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Molecules (Basel, Switzerland) Jun 2024Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer's. Current drug discovery efforts have focused on molecules with tau fibril...
Exploring Tau Fibril-Disaggregating and Antioxidating Molecules Binding to Membrane-Bound Amyloid Oligomers Using Machine Learning-Enhanced Docking and Molecular Dynamics.
Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer's. Current drug discovery efforts have focused on molecules with tau fibril disaggregation and antioxidation functions. However, recent studies suggest that membrane-bound tau-containing oligomers (mTCOs), smaller and less ordered than tau fibrils, are neurotoxic in the early stage of Alzheimer's. Whether tau fibril-targeting molecules are effective against mTCOs is unknown. The binding of epigallocatechin-3-gallate (EGCG), CNS-11, and BHT-CNS-11 to in silico mTCOs and experimental tau fibrils was investigated using machine learning-enhanced docking and molecular dynamics simulations. EGCG and CNS-11 have tau fibril disaggregation functions, while the proposed BHT-CNS-11 has potential tau fibril disaggregation and antioxidation functions like EGCG. Our results suggest that the three molecules studied may also bind to mTCOs. The predicted binding probability of EGCG to mTCOs increases with the protein aggregate size. In contrast, the predicted probability of CNS-11 and BHT-CNS-11 binding to the dimeric mTCOs is higher than binding to the tetrameric mTCOs for the homo tau but not for the hetero tau-amylin oligomers. Our results also support the idea that anionic lipids may promote the binding of molecules to mTCOs. We conclude that tau fibril-disaggregating and antioxidating molecules may bind to mTCOs, and that mTCOs may also be useful targets for Alzheimer's drug design.
Topics: tau Proteins; Molecular Dynamics Simulation; Machine Learning; Molecular Docking Simulation; Humans; Protein Binding; Antioxidants; Amyloid; Catechin; Protein Aggregates
PubMed: 38930883
DOI: 10.3390/molecules29122818 -
Micromachines Jun 2024Partial-thickness corneal transplants using a deep anterior lamellar keratoplasty (DALK) approach has demonstrated better patient outcomes than a full-thickness cornea...
Partial-thickness corneal transplants using a deep anterior lamellar keratoplasty (DALK) approach has demonstrated better patient outcomes than a full-thickness cornea transplant. However, despite better clinical outcomes from the DALK procedure, adoption of the technique has been limited because the accurate insertion of the needle into the deep stroma remains technically challenging. In this work, we present a novel hands-free eye mountable robot for automatic needle placement in the cornea, AutoDALK, that has the potential to simplify this critical step in the DALK procedure. The system integrates dual light-weight linear piezo motors, an OCT A-scan distance sensor, and a vacuum trephine-inspired design to enable the safe, consistent, and controllable insertion of a needle into the cornea for the pneumodissection of the anterior cornea from the deep posterior cornea and Descemet's membrane. AutoDALK was designed with feedback from expert corneal surgeons and performance was evaluated by finite element analysis simulation, benchtop testing, and ex vivo experiments to demonstrate the feasibility of the system for clinical applications. The mean open-loop positional deviation was 9.39 µm, while the system repeatability and accuracy were 39.48 µm and 43.18 µm, respectively. The maximum combined thrust of the system was found to be 1.72 N, which exceeds the clinical penetration force of the cornea. In a head-to-head ex vivo comparison against an expert surgeon using a freehand approach, AutoDALK achieved more consistent needle depth, which resulted in fewer perforations of Descemet's membrane and significantly deeper pneumodissection of the stromal tissue. The results of this study indicate that robotic needle insertion has the potential to simplify the most challenging task of the DALK procedure, enable more consistent surgical outcomes for patients, and standardize partial-thickness corneal transplants as the gold standard of care if demonstrated to be more safe and more effective than penetrating keratoplasty.
PubMed: 38930758
DOI: 10.3390/mi15060788 -
Microorganisms Jun 2024() , a leading cause of sexually transmitted infections (STIs) worldwide, continues to be a significant public health concern. The majority of infections are... (Review)
Review
() , a leading cause of sexually transmitted infections (STIs) worldwide, continues to be a significant public health concern. The majority of infections are asymptomatic and, when left untreated, severe sequelae such as infertility and chronic pelvic pain can occur. Despite decades of research, an effective vaccine remains elusive. This review focuses on the potential of Major Outer Membrane Protein (MOMP)-derived constructs as promising candidates for vaccination. MOMP, the most abundant protein in the outer membrane of , has been a focal point of vaccine research over the years due to its antigenic properties. To overcome issues associated with the use of full MOMP as a vaccine antigen, derivative constructs have been studied. As these constructs are often not sufficiently immunogenic, antigen delivery systems or accompanying adjuvants are required. Additionally, several immunization routes have been explored with these MOMP-derived vaccine antigens, and determining the optimal route remains an ongoing area of research. Future directions and challenges in the field of vaccination are discussed.
PubMed: 38930578
DOI: 10.3390/microorganisms12061196 -
Microorganisms May 2024This study extensively analyzed the bacterial information of biofilms and activated sludge in oxic reactors of full-scale moving bed biofilm reactor-integrated...
This study extensively analyzed the bacterial information of biofilms and activated sludge in oxic reactors of full-scale moving bed biofilm reactor-integrated fixed-film activated sludge (MBBR-IFAS) systems. The bacterial communities of biofilms and activated sludge differed statistically (R = 0.624, < 0.01). The denitrifying genera , , , and were more abundant in activated sludge ( < 0.05), while comammox was more abundant in biofilms ( < 0.05), with an average relative abundance of 8.13%. and had weak co-occurrence relationships with other genera in the MBBR-IFAS systems. Potential function analysis revealed no differences in pathways at levels 1 and 2 based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) between biofilms and activated sludge. However, in terms of pathways at level 3, biofilms had more potential in 26 pathways, including various organic biodegradation and membrane and signal transportation pathways. In comparison, activated sludge had more potential in only five pathways, including glycan biosynthesis and metabolism. With respect to nitrogen metabolism, biofilms had greater potential for nitrification (ammonia oxidation) (M00528), and complete nitrification (comammox) (M00804) concretely accounted for methane/ammonia monooxygenase (K10944, K10945, and K10946) and hydroxylamine dehydrogenase (K10535). This study provides a theoretical basis for MBBR-IFAS systems from the perspective of microorganisms.
PubMed: 38930504
DOI: 10.3390/microorganisms12061121 -
Microorganisms May 2024aeruginosa is a pathogen that causes healthcare-associated infections (HAIs) worldwide. It is unclear whether isolated from the natural environment has the same...
aeruginosa is a pathogen that causes healthcare-associated infections (HAIs) worldwide. It is unclear whether isolated from the natural environment has the same pathogenicity and antimicrobial resistance potential as clinical strains. In this study, virulence- and resistance-associated genes were compared in 14 genomic sequences of clinical and environmental isolates of using the VFDB, PATRIC, and CARD databases. All isolates were found to share 62% of virulence genes related to adhesion, motility, secretion systems, and quorum sensing and 72.9% of resistance genes related to efflux pumps and membrane permeability. Our results indicate that both types of isolates possess conserved genetic information associated with virulence and resistance mechanisms regardless of the source. However, none of the environmental isolates were associated with high-risk clones (HRCs). These clones (ST235 and ST111) were found only in clinical isolates, which have an impact on human medical epidemiology due to their ability to spread and persist, indicating a correlation between the clinical environment and increased virulence. The genomic variation and antibiotic susceptibility of environmental isolates of suggest potential biotechnological applications if obtained from sources that are under surveillance and investigation to limit the emergence and spread of antibiotic resistant strains.
PubMed: 38930498
DOI: 10.3390/microorganisms12061116 -
Microorganisms May 2024Chagas Disease is a neglected tropical disease caused by the protozoan parasite affecting 6-8 million people, mainly in Latin America. The medical treatment is based on...
A Promising Amphotericin B Derivative Induces Morphological Alterations, Mitochondrial Damage, and Oxidative Stress In Vitro and Prevents Mice from Death Produced by a Virulent Strain of .
Chagas Disease is a neglected tropical disease caused by the protozoan parasite affecting 6-8 million people, mainly in Latin America. The medical treatment is based on two compounds, benznidazole and nifurtimox, with limited effectiveness and that produce severe side effects; consequently, there is an urgent need to develop new, safe, and effective drugs. Amphotericin B is the most potent antimycotic known to date. A21 is a derivative of this compound with the property of binding to ergosterol present in cell membranes of some organisms. In the search for a new therapeutic drug against , the objective of this work was to study the in vitro and in vivo effects of A21 derivative on . Our results show that the A21 increased the reactive oxygen species and reduced the mitochondrial membrane potential, affecting the morphology, metabolism, and cell membrane permeability of in vitro. Even more important was finding that in an in vivo murine model of infection, A21 in combination with benznidazole was able to reduce blood parasitemia, diminish the immune inflammatory infiltrate in skeletal muscle and rescue all the mice from death due to a virulent strain.
PubMed: 38930447
DOI: 10.3390/microorganisms12061064 -
Microorganisms May 2024Tumors of the central nervous system (CNS) are severe and refractory diseases with poor prognosis, especially for patients with malignant glioblastoma and brain... (Review)
Review
Tumors of the central nervous system (CNS) are severe and refractory diseases with poor prognosis, especially for patients with malignant glioblastoma and brain metastases. Currently, numerous studies have explored the potential role of bacteria and intestinal flora in tumor development and treatment. Bacteria can penetrate the blood-brain barrier (BBB), targeting the hypoxic microenvironment at the core of tumors, thereby eliminating tumors and activating both the innate and adaptive immune responses, rendering them promising therapeutic agents for CNS tumors. In addition, engineered bacteria and derivatives, such as bacterial membrane proteins and bacterial spores, can also be used as good candidate carriers for targeted drug delivery. Moreover, the intestinal flora can regulate CNS tumor metabolism and influence the immune microenvironment through the "gut-brain axis". Therefore, bacterial anti-tumor therapy, engineered bacterial targeted drug delivery, and intervention of the intestinal flora provide therapeutic modalities for the treatment of CNS tumors. In this paper, we performed a comprehensive review of the mechanisms and therapeutic practices of bacterial therapy for CNS tumors and discussed potential future research directions in this field.
PubMed: 38930435
DOI: 10.3390/microorganisms12061053 -
Materials (Basel, Switzerland) Jun 2024In this study, the potential of silk fibroin biomaterials for enhancing wound healing is explored, focusing on their integration into a human 3D ex vivo wound model...
In this study, the potential of silk fibroin biomaterials for enhancing wound healing is explored, focusing on their integration into a human 3D ex vivo wound model derived from abdominoplasties. For this purpose, cast silk fibroin membranes and electrospun nonwoven matrices from silk cocoons were compared to untreated controls over 20 days. Keratinocyte behavior and wound healing were analyzed qualitatively and quantitatively by histomorphometric and immune histochemical methods (HE, Ki67, TUNEL). Findings reveal rapid keratinocyte proliferation on both silk fibroin membrane and nonwoven matrices, along with enhanced infiltration in the matrix, suggesting improved early wound closure. Silk fibroin membranes exhibited a significantly improved early regeneration, followed by nonwoven matrices ( < 0.05) compared to untreated wounds, resulting in the formation of multi-layered epidermal structures with complete regeneration. Overall, the materials demonstrated excellent biocompatibility, supporting cell activity with no signs of increased apoptosis or early degradation. These results underscore silk fibroin's potential in clinical wound care, particularly in tissue integration and re-epithelialization, offering valuable insights for advanced and-as a result of the electrospinning technique-individual wound care development. Furthermore, the use of an ex vivo wound model appears to be a viable option for pre-clinical testing.
PubMed: 38930373
DOI: 10.3390/ma17123004 -
Journal of Clinical Medicine Jun 2024Critical illness creates challenges for healthcare providers in determining the optimal treatment of severe disease, particularly in determining the most appropriate... (Review)
Review
Critical illness creates challenges for healthcare providers in determining the optimal treatment of severe disease, particularly in determining the most appropriate selection and dosing of medications. Critically ill patients experience endogenous physiologic changes that alter the pharmacokinetics (PKs) of medications. These alterations can be further compounded by mechanical support modalities such as extracorporeal membrane oxygenation (ECMO). Specific components of the ECMO circuit have the potential to affect drug PKs through drug sequestration and an increase in the volume of distribution. Factors related to the medications themselves also play a role. These PK alterations create problems when trying to properly utilize antimicrobials in this patient population. The literature seeking to identify appropriate antimicrobial dosing regimens is both limited and difficult to evaluate due to patient variability and an inability to determine the exact role of the ECMO circuit in reduced drug concentrations. Lipophilic and highly protein bound medications are considered more likely to undergo significant drug sequestration in an ECMO circuit, and this general trend represents a logical starting point in antimicrobial selection and dosing in patients on ECMO support. This should not be the only consideration, however, as identifying infection and evaluating the efficacy of treatments in this population is challenging. Due to these challenges, therapeutic drug monitoring should be utilized whenever possible, particularly in cases with severe infection or high concern for drug toxicity.
PubMed: 38930083
DOI: 10.3390/jcm13123554 -
Journal of Clinical Medicine Jun 2024Various representations exist in the literature to visualize electrocochleography (ECochG) recordings along the basilar membrane (BM). This lack of generalization...
Various representations exist in the literature to visualize electrocochleography (ECochG) recordings along the basilar membrane (BM). This lack of generalization complicates comparisons within and between cochlear implant (CI) users, as well as between publications. This study synthesized the visual representations available in the literature via a systematic review and provides a novel approach to visualize ECochG data in CI users. A systematic review was conducted within PubMed and EMBASE to evaluate studies investigating ECochG and CI. Figures that visualized ECochG responses were selected and analyzed. A novel visualization of individual ECochG data, the ZH-ECochG Bode plot (ZH = Zurich), was devised, and the recordings from three CI recipients were used to demonstrate and assess the new framework. Within the database search, 74 articles with a total of 115 figures met the inclusion criteria. Analysis revealed various types of representations using different axes; their advantages were incorporated into the novel visualization framework. The ZH-ECochG Bode plot visualizes the amplitude and phase of the ECochG recordings along the different tonotopic regions and angular insertion depths of the recording sites. The graph includes the pre- and postoperative audiograms to enable a comparison of ECochG responses with the audiometric profile, and allows different measurements to be shown in the same graph. The ZH-ECochG Bode plot provides a generalized visual representation of ECochG data, using well-defined axes. This will facilitate the investigation of the complex ECochG potentials generated along the BM and allows for better comparisons of ECochG recordings within and among CI users and publications. The scripts used to construct the ZH-ECochG Bode plot are provided by the authors.
PubMed: 38929998
DOI: 10.3390/jcm13123470