Spatial omics reveals molecular changes in focal cortical dysplasia type II.

Focal cortical dysplasia (FCD) represents a group of diverse localized cortical lesions that are highly epileptogenic and occur due to abnormal brain development caused by genetic mutations, involving the mammalian target of rapamycin (mTOR). These somatic mutations lead to mosaicism in the affected brain, posing challenges to unravel the direct and indirect functional consequences of these mutations. To comprehensively characterize the impact of mTOR mutations on the brain, we employed here a multimodal approach in a preclinical mouse model of FCD type II (Rheb), focusing on spatial omics techniques to define the proteomic and lipidomic changes. Mass Spectrometry Imaging (MSI) combined with fluorescence imaging and label free proteomics, revealed insight into the brain's lipidome and proteome within the FCD type II affected region in the mouse model. MSI visualized disrupted neuronal migration and differential lipid distribution including a reduction in sulfatides in the FCD type II-affected region, which play a role in brain myelination. MSI-guided laser capture microdissection (LMD) was conducted on FCD type II and control regions, followed by label free proteomics, revealing changes in myelination pathways by oligodendrocytes. Surgical resections of FCD type IIb and postmortem human cortex were analyzed by bulk transcriptomics to unravel the interplay between genetic mutations and molecular changes in FCD type II. Our comparative analysis of protein pathways and enriched Gene Ontology pathways related to myelination in the FCD type II-affected mouse model and human FCD type IIb transcriptomics highlights the animal model's translational value. This dual approach, including mouse model proteomics and human transcriptomics strengthens our understanding of the functional consequences arising from somatic mutations in FCD type II, as well as the identification of pathways that may be used as therapeutic strategies in the future.

Pileflebitis en pediatría: un desafío diagnóstico / Pylephlebitis in pediatrics: A diagnostic challenge

La pileflebitis es definida como la trombosis supurativa de la vena porta como complicación de infecciones abdominales. En pediatría, la etiología más frecuente es la apendicitis, generalmente de diagnóstico tardío, que se presenta como sepsis, con una elevada mortalidad. Para el diagnóstico son necesarios métodos de diagnóstico por imágenes; los más utilizados son la ecografía Doppler y la angiotomografía. El tratamiento se basa en la intervención quirúrgica, la antibioticoterapia y la anticoagulación. Esta última tiene indicación controvertida, pero podría mejorar el pronóstico y disminuir la morbimortalidad. Se presenta un caso clínico de pileflebitis secundaria a sepsis por Escherichia coli con punto de partida en una apendicitis aguda, en un paciente pediátrico que evoluciona a la transformación cavernomatosa de la vena porta. Es de importancia conocer el manejo de esta entidad, ya que, una vez superado el cuadro inicial, requerirá un minucioso seguimiento por la posibilidad de evolucionar a la insuficiencia hepática.

Pylephlebitis is defined as suppurative thrombosis of the portal vein as a complication of abdominal infections. In pediatrics, the most frequent etiology is appendicitis, generally of late diagnosis, presenting as sepsis, with a high mortality rate. Imaging methods are necessary for diagnosis; the most common are the Doppler ultrasound and computed tomography angiography. Treatment is based on surgery, antibiotic therapy, and anticoagulation. The indication for the latter is controversial, but it may improve prognosis and decrease morbidity and mortality. Here we describe a clinical case of pylephlebitis secondary to Escherichia coli sepsis, which started as acute appendicitis in a pediatric patient who progressed to cavernomatous transformation of the portal vein. It is important to know the management of this disease because, once the initial symptoms are overcome, it will require close follow-up due to a potential progression to liver failure.

Perceived Reportability of Intimate Partner Violence against Women to the Police and Help-seeking: A National Survey.

The literature has consistently found that victims of intimate partner violence (IPV) against women are reluctant to make their situation visible and report it to the police. Whether victims perceive and define IPV behaviors as reportable is key to understanding in which cases the police are seen as potential providers of help or whether other potential sources of help (family, friends, professionals, etc.) are preferred. The purpose of the present study was to analyze the influence of perceived reportability of IPV on women's selection of the police as a source of help compared to not seeking help or selecting other sources of help. Structural equation modeling was applied to data from 479 female participants drawn from a nationally representative sample of 1,112 male and female Chilean adolescents and young adults conducted by the National Youth Institute of Chile. The results showed that perceived reportability was a significant predictor of choosing the police as a source of help compared to other informal sources of help, such as family and friends. However, perceived reportability did not affect help-seeking choices between the police and other formal help sources (psychologists, public services). Participants' IPV victimization and attitudes toward IPV also played a specific role in selecting the police as a source of help. These findings highlight the complexity of the visibility of women's IPV victimization to the police and the need to examine its explanatory mechanisms.

Las publicaciones científicas señalan sistemáticamente la reticencia de las víctimas de violencia de pareja contra las mujeres a hacer visible su situación y denunciarla ante la policía. El hecho de que las víctimas perciban y definan las conductas de violencia de pareja como denunciables es clave para comprender en qué casos se considera a la policía como posible proveedora de ayuda o si se prefieren otros potenciales proveedores de ayuda (familiares, amigos, especialistas, etc.). El objetivo de la presente investigación ha sido analizar la influencia de la percepción de la capacidad de denunciar la violencia de pareja en la selección de la policía como proveedora de ayuda por parte de las mujeres, en comparación con la falta de búsqueda de ayuda o la selección de otros proveedores de la misma. Se han analizado los datos de 479 mujeres participantes en el estudio de una muestra representativa nacional de 1,112 adolescentes y jóvenes chilenos de ambos sexos realizado por el Instituto Nacional de la Juventud de Chile. Los resultados mostraron que la capacidad de denuncia percibida predice la selección de la policía como proveedor de ayuda en comparación con otras fuentes informales de ayuda, como la familia o los amigos. Sin embargo, no pareció tener efecto en la selección de la búsqueda de ayuda comparar a la policía con otras fuentes formales de ayuda (psicólogos, servicios públicos). La victimización y las actitudes hacia la violencia de pareja también desempeñan un papel específico en la selección de la policía como proveedora de ayuda. Los resultados demuestran la complejidad de la visibilidad para la policía de la violencia en la pareja contra las mujeres y la necesidad de examinar sus mecanismos explicativos.

Perceived Reportability of Intimate Partner Violence against Women to the Police and Help-seeking: A National Survey / [La percepción de la capacidad de denunciar la violencia de pareja contra la mujer ante la policía y búsqueda de ayuda: una encuesta nacional]

The literature has consistently found that victims of intimate partner violence (IPV) against women are reluctant to make their situation visible and report it to the police. Whether victims perceive and define IPV behaviors as reportable is key to understanding in which cases the police are seen as potential providers of help or whether other potential sources of help (family, friends, professionals, etc.) are preferred. The purpose of the present study was to analyze the influence of perceived reportability of IPV on women’s selection of the police as a source of help compared to not seeking help or selecting other sources of help. Structural equation modeling was applied to data from 479 female participants drawn from a nationally representative sample of 1,112 male and female Chilean adolescents and young adults conducted by the National Youth Institute of Chile. The results showed that perceived reportability was a significant predictor of choosing the police as a source of help compared to other informal sources of help, such as family and friends. However, perceived reportability did not affect help-seeking choices between the police and other formal help sources (psychologists, public services). Participants’ IPV victimization and attitudes toward IPV also played a specific role in selecting the police as a source of help. These findings highlight the complexity of the visibility of women’s IPV victimization to the police and the need to examine its explanatory mechanisms.(AU)

Las publicaciones científicas señalan sistemáticamente la reticencia de las víctimas de violencia de pareja contra las mujeres a hacer visible su situación y denunciarla ante la policía. El hecho de que las víctimas perciban y definan las conductas de violencia de pareja como denunciables es clave para comprender en qué casos se considera a la policía como posible proveedora de ayuda o si se prefieren otros potenciales proveedores de ayuda (familiares, amigos, especialistas, etc.). El objetivo de la presente investigación ha sido analizar la influencia de la percepción de la capacidad de denunciar la violencia de pareja en la selección de la policía como proveedora de ayuda por parte de las mujeres, en comparación con la falta de búsqueda de ayuda o la selección de otros proveedores de la misma. Se han analizado los datos de 479 mujeres participantes en el estudio de una muestra representativa nacional de 1,112 adolescentes y jóvenes chilenos de ambos sexos realizado por el Instituto Nacional de la Juventud de Chile. Los resultados mostraron que la capacidad de denuncia percibida predice la selección de la policía como proveedor de ayuda en comparación con otras fuentes informales de ayuda, como la familia o los amigos. Sin embargo, no pareció tener efecto en la selección de la búsqueda de ayuda comparar a la policía con otras fuentes formales de ayuda (psicólogos, servicios públicos). La victimización y las actitudes hacia la violencia de pareja también desempeñan un papel específico en la selección de la policía como proveedora de ayuda. Los resultados demuestran la complejidad de la visibilidad para la policía de la violencia en la pareja contra las mujeres y la necesidad de examinar sus mecanismos explicativos.(AU)

Pylephlebitis in pediatrics: A diagnostic challenge. / Pileflebitis en pediatría: un desafío diagnóstico.

Pylephlebitis is defined as suppurative thrombosis of the portal vein as a complication of abdominal infections. In pediatrics, the most frequent etiology is appendicitis, generally of late diagnosis, presenting as sepsis, with a high mortality rate. Imaging methods are necessary for diagnosis; the most common are the Doppler ultrasound and computed tomography angiography. Treatment is based on surgery, antibiotic therapy, and anticoagulation. The indication for the latter is controversial, but it may improve prognosis and decrease morbidity and mortality. Here we describe a clinical case of pylephlebitis secondary to Escherichia coli sepsis, which started as acute appendicitis in a pediatric patient who progressed to cavernomatous transformation of the portal vein. It is important to know the management of this disease because, once the initial symptoms are overcome, it will require close follow-up due to a potential progression to liver failure.

La pileflebitis es definida como la trombosis supurativa de la vena porta como complicación de infecciones abdominales. En pediatría, la etiología más frecuente es la apendicitis, generalmente de diagnóstico tardío, que se presenta como sepsis, con una elevada mortalidad. Para el diagnóstico son necesarios métodos de diagnóstico por imágenes; los más utilizados son la ecografía Doppler y la angiotomografía. El tratamiento se basa en la intervención quirúrgica, la antibioticoterapia y la anticoagulación. Esta última tiene indicación controvertida, pero podría mejorar el pronóstico y disminuir la morbimortalidad. Se presenta un caso clínico de pileflebitis secundaria a sepsis por Escherichia coli con punto de partida en una apendicitis aguda, en un paciente pediátrico que evoluciona a la transformación cavernomatosa de la vena porta. Es de importancia conocer el manejo de esta entidad, ya que, una vez superado el cuadro inicial, requerirá un minucioso seguimiento por la posibilidad de evolucionar a la insuficiencia hepática.

Absceso de Brodie en la clavícula: una forma poco frecuente de presentación / Brodie abscess in the clavicle: an uncommon presentation

La osteomielitis (OM) se define como la inflamación ósea de origen infeccioso. La forma aguda es frecuente en la edad pediátrica. El absceso de Brodie es un tipo de osteomielitis subaguda, históricamente con baja incidencia, pero que actualmente se presenta un aumento de la misma. De poca repercusión clínica, con pruebas de laboratorio inespecíficas y estudios radiológicos de difícil interpretación, es crucial la sospecha diagnóstica. Se asemeja a procesos neoplásicos, benignos o malignos. Recae en la experiencia del profesional realizar el diagnóstico adecuado. El tratamiento consiste en antibioticoterapia, tanto parenteral como por vía oral, y eventualmente drenaje quirúrgico. Presentamos una paciente sana que consultó por una tumoración en topografía de clavícula izquierda de 3 meses de evolución. Se realizó diagnóstico de absceso de Brodie, inició tratamiento y se obtuvo una buena respuesta. Resulta imprescindible tener un alto índice de sospecha de esta entidad para no someter al paciente a estudios, pruebas invasivas o tratamientos erróneos, y evitar secuelas a futuro.

Osteomyelitis is defined as an inflammation of the bone caused by infection. Acute osteomyelitis is common in pediatrics. A Brodie abscess is a type of subacute osteomyelitis, with a historically low incidence; however, its incidence is currently increasing. Given its little clinical impact, with non-specific laboratory tests and radiological studies of difficult interpretation, diagnostic suspicion is crucial. It resembles neoplasms, either benign or malignant. An adequate diagnosis falls on the health care provider's experience. Treatment consists of antibiotics, both parenteral and oral, with potential surgical drainage. Here we describe the case of a healthy female patient with a tumor found in the topography of the left clavicle 3 months before. She was diagnosed with Brodie abscess; treatment was started with a good response. A high index of suspicion of Brodie abscess is critical to avoid invasive tests and studies or inadequate treatments, and to prevent future sequelae.

A novel palladium complex with a coumarin-thiosemicarbazone hybrid ligand inhibits Trypanosoma cruzi release from host cells and lowers the parasitemia in vivo.

In this work, two analogous coumarin-thio and semicarbazone hybrid compounds were prepared and evaluated as a potential antichagasic agents. Furthermore, palladium and platinum complexes with the thiosemicarbazone derivative as ligand (L1) were obtained in order to establish the effect of metal complexation on the antiparasitic activity. All compounds were fully characterized both in solution and in solid state including the resolution of the crystal structure of the palladium complex by X-ray diffraction methods. Unexpectedly, all experimental and theoretical characterizations in the solid state, demonstrated that the obtained palladium and platinum complexes are structurally different: [PdCl(L1)] and [PtCl2(HL1)]. All the studied compounds lower the proliferation of the amastigote form of Trypanosoma cruzi while some of them also have an effect on the trypomastigote stage. Additionally, the compounds inhibit T. cruzi release from host cells in variable extents. The Pd compound presented a remarkable profile in all the in vitro experiments, and it showed no toxicity for mammalian cells in the assayed concentrations. In this sense, in vivo experiments were performed for this compound using an acute model of Chagas disease. Results showed that the complex significantly lowered the parasite count in the mice blood with no significant toxicity.

89Zr-DFO-Isatuximab for CD38-Targeted ImmunoPET Imaging of Multiple Myeloma and Lymphomas.

Multiple myeloma (MM) is the second most prevalent hematological malignancy. It remains incurable despite the availability of novel therapeutic approaches, marking an urgent need for new agents for noninvasive targeted imaging of MM lesions. CD38 has proven to be an excellent biomarker due to its high expression in aberrant lymphoid and myeloid cells relative to normal cell populations. Using isatuximab (Sanofi), the latest FDA-approved CD38-targeting antibody, we have developed Zirconium-89(89Zr)-labeled isatuximab as a novel immunoPET tracer for the in vivo delineation of MM and evaluated the extension of its applicability to lymphomas. In vitro studies validated the high binding affinity and specificity of 89Zr-DFO-isatuximab for CD38. PET imaging demonstrated the high performance of 89Zr-DFO-isatuximab as a targeted imaging agent to delineate tumor burden in disseminated models of MM and Burkitt's lymphoma. Ex vivo biodistribution studies confirmed that high accumulations of the tracer in bone marrow and bone skeleton correspond to specific disease lesions as they are reduced to background in blocking and healthy controls. This work demonstrates the promise of 89Zr-DFO-isatuximab as an immunoPET tracer for CD38-targeted imaging of MM and certain lymphomas. More importantly, its potential as an alternative to 89Zr-DFO-daratumumab holds great clinical relevance.

Craniofacial Fibrous Dysplasia: Surgical Management and Long-Term Outcomes at a Referral Center in Mexico City.

Background Craniofacial fibrous dysplasia (CFD) is an uncommon benign condition in which a bone is replaced by fibrous tissue. An adequate clinical characterization considering the number of affected bones and functional impairment is important to determine the most effective surgical intervention for its management. This study aims to present our institution's experience in the evaluation and management of CFD. Methods This was a retrospective study that included patients with CFD managed at our institution. Data included demographic characteristics, afflicted bones, surgical procedures performed, and recurrence. Results are presented as mean and percentages. Recurrence-free years and association between the type of surgery and recurrence was evaluated. Results Eighteen patients were included (11 females, 61%). The zygomatic, maxillary, and frontal bones were the most commonly affected with eight (18%) cases each. The most common procedure was bone burring, with 36 procedures. Recurrence was more prevalent after burring (58.3%) and occurred earlier than in the bone resection group (13 vs. 15 years, p > 0.05). Conclusion Surgery continues to be the cornerstone of CFD treatment. Bone burring is effective for debulking and contouring but increases the risk for recurrence. An individualized approach should be tailored according to the anatomical location of the disease, type of CFD, behavior of the lesion, and accompanying clinical complaints.

Development of Copper Complexes with Diimines and Dipicolinate as Anticancer Cytotoxic Agents.

Coordination complexes may act as anticancer agents. Among others, the formation of the complex may facilitate the ligand uptake by the cell. Searching for new copper compounds with cytotoxic activity, the complex Cu-dipicolinate was studied as a neutral scaffold to form ternary complexes with diimines. A series of [Cu(dipicolinate)(diimine)] complexes (where diimine: Phenanthroline, phen, 5-NO2-phenanthroline, 4-methyl-phenanthroline, neocuproine, 3,4,7,8-tetramethyl-phenanthroline, tmp, bathophenanthroline, bipyridine, dimethyl-bipyridine, as well as the ligand 2,2-dipyridil-amine, bam) were synthesized and characterized both in the solid state, including a new crystal structure of [Cu2(dipicolinate)2(tmp)2]·7H2O. Their chemistry in aqueous solution was explored by UV/vis spectroscopy, conductivity, cyclic voltammetry, and electron paramagnetic resonance studies. Their DNA binding was analyzed by electronic spectroscopy (determining Kb values), circular dichroism, and viscosity methods. The cytotoxicity of the complexes was assessed on human cancer cell lines MDA-MB-231, MCF-7 (breast, the first triple negative), A549 (lung epithelial) and A2780cis (ovarian, Cisplatin-resistant), and non-tumor cell lines MRC-5 (lung) and MCF-10A (breast). The major species are ternary, in solution and solid state. Complexes are highly cytotoxic as compared to Cisplatin. Complexes containing bam and phen are interesting candidates to study their in vivo activity in triple-negative breast cancer treatment.

Novel Adamantane-Linked Isothiourea Derivatives as Potential Chemotherapeutic Agents: Synthesis, Structural Insights, and Antimicrobial/Anti-Proliferative Profiles.

In this study, two adamantane-linked isothiourea derivatives containing a common 4-chlorophenyl substituent coupled with 4-nitrobenzyl or 4-bromobenzyl moieties were synthesized. Both derivatives were characterized, in the solid state and in solution, through a synergistic combination of experimental and in silico techniques, and the results are of great value for the chemical and structural characterization of related compounds. The crystal structures of both derivatives were analyzed in depth, including Hirshfeld surface analysis and lattice energy calculations, revealing a predominant dispersive component of the total energy that stabilizes crystal packing. Both compounds showed potent broad-spectrum antibacterial activity and moderate activity against the pathogenic fungus Candida albicans. In addition, in vitro anti-proliferative activity assays showed that the 4-bromobenzyl analogue displays higher activity than the 4-nitrobenzyl one, with IC50 values under 30 µM against five human cancer cell lines. Our results give evidence of the potential of the adamantane/isothiourea combination to render auspicious scaffolds for new potential chemotherapeutic agents.

Ciguatoxin-like toxicity distribution in flesh of amberjack (Seriola spp.) and dusky grouper (Epinephelus marginatus).

Ciguatoxins (CTXs) are marine neurotoxins that cause ciguatera poisoning (CP), mainly through the consumption of fish. The distribution of CTXs in fish is known to be unequal. Studies have shown that viscera accumulate more toxins than muscle, but little has been conducted on toxicity distribution in the flesh, which is the main edible part of fish, and the caudal muscle is also most commonly targeted for the monitoring of CTXs in the Canary Islands. At present, whether this sample is representative of the toxicity of an individual is undisclosed. This study aims to assess the distribution of CTXs in fish, considering different muscle samples, the liver, and gonads. To this end, tissues from four amberjacks (Seriola spp.) and four dusky groupers (Epinephelus marginatus), over 16.5 kg and captured in the Canary Islands, were analyzed by neuroblastoma-2a cell-based assay. Flesh samples were collected from the extraocular region (EM), head (HM), and different areas from the fillet (A-D). In the amberjack, the EM was the most toxic muscle (1.510 CTX1B Eq·g-1), followed by far for the caudal section of the fillet (D) (0.906 CTX1B Eq·g-1). In the dusky grouper flesh samples, D and EM showed the highest toxicity (0.279 and 0.273 CTX1B Eq·g-1). In both species, HM was one of the least toxic samples (0.421 and 0.166 CTX1B Eq·g-1). The liver stood out for its high CTX concentration (3.643 and 2.718 CTX1B Eq·g-1), as were the gonads (1.620 and 0.992 CTX1B Eq·g-1). According to these results, the caudal muscle next to the tail is a reliable part for use in determining the toxicity of fish flesh to guarantee its safe consumption. Additionally, the analysis of the liver and gonads could provide further information on doubtful specimens, and be used for CTX monitoring in areas with an unknown prevalence of ciguatera.

Brodie abscess in the clavicle: an uncommon presentation. / Absceso de Brodie en la clavícula: una forma poco frecuente de presentación.

Osteomyelitis is defined as an inflammation of the bone caused by infection. Acute osteomyelitis is common in pediatrics. A Brodie abscess is a type of subacute osteomyelitis, with a historically low incidence; however, its incidence is currently increasing. Given its little clinical impact, with non-specific laboratory tests and radiological studies of difficult interpretation, diagnostic suspicion is crucial. It resembles neoplasms, either benign or malignant. An adequate diagnosis falls on the health care provider's experience. Treatment consists of antibiotics, both parenteral and oral, with potential surgical drainage. Here we describe the case of a healthy female patient with a tumor found in the topography of the left clavicle 3 months before. She was diagnosed with Brodie abscess; treatment was started with a good response. A high index of suspicion of Brodie abscess is critical to avoid invasive tests and studies or inadequate treatments, and to prevent future sequelae.

La osteomielitis (OM) se define como la inflamación ósea de origen infeccioso. La forma aguda es frecuente en la edad pediátrica. El absceso de Brodie es un tipo de osteomielitis subaguda, históricamente con baja incidencia, pero que actualmente se presenta un aumento de la misma. De poca repercusión clínica, con pruebas de laboratorio inespecíficas y estudios radiológicos de difícil interpretación, es crucial la sospecha diagnóstica. Se asemeja a procesos neoplásicos, benignos o malignos. Recae en la experiencia del profesional realizar el diagnóstico adecuado. El tratamiento consiste en antibioticoterapia, tanto parenteral como por vía oral, y eventualmente drenaje quirúrgico. Presentamos una paciente sana que consultó por una tumoración en topografía de clavícula izquierda de 3 meses de evolución. Se realizó diagnóstico de absceso de Brodie, inició tratamiento y se obtuvo una buena respuesta. Resulta imprescindible tener un alto índice de sospecha de esta entidad para no someter al paciente a estudios, pruebas invasivas o tratamientos erróneos, y evitar secuelas a futuro.

Luminescent Carbon Nanodots Doped with Gadolinium (III): Purification Criteria, Chemical and Biological Characterization of a New Dual Fluorescence/MR Imaging Agent.

Carbon Dots (CDs) are luminescent quasi-spherical nanoparticles, possessing water solubility, high biocompatibility, and tunable chemical and physical properties for a wide range of applications, including nanomedicine and theranostics. The evaluation of new purification criteria, useful to achieve more reliable CDs, free from the interference of artifacts, is currently an object of debate in the field. Here, new CDs doped with gadolinium (Gd (III)), named Gd@CNDs, are presented as multifunctional probes for Magnetic Resonance Imaging (MRI). This new system is a case of study, to evaluate and/or combine different purification strategies, as a crucial approach to generate CDs with a better performance. Indeed, these new amorphous Gd@CNDs display good homogeneity, and they are free from emissive side products. Gd@CNDs (7-10 nm) contain 7% of Gd (III) w/w, display suitable and stable longitudinal relaxivity (r1 ) and with emissive behavior, therefore potentially useful for both MR and fluorescence imaging. They show good biocompatibility in both cellular and in vivo studies, cell permeability, and the ability to generate contrast in cellular pellets. Finally, MRI recording T1 -weighted images on mice after intravenous injection of Gd@CNDs, show signal enhancement in the liver, spleen, and kidney 30 min postinjection.

New Copper(II)-L-Dipeptide-Bathophenanthroline Complexes as Potential Anticancer Agents-Synthesis, Characterization and Cytotoxicity Studies-And Comparative DNA-Binding Study of Related Phen Complexes.

Searching for new copper compounds which may be useful as antitumor drugs, a series of new [Cu(L-dipeptide)(batho)] (batho:4,7-diphenyl-1,10-phenanthroline, L-dipeptide: Gly-Val, Gly-Phe, Ala-Gly, Ala-Ala, Ala-Phe, Phe-Ala, Phe-Val and Phe-Phe) complexes were synthesized and characterized. To interpret the experimental IR spectra, [Cu(ala-gly)(batho)] was modelled in the gas phase using DFT at the B3LYP/LANL2DZ level of theory and the calculated vibrational frequencies were analyzed. Solid-state characterization is in agreement with pentacoordinate complexes of the general formula [Cu(L-dipeptide)(batho)]·x solvent, similar to other [Cu(L-dipeptide)(diimine)] complexes. In solution, the major species are heteroleptic, as in the solid state. The mode of binding to the DNA was evaluated by different techniques, to understand the role of the diimine and the dipeptide. To this end, studies were also performed with complexes [CuCl2(diimine)], [Cu(L-dipeptide)(diimine)] and free diimines, with phenanthroline, neocuproine and 3,4,7,8-tetramethyl-phenanthroline. The cytotoxicity of the complexes was determined on human cancer cell lines MDA-MB-231, MCF-7 (breast, the first triple negative), and A549 (lung epithelial) and non-tumor cell lines MRC-5 (lung) and MCF-10A (breast). [Cu(L-dipeptide)(batho)] complexes are highly cytotoxic as compared to cisplatin and [Cu(L-dipeptide)(phenanthroline)] complexes, being potential candidates to study their in vivo activity in the treatments of aggressive tumors for which there is no curative pharmacological treatment.

Metabolic Hepatic Disorders Caused by Ciguatoxins in Goldfish (Carassius auratus).

Ciguatera poisoning (CP) is a foodborne disease known for centuries; however, little research has been conducted on the effects of ciguatoxins (CTXs) on fish metabolism. The main objective of this study was to assess different hepatic compounds observed in goldfish (Carassius auratus) fed C-CTX1 using nuclear magnetic resonance (NMR)-based metabolomics. Thirteen goldfish were treated with C-CTX1-enriched flesh and sampled on days 1, 8, 15, 29, 36, and 43. On day 43, two individuals, referred to as 'Detox', were isolated until days 102 and 121 to evaluate the possible recovery after returning to a commercial feed. At each sampling, hepatic tissue was weighed to calculate the hepatosomatic index (HSI) and analyzed for the metabolomics study; animals fed toxic flesh showed a higher HSI, even greater in the 'Detox' individuals. Furthermore, altered concentrations of alanine, lactate, taurine, glucose, and glycogen were observed in animals with the toxic diet. These disturbances could be related to an increase in ammonium ion (NH4+) production. An increase in ammonia (NH3) concentration in water was observed in the aquarium where the fish ingested toxic meat compared to the non-toxic aquarium. All these changes may be rationalized by the relationship between CTXs and the glucose-alanine cycle.

Calcitriol decreases HIV-1 transfer in vitro from monocyte-derived dendritic cells to CD4 + T cells, and downregulates the expression of DC-SIGN and SIGLEC-1.

Dendritic cells (DCs) promote HIV-1 transmission by acting as Trojan horses, capturing viral particles, facilitating the infection of CD4+ T-cells. Vitamin D (VitD) has shown to decrease T cell activation, reducing susceptibility to HIV-1 infection of CD4+ T-cells in vitro; however, if VitD decreases viral transfer from DCs to CD4+ T-cells is unknown. In this study, we co-cultured HIV-1-pulsed immature and LPS mature monocytes-derived DCs (iDCs and LmDCs, respectively), differentiated in presence or absence of calcitriol (VitD active form), with PHA-activated autologous CD4+ T-cells from 16 healthy donors. In co-cultures of iDCs and LmDCs treated with calcitriol, there was a significant decrease in frequency of infected CD4+ T-cells, evaluated by flow cytometry. However, p24 levels evaluated by ELISA were not significantly reduced in culture supernatants. Moreover, calcitriol-treated iDCs exhibited decreased expression of genes involved in HIV-1 transfer compared to the control. Both, calcitriol-treated iDCs and LmDCs exhibit a similar gene expression profile, probably related to a transcriptional balance achieved after long treatment with calcitriol. Since calcitriol-differentiated DCs express on their surface a lower amount of DC-SIGN and SIGLEC-1 molecules, widely associated with HIV-1 transfer, suggesting that this mechanism contributes to a lower transfer of viral particles by the DCs.

Kinetics of the invasion of a non-phagocytic fish cell line, RTG-2 by Yersinia ruckeri serotype O1 biotype 1.

Yersiniosis, caused by the fish pathogen Yersinia ruckeri, is a serious bacterial septicaemia affecting mainly salmonids worldwide. The acute infection may result in high mortality without apparent external disease signs, while the chronic one causes moderate to considerable mortality. Survivors of yersiniosis outbreaks become carriers. Y. ruckeri is able to adhere to, and to invade, phagocytic and non-phagocytic fish cells by using unknown molecular mechanisms. The aim of this study was to describe the kinetics of cell invasion by Y. ruckeri serotype O1 biotype 1 in a fish cell line (RTG-2) originating from rainbow trout gonads. The efficiency of invasion by Y. ruckeri was found to be temperature dependent, having a maximum at 20 °C. The bacterium was able to survive up to 96 h postinfection. The incubation of the cells at 4 °C and the pre-incubation of the bacteria with sugars or heat-inactivated antiserum significantly decreased the efficiency of invasion or even completely prevented the invasion of RTG-2 cells. These findings indicate that Y. ruckeri is capable of adhering to, entering and surviving within non-phagocytic cells, and that the intracellular environment may constitute a suitable niche for this pathogen that can favour the spread of infection and/or the maintenance of a carrier state of fish.

Global PBDE contamination in cetaceans. A critical review.

This review summarizes the most relevant information on PBDEs' occurrence and their impacts in cetaceans at global scale, with special attention on the species with the highest reported levels and therefore the most potentially impacted by the current and continuous release of these substances. This review also emphasizes the anthropogenic and environmental factors that could increase concentrations and associated risks for these species in the next future. High PBDE concentrations above the toxicity threshold and stationary trends have been related to continuous import of PBDE-containing products in cetaceans of Brazil and Australia, where PBDEs have never been produced. Non-decreasing levels documented in cetaceans from the Northwest Pacific Ocean might be linked to the increased e-waste import and ongoing production and use of deca-BDE that is still allowed in China. Moreover, high levels of PBDEs in some endangered species such as beluga whales (Delphinapterus leucas) in St. Lawrence Estuary and Southern Resident killer whales (Orcinus Orca) are influenced by the discharge of contaminated waters deriving from wastewater treatment plants. Climate change related processes such as enhanced long-range transport, re-emissions from secondary sources and shifts in migration habits could lead to greater exposure and accumulation of PBDEs in cetaceans, above all in those species living in the Arctic. In addition, increased rainfall could carry greater amount of contaminants to the marine environment, thereby, enhancing the exposure and accumulation especially for coastal species. Synergic effects of all these factors and ongoing emissions of PBDEs, expected to continue at least until 2050, could increase the degree of exposure and menace for cetacean populations. In this regard, it is necessary to improve current regulations on PBDEs and broader the knowledge about their toxicological effects, in order to assess health risks and support regulatory protection for cetacean species.

Tetramethyl-phenanthroline copper complexes in the development of drugs to treat cancer: synthesis, characterization and cytotoxicity studies of a series of copper(II)-L-dipeptide-3,4,7,8-tetramethyl-phenanthroline complexes.

New compounds to fight cancer are needed due to cancer high incidence and lack of curative treatments for several classes of this disease. Metal-based coordination compounds offer a variety of molecules that can turn into drugs. Among them, coordination copper complexes are emerging as an attractive class of compounds for cancer treatment. A series of [Cu(L-dipeptide)(tmp)] (tmp = 3,4,7,8-tetramethyl-1,10-phenanthroline) complexes were synthesized and characterized in the solid state, including the determination of the crystalline structure of [Cu(Gly-Gly)(tmp)]·3.5 H2O and [Cu2Cl4(tmp)2]. The complexes were studied in solution, where the major species are also ternary ones. The lipophilicity of the complexes was determined and the binding to the DNA was evaluated, suggesting that it occurs in the DNA's major groove. The cytotoxicity of the complexes was evaluated on different cancer cell lines: human metastatic breast adenocarcinoma MDA-MB-231 (triple negative, ATCC: HTB-26), MCF-7 (ATCC: HTB-22), SK-BR-3 (ATCC: HTB-30), human lung epithelial carcinoma A549 (ATCC: CCL-185), cisplatin resistant-human ovarian carcinoma A2780cis (SIGMA) and nontumoral cell lines: MRC-5 (lung; ATCC: CCL-171) and MCF-10A (breast, ATCC: CRL-10317). [Cu(L-dipeptide)(tmp)] complexes are highly cytotoxic as compared to [Cu(L-dipeptide)(phenanthroline)] and cisplatin. Therefore, [Cu(L-dipeptide)(tmp)] complexes are promising candidates to have their in vivo activity further studied toward new treatments for triple negative breast cancer and other aggressive tumors for which there is no curative pharmacological treatment to the date.