The “History” of Desmosines: Forty Years of Debate on the Hypothesis That These Two Unnatural Amino Acids May Be Potential Biomarkers of Chronic Obstructive Pulmonary Disease

Desmosine and isodesmosine (collectively known as desmosines), two unnatural amino acids unique to mature elastin in humans, have been widely discussed as being potential biomarkers of disorders, which involve connective tissue and whose clinical manifestations result in elastin degradation. In particular, experimental data accumulated over the last 40 years have demonstrated that patients with chronic obstructive pulmonary disease (COPD) excrete higher amounts of urinary desmosines than healthy controls. Based on this evidence, it has been speculated by several authors that these cross-links may be potential biomarkers of COPD with clinical significance. Nevertheless, a strict correlation between the amount of these amino acids and the severity of the disease still has to be demonstrated. For this reason, the debate on the opportunity to consider desmosines as biomarkers of COPD is still open, and the development of sophisticated methods aimed at obtaining very precise measurement of their concentration is still considered technically challenging. The aim of this chapter is to trace the history of this debate through the presentation and discussion of a large number of articles dealing with the detection and quantification of desmosines in different biological fluids, from early years until the present

Modelling potential maize yield with climate and crop conditions around flowering

Abstract Understanding, and then modelling, the effects of sowing date and cultivar on maize yield is essential to develop appropriate climate change adaptation strategies. Here we test the WOFOST model and a hybrid model, based on physiological crop conditions around flowering, against observed data collected during 4 years of field experiments in a Mediterranean environment under fully irrigated conditions. We simulate sowing date and cultivar responses by using 45-year historical meteorological records from the experimental weather station and future climate conditions till 2060 as projected by a set of regional climate models. Both WOFOST and the hybrid approach reveal good performance in simulating average maize yield. However, the hybrid one outperforms WOFOST with respect to its responsiveness to changes in sowing date and cultivar. These findings, besides stressing the importance of crop conditions around flowering in determining maize yield, point to lower yields (14 %–17 %, average reduction) under future climate conditions. The estimated losses may only be partially offset by changes in phenology and sowing dates

First-time mothers’ experiences of early labour in Italian maternity care services

OBJECTIVE: The aim of this study is to explore first-time mothers' experiences of early labour in Italian maternity care services when admitted to hospital or advised to return home after maternity triage assessment.SETTING: The study was conducted in a second-level maternity hospital in northern Italy with an obstetric unit for both low- and high-risk women.PARTICIPANTS: The participants included 15 first-time mothers in good general health with spontaneous labour at term of a low-risk pregnancy who accessed maternity triage during early labour, and were either admitted to hospital or advised to return home.DESIGN: A qualitative interpretive phenomenological study was conducted. A face-to-face recorded semi-structured interview was conducted with each participant 48-72h after birth.FINDINGS: Four key themes emerged from the interviews: (a) recognising signs of early labour; (b) coping with pain at home; (c) seeking reassurance from healthcare professionals; and (d) being admitted to hospital versus returning home. Uncertainty about the progression of labour and the need for reassurance were cited by women as the main reasons for hospital visit in early labour. An ambivalent feeling was reported by the participants when admitted to hospital in early labour. In fact, while the women felt reassured in the first instance, some women subsequently felt dissatisfied due to the absence of one-to-one dedicated care during early labour. When advised to return home, a number of women reported feelings of disappointment, anger, fear, discouragement and anxiety about not being admitted to hospital; however, some of these women reported a subsequent feeling of comfort due to being at home and putting in place the suggestions made by the midwives during the maternity triage assessment. The guidance provided by midwives during triage assessment seemed to be the key factor influencing women?s satisfaction when advised either to return home or to stay at the hospital during early labour.CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: During antenatal classes and clinics, midwives should provide clear information and advice about early labour in order to increase women?s confidence and self-efficacy, and decrease their anxiety and fear. During early labour, appropriate maternity care services should be offered according to individual needs. When home visits are not provided by midwives, a telephone triage run by midwives should be considered as a routine service for the first point of contact with women during early labour

Cathodal transcranial direct current stimulation improves focal hand dystonia in musicians: A two-case study

Focal hand dystonia (FHD) in musicians is a movement disorder causing abnormal movements and irregularities in playing. Since weak electrical currents applied to the brain induce persistent excitability changes in humans, cathodal tDCS was proposed as a possible non-invasive approach for modulating cortical excitability in patients with FHD. However, the optimal targets and modalities have still to be determined. In this pilot study, we delivered cathodal (2 mA), anodal (2 mA) and sham tDCS over the motor areas bilaterally for 20 min daily for five consecutive days in two musicians with FHD. After cathodal tDCS, both patients reported a sensation of general wellness and improved symptoms of FHD. In conclusion, our pilot results suggest that cathodal tDCS delivered bilaterally over motor-premotor (M-PM) cortex for 5 consecutive days may be effective in improving symptoms in FHD

The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization

During oligodendrocyte precursor cell (OPC) differentiation, defective control of the membrane receptor GPR17 has been suggested to block cell maturation and impair remyelination under demyelinating conditions. After the immature oligodendrocyte stage, to enable cells to complete maturation, GPR17 is physiologically down-regulated via phosphorylation/desensitization by G protein-coupled receptor kinases (GRKs); conversely, GRKs are regulated by the "mammalian target of rapamycin" mTOR. However, how GRKs and mTOR are connected to each other in modulating GPR17 function and oligodendrogenesis has remained elusive. Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of the onco-suppressor p53 protein. In maturing OPCs, both rapamycin and Nutlin-3, a small molecule inhibitor of Mdm2-p53 interactions, increased GRK2 sequestration by Mdm2, leading to impaired GPR17 down-regulation and OPC maturation block. Thus, Mdm2 intertwines mTOR with GRK2 in regulating GPR17 and oligodendrogenesis and represents a novel actor in myelination

The experiences of childbearing women who tested positive to COVID-19 during the pandemic in northern Italy

ProblemThe COVID-19 pandemic has significantly challenged maternity provision internationally. COVID-19 positive women are one of the childbearing groups most impacted by the pandemic due to drastic changes to maternity care pathways put in place.BackgroundSome quantitative research was conducted on clinical characteristics of pregnant women with COVID-19 and pregnant women’s concerns and birth expectations during the COVID-19 pandemic, but no qualitative findings on childbearing women’s experiences during the pandemic were published prior to our study.AimTo explore childbearing experiences of COVID-19 positive mothers who gave birth in the months of March and April 2020 in a Northern Italy maternity hospital.MethodsA qualitative interpretive phenomenological approach was undertaken. Audio-recorded semi-structured interviews were conducted with 22 women. Thematic analysis was completed using NVivo software. Ethical approval was obtained from the research site’s Ethics Committee prior to commencing the study.FindingsThe findings include four main themes: 1) coping with unmet expectations; 2) reacting and adapting to the ‘new ordinary’; 3) ‘pandemic relationships’; 4) sharing a traumatic experience with long-lasting emotional impact.DiscussionThe most traumatic elements of women’s experiences were the sudden family separation, self-isolation, transfer to a referral centre, the partner not allowed to be present at birth and limited physical contact with the newborn.ConclusionKey elements of good practice including provision of compassionate care, presence of birth companions and transfer to referral centers only for the most severe COVID-19 cases should be considered when drafting maternity care pathways guidelines in view of future pandemic waves

G PROTEIN-COUPLED RECEPTOR DESENSITISATION REGULATES STEM CELL DIFFERENTIATION

G-protein coupled receptors (GPCRs) play a key role in many complex biological processes, including regulation of stem cell pluripotency and differentiation. Signal transduction pathways that are activated during stem cell renewal and differentiation are shared, cross-activated or synergistic with GPCR stimulation [1]. Regulation of GPCR responses involved the activation of desensitization machinery, which started with phosphorylation of agonist-activated receptor by second messenger-dependent and/or GPCR kinases (GRKs)[1]. Besides controlling receptor responsiveness, GRKs can also act as agonist-regulated scaffolds assembling macromolecular signalosomes in the receptor environment, thereby contributing to signal propagation from cytosol to nucleus, and controlling gene transcription machinery [2]. Recent evidence suggests that the desensitization machinery fulfils a vital role in regulating cellular responses to GPCRs, and that changes in expression/functioning of these regulatory proteins may be crucial in the control of cell differentiation program [3]. These data are consistent with the notion that GPCR responsiveness may be differentially regulated during cell differentiation. In our hands, two different cellular models (oligodendrocyte precursor cells, OPCs, and mesenchymal stem cells, MSCs) were used to investigate the role of the GPCR desensitisation machinery in stem cell differentiation. During OPC differentiation, defective control of the membrane receptor GPR17 has been suggested to block cell maturation and impairs remyelination under demyelinating conditions [4]. Here we show, for the first time, a role for Murine double minute 2 (Mdm2), a ligase previously involved in ubiquitination/degradation of p53 protein. In maturing OPCs, the inhibition of Mdm2-p53 interactions increased GRK2 sequestration by Mdm2, leading to impaired GPR17 down-regulation and OPC maturation block. In MSCs, the A2B adenosine receptor (A2BAR) has been recently emerged as the major AR involved in osteoblastogenesis [5]. Proinflammatory cytokines, such as Tumour Necrosis Factor- (TNF-, have been demonstrated to regulate MSC differentiation and bone remodelling. Herein, we show that TNF- diminished GRK2 levels in MSCs, thus blocking A2BAR desensitization. As a result, TNF- enhanced the A2BAR-mediated responses and favoured MSC differentiation to osteoblasts in response to receptor agonists. The findings get new insights for discovering of the signals at the basis of cell differentiation

Monoclonal antibodies to human low density lipoprotein identify distinct areas on apolipoprotein B-100 relevant to the low density lipoprotein-receptor interaction.

We have characterized the epitopes for ten murine monoclonal antibodies (Mabs) to human low density lipoprotein (LDL) and studied their ability to interfere with the LDL-receptor interaction. The epitopes for the antibodies were defined by using the following approaches: 1) interaction with apoB-48; 2) interaction with apoB-100 thrombolytic fragments; and 3) interaction with beta-galactosidase-apoB fusion proteins spanning different areas of the apoB-100 sequence. The results obtained are consistent with the following map of epitopes: Mab 6E, amino acids (aa) 1-1297, Mabs 5A and 6B, aa 1480-1693, Mabs 2A, 7A, 3B, and 4B, aa 2152-2377, Mabs 8A and 9A, aa 2657-3248 and 3H, aa 4082-4306. Four Mabs (2A, 5A, 7A, and 9A) whose epitopes are located in three different areas of apoB, dramatically reduced (up to 95%) the LDL-receptor interaction on cultured human fibroblasts; Fab fragments were as effective as the whole antibodies. Mab 3H, on the other hand, increased LDL binding up to threefold. These findings are consistent with the hypothesis that several areas of apoB-100 are involved independently or in concert in modulating the apoprotein B conformation required for interaction with the LDL receptor

TiO2@BSA nano-composites investigated through orthogonal multi-techniques characterization platform.

Abstract Biocompatible coating based on bovine serum albumin (BSA) was applied on two different TiO2 nanoparticles (aeroxide P25 and food grade E171) to investigate properties and stability of resulting TiO2@BSA composites, under the final perspective to create a "Safe-by-Design" coating, able to uniform, level off and mitigate surface chemistry related phenomena, as naturally occurring when nano-phases come in touch with proteins enriched biological fluids. The first step towards validating the proposed approach is a detailed characterization of surface chemistry with the quantification of amount and stability of BSA coating deposited on nanoparticles' surfaces. At this purpose, we implemented an orthogonal multi-techniques characterization platform, providing important information on colloidal behavior, particle size distribution and BSA-coating structure of investigated TiO2 systems. Specifically, the proposed orthogonal approach enabled the quantitative determination of bound and free (not adsorbed) BSA, a key aspect for the design of intentionally BSA coated nano-structures, in nanomedicine and, overall, for the control of nano-surface reactivity. In fact, the BSA-coating strategy developed and the orthogonal characterisation performed can be extended to different designed nanomaterials in order to further investigate the protein-corona formation and promote the implementation of BSA engineered coating as a strategy to harmonize the surface reactivity and minimize the biological impact

Timing of hospital admission in labour: latent versus active phase, mode of birth and intrapartum interventions: a correlational study

Background Hospitalization of women in latent labour often leads to a cascade of unnecessary intrapartum interventions, to avoid potential disadvantages the recommendation should be to stay at home to improve women’s experience and perinatal outcomes. Aim The primary aim of this study was to investigate the association between hospital admission diagnosis (latent vs active phase) and mode of birth. The secondary aim was to explore the relationship between hospital admission diagnosis, intrapartum intervention rates and maternal/neonatal outcomes. Methods A correlational study was conducted in a large Italian maternity hospital. Data from January 2013 to December 2014 were collected from the hospital electronic records. 1.446 records of low risk women were selected. These were dichotomized into two groups based on admission diagnosis: ‘latent phase’ or ‘active phase’ of labour. Findings 52.7% of women were admitted in active labour and 47.3% in the latent phase. Women in the latent phase group were more likely to experience a caesarean section or an instrumental birth, artificial rupture of membranes, oxytocin augmentation and epidural analgesia. Admission in the latent phase was associated with higher intrapartum interventions, which were statistically correlated to the mode of birth. Conclusions Women admitted in the latent phase were more likely to experience intrapartum interventions, which increase the probability of caesarean section. Maternity services should be organized around women and families needs, providing early labour support, to enable women to feel reassured facilitating their admission in labour to avoid the cascade of intrapartum interventions which increases the risk of caesarean section