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MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are involved in the modulation of the DNA-damage response (DDR) and upon exposure to ionizing radiation (IR), their expression fluctuates. In this study, we propose a workflow that enables the creation of regulatory networks by integrating transcriptomics data as well as regulatory data in order to better understand the interplay between genes, transcription factors (TFs), miRNAs, and lncRNAs in the cellular response to IR. We preprocessed and analyzed publicly available gene expression profiles and then applied our consensus and integration approach using open source data and tools. To exemplify the benefits of our proposed workflow, we identified a total of 32 differentially expressed transcripts corresponding to 20 unique differentially expressed genes (DEGs) and using these DEGs, we constructed a regulatory network consisting of 106 interactions and 100 nodes (11 DEGs, 78 miRNAs, 1 DEG acting as a TF, and 10 lncRNAs). Overrepresentation analyses (ORAs) furthermore linked our DEGs and miRNAs to annotations pertaining to the DDR and to IR. Our results show that MDM2 and E2F7 function as network hubs, and E2F7, miR-25-3p, let-7a-5p, and miR-497-5p are the four nodes with the highest betweenness centrality. In brief, our workflow, that is based on open source data and tools, and that generates a regulatory network, provides novel insights into the regulatory mechanisms involving miRNAs and lncRNAs in the cellular response to IR.
Background: Little is known about how substance use affects health-related quality of life (HRQOL) in depressed individuals. Here, associations between alcohol consumption and HRQOL in hospital and ambulatory care patients with past-year depressive symptoms are analyzed. Method: The sample consisted of 590 participants (26.8% non-drinkers) recruited via consecutive screenings. Individuals with alcohol use disorders were excluded. HRQOL was assessed with the Veterans Rand 12-item health survey (VR-12). Multivariable fractional polynomials (MFP) regression analyses were conducted (1) to test for non-linear associations between average daily consumption and HRQOL and (2) to analyze associations between alcohol consumption and the physical and mental health component summaries of the VR-12 and their subdomains. Results: Alcohol consumption was positively associated with the physical health component summary of the VR-12 (p = 0.001) and its subdomains general health (p = 0.006), physical functioning (p < 0.001), and bodily pain (p = 0.017), but not with the mental health component summary (p = 0.941) or any of its subdomains. Average daily alcohol consumption was not associated with HRQOL. Conclusion: Alcohol consumption was associated with better physical HRQOL. Findings do not justify ascribing alcohol positive effects on HRQOL. Data indicate that non-drinkers may suffer from serious health disorders. The results of this study can inform the development of future alcohol- and depression-related interventions.
Background
Person-Centered-Care (PCC) requires knowledge about patient preferences. Among People-living-with-Dementia (PlwD) data on quantitative, choice-based preferences, which would allow to quantify, weigh and rank patient-relevant elements of dementia-care, and identify most/least preferred choices, are limited. The Analytic-Hierarchy-Process (AHP) may be one approach to elicit quantitative, choice-based preferences with PlwD, due to simple pairwise comparisons of individual criteria from a complex decision-problem, e.g. health care decisions. Furthermore, data on congruence of patient preferences with physicians’ judgements for PCC are missing. If patient preferences and physicians’ judgements differ, provision of PCC becomes unlikely. An understanding of patient preferences compared to physician’s judgements will support the implementation of truly PCC, i.e. state of the art dementia-care aligned with patient preferences.
Methods
This mixed-methods-study will be based on the results from a previous systematic review and conducted in three phases: (I) literature-based key intervention-categories of PCC will be investigated during qualitative interviews with Dementia-Care-Managers (DCMs) and PlwD to identify actually patient-relevant (sub) criteria of PCC; (II) based on findings from phase I, an AHP-survey will be designed and pre-tested for face- and content-validity, and consistency during face-to-face “thinking-aloud”-interviews with PlwD and two expert panels (DCMs and physicians); (III) the developed survey will elicit patient preferences and physicians’ judgements for PCC. To assess individual importance weights for (sub) criteria in both groups, the Principal-Eigenvector-Method will be applied. Weights will be aggregated per group by Aggregation-of-Individual-Priorities-mode. Descriptive and interferential statistical analyses will be conducted to assess congruence of importance-weights between groups. Subgroup-analyses shall investigate participant-heterogeneities, sensitivity of AHP-results shall be tested by inclusion/exclusion of inconsistent respondents.
Discussion
Little research is published on quantitative, choice-based preferences in dementia care. We expect that (1) PlwD have preferences and can express these, (2) that the AHP is a suitable technique to elicit quantitative, choice-based preferences among PlwD, and (3) to identify a divergence between patient preferences and physicians’ judgements for PCC. With the help of the AHP-technique, which supports systematic decision-making including multiple criteria, it may be possible to involve PlwD in future care decisions (patient participation) and ensure implementation of truly Person-Centered-Dementia-Care.
Trial registration
Approval of the study was granted by the Ethics Committee at the University Medicine Greifswald the 09Apr2021 (Reg.-Nr.: BB 018–21, BB 018-21a, BB 018-21b).
Background
Even with high standards of acute care and neurological early rehabilitation (NER) a substantial number of patients with neurological conditions still need mechanical ventilation and/or airway protection by tracheal cannulas when discharged and hence home-based specialised intensive care nursing (HSICN). It may be possible to improve the home care situation with structured specialized long-term neurorehabilitation support and following up patients with neurorehabilitation teams. Consequently, more people might recover over an extended period to a degree that they were no longer dependent on HSICN.
Methods
This healthcare project and clinical trial implements a new specialised neurorehabilitation outreach service for people being discharged from NER with the need for HSICN. The multicentre, open, parallel-group RCT compares the effects of one year post-discharge specialized outpatient follow-up to usual care in people receiving HSICN. Participants will randomly be assigned to receive the new form of healthcare (intervention) or the standard healthcare (control) on a 2:1 basis. Primary outcome is the rate of weaning from mechanical ventilation and/or decannulation (primary outcome) after one year, secondary outcomes include both clinical and economic measures. 173 participants are required to corroborate a difference of 30 vs. 10% weaning success rate statistically with 80% power at a 5% significance level allowing for 15% attrition.
Discussion
The OptiNIV-Study will implement a new specialised neurorehabilitation outreach service and will determine its weaning success rates, other clinical outcomes, and cost-effectiveness compared to usual care for people in need for mechanical ventilation and/or tracheal cannula and hence HSICN after discharge from NER.
Trial registration
The trial OptiNIV has been registered in the German Clinical Trials Register (DRKS) since 18.01.2022 with the ID DRKS00027326.
Generation of Inducible BCL11B Knockout in TAL1/LMO1 Transgenic Mouse T Cell Leukemia/Lymphoma Model
(2022)
The B-cell CLL/lymphoma 11B gene (BCL11B) plays a crucial role in T-cell development, but its role in T-cell malignancies is still unclear. To study its role in the development of T-cell neoplasms, we generated an inducible BCL11B knockout in a murine T cell leukemia/lymphoma model. Mice, bearing human oncogenes TAL BHLH Transcription Factor 1 (TAL1; SCL) or LIM Domain Only 1 (LMO1), responsible for T-cell acute lymphoblastic leukemia (T-ALL) development, were crossed with BCL11B floxed and with CRE-ER/lox mice. The mice with a single oncogene BCL11Bflox/floxCREtg/tgTAL1tg or BCL11Bflox/floxCREtg/tgLMO1tg were healthy, bred normally, and were used to maintain the mice in culture. When crossed with each other, >90% of the double transgenic mice BCL11Bflox/floxCREtg/tgTAL1tgLMO1tg, within 3 to 6 months after birth, spontaneously developed T-cell leukemia/lymphoma. Upon administration of synthetic estrogen (tamoxifen), which binds to the estrogen receptor and activates the Cre recombinase, the BCL11B gene was knocked out by excision of its fourth exon from the genome. The mouse model of inducible BCL11B knockout we generated can be used to study the role of this gene in cancer development and the potential therapeutic effect of BCL11B inhibition in T-cell leukemia and lymphoma.
Titin is a multifunctional filamentous protein anchored in the M-band, a hexagonally organized supramolecular lattice in the middle of the muscle sarcomere. Functionally, the M-band is a framework that cross-links myosin thick filaments, organizes associated proteins, and maintains sarcomeric symmetry via its structural and putative mechanical properties. Part of the M-band appears at the C-terminal end of isolated titin molecules in the form of a globular head, named here the “M-complex”, which also serves as the point of head-to-head attachment of titin. We used high-resolution atomic force microscopy and nanosurgical manipulation to investigate the topographical and internal structure and local mechanical properties of the M-complex and its associated titin molecules. We find that the M-complex is a stable structure that corresponds to the transverse unit of the M-band organized around the myosin thick filament. M-complexes may be interlinked into an M-complex array that reflects the local structural and mechanical status of the transversal M-band lattice. Local segments of titin and the M-complex could be nanosurgically manipulated to achieve extension and domain unfolding. Long threads could be pulled out of the M-complex, suggesting that it is a compact supramolecular reservoir of extensible filaments. Nanosurgery evoked an unexpected volume increment in the M-complex, which may be related to its function as a mechanical spacer. The M-complex thus displays both elastic and plastic properties which support the idea that the M-band may be involved in mechanical functions within the muscle sarcomere.