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Analysis of the biochemical differences in the energy metabolism among bi-dimensional (2D) and tri-dimensional (3D) cultured cancer cell models and actual human tumors was undertaken. In 2D cancer cells, the oxidative phosphorylation (OxPhos) fluxes range is 2.5-19 nmol O2/min/mg cellular protein. Hypoxia drastically decreased OxPhos flux by 2-3 times in 2D models, similar to what occurs in mature multicellular tumor spheroids (MCTS), a representative 3D cancer cell model. However, mitochondrial protein contents and enzyme activities were significantly different between both models. Moreover, glycolytic fluxes were also significantly different between 2D and MCTS. The glycolytic flux range in 2D models is 1-34 nmol lactate/min/mg cellular protein, whereas in MCTS the range of glycolysis fluxes is 60-80 nmol lactate/min/mg cellular. In addition, sensitivity to anticancer canonical and metabolic drugs was greater in MCTS than in 2D. Actual solid human tumor samples show lower (1.6-4.5 times) OxPhos fluxes compared to normoxic 2D cancer cell cultures. These observations indicate that tridimensional organization provides a unique microenvironment affecting tumor physiology, which has not been so far faithfully reproduced by the 2D environment. Thus, the analysis of the resemblances and differences among cancer cell models undertaken in the present study raises caution on the interpretation of results derived from 2D cultured cancer cells when they are extended to clinical settings. It also raises awareness about detecting which biological and environmental factors are missing in 2D and 3D cancer cell models to be able to reproduce the actual human tumor behavior., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Antipsychotic (AP) use has been associated to QT interval prolongation on the surface electrocardiogram (ECG). Our study aimed to determine the incidence of corrected QT (QTc) interval prolongation among patients admitted to a psychiatric hospitalization unit requiring AP treatment and to assess the relationship between administered dose and QTc interval changes. We enrolled 179 patients admitted to the Hospital Psiquiátrico Departamental Universitario del Valle in Cali, Colombia. ECGs were conducted upon admission, and again at 3 and 7 days postadmission. The QT interval was measured, and QTc interval correction was performed using Bazzet's formula. QTc interval prolongation at time points B or C was observed in 9.5% of patients. Clozapine was the most common AP associated with QTc interval prolongation (20.59%), followed by olanzapine (15.38%). The relative risk of QT interval prolongation with clozapine compared to haloperidol was 4.17 (95% confidence interval, 1.14-15.17, P = 0.02). AP use upon hospital admission was linked to early (within 3 days) QTc interval prolongation. Clozapine and olanzapine were associated with a greater increase in QTc interval compared to haloperidol, indicating a need for rigorous electrocardiographic monitoring with their use., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder. Worldwide, its prevalence is ~2% and its etiology is mostly unknown. Identifying biological factors contributing to OCD will elucidate underlying mechanisms and might contribute to improved treatment outcomes. Genomic studies of OCD are beginning to reveal long-sought risk loci, but >95% of the cases currently in analysis are of homogenous European ancestry. If not addressed, this Eurocentric bias will result in OCD genomic findings being more accurate for individuals of European ancestry than other ancestries, thereby contributing to health disparities in potential future applications of genomics. In this study protocol paper, we describe the Latin American Trans-ancestry INitiative for OCD genomics (LATINO, https://www.latinostudy.org). LATINO is a new network of investigators from across Latin America, the United States, and Canada who have begun to collect DNA and clinical data from 5000 richly phenotyped OCD cases of Latin American ancestry in a culturally sensitive and ethical manner. In this project, we will utilize trans-ancestry genomic analyses to accelerate the identification of OCD risk loci, fine-map putative causal variants, and improve the performance of polygenic risk scores in diverse populations. We will also capitalize on rich clinical data to examine the genetics of treatment response, biologically plausible OCD subtypes, and symptom dimensions. Additionally, LATINO will help elucidate the diversity of the clinical presentations of OCD across cultures through various trainings developed and offered in collaboration with Latin American investigators. We believe this study will advance the important goal of global mental health discovery and equity., (© 2023 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Background: Antimicrobial stewardship programs (ASPs) are recommended in nursing homes (NHs), although data are limited. We aimed to determine the clinical and ecological impact of an ASP for NHs., Methods: We performed a cluster, randomized, controlled trial and a before-after study with interrupted time-series analyses in 14 NHs for 30 consecutive months from July 2018 to December 2020 in Andalusia, Spain. Seven facilities implemented an ASP with a bundle of 5 educational measures (general ASP) and 7 added 1-to-1 educational interviews (experimental ASP). The primary outcome was the overall use of antimicrobials, calculated monthly as defined daily doses (DDD) per 1000 resident days (DRD)., Results: The total mean antimicrobial consumption decreased by 31.2% (-16.72 DRD; P = .045) with respect to the preintervention period; the overall use of quinolones and amoxicillin-clavulanic acid dropped by 52.2% (P = .001) and 42.5% (P = .006), respectively; and the overall prevalence of multidrug-resistant organisms (MDROs) decreased from 24.7% to 17.4% (P = .012). During the intervention period, 12.5 educational interviews per doctor were performed in the experimental ASP group; no differences were found in the total mean antimicrobial use between groups (-14.62 DRD; P = .25). Two unexpected coronavirus disease 2019 waves affected the centers increasing the overall mean use of antimicrobials by 40% (51.56 DRD; P < .0001)., Conclusions: This study suggests that an ASP for NHs appears to be associated with a decrease in total consumption of antimicrobials and prevalence of MDROs. This trial did not find benefits associated with educational interviews, probably due to the coronavirus disease 2019 pandemic. Clinical Trials Registration. NCT03543605., Competing Interests: Potential conflicts of interest. J. M. C. has received travel grants and honoraria as a speaker from Novartis, Astellas Pharma, Pfizer, MSD, Janssen Pharmaceuticals, and AstraZeneca outside the submitted work. A. R. V. has received honoraria as a speaker from Pfizer outside the submitted work. J. M. C. reports funding from Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Madrid, Spain. J. M. C., G. P., and J. C. C.-R. report grants from the Instituto de Salud Carlos III, Spanish Government, cofinanced by the European Development Regional Fund (A Way to Achieve Europe), and from the Spanish Network for Research in Infectious Diseases during the conduct of the study. A. B. G.-G. reports funding from the Subprograma Río Hortega and Juan Rodés, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spanish Government. L. H.-H. reports funding from the Subprograma Río Hortega. M. E. P.-I. is a researcher funded by the program Nicolás Monardes, Servicio Andaluz de Salud, Junta de Andalucía, Spain. A. R. V. is supported by the Subprograma Juan Rodés, Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spain. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The objectives of this work were to assess the diagnostic sensitivity and specificity of nasopharyngeal (NP) swabs for viral community-acquired pneumonia (CAP) and the performance of pneumonia severity index (PSI) and CURB-65 severity scores in the viral CAP in adults. A prospective observational cohort study of consecutive 341 hospitalized adults with CAP was performed between January 2018 and March 2020. Demographics, comorbidities, symptoms/signs, analytical data, severity scores, antimicrobials, and outcomes were recorded. Blood, NP swabs, sputum, and urine samples were collected at admission and assayed by multiplex real time-PCR, bacterial cultures, and Streptococcus pneumoniae and Legionella pneumophila antigens detection, to determine the etiologies and quantify the viral load. The etiology was identified in 174 (51.0%) patients, and in 85 (24.9%) it was viral, the most frequent rhinovirus and influenza virus. The sensitivity of viral detection in sputum (50.7%) was higher than in NP swabs (20.9%). Compared with sputum, the positive predictive value and specificity of NP swabs for viral diagnosis were 95.8% and 96.9%, respectively. Performance of PSI and CURB-65 scores in all CAP with etiologic diagnosis were as expected, with mortality associated with higher values, but they were not associated with mortality in patients with viral pneumonia. NP swabs have lower sensitivity but high specificity for the diagnosis of viral CAP in adults compared with sputum, reinforcing the use NP swabs for the diagnostic etiology work-up. The PSI and CURB-65 scores did not predict mortality in the viral CAP, suggesting that they need to be updated scores based on the identification of the etiological agent., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Several biological processes related to cancer malignancy are regulated by 17-β estradiol (E2) in ER+-breast cancer. To establish the role of E2 on the atypical cancer energy metabolism, a systematic study analyzing transcription factors, proteins, and fluxes associated with energy metabolism was undertaken in multicellular tumor spheroids (MCTS) from human ER+ MCF-7 breast cancer cells. At E2 physiological concentrations (10 and 100 nM for 24 h), both ERα and ERβ receptors, and their protein target pS2, increased by 0.6-3.5 times vs . non-treated MCTS, revealing an activated E2/ER axis. E2 also increased by 30-470% the content of several transcription factors associated to mitochondrial biogenesis and oxidative phosphorylation (OxPhos) (p53, PGC1-α) and glycolytic pathways (HIF1-α, c-MYC). Several OxPhos and glycolytic proteins (36-257%) as well as pathway fluxes (48-156%) significantly increased being OxPhos the principal ATP cellular supplier (>75%). As result of energy metabolism stimulation by E2, cancer cell migration and invasion processes and related proteins (SNAIL, FN, MM-9) contents augmented by 24-189% vs. non-treated MCTS. Celecoxib at 10 nM blocked OxPhos (60%) as well as MCTS growth, cell migration and invasiveness (>40%); whereas the glycolytic inhibitor iodoacetate (0.5 µM) and doxorubicin (70 nM) were innocuous. Our results show for the first time using a more physiological tridimensional cancer model, resembling the initial stages of solid tumors, that anti-mitochondrial therapy may be useful to deter hormone-dependent breast carcinomas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pacheco-Velázquez, Ortega-Mejía, Vargas-Navarro, Padilla-Flores, Robledo-Cadena, Tapia-Martínez, Peñalosa-Castro, Aguilar-Ponce, Granados-Rivas, Moreno-Sánchez and Rodríguez-Enríquez.)

Cocoa and coffee are natural sources of phenolic compounds, which are degraded during beans processing of both. For this reason, there is an interest in obtaining extracts of these bio compounds. The aim of this study was uncovering the radical scavenging activity (AC) of mixtures of cocoa and coffee extracts, and the bioavailability of their phenolic compounds, resorting to in vitro models: DPPH and ORAC antioxidant methods, and the characterization of the trans-epithelial transport of cocoa and coffee phenolics through Caco-2 cells monolayer model of the intestinal barrier. The cocoa displayed a higher AC than the coffee regarding both DPPH and ORAC assays, while the mixtures increased in parallel with the percentage of cocoa in the blends. The combination index was calculated to set up the type of interaction in the cocoa-coffee mixtures, obtaining that the mixture 25:75 was moderately antagonistic, 50:50 nearly additive, and 75:25 slightly synergistic. The absorption efficiency of the cocoa phenolic compounds was between 87.9%-97.4%, in the coffee compounds was 100%. The mixtures varied according to the proportion of cocoa and coffee. The results obtained allowed concluding that the phenolic compounds present in cocoa and coffee, respectively, are featured by high bioavailability and a valuable antioxidant capacity, while no pattern was found in the mixtures concerning the real benefit of using them combined.

The health benefits of cocoa depend on the flavan 3-ols, procyanidins, and methylxanthines, which decrease from the early stages of cocoa bean processing. The objective of this research was to obtain a cocoa extract high in these compounds with (-)-epicatechin as the primary reference. An evaluation of two pretreatments of cocoa beans with a control after harvesting was made: A (untreated/control), B (Frozen), and C (Polyphenol oxidase inhibition), all followed by dehydration at 45 °C until obtaining a cocoa powder. In terms of (-)-epicatechin content, the best pretreatment was put on to a hydroalcoholic extraction. Flavan 3-ols, procyanidins, methylxanthines, and total polyphenols content (TPC), were quantified in the cocoa powders and the hydroalcoholic extract. The results showed that the control (A), significantly conserves the (-)-epicatechin (24.964 ± 0.400 mg/g) ca. 7 times more than conventionally sun-dried and fermented beans (3.742 ± 1.977 mg/g) ca. The hydroalcoholic extraction increased the (-)-epicatechin ca. 3 times more based on pretreatment A (84.738 mg/g)., Competing Interests: Conflicts of interestThere is no conflict of interest, (© Association of Food Scientists & Technologists (India) 2021.)

Background: Long-term care facilities (LTCFs) are health-care settings with high antimicrobial consumption and hence need to develop effective antimicrobial stewardship programmes (ASPs)., Objective: To assess the effects of ASPs on care-related, clinical and ecological outcomes in LTCFs., Methods: Data sources were PubMed, EMBASE, CINAHL and SCOPUS. Study eligibility criteria were original research articles (controlled clinical trials or controlled before and after studies) published up to 1 October 2020. Participants were adult residents of LTCFs, residential aged-care facilities, nursing homes, veterans' homes, skilled nursing facilities and assisted living facilities for older people. Interventions included ASPs versus standard care. Outcomes assessed were antimicrobial consumption and appropriateness, infections, hospital admissions and mortality. Available data were pooled in a meta-analysis, and inconsistency between studies was evaluated using the I 2 statistic. Certainty of evidence was assessed using the GRADE approach., Results: Of the 3111 papers identified, 12 studies met the inclusion criteria. All of them analysed the impact of interventions on antimicrobial use based on consumption-related variables (n = 8) and/or percentage of inappropriate prescriptions (n = 6). Pooled data showed a mean difference of -0.47 prescriptions per 1000 resident-days in favour of ASPs (95% CI -0.87 to -0.07, I 2  = 71%). Five studies analysed the clinical effect of ASPs on the number of hospital admissions and/or resident mortality. The meta-analysis showed a mean difference of 0.17 hospital admissions per 1000 resident-days (95% CI -0.07 to 0.41, I 2  = 17%) and a mean difference of -0.02 deaths per 1000 resident-days (95% CI -0.14 to 0.09, I 2  = 0%). Only two studies included infections as a study outcome., Conclusions: ASPs appear to improve antimicrobial use in this setting without increasing hospital admissions or deaths, indicating that these programmes do not lead to under-treatment of infections. Nonetheless, further higher-quality clinical trials are required to understand the effects of ASPs in LTCFs., Prospero Registration Number: CRD42021225127., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin β7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19., (© 2021. The Author(s), under exclusive licence to CSI and USTC.)

The aim was to assess the ability of nasopharyngeal SARS-CoV-2 viral load at first patient's hospital evaluation to predict unfavorable outcomes. We conducted a prospective cohort study including 321 adult patients with confirmed COVID-19 through RT-PCR in nasopharyngeal swabs. Quantitative Synthetic SARS-CoV-2 RNA cycle threshold values were used to calculate the viral load in log 10 copies/mL. Disease severity at the end of follow up was categorized into mild, moderate, and severe. Primary endpoint was a composite of intensive care unit (ICU) admission and/or death (n = 85, 26.4%). Univariable and multivariable logistic regression analyses were performed. Nasopharyngeal SARS-CoV-2 viral load over the second quartile (≥ 7.35 log 10 copies/mL, p = 0.003) and second tertile (≥ 8.27 log 10 copies/mL, p = 0.01) were associated to unfavorable outcome in the unadjusted logistic regression analysis. However, in the final multivariable analysis, viral load was not independently associated with an unfavorable outcome. Five predictors were independently associated with increased odds of ICU admission and/or death: age ≥ 70 years, SpO 2 , neutrophils > 7.5 × 10 3 /µL, lactate dehydrogenase ≥ 300 U/L, and C-reactive protein ≥ 100 mg/L. In summary, nasopharyngeal SARS-CoV-2 viral load on admission is generally high in patients with COVID-19, regardless of illness severity, but it cannot be used as an independent predictor of unfavorable clinical outcome.

Elderly people confined to chronic care facilities face an increased risk of acquiring infections by multidrug-resistant organisms (MDROs). This review presents the current knowledge of the prevalence and risk factors for colonization by MDROs in long-term care facilities (LTCF), thereby providing a useful reference to establish objectives for implementing successful antimicrobial stewardship programs (ASPs). We searched in PubMed and Scopus for studies examining the prevalence of MDROs and/or risk factors for the acquisition of MDROs in LTCF. One hundred and thirty-four studies published from 1987 to 2020 were included. The prevalence of MDROs in LTCF varies between the different continents, where Asia reported the highest prevalence of extended-spectrum ß-lactamase (ESBL) Enterobacterales (71.6%), carbapenem resistant (CR) Enterobacterales (6.9%) and methicillin-resistant Staphylococcus aureus (MRSA) (25.6%) and North America the highest prevalence to MDR Pseudomonas aeruginosa (5.4%), MDR Acinetobacter baumannii (15.0%), vancomycin-resistant Enterococcus spp. (VRE) (4.0%), and Clostridioides difficile (26.1%). Furthermore, MDRO prevalence has experienced changes over time, with increases in MDR P. aeruginosa and extended spectrum ß-lactamase producing Enterobacterales observed starting in 2015 and decreases of CR Enterobacterales , MDR A. baumannii , VRE, MRSA and C. difficile. Several risk factors have been found, such as male sex, chronic wounds, the use of medical devices, and previous antibiotic use. The last of these aspects represents one of the most important modifiable factors for reducing colonization with MDROs through implementing ASPs in LTCF.

Background: Amnestic mild cognitive impairment (aMCI) is the most common preclinical stage of Alzheimer's disease (AD). A strategy to reduce the impact of AD is the early aMCI diagnosis and clinical intervention. Neuroimaging, neurobiological, and genetic markers have proved to be sensitive and specific for the early diagnosis of AD. However, the high cost of these procedures is prohibitive in low-income and middle-income countries (LIMCs). The neuropsychological assessments currently aim to identify cognitive markers that could contribute to the early diagnosis of dementia., Objective: Compare machine learning (ML) architectures classifying and predicting aMCI and asset the contribution of cognitive measures including binding function in distinction and prediction of aMCI., Methods: We conducted a two-year follow-up assessment of a sample of 154 subjects with a comprehensive multidomain neuropsychological battery. Statistical analysis was proposed using complete ML architectures to compare subjects' performance to classify and predict aMCI. Additionally, permutation importance and Shapley additive explanations (SHAP) routines were implemented for feature importance selection., Results: AdaBoost, gradient boosting, and XGBoost had the highest performance with over 80%success classifying aMCI, and decision tree and random forest had the highest performance with over 70%success predictive routines. Feature importance points, the auditory verbal learning test, short-term memory binding tasks, and verbal and category fluency tasks were used as variables with the first grade of importance to distinguish healthy cognition and aMCI., Conclusion: Although neuropsychological measures do not replace biomarkers' utility, it is a relatively sensitive and specific diagnostic tool for aMCI. Further studies with ML must identify cognitive performance that differentiates conversion from average MCI to the pathological MCI observed in AD.

Introduction: Normotensive hydrocephalus is a differential diagnosis in the evaluation of the dementia syndrome. The diagnostic protocols would allow detecting this pathology that has more effective treatment than other dementias., Objective: To describe a population with clinical suspicion of normal pressure hydrocephalus evaluated in a Colombian psychiatric hospital and discuss the possible reasons for its diagnostic and therapeutic delay., Materials and Methods: We conducted a retrospective study of medical records to identify patients with suspected normal pressure hydrocephalus during a 5-year period., Results: Thirty-five patients with suspected normal pressure hydrocephalus underwent diagnostic lumbar puncture and five of them were considered candidates for a peritonealvenous shunt, but none underwent this surgical procedure. After three to six months of the lumbar puncture, the gait pattern improved in 22.8% of the patients, cognition in 22.8%, and sphincter control in 11.4%. Improvement was not sustained in the long term (1 year) in any of them., Conclusion: This study suggests the poor implementation of the protocols for evaluating patients with cognitive deficits and delays in the diagnosis of normal pressure hydrocephalus. A small number of patients were identified as candidates for treatment. Normal pressure hydrocephalus is a potentially reversible clinical entity with the placement of a peritoneal ventricular shunt, but delays in diagnosis and treatment have deleterious consequences for patients and their families.

Immunotherapy has yielded impressive results, but only for a minority of patients with cancer. Therefore, new approaches that potentiate immunotherapy are a pressing medical need. Ferroptosis is a newly described type of programmed cell death driven by iron-dependent phospholipid peroxidation via Fenton chemistry. Here, we developed iron oxide-loaded nanovaccines (IONVs), which, chemically programmed to integrate iron catalysis, drug delivery, and tracking exploiting the characteristics of the tumor microenvironment (TME), improves immunotherapy and activation of ferroptosis. The IONVs trigger danger signals and use molecular disassembly and reversible covalent bonds for targeted antigen delivery and improved immunostimulatory capacity and catalytic iron for targeting tumor cell ferroptosis. IONV- and antibody-mediated TME modulation interfaced with imaging was important toward achieving complete eradication of aggressive and established tumors, eliciting long-lived protective antitumor immunity with no toxicities. This work establishes the feasibility of using nanoparticle iron catalytic activity as a versatile and effective feature for enhancing immunotherapy., Competing Interests: The authors declare no competing interests., (© 2020 The Authors.)

Objectives: Antibiotic stewardship programs (ASP) have already demonstrated clinical benefits. However, their effectiveness or safety in immunocompromised hosts needs to be proved., Methods: An ecologic quasi-experimental study was performed from January 2009 to June 2017 in the Oncology department of a tertiary-care hospital. A stable program of Infectious Diseases consultation (IDC) already existed at this unit, and an educational ASP was added in 2011. Its main intervention consisted of face-to-face educational interviews. Antibiotic consumption was assessed through quarterly Defined Daily Doses (DDD) per 100 occupied bed-days. Mortality was evaluated in patients with bloodstream infections through the quarterly incidence density per 1000 admissions, and the annual mortality rates at 7 and 30-days. Time-trends were analysed through segmented-regression analysis, and the impact of the ASP was assessed through before-after interrupted time-series analysis., Results: Mortality significantly decreased throughout the study period (-13.3% annual reduction for 7-day mortality rate, p < 0.01; -8.1% annual reduction for 30-day mortality, p = 0.03), parallel to a reduction in antibiotic consumption (quarterly reduction -0.4%, p = 0.01), especially for broader-spectrum antibiotics. The before-after study settled a significant inflexion point on the ASP implementation for the reduction of antibiotic consumption (change in level 0.95 DDD, p = 0.71; change in slope -1.98 DDD per quarter, p < 0.01). The decreasing trend for mortality before the ASP also continued after its implementation., Conclusions: The combination of an ASP with IDC improved antibiotic use among patients with cancer, and was accompanied by a reduction of mortality of bacteraemic infections. Implementation of the ASP was necessary to effectively change antibiotic use., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Rheumatoid arthritis (RA) patients with disease in clinical remission might show subclinical synovitis, which can be related to the progress of structural joint damage., Objective: To determine and compare the degree of synovial inflammation by ultrasound (US) in patients with RA in clinical remission, treated with DMARD or combination therapy with DMARD and anti-TNF., Methods: Hospital-based cross-sectional study of 58 patients with RA in sustained remission for at least 6 months by DAS28 <2.6, who attended the Rheumatology Service at the Hospital Universitario de Caracas. Patients underwent clinical, functional, and laboratory assessments. Ultrasound was performed in hands measuring synovial effusion, synovial hypertrophy and power Doppler signal; using a semiquantitative 4-point scale of 0=none to 3=severe. Chi-square and t-test were used to compare the clinical, functional, laboratory and US assessments between the DMARD (N=37) and combination therapy with DMARD and anti-TNF (N=21) groups. A p-value <0.05 was considered statistically significant., Results: Out of 58 patients, 25.9% had remission by US and 74.1% had synovial effusion or hypertrophy or positive power Doppler signal. Non-significant differences in US synovitis between the two groups were found., Conclusions: Persistent US activity was evident in a high percentage of rheumatoid arthritis patients in clinical remission by DAS28. No differences in subclinical synovitis measured by US were found between patients with DMARD and anti-TNF-induced clinical remission., (Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Members of Rhizobiaceae contain a homologue of the iron-responsive regulatory protein RirA. In different bacteria, RirA acts as a repressor of iron uptake systems under iron-replete conditions and contributes to ameliorate cell damage during oxidative stress. In Rhizobium leguminosarum and Sinorhizobium meliloti , mutations in rirA do not impair symbiotic nitrogen fixation. In this study, a rirA mutant of broad host range S. fredii HH103 has been constructed (SVQ780) and its free-living and symbiotic phenotypes evaluated. No production of siderophores could be detected in either the wild-type or SVQ780. The rirA mutant exhibited a growth advantage under iron-deficient conditions and hypersensitivity to hydrogen peroxide in iron-rich medium. Transcription of rirA in HH103 is subject to autoregulation and inactivation of the gene upregulates fbpA , a gene putatively involved in iron transport. The S. fredii rirA mutant was able to nodulate soybean plants, but symbiotic nitrogen fixation was impaired. Nodules induced by the mutant were poorly infected compared to those induced by the wild-type. Genetic complementation reversed the mutant's hypersensitivity to H₂O₂, expression of fbpA , and symbiotic deficiency in soybean plants. This is the first report that demonstrates a role for RirA in the Rhizobium -legume symbiosis.

Despite the tremendous potential of Toll-like receptor 4 (TLR4) agonists in vaccines, their efficacy as monotherapy to treat cancer has been limited. Only some lipopolysaccharides (LPS) isolated from particular bacterial strains or structures like monophosphoryl lipid A (MPLA) derived from lipooligosaccharide (LOS), avoid toxic overactivation of innate immune responses while retaining adequate immunogenicity to act as adjuvants. Here, different LOS structures are incorporated into nanoparticle-filled phospholipid micelles for efficient vaccine delivery and more potent cancer immunotherapy. The structurally unique LOS of the plant pathogen Xcc is incorporated into phospholipid micelles encapsulating iron oxide nanoparticles, producing stable pathogen-mimicking nanostructures suitable for targeting antigen presenting cells in the lymph nodes. The antigen is conjugated via a hydrazone bond, enabling rapid, easy-to-monitor and high-yield antigen ligation at low concentrations. The protective effect of these constructs is investigated against a highly aggressive model for tumor immunotherapy. The results show that the nanovaccines lead to a higher-level antigen-specific cytotoxic T lymphocyte (CTL) effector and memory responses, which when combined with abrogation of the immunosuppressive programmed death-ligand 1 (PD-L1), provide 100% long-term protection against repeated tumor challenge. This nanovaccine platform in combination with checkpoint inhibition of PD-L1 represents a promising approach to improve the cancer immunotherapy of TLR4 agonists., (© 2018 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The lifetime risk of stroke has been calculated in a limited number of selected populations. We sought to estimate the lifetime risk of stroke at the regional, country, and global level using data from a comprehensive study of the prevalence of major diseases., Methods: We used the Global Burden of Disease (GBD) Study 2016 estimates of stroke incidence and the competing risks of death from any cause other than stroke to calculate the cumulative lifetime risks of first stroke, ischemic stroke, or hemorrhagic stroke among adults 25 years of age or older. Estimates of the lifetime risks in the years 1990 and 2016 were compared. Countries were categorized into quintiles of the sociodemographic index (SDI) used in the GBD Study, and the risks were compared across quintiles. Comparisons were made with the use of point estimates and uncertainty intervals representing the 2.5th and 97.5th percentiles around the estimate., Results: The estimated global lifetime risk of stroke from the age of 25 years onward was 24.9% (95% uncertainty interval, 23.5 to 26.2); the risk among men was 24.7% (95% uncertainty interval, 23.3 to 26.0), and the risk among women was 25.1% (95% uncertainty interval, 23.7 to 26.5). The risk of ischemic stroke was 18.3%, and the risk of hemorrhagic stroke was 8.2%. In high-SDI, high-middle-SDI, and low-SDI countries, the estimated lifetime risk of stroke was 23.5%, 31.1% (highest risk), and 13.2% (lowest risk), respectively; the 95% uncertainty intervals did not overlap between these categories. The highest estimated lifetime risks of stroke according to GBD region were in East Asia (38.8%), Central Europe (31.7%), and Eastern Europe (31.6%), and the lowest risk was in eastern sub-Saharan Africa (11.8%). The mean global lifetime risk of stroke increased from 22.8% in 1990 to 24.9% in 2016, a relative increase of 8.9% (95% uncertainty interval, 6.2 to 11.5); the competing risk of death from any cause other than stroke was considered in this calculation., Conclusions: In 2016, the global lifetime risk of stroke from the age of 25 years onward was approximately 25% among both men and women. There was geographic variation in the lifetime risk of stroke, with the highest risks in East Asia, Central Europe, and Eastern Europe. (Funded by the Bill and Melinda Gates Foundation.).

Catechins, including catechin (C) and epicatechin (E), are the main type of flavonoids in cacao seeds. They play important roles in plant defense and have been associated with human health benefits. Although flavonoid biosynthesis has been extensively studied using in vitro and in vivo models, the regulatory mechanisms controlling their accumulation under light/dark conditions remain poorly understood. To identify differences in flavonoid biosynthesis (particularly catechins) under different light treatments, we used cacao cell suspensions exposed to white-blue light and darkness during 14 days. RNA-Seq was applied to evaluate differential gene expression. Our results indicate that light can effectively regulate flavonoid profiles, inducing a faster accumulation of phenolic compounds and shifting E/C ratios, in particular as a response to switching from white to blue light. The results demonstrated that HY5, MYB12, ANR and LAR were differentially regulated under light/dark conditions and could be targeted by overexpression aiming to improve catechin synthesis in cell cultures. In conclusion, our RNA-Seq analysis of cacao cells cultured under different light conditions provides a platform to dissect key aspects into the genetic regulatory network of flavonoids. These light-responsive candidate genes can be used further to modulate the flavonoid production in in vitro systems with value-added characteristics.

Encouraging results are emerging from systems that exploit Toll like receptor (TLR) signaling, nanotechnology, checkpoint inhibition and molecular imaging for cancer immunotherapy. A major remaining challenge is developing effective, durable and tumour-specific immune responses without systemic toxicity. Here, we report a simple and versatile system based on synergistic activation of immune responses and direct cancer cell killing by combined TLR ligation using polyIC as TLR3 and imiquimod (R837) as TLR7 agonist, in combination with the model antigen ovalbumin (OVA) and phospholipid micelles loaded with zinc-doped iron oxide magnetic nanoparticles (MNPs). The combination of TLR agonists triggered a strong innate immune response in the lymph nodes (LNs) without systemic release of pro-inflammatory cytokines. The vaccines showed excellent efficacy against aggressive B16-F10 melanoma cells expressing OVA, which was improved with immune checkpoint abrogation of the immunosuppressive programmed death-ligand 1 (PD-L1) at the level of the cancer cells. By magnetic resonance (MR) and nuclear imaging we could track the vaccine migration from the site of injection to LNs and tumour. Overall, we show this synergistic TLR agonists and their combination with MNPs and immune checkpoint blockade to have considerable potential for preclinical and clinical development of vaccines for cancer immunotherapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Neurosyphilis is the clinical manifestation of syphilis that can arise during either the early or late stages of infection. Even though dedicated treatment for all clinical forms of syphilis has been available for many years, the advanced stages of the disease are still prevalent, with irreversible sequelae. This article reviews the current evidence, diagnostic methods and specific treatment for tertiary syphilis., (Copyright © 2017 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.)

Background: The far-lateral transcondylar surgical approach is often used to clip vertebral artery (VA) and posterior inferior cerebellar artery (PICA) aneurysms. The role of condyle resection during this approach is controversial., Objective: To evaluate patient outcomes in patients with VA-PICA aneurysms in whom drilling the occipital condyle was not necessary., Methods: Between May 2005 and December 2012, a total of 56 consecutive patients with incidental or ruptured VA-PICA aneurysms underwent surgery with a far-lateral approach without condylar resection. Clinical presentation, surgical reports, presurgery and postsurgery radiological examinations, and clinical follow-up reports were assessed. Anatomic aneurysm location was analyzed through angiography or computed tomography angiography. We compared postsurgical Glasgow Outcome Scale scores, modified Rankin Scale scores, and morbidity in 2 groups: those with aneurysms in the anterior medullary segment and those with aneurysms in the lateral medullary segment., Results: The predominant presentation was subarachnoid hemorrhage in 34 patients (60.7%). Most aneurysms (n = 27 [48.2%]) were located in the lateral medullary segment of the PICA, followed by the anterior medullary segment (n = 25 [44.6%]). Total aneurysm occlusion was achieved in 100% of patients, and bypass techniques were necessary in 3 patients (5.4%). Fifty-two patients (92.8%) had Glasgow Outcome Scale scores of 4 or 5 postsurgery., Conclusions: A far-lateral approach that leaves the occipital condyle intact is adequate for treating most patients with VA-PICA aneurysms., (Copyright © 2017 by the Congress of Neurological Surgeons)

Encouraging developments demonstrate that few transition metal and organometallic catalysts can operate in a bioorthogonal fashion and promote non-natural chemistry in living systems by minimizing undesired side reactions with cellular components. These catalytic processes have potential for applications in medicinal chemistry and chemical biology. However, the stringent conditions of the cell environment severely limit the number of accessible metal catalysts and exogenous reactions. Herein, we report an unorthodox approach and a new type of bioorthogonal catalytic reaction, in which a metal complex is an unconventional substrate and an exogenous biological molecule acts as a catalyst. In this reaction, riboflavin photocatalytically converts a Pt IV prodrug into cisplatin within the biological environment. Due to the catalytic activity of riboflavin, cisplatin-like apoptosis is induced in cancer cells under extremely low doses of light, potentially preventing systemic off-target reactions. Photocatalytic and bioorthogonal turnover of Pt IV into Pt II species is an attractive strategy to amplify the antineoplastic action of metal-based chemotherapeutics with spatio-temporal control.

In rhizobial species that nodulate inverted repeat-lacking clade (IRLC) legumes, such as the interaction between Sinorhizobium meliloti and Medicago, bacteroid differentiation is driven by an endoreduplication event that is induced by host nodule-specific cysteine rich (NCR) antimicrobial peptides and requires the participation of the bacterial protein BacA. We have studied bacteroid differentiation of Sinorhizobium fredii HH103 in three host plants: Glycine max, Cajanus cajan and the IRLC legume Glycyrrhiza uralensis. Flow cytometry, microscopy analyses and viability studies of bacteroids as well as confocal microscopy studies carried out in nodules showed that S. fredii HH103 bacteroids, regardless of the host plant, had deoxyribonucleic acid (DNA) contents, cellular sizes and survival rates similar to those of free-living bacteria. Contrary to S. meliloti, S. fredii HH103 showed little or no sensitivity to Medicago NCR247 and NCR335 peptides. Inactivation of S. fredii HH103 bacA neither affected symbiosis with Glycyrrhiza nor increased bacterial sensitivity to Medicago NCRs. Finally, HH103 bacteroids isolated from Glycyrrhiza, but not those isolated from Cajanus or Glycine, showed an altered lipopolysaccharide. Our studies indicate that, in contrast to the S. meliloti-Medicago model symbiosis, bacteroids in the S. fredii HH103-Glycyrrhiza symbiosis do not undergo NCR-induced and bacA-dependent terminal differentiation., (© 2015 Society for Applied Microbiology and John Wiley & Sons Ltd.)

In the rhizobia-legume symbiotic interaction, bacterial surface polysaccharides, such as exopolysaccharide (EPS), lipopolysaccharide (LPS), K-antigen polysaccharide (KPS) or cyclic glucans (CG), appear to play crucial roles either acting as signals required for the progression of the interaction and/or preventing host defence mechanisms. The symbiotic significance of each of these polysaccharides varies depending on the specific rhizobia-legume couple. In this work we show that the production of exopolysaccharide by Sinorhizobium fredii HH103, but not by other S. fredii strains such as USDA257 or NGR234, is repressed by nod gene inducing flavonoids such as genistein and that this repression is dependent on the presence of a functional NodD1 protein. In agreement with the importance of EPS for bacterial biofilms, this reduced EPS production upon treatment with flavonoids correlates with decreased biofilm formation ability. By using quantitative RT-PCR analysis we show that expression of the exoY2 and exoK genes is repressed in late stationary cultures of S. fredii HH103 upon treatment with genistein. Results presented in this work show that in S. fredii HH103 EPS production is regulated just in the opposite way than other bacterial signals such as Nod factors and type 3 secreted effectors: it is repressed by flavonoids and NodD1 and enhanced by the nod repressor NolR. These results are in agreement with our previous observations showing that lack of EPS production by S. fredii HH103 is not only non-detrimental but even beneficial for symbiosis with soybean.

Correction for 'Near infrared activation of an anticancer Pt(IV) complex by Tm-doped upconversion nanoparticles' by Emmanuel Ruggiero et al., Chem. Commun., 2015, 51, 2091-2094.

The synthesis and full characterisation (including X-ray diffraction studies and DFT calculations) of two new piano-stool Ru(II) -arene complexes, namely [(η(6) -p-cym)Ru(bpy)(m-CCH-Py)][(PF)6]2 (1) and [(η(6) -p-cym)Ru(bpm)(m-CCH-Py)][(PF)6]2 (2; p-cym=p-cymene, bpy=2,2'-bipyridine, bpm=2,2'-bipyrimidine, and m-CCH-Py=3-ethynylpyridine), is described and discussed. The reaction of the m-CCH-Py ligand of 1 and 2 with diethyl-3-azidopropyl phosphonate by Cu-catalysed click chemistry affords [(η(6) -p-cym)Ru(bpy)(P-Trz-Py)][(PF)6]2 (3) and [(η(6) -p-cym)Ru(bpm)(P-Trz-Py)][(PF)6]2 (4; P-Trz-Py=[3-(1-pyridin-3-yl-[1,2,3]triazol-4-yl)-propyl]phosphonic acid diethyl ester). Upon light excitation at λ=395 nm, complexes 1-4 photodissociate the monodentate pyridyl ligand and form the aqua adduct ions [(η(6) -p-cym)Ru(bpy)(H2O)](2+) and [(η(6) -p-cym)Ru(bpm)(H2O)](2+). Thulium -doped upconverting nanoparticles (UCNPs) are functionalised with 4, thus exploiting their surface affinity for the phosphonate group in the complex. The so-obtained nanosystem UCNP@4 undergoes near-infrared (NIR) photoactivation at λ=980 nm, thus producing the corresponding reactive aqua species that binds the DNA-model base guanosine 5'-monophosphate., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Development of vaccines to prevent and treat emerging new pathogens and re-emerging infections and cancer remains a major challenge. An attractive approach is to build the vaccine upon a biocompatible NP that simultaneously acts as accurate delivery vehicle and radiotracer for PET/SPECT imaging for ultrasensitive and quantitative in vivo imaging of NP delivery to target tissues/organs. Success in developing these nanovaccines will depend in part on having a "correct" NP size and accommodating and suitably displaying antigen and/or adjuvants (e.g., TLR agonists). Here we develop and evaluate a NP vaccine based on iron oxide-selective radio-gallium labeling suitable for SPECT((67)Ga)/PET((68)Ga) imaging and efficient delivery of antigen (OVA) and TLR 9 agonists (CpGs) using lipid-coated magnetite micelles. OVA, CpGs and rhodamine are easily accommodated in the hybrid micelles, and the average size of the construct can be controlled to be ca. 40 nm in diameter to target direct lymphatic delivery of the vaccine cargo to antigen presenting cells (APCs) in the lymph nodes (LNs). While the OVA/CpG-loaded construct showed effective delivery to endosomal TLR 9 in APCs, SPECT imaging demonstrated migration from the injection site to regional and nonregional LNs. In correlation with the imaging results, a range of in vitro and in vivo studies demonstrate that by using this microdosed nanosystem the cellular and humoral immune responses are greatly enhanced and provide protection against tumor challenge. These results suggest that these nanosystems have considerable potential for image-guided development of targeted vaccines that are more effective and limit toxicity.

Sinorhizobium fredii HH103 is a fast-growing rhizobial strain infecting a broad range of legumes including both American and Asiatic soybeans. In this work, we present the sequencing and annotation of the HH103 genome (7.25 Mb), consisting of one chromosome and six plasmids and representing the structurally most complex sinorhizobial genome sequenced so far. Comparative genomic analyses of S. fredii HH103 with strains USDA257 and NGR234 showed that the core genome of these three strains contains 4,212 genes (61.7% of the HH103 genes). Synteny plot analysis revealed that the much larger chromosome of USDA257 (6.48 Mb) is colinear to the HH103 (4.3 Mb) and NGR324 chromosomes (3.9 Mb). An additional region of the USDA257 chromosome of about 2 Mb displays similarity to plasmid pSfHH103e. Remarkable differences exist between HH103 and NGR234 concerning nod genes, flavonoid effect on surface polysaccharide production, and quorum-sensing systems. Furthermore a number of protein secretion systems have been found. Two genes coding for putative type III-secreted effectors not previously described in S. fredii, nopI and gunA, have been located on the HH103 genome. These differences could be important to understand the different symbiotic behavior of S. fredii strains HH103, USDA257, and NGR234 with soybean.

There is major current interest in harnessing the immune system against cancer and in developing drugs that provide complementary cancer killing mechanisms. Although the recent advent of nanoparticle-based drug delivery systems has improved the efficacy of platinum drugs for chemotherapy, one of the fundamental paradigms in their design and use is evading surveillance by the immune system to enhance anticancer efficacy. However, new studies are showing that chemotherapy can profit from actively targeting stimulation of the immune system and that suitably functionalized nanomaterials might be ideal for overcoming some key challenges in immunotherapy. Pt(IV) prodrug-modified PEGylated phospholipid micelles that encapsulate biocompatible iron oxide nanoparticles (IONPs) as a new delivery system for cisplatin are reported. The Pt(IV)-IONPs are functionalized with polyinosinic-polycytidylic acid (poly (I:C))--a double stranded RNA (dsRNA) analog widely used as an adjuvant in clinical trials of cancer immunotherapy. The Pt(IV)-IONPs and poly (I:C)--Pt(IV)-IONPs enhance by more than an order of magnitude the prodrug cytotoxicity in different tumor cells, while greatly increasing the ability of cisplatin and poly (I:C) to activate dendritic cells--the key cellular players in immunotherapy. The results suggest that these constructs hold promise for targeted chemoimmunotherapy., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The cisplatin prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2)2](2-) (1) forms outer-sphere coordination interactions with non-toxic low MW PEI, which results in enhanced cancer cell killing, also achieved using PEI-coated AuNPs.

New Ru(II) arene complexes of formula [(η6-p-cym)Ru(N-N)(X)]2+ (where p-cym = para-cymene, N-N = 2,2'-bipyrimidine (bpm) or 2,2'-bipyridine (bpy) and X = m/p-COOMe-Py, 1-4) were synthesised and characterized, including the molecular structure of complexes [(η6-p-cym)Ru(bpy)(m-COOMe-Py)]2+ (3) and [(η6-p-cym)Ru(bpy) (p-COOMe-Py)]2+ (4) by single-crystal X-ray diffraction. Complexes 1-4 are stable in the dark in aqueous solution over 48 h and photolysis studies indicate that they can photodissociate the monodentate m/p-COOMe-Py ligands selectively with yields lower than 1%. DFT and TD-DFT calculations (B3LYP/LanL2DZ/6-31G**) performed on singlet and triplet states pinpoint a low-energy triplet state as the reactive state responsible for the selective dissociation of the monodentate pyridyl ligands.

The Pt(IV) complex cis,cis,trans-[Pt(NH3)2(Cl)2(O2CCH2CH2CO2H)2] is photoactivated by near infrared light (980 nm) using NaYF4:Yb(3+)/Tm(3+)@NaYF4 core-shell upconversion nanoparticles. Coupling of this cisplatin precursor with the biocompatible PEGylated phospholipid DSPE-PEG(2000)-NH2 affords a valuable approach to decorate the surface of the nanoparticles, providing novel photoactivatable nanomaterials capable of releasing Pt(II) species upon NIR light excitation.

The success of nanoparticle-based therapies will depend in part on accurate delivery to target receptors and organs. There is, therefore, considerable potential in nanoparticles which achieve delivery of the right drug(s) using the right route of administration to the right location at the right time, monitoring the process by non-invasive molecular imaging. A challenge is harnessing immunotherapy via activation of Toll-like receptors (TLRs) for the development of vaccines against major infectious diseases and cancer. In immunotherapy, delivery of the vaccine components to lymph nodes (LNs) is essential for effective stimulation of the immune response. Although some promising advances have been made, delivering therapeutics to LNs remains challenging. It is here shown that iron-oxide nanoparticles can be engineered to combine in a single and small (<50 nm) nanocarrier complementary multimodal imaging features with the immunostimulatory activity of polyinosinic-polycytidylic acid (poly (I:C)). Whilst the fluorescence properties of the nanocarrier show effective delivery to endosomes and TLR3 in antigen presenting cells, MRI/SPECT imaging reveals effective delivery to LNs. Importantly, in vitro and in vivo studies show that, using this nanocarrier, the immunostimulatory activity of poly (I:C) is greatly enhanced. These nanocarriers have considerable potential for cancer diagnosis and the development of new targeted and programmable immunotherapies., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Here we report that the structure of the Sinorhizobium fredii HH103 exopolysaccharide (EPS) is composed of glucose, galactose, glucuronic acid, pyruvic acid, in the ratios 5∶2∶2∶1 and is partially acetylated. A S. fredii HH103 exoA mutant (SVQ530), unable to produce EPS, not only forms nitrogen fixing nodules with soybean but also shows increased competitive capacity for nodule occupancy. Mutant SVQ530 is, however, less competitive to nodulate Vigna unguiculata. Biofilm formation was reduced in mutant SVQ530 but increased in an EPS overproducing mutant. Mutant SVQ530 was impaired in surface motility and showed higher osmosensitivity compared to its wild type strain in media containing 50 mM NaCl or 5% (w/v) sucrose. Neither S. fredii HH103 nor 41 other S. fredii strains were recognized by soybean lectin (SBL). S. fredii HH103 mutants affected in exopolysaccharides (EPS), lipopolysaccharides (LPS), cyclic glucans (CG) or capsular polysaccharides (KPS) were not significantly impaired in their soybean-root attachment capacity, suggesting that these surface polysaccharides might not be relevant in early attachment to soybean roots. These results also indicate that the molecular mechanisms involved in S. fredii attachment to soybean roots might be different to those operating in Bradyrhizobium japonicum.

NaYF4:Yb(3+)/Er(3+)nanocrystals upconvert near infrared light (980 nm) into higher energy visible photons capable of effecting the photodissociation of the monodentate pyridyl ligand in cis-[Ru(bpy)2(py)2]Cl2: opening an opportunity for advancing the use of photoactivatable metal complexes in medicine and biology.

Two novel (μ-guanazole)-bridged binuclear copper(II) complexes with 1,10-phenanthroline (phen) or 2,2'-bipyridine (bipy), [Cu2(μ-N2,N4-Hdatrz)(phen)2(H2O)(NO3)4] (1) and [Cu2(μ-N1,N2-datrz)2(μ-OH2)(bipy)2](ClO4)2 (2) (Hdatrz = 3,5-diamino-1,2,4-triazole = guanazole), have been prepared and characterized by X-ray diffraction, spectroscopy, and susceptibility measurements. Compounds 1 and 2 differ in the aromatic amine, which acts as a coligand, and in the Cu···Cu'-bridging system. Compound 1, which contains two mono-bridged copper ions, represents the first example of a discrete Cu-(NCN-trz)-Cu' complex. Compound 2, with two triply bridged copper ions, is one of the few compounds featuring a Cu-[(NN-trz)2 + (O-aquo)]-Cu' unit. Both compounds display antiferromagnetic coupling but of different magnitude: J (μ2,4-triazole) = -52 cm(-1) for 1 and J (μ1,2-triazolate) = -115 cm(-1) for 2. The DNA binding and cleavage properties of the two compounds have been investigated. Fluorescence, viscosimetry, and thermal denaturation studies reveal that both complexes have high affinity for DNA (1 > 2) and that only 1 acts as an intercalator. In the presence of a reducing agent like 3-mercaptopropionic acid, 1 produces significant oxidative DNA cleavage, whereas 2 is inactive. However, in the presence of very small quantities of micelles filled with core-shell CdSe-ZnS quantum dots (15 nM), 1 and 2 are considerably more active and become highly efficient nucleases as a result of the different possible mechanisms for promoting cooperative catalysis (metal-metal, metal-hydrogen bonding, metal-intercalation, and metal-nanoparticle). Electrophoresis DNA-cleavage inhibition experiments, X-ray photoelectron spectroscopy studies, and fluorescence ethidium bromide displacement assays reveal that in these novel nucleases the QDs act as redox-active protein-like nanoparticle structures that bind to the DNA and deliver electrons to the copper(II) centers for the generation of Cu(I) and reactive oxygen species.

The fac-[(99m)Tc(OH2)3(CO)3](+) complex reacts with QD-filled micelles to create a bimodal SPECT-optical imaging probe which upon visible light irradiation generates cisplatin from an inert Pt(IV) prodrug.