termed “SAFE,” which includes trichiasis surgery, health education and water/sanitation interventions. There are little data on how much the different components of a trachoma control programme cost and none from South Sudan. To inform budgeting to scale up control of trachoma, and of other NTDs whose control relies on large-scale mass drug administration (MDA), the present study set out to determine the cost per person treated when antibiotics were delivered through a vertical campaign that covered 94% of the target population in a remote trachoma endemic area of South Sudan. The average economic cost per person treated was USD 1.53, which included all inputs not paid for in cash except for the cost of the donated azithromycin and the opportunity cost of community members attending treatment

Molecular characterization of the EhaG and UpaG trimeric autotransporter proteins from pathogenic Escherichia coli

Trimeric autotransporter proteins (TAAs) are important virulence factors of many Gram-negative bacterial pathogens. A common feature of most TAAs is the ability to mediate adherence to eukaryotic cells or extracellular matrix (ECM) proteins via a cell surface-exposed passenger domain. Here we describe the characterization of EhaG, a TAA identified from enterohemorrhagic Escherichia coli (EHEC) O157:H7. EhaG is a positional orthologue of the recently characterized UpaG TAA from uropathogenic E. coli (UPEC). Similarly to UpaG, EhaG localized at the bacterial cell surface and promoted cell aggregation, biofilm formation, and adherence to a range of ECM proteins. However, the two orthologues display differential cellular binding: EhaG mediates specific adhesion to colorectal epithelial cells while UpaG promotes specific binding to bladder epithelial cells. The EhaG and UpaG TAAs contain extensive sequence divergence in their respective passenger domains that could account for these differences. Indeed, sequence analyses of UpaG and EhaG homologues from several E. coli genomes revealed grouping of the proteins in clades almost exclusively represented by distinct E. coli pathotypes. The expression of EhaG (in EHEC) and UpaG (in UPEC) was also investigated and shown to be significantly enhanced in an hns isogenic mutant, suggesting that H-NS acts as a negative regulator of both TAAs. Thus, while the EhaG and UpaG TAAs contain some conserved binding and regulatory features, they also possess important differences that correlate with the distinct pathogenic lifestyles of EHEC and UPEC

Prevalence of Trachoma in Unity State, South Sudan: Results from a Large-Scale Population-Based Survey and Potential Implications for Further Surveys

Large parts of South Sudan are thought to be trachoma endemic but baseline data, required to initiate interventions, are few. District-by-district surveys, currently recommended by the World Health Organization (WHO), are often not financially or logistically viable. We therefore adapted existing WHO guidelines and combined eight counties (equivalent to districts) of Unity State into one survey area, randomly sampling 40 villages using a population-based survey design. This decision was based on a trachoma risk map and a trachoma rapid assessment, both identifying the state as likely to be highly endemic. The survey confirmed trachoma as being hyperendemic throughout Unity State, meaning that large-scale intervention should be initiated now. Simulation studies were conducted to determine the likely outcome if fewer (n = 20) or more (n = 60) villages had been sampled, confirming that precision decreased or increased, respectively. Importantly, simulation results also showed that all three sample sizes would have led to the same conclusion, namely the need for large-scale intervention. This finding suggests that district-by-district surveys may not be required for areas where trachoma is suspected to be highly prevalent but that are lacking baseline data; instead districts may be combined into a larger survey area

An Insect Herbivore Microbiome with High Plant Biomass-Degrading Capacity

Herbivores can gain indirect access to recalcitrant carbon present in plant cell walls through symbiotic associations with lignocellulolytic microbes. A paradigmatic example is the leaf-cutter ant (Tribe: Attini), which uses fresh leaves to cultivate a fungus for food in specialized gardens. Using a combination of sugar composition analyses, metagenomics, and whole-genome sequencing, we reveal that the fungus garden microbiome of leaf-cutter ants is composed of a diverse community of bacteria with high plant biomass-degrading capacity. Comparison of this microbiome's predicted carbohydrate-degrading enzyme profile with other metagenomes shows closest similarity to the bovine rumen, indicating evolutionary convergence of plant biomass degrading potential between two important herbivorous animals. Genomic and physiological characterization of two dominant bacteria in the fungus garden microbiome provides evidence of their capacity to degrade cellulose. Given the recent interest in cellulosic biofuels, understanding how large-scale and rapid plant biomass degradation occurs in a highly evolved insect herbivore is of particular relevance for bioenergy

Comparative Genomics of the Mating-Type Loci of the Mushroom Flammulina velutipes Reveals Widespread Synteny and Recent Inversions

Mating-type loci of mushroom fungi contain master regulatory genes that control recognition between compatible nuclei, maintenance of compatible nuclei as heterokaryons, and fruiting body development. Regions near mating-type loci in fungi often show adapted recombination, facilitating the generation of novel mating types and reducing the production of self-compatible mating types. Compared to other fungi, mushroom fungi have complex mating-type systems, showing both loci with redundant function (subloci) and subloci with many alleles. The genomic organization of mating-type loci has been solved in very few mushroom species, which complicates proper interpretation of mating-type evolution and use of those genes in breeding programs.We report a complete genetic structure of the mating-type loci from the tetrapolar, edible mushroom Flammulina velutipes mating type A3B3. Two matB3 subloci, matB3a that contains a unique pheromone and matB3b, were mapped 177 Kb apart on scaffold 1. The matA locus of F. velutipes contains three homeodomain genes distributed over 73 Kb distant matA3a and matA3b subloci. The conserved matA region in Agaricales approaches 350 Kb and contains conserved recombination hotspots showing major rearrangements in F. velutipes and Schizophyllum commune. Important evolutionary differences were indicated; separation of the matA subloci in F. velutipes was diverged from the Coprinopsis cinerea arrangement via two large inversions whereas separation in S. commune emerged through transposition of gene clusters.In our study we determined that the Agaricales have very large scale synteny at matA (∼350 Kb) and that this synteny is maintained even when parts of this region are separated through chromosomal rearrangements. Four conserved recombination hotspots allow reshuffling of large fragments of this region. Next to this, it was revealed that large distance subloci can exist in matB as well. Finally, the genes that were linked to specific mating types will serve as molecular markers in breeding

Target-based therapeutic matching of phase I trials in patients with metastatic breast cancer in a tertiary referral centre.

Background Greater understanding of the molecular classification of breast cancer has permitted the development of rational drug design strategies. In a phase I clinical trial setting, molecular profiling with next-generation sequencing of individual tumour samples has been employed to guide treatment.Methods We conducted a retrospective evaluation of clinical outcomes of patients with metastatic breast cancer (MBC) treated in phase I clinical trials at our institution to assess the benefit of molecularly matched compared to non-matched treatments.Results A total of 97 consecutive patients with MBC were enrolled onto ≥1 trial between 2009 and 2015. Fourteen patients participated in multiple trials, and a total of 113 trial encounters were reviewed in this retrospective study. Eighty-three percent of patients with molecular data available were able to participate in trials matched to molecular aberrations. Patients who were treated on matched studies had improved clinical benefit (RR: 1.80, p = 0.005), progression-free (HR: 0.52, p = 0.003) and overall survival (HR: 0.54, p < 0.001). Treatment was well tolerated with low rates of treatment discontinuation for toxicity (8% overall) that did not differ between groups. No toxicity-related deaths were observed.Conclusions Molecular profiling for MBC patients in a phase I setting is feasible and aids therapeutic decisions with improved patient outcomes