Ovarian hormones predict cooperative strategies updating during multiple rounds of the prisoner's dilemma.

Increasing research has focused on how ovarian hormones influence individual prosocial motivation and cooperation. However, most results remain ambiguous and contradictory. Here, we collected progesterone (PROG) and oestradiol from 62 healthy women with regular menstrual cycles to explore whether variations in ovarian hormones could flexibly change their cooperative preference according to their opponents' strategies in multiple rounds of a prisoner's dilemma (PD) game. Participants in different menstrual phases (32 in the follicular phase [FP] and 30 in the luteal phase [LP]) were asked to complete 20 rounds of PD games with each of three computer opponents holding different cooperative strategies. The results revealed that in PD games that did not require cooperation for increased outcomes, women in the LP (high PROG) reduced their cooperation rate more significantly than women in the FP (low PROG). In contrast, when the game design required reciprocity, simultaneously elevated levels of PROG and oestradiol predicted greater instances of participants choosing to cooperate. Furthermore, we found that elevated PROG levels accounted for women's elevated prosocial choices, regardless of the need to increase outcomes through cooperation. These results implied higher levels of PROG and oestradiol influence women's cooperative strategies resulting in increased social interactions.

[Retracted] Tanshinone IIA enhances the inhibitory effect of imatinib on proliferation and motility of acute leukemia cell line TIB­152 in vivo and in vitro by inhibiting the PI3K/AKT/mTOR signaling pathway.

Following the publication of the above article, a concerned reader drew to the Editor's attention that the Transwell cell invasion assay data featured in Figs. 2D and 4E, certain of the tumor images in Fig. 5A and the TUNEL assay data in Fig. 5C were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published elsewhere prior to the submission of this paper to Oncology Reports, or which under consideration for publication at around the same time (some papers of which have been retracted). In view of the fact that certain of these data had already apparently been published prior to the submission of this article for publication, the Editor of Oncology Reports has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 43: 503­515, 2020; DOI: 10.3892/or.2019.7453].

Performance evaluation and stabilization mechanism of red clay treated with polyurethane.

Red clay, a widely distributed soil, weakens significantly when exposed to water. This poses challenges for using it as a foundation for urban infrastructure, as rainwater scouring, infiltration, and external loads can cause uneven settlement and landslides, compromising structural integrity. To address this issue, we propose the use of a green highly permeable water-soluble polyurethane material (PSP) as an alternative to conventional curing agents. We conducted a series of tests to evaluate the efficacy of PSP in improving the mechanical properties of red clay. Acoustic emission tests were used to examine the failure mode of PSP-stabilized red clay, while scanning electron microscopy provided microscopic insights into clay stabilization mechanisms. The triaxial test results establish empirical relationships between strength, stiffness, toughness, and control parameters (PSP content, moisture content, and confining pressure) of the stabilized clay. We found that PSP-stabilized soils exhibit ductile failure and strain hardening, with PSP curing agents effectively enhancing clay strength and stiffness within a 3-day curing period. Univariate analysis reveals positive correlations between peak energy absorption values, peak stress rates, and PSP content, while showing a negative correlation with moisture content. Confining pressure variations have relatively little effect on peak stress ratios of PSP soils, and PSP soil stiffness minimally influences confining pressure as PSP content increases. Importantly, PSP treatment significantly increases ductility compared to untreated clay soils, distinguishing PSP soils from hydric soils.

Synthesis, characterization and performance of lignin carboxyl betaine zwitterionic surfactants for application in enhanced oil recovery.

The objective of this study was to synthesize lignin carboxyl betaine zwitterionic surfactants (LCBS) from alkali lignin through a three-step reaction involving epoxidation, amination, and quaternization. The synthesized LCBS were characterized using infrared spectroscopy (IR) and thermogravimetric (TG) analysis. To assess their potential for enhanced oil recovery (EOR), the physicochemical properties of the LCBS surfactants, such as surface tension, emulsification, temperature resistance, salt resistance, and interfacial properties, were evaluated using standard experimental methods for surfactants applied in oil displacement. The LCBS surfactants exhibited higher surface activity, with low surface tension values ranging from 29.65 mN m-1 to 31.85 mN m-1 at the corresponding critical micelle concentration (cmc), also the significant emulsifying performance of LCBS surfactants was proved in the emulsifying experiments. Moreover, the synthesized LCBS surfactants were found to be suitable for use in harsh reservoirs of high-salinity and high-temperature, as confirmed by the temperature and salt resistance measurements. The interfacial tension (IFT) tests between Huabei crude oil and LCBS surfactants suggested that these surfactants could effectively extract the crude oil containing heavy components such as colloid and asphaltene, and ultra-low IFT values could be achieved with the addition of weak alkali.

Highly selective titanium (IV)-immobilized O-phospho-L-tyrosine modified magnetic nanoparticles for the enrichment of intact phosphoproteins.

Phosphorylation is one of the most important protein post-translational modifications, which possesses dramatic regulatory effects on the function of proteins. In consideration of the low abundance and low stoichiometry of phosphorylation and non-specific signal suppression, efficient capture of the phosphoproteins from complex biological samples is critical to meet the need for protein profiling. In this work, a facile preparation of titanium (IV)-immobilized O-phospho-L-tyrosine modified magnetic nanoparticles was developed for the enrichment of intact phosphoproteins. The prepared magnetic nanoparticles were characterized by various instruments and had a spherical shape with an average diameter of 300 nm. The adsorption isotherms were investigated and the maximum capacity for ß-casein was calculated to be 961.5 mg/g. Standard protein mixtures and biological samples (non-fat milk and human serum) were selected to test the enrichment performance. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis demonstrated the excellent enrichment performance with high selectivity. With the superparamagnetic property, titanium (IV)-immobilized O-phospho-L-tyrosine modified magnetic nanoparticles were convenient for the practical application and clinical promotion, thus having a promising prospect in the field of phosphoprotein research.

Coordinated DNA and histone dynamics drive accurate histone H2A.Z exchange.

Nucleosomal histone H2A is exchanged for its variant H2A.Z by the SWR1 chromatin remodeler, but the mechanism and timing of histone exchange remain unclear. Here, we quantify DNA and histone dynamics during histone exchange in real time using a three-color single-molecule FRET assay. We show that SWR1 operates with timed precision to unwrap DNA with large displacement from one face of the nucleosome, remove H2A-H2B from the same face, and rewrap DNA, all within 2.3 s. This productive DNA unwrapping requires full SWR1 activation and differs from unproductive, smaller-scale DNA unwrapping caused by SWR1 binding alone. On an asymmetrically positioned nucleosome, SWR1 intrinsically senses long-linker DNA to preferentially exchange H2A.Z on the distal face as observed in vivo. The displaced H2A-H2B dimer remains briefly associated with the SWR1-nucleosome complex and is dissociated by histone chaperones. These findings reveal how SWR1 coordinates DNA unwrapping with histone dynamics to rapidly and accurately place H2A.Z at physiological sites on chromatin.

Preliminary application of brachytherapy with double-strand 125I seeds and biliary drainage for malignant obstructive jaundice.

AIM: To evaluate the efficacy and safety of brachytherapy with double-strand 125I seeds and biliary drainage for malignant obstructive jaundice. METHODS AND MATERIALS: 42 patients with obstructive jaundice because of extrahepatic cholangiocarcinoma were enrolled. 22 patients (group A) received a biliary stent with common drainage tube implantation, and 20 patients (group B) received a biliary stent with double-strand 125I seeds radiotherapy drainage tube placement. The length, location and pathological stage of biliary stricture were recorded in the two groups. Total bilirubin (TBIL), direct bilirubin (DBIL), IgA, IgG, IgM, alanine aminotransferase and white blood cell (WBC) count were measured before and after percutaneous transhepatic cholangial drainage (PTCD). Tumor diameter was measured before and three months after PTCD, and the difference were calculated. Stent patency time, survival time, and complications were recorded. RESULTS: There was no significant difference in the length, location and pathological stage of biliary stenosis between the two groups. There was no significant difference in TBIL, DBIL, IgA, IgG, IgM, alanine aminotransferase and WBC count between the two groups before or after PTCD (P > 0.05). Three months after PTCD, tumors growth in group A and tumors shrinkage in group B. The difference in tumor size between the two groups before and after PTCD was statistically significant (P < 0.05). The average stent patency times in groups A and B were 3.55 ± 0.76 months and 8.76 ± 1.85 months, respectively (P < 0.05). The average survival times in groups A and B were 133.5 ± 27.8 days and 252.5 ± 114.5 days, respectively (P < 0.05). There was no statistically significant difference in the incidence of complications between the two groups (P > 0.05). CONCLUSION: Double-strand 125I seeds radiotherapy biliary drainage tubes can safely and effectively control tumors, prolong the patency of biliary stents, and prolong patient survival.

Identification and Exploration of Novel Macrophage M2-Related Biomarkers and Potential Therapeutic Agents in Endometriosis.

Endometriosis (EM) is a chronic neuroinflammatory disorder that is associated with pain and infertility that affects ∼10% of reproductive-age women. The pathophysiology and etiology of EM remain poorly understood, and diagnostic delays are common. Exploration of the underlying molecular mechanism, as well as novel diagnostic biomarkers and therapeutic targets, is urgently needed. Inflammation is known to play a key role in the development of lesions, which are a defining feature of the disorder. In our research, the CIBERSORT and WGCNA algorithms were used to establish a weighted gene co-expression network and to identify macrophage-related hub genes using data downloaded from the GEO database (GSE11691, 7305). The analysis identified 1,157 differentially expressed genes (DEGs) in EM lesions, of which five were identified as being related to M2 macrophages and were validated as differentially expressed by qRT-PCR and immunohistochemistry (IHC). Of these putative novel biomarker genes, bridging integrator 2 (BIN2), chemokine receptor 5 (CCR5), and macrophage mannose receptor 1 (MRC1) were upregulated, while spleen tyrosine kinase (SYK) and metalloproteinase 12 (ADAM12) were downregulated in ectopic endometria vs. normal endometria. Meanwhile, 23 potentially therapeutic small molecules for EM were obtained from the cMAP database, among which topiramate, isoflupredone, adiphenine, dexverapamil, MS-275, and celastrol were the top six molecules with the highest absolute enrichment values. This is our first attempt to use the CIBERSORT and WGCNA algorithms for the identification of novel Mϕ2 macrophage-related biomarkers of EM. Our findings provide novel insights into the impact of immune cells on the etiology of EM; nevertheless, further investigation of these key genes and therapeutic drugs is needed to validate their effects on EM.

Entropy-Based Classification of Elementary Cellular Automata under Asynchronous Updating: An Experimental Study.

Classification of asynchronous elementary cellular automata (AECAs) was explored in the first place by Fates et al. (Complex Systems, 2004) who employed the asymptotic density of cells as a key metric to measure their robustness to stochastic transitions. Unfortunately, the asymptotic density seems unable to distinguish the robustnesses of all AECAs. In this paper, we put forward a method that goes one step further via adopting a metric entropy (Martin, Complex Systems, 2000), with the aim of measuring the asymptotic mean entropy of local pattern distribution in the cell space of any AECA. Numerical experiments demonstrate that such an entropy-based measure can actually facilitate a complete classification of the robustnesses of all AECA models, even when all local patterns are restricted to length 1. To gain more insights into the complexity concerning the forward evolution of all AECAs, we consider another entropy defined in the form of Kolmogorov-Sinai entropy and conduct preliminary experiments on classifying their uncertainties measured in terms of the proposed entropy. The results reveal that AECAs with low uncertainty tend to converge remarkably faster than models with high uncertainty.

Social Orientation in the Luteal Phase: Increased Social Feedback Sensitivity, Inhibitory Response, Interpersonal Anxiety and Cooperation Preference.

Cyclical fluctuations of the ovarian hormones estrogen (E2) and progesterone (PROG) have multiple effects on reproduction and development. However, little is known about the roles of E2 and PROG in women's social behaviors. Here, based on evolutionary theory suggesting social sensitivity and inhibition ability are conductive to maintaining social relationships, we provide evidence for the association between menstrual phases and social orientation. In Study 1, 78 women provided saliva samples and reported their intensity of behavioral activation/inhibition system (BAS/BIS) and interpersonal sensitivity at either of two phases of the menstrual cycle: late follicular phase (FP), and mid-luteal phase (LP). A significant between-subject association emerged, revealing that women with higher PROG levels reported higher levels of social feedback sensitivity, and women with relatively high PROG levels showed a positive association between their E2 levels and inhibitory response. In Study 2, 30 women reported their interpersonal anxiety and finished the social value orientation (SVO) measures at both late FP and mid-LP. A significant within-person effect emerged: women in the mid-LP, which is characterized by higher PROG levels, reported higher levels of interpersonal anxiety and SVO. In sum, these findings revealed that women's social orientation could fluctuate naturally with ovarian hormones across the menstrual cycle.

Preparation of graphene oxide-modified palygorskite nanocomposites for high-efficient removal of Co(II) from wastewater.

Removing Co(II) from wastewater is urgent due to the threat to the environment and human health. In the work, the nanocomposite of graphene oxide-modified palygorskite (mPal-GO) is synthesized by cross-linking one-dimensional palygorskite (Pal) with two-dimensional material graphene oxide (GO), and used to remove Co(II) from wastewater. Its structure is characterized by Fourier transformed infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and Brunauer-Emmett-Teller (BET) surface area measurement. The parameters, such as mass ratio (GO:mPal), temperature, pH, and contact time, are carefully investigated. The results indicate that pseudo-second-order equation and Langmuir isotherm model are the best fitting one in the adsorption process of Co(II) onto mPal-GO. The maximum adsorption capacity achieves 16.9 mg/g at pH = 6.0 and T = 298 K according to the Langmuir model analysis. Furthermore, mPal-GO can be reused more than 5 times with a slight decrease according to the adsorption-desorption cycle experiments. Finally, mPal-GO with the low-cost and easy separation is a promising candidate for removing of Co(II) from wastewater.

Neural Basis of Increased Cognitive Control of Impulsivity During the Mid-Luteal Phase Relative to the Late Follicular Phase of the Menstrual Cycle.

Hormonal changes across the menstrual cycle have been shown to influence reward-related motivation and impulsive behaviors. Here, with the aim of examining the neural mechanisms underlying cognitive control of impulsivity, we compared event-related monetary delay discounting task behavior and concurrent functional magnetic resonance imaging (fMRI) revealed brain activity as well as resting state (rs)-fMRI activity, between women in the mid-luteal phase (LP) and women in the late follicular phase (FP). The behavioral data were analyzed and related to neural activation data. In the delay discounting task, women in the late FP were more responsive to short-term rewards (i.e., showed a greater discount rate) than women in the mid-LP, while also showing greater activity in the dorsal striatum (DS). Discount rate (transformed k) correlated with functional connectivity between the DS and dorsal lateral prefrontal cortex (dlPFC), consistent with previous findings indicating that DS-dlPFC circuitry may regulate impulsivity. Our rs-fMRI data further showed that the right dlPFC was significantly more active in the mid-LP than in late FP, and this effect was sensitive to absolute and relative estradiol levels during the mid-LP. DS-dlPFC functional connectivity magnitude correlated negatively with psychometric impulsivity scores during the late FP, consistent with our behavioral data and further indicating that relative estradiol levels may play an important role in augmenting cognitive control. These findings provide new insight into the treatment of conditions characterized by hyper-impulsivity, such as obsessive compulsive disorder, Parkinson disease, and attention deficit hyperactivity disorder. In conclusion, our results suggest that cyclical gonadal hormones affect cognitive control of impulsive behavior in a periodic manner, possibility via DS-dlPFC circuitry.

Novel brachytherapy drainage tube loaded with double 125I strands for hilar cholangiocarcinoma: A case report.

BACKGROUND: Hilar cholangiocarcinoma (CC) is a common malignant tumor with high malignancy and poor prognosis. Most patients have lost the opportunity to undergo radical surgery when diagnosed. Although palliative drainage or biliary stent placement is a preferable choice, the tumor cannot be controlled. This study aimed to develop a novel brachytherapy drainage tube for low-dose-rate brachytherapy with an effective drainage, thereby prolonging the survival time of patients. CASE SUMMARY: A 54-year-old male patient had undergone choledochal stent implantation due to obstructive jaundice. He was admitted to the hospital because of the recurrence of jaundice. Preoperative imaging and pathological biopsy revealed hilar CC (Bismuth-Corlette type IIIa). First, the patient underwent percutaneous transhepatic cholangial drainage and the symptoms of jaundice gradually relieved. To further treat hilar CC and remove the biliary drainage tube as far as possible, the patient chose to use the novel brachytherapy drainage tube after a multi-disciplinary consultation. After 1 mo of brachytherapy, the re-examination revealed that the obstructive lesions disappeared, and the drainage tube was finally removed. During the following 10 mo of follow-up, the patient's hilar CC did not recur. CONCLUSION: The novel brachytherapy drainage tube may be a new choice for patients with unresectable hilar CC.

How ovarian hormones influence the behavioral activation and inhibition system through the dopamine pathway.

The behavioral activation system (BAS) and the behavioral inhibition system (BIS) have been proposed to relate to stable traits that predict inter-individual differences in motivation. Prior reports point dopamine (DA) pathways, mainly including ventral tegmental area (VTA) and substantia nigra (SN), implicate in subserving reward-related functions associated with BAS and inhibitory functions related with BIS. However, as an important factor that affects DA releasing, it remains an open question whether the ovarian hormones may also be related to BIS/BAS. Here, to investigate effects of the estradiol (E2) and progesterone (PROG) on BIS/BAS and related DA pathways, we employed a BIS/BAS scale and the resting-state functional magnetic resonance imaging (fMRI) during the late follicular phase (FP) and the mid-luteal phase (LP). On the behavioral level, when women had high PROG levels, their E2 levels were found positively correlated with BIS scores, but those women whose PROG levels were low, their E2 levels were negative correlation with BIS scores. On the neural level, we demonstrated BAS was related with the VTA pathway, included brain reward regions of nucleus accumbens (NAc) and orbitofrontal cortex (OFC). Meanwhile, the BIS was correlated with the SN-dorsolateral prefrontal cortex (dlPFC) pathway. ROI-based resting-state functional connectivity (RSFC) analyses further revealed that, RSFC between the SN and dlPFC was modulated by ovarian hormones. With higher PROG levels, increased E2 levels among women were accompanied by stronger RSFC of the SN-dlPFC, but when PROG levels were low, E2 levels were negatively correlated with the SN-dlPFC RSFC. These findings revealed a combined enhancement effect of E2 and PROG on BIS, and the SN-dlPFC pathway was mainly involved in this process.

Tuning of the Oxygen Species Linker on the Surface of Polymeric Carbon Nitride to Promote the Photocatalytic Hydrogen Evolution Performance.

Invited for this month's cover is the research group of Rongzhi Chen at the University of Chinese Academy of Sciences and Xinming Wang at Guangzhou Institute of Geochemistry, Chinese Academy of Sciences. The image proposes an effective strategy to tune bonded oxygen species of carbon nitride for improving photocatalytic hydrogen production. The Full Paper itself is available at 10.1002/cssc.202001027.

Association of ovarian hormones with mapping concept of self and others in the brain's default mode network.

The brain's default mode network (DMN) has become closely associated with self-referential mental activity, particularly in the resting-state. Prior reports point that the sex hormones are potent modulators of brain plasticity and functional connectivity. However, it is uncertain whether changes in ovarian hormones, as occur during the monthly menstrual cycle, substantially affects the functional connectivity of DMN. Here, we employed a Self-Awareness Scale (SAS) and the resting-state functional MRI in the late follicular phase and the mid-luteal phase to investigate the effect of the estradiol (E2) and progesterone on the SAS and DMN. On the behavioral level, increased progesterone facilitated women's other-focused attention. The regions of interest-based resting-state functional connectivity analyses continued to demonstrate a negative correlation of the relative progesterone and the medial prefrontal cortex-inferior temporal gyrus (mPFC-ITG) functional connectivity, and a facilitated effect of relative E2 on the mPFC-inferior parietal lobule functional connectivity in the DMN. Furthermore, as a core hub of the 'theory of mind', the functional connectivity between the ITG and thalamus was found negatively correlated with the relative E2. Meanwhile, the mid-luteal phase, which had significantly lower relative E2 levels, was indicated had stronger ITG-thalamus functional connectivity during the resting state. These results demonstrated an opposite effect of E2 and progesterone on the DMN and the other-focused preference in the mid-luteal phase, extended previous evidence of the potentially adaptive psychological effects of ovarian hormones on mapping self and others in the brain networks.

Tuning of the Oxygen Species Linker on the Surface of Polymeric Carbon Nitride to Promote the Photocatalytic Hydrogen Evolution Performance.

Polymeric carbon nitrides (CNs) have been identified as attractive photocatalysts owing to their comparatively low cost and facile modification of their electronic structure. Herein, we report an effective strategy to tune the surface oxygen species linking site of polymeric CN, achieving more effective charge separation. A high photocatalytic hydrogen production rate of approximately 10225 µmol h-1 g-1 under visible light irradiation (λ>420 nm) and an impressive apparent quantum efficiency (AQE) of 5.7 % at 430 nm were recorded. Specifically, thermal treatment under a H2 and then an air atmosphere allowed the oxygen species linker on the surface of CN to be changed from -C=O to N=C-OH and then -C-O-C-, resulting in unbalanced charge distribution, which significantly enhanced the photogenerated charge separation, further contributing to the high hydrogen production performance. This linker regulation strategy may provide a new path for the development of highly efficient photocatalysts.

Photoelectric effect driving PANI/PB multicolor visualized detection of CEA based on Ag2S NPs@ZnO NTs.

In this work, a multicolor visual immunoassay platform was developed. The photoelectric effects of Ag2S NPs@ZnO NTs made the color changes of PANI/PB, which enabled visual inspection of CEA. Under the visible light excitation, Ag2S NPs@ZnO NTs generates electron-holes. Where, photoelectrons will pass electrical circuit to PB and photoinduced holes will oxidize PANI, which making the PANI/PB composite changes from emerald green-blue-purple-black colors. When CEA was incubated, the migration rate of photogenerated carriers is slowed down owing to the steric hindrance, resulting in different color changes of PANI/PB. In addition, the average green channel of PANI/PB read by photoshop has a certain correlated linear relationship with the concentration of CEA. Meanwhile, we can observe the color transformation of PANI/PB with our own eyes. By integrating advantages of photoelectrochemistry and colorimetry, the linear range of CEA detection was 0.1-20 ng/mL, and the detection limit was 0.05 ng/mL (S/N = 3). More importantly, this multicolor sensing method is very convenient, simple and low-cost. The photocarriers-modulated colorimetric strategy also provides a novel idea for visual portable platform design in clinical diagnosis.

Tanshinone IIA enhances the inhibitory effect of imatinib on proliferation and motility of acute leukemia cell line TIB­152 in vivo and in vitro by inhibiting the PI3K/AKT/mTOR signaling pathway.

Acute lymphoblastic leukemia (ALL) is a malignant hematological disease. Tanshinone IIA (Tan IIA) has antitumor activity in vitro and in vivo. The aim of the present study was to investigate the effects of Tan IIA in combination with imatinib (IM) on the proliferation, apoptosis, migration and invasion of acute T lymphocytic leukemia TIB­152 cells in vivo and in vitro, and analyze the potential underlying mechanism. Tan IIA and IM, alone and in combination, significantly inhibited proliferation, migration and invasion of TIB­152 cells, and promoted apoptosis; the effect of co­treatment with Tan IIA plus IM was enhanced. IGF­1 promoted the proliferation, migration and invasion of TIB­152 cells and inhibited apoptosis, while Tan IIA treatment significantly reversed these effects. In vivo experiments demonstrated that treatment with Tan IIA and IM, alone or in combination, significantly inhibited tumor growth in TIB­152 xenograft mice; the growth inhibition of Tan IIA plus IM was the strongest observed. Western blot analysis revealed that the combination of Tan IIA and IM resulted in significantly lower levels of p­PI3K, p­AKT and p­mTOR in cells and tissues compared with the IM and Tan alone treatment groups. In addition, the combination of Tan IIA and IM significantly decreased the levels of Ki67, cleaved caspase­3, VEGF and MMP­9 in cells and tissues, and the level of caspase­3 was significantly increased. Taken together, the results revealed that Tan IIA enhanced the inhibitory effect of imatinib on TIB­152 cell proliferation, migration and invasion, and induced apoptosis, which may be associated with inhibition of the PI3K/AKT/mTOR signaling pathway.