Effects of appraisal training on responses to a distressing autobiographical event

Dysfunctional appraisals are a key factor suggested to be involved in the development and maintenance of PTSD. Research has shown that experimental induction of a positive or negative appraisal style following a laboratory stressor affects analogue posttraumatic stress symptoms. This supports a causal role of appraisal in the development of traumatic stress symptoms and the therapeutic promise of modifying appraisals to reduce PTSD symptoms. The present study aimed to extend previous findings by investigating the effects of experimentally induced appraisals on reactions to a naturally occurring analogue trauma and by examining effects on both explicit and implicit appraisals. Participants who had experienced a distressing life event were asked to imagine themselves in the most distressing moment of that event and then received either a positive or negative Cognitive Bias Modification training targeting appraisals (CBM-App). The CBM-App training induced training-congruent appraisals, but group differences in changes in appraisal over training were only seen for explicit and not implicit appraisals. However, participants trained positively reported less intrusion distress over the subsequent week than those trained negatively, and lower levels of overall posttraumatic stress symptoms. These data support the causal relationship between appraisals and trauma distress, and further illuminate the mechanisms linking the two

Alternative splicing and nonsense-mediated decay regulate telomerase reverse transcriptase (TERT) expression during virus-induced lymphomagenesis in vivo

<p>Abstract</p> <p>Background</p> <p>Telomerase activation, a critical step in cell immortalization and oncogenesis, is partly regulated by alternative splicing. In this study, we aimed to use the Marek's disease virus (MDV) T-cell lymphoma model to evaluate TERT regulation by splicing during lymphomagenesis <it>in vivo</it>, from the start point to tumor establishment.</p> <p>Results</p> <p>We first screened cDNA libraries from the chicken MDV lymphoma-derived MSB-1 T- cell line, which we compared with B (DT40) and hepatocyte (LMH) cell lines. The chTERT splicing pattern was cell line-specific, despite similar high levels of telomerase activity. We identified 27 alternative transcripts of chicken TERT (chTERT). Five were in-frame alternative transcripts without <it>in vitro </it>telomerase activity in the presence of viral or chicken telomerase RNA (vTR or chTR), unlike the full-length transcript. Nineteen of the 22 transcripts with a premature termination codon (PTC) harbored a PTC more than 50 nucleotides upstream from the 3' splice junction, and were therefore predicted targets for nonsense-mediated decay (NMD). The major PTC-containing alternatively spliced form identified in MSB1 (ie10) was targeted to the NMD pathway, as demonstrated by UPF1 silencing. We then studied three splicing events separately, and the balance between in-frame alternative splice variants (d5f and d10f) plus the NMD target i10ec and constitutively spliced chTERT transcripts during lymphomagenesis induced by MDV indicated that basal telomerase activity in normal T cells was associated with a high proportion of in-frame non functional isoforms and a low proportion of constitutively spliced chTERT. Telomerase upregulation depended on an increase in active constitutively spliced chTERT levels and coincided with a switch in alternative splicing from an in-frame variant to NMD-targeted variants.</p> <p>Conclusions</p> <p>TERT regulation by splicing plays a key role in telomerase upregulation during lymphomagenesis, through the sophisticated control of constitutive and alternative splicing. Using the MDV T-cell lymphoma model, we identified a chTERT splice variant as a new NMD target.</p

Herpesvirus Telomerase RNA(vTR)-Dependent Lymphoma Formation Does Not Require Interaction of vTR with Telomerase Reverse Transcriptase (TERT)

Telomerase is a ribonucleoprotein complex involved in the maintenance of telomeres, a protective structure at the distal ends of chromosomes. The enzyme complex contains two main components, telomerase reverse transcriptase (TERT), the catalytic subunit, and telomerase RNA (TR), which serves as a template for the addition of telomeric repeats (TTAGGG)n. Marek's disease virus (MDV), an oncogenic herpesvirus inducing fatal lymphoma in chickens, encodes a TR homologue, viral TR (vTR), which significantly contributes to MDV-induced lymphomagenesis. As recent studies have suggested that TRs possess functions independently of telomerase activity, we investigated if the tumor-promoting properties of MDV vTR are dependent on formation of a functional telomerase complex. The P6.1 stem-loop of TR is known to mediate TR-TERT complex formation and we show here that interaction of vTR with TERT and, consequently, telomerase activity was efficiently abrogated by the disruption of the vTR P6.1 stem-loop (P6.1mut). Recombinant MDV carrying the P6.1mut stem-loop mutation were generated and tested for their behavior in the natural host in vivo. In contrast to viruses lacking vTR, all animals infected with the P6.1mut viruses developed MDV-induced lymphomas, but onset of tumor formation was significantly delayed. P6.1mut viruses induced enhanced metastasis, indicating functionality of non-complexed vTR in tumor dissemination. We discovered that RPL22, a cellular factor involved in T-cell development and virus-induced transformation, directly interacts with wild-type and mutant vTR and is, consequently, relocalized to the nucleoplasm. Our study provides the first evidence that expression of TR, in this case encoded by a herpesvirus, is pro-oncogenic in the absence of telomerase activity

Vitamin D3 (Cholecalciferol) and Pelvic Pain Caused by Ovarian Endometriosis

Статья посвящена изучению взаимосвязи концентрации витамина D с наличием и интенсивностью тазовой боли у женщин, страдающих эндометриозом яичников. Цель исследования: установить взаимосвязь уровня витамина D и интенсивности тазовой боли у женщин, страдающих эндометриозом яичников. В исследование были включены 190 женщин репродуктивного возраста с верифицированным диагнозом эндометриоз яичников, в возрасте от 20 до 41 года (средний возраст – 29,1±3,3 года). Для определения интенсивности тазовой боли использовали визуальную аналоговую шкалу (ВАШ). Всем пациенткам (n=190) исходно оценку уровня витамина D проводили путем определения уровня общего 25(ОН)D в сыворотке крови методом масс-спектрометрии, адаптированным к клинической практике, согласно международным стандартам, на тандемном масс-спектрометре AB SCIEX QTRAP 5500.The article studies the relation between vitamin D concentration and the presence and intensity of pelvic pain in women suffering from ovarian endometriosis. The aim of the study is to examine the relation between vitamin D levels and intensity of pelvic pain in women with ovarian endometriosis. Study design: cohort, prospective, non-comparative study. The study included 190 women of reproductive age suffering from ovarian endometriosis (OE), aged 20 to 41 years (mean age 29.1±3.3 years). Visual analogue scale (VAS) was used to determine the intensity of pelvic pain.The evaluation of vitamin D level in all patients (n=190) was initially performed by determining the level of total 25 (OH) D in blood serum by the method of mass spectrometry. Study Results: The average vitamin D level in the study was 23.98±6.82 ng/ml. The average concentration of vitamin D in the blood of the patients with low-intensity pelvic pain was 26.7±5.92 ng/ml, with moderate-intensity – 23.06±of 5.55 ng/ml, with high pain intensity – 19.26±6,01 ng/ml. The content of vitamin D in the blood of the patients in the control group was 28.83±6.15 ng/ml, which met the criteria of insufficiency. Аn inverse correlation between the severity of pain based on VAS and vitamin D in women with endometriosis of the main group was established in the study, it amounted to 0.502 (p<0.001)

Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function

Albuminuria affects millions of people, and is an independent risk factor for kidney failure, cardiovascular morbidity and death. The key cell that prevents albuminuria is the terminally differentiated glomerular podocyte. Here we report the evolutionary importance of the enzyme Glycogen Synthase Kinase 3 (GSK3) for maintaining podocyte function in mice and the equivalent nephrocyte cell in Drosophila. Developmental deletion of both GSK3 isoforms (α and β) in murine podocytes causes late neonatal death associated with massive albuminuria and renal failure. Similarly, silencing GSK3 in nephrocytes is developmentally lethal for this cell. Mature genetic or pharmacological podocyte/nephrocyte GSK3 inhibition is also detrimental; producing albuminuric kidney disease in mice and nephrocyte depletion in Drosophila. Mechanistically, GSK3 loss causes differentiated podocytes to re-enter the cell cycle and undergo mitotic catastrophe, modulated via the Hippo pathway but independent of Wnt-β-catenin. This work clearly identifies GSK3 as a critical regulator of podocyte and hence kidney functio

Investigation of ornamental cultivars both Louiseania triloba (Lindl.) Pachom. and its hybrids under the conditions of the South-East of Ukraine

Results of introduction investigations both 9 cultivars of Louiseania triloba (Lindl.) Pachom. and 6 cultivars of Louiseania Carr. × Prunus L. hybrids under the conditions of the South-East of Ukraine have been presented. The new combination ×Prunoseania arnoldiana (Rehder) Mezh. comb. nov. for the hybrids of Louiseania triloba × Prunus cerasifera Ehrh. is proposed

The effects of modifying dysfunctional appraisals in posttraumatic stress disorder using a form of cognitive bias modification

$\bf Introduction:$ Dysfunctional appraisals about traumatic events and their sequelae are a key mechanism in posttraumatic stress disorder (PTSD). Experimental studies have shown that a computerized cognitive training, cognitive bias modification for appraisals (CBM-APP), can modify dysfunctional appraisals and reduce analogue trauma symptoms amongst healthy and subclinical volunteers. $\bf Objective:$ We aimed to test whether CBM-APP could reduce dysfunctional appraisals related to trauma reactions in PTSD patients, and whether this would lead to improvements in PTSD symptoms. $\bf Methods:$ We compared CBM-APP to sham training in a parallel-arm proof-of-principle double-blind randomized controlled trial amongst 80 PTSD patients admitted to an inpatient clinic. Both arms comprised a training schedule of 8 sessions over a 2-week period and were completed as an adjunct to the standard treatment programme. $\bf Results:$ In intention-to-treat analyses, participants receiving CBM-APP showed a greater reduction in dysfunctional appraisals on a scenario task from pre- to posttraining (primary outcome) assessments, compared to those receiving sham training ($\it d$= 1.30, 95% CI 0.82–1.80), with between-group differences also found on the Posttraumatic Cognitions Inventory (PTCI; $\it d$ = 0.85, 95% CI 0.39–1.32) and the PTSD Checklist for DSM-5 (PCL-5; $\it d$ = 0.68, 95% CI 0.23–1.14), but not for long-term cortisol concentrations ($\it d$ = 0.25, 95% CI –0.28 to 0.78). Reductions in dysfunctional appraisals assessed via the scenario task correlated with reductions on the PTCI, PCL-5, and hair cortisol concentrations from pre- to posttraining time points. $\bf Conclusions:$ Results support dysfunctional appraisals as a modifiable cognitive mechanism, and that their proximal modification transfers to downstream PTSD symptoms. These findings could open new avenues for improving present therapeutic approaches

Telomere protection and TRF2 expression are enhanced by the canonical Wnt signalling pathway

International audienceThe DNA-binding protein TRF2 is essential for telomere protection and chromosome stability in mammals. We show here that TRF2 expression is activated by the Wnt/b-catenin signalling pathway in human cancer and normal cells as well as in mouse intestinal tissues. Furthermore, b-catenin binds to TRF2 gene regulatory regions that are functional in a luciferase transactivat-ing assay. Reduced b-catenin expression in cancer cells triggers a marked increase in telomere dysfunction, which can be reversed by TRF2 overexpression. We conclude that the Wnt/b-catenin signalling pathway maintains a level of TRF2 critical for telomere protection. This is expected to have an important role during development, adult stem cell function and oncogenesis