Search Results (21,967)

Inappropriate use of antibiotics can stimulate antimicrobial resistance, since bacteria are capable of circumventing pharmacological action through various resistance mechanisms. Recently, during the COVID-19 pandemic, there has been an increase in the use of antimicrobials. This is an analytical, quantitative, and retrospective study on bacterial resistance and mortality in Intensive Care Unit (ICU) patients from 2017 to 2022. This study analyzed sociodemographic aspects, clinical, and laboratory parameters in patients admitted to the ICU. A total of 221 medical records of patients with multidrug-resistant bacteria in the ICU were included, with an outcome of 95 discharges (42.98%) and 126 deaths (53.01%). An increase in the prevalence of bacterial resistance in the ICU was identified during the Pandemic period, when compared to the Pre-Pandemic period. It was identified that the increase in bacterial resistance of some pathogens was associated with death. It was also observed that age was a factor for an increased risk of mortality in the ICU, no matter the sex of the patient. Importance of careful analysis in the use of antimicrobials, as well as in the care of ICU patients and in the surveillance of bacterial infections by health professionals. Full article

To address the low trajectory tracking accuracy and limited robustness of conventional reinforcement learning algorithms under complex marine environments involving wind, wave, and current disturbances, this study proposes a proximal policy optimization (PPO) algorithm incorporating an intrinsic curiosity mechanism to solve the unmanned surface vehicle (USV) trajectory tracking control problem. The proposed approach is developed on the basis of a three-degree-of-freedom (3-DOF) USV model and formulated within a Markov decision process (MDP) framework, where a multidimensional state space and a continuous action space are defined, and a multi-objective composite reward function is designed. By incorporating a pure pursuit guidance algorithm, the complexity of engineering implementation is reduced. Furthermore, an improved PPO algorithm integrated with an intrinsic curiosity mechanism is adopted as the trajectory tracking controller, in which the exploration incentives provided by the intrinsic curiosity module (ICM) guide the agent to explore the state space efficiently and converge rapidly to an optimal control policy. The final experimental results indicate that, compared with the conventional PPO algorithm, the improved PPO–ICM controller achieves a reduction of 54.2% in average lateral error and 47.1% in average heading error under simple trajectory conditions. Under the complex trajectory condition, the average lateral error and average heading error are reduced by 91.8% and 41.9%, respectively. These results effectively demonstrate that the proposed PPO–ICM algorithm attains high tracking accuracy and strong generalization capability across different trajectory scenarios, and can provide a valuable reference for the application of intelligent control algorithms in the USV domain. Full article

Background/Objectives: Colistin (polymyxin E) has re-emerged as a last-hope treatment against MDR Gram-negative pathogens due to the development of extensively drug-resistant Gram-negative bacteria. Unfortunately, rapid global resistance towards colistin has emerged, which represents a major public health concern. In this context (CBD), a lipophilic molecule derived from Cannabis sativa, exhibits antimicrobial activity mainly against Gram-positive bacteria but is generally ineffective against Gram-negative species. However, synergistic antibacterial activity between CBD and polymyxin B has been reported. The objective of this work is to analyze the colistin–CBD synergy against clinically relevant Gram-negative isolates displaying diverse mechanisms of colistin resistance and to explore the basis of the possible mechanism of action involved in the first steps of this synergy. Methods: Microbiological assays, minimal inhibitory concentration, cell culture, synergy tests by checker board and time kill, biofilm inhibition evaluation by crystal violet and MTT, SEM (scanning electron microscopy), molecules interaction analysis by nuclear magnetic resonance (NMR). Results: The colistin–CBD combination displayed synergy in colistin resistant Gram-negative bacteria and also disrupted preformed biofilms and killed bacteria within them. Time-kill assays revealed rapid bactericidal activity and SEM showed mild surface alterations on bacterial outer membranes after sublethal colistin monotherapy. Furthermore, a series of sequential treatment assays on colistin-resistant Escherichia coli showed that simultaneous exposure to both compounds was required for activity, as introducing a washing step between treatments abolished the antibacterial effect. In order to obtain deeper insight into this mechanism, NMR analyses were performed, revealing specific molecular interactions between CBD and colistin molecules. Conclusions: These results provide evidence for the first time that both molecules engage through a specific and structurally meaningful interaction and only display synergy when acting together on colistin-resistant bacteria. Full article

The integration of large-scale renewable energy sources has increased the complexity of operation and maintenance in modern power systems, causing on-site substation operation and maintenance activities to exhibit stronger continuity and dynamics, and thereby placing higher demands on real-time operational perception and safety judgment. However, existing behavior recognition methods have difficulty accurately identifying operational states in complex scenarios involving continuous actions, partial occlusions, and fine-grained manipulations. To address these challenges, this paper proposes a safety behavior recognition method for substation operations based on a dual-path spatiotemporal network. Personnel localization is achieved using YOLOv8, while behavior classification is performed through the SlowFast framework. In the Slow pathway, an ECA attention mechanism is integrated with residual structures to enhance the representation of sustained operational postures. In the Fast pathway, a multi-path excitation residual network is introduced to fuse temporal, channel, and motion information, improving the multi-scale representation of local action variations. Furthermore, to mitigate the issue of class imbalance in substation operation data, Focal Loss based on binary cross-entropy is incorporated to adaptively down-weight easily classified samples. Experimental results demonstrate that the proposed method achieves a recognition accuracy of 87.77% and an F1-score of 85.56% across multiple operation scenarios. The results further indicate improved recognition stability and adaptability, supporting safe substation operation and maintenance in renewable energy-integrated power systems. Full article

Background: A benzotriazole is a heterocycle frequently used in medicinal chemistry to obtain potent drug candidates, including anticancer agents. Nonetheless, the available literature lacks a comprehensive review of the in vitro and in vivo studies regarding these derivatives. Thus, our study aims to review the preclinical evidence on benzotriazole derivatives that showed potential as anticancer candidates, focusing on the cytotoxicity, mechanisms of action, structure–activity relationship, and methodological rigor of the included studies. Methods: We searched PubMed, Scopus, and Web of Science and included 41 studies in our analysis following the selection process. Additionally, we assessed the risk of bias using the QUIN tool for in vitro and the SYRCLE tool for in vivo studies in order to assess the methodological rigor of the included studies. Results: The benzotriazole derivatives were classified according to their structure in four classes, namely N-derivatives, C-derivatives, fused derivatives, and organometallic compounds. The in vitro results showed that certain derivatives, such as halogen, alkyl-aryl, or natural-base hybrids, can have superior cytotoxicity compared to parent molecules, exerted through multiple mechanisms, such as apoptosis and cell cycle arrest. Additionally, the in vivo analysis highlighted that benzotriazole derivatives can reduce tumor mass in a dose-dependent manner, with only a slight degree of hepatotoxicity reported in one case. However, histopathological data were generally absent or limited and based on a very limited number of in vivo studies. Conclusions: Overall, benzotriazole derivatives remain promising candidates for cancer treatment. However, limited mechanistic and toxicity data, as well as the moderate risk of bias identified across studies, may limit our assessment. Therefore, future studies should employ more rigorous methodologies and explore the underlying anticancer and toxicity mechanisms to fully assess the therapeutic potential of benzotriazole derivatives. Full article

Maintaining grape cultivation requires the continuous production of healthy propagating material and the control of economically important viruses. For more effective virus eradication, it is beneficial to try chemotherapeutic agents that have not yet been used on grapevine. We therefore tested two chemotherapeutic agents with different mechanisms of action (2-thiouracil and zidovudine) in addition to ribavirin, which is already used on grapevine. Viruses and viroids were identified in the mother plants of different grapevine cultivars by small RNA HTS (High-Throughput Sequencing), and RT-PCR verified the results. After chemotherapy, the regenerated plants were tested using RT-PCR and the efficacy of the three chemotherapeutic compounds was evaluated. Among the tested agents, ribavirin had the broadest elimination effect (the virus was not detectable by RT-PCR after 8 months) on most viruses. It proved to be particularly effective (the virus was not detectable by RT-PCR in most of the tested plants) against GFkV, GLRaV-4, GPGV and GRSPaV. The use of 2-thiouracil caused high phytotoxicity and was effective against GLRaV-4 among the viruses tested, having no effect on the other viruses. Zidovudine alone failed to eliminate any of the viruses we tested. 2-thiouracil, ribavirin and zidovudine were unable to eliminate HSVd and GYSVd-1 viroids. Full article

Background/Objectives: Tumor-induced immune reprogramming is increasingly recognized as a key mechanism by which cancers evade surveillance and promote disease progression. The interaction between cancer and immune cells within the tumor microenvironment (TME) can drive phenotypic and functional changes in immune populations, facilitating metastasis and immune evasion. Methods: In this study, we used co-culture models to expose THP1 monocytes to triple-negative breast cancer (TNBC) cells, MDA-MB-231 and BT-549, either directly or indirectly via tumor-conditioned media, to mimic tumor–immune cell communication. Transcriptomic and pathway analyses revealed that cancer-exposed monocytes adopt a reprogrammed phenotype marked by activation of pro-tumorigenic signaling pathways, enhanced proliferative capacity, and elevated expression of pro-inflammatory cytokines such as IL6. Results: Functional assays confirmed a significant increase in monocyte proliferation under both direct and indirect tumor exposure. Importantly, we demonstrated that this tumor-driven proliferation of THP1 cells could be suppressed by the STAT3 inhibitor STAT3-IN-12. This highlights the critical role of STAT3 signaling in mediating immune cell transformation and supporting a novel immunomodulatory approach for therapeutic intervention. Conclusions: These findings support the potential for targeting tumor-educated transcriptional programs as a novel immunomodulatory strategy in cancer treatment. Restoring immune cell homeostasis and suppressing pro-tumor phenotypes through pharmacological inhibition of the key signaling nodes such as STAT3 may complement existing cancer therapies. This study provides new insights into immune cell plasticity in cancer and identifies actionable strategies to counteract tumor-driven immune dysregulation. Full article

Chinese wolfberry (Lycium barbarum L.), a specialty crop with ecological, medical, and economic value in Ningxia province of China, is subject to severe damage from Aphis gossypii Glover. Currently, A. gossypii populations show extremely high-level resistance to beta-cypermethrin in the major wolfberry planting areas in Ningxia. The specific resistance mechanisms, however, are still not known. In this work, we collected a field A. gossypii strain (HSP) from a wolfberry orchard in Ningxia in 2021 using a single-time sampling method, and its resistance to beta-cypermethrin was determined to be extremely high (994.74-fold) as compared with that of a susceptible strain (SS). Then we explored the potential resistance mechanisms from two aspects, namely, metabolic detoxification and target-site alterations. Bioassays of beta-cypermethrin with or without a synergist showed that piperonyl butoxide (PBO) significantly increased the toxicity of beta-cypermethrin (4.72-fold) to the HSP strain, while triphenyl phosphate (TPP) and diethyl maleate (DEM) exhibited no significant synergistic effects. Correspondingly, the O-demethylase activity of cytochrome P450s in the HSP strain was 1.68-fold higher than that in the susceptive strain (SS), whereas changes in carboxylesterases and glutathione S-transferases activities were unremarkable. Also, fifteen upregulated P450 genes were identified by both RNA-Seq and qRT-PCR technologies, containing eleven CYP6 genes, three CYP4 genes, and one CYP380 gene. Especially, five CYP6 genes with high relative expression levels (>3.00-fold) were intensively expressed by beta-cypermethrin induction in the HSP aphids. These metabolism-related results indicate the key role of P450-mediated metabolic detoxification in HSP resistance to beta-cypermethrin. Sequencing of voltage-gated sodium channel (VGSC) genes identified a prevalent M918L mutation and a new G1012D mutation in HSP A. gossypii. Moreover, heterozygous 918 M/L and 918 M/L + G1012D mutations were the dominant genotypes with frequencies of 60.00% and 36.67% in the HSP population, respectively. Overall, VGSC mutations along with P450-mediated metabolic resistance contributed to the extremely high resistance of the HSP wolfberry aphids to beta-cypermethrin, providing support for A. gossypii control and resistance management in the wolfberry planting areas of Ningxia using insecticides with different modes of action. Full article

Varicella-zoster virus (VZV) is a human neurotropic herpesvirus. The primary infection with VZV causes chickenpox and establishes latency in sensory and dorsal root ganglia. Viral reactivation leads to herpes zoster (HZ), which is accompanied by complications such as postherpetic neuralgia (PHN), causing a significant disease burden. At present, vaccination is the most effective preventive measure. We developed a recombinant zoster vaccine, gE/BFA01, which comprises truncated VZV glycoprotein E and the liposome-based adjuvant BFA01 (containing MPL and QS-21). In this study, we evaluated the recombinant zoster vaccine’s immunogenicity in a live attenuated VZV-primed C57BL/6N mouse model and explored the mechanism of action of the BFA01 adjuvant. The results indicate that the gE/BFA01 vaccine induces superior antibody responses and stronger cellular immune responses compared with gE with aluminum hydroxide. Furthermore, gE/BFA01 showed comparable immunogenicity to the licensed vaccine Shingrix. Mechanistic investigations revealed that the BFA01 adjuvant can enhance the recruitment of innate immune cells at the injection site, increase the expression of DCs surface maturation markers, and activate multiple inflammatory signaling pathways in lymph nodes. Collectively, these findings indicate that gE/BFA01 can induce potent humoral and cellular responses, supporting its further development as a high-efficiency vaccine candidate. Full article

The adenosine 3′,5′-cyclic monophosphate–protein kinase A (cAMP-PKA) signaling pathway is highly utilized in human physiology. It is a crucial component of development and is vital to cellular function in nearly all tissues. Indeed, genetic mutations to cAMP-PKA machinery are found in many pathologies, including multiple cancers, cardiac myxoma, neurodevelopmental disorders, and hypercortisolism. Cyclic AMP and PKA were first identified as vital components in cortisol synthesis over 50 years ago, yet the cellular mechanisms connecting PKA to cortisol production are still not well understood. This article will review evidence for PKA’s roles in adrenal gland zona fasciculata steroidogenesis and consider recent studies of the stress hormone disease adrenal Cushing’s syndrome to synthesize a current model for cAMP-PKA actions in cortisol production. Full article

The cosmological constant (CC, $\Lambda$) problem stands as one of the most profound puzzles in the theory of gravity, representing a remarkable discrepancy of about 120 orders of magnitude between the observed value of dark energy and its natural expectation from quantum field theory. This paper synthesizes two innovative paradigms—holographic naturalness (HN) and pre-geometric gravity (PGG)—to propose a unified and natural resolution to the problem. The HN framework posits that the stability of the CC is not a matter of radiative corrections but rather of quantum information and entropy. The large entropy $S_{\mathrm{dS}}\sim M_{\mathrm{P}}^2/\Lambda$ of the de Sitter (dS) vacuum (with $M_{\mathrm{P}}$ being the Planck mass) acts as an entropic barrier, exponentially suppressing any quantum transitions that would otherwise destabilize the vacuum. This explains why the universe remains in a state with high entropy and relatively low CC. We then embed this principle within a pre-geometric theory of gravity, where the spacetime geometry and the Einstein–Hilbert action are not fundamental, but emerge dynamically from the spontaneous symmetry breaking of a larger gauge group, SO($1,4$)→SO($1,3$), driven by a Higgs-like field ${\varphi }^A$. In this mechanism, both $M_{\mathrm{P}}$ and $\Lambda$ are generated from more fundamental parameters. Crucially, we establish a direct correspondence between the vacuum expectation value (VEV) v of the pre-geometric Higgs field and the de Sitter entropy: $S_{\mathrm{dS}}\sim v$ (or $v^3$). Thus, the field responsible for generating spacetime itself also encodes its information content. The smallness of $\Lambda$ is therefore a direct consequence of the largeness of the entropy $S_{\mathrm{dS}}$, which is itself a manifestation of a large Higgs VEV v. The CC is stable for the same reason a large-entropy state is stable: the decay of such state is exponentially suppressed. Our study shows that new semi-classical quantum gravity effects dynamically generate particles we call “hairons”, whose mass is tied to the CC. These particles interact with Standard Model matter and can form a cold condensate. The instability of the dS space, driven by the time evolution of a quantum condensate, points at a dynamical origin for dark energy. This paper provides a comprehensive framework where the emergence of geometry, the hierarchy of scales and the quantum-information structure of spacetime are inextricably linked, thereby providing a novel and compelling path toward solving the CC problem. Full article

Background: Inventory record inaccuracy (IRI) causes discrepancies between physical and digital inventories, leading to production delays and customer dissatisfaction. Cycle counting, in this context, is a common corrective action. Pareto-based ABC analysis is widely used to decide which items to inspect, but it often oversimplifies inventory decisions, and recent studies suggest that multi-criteria decision-making (MCDM) and machine learning (ML) may offer more effective solutions. Methods: This study applies the analytic hierarchy process (AHP) method, combined with K-means (AHP-K), to classify stock-keeping units (SKUs) into three groups with distinct counting policies. A selection procedure is then applied to identify an optimal ML algorithm and compare its classification with the original AHP-K results; each model in this phase is trained on a subsets of 100 SKUs. A Veto method is also introduced to improve output consistency for both AHP-K and the best ML method, and a comparative cost evaluation is presented. Results: The ML-AHP-K-Veto classification achieves over 90% accuracy. Analysis of a dataset of 12,863 SKUs from a mechanical manufacturing company shows minimal cost differences between ML-based and MCDM classifications, but significant differences compared to Pareto-based costs. Conclusions: ML can effectively address IRI, supporting the development of pure ML applications, including decision-maker (DM) preferences, to manage cycle counting strategies. Full article

Community gardening has become an important urban sustainability initiative that integrates ecological restoration with social participation. However, little is known about the psychological and social mechanisms that drive citizens’ willingness to engage in such activities, particularly in densely populated cities with limited green space. This study develops and empirically tests an integrative behavioral model combining environmental psychology, social cognitive theory, and environmental identity theory to explain citizens’ participation in community gardening in Tehran, Iran. Using survey data from 416 residents and analyzing results through structural equation modeling, the study evaluates the effects of six key predictors, including childhood nature experience, connectedness to nature, self-efficacy, outcome expectancy, psychological restoration, and collective environmental responsibility, on willingness to participate. The model explained 54% of the variance in participation, indicating high explanatory power. Five predictors significantly influenced willingness to participate: childhood nature experience, connectedness to nature, outcome expectancy, psychological restoration, and collective environmental responsibility, while self-efficacy was not significant. The findings reveal that engagement in community gardening is shaped more by emotional, restorative, and moral motivations than by perceived capability alone. Theoretically, this research advances understanding of pro-environmental participation by integrating memory-based, affective, and normative dimensions of behavior. Practically, it provides actionable insights for urban planners and policymakers to design inclusive, emotionally restorative, and collectively managed green initiatives that strengthen citizen participation and enhance urban resilience. Full article

For the first time, a comparative analysis has been conducted to elucidate the biosynthesis of three families of natural products—staurosporines/rebeccamycins, cladoniamides, and fascaplysins. Based on the available data, a well-founded hypothesis was formed that these metabolites arise through a shared biosynthetic pathway. A comparative evaluation of biological activity profiles and molecular mechanisms of action of the major representatives of these alkaloid families and their derivatives shows that, despite an apparent similarity between the activity spectra of indo-lo[2,3-a]pyrrolo[3,4-c]carbazoles and fascaplysins, they operate through different mechanisms. The biological effects of fascaplysin are driven primarily by the induction of metabolic stress rather than by the inhibition of DNA topoisomerase I or of a broad-spectrum protein kinases. The successful optimization of natural indolo[2,3-a]pyrrolo[3,4-c]carbazoles—compounds with initially poorer pharmacokinetic properties than those of fascaplysin—to drug-like candidates underscores the substantial pharmaceutical potential of the fascaplysin scaffold. Several existing fascaplysin derivatives, after the improvement of their pharmacokinetic characteristics, may serve as promising leads for the development of a new class of antibiotics. Full article

Background: The in vivo accumulation of Advanced Glycation End products (AGEs) is associated with the development of several chronic aging-related and degenerative diseases, as they alter protein structures and activate oxidative and inflammatory processes through interactions with the receptor for AGEs (RAGE). Plant secondary metabolites play a key role in counteracting the glycation process through various mechanisms of action. Therefore, Aloysia citrodora leaf polyphenolic extract could represent a source of anti-glycative compounds. Methods: The methanolic extract was characterized by RP-HPLC-DAD-MSⁿ, and its anti-glycative properties were investigated using several in vitro assays mimicking the different steps of the glycation reaction. In parallel, molecular docking studies were carried out to evaluate potential interactions between the identified metabolites and RAGE. Furthermore, A. citrodora metabolites’ stability under simulated in vitro digestion was assessed, and the anti-glycative activity of the bioaccessible fraction was investigated. Results:A. citrodora extract, rich in iridoid glycosides, phenylethanoid glycosides, and flavones, strongly inhibited AGE formation (from 10% to 100%) in both the middle and end step of the reaction and had high methylglyoxal and glyoxal trapping capacity. However, the digestion process affected extract stability, particularly under intestinal conditions, yielding an overall bioaccessibility of about 40% and leading to a subsequent reduction in anti-glycative properties. Finally, molecular modeling analysis highlighted the ability of the studied metabolites to bind RAGE. Conclusions:A. citrodora represents a promising source of natural anti-glycative agents with potential applications as food ingredients. However, it is essential to improve the extract bioaccessibility and to preserve its anti-glycative properties by developing a suitable formulation. Full article