Contextual control of orienting eye-head gaze shifts in the monkey

Vision is one of the principal methods used by primates to acquire information about the surrounding environment. As a result, both humans and monkeys have a highly evolved oculomotor system that functions to rapidly relocate the line of sight to areas of interest. These orienting movements are called gaze shifts. Gaze shifts commonly include the coordinated movement of the eyes-in-head and the head-in-space. This thesis examines the muscular and neural control of orienting head movements. The contextual control of behavior is important as it allows one to act appropriately in response to different situations. A common task used to examine the contextual control of behavior is the pro- and anti-saccade task. Pro-saccades simply require a subject to look towards a stimulus. Anti-saccades require a subject to inhibit a movement towards a stimulus in favor of a volitional movement to the diametrically opposite position. This task is can reveal capabilities of the oculomotor system and its response to varying behavioral states. To understand the neuromuscular control of orienting head movements during various tasks, we recorded the electromyographic (EMG) activity in ten turner and extensor neck muscles. Recording neck EMGs provides an objective and precise measurement of the neural signals received at the neck muscles, circumventing some of the structural and biomechanical complexities of head motion. Chapter two examines neck muscle activity in a pro- and anti-saccade task. Many neural areas and certain neck muscles become active in response to the presentation of a visual stimulus. This visual response on the neck muscles can result in a head turning synergy that orients the head towards the stimulus. By dissociating the typical stimulus-response paradigm, we can analyze if and how the bottom-up visual activity changes in relation to different contexts. A number of cortical and subcortical areas are involved in the generation of correct anti-saccades. By combining EMG recordings while subjects perform this task, we can examine whether top-down task-related activity is present in the neck muscles. This experiment could reveal flexibility in the eye-head gaze shift system that has previously gone unreported. Chapter three will elucidate the supplementary eye fields (SEF) role in the control of orienting eye-head gaze shifts. Neck EMG activity was recorded while providing electrical microstimulation to the SEF in a pro-saccade task The combination of EMGs and SEF stimulation is the first to systematically study the cephalomotor command during head-restrained and head-unrestrained orienting eye-head gaze shifts. The evoked activity of EMGs could reveal functional properties of the neural circuitry between the SEF and the motor related neurons responsible for eye and head movements. The timing and metrics of evoked EMG activity and eye-head gaze shifts are consistent with other frontal areas suggesting a functional role of the frontal cortex in influencing eye-head gaze shifts. Chapter four will combine EMG recordings with SEF stimulation during a pro- and anti-saccade task. The SEF is thought to serve as an interface between high-level cognitive control of gaze shifts and low-level activity associated with the production of saccades. As will be described later in the thesis, neck muscles demonstrate top-down task related activity during anti-saccades. The SEF is a likely candidate for the generation of task-dependent signals observed during anti-saccades. By combining SEF stimulation and neck EMGs in an anti-saccade task, we can reveal if neck muscle activity is consistent with a role for the SEF in the contextual control of eye-head gaze shifts. In summary, this thesis identifies three central point’s concerning orienting eye-head gaze shifts. First, chapter two emphasizes the complex interaction of sensori-motor processes in orienting head movements. Second, chapter three attests to the consistent nature of certain areas in frontal cortex and their impact on eye-head gaze shifts. Finally, chapter four demonstrates a potential candidate for influencing the contextual control of cephalomotor commands. Combined, these results highlight the complex interactions of sensori-motor transformations in the motor periphery and emphasize the parallel nature of information processing during the contextual control of eye-head gaze shifts

A target repurposing approach identifies N-myristoyltransferase as a new candidate drug target in filarial nematodes

Myristoylation is a lipid modification involving the addition of a 14-carbon unsaturated fatty acid, myristic acid, to the N-terminal glycine of a subset of proteins, a modification that promotes their binding to cell membranes for varied biological functions. The process is catalyzed by myristoyl-CoA:protein N-myristoyltransferase (NMT), an enzyme which has been validated as a drug target in human cancers, and for infectious diseases caused by fungi, viruses and protozoan parasites. We purified Caenorhabditis elegans and Brugia malayi NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and peptide substrates. Biochemical and structural analyses both revealed that the nematode enzymes are canonical NMTs, sharing a high degree of conservation with protozoan NMT enzymes. Inhibitory compounds that target NMT in protozoan species inhibited the nematode NMTs with IC50 values of 2.5-10 nM, and were active against B. malayi microfilariae and adult worms at 12.5 µM and 50 µM respectively, and C. elegans (25 µM) in culture. RNA interference and gene deletion in C. elegans further showed that NMT is essential for nematode viability. The effects observed are likely due to disruption of the function of several downstream target proteins. Potential substrates of NMT in B. malayi are predicted using bioinformatic analysis. Our genetic and chemical studies highlight the importance of myristoylation in the synthesis of functional proteins in nematodes and have shown for the first time that NMT is required for viability in parasitic nematodes. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against nematode diseases including filariasis

Magazine and reader constructions of 'metrosexuality' and masculinity: a membership categorisation analysis

Since the launch of men's lifestyle magazines in the 1980s, academic literature has predominantly focused on them as a cultural phenomenon arising from entrepreneurial and commercial initiatives and/or as cultural texts that proffer representations of masculinity such as 'new lad' and 'new dad'. This paper steps aside from the focus on culture and, instead, treats magazine content as a discursive space in which gender and sexuality are oriented to, negotiated, and accomplished within and beyond the magazine itself (i.e. through readers' responses). Specifically, membership categorisation analysis is deployed to explore how the relatively new (and perhaps alternative) category for men - 'metrosexual' - is presented and received. Our analysis suggests that masculinity concerns are central in debates about 'metrosexuality', with self-identified 'metrosexuals' invoking heterosexual prowess and self-respect on the one hand, and critics (e.g. selfidentified 'real men') lamenting 'metrosexuality' for its perceived effeminacy and lack of authenticity on the other. Implications for understanding contemporary masculinities are discussed

The elusive stellar halo of the Triangulum galaxy

The stellar haloes of large galaxies represent a vital probe of the processes of galaxy evolution. They are the remnants of the initial bouts of star formation during the collapse of the protogalactic cloud, coupled with imprint of ancient and ongoing accretion events. Previously, we have reported the tentative detection of a possible, faint, extended stellar halo in the Local Group spiral, the Triangulum galaxy (M33). However, the presence of substructure surrounding M33 made interpretation of this feature difficult. Here, we employ the final data set from the Pan-Andromeda Archaeological Survey, combined with an improved calibration and a newly derived contamination model for the region to revisit this claim. With an array of new fitting algorithms, fully accounting for contamination and the substantial substructure beyond the prominent stellar disc in M33, we reanalyse the surrounds to separate the signal of the stellar halo and the outer halo substructure. Using more robust search algorithms, we do not detect a large-scale smooth stellar halo and place a limit on the maximum surface brightness of such a feature of μV = 35.5 mag arcsec−2, or a total halo luminosity of L < 106 L⊙

Aging syndrome genes and premature coronary artery disease

BACKGROUND: Vascular disease is a feature of aging, and coronary vascular events are a major source of morbidity and mortality in rare premature aging syndromes. One such syndrome is caused by mutations in the lamin A/C (LMNA) gene, which also has been implicated in familial insulin resistance. A second gene related to premature aging in man and in murine models is the KLOTHO gene, a hypomorphic variant of which (KL-VS) is significantly more common in the first-degree relatives of patients with premature coronary artery disease (CAD). We evaluated whether common variants at the LMNA or KLOTHO genes are associated with rigorously defined premature CAD. METHODS: We identified 295 patients presenting with premature acute coronary syndromes confirmed by angiography. A control group of 145 patients with no evidence of CAD was recruited from outpatient referral clinics. Comprehensive haplotyping of the entire LMNA gene, including the promoter and untranslated regions, was performed using a combination of TaqMan(® )probes and direct sequencing of 14 haplotype-tagging single nucleotide polymorphisms (SNPs). The KL-VS variant of the KLOTHO gene was typed using restriction digest of a PCR amplicon. RESULTS: Two SNPs that were not in Hardy Weinberg equilibrium were excluded from analysis. We observed no significant differences in allele, genotype or haplotype frequencies at the LMNA or KLOTHO loci between the two groups. In addition, there was no evidence of excess homozygosity at the LMNA locus. CONCLUSION: Our data do not support the hypothesis that premature CAD is associated with common variants in the progeroid syndrome genes LMNA and KLOTHO

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population

Genetic variation across the HLA is known to influence renal‐transplant outcome. However, the impact of genetic variation beyond the HLA is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with post‐transplant eGFR at different time‐points, out to 5‐years post‐transplantation. We conducted GWAS meta‐analyses across 10,844 donors and recipients from five European ancestry cohorts. We also analysed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with non‐transplant eGFR, on post‐transplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1‐year post‐transplant. 32% of the variability in eGFR at 1‐year post‐transplant was explained by our model containing clinical covariates (including weights for death/graft‐failure), principal components and combined donor‐recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR post‐transplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a post‐transplant context. Despite PRS being a significant predictor of eGFR post‐transplant, the effect size of common genetic factors is limited compared to clinical variables

Minimal residual disease in Myeloma: Application for clinical care and new drug registration

The development of novel agents has transformed the treatment paradigm for multiple myeloma, with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow–based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in patients with multiple myeloma. Complementary liquid biopsy–based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid–based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real-world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory multiple myeloma, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in multiple myeloma is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes

Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips

The Brassica napus 60K Illumina Infinium™ SNP array has had huge international uptake in the rapeseed community due to the revolutionary speed of acquisition and ease of analysis of this high-throughput genotyping data, particularly when coupled with the newly available reference genome sequence. However, further utilization of this valuable resource can be optimized by better understanding the promises and pitfalls of SNP arrays. We outline how best to analyze Brassica SNP marker array data for diverse applications, including linkage and association mapping, genetic diversity and genomic introgression studies. We present data on which SNPs are locus-specific in winter, semi-winter and spring B. napus germplasm pools, rather than amplifying both an A-genome and a C-genome locus or multiple loci. Common issues that arise when analyzing array data will be discussed, particularly those unique to SNP markers and how to deal with these for practical applications in Brassica breeding applications

FUTURE PERSPECTIVES IN MELANOMA RESEARCH. Meeting report from the “Melanoma Research: a bridge from Naples to the World. Napoli, December 5th–6 th2011”

After more than 30 years, landmark progress has been made in the treatment of cancer, and melanoma in particular, with the success of new molecules such as ipilimumab, vemurafenib and active specific immunization

The NANOGrav 15-year Data Set: Observations and Timing of 68 Millisecond Pulsars

We present observations and timing analyses of 68 millisecond pulsars (MSPs) comprising the 15-year data set of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav). NANOGrav is a pulsar timing array (PTA) experiment that is sensitive to low-frequency gravitational waves. This is NANOGrav's fifth public data release, including both "narrowband" and "wideband" time-of-arrival (TOA) measurements and corresponding pulsar timing models. We have added 21 MSPs and extended our timing baselines by three years, now spanning nearly 16 years for some of our sources. The data were collected using the Arecibo Observatory, the Green Bank Telescope, and the Very Large Array between frequencies of 327 MHz and 3 GHz, with most sources observed approximately monthly. A number of notable methodological and procedural changes were made compared to our previous data sets. These improve the overall quality of the TOA data set and are part of the transition to new pulsar timing and PTA analysis software packages. For the first time, our data products are accompanied by a full suite of software to reproduce data reduction, analysis, and results. Our timing models include a variety of newly detected astrometric and binary pulsar parameters, including several significant improvements to pulsar mass constraints. We find that the time series of 23 pulsars contain detectable levels of red noise, 10 of which are new measurements. In this data set, we find evidence for a stochastic gravitational-wave background.Comment: 90 pages, 74 figures, 6 tables; published in Astrophysical Journal Letters as part of Focus on NANOGrav's 15-year Data Set and the Gravitational Wave Background. For questions or comments, please email [email protected]