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The aim of this study was to analyse the association between human immunodeficiency virus (HIV) related clinical and analytical parameters and the presence of subclinical atherosclerosis as well as endothelial dysfunction. This was a prospective cohort study of HIV-positive patients who underwent intima media thickness (IMT) determination and coronary artery calcium scoring to determine subclinical atherosclerosis. To detect endothelial dysfunction, the breath holding index, flow-mediated dilation and the concentration of endothelial progenitor cells (EPCs) were measured. Patients with an IMT ≥ 0.9 mm had an average of 559.3 ± 283.34 CD4/μl, and those with an IMT 4 ± 5 × 104 copies/ml vs 23.4 × 104 ± 19 × 104 copies/ml (p = 0.02)). The number of early EPCs in patients with a CD4 nadir

Cancer stem cells (CSCs) are highly tumorigenic, spared by chemotherapy, sustain tumor growth, and are implicated in tumor recurrence after conventional therapies in triple negative breast cancer (TNBC). Lysine-specific histone demethylase 1A (KDM1A) is highly expressed in several human malignancies and CSCs including TNBC. However, the precise mechanistic role of KDM1A in CSC functions and therapeutic utility of KDM1A inhibitor for treating TNBC is poorly understood. The effect of KDM1A inhibition on cell viability, apoptosis, and invasion were examined by Cell Titer Glo, Caspase 3/7 Glo, and matrigel invasion assays, respectively. Stemness and self-renewal of CSCs were examined using mammosphere formation and extreme limiting dilution assays. Mechanistic studies were conducted using RNA-sequencing, RT-qPCR, Western blotting and reporter gene assays. Mouse xenograft and patient derived xenograft models were used for preclinical evaluation of KDM1A inhibitor. TCGA data sets indicated that KDM1A is highly expressed in TNBC. CSCs express high levels of KDM1A and inhibition of KDM1A reduced the CSCs enrichment in TNBC cells. KDM1A inhibition reduced cell viability, mammosphere formation, self-renewal and promoted apoptosis of CSCs. Mechanistic studies suggested that IL6-JAK-STAT3 and EMT pathways were downregulated in KDM1A knockdown and KDM1A inhibitor treated cells. Importantly, doxycycline inducible knockout of KDM1A reduced tumor progression in orthotopic xenograft models and KDM1A inhibitor NCD38 treatment significantly reduced tumor growth in patient derived xenograft (PDX) models. Our results establish that KDM1A inhibition mitigates CSCs functions via inhibition of STAT3 and EMT signaling, and KDM1A inhibitor NCD38 may represent a novel class of drug for treating TNBC.

Highlights • Pneumatosis cystoides intestinalis is a rare condition with a broad spectrum of clinical symptoms. • Images are typically striking, which can confuse the medical team and lead to unnecessary procedures. • Close follow up is needed as complications can lead to a troublesome outcome., Background Pneumatosis cystoides intestinalis (PCI) is a rare condition characterized by gas infiltration into the intestine wall. When gas is seen in the intestinal wall, it is usually a sign of bowel wall infarction and a surgical emergency; therefore, an adequate differentiation of benign and urgent conditions of pneumatosis intestinalis is necessary to prevent misdiagnosis and inadequate therapies. Case presentation We present the case of a 79-year-old male with past medical history of Alzheimer’s, cholecystectomy, and umbilical hernia. PCI was identified, and conservative therapy was started. Since the patient's pain persisted, a complication was suspected, and surgery was decided. After successful treatment, the patient completely recovered. Conclusion There are many benign and life-threatening causes of pneumatosis intestinalis, the imaging appearance of both may look very similar. Therefore, clinical history, physical examination, and laboratory test results are the best indicators of whether it is due to a benign or life-threatening cause. PCI must be managed with a multidisciplinary team of clinicians, radiologists, and surgeons to achieve better results for our patients.

Recent data suggest that interactions between systems involved in higher order knowledge and associative learning drive responses during appetitive and aversive learning. However, it is unknown how these systems impact subjective responses, such as pain. We tested how instructions and reversal learning influence pain and pain-evoked brain activation. Healthy volunteers (n = 40) were either instructed about contingencies between cues and aversive outcomes or learned through experience in a paradigm where contingencies reversed three times. We measured predictive cue effects on pain and heat-evoked brain responses using functional magnetic resonance imaging. Predictive cues dynamically modulated pain perception as contingencies changed, regardless of whether participants received contingency instructions. Heat-evoked responses in the insula, anterior cingulate, and putamen updated as contingencies changed, whereas the periaqueductal gray and thalamus responded to initial contingencies throughout the task. Quantitative modeling revealed that expected value was shaped purely by instructions in the Instructed Group, whereas expected value updated dynamically in the Uninstructed Group as a function of error-based learning. These differences were accompanied by dissociations in the neural correlates of value-based learning in the rostral anterior cingulate, medial prefrontal cortex, and orbitofrontal cortex. These results show how predictions impact subjective pain. Moreover, imaging data delineate three types of networks involved in pain generation and value-based learning: those that respond to initial contingencies, those that update dynamically during feedback-driven learning as contingencies change, and those that are sensitive to instruction. Together, these findings provide multiple points of entry for therapies designs to impact pain.

Endometrial cancer (EC) often exhibit aberrant activation of PI3K/Akt/mTOR signaling and targeted therapies using mTOR inhibitors showed limited success. The epigenetic modifier, lysine-specific histone demethylase-1A (KDM1A/LSD1) is overexpressed in EC, however, the mechanistic and therapeutic implications of KDM1A in EC are poorly understood. Here, using 119 FDA-approved drugs screen, we identified that KDM1A inhibition is highly synergistic with mTOR inhibitors. Combination therapy of KDM1A and mTOR inhibitors potently reduced the cell viability, survival, and migration of EC cells. Mechanistic studies demonstrated that KDM1A inhibition attenuated the activation of mTOR signaling cascade and abolished rapamycin induced feedback activation of Akt. RNA-seq analysis identified that KDM1A inhibition downregulated the expression of genes involved in rapamycin induced activation of Akt, including the mTORC2 complex. Chromatin immunoprecipitation experiments confirmed KDM1A recruitment to the promoter regions of mTORC2 complex genes and that KDM1A inhibition promoted enrichment of repressive H3K9me2 marks at their promoters. Combination therapy of KDM1A inhibitor and rapamycin reduced the tumor growth in EC xenograft and patient derived xenograft models in vivo and patient derived tumor explants ex vivo. Importantly, in silico analysis of TCGA EC patients data sets revealed that KDM1A expression positively correlated with the levels of PI3K/Akt/mTOR genes. Collectively, our results provide compelling evidence that KDM1A inhibition potentiates the activity of mTOR inhibitors by attenuating the feedback activation of Akt survival signaling. Furthermore, the use of concurrent KDM1A and mTOR inhibitors may be an attractive targeted therapy for EC patients.

Medulloblastoma (MB) is the most common and deadliest brain tumor in children. Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a scaffolding protein and its oncogenic signaling is implicated in the progression of several cancers. However, the role of PELP1 in the progression of MB remains unknown. The objective of this study is to examine the role of PELP1 in the progression of MB. Immunohistochemical analysis of MB tissue microarrays revealed that PELP1 is overexpressed in the MB specimens compared to normal brain. Knockdown of PELP1 reduced cell proliferation, cell survival, and cell invasion of MB cell lines. The RNA-sequencing analysis revealed that PELP1 knockdown significantly downregulated the pathways related to inflammation and extracellular matrix. Gene set enrichment analysis confirmed that the PELP1-regulated genes were negatively correlated with nuclear factor-κB (NF-κB), extracellular matrix, and angiogenesis gene sets. Interestingly, PELP1 knockdown reduced the expression of NF-κB target genes, NF-κB reporter activity, and inhibited the nuclear translocation of p65. Importantly, the knockdown of PELP1 significantly reduced in vivo MB progression in orthotopic models and improved the overall mice survival. Collectively, these results suggest that PELP1 could be a novel target for therapeutic intervention in MB.

The development of convenient synthetic methods and improved materials for the production of high load-capacity and biocompatible drug delivery systems is a challenging task with important implications in health sciences. In this work, acrylamide/2-hydroxyethylmethacrylate and N-isopropylacrylamide/2-hydroxyethylmethacrylate hydrogels were synthesized by photopolymerization using energy-efficient green-LEDs. A functionalized silsesquioxane was used as both crosslinker and co-initiator for the photopolymerization. The hybrid organic-inorganic nature of the silsesquioxane improved the resulting hydrogels´ properties increasing their swelling capacity and biocompatibility. Additionally, the mild conditions used during the photopolymerization allowed the synthesis of hydrogels in the presence of antibiotics yielding high load-capacity materials in which the drug preserves its molecular structure and antimicrobial activity (as confirmed by HPLC and microbiological assays). The materials were characterized by FTIR, DSC and SEM. Additionally, the kinetics of gels´ swelling and drug release were studied under physiological conditions (pH 7.4 and 37 °C). The results demonstrate how hydrogel composition affects the antibiotics-release kinetics. The final drug release percentage increased with increasing molar fraction of acrylamide or N-isopropylacrylamide and in most cases exceeded 85%. Finally, the antibacterial effect of loaded gels was characterized using a number of assays against Gram negative and Gram positive bacteria. The observed antibacterial effect correlated well with swelling and drug release results. Furthermore, gels are not toxic for isolated erythrocytes as demonstrated by haemolytic tests. Overall, our results indicate that the produced hydrogels are promising materials to develop controlled drug-delivery devices such as capsules, dermatological patches and others. Fil: Gallastegui, Antonela. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados; Argentina Fil: Spesia, Mariana Belen. Universidad Nacional de Río Cuarto. Instituto para el Desarrollo Agroindustrial y de la Salud. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto para el Desarrollo Agroindustrial y de la Salud; Argentina Fil: Dell'Erba, Ignacio Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones en Ciencia y Tecnología de Materiales. Universidad Nacional de Mar del Plata. Facultad de Ingeniería. Instituto de Investigaciones en Ciencia y Tecnología de Materiales; Argentina Fil: Chesta, Carlos Alberto. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados; Argentina Fil: Previtali, Carlos Mario. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Palacios, Rodrigo Emiliano. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados; Argentina Fil: Gomez, María Lorena. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados; Argentina

Minimally invasive glaucoma surgery for chronic open-angle glaucoma treatment tries to reduce the amount of chronic topical drug treatment, delaying invasive glaucoma surgery and diminishing the number of surgical complications. XEN45 uses subconjunctival drainage in order to reduce intraocular pressure. The report is presented of a patient following phacoemulsification, intraocular lens implantation and XEN45 implant. After four days acute malignant glaucoma was observed, with stage 3 athalamia requiring pars plana vitrectomy and secondary Ahmed valve implantation. The lower rate of complications due to minimally invasive glaucoma surgery has increased its use. Nevertheless, it is not free of severe adverse events, even requiring a multidisciplinary approach as in our malignant glaucoma report.

Background: Threat anticipation engages neural circuitry that has evolved to promote defensive behaviours; perturbations in this circuitry could generate excessive threat-anticipation response, a key characteristic of pathological anxiety. Research into such mechanisms in youth faces ethical and practical limitations. Here, we use thermal stimulation to elicit pain-anticipatory psychophysiological response and map its correlates to brain structure among youth with anxiety and healthy youth. Methods: Youth with anxiety (n = 25) and healthy youth (n = 25) completed an instructed threat-anticipation task in which cues predicted nonpainful or painful thermal stimulation; we indexed psychophysiological response during the anticipation and experience of pain using skin conductance response. High-resolution brain-structure imaging data collected in another visit were available for 41 participants. Analyses tested whether the 2 groups differed in their psychophysiological cue-based pain-anticipatory and pain-experience responses. Analyses then mapped psychophysiological response magnitude to brain structure. Results: Youth with anxiety showed enhanced psychophysiological response specifically during anticipation of painful stimulation (b = 0.52, p = 0.003). Across the sample, the magnitude of psychophysiological anticipatory response correlated negatively with the thickness of the dorsolateral prefrontal cortex (pFWE < 0.05); psychophysiological response to the thermal stimulation correlated positively with the thickness of the posterior insula (pFWE < 0.05). Limitations: Limitations included the modest sample size and the cross-sectional design. Conclusion: These findings show that threat-anticipatory psychophysiological response differentiates youth with anxiety from healthy youth, and they link brain structure to psychophysiological response during pain anticipation and experience. A focus on threat anticipation in research on anxiety could delineate relevant neural circuitry.

© 2021 by the authors., Conjugated polymer nanoparticles (CPNs) have emerged as advanced polymeric nanoplatforms in biomedical applications by virtue of extraordinary properties including high fluorescence brightness, large absorption coefficients of one and two-photons, and excellent photostability and colloidal stability in water and physiological medium. In addition, low cytotoxicity, easy functionalization, and the ability to modify CPN photochemical properties by the incorporation of dopants, convert them into excellent theranostic agents with multifunctionality for imaging and treatment. In this work, CPNs were designed and synthesized by incorporating a metal oxide magnetic core (Fe3O4 and NiFe2O4 nanoparticles, 5 nm) into their matrix during the nanoprecipitation method. This modification allowed the in vivo monitoring of nanoparticles in animal models using magnetic resonance imaging (MRI) and intravital fluorescence, techniques widely used for intracranial tumors evaluation. The modified CPNs were assessed in vivo in glioblastoma (GBM) bearing mice, both heterotopic and orthotopic developed models. Biodistribution studies were performed with MRI acquisitions and fluorescence images up to 24 h after the i.v. nanoparticles administration. The resulting IONP-doped CPNs were biocompatible in GBM tumor cells in vitro with an excellent cell incorporation depending on nanoparticle concentration exposure. IONP-doped CPNs were detected in tumor and excretory organs of the heterotopic GBM model after i.v. and i.t. injection. However, in the orthotopic GBM model, the size of the nanoparticles is probably hindering a higher effect on intratumorally T2-weighted images (T2WI) signals and T2 values. The photodynamic therapy (PDT)—cytotoxicity of CPNs was not either affected by the IONPs incorporation into the nanoparticles., This research was funded by grants from Ministerio de Economía y Competitividad (SAF2017-83043-R, MINECO/AEI/FEDER, UE), Comunidad de Madrid (S2017/BMD-3688, CM/FEDER/FSE, UE), Agencia Nacional de Promoción Científica y Tecnológica (PICT) (2676/18, 3577/18), and Secretaría de Ciencia y Técnica Universidad Nacional de Río Cuarto (PPI-SECyT UNRC).

Glioblastoma is the most severe form of brain cancer. Despite multimodal therapy combining surgery, radiotherapy and chemotherapy, prognosis of patients is dismal. It has been observed that the surgical resection guided by photosensitizer fluorescence followed by photodynamic therapy (PDT) prolongs the average survival in patients with glioblastoma. The main problem with all oncological treatments, including PDT, is the presence of resistant cells. The objective of this study was to isolate and perform an initial characterization of human glioblastoma cells resistant to PDT employing methyl-5-aminolevulinic acid. We obtained resistant cells from the T98 G cell line. Resistant populations accumulated less photosensitizer, formed spheroids of higher number of cells, had higher tumorigenic capacity, and expressed higher mRNA levels of fibroblastic growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and β-platelet-derived growth factor receptor (βPDGFR) than parental cells. The studies of glioblastoma resistance to PDT would help to better understand the causes of tumor recurrence after PDT and to develop new therapeutic proposals in this field of oncology.

[Aim]: To assess monocyte-based delivery of conjugated polymer nanoparticles (CPNs) for improved photodynamic therapy (PDT) in glioblastoma (GBM)., [Materials and methods]: Human monocyte cells (THP-1) and murine monocytes isolated from bone marrow (mBMDMs) were employed as stealth CPN carriers to penetrate into GBM spheroids and an orthotopic model of the tumor. The success of PDT, using this cell-mediated targeting strategy, was determined by its effect on the spheroids., [Results]: CPNs did not affect monocyte viability in the absence of light and did not show nonspecific release after cell loading. Activated monocytes incorporated CPNs in a higher proportion than monocytes in their naive state, without a loss of cellular functionality. In vitro PDT efficacy using cell-mediated delivery was superior to that using non vehiculized CPNs., [Conclusion]: CPN-loaded monocytes could efficiently deliver CPNs into GBM spheroids and the orthotopic model. Improved PDT in spheroids was confirmed using this delivery strategy.

Due to their superb light absorption and photostability conjugated polymer nanoparticles are promising photosensitizers (PS) for their use in Photodynamic therapy (PDT). Recently, we developed metallated porphyrin-doped conjugated polymer nanoparticles (CPNs) for PDT that efficiently eliminate tumor cells through reactive oxygen species (ROS) mediated photoinduced damage of apoptotic nature. These nanoaggregates act as densely packed multi-chromophoric systems having exceptional light harvesting and (intra-particle) energy transfer capabilities which lead to efficient photosensitized formation of ROS. In general, three key components; light, PS, and oxygen; are considered in the prediction of the PDT outcome. However, recent studies led to the discovery of a profound genetic heterogeneity among glioblastoma (GBM) cells which include the adaptation to ROS. Thus, tumor heterogeneity and their associated difference in sensitivity to ROS-producing therapeutic agents must be considered in the design of PDT protocols for the prediction of its outcome. In this study, anticancer activity through ROS-mediated PDT using CPNs was compared in three GBM cell lines with different initial redox status. T98G cells were the most effective incorporating nanoparticles but also were the most resistant to CPN-PDT effect. In part, this feature could be attributed to the differential basal and PDT-induced antioxidant enzyme levels found in these cells measured by gene expression analysis. Furthermore, considering that cell-specific antioxidant enzyme status is a significant feature of GBM heterogeneity, establishing its correlation with CPN-PDT outcome might be important for designing novel and improved CPN-based treatments.

While animal welfare advocates have effectively called attention to the mistreatment of animals in livestock production and dairying, occupational justice for the farmworkers who care for them has been largely overlooked. This chapter comprehensively examines the health and safety issues faced by Latinx workers in the dairy, poultry, swine, and equine industries. As the size and scale of animal agriculture operations grows, farmers have become increasingly dependent on a Latinx workforce, which is exposed to safety and health risks. Working with livestock poses physical risks to workers, including direct traumatic injury from being kicked, bitten, or otherwise hurt by animals; musculoskeletal disorder from repetitive and awkward motions; respiratory illness or dysfunction from air pollutants; and mental health disorder related to stress, sleep disorders, and social isolation. These injuries, illnesses, and disorders are compounded by difficulty accessing healthcare and social services for Latinx workers in the eastern United States, who tend to be socially isolated and live in rural and remote communities. This chapter also identifies significant gaps in the literature on occupational safety and health among livestock workers and concludes with recommendations to policymakers and farmers to improve occupational safety and health for Latinx livestock workers.

OBJECTIVE: Naturalistic studies suggest that expectation of adverse experiences such as pain exerts particularly strong effects on anxious youth. In healthy adults, expectation influences the experience of pain. The current study uses experimental methods to compare the effects of expectation on pain among adults, healthy youth, and youth with an anxiety disorder. METHODS: Twenty-three healthy adults, 20 healthy youth, and 20 youth with an anxiety disorder underwent procedures in which auditory cues were paired with noxious thermal stimulation. Through instructed conditioning, one cue predicted low pain stimulation and the other predicted high pain stimulation. At test, each cue was additionally followed by a single temperature calibrated to elicit medium pain ratings. We compared cue-based expectancy effects on pain across the three groups, based on cue effects on pain elicited on medium heat trials. RESULTS: Across all groups, as expected, participants reported greater pain with increasing heat intensity (β = 2.29, t(41) = 29.94, p < .001). Across all groups, the critical medium temperature trials were rated as more painful in the high-relative to low-expectancy condition (β = 1.72, t(41) = 10.48, p < .001). However, no evidence of between-group differences or continuous associations with age or anxiety were observed. CONCLUSIONS: All participants showed strong effects of expectancy on pain. No influences of development or anxiety arose. Complex factors may influence associations among anxiety, development, and pain reports in naturalistic studies. Such factors may be identified using experiments that employ more complex, yet controlled manipulations of expectancy or assess neural correlates of expectancy.

Bismuth oxychloride (BiOCl) powders were synthesized via a hydro/solvothermal method from BiCl3. Synthesis were performed in the presence of different capping agents namely polyvinylpyrrolidone (PVP), ethylenediamine (C2H4(NH2)2) or dextrose (C6H12O6). The reaction media, nature of capping agent, weight or molar ratio Bi:capping agent and temperature play an important role in the formation of well-defined morphology of BiOCl powders, which varies from melt crystals to plate-like structures. The as-obtained BiOCl/capping agent systems were characterized by X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy and IR spectroscopy. Among the selected capping agents, the C2H4(NH2)2 promote a defined morphology of the BiOCl crystals being a potential soft template. BiOCl/C2H4(NH2)2 system synthesized in aqueous medium clearly illustrate the effect of the Bi:C2H4(NH2)2 ratio on the morphology of BiOCl powders. The photocatalytic activity of BiOCl/C2H4(NH2)2 (1:0.5 molar ratio or 0.5 equiv.) and TiO2:BiOCl composites were evaluated on the degradation of methylene blue (MB) under UV–Vis light irradiation and compared with commercial TiO2 (Degussa, P25). It was pointed out that BiOCl powders with well-defined rectangular plate-like morphology have a higher photocatalytic activity during MB photodegradation in comparison to TiO2:BiOCl composites and similar to commercial TiO2.

Background: Glioblastoma (GBM) is the most common malignant brain tumor with a dismal prognosis and median survival of 20 months. Standard therapy consists of surgical resection, external beam radiation therapy, adjuvant chemotherapy with temozolomide, and tumor-treating fields. Despite these therapies, GBM patients inevitably experience tumor progression and eventually succumb to their disease. Glioma stem cells (GSCs) play a central role in GBM development and contribute to treatment resistance. Recently we showed that lysine-specific histone demethylase 1A (KDM1A/LSD1) is essential for GSCs stemness, and inhibition of KDM1A induces unfolded protein response (UPR) in GSCs. In this study, we tested the hypothesis that inhibition of KDM1A sensitizes GSCs to ER stress inducers by inducing UPR. Methods: KDM1A knockdown (KDM1A-KD) cells were generated using KDM1A specific shRNA. We studied the effect of KDM1A-KD or pharmacological KDM1A inhibitors (NCD38 and NCL-1) in combination with ER stress inducers (thapsigargin and brefeldin A) on GSCs viability using CellTiter-Glo assay. Stemness was determined using extreme limiting dilution analysis (ELDA) and sphere formation assays. Mechanistic studies were conducted using RNA-seq, ChIP, RT-qPCR, and Western blotting analysis. Furthermore, the in vivo efficacy of KDM1A inhibitor and ER stress inducer was studied using orthotopic models of GBM. Results: Cell viability assays demonstrated that knockdown or inhibition of KDM1A sensitized GSCs to ER stress inducers thapsigargin and brefeldin A. Furthermore, KDM1A-KD, NCD38, or NCL-1, in combination with ER stress inducers, significantly decreased the stemness and sphere-forming ability of GSCs. RNA-seq analysis revealed that UPR was activated after knockdown or inhibition of KDM1A in GSCs. Western blot and RT-qPCR analysis showed that a combination of KDM1A inhibitors and ER stress inducers increased UPR signaling in GSCs. ChIP analysis indicated that KDM1A inhibition enriched the active histone methylation mark (H3K4me2) at the promoter of UPR target genes. In vivo studies showed that KDM1A inhibition activates UPR in tumors and improved overall survival. Conclusions: Our results support that KDM1A knockdown or inhibition sensitizes GSCs to ER stress inducers and that the use of KDM1A inhibitors in conjunction with ER stress inducers is a potential novel therapy for GBM patients. Citation Format: Yi He, Prabhakar Pitta Venkata, Salvador Alejo, Yihong Chen, Bridgitte Palacios, Gabrielle Gray, Uday P. Pratap, Suryavathi Viswanadhapalli, Siyuan Zheng, Rajeshwar R. Tekmal, Andrew J. Brenner, Gangadhara R. Sareddy. KDM1A inhibition augment ER stress inducers efficacy to reduce glioblastoma stemness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2026.

A dielectric liquid provides two main functions in power transformers: an insulant and a cooling medium. Mineral oil, largely due to its availability and low cost, has predominantly been used in power transformers for more than 100 years [1]-[3]. However, mainly due to its low biodegradability, a spill contaminating soil and water can be detrimental to the environment [4]. This shortcoming has prompted researchers to focus on safety, biodegradability, and renewability of dielectric fluids. The dielectric fluids based on vegetable oils (natural esters) are an innovative alternative since they have shown comparable, and sometimes better, dielectric, physical, and chemical properties to mineral insulating oils [5]-[8].

Photodynamic Therapy (PDT) has recently gain attention as alternative treatment of Central Nervous System (CNS) cancer diseases, due to the demonstration of successfully elimination of gliomas in patients. The implementation of PDT for brain tumors, and especially glioblastoma (GBM), has already been approved in some countries. Due to their superb light absorption and photostability conjugated polymer nanoparticles (CPNs) are promising photosensitizers (PS) for use in PDT. Recently, we developed metallated porphyrin-doped CPNs for PDT and demonstrated that they were effective eliminating glioma cells trough ROS-mediated photoinduced damage. A problem of many therapies used to eradicate brain gliomas is the difficulty of arrival and preferential accumulation of the active drug into the tumor upon systemic administration due to the selective permeability of the blood-brain barrier (BBB). To solve this problem our approach employs mononuclear cells, which can cross BBB and infiltrate tumors, as stealth carriers for drug delivery into brain tumors. In this study loading of CPNs into monocytes/macrophages was demonstrated and the cellular functionality, chemotaxis and penetration of these loaded monocytes/macrophages into GBM spheroids (3D tumor models) was tested. CPNs loading was successfully achieved using human monocytes THP-1 and mouse bone marrow-derived monocytes (BMdM) without disturbing cell viability and differentiation potential towards macrophage state. CPNs-loaded monocytes were found to better infiltrate spheroids as compared to CPNs. Furthermore, PDT efficacy on GBM spheroids was improved when using our monocyte-mediated delivery strategy

Nociception reliably elicits an autonomic nervous system (ANS) response. Because pain and ANS circuitry interact on multiple spinal, subcortical, and cortical levels, it remains unclear whether autonomic responses are simply a reflexive product of noxious stimulation regardless of how stimulation is consciously perceived or whether the experience of pain mediates ANS responses to noxious stimulation. To test these alternative predictions, we examined the relative contribution of noxious stimulation and individual pain experience to ANS responses in healthy volunteers who underwent 1 or 2 pain assessment tasks. Participants received 8 seconds of thermal stimulation of varied temperatures and judged pain intensity on every trial. Skin conductance responses and pupil dilation responses to stimulation served as measures of the heat-evoked autonomic response. We used multilevel modelling to examine trial-by-trial relationships between heat, pain, and ANS response. Although both pain and noxious heat stimulation predicted skin conductance response and pupil dilation response in separate analyses, the individual pain experience statistically mediated effects of noxious heat on both outcomes. Furthermore, moderated mediation revealed that evidence for this process was stronger when stimulation was perceived as painful compared with when stimulation was perceived as nonpainful, although this difference emerged late, in the 4-second period after thermal stimulation. These findings suggest that pain appraisal regulates the heat-evoked autonomic response to noxious stimulation, documenting the flexibility of the autonomic pain response to adjust to perceived or actual changes in environmental affordances above and beyond nociceptive input.

[Introduction]: Goblet cell carcinoma (GCC) is an appendicular neoplasia representing less than 5% of all appendicular tumors, found in 0.3–0.9% of the appendectomies, 35–58% of all appendicular neoplasms, and less than 14% of malign appendix tumors. The most frequent clinical presentation is abdominal pain associated with a picture of acute appendicitis., [Materials and methods]: We present 3 clinical cases of appendix GCC, 2 subjected to cytoreductory surgery plus intraperitoneal hyperthermic chemotherapy and a third, who is currently receiving neoadjuvant treatment with a good response to chemotherapy and who will be offered the same treatment as the first two patients. Given the unpredictable behavior of these tumors, the use of molecular markers could help us to predict their behavior and prognosis. In this context, the TP73 gene would make an interesting putative marker. ∆Np73 has been described as overexpressed in a great variety of tumor types including colon cancer and this up-regulation is associated with a poor prognosis. To evidence its role in this malignancy, we evaluate here the status of ∆Np73 in the primary tumor and normal counterpart tissues, in the metastatic implants and in healthy areas of the peritoneum from the appendicular GCC patients. In addition, we checked the expression levels of this p73 variant in the tumor and normal tissue of 26 patients with colon cancer., [Results]: Remarkably, 2 patients showed significant ∆Np73 down-regulation in both the primary tumor and the implants. Case 1 presented a fourfold decrease of levels in the primary tumor and 20-fold decrease in the implants. Case 2 showed a seven- and fourfold down-regulation in the primary tumor and implants, respectively. However, Case 3 showed an up-regulation of 53- and threefold in the primary tumor and implants, respectively., [Conclusion]: Goblet cell carcinoma of the appendix is very rate. It tends to seed throughout the peritoneum, making aggressive surgical cytoreduction and chemotherapy viable treatment options. Investigation into the molecular basis of these tumors may improve the diagnosis, prognosis and therapeutic decisions regarding these patients. ∆Np73 seems a good candidate for further analysis in longer series., We acknowledge ISCIII, FIS, FEDER and Cátedra UAM-ROCHE de Medicina de Innovación for funding our current research through the PI18/00473 and CIBERONIC. Gemma Domínguez and Nuria Rodriguez have received research grants from Roche Farma SA.

The development of new and improved aqueous soluble cross-linkers and eco-friendly co-initiators for photopolymerization applications represents a significant challenge. In this work, novel water-soluble eco-friendly hybrid photoinitiator systems were prepared and characterized. The developed photoinitiators consist of hybrid compounds based on silsesquioxanes, functionalized with acrylate and amine groups with dual capacity as co-initiators and cross-linkers; and B2 vitamin (riboflavin) that performs as a biocompatible photosensitiser. The materials were characterized by FTIR, MALDI-TOF MS, and 29Si-NMR. The efficiency of co-initiators in photopolymerization was evaluated monitoring C=C conversion using FTIR as a function of irradiation time. The photoinitiator systems showed different polymerization rates depending on the employed silsesquioxane. Polymerization rates of the new photoinitiator systems are higher than that of a reference system based on riboflavin/triethanolamine. Hydrogels and nanogels were successfully synthesized, demonstrating the versatility of the developed photoinitiators.

Perinatal asphyxia (PA) is associated to delayed cell death, affecting neurocircuitries of basal ganglia and hippocampus, and long-term neuropsychiatric disabilities. Several compensatory mechanisms have been suggested to take place, including cell proliferation and neurogenesis. There is evidence that PA can increase postnatal neurogenesis in hippocampus and subventricular zone (SVZ), modulated by dopamine, by still unclear mechanisms. We have studied here the effect of selective dopamine receptor agonists on cell death, cell proliferation and neurogenesis in organotypic cultures from control and asphyxia-exposed rats. Hippocampus and SVZ sampled at 1–3 postnatal days were cultured for 20–21 days. At day in vitro (DIV) 19, cultures were treated either with SKF38393 (10 and 100 µM, a D1 agonist), quinpirole (10 µM, a D2 agonist) or sulpiride (10 μM, a D2 antagonist) + quinpirole (10 μM) and BrdU (10 μM, a mitosis marker) for 24 h. At DIV 20–21, cultures were processed for immunocytochemistry for microtubule-associated protein-2 (MAP-2, a neuronal marker), and BrdU, evaluated by confocal microscopy. Some cultures were analysed for cell viability at DIV 20–21 (LIVE/DEAD kit). PA increased cell death, cell proliferation and neurogenesis in hippocampus and SVZ cultures. The increase in cell death, but not in cell proliferation, was inhibited by both SKF38393 and quinpirole treatment. Neurogenesis was increased by quinpirole, but only in hippocampus, in cultures from both asphyxia-exposed and control-animals, effect that was antagonised by sulpiride, leading to the conclusion that dopamine modulates neurogenesis in hippocampus, mainly via D2 receptors.

BACKGROUND Despite treatment advances, glioblastoma (GBM) is the deadliest tumor of the central nervous system. Patients face a dismal 15-month median survival and average 5-year survival rate of 13%. Current standard of care includes surgical resection, external beam radiation therapy, and adjuvant chemotherapy with temozolomide (TMZ). Unfortunately, GBM patients often relapse and succumb to their disease. Recently, we have shown that lysine-specific histone demethylase 1A (KDM1A/LSD1) is overexpressed in GBM. In this study, we tested the hypothesis that KDM1A is essential for DNA damage response (DDR), inhibiting KDM1A thereby sensitizes GBM to either TMZ or radiation therapy. METHODS KDM1A knockout (KDM1A-KO) and knockdown (KDM1A-KD) cells were generated using CRISPR/Cas9 and KDM1A specific shRNA, respectively. Cell viability, clonogenic survival, and apoptotic assays were used to study the effect of KDM1A-KO, -KD, or pharmacological KDM1A inhibitors (NCD-38 and NCL-1) on radiation and TMZ sensitization. Mechanistic studies were conducted using RNA-seq, RT-qPCR, and western blot analysis. Furthermore, in vivo efficacy of KDM1A inhibitor and TMZ was established using orthotopic models of GBM. RESULTS Cell viability, survival, and apoptotic assays demonstrated that knockout/knockdown or inhibition of KDM1A sensitized GBM cells to both TMZ or radiation therapy. KDM1A inhibitors used in combination with radiation or TMZ significantly increased apoptosis in GBM cells. RNA-seq analysis and signaling studies showed attenuation of DDR pathways in KDM1A-KD cells. Radiation or TMZ treatment enhanced DNA damage in KDM1A-KD cells compared to controls. Importantly, combination of KDM1A inhibitor and TMZ significantly reduced in vivo tumor progression and improved overall survival in orthotopic GBM murine models. CONCLUSIONS Our results provide strong evidence that KDM1A inhibition sensitizes GBM to TMZ or radiation therapy via modulation of DDR. This suggests combination of KDM1A inhibitors with TMZ or radiation therapy could serve as a novel treatment for GBM patients.

Background: Glioblastoma (GBM) is the most common brain tumor. Despite advancements in multimodal treatment strategies, GBM patients exhibit a dismal prognosis with a median survival of 20 months and a 5-year survival rate post diagnosis of 13%. Standard of care consists of surgical resection, external beam radiation therapy, and adjuvant chemotherapy with temozolomide (TMZ). Despite heavy investment in therapy, GBM patients inevitably experience tumor progression and eventually succumb to their disease. Recently, we showed that lysine-specific histone demethylase 1A (KDM1A), an epigenetic modifier, is overexpressed in GBM. In this study, we tested the hypothesis that KDM1A is essential for DNA damage response (DDR) and inhibition of KDM1A sensitizes GBM to TMZ therapy. Methods: KDM1A knockout (KDM1A-KO) cells were generated using the CRISPR/Cas9 system and knockdown cells were generated using KDM1A specific shRNA (KDM1A-KD). We studied the effect of KDM1A-KO, -KD, or pharmacological KDM1A inhibitors (NCD-38 and NCL-1) on TMZ sensitization using Cell Titer-Glo luminescent cell viability assay, and survival assays. Apoptosis was determined using Caspase 3/7 and TUNEL assays. Mechanistic studies were conducted using RNA-seq, RT-qPCR, and Western blot analysis. Furthermore, the in vivo efficacy of KDM1A inhibitor and TMZ therapy was studied using orthotopic models of GBM using both male and female mice. Results: Cell viability and survival assays demonstrated that knockout/knockdown or inhibition of KDM1A sensitized patient derived glioma stem cells (GSCs) to TMZ treatment. Further, combination of NCD-38 or NCL-1 and TMZ significantly increased the apoptosis of GSCs. RNA-seq analysis revealed the modulation of DDR and apoptotic pathways following combination therapy. Pharmacokinetics (PK) and brain bioavailability studies showed that NCD-38 has favorable PK properties and exhibited a significant penetration through the blood brain barrier. Importantly, combination of NCD-38 and TMZ significantly reduced the in vivo tumor progression and improved the overall survival of both male and female mice compared to single drug treatment in GBM orthotopic models. Conclusions: Our results provide evidence that KDM1A knockdown/inhibition sensitizes GBM to TMZ therapy via modulation of DDR and that the use of KDM1A inhibitor in conjunction with TMZ could serve as a novel therapy for GBM patients. Citation Format: Bridgitte E. Palacios, Prabhakar Pitta Venkata, Yihong Chen, Salvador Alejo, Yi He, Suryavathi Viswanadhapalli, Uday Pratap, Junhao Liu, Xiaonan Li, Takayoshi Suzuki, Siyuan Zheng, Andrew Brenner, Ratna Vadlamudi, Gangadhara Sareddy. KDM1A inhibition sensitizes glioblastoma cells to temozolomide therapy through DNA damage and apoptosis pathway modulation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6220.

Background: Ovarian cancer (OCa) is the deadliest gynecologic cancer. Recent studies suggest that OCa cells express estrogen receptor beta (ESR2), which functions as a tumor suppressor. However, ESR2 expression decreases during tumor progression and under the selection pressure of chemotherapy; this decrease occurs via epigenetic mechanisms. The lysine-specific histone demethylase 1A (KDM1A), an epigenetic regulator, is overexpressed in OCa. We reason that agents that restore the expression/functions of ESR2 may provide a novel therapeutic opportunity for suppression of OCa. In this study we tested the hypothesis that KDM1A suppresses ESR2 expression/functions and that inhibition of KDM1A potentiates ESR2 mediated tumor suppression. Methods: We examined the utility of combination therapy of KDM1A inhibitor and ESR2 agonist on established and patient derived OCa cells using cell viability, survival, apoptosis and invasion assays. KDM1A knockout (KDM1A-KO) cells were generated using the CRISPR/Cas9 system. Mechanistic studies were conducted using RNA-seq, ERE-Luc reporter assays, RT-qPCR, co-IP, ChIP and Western blot analysis. The efficacy of combination therapy on primary ovarian tumors was examined using patient derived explant (PDEx) models. In vivo efficacy of KDM1A inhibitor and ESR2 agonist was studied using orthotopic OCa and patient derived xenograft models. Results: Analysis of the gene expression profiles of OCa patients showed that KDM1A negatively correlates with ESR2. Combination of KDM1A inhibitor NCD-38 and ESR2 agonist LY500307 synergistically reduced cell viability, survival and invasion and increased apoptosis of established and patient derived primary OCa cells. Inhibition or knockout of KDM1A sensitized OCa cells to ESR2 agonist treatment and significantly increased the expression of ESR2 and its target genes. Further, we found that KDM1A is recruited to the ESR2 0N promoter and interacts with ESR2. In addition, inhibition of KDM1A increased the active histone methylation mark H3K4-me2 at the ESR2 0N promoter. RNA-seq analysis demonstrated that ESR2 agonist treatment resulted in modulation of pathways related to cell cycle, apoptosis and DNA damage. Importantly, combination treatment significantly reduced the tumor growth in orthotopic and patient derived xenograft models and reduced the proliferation of OCa cells in PDEx models. Conclusions: Our results demonstrate that KDM1A inhibition enhances ESR2 expression/functions and combination therapy of KDM1A inhibitor and ESR2 agonist is an attractive therapy for treating OCa. Citation Format: Prabhakar Pitta Venkata, Bridgitte E. Palacios, Yihong Chen, Salvador Alejo, Yi He, Ilanna Loeffel, Uday Pratap, Kristin Altwegg, Suryavathi Viswanadhapalli, Takayoshi Suzuki, Rajeshwar Tekmal, Edward Kost, Gangadhara Sareddy. KDM1A inhibition activates estrogen receptor beta pathway to suppress ovarian cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1764.

Many animals can orient using the earth’s magnetic field. In a recent study, we performed three distinct behavioral assays providing evidence that the nematode Caenorhabditis elegans orients to earth-strength magnetic fields (Vidal-Gadea et al., 2015). A new study by Landler et al. suggests that C. elegans does not orient to magnetic fields (Landler et al., 2018). They also raise conceptual issues that cast doubt on our study. Here, we explain how they appear to have missed positive results in part by omitting controls and running assays longer than prescribed, so that worms switched their preferred migratory direction within single tests. We also highlight differences in experimental methods and interpretations that may explain our different results and conclusions. Together, these findings provide guidance on how to achieve robust magnetotaxis and reinforce our original finding that C. elegans is a suitable model system to study magnetoreception.

Assess biocompatibility, uptake and photodynamic therapy (PDT) mechanism of metallated porphyrin doped conjugated polymer nanoparticles (CPNs) in human brain and colorectal tumor cells and macrophages. CPNs were developed employing 9,9-dioctylfluorene-altbenzothiadiazole, an amphiphilic polymer (PS-PEG-COOH), and platinum octaethylporphyrin. T98G, SW480 and RAW 264.7 cell lines were exposed to CPNs to assess uptake and intracellular localization. Additionally, a PDT protocol using CPNs was employed for the in vitro killing of cancer and macrophage cell lines. CPNs were well incorporated into glioblastoma and macrophage cells with localization in lysosomes. SW480 cells were less efficient incorporating CPNswith localization in the plasma membrane. In all cell lines PDT treatment was efficient inducing oxidative stress that triggered apoptosis. Fil: Ibarra, Luis Exequiel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina Fil: Porcal, Gabriela Valeria. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Macor, Lorena Paola. Universidad Nacional de Río Cuarto. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Ponzio, Rodrigo Andrés. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Spada, Ramiro Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Química; Argentina Fil: Lorente, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; Argentina Fil: Chesta, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Río Cuarto. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados; Argentina Fil: Rivarola, Viviana Alicia. Universidad Nacional de Río Cuarto; Argentina Fil: Palacios, Rodrigo Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Río Cuarto. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados; Argentina

Introduction Autologous tumor cell vaccines rely on the concept of preserving an individual’s own tumorigenic makeup, expressing its unique set of tumor-associated antigens as well as antigenic elements from the surrounding stroma. These autologous tumor characteristics are usually presented with an immune adjuvant in the hopes of enhancing an immune response. Methods The autologous vaccine we used was composed of tumor cells combined with BCG and formalin. Animal safety and toxicity were evaluated using mice tumors for the immunotherapy. A small number of patients with advanced stage breast cancer were recruited for an uncontrolled study, using the vaccine solely or combined with chemotherapy/radiotherapy. Results The immunotherapy had shown to be safe in mice and humans. Upon a 5-year follow-up, the survival rate was 60 % for the combined treatment. Conclusions The data suggest that the combined treatment could be a feasible and safe therapeutic strategy. However, further controlled studies should be conducted.

Nociception reliably elicits an autonomic nervous system (ANS) response. Because pain and ANS circuitry interact on multiple spinal, subcortical, and cortical levels, it remains unclear whether autonomic responses are simply a reflexive product of noxious stimulation regardless of how stimulation is consciously perceived or whether the experience of pain mediates ANS responses to noxious stimulation. To test these alternative predictions, we examined the relative contribution of noxious stimulation and individual pain experience to ANS responses in healthy volunteers who underwent 1 or 2 pain assessment tasks. Participants received 8 seconds of thermal stimulation of varied temperatures and judged pain intensity on every trial. Skin conductance responses and pupil dilation responses to stimulation served as measures of the heat-evoked autonomic response. We used multilevel modelling to examine trial-by-trial relationships between heat, pain, and ANS response. Although both pain and noxious heat stimulation predicted skin conductance response and pupil dilation response in separate analyses, the individual pain experience statistically mediated effects of noxious heat on both outcomes. Furthermore, moderated mediation revealed that evidence for this process was stronger when stimulation was perceived as painful compared with when stimulation was perceived as nonpainful, although this difference emerged late, in the 4-second period after thermal stimulation. These findings suggest that pain appraisal regulates the heat-evoked autonomic response to noxious stimulation, documenting the flexibility of the autonomic pain response to adjust to perceived or actual changes in environmental affordances above and beyond nociceptive input.

The hypothesis of enhanced vulnerability following perinatal asphyxia was investigated with a protocol combining in vivo and in vitro experiments. Asphyxia-exposed (AS) (by 21 min water immersion of foetuses containing uterine horns) and caesarean-delivered control (CS) rat neonates were used at P2-3 for preparing triple organotypic cultures (substantia nigra, neostriatum and neocortex). At DIV 18, cultures were exposed to different concentrations of H2O2 (0.25–45 mM), added to the culture medium for 18 h. After a 48-h recovery period, the cultures were either assessed for cell viability or for neurochemical phenotype by confocal microscopy. Energy metabolism (ADP/ATP ratio), oxidative stress (GSH/GSSG) and a modified ferric reducing/antioxidant power assay were applied to homogenates of parallel culture series. In CS cultures, the number of dying cells was similar in substantia nigra, neostriatum and neocortex, but it was several times increased in AS cultures evaluated under the same conditions. A H2O2 challenge led to a concentration-dependent increase in cell death (>fourfold after 0.25 mM of H2O2) in CS cultures. In AS cultures, a significant increase in cell death was only observed after 0.5 mM of H2O2. At higher than 1 mM of H2O2 (up to 45 mM), cell death increased several times in all cultures, but the effect was still more prominent in CS than in AS cultures. The cell phenotype of dying/alive cells was investigated in formalin-fixed cultures exposed to 0 or 1 mM of H2O2, co-labelling for TUNEL (apoptosis), MAP-2 (neuronal phenotype), GFAP (astroglial phenotype) and TH (tyrosine hydroxylase; for dopamine phenotype), counterstaining for DAPI (nuclear staining), also evaluating the effect of a single dose of nicotinamide (0.8 nmol/kg, i.p. injected in 100 μL, 60 min after delivery). Perinatal asphyxia produced a significant increase in the number of DAPI/TUNEL cells/mm3, in substantia nigra and neostriatum. One millimolar of H202 increased the number of DAPI/TUNEL cells/mm3 by ≈twofold in all regions of CS and AS cultures, an effect that was prevented by neonatal nicotinamide treatment. In substantia nigra, the number of MAP-2/TH-positive cells/mm3 was decreased in AS compared to CS cultures, also by 1 mM of H202, both in CS and AS cultures, prevented by nicotinamide. In agreement, the number of MAP-2/TUNEL-positive cells/mm3 was increased by 1 mM H2O2, both in CS (twofold) and AS (threefold) cultures, prevented by nicotinamide. The number of MAP-2/TH/TUNEL-positive cells/mm3 was only increased in CS (>threefold), but not in AS (1.3-fold) cultures. No TH labelling was observed in neostriatum, but 1 mM of H2O2 produced a strong increase in the number of MAP-2/TUNEL-positive cells/mm3, both in CS (>2.9-fold) and AS (>fourfold), decreased by nicotinamide. In neocortex, H2O2 increased the number of MAP-2/TUNEL-positive cells/mm3, both in CS and AS cultures (≈threefold), decreased by nicotinamide. The ADP/ATP ratio was increased in AS culture homogenates (>sixfold), compared to CS homogenates, increased by 1 mM of H202, both in CS and AS homogenates. The GSH/GSSG ratio was significantly decreased in AS, compared to CS cultures. One millimolar of H2O2 decreased that ratio in CS and AS homogenates. The present results demonstrate that perinatal asphyxia induces long-term changes in metabolic pathways related to energy and oxidative stress, priming cell vulnerability with both neuronal and glial phenotype. The observed effects were region dependent, being the substantia nigra particularly prone to cell death. Nicotinamide administration in vivo prevented the deleterious effects observed after perinatal asphyxia in vitro, a suitable pharmacological strategy against the deleterious consequences of perinatal asphyxia.

Development of multifunctional nanofluids for applications such as thermal management and lubrication is very essential for the advancement of many energy efficient modern industries. Here, we demonstrate the tribological improvement of two dimensional (2D) atomic sheets, such as hexagonal boron nitride (h-BN) and graphene (G), reinforced mineral oils over bare mineral oil, which was proven earlier by its better thermal performance. Latter, thermal and tribological properties of dielectric and metal-cutting lubricants reinforced with h-BN and G were investigated with a detailed study on their viscosity variation with temperature and nanofiller concentration. Two different tribological tests were performed for coefficient of friction and wear studies, namely ITEePib Polish method, and ASTM D5183. Results from these methods are compared and they show in agreement with each other. Tribological tests showed that the addition of nanofillers, even in small filler fraction, resulted in to a significant decrease in the wear scar and friction coefficient along with a huge enhancement in thermal performance.

Ricinus communis or castor oil seed is an agricultural product which possesses a large amount of proteins and lipids that could be useful in food and energy industries. Drying process can be helpful to conserve the castor oil seed during long storage periods, for this reason in this research, the drying kinetics of castor oil seeds during fluidized bed drying at a constant air velocity of 7 m/s and high air temperatures (80, 90, 100, 110 °C) were studied. Six empirical mathematical models were selected to describe and compare the drying characteristic of R. communis seeds at previous described conditions. Drying rate constants, coefficients and statistical parameters were determined by non-linear regression analysis. Among the tested models used to describe the drying kinetics of castor oil seeds, the diffusion approach model was selected as the best one. The moisture loss from the seeds was described by the Fick's diffusion equation, and based on the obtained results the effective moisture diffusivity was estimated, getting a value in the range from 8.21 × 10 −10 to 2.61 × 10 −9 m 2 /s. The relationship between the temperature and the effective moisture diffusivity was described adequately by means of Arrhenius-type equation. An activation energy value of 41.41 kJ/mol was obtained. The findings allow the successful simulation of R. communis seeds fluidized bed drying between 80 and 110 °C. This study provides information to dry castor oil seed by fluidized bed at high temperatures that could be useful for biofuel production.

We evaluated the effects of casein-based semipurified diets, alone or supplemented with native Peruvian plants, on growth, feed efficiency, and histology of the digestive tract of red pacu, Piaractus brachypomus, juveniles over an 8-wk feeding trial. Three tanks were randomly assigned to one of four casein–gelatin (40:8) diets containing a supplement of 15% wheat meal (control) or an identical level of substitution of three South American native plant as follows: camu-camu fruit (Myrciaria dubia), aguaje fruit (Mauritia flexuosa), or maca tuber meal (Lepidium meyenii). The fish (initial weight, 2.04 ± 0.06 g) were fed experimental diets at decreasing feeding rates from 4 to 2.6% of body weight. After 8 weeks of feeding, fish fed a diet supplemented with maca meal showed significantly higher (P

This study presents an advisory/control algorithm for a type 1 diabetes mellitus (TIDM) patient, in a chronic stage, under an intensive insulin treatment based on a multiple daily injections regimen (MDIR). In order to incorporate expert knowledge about the treatment of this disease, the design methodology is carried out using Mamdani–type fuzzy logic controllers to regulate the blood glucose level (BGL). The overall control strategy is based on a two–loop feedback strategy to overcome the variability in the glucose-insulin dynamics from patient–to–patient. In this way, it is pursued to compute the correct amounts of insulin required to maintain the glucose in the euglycemic interval. In order to analyze the performance of the control algorithm, extensive closed-loop simulations are illustrated using a detailed nonlinear model of the subcutaneous insulin-glucose dynamics in a TIDM patient with meal intake.

Artificial light-harvesting constructs were synthesized by covalently linking two carotenoids to the central silicon atom of a phthalocyanine (Pc) derivative. Triad 1 binds two carotenoids having nine conjugated double bonds, whereas triad 2 binds two carotenoids having 10 carbon−carbon double bonds in conjugation. Fluorescence excitation experiments indicated that, in triad 1 dissolved in n-hexane, the carotenoid to Pc singlet energy transfer efficiency is ca. 92%, whereas in triad 2, it is 30%. Results from ultrafast laser spectroscopy indicate that upon population of the optically allowed S2 state of the carotenoid the optically forbidden states S1 and S* are rapidly generated in both triad 1 and triad 2. In triad 1, S2, S1, and S* all contribute singlet electronic energy to Pc. In triad 2, singlet electronic energy transfer to Pc occurs primarily from the optically allowed S2 state with little energy transfer to Pc via the S1 state, and there is no evidence for energy transfer via S*. Instead, in tria...

In order to evaluate the association of influenza viruses with hospitalizations for acute respiratory infection in infants younger than two years old during epidemics of respiratory syncytial virus infection, we studied 512 nasal washes from this population. The samples were obtained from 1997 to 2000. A total of 337 viruses were isolated: 264 respiratory syncytial viruses, 62 influenza viruses, eight parainfluenza viruses, two adenovirus and one rhinovirus. Hospitalizations for acute respiratory infection were owing to influenza and respiratory syncytial viruses in 18.3% vs. 78.3% of all cases, and 32.5% vs. 65.8%, respectively, in the group of infants between 6 months and 2 years old.

Direct current measurements reveal that the circulation of the northern Gulf of California in the annual timescale consists of a cyclonic basinwide gyre (∼0.35 m s−1) that lasts from June to September (4 months), and an anticyclonic gyre (∼0.35 m s−1) lasting from November to April (6 months). The transitions between regimes take about three weeks each. The hypothesis that the difference in duration of the two circulation regimes is due to the seasonal variation of stratification of the water column is explored by simulations with a nonlinear two-layer numerical model of circulation and thermodynamics that includes vertical mixing, parameterized as an entrainment velocity. The model results agree remarkably well with the observations, considering its simplified vertical structure. In addition, the model predicts a net circulation consisting of an anticyclonic gyre of ∼0.05 m s−1, with a corresponding average concavity of the interface, and a two-layer exchange through the main channels of the arc...

A Pressure Bed Sensor (PBS) can offer an unobtrusive method for sleep monitoring. This study focuses on the detection of the sleep related breathing disorders using a PBS in comparison to the methods used in a sleep laboratory. A newly developed PCA modeling approach for the eight sensor signals of the PBS is evaluated using the Reduced Respiratory Amplitude Index (RRAI) as a central measure. The method computes the respiration amplitude with the Hilbert transform, and then detects the events based on a 20% amplitude reduction from the baseline signal. A similar calculation was used for the sleep laboratory RIP measurements, and both PBS and RIP were compared against the reference based on the nasal flow signal. In the reference RRAI method, the respiratory-disordered events were obtained using RemLogic respiration analyzer to detect over 50% amplitude reduction in the nasal respiratory flow, but removing the RemLogic standard hypopnea event associations on the oxygen desaturation events and the sleep arousals. The movement artifacts were automatically detected based on the movement activity signal of the PBS. Twenty-five (25) out of 28 patients were finally analysed. On average 87% of a night measurement has been covered by the system. The correlation coefficient was 0.92 between the PBS and the reference RRAI, and the performance of the PBS was similar with the RIP belts. Classifying the severity of the sleep related breathing by dividing RRAI in groups according to the severity criteria, the sensitivity was 92% and the specificity was 70% for the PBS. The results suggest that PBS recording can provide an easy and un-obstructive alternative method for the detection of the sleep disordered breathing and thus has a great promise for the home monitoring.