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Theragnostic platforms, which integrate therapeutic and diagnostic capabilities, have gained significant interest in drug research because of to their potential advantages. This study reports the development of a novel multifunctional nanoparticle carrier system based on poly(ᴅ,ʟ-lactic-co-glycolic acid) (PLGA) for the targeted delivery of the chemotherapeutic agent chlorambucil (CHL) and the imaging agent IR780. The approach in this study incorporates Pluronic F127-folate onto the PLGA nanoparticles, which enables targeted delivery to folate receptor-expressing cancer cells. The F127-folate@PLGA/CHL/IR780 nanoparticles were formulated using a nanoprecipitation technique, resulting in small size, high homogeneity, and negative surface charge. Importantly, the folate-targeted nanoparticles demonstrated enhanced uptake and cytotoxicity in folate receptor-positive cancer cell lines (MCF-7 and HepG-2) compared to folate receptor-negative cells (HEK 293). Additionally, the F127-folate@PLGA/CHL/IR780 nanoparticles exhibited a lower IC50 value against cancer cells than non-targeted F127@PLGA/CHL/IR780 nanoparticles. These findings suggest that the developed F127-folate@PLGA/CHL/IR780 nanoparticles hold promise as a theragnostic system for targeted cancer therapy and diagnosis, leveraging the advantages of PLGA, folate targeting, and the integration of therapeutic and imaging agents.

Theragnostics has become a popular term nowadays, since it enables both diagnosis and therapy at the same time while only using one carrier platform. Therefore, formulating a nanocarrier system that could serve as theragnostic agent by using simple techniques would be an advantage during production. In this project, we aimed to develop a nanocarrier that can be loaded with the chemotherapeutic medication chlorambucil and magnetic resonance imaging agents (e.g., iron oxide nanoparticles and near-infrared fluorophore IR780) for theragnostics. Poly(lactic-co-glycolic acid) was combined with the aforementioned ingredients to generate poly(vinyl alcohol)-based nanoparticles (NPs) using the single emulsion technique. Then the NPs were coated with F127 and F127-folate by simple incubation for five days. The nanoparticles have the hydrodynamic size of approx. 250 nm with negative charge. Similar to chlorambucil and IR780, iron oxide loadings were observed for all three kinds of NPs. The release of chlorambucil was quicker at pH 5.4 than at pH 7.4 at 37 °C. The F127@NPs and F127-folate@NPs demonstrated much greater cell uptake and toxicity up to 72 h after incubation. Our in vitro results of F127@NPs and F127-folate@NPs have demonstrated the ability of these systems to serve as medication and imaging agent carriers for cancer treatment and diagnostics, respectively.

A well-known phenomenon in machinery systems is the easing of a blocked connection of mechanical parts after an impact hit close to the connection. Such impact hits may also arise in shaft–hub connections such as gears, crankshafts, or other parts. The objective of this study is to investigate the influence of local impact loads on the transmittable torque of smooth shaft–hub connections. In a specially designed test rig, it was demonstrated that the transmittable torque of the shaft–hub connection is reduced as a consequence of the impact, resulting in a reduction in the frictional force and slippage of the hub. Increasing the impact load leads to an increase in the reduction in the frictional force as well as the slippage and reduces the transmittable torque. By carrying out a modal analysis of the relevant parts and FE simulations of the impact, two possible reasons have been identified: (i) the impact load excites a vibration mode in the connection which reduces the frictional force and the transmittable torque; and (ii) the impact causes local deformation of the shaft, which results in local slip.

Abstract Background Parasitic infections can increase susceptibility to bacterial co-infections. This may be true for urogenital schistosomiasis and bacterial urinary tract co-infections (UTI). We previously reported that this co-infection is facilitated by S. haematobium eggs triggering interleukin-4 (IL-4) production and sought to dissect the underlying mechanisms. The interleukin-4-inducing principle from Schistosoma mansoni eggs (IPSE) is one of the most abundant schistosome egg-secreted proteins and binds to IgE on the surface of basophils and mast cells to trigger IL-4 release. IPSE can also translocate into host nuclei using a nuclear localization sequence (NLS) to modulate host transcription. We hypothesized that IPSE is the factor responsible for the ability of S. haematobium eggs to worsen UTI pathogenesis. Methods Mice were intravenously administered a single 25 μg dose of recombinant S. haematobium-derived IPSE, an NLS mutant of IPSE or PBS. Following IPSE exposure, mice were serially weighed and organs analyzed by histology to assess for toxicity. Twenty-four hours after IPSE administration, mice were challenged with the uropathogenic E. coli strain UTI89 by urethral catheterization. Bacterial CFU were measured using urine. Bladders were examined histologically for UTI-triggered pathogenesis and by PCR for antimicrobial peptide and pattern recognition receptor expression. Results Unexpectedly, IPSE administration did not result in significant differences in urine bacterial CFU. However, IPSE administration did lead to a significant reduction in UTI-induced bladder pathogenesis and the expression of anti-microbial peptides in the bladder. Despite the profound effect of IPSE on UTI-triggered bladder pathogenesis and anti-microbial peptide production, mice did not demonstrate systemic ill effects from IPSE exposure. Conclusions Our data show that IPSE may play a major role in S. haematobium-associated urinary tract co-infection, albeit in an unexpected fashion. These findings also indicate that IPSE either works in concert with other IL-4-inducing factors to increase susceptibility of S. haematobium-infected hosts to bacterial co-infection or does not contribute to enhancing vulnerability to this co-infection.

Abstract Background Schistosomiasis continues to inflict significant morbidity and mortality in the tropical and subtropical regions of the world. The disease endemicity overlaps with the transmission of other parasitic diseases. Despite the ubiquity of polyparasitism in tropical regions, particularly in rural communities, little is known about the impact of multiple helminth infections on disease progression. In this pilot study, we describe the influence of chronic Trichuris trichiura infection on Schistosoma mansoni egg-induced hepatopathology in infected baboons. Methods Baboons with or without underlying whipworm infection were challenged with S. mansoni cercariae to establish schistosomiasis. Adult S. mansoni worms were recovered by perfusion and enumerated, hepatic granulomas were quantified via light microscopy, and transcriptional profiling of tissues were completed using RNA sequencing technologies. Results Co-infection with both S. mansoni and T. trichiura resulted in higher female schistosome worm burden and significantly larger liver granuloma sizes. Systems biology analyses of peripheral blood mononuclear cells (PBMC) revealed pathways associated with increased liver damage in co-infected baboons. Conclusions Underlying chronic whipworm infection intensified schistosome egg-induced liver pathology in infected baboons. RNA-Seq analysis provided insight into pathways associated with increased liver damage, corroborating histological findings.

Recent advances in systems biology have shifted vaccine development from a largely trial-and-error approach to an approach that promote rational design through the search for immune signatures and predictive correlates of protection. These advances will doubtlessly accelerate the development of a vaccine for schistosomiasis, a neglected tropical disease that currently affects over 250 million people. For over 15 years and with contributions of over 120 people, we have endeavored to test and optimize Sm-p80-based vaccines in the non-human primate model of schistosomiasis. Using RNA-sequencing on eight different Sm-p80-based vaccine strategies, we sought to elucidate immune signatures correlated with experimental protective efficacy. Furthermore, we aimed to explore the role of antibodies through in vivo passive transfer of IgG obtained from immunized baboons and in vitro killing of schistosomula using Sm-p80-specific antibodies. We report that passive transfer of IgG from Sm-p80-immunized baboons led to significant worm burden reduction, egg reduction in liver, and reduced egg hatching percentages from tissues in mice compared to controls. In addition, we observed that sera from Sm-p80-immunized baboons were able to kill a significant percent of schistosomula and that this effect was complement-dependent. While we did not find a universal signature of immunity, the large datasets generated by this study will serve as a substantial resource for further efforts to develop vaccine or therapeutics for schistosomiasis.

For decades, mass drug treatment with praziquantel (PZQ) has been utilized to treat schistosomiasis, yet reinfection and the risk of drug resistance are among the various factors precluding successful elimination of schistosomiasis. Tractable models that replicate “real world” field conditions are crucial to effectively evaluate putative schistosomiasis vaccines. Herein, we describe the cellular immune responses and cytokine expression profiles under field conditions that include prior infection with schistosomes followed by treatment with PZQ. Baboons were exposed to Schistosoma mansoni cercariae through trickle infection over 5 weeks, allowed for chronic disease to develop, and then treated with PZQ. Peripheral blood mononuclear cells (PBMCs) were monitored for cellular immune response(s) at each disease stage and PZQ therapy. After initial infection and during chronic disease, there was an increase in non-classical monocytes, NK and NKT cells while the CD4:CD8 T cell ratio inverted from a 2:1 to 1:2.5. The cytokine expressions of PBMCs after trickle infections were polarized more toward a Th2 response with a gradual increase in Th1 cytokine expression at chronic disease stage. Following PZQ treatment, with the exception of an increase in B cells, immune cell populations reverted back toward naïve levels; however, expression of almost all Th1, Th2, and Th17 cytokines was significantly increased. This preliminary study is the first to follow the cellular immune response and cytokine expression profiles in a non-human primate model simulating field conditions of schistosomiasis and PZQ therapy, providing a promising reference in predicting the immune response to future vaccines for schistosomiasis.

This study presents a multilayer interval type-2 fuzzy controller, which applies to synchronize the hyperchaotic systems. The main contribution of this study is the design of a multilayer structure in the membership function space, which can improve the learning ability and flexibility of the type-2 fuzzy network. Using the proposed multilayer structure, the fuzzy network can reduce the number of rules while ensuring synchronization performance. Particularly, the design of 3-dimensional Gaussian membership functions (3-DGMFs) enhances the ability to against system uncertainties and external disturbances. Moreover, the structure of the proposed network can be autonomously constructed by using the self-evolving algorithm. The parameters of the proposed network are online updated using an adaptive law obtained by the gradient descent method. Finally, numerical simulations on the synchronization of hyperchaotic systems are conducted to validate the efficiency and performance of the proposed method.

In this study, we apply the Deep Deterministic Policy Gradient (DDPG) algorithm in reinforcement learning to control a double inverted pendulum on a cart (DIPC)-a high order single input-multi output (SIMO) system. The simulation results demonstrate DDPG's stability and effectiveness in achieving swing-up and balance, showing its potential for tackling challenging control tasks in robotics. [ABSTRACT FROM AUTHOR]