Action Of Agents Research Articles

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient’s quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles – AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

Hybrid dynamical systems logic and its refinements

Hybrid dynamical systems describe the mixed discrete dynamics and continuous dynamics of cyber-physical systems such as aircraft, cars, trains, and robots. To justify correctness properties of the safety-critical control algorithms for their physical models, differential dynamic logic (▪) provides deductive specification and verification techniques implemented in the theorem prover ▪. The logic ▪ is useful for proving, e.g., that all runs of a hybrid dynamical system α satisfy safety property φ (i.e., ▪), or that there is a run of the hybrid dynamical system α ultimately reaching the desired goal φ (i.e., ▪). Logical combinations of ▪'s operators naturally represent safety, liveness, stability and other properties. Variations of ▪ serve additional purposes. Differential refinement logic (▪) adds an operator α≤β expressing that hybrid system α refines hybrid system β, which is useful, e.g., for relating concrete system implementations α to their abstract verification models β. Just like ▪, ▪ is a logic closed under all operators, which opens up systematic ways of simultaneously relating systems and their properties, of reducing system properties to system relations or, vice versa, reducing system relations to system properties. A second variant of ▪, differential game logic (▪), adds the ability of referring to winning strategies of players in hybrid games, which is useful for establishing correctness properties where the actions of different agents may interfere either because they literally compete with one another or because they may interact accidentally. In the theorem prover ▪, ▪ and its variations have been used for verifying ground robot obstacle avoidance, the Federal Aviation Administration's Next-Generation Airborne Collision Avoidance System ACAS X, and the Federal Railroad Administration's train control model.

Recent Updates in the Diagnosis and Management of Kidney Diseases in Multiple Myeloma

Multiple myeloma (MM) represents a difficult-to-treat plasma cell malignancy and the second most common hematologic malignancy in adults, significantly impacting kidney function. The spectrum of kidney involvement in MM is broad, encompassing electrolyte imbalances, tubular injury, and even rare glomerular diseases. The evolution of MM treatment modalities has led to notable improvements in the long-term survival of patients experiencing kidney-related complications. Over the past decade, groundbreaking therapeutic agents have emerged, including proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, selective inhibitors of nuclear export, and antibody-drug conjugates. These novel therapies have revolutionized the landscape of MM management, offering new hope for patients and challenging the traditional treatment paradigms. This comprehensive review explores recent advances in the diagnosis and management of MM, emphasizing the pivotal role of these innovative therapeutic agents in improving patient outcomes. We delve into the intricacies of diagnosing MM, highlighting the significance of early detection and precise diagnostic tools. We elucidate the evolving treatment strategies, emphasizing the mechanisms of action and clinical efficacy of the latest agents. This manuscript provides valuable insights into the ever-evolving field of MM management, shedding light on the remarkable progress achieved in enhancing the prognosis and quality of life of MM patients.

Imidazole-based hydrazones as potent anti-colon cancer agents: Design, synthesis, biological evaluation and computational studies

Compounds containing imidazole and hydrazone structural frameworks have been widely studied and demonstrated to exhibit a wide range of pharmacological properties. In this study, a descriptive series of 20 new hybrid compounds composed of an imidazole ring and a hydrazone moiety were designed and synthesized through multistep chemical reactions. Synthesized compounds were characterized by various spectral techniques, including FT-IR, 1H NMR, 13C NMR and HRMS. Furthermore, the proposed structure of AB-1 was resolved by single-crystal X-ray analysis. The compounds were evaluated for their in vitro anti-colon cancer activity, and the most promising compounds (i.e., AB-6, AB-9, AB-11 and AB-18) exhibited significant dose- and time-dependent cytotoxicity with selectivity to HT-29 and HCT-116 cells. In addition, Molecular docking, molecular dynamics simulations, and binding free energy analyses were carried out to better understand the structure-activity relationships and mechanisms of action of the potential anticancer agents. Our preliminary findings suggest that compounds AB-6, AB-9, AB-11, and AB-18 could be exploited as a leading structure for further anticancer drug development.

Grasping the Situation: analyzing how situational dynamics shape agency.

Despite the intimacy between the situation and our agency, "situation" remains an ambiguous concept in theory. Even within the context of situated theories of cognition and agency that take the organism-environment system as central in their investigations, the notion of "situation" has been undertheorized. Yet, whether affordances are relevant depends on the situation. Therefore, Van Dijk and Rietveld argue that we must understand the practical situation in which behavior occurs in order to know how we respond to the affordances that the materials and other people offer. Taking John Dewey's notion of "situation" as the basis for investigation, I follow Shaun Gallagher's analysis of how we are not just part of a situation, but we understand what an action is only in relation to a situation. Situations act like large-scale affordances, but this does not mean that affordances are inviting or soliciting as such. Because of the situational transactions with the environment that an agent has, the environment pushes and pulls the agent from and toward certain actions. This means that environments have expressive qualitative features that are non-subjective emotional qualities and social gestalt. I propose four overlapping but distinct features or axes of analysis of situations that can be identified and analyzed in terms of how they shape our agency: complexity, determinedness, the establishment of expectations, and restrictiveness. Situations can be more or less complex in a spatial, temporal, or layered way. They can also be more or less determined, meaning that the agent's actions are more or less obvious. Third, they can be characterized as socially established, meaning that certain behavior is expected. Finally, situations are more or less restricted, denoting the number of activities available to an agent.

Local parallel free generation and dynamic affine transformation method for soil three-dimensional pore structure information model

The soil three-dimensional (3D) pore structure information model has become a new hotspot in the research of cross-scale disposal of information such as ecology, engineering, and geology. It can solve problems such as the intelligent evaluation of ecological water–soil–air–plant feedback, intelligent risk control of foundation compression deformation, and multiscale intelligent disaster prediction and prevention. However, the current soil 3D pore structure model primarily draws on the global one-time static generation in simulation software, leading to low reliability, low stability of multiple generations, poor variability, difficulty in real-time transformation, high consumption of computing resources, and long generation time, making it challenging to meet the requirements of the rapid processing of information models. Therefore, this study adopts the 3D Drawing Protocol (WebGL) technology and implements the scaling, rotation, and translation transformation of 3D pore structures based on the principle of dynamic affine transformation. The random generation and distribution of pores are realized using the improved Monte Carlo method, and the loading response efficiency of the system is optimized. The dynamic interactive operation of arbitrary increasing and decreasing of pore model is realized using the ray and plane intersection detection principle. Finally, this information system established a visual correlation between the content and reaction time of water-retaining agents and soil porosity and pore distribution through tests on the impact of water-retaining agents on soil pore changes. The information system achieved the real-time tracking of soil pore changes under the action of water-retaining agents. This research solves the problems of static and low generation efficiency of the soil mesopore structure in traditional models and realizes the real-time characterization and visualization of dynamic changes and the distribution of the soil pore structure under the influence of external conditions, which can provide an intuitive visualization platform for mesogeological structure research.

Properties of Cemented Filling Materials Prepared from Phosphogypsum-Steel Slag-Blast-Furnace Slag and Its Environmental Effect.

Phosphogypsum (PG) occupies a large amount of land due to its large annual production and low utilization rate, and at the same time causes serious environmental problems due to toxic impurities. PG is used for mine backfill, and industrial solid waste is a curing agent for PG, which can save the filling cost and reduce environmental pollution. In this paper, PG was used as a raw material, combined with steel slag (SS) and ground granulated blast-furnace slag (GGBS) under the action of an alkali-activated agent (NaOH) to prepare all-solid waste phosphogypsum-based backfill material (PBM). The effect of the GGBS to SS ratio on the compressive strength and toxic leaching of PBM was investigated. The chemical composition of the raw materials was obtained by XRF analysis, and the mineral composition and morphology of PBM and its stabilization/curing mechanism against heavy metals were analyzed using XRD and SEM-EDS. The results showed that the best performance of PBM was achieved when the contents of PG, GGBS, and SS were 80%, 13%, and 7%, the liquid-to-solid ratio was 0.4, and the mass concentration of NaOH was 4%, with a strength of 2.8 MPa at 28 days. The leaching concentration of fluorine at 7 days met the standard of groundwater class IV (2 mg/L), and the leaching concentration of phosphorus was detected to be less than 0.001 mg/L, and the leaching concentration of heavy metals met the environmental standard at 14 d. The hydration concentration in PBM met the environmental standard. The hydration products in PBM are mainly ettringite and C-(A)-S-H gel, which can effectively stabilize the heavy metals in PG through chemical precipitation, physical adsorption, and encapsulation.

Exploration of the passivation effect of different types of passivators on cadmium contaminated soil

The problem of excessive cadmium in farmland soil in China is severe, and it is of great significance to explore suitable passivators for specific polluted soils. Three typical and representative commercially available passivators were selected as the test agents, and simulated the natural production process of irrigation and drainage in farmland soil. Through soil cultivation experiments, the remediation effects of different types of passivators and water management on Cd contaminated farmland soil in a certain area of Sichuan were explored. The results showed that the passivator agent 1# based on organic matter reduced the soil pH value, the passivator agent 2# based on alkaline substance and the passivator agent 3# based on clay mineral could increase the soil pH value in different degrees, and the passivator agent 2# was better than the passivator agent 3#. Under flooding condition, soil pH value can be increased. The three passivator agents can increase the content of soil organic matter in different degrees, and the maximum increase rate was 35.2% under 8%. The three passivator agents can reduce the available Cd in different degrees, and the maximum reduction of passivator agents 1#, 2# and 3# was 61.8%, 67.1% and 46.4% respectively. The correlation analysis showed that the flooding state was conducive to the decrease of available Cd. Under the action of passivator agent 1# , the correlation between available Cd and pH was weak, and there was a strong negative correlation between Cd and organic matter (R=0.9922). Under the action of passivator agent 2#, available Cd had a strong negative correlation with pH (R=0.8702) and a weak negative correlation with organic matter (R=0.4041). Under the action of passivator agent 3#, available Cd was strongly negatively correlated with soil pH value and organic matter.

The effect of freeze-thaw cycles and sulfuric acid attack separately on the compressive strength and microstructure of 3D-printed air-entrained concrete

3D-printed concrete (3DPC) is a promising technique for constructing structures and intricate designs. To ensure the successful performance of these structures throughout their service life, it is essential to understand their long-term properties and durability. While the use of air-entraining additives can enhance the durability of concrete against freeze-thaw cycles, investigating their impact on other properties is crucial. This study examines the effect of freeze-thaw cycles and sulfuric acid attack on the durability of 3D-printed concrete containing air-entraining additives. The results indicate that, in addition to improving resistance to freeze-thaw cycles, air-entraining additives also increases resistance to sulfuric acid attack. The drop in compressive strength of the samples containing air-entrained additive (0.08–0.12 % AEA) is 1.4–5.3 % less than the control samples against the freezing and thawing cycles. Examining the mechanisms of action of these invasive agents also shows this. Creating intentional voids to reduce the internal pressure of water expansion during freezing and reducing the number and width of possible microcracks are the dominant mechanisms of air-entraining additives against freeze-thaw cycles. Besides, their performance mechanisms during acid attacks are somewhat similar. Analysis of elements created in the matrix of the samples after acid attack indicates a decrease in calcium concentration and an increase in silica concentration. Among the observed reactions, the second reaction prevails, leading to the breakdown of the C-S-H structure into gypsum and silica hydroxide. This phenomenon is associated with changes in acid concentration. However, the presence of air bubbles causes surplus plate-like Calcium hydroxide crystals resulting from the elevated cement content in printed mixes to form within these bubbles, making them susceptible to damage and fracture during freeze-thaw and acid attacks.

Model-Informed Reinforcement Learning for Enabling Precision Dosing Via Adaptive Dosing.

Precision dosing, the tailoring of drug doses to optimize therapeutic benefits andminimize risks in each patient, is essential for drugs with a narrow therapeutic window and severe adverse effects. Adaptive dosing strategies extend the precision dosing concept to time-varying treatments which require sequential dose adjustments based on evolving patient conditions. Reinforcement learning (RL) naturally fits this paradigm: it perfectly mimics the sequential decision-making process where clinicians adapt dose administration based on patient response and evolution monitoring. This paper aims to investigate the potentiality of coupling RL with population PK/PD models to develop precision dosing algorithms, reviewing the most relevant works in the field. Case studies in which PK/PD models were integrated within RL algorithms as simulation engine to predict consequences of any dosing action have been considered and discussed. They mainly concern propofol-induced anesthesia, anticoagulant therapy with warfarin and a variety of anticancer treatments differing for administered agents and/or monitored biomarkers. The resulted picture highlights a certain heterogeneity in terms of precision dosing approaches, applied methodologies, and degree of adherence to the clinical domain. In addition, a tutorial on how a precision dosing problem should be formulated in terms of the key elements composing the RL framework (i.e., system state, agent actions and reward function), and on how PK/PD models could enhance RL approaches is proposed for readers interested in delving in this field. Overall, the integration of PK/PD models into a RL-framework holds great promise for precision dosing, but further investigations and advancements are still needed to address current limitations and extend the applicability of this methodology to drugs requiring adaptive dosing strategies.

Preparation of p-isopropylphenol polyoxyethylene ether and evaluation of its performance in concrete

P-isopropenylphenol polyoxylates (IPP-PE) were obtained by alkoxylation reaction using p-isopropylphenol phenol (IPP) and ethylene oxide (EO) as raw materials, and P-PCE polycarboxylic acid superplasticizer was obtained by free radical polymerization of ipp-PE and acrylic acid (AA) under the action of initiator and chain transfer agent. The effects of reaction temperature, acid-ether ratio, amount of chain transfer agent and initiator, and reaction time on the dispersion properties of superplasticizer were studied, and the molecular structure and microscopic morphology of the superplasticizer were characterized by FTIR,1HNMR, and SEM, and the influence of superplasticizer on concrete properties was evaluated by concrete performance tests. The test results determined that the optimal synthesis process of polycarboxylic acid superplasticizer was as follows: reaction temperature 40 °C, n(AA):n(IPP-PE)=6:1, chain transfer agent and initiator were 0.4% and 0.6% of the mass of large monomer, respectively, and the reaction time was 4.5h. The experimental results of the concrete performance test showed that the workability of concrete mixed with the self-made superplasticizer was excellent, and the initial and 1h longitudinal flowability of the superplasticizer reached 228 mm and 215 mm, respectively. The water reduction rate reached 36%, the 28d compressive strength reached 56.8 MPa, the initial slump reached 226 mm, and it had a certain retarding and air entrainment effect.

Antifouling coatings based on the synergistic action of biogenic antimicrobial agents and low surface energy silicone resins and their application to marine aquaculture nets

Aquaculture nets used in seawater for a long time are susceptible to biofouling, and antifouling coatings are a cost-effective way to solve this problem. In this study, biogenic antimicrobial components were extracted from two plants, Houttuynia and Scutellarin, and modified with methylphenyl silicone resin (MSR) by physical blending. Two flexible antifouling coatings with synergistic action of biogenic antimicrobial agents and low surface energy silicone resin for marine aquaculture nets were prepared separately. The prepared coatings retained the low surface energy properties of silicone resin: the contact angles (CA) were all over 130°, and the surface energy (SE) were all below 1.5 mN/m. Meanwhile, the coatings with Houttuynia and Scutellarin additives showed inhibition rates of more than 90 % against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), and more than 50 % against Chlorella vulgaris. Marine Field Test showed that the coatings containing Scutellarin and Houttuynia additives reduced fouling adhesion by 17.24 % and 35.92 %, respectively, compared with Ultra-high molecular weight polyethylene (UHMWPE) net coats without any additives. This study provides an efficient and environmentally friendly solution for antifouling treatment of marine aquaculture nets, which is of positive significance for enhancing the sustainable development of Marine Ranching.

Soil surface erosion susceptibility analysis using the USLE model. Case study: Bran - Dragoslavele Corridor, Romania

The present study falls within the scope of the analysis of the morphodynamic potential of the Bran - Dragoslavele Corridor (Romania), a low mountain area, favorable to erosion processes due to the high energy of the relief, diversified lithology, tectonic complexity, and due to the variation in the energy of atmospheric risk phenomena. For the expansion of pastoral agricultural areas and those intended for human settlements, the deforestation of the last 3-4 centuries deprived the slopes and the soil of the protective forest cover on an area of 55.44%, favoring the amplification of the action of natural morphodynamic agents. In this context, the quantitative and spatial assessment of sheet erosion, expressed as the average annual rate of surface soil erosion (measured in tons hectare–1) was approached by applying the calculation model implemented in the GIS environment by using the universal soil loss equation (USLE). Implementation of the model was realized through the spatial delimitation of the potential erosion and the rendering by susceptibility classes of the quantitative results which reveal the fact that the largest surface of the studied mountain unit (91.68%) presents tolerable values, of 0-1.5 t ha–1 year–1. The highest values, over 4 t ha–1 year–1 (1.24%), are characteristic of the calcareous areas belonging to the many sectors of the gorges with discontinuous vegetation, as well as the limestone exploitation area from Mateiaș mountain. The quantitative knowledge and spatial distribution of surface erosion becomes important for communities and local authorities, interested in the planning and management of the implementation of some agrotechnical measures to improve the quality and productivity of soils or to prevent and restrict erosion processes with a tendency to expand areally and in depth.

AGE-DEPENDENCE OF BIOCHEMICAL MANIFESTATIONS OF HEPATOTOXICINJURY IN RAT EXPOSED TO XENOBIOTICS OF VARIOUS GENESIS

Currently, the problem of liver diseases against the backdrop of the toxic effects of medicinal and industrial (herbicides) xenobiotics on the body is becoming increasingly relevant. The activation of compensatory mechanisms in response to the action of toxic agents –acetaminophen and/or diquat is closely related to age-specific features. Heightened focus on acetaminophen-induced injury is linked to the widespread use of this medication as an analgesic and antipyretic during pandemics of infectious and inflammatory diseases, especially under the conditions of warfare in Ukraine. In return, the widespread use of the herbicide diquat is accompanied by an increase in the registration of cases of diquat -induced acute poisoning. The aim of study was to evaluation the biochemical parameters of the functional state of the liver of different-aged rats under conditions of acetaminophen-and diquat-induced toxic injury. Animals were divided into three age groups: adolescent (60 days), reproductive (150 days), and mature age rats (360 days). Acute toxic injury by acetaminophen was modeled by its oral administration through gastric intubation at a daily dose of 1250 mg/kg of the animal's body weight during the last 2 days of the experiment. Acute toxic damage by diquat was modeled by a single intragastric administration using a probe at a dose of 115.5 mg/kg of the animal's body weight. The functional state of the liver was assessed on an automatic biochemical analyzer NTI Biochem FC-120.Acetaminophen intoxication led to an increase in the absolute liver mass indicator, organ index, changes in the macroscopic structure of the organ, increased serum activities of ALT and AST, total LDH, and a decrease in the De Ritis ratio amidst increased activities of ALP, GGT, and levels of total and indirect bilirubin in all age groups compared to the control. The most significant changes were observed in mature age animals (increase in ALT activity by 76%, AST by 56%, ALP by 51%, GGT by 51%, and a decrease in the De Ritis ratio by 47%). Under conditionsof diquat-induced toxic injury, a slightly different trend and degree in manifestation of established changes are observed. A more pronounced hepatotoxic effect was registered in adolescent animals, manifested by the maximum increase in absolute liver mass by 26%, ALT activity by 71%, AST by 47%, ALP by 50%, Bili-T level by 69%. No statistically significant differences compared to the control and APAP-induced injury in the activity of total LDH and GGT upon administration of toxic doses of the herbicide diquat regardless of age category were observed.Based on the experimental results, an age-related multidirectionality in the adverse effects of the medicinal xenobiotic acetaminophen and the industrial xenobiotic diquat on indicators of the morpho-functional state of the liver is observed. The most sensitive age group of animals to toxic injury by acetaminophen are rats of 360 days of age, while for diquat –60 days of age

P-266 Profiling redox effects induced by micro-nanoplastics in the female reproductive system: insights from human granulosa cells

Abstract Study question Are nano-microplastics (NMPs) taken up into human granulosa cells causing redox alterations? Summary answer NMPs enter into human granulosa cells and influence viability, energy production and antioxidant response. What is known already In recent decades, anthropogenic activities have increased the production of global plastic with millions of tons produced every year. Under the action of different physical, chemical or biological agents, plastic waste breaks down into (NMP) particles that propagate in the environment posing threats for human health. NMPs translocate from digestive tract to circulatory systems reaching organs and cells, including female gonads. Nevertheless, there is insufficient knowledge of their effects on reproductive functions in mammals to allow for an accurate risk assessment to be conducted and any risks managed in animal and human being contexts. Study design, size, duration Human ovarian granulosa cells (KGN cell line) were exposed to NMPs of different sizes (40 nm, 70 nm, 100 nm, and 200 nm) at concentrations ranging from 5 to 1000 μg/ml for 24 h and then processed for cellular and biochemical analyses Participants/materials, setting, methods NMPs uptake by granulosa cells was tested by the employment of fluorescent NMPs and observation under confocal laser scanning microscopy. Cell viability was assed by Cell Counting Kit8. The effects of NMPs on mitochondrial bioenergetics was evaluated by MitoStress kit (Seahorse Xfe96, Agilent). ATP production was evaluated by Cell Titer-Glo ATP assay kit (Promega). Key enzymes of antioxidant response were analysed at transcript and protein level by using real-time Taqman PCR and Western blotting, respectively. Main results and the role of chance We demonstrated that NMPs are taken up by granulosa cells at all tested concentrions along with significant decrease of cell vitality with all sizes and concentrations. Seahorse analysis revealed an altered bioenergetic profiles. ATP levels increase at 70, 100 and 200 nm (one way ANOVA p = 0.001) at all tested concentrations (one way ANOVA p < 0.001). The gene and protein expression of catalase (CAT) superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2) increased at 5 and 100 µg/ml with all sizes except 100 nm, whereas the level of sirtuins (SIRT1 and SIRT3) transcripts and protein decreased. Reduced levels of phosphorylated NRF2, the transcription factor that activates antioxidant responsive elements (ARE)-mediated gene expression were observed. Limitations, reasons for caution The use of human cell lines requires careful consideration when transferring to human testing. Wider implications of the findings Our results contribute to understanding the effects of NMPs on mammalian fertility in order to find possible protective approaches. Considering that the level of susceptibility of mammalian female germ cells to NMPs is still unknown, present results contribute to evidence-based strategies allowing living and working in a health promoting environment. Trial registration number Effects of combined exposure to nano/microplastics and plastic additives on mammalian female fertility (CUP E53D2301100006)

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient's quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

Is it personal or is it social? The interaction of knowledge domain and statistical evidence in U.S. and Chinese preschoolers' social generalizations.

Children make inferences about the social world by observing human actions. However, human actions can be ambiguous: They can be sources of information about personal, idiosyncratic characteristics of individuals or socially shared knowledge. In two cross-cultural studies (N = 420; Mage = 4.05 years, SD = 0.77, 47% female), we ask if U.S. and Chinese children's inferences about whether an action is personal or social vary by domain, statistical evidence, and culture. We did this with a generalization method: Preschoolers learn about one agent's actions and then are asked what they think a new agent will do. Low rates of generalization suggest children inferred something unique to an individual, while high rates suggest that children inferred that the action represented socially shared knowledge. In a mixed between- and within-participant design, children observed agents demonstrate sequences of statistically random (or nonrandom, between participants) actions that were verbally framed as relevant to a particular domain (agent's personal preferences, labels, object functions, or game rules). We found that children's social generalizations about actions were on a continuum: with linguistic conventions (e.g., labels) being the most social, preferences being the most personal, and nonlinguistic conventions (i.e., object functions, game rules) falling somewhere in between. Furthermore, the influence of statistical evidence and cultural variation varied for each domain. These findings highlight how children combine knowledge and evidence to infer social meaning from actions and have implications for rational constructivist accounts of cultural learning. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Unraveling the interplay between humans and carnivores in El Olivo Cave during the Middle and Upper Paleolithic period (Llanera, Asturias, Spain)

El Olivo Cave (Llanera, Asturias, Spain) is a small karst cave within the Aboño River watershed. It holds a significant archaeological and paleontological record dating from the Middle and late Upper Paleolithic, featuring several lithic artifacts and faunal remains in each archaeological level. The study of the faunal remains reveals a high representation of ungulates, with Cervus elaphus and Equus ferus being the main ones. Carnivores are also represented by diverse species such as Vulpes vulpes and Canis lupus, among others. The taphonomic analysis evidenced the presence of human activity, accompanied by a significant incidence of tooth marks across all stratigraphic units and water-related processes in the lower part of the sequence. During this temporal range, there were faunal accumulations of anthropogenic origin altered by the action of other agents, especially carnivores. A diverse array of carnivore used the same space and taking advanced of the anthropogenic residues as scavengers. Moreover, we suggest a commensal synanthropic behavior exhibited by foxes. Consequently, El Olivo Cave is an illustrative case to explore the carnivore action in levels with human presence, something unusual at the late Upper Paleolithic sites in Northern Iberia.

Allowing and the Failure to Act

Abstract This article aims to defend the thesis—originally defended by Alan Donagan but rejected by Philippa Foot and most others—that the doing/allowing distinction is based upon the difference between acting and failing to act. The paper restricts its focus to the second aspect of this thesis: that every allowing is most fundamentally a failure to act. Foot rejects the thesis because of cases of ‘enabling harm’—such as removing a respirator—in which the agent allows some harm by way of doing something. The troubling aspect of these cases, however, disappears when two points are better understood. First, an independent sequence must be understood in relation to the agent's own actions. Second, sometimes an agent has ongoing actions, such as the use of a respirator.

Multi-Agent Reinforcement Learning for Stand Structure Collaborative Optimization of Pinus yunnanensis Secondary Forests

This study aims to investigate the potential and advantages of multi-agent reinforcement learning (MARL) in forest management, offering innovative insights and methodologies for achieving sustainable management of forest ecosystems. Focusing on the Pinus yunnanensis secondary forests in Southwest China, we formulated the objective function and constraints based on both spatial and non-spatial structural indices of the forest stand structure (FSS). The value of the objective function (VOF) served as an indicator for assessing FSS. Leveraging the random selection method (RSM) to select harvested trees, we propose the replanting foreground index (RFI) to enhance replanting optimization. The decision-making processes involved in selection harvest optimization and replanting were modeled as actions within MARL. Through iterative trial-and-error and collaborative strategies, MARL optimized agent actions and collaboration to address the collaborative optimization problem of FSS. We conducted optimization experiments for selection felling and replanting across four circular sample plots, comparing MARL with traditional combinatorial optimization (TCO) and single-agent reinforcement learning (SARL). The findings illustrate the superior practical efficacy of MARL in collaborative optimization of FSS. Specifically, replanting optimization based on RFI outperformed the classical maximum Delaunay generator area method (MDGAM). Across different plots (P1, P2, P3, and P4), MARL consistently improved the maximum VOFs by 54.87%, 88.86%, 41.34%, and 22.55%, respectively, surpassing those of the TCO (38.81%, 70.04%, 41.23%, and 18.73%) and SARL (54.38%, 70.04%, 41.23%, and 18.73%) schemes. The RFI demonstrated superior performance in replanting optimization experiments, emphasizing the importance of considering neighboring trees’ influence on growth space and replanting potential. Following selective logging and replanting adjustments, the FSS of each sample site exhibited varying degrees of improvement. MARL consistently achieved maximum VOFs across different sites, underscoring its superior performance in collaborative optimization of logging and replanting within FSS. This study presents a novel approach to optimizing FSS, contributing to the sustainable management of Pinus yunnanensis secondary forests in southwestern China.