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Cellular senescence is a dynamic biological process triggered by sublethal cell damage and driven by specific changes in gene expression programs. We recently identified ANKRD1 (ankyrin repeat domain 1) as a protein strongly elevated after triggering senescence in fibroblasts. Here, we set out to investigate the mechanisms driving the elevated production of ANKRD1 in the early stages of senescence. Our results indicated that the rise in ANKRD1 levels after triggering senescence using etoposide (Eto) was the result of moderate increases in transcription and translation, and robust mRNA stabilization. Antisense oligomer (ASO) pulldown followed by mass spectrometry revealed a specific interaction of the RNA-binding protein RBMS1 with ANKRD1 mRNA that was confirmed by ribonucleoprotein immunoprecipitation analysis. RBMS1 abundance decreased in the nucleus and increased in the cytoplasm during Eto-induced senescence; in agreement with the hypothesis that RBMS1 may participate in post-transcriptional stabilization of ANKRD1 mRNA, silencing RBMS1 reduced, while overexpressing RBMS1 enhanced ANKRD1 mRNA half-life after Eto treatment. A segment proximal to the ANKRD1 coding region was identified as binding RBMS1 and conferring RBMS1-dependent increased expression of a heterologous reporter. We propose that RBMS1 increases expression of ANKRD1 during the early stages of senescence by stabilizing ANKRD1 mRNA. [ABSTRACT FROM AUTHOR]

Introduction: Research into the first phase of the COVID-19 lockdown in Italy showed an association with an increased susceptibility to adverse mental health (MH) in the general population. We investigated in the same population the correlations between the various demographic, socioeconomic, biological/clinical history and psychological dimensions and MH in the second, "opening-up", phase of the lockdown. Methods: An anonymous online survey collected data from 26 May to 4 July 2020 on demographic, socioeconomic, perceived risk, general health and quality of life appraisals, worry, interference in life, life satisfaction, perceived happiness and MH by using Mental Health Inventory-5 (MHI-5). Results: Of the 300 participants, only 195 responded to MH questions. Older age was positively associated with better MH (r=.15), as was education (r=.19). A negative correlation with MH, with medium-high effect size, was found with quality of life (r=.40) and health (r=.34) appraisals, and the factors "worry about sustenance" (r=.23) and "interference with life" (r=.32). A positive correlation, with strong effect size, was found between MH and life satisfaction (r=.53) and perception of happiness (r=.64). Discussion: During phase two of the lockdown, rather the real impact of COVID-19 restrictions on employment or economic resources, it was worry about finances that was associated with worse MH. Mental distress was associated with the loss of some positive psychological factors. From a homeostatic and biopsychosocial perspective of MH, life satisfaction and perceived happiness represent important mental resources for counteracting the effects of lockdown on MH. [ABSTRACT FROM AUTHOR]

The origin of Carbon Enhanced Metal-Poor (CEMP-no) stars with low abundances of neutron-capture elements is still unclear. These stars are ubiquitous, found primarily in the Milky Way halo and ultra-faint dwarf galaxies (UFDs). To make a major step forward, we developed a data-calibrated model for Böotes I that simultaneously includes all carbon sources: supernovae and asymptotic giant branch (AGB) stars both from first (Pop III) stars, and subsequent normal star formation (Pop II). We demonstrate that each of these sources leaves a specific chemical signature in the gas, allowing us to identify the origin of present day CEMP-no stars through their location in the A(C)–[Fe/H] diagram. The CEMP stars with A(C) > 6 are predominantly enriched by AGB Pop II stars. We identify a new class of moderate CEMP-s stars with A(C) ∼7 and 0 < [Ba/Fe] < + 1, imprinted by winds from AGB stars. True Pop III descendants are predicted to have A(C) < 6 and a constant [C/Mg] with [Fe/H], in perfect agreement with observations in Böotes I and the Milky Way halo. For the first time we now have a complete picture of the origins of CEMP-no stars which can and will be verified with future observations. [ABSTRACT FROM AUTHOR]

Senescent cells release a variety of cytokines, proteases, and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Sustained SASP contributes to a pattern of chronic inflammation associated with aging and implicated in many age-related diseases. Here, we investigated the expression and function of the immunomodulatory cytokine BAFF (B-cell activating factor; encoded by the TNFSF13B gene), a SASP protein, in multiple senescence models. We first characterized BAFF production across different senescence paradigms, including senescent human diploid fibroblasts (WI-38, IMR-90) and monocytic leukemia cells (THP-1), and tissues of mice induced to undergo senescence. We then identified IRF1 (interferon regulatory factor 1) as a transcription factor required for promoting TNFSF13B mRNA transcription in senescence. We discovered that suppressing BAFF production decreased the senescent phenotype of both fibroblasts and monocyte-like cells, reducing IL6 secretion and SA-ß-Gal staining. Importantly, however, the influence of BAFF on the senescence program was cell type-specific: in monocytes, BAFF promoted the early activation of NF-κB and general SASP secretion, while in fibroblasts, BAFF contributed to the production and function of TP53 (p53). We propose that BAFF is elevated across senescence models and is a potential target for senotherapy. [ABSTRACT FROM AUTHOR]

The Cre-lox system is a versatile and powerful tool used in mouse genetics. It allows spatial and/or temporal control of the deletion of a target gene. The Rosa26-CreERT2 (R26CreERT2) mouse model allows ubiquitous expression of CreERT2. Once activated by tamoxifen, CreERT2 will enter into the nuclei and delete floxed DNA sequences. Here, we show that intraperitoneal injection of tamoxifen in young R26CreERT2 mice leads to morbidity and mortality within 10 days after the first injection, in the absence of a floxed allele. Activation of CreERT2 by tamoxifen led to severe hematological defects, with anemia and a strong disorganization of the bone marrow vascular bed. Cell proliferation was significantly reduced in the bone marrow and the spleen resulting in the depletion of several hematopoietic cells. However, not all cell types or organs were affected to the same extent. We realized that many research groups are not aware of the potential toxicity of Cre recombinases, resulting in misinterpretation of the observed phenotype and in a waste of time and resources. We discuss the necessity to include tamoxifen injected CreERT2 controls lacking a floxed allele in experimental designs and to improve communication about the limitations of Cre-lox mouse models among the scientific community. [ABSTRACT FROM AUTHOR]

Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is also expressed in neurons, skin melanocytes, and peripheral nerve fibers. Immunotherapy with monoclonal anti-GD2 antibodies has a proven efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma. However, the strong neuro-toxicity associated with anti-GD2 antibodies administration has hindered, until now, the possibility for dose-escalation and protracted use, thus restraining their therapeutic potential. Strategies to increase the efficacy of anti-GD2 antibodies are actively sought, with the aim to enable chronic treatments that could eradicate minimal residual disease and subsequent relapses, often occurring after treatment. Here, we report that Nanofenretinide and Nanospermidine improved the expression of GD2 in neuroblastoma cells (CHP-134) and provided different effects in combination with the anti-GD2 antibody naxitamab. In particular, Nanofenretinide significantly increased the cytotoxic effect of naxitamab while Nanospermidine inhibited cell motility at extents proportional to naxitamab concentration. In neuroblastoma cells characterized by a low and heterogeneous basal expression of GD2, such as SH-SY5Y, which may represent the cell heterogeneity in tumors after chemotherapy, both Nanofenretinide and Nanospermidine increased GD2 expression in approximately 50% of cells, thus shifting the tumor population towards improved sensitivity to anti-GD2 antibodies. [ABSTRACT FROM AUTHOR]

Among the functions exerted by eukaryotic lactate dehydrogenases, it is of importance the generation of lactate in muscles subjected to fatigue or to limited oxygen availability, with both these conditions triggering a decrease of cellular pH. However, the mutual dependence between lactate dehydrogenase (LDH) catalytic action and lactic acidosis is far from being fully understood. Here we show that the tetrameric LDH from rabbit skeletal muscle undergoes allosteric transitions as a function of pH, i.e. the enzyme obeys Michaelis-Menten kinetics at neutral or slightly alkaline pH values, and features sigmoidal kinetics at pH 6.5 or lower. Remarkably, we also report that a significant dissociation of tetrameric rabbit LDH occurs under acidic conditions, with pyruvate/NAD+ or citrate counteracting this effect. Moreover, citrate strongly activates rabbit LDH, inducing the enzyme to feature Michaelis-Menten kinetics. Further, using primary rabbit skeletal muscle cells we tested the generation of lactate as a function of pH, and we detected a parallel decrease of cytosolic pH and secretion of lactate. Overall, our observations indicate that lactic acidosis is antagonized by LDH dissociation, the occurrence of which is regulated by citrate and by allosteric transitions of the enzyme induced by pyruvate. • Acidic pH conditions trigger allosteric transitions in rabbit lactate dehydrogenase. • The dissociation of lactate dehydrogenase tetramer induces allosteric kinetics. • Allosteric kinetics does not depend on enzyme post-translational modifications. • Citrate, isocitrate, fructose 1,6-bisphosphate, and malate activate rabbit lactate dehydrogenase. • The acidification of cytosolic pH inhibits lactate secretion by rabbit muscle cells. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is a malignant disease characterized by poor prognosis due to a high incidence of metastasis and chemoresistance. Recently, Licochalcone A (Lic-A) has been reported as a promising agent against OS. Starting from chalcones selected from a wide in-house library, a new series was designed and synthetized. The antitumor activity of the compounds was tested on the MG63 OS cell line through the innovative Quantitative Phase Imaging technique and MTT assay. To further investigate the biological profile of active derivatives, cell cycle progression and apoptosis induction were evaluated. An earlier and more consistent arrest in the G2-M phase with respect to Lic-A was observed. Moreover, apoptosis was assessed by Annexin V staining as well as by the detection of typical morphological features of apoptotic cells. Among the selected compounds, 1e, 1q, and 1r proved to be the most promising antitumor molecules. This study pointed out that an integrated methodological approach may constitute a valuable platform for the rapid screening of large series of compounds. [ABSTRACT FROM AUTHOR]

A new strategy to cause cell death in tumors might be the increase of intracellular polyamines at concentrations above their physiological values to trigger the production of oxidation metabolites at levels exceeding cell tolerance. To test this hypothesis, we prepared nanospermidine as a carrier for spermidine penetration into the cells, able to escape the polyamine transport system that strictly regulates intracellular polyamine levels. Nanospermidine was prepared by spermidine encapsulation in nanomicelles and was characterized by size, zeta potential, loading, dimensional stability to dilution, and stability to spermidine leakage. Antitumor activity, ROS production, and cell penetration ability were evaluated in vitro in two neuroblastoma cell lines (NLF and BR6). Nanospermidine was tested as a single agent and in combination with nanofenretinide. Free spermidine was also tested as a comparison. The results indicated that the nanomicelles successfully transported spermidine into the cells inducing cell death in a concentration range (150–200 μM) tenfold lower than that required to provide similar cytotoxicity with free spermidine (1500–2000 μM). Nanofenretinide provided a cytostatic effect in combination with the lowest nanospermidine concentrations evaluated and slightly improved nanospermidine cytotoxicity at the highest concentrations. These data suggest that nanospermidine has the potential to become a new approach in cancer treatment. At the cellular level, in fact, it exploits polyamine catabolism by means of biocompatible doses of spermidine and, in vivo settings, it can exploit the selective accumulation of nanomedicines at the tumor site. Nanofenretinide combination further improves its efficacy. Furthermore, the proven ability of spermidine to activate macrophages and lymphocytes suggests that nanospermidine could inhibit immunosuppression in the tumor environment. [ABSTRACT FROM AUTHOR]

Senescent cells accumulate with aging and have been shown to contribute to age-associated diseases and organ dysfunction. Eliminating senescent cells with senolytic drugs has been shown to improve age phenotypes in mouse models and there is some initial evidence that it may improve the health of persons with chronic diseases. In this study, we employed WI-38 human fibroblasts rendered senescent by exposure to ionizing radiation (IR) to screen several plant extracts for their potential senolytic and/or senomorphic activity. Of these, ginger extract (Zingiber officinale Rosc.) selectively caused the death of senescent cells without affecting proliferating cells. Among the major individual components of ginger extract, gingerenone A and 6-shogaol showed promising senolytic properties, with gingerenone A selectively eliminating senescent cells. Similar to the senolytic cocktail dasatinib and quercetin (D+Q), gingerenone A and 6-shogaol elicited an apoptotic program. Additionally, both D+Q and gingerenone A had a pronounced effect on suppressing the senescence-associated secretory phenotype (SASP). Gingerenone A selectively promotes the death of senescent cells with no effect on non-senescent cells and these characteristics strongly support the idea that this natural compound may have therapeutic benefit in diseases characterized by senescent cell accumulation. [ABSTRACT FROM AUTHOR]

The non-detection of zero-metallicity stars in ultra-faint dwarf galaxies (UFDs) can be used to constrain the initial mass function (IMF) of the first (PopIII) stars by means of a statistical comparison between available data and predictions from chemical evolution models. To this end we develop a model that follows the formation of isolated UFDs, calibrated to best reproduce the available data for the best studied system: Boötes I. Our statistical approach shows that UFDs are the best suitable systems to study the implications of the persisting non-detection of zero-metallicity stars on the PopIII IMF, i.e. its shape, the minimum mass (m min), and the characteristic mass (m ch). We show that accounting for the incomplete sampling of the IMF is essential to compute the expected number of long-lived PopIII stars in inefficiently star-forming UFDs. By simulating the colour–magnitude diagram of Boötes I, and thus take into account the mass-range of the observed stars, we can obtain even tighter constrains on m min. By exploiting the 96 stars with measured metallicities (⁠|$\rm i \lt 19$|⁠) in the UFDs represented by our model, we demonstrate that |$m_{\mathrm{ ch}} \gt 1\: \rm {M_{\odot }}$| or |$m_{\mathrm{ min}} \gt 0.8 \:\rm {M_{\odot }}$| at |$99\%$| confidence level. This means that a present-day IMF for PopIII stars is excluded by our model, and a top-heavy PopIII IMF is strongly favoured. We can limit |$m_{\mathrm{ min}} \gt 0.8\: \rm {M_{\odot }}$| independent of the PopIII IMF shape by targeting the four UFDs Boötes I, Hercules, Leo IV, and Eridanus II with future generation instruments, such as ELT/MOSAIC (⁠|$\rm i \lt 25$|⁠), which can provide samples of >10 000 stars. [ABSTRACT FROM AUTHOR]

Collaboration has currently become a must within design practices. Ranging from public to private sector, from social to business, the design activity is no longer commissioned 'for' the client, but is carried out 'with' the client and with all the stakeholders involved. This tendency introduces a reflection on the shift in design practice and the role of the designer within the community with which she is designing. This article focuses on collaborative design practices within the private sector, providing a set of case studies analysed through variables that define the main qualities of such processes. Those variables become lenses through which it is possible to zoom in on the peculiarity of the session and ultimately draw an evaluation. The correlations of the variables represent a first draft of a compass aimed at building awareness and providing guidelines for future practices. [ABSTRACT FROM AUTHOR]

Oligomeric enzymes containing multiple active sites are usually considered to perform their catalytic action at higher rates when compared with their monomeric counterparts. This implies, in turn, that the activity performed by different holoenzyme subunits features additivity. Nevertheless, the extent of this additivity occurring in holoenzymes is far from being adequately understood. To tackle this point, we used tetrameric rabbit lactate dehydrogenase (rbLDH) as a model system to assay the reduction of pyruvate catalysed by this enzyme at the expense of β-NADH under pre-steady-state conditions. In particular, we observed the kinetics of reactions triggered by concentrations of β-NADH equimolar to 1, 2, 3, or all 4 subunits of the rbLDH holoenzyme, in the presence of an excess of pyruvate. Surprisingly, when the concentration of the limiting reactant exceeded that of a single holoenzyme subunit, we observed a sharp slowdown of the enzyme conformational rearrangements associated to the generation and the release of l -lactate. Furthermore, using a model to interpret the complex kinetics observed under the highest concentration of the limiting reactant, we estimated the diversity of the rates describing the action of the different rbLDH subunits. • Pre-steady-state kinetics of reactions catalysed by rabbit lactate dehydrogenase. • The four subunits of lactate dehydrogenase do not exert their action additively. • When a single subunit is engaged in catalysis, highest reaction rate is observed. • The different subunits feature diversity of catalytic action. [ABSTRACT FROM AUTHOR]

Aging is a universal and time-dependent biological decline associated with progressive deterioration of cells, tissues, and organs. Age-related decay can eventually lead to pathology such as cardiovascular and neurodegenerative diseases, cancer, and diabetes. A prominent molecular process underlying aging is the progressive shortening of telomeres, the structures that protect the ends of chromosomes, eventually triggering cellular senescence. Noncoding (nc)RNAs are emerging as major regulators of telomere length homeostasis. In this review, we describe the impact of ncRNAs on telomere function and discuss their implications in senescence and age-related diseases. We discuss emerging therapeutic strategies targeting telomere-regulatory ncRNAs in aging pathology. Senescent cells accumulating in aging tissues display indefinite cell cycle arrest, shortened telomeres, and enhanced secretion of proinflammatory factors. ncRNAs critically regulate gene expression programs in many physiological and pathological processes, including those associated with aging. ncRNAs regulate telomere homeostasis, either directly or indirectly, and thereby coordinate molecular processes inherent to cellular senescence and aging. [ABSTRACT FROM AUTHOR]

Case presentation: A 55-year-old man with a history of basaloid squamous cell carcinoma of the oropharynx with laterocervical lymph node metastases 6 years before (and treated with chemoradiation) presented with flank pain and hematuria. Computed tomography scan found a renal lesion, with radiological features more suspicious for primitive renal neoplasia. Histopathological and immunohistochemical examination after surgical excision revealed a basaloid squamous cell carcinoma involving renal parenchyma. Conclusion: Basaloid squamous cell carcinoma is a rare tumor but with a high percentage of distant metastasis, and it is mandatory, also for a general pathologist, to know this disease. Moreover, in a patient with renal metastases, any type of cancer should be taken into account, and this case is emblematic of why the previous medical history is crucial for differential diagnosis. [ABSTRACT FROM AUTHOR]

Purpose: Dehydration is a paediatric medical emergency but there is no single standard parameter to evaluate it at the emergency department. Our aim was to evaluate the reliability and validity of capillary refilling time as a triage parameter to assess dehydration in children. Methods: This was a prospective pilot cohort study of children who presented to two paediatric emergency departments in Italy, with symptoms of dehydration. Reliability was assessed by comparing the triage nurse's measurements with those obtained by the physician. Validity was demonstrated by using 6 parameters suggestive of dehydration. Comparison between refilling time (RT) and a validated Clinical Dehydration Score (CDS) was also considered. The scale's discriminative ability was evaluated for the outcome of starting intravenous rehydration therapy by using a receiver operating characteristic (ROC) curve. Results: Participants were 242 children. All nurses found easy to elicit the RT after being trained. Interobserver reliability was fair, with a Cohen's kappa of 0.56 (95% confidence interval [CI], 0.41 to 0.70). There was a significant correlation between RT and weight loss percentage (r-squared=-0.27; 95% CI, -0.47 to -0.04). The scale's discriminative ability yielded an area under the ROC curve (AUC) of 0.65 (95% CI, 0.57 to 0.73). We found a similarity between RT AUC and CDS-scale AUC matching the two ROC curves. Conclusion: The study showed that RT represents a fast and handy tool to recognize dehydrated children who need a prompt rehydration and may be introduced in the triage line-up. [ABSTRACT FROM AUTHOR]

Compounds known as chemical mediators, including acetylcholine, have been found not only in animals and humans, but also in living organisms, like protozoa, which lack nervous system. In Paramecium primaurelia has been described a cholinergic system, which is proven to play an important role in cell-cell interactions during its developmental cycle. In our work we investigated the effects of exposure to simulated microgravity (3D Random Positioning Machine, 56 rpm, 10-6 g) on the cholinesterase activity of the eukaryote unicellular-organism alternative-model P. primaurelia. Our results show that the exposure of P. primaurelia to microgravity for 6 h, 24 h, 48 h affects the localization and the amount of cholinesterase activity compared to cells grown under Earth gravity conditions (1 g). However, these effects are transient since P. primaurelia restores its normal cholinesterase activity after 72 h under microgravity conditions, as well as cells exposed up to 72 h to microgravity and then placed under terrestrial gravity for 48 h. [ABSTRACT FROM AUTHOR]

Background: The study of lipid metabolism in stem cell physiology has recently raised great interest. The role of lipids goes beyond the mere structural involvement in assembling extra- and intra-cellular compartments. Nevertheless, we are still far from understanding the impact of membrane lipidomics in stemness maintenance and differentiation patterns. In the last years, it has been reported how in vitro cell culturing can modify membrane lipidomics. The aim of the present work was to study the membrane fatty acid profile of mesenchymal stromal cells (MSCs) derived from human fetal membranes (hFM-MSCs) and to correlate this to specific biological properties by using chemically defined tailored lipid supplements (Refeed®). Methods: Freshly isolated hFM-MSCs were characterized for their membrane fatty acid composition. hFM-MSCs were cultivated in vitro following a classical protocol and their membrane fatty acid profile at different passages was compared to the profile in vivo. A tailored Refeed® lipid supplement was developed with the aim of reducing the differences created by the in vitro cultivation and was tested on cultured hFM-MSCs. Cell morphology, viability, proliferation, angiogenic differentiation, and immunomodulatory properties after in vitro exposure to the tailored Refeed® lipid supplement were investigated. Results: A significant modification of hFM-MSC membrane fatty acid composition occurred during in vitro culture. Using a tailored lipid supplement, the fatty acid composition of cultured cells remained more similar to their in vivo counterparts, being characterized by a higher polyunsaturated and omega-6 fatty acid content. These changes in membrane composition had no effect on cell morphology and viability, but were linked with increased cell proliferation rate, angiogenic differentiation, and immunomodulatory properties. In particular, Refeed®-supplemented hFM-MSCs showed greater ability to express fully functional cell membrane molecules. Conclusions: Culturing hFM-MSCs alters their fatty acid composition. A tailored lipid supplement is able to improve in vitro hFM-MSC functional properties by recreating a membrane environment more similar to the physiological counterpart. This approach should be considered in cell therapy applications in order to maintain a higher cell quality during in vitro passaging and to influence the outcome of cell-based therapeutic approaches when cells are administered to patients. [ABSTRACT FROM AUTHOR]

Gentiana lutea L. (yellow gentian, Gentianaceae) is a protected orophyte of central and southern Europe, mainly threatened by the uncontrolled collection of its rhizome, used in traditional medicine and for liquor production. The species is self-compatible, but outcrossing mediated by pollinators is needed to obtain a viable progeny. In this study, we considered five natural populations belonging to the four subspecies of G. lutea. We performed controlled pollinations in the field (self- versus cross-pollination) followed by seed germination tests in laboratory conditions, adding a solution of gibberellic acid, in order to evaluate the seed performance. A cumulative index of inbreeding depression was calculated considering maternal reproductive output as well as seed performance traits. Seed weight and seed germination performance was similar between seeds resulting from naturally pollinated and pollen-augmented flowers and higher compared to selfed flowers, highlighting a disadvantage of selfing and the importance of cross-pollen transfer in natural conditions. However, in the small and isolated population of G. lutea subsp. symphyandra on Mt Grande we found a general reduction in seed germination rate, likely due to increased selfing or mating among close relatives as a consequence of a severe bottleneck. We discuss our results with regards to implications for conservation practices. [ABSTRACT FROM AUTHOR]

Introduction Several definitions of erectile function (EF) recovery after bilateral nerve-sparing radical prostatectomy (BNSRP) have been proposed based on the results of the International Index of EF (IIEF). Aim We aimed at evaluating overall satisfaction (OS) after BNSRP according to the ability to achieve the pretreatment EF. Methods We evaluated data of 652 patients treated with BNSRP for clinically localized prostate cancer (PCa). Erectile dysfunction (ED) was classified according to the IIEF-EF domain score. Return to baseline EF was defined as patients who reached the same preoperative ED category during the 3-year follow-up. Cox regression analyses were fitted to predict return to baseline IIEF-EF and to predict OS defined according to the IIEF-OS in the overall population. Logistic regression analyses were performed to analyze OS in men who reached the back to baseline status. Main Outcome Measures The outcome of the study was to evaluate back to baseline EF status and to correlate it with postoperative OS. Results Preoperative satisfaction was reported by 218 (33.4%) patients. Postoperative satisfaction was achieved by 103 patients. Overall, 383 patients were able to achieve the preoperative IIEF-EF score. However, only 26.9% reported being satisfied. Age and preoperative IIEF-EF score were significantly associated with baseline IIEF-EF recovery (all P ≤ .02). Patients who were able to return to baseline IIEF-EF were more likely to be satisfied ( P < .001). Time elapsed between surgery and achievement of baseline IIEF-EF was significantly associated with OS ( P < .001). Among patients who were able to achieve the baseline IIEF-EF score, a preoperative IIEF-EF of 22–25 and 26–30 was significantly associated with postoperative satisfaction (all P < .001). Conclusion After BNSRP, reaching the baseline IIEF-EF score is not always sufficient to obtain patient satisfaction. Only patients with a preoperative IIEF-EF ≥22 who reached the baseline score after surgery considered themselves satisfied. This should be taken into account in preoperative patient counseling. [ABSTRACT FROM AUTHOR]

Background:Taxonomic analysis provides a basic understanding for taxon identification and contributes to preliminary information for several branches of applied biology, while studies on reproductive strategies and plant fitness are essential to interpret population status and dynamics. Aims:We tested the reliability of diagnostic characters for identification and to characterise sexual resource allocation, the breeding system and seed predation among subspecies ofGentiana lutea. Methods:We analysed morphological characters in 70 herbarium specimens. In five natural populations we counted pollen and ovule numbers, assessed reproductive output after pollination treatments and evaluated pre-dispersal predation. Results:Taxonomic traits previously indicated as diagnostic were not sufficient to discriminate among subspecies. The pollen number and pollen:ovule (P:O) ratio varied strongly among subspecies; self-pollinated flowers produced a significantly lower number of seeds than open-pollinated flowers. Retention of empty fruits and high levels of pre-dispersal seed predation were observed in every case. Conclusions:The variation of P:O ratios among subspecies suggests different efficiency in pollen transfer. The species is self-compatible, nevertheless all subspecies require pollen vectors to enhance cross pollination and viable seed production. Fruit retention may have evolved as a strategy to reduce predation, ensuring higher plant fitness. [ABSTRACT FROM PUBLISHER]

Background: A molecular profile including BRAF and RAS mutations as well as RET/PTC rearrangement evaluation has been proposed to provide an accurate presurgical assessment of thyroid nodules and to reduce the number of unnecessary diagnostic surgeries, sparing patients' health and saving healthcare resources. However, the application of such molecular analyses may provide different results among different centers and populations in real-life settings. Our aims were to evaluate the diagnostic utility of assessing the presence of BRAF and RAS mutations and RET/PTC1 and RET/PTC3 rearrangements in all cytological categories in an Italian group of thyroid nodule patients assessed prospectively, and to understand whether and which mutation testing might be helpful in cytologically indeterminate nodules. Methods: A total of 911 patients were submitted to ultrasound and fine-needle aspiration biopsy examination. Cytological evaluation was performed in parallel with molecular testing and compared to pathological results in 940 thyroid nodules, including 140 indeterminate lesions. Results: BRAF mutation testing provided the best contribution to cancer diagnosis, allowing the disease to be detected at an early stage, and identifying indeterminate nodules in which diagnostic lobectomy could be spared. On the contrary, RAS and RET/PTC analysis did not further increase diagnostic sensitivity for thyroid cancer. In addition, we found RET/PTC rearrangements in benign lesions, indicating that this molecular marker might not be useful for the detection of thyroid cancer. Conclusion: BRAFV600E mutation analysis is superior to RAS point mutations and evaluation of RET/PTC rearrangements in the diagnosis of thyroid cancer, even in indeterminate lesions. [ABSTRACT FROM AUTHOR]

Abstract: Generalist flowers are visited by a broad variety of insects that function as pollinators, occasional visitors and as pollen and/or nectar robbers. Moreover, among legitimate pollinators the pollination efficiency can be different. Nectar greatly affects visitor behaviour and fidelity to a certain species, influencing plant reproductive effort. In this study we have investigated a generalist system (Gentiana lutea L.), examining the role of flower visitors and quantifying the contribution of each pollinating taxon in three natural populations. In order to verify the level of generalization, we introduce an index of Pollinator Performance (PoP), based on insect visitation rate and cross-pollen transport efficiency. Our results confirm the high degree of pollinator-generalization of the study species. Nevertheless, flower visitors show various degree of pollinating performance, mainly defined by their sedentary versus dynamic behaviour. Sedentary insects enhance geitonogamous pollen transfer, which results in reduced seed set and pollen limitation. In particular, an unusual sluggish behaviour was observed in bumblebees feeding on nectar. The hexose-rich abundant nectar offered by G. lutea flowers is remarkably rich in proline and β-alanine amino acids: this composition presumably influences feeding choice and insect dynamism, likely exerting a narcotic effect on pollinators. The consequences on plant fitness are discussed in an evolutionary perspective. [Copyright &y& Elsevier]

Different molecular mechanisms contribute to the development of multidrug resistance in cancer, including increased drug efflux, enhanced cellular repair mechanisms and alterations of drug metabolism or drug targets. ABCG2 is a member of the ATP-binding cassette superfamily transporters that promotes drug efflux, inducing chemotherapeutic resistance in malignant cells. In this context, the development of selective ABCG2 inhibitors might be a suitable strategy to improve chemotherapy efficacy. Thus, through a multidisciplinary approach, we identified a new ABCG2 selective inhibitor (8), highlighting its ability to increase mitoxantrone cytotoxicity in both hepatocellular carcinoma (EC50from 8.67 ± 2.65 to 1.25 ± 0.80 μM) and transfected breast cancer cell lines (EC50from 9.92 ± 2.32 to 2.45 ± 1.40 μM). Moreover, mitoxantrone co-administration in both transfected and non-transfected HEK293 revealed that compound 8 notably lowered the mitoxantrone EC50, demonstrating its efficacy along with the importance of the ABCG2 extrusion pump overexpression in MDR reversion. These results were corroborated by evaluating the effect of inhibitor 8 on mitoxantrone cell uptake in multicellular tumor spheroids and via proteomic experiments. [ABSTRACT FROM AUTHOR]

Senescence is linked to a wide range of age-associated diseases and physiological declines. Thus, senotherapeutics are emerging to suppress the detrimental effects of senescence either by senomorphics or senolytics. Senomorphics suppress the traits associated with senescence phenotypes, while senolytics aim to clear senescent cells by suppressing their survival and enhancing the apoptotic pathways. The main goal of these approaches is to suppress the proinflammatory senescence-associated secretory phenotype (SASP) and to promote the immune recognition and elimination of senescent cells. One increasingly attractive approach is the targeting of molecules or proteins specifically present on the surface of senescent cells. These proteins may play roles in the maintenance and survival of senescent cells and hence can be targeted for senolysis. In this review, we summarize the recent knowledge regarding senolysis with a focus on novel surface biomarkers of cellular senescence and discuss their emergence as senotherapeutic targets. [ABSTRACT FROM AUTHOR]

Acute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective in the treatment of this disease, inducing promyelocytes differentiation. Current therapy, based on ATRA in combination with arsenic trioxide, with or without chemotherapy, provides high rates of event-free survival and overall survival. However, a decline in the drug activity, due to increased ATRA metabolism and RARα mutations, is often observed over long-term treatments. Furthermore, dedifferentiation can occur providing relapse of the disease. In this study we evaluated fenretinide, a semisynthetic ATRA derivative, encapsulated in nanomicelles (nano-fenretinide) as an alternative treatment to ATRA in APL. Nano-fenretinide was prepared by fenretinide encapsulation in a self-assembling phospholipid mixture. Physico-chemical characterization was carried out by dinamic light scattering and spectrophotometry. The biological activity was evaluated by MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy. Nano-fenretinide induced apoptosis in acute promyelocytic leukemia cells (HL60) by an early increase of reactive oxygen species and a mitochondrial potential decrease. The fenretinide concentration that induced 90–100% decrease in cell viability was about 2.0 µM at 24 h, a concentration easily achievable in vivo when nano-fenretinide is administered by oral or intravenous route, as demonstrated in previous studies. Nano-fenretinide was effective, albeit at slightly higher concentrations, also in doxorubicin-resistant HL60 cells, while a comparison with TK6 lymphoblasts indicated a lack of toxicity on normal cells. The results indicate that nano-fenretinide can be considered an alternative therapy to ATRA in acute promyelocytic leukemia when decreased efficacy, resistance or recurrence of disease emerge after protracted treatments with ATRA. [ABSTRACT FROM AUTHOR]

Aims BMP9 and BMP10 mutations were recently identified in patients with pulmonary arterial hypertension, but their specific roles in the pathogenesis of the disease are still unclear. We aimed to study the roles of BMP9 and BMP10 in cardiovascular homeostasis and pulmonary hypertension using transgenic mouse models deficient in Bmp9 and/or Bmp10. Methods and results Single- and double-knockout mice for Bmp9 (constitutive) and/or Bmp10 (tamoxifen inducible) were generated. Single-knock-out (KO) mice developed no obvious age-dependent phenotype when compared with their wild-type littermates. However, combined deficiency in Bmp9 and Bmp10 led to vascular defects resulting in a decrease in peripheral vascular resistance and blood pressure and the progressive development of high-output heart failure and pulmonary hemosiderosis. RNAseq analysis of the lungs of the double-KO mice revealed differential expression of genes involved in inflammation and vascular homeostasis. We next challenged these mice to chronic hypoxia. After 3 weeks of hypoxic exposure, Bmp10 -cKO mice showed an enlarged heart. However, although genetic deletion of Bmp9 in the single- and double-KO mice attenuated the muscularization of pulmonary arterioles induced by chronic hypoxia, we observed no differences in Bmp10- cKO mice. Consistent with these results, endothelin-1 levels were significantly reduced in Bmp9 deficient mice but not Bmp10 -cKO mice. Furthermore, the effects of BMP9 on vasoconstriction were inhibited by bosentan, an endothelin receptor antagonist, in a chick chorioallantoic membrane assay. Conclusions Our data show redundant roles for BMP9 and BMP10 in cardiovascular homeostasis under normoxic conditions (only combined deletion of both Bmp9 and Bmp10 was associated with severe defects) but highlight specific roles under chronic hypoxic conditions. We obtained evidence that BMP9 contributes to chronic hypoxia-induced pulmonary vascular remodelling, whereas BMP10 plays a role in hypoxia-induced cardiac remodelling in mice. [ABSTRACT FROM AUTHOR]

The metal-poor stars in the Galactic halo are thought to show the imprints of the first (Pop III) stars, and thus provide a glance at the first episodes of star formation. In this work, we aim at understanding whether all very metal-poor stars formed in environments polluted by Pop III supernovae (SNe) and at what level. With a general parametric model for early metal enrichment, we study the chemical abundances (from C to Zn) of an environment imprinted by a single Pop III SN. We investigate how these abundances depend on the initial mass and internal mixing of Pop III stars, as well as on their SN explosion energy. We then study how subsequent generations of normal (Pop II) SNe affect the Pop III chemical signatures. By comparing the observed chemical abundances with our model predictions, we show that stars with [C/Fe] > +2.5 form in environments polluted purely by low-energy Pop III SNe (E SN < 2 × 1051 erg). At lower [C/Fe], stars can be imprinted either by Pop III only, or also by normal Pop II SNe. The probability of being enriched by Pop II SNe increases as [C/Fe] decreases. When Pop II stars contribute more to the pollution, they wash out the diverse chemical peculiarities left by the different Pop III SNe, and the chemical dispersion between their descendants decreases. We conclude that C-normal stars (⁠|$\rm [C/Fe] \le +0.7$|⁠) have likely been enriched by Pop II SNe at a |$\ge 50~{{\ \rm per\ cent}}$| level and we identify in the abundance scatter a key diagnostic to pinpoint the signature of Pop III SNe. [ABSTRACT FROM AUTHOR]

Senescent cells are beneficial for repairing acute tissue damage, but they are harmful when they accumulate in tissues, as occurs with advancing age. Senescence-associated extracellular vesicles (S-EVs) can mediate cell-to-cell communication and export intracellular content to the microenvironment of aging tissues. Here, we studied the uptake of EVs from senescent cells (S-EVs) and proliferating cells (P-EVs) and found that P-EVs were readily taken up by proliferating cells (fibroblasts and cervical cancer cells) while S-EVs were not. We thus investigated the surface proteome (surfaceome) of P-EVs relative to S-EVs derived from cells that had reached senescence via replicative exhaustion, exposure to ionizing radiation, or treatment with etoposide. We found that relative to P-EVs, S-EVs from all senescence models were enriched in proteins DPP4, ANXA1, ANXA6, S10AB, AT1A1, and EPHB2. Among them, DPP4 was found to selectively prevent uptake by proliferating cells, as ectopic overexpression of DPP4 in HeLa cells rendered DPP4-expressing EVs that were no longer taken up by other proliferating cells. We propose that DPP4 on the surface of S-EVs makes these EVs refractory to internalization by proliferating cells, advancing our knowledge of the impact of senescent cells in aging-associated processes. [ABSTRACT FROM AUTHOR]

Extracellular vesicles and particles (EVPs) are secreted by organs across the body into different circulatory systems, including the bloodstream, and reflect pathophysiologic conditions of the organ. However, the heterogeneity of EVPs in the blood makes it challenging to determine their organ of origin. We hypothesized that small (s)EVPs (<100 nmin diameter) in the bloodstreamcarry distinctive protein signatures associated with each originating organ, and we investigated this possibility by studying the proteomes of sEVPs produced by six major organs (brain, liver, lung, heart, kidney, and fat). We found that each organ contained distinctive sEVP proteins: 68 proteins were preferentially found in brain sEVPs, 194 in liver, 39 in lung, 15 in heart, 29 in kidney, and 33 in fat. Furthermore, we isolated sEVPs from blood and validated the presence of sEVP proteins associated with the brain (DPP6, SYT1,DNM1L), liver (FABPL, ARG1, ASGR1/2), lung (SFPTA), heart (CPT1B), kidney (SLC31), and fat (GDN). We further discovered altered levels of these proteins in serum sEVPs obtained from old mice compared to young mice. In sum, we have cataloged sEVP proteins that can serve as potential biomarkers for organ identification in serum and show differential expression with age. [ABSTRACT FROM AUTHOR]

Objective: To test the prognostic role of treatment delay in patients affected by prostate cancer (PCa).Materials and Methods: The study included 2,653 patients treated with radical prostatectomy (RP) at a single institution between 2006 and 2011. The evaluated outcomes were biochemical recurrence (BCR) and clinical recurrence (CR). Multivariable Cox regression analysis was used to test the association between time from diagnosis to RP and oncological outcomes. Nonparametric curve fitting methods were used to graphically explore the relationship between time from diagnosis to RP and oncological outcomes. Sensitivity analyses were repeated in the subgroups of low-, intermediate-, and high-risk patients.Results: At median follow-up of 56 months (interquartile range: 26, 92), 283 patients experienced BCR, and 84 patients developed CR. Median time from PCa diagnosis to surgery was 2.8 months (interquartile range: 1.6, 4.7). At multivariable Cox regression analysis, time from biopsy to RP was significantly associated with an increased risk of BCR (hazard ratio = 1.02, P = 0.0005) and CR (hazard ratio = 1.03, P = 0.0002). Using Nonparametric curve fitting methods, a significant increased risk of BCR and CR after approximately 18 months was observed. However, when sensitivity analyses were repeated according to risk groups, this effect was maintained in high-risk patients only, and such time interval was reduced to 12 months.Conclusions: Despite the overall trend on higher rate of cancer relapse after RP, the effect of treatment delay from biopsy to RP was significantly evident in high-risk patients only. Even in high-risk patients surgical treatment can be postponed safely, but not beyond the 12-month landmark. [ABSTRACT FROM AUTHOR]

(1) Background: Glucose metabolism derangements (GMD) and thyroid nodules (TNs) are the most frequent endocrine disorders, and their relationship is still controversial; little evidence is reported regarding sex differences. We aim to evaluate the association between GMDs and TNs according to sex and the sex differences in glucose metabolism and insulin sensitivity (IS). (2) Methods: We evaluated 342 patients (268 females and 74 males) at high GMD risk undergoing an oral glucose tolerance test and a thyroid ultrasound. (3) Results: The TN prevalence was 61% (n = 210), with no significant differences according to sex and GMD classes. The TN presence is significantly associated with age and impaired fasting glucose (IFG) in females. Males and females with normal fasting glucose (NFG) had a significantly lower OR of having TNs than females with IFG. IFG females had a significantly higher predicted probability of having TNs than NFG males and females but not IFG males. Impaired glucose tolerance/Type 2 diabetes mellitus (IGT/T2DM) is significantly associated with age and male sex, while IFG is associated with age. Females had significantly lower HOMA-index values than males. (4) Conclusions: No significant association between IGT/T2DM and TNs according to sex was found. IFG seems to play a role in TN development independently of sex. Further studies are needed to explore the relationship between TNs and GMD to identify subgroups with a higher TN risk. [ABSTRACT FROM AUTHOR]

Alkaptonuria (AKU) is an ultra-rare genetic disease caused by a deficient activity of the enzyme homogentisate 1,2-dioxygenase (HGD) leading to the accumulation of homogentisic acid (HGA) on connective tissues. Even though AKU is a multi-systemic disease, osteoarticular cartilage is the most affected system and the most damaged tissue by the disease. In chondrocytes, HGA causes oxidative stress dysfunctions, which induce a series of not fully characterized cellular responses. In this study, we used a human chondrocytic cell line as an AKU model to evaluate, for the first time, the effect of HGA on autophagy, the main homeostasis system in articular cartilage. Cells responded timely to HGA treatment with an increase in autophagy as a mechanism of protection. In a chronic state, HGA-induced oxidative stress decreased autophagy, and chondrocytes, unable to restore balance, activated the chondroptosis pathway. This decrease in autophagy also correlated with the accumulation of ochronotic pigment, a hallmark of AKU. Our data suggest new perspectives for understanding AKU and a mechanistic model that rationalizes the damaging role of HGA. • In an in vitro model of Alkaptonuria, HGA cells treatment leads the activation of the autophagic pathway. • In long-term HGA cells treatment, there is a block of autophagic flux and the activation of apoptotic pathway. • HGA induces in cells oxidative stress, mitochondrial damage, nucleolar morphology alteration and ochronotic pigment deposition. [ABSTRACT FROM AUTHOR]

Primula apennina Widmer is endemic to the North Apennines (Italy). ISSR were used to detect the genetic diversity within and among six populations representative of the species distribution range. High levels of genetic diversity were revealed both at population percentage of polymorphic band (PPB = 75.92%, HS = 0.204, Hpop = 0.319) and at species level (PPB = 96.95%, HT = 0.242, Hsp = 0.381). Nei gene diversity statistics (15.7%), Shannon diversity index (16.3%) and AMOVA (14%) detected a moderate level of interpopulation diversity. Principal coordinate and Bayesian analyses clustered the populations in three major groups along a geographic gradient. The correlation between genetic and geographic distances was positive (Mantel test, r = 0.232). All together, these analyses revealed a weak but significant spatial genetic structure in P. apennina, with gene flow acting as a homogenizing force that prevents a stronger differentiation of populations. Conservation measures are suggested based on the observed pattern of genetic variability. [ABSTRACT FROM AUTHOR]

Abstract: Three experiments on healthy humans investigated the degree of automaticity of crossmodal spatial attention shifts by assessing the intentionality criterion. We used the orthogonal cuing paradigm in which a lateralized cue, either visual or auditory was followed by a unimodal or crossmodal target that occurred at the same or opposite side. In all experiments, the cue was always uninformative as to target location. In Experiment 1, where both side and modality of targets were unpredictable, we found faster discriminations for visual targets following uninformative auditory cues on the same side. This result was replicated in Experiment 2, where target side was blocked and participants could orient attention in advance toward the appropriate side, and in Experiment 3, where they were additionally informed about target modality. Our results suggest that this sort of crossmodal orienting is automatic because it occurred even when participants were provided with detailed information about the target to prevent uninformative auditory cues from orienting attention. This is consistent with the notion that peripheral auditory stimuli are very powerful in capturing visual attention. [Copyright &y& Elsevier]

It is currently debated whether specific psychiatric disorders or Internalizing versus Externalizing psychopathological dimensions are associated to Internet Addiction Disorder (IAD). We explored this issue in youth with and without IAD referred to a third-level Department of Adolescent Psychiatry during a 12-month period. All the 101 consecutively referred adolescents were assessed using categorical (Schedule for Affective Disorders and Schizophrenia for School- Age Children-K-SADS) and dimensional (Child Behavior Checklist-CBCL) measures of psychopathology, and two measures for addictive behaviors, Internet Addiction Test (IAT) (used as screening for detecting IAD patients) and Use, Abuse, Dependence on the Internet (UADI) inventory. According to an IAT cutoff score of 50, 39 patients (38.6%) presented IAD. The IAD and the no IAD groups did not differ according to age and gender. Most of the IAD patients (92.3%) endorsed multiple addictions. The IAD group had higher scores in all the UADI dimensions, except for Impact of Life. All the IAD patients endorsed psychiatric diagnoses, but only Autism Spectrum Disorders were more represented in the IAD group. According to the CBCL, patients with IAD had more social problems and anxiety symptoms. However, clusters analysis with the t-scores of the CBCL scales of Internalizing and Externalizing domains showed no differences in IAT and UADI scores among clusters. The small sample size and a selection bias (referrals for severe symptomatology) limit the generalization of the findings. Comorbidity should be systematically assessed in IAD adolescents, with categorical and dimensional measures, as it may guide personalized treatments. [ABSTRACT FROM AUTHOR]

Self‐incompatibility (SI) in flowering plants potentially represents a major obstacle for sexual reproduction, especially when the number of S‐alleles is low. The situation is extreme in the commercially important olive tree, where in vitro pollination assays suggested the existence of a diallelic SI (DSI) system involving only two groups (G1 and G2). Varieties belonging to the same SI group cannot fertilize each other, such that successful fruit production is predicted to require pollination between varieties of different groups. To test this prediction, we explored the extent to which the DSI system determines fertilization patterns under field conditions. One hundred and seventeen olive cultivars were first genotyped using 10 highly polymorphic dinucleotide Simple Sequence Repeat (SSR) markers to ascertain varietal identity. Cultivars were then phenotyped through controlled pollination tests to assign each of them to one of the two SI groups. We then collected and genotyped 1440 open pollinated embryos from five different orchards constituted of seven local cultivars with known group of incompatibility groups. Embryos genotype information were used: (i) to assign embryos to the most likely pollen donor genotype in the neighbourhood using paternity analysis, and (ii) to compare the composition of the pollen cloud genetic among recipient trees in the five sites. The paternity analysis showed that the DSI system is the main determinant of fertilization success under field open pollination conditions: G1 cultivars sired seeds exclusively on G2 cultivars, and reciprocally. No self‐fertilization events were observed. Our results demonstrate that DSI is a potent force determining pollination success among varieties within olive orchards used for production. They have the potential to improve management practices by guiding the selection of compatible varieties to avoid planting orchards containing sets of varieties with strongly unbalanced SI groups, as these would lead to suboptimal olive production. [ABSTRACT FROM AUTHOR]

Aim: The success of Robot Assisted Laparoscopic Prostatectomy (RALP) is mainly due to his relatively short learning curve. Twenty cases are needed to reach a "4 hours-proficiency". However, to achieve optimal functional outcomes such as urinary continence and potency recovery may require more experience. We aim to report the perioperative and early functional outcomes of patients undergoing RALP, after a structured modular training program. Methods: A surgeon with no previous laparoscopic or robotic experience attained a 3 month modular training including: a) e-learning; b) assistance and training to the operating table; c) dry console training; d) step by step in vivo modular training performing 40 surgical steps in increasing difficulty, under the supervision of an experienced mentor. Demographics, intraoperative and postoperative functional outcomes were recorded after his first 120 procedures, considering four groups of 30 cases. Results: All procedures were completed successfully without conversion to open approach. Overall 19 (15%) post operative complications were observed and 84% were graded as minor (Clavien I-II). Overall operative time and console time gradually decreased during the learning curve, with statistical significance in favour of Group 4. The overall continence rate at 1 and 3 months was 74% and 87% respectively with a significant improvement in continence rate throughout the four groups (p = 0.04). Considering those patients submitted to nerve-sparing procedure we found a significant increase in potency recovery over the four groups (p = 0.04) with the higher potency recovery rate up to 80% in the last 30 cases. Conclusions: Optimal perioperative and functional outcomes have been attained since early phase of the learning curve after an intensive structured modular training and less than 100 consecutive procedures seem needed in order to achieve optimal urinary continence and erectile function recovery. [ABSTRACT FROM AUTHOR]

The olive ( Olea europaea L.) is a typical important perennial crop species for which the genetic determination and even functionality of self-incompatibility ( SI) are still largely unresolved. It is still not known whether SI is under gametophytic or sporophytic genetic control, yet fruit production in orchards depends critically on successful ovule fertilization. We studied the genetic determination of SI in olive in light of recent discoveries in other genera of the Oleaceae family. Using intra- and interspecific stigma tests on 89 genotypes representative of species-wide olive diversity and the compatibility/incompatibility reactions of progeny plants from controlled crosses, we confirmed that O. europaea shares the same homomorphic diallelic self-incompatibility ( DSI) system as the one recently identified in Phillyrea angustifolia and Fraxinus ornus. SI is sporophytic in olive. The incompatibility response differs between the two SI groups in terms of how far pollen tubes grow before growth is arrested within stigma tissues. As a consequence of this DSI system, the chance of cross-incompatibility between pairs of varieties in an orchard is high (50%) and fruit production may be limited by the availability of compatible pollen. The discovery of the DSI system in O. europaea will undoubtedly offer opportunities to optimize fruit production. [ABSTRACT FROM AUTHOR]

In the field of sleep disorders, the quality of couple relationship is arousing increasing attention, given its implications for quality of life and treatment adherence. The aim of the present study was to evaluate relationship quality in a sample of treated or untreated patients with Obstructive Sleep Apnoea Syndrome. Eighty-seven patients were recruited in a hospital-based Centre for Sleep Medicine. Subjects were administered the Dyadic Adjustment Scale (DAS) to evaluate relationship quality, and the Epworth Sleepiness Scale (ESS). Apnoea-hypopnoea indexes (AHI) were collected through nocturnal polysomnography or home testing with a portable monitoring device. Although the DAS average scores were similar to local normative values, relationship quality was significantly lower in the untreated patients when compared with the ones treated. The ESS scores showed a negative correlation with many DAS scores, whereas no significant correlation emerged for AHI. Such data suggest a significant impact of perceived sleep apnoea symptoms on marital satisfaction, even though in the absence of striking differences between the whole sample and the general population. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Perioperative transfusions have been recently associated to poor outcomes as an indirect consequence of immune-hematological changes related to transfusion itself and blood type. We tested the role of blood transfusion on cancer-specific mortality (CSM) and overall mortality (OM), considering the effect of ABO system, Rh factor, and timing of transfusions.Materials and Methods: The study focused on 728 patients with bladder cancer treated with radical cystectomy at a single tertiary care referral center between January 1995 and August 2013 with complete ABO blood type information. Kaplan-Meier analysis was used to assess the effect of transfusions, stratified according to ABO type and Rh factor, on CSM and OM. The same endpoints were tested in Cox regression models, after adjusting for all available confounders.Results: A total of 341 (46.8%), 277 (38.0%), 83 (11.4%), and 27 (3.7%) patients had blood type O, A, B and AB, respectively. Overall, 630 (86.5%) and 98 (13.5%) patients were Rh-and Rh+, respectively. At a median follow-up time of 65 months, 225 (30.9%) and 282 (38.7%) patients recorded CSM and OM, respectively. At univariable analyses, ABO blood type and Rh status were not associated to either CSM or OM (all P>0.2). Similar results were observed when ABO blood type and Rh factor were tested in multivariable models (all P>0.3). Conversely, Charlson score, preoperative hemoglobin, number of nodes removed, pathological T stage, and number of positive nodes were associated to both CSM and OM (all P<0.05). Interestingly, intraoperative transfusion (all P<0.03) but not the administration of blood units in the postoperative period (P>0.05) was associated with an increase of CSM and OM.Conclusions: Although ABO type or Rh factor or both were associated with several adverse outcomes in many cancers, we were not able to confirm this association in bladder cancer. Based on our results, the effect of transfusion on survival is independent by ABO type but is associated to the timing of blood supply administration. [ABSTRACT FROM AUTHOR]

The identification and characterization of transcripts involved in flower organ development, plant reproduction and metabolism represent key steps in plant phenotypic and physiological pathways, and may generate high-quality transcript variants useful for the development of functional markers. This study was aimed at obtaining an extensive characterization of the olive flower transcripts, by providing sound information on the candidate MADS-box genes related to the ABC model of flower development and on the putative genetic and molecular determinants of ovary abortion and pollen-pistil interaction. The overall sequence data, obtained by pyrosequencing of four cDNA libraries from flowers at different developmental stages of three olive varieties with distinct reproductive features (Leccino, Frantoio and Dolce Agogia), included approximately 465,000 ESTs, which gave rise to more than 14,600 contigs and approximately 92,000 singletons. As many as 56,700 unigenes were successfully annotated and provided gene ontology insights into the structural organization and putative molecular function of sequenced transcripts and deduced proteins in the context of their corresponding biological processes. Differentially expressed genes with potential regulatory roles in biosynthetic pathways and metabolic networks during flower development were identified. The gene expression studies allowed us to select the candidate genes that play well-known molecular functions in a number of biosynthetic pathways and specific biological processes that affect olive reproduction. A sound understanding of gene functions and regulatory networks that characterize the olive flower is provided. [ABSTRACT FROM AUTHOR]

Objective: To investigate the staging of lymphadenectomy during radical cystectomy (RC) due to bladder cancer. No data exist about the possibility to limit the extension of pelvic lymph node dissection (PLND) on the basis of preoperative or intraoperative parameters without losing accuracy in the staging procedure.Materials and Methods: Between 1995 and 2012, 1016 RC due to bladder cancer were performed at a single tertiary care institution. The relationship between the number of nodes removed and the probability to find node metastases at final pathology examination was assessed using receiver operating characteristic analyses.Results: Among the patients who underwent RC plus PLND, the lymph node metastases prevalence was 35.7% (363 of 1016). Receiver operating characteristic curve analyses were used to explore graphically the relationship between the numbers of removed and examined nodes and the probability of finding one or more metastatic nodes in the overall population. The curve indicated that 25, 35, and 45 nodes need to be removed to achieve 75%, 90%, and 95% probability, respectively, of detecting one or more lymph node metastases. When the analyses were stratified according to preoperative characteristics, only slight differences were recorded among the sensitivity analyses stratified for pathological stage, primary or progressive status, or radiological N status.Conclusion: Our results show that it is necessary to extend PLND to improve the ability to stage node metastases accurately. Preoperative parameters can minimally change this indication and an extended PLND should be always performed. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the influence of preservation of the muscular internal sphincter and proximal urethra on continence recovery after radical prostatectomy. Methods This was a prospective single-center, case-control study. A total of 40 consecutive patients with organ-confined prostate cancer were submitted to radical prostatectomy with the preservation of the muscular internal sphincter and the proximal urethra (group 1), and their outcomes were compared with those of 40 patients submitted to a standard procedure (group 2). Continence rates were assessed using a self-administrated questionnaire at 3, 7 and 30 days, and 3 and 12 months after removal of the catheter. Results Group 1 had a faster recovery of early continence than group 2 at day 3 (45% vs 22%; P = 0.029) and at day 7 (75% vs 50%; P = 0.018). Considering the number of pads, group 1 had a faster recovery of continence at 3, 7 and 30 days, and also had less incidence of severe incontinence. There was no statistically significant difference in terms of continence at 3 and 12 months among the two groups. Multivariate logistic regression analysis showed that surgical technique and young age were significantly associated with earlier time to continence at 3 and 7 days. The two groups had no significant differences in terms of surgical margins. Conclusions Our modified technique of radical retropubic prostatectomy with preservation of the smooth muscular internal sphincter, as well as of the proximal urethra during bladder neck dissection, results in a significantly increased urinary continence at 3, 7 and 30 days after catheter removal, with a minor incidence of severe incontinence. The technique is also oncologically safe, and it does not increase the operative duration of the procedure. [ABSTRACT FROM AUTHOR]

Aim The aim of our study was to explore the effects on symptoms and female sexual function of the medical management with gonadotropin-releasing hormone agonist ( GnRHa) in women of more than 45 years old compared to surgical management. Methods Women with symptomatic uterine fibroids were enrolled to participate to the present open-label study. We offered two different treatment options: medical with GnRHa for 6 months (group A) or hysterectomy (group B). The patients were reviewed in follow-up for 24 months. The impact of medical or surgical therapy on sexual life was evaluated. Results No significant differences were found in population characteristics between the two groups. GnRHa treatment was efficient in reducing symptoms in 88% of patients but 22% of patients needed adjunctive cycles of medical therapy. After 24 months, 16% of the patients did not complete the study. The failure percentage of the medical treatment was 12%. No severe side-effects were recorded, and eight patients had reached menopause. No significant differences were observed in the Female Sexual Function Index score in each domain between the medical and surgical groups, with total scores of 18.94 ± 10.16 and 22.00 ± 8.86, respectively (mean ± standard deviation), and the prevalence of dysfunction was 12% and 22%, respectively, similar to the general population of the same age. Conclusion We found that medical therapy with GnRHa is a satisfactory alternative to surgery for fibroids in women of more than 45 years old. [ABSTRACT FROM AUTHOR]

(XLSX) Reference 1 Alagna F, Cirilli M, Galla G, Carbone F, Daddiego L, Facella P, et al. (2016) Transcript Analysis and Regulative Events during Flower Development in Olive ( I Olea europaea i L.). Raw data underlying quantitative RT-qPCR results in Figs 5, 6, and 7 of this article [[1]] are provided with this notice in S1-S3 Files. [Extracted from the article]

The selection of an appropriate dressing for each type of wound is a very important procedure for a faster and more accurate healing process. So, the aim of this study was to develop innovative Spanish Broom and flax wound dressings, as alternatives to cotton used as control, with polymeric films containing glycyrrhetinic acid (GA) to promote wound-exudate absorption and the healing process. The different wound dressings were prepared by a solvent casting method, and characterized in terms of drug loading, water uptake, and in vitro release. Moreover, biological studies were performed to evaluate their biocompatibility and wound-healing efficacy. Comparing the developed wound dressings, Spanish Broom dressings with GA-loaded sodium hyaluronate film had the best functional properties, in terms of hydration ability and GA release. Moreover, they showed a good biocompatibility, determining a moderate induction of cell proliferation and no cytotoxicity. In addition, the wound-healing test revealed that the Spanish Broom dressings promoted cell migration, further facilitating the closure of the wound. [ABSTRACT FROM AUTHOR]