Tau- and α-synuclein-targeted gold nanoparticles: applications, opportunities, and future outlooks in the diagnosis and therapy of neurodegenerative diseases.

The use of nanomaterials in medicine offers multiple opportunities to address neurodegenerative disorders such as Alzheimer's and Parkinson's disease. These diseases are a significant burden for society and the health system, affecting millions of people worldwide without sensitive and selective diagnostic methodologies or effective treatments to stop their progression. In this sense, the use of gold nanoparticles is a promising tool due to their unique properties at the nanometric level. They can be functionalized with specific molecules to selectively target pathological proteins such as Tau and α-synuclein for Alzheimer's and Parkinson's disease, respectively. Additionally, these proteins are used as diagnostic biomarkers, wherein gold nanoparticles play a key role in enhancing their signal, even at the low concentrations present in biological samples such as blood or cerebrospinal fluid, thus enabling an early and accurate diagnosis. On the other hand, gold nanoparticles act as drug delivery platforms, bringing therapeutic agents directly into the brain, improving treatment efficiency and precision, and reducing side effects in healthy tissues. However, despite the exciting potential of gold nanoparticles, it is crucial to address the challenges and issues associated with their use in the medical field before they can be widely applied in clinical settings. It is critical to ensure the safety and biocompatibility of these nanomaterials in the context of the central nervous system. Therefore, rigorous preclinical and clinical studies are needed to assess the efficacy and feasibility of these strategies in patients. Since there is scarce and sometimes contradictory literature about their use in this context, the main aim of this review is to discuss and analyze the current state-of-the-art of gold nanoparticles in relation to delivery, diagnosis, and therapy for Alzheimer's and Parkinson's disease, as well as recent research about their use in preclinical, clinical, and emerging research areas.

Palladium-catalysed transannular C-H functionalization of alicyclic amines.

Discovering pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. C-H bonds are present in almost all pharmaceutical agents. Consequently, the development of selective, rapid and efficient methods for converting these bonds into new chemical entities has the potential to streamline pharmaceutical development. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, such as treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukaemia (alvocidib), schizophrenia (risperidone, belaperidone), malaria (mefloquine) and nicotine addiction (cytisine, varenicline). However, existing methods for the C-H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited. Here we report a transannular approach to selectively manipulate the C-H bonds of alicyclic amines at sites remote to nitrogen. Our reaction uses the boat conformation of the substrates to achieve palladium-catalysed amine-directed conversion of C-H bonds to C-C bonds on various alicyclic amine scaffolds. We demonstrate this approach by synthesizing new derivatives of several bioactive molecules, including varenicline.

Surface enhanced fluorescence effect improves the in vivo detection of amyloid aggregates.

The ß-amyloid (Aß) peptide is one of the key etiological agents in Alzheimer's disease (AD). The in vivo detection of Aß species is challenging in all stages of the illness. Currently, the development of fluorescent probes allows the detection of Aß in animal models in the near-infrared region (NIR). However, considering future applications in biomedicine, it is relevant to develop strategies to improve detection of amyloid aggregates using NIR probes. An innovative approach to increase the fluorescence signal of these fluorophores is the use of plasmonic gold nanoparticles (surface-enhanced fluorescence effect). In this work, we improved the detection of Aß aggregates in C. elegans and mouse models of AD by co-administering functionalized gold nanorods (GNRs-PEG-D1) with the fluorescent probes CRANAD-2 or CRANAD-58, which bind selectively to different amyloid species (soluble and insoluble). This work shows that GNRs improve the detection of Aß using NIR probes in vivo.

Plasmonic Nanoparticles as Optical Sensing Probes for the Detection of Alzheimer's Disease.

Alzheimer's disease (AD), considered a common type of dementia, is mainly characterized by a progressive loss of memory and cognitive functions. Although its cause is multifactorial, it has been associated with the accumulation of toxic aggregates of the amyloid-ß peptide (Aß) and neurofibrillary tangles (NFTs) of tau protein. At present, the development of highly sensitive, high cost-effective, and non-invasive diagnostic tools for AD remains a challenge. In the last decades, nanomaterials have emerged as an interesting and useful tool in nanomedicine for diagnostics and therapy. In particular, plasmonic nanoparticles are well-known to display unique optical properties derived from their localized surface plasmon resonance (LSPR), allowing their use as transducers in various sensing configurations and enhancing detection sensitivity. Herein, this review focuses on current advances in in vitro sensing techniques such as Surface-enhanced Raman scattering (SERS), Surface-enhanced fluorescence (SEF), colorimetric, and LSPR using plasmonic nanoparticles for improving the sensitivity in the detection of main biomarkers related to AD in body fluids. Additionally, we refer to the use of plasmonic nanoparticles for in vivo imaging studies in AD.

Second-Generation Palladium Catalyst System for Transannular C-H Functionalization of Azabicycloalkanes.

This article describes the development of a second-generation catalyst system for the transannular C-H functionalization of alicyclic amines. Pyridine- and quinoline-carboxylate ligands are shown to be highly effective for increasing the reaction rate, yield, and scope of Pd-catalyzed transannular C-H arylation reactions of azabicyclo[3.1.0]hexane, azabicyclo[3.1.1]heptane, azabicyclo[3.2.1]octane, and piperidine derivatives. Mechanistic studies reveal that the pyridine/quinoline-carboxylates play a role in impeding both reversible and irreversible catalyst decomposition pathways. These ligands enable the first reported examples of the transannular C-H arylation of the ubiquitous tropane, 7-azanorbornane, and homotropane cores. Finally, the pyridine/quinoline-carboxylates are shown to promote both transannular C-H arylation and transannular C-H dehydrogenation on a homotropane substrate.

Microbiome analysis and bacterial isolation from Lejía Lake soil in Atacama Desert.

As a consequence of the severe climatic change affecting our entire world, many lakes in the Andes Cordillera are likely to disappear within a few decades. One of these lakes is Lejía Lake, located in the central Atacama Desert. The objectives of this study were: (1) to characterize the bacterial community from Lejía Lake shore soil (LLS) using 16S rRNA sequencing and (2) to test a culture-based approach using a soil extract medium (SEM) to recover soil bacteria. This extreme ecosystem was dominated by three phyla: Bacteroidetes, Proteobacteria, and Firmicutes with 29.2, 28.2 and 28.1% of the relative abundance, respectively. Using SEM, we recovered 7.4% of the operational taxonomic units from LLS, all of which belonged to the same three dominant phyla from LLS (6.9% of Bacteroidetes, 77.6% of Proteobacteria, and 15.3% of Firmicutes). In addition, we used SEM to recover isolates from LLS and supplemented the culture medium with increasing salt concentrations to isolate microbial representatives of salt tolerance (Halomonas spp.). The results of this study complement the list of microbial taxa diversity from the Atacama Desert and assess a pipeline to isolate selective bacteria that could represent useful elements for biotechnological approaches.

[Response capacity and challenges of the Cuban health system against communicable diseasesCapacidade de resposta e desafios do sistema de saúde cubano contra doenças transmissíveis]. / Capacidad de respuesta y desafíos del sistema de salud cubano frente a las enfermedades transmisibles.

This article presents distinctive and essential features in the transformations of the Cuban health system that have allowed the eradication and reduction of the incidence rates of some communicable diseases at levels lower than 0.1 per 100 000 inhabitants. The results obtained are a consequence of the importance given to the prevention and control, as well as to the risks and potential damages, of these diseases. The structure and functioning of the hygiene and epidemiology subsystem and its interrelations with the rest of the system, based on the different models of service provision, have been permanent integration scenarios for decision making. Diseases such as poliomyelitis, malaria, diphtheria, whooping cough, rubella, mumps, post-mumps meningitis, measles, yellow fever, cholera, severe forms of tuberculosis, human rabies transmitted by canines, leishmaniasis, Chagas disease, vertical transmission of HIV, congenital syphilis and clinical forms such as neonatal tetanus and congenital rubella syndrome were eliminated. Some communicable diseases are analyzed in more detail and, in particular, the social response developed against tuberculosis, leprosy, AIDS and vector-borne diseases. However, the current health context presents challenges for the sustainability of the achievements made in the country. Assuring the maintenance of universal coverage with access of the Cuban population to health services will always be a principle of Cuban public health.

No presente artigo se identificam características específicas e essenciais nas transformações do sistema de saúde cubano que permitiram a erradicação e redução das taxas de incidência de algumas doenças transmissíveis a níveis inferiores a 0,1 por 100 000 habitantes. Os resultados obtidos são uma conseqüência da importância dada à prevenção e controle dessas doenças, bem como aos riscos e danos potenciais. A estrutura e o funcionamento do subsistema de higiene e epidemiologia e suas inter-relações com o resto do sistema, com base nos diferentes modelos de prestação de serviços, constituíram cenários de integração permanente para a tomada de decisões. Foram eliminadas doenças como a poliomielite, malária, difteria, coqueluche, rubéola, parotidite, meningite pós-parotidite, sarampo, febre amarela, cólera, formas graves de tuberculose, raiva humana transmitida por cães, leishmaniose, doença de Chagas, a transmissão vertical do vírus da imunodeficiência humana, sífilis congênita e formas clínicas como o tétano neonatal e a síndrome da rubéola congênita. É dada ênfase a algumas doenças transmissíveis e, em particular, à resposta social desenvolvida contra a tuberculose, a hanseniasis, a AIDS e as doenças transmitidas por vetores. Mostra-se que o atual contexto de saúde revela desafios para a sustentabilidade das realizações no país. Garantir a manutenção da cobertura universal com acesso da população cubana aos serviços de saúde sempre será um princípio da saúde pública cubana.

Evaluation of Tris-Bipyridine Chromium Complexes for Flow Battery Applications: Impact of Bipyridine Ligand Structure on Solubility and Electrochemistry.

This report describes the design, synthesis, solubility, and electrochemistry of a series of tris-bipyridine chromium complexes that exhibit up to six reversible redox couples as well as solubilities approaching 1 M in acetonitrile. We have systematically modified both the ligand structure and the oxidation state of these complexes to gain insights into the factors that impact solubility and electrochemistry. The results provide a set of structure-solubility-electrochemistry relationships to guide the future development of electrolytes for nonaqueous flow batteries. In addition, we have identified a promising candidate from the series of chromium complexes for further electrochemical and battery assessment.

N-Acyloxyphthalimides as nitrogen radical precursors in the visible light photocatalyzed room temperature C-H amination of arenes and heteroarenes.

This paper reports a room temperature visible light photocatalyzed method for the C-H amination of arenes and heteroarenes. A key enabling advance in this work is the design of N-acyloxyphthalimides as precursors to nitrogen-based radical intermediates for these transformations. A broad substrate scope is presented, including the selective meta-amination of pyridine derivatives. A radical aromatic substitution mechanism is proposed.

Adding vortexing to the Maki technique provides no benefit for the diagnosis of catheter colonization or catheter-related bacteremia.

BACKGROUND: A previous study compared vortexing and Maki techniques for the diagnosis of catheter-related bloodstream infection (CRBSI), and concluded that vortexing was not superior to Maki method. AIM: To determine whether the combined use of vortexing and Maki techniques provides profitability versus the Maki technique for the diagnosis of catheter tip colonization (CTC) and CRBSI. METHODS: Observational and prospective study carried out in an Intensive Care Unit. Patients with suspected catheter-related infection (CRI) and with one central venous catheter for at least 7 days were included. The area under the curve (AUC) of the Maki technique, the vortexing technique and the combination of both techniques for the diagnosis of CTC and CRBSI were compared. RESULTS: We included 136 episodes of suspected CRI. We found 21 cases of CTC of which 10 were also CRBSI cases. Of the 21 CTC episodes, 18 (85.7%) were diagnosed by Maki technique and vortexing technique, 3 (14.3%) only by the technique of Maki, and none only by technique of vortexing. Of the 10 CRBSI episodes, 9 (90.0%) were diagnosed by the techniques of Maki and vortexing, 1 (10.0%) was diagnosed only by the technique of Maki, and none only by the technique of vortexing. We no found differences in the comparison of AUC between the technique of Maki and the combination of Maki and vortexing techniques for the diagnosis of CTC (P = 0.99) and CRBSI (P = 0.99). CONCLUSION: The novel finding of our study was that the combined use of vortexing and Maki techniques did not provide profitability to the technique of Maki alone to CRBSI diagnosis of.

Buccal delivery of small molecules and biologics: Of mucoadhesive polymers, films, and nanoparticles - An update.

Buccal delivery of small and large molecules is an attractive route of administration that has been studied extensively over the past few decades. This route bypasses first-pass metabolism and can be used to deliver therapeutics directly to systemic circulation. Moreover, buccal films are efficient dosage forms for drug delivery due to their simplicity, portability, and patient comfort. Films have traditionally been formulated using conventional techniques, including hot-melt extrusion and solvent casting. However, newer methods are now being exploited to improve the delivery of small molecules and biologics. This review discusses recent advances in buccal film manufacturing, using the latest technologies, such as 2D and 3D printing, electrospraying, and electrospinning. This review also focuses on the excipients used in the preparation of these films, with emphasis on mucoadhesive polymers and plasticizers. Along with advances in manufacturing technology, newer analytical tools have also been used for the assessment of permeation of the active agents across the buccal mucosa, the most critical biological barrier and limiting factor of this route. Additionally, preclinical and clinical trial challenges are discussed, and some small molecule products already on the market are explored.

Survey of Commercial Food Products for Detection of Walnut (Juglans regia) by Two ELISA Methods and Real Time PCR.

Labeling of food allergens in accordance with legal regulations is important to protect the health of allergic consumers. The requirements for detecting allergens in foods involve adequate specificity and sensitivity to identify very small amounts of the target allergens in complex food matrices and processed foods. In this work, one hundred commercial samples were analyzed for walnut detection using three different methods: a sandwich enzyme-linked immunosorbent assay (ELISA) kit based on polyclonal antibodies, a direct ELISA using a recombinant multimeric scFv, and a real time PCR. The most sensitive method was real time PCR followed by sandwich ELISA kit and multimeric scFv ELISA. There was agreement between the three methods for walnut detection in commercial products, except for some heat-treated samples or those that contained pecan. The walnut ELISA kit was less affected by sample processing than was the multimeric scFv ELISA, but there was cross-reactivity with pecan, producing some false positives that must be confirmed by real time PCR. According to the results obtained, 7.0 to 12.6% of samples (depending on the analytical method) contained walnut but did not declare it, confirming there is a risk for allergic consumers. Moreover, there was one sample (3.7%) labelled as containing walnut but that tested negative for this tree nut. Genetic and immunoenzymatic techniques offer complementary approaches to develop a reliable verification for walnut allergen labeling.

Insulin-like Growth Factor II Prevents MPP+ and Glucocorticoid Mitochondrial-Oxidative and Neuronal Damage in Dopaminergic Neurons.

Stress seems to contribute to Parkinson's disease (PD) neuropathology, probably by dysregulation of the hypothalamic-pituitary-adrenal axis. Key factors in this pathophysiology are oxidative stress and mitochondrial dysfunction and neuronal glucocorticoid-induced toxicity. The insulin-like growth factor II (IGF-II), a pleiotropic hormone, has shown antioxidant and neuroprotective effects in some neurodegenerative disorders. Our aim was to examine the protective effect of IGF-II on a dopaminergic cellular combined model of PD and mild to moderate stress measuring oxidative stress parameters, mitochondrial and neuronal markers, and signalling pathways. IGF-II counteracts the mitochondrial-oxidative damage produced by the toxic synergistic effect of corticosterone and 1-methyl-4-phenylpyridinium, protecting dopaminergic neurons from death and neurodegeneration. IGF-II promotes PKC activation and nuclear factor (erythroid-derived 2)-like 2 antioxidant response in a glucocorticoid receptor-dependent pathway, preventing oxidative cell damage and maintaining mitochondrial function. Thus, IGF-II is a potential therapeutic tool for treatment and prevention of disease progression in PD patients suffering mild to moderate emotional stress.

Lower ΔFosB expression in the dopaminergic system after stevia consumption in rats housed under environmental enrichment conditions.

Environmental enrichment (EE) has been proven to reduce drug seeking and the development of addiction-related behaviors in rodent models, but the effects of EE on natural reward acquisition in the form of sweet beverages are poorly understood. Accumulating evidence shows that the intake of sugar, the main ingredient of sweet beverages, alters the dopaminergic system, leading to addiction-related physiological and molecular changes. Sugar in sweet beverages has been replaced with natural sweeteners, such as stevia extract, which has greater sweetener potential but no energy content. Our research group found that sucralose consumption increased the expression of ΔFosB in reward-related nuclei, suggesting activation of the dopaminergic system. The present study assessed the effects of EE on stevia consumption and the expression of ΔFosB in the nucleus accumbens, caudate putamen, and prefrontal cortex. Sixteen male Wistar rats, 21 days old, were randomly assigned to an EE group (n = 8) or standard environment (SE) group (n = 8) and reared for 30 days. On postnatal day 52 (PND52), the brains of four animals in each housing condition were extracted to determine basal ΔFosB levels. Stevia consumption with intermittent access and ΔFosB immunoreactivity were measured for 21 days in the remainder of the rats. Compared with SE animals, EE animals exhibited a reduction of stevia consumption and alterations of ΔFosB immunoreactivity in the reward system. These results indicate that EE reduces stevia consumption and the stevia-induced ΔFosB expression, suggesting addiction-related changes in dopaminergic nuclei, which may be interpreted as a neuroprotective effect.

Gold Nanoparticles Mediate Improved Detection of ß-amyloid Aggregates by Fluorescence.

The early detection of the amyloid beta peptide aggregates involved in Alzheimer's disease is crucial to test new potential treatments. In this research, we improved the detection of amyloid beta peptide aggregates in vitro and ex vivo by fluorescence combining the use of CRANAD-2 and gold nanorods (GNRs) by the surface enhancement fluorescence effect. We synthetized GNRs and modified their surface with HS-PEG-OMe and HS-PEG-COOH and functionalized them with the D1 peptide, which has the capability to selectively bind to amyloid beta peptide. For an in vitro detection of amyloid beta peptide, we co-incubated amyloid beta peptide aggregates with the probe CRANAD-2 and GNR-PEG-D1 observing an increase in the intensity of the fluorescence signal attributed to surface enhancement fluorescence. Furthermore, the surface enhancement fluorescence effect was observed in brain slices of transgenic mice with Alzheimer´s disease co-incubated with CRANAD-2 and GNR-PEG-D1. An increase in the fluorescence signal was observed allowing the detection of aggregates that cannot be detected with the single use of CRANAD-2. Gold nanoparticles allowed an improvement in the detection of the amyloid aggregated by fluorescence in vitro and ex vivo.

The zebrafish prospero homolog prox1 is required for mechanosensory hair cell differentiation and functionality in the lateral line.

BACKGROUND: The lateral line system in zebrafish is composed of a series of organs called neuromasts, which are distributed over the body surface. Neuromasts contain clusters of hair cells, surrounded by accessory cells. RESULTS: In this report we describe zebrafish prox1 mRNA expression in the migrating primordium and in the neuromasts of the posterior lateral line. Furthermore, using an antibody against Prox1 we characterize expression of the protein in different cell types within neuromasts, and we show distribution among the supporting cells and hair cells. CONCLUSION: Functional analysis using antisense morpholinos indicates that prox1 activity is crucial for the hair cells to differentiate properly and acquire functionality, while having no role in development of other cell types in neuromasts.

Structure and co-occurrence patterns in microbial communities under acute environmental stress reveal ecological factors fostering resilience.

Understanding the factors that modulate bacterial community assembly in natural soils is a longstanding challenge in microbial community ecology. In this work, we compared two microbial co-occurrence networks representing bacterial soil communities from two different sections of a pH, temperature and humidity gradient occurring along a western slope of the Andes in the Atacama Desert. In doing so, a topological graph alignment of co-occurrence networks was used to determine the impact of a shift in environmental variables on OTUs taxonomic composition and their relationships. We observed that a fraction of association patterns identified in the co-occurrence networks are persistent despite large environmental variation. This apparent resilience seems to be due to: (1) a proportion of OTUs that persist across the gradient and maintain similar association patterns within the community and (2) bacterial community ecological rearrangements, where an important fraction of the OTUs come to fill the ecological roles of other OTUs in the other network. Actually, potential functional features suggest a fundamental role of persistent OTUs along the soil gradient involving nitrogen fixation. Our results allow identifying factors that induce changes in microbial assemblage configuration, altering specific bacterial soil functions and interactions within the microbial communities in natural environments.

Acceso a servicios de salud en pacientes con tuberculosis en Cuba. La percepción de directivos / Access to health services in patients with tuberculosis in Cuba. The perception of managers

Resumen Objetivo: Indagar las percepciones de los directores sobre el acceso a los servicios de salud en pacientes con tuberculosis pulmonar. Materiales y métodos: Investigación descriptiva, en informantes claves seleccionados de forma intencional no aleatoria a partir de criterios de inclusión relevantes. Resultaron seleccionados 5 jefes de los Programa de Prevención y Control de la Tuberculosis pulmonar y VIH/sida, del nivel nacional y provincial. Se elaboró y validó por expertos una guía de entrevista, con los aspectos de acceso a los servicios de salud. La entrevista se realizó en óptimas condiciones y se solicitó su consentimiento para grabar. El análisis de contenido de la información, se organizó según la metodología de Bardin, preanálisis, exploración del material y tratamiento de los resultados e interpretación. Resultados: Las percepciones reportadas por los directivos fueron alteraciones en la dinámica de la atención, oportunidad y su continuidad, la educación a la comunidad y compañeros de trabajo, afectación de grupos poblacionales con indisciplina social, existencia de estigmas sociales hacia la enfermedad, poca participación de los sectores de la comunidad para resolver sus dificultades, imposibilidad de asumir siempre la alimentación y transportación, la calidad de los recursos humanos y gestión del programa. Conclusiones: Los directivos del programa de prevención y control de tuberculosis percibieron que existen dificultades en la disponibilidad, la accesibilidad, la aceptabilidad y la calidad de los servicios de salud en pacientes con tuberculosis pulmonar, estos elementos identificados pueden contribuir al rediseñó de la estrategia de eliminación de la enfermedad en La Habana.

Abstract Objective: to investigate direct perceptions of access to health services in patients with pulmonary tuberculosis. Methodo: descriptive, in key informants selected intentionally not randomly based on relevant inclusion criteria. The Heads of the Prevention and Control Program for Pulmonary Tuberculosis and HIV / AIDS, at the national and provincial level, were selected. An interview guide was developed and validated by experts, with aspects of access to health services. This was done in optimal conditions and your consent to record was requested. The analysis of information content was organized according to Bardin's methodology, pre-analysis, exploration of the material and treatment of the results and interpretation. Results: There were perceptions by managers of alterations in the dynamics of care, opportunity and its continuity, education to the community and coworkers, involvement of population groups with social indiscipline, existence of social stigmas towards the disease, low participation of the sectors of the community to solve their difficulties, impossibility of always assuming food and transportation, the quality of human resources and program management. Conclusions: The directors of the tuberculosis prevention and control program perceived that there are difficulties in the availability, accessibility, acceptability and quality of health services in patients with pulmonary tuberculosis, these identified elements can contribute to the redesign of the strategy of Elimination of the disease in Havana.