The regulation of matrix metalloproteinases and their inhibitors

The matrix metalloproteinases (MMP) are a family of 23 enzymes in man. These enzymes were originally described as cleaving extracellular matrix (ECM) substrates with a predominant role in ECM homeostasis, but it is now clear that they have much wider functionality. Control over MMP and/or tissue inhibitor of metalloproteinases (TIMP) activity in vivo occurs at different levels and involves factors such as regulation of gene expression, activation of zymogens and inhibition of active enzymes by specific inhibitors. Whilst these enzymes and inhibitors have clear roles in physiological tissue turnover and homeostasis, if control of their expression or activity is lost, they contribute to a number of pathologies including e.g. cancer, arthritis and cardiovascular disease. The expression of many MMPs and TIMPs is regulated at the level of transcription by a variety of growth factors, cytokines and chemokines, though post-transcriptional pathways may contribute to this regulation in specific cases. The contribution of epigenetic modifications has also been uncovered in recent years. The promoter regions of many of these genes have been, at least partly, characterised including the role of identified single nucleotide polymorphisms. This article aims to review current knowledge across these gene families and use a bioinformatic approach to fill the gaps where no functional data are available

Molecular diversity within the genus Laeonereis (Annelida, Nereididae) along the west Atlantic coast: paving the way for integrative taxonomy

The polychaete genus Laeonereis (Annelida, Nereididae) occurs over a broad geographic range and extends nearly across the entire Atlantic coast of America, from the USA to Uruguay. Despite the research efforts to clarify its diversity and systematics, mostly by morphological and ecological evidence, there is still uncertainty, mainly concerning the species Laeonereis culveri, which constitutes an old and notorious case of taxonomic ambiguity. Here, we revised the molecular diversity and distribution of Laeonereis species based on a multi-locus approach, including DNA sequence analyses of partial segments of the cytochrome c oxidase subunit I (COI), 16S rRNA, and 28S rRNA genes. We examined Laeonereis specimens collected from 26 sites along the American Atlantic coast from Massachusetts (USA) to Mar del Plata (Argentina). Although no comprehensive morphological examination was performed between different populations, the COI barcodes revealed seven highly divergent MOTUs, with a mean K2P genetic distance of 16.9% (from 6.8% to 21.9%), which was confirmed through four clustering algorithms. All MOTUs were geographically segregated, except for MOTUs 6 and 7 from southeastern Brazil, which presented partially overlapping ranges between Rio de Janeiro and Sao Paulo coast. Sequence data obtained from 16S rRNA and 28S rRNA markers supported the same MOTU delimitation and geographic segregation as those of COI, providing further evidence for the existence of seven deeply divergent lineages within the genus. The extent of genetic divergence between MOTUs observed in our study fits comfortably within the range reported for species of polychaetes, including Nereididae, thus providing a strong indication that they might constitute separate species. These results may therefore pave the way for integrative taxonomic studies, aiming to clarify the taxonomic status of the Laeonereis MOTUs herein reported.This work was supported by the FAPESP (Grants n~ 2011/50317-5, 2015/25623-6, 2017/06167-5, 2018/10313-0) and CNPq through a productivity grant to A.C.Z.A (301551/2019-7). Marcos AL Teixeira was supported by a PhD fellowship (SFRH/BD/131527/2017) from FCT. Pedro Vieira was supported by a Post-Doctoral Fellowships (BPD1/next-sea/2018, NORTE-01-0145-FEDER-000032). Filipe Costa and the University of Minho's contribution was supported by the strategic program UID/BIA/04050/2013 POCI-010145-FEDER-007569. Victor C Seixas was supported by a Post-Doctoral Fellowship sponsored by CAPES-PNPD (88882.316714/2019-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Examining the Relationship Between Trait Energy and Fatigue and Feelings of Depression in Young Healthy Adults

Depression is usually co-morbid with fatigue. However, we are unaware of studies exploring the relationship between trait energy and fatigue and feelings of depression. Recent evidence suggests that energy and fatigue are two distinct moods. PURPOSE: To examine the association between trait mental and physical energy and fatigue and feelings of depression, within an otherwise healthy young adult cohort. METHODS: Using a cross-sectional design, healthy respondents (n=495) completed a series of self-reported surveys measuring depression, lifestyle factors (sleep, diet, physical activity), and trait mental and physical energy and fatigue. Using a step-wise regression, we controlled for demographics and lifestyle and added trait mental and physical energy and fatigue to the second model. RESULTS: When trait mental and physical energy and fatigue were added to the models, the adjusted R2 increased by 5% (R2 = .112, F(13, 457) = 4.455, p \u3c .001). In our second model, trait mental fatigue was the only significant predictor of depressive mood states (Β = .159, t (457) = 2.512, p = 0.01). CONCLUSION: Young adults, who struggle with high mental fatigue, may also be more likely to report feeling depressed suggesting that fatigue and depression are co-morbid, while low energy and depression are not. Future research should aim to identify epigenetic/genetic factors that influence mental fatigue and how those may be associated with feelings of depression

Effects of a brief mindfulness-based intervention on emotional regulation and levels of mindfulness in senior students

Mindfulness-based interventions have been applied in diverse populations and achieved mental health benefits. This study examined the effects of a brief mindfulness program for emotional regulation and levels of mindfulness on senior students in Brazil. The intervention consisted of six weekly meetings attended by 30 participants. It is a pre-experimental research, with pre- and post-test comparative and correlation measurements. The preliminary results, which relied on parametrical and non-parametrical tests, revealed a reduction in total emotional regulation difficulties (p = 0.0001; r = − 0.55). Also, there was an increase in the levels of mindfulness in the subtests for both dimensions under evaluation: “Awareness” (p = 0.0001; d = 0.77) and “Acceptance” (p = 0.048; d = 0.37). By associating the amount of meditative practices performed by students with the variables, a significant positive correlation was found with the mindfulness dimension “Awareness” (rP = 0.422; p = 0.020), and there was a significant negative correlation with Difficulties in emotion regulation (rS = − 0.478; p = 0.008) and with its respective subscales “Non-acceptance” (rS = − 0.654; p = 0.0001) and “Clarity” (rS = − 0.463; p = 0.010). In conclusion, the application of a brief mindfulness-based intervention is promising in Brazilian university contexts; moreover, it can bring benefits to students, e.g., an increase in emotion regulation as well as in levels of mindfulness. We suggest that further research should use an experimental design and follow-up.info:eu-repo/semantics/publishedVersio

Exploring host-pathogen interactions through genome wide protein microarray analysis

During bacterial pathogenesis extensive contacts between the human and the bacterial extracellular proteomes take place. The identification of novel host-pathogen interactions by standard methods using a case-by-case approach is laborious and time consuming. To overcome this limitation, we took advantage of large libraries of human and bacterial recombinant proteins. We applied a large-scale protein microarray-based screening on two important human pathogens using two different approaches: (I) 75 human extracellular proteins were tested on 159 spotted Staphylococcus aureus recombinant proteins and (II) Neisseria meningitidis adhesin (NadA), an important vaccine component against serogroup B meningococcus, was screened against ∼2300 spotted human recombinant proteins. The approach presented here allowed the identification of the interaction between the S. aureus immune evasion protein FLIPr (formyl-peptide receptor like-1 inhibitory protein) and the human complement component C1q, key players of the offense-defense fighting; and of the interaction between meningococcal NadA and human LOX-1 (low-density oxidized lipoprotein receptor), an endothelial receptor. The novel interactions between bacterial and human extracellular proteins here presented might provide a better understanding of the molecular events underlying S. aureus and N. meningitidis pathogenesis

Poly lactic-co-glycolic acid controlled delivery of Disulfiram to target liver cancer stem-like cells

Disulfiram (DS), an anti-alcoholism drug, shows very strong cytotoxicity in many cancer types. However its clinical application in cancer treatment is limited by the very short half-life in the bloodstream. In this study, we developed a poly lactic-co-glycolic acid (PLGA)-encapsulated DS protecting DS from the degradation in the bloodstream. The newly developed DS-PLGA was characterized. The DS-PLGA has very satisfactory encapsulation efficiency, drug-loading content and controlled release rate in vitro. PLGA encapsulation extended the half-life of DS from shorter than 2 minutes to 7 hours in serum. In combination with copper, DS-PLGA significantly inhibited the liver cancer stem cell population. CI-isobologram showed a remarkable synergistic cytotoxicity between DS-PLGA and 5-FU or Sorafenib. It also demonstrated very promising anticancer efficacy and antimetastatic effect in liver cancer mouse model. Both DS and PLGA are FDA approved products for clinical application. Our study may lead to repositioning of DS into liver cancer treatment

How reliable is assessment of true vocal cord-arytenoid unit mobility in patients affected by laryngeal cancer? a multi-institutional study on 366 patients from the ARYFIX collaborative group

Purpose: In clinical practice the assessment of the “vocal cord-arytenoid unit” (VCAU) mobility is crucial in the staging, prognosis, and choice of treatment of laryngeal squamous cell carcinoma (LSCC). The aim of the present study was to measure repeatability and reliability of clinical assessment of VCAU mobility and radiologic analysis of posterior laryngeal extension. Methods: In this multi-institutional retrospective study, patients with LSCC-induced impairment of VCAU mobility who received curative treatment were included; pre-treatment endoscopy and contrast-enhanced imaging were collected and evaluated by raters. According to their evaluations, concordance, number of assigned categories, and inter- and intra-rater agreement were calculated. Results: Twenty-two otorhinolaryngologists evaluated 366 videolaryngoscopies (total evaluations: 2170) and 6 radiologists evaluated 237 imaging studies (total evaluations: 477). The concordance of clinical rating was excellent in only 22.7% of cases. Overall, inter- and intra-rater agreement was weak. Supraglottic cancers and transoral endoscopy were associated with the lowest inter-observer reliability values. Radiologic inter-rater agreement was low and did not vary with imaging technique. Intra-rater reliability of radiologic evaluation was optimal. Conclusions: The current methods to assess VCAU mobility and posterior extension of LSCC are flawed by weak inter-observer agreement and reliability. Radiologic evaluation was characterized by very high intra-rater agreement, but weak inter-observer reliability. The relevance of VCAU mobility assessment in laryngeal oncology should be re-weighted. Patients affected by LSCC requiring imaging should be referred to dedicated radiologists with experience in head and neck oncology