The arginine stimulation test: Timing of peak is not a helpful parameter in the diagnosis of growth hormone deficiency

Background: A typical peak timing in the glucagon stimulation test has been reported as an indication of growth hormone (GH) deficiency. Other stimulation tests have not been evaluated.Objective: To evaluate the clinical usefulness of peak timing in the arginine stimulation test (AST) for growth hormone deficiency.Methods: Retrospective review of 199 ASTs from one center. Outcomes included correlation of peak times with (a) frequency of deficient peak; (b) growth velocity standard deviation scores (GVSDSs); (c) other evidence of pituitary pathology; (d) results of confirmatory clonidine test; and (e) response to GH treatment.Results: The peak in 83/109 (76.14%) sufficient tests occurred at typical times vs. 45/72 (62.5%) deficient tests (p < 0.05). GVSDS on GH treatment was greater among patients with typical timing in the AST compared with atypical timing (2.67 +/- 0.59 vs. 0.46 +/- 1.17, p = 0.021). No other variable correlated significantly with AST timing.Conclusions: Timing of peak in the AST is not a clinically useful parameter

Cyclin C Regulated Oxidative Stress Responsive Transcriptome in Mus Musculus Embryonic Fibroblasts

The transcriptional changes that occur in response to oxidative stress help direct the decision to maintain cell viability or enter a cell death pathway. Cyclin C-Cdk8 is a conserved kinase that associates with the RNA polymerase II Mediator complex that stimulates or represses transcription depending on the locus. In response to oxidative stress, cyclin C, but not Cdk8, displays partial translocation into the cytoplasm. These findings open the possibility that cyclin C relocalization is a regulatory mechanism governing oxidative stress-induced transcriptional changes. In the present study, the cyclin C-dependent transcriptome was determined and compared to transcriptional changes occurring in oxidatively stresse

Snf1 Dependent Destruction of Med13 is Required for Programmed Cell Death Following Oxidative Stress in Yeast

All eukaryotic cells, when faced with unfavorable environmental conditions, have to decide whether to mount a survival or cell death response. The conserved cyclin C and its kinase partner Cdk8 play a key role in this decision. Both are members of the Cdk8 kinase module that, along with Med12 and Med13, associate with the core mediator complex of RNA polymerase II. In S. cerevisiae, oxidative stress triggers Med13 destruction1, which thereafter releases cyclin Ci nto the cytoplasm. Cytoplasmic cyclin C associates with mitochondria where it induces hyper-fragmentation and programmed cell death2. This suggests a model in which oxidative stress mediated destruction o fMed13 represents a key molecular switch which commits the cell to programmed cell death. Thus it is important to decipher the precise molecular mechanisms that control Med13 destruction following exposure to oxidative stress

The Role of MAPK and SCF in the Destruction of Med13 in Cyclin C Mediated Cell Death

In response to stress, the yeast1 and mammalian2 cyclin C translocate from the nucleus to the cytoplasm, where it associates with the GTPase Drp1/Dnm1 to drive mitochondrial fragmentation and apoptosis. Therefore, the decision to release cyclin C represents a key life or death decision. In unstressed cells, the cyclin C‐Cdk8 kinase regulates transcription by associating with the Mediator of RNA polymerase II. We previously reported that the Mediator component Med13 anchors cyclin C in the nucleus3. Loss of Med13 function leads to constitutive cytoplasmic localization of cyclin C, resulting in fragmented mitochondria, hypersensitivity to stress and mitochondrial dysfunction due to loss of mtDNA. Recently we showed that this molecular switch operates in a two-step process

Snf1 cooperates with the CWI MAPK pathway to mediate the degradation of Med13 following oxidative stress

Eukaryotic cells, when faced with unfavorable environmental conditions, mount either pro-survival or pro-death programs. The conserved cyclin C-Cdk8 kinase plays a key role in this decision. Both are members of the Cdk8 kinase module that, along with Med12 and Med13, associate with the core Mediator complex of RNA polymerase II. In Saccharomyces cerevisiae, oxidative stress triggers Med13 destruction, which releases cyclin C into the cytoplasm to promote mitochondrial fission and programmed cell death. The SCFGrr1 ubiquitin ligase mediates Med13 degradation dependent on the cell wall integrity pathway, MAPK Slt2. Here we show that the AMP kinase Snf1 activates a second SCFGrr1 responsive degron in Med13. Deletion of Snf1 resulted in nuclear retention of cyclin C and failure to induce mitochondrial fragmentation. This degron was able to confer oxidative-stress-induced destruction when fused to a heterologous protein in a Snf1 dependent manner. Although snf1∆ mutants failed to destroy Med13, deleting the degron did not prevent destruction. These results indicate that the control of Med13 degradation following H2O2 stress is complex, being controlled simultaneously by CWI and MAPK pathways

Alterations in the plasma proteome persist ten months after recovery from mild to moderate SARS-CoV-2 infection

BackgroundLimited data are available describing the effects of SARS-CoV-2 breakthrough infections on the plasma proteome.MethodsPCR-positive SARS-CoV-2 patients, enrolled in a natural history study, underwent analysis of the plasma proteome. A prospective cohort of 66 unvaccinated and 24 vaccinated persons with different degrees of infection severity were evaluated acutely (within 40 days of symptom onset), and at three and ten months. Comparisons based on vaccination status alone and unsupervised hierarchical clustering were performed. A second cohort of vaccinated Omicron patients were evaluated acutely and at ten months.ResultsAcutely, unvaccinated patients manifested overexpression of proteins involved in immune and inflammatory responses, while vaccinated patients exhibited adaptive immune responses without significant inflammation. At three and ten months, only unvaccinated patients had diminished but sustained inflammatory (C3b, CCL15, IL17RE) and immune responses (DEFA5,TREM1). Both groups had underexpression of pathways essential for cellular function, signaling, and angiogenesis (AKT1, MAPK14, HSPB1) across phases. Unsupervised clustering, based on protein expression, identified four groups of patients with variable vaccination rates demonstrating that additional clinical factors influence the plasma proteome. The proteome of vaccinated Omicron patients did not differ from vaccinated pre-Omicron patients.ConclusionsVaccination attenuates the inflammatory response to SARS-CoV-2 infection across phases. However, at ten months after symptom onset, changes in the plasma proteome persist in both vaccinated and unvaccinated individuals, which may be relevant to post-acute sequelae of SARS-CoV-2 and other viral infections associated with post-acute infection syndromes

Exploring students' understandings and perspectives of place : the case of place in a Skagit Valley school

Drawing upon notions of Aldo Leopold’s Land Ethic and Robin Wall Kimmerer’s Becoming Naturalized to Place, this dissertation explored how students revealed their perspectives and understandings of place at their school in the Skagit Valley, Washington State. This study employed an ethnographic case study approach guided by phenomenographic principles and informed by Indigenous perspectives to document students’ stories of place. Data were collected through an introductory questionnaire and stationary and walking interviews. Findings revealed that the students’ understandings and perspectives of place were situated within the following themes: Place as Action; Place as People; Place as Social Arena; Place as Nature; Place as Journey and Time; and Place as Displacement. This study contributes to the current research on Place and related phenomena due to the unique context of the school and the individual students’ stories which give voice to diverse and distinctive narratives of place.Education, Faculty ofCurriculum and Pedagogy (EDCP), Department ofGraduat

TSH enhancement of FT4 to FT3 conversion is age dependent

ObjectiveWe previously reported increasing free T3 (FT3) to free T4 (FT4) ratios as thyroid-stimulating hormone (TSH) increases within the normal range in children. It is not known if this phenomenon is age-related among humans, as previously reported in rats. This study examines the relationships between TSH and FT3/FT4 ratios in different ages.DesignRetrospective examination of thyroid tests from patients without thyroid disease from community clinics.MethodsFree T3, free T4, and TSH levels from 527 564 sera collected from patients aged 1 year or greater were studied. Exclusion criteria were the following: missing data, TSH greater than 7.5mIU/L, and medications that may interfere with thyroid hormone activity. A total of 27 940 samples remaining after exclusion were stratified by age. Samples with available anthropometric data were additionally stratified for body mass index (BMI). Correlations of TSH to FT4, FT3, and FT3/FT4 ratios by age group were examined.ResultsUp to age 40, for each increasing TSH quartile, FT3 and the FT3/FT4 ratio increased and FT4 decreased significantly (for both FT3, FT4 and FT3/FT4 ratio,P&lt;0.05 for every TSH quartile when compared with the 1st quartile, except FT3 in the 30–40 age group). In older age groups, increasing TSH was not associated with increased FT3/FT4 ratio.ConclusionAs TSH levels increase, FT3/FT4 ratios increase until age 40, but this differential increase does not occur in older age groups. This may reflect a decrease in thyroxine (T4) to triiodothyronine (T3) conversion with age, which may be part of the aging process.</jats:sec