Click method preserves but EDC method compromises the therapeutic activities of the peptide-activated hydrogels for critical ischemic vessel regeneration.

Peptide-functionalized hydrogel is one of commonly used biomaterials to introduce hydrogel-induced vessel regeneration. Despite many reports about the discoveries of high-active peptides (or ligands) for regeneration, the study on the conjugating methods for the hydrogel functionalization with peptides is limited. Here, we compared the vasculogenic efficacy of the peptide-functionalized hydrogels prepared by two commonly used conjugating methods, 1-ethyl-3-(3-dimethylamino propyl) carbodiimide (EDC) and Click methods, through cell models, organ-on-chips models, animal models, and RNA sequencing analysis. Two vascular-related cell types, the human umbilical vein endothelial cells (HUVECs) and the adipose-derived stem cells (ADSCs), have been cultured on the hydrogel surfaces prepared by EDC/Click methods. It showed that the hydrogels prepared by Click method supported the higher vasculogenic activities while the ones made by EDC method compromised the peptide activities on hydrogels. The vasculogenesis assays further revealed that hydrogels prepared by Click method promoted a better vascular network formation. In a critical ischemic hindlimb model, only the peptide-functionalized hydrogels prepared by Click method successfully salvaged the ischemic limb, significantly improved blood perfusion, and enhanced the functional recoveries (through gait analysis and animal behavior studies). RNA sequencing studies revealed that the hydrogels prepared by Click method significantly promoted the PI3K-AKT pathway activation compared to the hydrogels prepared by EDC method. All the results suggested that EDC method compromised the functions of the peptides, while Click method preserved the vascular regenerating capacities of the peptides on the hydrogels, illustrating the importance of the conjugating method during the preparation of the peptide-functionalized hydrogels.

Neuroendoscopy-Assisted Entire-Process Visualization Technique of Ventricular Puncture for External Ventricular Drainage.

OBJECTIVE: This study aimed to investigate the feasibility, safety, and efficacy of the neuroendoscopy-assisted entire-process visualization technique (NEAEVT) of ventricular puncture for external ventricular drainage. METHODS: Eighty-eight patients with cerebral hemorrhage who underwent unilateral ventricular puncture for external ventricular drainage in our hospital from June 2021 to June 2023 were analyzed. Patients were grouped according to puncture technique: NEAEVT (30 patients), freehand (30 patients), and laser-navigation-assisted (28 patients). Operation time, drainage tube placement, and catheter-related hemorrhage incidence were compared between the groups. RESULTS: Mean operation time significantly differed between the freehand, NEAEVT, and laser-assisted groups (17.07, 18.37, and 34.04 min, respectively; P <0.0001). The position of the drainage tube was optimal or adequate in all patients of the NEAEVT group; optimal/adequate positioning was achieved in 80% of the freehand group. No catheter-related hemorrhage occurred in the NEAEVT group. Three freehand group patients and 2 laser-assisted group patients experienced catheter-related hemorrhage. CONCLUSION: The NEAEVT of ventricular puncture is accurate and achieves ventricular drainage without significantly increasing surgical trauma, operation time, or incidence of hemorrhage.

Effects of T2DM on postoperative outcome of patients with colorectal cancer: a study on the relationship between blood glucose control and survival rate.

To investigate the impact of type 2 diabetes (T2DM) on the prognosis of colorectal cancer (CRC). The data of 312 patients with CRC treated in the First Affiliated Hospital of Huzhou University from 2012 to 2018 were analyzed retrospectively. The patients were divided into a comorbidity group (n = 62) and a non-comorbidity group (n = 250) according to the presence of T2DM. The baseline data of the two groups were balanced by 1:2 propensity score matching (PSM). Kaplan-Meier analysis and Log-rank test were employed to compare the 5-year overall survival (OS) rates of patients. Cox regression model and inverse probability of treatment weighting (IPTW) were utilized to assess the influence of T2DM on 5-year OS of patients. Based on the results of Cox regression, a nomogram model of T2DM on 5-year OS of patients was constructed. A total of 62 patients in the comorbidity group and 124 patients in the non-comorbidity group were matched using PSM. The 5-year OS rate was lower in the comorbidity group than in the non-comorbidity group (82.23% VS 90.32%, P = 0.038). Subgroup analysis showed that the 5-year overall survival rate was higher in the good blood glucose control group than in the poor blood glucose control group (97.14% VS 62.96%, P<0.01). Multivariate Cox regression showed that the 5-year mortality risk in the comorbidity group was 2.641 times higher than that in the non-comorbidity group (P = 0.026). IPTW analysis showed that the 5-year risk of death in the comorbidity group was 2.458 times that of the non-comorbidity group (P = 0.019). The results showed that poor blood glucose control, BMI≥25 kg/m2, low differentiation, III/IV stage, and postoperative infection were independent factors affecting the 5-year overall survival rate of CRC patients (P<0.05). The ROC curve showed that the AUCs of the constructed model in predicting the 5-year OS in the training set and the testing set were 0.784 and 0.776, respectively. T2DM is identified as a risk factor for reduced 5-year survival among CRC patients, necessitating increased attention for this subgroup, particularly those with poor blood glucose control.

Ant-eating spiders from Xizang, China (Araneae, Zodariidae).

Six species of the ant-eating spider of the family Zodariidae are described from Xizang, China, including five new species: Asceuachayusp. nov. (♀), A.dawaisp. nov. (♂♀), Mallinellamigusp. nov. (♂), M.mеdogsp. nov. (♂♀), and M.yadongsp. nov. (♂♀). The female of Cydrelalinzhiensis (Hu, 2001) is described here for the first time. Descriptions and photographs of all the species are provided.

A Loss Differentiation Method Based on Heterogeneous Ensemble Learning Model for Low Earth Orbit Satellite Networks.

In light of the high bit error rate in satellite network links, the traditional transmission control protocol (TCP) fails to distinguish between congestion and wireless losses, and existing loss differentiation methods lack heterogeneous ensemble learning models, especially feature selection for loss differentiation, individual classifier selection methods, effective ensemble strategies, etc. A loss differentiation method based on heterogeneous ensemble learning (LDM-HEL) for low-Earth-orbit (LEO) satellite networks is proposed. This method utilizes the Relief and mutual information algorithms for selecting loss differentiation features and employs the least-squares support vector machine, decision tree, logistic regression, and K-nearest neighbor as individual learners. An ensemble strategy is designed using the stochastic gradient descent method to optimize the weights of individual learners. Simulation results demonstrate that the proposed LDM-HEL achieves higher accuracy rate, recall rate, and F1-score in the simulation scenario, and significantly improves throughput performance when applied to TCP. Compared with the integrated model LDM-satellite, the above indexes can be improved by 4.37%, 4.55%, 4.87%, and 9.28%, respectively.

Patient-related characteristics predict prostate cancers in men with PI-RADS 4-5 to further optimize the diagnostic performance of MRI.

PURPOSE: To develop a prediction model based on patient-related characteristics for detecting prostate cancer (PCa) in patients with Prostate Imaging Reporting and Data System (PI-RADS) 4-5 in multiparametric magnetic resonance imaging (mp-MRI), aiming to optimize pre-biopsy risk stratification in MRI. MATERIALS AND METHODS: The patient-related characteristics including the lesion location, age, prostate-specific antigen (PSA), free prostate-specific antigen (fPSA), fPSA/PSA, prostate-specific antigen density (PSAD) and body mass index (BMI) were collected for patients who underwent mp-MRI and prostate biopsy between February 2014 and October 2022. Univariate and multivariate logistic regression analyses were conducted to select independent predictors of PCa and further create a prediction model. The diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC). Moreover, sensitivity, specificity, positive-predictive value (PPV) and negative-predictive value (NPV) were also calculated. RESULTS: A total of 833 patients were included in this study. In the subgroup PI-RADS 4, the independent characteristics of lesion location, age, fPSA/PSA and PSAD were selected to create the prediction model with an AUC of 0.748 (95% CI 0.694-0.803), sensitivity of 61.88%, specificity of 85.32%, PPV of 92.52%, and NPV of 43.26%. Besides, the prediction model in PI-RADS 5 was created using PSA and PSAD with an AUC of 0.893 (95% CI 0.844-0.941), sensitivity of 81.40%, specificity of 84.85%, PPV of 98.37% and NPV of 28.87%. CONCLUSION: The patient-related clinical characteristics were significant predictors of PCa and the prediction model based on selected characteristics could achieve a medium risk prediction of PCa in PI-RADS 4-5.

PFT-α protects the blood-brain barrier through the Wnt/ß-catenin pathway after acute ischemic stroke.

The dysfunction of blood-brain barrier (BBB) plays a pivotal role in brain injury and subsequent neurological deficits of ischemic stroke. The current study aimed to examine the potential correlation between p53 inhibition and the neuroprotective effect of on the BBB. Rat middle cerebral artery occlusion and reperfusion model (MCAO/R) and oxygen-glucose deprivation/re-oxygenation model (OGD/R) were employed to simulate cerebral ischemia-reperfusion (CI/R) injury occurrence in vivo and in vitro. mNSS and TTC staining were applied to evaluate neurological deficits and brain infarct volumes. Evans blue (EB) staining was carried out to examine the permeability of BBB. RT-qPCR and Western blot to examine the mRNA and protein levels. Cell viabilities were detected by CCK-8. Flow cytometry and ELISA assay were employed to examine apoptosis and neuroinflammation levels. TEER value and sodium fluorescein were carried out to explore the permeability of HBMEC cells. PFT-α inhibited P53 and promoted the expression of ß-catenin and cyclin D1, which were reversed by DKK1. PFT-α inhibited neurological deficits, brain infarct volume, neuroinflammation, apoptosis, and BBB integrity than the MCAO/R rats; however, this inhibition was reversed by DKK1. PFT-α promoted OGD/R-induced cell viability in NSCs, and suppressed inflammation and apoptosis, but DKK1 weakened the effect of PFT-α. PFT-α increased OGD/R-induced TEER values in cerebrovascular endothelial cells, inhibited sodium fluorescein permeability, and increased the mRNA levels of tight junction protein, but they were all attenuated by DKK1. PFT-α protects the BBB after acute ischemic stroke via the Wnt/ß-catenin pathway, which in turn improves neurological function.

A new species and a new provincial record of the genus Acidota Stephens from China (Coleoptera, Staphylinidae, Omaliinae).

New taxonomic and faunistic data for two species of the genus Acidota Stephens, 1829 from China are provided. A new species from Xizang (Linzhi) is described and illustrated: A.dawai Peng & Chen, sp. nov. Additional data (including photographs of the habitus and the type labels) on the type specimens of taxa described from Japan (A.crenatajaponica Watanabe, 1990) and Taiwan (A.montana Smetana, 1993 and A.nivicola Smetana, 1993) are given. A key to Chinese species of Acidota is given. Acidotacrenata (Fabricius, 1792) is recorded from Heilongjiang for the first time.

Intrinsic Strain-Mediated Ultrathin Ceria Nanoantioxidant.

Metal oxide nanozymes have emerged as the most efficient and promising candidates to mimic antioxidant enzymes for treatment of oxidative stress-mediated pathophysiological disorders, but the current effectiveness is unsatisfactory due to insufficient catalytic performance. Here, we report for the first time an intrinsic strain-mediated ultrathin ceria nanoantioxidant. Surface strain in ceria with variable thicknesses and coordinatively unsaturated Ce sites was investigated by theoretical calculation analysis and then was validated by preparing ∼1.2 nm ultrathin nanoplates with ∼3.0% tensile strain in plane/∼10.0% tensile strain out of plane. Compared with nanocubes, surface strain in ultrathin nanoplates could enhance the covalency of the Ce-O bond, leading to increasing superoxide dismutase (SOD)-mimetic activity by ∼2.6-fold (1533 U/mg, in close proximity to that of natural SOD) and total antioxidant activity by ∼2.5-fold. As a proof of concept, intrinsic strain-mediated ultrathin ceria nanoplates could boost antioxidation for improved ischemic stroke treatment in vivo, significantly better than edaravone, a commonly used clinical drug.

RGA1 Negatively Regulates Thermo-tolerance by Affecting Carbohydrate Metabolism and the Energy Supply in Rice.

BACKGROUND: Signal transduction mediated by heterotrimeric G proteins, which comprise the α, ß, and γ subunits, is one of the most important signaling pathways in rice plants. RGA1, which encodes the Gα subunit of the G protein, plays an important role in the response to various types of abiotic stress, including salt, drought, and cold stress. However, the role of RGA1 in the response to heat stress remains unclear. RESULTS: The heat-resistant mutant ett1 (enhanced thermo-tolerance 1) with a new allele of the RGA1 gene was derived from an ethane methyl sulfonate-induced Zhonghua11 mutant. After 45 °C heat stress treatment for 36 h and recovery for 7 d, the survival rate of the ett1 mutants was significantly higher than that of wild-type (WT) plants. The malondialdehyde content was lower, and the maximum fluorescence quantum yield of photosystem II, peroxidase activity, and hsp expression were higher in ett1 mutants than in WT plants after 12 h of exposure to 45 °C. The RNA-sequencing results revealed that the expression of genes involved in the metabolism of carbohydrate, nicotinamide adenine dinucleotide, and energy was up-regulated in ett1 under heat stress. The carbohydrate content and the relative expression of genes involved in sucrose metabolism indicated that carbohydrate metabolism was accelerated in ett1 under heat stress. Energy parameters, including the adenosine triphosphate (ATP) content and the energy charge, were significantly higher in the ett1 mutants than in WT plants under heat stress. Importantly, exogenous glucose can alleviate the damages on rice seedling plants caused by heat stress. CONCLUSION: RGA1 negatively regulates the thermo-tolerance in rice seedling plants through affecting carbohydrate and energy metabolism.

Probing Two Driven Double Quantum Dots Strongly Coupled to a Cavity.

We experimentally and theoretically study a driven hybrid circuit quantum electrodynamics (cQED) system beyond the dispersive coupling regime. Treating the cavity as part of the driven system, we develop a theory applicable to such strongly coupled and to multiqubit systems. The fringes measured for a single driven double quantum dot (DQD)-cavity setting and the enlarged splittings of the hybrid Floquet states in the presence of a second DQD are well reproduced with our model. This opens a path to study Floquet states of multiqubit systems with arbitrarily strong coupling and reveals a new perspective for understanding strongly driven hybrid systems.

Collective Microwave Response for Multiple Gate-Defined Double Quantum Dots.

We fabricate and characterize a hybrid quantum device that consists of five gate-defined double quantum dots (DQDs) and a high-impedance NbTiN transmission resonator. The controllable interactions between DQDs and the resonator are spectroscopically explored by measuring the microwave transmission through the resonator in the detuning parameter space. Utilizing the high tunability of the system parameters and the high cooperativity (Ctotal > 17.6) interaction between the qubit ensemble and the resonator, we tune the charge-photon coupling and observe the collective microwave response changing from linear to nonlinear. Our results present the maximum number of DQDs coupled to a resonator and manifest a potential platform for scaling up qubits and studying collective quantum effects in semiconductor-superconductor hybrid cavity quantum electrodynamics systems.

Baseline white matter function predicts short-term treatment response in first-episode schizophrenia.

BACKGROUND AND PURPOSE: The detection and characterization of functional activities in the gray matter of schizophrenia (SZ) have been widely explored. However, the relationship between resting-state functional signals in the white matter of first-episode SZ and short-term treatment response remains unclear. METHODS: Thirty-six patients with first-episode SZ and 44 matched healthy controls were recruited in this study. Patients were classified as nonresponders and responders based on response to antipsychotic medication during a single hospitalization. The fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and functional connectivity (FC) of white matter were calculated. The relationships between functional changes and clinical features were analyzed. In addition, voxel-based morphometry was performed to analyze the white matter volume. RESULTS: One-way analysis of variance showed significant differences of fALFF and ReHo in the left posterior thalamic radiation and left cingulum (hippocampus) in the patient group, and the areas were regarded as seeds. The FC was calculated between seeds and other white matter networks. Compared with responders, nonresponders showed significantly increased FC between the left cingulum (hippocampus) and left posterior thalamic radiation, splenium of corpus callosum, and left tapetum, and were associated with the changes of clinical assessment. However, there was no difference in white matter volume between groups. CONCLUSION: Our work provides a novel insight that psycho-neuroimaging-based white matter function holds promise for influencing the clinical diagnosis and treatment of SZ.

Cu-In-S/ZnS:Gd3+ quantum dots with isolated fluorescent and paramagnetic modules for dual-modality imaging in vivo.

Gd3+-doped quantum dots (QDs) have been widely used as small-sized bifunctional contrast agents for fluorescence/magnetic resonance (FL/MR) dual-modality imaging. However, Gd3+ doping will always compromise the FL of host QDs. Therefore, balancing the Gd3+ doping and the optical properties of QDs is crucial for constructing high-performance bifunctional nanoprobes. Additionally, most paramagnetic QDs are synthesized in the organic phase and need to be transferred to the aqueous phase for bioimaging. Herein, ingeniously designed shell-doped Cu-In-S/ZnS:Gd3+ QDs have been prepared in the aqueous phase. It has been demonstrated that isolating paramagnetic Gd3+ from fluorescent Cu-In-S core via doping Gd3+ into ZnS shell not only avoided the decrease of FL quantum yield (QY), but also ensured the water accessibility of paramagnetic Gd3+ ions, by which the FL QY and r1 relaxivity of Cu-In-S/ZnS:Gd3+ QDs achieved as much as 15.6% and 15.33 mM-1·s-1, respectively. These high-performance QDs with excellent stability, low biotoxicity, and good tumor permeability were successfully applied for in vivo tumor FL/MR dual-modality imaging, and have shown significant potential in the precision detection and diagnosis of diseases.

[Accumulation Characteristics and Health Risk Assessment of Heavy Metals in Soil-Crop System Based on Soil Parent Material Zoning].

This study used both the element occurrence form analysis and the chronic health risk assessment method to investigate the accumulation characteristics of heavy metals in the soil-crop system and the health risk assessment of agricultural products in northeastern Yunnan, which is a typical area of Southwest China where heavy metals are enriched in soil. Based on the study of 1137 groups of agricultural products and corresponding root soils, the results showed that the soil cadmium (Cd) and lead (Pb) in the lead-zinc ore concentration area were higher than the risk-intervention values of the "Soil Environmental Quality Risk control standard for soil contamination of agricultural land" (GB 15618-2018), whereas the soil Cd in the other parent material areas was within the screening-intervention buffer zone, and Pb was below the minimum risk-screening value. According to the National Food Safety Standard of China (GB 2762-2017), the heavy metal Cd in potatoes and soybeans in the area seriously exceeded the standard, the heavy metal Pb in tartary buckwheat and walnut exceeded the limit value, and the exceeding rate of heavy metal Cd in crops from these parent material areas showed: clastic rock>basalt>lead-zinc ore>carbonate ≈ Quaternary sedimentary>sand (mud) rock. According to the U.S. Environmental Protection Agency's assessment method for the chronic health risk of heavy metal intake by humans, the grains and potatoes, staple foods, and fruits had low chronic health risks of heavy metal intake. Agricultural products from the parent material area of clastic rock, sand (mud) rock, Quaternary sedimentary, and lead-zinc ore concentration showed health risks; with the change in soil physical and chemical properties and the increase in the types of edible crops, the risk will gradually increase. Based on this research, it is urgent to carry out real-time monitoring of agricultural products in the area.

Multi-layer reconstruction of skull base after endoscopic transnasal surgery for invasive pituitary adenomas.

OBJECTIVE: To explore the efficacy of multi-layer skull base reconstruction after endoscopic transnasal surgery for invasive pituitary adenomas (IPAs). CLINICAL RATIONALE FOR THE STUDY: Skull base reconstruction for IPAs. MATERIAL AND METHODS: This retrospective analysis involved 160 patients with IPAs who underwent operations from October 2018 to October 2020. All patients were diagnosed with IPAs by pituitary enhanced magnetic resonance imaging, and all tumours were confirmed to be Knosp grades 3a, 3b, or 4. The experimental group and the control group comprised 80 patients in each, and we used different methods to reconstruct the skull base in each group. The comparison indicators included cerebrospinal fluid leakage, sellar floor bone flap (or middle turbinate) shifting, delayed healing of the skull base reconstructed tissue, nasal discomfort, and epistaxis. We used the chi-square test, and p < 0.05 was considered statistically significant. RESULTS: In the experimental group, cerebrospinal fluid leakage occurred intraoperatively in 73 patients, two of whom had cerebrospinal fluid leakage postoperatively. Brain CT 12 months postoperatively showed no sellar floor bone flap (or middle turbinate) shifting. Endoscopic transnasal checks performed seven days after surgery showed that the skull base reconstructed tissue had healed in 74 patients and had failed to heal in six. However, endoscopic transnasal checks showed that all six of these patients' pedicled nasoseptal flaps had healed well by 14 days after surgery. Other sequelae comprised nasal discomfort in four patients, and epistaxis in four. In the control group, cerebrospinal fluid leakage occurred intraoperatively in 71 patients, 14 of whom had cerebrospinal fluid leakage postoperatively. Brain CT 12 months postoperatively showed floor bone flap (or middle turbinate) shifting in 12 patients. Endoscopic transnasal checks performed seven days after surgery showed that the skull base reconstructed tissue had healed in 65 patients. In 12 patients, pedicled nasoseptal flaps had healed well by 14 days after surgery, while the remaining three patients required reoperation. Other sequelae comprised nasal discomfort in five patients, and epistaxis in six. CONCLUSIONS: This new method of multi-layer skull base reconstruction could play an important role in endoscopic transnasal IPA surgery.

Helical ß-isoindigo-Based Chromophores with B-O-B Bridge: Facile Synthesis and Tunable Near-Infrared Circularly Polarized Luminescence.

It is essential to create organic compounds that exhibit circularly polarized luminescence (CPL) in the near-infrared (NIR) range. Helicene-type emitters possess appealing chiroptical features, however, such NIR molecules are scarce due to a paucity of synthetic strategies. Herein, we developed a series of helical ß-isoindigo-based B-O-B bridged aza-BODIPY analogs that were synthesized conveniently. The reaction of diimino-ß-isoindigo with a heteroaromatic amine produced a restricted ligand cavity, which triggered off the generation of a B-O-B bridge. The B-O-B bridge led to distorted conformations that satisfy the helical requirements, resulting in excellent spectroscopic and chiroptical properties. Tunable CPL with the highest luminescence dissymmetry factor (glum ) of 1.3×10-3 and a CPL brightness (BCPL =11.5 M-1 cm-1 ) in the NIR region was achieved. This synthetic approach is expected to offer a new opportunity to chiral chemistry and increase flexibility for chiroptical tuning.

Primary Intrasellar Amyloidoma.

Amyloidomas of the nervous system are rare in clinical practice and rarely reported in the literature. Primary intrasellar amyloidomas are even rarer. We encountered a 39-year-old male patient, whose chief complaint was headache and who had been hospitalized for 10 days. The patient did not have any past medical history. Preoperative computed tomography and magnetic resonance were nevertheless performed to exclude the possibility of pituitary apoplexy or Rathke cleft cyst. Due to the progressive worsening of his headache, a neuroendoscopic transsphenoidal tumor resection was carried out. During surgery it was found that the tumor exhibited a yellow crystalline substance with an inadequate blood supply and no obvious encapsulation. The tumor was completely resected under endoscopy, the amyloidoma was confirmed by postoperative pathological results, and no pituitary adenoma was found. The patient's headache resolved after surgery, and after a 1-year follow-up, the tumor had not recurred.

Contribution to the knowledge of the genus Agalope Walker from mainland China, with descriptions of four new species (Lepidoptera, Zygaenidae, Chalcosiinae).

New information of the genus Agalope Walker, 1854 from mainland China is presented. Three new species of the Agalope pica species-group are described: A. haoi S.-Y. Huang sp. n. from Weixi County, Yunnan, A. chayuensis S.-Y. Huang Pan sp. n. from Chayu County, Southeastern Xizang and A. owadai S.-Y. Huang sp. n. from Bomi and Jiali Counties, Southeastern and Eastern Xizang. The little-known Agalope aurelia Oberthr, 1923 and A. lucia Oberthr, 1923 were rediscovered, with the male of the latter reported for the first time. Based on the newly discovered male, Agalope lucia is found to be a close relative of A. dejeani, hence it is excluded from the A. pica species-group and transferred to the A. bieti species-group. A new species of the Agalope hyalina species-group is also described: A. jianqingi S.-Y. Huang sp. n. from Pianma, Western Yunnan. Adults and genitalia of the aforementioned and related taxa are illustrated. An updated checklist of the genus is also provided.

Corrigendum: Classifying Vulnerability to Sleep Deprivation Using Resting-State Functional MRI Graph Theory Metrics.

[This corrects the article DOI: 10.3389/fnins.2021.660365.].