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IUCN WCPA was one of many sponsors supporting two important conservation congresses over the last few months. The World Wilderness Congress (WILD12) and the 10th International Rangers Federation World Ranger Congress (WRC10) brought together two groups on the frontline of conservation, Indigenous peoples and rangers, with parallel goals of fostering connections, building capacity and understanding and renewing hope and energy for reversing biodiversity loss. This short editorial essay provides an overview of both events and how they relate to the global decision-making around implementation of the Kunming-Montreal Global Biodiversity Framework.

Introduction Migrant women in transit face high risk of developing mental health problems such as depression and anxiety, driven by gendered social-structural factors including violence, social isolation, migration uncertainty, limited access to services and gender inequities. Although migrant women who endure such conditions have high need for mental health prevention, few evidence-based interventions are tailored to this population. Moreover, while women and children’s mental health are interconnected, few mental health interventions address parenting needs. The aim of this study is to pilot-test a novel parenting and mental health prevention intervention for migrant mothers with young children (MMC) in Tijuana, Mexico, including (a) assessing acceptability; (b) estimating effect sizes on symptoms of depression, anxiety, and parenting stress; (c) identifying which theory-based mechanisms of action predict changes in outcomes; and (d) identifying factors associated with differential intervention response.Methods and analysis ‘Mamá Empoderada’ (Mom Power) is a theory-based, trauma-informed group intervention to promote mental health and responsive parenting among mothers with young children (0–5 years). This is an evidence-based intervention that has been previously evaluated in the USA and has been recently adapted for Spanish-speaking mothers. We have recently adapted this intervention for MMC in Mexico and will conduct a pilot randomised controlled trial (RCT) of the intervention with MMC (n=100; Ntreatment=50; Ncontrol=50). The intervention group (IG) will receive 10 group and three individual sessions addressing attachment-based parenting skills, linkage to resources (eg, food, shelter), social support, and self-care and resilience over a 5-week period. The control group will receive standard of care programming and will be offered participation in the intervention following completion. Both groups will complete baseline and exit surveys, as well as follow-up surveys at 2, 4 and 6 months postintervention. Statistical analyses will compare primary (ie, symptoms of depression and anxiety; parenting stress) and intermediate outcomes (eg, resilience, service utilisation) by exposure to intervention condition.Ethics and dissemination This study is approved by the San Diego State University and El Colegio de la Frontera Norte Institutional Research Boards. Findings will inform a larger trial to evaluate intervention efficacy. In collaboration with our community partners, results will be disseminated via peer-reviewed publications; presentations; and plain-language reports, infographics, and presentations to community, clinical, and policy audiences. If efficacious, this intervention is highly promising as a novel, low-cost, and feasible model that could be implemented in border settings in Mexico, the USA and elsewhere. Amid rising population displacement and prolonged and traumatic migration journeys, this study addresses an urgent need for scalable and tailored mental health prevention for MMC in border contexts.Trial registration number NCT06468046.

En la provincia de La Pampa, Argentina, una parte importante del territorio se encuentra ocupada por bosques xerófilos de caldén. Estos bosques han sido objeto de un intenso proceso de degradación derivado de manejos silvícolas y ganaderos inadecuados, resultando en formaciones arbustizadas, de baja productividad, denominadas “fachinal”. Para aumentar la productividad de estos ambientes, asociado principalmente a la actividad ganadera y disminuir los riesgos de incendios, se realizan una serie de intervenciones como estrategia de manejo, de las cuales se generan un gran volumen de residuos forestales que no se utilizan o aprovechan. La bioeconomía circular es un marco que desafía la linealidad del modelo económico actual y propone el aprovechamiento de todos los residuos y derivados de las actividades productivas. El presente trabajo tiene como objetivo analizar económicamente el potencial aprovechamiento en campo de los residuos forestales derivados de las intervenciones en los bosques nativos de caldén. Las cantidades estimadas mínimas y máximas de residuos forestales potenciales de generación por distintas intervenciones oscilaron en 33,12 y 44,81 Mg.ha-1. Se estimaron los costos necesarios para poner los residuos a disposición; se calcularon indicadores económicos-financieros para determinar volúmenes necesarios para cubrir los costos y obtener beneficios. El aprovechamiento circular de los residuos forestales de los bosques nativos es factible, siempre y cuando se generen escalas viables y los precios de referencia sean atractivos para productores agropecuarios y agentes económicos involucrados.

Building materials used at the Former Workers Hospital of Maudes, Madrid (Spain) were studied. The study addressed the information both achieved from documental resources and characterization techniques. Documentary work has enabled to know about the architect thought, the ideology of the project or the grounds that conditioned such materials selection; it also permitted to learn about materials provenance and/or its elaboration. Analytical studies provided information about petrographic features of the materials and their composition; limestone provenance was confirmed and new data on material manufacture were provided. Such information, which deserves to be known and disseminated, provides a significant heritage value to materials that shape cultural assets. Studies with a multidisciplinary approach represent a commitment to improve the knowledge and conservation of heritage.

This special issue constitutes an excellent and representative testimony of the variety of contributions presented during YOCOCU 2016. The reader will find that the 41 papers in this special issue cover a wide range of materials (stone, gypsum, lime, mortar, ceramics, metal, paper, videos, textiles, paintings, plastics, pigments …), from different types of art and heritage: architectural and archaeological; contemporary and digital art; industrial heritage, vernacular, art caves and ethnographic heritage; museum collections, landscapes and intangible cultural heritage (CH).

Este artigo apresenta um estudo cognitivista do processamento da ironia, seguindo as pesquisas de FAUCONNIER; TURNER (2002) e COULSON (2001), principalmente. Procura-se mostrar os mecanismos de mescla e reenquadre suportam cognitivamente a leitura irônica do enunciado, criando desanalogias entre um dos inputs e o espaço mescla. O corpus deste trabalho constitui-se de matéria jornalística de natureza opinativa.

Air pollution induces the development of black crusts on the surface of built heritage materials. Black layers on the limestone used on an emblematic Madrilenian building dating from the early twentieth century, mainly built up in the 20 years lapsing between two façade cleaning operations, was studied with POM and SEM-EDS. Particulate matter deposited on surfaces in the same period was analyzed with XRD and IC. Climate change in the environs was also studied and façade coloring patterns were compared. Since black crust and settled dust composition, as well as façade soling intensity, were found to be closely related to the surrounding environment, both are proposed as environment and climate change markers. These are considerations, moreover, that must be addressed when designing conservation strategies. Domestic heating systems and vehicle traffic were identified as the two main sources of pollution throughout the period studied in the target area, where the temperature steadily rose and relative humidity declined. The progressive replacement of coal with gas oil in domestic heating boilers and the proliferation of vehicles with diesel engines have mostly determined the evolution of the pollutants emitted. The color of façade soiling, in turn, has been primarily conditioned by the typology of the particles deposited on the limestone surface, declining humidity and the passage of time.

Abstract Background Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic neurological disorders frequently associated with iron accumulation in the basal nuclei of the brain characterized by progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. Pantothenate kinase-associated neurodegeneration (PKAN) is one of the most widespread NBIA disorders. The diagnosis of PKAN is established with clinical features and the “eye of the tiger” sign identified on brain MRI and the identification of biallelic pantothenate kinase 2 (PANK2) pathogenic variants on molecular genetic testing. PANK2 catalyzes the first reaction of coenzyme A (CoA) biosynthesis, thus, altered PANK2 activity is expected to induce CoA deficiency as well as low levels of essential metabolic intermediates such as 4′-phosphopantetheine which is a necessary cofactor for critical proteins involved in cytosolic and mitochondrial pathways such as fatty acid biosynthesis, mitochondrial respiratory complex I assembly and lysine and tetrahydrofolate metabolism, among other metabolic processes. Methods In this manuscript, we examined the effect of a multitarget complex supplements (pantothenate, pantethine, omega-3 and vitamin E) on in vitro patient-derived cellular models and the clinical outcome of the adjuvant supplements in combination with the baseline neurological medication in three PKAN patients. Results Multitarget complex supplements significantly reduced iron accumulation and increased PANK2 and ACP expression levels in the cellular models derived from all three PKAN patients. In addition, the adjunct treatment to the standard neurological medication improved or stabilized the clinical symptoms of patients. Conclusions Our results suggest that multitarget complex supplements can be clinically useful as augmentation therapy for PKAN patients harboring pathogenic variants with residual enzyme levels. Trial registration: CAAE: 58219522.6.0000.5330. Registered 25 May 2022—Retrospectively registered, https://plataformabrasil.saude.gov.br/visao/pesquisador/gerirPesquisa/gerirPesquisaAgrupador.jsf .

Summary: Cell cycle progression is regulated by the orderly balance between kinase and phosphatase activities. PP2A phosphatase holoenzymes containing the B55 family of regulatory B subunits function as major CDK1-counteracting phosphatases during mitotic exit in mammals. However, the identification of the specific mitotic roles of these PP2A-B55 complexes has been hindered by the existence of multiple B55 isoforms. Here, through the generation of loss-of-function genetic mouse models for the two ubiquitous B55 isoforms (B55α and B55δ), we report that PP2A-B55α and PP2A-B55δ complexes display overlapping roles in controlling the dynamics of proper chromosome individualization and clustering during mitosis. In the absence of PP2A-B55 activity, mitotic cells display increased chromosome individualization in the presence of enhanced phosphorylation and perichromosomal loading of Ki-67. These data provide experimental evidence for a regulatory mechanism by which the balance between kinase and PP2A-B55 phosphatase activity controls the Ki-67-mediated spatial organization of the mass of chromosomes during mitosis.

Pediatric elbow fractures are quite common, accounting for up to 34% of bone fractures in children. Among these, acute lateral humeral condyle (LHC) fractures represent up to 22%. The accurate diagnosis and early treatment of LHC fractures are crucial due to the potential for abnormal growth and significant long-term impacts on joint motion. With the aim of enhancing the understanding of pediatric LHC fracture management among pediatric healthcare practitioners, we present a literature review combined with our technical recommendations based on our experience. Imaging through AP, lateral, and internal oblique X-rays remains the gold standard for diagnosis, although there is increasing focus on non-irradiating techniques, considering the skeletally immature nature of the patients. Several classification systems aid in fracture assessment, each varying in their simplicity, reproducibility, and inter- and intra-observer correlations. The treatment approaches for LHC fractures include conservative management with immobilization for minimally displaced fractures and surgical intervention for displaced fractures. The surgical options encompass closed and open reductions, using Kirschner wires or cannulated screws for fixation. While both methods show favorable outcomes, recent years have seen a growing interest in expanding the traditional indications for closed approaches. After a period of post-surgical immobilization of the limb, rehabilitation care is recommended to assist in the recovery of the range of motion. During the postoperative period, the most frequent complications are bony overgrowth, malunion, and infection, although with highly variable rates, which typically do not result in functional impairment if managed properly. Regular follow-up and monitoring are essential for optimal recovery and minimizing long-term complications.

The growing trend of analyzing all performance factors involved in a game makes identifying offensive patterns a determining factor in improving tactical performance and decision making during a game. The main objective of this research was to analyze the effectiveness and detect successful patterns on offense at critical moments in the men’s EuroBasket 2022 and women’s EuroBasket 2021. The sample was composed of 509 technical–tactical offensive actions obtained from the last 2 min of the final quarters and overtime from the group stage and final round, whose difference in the final score was equal to or less than five points. For this purpose, observational methodology was employed using LINCE PLUS software through an observational instrument designed ad hoc. Descriptive analysis and chi-square (χ2) tests were performed with SPSS 25, and a pattern analysis (T-Patterns) was performed with Theme 5 software. Statistical significance was set at p < 0.05. The teams that were losing when performing the offense finished a greater number of plays and with greater effectiveness. Fastbreaks seem to be more effective in the closing minutes, a play characterized by a maximum of three passes and by finishing with individual play such as 1 × 1. In turn, actions finished near the hoop by inside players seem to be more effective when the possession is finished before 17 s. The practical implications described in this research will enable coaches to tailor their strategies and training to the critical moments of the game.

El rolado selectivo es una técnica aplicada para el control de leñosas en los ecosistemas semiáridos con el fin de mejorar la condición del pastizal y reducir el riesgo de incendios. Hay antecedentes de estudios sobre el efecto del rolado en el suelo y vegetación herbácea y arbustiva en La Pampa, pero no existen estudios científicos sobre el comportamiento de la vegetación arbórea ante esta práctica. El objetivo del estudio fue evaluar la capacidad de rebrote de renuevos de Neltuma flexuosa (algarrobo) ante distintas frecuencias de rolado en la región del ecotono Caldenal-Monte Occidental en La Pampa. El estudio se desarrolló en el Campo Anexo INTA Chacharramendi en dos sitios: sitio 1 con una sola intervención de rolado y sitio 2 con cuatro intervenciones. Ambos sitios fueron afectados por un incendio en 2016. La capacidad de rebrote se evaluó a partir de la medición de la longitud, diámetro y número de rebrotes medidos en 39 algarrobos por sitio. No se encontraron diferencias significativas entre las variables medidas entre sitios. Estos resultados podrían deberse a la baja intensidad del disturbio que no logró afectar los niveles de reservas, permitiendo la regeneración de la especie. La información generada en este estudio aporta mayores conocimientos sobre la efectividad de la práctica de rolado como estrategia de control de leñosas en ambientes áridos-semiáridos.

Mutations in the lipoyltransferase 1 (LIPT1) gene are rare inborn errors of metabolism leading to a fatal condition characterized by lipoylation defects of the 2-ketoacid dehydrogenase complexes causing early-onset seizures, psychomotor retardation, abnormal muscle tone, severe lactic acidosis, and increased urine lactate, ketoglutarate, and 2-oxoacid levels. In this article, we characterized the disease pathophysiology using fibroblasts and induced neurons derived from a patient bearing a compound heterozygous mutation in LIPT1. A Western blot analysis revealed a reduced expression of LIPT1 and absent expression of lipoylated pyruvate dehydrogenase E2 (PDH E2) and alpha-ketoglutarate dehydrogenase E2 (α-KGDH E2) subunits. Accordingly, activities of PDH and α-KGDH were markedly reduced, associated with cell bioenergetics failure, iron accumulation, and lipid peroxidation. In addition, using a pharmacological screening, we identified a cocktail of antioxidants and mitochondrial boosting agents consisting of pantothenate, nicotinamide, vitamin E, thiamine, biotin, and α-lipoic acid, which is capable of rescuing LIPT1 pathophysiology, increasing the LIPT1 expression and lipoylation of mitochondrial proteins, improving cell bioenergetics, and eliminating iron overload and lipid peroxidation. Furthermore, our data suggest that the beneficial effect of the treatment is mainly mediated by SIRT3 activation. In conclusion, we have identified a promising therapeutic approach for correcting LIPT1 mutations.

Abstract Background Neurodegeneration with brain iron accumulation (NBIA) disorders are a group of neurodegenerative diseases that have in common the accumulation of iron in the basal nuclei of the brain which are essential components of the extrapyramidal system. Frequent symptoms are progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. One of the most prevalent subtypes of NBIA is Pantothenate kinase-associated neurodegeneration (PKAN). It is caused by pathogenic variants in the gene of pantothenate kinase 2 (PANK2) which encodes the enzyme responsible for the first reaction on the coenzyme A (CoA) biosynthesis pathway. Thus, deficient PANK2 activity induces CoA deficiency as well as low expression levels of 4′-phosphopantetheinyl proteins which are essential for mitochondrial metabolism. Methods This study is aimed at evaluating the role of alpha-lipoic acid (α-LA) in reversing the pathological alterations in fibroblasts and induced neurons derived from PKAN patients. Iron accumulation, lipid peroxidation, transcript and protein expression levels of PANK2, mitochondrial ACP (mtACP), 4′′-phosphopantetheinyl and lipoylated proteins, as well as pyruvate dehydrogenase (PDH) and Complex I activity were examined. Results Treatment with α-LA was able to correct all pathological alterations in responsive mutant fibroblasts with residual PANK2 enzyme expression. However, α-LA had no effect on mutant fibroblasts with truncated/incomplete protein expression. The positive effect of α-LA in particular pathogenic variants was also confirmed in induced neurons derived from mutant fibroblasts. Conclusions Our results suggest that α-LA treatment can increase the expression levels of PANK2 and reverse the mutant phenotype in PANK2 responsive pathogenic variants. The existence of residual enzyme expression in some affected individuals raises the possibility of treatment using high dose of α-LA.

This paper presents results on the protective properties of different coatings over metals representative of those found in scientific–technical heritage collections. An examination of several objects in the collection of the Spanish National Museum of Science and Technology have allowed the identification of brass and steel as the most representative metals, and the existence of coatings (mainly shellac and acrylic resins) applied for aesthetic and/or conservation purposes. Based on these findings, brass and steel coupons coated with Paraloid B-44, B-48, B-67, B-72, Incralac, Cosmolloid H80, B-72 + H80 double layer and shellac have been studied to carry out a first screening in order to select the most promising candidates and determine the most appropriate methodology and key factors for the study. Coatings have been aged up to 336 h using cycles of UV light and water condensation. The change in the aspect of the coupons has been assessed via visual examination, optical microscopy and colorimetric measurements, with B-44 and Incralac showing the least change. EIS has been used for a quantitative evaluation of the protective properties and FTIR to measure chemical changes experienced by some coatings, such as B-48 and B-67. These evaluations allowed us to follow, understand and compare the behaviour of the different coatings and substrates after artificial ageing.

Lipid peroxidation and iron accumulation are closely associated with neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, or neurodegeneration with brain iron accumulation disorders. Mitochondrial dysfunction, lipofuscin accumulation, autophagy disruption, and ferroptosis have been implicated as the critical pathomechanisms of lipid peroxidation and iron accumulation in these disorders. Currently, the connection between lipid peroxidation and iron accumulation and the initial cause or consequence in neurodegeneration processes is unclear. In this review, we have compiled the known mechanisms by which lipid peroxidation triggers iron accumulation and lipofuscin formation, and the effect of iron overload on lipid peroxidation and cellular function. The vicious cycle established between both pathological alterations may lead to the development of neurodegeneration. Therefore, the investigation of these mechanisms is essential for exploring therapeutic strategies to restrict neurodegeneration. In addition, we discuss the interplay between lipid peroxidation and iron accumulation in neurodegeneration, particularly in PLA2G6-associated neurodegeneration, a rare neurodegenerative disease with autosomal recessive inheritance, which belongs to the group of neurodegeneration with brain iron accumulation disorders.

Primary mitochondrial diseases result from mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes, encoding proteins crucial for mitochondrial structure or function. Given that few disease-specific therapies are available for mitochondrial diseases, novel treatments to reverse mitochondrial dysfunction are necessary. In this work, we explored new therapeutic options in mitochondrial diseases using fibroblasts and induced neurons derived from patients with mutations in the GFM1 gene. This gene encodes the essential mitochondrial translation elongation factor G1 involved in mitochondrial protein synthesis. Due to the severe mitochondrial defect, mutant GFM1 fibroblasts cannot survive in galactose medium, making them an ideal screening model to test the effectiveness of pharmacological compounds. We found that the combination of polydatin and nicotinamide enabled the survival of mutant GFM1 fibroblasts in stress medium. We also demonstrated that polydatin and nicotinamide upregulated the mitochondrial Unfolded Protein Response (mtUPR), especially the SIRT3 pathway. Activation of mtUPR partially restored mitochondrial protein synthesis and expression, as well as improved cellular bioenergetics. Furthermore, we confirmed the positive effect of the treatment in GFM1 mutant induced neurons obtained by direct reprogramming from patient fibroblasts. Overall, we provide compelling evidence that mtUPR activation is a promising therapeutic strategy for GFM1 mutations.

Abstract Background Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain characterized by progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. Pantothenate kinase-associated neurodegeneration (PKAN) is one of the most widespread NBIA subtypes. It is caused by mutations in the gene of pantothenate kinase 2 (PANK2) that result in dysfunction in PANK2 enzyme activity, with consequent deficiency of coenzyme A (CoA) biosynthesis, as well as low levels of essential metabolic intermediates such as 4′-phosphopantetheine, a necessary cofactor for essential cytosolic and mitochondrial proteins. Methods In this manuscript, we examined the therapeutic effectiveness of pantothenate, panthetine, antioxidants (vitamin E and omega 3) and mitochondrial function boosting supplements (L-carnitine and thiamine) in mutant PANK2 cells with residual expression levels. Results Commercial supplements, pantothenate, pantethine, vitamin E, omega 3, carnitine and thiamine were able to eliminate iron accumulation, increase PANK2, mtACP, and NFS1 expression levels and improve pathological alterations in mutant cells with residual PANK2 expression levels. Conclusion Our results suggest that several commercial compounds are indeed able to significantly correct the mutant phenotype in cellular models of PKAN. These compounds alone or in combinations are of common use in clinical practice and may be useful for the treatment of PKAN patients with residual enzyme expression levels.

Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich’s Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR’s role as a promising therapeutic target in combating these devastating disorders.

Abstract Background Mitochondrial diseases represent one of the most common groups of genetic diseases. With a prevalence greater than 1 in 5000 adults, such diseases still lack effective treatment. Current therapies are purely palliative and, in most cases, insufficient. Novel approaches to compensate and, if possible, revert mitochondrial dysfunction must be developed. Results In this study, we tackled the issue using as a model fibroblasts from a patient bearing a mutation in the GFM1 gene, which is involved in mitochondrial protein synthesis. Mutant GFM1 fibroblasts could not survive in galactose restrictive medium for more than 3 days, making them the perfect screening platform to test several compounds. Tetracycline enabled mutant GFM1 fibroblasts survival under nutritional stress. Here we demonstrate that tetracycline upregulates the mitochondrial Unfolded Protein Response (UPRmt), a compensatory pathway regulating mitochondrial proteostasis. We additionally report that activation of UPRmt improves mutant GFM1 cellular bioenergetics and partially restores mitochondrial protein expression. Conclusions Overall, we provide compelling evidence to propose the activation of intrinsic cellular compensatory mechanisms as promising therapeutic strategy for mitochondrial diseases.

Nemaline myopathy (NM) is one of the most common forms of congenital myopathy and it is identified by the presence of “nemaline bodies” (rods) in muscle fibers by histopathological examination. The most common forms of NM are caused by mutations in the Actin Alpha 1 (ACTA1) and Nebulin (NEB) genes. Clinical features include hypotonia and muscle weakness. Unfortunately, there is no curative treatment and the pathogenetic mechanisms remain unclear. In this manuscript, we examined the pathophysiological alterations in NM using dermal fibroblasts derived from patients with mutations in ACTA1 and NEB genes. Patients’ fibroblasts were stained with rhodamine–phalloidin to analyze the polymerization of actin filaments by fluorescence microscopy. We found that patients’ fibroblasts showed incorrect actin filament polymerization compared to control fibroblasts. Actin filament polymerization defects were associated with mitochondrial dysfunction. Furthermore, we identified two mitochondrial-boosting compounds, linoleic acid (LA) and L-carnitine (LCAR), that improved the formation of actin filaments in mutant fibroblasts and corrected mitochondrial bioenergetics. Our results indicate that cellular models can be useful to study the pathophysiological mechanisms involved in NM and to find new potential therapies. Furthermore, targeting mitochondrial dysfunction with LA and LCAR can revert the pathological alterations in NM cellular models.

The term neurodegeneration with brain iron accumulation (NBIA) brings together a broad set of progressive and disabling neurological genetic disorders in which iron is deposited preferentially in certain areas of the brain. Among NBIA disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by pathologic variants in the PANK2 gene codifying the enzyme pantothenate kinase 2 (PANK2). To date, there are no effective treatments to stop the progression of these diseases. This review discusses the utility of patient-derived cell models as a valuable tool for the identification of pharmacological or natural compounds for implementing polytarget precision medicine in PKAN. Recently, several studies have described that PKAN patient-derived fibroblasts present the main pathological features associated with the disease including intracellular iron overload. Interestingly, treatment of mutant cell cultures with various supplements such as pantothenate, pantethine, vitamin E, omega 3, α-lipoic acid L-carnitine or thiamine, improved all pathophysiological alterations in PKAN fibroblasts with residual expression of the PANK2 enzyme. The information provided by pharmacological screenings in patient-derived cellular models can help optimize therapeutic strategies in individual PKAN patients.

Describimos a un paciente con neuropatía periférica sensora motora y neuropatía craneal debido a neurolinfomatosis y definida por la infiltración de nervios periféricos por células tumorales y hacemos una revisión de hallazgos en 39 pacientes previamente descritos a través de confirmaciones de autopsia de casos examinados dentro de los archivos del centro presbiteriano de Columbia. La causa de la neuropatía es desconocida. La asociación con estados de inmunodeficiencias sugieren una patogénesis mediada por virus posiblemente retrovirus.

Abstract Background Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic neurological disorders frequently associated with iron accumulation in the basal nuclei of the brain characterized by progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. Pantothenate kinase-associated neurodegeneration (PKAN) is the most widespread NBIA disorder. It is caused by mutations in the gene of pantothenate kinase 2 (PANK2) which catalyzes the first reaction of coenzyme A (CoA) biosynthesis. Thus, altered PANK2 activity is expected to induce CoA deficiency as well as low levels of essential metabolic intermediates such as 4′-phosphopantetheine which is a necessary cofactor for critical proteins involved in cytosolic and mitochondrial pathways such as fatty acid biosynthesis, mitochondrial respiratory complex I assembly and lysine and tetrahydrofolate metabolism, among other metabolic processes. Methods In this manuscript, we examined the effect of PANK2 mutations on the expression levels of proteins with phosphopantetheine cofactors in fibroblast derived from PKAN patients. These proteins include cytosolic acyl carrier protein (ACP), which is integrated within the multifunctional polypeptide chain of the fatty acid synthase involved in cytosolic fatty acid biosynthesis type I (FASI); mitochondrial ACP (mtACP) associated with mitocondrial fatty acid biosynthesis type II (FASII); mitochondrial alpha-aminoadipic semialdehyde synthase (AASS); and 10-formyltetrahydrofolate dehydrogenases (cytosolic, ALD1L1, and mitochondrial, ALD1L2). Results In PKAN fibroblasts the expression levels of cytosolic FAS and ALD1L1 were not affected while the expression levels of mtACP, AASS and ALD1L2 were markedly reduced, suggesting that 4′-phosphopantetheinylation of mitochondrial but no cytosolic proteins were markedly affected in PKAN patients. Furthermore, the correction of PANK2 expression levels by treatment with pantothenate in selected mutations with residual enzyme content was able to correct the expression levels of mitochondrial phosphopantetheinyl-proteins and restore the affected pathways. The positive effects of pantothenate in particular mutations were also corroborated in induced neurons obtained by direct reprograming of mutant PANK2 fibroblasts. Conclusions Our results suggest that the expression levels of mitochondrial phosphopantetheinyl-proteins are severely reduced in PKAN cells and that in selected mutations pantothenate increases the expression levels of both PANK2 and mitochondrial phosphopantetheinyl-proteins associated with remarkable improvement of cell pathophysiology.

ABSTRACT We conducted a prospective, multicenter, specific pilot study on uncomplicated urinary tract infections (uUTI). One-hundred non-duplicated uropathogenic Escherichia coli (UPEC) from uUTI occurred in 2020 in women attending 15 primary care centers of a single health region of northern Spain were characterized using a clonal diagnosis approach. Among the high genetic diversity showed by 59 different phylogroup-clonotype combinations, 11 clones accounted for 46% of the isolates: B2-ST73 (CH24-30); B2-ST73 (CH24-103); B2-ST131 (CH40-30); B2-ST141 (CH52-5); B2-ST372 (CH103-9); B2-ST404 (CH14-27); B2-ST404 (CH14-807); B2-ST1193 (CH14-64); D-ST69 (CH35-27); D-ST349 (CH36-54), and F-ST59 (CH32-41). The screening of the UPEC status found that 69% of isolates carried ≥ 3 of chuA, fyuA, vat, and yfcV genes. Multidrug resistance to at least one antibiotic of ≥ 3 antimicrobial categories were exhibited by 30% of the isolates, with the highest rates of resistance against ampicillin/amoxicillin (48%), trimethoprim (35%), norfloxacin (28%), amoxicillin-clavulanic acid (26%), and trimethoprim-sulfamethoxazole (24%). None extended-spectrum beta-lactamase/carbapenemase producer was recovered. According to our results, fosfomycin and nitrofurantoin should be considered as empirical treatment of choice for uUTI by E. coli (resistance rates 4% and 2%, respectively). We uncover the high prevalence of the pandemic fluoroquinolone-resistant ST1193 clone (6%) in uUTI, which represents the first report in Spain in this pathology. The genomic analysis showed similar key traits than those ST1193 clones disseminated worldwide. Through the SNP comparison based on the core genome, the Spanish ST1193 clustered with isolates retrieved from the Enterobase, showing high genomic similarity than the global ST1193 described in the United States, Canada and Australia. IMPORTANCE Analyzing the clonal structure and antimicrobial resistance of E. coli isolates implicated in uncomplicated urinary tract infections, one of the most frequent visits managed in primary health care, is of interest for clinicians to detect changes in the dynamics of emerging uropathogenic clones associated with the spread of fluoroquinolone resistance. It can also provide consensus concerning optimal control and antibiotic prescribing.

Background: PLA2G6-Associated Neurodegeneration (PLAN) is a rare neurodegenerative disease with autosomal recessive inheritance, which belongs to the NBIA (Neurodegeneration with Brain Iron Accumulation) group. Although the pathogenesis of the disease remains largely unclear, lipid peroxidation seems to play a central role in the pathogenesis. Currently, there is no cure for the disease. Objective: In this work, we examined the presence of lipid peroxidation, iron accumulation and mitochondrial dysfunction in two cellular models of PLAN, patients-derived fibroblasts and induced neurons, and assessed the effects of α-tocopherol (vitamin E) in correcting the pathophysiological alterations in PLAN cell cultures. Methods: Pathophysiological alterations were examined in fibroblasts and induced neurons generated by direct reprograming. Iron and lipofuscin accumulation were assessed using light and electron microscopy, as well as biochemical analysis techniques. Reactive Oxygen species production, lipid peroxidation and mitochondrial dysfunction were measured using specific fluorescent probes analysed by fluorescence microscopy and flow cytometry. Results: PLAN fibroblasts and induced neurons clearly showed increased lipid peroxidation, iron accumulation and altered mitochondrial membrane potential. All these pathological features were reverted with vitamin E treatment. Conclusions: PLAN fibroblasts and induced neurons reproduce the main pathological alterations of the disease and provide useful tools for disease modelling. The main pathological alterations were corrected by Vitamin E supplementation in both models, suggesting that blocking lipid peroxidation progression is a critical therapeutic target.