Atractylenolide II combined with Interferon-γ synergistically ameliorates colorectal cancer progression in vivo and in vitro by blocking the NF-kB p65/PD-L1 pathway.

Purpose: Atractylodes macrocephala Koidz is a widely used classical traditional Chinese herbal medicine, that has shown remarkable efficacy in cancers. Colorectal cancer (CRC) is the most common malignant tumor globally. Interferon (IFN)-γ, a prominent cytokine involved in anti-tumor immunity that has cytostatic, pro-apoptotic, and immune-stimulatory properties for the detection and removal of transformed cells. Atractylenolides-II (AT-II) belongs to the lactone compound that is derived from Atractylodes macrocephala Koidz with anti-cancer activity. However, whether AT-II combined with IFN-γ modulates CRC progression and the underlying mechanisms remain unclear. The present study aimed to elucidate the efficacy and pharmaceutical mechanism of action of AT-II combined with IFN-γ synergistically against CRC by regulating the NF-kB p65/PD-L1 signaling pathway. Methods: HT29 and HCT15 cells were treated with AT-II and IFN-γ alone or in combination and cell viability, migration, and invasion were then analyzed using Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. Furthermore, the underlying mechanism was investigated through western blot assay. The role of AT-II combined with IFN-γ on tumor growth and lung metastases was estimated in vivo. Finally, the population of lymphocytes in tumor tissues of lung metastatic C57BL/6 mice and the plasma cytokine levels were confirmed by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Results: AT-II or the combination IFN-γ significantly inhibited the growth and migration abilities of CRC cells in vitro and in vivo. The biological mechanisms behind the beneficial effects of AT-II combined with IFN-γ were also measured and inhibition of p38 MAPK, FAK, Wnt/ß-catenin, Smad, and NF-kB p65/PD-L1 pathways was observed. Moreover, AT-II combined with IFN-γ significantly inhibited HCT15 xenograft tumor growth and lung metastases in C57BL/6 mice, which was accompanied by lymphocyte infiltration into the tumor tissues and inflammatory response inactivation. Conclusions: The results showed that the AT-II in combination with IFN-γ could be used as a potential strategy for tumor immunotherapy in CRC. More importantly, the mechanism by which AT-II suppressed CRC progressions was by inhibiting the NF-kB p65/PD-L1 signal pathway.

A unified framework to control estimation error in reinforcement learning.

In reinforcement learning, accurate estimation of the Q-value is crucial for acquiring an optimal policy. However, current successful Actor-Critic methods still suffer from underestimation bias. Additionally, there exists a significant estimation bias, regardless of the method used in the critic initialization phase. To address these challenges and reduce estimation errors, we propose CEILING, a simple and compatible framework that can be applied to any model-free Actor-Critic methods. The core idea of CEILING is to evaluate the superiority of different estimation methods by incorporating the true Q-value, calculated using Monte Carlo, during the training process. CEILING consists of two implementations: the Direct Picking Operation and the Exponential Softmax Weighting Operation. The first implementation selects the optimal method at each fixed step and applies it in subsequent interactions until the next selection. The other implementation utilizes a nonlinear weighting function that dynamically assigns larger weights to more accurate methods. Theoretically, we demonstrate that our methods provide a more accurate and stable Q-value estimation. Additionally, we analyze the upper bound of the estimation bias. Based on two implementations, we propose specific algorithms and their variants, and our methods achieve superior performance on several benchmark tasks.

Enzyme-Enabled Droplet Biobattery for Powering Synthetic Tissues.

Enzyme-enabled biobatteries are promising green options to power the next-generation of bioelectronics and implantable medical devices. However, existing power sources based on enzymatic biofuel chemistry exhibit limited scale-down feasibility due to the solid and bulky battery structures. Therefore, miniature and soft alternatives are needed for integration with implants and tissues. Here, a biobattery built from nanolitre droplets, fuelled by the enzyme-enabled oxidation of reduced nicotinamide adenine dinucleotide, generates electrical outputs and powers ion fluxes in droplet networks. Optimization of the droplet biobattery components ensures a stable output current of ~13,000 pA for over 24 h, representing a more than 600-fold increase in output over previous approaches, including light-driven processes. The enzyme-enabled droplet biobattery opens new avenues in bioelectronics and bioiontronics, exemplified by tasks such as the ability to drive electrochemical signal transmission in integrated synthetic tissues.

A few-shot identification method for stochastic dynamical systems based on residual multipeaks adaptive sampling.

Neural networks are popular data-driven modeling tools that come with high data collection costs. This paper proposes a residual-based multipeaks adaptive sampling (RMAS) algorithm, which can reduce the demand for a large number of samples in the identification of stochastic dynamical systems. Compared to classical residual-based sampling algorithms, the RMAS algorithm achieves higher system identification accuracy without relying on any hyperparameters. Subsequently, combining the RMAS algorithm and neural network, a few-shot identification (FSI) method for stochastic dynamical systems is proposed, which is applied to the identification of a vegetation biomass change model and the Rayleigh-Van der Pol impact vibration model. We show that the RMAS algorithm modifies residual-based sampling algorithms and, in particular, reduces the system identification error by 76% with the same sample sizes. Moreover, the surrogate model accurately predicts the first escape probability density function and the P bifurcation behavior in the systems, with the error of less than 1.59×10-2. Finally, the robustness of the FSI method is validated.

High Overexpression of SiAAP9 Leads to Growth Inhibition and Protein Ectopic Localization in Transgenic Arabidopsis.

Amino acid permeases (AAPs) transporters are crucial for the long-distance transport of amino acids in plants, from source to sink. While Arabidopsis and rice have been extensively studied, research on foxtail millet is limited. This study identified two transcripts of SiAAP9, both of which were induced by NO3- and showed similar expression patterns. The overexpression of SiAAP9L and SiAAP9S in Arabidopsis inhibited plant growth and seed size, although SiAAP9 was found to transport more amino acids into seeds. Furthermore, SiAAP9-OX transgenic Arabidopsis showed increased tolerance to high concentrations of glutamate (Glu) and histidine (His). The high overexpression level of SiAAP9 suggested its protein was not only located on the plasma membrane but potentially on other organelles, as well. Interestingly, sequence deletion reduced SiAAP9's sensitivity to Brefeldin A (BFA), and SiAAP9 had ectopic localization on the endoplasmic reticulum (ER). Protoplast amino acid uptake experiments indicated that SiAAP9 enhanced Glu transport into foxtail millet cells. Overall, the two transcripts of SiAAP9 have similar functions, but SiAAP9L shows a higher colocalization with BFA compartments compared to SiAAP9S. Our research identifies a potential candidate gene for enhancing the nutritional quality of foxtail millet through breeding.

Metabolomic Profiling Reveals the Anti-Herbivore Mechanisms of Rice (Oryza sativa).

The use of secondary metabolites of rice to control pests has become a research hotspot, but little is known about the mechanism of rice self-resistance. In this study, metabolomics analysis was performed on two groups of rice (T1, with insect pests; T2, without pests), indicating that fatty acids, alkaloids, and phenolic acids were significantly up-regulated in T1. The up-regulated metabolites (p-value < 0.1) were enriched in linoleic acid metabolism, terpene, piperidine, and pyridine alkaloid biosynthesis, α-linolenic acid metabolism, and tryptophan metabolism. Six significantly up-regulated differential metabolites in T1 were screened out: N-trans-feruloyl-3-methoxytyramine (1), N-trans-feruloyltyramine (2), N-trans-p-coumaroyltyramine (3), N-cis-feruloyltyramine (4), N-phenylacetyl-L-glutamine (5), and benzamide (6). The insect growth inhibitory activities of these six different metabolites were determined, and the results show that compound 1 had the highest activity, which significantly inhibited the growth of Chilo suppressalis by 59.63%. Compounds 2-4 also showed a good inhibitory effect on the growth of Chilo suppressalis, while the other compounds had no significant effect. RNA-seq analyses showed that larval exposure to compound 1 up-regulated the genes that were significantly enriched in ribosome biogenesis in eukaryotes, the cell cycle, ribosomes, and other pathways. The down-regulated genes were significantly enriched in metabolic pathways, oxidative phosphorylation, the citrate cycle (TCA cycle), and other pathways. Eighteen up-regulated genes and fifteen down-regulated genes from the above significantly enriched pathways were screened out and verified by real-time quantitative PCR. The activities of detoxification enzymes (glutathione S-transferase (GST); UDP-glucuronosyltransferase (UGT); and carboxylesterase (CarE)) under larval exposure to compound 1 were measured, which indicated that the activity of GST was significantly inhibited by compound 1, while the activities of the UGT and CarE enzymes did not significantly change. As determined by UPLC-MS, the contents of compound 1 in the T1 and T2 groups were 8.55 ng/g and 0.53 ng/g, respectively, which indicated that pest insects significantly induced the synthesis of compound 1. Compound 1 may enhance rice insect resistance by inhibiting the detoxification enzyme activity and metabolism of Chilo suppressalis, as well as promoting cell proliferation to affect its normal growth and development process. The chemical-ecological mechanism of the insect resistance of rice is preliminarily clarified in this paper.

Photocatalytic Hydrogen and Oxygen Evolution Performed by a Long-Afterglow Material.

A micron-sized long-afterglow material, Sr2MgSi2O7:Eu,Ce, was utilized to conduct the hydrogen evolution reaction and oxygen evolution reaction, two half-reactions of water splitting, in the presence of sacrificial agents under both light and dark conditions for the first time. The as-synthesized Sr2MgSi2O7:Eu,Ce exhibited higher photocatalytic activity compared to that of the referenced Sr2MgSi2O7:Eu and Sr2MgSi2O7:Ce samples. Herein, in addition to benefiting from the long photogenerated carrier lifetime of long-afterglow materials, the higher photocatalytic activity was attributed to the conjugated electronic structure between Eu and Ce ions. This structure facilitates charge and energy transfer between them, leading to an enhanced photocatalytic efficiency. This research provides a new strategy for designing efficient long-afterglow material photocatalysts through the construction of conjugated electronic structures.

Screening and Characterization of Antioxidant Film Applicable to Walnut Kernels from Juglans sigillata.

Walnuts play a positive role in human health due to their large amounts of unsaturated fatty acids, whereas lipid oxidation can easily occur during storage. Herein, three natural antioxidants (epicatechin, sesamol, and myricetin) were added to the composite film cross-linked with chitosan and soy protein peptide, and the antioxidant film appropriate for the preservation of walnut kernels from Juglans sigillata was screened to improve the storage quality of walnuts. The results showed that three antioxidant films could all enhance the storage performance of walnut kernels, with sesamol being the best. The characterization of antioxidant film cross-linked with chitosan and soy protein peptide containing sesamol (C/S-ses film) revealed that the composite film improved the slow release and stability of sesamol; in addition, the presence of sesamol could effectively reduce the light transmittance and water vapor permeability of the composite film, together with significantly enhancing the antioxidant and antimicrobial activities, resulting in an effective prolongation of the storage period of walnut kernels. These findings indicated that C/S-ses possess excellent potential for retarding the oxidative rancidity of unsaturated fatty acids and will provide an effective strategy for the preservation of walnut kernels.

Multi-Stage Image-Language Cross-Generative Fusion Network for Video-Based Referring Expression Comprehension.

Video-based referring expression comprehension is a challenging task that requires locating the referred object in each video frame of a given video. While many existing approaches treat this task as an object-tracking problem, their performance is heavily reliant on the quality of the tracking templates. Furthermore, when there is not enough annotation data to assist in template selection, the tracking may fail. Other approaches are based on object detection, but they often use only one adjacent frame of the key frame for feature learning, which limits their ability to establish the relationship between different frames. In addition, improving the fusion of features from multiple frames and referring expressions to effectively locate the referents remains an open problem. To address these issues, we propose a novel approach called the Multi-Stage Image-Language Cross-Generative Fusion Network (MILCGF-Net), which is based on one-stage object detection. Our approach includes a Frame Dense Feature Aggregation module for dense feature learning of adjacent time sequences. Additionally, we propose an Image-Language Cross-Generative Fusion module as the main body of multi-stage learning to generate cross-modal features by calculating the similarity between video and expression, and then refining and fusing the generated features. To further enhance the cross-modal feature generation capability of our model, we introduce a consistency loss that constrains the image-language similarity and language-image similarity matrices during feature generation. We evaluate our proposed approach on three public datasets and demonstrate its effectiveness through comprehensive experimental results.

The effect of intermittent theta burst stimulation for cognitive dysfunction: a meta-analysis.

BACKGROUND: Growing evidence suggests that cognitive dysfunction significantly impacts patients' quality of life. Intermittent theta burst stimulation (iTBS) has emerged as a potential intervention for cognitive dysfunction. However, consensus on the iTBS protocol for cognitive impairment is lacking. METHODS: We conducted searches in the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, Chinese National Knowledge Infrastructure, Wanfang Database and the Chongqing VIP Chinese Science and Technology Periodical Database from their inception to January 2024. Random-effects meta-analyzes were used to calculate standardized mean differences and 95% confidence intervals. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: Twelve studies involving 506 participants were included in the meta-analysis. The analysis showed a trend toward improvement of total cognitive function, activities of daily living and P300 latency compared to sham stimulation in patients with cognitive dysfunction. Subgroup analysis demonstrated that these effects were restricted to patients with post-stroke cognitive impairment but not Alzheimer's disease or Parkinson's disease. Furthermore, subthreshold stimulation also exhibited a significant improvement. CONCLUSIONS: The results suggest that iTBS may improve cognitive function in patients with cognitive dysfunction, although the quality of evidence remains low. Further studies with better methodological quality should explore the effects of iTBS on cognitive function.

Systematic Review and Meta-analysis of Tongxinluo Capsule Therapy for Acute Myocardial Infarction.

Context: An acute myocardial infarction (AMI) is a serious, life-threatening disease. Practitioners of traditional Chinese medicine (TCM) commonly use the Tongxinluo (TXL) capsule, a Chinese patent medicine, to treat AMIs. The benefits of TXL capsules for AMIs remain unknown. Objective: The systematic review and meta-analysis intended to investigate the effects of TXL capsules for AMI patients. Design: The research team conducted a comprehensive literature search of the PubMed, Embase, Cochrane Library, and Web of Science databases from inception to February 2023. The team used the search terms acute myocardial infarction, myocardial infarction, TXL Capsule Therapy, and TXL Capsule. The team also performed a meta-analysis and evaluated the features of the included studies using the Cochrane Collaboration tool for assessing the risk of bias. Setting: The study took place at the Second Affiliated Hospital at Heilongjiang University of Chinese Medicine in Harbin City, Heilongjiang Province, China. Outcome Measures: The research team: (1) evaluated the studies' quality using the Cochrane Collaboration tool for assessing the risk of bias; (2) analyzed the curative effect of the TXL capsules for AMI; (3) explored the effects of the TXL capsules on left ventricular end-diastolic dimension (LVEDD), left ventricular end systolic diameter (LVESD), and left ventricular ejection fraction (LVEF); and (4) explored the effects of the TXL capsules on creatine kinase isoenzyme (CK-MB) peak time, CK-MB peak value, and cardiac index. Results: The literature search found ten studies. Compared with routine treatment alone, a combination of routine treatment and TXL capsules significantly improved the curative effects (odds ratio = 3.48; 95% CI: 2.34, 5.17; P < .00001) Compared with the control groups, the TXL capsule groups' LVESD and LVEF were significantly lower, with MD=-0.23; 95% CI: -0.37, -0.10; and P = .0007 and MD=-0.43; 95% CI: -0.61, -0.25; and P < .00001, respectively, and its LVEDD was significantly higher, with MD=5.27; 95% CI: 4.33, 6.21; and P < .00001. For myocardial enzymes, the TXL capsule groups' creatine kinase isoenzyme (CK-MB) peak values and cardiac indexes were significantly lower than those of the control groups, with MD=-53.11; 95% CI: -55.26, -50.97; and P < .00001 and MD=-1.87; 95% CI: -2.03, -1.70; and P < .00001, respectively. Conclusions: The meta-analysis showed that the TXL capsule can bring greater therapeutic benefits for AMI patients in combination with routine treatment. The current study was a meta-analysis, and the field needs more well-designed studies.

The Role of Multiple Birth and Birth Complications in the Association Between Assisted Reproductive Technology Conception and Autism Diagnosis.

In recent decades, the use of assisted reproductive technology (ART) has increased rapidly. To assess the relationship between ART and autism diagnosis, we linked California birth records from 2000 through 2016 with contemporaneous records from the National ART Surveillance System (NASS) and autism caseload records from California's Department of Developmental Services from 2000 through November 2019. All 95,149 birth records that were successfully linked to a NASS record, indicating an ART birth, were matched 1:1 using propensity scores to non-ART births. We calculated the hazard risk ratio (HRR) for autism diagnosis and the proportions of the relationship between ART conception and autism diagnosis mediated by multiple birth pregnancy and related birth complications. The HRR for autism diagnosis following ART compared with non-ART conception is 1.26 (95% CI, 1.17-1.35). Multiple birth, preterm birth, and Cesarean delivery jointly mediate 77.9% of the relationship between ART conception and autism diagnosis. Thus, increased use of single embryo transfer in the United States to reduce multiple births and related birth complications may be a strategy to address the risk of autism diagnosis among ART-conceived children.

Specialized spatially-arranged non-circular fibers enhance filtration performance of African shrimp (Atya gabonensis).

African shrimp (Atya gabonensis) inhabit clear freshwaters, where the notably low concentration of food may pose a challenge to the efficacy of filter fibers on the chela for filter-feeding. Here, we investigate how the distinctive cross-sectional characteristics and spatial arrangement of the African shrimp's non-circular fibers contribute to the enhanced filtration performance of these specialized fibers. The unilateral thickening of the wall along the long axis of the elliptical cross-section of African shrimp fibers markedly enhances the filtration performance. The staggered and twisted arrangement of the fibers optimizes the surrounding flow field, achieving a favorable balance between pressure drop and collection efficiency, consequently improving their filtration performance in collecting fine particles (diameter: 2-10µm). Moreover, the arrangement of the fibers substantially increases the effective flow-facing filtering area of the fiber bundles, thus facilitating their efficiency in collecting larger particles (diameter > 10µm). The unique fiber properties of the African shrimp offer novel insights for the design and optimization of new fiber-filtering robots, presenting a wide range of potential applications, such as marine in-situ resource extraction, medical filtration, and industrial filtration.

Investigation of Microstructure, Oxides, Cracks, and Mechanical Properties of Ti-4Al-2V Joints Prepared Using Underwater Wet Laser Welding.

Developing advanced underwater welding technology for titanium, which is the key structural material for underwater applications, is of great significance for the design, fabrication, and maintenance of submarine equipment. In this study, in order to investigate the underwater welding microstructure and mechanical properties of Ti-4Al-2V alloy, underwater wet laser welding was conducted on Ti-4Al-2V alloy using varying laser power. The microstructure and properties of the welding joints were characterized and analyzed. The microstructure of the heat-affected zone and fusion zone in the welding joints are not significantly different from those of welding in air, but a mixed oxide layer composed of Al2O3 and TiO2 is formed on the surface of the fusion zone. Due to internal stress, a large number of cracks initiate on the oxide layer and propagate to the joints. In the 4 kW and 5 kW joints, a penetrating crack formed due to the excessive accumulation of internal stress breaking up the α phase. The mechanical properties of the joints are significantly affected by the laser power. The tensile strength of the 3 kW and 4 kW joints is comparable to that of the base metal, which is about 600 MPa, while the 5 kW joint shows brittle fracture with no plastic deformation and 228 MPa strength. This research lays a solid foundation for understanding the underwater wet laser welding behavior of titanium alloys.

Effects of robot-assisted upper limb training combined with intermittent theta burst stimulation (iTBS) on cortical activation in stroke patients: A functional near-infrared spectroscopy study.

BACKGROUND: The therapeutic effect and mechanism of robot-assisted upper limb training (RT) combined with intermittent theta burst stimulation (iTBS) for stroke patients are unclear. OBJECTIVE: The purpose of this study was to evaluate changes in brain activation after combination therapy and RT alone using functional near-infrared spectroscopy (fNIRS). METHODS: Patients were randomly assigned to two groups (iTBS + RT Group, n = 18, and RT Group, n = 18). Training was conducted five times a week for four weeks. fNIRS was used to measure changes in oxyhemoglobin in both the primary motor cortex (M1) and pre-motor and supplementary motor area (pSMA) during affected limb movement. Fugl-Meyer Assessment-Upper Extremity (FMA-UE) was employed for evaluating the function of upper limbs. RESULTS: Thirty-two patients with subacute stroke completed the study. The cortex of both hemispheres was extensively activated prior to treatment in the RT group. After training, overactivation decreased. The brain activation of the combined treatment group transferred to the affected side after the treatment. There was a notable enhancement in the FMA-UE scores for both groups, with the combined group's progress significantly surpassing that of the RT group. CONCLUSION: RT combined with iTBS can improve the motor function of stroke patients and promote the balance between cerebral hemispheres.

Population pharmacokinetic analyses of methotrexate in pediatric patients: a systematic review.

BACKGROUND AND OBJECTIVES: Methotrexate is widely utilized in the chemotherapy of malignant tumors and autoimmune diseases in the pediatric population, but dosing can be challenging. Several population pharmacokinetic models were developed to characterize factors influencing variability and improve individualization of dosing regimens. However, significant covariates included varied across studies. The primary objective of this review was to summarize and discuss population pharmacokinetic models of methotrexate and covariates that influence pharmacokinetic variability in pediatric patients. METHODS: Systematic searches were conducted in the PubMed and EMBASE databases from inception to 7 July 2023. Reporting Quality was evaluated based on a checklist with 31 items. The characteristics of studies and information for model construction and validation were extracted, summarized, and discussed. RESULTS: Eighteen studies (four prospective studies and fourteen retrospective studies with sample sizes of 14 to 772 patients and 2.7 to 93.1 samples per patient) were included in this study. Two-compartment models were the commonly used structural models for methotrexate, and the clearance range of methotrexate ranged from 2.32 to 19.03 L/h (median: 6.86 L/h). Body size and renal function were found to significantly affect the clearance of methotrexate for pediatric patients. There were limited reports on the role of other covariates, such as gene polymorphisms and co-medications, in the pharmacokinetic parameters of methotrexate pediatric patients. Internal and external evaluations were used to assess the performance of the population pharmacokinetic models. CONCLUSION: A more rigorous external evaluation needs to be performed before routine clinical use to select the appropriate PopPK model. Further research is necessary to incorporate larger cohorts or pool analyses in specific susceptible pediatric populations to improve the understanding of predicted exposure profiles and covariate identification.

Research and Verification of a Novel Interferometry Method by Joint Processing of Downlink Pseudo-Noise Ranging and DOR Signals for Deep Space Exploration.

The remarkably long distances covered by deep space probes result in extremely weak downlink signals, which poses great challenges for ground measurement systems. In the current climate, improving the comprehensive utilization of downlink signal power to increase the detection distance or enhance the measurement accuracy is of great significance in deep space exploration. Facing this problem, we analyze the delta Differential One-way Range (ΔDOR) error budget of the X-band of the China Deep Space Network (CDSN). Then, we propose a novel interferometry method that detunes one group of DOR beacons and reuses the clock components of regenerative pseudo-code ranging signals for interferometry delay estimation. The primary advantage of this method is its ability to enhance the power utilization efficiency of downlink signals, thereby facilitating more efficient tracking and measurement without necessitating additional design requirements for deep space transponders. Finally, we analyze and verify the correctness and effectiveness of our proposed method using measured data from CDSN. Our results indicate that the proposed method can save approximately 13% of the downlink signal power and increase the detection distance by about 6.25% using typical modulation parameters. Furthermore, if the relative power of other signal components remains unchanged, the power of the DOR tone can be directly increased by more than 100%, improving the deep space exploration ability more significantly.

Magnitude shifts spatial attention from left to right in rhesus monkeys as in the human mental number line.

Humans typically represent numbers and quantities along a left-to-right continuum. Early perspectives attributed number-space association to culture; however, recent evidence in newborns and animals challenges this hypothesis. We investigate whether the length of an array of dots influences spatial bias in rhesus macaques. We designed a touch-screen task that required monkeys to remember the location of a target. At test, monkeys maintained high performance with arrays of 2, 4, 6, or 10 dots, regardless of changes in the array's location, spacing, and length. Monkeys remembered better left targets with 2-dot arrays and right targets with 6- or 10-dot arrays. Replacing the 10-dot array with a long bar, yielded more accurate performance with rightward locations, consistent with an underlying left-to-right oriented magnitude code. Our study supports the hypothesis of a spatially oriented mental magnitude line common to humans and animals, countering the idea that this code arises from uniquely human cultural learning.