Cancer-associated TERT promoter mutations abrogate telomerase silencing.

Mutations in the human telomerase reverse transcriptase (TERT) promoter are the most frequent non-coding mutations in cancer, but their molecular mechanism in tumorigenesis has not been established. We used genome editing of human pluripotent stem cells with physiological telomerase expression to elucidate the mechanism by which these mutations contribute to human disease. Surprisingly, telomerase-expressing embryonic stem cells engineered to carry any of the three most frequent TERT promoter mutations showed only a modest increase in TERT transcription with no impact on telomerase activity. However, upon differentiation into somatic cells, which normally silence telomerase, cells with TERT promoter mutations failed to silence TERT expression, resulting in increased telomerase activity and aberrantly long telomeres. Thus, TERT promoter mutations are sufficient to overcome the proliferative barrier imposed by telomere shortening without additional tumor-selected mutations. These data establish that TERT promoter mutations can promote immortalization and tumorigenesis of incipient cancer cells

Human Performance Assessments in Cadet Populations

This study assessed potential physiological differences between the Ranger Challenge (RC) Competition team and junior year cadets in an Army Reserve Officer Training Corps (ROTC) program. The method included: RC (m = 11, f = 2) and junior year cadets (m = 7, f = 3) were assessed in the following areas: 1) quickness and agility (5-10-5 shuttle run), 2) total-body power (standing broad jump), and 3) grip strength (hand grip dynamometry) assessed. The 5-10-5 shuttle run was performed twice (opening once to the left and once to the right). The standing broad jump required that cadets stand with their toes behind a line, perform a maximum of three preparatory movements, triple extend their knees, hips, and ankles while using their upper body to propel them as far forward as possible. After the jump the distanced reached was measured from the line to the heel of the nearest foot. Hand grip dynamometry was performed once on each hand. The cadet held the dynamometer out to his or her side and squeezed it as they lowered it to their hip. The results were that there were no significant differences between groups for the 5-10-5 shuttle run (p = 0.91), standing broad jump (p = 0.49), or grip strength (p = 0.31). RC did not outperform

Multiple functions of Na/K-ATPase in dopamine-induced salivation of the Blacklegged tick, Ixodes scapularis

Citation: Kim, D., Urban, J., Boyle, D. L., & Park, Y. (2016). Multiple functions of Na/K-ATPase in dopamine-induced salivation of the Blacklegged tick, Ixodes scapularis. Scientific Reports, 6, 13. doi:10.1038/srep21047Control of salivary secretion in ticks involves autocrine dopamine activating two dopamine receptors: D1 and Invertebrate-specific D1-like dopamine receptors. In this study, we investigated Na/K-ATPase as an important component of the secretory process. Immunoreactivity for Na/K-ATPase revealed basal infolding of lamellate cells in type-I, abluminal interstitial (epithelial) cells in type-II, and labyrinth-like infolding structures opening towards the lumen in type-III acini. Ouabain (10 mu mol l(-1)), a specific inhibitor of Na/K-ATPase, abolished dopamine-induced salivary secretion by suppressing fluid transport in type III acini. At 1 mu mol l(-1), ouabain, the secreted saliva was hyperosmotic. This suggests that ouabain also inhibits an ion resorptive function of Na/K-ATPase in the type I acini. Dopamine/ouabain were not involved in activation of protein secretion, while dopamine-induced saliva contained constitutively basal level of protein. We hypothesize that the dopamine-dependent primary saliva formation, mediated by Na/K-ATPase in type III and type II acini, is followed by a dopamine-independent resorptive function of Na/K-ATPase in type I acini located in the proximal end of the salivary duct

A Unified Approach to Carbocyclic Frameworks: DTDA Sequences in Total Synthesis

[3]Dendralene is a small π-­rich hydrocarbon that is capable of taking part in a wide range of chemical reactions, not least of which is the diene transmissive Diels–Alder (DTDA) reaction sequence. Unfortunately, the synthesis of this molecule relies on highly toxic and commercially unavailable intermediates, namely chloroprene. Chapter 1 of this thesis details a new synthetic approach to [3]dendralene via a double cross coupling reaction beginning with 1,1-­‐‑ dichloroethylene and vinyl magnesium bromide. This work was extended to the synthesis of a variety of symmetrically substituted [3]dendralenes. Chapter 2 details the exploration of the Diels–Alder reactivity of [3]dendralene. While there has been some experimental work examining [3]dendralene in DTDA sequences, these have tended to focus on symmetrical and highly reactive dienophiles. This chapter describes the use of unsymmetrical dienophiles, which are either cyclic or acyclic in nature. This enables the synthesis of a range of polycyclic frameworks in just two steps. Through this methodology, the synthesis of bicyclic, linear tricyclic, angular tricyclic and angular tetracyclic structures is possible. The angular tetracyclic framework mentioned above is present in a number of natural products, including marine sponge derived compounds xestoquinone and halenaquinone. Chapter 3 presents a comprehensive review into previous syntheses of these two natural products as well as briefly examining work towards related natural products. Finally, Chapter 4 details our attempts to apply a DTDA reaction sequence beginning with [3]dendralene to the total synthesis of the natural product xestoquinone. [3]dendralene was reacted sequentially with two carbocyclic dienophiles before a series of functional group manipulations led to an advanced precursor of the targeted natural product

Lithium bis­(2-methyl­lactato)borate monohydrate

The title compound {systematic name: poly[[aqua­lithium]-μ-3,3,8,8-tetra­methyl-1,4,6,9-tetra­oxa-5λ4-borataspiro­[4.4]nonane-2,7-dione]}, [Li(C8H12BO6)(H2O)]n (LiBMLB), forms a 12-membered macrocycle, which lies across a crystallographic inversion center. The lithium cations are pseudo-tetra­hedrally coordinated by three methyl­lactate ligands and a water mol­ecule. The asymmetric units couple across crystallographic inversion centers, forming the 12-membered macrocycles. These macrocycles, in turn, cross-link through the Li+ cations, forming an infinite polymeric structure in two dimensions parallel to (101)

Characterization and comparison of lesions on ornamental sweetpotato 'Blackie', tomato 'Maxifort', interspecific geranium 'Caliente Coral', and bat-faced cuphea 'Tiny Mice'.

Many plant species are prone to physiological disorders in which lesions develop on the leaf tissue. Nomenclature for such lesions has included intumescences, excrescences, neoplasms, galls, genetic tumors, enations, and oedemata. Interchangeably using these terms causes confusion as to whether these names refer to the same or different disorders. Two of the most commonly used names are oedema and intumescence. The objective of this research was to characterize the development of lesions on ornamental sweetpotato (Ipomoea batatas ‘Blackie’), tomato (Solanum lycopersicum ‘Maxifort’), interspecific hybrid geranium(Pelargonium· ‘CalienteCoral’), and bat-faced cuphea (Cuphea llavea ‘TinyMice’) to determine similarities and differences in morphology and nomenclature among these physiological disorders. Light microscopy was used to characterize differences in cross-sectional height, width, and area of lesions on each species. Additionally, leaf tissue samples were embedded in paraffin, and 10-mm cross-sections were stained with Toluidine blue O and observed using light microscopy to identify specific cell layers involved with lesion development. Field emission scanning electron microscopy (SEM) and digital photography were used to observe the microscopic and macroscopic stages of lesion development, respectively, on each species. The lesions observed on ornamental sweetpotato were significantly greater in height and area than on the other three species, whereas tomato lesions were significantly greater in width. Lesions on ornamental sweetpotato and bat-faced cuphea occurred predominantly on the adaxial surface of the leaf, whereas lesions on geraniumand tomato occurred predominantly on the abaxial surface.With lesions on tomato, ornamental sweetpotato, and bat-faced cuphea, the epidermis was often subjected to the same hypertrophy apparent in the underlying parenchyma cells, ultimately allowing for greater cell expansion. However, in geranium, the epidermis resisted the expansion of the underlying cells, resulting in the eventual tearing of this tissue layer. Previous research indicates that lesion development on geranium is closely related to water status within the plant and may result in a wound response or provide a means of facilitated gas exchange. On the contrary, development of lesions on ornamental sweetpotato and tomato is believed to involve light quality. Based on these results and observations, two disorders occur across these species. The term "intumescence’’ should be used when referring to abnormal lesions on ornamental sweetpotato and tomato, and the term ‘‘oedema’’ should be used when referring to lesions on geranium. The term ‘‘intumescence’’ should also be used when referring to bat-faced cuphea lesions resulting from the morphological and anatomical aspects of these lesions closely resembling development on ornamental sweetpotato and tomato. Future research should investigate the role of light quality regarding development on this species

Harm avoidance is associated with progression of parkinsonism in community-dwelling older adults: a prospective cohort study

BACKGROUND: We tested the hypothesis that harm avoidance, a trait associated with behavioral inhibition, is associated with the rate of change in parkinsonism in older adults. METHODS: At baseline harm avoidance was assessed with a standard self-report instrument in 969 older people without dementia participating in the Rush Memory and Aging Project, a longitudinal community-based cohort study. Parkinsonism was assessed annually with a modified version of the motor section of the Unified Parkinson’s Disease Rating Scale (mUPDRS). RESULTS: Average follow-up was 5 years. A linear mixed-effects model controlling for age, sex and education showed that for an average participant (female, 80 years old at baseline, with 14 years of education and a harm avoidance score of 10), the overall severity of parkinsonism increased by about 0.05 unit/ year (Estimate, 0.054, S.E., 0.007, p <0.001) and that the level of harm avoidance was associated with the progression of parkinsonism (Estimate, 0.004, S.E., 0.001, p <0.001). Thus, for an average participant, every 6 point (~1 SD) increase in harm avoidance score at baseline, the rate of progression of parkinsonism increased about 50% compared to an individual with an average harm avoidance score. This amount of change in parkinsonism over the course of the study was associated with about a 5% increased risk of death. The association between harm avoidance and progression of parkinsonism persisted when controlling for cognitive function, depressive symptoms, loneliness, neuroticism, late-life cognitive, social and physical activities and chronic health conditions. CONCLUSION: A higher level of the harm avoidance trait is associated with a more rapid progression of parkinsonism in older adults

Poly[diacetonitrile­[μ3-difluoro­(oxalato)borato]sodium]

The title compound, [Na(C2BF2O4)(CH3CN)2]n, forms infinite two-dimensional layers running parallel to (010). The layers lie across crystallographic mirror planes at y = 1/4 and 3/4. The Na, B and two F atoms reside on these mirror planes. The Na+ cations are six-coordinate. Two equatorial coordination positions are occupied by acetonitrile mol­ecules. The other two equatorial coordination sites are occupied by the chelating O atoms from the difluoro­(oxalato)borate anion (DFOB−). The axial coordination sites are occupied by two F atoms from two different DFOB− anions

Lithium difluoro­(oxalato)borate tetra­methyl­ene sulfone disolvate

The title compound, Li+·C2BF2O4 −·2C4H8O2S, is a dimeric species, which resides across a crystallographic inversion center. The dimers form eight-membered rings containing two Li+ cations, which are joined by O2S sulfone linkages. The Li+ cations are ligated by four O atoms from the anions and solvent mol­ecules, forming a pseudo-tetra­hedral geometry. The exocyclic coordination sites are occupied by O atoms from the oxalate group of the difluoro­(oxalato)borate anion and an additional tetra­methyl­ene sulfone ligand