The Combination of Methionine Restriction and Docetaxel Synergistically Arrests Androgen-independent Prostate Cancer But Not Normal Cells.

Background/Aim: Androgen-independent prostate cancer (AIPC) is resistant to androgen-depletion therapy and is a recalcitrant disease. Docetaxel is the first-line treatment for AIPC, but has limited efficacy and severe side-effects. All cancers are methionine-addicted, which is termed the Hoffman effect. Recombinant methioninase (rMETase) targets methionine addiction. The purpose of the present study was to determine if the combination of docetaxel and rMETase is effective for AIPC. Materials and Methods: The half-maximal inhibitory concentrations (IC50) of docetaxel and rMETase alone were determined for the human AIPC cell line PC-3 and Hs27 normal human fibroblasts in vitro. The synergistic efficacy for PC-3 and Hs27 using the combination of docetaxel and rMETase at their IC50s for PC-3 was determined. Results: The IC50 of docetaxel for PC-3 and for Hs27 was 0.72 nM and 0.94 nM, respectively. The IC50 of rMETase for PC-3 and for Hs27 was 0.67 U/ml and 0.76 U/ml, respectively. The combination of docetaxel and rMETase was synergistic for PC-3 but not Hs27 cells. Conclusion: The combination of a relatively low concentration of docetaxel and rMETase was synergistic and effective for AIPC. The present results also suggest that the effective concentration of docetaxel can be reduced by using rMETase, which may reduce toxicity. The present results also suggest the future clinical potential of the combination of docetaxel and rMETase for AIPC.

Synergy of Rapamycin and Methioninase on Colorectal Cancer Cells Requires Simultaneous and Not Sequential Administration: Implications for mTOR Inhibition.

Background/Aim: Rapamycin inhibits the mTOR protein kinase. Methioninase (rMETase), by degrading methionine, targets the methionine addiction of cancer cells and has been shown to improve the efficacy of chemotherapy drugs, reducing their effective doses. Our previous study demonstrated that rapamycin and rMETase work synergistically against colorectal-cancer cells, but not on normal cells, when administered simultaneously in vitro. In the present study, we aimed to further our previous findings by exploring whether  synergy exists between rapamycin and rMETase when used sequentially against HCT-116 colorectal-carcinoma cells, compared to simultaneous administration, in vitro. Materials and Methods: The half-maximal inhibitory concentrations (IC50) of rapamycin alone and rMETase alone against the HCT-116 human colorectal-cancer cell line were previously determined using the CCK-8 cell viability assay (11). We then examined the efficacy of rapamycin and rMETase, both at their IC50, administered simultaneously or sequentially on the HCT-116 cell line, with rapamycin administered before rMETase and vice versa. Results: The IC50 for rapamycin and rMETase, determined from previous experiments (11), was 1.38 nM and 0.39 U/ml, respectively, of HCT-116 cells. When rMETase was administered four days before rapamycin, both at the IC50, there was a 30.46% inhibition of HCT-116 cells. When rapamycin was administered four days before rMETase, both at the IC50, there was an inhibition of 41.13%. When both rapamycin and rMETase were simultaneously administered, both at the IC50, there was a 71.03% inhibition. Conclusion: Rapamycin and rMETase have synergistic efficacy against colorectal-cancer cells in vitro when administered simultaneously, but not sequentially.

Sensomics-assisted analysis unravels the formation of the Fungus Aroma of Fu Brick Tea.

Fu Brick Tea (FBT) is characterized by Fungus Aroma (FA), which determines the quality of FBT products. However, the aroma constituents and their interactive mechanism for FA remain unclear. In this study, the FBT sample with the optimal FA characteristics was selected from 29 FBTs. Then, 19 components with OAV ≥ 1 were identified as the odorants involved in the FA formation. The aroma recombination test suggested that the FA was potentially produced by the synergistic interplay among the 15 key odorants, including (E,E)-2,4-heptadienal, (E,E)-2,4-nonadienal, (E)-2-nonenal, (E,Z)-2,6-nonadienal, (E)-2-octenal, (E)-ß-ionone, 4-ketoisophorone, dihydroactinidiolide, (E)-ß-damascenone, 1-octen-3-ol, linalool, geraniol, heptanal, hexanal, and phenylacetaldehyde. And, the synergistic effects between them were preliminarily studied by aroma omissions, such as modulatory effects, masking effects, compensatory effects, and novelty effects, ultimately contributing to the FA. In all, this work helps us better understand the formation of the FA and provides a basis for the improvement of FBT production technology.

MnFe2O4/MoS2 catalyst used for ozonation: optimization and mechanism analysis of phenolic wastewater treatment.

The performance of catalytic ability of MFe2O4/MoS2 in the ozonation process was investigated in this work. The synthesized MnFe2O4/MoS2 was optimize prepared and then characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray photo-electron spectroscopy, and magnetic saturation strength. The results showed that when Cphenol = 200 mg/L, initial pH = 9.0, Q = 0.10 L/min, and CMnFe2O4/MoS2 = 0.10 g/L, MnFe2O4/MoS2 addition improved the degradation efficiency of phenol by 20.0%. The effects of pH, catalyst dosage, and inorganic ions on the phenol removal by the MnFe2O4/MoS2 catalytic ozonation were investigated. Five cycle experiments proved that MnFe2O4/MoS2 had good recyclability and stability. MnFe2O4/MoS2 also showed good catalytic performance in the treatment of coal chemical wastewater pesticide wastewater. The MnFe2O4 doped with MoS2 could provide abundant surface active sites for ozone and promote the stable cycle of Mn2+/Mn3+and Fe2+/Fe3+, thus generating large amounts of •OH and improving the degradation of phenol by ozonation. The MnFe2O4/MoS2/ozonation treatment system provides a technical reference and theoretical basis for industrial wastewater treatment.

Antioxidant synergistic anti-inflammatory effect in the MAPK/NF-κB pathway of peptide KGEYNK (KK-6) from giant salamander (Andrias davidianus).

BACKGROUND: Giant salamander protein peptide is a peptide with rich functional properties. Giant salamander protein peptide KGEYNK (KK-6) is a peptide with both antioxidant and anti-inflammatory properties. The antioxidant and anti-inflammatory mechanisms of KK-6 are still unclear. When we studied the functional mechanism of KK-6, we found that the antioxidant property of KK-6 has a synergistic and promoting effect on anti-inflammatory properties. RESULTS: KK-6 enhances cellular resistance to LPS via the MAPK/NF-κB signaling pathway, leading to increased levels of inflammatory factors: interleukin-1ß (764.81 ng mL-1), interleukin-6 (1.06 ng mL-1) and tumor necrosis factor-α (4440.45 ng mL-1). KK-6 demonstrates potent antioxidant properties by activating the Nrf2 signaling pathway, resulting in elevated levels of antioxidant enzymes (glutathione peroxidase: 0.03 µg mL-1; superoxide dismutase: 0.589 µg mL-1) and a reduction in the concentration of the oxidative product malondialdehyde (967.05 µg mL-1). CONCLUSION: Our findings highlight the great potential of KK-6, a peptide extracted from giant salamander protein, as a remedy for intestinal inflammation. Through its dual role as an antioxidant and anti-inflammatory agent, KK-6 offers a promising avenue for alleviating inflammation-related damage and oxidative stress. This study lays the foundation for further exploration of giant salamander products and highlights their importance in health and novel food development. © 2024 Society of Chemical Industry.

Modulate synthesis of CeMn solid solution using various alcohols for toluene catalytic oxidation: synergistic effect of Ce-Mn and reaction mechanism.

A redox co-precipitation method was employed to synthesize CeMn homogeneous solid solutions, utilizing various alcohols as activating agents. Ethanol effectively orchestrated the precipitation of CeO2 and MnOx, promoting their co-growth. As a result, the CeMn-EA achieved 90 % toluene conversion at 218 â„ƒ (T90 =218 â„ƒ) with a weight hourly space velocity (WHSV) of 48000 ml/(g·h). It also demonstrated high adaptability to increased WHSV, suggesting its potential for industrial-scale applications. The uniform dispersion of Ce and Mn accelerated the coupling between Ce3+/Ce4+ and Mn4+/Mn3+, engineering numerous oxygen vacancies, which enhanced the activation of gas-phase oxygen and the mobility of lattice oxygen. In situ DRIFTS confirmed that toluene oxidation accommodated both Langmuir-Hinshelwood (L-H) and Mars-van Krevelen (MvK) mechanisms, with benzoate identified as a pivotal intermediate. Enhanced oxygen mobility facilitated the cleavage of the benzene ring, which was the rate-determining step. Additionally, the introduction of H2O significantly enhanced the dissociation and adsorption of toluene and facilitated the activation of gas-phase oxygen. At higher temperatures, H2O could further activate lattice oxygen engaging in toluene oxidation. ENVIRONMENTAL IMPLICATION: Volatile organic compounds (VOCs) have emerged as major air pollutants due to the changes in air pollution patterns. They can act as precursors to near-surface ozone and haze. Toluene, a typical VOC, is primarily released from anthropogenic sources and poses significant risks to human health and the environment. Ce-based catalysts have been demonstrated efficiency in toluene oxidation due to their excellent oxygen storage and release properties. This study synthesized CeMn homogeneous solid solutions utilizing various alcohols as activating agents, which possessed abundant oxygen vacancies and optimum oxygen activation capacity to oxidize toluene in time.

Potent synergy and sustained bactericidal activity of polymyxins combined with Gram-positive only class of antibiotics versus four Gram-negative bacteria.

BACKGROUND: Gram-negative bacteria (GNB) are becoming increasingly resistant to a wide variety of antibiotics. There are currently limited treatments for GNB, and the combination of antibiotics with complementary mechanisms has been reported to be a feasible strategy for treating GNB infection. The inability to cross the GNB outer membrane (OM) is an important reason that a broad spectrum of Gram-positive only class of antibiotics (GPOAs) is lacking. Polymyxins may help GPOAs to permeate by disrupting OM of GNB. OBJECTIVE: To identify what kind of GPOAs can be aided to broaden their anti-GNB spectrum by polymyxins, we systematically investigated the synergy of eight GPOAs in combination with colistin (COL) and polymyxin B (PMB) against GNB in vitro. METHODS: The synergistic effect of COL or PMB and GPOAs combinations against GNB reference strains and clinical isolates were determined by checkerboard tests. The killing kinetics of the combinations were assessed using time-kill assays. RESULTS: In the checkerboard tests, polymyxins-GPOAs combinations exert synergistic effects characterized by species and strain specificity. The synergistic interactions on P. aeruginosa strains are significantly lower than those on strains of A. baumannii, K. pneumoniae and E. coli. Among all the combinations, COL has shown the best synergistic effect in combination with dalbavancin (DAL) or oritavancin (ORI) versus almost all of the strains tested, with FICIs from 0.16 to 0.50 and 0.13 to < 0.28, respectively. In addition, the time-kill assays demonstrated that COL/DAL and COL/ORI had sustained bactericidal activity. CONCLUSIONS: Our results indicated that polymyxins could help GPOAs to permeate the OM of specific GNB, thus showed synergistic effects and bactericidal effects in the in vitro assays. In vivo combination studies should be further conducted to validate the results of this study.

Combined effects of microplastics and pharmaceutical and personal care products on algae: A critical review.

Microplastics (MPs) and pharmaceuticals and personal care products (PPCPs) are ubiquitous in aquatic environments. Algae play an important role in aquatic environments. Thus, it is important to study the response of algae to combined exposure of MPs and PPCPs. Here, we review the effects of MPs and PPCPs on algae. First, the individual effects of MPs and PPCPs on algae were summarized. Second, the combined effects of MPs and PPCPs on algae were systematically analyzed. (1) Antagonism: ① when the MPs are too large to enter the algal cells, the adsorption of PPCPs onto MPs results in decreased the contact of MPs and PPCPs with algae; ② PPCPs and MPs have opposing actions on the same biological target; ③ MPs increase the activity of metabolic enzymes in algae, thus promoting the PPCP degradation. (2) Synergy: ① when the MPs are small enough to enter algal cells, the adsorption of PPCPs on MPs promotes the entry of PPCPs; ② when MPs are negatively charged, the adsorption of positively charged PPCPs by MPs decreases the electrostatic repulsion, increasing the interaction between algae and MPs; ③ complementary modes of action between MPs and PPCPs show combined effects on the same biological target. Third, the relative importance of the factors that impact the combined effects are evaluated using the random forest model decreased in the following order: PPCP types > algal species > MP size > MP concentration > MP types > exposure time. Finally, future directions for the combined effects of MPs and PPCPs are proposed, which will facilitate a better understanding of the environmental fate and risks of both MPs and PPCPs.

The interactive effects of medicinal dyes with conventional antimicrobials against skin pathogens.

AIMS: This study aimed to explore potential synergistic effects of medicinal dyes with antimicrobials against pathogens responsible for skin infections. METHODS AND RESULTS: Antimicrobial testing was conducted using minimum inhibitory concentrations and minimum bactericidal/fungicidal concentration assays. The fractional inhibitory index (ΣFIC) of combinations was calculated, and isobolograms were constructed on selected combinations. Toxicity studies were conducted using the brine-shrimp lethality assay. Combination (1:1 ratio) studies noted that 26% of dye-antibiotic combinations were synergistic against the Gram-positive strains, 15% against the Gram-negative strains, and 14% against the yeasts. The Mercurochrome: Betadine® combination noted synergy at ratios against all the Staphylococcus aureus strains with ΣFIC values ranging from 0.05 to 0.48. The combination of Gentian violet with Gentamycin noted a 15-fold decrease in toxicity, and a selectivity index of 977.50 against the Escherichia coli (DSM 22314) strain. Time-kill studies were conducted on the combinations with the highest safe selectivity index (SI) value and lowest safe SI value i.e. Gentian violet with Gentamycin and Malachite green with Neomycin. Both combinations demonstrated better antimicrobial activity in comparison to the independent values and the controls. CONCLUSION: This study highlights the potential for medicinal dye combinations as a treatment for skin infections.

Improved control of Trialeurodes vaporariorum using mixture combinations of entomopathogenic fungi and the chemical insecticide spiromesifen.

Greenhouse whitefly (Trialeurodes vaporariorum) is a major global pest, causing direct damage to plants and transmitting viral plant diseases. Management of T. vaporariorum is problematic because of widespread pesticide resistance, and many greenhouse growers rely on biological control agents to regulate T. vaporariorum populations. However, these are often slow and vary in efficacy, leading to subsequent application of chemical insecticides when pest populations exceed threshold levels. Combining chemical and biological pesticides has great potential but can result in different outcomes, from positive to negative interactions. In this study, we evaluated co-applications of the entomopathogenic fungi (EPF) Beauveria bassiana and Cordyceps farinosa and the chemical insecticide spiromesifen in laboratory bioassays. Complex interactions between the EPFs and insecticide were described using an ecotoxicological mixtures model, the MixTox analysis. Depending on the EPF and chemical concentrations applied, mixtures resulted in additivity, synergism, or antagonism in terms of total whitefly mortality. Combinations of B. bassiana and spiromesifen, compared to single treatments, increased the rate of kill by 5 days. Results indicate the potential for combined applications of EPF and spiromesifen as an effective integrated pest management strategy and demonstrate the applicability of the MixTox model to describe complex mixture interactions.

Spatial scale effects on the value of ecosystem services in China's terrestrial area.

Identifying the response characteristics of ecosystem service value (ESV) to changes in spatial scales, known as spatial scale effects, is crucial in guiding the development of corresponding management strategies. This paper examines ESV in China's terrestrial area during the year 2020, revealing the spatial aggregation characteristics of ESV and the trade-off and synergistic relationships of ecosystem services at different spatial scales, ranging from 1 km × 1 km-10 km × 10 km, with a gradient of 1 km. The results indicate: 1) The distribution pattern of ESV in China's terrestrial area is "high in the southeast and low in the northwest." 2) The spatial characteristics of ESV in China's terrestrial area undergo a distinct transition at the 3 km × 3 km scale. In detail, the spatial clustering features show a trend of first rising and then falling with the increase in spatial scale, while the synergistic relationships between different ecosystem services strengthen and the trade-off relationships weaken with the increase of the spatial scale. These findings can inform the formulation of differentiated ecological protection compensation policies and enable cross-area trading of ecological values in China.

Two aspects of feed-forward control of action stability: effects of action speed and unexpected events.

We explored two types of anticipatory synergy adjustments (ASA) during accurate four-finger total force production task. The first type is a change in the index of force-stabilizing synergy during a steady state when a person is expecting a signal to produce a quick force change, which is seen even when the signal does not come (steady-state ASA). The other type is the drop in in the synergy index prior to a planned force change starting at a known time (transient ASA). The subjects performed a task of steady force production at 10% of maximal voluntary contraction (MVC) followed by a ramp to 20% MVC over 1 s, 3 s, and as a step function (0 s). In another task, in 50% of the trials during the steady-state phase, an unexpected signal could come requiring a quick force pulse to 20% MVC (0-surprise). Inter-trial variance in the finger force space was used to quantify the index of force-stabilizing synergy within the uncontrolled manifold hypothesis. We observed significantly lower synergy index values during the steady state in the 0-ramp trials compared to the 1-ramp and 3-ramp trials. There was also larger transient ASA during the 0-ramp trials. In the 0-surprise condition, the synergy index was significantly higher compared to the 0-ramp condition whereas the transient ASA was significantly larger. The finding of transient ASA scaling is of importance for clinical studies, which commonly involve populations with slower actions, which can by itself be associated with smaller ASAs. The participants varied the sharing pattern of total force across the fingers more in the task with "surprises". This was coupled to more attention to precision of performance, i.e., inter-trial deviations from the target as reflected in smaller variance affecting total force, possibly reflecting higher concentration on the task, which the participants perceived as more challenging compared to a similar task without surprise targets.

Atomically Dispersed Fe-Cu Dual-Metal Sites Synergistically Boost Carbonylation of Methane.

The production of acetic acid, an important industrial chemical traditionally obtained through the carbonylation of methanol using noble metal-based homogeneous catalysts, encounters challenges arising from high equipment costs and sustainability concerns. The direct liquid-phase oxidative carbonylation of methane emerges as a promising alternative, capitalizing on abundant natural gas resources and featuring a potentially mild and straightforward process. However, most catalysts proposed for this process suffer from low acetic acid yields due to the scarcity of active sites and the swift generation of C1 oxygenates, posing difficulties for subsequent carbonylation and impeding their industrial feasibility. Herein, we report a highly efficient 0.1Cu/Fe-HZ5-TF catalyst featuring exclusively mononuclear Fe and Cu anchored in the ZSM-5 channels. Under optimized conditions, the catalyst achieved an unprecedented acetic acid yield of 40.5 mmol gcat-1 h-1 at 50 °C, surpassing the previous maximum (12.0 mmol gcat-1h-1) by more than threefold. Comprehensive characterization, isotope-labeled experiments and DFT calculations reveal that the homogeneous mononuclear Fe sites are responsible for the activation and oxidation of methane, while the neighboring Cu sites play a key role in retarding the oxidation process. This synergistic action promotes C-C coupling, resulting in the efficient synthesis of acetic acid.

Investigating Combination Therapy as a Means to Enhance Activity and Repurpose Antimicrobials.

Current clinical practice assumes that a single antibiotic given as a bolus or as a course will successfully treat most infections. In modern medicine, this is becoming less and less true with drug-resistant, multi-drug-resistant, extensively drug-resistant, and untreatable infections becoming more common. Where single-drug therapy (monotherapy) fails, we will turn to multi-drug therapy. Alternatively, combination therapy could be useful to prevent the emergence of resistance. Multi-drug therapy is already standard for some multi-drug resistant infections and is the standard for the treatment of some pathogens such as Mycobacterium tuberculosis.The use of combination therapy for everyday infections could be a clear course out of the current AMR crisis we are facing. With every additional drug added to a combination (n + 1) the likelihood of the pathogen evolving resistance drops exponentially.Many generic antibiotics are cheap to manufacture as they have fallen out of patent protection but are less effective at pharmacologically effective doses due to overuse in the past. Combination therapy can combine these generic compounds into cocktails that can not only treat susceptible and resistant infections but can also reduce the risk of new resistances arising and can resuscitate the use of antimicrobials once thought defunct.In this chapter, we will summarize theory behind combination therapy and standard in vitro methodologies used.

Concerto of movement: how expertise shapes the synergistic control of upper limb muscles in complex motor tasks with varying tempo and dynamics.

Objective. This research aims to reveal how the synergistic control of upper limb muscles adapts to varying requirements in complex motor tasks and how expertise shapes the motor modules.Approach. We study the muscle synergies of a complex, highly skilled and flexible task-piano playing-and characterize expertise-related muscle-synergy control that permits the experts to effortlessly execute the same task at different tempo and force levels. Surface EMGs (28 muscles) were recorded from adult novice (N= 10) and expert (N= 10) pianists as they played scales and arpeggios at different tempo-force combinations. Muscle synergies were factorized from EMGs.Main results. We found that experts were able to cover both tempo and dynamic ranges using similar synergy selections and achieved better performance, while novices altered synergy selections more to adapt to the changing tempi and keystroke intensities compared with experts. Both groups relied on fine-tuning the muscle weights within specific synergies to accomplish the different task styles, while the experts could tune the muscles in a greater number of synergies, especially when changing the tempo, and switch tempo over a wider range.Significance. Our study sheds light on the control mechanism underpinning expertise-related motor flexibility in highly skilled motor tasks that require decade-long training. Our results have implications on musical and sports training, as well as motor prosthetic design.

Stretchable and Self-Powered Mechanoluminescent Triboelectric Nanogenerator Fibers toward Wearable Amphibious Electro-Optical Sensor Textiles.

Flexible electro-optical dual-mode sensor fibers with capability of the perceiving and converting mechanical stimuli into digital-visual signals show good prospects in smart human-machine interaction interfaces. However, heavy mass, low stretchability, and lack of non-contact sensing function seriously impede their practical application in wearable electronics. To address these challenges, a stretchable and self-powered mechanoluminescent triboelectric nanogenerator fiber (MLTENGF) based on lightweight carbon nanotube fiber is successfully constructed. Taking advantage of their mechanoluminescent-triboelectric synergistic effect, the well-designed MLTENGF delivers an excellent enhancement electrical signal of 200% and an evident optical signal whether on land or underwater. More encouragingly, the MLTENGF device possesses outstanding stability with almost unchanged sensitivity after stretching for 200%. Furthermore, an extraordinary non-contact sensing capability with a detection distance of up to 35 cm is achieved for the MLTENGF. As application demonstrations, MLTENGFs can be used for home security monitoring, intelligent zither, traffic vehicle collision avoidance, and underwater communication. Thus, this work accelerates the development of wearable electro-optical textile electronics for smart human-machine interaction interfaces.

Isolation and characterization of bacteriophages against E.coli urinary tract infection and evaluating their anti-biofilm activity and antibiotic synergy.

Urinary tract infections (UTIs) by Uropathogenic Escherichia coli (UPEC) are a significant health concern, especially due to the increasing prevalence of antibiotic resistance. This study focuses on isolating and characterizing bacteriophages specific to UPEC strains isolated from UTI samples. The isolated phages were assessed for their ability to target and lyse UPEC in vitro, focusing on their efficacy in disrupting biofilms, a key virulence factor contributing to UTI recurrence and antibiotic resistance. The morphological structure observed by TEM belongs to Myoviridae, the phage exhibited icosahedral symmetry with a long non-constricting tail, the approximate measurement of the phage head was 39 nm in diameter, and the phage tail was 105.317 nm in length. One-step growth experiments showed that the latent period was approximately 20 min, followed by a rise period of 40 min, and a growth plateau was reached within 20 min and the burst size observed was 26 phages/infected bacterial cells. These phages were capable of killing cells within the biofilms, leading to a reduction in living cell counts after a single treatment. This study highlights the potential of phages to play a significant role in disrupting, inactivating, and destroying Uropathogenic Escherichia coli (UPEC) biofilms. Such findings could be instrumental in developing treatment strategies that complement antibiotics and disinfectants. The phage-antibiotic synergistic activity was compared to have the possibility to facilitate the advancement of focused and enduring alternatives to traditional antibiotic therapies for UTIs.

Microbial diversity and ecological complexity emerging from environmental variation and horizontal gene transfer in a simple mathematical model.

BACKGROUND: Microbiomes are generally characterized by high diversity of coexisting microbial species and strains, and microbiome composition typically remains stable across a broad range of conditions. However, under fixed conditions, microbial ecology conforms with the exclusion principle under which two populations competing for the same resource within the same niche cannot coexist because the less fit population inevitably goes extinct. Therefore, the long-term persistence of microbiome diversity calls for an explanation. RESULTS: To explore the conditions for stabilization of microbial diversity, we developed a simple mathematical model consisting of two competing populations that could exchange a single gene allele via horizontal gene transfer (HGT). We found that, although in a fixed environment, with unbiased HGT, the system obeyed the exclusion principle, in an oscillating environment, within large regions of the phase space bounded by the rates of reproduction and HGT, the two populations coexist. Moreover, depending on the parameter combination, all three major types of symbiosis were obtained, namely, pure competition, host-parasite relationship, and mutualism. In each of these regimes, certain parameter combinations provided for synergy, that is, a greater total abundance of both populations compared to the abundance of the winning population in the fixed environment. CONCLUSIONS: The results of this modeling study show that basic phenomena that are universal in microbial communities, namely, environmental variation and HGT, provide for stabilization and persistence of microbial diversity, and emergence of ecological complexity.

Synergistic Targeting of Innate Receptors TLR7 and NOD2 for Therapeutic Intervention in Multiple Sclerosis.

Regulation of neuroinflammation is critical for maintaining central nervous system (CNS) homeostasis and holds therapeutic promise in autoimmune diseases such as multiple sclerosis (MS). Previous studies have highlighted the significance of selective innate signaling in triggering anti-inflammatory mechanisms, which play a protective role in an MS-like disease, experimental autoimmune encephalomyelitis (EAE). However, the individual intra-CNS administration of specific innate receptor ligands or agonists, such as for toll-like receptor 7 (TLR7) and nucleotide-binding oligomerization-domain-containing protein 2 (NOD2), failed to elicit the desired anti-inflammatory response in EAE. In this study, we investigated the potential synergistic effect of targeting both TLR7 and NOD2 simultaneously to prevent EAE progression. Our findings demonstrate that simultaneous intrathecal administration of NOD2- and TLR7-agonists led to synergistic induction of Type I IFN (IFN I) and effectively suppressed EAE in an IFN I-dependent manner. Suppression of EAE was correlated with a significant decrease in the infiltration of monocytes, granulocytes, and natural killer cells, reduced demyelination, and downregulation of IL-1ß, CCL2, and IFNγ gene expression in the spinal cord. These results underscore the therapeutic promise of concurrently targeting the TLR7 and NOD2 pathways in alleviating neuroinflammation associated with MS, paving the way for novel and more efficacious treatment strategies.

Investigation of the Antitrichomonal Activity of Cinnamaldehyde, Carvacrol and Thymol and Synergy with Metronidazole.

Objective: Trichomonas vaginalis is a sexually transmitted protozoan parasite that usually causes infections in women. Metronidazole is used as the first choice in the treatment of this parasitic disease, but there is a need for new drugs since 1980's with increasing numbers of reported resistance. In this study, it was aimed to determine the antitrichomonal activity of the major components of Cinnamomum zeylanicum (cinnamon) and Thymus vulgaris (thyme) essential oils, cinnamaldehyde, carvacrol and thymol against metronidazole resistant and susceptible T. vaginalis strains, and to determine their interaction with metronidazole by checkerboard method. Methods: Cinnamaldehyde, carvacrol, thymol and metronidazole were obtained commercially. Two clinical isolates and one metronidazole resistant T. vaginalis reference strain were used in the study. MIC50 and MLC values of essential oil components and metronidazole were determined by broth microdilution method. The combinations of essential oil components with metronidazole were determined by the checkerboard method. Results: According to in vitro activity tests, cinnamaldehyde was determined to be most effective essential oil component. Clinical isolates were susceptible to metronidazole. In combination study, metronidazole showed synergy with cinnamaldehyde and carvacrol, and partial synergy with thymol. Conclusion: It was determined that cinnamaldehyde, carvacrol and thymol, which are known to have high antimicrobial activity, also have strong activity against T. vaginalis isolates and show a synergistic interaction with metronidazole. The use of metronidazole at lower doses in the synergistic interaction may contribute to the literature in terms of reducing drug side effects, creating a versatile antimicrobial target, and reducing the rate of resistance development.