Characterization of GECPAR, a noncoding RNA that regulates the transcriptional program of diffuse large B cell lymphoma

Enhancers are regulatory regions of DNA, which play a key role in cell-type specific differentiation and development. Most active enhancers are transcribed into enhancer RNAs (eRNAs) that can regulate transcription of target genes by means of in cis as well as in trans action. eRNAs stabilize contacts between distal genomic regions and mediate the interaction of DNA with master transcription factors. Here, we characterised an enhancer RNA, GECPAR (GErminal Center Proliferative Adapter RNA), that is specifically transcribed in normal and neoplastic germinal center B-cells from the super-enhancer of POU2AF1, a key regulatory gene of the germinal center reaction. Using diffuse large B cell lymphoma cell line models, we demonstrated the tumor suppressor activity of GECPAR, which is mediated via its transcriptional regulation of proliferation and differentiation genes, particularly MYC and the Wnt pathway

The multifaceted spectrum of liver cirrhosis in older hospitalised patients: Analysis of the REPOSI registry

Background: Knowledge on the main clinical and prognostic characteristics of older multimorbid subjects with liver cirrhosis (LC) admitted to acute medical wards is scarce. Objectives: To estimate the prevalence of LC among older patients admitted to acute medical wards and to assess the main clinical characteristics of LC along with its association with major clinical outcomes and to explore the possibility that well-distinguished phenotypic profiles of LC have classificatory and prognostic properties. Methods: A cohort of 6,193 older subjects hospitalised between 2010 and 2018 and included in the REPOSI registry was analysed. Results: LC was diagnosed in 315 patients (5%). LC was associated with rehospitalisation (age-sex adjusted hazard ratio, [aHR] 1.44; 95% CI, 1.10-1.88) and with mortality after discharge, independently of all confounders (multiple aHR, 2.1; 95% CI, 1.37-3.22), but not with in-hospital mortality and incident disability. Three main clinical phenotypes of LC patients were recognised: relatively fit subjects (FIT, N = 150), subjects characterised by poor social support (PSS, N = 89) and, finally, subjects with disability and multimorbidity (D&M, N = 76). PSS subjects had an increased incident disability (35% vs 13%, P < 0.05) compared to FIT. D&M patients had a higher mortality (in-hospital: 12% vs 3%/1%, P < 0.01; post-discharge: 41% vs 12%/15%, P < 0.01) and less rehospitalisation (10% vs 32%/34%, P < 0.01) compared to PSS and FIT. Conclusions: LC has a relatively low prevalence in older hospitalised subjects but, when present, accounts for worse post-discharge outcomes. Phenotypic analysis unravelled the heterogeneity of LC older population and the association of selected phenotypes with different clinical and prognostic features

Computational analysis of sense-antisense chimeric transcripts reveals their potential regulatory features and the landscape of expression in human cells

Many human genes are transcribed from both strands and produce sense-antisense gene pairs. Sense-antisense (SAS) chimeric transcripts are produced upon the coalescing of exons/introns from both sense and antisense transcripts of the same gene. SAS chimera was first reported in prostate cancer cells. Subsequently, numerous SAS chimeras have been reported in the ChiTaRS-2.1 database. However, the landscape of their expression in human cells and functional aspects are still unknown. We found that longer palindromic sequences are a unique feature of SAS chimeras. Structural analysis indicates that a long hairpin-like structure formed by many consecutive Watson-Crick base pairs appears because of these long palindromic sequences, which possibly play a similar role as double-stranded RNA (dsRNA), interfering with gene expression. RNA–RNA interaction analysis suggested that SAS chimeras could significantly interact with their parental mRNAs, indicating their potential regulatory features. Here, 267 SAS chimeras were mapped in RNA-seq data from 16 healthy human tissues, revealing their expression in normal cells. Evolutionary analysis suggested the positive selection favoring sense-antisense fusions that significantly impacted the evolution of their function and structure. Overall, our study provides detailed insight into the expression landscape of SAS chimeras in human cells and identifies potential regulatory features.Israeli Council for Higher Education [PBC Fellowship for Outstanding Post-Doctoral Fellows, 2019-2021 to S.M.]; Israel Innovation Authority [66824, 2019–2021 to M.F-M.]; RSF [18–14-00240 to Y.A.M. (in part)].Peer ReviewedPostprint (published version

Lanthanide-Based Complexes Containing a Chiral trans-1,2-Diaminocyclohexane (DACH) Backbone: Spectroscopic Properties and Potential Applications

In this minireview, we give an overview on the use of the chiral molecule trans-1,2-diaminocyclohexane (DACH) in several fields of application. This chiral backbone is present in a variety of metal complexes which are employed in (enantioselective) catalysis, chiral discrimination, molecular recognition and supramolecular chemistry. Metal extraction and biochemical and pharmaceutical applications also use the DACH molecule. This contribution is particularly focused on the interesting chemical-physical properties discussed so far in the literature concerning lanthanide-based complexes containing chiral ligands characterized by the presence of DACH in the structure. In particular, the interconnection between luminescence (total and circularly polarized), structure and thermodynamics of Eu(III), Tb(III) and Sm(III) complexes will be discussed also in light of their use as optical or chiroptical probes for the sensing of important analytes dissolved in aprotic and protic polar solvents. Several complexes show potential interest in the solid state as phosphors for light emitting devices or for the detection of volatile organic compounds

New Fabrication Approaches for High Efficiency CdS/CdTe Solar Cells

Vedasi abstract in lingua inglesePresented in this thesis are the results from the study of new fabrication approaches for high efficiency thin film CdS/CdTe solar cells grown in superstrate configuration. Hereinafter the phrases CdS/CdTe solar cells and thin film CdS/CdTe solar cell will imply thin film CdS/CdTe solar cell grown in superstrate configuration. This thesis contains four main parts. The first part (chapters 1 and 2) presents general information about thin film CdS/CdTe solar cells, and their place among other types of solar cells. A definition of the device is given and explained. Possible configurations of thin film CdS/CdTe solar cells are shown. A historical overview of the evolution of thin film CdS/CdTe solar cell efficiency from 1969 - advent of the first thin film CdS/CdTe solar cell \u2013 up to now is presented. A short overview of the main ongoing research and present challenges is given in the paragraph \u201cCurrent research directions\u201d. Also included in the first part is the aim of this study defined according to present-day challenges for CdTe photovoltaic. In the second part (chapter 3) the fabrication process for thin film CdS/CdTe solar cells preparation developed in our laboratory by the author is presented. All steps starting from substrate up to the finished working device are mentioned. All the required techniques and materials are specified. Moreover in the second part the experimental techniques, which were used for solar cells characterization, are presented. The operating modes for each type of characterization are also presented. The third part (from chapter 4 to chapter 7) focuses on the new fabrication approaches for thin film CdS/CdTe solar cells. Influence of alternative fabrication steps in lieu of our standard fabrication process steps on solar cells performance is presented. We examined how the performance of CdS/CdTe solar cells is influenced by: different fabrication methods of CdS window layer and different Bromine-Methanol etching. An alternative recrystallization process for low substrate temperature deposited CdTe solar cells was studied. The influence of alternative treatment on CdS/CdTe solar cells behavior and performance is presented. Results are compared with the results from the standard process. Results of this study addressed by tellurium scarcity are presented in chapter 5. Influence of CdTe thickness on structural and electrical properties of CdTe/CdS solar cells was investigated. In chapter 7 flexible solar cells production process developed in our laboratory is presented. Results and challenges addressed by the fabrication of flexible CdTe solar cells by a low temperature process on ITO/ZnO coated polymers are presented in this chapter. In the fourth part all results obtained during this study are summarized and presented. The results have already been partly published in peer-reviewed journals and conferences proceedings

Investigating Natural Antisense Transcripts in Toxoplasma gondii

Natural antisense transcripts (NATs) are non-coding RNAs that can regulate the expression of their counterpart protein-coding transcript. While NATs are widespread in eukaryotic genomes, very little is known about their mechanism. Our study focuses on gaining a better understanding of the function of NATs in Toxoplasma gondii, a pathogenic unicellular eukaryote. We recently characterized the gene encoding the first committed enzyme in SUMOylation, named Ubiquitin-like protease 1 (TgUlp1), and showed that the expression of TgUlp1 is vital to the life cycle of T. gondii. Interestingly, the locus of TgUlp1 also transcribes a NAT species. Using a dual luciferase assay and RT-qPCR, we identified the promoters of TgUlp1 mRNA and NAT and measured their transcript levels in tachyzoites and bradyzoites. We found that TgUlp1 mRNA and NAT are differentially regulated at the transcriptional level via promoter activity and transcript turnover. Furthermore, the products of TgUlp1 NAT processed by RNase III retain the ability to lower the expression of reporters carrying TgUlp1 mRNA sequences, suggesting the involvement of RNA interference pathway. In Dicer-knockout (TgDicer-KO) and Argonaute-knockout (TgAgo-KO) transgenic strains, a higher level of TgUlp1 NAT, and much lower level of TgUlp1 mRNA was detected, suggesting that Dicer and Ago may be involved in maintaining TgUlp1 mRNA. Although we were unable to determine the direct effect of TgUlp1 NAT on mRNA, we showed that the introduction of TgUlp1 NAT by electroporation negatively affected the level of TgUlp1 mRNA. Consequently, regulation by TgUlp1 NAT would also affect TgUlp1 protein levels and ultimately the SUMOylation pathway in T. gondii which plays an important role in host cell invasion and cyst genesis. However, underlying mechanisms remain to be investigated

Intricate crosstalk between MYC and non-coding RNAs regulates hallmarks of cancer

Myelocytomatosis viral oncogene homolog (MYC) plays an important role in the regulation of many cellular processes, and its expression is tightly regulated at the level of transcription, translation, protein stability, and activity. Despite this tight regulation, MYC is overexpressed in many cancers and contributes to multiple hallmarks of cancer. In recent years, it has become clear that noncoding RNAs add a crucial additional layer to the regulation of MYC and its downstream effects. So far, twenty‐five microRNAs and eighteen long noncoding RNAs that regulate MYC have been identified. Thirty‐three miRNAs and nineteen lncRNAs are downstream effectors of MYC that contribute to the broad oncogenic role of MYC, including its effects on diverse hallmarks of cancer. In this review, we give an overview of this extensive, multilayered noncoding RNA network that exists around MYC. Current data clearly show explicit roles of crosstalk between MYC and ncRNAs to allow tumorigenesis

Identifizierung und Charakterisierung der Rolle langer nichtkodierender RNA (lncRNA) bei der Genregulation von Stoffwechselprozessen beim Rind

Die Rolle der Klasse der langen nichtkodierenden RNA (lncRNA) bei der Merkmalsausprägung von Nutztieren ist bisher wenig erforscht. In dieser Dissertation wurden in einem integrativen Ansatz das Transkriptom, Phänom und Metabolom von Bullen (N = 24) und Kühen (N = 24) einer Kreuzungspopulation (Fleischrind x Milchvieh) der zweiten Generation analysiert, um neue, unbekannte lncRNAs und ihre möglichen biologischen Funktionen und ihren Einfluss auf die Nährstoffverteilung zu ermitteln. Die Ergebnisse haben zur weiterten Annotation des Rindergenoms beigetragen.The role of the class of long non-coding RNA (lncRNA) in trait expression in livestock has been poorly studied. In this dissertation, an integrative approach was used to analyze the transcriptome, phenome, and metabolome of bulls (N = 24) and cows (N = 24) from a second-generation crossbred population (beef cattle x dairy cattle) to identify novel, unknown lncRNAs and their potential biological functions and influence on nutrient partitioning. The results have contributed to the further annotation of the bovine genome

Pain and Frailty in Hospitalized Older Adults

Introduction: Pain and frailty are prevalent conditions in the older population. Many chronic diseases are likely involved in their origin, and both have a negative impact on quality of life. However, few studies have analysed their association. Methods: In light of this knowledge gap, 3577 acutely hospitalized patients 65 years or older enrolled in the REPOSI register, an Italian network of internal medicine and geriatric hospital wards, were assessed to calculate the frailty index (FI). The impact of pain and some of its characteristics on the degree of frailty was evaluated using an ordinal logistic regression model after adjusting for age and gender. Results: The prevalence of pain was 24.7%, and among patients with pain, 42.9% was regarded as chronic pain. Chronic pain was associated with severe frailty (OR = 1.69, 95% CI 1.38–2.07). Somatic pain (OR = 1.59, 95% CI 1.23–2.07) and widespread pain (OR = 1.60, 95% CI 0.93–2.78) were associated with frailty. Osteoarthritis was the most common cause of chronic pain, diagnosed in 157 patients (33.5%). Polymyalgia, rheumatoid arthritis and other musculoskeletal diseases causing chronic pain were associated with a lower degree of frailty than osteoarthritis (OR = 0.49, 95%CI 0.28–0.85). Conclusions: Chronic and somatic pain negatively affect the degree of frailty. The duration and type of pain, as well as the underlying diseases associated with chronic pain, should be evaluated to improve the hospital management of frail older people

Sex-Differences in the Pattern of Comorbidities, Functional Independence, and Mortality in Elderly Inpatients: Evidence from the RePoSI Register.

BACKGROUND: The RePoSi study has provided data on comorbidities, polypharmacy, and sex dimorphism in hospitalised elderly patients. METHODS: We retrospectively analysed data collected from the 2010, 2012, 2014, and 2016 data sets of the RePoSi register. The aim of this study was to explore the sex-differences and to validate the multivariate model in the entire dataset with an expanded follow-up at 1 year. RESULTS: Among 4714 patients, 51% were women and 49% were men. The disease distribution showed that diabetes, coronary artery disease, chronic obstructive pulmonary disease, chronic kidney disease, and malignancy were more frequent in men but that hypertension, anaemia, osteoarthritis, depression, and diverticulitis disease were more common in women. Severity and comorbidity indexes according to the Cumulative Illness Rating Scale (CIRS-s and CIRS-c) were higher in men, while cognitive impairment, mood disorders, and disability in daily life measured by the Barthel Index (BI) were worse in women. In the multivariate analysis, BI, CIRS, and malignancy significantly increased the risk of death in men at the 1-year follow-up, while age was independently associated with mortality in women. CONCLUSIONS: Our study highlighted the relevance and the validity of our previous predictive model in the identification of sex dimorphism in hospitalised elderly patients underscoring the need of sex-personalised health-care