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"Williams, Charles C"
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Wait finds C. K. Williams by turns ruminative, stalked by \"the conscience-beast, who harries me,\" and \"riven by idiot vigor, voracious as the youth I was for whom everything was going too slowly, too slowly.\" Poems about animals and rural life are set hard by poems about shrapnel in Iraq and sudden desire on the Paris Mâetro; grateful invocations of Herbert and Hopkins give way to fierce negotiations with the shades of Coleridge, Dostoevsky, and Celan. What the poems share is their setting in the cool, spacious, spotlit, book-lined place that is Williams's consciousness, a place whose workings he has rendered for fifty years with inimitable candor and style.
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LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells
Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of
Lrig1
in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.
How neural stem cells can transition between states of proliferation and quiescence is unclear. Here, the authors identify Lrig1 as a specific marker for the primed quiescent state and demonstrate that Lrig1 maintains cells in a quiescent state via modulation of the EGFR pathway.
Journal Article
Squat Jump Movement Onset Thresholds Influence on Kinetics and Kinematics
Background of Study: Differing movement onset thresholds have been used when analyzing the squat jump movement from force-time data obtained from a force platform. This makes comparisons difficult between investigations as this will impact the amount of the force-time curve that is analyzed. Objective: Thus, study examined the effect onset threshold had on kinetic and kinematic variables used in the assessment of the squat jump. Methods: Using a within-subject study design, fifteen recreational trained males performed three trials of squat jumps on a force platform. Each trial was analyzed using one of five different onset thresholds (2.5% SW, 5% SW, 10% SW, 20N, 5SD). Force, velocity, and power, as well as time to peak force, velocity, power and jump height were calculated using the vertical force data obtain from the force plate. Reliability was assessed using intraclass correlation coefficients and coefficients of variation. A one-way ANOVA was used to examine the impact of onset thresholds on all variables of interest. Results: The use of 10% SW and 5SD met minimum reliability criteria for all variables. Temporal related variables were impact to the greatest extent by differing thresholds with large (d > 1.20) significant differences. 10% SW showed the highest mean values of force, velocity, and power. Conclusions: The use of 5SD of the weighting phase is recommended as this showed high level of both absolute and relative reliability in addition to preserving a large portion of the force – time curve to be used in the analysis.
Journal Article
Neurophysiology of Drosophila Models of Parkinson's Disease
We provide an insight into the role Drosophila has played in elucidating neurophysiological perturbations associated with Parkinson’s disease- (PD-) related genes. Synaptic signalling deficits are observed in motor, central, and sensory systems. Given the neurological impact of disease causing mutations within these same genes in humans the phenotypes observed in fly are of significant interest. As such we observe four unique opportunities provided by fly nervous system models of Parkinson’s disease. Firstly, Drosophila models are instrumental in exploring the mechanisms of neurodegeneration, with several PD-related mutations eliciting related phenotypes including sensitivity to energy supply and vesicular deformities. These are leading to the identification of plausible cellular mechanisms, which may be specific to (dopaminergic) neurons and synapses rather than general cellular phenotypes. Secondly, models show noncell autonomous signalling within the nervous system, offering the opportunity to develop our understanding of the way pathogenic signalling propagates, resembling Braak’s scheme of spreading pathology in PD. Thirdly, the models link physiological deficits to changes in synaptic structure. While the structure-function relationship is complex, the genetic tractability of Drosophila offers the chance to separate fundamental changes from downstream consequences. Finally, the strong neuronal phenotypes permit relevant first in vivo drug testing.
Journal Article
The Impact of Not Having a Periodized Strength Training Program on Baseball Hitting Metrics in Collegiate Baseball Players
Background: Strength training programs are designed to enhance sport performance while reducing the risk of injury. Little is known regarding the impact of not completing a concurrent strength program during the fall season on baseball hitting performance in collegiate baseball players. Objective: The purpose of this study examined the influence an individualized hitting program has on hitting metrics during an 8-week fall season without a concurrent strength training program. Methodology: This experimental study design involved fifteen NCAA Division I baseball players completed the study using a Blast Motion sensor to track peak bat speed, peak hand speed, attack angle, vertical bat angle, on-plane efficiency, rotational acceleration, early connection, connection at impact, and time to contact. An 8-week hitting program was implemented where participants were instructed to hit off a tee placed in the middle of their respective strike zone. The program consisted of 30 maximal effort swings during week one and progressively increased by 5 swings every 2 weeks, concluding with 50 swings during week 8. Results: Paired samples t-tests analyzed all hitting metrics of interest before and after the 8-week fall season. Peak hand speed, vertical bat angle, and time to contact significantly decreased from pre-test values (p.05). No significant differences were seen in peak bat speed, attack angle, on-plane efficiency, rotational acceleration and connection at impact between pre-and post-test measurements (p.05). Conclusions: Results from this study support the need to complement sport practice with periodized strength training with the aims of improving sport specific skills.
Journal Article
Randomized-controlled phase II trial of salvage chemotherapy after immunization with a TP53-transfected dendritic cell-based vaccine (Ad.p53-DC) in patients with recurrent small cell lung cancer
Small cell lung cancer TP53 mutations lead to expression of tumor antigens that elicits specific cytotoxic T-cell immune responses. In this phase II study, dendritic cells transfected with wild-type TP53 (vaccine) were administered to patients with extensive-stage small cell lung cancer after chemotherapy. Patients were randomized 1:1:1 to arm A (observation), arm B (vaccine alone), or arm C (vaccine plus all-trans-retinoic acid). Vaccine was administered every 2 weeks (3 times), and all patients were to receive paclitaxel at progression. Our primary endpoint was overall response rate (ORR) to paclitaxel. The study was not designed to detect overall response rate differences between arms. Of 69 patients enrolled (performance status 0/1, median age 62 years), 55 were treated in stage 1 (18 in arm A, 20 in arm B, and 17 in arm C) and 14 in stage 2 (arm C only), per 2-stage Simon Minimax design. The vaccine was safe, with mostly grade 1/2 toxicities, although 1 arm-B patient experienced grade 3 fatigue and 8 arm-C patients experienced grade 3 toxicities. Positive immune responses were obtained in 20% of arm B (95% confidence interval [CI], 5.3–48.6) and 43.3% of arm C (95% CI 23.9–65.1). The ORRs to the second-line chemotherapy (including paclitaxel) were 15.4% (95% CI 2.7–46.3), 16.7% (95% CI 2.9–49.1), and 23.8% (95% CI 9.1–47.5) for arms A, B, and C, with no survival differences between arms. Although our vaccine failed to improve ORRs to the second-line chemotherapy, its safety profile and therapeutic immune potential remain. Combinations with the other immunotherapeutic agents are reasonable options.
Journal Article