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As part of a long-term investigation on the evolution of Passiflora L., we investigated the divergence ages of the genus and diversification of its subgenera, relating them with biogeographical and/or historical events, and other characteristics of this taxon. The main aim of the present work was to evaluate the biogeographic distribution of this genus to better understand its evolutionary history. This is the first time that representatives from South American and Old World Passifloraceae genera have been studied as a group comprising a total of 106 widely distributed species, with representative samples of the four suggested subgenera. Seven DNA regions were studied, comprising 7,431 nucleotides from plastidial, mitochondrial and nuclear genomes. Divergence time estimates were obtained by using a Bayesian Markov Chain Monte Carlo method and a random local clock model for each partition. Three major subgenera have been shown to be monophyletic and here we are proposing to include another subgenus in the Passiflora infrageneric classification. In general, divergence among the four subgenera in Passiflora is very ancient, ranging from ~32 to ~38 Mya, and Passifloraceae seems to follow a biogeographic scenario proposed for several plant groups, originating in Africa, crossing to Europe/Asia and arriving in the New World by way of land bridges. Our results indicated that Passiflora ancestors arrived in Central America and diversified quickly from there, with many long distance dispersion events.

The discovery and characterization of informative intraspecific genetic markers is fundamental for evolutionary and conservation genetics studies. Here, we used nuclear ribosomal ITS sequences to access intraspecific genetic diversity in 23 species of the genus Passiflora L. Some degree of variation was detected in 21 of these. The Passiflora and Decaloba (DC.) Rchb. subgenera showed significant differences in the sizes of the two ITS regions and in GC content, which can be related to reproductive characteristics of species in these subgenera. Furthermore, clear geographical patterns in the spatial distribution of sequence types were identified in six species. The results indicate that ITS may be a useful tool for the evaluation of intraspecific genetic variation in Passiflora.

Abstract Recently, it has been suggested that internal transcribed spacer (ITS) sequences are under selective constraints to preserve their secondary structure. Here, we investigate the patterns of the ITS nucleotide and secondary structure conservation across the Passiflora L. genus to evaluate the potential use of secondary structure data as a helpful tool for the alignment in taxonomically complex genera. Considering the frequent use of ITS, this study also presents a perspective on future analyses in other plant groups. The ITS1 and ITS2 sequences presented significant differences for mean values of the lowest energy state (LES) and for number of hairpins in different Passiflora subgenera. Statistical analyses for the subgenera separately support significant differences between the LES values and the total number of secondary structures for ITS. In order to evaluate whether the LES values of ITS secondary structures were related to selective constraints, we compared these results among 120 ITS sequences from Passiflora species and 120 randomly generated sequences. These analyses indicated that Passiflora ITS sequences present characteristics of a region under selective constraint to maintain the secondary structure showing to be a promising tool to improve the alignments and identify sites with non-neutral substitutions or those correlated evolutionary steps.

Background: Mitochondrial fusion and fission proteins have been nominated as druggable targets in cancer. Whether their inhibition is efficacious in triple negative breast cancer (TNBC) that almost invariably develops chemoresistance is unknown., Methods: We used a combination of bioinformatics analyses of cancer genomic databases, genetic and pharmacological Optic Atrophy 1 (OPA1) inhibition, mitochondrial function and morphology measurements, micro-RNA (miRNA) profiling and formal epistatic analyses to address the role of OPA1 in TNBC proliferation, migration, and invasion in vitro and in vivo., Results: We identified a signature of OPA1 upregulation in breast cancer that correlates with worse prognosis. Accordingly, OPA1 inhibition could reduce breast cancer cells proliferation, migration, and invasion in vitro and in vivo. Mechanistically, while OPA1 silencing did not reduce mitochondrial respiration, it increased levels of miRNAs of the 148/152 family known to inhibit tumor growth and invasiveness. Indeed, these miRNAs were epistatic to OPA1 in the regulation of TNBC cells growth and invasiveness., Conclusions: Our data show that targeted inhibition of the mitochondrial fusion protein OPA1 curtails TNBC growth and nominate OPA1 as a druggable target in TNBC., (© 2022. The Author(s).)

While endothelial cell (EC) function is influenced by mitochondrial metabolism, the role of mitochondrial dynamics in angiogenesis, the formation of new blood vessels from existing vasculature, is unknown. Here we show that the inner mitochondrial membrane mitochondrial fusion protein optic atrophy 1 (OPA1) is required for angiogenesis. In response to angiogenic stimuli, OPA1 levels rapidly increase to limit nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) signaling, ultimately allowing angiogenic genes expression and angiogenesis. Endothelial Opa1 is indeed required in an NFκB-dependent pathway essential for developmental and tumor angiogenesis, impacting tumor growth and metastatization. A first-in-class small molecule-specific OPA1 inhibitor confirms that EC Opa1 can be pharmacologically targeted to curtail tumor growth. Our data identify Opa1 as a crucial component of physiological and tumor angiogenesis., Competing Interests: Declaration of Interests L.S. and A.P. disclose that they are inventors of a submitted patent application by University of Padova and Veneto Institute of Molecular Medicine covering MYLS22 and its derivatives as Opa1 inhibitors. All other authors do not have competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mental health concerns are associated with worse outcomes after adult heart transplant. Illness-specific anxiety is associated with worsened psychological well-being after other solid organ transplants but has never been characterized after pediatric heart transplant. This single-center cross-sectional study aimed to evaluate illness-specific and generalized anxiety after heart transplantation in adolescents. A novel 12-item PHTF, GAD-7, and the PedsQL were administered. Univariate associations of demographics, clinical features, and medication adherence as measured by immunosuppression standard deviation with the PHTF and GAD-7 scores were evaluated. Internal consistency and validity of the PHTF were examined. In total, 30 patients participated. The most common illness-specific fears were retransplantation, rejection, and more generally post-transplant complications. The PHTF had good internal consistency (Cronbach α = .88). Construct validity was demonstrated between PHTF and GAD-7 (r = .62) and PedsQL (r = -.54 to -.62). 23% endorsed moderate to severe generalized anxiety symptoms. More severe symptoms were associated with older age at survey (P = .03), older age at listing (P = .01) and having post-transplant complications (P = .004). Patients with moderate or severe symptoms were more likely to report late immunosuppression doses (P = .004). Illness-specific and generalized anxiety may be prevalent after pediatric heart transplant. Screening for anxiety in adolescents post-transplant may identify those at risk for adverse outcomes including non-adherence. The PHTF is a brief, valid, and reliable instrument identifying illness-specific anxiety in this population., (© 2019 Wiley Periodicals, Inc.)

Across pediatric organ transplant populations, patient and family psychosocial functioning is associated with important health-related outcomes. Research has suggested that pediatric heart transplant recipients and their families are at increased risk for adverse psychosocial outcomes; however, recent investigation of psychosocial functioning in this population is lacking. This study aimed to provide a contemporary characterization of psychosocial functioning in pediatric heart transplant recipients and their families. Associations between psychosocial function, demographic variables, and transplant-related variables were investigated. Fifty-six parents/guardians of pediatric heart transplant recipients completed a comprehensive psychosocial screening measure during transplant follow-up clinic visits. Descriptive statistics, correlational analyses, and independent samples t tests were performed. Forty percent of pediatric heart transplant recipients and their families endorsed clinically meaningful levels of total psychosocial risk. One-third of patients presented with clinically significant psychological problems per parent report. Psychosocial risk was unassociated with demographic or transplant-related factors. Despite notable improvements in the survival of pediatric heart transplant recipients over the past decade, patients and families present with sustained psychosocial risks well beyond the immediate post-transplant period, necessitating mental health intervention to mitigate adverse impact on health-related outcomes., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In pediatric heart transplant recipients, elevated pulmonary capillary wedge pressure (PCWP) is associated with rejection and coronary artery vasculopathy. This study aimed to evaluate which echocardiographic parameters track changes in PCWP and predict adverse outcomes (rejection or coronary artery vasculopathy). This prospective single-center study enrolled 49 patients (median 11.4 years old, interquartile range 7.4 to 16.5) at time of cardiac catheterization and echocardiography. Median follow-up was 2.4 years (range 1.2 to 3.1 years), with serial testing per clinical protocol. Ratio of early mitral inflow to annular velocity (E/E'), left atrial (LA) distensibility, peak LA systolic strain, E/left ventricular (LV) diastolic strain, and E/LV diastolic strain rate were measured from echocardiograms. Increase in PCWP ≥3 mm Hg was associated with changes in LA distensibility, E/E', and E/LV diastolic strain, with highest area under the receiver operating characteristic curve for E/LV diastolic strain (0.76). In 9 patients who subsequently developed rejection or coronary artery vasculopathy, E/LV diastolic strain rate at baseline differed from patients without events (median 57.0 vs 43.6, p = 0.02). On serial studies, only change in LV ejection fraction differed in patients with events (median -10% vs -1%, p = 0.01); decrease in LV ejection fraction of -19% had a specificity of 100% and sensitivity of 44%. In conclusion, LV diastolic strain and strain rate measurements can track changes in PCWP and identify patients at risk for subsequent rejection or coronary artery vasculopathy. Further studies are necessary to confirm these data in a larger cohort., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Post-Fontan protein-losing enteropathy (PLE) is associated with significant morbidity and mortality. Although heart transplantation (HTx) can be curative, PLE may increase the risk of morbidity before and after HTx. This study analyzed the influence of PLE influence on waiting list and post-HTx outcomes in a pediatric cohort., Methods: Fontan patients listed for HTx and enrolled in the Pediatric Heart Transplant Study from 1999 to 2012 were stratified by a diagnosis of PLE, and the association of PLE with waiting list and post-HTx mortality, rejection, and infection was analyzed., Results: Compared with non-PLE Fontan patients (n = 260), PLE patients listed for HTx (n = 96) were older (11.9 years vs 7.6 years; p = 0.003), had a larger body surface area (1.1 m(2) vs 0.9 m(2); p = 0.0001), had lower serum bilirubin (0.5 vs 0.9 mg/dl; p = 0.01), lower B-type natriuretic peptide (59 vs 227 pg/ml; p = 0.006), and were less likely to be on a ventilator (3% vs 13%; p = 0.006). PLE patients had lower waiting list mortality than non-PLE Fontan patients (p < 0.0001). There were no intergroup differences for post-HTx survival or times to the first infection or rejection. PLE was not independently associated with increased post-HTx mortality at any time point., Conclusions: In this multicenter cohort, the diagnosis of PLE alone was not associated with increased waiting list mortality or post-HTx morbidity or mortality. Given the limitations of our data, this analysis suggests that PLE patients in the pediatric age group have outcomes similar to their non-PLE counterparts. Additional multicenter studies of PLE patients with targeted collection of PLE-specific information will be necessary to fully delineate the risks conferred by PLE for HTx., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Pediatric data on the impact of pre-heart transplantation (HTx) risk factors on early post-HTx outcomes remain inconclusive. Thus, among patients with previous congenital heart disease or cardiomyopathy, disease-specific risk models for graft loss were developed with the use pre-HTx recipient and donor characteristics., Methods and Results: Patients enrolled in the Pediatric Heart Transplant Study (PHTS) from 1996 to 2006 were stratified by pre-HTx diagnosis into cardiomyopathy and congenital heart disease cohorts. Logistic regression identified independent, pre-HTx risk factors. Risk models were constructed for 1-year post-HTx graft loss. Donor factors were added for model refinement. The models were validated with the use of patients transplanted from 2007 to 2009. Risk factors for graft loss were identified in patients with cardiomyopathy (n=896) and congenital heart disease (n=965). For cardiomyopathy, independent risk factors were earlier year of transplantation, nonwhite race, female sex, diagnosis other than dilated cardiomyopathy, higher blood urea nitrogen, and panel reactive antibody >10%. The recipient characteristic risk model had good accuracy in the validation cohort, with predicted versus actual survival of 97.5% versus 95.3% (C statistic, 0.73). For patients with congenital heart disease, independent risk factors were nonwhite race, history of Fontan, ventilator dependence, higher blood urea nitrogen, panel reactive antibody >10%, and lower body surface area. The risk model was less accurate, with 86.6% predicted versus 92.4% actual survival, in the validation cohort (C statistic, 0.63). Donor characteristics did not enhance model precision., Conclusions: Risk factors for 1-year post-HTx graft loss differ on the basis of pre-HTx cardiac diagnosis. Modeling effectively stratifies the risk of graft loss in patients with cardiomyopathy and may be an adjunctive tool in allocation policies and center performance metrics., (© 2015 American Heart Association, Inc.)

Background: Little is known about the quality of life (QOL) of children with heart disease who undergo life-saving surgery. The aim of this multicenter study was to examine self- and parent-reported QOL outcomes in pediatric heart transplant recipients., Methods: Pediatric heart transplant recipients/families (n = 174) from 7 transplant programs completed the Pediatric Quality of Life Inventory Generic Core Scales and Cardiac Module. Scores for the heart transplant sample were compared with non-transplant patients who had undergone conventional cardiac surgery and with a healthy child sample. Within the cardiac surgery group, heart disease/surgery was further categorized by severity/complexity., Results: Heart transplant recipients were a mean age of 10.6 ± 4.7 years at a mean time post-transplant of 6.0 ± 4.1 years. By both self-report and parent proxy report, mean scores for heart transplant recipients were significantly lower than those in healthy children for physical and psychosocial QOL, including emotional and social functioning (p < 0.001), with 31.3% self-reporting significantly impaired psychosocial QOL scores. By self-report, there were no significant differences in emotional and social mean scores between the transplant and cardiac surgery groups. Transplant recipients reported significantly fewer cardiac symptoms than children with cardiac surgery (p < 0.01). Their self-reported school functioning scores were not significantly different from children with moderate to severe disease., Conclusion: Although pediatric heart transplant recipients experience significant symptomatic improvement, they remain at-risk for impaired psychosocial QOL, similar to children with residual or palliated heart disease. Assessment is needed to identify children at-risk and improve psychosocial outcomes., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

This paper will present the workflow developed for the application of serious games in the design of complex cooperative work settings. The project was based on ergonomic studies and development of a control room among participative design process. Our main concerns were the 3D human virtual representation acquired from 3D scanning, human interaction, workspace layout and equipment designed considering ergonomics standards. Using Unity3D platform to design the virtual environment, the virtual human model can be controlled by users on dynamic scenario in order to evaluate the new work settings and simulate work activities. The results obtained showed that this virtual technology can drastically change the design process by improving the level of interaction between final users and, managers and human factors team.

The aim in this paper is to present a research on the application of serious games for the design of laboratories in the oil and gas industries. The focus is in human virtual representation acquired from 3D scanning, human interaction, workspace layout and equipment designed considering ergonomics standards. The laboratory studies were simulated in Unity3D platform, which allows the users to control the DHM1 on the dynamic virtual scenario, in order to simulate work activities. This methodology can change the design process by improving the level of interaction between final users, managers and human factor teams. That helps to better visualize future work settings and improve the level of participation between all stakeholders.

Background: The course of pediatric hypertrophic cardiomyopathy (HCM) is variable, and the indications for heart transplantation (HTx) are ill defined. This study investigated outcomes and risk factors for adverse outcomes after listing for HTx., Methods: A multicenter, event-driven data registry of patients aged < 18 years listed for HTx between January 1993 and December 2007 was used., Results: During the study period, 3,147 children were listed for HTx (mean age, 7.6 +/- 0.8 years). Of l,320 with CM at listing, 77 (6%) had HCM (61% boys; 79% white); 59% were United Network of Organ Sharing (UNOS) status I, 30% were receiving inotropes, 27% were ventilated, and 8% required extracorporeal membrane oxygenation. Arrhythmia had occurred in 27%, and 14% had failure to thrive. Within 1 year, 65% underwent HTx. Overall, 25 patients died after listing: 11 (14%) while waiting and 14 of 49 (29%) after HTx. Pre-HTx survival was lower for those listed at age < 1 year (p = 0.0005). Risk factors for death after listing included UNOS status 1 (p = 0.01) and younger age (relative risk, 2.3; p = 0.001). Late (10-year) survival after HTx for HCM patients was 47% vs 63% for non-CM patients within the database., Conclusions: Children with HCM listed for HTx age < 1 year and UNOS status 1 have the highest mortality awaiting HTx. A more rigorous identification of additional risk factors should be performed to better define timing of listing and which patient sub-group may derive optimal benefit from HTx.

Background: HLA sensitization rates in children on extracorporeal membrane oxygenation (ECMO) or ventricular assist devices (VADs) are unknown. In addition, panel-reactive antibody (PRA) assessment is increasingly being performed by Luminex, whose role in comparison to other conventional methods is unclear. We investigated HLA sensitization of mechanically supported children using established PRA methods and then retested stored serum using Luminex to assess its impact on initial PRA results and post-heart transplant (post-HTx) outcomes., Methods: Data on 22 pre-HTx ECMO or VAD patients (0 to 18 years of age) included: age; duration of mechanical support; use of homograft; red cell transfusion volume; PRAs; and outcome. Comparative data were collected from 10 non-supported, age-matched controls., Results: Median age of the 13 ECMO and 9 VAD patients was 1.4 and 192 months (p < 0.001), respectively. Six (27%) device patients and 4 (40%) controls had baseline PRAs >10% (p = 0.7). No ECMO but 6 VAD patients were sensitized after 50 +/- 51 days of support (p = 0.02). Compared with ECMO, VAD patients had higher Class I PRAs according to enzyme-linked immunoassay (p = 0.03). VAD patients had higher final vs initial PRAs for Class I (p = 0.05) and II (p = 0.04) antigens. HLA sensitization was independent of transfusion volume. Only complement-dependent cytotoxicity (CDC) Class I PRAs were different from their respective Luminex values (p = 0.03). Four HTx patients with initially low PRAs but elevated post hoc Luminex assays had no rejection at 3.8 +/- 1.6 years post-HTx., Conclusions: Infants supported with ECMO are at low risk for HLA sensitization. Because it provides full antibody specificity disclosure, Luminex complements more conventional PRA assays by quantitatively identifying potential donor-specific antibodies, which should facilitate the virtual crossmatch process, thereby minimizing post-HTx humoral rejection risk.