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Abstract Cancer stem cells (CSCs) are defined as a rare population of cancer cells related to tumor initiation and maintenance. These cells are primarily responsible for tumor growth, invasion, metastasis, recurrence, and resistance to chemotherapy. In this paper, we demonstrated the ability of Ru(II)-based complexes containing 2-thiouracil derivatives with the chemical formulas trans-[Ru(2TU)(PPh3)2(bipy)]PF6 (1) and trans-[Ru(6m2TU)(PPh3)2(bipy)]PF6 (2) (where 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil) to suppress liver CSCs by targeting NF-κB and Akt/mTOR signaling. Complexes 1 and 2 displayed potent cytotoxic effects on cancer cell lines and suppressed liver CSCs from HepG2 cells. Increased phosphatidylserine exposure, loss of mitochondrial transmembrane potential, increased PARP (Asp214) cleavage, DNA fragmentation, chromatin condensation and cytoplasmic shrinkage were detected in HepG2 cells treated with these complexes. Mechanistically, complexes 1 and 2 target NF-κB and Akt/mTOR signaling in HepG2 cells. Cell motility inhibition was also detected in HepG2 cells treated with these complexes. Complexes 1 and 2 also inhibited tumor progression in mice with HepG2 cell xenografts and exhibited tolerable systemic toxicity. Taken together, these results indicate that these complexes are new anti-HCC drug candidates that can suppress liver CSCs.

Abstract We sought to investigate possible impaired hyperaemia during dynamic handgrip exercise (HGE) in young healthy individuals who had recovered from COVID‐19. We tested the vascular function in individuals recovered from COVID‐19 using a nitric oxide donor (i.e., sodium nitroprusside; SNP), which could revert a possible impaired endothelial function during HGE. Further, we tested whether individuals who recovered from COVID‐19 would present exaggerated brachial vascular resistance under an adrenergic agonist (i.e., phenylephrine; PHE) stimuli during HGE. Participants were distributed into two groups: healthy controls (Control; men: n = 6, 30 ± 3 years, 26 ± 1 kg/m2; and women: n = 5, 25 ± 1 years, 25 ± 1 kg/m2) and subjects recovered from COVID‐19 (post‐COVID; men: n = 6, 29 ± 3 years, 25 ± 1 kg/m2; and women: n = 10, 32 ± 4 years, 22 ± 1 kg/m2). Participants in the post‐COVID group tested positive (RT‐PCR) 12–14 weeks before the protocol. Heart rate (HR), brachial blood pressure (BP), brachial blood flow (BBF) and vascular conductance (BVC) at rest were not different between groups. The HGE increased HR (Control: Δ9 ± 0.4 bpm; and post‐COVID: Δ11 ± 0.4 bpm) and BP (Control: Δ6 ± 1 mmHg; and post‐COVID: Δ12 ± 0.6 mmHg) in both groups. Likewise, BBF (Control: Δ632 ± 38 ml/min; and post‐COVID: Δ620 ± 27 ml/min) and BVC (Control: Δ6.6 ± 0.4 ml/min/mmHg; and post‐COVID: Δ6.1 ± 0.3 ml/min/mmHg) increased during HGE. SNP did not change HGE‐induced hyperaemia but did decrease BP, which induced a reflex‐related increase in HR. PHE infusion also did not change the HGE‐induced hyperaemia but raised BP and reduced HR. In conclusion, exercise‐induced hyperaemia is preserved in healthy young subjects 12–14 weeks after recovery from COVID‐19 infection.

ABSTRACT Objective In psychiatry, History Taking(HT) and Mental Status Examination are the only information source for diagnosis, resulting in reliability and validity issues. Standard Diagnostic Interviews(SDI) were prescribed as a solution for diagnostic unreliability but not used in clinical practice. Our objective is to describe and consolidate the “must be collected data” in psychiatric HT, and reasons why some information must be collected for an adequate diagnostic hypothesis generation. Methods Researchers and lecturers from different countries were consulted about Textbooks of Clinical Psychiatry, as a privileged source of consolidated HT information in psychiatric training, using a snowball methodology, complemented by references review and most sold textbooks. Data were systematically extracted by two authors, and then comprehensively synthesized. Results Twenty-five textbooks, from sixteen different countries, were accessed. We did not find a standard model, nor clear reasons for why HT components were chosen, but the manual’s information grossly overlaps, suggesting a “validated by tradition” model in psychiatry. Conclusion The “must be collected data” are both risk factors and prototype building blocks for mental disorders, with different anti-bias strategies. HT content suggested by textbooks is different from what is addressed by SDI, and a consensual “minimum information” for diagnostic reasoning was described.

Abstract Acute myeloid leukemia (AML) is a fatal malignancy of the blood and bone marrow. Leukemic stem cells (LSCs) are a rare subset of leukemic cells that promote the development and progression of AML, and eradication of LSCs is critical for effective control of this disease. Emetine is an FDA-approved antiparasitic drug with antitumor properties; however, little is known about its potential against LSCs. Herein, we explored the antileukemic potential of emetine, focusing on its effects on AML stem/progenitor cells. Emetine exhibited potent cytotoxic activity both in hematologic and solid cancer cells and induced AML cell differentiation. Emetine also inhibited AML stem/progenitor cells, as evidenced by decreased expression of CD34, CD97, CD99, and CD123 in KG-1a cells, indicating anti-AML stem/progenitor cell activities. The administration of emetine at a dosage of 10 mg/kg for two weeks showed no significant toxicity and significantly reduced xenograft leukemic growth in vivo. NF-κB activation was reduced in emetine-treated KG-1a cells, as shown by reduced phospho-NF-κB p65 (S529) and nuclear NF-κB p65. DNA fragmentation, YO-PRO-1 staining, mitochondrial depolarization and increased levels of active caspase-3 and cleaved PARP (Asp214) were detected in emetine-treated KG-1a cells. Moreover, treatment with the pancaspase inhibitor Z-VAD(OMe)-FMK partially prevented the apoptotic cell death induced by emetine. Emetine treatment also increased cellular and mitochondrial reactive oxygen species, and emetine-induced apoptosis in KG-1a cells was partially prevented by the antioxidant N-acetylcysteine, indicating that emetine induces apoptosis, at least in part, by inducing oxidative stress. Overall, these studies indicate that emetine is a novel potential anti-AML agent with promising activity against stem/progenitor cells, encouraging the development of further studies aimed at its clinical application.

Abstract Acute myeloid leukaemia (AML) is a haematological malignancy characterised by the accumulation of transformed myeloid progenitors in the bone marrow. Piplartine (PL), also known as piperlongumine, is a pro-oxidant small molecule extracted from peppers that has demonstrated antineoplastic potential in solid tumours and other haematological malignancies. In this work, we explored the potential of PL to treat AML through the use of a combination of cellular and molecular analyses of primary and cultured leukaemia cells in vitro and in vivo. We showed that PL exhibits in vitro cytotoxicity against AML cells, including CD34+ leukaemia-propagating cells, but not healthy haematopoietic progenitors, suggesting anti-leukaemia selectivity. Mechanistically, PL treatment increased reactive oxygen species (ROS) levels and induced ROS-mediated apoptosis in AML cells, which could be prevented by treatment with the antioxidant scavenger N-acetyl-cysteine and the pancaspase inhibitor Z-VAD(OMe)-FMK. PL treatment reduced NFKB1 gene transcription and the level of NF-κB p65 (pS536), which was depleted from the nucleus of AML cells, indicating suppression of NF-κB p65 signalling. Significantly, PL suppressed AML development in a mouse xenograft model, and its combination with current AML treatments (cytarabine, daunorubicin and azacytidine) had synergistic effects, indicating translational therapeutic potential. Taken together, these data position PL as a novel anti-AML candidate drug that can target leukaemia stem/progenitors and is amenable to combinatorial therapeutic strategies.

Abstract Ascorbic acid (AA) may contribute to restoring hemostatic balance after mental stress (MS) in overweight/obese adults. We aimed to determine the effects of AA administration on hemostatic responses to MS in overweight/obese men. Fourteen overweight/obesity men (27 ± 7 years; BMI: 29.7 ± 2.6 kg m−2) performed the Stroop color-word stress task for 5 min after non-simultaneous infusion of placebo (PL, 0.9% NaCl) and AA (3 g). Blood was collected at baseline, during MS, and 60 min after MS to measure: activated partial thromboplastin time, prothrombin time, and fibrinogen concentration, by coagulometer; platelet-derived microvesicles (PMV, mv/μL), by flow cytometry; nitrite (μM), by chemiluminescence. In PL session, MS led to decreases in PTs (stress, p = 0.03; 60 min, p

Abstract [Ru(5-FU)(PPh3)2(bipy)]PF6 (Ru/5-FU) is a novel ruthenium complex with 5-fluorouracil with promising potential against colorectal cancer (CRC). In the present study, we investigated the molecular mechanism of Ru/5-FU action in HCT116 CRC cells. Ru/5-FU exhibited potent cytotoxicity on a panel of cancer cell lines and on primary cancer cells and induced apoptosis in HCT116 CRC cells. Ru/5-FU reduced AKT1 gene transcripts, as well as the expression of Akt1 and Akt (pS473) and downstream Akt proteins mTOR (pS2448), S6 (pS235/pS236), 4EBP1 (pT36/pT45), GSK-3β (pS9) and NF-κB p65 (pS529), but not Akt upstream proteins Hsp90 and PI3K p85/p55 (pT458/pT199), indicating an inhibitory action of Akt/mTOR signaling. Ru/5-FU increased LC3B expression and reduced p62/SQSTM1 levels, indicating autophagy induction. Curiously, the autophagy inhibitors 3-methyladenine and chloroquine increased Ru/5-FU-induced cell death, indicating an induction of cytoprotective autophagy by this compound. Ru/5-FU also reduced clonogenic survival, as well as the percentage of CD133+ cells and colonosphere formation, indicating that Ru/5-FU can suppress stem cells in HCT116 cells. Ru/5-FU inhibited cell migration and invasion in wound healing assays and Transwell cell invasion assays, along with a reduction in vimentin expression and an increase in E-cadherin levels, indicating that Ru/5-FU can interfere with epithelial-mesenchymal transition. Ru/5-FU also inhibited in vivo HCT116 cell development and experimental lung metastases in mouse xenograft models. Altogether, these results indicate that Ru/5-FU is an anti-CRC chemotherapy drug candidate with the ability to suppress stemness in CRC cells by inhibiting Akt/mTOR signaling.

Abstract In this work, we describe a novel ruthenium-xanthoxylin complex, [Ru(phen)2(xant)](PF6) (RXC), that can eliminate colorectal cancer (CRC) stem cells by targeting the chaperone Hsp90. RXC exhibits potent cytotoxicity in cancer cell lines and primary cancer cells, causing apoptosis in HCT116 CRC cells, as observed by cell morphology, YO-PRO-1/PI staining, internucleosomal DNA fragmentation, mitochondrial depolarization, and PARP cleavage (Asp214). Additionally, RXC can downregulate the HSP90AA1 and HSP90B1 genes and the expression of HSP90 protein, as well as the expression levels of its downstream/client elements Akt1, Akt (pS473), mTOR (pS2448), 4EBP1 (pT36/pT45), GSK-3β (pS9), and NF-κB p65 (pS529), implying that these molecular chaperones can be molecular targets for RXC. Moreover, this compound inhibited clonogenic survival, the percentage of the CRC stem cell subpopulation, and colonosphere formation, indicating that RXC can eliminate CRC stem cells. RXC reduced cell migration and invasion, decreased vimentin and increased E-cadherin expression, and induced an autophagic process that appeared to be cytoprotective, as autophagy inhibitors enhanced RXC-induced cell death. In vivo studies showed that RXC inhibits tumor progression and experimental metastasis in mice with CRC HCT116 cell xenografts. Taken together, these results highlight the potential of the ruthenium complex RXC in CRC therapy with the ability to eliminate CRC stem cells by targeting the chaperone Hsp90.

ObjectiveOur objective was to check if the ICD-10 operational criteria application changes non-operational, prototype-based diagnoses obtained in a real-life scenario.MethodsPsychiatry residents applied the diagnostic criteria of the ICD-10 as a “diagnostic test” to five outpatient patients they were already following who had a prototype-based diagnosis. Tests were used to ascertain whether changes in opinion were significant and if any of the diagnostic groups were more prone to change than others. The present paper is part of the study with UTN U1111-1260-1212.ResultsSeventeen residents reviewed their last five case files, retrieving 85 diagnostic pairs of non-operational-based vs. operational-based diagnoses. The Stuart–Maxwell test did not indicate a significant opinion change (χ2 = 5.25, p = 0.39; power = 0.94) besides 30% of diagnostic changes. Despite not being statistically significant, 20.2% of all evaluations resulted in a change that would affect treatment choices. Using ICD-10 operational criteria slightly increased the number of observed diagnoses, but probably without clinical relevance. None of the non-operational diagnoses have a higher tendency to change with operational criteria application (χ2 = 11.6, p = 0.07). The female gender was associated with a higher diagnostic change tendency.ConclusionApplying ICD-10 operational criteria as a diagnostic test does not induce a statistically significant diagnostic opinion change in residents and no diagnostic group seems more sensible to diagnostic change. Gender-related differences in diagnostic opinion changes might be evidence of sunk cost bias. Although not statistically significant, using operational criteria after diagnostic elaboration might help to deal with subjects without adequate treatment response.

Abstract The proper establishment of plants is essential for the efficient use of resources such as water and light. Besides, even after seed storage and sowing the uniform establishment of plants is essential for their success. Crotalaria ochroleuca and Crotalaria spectabilis are important medicinal plants with poor seed germination rate, occasionally. The effects of seed priming in both C. ochroleuca and C. spectabilis were evaluated in seed performance even after seeds storage for up 90-days. Experimental assays were performed in a randomized design with gibberellic acid (GA3, 100 ppm), polyethylene glycol (PEG 6000, -0.2 MPa) and PEG (-0.2 MPa) + GA3 (100 ppm) solutions during seed priming in four replicates. Seeds not submitted to priming treatments constituted control. Seeds physiological performance were evaluated immediately and even after 30, 60 and 90-days seed dry-storage. The data obtained in each experiment were submitted to variance analysis (ANOVA) adopting a confidence level of 95%. The effects of seed priming with PEG and GA3 during seed ageing were significant for germination variables of C. ochroleuca and C. spectabilis. During dry storage, seed viability of both species gradually decreased and the first symptoms were delayed seed germination, especially more evident for C. ochroleuca, even in primed or non-primed seeds. Afterwards, C. ochroleuca seeds previously GA3 primed had higher results of root protrusion (86%), hypocotyls elongation (76%) and complete seedlings (75%) than non-primed seeds (control). These findings shown a good potential of hormopriming to attenuate damage during the seed aging of C. ochroleuca.

Biodistribution assays are integral to gene therapy commercialization and have traditionally used real-time qPCR. Droplet digital PCR (ddPCR), however, has distinct advantages including higher sensitivity and absolute quantification but is underused because of lacking regulatory guidance and meaningful examples in the literature. We report a fit-for-purpose model process to validate a good laboratory practice (GLP)-compliant ddPCR assay for AVGN7, a Smad7 gene therapeutic for muscle wasting. Duplexed primer/probe sets for Smad7 and mouse TATA-box binding protein were optimized using gBlock DNA over a dynamic range of 10–80,000 copies/reaction in 250 ng mouse gDNA. Linearized plasmid and mouse gDNA were used for validation, which determined precision, accuracy, ruggedness/robustness, selectivity, recovery, specificity, dilution linearity, and stability. Inter-run precision and accuracy met previously established criteria with bias between −5% and 15%, coefficient of variation (CV) less than 19%, and total error within 8%–35%. The limit of detection was 2.5 copies/reaction, linearity was confirmed at 40–80,000 copies/reaction, specificity was demonstrated by single droplet populations and assay stability was demonstrated for benchtop, refrigerated storage, and repeated freeze-thaw cycles. The procedural road map provided exceeds recently established standards. It is also relevant to many IND-enabling processes, as validated ddPCR assays can be used in biodistribution studies and with vector titering and manufacturing quality control.

Abstract Background Current guidelines emphasize cancer patients should increase their physical activity levels, encouraging physical exercise practice as a complementary therapy to mitigate adverse effects during treatment. Telehealth can be a feasible method to improve adherence and interventional support for breast cancer patients, of which most do not meet sufficient physical activity levels after diagnosis. The Adaptations to Breast Cancer and Exercise Using Telehealth (ABRACE: Telehealth) study aims to investigate the effects of a 12-week telehealth multicomponent training program plus a health education program (MTHE), compared to a health education program alone (HE), on physical and psychological outcomes in breast cancer patients undergoing treatment. Methods This study is a randomized controlled trial. Women undergoing primary treatment (during or after chemotherapy) for breast cancer (stages I–III) will be randomly assigned to MTHE (twice a week) or HE (once a week). MTHE components are mobility, aerobic, balance, resistance, and flexibility home-based exercises, supervised by video call. The primary study outcome is cancer-related fatigue. The secondary outcomes are quality of life, symptoms of depression and anxiety, physical activity level, cancer-related cognitive impairment, and functional capacity. Other outcomes are adherence to interventions and a follow-up questionnaire evaluating the individual perception in motivation, lifestyle changes, and main barriers to participation. All outcomes will be remotely assessed before and after intervention. Our analysis will follow the intention-to-treat approach and per-protocol criteria, with additional sub-group analysis. Discussion To our knowledge, this is the first randomized clinical trial in breast cancer patients using a face-to-face videoconference strategy to supervise physical exercise. Our hypothesis is of superiority for the effects of MTHE on primary and secondary outcomes compared to the effects of only the health education intervention. Trial registration Adaptations to Breast Cancer and Exercise Using Telehealth (ABRACE: Telehealth), NCT04641377. Registered on 23 November 2021, https://clinicaltrials.gov/ct2/show/NCT04641377

Colorectal cancer is the second leading cause of cancer-related deaths in the United States and accounts for an estimated 1 million deaths annually worldwide. The liver is the most common site of metastatic spread from colorectal cancer, significantly driving both morbidity and mortality. Although remarkable advances have been made in recent years in the management for patients with colorectal cancer liver metastases, significant challenges remain in early detection, prevention of progression and recurrence, and in the development of more effective therapeutics. In 2017, our group held a multidisciplinary state-of-the-science symposium to discuss the rapidly evolving clinical and scientific advances in the field of colorectal liver metastases, including novel early detection and prognostic liquid biomarkers, identification of high-risk cohorts, advances in tumor-immune therapy, and different regional and systemic therapeutic strategies. Since that time, there have been scientific discoveries translating into therapeutic innovations addressing the current management challenges. These innovations are currently reshaping the treatment paradigms and spurring further scientific discovery. Herein, we present an updated discussion of both the scientific and clinical advances and future directions in the management of colorectal liver metastases, including adoptive T-cell therapies, novel blood-based biomarkers, and the role of the tumor microbiome. In addition, we provide a comprehensive overview detailing the role of modern multidisciplinary clinical approaches used in the management of patients with colorectal liver metastases, including considerations toward specific molecular tumor profiles identified on next generation sequencing, as well as quality of life implications for these innovative treatments.

Graphene materials, used as electrocatalyst support in green hydrogen production, contribute to increasing the efficiency and robustness of various systems. However, the preparation of a hybrid catalyst containing graphene materials from industrial wastes is still a challenge due to the heterogeneity of the waste. We report the synthesis of 3D electrodes using graphene oxides (GOs) from industrial waste (IW) prepared by immersion onto Toray carbon paper as a 3D support onto GO suspensions and electrodepositing NiFe layered double hydroxides (LDHs). Standard graphite was also used as the reference. The morphology of the two hybrid electrodes was determined by SEM, HRTEM, XPS. Although very similar in both, the sample containing graphene from IW (higher Csp3 hybridization in the graphene layer) has a NiFe phase with less crystallinity and larger presence of Fe2+ ions. These electrodes exhibited similar activity and stability as electrocatalysts of the oxygen evolution reaction (OER), demonstrating the proactive effect of the graphene into the 3D electrode even when this is prepared from heterogeneous industrial waste. Moreover, the defective graphenic structure of the waste GO enhances the reaction kinetics and improves the electron transfer rate, possibly due to the small differences in the electrodeposited NiFe LDH structure.

ABSTRACT: We aimed to evaluate the incidence of unstable non-acid milk (UNAM) in cows fed either sugarcane or corn silage. Second, we aimed to evaluate the effect of daily variation (d 1 to 4) and alcohol grades (72, 78, and 80%) on UNAM incidence. The experiment was conducted as a split-plot crossover design, with 2 periods and 2 roughage types (sugarcane or corn silage). Thirteen multiparous Holstein cows with an average of 281 ± 29 d in milk were randomly distributed into 2 diets. Individual blood (analysis of total proteins, albumin, urea, calcium, phosphorus, magnesium, iron, chloride, glucose, and lactate) and milk samples (analysis of protein, fat, lactose and total solids, somatic cell count, and characterization of the protein profile) were collected during the last 4 d of each period. For UNAM identification, the alcohol test was conducted in milk samples at 4°C; specifically, if the sample presented the formation of clots, this would be noted as positive for UNAM. In addition, the Dornic acidity analysis was performed in the same samples to evaluate the true milk acidity. The use of sugarcane and higher degrees of alcohol were associated with increased UNAM. We observed no daily variation in UNAM. Nevertheless, we found no roughage type effect on the variables most commonly associated with UNAM, such as changes in salts in the casein micelle and, consequently, the zeta potential and the κ-casein (CN) fraction. The Pearson correlation analysis showed that the zeta potential and the concentrations of αS2-CN, blood ionic calcium, lactate, and glucose increased as the incidence of UNAM increased, showing a positive correlation among these variables. In contrast, the concentrations of lactose, phosphorus, and potassium decreased as UNAM increased, presenting a negative correlation. This study brought important discoveries to unveil why cows manifest UNAM. For instance, higher alcohol grades and cows fed with sugarcane had increased the incidence of UNAM. Additionally, animals with a higher incidence of UNAM (sugarcane-fed cows) were related to increased ionic calcium and glucose and changes in milk protein profile, with lower levels of BSA, β-CN, and α-lactalbumin and greater αS1-CN content, all of which were correlated with UNAM. Nonetheless, this trial also provides evidence for the need for further studies to better understand the physiological mechanisms that directly affect the stability of milk protein.

Abstract Alpinia zerumbet is a plant popularly used to treat hypertension and anxiety. Studies with Alpinia zerumbet demonstrate antihypertensive and vasodilator effects, among others. The objective of this study was to analyze the effect of essential oil of Alpinia zerumbet (EOAz) on cardiovascular and autonomic function in rats with isoproterenol-induced myocardial infarction. Male Wistar rats (n=32) were equally allocated into four groups: Control, ISO (150mg/kg, subcutaneous), EOAz (100mg/kg by gavage), ISO+EOAz. The rats were evaluated for cardiovascular and, autonomic parameters, electrocardiogram, and infarct size. EOAz was not able to reduce the electrocardiographic variations induced by ISO. Heart rate variability showed a decrease in sympathetic modulation on the heart in the groups treated with EOAz. The cardiopulmonary reflex induced by serotonin invoked a superior blood pressure variation at the 2 µg/kg dose in the EOAz treated groups, while the heart rate variation was significantly higher at the 16 µg/kg dose, when compared to other doses, in all groups, except EOAz+ISO. The sympathetic vagal index was higher in ISO group than in control. EOAz did not reduce the infarct size. We conclude that pretreatment with EOAz does not reverse the hemodynamic and electrocardiographic damage caused by isoproterenol but does reduce sympathetic modulation.

The good properties and high productivity obtained through injection molding have enabled the use of composites reinforced with short carbon fibers for the production of automobile components. Their low strength and stiffness, however, have limited the use of these materials in some applications. The incorporation of inorganic nanoparticles such as alumina (Al2O3) is a proposed solution to this problem. There is evidence that nanoparticles promote better interfacial interaction between the polymer and short carbon fibers, improving the mechanical performance of composites. The aim of this work was to develop polypropylene (PP) composites reinforced with alumina nanoparticles and short carbon fibers for the automotive industry. The composites were processed in a twin-screw extruder. The response surface methodology was used to define the content of nanoparticles in the composites and to evaluate the effect of the incorporation of the alumina and polypropylene-grafted maleic anhydride (PP-g-MA) on the properties obtained. The hybrid composite that showed the best tensile properties was used as a matrix for reinforcement with different levels of short carbon fiber. The tensile properties were determined by the standard techniques. The results showed that the materials obtained can be used in applications that require low density along with high productivity, rigidity and resistance.

Diabetic papillopathy (DP) is a rare ocular manifestation of diabetes mellitus. The exact etiology is not well understood, but in some cases, it may be associated with a rapid correction of the blood glucose level. There are limited case reports describing the use of intravitreal anti-vascular endothelial growth factor antibodies which have shown effectiveness in reducing disc swelling. In this case, we present the case of an 80-year-old diabetic woman diagnosed with DP during a diabetic retinopathy (DR) screening. Her visual acuity (VA) was counting fingers on her right eye and 20/160 on her left eye. At the fundoscopy, an exuberant bilateral hemorrhagic disc edema was observed, along with a nonproliferative DR. This edema was also evident in the fluorescein angiography and was documented through the optical coherence tomography. Brain computed tomography normal. She was treated with ranibizumab with significant improvement of the optic disc edema and the VA.

Renewable energy sources, such as floating photovoltaic systems (FPVs), are crucial to mitigating the climate crisis. FPV deployments on freshwater bodies are rapidly growing, as they avert land-use change, operate with increased efficiency, and potentially improve water availability by reducing evaporation and the frequency of algal blooms. However, understanding of the ecological consequences for water bodies is very limited despite the variable and far-reaching range of potential impacts. Here, we bring novel insight by combining an established theoretical approach—techno-ecological synergies (TES)—with robust understanding of water body functioning, to direct sustainable FPV deployments. Specifically, we show the potential to integrate consideration of both energy and ecological systems for FPV deployment decisions based on current evidence and fundamental understanding of freshwater body states and processes. Based on 422 pieces of evidence from a systematic review of known physical ( n = 283), chemical ( n = 96) and biological ( n = 43) effects of FPV on freshwater systems, we outline eight potential TES that could be realised through FPV location, design, and operation decisions. There was most evidence ( n = 114) for the Water Use Efficiency TES, which all reported decreased evaporation rates, or increased water savings, due to panel shading. We highlight a lack of understanding of chemical and biological effects of FPV on hosting water bodies, as well as a need for comprehensive studies in which physical, chemical, and biological aspects of water body dynamics are integrated. Finally, we detail research priorities to ensure future FPV deployments bring benefit for both energy and water bodies. Ultimately, integrated energy and water body system knowledge, FPV deployments could mitigate both the climate and ecological emergencies, with notable benefits for society.

Abstract The main goal was to determine the impact of mental stress (MS) on blood flow regulation in overweight/obese men. Fourteen overweight/obese men (27 ± 7 years; 29.8 ± 2.6 kg/m2) participated in two randomized experimental sessions with oral administration of the AT1R blocker Olmesartan (40 mg; AT1RB) or placebo (PL). After 2 h, a 5‐min acute MS session (Stroop Color Word Test) was administered. Blood flow was assessed at baseline and during the first 3 min of MS by vascular ultrasound in the brachial artery. Blood was collected before (baseline) and during mental stress (MS) for measurement of nitrite (chemiluminescence) and endothelin‐1 (ELISA kit). The AT1R blocker was able to reverse the MS responses observed in the placebo session for retrograde flow (p 0.05) responses to MS between experimental sessions. However, for nitrite responses, the administration of the AT1R blocker was able to increase circulating levels of NO (p = 0.03) Blockade of AT1R appears to prevent the decrease in endothelial function by reducing low shear stress and maintaining the vasoactive substances balance after MS in overweight/obese men.

ABSTRACT Objective: To describe the history of creation, development, and topics covered by the Study Center of the Institute of Psychiatry of the Federal University of Rio de Janeiro (CE – IPUB/UFRJ) over its 70 years. Methods: Research in newspapers of the Hemeroteca Brasileira Digital, internal documents of IPUB/UFRJ, and interviews with eyewitnesses of the functioning of the CE. Results: The Study Center has been operating on an uninterrupted basis for 70 years, every week. 472 events have been identified since the founding of the CE, but numerous other meetings have taken place. The findings were described in three major groups: 1. Academic meetings in the first half of the 20th century and insertion of the CE in the history of IPUB; 2. Topics discussed and presentations; 3. Changes in periodicity and format. Conclusions: The CE produces cultural and scientific dissemination continuously since its foundation. The type and format of events have changed over time, adapting to the needs of their community, but always serving as an important beacon for the training of specialists in mental health, dissemination of research, and tendencies about psychiatry worldwide, Latin America, and Brazil.

Corynebacterium amycolatum is a nonlipophilic coryneform which is increasingly being recognized as a relevant human and animal pathogen showing multidrug resistance to commonly used antibiotics. However, little is known about the molecular mechanisms involved in transition from colonization to the MDR invasive phenotype in clinical isolates. In this study, we performed a comprehensive pan-genomic analysis of C. amycolatum, including 26 isolates from different countries. We obtained the novel genome sequences of 8 of them, which are multidrug resistant clinical isolates from Spain and Tunisia. They were analyzed together with other 18 complete or draft C. amycolatum genomes retrieved from GenBank. The species C. amycolatum presented an open pan-genome (α = 0.854905), with 3,280 gene families, being 1,690 (51.52%) in the core genome, 1,121 related to accessory genes (34.17%), and 469 related to unique genes (14.29%). Although some classic corynebacterial virulence factors are absent in the species C. amycolatum, we did identify genes associated with immune evasion, toxin, and antiphagocytosis among the predicted putative virulence factors. Additionally, we found genomic evidence for extensive acquisition of antimicrobial resistance genes through genomic islands.

Abstract This mini‐review presents an overview of recent trends for 3D printed sensors and biosensors (with a focus on Fused Deposition Modeling (FDM) based technology), along with their posttreatment surfaces to improve electrochemical applications. The protocols described in the literature and advances in this field were covered, bringing a critical discussion about the achievements and limitations to improve the electrical properties of conducting filaments, as well as their electroanalytical performance. In addition, the pros and cons of the processes used in surface posttreatment to improve the performance of electrodes constructed by FDM are presented, comparing the time consumed during chemical and electrochemical treatments or combining the two to improve the characteristics of the sensors. Finally, the discussion about the real necessity of surface treatments of electrodes constructed by FDM technology, the techniques used for this, and some ecological protocols are discussed (surface posttreatments with and without reagents) or whether the simple optimization of printing parameters could also significantly improve the electrochemical performance of sensors built with such technologies.

Abstract Background: Noninvasive stimulation has been widely used in the past 30 years to study and treat a large number of neurological diseases, including movement disorders. Objective: In this critical review, we illustrate the rationale for use of these techniques in movement disorders and summarize the best medical evidence based on the main clinical trials performed to date. Methods: A nationally representative group of experts performed a comprehensive review of the literature in order to analyze the key clinical decision-making factors driving transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) in movement disorders. Classes of evidence and recommendations were described for each disease. Results: Despite unavoidable heterogeneities and low effect size, TMS is likely to be effective for treating motor symptoms and depression in Parkinson’s disease (PD). The efficacy in other movement disorders is unclear. TMS is possibly effective for focal hand dystonia, essential tremor and cerebellar ataxia. Additionally, it is likely to be ineffective in reducing tics in Tourette syndrome. Lastly, tDCS is likely to be effective in improving gait in PD. Conclusions: There is encouraging evidence for the use of noninvasive stimulation on a subset of symptoms in selected movement disorders, although the means to optimize protocols for improving positive outcomes in routine clinical practice remain undetermined. Similarly, the best stimulation paradigms and responder profile need to be investigated in large clinical trials with established therapeutic and assessment paradigms that could also allow genuine long-term benefits to be determined.

A rapid and simple method for the amperometric determination of glucose using a nanocomposite film of nickel oxyhydroxide and multi-walled carbon nanotube (MWCNTs) was evaluated. The NiHCF)/MWCNT electrode film was fabricated using the liquid–liquid interface method, and it was used as a precursor for the electrochemical synthesis of nickel oxy-hydroxy (Ni(OH)2/NiOOH/MWCNT). The interaction between nickel oxy-hydroxy and the MWCNTs provided a film that is stable over the electrode surface, with high surface area and excellent conductivity. The nanocomposite presented an excellent electrocatalytic activity for the oxidation of glucose in an alkaline medium. The sensitivity of the sensor was found to be 0.0561 μA μmol L−1, and a linear range from 0.1 to 150 μmol L−1 was obtained, with a good limit of detection (0.030 μmol L−1). The electrode exhibits a fast response (150 injections h−1) and a sensitive catalytic performance, which may be due to the high conductivity of MWCNT and the increased active surface area of the electrode. Additionally, a minimal difference in the slopes for ascending (0.0561 µA µmol L−1) and descending (0.0531 µA µmol L−1) was observed. Moreover, the sensor was applied to the detection of glucose in artificial plasma blood samples, achieving values of 89 to 98% of recovery.

Among the many biological entities employed in the development of biosensors, enzymes have attracted the most attention. Nanotechnology has been fostering excellent prospects in the development of enzymatic biosensors, since enzyme immobilization onto conductive nanostructures can improve characteristics that are crucial in biosensor transduction, such as surface-to-volume ratio, signal response, selectivity, sensitivity, conductivity, and biocatalytic activity, among others. These and other advantages of nanomaterial-based enzymatic biosensors are discussed in this work via the compilation of several reports on their applications in different industrial segments. To provide detailed insights into the state of the art of this technology, all the relevant concepts around the topic are discussed, including the properties of enzymes, the mechanisms involved in their immobilization, and the application of different enzyme-derived biosensors and nanomaterials. Finally, there is a discussion around the pressing challenges in this technology, which will be useful for guiding the development of future research in the area.

Resumo: A utilização da internet representa uma alternativa que possibilita maior interação entre o corpo docente e o discente, além de permitir a difusão e a incorporação de conteúdo atualizado eficientemente. OBJETIVO: Apresentar a estrutura de uma homepage (HP) desenvolvida para apoiar o ensino de Epidemiologia no curso de Medicina da UFRJ e realizar uma análise exploratória do acesso à mesma. MÉTODOS: A estrutura da HP foi definida a partir dos resultados obtidos durante a fase experimental de um projeto de monitoria virtual. Foi construído um banco de dados com informações sobre a data e hora do acesso à HP e o endereço IP (Internet Protocol) de onde o mesmo foi originado. O período estudado correspondeu às dez primeiras semanas do curso de Epidemiologia ministrado a uma turma do primeiro semestre de 2002. RESULTADOS: A homepage (http://www.nesc.ufrj.br/ epidemiologia) contém as seguintes seções: perguntas mais frequentes, entrevistas, material do curso, projetos de pesquisa na área de Epidemiologia, conexões paro outros sites e questões antigas de residência médica. Durante o período estudado, foram registrados 3.005 acessos, a maior parte deles (44,7%) realizada nas semanas que antecederam as avaliações do curso. Apenas 6,6% dos acessos foram efetuados dentro da UFRJ, sendo o período de maior utilização compreendido entre 78 e 24 horas (38,1%). CONCLUSÕES: Os resultados sobre o perfil de acesso sugerem um padrão de utilização orientado primordialmente para a obtenção de um bom desempenho nas avaliações, o que pode ser explicado pela dificuldade de incorporação de uma nova cultura de aprendizagem. Por outro lado, a melhor utilização do site depende do desenvolvimento e disponibilização de aplicativos que estimulem uma participação ativa do aluno no processo de ensino-aprendizado.

ABSTRACT Like other members of the phylum Bacteroidetes, the oral anaerobe Porphyromonas gingivalis synthesizes a variety of sphingolipids, similar to its human host. Studies have shown that synthesis of these lipids (dihydroceramides [DHCs]) is involved in oxidative stress resistance, the survival of P. gingivalis during stationary phase, and immune modulation. Here, we constructed a deletion mutant of P. gingivalis strain W83 with a deletion of the gene encoding DhSphK1, a protein that shows high similarity to a eukaryotic sphingosine kinase, an enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate. Our data show that deletion of the dhSphK1 gene results in a shift in the sphingolipid composition of P. gingivalis cells; specifically, the mutant synthesizes higher levels of phosphoglycerol DHCs (PG-DHCs) than the parent strain W83. Although PG1348 shows high similarity to the eukaryotic sphingosine kinase, we discovered that the PG1348 enzyme is unique, since it preferentially phosphorylates dihydrosphingosine, not sphingosine. Besides changes in lipid composition, the W83 ΔPG1348 mutant displayed a defect in cell division, the biogenesis of outer membrane vesicles (OMVs), and the amount of K antigen capsule. Taken together, we have identified the first bacterial dihydrosphingosine kinase whose activity regulates the lipid profile of P. gingivalis and underlies a regulatory mechanism of immune modulation. IMPORTANCE Sphingoid base phosphates, such as sphingosine-1-phosphate (S1P) and dihydrosphingosine-1-phosphate (dhS1P), act as ligands for S1P receptors, and this interaction is known to play a central role in mediating angiogenesis, vascular stability and permeability, and immune cell migration to sites of inflammation. Studies suggest that a shift in ratio to higher levels of dhS1P in relation to S1P alters downstream signaling cascades due to differential binding and activation of the various S1P receptor isoforms. Specifically, higher levels of dhS1P are thought to be anti-inflammatory. Here, we report on the characterization of a novel kinase in Porphyromonas gingivalis that phosphorylates dihydrosphingosine to form dhS1P.

Background and ObjectivesThe use of “operational criteria” is a solution for low reliability, contrasting with a prototypical classification that is used in clinics. We aim to measure the reliability of prototypical and ICD-10 diagnoses.MethodsThis is a retrospective study, with a convenience sample of subjects treated in a university clinic. Residents reviewed their diagnosis using ICD-10 criteria, and Cohen's kappa statistic was performed on operational and prototype diagnoses.ResultsThree out of 30 residents participated, reviewing 146 subjects under their care. Diagnoses were grouped in eight classes: organic (diagnoses from F00 to F09), substance disorders (F10–F19), schizophrenia spectrum disorders (F20–F29), bipolar affective disorder (F30, F31, F34.0, F38.1), depression (F32, F33), anxiety-related disorders (F40–F49), personality disorders (F60–F69), and neurodevelopmental disorders (F70–F99). Overall, agreement was high [K = 0.77, 95% confidence interval (CI) = 0.69–0.85], with a lower agreement related to personality disorders (K = 0.58, 95% CI = 0.38–0.76) and higher with schizophrenia spectrum disorders (K = 0.91, 95% CI = 0.82–0.99).DiscussionUse of ICD-10 criteria did not significantly increase the number of diagnoses. It changed few diagnoses, implying that operational criteria were irrelevant to clinical opinion. This suggests that reliability among interviewers is more related to information gathering than diagnostic definitions. Also, it suggests an incorporation of diagnostic criteria according to training, which then became part of the clinician's prototypes. Residents should be trained in the use of diagnostic categories, but presence/absence checking is not needed to achieve operational compatible diagnoses.

Background: The tumor microenvironment (TME) in cholangiocarcinoma (CCA) influences the immune environment. Checkpoint blockade is promising, but reliable biomarkers to predict response to treatment are still lacking. Materials and Methods: The levels of checkpoint molecules (PD-1, PD-L1, PD-L2, LAG-3, ICOS, TIGIT, TIM-3, CTLA-4), macrophages (CD68), and T cells (CD4 and CD8 cells) were assessed by multiplexed immunofluorescence in 50 intrahepatic cases. Associations between marker expression, immune cells, and region of expression were studied in the annotated regions of tumor, interface, sclerotic tumor, and tumor-free tissue. Results: ICCA demonstrated CD4_TIM-3 high densities in the tumor region of interest (ROI) compared to the interface (p = 0.014). CD8_PD-L1 and CD8_ICOS densities were elevated in the sclerotic tumor compared to the interface (p = 0.011 and p = 0.031, respectively). In a multivariate model, high expression of CD8_PD-L2 (p = 0.048) and CD4_ICOS_TIGIT (p = 0.011) was associated with nodal metastases. Conclusions: High densities of PD-L1 were more abundant in the sclerotic tumor region; this is meaningful for the stratification of immunotherapy. Lymph node metastasis correlates with CD4_ICOS_TIGIT co-expression and CD8_PD-L2 expression, indicating the checkpoint expression profile of patients with a poor prognosis. Also, multiple co-expressions occur, and this potentially suggests a role for combination therapy with different immune checkpoint targets than just PD-1 blockade monotherapy.

AimsBoth postprandial lipemia (PPL) and disturbed blood flow (DBF) induce endothelial dysfunction. However, the interactive effect of these stimuli on endothelial function is currently unknown. In the present study, we tested whether PPL plus DBF causes a greater reduction in flow-mediated dilation (FMD) than PPL and if this response is associated with elevations in oxidative stress and endothelial microvesicles (EMVs).MethodsEighteen individuals (aged 28 ± 1yrs, 3 females, and BMI 24.43 ± 0.8kg/m2) randomly underwent two experimental sessions: PPL and PPL plus DBF. FMD and venous blood samples were obtained at baseline and 30, 70, and 110 min after stimulation. PPL was induced by fat overload via mozzarella pizza ingestion and DBF by forearm cuff inflation to 75 mm Hg per 30 min. Lipidic profile, oxidative stress (thiobarbituric acid reactive substances, TBARS; ferric reducing/antioxidant power, FRAP; hydrogen peroxide, H2O2) and EMVs were measured in blood samples.ResultsHypertriglyceridemia was observed in both sessions. Retrograde shear rate and oscillatory index responses were significantly higher in the PPL plus DBF compared with PPL. PPL plus DBF evoked a greater reduction in FMD than did PPL and EMVs, NADPH oxidase, and H2O2 similarly increased in both sessions, but TBARS and FRAP did not change.ConclusionThese data indicate that the association of PPL plus DBF additively impairs endothelium-dependent function in 110 min after stimulus in healthy individuals, despite a similar increase in oxidative stress and EMVs. Further studies are needed to understand the mechanisms associated with the induced-endothelial dysfunction by association of PPL and DBF.