First Detection of Algal Caribbean Ciguatoxin in Amberjack Causing Ciguatera Poisoning in the Canary Islands (Spain).

Ciguatera Poisoning (CP) is an illness associated with the consumption of fish contaminated with potent natural toxins found in the marine environment, commonly known as ciguatoxins (CTXs). The risk characterization of CP has become a worldwide concern due to the widespread expansion of these natural toxins. The identification of CTXs is hindered by the lack of commercially available reference materials. This limitation impedes progress in developing analytical tools and conducting toxicological studies essential for establishing regulatory levels for control. This study focuses on characterizing the CTX profile of an amberjack responsible for a recent CP case in the Canary Islands (Spain), located on the east Atlantic coast. The exceptional sensitivity offered by Capillary Liquid Chromatography coupled with High-Resolution Mass Spectrometry (cLC-HRMS) enabled the detection, for the first time in fish contaminated in the Canary Islands, of traces of an algal ciguatoxin recently identified in G. silvae and G. caribeaus from the Caribbean Sea. This algal toxin was structurally characterized by cLC-HRMS being initially identified as C-CTX5. The total toxin concentration of CTXs was eight times higher than the guidance level proposed by the Food and Drug Administration (0.1 ng C-CTX1/g fish tissue), with C-CTX1 and 17-hydroxy-C-CTX1 as major CTXs.

Cooperative Effects Drive Water Oxidation Catalysis in Cobalt Electrocatalysts through the Destabilization of Intermediates.

A barrier to understanding the factors driving catalysis in the oxygen evolution reaction (OER) is understanding multiple overlapping redox transitions in the OER catalysts. The complexity of these transitions obscure the relationship between the coverage of adsorbates and OER kinetics, leading to an experimental challenge in measuring activity descriptors, such as binding energies, as well as adsorbate interactions, which may destabilize intermediates and modulate their binding energies. Herein, we utilize a newly designed optical spectroelectrochemistry system to measure these phenomena in order to contrast the behavior of two electrocatalysts, cobalt oxyhydroxide (CoOOH) and cobalt-iron hexacyanoferrate (cobalt-iron Prussian blue, CoFe-PB). Three distinct optical spectra are observed in each catalyst, corresponding to three separate redox transitions, the last of which we show to be active for the OER using time-resolved spectroscopy and electrochemical mass spectroscopy. By combining predictions from density functional theory with parameters obtained from electroadsorption isotherms, we demonstrate that a destabilization of catalytic intermediates occurs with increasing coverage. In CoOOH, a strong (∼0.34 eV/monolayer) destabilization of a strongly bound catalytic intermediate is observed, leading to a potential offset between the accumulation of the intermediate and measurable O2 evolution. We contrast these data to CoFe-PB, where catalytic intermediate generation and O2 evolution onset coincide due to weaker binding and destabilization (∼0.19 eV/monolayer). By considering a correlation between activation energy and binding strength, we suggest that such adsorbate driven destabilization may account for a significant fraction of the observed OER catalytic activity in both materials. Finally, we disentangle the effects of adsorbate interactions on state coverages and kinetics to show how adsorbate interactions determine the observed Tafel slopes. Crucially, the case of CoFe-PB shows that, even where interactions are weaker, adsorption remains non-Nernstian, which strongly influences the observed Tafel slope.

Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial.

Mucosal (MM) and acral melanomas (AM) are rare melanoma subtypes of unmet clinical need; 15%-20% harbor KIT mutations potentially targeted by small-molecule inhibitors, but none yet approved in melanoma. This multicenter, single-arm Phase II trial (NICAM) investigates nilotinib safety and activity in KIT mutated metastatic MM and AM. KIT mutations are identified in 39/219 screened patients (18%); of 29/39 treated, 26 are evaluable for primary analysis. Six patients were alive and progression free at 6 months (local radiology review, 25%); 5/26 (19%) had objective response at 12 weeks; median OS was 7.7 months; ddPCR assay correctly identifies KIT alterations in circulating tumor DNA (ctDNA) in 16/17 patients. Nilotinib is active in KIT-mutant AM and MM, comparable to other KIT inhibitors, with demonstrable activity in nonhotspot KIT mutations, supporting broadening of KIT evaluation in AM and MM. Our results endorse further investigations of nilotinib for the treatment of KIT-mutated melanoma. This clinical trial was registered with ISRCTN (ISRCTN39058880) and EudraCT (2009-012945-49).

Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity by replenishing diminished NAD+ with PARP inhibition. Although NAD+ was not affected, overexpressing SIRT3 with PARP inhibition fully restored hexokinase activity, correcting the glycolytic pathway in AR100Q quadriceps, and rescued motor endurance of SBMA mice. These data demonstrate that targeting metabolic anomalies can restore motor function downstream of polyQ-expanded AR.

Synthesis and characterization of highly diluted polyanionic iron(II) spin crossover systems.

Spin crossover (SCO) complexes, through their reversible spin transition under external stimuli, can work as switchable memory materials. Here, we present a protocol for the synthesis and characterization of a specific polyanionic iron SCO complex and its diluted systems. We describe steps for its synthesis and the determination of crystallographic structure of the SCO complex in diluted systems. We then detail a range of spectroscopic and magnetic techniques employed to monitor the spin state of the SCO complex in both diluted solid- and liquid-state systems. For complete details on the use and execution of this protocol, please refer to Galán-Mascaros et al.1.

Structural Characterization and Anticancer Activity of a New Anthraquinone from Senna velutina (Fabaceae).

In this study, a novel compound was isolated, identified, and its chemical structure was determined from the extract of the roots of Senna velutina. In addition, we sought to evaluate the anticancer potential of this molecule against melanoma and leukemic cell lines and identify the pathways of cell death involved. To this end, a novel anthraquinone was isolated from the barks of the roots of S. velutina, analyzed by HPLC-DAD, and its molecular structure was determined by nuclear magnetic resonance (NMR). Subsequently, their cytotoxic activity was evaluated by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) method against non-cancerous, melanoma, and leukemic cells. The migration of melanoma cells was evaluated by the scratch assay. The apoptosis process, caspase-3 activation, analysis of mitochondrial membrane potential, and measurement of ROS were evaluated by flow cytometry technique. In addition, the pharmacological cell death inhibitors NEC-1, RIP-1, BAPTA, Z-VAD, and Z-DEVD were used to confirm the related cell death mechanisms. With the results, it was possible to elucidate the novel compound characterized as 2'-OH-Torosaol I. In normal cells, the compound showed no cytotoxicity in PBMC but reduced the cell viability of all melanoma and leukemic cell lines evaluated. 2'-OH-Torosaol I inhibited chemotaxis of B16F10-Nex2, SK-Mel-19, SK-Mel-28 and SK-Mel-103. The cytotoxicity of the compound was induced by apoptosis via the intrinsic pathway with reduced mitochondrial membrane potential, increased levels of reactive oxygen species, and activation of caspase-3. In addition, the inhibitors demonstrated the involvement of necroptosis and Ca2+ in the death process and confirmed caspase-dependent apoptosis death as one of the main programmed cell death pathways induced by 2'-OH-Torosaol I. Taken together, the data characterize the novel anthraquinone 2'-OH-Torosaol I, demonstrating its anticancer activity and potential application in cancer therapy.

EuroClonality-NGS Recommendations for Evaluation of B-Cell Clonality Analysis by Next-Generation Sequencing: A Structured Approach with the DEPART Algorithm.

Next-generation sequencing (NGS)-based clonality analysis allows in-depth assessment of the clonal composition of a sample with high sensitivity for detecting small clones. Within the EuroClonality-NGS Working Group, a protocol for NGS Ig clonality analysis was developed and validated previously. This NGS-based approach was designed to generate small amplicons, making it suitable for samples with suboptimal DNA quality, especially material derived from formalin-fixed, paraffin-embedded tissue. Using expert assessment of NGS Ig clonality results as a reference, a structured algorithmic approach to the assessment of NGS-amplicon-based B-cell clonality analysis was developed. A structured approach with the Detection of clonality through Evaluation of sample quality and assessment of Pattern, Abundance and RaTio (DEPART) algorithm was proposed, which consecutively evaluates sample quality, the pattern of the clonotypes present, the abundance of the most dominant clonotypes, and the ratio between the dominant clonotypes and the background to evaluate the different Ig gene targets. Specific issues with respect to evaluation of the various Ig targets as well as the integration of results of individual targets into a molecular clonality conclusion are discussed and illustrated with case examples. Finally, the importance of interpretation of NGS-based clonality results in clinical and histopathologic contexts is discussed. It is expected that these recommendations will have clinical utility to facilitate proper evaluation of clonality assessment.

Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer Cells by a High-Affinity Benzimidazoisoquinoline.

Triple-negative breast cancer (TNBC) remains a disease with a paucity of targeted treatment opportunities. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is involved in a wide range of physiological processes, including the sensing of xenobiotics, immune function, development, and differentiation. Different small-molecule AhR ligands drive strikingly varied cellular and organismal responses. In certain cancers, AhR activation by select small molecules induces cell cycle arrest or apoptosis via activation of tumor-suppressive transcriptional programs. AhR is expressed in triple-negative breast cancers, presenting a tractable therapeutic opportunity. Here, we identify a novel ligand of the aryl hydrocarbon receptor that potently and selectively induces cell death in triple-negative breast cancer cells and TNBC stem cells via the AhR. Importantly, we found that this compound, Analog 523, exhibits minimal cytotoxicity against multiple normal human primary cells. Analog 523 represents a high-affinity AhR ligand with potential for future clinical translation as an anticancer agent.

Singular boundary behaviour and large solutions for fractional elliptic equations.

We perform a unified analysis for the boundary behaviour of solutions to nonlocal fractional equations posed in bounded domains. Based on previous findings for some models of the fractional Laplacian operator, we show how it strongly differs from the boundary behaviour of solutions to elliptic problems modelled upon the Laplace-Poisson equation with zero boundary data. In the classical case it is known that, at least in a suitable weak sense, solutions of the homogeneous Dirichlet problem with a forcing term tend to zero at the boundary. Limits of these solutions then produce solutions of some non-homogeneous Dirichlet problem as the interior data concentrate suitably to the boundary. Here, we show that, for equations driven by a wide class of nonlocal fractional operators, different blow-up phenomena may occur at the boundary of the domain. We describe such explosive behaviours and obtain precise quantitative estimates depending on simple parameters of the nonlocal operators. Our unifying technique is based on a careful study of the inverse operator in terms of the corresponding Green function.

Soil Microbiome Influences on Seedling Establishment and Growth of Prosopis chilensis and Prosopis tamarugo from Northern Chile.

Prosopis chilensis and Prosopis tamarugo, two woody legumes adapted to the arid regions of Chile, have a declining distribution due to the lack of new seedling establishment. This study investigated the potential of both species to establish in soil collected from four locations in Chile, within and outside the species distribution, and to assess the role of the root-colonizing microbiome in seedling establishment and growth. Seedling survival, height, and water potential were measured to assess establishment success and growth. 16S and ITS2 amplicon sequencing was used to characterize the composition of microbial communities from the different soils and to assess the ability of both Prosopis species to recruit bacteria and fungi from the different soils. Both species were established on three of the four soils. P. tamarugo seedlings showed significantly higher survival in foreign soils and maintained significantly higher water potential in Mediterranean soils. Amplicon sequencing showed that the four soils harbored distinct microbial communities. Root-associated microbial composition indicated that P. chilensis preferentially recruited mycorrhizal fungal partners while P. tamarugo recruited abundant bacteria with known salt-protective functions. Our results suggest that a combination of edaphic properties and microbial soil legacy are potential factors mediating the Prosopis establishment success in different soils.

Characterization of the Sensory Nerve Action Potential of the Sural Nerve in Patients Over 60 Years of Age without Peripheral Neuropathy.

Demonstration of the possibility to obtain the sensory nerve action potential (SNAP) of sural nerve in patients over 60 years old, without peripheral neuropathy. Prospective study on 101 patients older than 60 years of age. Stimulation was applied 12 cm proximal to the recording point. Two hundred and two SNAPs of the sural nerve were collected with an average peak latency of 3.2 ms, onset latency of 2.6 ms, peak-to-peak amplitude of 15.2 µV and velocity of 45.7 m/s. It was possible to obtain the sural nerve SNAP in all tested patients older than 60, without peripheral neuropathy. The values obtained in this study prove to be useful as a reference in the evaluation of patients older than 60 years of age.

Effect of processing parameters on texture and variant selection of as-built 300 maraging steel processed by laser powder bed fusion.

Among the materials that might be manufactured with laser powder bed fusion (LPBF), one can highlight maraging steels, with excellent weldability, strength and fracture toughness. However, the effects of the processing parameters and the mechanisms governing the as-built texture are not clear yet. A recent publication showed a low texture index in the prior austenite, in contrast to other alloys subjected to LPBF with the same strategy. Authors suggested several hypotheses, although no conclusions were drawn. This work aims to investigate these findings by using a 300 maraging steel processed under different conditions, i.e. different printer, powder layer thickness and laser emission mode. To do so, X-Ray Diffraction, Electron Backscattered Diffraction and Scanning Electron Microscopy have been used. Results show that the heat treatment intrinsic to the LPBF process does not affect the prior austenite grains, whose texture and morphology remain unchanged throughout the process. Also, for the studied ranges, the microstructure texture is not related to the powder layer thickness or to the laser emission mode, although it could be affected by the laser power or the scan strategy. Finally, a low degree of variant selection has been observed, where the selected variants are those that contribute to a martensite cubic rotated texture.

Bilateral Martin-Gruber and Marinacci Anastomosis Associated with Carpal Tunnel and Guyon's Canal Syndrome: Case Report.

Anastomoses between the median and ulnar nerves are commonly found on electrodiagnostic studies. These anastomoses are usually asymptomatic and are not discovered until nerve injuries occur that lead to unusual motor or sensory deficits. Their presence can cause difficulties in the interpretation of electrophysiological findings for the diagnosis of neuropathies and suppose a risk of iatrogenic damage during surgical procedures. We describe a rare case of bilateral Martin Gruber and Marinacci anastomosis, associated with median and ulnar nerve injuries in the carpal tunnel and Guyon's canal, respectively. The detailed anatomical knowledge of these anastomosis allows the electromyographist to identify them correctly, facilitating the interpretation of the findings and, incidentally, preventing iatrogenic injuries.

Design of a mobile application for home monitoring of babies with complex congenital heart disease / Diseño de una aplicación móvil para la monitorización domiciliaria de bebés con cardiopatías congénitas complejas / Projeto de um aplicativo móvel para monitoramento domiciliar de bebês com cardiopatias congênitas complexas

Introduction: Congenital heart diseases are related to heart defects that develop during pregnancy and are present at birth. Children must regularly attend specialized clinical centers for treatment, which includes medical check-ups, hemodynamic procedures, and surgery. Nevertheless, the success of interventions largely depends on the education of parents and caregivers about the symptoms and warning signs that babies with complex congenital heart disease may present during the period between stages. Likewise, it is necessary for caregivers to have tools to face the barriers of the health system, such as, obstacles or delays in obtaining healthcare services. This facilitates timely health care for patients and avoids fatal outcomes or deterioration in quality of life. Materials and Methods: This document presents a system that provides support to patients with complex congenital heart disease in follow-up by a home monitoring program. The system consists of a mobile application that allows parents/caregivers to monitor physiological variables of the patients (weight, intake, and oximetry). The information registered in the application is sent for real-time evaluation by the medical team. Results:The application provides an effective means for sending data and communicating with the medical control center, in addition to offering educational and informative material. In this way, parents/caregivers get constant help and feedback about their baby's condition. Conclusions: The mobile application could help mitigate the costs of medical care and overcome the limitations of follow-up at home, giving doctors the possibility to see the patient's evolution and give timely recommendations.

Introducción: Las cardiopatías congénitas están relacionadas con defectos cardíacos que se desarrollan durante el embarazo y están presentes al nacer. El éxito de las intervenciones depende en gran medida de la educación de los padres/cuidadores sobre los signos y síntomas de alerta. Los cuidadores necesitan tener herramientas para hacer frente a las barreras del sistema de salud. Objetivo: crear un sistema como herramienta de seguimiento para los bebés con cardiopatías congénitas complejas que ayude a los padres/cuidadores y a los profesionales médicos a observar las variables fisiológicas del paciente y a brindar una retroalimentación oportuna y profesional a los padres/cuidadores desde la atención domiciliaria. Materiales y métodos:se presenta un sistema que proporciona apoyo a los pacientes que necesitan seguimiento de cardiopatías congénitas complejas mediante un programa de monitoreo en casa. El sistema consiste en una aplicación móvil que permite a los padres/cuidadores controlar las variables fisiológicas del paciente (peso, ingesta de alimento y oximetría). La información registrada en la aplicación se envía para ser evaluada en tiempo real por el equipo médico. Resultados: la aplicación proporciona un medio eficaz para enviar datos y comunicarse con el centro de control médico, además de ofrecer material educativo e informativo. De este modo, los padres/cuidadores reciben constantemente ayuda e información acerca del estado de su bebé. Conclusiones: la aplicación móvil podría ayudar a minimizar los costos de la atención médica y superar las limitaciones del seguimiento domiciliario, dando a los médicos la posibilidad de ver la evolución del paciente y dar recomendaciones oportunas.

Introdução: as doenças cardíacas congênitas estão relacionadas a defeitos cardíacos que se desenvolvem durante a gravidez e estão presentes no nascimento. O sucesso das intervenções depende em grande parte da educação dos pais/responsáveis sobre os sinais e sintomas de alerta. Os cuidadores precisam ter ferramentas para lidar com as barreiras do sistema de saúde. Objetivo: Criar uma ferramenta de sistema de monitoramento para bebês com doenças cardíacas congênitas complexas, que ajude pais/cuidadores e profissionais médicos a observar as variáveis fisiológicas do paciente e manter um feedback profissional e oportuno para os pais/cuidadores dos cuidados domiciliares. Materiais e Métodos: é apresentado um sistema que fornece suporte aos pacientes com cardiopatias congênitas complexas em acompanhamento através de um programa de monitoramento domiciliar. O sistema consiste em uma aplicação móvel que permite aos pais/responsáveis pelo acompanhamento das variáveis fisiológicas do paciente (peso, ingestão e oximetria). As informações registradas no aplicativo são enviadas para serem avaliadas em tempo real pela equipe médica. Resultados: a aplicação fornece um meio eficiente para enviar dados e se comunicar com o centro de controle médico, além de oferecer material educativo e informativo. Desta forma, os pais/responsáveis recebem ajuda constante e feedback sobre a condição de seu bebê. Conclusões: a aplicação móvel pode ajudar a minimizar os custos do atendimento médico e superar as limitações do acompanhamento domiciliar, dando aos médicos a possibilidade de ver a evolução do paciente e dar recomendações oportunas.

TP53 Mutations Identified Using NGS Comprise the Overwhelming Majority of TP53 Disruptions in CLL: Results From a Multicentre Study.

Limited data exists to show the correlation of (tumour protein 53) TP53 mutation detected by Next generation sequencing (NGS) and the presence/absence of deletions of 17p13 detected by FISH. The study which is the largest series to date includes 2332 CLL patients referred for analysis of del(17p) by FISH and TP53 mutations by NGS before treatment. Using a 10% variant allele frequency (VAF) threshold, cases were segregated into high burden mutations (≥10%) and low burden mutations (<10%). TP53 aberrations (17p [del(17p)] and/or TP53 mutation) were detected in 320/2332 patients (13.7%). Using NGS analysis, 429 TP53 mutations were identified in 303 patients (13%). Of these 238 (79%) and 65 (21%) were cases with high burden and low burden mutations respectively. In our cohort, 2012 cases did not demonstrate a TP53 aberration (86.3%). A total of 159 cases showed TP53 mutations in the absence of del(17p) (49/159 with low burden TP53 mutations) and 144 cases had both TP53 mutation and del(17p) (16/144 with low burden mutations). Only 17/2332 (0.7%) cases demonstrated del(17p) with no TP53 mutation. Validated NGS protocols should be used in clinical decision making to avoid missing low-burden TP53 mutations and can detect the vast majority of TP53 aberrations.

Redefining the high-grade B cell lymphoma with double/triple rearrangements of MYC and BCL2/BCL6 genes. Learning from a case report.

We report a patient initially diagnosed with a triple hit high-grade B cell lymphoma (HGBL-TH), in which further morphologic, immunohistochemical, and next-generation sequencing studies of subsequent specimens disclosed it to be a germinal center diffuse large B cell lymphoma (GC-DLBCL) with BCL2/BCL6 gene translocations, PVT1-deletion, and gain of MYC genes evolving from a previous follicular lymphoma. However, fluorescence in situ hybridization (FISH) studies with the break-apart probe for MYC gene showed a fusion and two separated signals (red and green, respectively) leading to the interpretation of MYC gene translocation and a false diagnosis of a TH-lymphoma, according to the recent WHO classification. Nevertheless, PVT1 deletion plus MYC gain/amplification has been described as a cause of the double-hi transcription profile. These data highlight the need for new criteria to identify these highly aggressive lymphomas.

Metatranscriptomics captures dynamic shifts in mycorrhizal coordination in boreal forests.

Carbon storage and cycling in boreal forests-the largest terrestrial carbon store-is moderated by complex interactions between trees and soil microorganisms. However, existing methods limit our ability to predict how changes in environmental conditions will alter these associations and the essential ecosystem services they provide. To address this, we developed a metatranscriptomic approach to analyze the impact of nutrient enrichment on Norway spruce fine roots and the community structure, function, and tree-microbe coordination of over 350 root-associated fungal species. In response to altered nutrient status, host trees redefined their relationship with the fungal community by reducing sugar efflux carriers and enhancing defense processes. This resulted in a profound restructuring of the fungal community and a collapse in functional coordination between the tree and the dominant Basidiomycete species, and an increase in functional coordination with versatile Ascomycete species. As such, there was a functional shift in community dominance from Basidiomycetes species, with important roles in enzymatically cycling recalcitrant carbon, to Ascomycete species that have melanized cell walls that are highly resistant to degradation. These changes were accompanied by prominent shifts in transcriptional coordination between over 60 predicted fungal effectors, with more than 5,000 Norway spruce transcripts, providing mechanistic insight into the complex molecular dialogue coordinating host trees and their fungal partners. The host-microbe dynamics captured by this study functionally inform how these complex and sensitive biological relationships may mediate the carbon storage potential of boreal soils under changing nutrient conditions.

Genome of a novel Sediminibacterium discovered in association with two species of freshwater cyanobacteria from streams in Southern California.

Here, we report the discovery of a novel Sediminibacterium sequenced from laboratory cultures of freshwater stream cyanobacteria from sites in Southern California, grown in BG11 medium. Our genome-wide analyses reveal a highly contiguous and complete genome (97% BUSCO) that is placed within sediminibacterial clades in phylogenomic analyses. Functional annotation indicates the presence of genes that could be involved in mutualistic/commensal relationship with associated cyanobacterial hosts.