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Stability of Wake-Sleep Cycles Requires Robust Degradation of the PERIOD Protein
D’Alessandro, Matthew,Beesley, Stephen,Kim, Jae Kyoung,Jones, Zachary,Chen, Rongmin,Wi, Julie,Kyle, Kathleen,Vera, Daniel,Pagano, Michele,Nowakowski, Richard,Lee, Choogon Elsevier 2017 Current biology Vol.27 No.22
<P><B>Summary</B></P> <P>Robustness in biology is the stability of phenotype under diverse genetic and/or environmental perturbations. The circadian clock has remarkable stability of period and phase that—unlike other biological oscillators—is maintained over a wide range of conditions. Here, we show that the high fidelity of the circadian system stems from robust degradation of the clock protein PERIOD. We show that PERIOD degradation is regulated by a balance between ubiquitination and deubiquitination, and that disruption of this balance can destabilize the clock. In mice with a loss-of-function mutation of the E3 ligase gene <I>β-Trcp2</I>, the balance of PERIOD degradation is perturbed and the clock becomes dramatically unstable, presenting a unique behavioral phenotype unlike other circadian mutant animal models. We believe that our data provide a molecular explanation for how circadian phases, such as wake-sleep onset times, can become unstable in humans, and we present a unique mouse model to study human circadian disorders with unstable circadian rhythm phases.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Nonlinear degradation of PER is required for the robustness of circadian rhythms </LI> <LI> PER degradation is regulated by a balance between ubiquitination and deubiquitination </LI> <LI> Disrupting this balance causes irregular wake-sleep cycles in mice </LI> </UL> </P>
Ashley Smith,Siyong Kim,Kathleen Hintenlang,Stephen Ko,Laura Vallow,Jennifer Peterson,David Hintenlang,Michael Heckman,Steven Buskirk 한국의학물리학회 2014 의학물리 Vol.25 No.4
Dynamic conformal arc therapy (DCAT) and flattening-filter-free (FFF) beams are commonly adopted for efficientconformal dose delivery in stereotactic body radiation therapy (SBRT). Off-axis geometry (OAG) may benecessary to obtain full gantry rotation without collision, which has been shown to be beneficial for peripheraltargets using flattened beams. In this study dose distributions in OAG using FFF were evaluated and the effectof mechanical rotation induced uncertainty was investigated. For the lateral target, OAG evaluation, sphere targets(2, 4, and 6 cm diameter) were placed at three locations (central axis, 3 cm off-axis, and 6 cm off-axis) ina representative patient CT set. For each target, DCAT plans under the same objective were obtained for 6X,6FFF, 10X, and 10FFF. The parameters used to evaluate the quality of the plans were homogeneity index (HI),conformality indices (CI), and beam on time (BOT). Next, the mechanical rotation induced uncertainty wasevaluated using five SBRT patient plans that were randomly selected from a group of patients with laterally locatedtumors. For each of the five cases, a plan was generated using OAG and CAG with the same prescription andcoverage. Each was replanned to account for one degree collimator/couch rotation errors during delivery. Prescription isodose coverage, CI, and lung dose were evaluated. HI and CI values for the lateral target, OAGevaluation were similar for flattened and unflattened beams; however, 6FFF provided slightly better values than10FFF in OAG. For all plans the HI and CI were acceptable with the maximum difference between flattened andunflattend beams being 0.1. FFF beams showed better conformality than flattened beams for low doses andsmall targets. Variation due to rotational error for isodose coverage, CI, and lung dose was generally smallerfor CAG compared to OAG, with some of these comparisons reaching statistical significance. However, thevariations in dose distributions for either treatment technique were small and may not be clinically significant. FFF beams showed acceptable dose distributions in OAG. Although 10FFF provides more dramatic BOTreduction, it generally provides less favorable dosimetric indices compared to 6FFF in OAG. Mechanicaluncertainty in collimator and couch rotation had an increased effect for OAG compared to CAG; however, thevariations in dose distributions for either treatment technique were minimal.
Smith, Ashley,Kim, Siyong,Serago, Christopher,Hintenlang, Kathleen,Ko, Stephen,Vallow, Laura,Peterson, Jennifer,Hintenlang, David,Heckman, Michael,Buskirk, Steven Korean Society of Medical Physics 2014 의학물리 Vol.25 No.4
Dynamic conformal arc therapy (DCAT) and flattening-filter-free (FFF) beams are commonly adopted for efficient conformal dose delivery in stereotactic body radiation therapy (SBRT). Off-axis geometry (OAG) may be necessary to obtain full gantry rotation without collision, which has been shown to be beneficial for peripheral targets using flattened beams. In this study dose distributions in OAG using FFF were evaluated and the effect of mechanical rotation induced uncertainty was investigated. For the lateral target, OAG evaluation, sphere targets (2, 4, and 6 cm diameter) were placed at three locations (central axis, 3 cm off-axis, and 6 cm off-axis) in a representative patient CT set. For each target, DCAT plans under the same objective were obtained for 6X, 6FFF, 10X, and 10FFF. The parameters used to evaluate the quality of the plans were homogeneity index (HI), conformality indices (CI), and beam on time (BOT). Next, the mechanical rotation induced uncertainty was evaluated using five SBRT patient plans that were randomly selected from a group of patients with laterally located tumors. For each of the five cases, a plan was generated using OAG and CAG with the same prescription and coverage. Each was replanned to account for one degree collimator/couch rotation errors during delivery. Prescription isodose coverage, CI, and lung dose were evaluated. HI and CI values for the lateral target, OAG evaluation were similar for flattened and unflattened beams; however, 6FFF provided slightly better values than 10FFF in OAG. For all plans the HI and CI were acceptable with the maximum difference between flattened and unflattend beams being 0.1. FFF beams showed better conformality than flattened beams for low doses and small targets. Variation due to rotational error for isodose coverage, CI, and lung dose was generally smaller for CAG compared to OAG, with some of these comparisons reaching statistical significance. However, the variations in dose distributions for either treatment technique were small and may not be clinically significant. FFF beams showed acceptable dose distributions in OAG. Although 10FFF provides more dramatic BOT reduction, it generally provides less favorable dosimetric indices compared to 6FFF in OAG. Mechanical uncertainty in collimator and couch rotation had an increased effect for OAG compared to CAG; however, the variations in dose distributions for either treatment technique were minimal.
Cha, Sang-Ho,Bandaranayaka-Mudiyanselage, Carey,Bandaranayaka-Mudiyanselage, Chandima B.,Ajiththos, Dharani,Yoon, Kyoung-Jin,Gibson, Kathleen A.,Yu, Ji-Eun,Cho, In-Soo,Lee, Stephen S.,Chung, Chungwon The Korean Society of Veterinary Science 2018 大韓獸醫學會誌 Vol.58 No.1
A preliminary study into the protective mechanisms of adaptive immunity against porcine reproductive and respiratory syndrome virus (PRRSV) in piglets (n = 9) born to a gilt challenged intranasally with a type-2 PRRSV. Immune parameters (neutralizing antibodies, $CD3^+CD4^+$, $CD3^+CD8^+$, $CD3^+CD4^+CD8^+$ T-lymphocytes, and PRRSV-specific interferon $(IFN)-{\gamma}$ secreting T-lymphocytes) were compared with infection parameters (macro- and microscopic lung lesion, and PRRSV-infected porcine alveolar macrophages ($CD172{\alpha}^+PRRSV-N^+\;PAM$) as well as with plasma and lymphoid tissue viral loads. Percentages of three T-lymphocyte phenotypes in 14-days post-birth (dpb) peripheral blood mononuclear cell (PBMC) had significant negative correlations with percentages of $CD172{\alpha}^+PRRSV-N^+\;PAM$ (p < 0.05) as well as with macroscopic lung lesion (p < 0.01). Plasma and tissue viral loads had significant (p < 0.05) negative correlations with $CD3^+CD4^+CD8^+$ T-lymphocyte percentage in PBMC. Frequencies of $CD3^+CD8^+$ and $CD3^+CD4^+$ T-lymphocytes in 14-dpb PBMC had significant negative correlations with of lymph node (p = 0.04) and lung (p = 0.002) viral loads. $IFN-{\gamma}$-secreting T-lymphocytes frequency had a significant negative correlation with gross lung lesion severity (p = 0.002). However, neutralizing antibody titers had no significant negative correlation (p > 0.1) with infection parameters. The results indicate that T-lymphocytes contribute to controlling PRRSV replication in young piglets born after in-utero infection.