YAP/TAZ link cell mechanics to Notch signalling to control epidermal stem cell fate

AbstractHow the behaviour of somatic stem cells (SCs) is influenced by mechanical signals remains a black-box in cell biology. Here we show that YAP/TAZ regulation by cell shape and rigidity of the extracellular matrix (ECM) dictates a pivotal SC decision: to remain undifferentiated and grow, or to activate a terminal differentiation programme. Notably, mechano-activation of YAP/TAZ promotes epidermal stemness by inhibition of Notch signalling, a key factor for epidermal differentiation. Conversely, YAP/TAZ inhibition by low mechanical forces induces Notch signalling and loss of SC traits. As such, mechano-dependent regulation of YAP/TAZ reflects into mechano-dependent regulation of Notch signalling. Mechanistically, at least in part, this is mediated by YAP/TAZ binding to distant enhancers activating the expression of Delta-like ligands, serving as ‘in cis’ inhibitors of Notch. Thus YAP/TAZ mechanotransduction integrates with cell–cell communication pathways for fine-grained orchestration of SC decisions.</jats:p

Orthostatic hypotension in a cohort of hypertensive patients referring to a hypertension clinic

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PTPN22 1858C>T Polymorphism Distribution in Europe and Association with Rheumatoid Arthritis: Case-Control Study and Meta-Analysis

The PTPN22 rs2476601 polymorphism is associated with rheumatoid arthritis (RA); nonetheless, the association is weaker or absent in some southern European populations. The aim of the study was to evaluate the association between the PTPN22 rs2476601 polymorphism and RA in Italian subjects and to compare our results with those of other European countries, carrying out a meta-analysis of European data

Reprogramming normal cells into tumour precursors requires ECM stiffness and oncogene-mediated changes of cell mechanical properties

Defining the interplay between the genetic events and microenvironmental contexts necessary to initiate tumorigenesis in normal cells is a central endeavour in cancer biology. We found that receptor tyrosine kinase (RTK)–Ras oncogenes reprogram normal, freshly explanted primary mouse and human cells into tumour precursors, in a process requiring increased force transmission between oncogene-expressing cells and their surrounding extracellular matrix. Microenvironments approximating the normal softness of healthy tissues, or blunting cellular mechanotransduction, prevent oncogene-mediated cell reprogramming and tumour emergence. However, RTK–Ras oncogenes empower a disproportional cellular response to the mechanical properties of the cell’s environment, such that when cells experience even subtle supra-physiological extracellular-matrix rigidity they are converted into tumour-initiating cells. These regulations rely on YAP/TAZ mechanotransduction, and YAP/TAZ target genes account for a large fraction of the transcriptional responses downstream of oncogenic signalling. This work lays the groundwork for exploiting oncogenic mechanosignalling as a vulnerability at the onset of tumorigenesis, including tumour prevention strategies

Influence of involvement of anterior leaflet versus posterior leaflet on residual regurgitation as assessed by transesophageal echocardiography in patients undergoing valve repair for mitral regurgitation due to mitral valve prolapse

<p>Abstract</p> <p>Background</p> <p>Repair of anterior leaflet prolapse is technically more challenging and this might influence outcomes as compared to the repair of posterior leaflet prolapse in patients undergoing surgical correction of mitral regurgitation. We investigated the association of anterior leaflet prolapse with minor residual mitral regurgitation (MR) in patients with mitral valve prolapse (MVP) who underwent valve repair.</p> <p>Methods</p> <p>Eligible for this study were consecutive patients with severe MR due to MVP, who underwent mitral valve repair with residual MR by postpump transesophageal echocardiography ≤2+ during a 20-month period at Pasquinucci Hospital, Massa. Patients undergoing other cardiovascular surgical interventions were excluded. Two groups were defined according to the involvement of mitral valve leaflets: group 1, consisting of patients with anterior leaflet prolapse (isolated or not); and group 2, consisting of patients with isolated posterior leaflet prolapse.</p> <p>Results</p> <p>A total of 70 patients (18 in group 1 and 52 in group 2) were analyzed. Patients in group 2 were younger than those in group 1, but the difference was not significant (P = 0.052). There were no significant differences between the 2 study groups with respect to other variables. The proportion of patients with residual MR 1+/2+ was higher in group 1 than in group 2 (61.1% vs. 32.7%, respectively; P = 0.034). In a logistic regression model, anterior leaflet prolapse was an independent predictor of residual MR 1+/2+ (odds ratio, 4.0; 95% confidence interval, 1.14 to 14.04; P = 0.03).</p> <p>Conclusion</p> <p>In our study population, patients with anterior leaflet prolapse had a higher proportion of residual MR 1+/2+ as compared to those with posterior leaflet prolapse after repair of mitral valve.</p

Business for ocean sustainability: Early responses of ocean governance in the private sector

Este artículo contiene 18 páginas, 2 tablas, 6 figuras.A large sample of 1664 companies—69 directly working in the ocean economy—distributed across 19 industrial sectors was investigated to explore awareness and activation regarding direct and indirect pressures on the ocean, their responses to these pressures, and the disclosure tools used. We examined their accountability and disclosure practices on sustainable development goals (SDGs) using the drivers, pressures, state, welfare, and response accounting framework. Based on their 2019 sustainability reports, just 7% of the companies assessed disclosed on SDG14. However, 51% of these companies can be considered as aware, albeit to varying degrees, of the pressures their industries place on the oceans, 44% deploy mitigating activities, and 26% are aware and actively lead business responses to ocean challenges. Although we have seen just early responses in addressing ocean challenges, companies’ awareness and activation must converge to achieve ocean sustainability and move businesses into a truly blue economy.This research was funded by the One Ocean Foundation (www.1ocean.org), as part of its commitment to the research and diffusion of ocean literacy. Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature.Peer reviewe

Fertility specialists’ views, behavior, and attitudes towards the use of endometrial scratching in Italy

Background: Endometrial scratching (ES) or injury is intentional damage to the endometrium performed to improve reproductive outcomes for infertile women desiring pregnancy. Moreover, recent systematic reviews with meta-analyses and randomized controlled trials demonstrated that ES is not effective, data on the safety are limited, and it should not be recommended in clinical practice. The aim of the current study was to assess the view and behavior towards ES among fertility specialists throughout infertility centers in Italy, and the relationship between these views and the attitudes towards the use of ES as an add-on in their commercial setting. Methods: Online survey among infertility centers, affiliated to Italian Society of Human Reproduction (SIRU), was performed using a detailed questionnaire including 45 questions with the possibility to give "closed" multi-choice answers for 41 items and "open" answers for 4 items. Online data from the websites of the infertility centers resulting in affiliation with the specialists were also recorded and analyzed. The quality of information about ES given on infertility centers websites was assessed using a scoring matrix including 10 specific questions (scored from 0 to 2 points), and the possible scores ranged from 0 to 13 points ('excellent' if the score was 9 points or more, 'moderate' if the score was between 5 and 8, and 'poor' if it was 4 points or less). Results: The response rate was of 60.6% (43 questionnaires / 71 infertility SIRU-affiliated centers). All included questionnaires were completed in their entirety. Most physicians (~ 70%) reported to offer ES to less than 10% of their patients. The procedure is mainly performed in the secretory phase (69.2%) using pipelle (61.5%), and usually in medical ambulatory (56.4%) before IVF cycles to improve implantation (71.8%) without drugs administration (e.g., pain drugs, antibiotics, anti-hemorrhagics, or others) before (76.8%) or after (64.1%) the procedure. Only a little proportion of infertility centers included in the analysis proposes formally the ES as an add-on procedure (9.3%), even if, when proposed, the full description of the indications, efficacy, safety, and costs is never addressed. However, the overall information quality of the websites was generally "poor" ranging from 3 to 8 and having a low total score (4.7 ± 1.6; mean ± standard deviation). Conclusions: In Italy, ES is a procedure still performed among fertility specialists for improving the implantation rate in IVF patients. Moreover, they have a poor attitude in proposing ES as an add-on in the commercial setting

Diagnosis of prostate cancer with magnetic resonance imaging in men treated with 5-alpha-reductase inhibitors

Purpose The primary aim of this study was to evaluate if exposure to 5-alpha-reductase inhibitors (5-ARIs) modifies the effect of MRI for the diagnosis of clinically significant Prostate Cancer (csPCa) (ISUP Gleason grade &gt;= 2).Methods This study is a multicenter cohort study including patients undergoing prostate biopsy and MRI at 24 institutions between 2013 and 2022. Multivariable analysis predicting csPCa with an interaction term between 5-ARIs and PIRADS score was performed. Sensitivity, specificity, and negative (NPV) and positive (PPV) predictive values of MRI were compared in treated and untreated patients.Results 705 patients (9%) were treated with 5-ARIs [median age 69 years, Interquartile range (IQR): 65, 73; median PSA 6.3 ng/ml, IQR 4.0, 9.0; median prostate volume 53 ml, IQR 40, 72] and 6913 were 5-ARIs naive (age 66 years, IQR 60, 71; PSA 6.5 ng/ml, IQR 4.8, 9.0; prostate volume 50 ml, IQR 37, 65). MRI showed PIRADS 1-2, 3, 4, and 5 lesions in 141 (20%), 158 (22%), 258 (37%), and 148 (21%) patients treated with 5-ARIs, and 878 (13%), 1764 (25%), 2948 (43%), and 1323 (19%) of untreated patients (p &lt; 0.0001). No difference was found in csPCa detection rates, but diagnosis of high-grade PCa (ISUP GG &gt;= 3) was higher in treated patients (23% vs 19%, p = 0.013). We did not find any evidence of interaction between PIRADS score and 5-ARIs exposure in predicting csPCa. Sensitivity, specificity, PPV, and NPV of PIRADS &gt;= 3 were 94%, 29%, 46%, and 88% in treated patients and 96%, 18%, 43%, and 88% in untreated patients, respectively.Conclusions Exposure to 5-ARIs does not affect the association of PIRADS score with csPCa. Higher rates of high-grade PCa were detected in treated patients, but most were clearly visible on MRI as PIRADS 4 and 5 lesions.Trial registration The present study was registered at ClinicalTrials.gov number: NCT05078359