Dual-Modal Cellular Nanoparticles for Continuous Neurotoxin Detoxification.

Neurotoxins are known for their extreme lethality. However, due to their enormous diversity, effective and broad-spectrum countermeasures are lacking. This study presents a dual-modal cellular nanoparticle (CNP) formulation engineered for continuous neurotoxin neutralization. The formulation involves encapsulating the metabolic enzyme N-sulfotransferase (SxtN) into metal-organic framework (MOF) nanoparticle cores and coating them with a natural neuronal membrane, termed "Neuron-MOF/SxtN-NPs". The resulting nanoparticles combine membrane-enabled broad-spectrum neurotoxin neutralization with enzyme payload-enabled continuous neurotoxin neutralization. The studies confirm the protection of the enzyme payload by the MOF core and validate the continuous neutralization of saxitoxin (STX). In vivo studies conducted using a mouse model of STX intoxication reveal markedly improved survival rates compared with control groups. Furthermore, acute toxicity assessments show no adverse effects associated with the administration of Neuron-MOF/SxtN-NPs in healthy mice. Overall, Neuron-MOF/SxtN-NPs represent a unique biomimetic nanomedicine platform poised to effectively neutralize neurotoxins, marking an important advancement in the field of countermeasure nanomedicine.

Protein-Loaded Cellular Nanosponges for Dual-Biomimicry Neurotoxin Countermeasure.

Neurotoxins present a substantial threat to human health and security as they disrupt and damage the nervous system. Their potent and structurally diverse nature poses challenges in developing effective countermeasures. In this study, a unique nanoparticle design that combines dual-biomimicry mechanisms to enhance the detoxification efficacy of neurotoxins is introduced. Using saxitoxin (STX), one of the deadliest neurotoxins, and its natural binding protein saxiphilin (Sxph) as a model system, human neuronal membrane-coated and Sxph-loaded metal-organic framework (MOF) nanosponges (denoted "Neuron-MOF/Sxph-NS") are successfully developed. The resulting Neuron-MOF/Sxph-NS exhibit a biomimetic design that not only emulates host neurons for function-based detoxification through the neuronal membrane coating, but also mimics toxin-resistant organisms by encapsulating the Sxph protein within the nanoparticle core. The comprehensive in vitro assays, including cell osmotic swelling, calcium flux, and cytotoxicity assays, demonstrate the improved detoxification efficacy of Neuron-MOF/Sxph-NS. Furthermore, in mouse models of STX intoxication, the application of Neuron-MOF/Sxph-NS shows significant survival benefits in both therapeutic and prophylactic regimens, without any apparent acute toxicity. Overall, the development of Neuron-MOF/Sxph-NS represents an important advancement in neurotoxin detoxification, offering promising potential for treating injuries and diseases caused by neurotoxins and addressing the current limitations in neurotoxin countermeasures.

Design Strategies for Cellular Nanosponges as Medical Countermeasures.

The interest in using therapeutic nanoparticles to bind with harmful molecules or pathogens and subsequently neutralize their bioactivity has grown tremendously. Among various nanomedicine platforms, cell membrane-coated nanoparticles, namely, "cellular nanosponges," stand out for their broad-spectrum neutralization capability challenging to achieve in traditional countermeasure technologies. Such ability is attributable to their cellular function-based rather than target structure-based working principle. Integrating cellular nanosponges with various synthetic substrates further makes their applications exceptionally versatile and adaptive. This review discusses the latest cellular nanosponge technology focusing on how the structure-function relationship in different designs has led to versatile and potent medical countermeasures. Four design strategies are discussed, including harnessing native cell membrane functions for biological neutralization, functionalizing cell membrane coatings to enhance neutralization capabilities, combining cell membranes and functional cores for multimodal neutralization, and integrating cellular nanosponges with hydrogels for localized applications. Examples in each design strategy are selected, and the discussion is to highlight their structure-function relationships in complex disease settings. The review may inspire additional design strategies for cellular nanosponges and fulfill even broader medical applications.

Programmed T cells infiltration into lung metastases with harnessing dendritic cells in cancer immunotherapies by catalytic antigen-capture sponges.

T lymphocytes served as immune surveillance to suppress metastases by physically interacting with cancer cells. Whereas tumor immune privilege and heterogeneity protect immune attack, it limits immune cell infiltration into tumors, especially in invasive metastatic clusters. Here, a catalytic antigen-capture sponge (CAS) containing the catechol-functionalized copper-based metal organic framework (MOF) and chloroquine (CQ) for programming T cells infiltration is reported. The intravenously injected CAS accumulates at the tumor via the folic acid-mediated target and margination effect. In metastases, Fenton-like reaction induced by copper ions of CAS disrupts the intracellular redox potential, i.e., chemodynamic therapy (CDT), thereby reducing glutathione (GSH) levels. Furthermore, CQ helps inhibit autophagy by inducing lysosomal deacidification during CDT. This process leads to the breakdown of self-defense mechanisms, which exacerbates cytotoxicity. The therapies promote the liberation of tumor-associated antigens, such as neoantigens and damage-associated molecular patterns (DAMPs). Subsequently, the catechol groups present on CAS perform as antigen reservoirs and transport the autologous tumor-associated antigens to dendritic cells, resulting in prolonged immune activation. The CAS, which is capable of forming in-situ, serves as an antigen reservoir in CDT-mediated lung metastasis and leads to the accumulation of immune cells in metastatic clusters, thus hindering metastatic tumors.

Exosome Processing and Characterization Approaches for Research and Technology Development.

Exosomes are extracellular vesicles that share components of their parent cells and are attractive in biotechnology and biomedical research as potential disease biomarkers as well as therapeutic agents. Crucial to realizing this potential is the ability to manufacture high-quality exosomes; however, unlike biologics such as proteins, exosomes lack standardized Good Manufacturing Practices for their processing and characterization. Furthermore, there is a lack of well-characterized reference exosome materials to aid in selection of methods for exosome isolation, purification, and analysis. This review informs exosome research and technology development by comparing exosome processing and characterization methods and recommending exosome workflows. This review also provides a detailed introduction to exosomes, including their physical and chemical properties, roles in normal biological processes and in disease progression, and summarizes some of the on-going clinical trials.

Nexus between Organizational Behavior and Managerial Skill of Sports Clubs in Olympic Games / Nexo entre Comportamiento Organizacional y Habilidad Gerencial de Clubes Deportivos en Juegos Olímpicos

Volunteers in sports, full-time employees, trainers, coaches, and administrative support personnel all have varying degrees of commitment to their careers and organizations. Athletes are encouraged to participate actively in sports by coaches, parents, and trainers. This benefits players by promoting physical fitness and a healthy lifestyle to increase international and local collaboration. A sports organization comprises a championship, players, managing board, local cooperation, leagues, sports clubs, and men's and women's teams that oversee and conduct the organization's activities. Whether temporary or permanent, sports organizations are tasked with the responsibility of safeguarding the rights of their members. The research design was chosen to collect data using a combination of purposive sampling and snowball sampling. Purposive sampling enabled researchers to select respondents familiar with the requisite degree of knowledge. A questionnaire was used to obtain the data. Fifty respondents took part in this study. Out of 50 responders, 35 were male, and 15 were female. SEM PLS 3.3.7v was used to evaluate the collected data. The findings demonstrated a high positive correlation between the factors.(AU)

Marginative Delivery-Mediated Extracellular Leakiness and T Cell Infiltration in Lung Metastasis by a Biomimetic Nanoraspberry.

T lymphocytes infiltrate the most devastating metastatic tumors for immunotherapy, allowing the potential for tumor metastasis suppression. However, tumor heterogeneity often restricts the infiltration of immune cells and possesses immune privilege that leads to protection from the immune attack, especially for invading metastatic clusters. Here, an exosome-camouflaged nanoraspberry (RB@Exo) doubling as a metastases-targeting agent and T cell-infiltration inducer that delivers an anticancer drug and energy is reported. The RB@Exo integrated an exosome-derived margination effect, and density-mediated nanoparticle-induced extracellular leakiness (nanoEL) exhibited more than a 70% colocalization of the RB@Exo to metastatic tumors in the lung in vivo. The release of cancer cell-cell interactions at the metastasis via nanoEL also elicited the 10-fold infiltration of T lymphocytes. The synergy of the T cell infiltration and photolytic effects transported by the RB@Exo deep into the metastatic tumors effectively inhibited the tumor in 60 days when treated with a single alternating magnetic field (AMF).

Injectable DNA-architected nanoraspberry depot-mediated on-demand programmable refilling and release drug delivery.

Drug delivery depots boosting a local concentration of therapeutic agents have received great attention in clinical applications due to their low occurrence of side effects and high therapeutic efficacy. However, once the payload is exhausted, the local drug concentration will be lower than the therapeutic window. To address this issue, an injectable double-strand deoxyribonucleic acid (DNA)-architected nanoraspberry depot (DNR-depot) was developed that can refill doxorubicin (Dox, an anticancer drug) from the blood and remotely control drug release on demand. The large porous surface on a uniform nanoraspberry (NR) filled covalently with DNA serves as a Dox sponge-like refilling reservoir, and the NR serves as a magnetic electrical absorber. Via the strong affinity between Dox and DNA molecules, the refilling process of Dox can be achieved on DNR-depot both in vitro and in vivo. Upon high-frequency magnetic field (HFMF) treatment, the remotely triggered release of Dox is actuated by the dissociation of Dox and DNA molecules, facilitating an approximately 800% improvement in drug concentration at the tumor site compared to free Dox injection alone. Furthermore, the cycles of refilling and release can be carried out more than 3 times in vivo within 21 days. The combination of refilling and HFMF-programmable Dox release in tumors via DNR-depot can effectively inhibit tumor growth for 30 days.

Palladium(II)-catalyzed one-pot syntheses of 9-(pyridin-2-yl)-9H-carbazoles through a tandem C-H activation/C-X (X=C or N) formation process.

A new one-pot synthesis of 9-(pyridin-2-yl)-9H-carbazoles through the simultaneous C-H activation and palladium(II)-catalyzed cross-coupling of N-phenylpyridin-2-amines with potassium aryltrifluoroborates is presented. Silver acetate and 1,4-dioxane proved to be the best oxidant and solvent, respectively. The product yields fluctuated from modest to excellent and the reaction showed sufficient functional group tolerance. p-Benzoquinone served as an important ligand for the transmetalation and reductive elimination steps in the catalytic process. The kinetic isotope effects (k(H)/k(D)) for the first and second C-H activation/C-C or C-N formation steps were measured as 2.14 and 1.18, respectively. Finally, a rational catalytic mechanism is presented based on all experimental evidence.

Residual stress in obliquely deposited MgF2 thin films.

MgF(2) films with a columnar microstructure are obliquely deposited on glass substrates by resistive heating evaporation. The columnar angles of the films increases with the deposition angle. Anisotropic stress does not develop in the films with tilted columns. The residual stresses in the films depend on the deposition and columnar angles in a columnar microstructure.