Liver δ aminolevulinate dehydratase activity is inhibited by neonicotinoids and restored by antioxidant agents

Currently, the neonicotinoid represent class of insecticides most used worldwide, and its precursor, imidacloprid, the most widely marketed. They are classified as agents of low toxicity, however there are recent reports of neonicotinoid poisoning and studies in vitro and in vivo demonstrate their toxicity as well as potential oxidizing effect. In this line, the aim of this study was to evaluate the effect of imidacloprid on the activity of hepatic δ ALA-D and the protective effect of potential antioxidants against this potential effect. Furthermore, we investigated the presence of metals in the constitution of this pesticide. We observed that the activity of hepatic δ ALA-D was significantly inhibited in the presence of imidacloprid at all concentrations tested (2, 5, 10, 20 and 40 mM) and this inhibition was dose-dependent. IC50 value obtained was 20.06±0.17 mM and used to evaluate the restoration of the enzymatic activity. This inhibition was completely restored by addition of DTT and partly by ZnCl2, demonstrating that the inhibition occurs by oxidation of thiol groups and by displacement of the Zn (II), which can be explained by the presence of metals found also in the constitution of pesticides, which are probably contributing with the insecticide toxicity. The main endogenous antioxidant GSH (1000M) had the best antioxidant (67%) against to the effect of imidacloprid, followed by curcumin (5M) and resveratrol (5M/10M) (65 % and 61% respectively). Knowing that inhibition of the enzyme δ ALA-D results in accumulation of its substrate neurotoxic δ-ALA, further studies are needed to investigate the possible neurotoxicity induced by neonicotinoids and usability of these antioxidants as antidotes for poisoning cases neonicotinoids

Ocular metabolism and distribution of drugs in the rabbit eye : Quantitative assessment after intracameral and intravitreal administrations

Quantitation of ocular drug metabolism is important, but only sparse data is currently available. Herein, the pharmacokinetics of four drugs, substrates of metabolizing enzymes, was investigated in albino rabbit eyes after intracameral and intravitreal administrations. Acetaminophen, brimonidine, cefuroxime axetil, and sunitinib and their corresponding metabolites were quantitated in the cornea, iris-ciliary body, aqueous humor, lens, vitreous humor, and neural retina with LC-MS/MS analytics. Non-compartmental analysis was employed to estimate the pharmacokinetic parameters of the parent drugs and metabolites. The area under the curve (AUC) values of metabolites were 12-70 times lower than the AUC values of the parent drugs in the tissues with the highest enzymatic activity. The ester prodrug cefuroxime axetil was an exception because it was efficiently and quantitatively converted to cefuroxime in the ocular tissues. In contrast to the liver, sulfotransferases, aldehyde oxidase, and cytochrome P450 3A activities were low in the eye and they had negligible impact on ocular drug clearance. With the exception of esterase substrates, metabolism seems to be a minor player in ocular pharmacokinetics. However, metabolites might contribute to ocular toxicity, and drug metabolism in various eye tissues should be investigated and understood thoroughly.Peer reviewe

Advancing Participation in the Conservation & Sustainable Use of Marine Biodiversity of Areas beyond National Jurisdiction (BBNJ)

Participation of civil society in the negotiations on marine biodiversity of areas beyond national jurisdiction (BBNJ) remains limited and below the standards adopted under other multilateral environmental negotiations (Morgera et al., 2022), both in terms of participation and access to information. This policy brief underscores that public participation in the future implementation of the BBNJ Agreement is an international human rights issue, particularly with regard to Indigenous and local knowledge (ILK) holders and children. Participation is necessary to ensure that the most affected are not excluded from determining the future of our ocean and all the dimensions of human wellbeing that depended on it (Morgera et al., 2022). Public participation should be informed by existing international human rights obligations of the States participating in the BBNJ negotiations as a response to the recommendation by the UN Special Rapporteur on Human Rights and the Environment that the BBNJ negotiations should consider human rights (Boyd, 2020).This policy brief also underscores that capacitybuilding under the BBNJ Agreement needs to support public participation in the implementation of the Agreement, as well as knowledge sharing and co-production. The policy brief includes specific textual recommendations to inform the upcoming session of the Intergovernmental Conference from 15th to 26th August 2022. All comments refer to the latest revised draft text of the BBNJ Agreement prepared by the President of the Intergovernmental Conference in July 2022

Babesia spp. and Ehrlichia chaffeensis infection in Dogs from Southeastern Bahia, Brazil

Background: Tickborne diseases are frequent in tropical countries such as Brazil. Protozoa of the Babesia genus and bacteria of the Ehrlichia genus spread throughout the country with high prevalences in urban and rural areas, causing clinical or subclinical diseases in dogs. This study aimed to investigate the prevalence of infection from Babesia spp. and Ehrlichia chaffeensis in the dog population in the municipality of Ituberá, Bahia, Brazil, and to verify the risk factors associated with the infections.Materials, Methods & Results: A cross-sectional study was conducted, consisting of the following procedures: clinical examination and blood samples collection from 380 dogs and application of a structure questionnaire to dog owners to collect epidemiological data. All dogs were evaluated for the presence of ticks and clinical signs associated with the infections. Blood samples were collected and tested for Babesia spp. through capillary blood smears, indirect immunofluorescence assays (IFAT), and polymerase chain reaction (PCR); all the samples were also tested for E. chaffeensis through nested PCR. Intra-erythrocyte piroplasms were visualized in the blood smears of two animals (2/380; 0.5%) in the cytology exams. Anti-B. canis antibodies were detected in 140/380 (36.8%) dogs, at 1:40 dilution. By PCR, 147/380 (38.7%) dogs tested positive for infection by Babesia sp., but no animal was infected by E. chaffeensis. Only 115/380 dogs (30.3%) were infested by ticks. In total, 223/380 dogs (58.7%) were found infected by Babesia spp. No clinical signs were it found to be significant for the infection. The infected (Ht = 40%) and uninfected dogs’ (Ht = 39%) hematocrit averages were not found to significantly differ (P = 0.47). No hematological changes were found to be significant for the disease. The evaluated variables sex, habitat (urban or rural), exposure to other dogs, age, and infestation by ticks were not found to be risk factors. The condition of semirestriction of 175/223 (78.4%) dogs was found as a risk factor for the infection (P = 0.01; OR = 1.75; IC 95% = 1.10-2.78).Discussion: The low detection from blood smears was inferior to the lowest prevalences found in Brazil. On the other hand, the high seroprevalence rate by IFAT observed in this study was found in other Brazilian states.  The low infection prevalence in the cytologic analysis associated with high seroprevalence are characteristics of chronic or subclinical infections. The high seroprevalence rates may also indicate chronicity and/or subclinical disease when associated with low parasitemia and may also be indicated by the low title variation observed. In this study, some dogs that tested positive for Babesia by serology tested negative in the PCR, which suggests a previously exposure to this pathogen and maintenance of detectable levels of antibodies, or that they were subclinical or chronic carriers of the infection. The equal hematocrit averages of dogs either carrying or not the disease suggests that the infected animals, especially the seemingly healthy dogs, are subclinical or chronic carriers, either asymptomatic or otherwise, that are adapted to the disease, which may contribute to the agent remaining in this population. The fact that no clinical sign of hematological change was significant for the infection may demonstrate the low pathogenicity of this agent in the evaluated population. The semi-restricted condition of the dogs as a risk factor is probably due to the increased exposure of these animals to canine babesiosis vectors during their movement through different neighborhood areas and villages in the municipality. The combination of diagnostic methods is important to identify the infection and determine its prevalence in epidemiological studies. Also, PCR was fundamental in this study, to identify the infection in asymptomatic dogs

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome. Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT\ubcT0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4\u20138 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR. Results: Plasma levels of TERT were significantly lower at T2 (Po0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73\u20130.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10\u20134.11)-fold and 4.55 (95% CI 1.48\u201313.95)-fold higher, respectively, than those with undetectable plasma TERT levels. Conclusions: Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy

Addressing the ocean-climate nexus in the BBNJ agreement : strategic environmental assessments, human rights and equity in ocean science

The Agreement on Marine Biodiversity of Areas beyond National Jurisdiction (BBNJ Agreement) opens a new path in international law towards addressing issues at the ocean-climate nexus, as well as considering implications for the protection of human rights and achieving equity among States in the context of ocean knowledge production and environmental management. Based on an interdisciplinary reflection, the new international obligations on strategic environmental assessments (SEAs), and new institutional arrangements, are identified as crucial avenues to addressing climate change mitigation and ensuring fair research partnerships, mutual capacity-building and technology co-development between the Global North and South. SEAs can also support integrated implementation of other parts of the BBNJ Agreement and contribute to the broader effectiveness of the general provisions of the United Nations Convention on the Law of the Sea on the protection of the marine environment, within and beyond national jurisdiction

Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress.

Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in the energy homeostasis of all tissues. The AK2 isoenzyme is expressed in the mitochondrial intermembrane space and is mutated in reticular dysgenesis (RD), a rare form of severe combined immunodeficiency (SCID) in humans. RD is characterized by a maturation arrest in the myeloid and lymphoid lineages, leading to early onset, recurrent, and overwhelming infections. To gain insight into the pathophysiology of RD, we studied the effects of AK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of an RD patient. In zebrafish, Ak2 deficiency affected hematopoietic stem and progenitor cell (HSPC) development with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and demonstrated an increased AMP/ADP ratio, indicative of an energy-depleted adenine nucleotide profile. Antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2 mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Our results link hematopoietic cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress. This points to the potential use of antioxidants as a supportive therapeutic modality for patients with RD

New World Civitas, Contested Jurisdictions and Intercultural Conversation in the Construction of the Spanish Monarchy

Jurisdictional frontiers were created, contested, and negotiated among a wide range of actors, including native Americans and Europeans, with reference to the cities founded in Castilla del Oro (roughly present-day Panama). This research deals, first, with the reshaping of the concept of a city in the New World, based on its inhabitants' sense of civitas. It analyses, secondly, the creation and redefinition of jurisdiction during political conflicts and, third, the construction and maintenance of jurisdiction through local relations with indigenous populations described as "conversation". The analysis of the creation and preservation of local jurisdictions allows for an interpretation of the complexities involved in the configuration of political power and political space from below in the territories claimed by the Spanish Monarchy.Art Empir