196,020 research outputs found
Raman and FTIR imaging of lung tissue: methodology for controlsamples
No full textThe paper describes Raman and FTIR images of normal lung tissue of an infant patient which is a prerequisite to understand the biochemical changes that accompany pediatric lung pathologies and malformations. A Raman image of 3420 spectra was recorded from a 5.7 mm x 6 mm tissue section in mapping mode using 785 nm excitation laser and a step size of 100 mu m. A Fourier transform infrared (FTIR) image of 4096 spectra was recorded from the same sample at a lateral resolution of 63 mu m using a spectrometer coupled to a focal plane array detector. Whereas the analysis of the FTIR image was complicated by dispersion artifacts, the analysis of the Raman image was impaired by intense spectral contributions of hemoglobin which overlap with spectral contributions of other proteins, lipids and nucleic acids. Data analysis procedures were optimized to reduce these effects. A multiplicative signal correction was performed to normalize the spectra within each dataset. Then, pseudo color images were constructed using cluster analyses. The most significant variations within both images were assigned to different concentrations of red blood cells. Furthermore, mucus and blood vessels were identified in the vibrational spectroscopic images. The different sensitivity of Raman and FTIR imaging for lung tissue constituents supports the combined use of both modalities
Coping with RNA damage with a focus on APE1, a BER enzyme at the crossroad between DNA damage repair and RNA processing/decay
No full textInterest in RNA damage as a novel threat associated with several human pathologies is rapidly increasing. Knowledge on damaged RNA recognition, repair, processing and decay is still scanty. Interestingly, in the last few years, more and more evidence put a bridge between DNA damage repair enzymes and the RNA world. The Apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) was firstly identified as a crucial enzyme of the base excision repair (BER) pathway preserving genome stability toward non-distorting DNA lesion-induced damages. Later, an unsuspected role of APE1 in controlling gene expression was discovered and its pivotal involvement in several human pathologies, ranging from tumor progression to neurodegenerative diseases, has emerged. Recent novel findings indicate a role of APE1 in RNA metabolism, particularly in processing activities of damaged (abasic and oxidized) RNA and in the regulation of oncogenic microRNAs (miRNAs). Even though the role of miRNAs in human pathologies is well-known, the mechanisms underlying their quality control are still totally unexplored. A detailed knowledge of damaged RNA decay processes in human cells is crucial in order to understand the molecular processes involved in multiple pathologies. This cutting-edge perspective article will highlight these emerging aspects of damaged RNA processing and decay, focusing the attention on the involvement of APE1 in RNA world
TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains
No full textParkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the Substantia Nigra and the formation of ubiquitin- and alpha-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs). Although most PD cases are sporadic, families with genetic mutations have been found. Mutations in PARK7/DJ-1 have been associated with autosomal recessive early-onset PD, while missense mutations or duplications of aSYN (PARK1, PARK4) have been linked to dominant forms of the disease. In this study, we identify the E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6) as a common player in genetic and sporadic cases. TRAF6 binds misfolded mutant DJ-1 and aSYN. Both proteins are substrates of TRAF6 ligase activity in vivo. Interestingly, rather than conventional K63 assembly, TRAF6 promotes atypical ubiquitin linkage formation to both PD targets that share K6-, K27- and K29- mediated ubiquitination. Importantly, TRAF6 stimulates the accumulation of insoluble and polyubiquitinated mutant DJ-1 into cytoplasmic aggregates. In human post-mortem brains of PD patients, TRAF6 protein colocalizes with aSYN in LBs. These results reveal a novel role for TRAF6 and for atypical ubiquitination in PD pathogenesis
Hemoglobin is present as a canonical α2β2 tetramer in dopaminergic neurons
No full textAbstractHemoglobin is the oxygen carrier in blood erythrocytes. Oxygen coordination is mediated by α2β2 tetrameric structure via binding of the ligand to the heme iron atom. This structure is essential for hemoglobin function in the blood. In the last few years, expression of hemoglobin has been found in atypical sites, including the brain. Transcripts for α and β chains of hemoglobin as well as hemoglobin immunoreactivity have been shown in mesencephalic A9 dopaminergic neurons, whose selective degeneration leads to Parkinson's disease. To gain further insights into the roles of hemoglobin in the brain, we examined its quaternary structure in dopaminergic neurons in vitro and in vivo. Our results indicate that (i) in mouse dopaminergic cell line stably over-expressing α and β chains, hemoglobin exists as an α2β2 tetramer; (ii) similarly to the over-expressed protein, endogenous hemoglobin forms a tetramer of 64kDa; (iii) hemoglobin also forms high molecular weight insoluble aggregates; and (iv) endogenous hemoglobin retains its tetrameric structure in mouse mesencephalon in vivo. In conclusion, these results suggest that neuronal hemoglobin may be endowed with some of the biochemical activities and biological function associated to its role in erythroid cells. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins
Linfoadenite laterocervicale tubercolare: terapia medica, chirurgica ed effetti paradossi
No full textWe report a case of a 1-year-old girl with persistent fever and enlargement of laterocervical lymph nodes on the left side, fluctuant and with erythematous overlying skin. A positive Mantoux skin test first (induration of 20 mm in 72 hours) and then the DNA amplification by polymerase chain reaction (PCR) as well as the culture confirmed the diagnosis of Mycobacterium tuberculosis complex, in particular M. bovis. Nonetheless, after 1 month of standard mycobacterial regimen (isoniazid, rimpaficin, ethambutol, pyrazinamide), she developed new lymph nodes on the same and on the opposite side, apart from the residual ones. She underwent surgery three times (excision of a lymph node, incision and drainage of the others) for the definitive diagnosis and for the excessive enlargement of the nodes with risk of compression of underlying structures and diffusion. A drug resistance was ruled out by antibiogram. Paradoxical upgrading reaction (PUR) to the therapy offers a plausible explanation for this phenomenon, and this is supported by a prompt answer to steroids
New perspectives in cancer biology from a study of canonical and non-canonical functions of base excision repair proteins with a focus on early steps
No full textAlterations of DNA repair enzymes and consequential triggering of aberrant DNA damage response (DDR) pathways are thought to play a pivotal role in genomic instabilities associated with cancer development, and are further thought to be important predictive biomarkers for therapy using the synthetic lethality paradigm. However, novel unpredicted perspectives are emerging from the identification of several non-canonical roles of DNA repair enzymes, particularly in gene expression regulation, by different molecular mechanisms, such as (i) non-coding RNA regulation of tumour suppressors, (ii) epigenetic and transcriptional regulation of genes involved in genotoxic responses and (iii) paracrine effects of secreted DNA repair enzymes triggering the cell senescence phenotype. The base excision repair (BER) pathway, canonically involved in the repair of non-distorting DNA lesions generated by oxidative stress, ionising radiation, alkylation damage and spontaneous or enzymatic deamination of nucleotide bases, represents a paradigm for the multifaceted roles of complex DDR in human cells. This review will focus on what is known about the canonical and non-canonical functions of BER enzymes related to cancer development, highlighting novel opportunities to understand the biology of cancer and representing future perspectives for designing new anticancer strategies. We will specifically focus on APE1 as an example of a pleiotropic and multifunctional BER protein
Role of condensates in modulating DNA repair pathways and its implication for chemoresistance
No full textFor cells, it is important to repair DNA damage, such as double-strand and single-strand DNA breaks, because unrepaired DNA can compromise genetic integrity, potentially leading to cell death or cancer. Cells have multiple DNA damage repair pathways that have been the subject of detailed genetic, biochemical, and structural studies. Recently, the scientific community has started to gain evidence that the repair of DNA double-strand breaks may occur within biomolecular condensates and that condensates may also contribute to DNA damage through concentrating genotoxic agents used to treat various cancers. Here, we summarize key features of biomolecular condensates and note where they have been implicated in the repair of DNA double-strand breaks. We also describe evidence suggesting that condensates may be involved in the repair of other types of DNA damage, including single-strand DNA breaks, nucleotide modifications (e.g., mismatch and oxidized bases), and bulky lesions, among others. Finally, we discuss old and new mysteries that could now be addressed considering the properties of condensates, including chemoresistance mechanisms
Primary pulmonary Hodgkin's disease and tuberculosis in an 11-year-old boy: case report and review of the literature
No full textTuberculosis (TB) has been described in association with different malignancies including Hodgkin's disease. However, the association with primary pulmonary Hodgkin's disease (PPHD) is hardly reported in literature and in teenage is quite exceptional. We report a case of an 11 years old boy in whom the diagnosis of tuberculosis preceded and delayed the diagnosis of PPHL
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