Genetics of strabismus

Strabismus, or misalignment of the eyes, is the most common ocular disorder in the pediatric population, affecting approximately 2%–4% of children. Strabismus leads to the disruption of binocular vision, amblyopia, social and occupational discrimination, and decreased quality of life. Although it has been recognized since ancient times that strabismus runs in families, its inheritance patterns are complex, and its precise genetic mechanisms have not yet been defined. Family, population, and twin studies all support a role of genetics in the development of strabismus. There are multiple forms of strabismus, and it is not known if they have shared genetic mechanisms or are distinct genetic disorders, which complicates studies of strabismus. Studies assuming that strabismus is a Mendelian disorder have found areas of linkage and candidate genes in particular families, but no definitive causal genes. Genome-wide association studies searching for common variation that contributes to strabismus risk have identified two risk loci and three copy number variants in white populations. Causative genes have been identified in congenital cranial dysinnervation disorders, syndromes in which eye movement is limited or paralyzed. The causative genes lead to either improper differentiation of cranial motor neurons or abnormal axon guidance. This article reviews the evidence for a genetic contribution to strabismus and the recent advances that have been made in the genetics of comitant strabismus, the most common form of strabismus

Influence of Inflammatory and Oxidative Stress Pathways on Longitudinal Symptom Experiences in Children With Leukemia

Purpose: The purpose of this study was to explore the influence of oxidative stress (F2-isoprostanes) and inflammatory (interleukin [IL]-8) biomarkers on symptom trajectories during the first 18 months of childhood leukemia treatment. Method: A repeated-measures design was used to evaluate symptoms experienced by 218 children during treatment. A symptom cluster (fatigue, pain, and nausea) was explored over four time periods: initiation of post-induction therapy, 4 and 8 months into post-induction therapy, and the beginning of maintenance therapy (12 months postinduction). F2-isoprostanes and IL-8 were evaluated in cerebrospinal fluid (CSF) samples collected at baseline (diagnosis) and then at the four time periods. The longitudinal relationships of these biomarkers with the symptom cluster were examined using the longitudinal parallel process. Results: Pain and fatigue levels were highest during the post-induction phases of treatment and decreased slightly during maintenance therapy, while nausea scores were relatively stable. Even in the later phases of treatment, children continued to experience symptoms. CSF levels of the biomarkers increased during the post-induction phases of treatment. Early increases in the biomarkers were associated with more severe symptoms during the same period; patients who had increased biomarkers over time also experienced more severe symptoms over time. Conclusions: Findings reveal that children experienced symptoms throughout the course of leukemia treatment and support hypothesized longitudinal relationships of oxidative stress and inflammatory biomarkers with symptom severity. Activation of the biomarker pathways during treatment may explain underlying mechanisms of symptom experiences and identify which children are at risk for severe symptoms.National Institutes of Health [R01CA1693398]This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Principles of Glomerular Organization in the Human Olfactory Bulb – Implications for Odor Processing

Olfactory sensory neurons (OSN) in mice express only 1 of a possible 1,100 odor receptors (OR) and axons from OSNs expressing the same odor receptor converge into ∼2 of the 1,800 glomeruli in each olfactory bulb (OB) in mice; this yields a convergence ratio that approximates 2∶1, 2 glomeruli/OR. Because humans express only 350 intact ORs, we examined human OBs to determine if the glomerular convergence ratio of 2∶1 established in mice was applicable to humans. Unexpectedly, the average number of human OB glomeruli is >5,500 yielding a convergence ratio of ∼16∶1. The data suggest that the initial coding of odor information in the human OB may differ from the models developed for rodents and that recruitment of additional glomeruli for subpopulations of ORs may contribute to more robust odor representation

Nodal-Dependent Mesendoderm Specification Requires the Combinatorial Activities of FoxH1 and Eomesodermin

Vertebrate mesendoderm specification requires the Nodal signaling pathway and its transcriptional effector FoxH1. However, loss of FoxH1 in several species does not reliably cause the full range of loss-of-Nodal phenotypes, indicating that Nodal signals through additional transcription factors during early development. We investigated the FoxH1-dependent and -independent roles of Nodal signaling during mesendoderm patterning using a novel recessive zebrafish FoxH1 mutation called midway, which produces a C-terminally truncated FoxH1 protein lacking the Smad-interaction domain but retaining DNA–binding capability. Using a combination of gel shift assays, Nodal overexpression experiments, and genetic epistasis analyses, we demonstrate that midway more accurately represents a complete loss of FoxH1-dependent Nodal signaling than the existing zebrafish FoxH1 mutant schmalspur. Maternal-zygotic midway mutants lack notochords, in agreement with FoxH1 loss in other organisms, but retain near wild-type expression of markers of endoderm and various nonaxial mesoderm fates, including paraxial and intermediate mesoderm and blood precursors. We found that the activity of the T-box transcription factor Eomesodermin accounts for specification of these tissues in midway embryos. Inhibition of Eomesodermin in midway mutants severely reduces the specification of these tissues and effectively phenocopies the defects seen upon complete loss of Nodal signaling. Our results indicate that the specific combinations of transcription factors available for signal transduction play critical and separable roles in determining Nodal pathway output during mesendoderm patterning. Our findings also offer novel insights into the co-evolution of the Nodal signaling pathway, the notochord specification program, and the chordate branch of the deuterostome family of animals

HIV-1 pol Diversity among Female Bar and Hotel Workers in Northern Tanzania

A national ART program was launched in Tanzania in October 2004. Due to the existence of multiple HIV-1 subtypes and recombinant viruses co-circulating in Tanzania, it is important to monitor rates of drug resistance. The present study determined the prevalence of HIV-1 drug resistance mutations among ART-naive female bar and hotel workers, a high-risk population for HIV-1 infection in Moshi, Tanzania. A partial HIV-1 pol gene was analyzed by single-genome amplification and sequencing in 45 subjects (622 pol sequences total; median number of sequences per subject, 13; IQR 5–20) in samples collected in 2005. The prevalence of HIV-1 subtypes A1, C, and D, and inter-subtype recombinant viruses, was 36%, 29%, 9% and 27%, respectively. Thirteen different recombination patterns included D/A1/D, C/A1, A1/C/A1, A1/U/A1, C/U/A1, C/A1, U/D/U, D/A1/D, A1/C, A1/C, A2/C/A2, CRF10_CD/C/CRF10_CD and CRF35_AD/A1/CRF35_AD. CRF35_AD was identified in Tanzania for the first time. All recombinant viruses in this study were unique, suggesting ongoing recombination processes among circulating HIV-1 variants. The prevalence of multiple infections in this population was 16% (n = 7). Primary HIV-1 drug resistance mutations to RT inhibitors were identified in three (7%) subjects (K65R plus Y181C; N60D; and V106M). In some subjects, polymorphisms were observed at the RT positions 41, 69, 75, 98, 101, 179, 190, and 215. Secondary mutations associated with NNRTIs were observed at the RT positions 90 (7%) and 138 (6%). In the protease gene, three subjects (7%) had M46I/L mutations. All subjects in this study had HIV-1 subtype-specific natural polymorphisms at positions 36, 69, 89 and 93 that are associated with drug resistance in HIV-1 subtype B. These results suggested that HIV-1 drug resistance mutations and natural polymorphisms existed in this population before the initiation of the national ART program. With increasing use of ARV, these results highlight the importance of drug resistance monitoring in Tanzania

Prader-Willi syndrome: A primer for clinicians

The advent of sensitive genetic testing modalities for the diagnosis of Prader-Willi syndrome has helped to define not only the phenotypic features of the syndrome associated with the various genotypes but also to anticipate clinical and psychological problems that occur at each stage during the life span. With advances in hormone replacement therapy, particularly growth hormone children born in circumstances where therapy is available are expected to have an improved quality of life as compared to those born prior to growth hormone

Going Deeper: Metagenome of a Hadopelagic Microbial Community

The paucity of sequence data from pelagic deep-ocean microbial assemblages has severely restricted molecular exploration of the largest biome on Earth. In this study, an analysis is presented of a large-scale 454-pyrosequencing metagenomic dataset from a hadopelagic environment from 6,000 m depth within the Puerto Rico Trench (PRT). A total of 145 Mbp of assembled sequence data was generated and compared to two pelagic deep ocean metagenomes and two representative surface seawater datasets from the Sargasso Sea. In a number of instances, all three deep metagenomes displayed similar trends, but were most magnified in the PRT, including enrichment in functions for two-component signal transduction mechanisms and transcriptional regulation. Overrepresented transporters in the PRT metagenome included outer membrane porins, diverse cation transporters, and di- and tri-carboxylate transporters that matched well with the prevailing catabolic processes such as butanoate, glyoxylate and dicarboxylate metabolism. A surprisingly high abundance of sulfatases for the degradation of sulfated polysaccharides were also present in the PRT. The most dramatic adaptational feature of the PRT microbes appears to be heavy metal resistance, as reflected in the large numbers of transporters present for their removal. As a complement to the metagenome approach, single-cell genomic techniques were utilized to generate partial whole-genome sequence data from four uncultivated cells from members of the dominant phyla within the PRT, Alphaproteobacteria, Gammaproteobacteria, Bacteroidetes and Planctomycetes. The single-cell sequence data provided genomic context for many of the highly abundant functional attributes identified from the PRT metagenome, as well as recruiting heavily the PRT metagenomic sequence data compared to 172 available reference marine genomes. Through these multifaceted sequence approaches, new insights have been provided into the unique functional attributes present in microbes residing in a deeper layer of the ocean far removed from the more productive sun-drenched zones above

Is there a common water-activity limit for the three domains of life?

Archaea and Bacteria constitute a majority of life systems on Earth but have long been considered inferior to Eukarya in terms of solute tolerance. Whereas the most halophilic prokaryotes are known for an ability to multiply at saturated NaCl (water activity (a w) 0.755) some xerophilic fungi can germinate, usually at high-sugar concentrations, at values as low as 0.650-0.605 a w. Here, we present evidence that halophilic prokayotes can grow down to water activities of <0.755 for Halanaerobium lacusrosei (0.748), Halobacterium strain 004.1 (0.728), Halobacterium sp. NRC-1 and Halococcus morrhuae (0.717), Haloquadratum walsbyi (0.709), Halococcus salifodinae (0.693), Halobacterium noricense (0.687), Natrinema pallidum (0.681) and haloarchaeal strains GN-2 and GN-5 (0.635 a w). Furthermore, extrapolation of growth curves (prone to giving conservative estimates) indicated theoretical minima down to 0.611 a w for extreme, obligately halophilic Archaea and Bacteria. These were compared with minima for the most solute-tolerant Bacteria in high-sugar (or other non-saline) media (Mycobacterium spp., Tetragenococcus halophilus, Saccharibacter floricola, Staphylococcus aureus and so on) and eukaryotic microbes in saline (Wallemia spp., Basipetospora halophila, Dunaliella spp. and so on) and high-sugar substrates (for example, Xeromyces bisporus, Zygosaccharomyces rouxii, Aspergillus and Eurotium spp.). We also manipulated the balance of chaotropic and kosmotropic stressors for the extreme, xerophilic fungi Aspergillus penicilloides and X. bisporus and, via this approach, their established water-activity limits for mycelial growth (∼0.65) were reduced to 0.640. Furthermore, extrapolations indicated theoretical limits of 0.632 and 0.636 a w for A. penicilloides and X. bisporus, respectively. Collectively, these findings suggest that there is a common water-activity limit that is determined by physicochemical constraints for the three domains of life