The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution.

Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity1. In this study, we investigated the evolution of genomic signatures caused by endogenous and external mutagenic processes and their interplay with complex structural variants (SVs). We superimposed mutational signatures and phylogenetic analyses of matched serial tumours from patients with urothelial cancer to define the evolutionary dynamics of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas chemotherapy induces mutational bursts of hundreds of late subclonal mutations. Using a genome graph computational tool2, we observed frequent high copy-number circular amplicons characteristic of extrachromosomal DNA (ecDNA)-forming SVs. We characterized the distinct temporal patterns of APOBEC3-induced and chemotherapy-induced mutations within ecDNA-forming SVs, gaining new insights into the timing of these mutagenic processes relative to ecDNA biogenesis. We discovered that most CCND1 amplifications in urothelial cancer arise within circular ecDNA-forming SVs. ecDNA-forming SVs persisted and increased in complexity, incorporating additional DNA segments and contributing to the evolution of treatment resistance. Oxford Nanopore Technologies long-read whole-genome sequencing followed by de novo assembly mapped out CCND1 ecDNA structure. Experimental modelling of CCND1 ecDNA confirmed its role as a driver of treatment resistance. Our findings define fundamental mechanisms that drive urothelial cancer evolution and have important therapeutic implications.

Continuing Professional Development (CPD) and Vocational Education and Training (VET) in Periodontology and Implant Dentistry.

AIM: To (i) evaluate structured postgraduate part-time programs in periodontology, including those addressing peri-implant diseases, among members of the European Federation of Periodontology (EFP), (ii) the impact of the 2018 classification scheme and EFP clinical practice guidelines and (iii) propose a framework for periodontal vocational education and training. MATERIALS AND METHODS: A summary of relevant European guidelines for vocational education and training was compiled. In a survey and in a systematic review, current part-time programs in continuing professional education in periodontology as well as in prevention and management of peri-implant diseases were examined. The implementation and dissemination of the 2018 classification scheme and the EFP clinical practice guidelines were assessed by literature analysis. Based on these findings, a framework for periodontal vocational education and training was generated. RESULTS: Part-time programs for professional development in periodontology are established in nine EFP member countries. The systematic review identified lack of knowledge in prevention and management of peri-implant diseases among dental practitioners and hygienists. Continuing professional development was found to be important for education in prevention, classification and management of periodontal as well as peri-implant diseases. The proposed European framework consists of an escalator model with three levels (certificate, diploma and master). DISCUSSION: Considering the identified variation in the national programs, there is a need to improve education in periodontal and peri-implant diseases. The proposed frameworkmay will help harmonize the national structures. CONCLUSION: The proposed framework for part-time professional development is expected to enhance professional qualification.

The role of polymers in enabling RNAi-based technology for sustainable pest management.

The growing global food demand, coupled with the limitations of traditional pest control methods, has driven the search for innovative and sustainable solutions in agricultural pest management. In this review, we highlight polymeric nanocarriers for their potential to deliver double-stranded RNA (dsRNA) and control pests through the gene-silencing mechanism of RNA interference (RNAi). Polymer-dsRNA systems have shown promise in protecting dsRNA, facilitating cellular uptake, and ensuring precise release. Despite these advances, challenges such as scalability, cost-efficiency, regulatory approval, and public acceptance persist, necessitating further research to overcome these obstacles and fully unlock the potential of RNAi in sustainable agriculture.

Maternal dietary antioxidant supplementation regulates weaned piglets' adipose tissue transcriptome and morphology.

Antioxidant supplementation in critical periods may be useful for improvement of piglet early viability and development. We have evaluated the effects of maternal perinatal diet inclusion of a high vitamin E level (VE, 100 mg all-rac-α-tocopheryl acetate /kg), hydroxytyrosol (HT, 1.5 mg/kg), or their combination (VEHT), in comparison to a control diet (C, 30 mg all-rac-α-tocopheryl acetate /kg), on the offspring homeostasis and metabolism, analysing the weaned piglets' adipose tissue transcriptome and adipocyte morphology. Diets were provided to pregnant Iberian sows (n = 48, 12 per treatment) from gestation day 85 to weaning (28 days postpartum) and 48 piglets (n = 12 per treatment) were sampled 5 days postweaning for dorsal subcutaneous adipose tissue analyses. RNA obtained from 6 animals for each diet was used for paired-end RNA sequencing. Results show that supplementation of sows' diet with either vitamin E or hydroxytyrosol had substantial effects on weaned piglet adipose transcriptome, with 664 and 587 genes being differentially expressed, in comparison to C, respectively (q-value<0.10, Fold Change>1.5). Genes upregulated in C were mainly involved in inflammatory and immune response, as well as oxidative stress, and relevant canonical pathways and upstream regulators involved in these processes were predicted as activated, such as TNF, IFNB or NFKB. Vitamin E, when supplemented alone at high dose, activated lipid biosynthesis functions, pathways and regulators, this finding being accompanied by increased adipocyte size. Results suggest an improved metabolic and antioxidant status of adipose tissue in animals born from sows supplemented with individual antioxidants, while the combined supplementation barely affected gene expression, with VEHT showing a prooxidant/proinflamatory functional profile similar to C animals. Different hypothesis are proposed to explain this unexpected result. Findings allow a deeper understanding of the processes taking place in adipose tissue of genetically fat animals and the role of antioxidants in the regulation of fat cells function.

Uncovering the Potent Antiviral Activity of the Sesterterpenoids from the Sponge Ircinia felix against Human Adenoviruses: from the Natural Source to the Total Synthesis.

Human Adenovirus (HAdV) infections in immunocompromised patients can result in disseminated diseases with high morbidity and mortality rates due to the absence of available treatments for these infections. Ircinia felix sponge was selected for the significant anti-HAdV activity displayed by its organic extracts. Its chemical analysis yielded three novel sesterterpene lactams, ircinialactams J-L, along with three known sesterterpene furans which structures were established by a deep spectrometric analysis. Ircinialactam J displayed significant antiviral activity against HAdV without significant cytotoxicity, showing an effectiveness 11 times greater than that of the standard treatment, cidofovir®. Some structure-activity relationships were deduced. Mechanistic assays suggest that ircinialactam J targets an early step of the HAdV replicative cycle before HAdV genome reaches the nucleus of the host cell. The first total synthesis of ircinialactam J was also accomplished to prove the structure and to provide access to analogues. Key steps are a regio- and stereoselective construction of the trisubstituted Z-olefin at Δ7 by iron-catalyzed carbometallation of a homopropargylic alcohol, a stereoselective methylation to generate the stereogenic center at C18, and the formation of the (Z)-Δ20 by stereoselective aldol condensation to introduce the tetronic acid unit. Ircinialactam J is a promising antiviral drug against HAdV infections.

Association between periodontitis and cardiovascular risk in Spanish employed adults-The Workers' Oral Health study.

AIMS: Periodontitis and cardiovascular diseases (CVD) are highly prevalent non-communicable diseases, sharing an inflammatory pathogenesis and common risk factors. The objective of the present research is to assess the association between periodontitis and cardiovascular disease risk in a representative sample of the Spanish-employed population. METHODS: Cross-sectional data were obtained between 2008 and 2011 in the Workers' Oral Health (WORALTH) epidemiological study. Periodontal examinations were based on the evaluation of clinical attachment loss (CAL) and community periodontal index (CPI). Participants also underwent a medical check-up and answered a comprehensive health questionnaire. With this information, participants were categorized into three levels of CVD risk using the systemic coronary risk estimation (SCORE) algorithm for low-risk European countries. Crude and adjusted odds ratios (ORs) were determined with multiple logistic regression models for the association between periodontal status and CVD risk. RESULTS: Data from 4224 individuals were analyzed. The overall prevalence of high CVD risk (SCORE ≥ 5%) was 5.1%. The prevalence of SCORE ≥ 5% was 3.4%, 9.4%, and 15.2% for CAL 0-3 mm, 4-5 mm, and ≥6 mm, respectively (p < .001), and 6.2%, 6.5%, and 14.6% for CPI ≤2, 3, and 4, respectively (p < .001). Individuals with CPI = 4 presented an OR of 1.50 (95% confidence interval, CI [1.04; 2.17]) for high SCORE values, after adjusting for confounders (age, sex, and smoking habit). CONCLUSIONS: Periodontitis, defined by the presence of deep periodontal pockets (≥6 mm), was significantly associated with high CVD risk (SCORE ≥ 5%) in a representative sample of the employed population in Spain.

Association between Mid-Term Functionality and Clinical Severity in Patients Hospitalized for Pulmonary Embolism.

The aim of this study is to evaluate the relationship between clinical severity and functionality, occupational performance, and health-related quality of life in patients hospitalized with pulmonary embolism. Pulmonary embolism patients were grouped by clinical severity using the Pulmonary Embolism Severity Index. Those scoring ≥160 were in the high-severity group (HSG); those scoring < 160 in the low-moderate group (LMSG). The main variables were functionality assessed by the World Health Organization Disability Assessment Schedule (WHODAS), self-perception of occupational performance assessed by the Canadian Occupational Performance Measure (COPM), pain and fatigue assessed by a Visual Analogue Scale (VAS), and health-related quality of life assessed by the EuroQol-5Dimensions (EQ-5D). Patients were evaluated at hospital admission and at 1-month and 3-month follow-up. At admission, there were significant differences between groups in the WHODAS and health-related quality of life in favor of the LMSG. At 1-month and at 3-month follow-up, there were significant differences between the LMSG and HSG in WHODAS, COMP, NRS pain, fatigue and EQ-5D scores in favor of the LMSG. An association exists between clinical severity and mid-term functionality, self-perception of occupational performance, pain, fatigue, and health-related quality of life in PE patients.

Effectiveness of Treatment Approaches in COVID-19 Pneumonia: A Comparative Evaluation between a Specialized Center and Conventional Hospitals.

BACKGROUND: The early stages of the COVID-19 pandemic overwhelmed general hospitals in Spain. In response, a dedicated hospital for COVID-19 care, the Hospital de Emergencias Enfermera Isabel Zendal (HEEIZ), was established. This study aimed to compare clinical outcomes of COVID-19 patients treated at the specialized HEEIZ with those at conventional general hospitals (CGHs) in Madrid, Spain. METHODS: The study was a prospective, observational cohort study including COVID-19 patients admitted to the HEEIZ and 14 CGHs (December 2020 to August 2021). Patients were assigned based on hospital preference. Clinical data were collected and analyzed using multivariate regression to assess primary and secondary outcomes, including hospital mortality, need of invasive mechanical ventilation (IMV), and pharmacological treatments. RESULTS: The HEEIZ cohort (n = 2997) was younger and had lower Charlson comorbidity scores than the CGH cohort (n = 1526). Adjusted HEEIZ hospital mortality was not significantly higher compared with CGHs (OR: 1.274; 95% CI: 0.781-2.079; p = 0.332). CONCLUSIONS: During the study period, patients admitted to the HEEIZ showed no significant differences in clinical outcomes, compared with patients admitted at CGHs. These results might support the use of specialized centers in managing pandemic surges, allowing CGHs to handle other needs.

Natural history and surgical outcomes of Rathke's cleft cysts: a Spanish multicenter study.

Rathke's cleft cysts (RCC) are a common type of lesion found in the sellar or suprasellar area. They are usually monitored clinically, but in some cases, surgery may be required. However, their natural progression is not yet well understood, and the outcomes of surgery are uncertain. The objective of this study is to evaluate the natural history of Rathke's cleft cysts in patients who are clinically monitored without treatment, and to determine the outcomes of surgery and the incidence of recurrences over time. Design and patients: National multicentric study of patients diagnosed of Rathke's cleft cyst (RCC- Spain) from 2000 onwards and followed in 15 tertiary centers of Spain. A total of 177 patients diagnosed of RCC followed for 67.3 months (6-215) and 88 patients who underwent surgery, (81 patients underwent immediate surgery after diagnosis and 7 later for subsequent growth) followed for 68.8 months (3-235). Results: The cyst size remained stable or decreased in 73.5% (133) of the patients. Only 44 patients (24.3%) experienced a cyst increase and 9 of them (5.1%) experienced an increase greater than 3 mm. In most of the patients who underwent surgery headaches and visual alterations improved, recurrence was observed in 8 (9.1%) after a median time of 96 months, and no predictors of recurrence were discovered. Conclusions: Rathke's cleft cysts without initial compressive symptoms have a low probability of growth, so conservative management is recommended. Patients who undergo transsphenoidal surgery experience rapid clinical improvement, and recurrences are infrequent. However, they can occur after a long period of time, although no predictors of recurrence have been identified.

COVID-19 in patients with haematologic malignancies: Effect of RNAemia on clinical outcome in vaccinated patients.

OBJECTIVES: Patients with haematologic malignancies (HM) COVID-19 have more severe disease, with increased risk of mortality. Therefore, this study aimed to evaluate the effect of SARS-CoV-2 RNAemia and the specific humoral immune responses on the clinical outcomes of patients with HM and COVID-19. METHODS: Interferon-α/γ (IFN-α/IFN-γ) serum levels, neutralizing antibodies and RNAemia at COVID-19 diagnosis, and persistent RNAemia during the follow-up were evaluated. RESULTS: Overall, 63 (58.9%) out of 107 patients had RNAemia, which was persistent in 26 (41.3%) patients. RNAemia at diagnosis and persistent RNAemia were associated with the need for high-flow nasal oxygen therapy during admission. Persistent RNAemia, age >70 years, and CURB-65 score ≥2 in patients with pneumonia were associated with increased 90-day mortality (P = 0.009, P = 0.030 and P = 0.001, respectively). The 90-day overall survival was lower (P = 0.006) in patients with persistent RNAemia. In addition, dexamethasone administration was associated with a COVID-19 episode with persistent RNAemia. CONCLUSION: Our results suggest that in patients with HM, RNAemia at the time of COVID-19 diagnosis and during the follow-up can be used to stratify patients with HM according to their clinical evolution and to guide clinical decisions tailored to the specific needs of each patient.

Involvement of serotonergic receptors in depressive processes and their modulation by ß-arrestins: A review.

Over time, several studies have been conducted to demonstrate the functions of the neurotransmitter 5-hydroxytryptamine (5-HT), better known as serotonin. This neurotransmitter is associated with the modulation of various social and physiological behaviors, and its dysregulation has consequences at the behavioral level, leading to various neurophysiological disorders. Disorders such as anxiety, depression, schizophrenia, epilepsy, sexual disorders, and eating disorders, have been closely linked to variations in 5-HT concentrations and modifications in brain structures, including the raphe nuclei (RN), prefrontal cortex, basal ganglia, hippocampus, and hypothalamus, among others. The involvement of ß-arrestin proteins has been implicated in the modulation of the serotonergic receptor response, as well as the activation of different signaling pathways related to the serotonergic system, this is particularly relevant in depressive disorders. This review will cover the implications of alterations in 5-HT receptor expression in depressive disorders in one hand and how ß-arrestin proteins modulate the response mediated by these receptors in the other hand.

Effect of one-time placement of the definitive abutment versus multiple healing abutment disconnections and reconnections during the prosthetic phase on radiographic and clinical outcomes: A 12-month randomized clinical trial.

OBJECTIVE: The aim of this investigation was to evaluate the effect on clinical and radiological outcomes of the one-abutment, one-time protocol (test) versus placing the definitive abutment on the day of functional loading after having disconnected and connected three times the healing abutment during the prosthetic phase (control). MATERIALS AND METHODS: Forty patients with 80 implants were randomly allocated to either the test or the control group. Changes in the radiographic marginal bone levels (MBLs), clinical outcomes, prosthetic-related outcomes, and patient-reported outcomes measures (PROMs) were assessed and compared 6 and 12 months after functional loading. RESULTS: Thirty-seven patients with 74 implants were followed at 12 months. A statistically significant bone remodeling was observed in both groups following implant placement. MBLs were significantly greater in the control group at the 6- (-0.13 mm vs. -0.61 mm) and 12-month visits (-0.01 mm vs. -0.53 mm). Bone loss was significantly greater in the control group from surgery to 6 and 12 months and from loading to 6 and 12 months. The abutment height was significantly greater in the test group, however, there were no significant differences in the restorative angle. Similarly, there were no statistically significant differences between groups for the measured clinical variables (probing depth, plaque, and bleeding index) and PROMs. CONCLUSIONS: Disconnecting and reconnecting the healing abutment was associated with significantly higher bone loss after 12 months, as compared to the placement of the definitive abutment at implant installation.

Precision nutrition impact on metabolic health and quality of life in aging population after a 3-month intervention: A randomized intervention.

OBJECTIVES: Innovative precision dietary procedures are required to promote healthy aging. This study aimed to evaluate the effects of a personalised strategy based on the inclusion of individualised foods and digital tools on overall health status and quality of life within a follow-up of 3 months in older adults with overweight or obesity. METHODS: 127 men and women aged between 50 and 80 years with overweight/obesity participated in the study-between January 2020 and September 2020 at the Center for Nutrition Research-University of Navarra and IMDEA-ALIMENTACIÓN-and were randomly assigned to a usual-care group (standard recommendations) or precision group (precision nutrition strategy based on the inclusion of individualised foods and a mobile application). Anthropometry, body fat percentage, biochemical parameters, diet, and quality of life (SF-36 Health Survey) were assessed at baseline and after 3 months. RESULTS: Both strategies were found to improve overall metabolic health; however, the precision approach demonstrated significantly better outcomes. The precision strategy reduced body weight at 3 months (-4.3 kg; p < 0.001) with significant improvements in body fat percentage, blood pressure and general metabolic health (glycated haemoglobin; alanine aminotransferase; aspartate aminotransferase; hepatic steatosis index) in comparison with the standard recommendations. The precision approach significantly enhanced the quality of life (SF-36) of individuals, with additional improvements in emotional well-being (p = 0.024) and vitality (p = 0.008). Adherence to the Mediterranean diet was significantly associated with a higher quality of life and vitality. CONCLUSION: These results support the benefit of precision nutrition approaches for promoting healthy aging and emotional well-being, enhancing the quality of life in aging populations, during the COVID-19 pandemic.

A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.

The mechanistic target of rapamycin complex 1 controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan. Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity.

Novel bioactive extract from yarrow obtained by the supercritical antisolvent-assisted technique inhibits lipid metabolism in colorectal cancer.

Background: Altered lipid metabolism in cancer is associated to dissemination and prognosis. Bioactive compounds naturally occurring in Achillea millefolium L. (yarrow) have been reported to exert antitumour activities. Food biotechnology may provide on-demand mixtures of bioactive compounds with complementary activities in cancer treatment. Methods: Supercritical-antisolvent-precipitation (SAS) has been applied to fractionate the bioactive compounds from an Ultrasound-Assisted-Extraction yarrow extract resulting in two extracts with distinct polarity, yarrow-precipitate-(PP) and yarrow-separator-(Sep). Total phenolic content and relevant essential oils have been characterized. Antioxidant, anti-inflammatory and antiproliferative activities have been compared. Moreover, the effect on the inhibition of colorectal cancer cells' bioenergetics has been evaluated. Results: Yarrow-PP exerted the highest antioxidant activity, even higher than the complete UAE-yarrow extract, meanwhile yarrow-Sep showed the highest anti-inflammatory activity, even higher than the complete UAE-yarrow extract. Interestingly, yarrow-Sep inhibited key lipid metabolic targets in CRC cells extensively shown to be implicated in cancer dissemination and prognosis -SREBF1, FASN, ABCA1 and HMGCR- and epithelial to mesenchymal targets-CDH1, ATP1B1, CDH2 and Vimentin-augmenting cell adhesion. Conclusions: In summary, SAS technology has been applied to provide a novel combination of bioactive compounds, yarrow-Sep, which merits further research to be proposed as a potential complementary nutraceutical in the treatment of CRC.

The effect of one-time abutment placement on clinical and radiographic outcomes: A 5-year randomized clinical trial.

OBJECTIVE: The aim of this study was to evaluate the long-term (5 years) clinical efficacy of the one-abutment one-time protocol (test) versus the standard of care by placing the definitive abutment on the day of the prosthetic delivery (control). MATERIALS AND METHODS: In this study, 39 subjects with 60 implants were randomly allocated to either the test or the control group. Changes in the radiographic interproximal bone levels (DIB), modified sulcus bleeding index, probing depth, modified plaque index, papilla fill (Jemt score), incidence of peri-implantitis and peri-implant mucositis as well as patient-reported outcomes measures (PROMs) were collected and compared at 1, 3 and 5 years. RESULTS: At 5 years, the control group showed a greater, although not statistically significant, change in mean DIB values (0.97 mm vs. 0.53 mm). Regarding the other clinical parameters evaluated, no statistically significant differences were observed between groups at any time point. At 5 years, 51% of the implants presented peri-implant mucositis (25.5% in the control and 23.5% in the test), and only one implant in the test group developed peri-implantitis. CONCLUSIONS: The connection and disconnection of healing abutments during the healing period was not associated with higher long-term bone loss. Clinical outcomes and PROMs were similar between groups.

Periodontal diseases and cardiovascular diseases, diabetes, and respiratory diseases: Summary of the consensus report by the European Federation of Periodontology and WONCA Europe.

BACKGROUND: Periodontitis is a chronic inflammatory non-communicable disease (NCD) characterised by the destruction of the tooth-supporting apparatus (periodontium), including alveolar bone, the presence of periodontal pockets, and bleeding on probing. OBJECTIVES: To outline, for family doctors, the implications of the association between periodontal and systemic diseases; to explore the role of family doctors in managing periodontitis as an ubiquitous non-communicable disease (NCD). METHODS: The consensus reports of previous focused collaborative workshops between WONCA Europe and the European Federation of Periodontology (using previously undertaken systematic reviews), and a specifically commissioned systematic review formed the technical papers to underpin discussions. Working groups prepared proposals independently, and the proposals were subsequently discussed and approved at plenary meetings. RESULTS: Periodontitis is independently associated with cardiovascular diseases, diabetes, chronic obstructive pulmonary disease, obstructive sleep apnoea, and COVID-19 complications. Treatment of periodontitis has been associated with improvements in systemic health outcomes. The article also presents evidence gaps. Oral health care professionals (OHPs) and family doctors should collaborate in managing these conditions, including implementing strategies for early case detection of periodontitis in primary medical care centres and of systemic NCDs in oral/dental care settings. There is a need to raise awareness of periodontal diseases, their consequences, and the associated risk factors amongst family doctors. CONCLUSION: Closer collaboration between OHPs and family doctors is important in the early case detection and management of NCDs like cardiovascular diseases, diabetes mellitus, and respiratory diseases. Strategies for early case detection/prevention of NCDs, including periodontitis, should be developed for family doctors, other health professionals (OHPs), and healthcare funders. Evidence-based information on the reported associations between periodontitis and other NCDs should be made available to family doctors, OHPs, healthcare funders, patients, and the general population.

Periodontitis is independently associated with cardiovascular diseases, diabetes, chronic obstructive pulmonary disease, obstructive sleep apnoea, and COVID-19.Periodontal treatment for optimal outcomes improves diabetes outcomes and surrogate measures of cardiovascular risk.Closer collaboration between oral health care professionals and family doctors is important in the early case detection and management of non-communicable diseases.Information on the reported associations should be made available to family doctors, oral health professionals, healthcare funders, patients, and the general population.

Fluorimetric Detection of Insulin Misfolding by Probes Derived from Functionalized Fluorene Frameworks.

A group of functionalized fluorene derivatives that are structurally similar to the cellular prion protein ligand N,N'-(methylenedi-4,1-phenylene)bis [2-(1-pyrrolidinyl)acetamide] (GN8) have been synthesized. These compounds show remarkable native fluorescence due to the fluorene ring. The substituents introduced at positions 2 and 7 of the fluorene moiety are sufficiently flexible to accommodate the beta-conformational folding that develops in amyloidogenic proteins. Changes in the native fluorescence of these fluorene derivatives provide evidence of transformations in the amyloidogenic aggregation processes of insulin. The increase observed in the fluorescence intensity of the sensors in the presence of native insulin or amyloid aggregates suggest their potential use as fluorescence probes for detecting abnormal conformations; therefore, the compounds can be proposed for use as "turn-on" fluorescence sensors. Protein-sensor dissociation constants are in the 5-10 µM range and an intermolecular charge transfer process between the protein and the sensors can be successfully exploited for the sensitive detection of abnormal insulin conformations. The values obtained for the Stern-Volmer quenching constant for compound 4 as a consequence of the sensor-protein interaction are comparable to those obtained for the reference compound GN8. Fluorene derivatives showed good performance in scavenging reactive oxygen species (ROS), and they show antioxidant capacity according to the FRAP and DPPH assays.

The Comparative Effect of Occupational and Musical Enrichment on Fecal Glucocorticoid Metabolite Levels in a Captive Colony of Stumptail Macaques (Macaca arctoides).

Environmental enrichment improves captive animal welfare by reducing stress-related behaviors. Previous studies in a captive colony of stumptail macaques (Macaca arctoides) reported a reduction of aggression, coprophilia, and stereotypic behaviors after an occupational enrichment program; however, the effect on stress hormones such as glucocorticoids has not been investigated yet. The goal of this study was to compare the effect of sex, age, and social rank on changes in fecal glucocorticoid metabolites (fGCM) after applying two kinds of enrichments (occupational vs. musical) in a captive colony of stumptail macaques. We collected 234 fecal samples from 25 stumptail macaques under the following conditions: (1) basal (no enrichment), (2) three weeks of occupational enrichment, and (3) three weeks of relaxing/classical music. The Generalized Estimated Equation Model showed an increase in fGCM levels after the occupational enrichment only in adult subjects (p = 0.003 compared to basal). The fGCM levels reached by the adults after the occupational enrichment was higher than that of juveniles (p = 0.002) and subadults (p = 0.02). Occupational and musical enrichment decreased fGCM levels only in middle-ranking individuals (p < 0.001 and p = 0.013, respectively). No sex differences were found. In conclusion, there were age and rank differences in individuals' physiological reactivity to the effects of environmental enrichment which need to be considered when planning enrichment programs.

Correction: Limited Role of Murine ATM in Oncogene-Induced Senescence and p53-Dependent Tumor Suppression.

[This corrects the article DOI: 10.1371/journal.pone.0005475.].