Chronic diabetic wounds, severely complicated by multidrug-resistant (MDR) bacterial infections, represent a profound and escalating global health crisis. The intrinsically hostile microenvironment of diabetic wounds, characterized by localized hypoxia, persistent oxidative stress, and poor vascularization, creates an ideal niche for opportunistic pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. These bacteria readily construct dense extracellular polymeric substance (EPS) biofilms, which not only physically shield the microbes from host immune responses but also actively trap the wound in a state of chronic, unresolved inflammation. Consequently, conventional systemic and topical antibiotic therapies are becoming increasingly futile, as poor perfusion at the wound site restricts drug bioavailability, while the rapid genetic evolution of bacteria and the impenetrable nature of biofilms lead to catastrophic treatment failures, often culminating in severe tissue necrosis and lower-extremity amputations. To circumvent the limitations of traditional antimicrobials, therapeutic gas delivery has emerged as a highly promising, paradigm-shifting strategy. Gaseous signaling molecules, particularly nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H₂S), and hydrogen (H₂), possess unique physicochemical properties that allow them to seamlessly penetrate dense biofilm matrices and cellular membranes. Once inside, these gases operate via multi-targeted mechanisms that are incredibly difficult for bacteria to develop resistance against; for instance, NO induces severe lipid peroxidation and DNA cleavage in bacteria, CO downregulates pro-inflammatory cytokines, H₂S significantly accelerates endothelial cell migration for neovascularization, and H₂ acts as a powerful selective antioxidant to neutralize tissue-damaging reactive oxygen species (ROS). Together, these therapeutic gases not only exert broad-spectrum bactericidal effects but also actively reprogram the wound bed by promoting the critical M1-to-M2 macrophage polarization and stimulating angiogenesis. Despite their immense biological potential, the direct clinical translation of gas therapies is severely hindered by inherent physicochemical drawbacks, including extreme volatility, short physiological half-lives, poor aqueous solubility, and the high risk of off-target systemic toxicity, if applied indiscriminately. To conquer these immense pharmacokinetic barriers, cutting-edge advancements in materials science have driven the development of gas-releasing micro- and nanoplatforms. Utilizing sophisticated carriers such as metal-organic frameworks (MOFs), mesoporous silica, polymeric nanoparticles, liposomes, and injectable hydrogels, researchers can now encapsulate gas-donor molecules to achieve sustained, localized delivery. More importantly, these advanced nanoplatforms are ingeniously engineered to be stimuli-responsive. By exploiting the pathological hallmarks of the diabetic wound environment, such as elevated glucose concentrations, acidic pH, and overexpressed ROS, or by utilizing external triggers like near-infrared (NIR) light irradiation and ultrasound, these intelligent platforms ensure on-demand, precise spatio-temporal gas release. This often allows for powerful synergistic combinations, such as photothermal or photodynamic therapy coupled with gas release, thereby obliterating biofilms while sparing healthy tissue. While the therapeutic outcomes of these smart delivery systems in eradicating MDR infections and accelerating tissue repair are unprecedented, several critical challenges remain before widespread clinical adoption, as long-term biosafety profiles of the carrier nanomaterials, complexities in large-scale good manufacturing practice (GMP) production, and stringent regulatory hurdles must be rigorously addressed. Looking forward, the next frontier lies in the realm of precision medicine and theranostics, where future research must focus on the seamless integration of these gas-releasing platforms with flexible, wearable biosensors capable of continuously monitoring wound biomarkers (e.g., pH, temperature, uric acid) in real-time. Coupled with artificial intelligence algorithms to govern automated, closed-loop adaptive dosing, these next-generation smart dressings hold the ultimate potential to comprehensively transform the clinical management of complex, infected diabetic wounds.

Objective To establish an epirubicin (EPI)-resistant murine triple-negative breast cancer (TNBC) (4T1/EPI) cell line and evaluate its biological characteristics and drug resistance. Methods The EPI-resistant cell line 4T1/EPI was developed through intermittent induction with gradually increasing EPI concentrations in vitro. Morphological changes were observed under an inverted microscope. Drug resistance index (MTT assay), cell doubling time (CCK-8 assay), and migration ability (wound healing assay) were evaluated. Western blot was used to detect the expression of drug resistance-related proteins. Transcriptome sequencing and KEGG pathway enrichment analysis were performed to identify the pathways and targets involved in EPI resistance, followed by experimental validation. Results The 4T1 cells eventually grew normally in a medium containing 100 ng/mL EPI, confirming the establishment of the 4T1/EPI resistant cell line. After stable resistance was acquired, morphological alterations were observed. Compared with their parental 4T1 cells, 4T1/EPI cells showed significantly prolonged doubling time (P<0.01) and enhanced migration ability (P<0.05). Expression levels of drug resistance-related proteins MDR1, MRP1 (P<0.01), and ABCG2 (P<0.05) were elevated in 4T1/EPI cells. In vivo models also demonstrated significant EPI resistance in 4T1/EPI tumors in terms of tumor weight and volume. Transcriptome sequencing highlighted the involvement of the PI3K/Akt signaling pathway and ABC transporter pathway. Validation experiments showed the upregulation of Erbb3, Egfr, PI3K, and Akt (P<0.05) and significant downregulation of Fgfr1 (P<0.01) in 4T1/EPI cells. Conclusion The EPI-resistant TNBC cell line 4T1/EPI was successfully established, exhibiting significant resistance in vitro and in vivo. The mechanism may involve the EPI-induced upregulation of Egfr and Erbb3, activating the PI3K/Akt pathway and subsequently enhancing ABC transporter expression.

Chronic diabetic wounds, severely complicated by multidrug-resistant (MDR) bacterial infections, represent a profound and escalating global health crisis. The intrinsically hostile microenvironment of diabetic wounds, characterized by localized hypoxia, persistent oxidative stress, and poor vascularization, creates an ideal niche for opportunistic pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. These bacteria readily construct dense extracellular polymeric substance (EPS) biofilms, which not only physically shield the microbes from host immune responses but also actively trap the wound in a state of chronic, unresolved inflammation. Consequently, conventional systemic and topical antibiotic therapies are becoming increasingly futile, as poor perfusion at the wound site restricts drug bioavailability, while the rapid genetic evolution of bacteria and the impenetrable nature of biofilms lead to catastrophic treatment failures, often culminating in severe tissue necrosis and lower-extremity amputations. To circumvent the limitations of traditional antimicrobials, therapeutic gas delivery has emerged as a highly promising, paradigm-shifting strategy. Gaseous signaling molecules, particularly nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H₂S), and hydrogen (H₂), possess unique physicochemical properties that allow them to seamlessly penetrate dense biofilm matrices and cellular membranes. Once inside, these gases operate via multi-targeted mechanisms that are incredibly difficult for bacteria to develop resistance against; for instance, NO induces severe lipid peroxidation and DNA cleavage in bacteria, CO downregulates pro-inflammatory cytokines, H₂S significantly accelerates endothelial cell migration for neovascularization, and H₂ acts as a powerful selective antioxidant to neutralize tissue-damaging reactive oxygen species (ROS). Together, these therapeutic gases not only exert broad-spectrum bactericidal effects but also actively reprogram the wound bed by promoting the critical M1-to-M2 macrophage polarization and stimulating angiogenesis. Despite their immense biological potential, the direct clinical translation of gas therapies is severely hindered by inherent physicochemical drawbacks, including extreme volatility, short physiological half-lives, poor aqueous solubility, and the high risk of off-target systemic toxicity, if applied indiscriminately. To conquer these immense pharmacokinetic barriers, cutting-edge advancements in materials science have driven the development of gas-releasing micro- and nanoplatforms. Utilizing sophisticated carriers such as metal-organic frameworks (MOFs), mesoporous silica, polymeric nanoparticles, liposomes, and injectable hydrogels, researchers can now encapsulate gas-donor molecules to achieve sustained, localized delivery. More importantly, these advanced nanoplatforms are ingeniously engineered to be stimuli-responsive. By exploiting the pathological hallmarks of the diabetic wound environment, such as elevated glucose concentrations, acidic pH, and overexpressed ROS, or by utilizing external triggers like near-infrared (NIR) light irradiation and ultrasound, these intelligent platforms ensure on-demand, precise spatio-temporal gas release. This often allows for powerful synergistic combinations, such as photothermal or photodynamic therapy coupled with gas release, thereby obliterating biofilms while sparing healthy tissue. While the therapeutic outcomes of these smart delivery systems in eradicating MDR infections and accelerating tissue repair are unprecedented, several critical challenges remain before widespread clinical adoption, as long-term biosafety profiles of the carrier nanomaterials, complexities in large-scale good manufacturing practice (GMP) production, and stringent regulatory hurdles must be rigorously addressed. Looking forward, the next frontier lies in the realm of precision medicine and theranostics, where future research must focus on the seamless integration of these gas-releasing platforms with flexible, wearable biosensors capable of continuously monitoring wound biomarkers (e.g., pH, temperature, uric acid) in real-time. Coupled with artificial intelligence algorithms to govern automated, closed-loop adaptive dosing, these next-generation smart dressings hold the ultimate potential to comprehensively transform the clinical management of complex, infected diabetic wounds.

Objective:To analyze the patterns of change of brain function among civil pilots in prospective memory tasks by using task-state functional magnetic resonance imaging (fMRI) and a cue-based repetitive search task.Methods:A total of 85 subjects were enrolled, including 47 civil pilots (pilot group) and 38 ordinary workers (control group). The task-state fMRI data during the execution of the prospective memory task was analyzed using a general linear model to find out about the activation patterns of brain functions in the 2 groups in the 3 phases of encoding, maintenance, and retrieval of the prospective memory task. The differences in activation patterns between the 2 groups and correlations between regions of interest and the rate of accuracy, reaction time and flying hours were analyzed.Results:The repeated measurement analysis of variance showed that there were no interactions of reaction time or of the rate of accuracy between the task and grouping ( P>0.05), and that the difference in the main effect of grouping was significant ( F=5.67, 15.46, P=0.020, <0.001). The difference in the main effect of grouping on the rate of accuracy was significant ( F=5.42, P=0.022), and the rate of accuracy in the pilot group was higher than in the control group ( P=0.048). In the phase of encoding, the activation in the bilateral cerebellum, bilateral superior frontal gyrus, bilateral fusiform gyrus, and temporal lobe regions decreased in the pilot group compared with the control group ( t=2.68-4.13, all P<0.05), while the activation in the fusiform gyrus and the right parietal superior gyrus increased, and the differences were statistically significant ( t=3.28, 3.35, 3.02, P=0.038, 0.024, 0.042). During the phase of maintenance, the pilot group showed significantly reduced activation in the bilateral cerebellum, bilateral medial superior frontal gyrus, bilateral middle occipital gyri, and the right middle temporal gyrus compared with the control group ( t=2.24-3.36, P<0.05 or 0.01). In the retrieval phase, activation in the right peri-calcarine cortex, bilateral caudate nuclei, and bilateral precentral and postcentral gyri was enhanced in the pilot group compared with the control group ( t=2.57-3.35, all P<0.05), especially in the right middle frontal gyrus ( t=3.12, P=0.007). In the encoding phase, activation was increased in the left fusiform gyrus and right parietal superior gyrus of the pilot group, which was positively correlated with flying hours in the last 3 months ( r=0.347, 0.418, P=0.020, 0.005). Conclusions:Due to long-term flights, the way in which such regions as the frontal lobe, cerebellum, and default mode network are activated in civil pilots is likely to undergo some changes during prospective memory activities, which is why they have higher processing efficiency when performing prospective memory tasks.

ObjectiveGliomas in the motor functional area can damage the corticospinal tract (CST), leading to motor dysfunction. Currently, there is a lack of unified methods for evaluating the extent of CST damage, especially in patients with high surgical risk where the minimum distance from the lesion to the CST is less than 10 mm. This study aims to further clarify the classification method and clinical significance of CST morphological changes in these patients. MethodsThis retrospective study analyzed 109 high-risk functional area glioma patients who underwent neurosurgical treatment with preoperative diffusion tensor imaging (DTI) imaging and intraoperative neurostimulation guidance between 2014 and 2024. All patients had a lesion-to-tract distance (LTD) of less than 10 mm between the CST and the lesion. Preoperative DTI evaluation of CST involvement-induced morphological changes were reviewed. Patients were divided into 3 groups: 17 cases (15.6%) with symmetric CST morphology compared to the healthy side (CST symmetry), 48 cases (44.0%) with significant CST morphology changes compared to the healthy side (CST deformation), and 44 cases (40.4%) with CST overlap with the tumor (CST overlap). Then we classified patients according to preoperative assessment of tumor-induced morphological changes, and analyze postoperative motor function for each category. ResultsPostoperative pathology showed a significantly higher proportion of high-grade gliomas (HGG) in the CST overlap group compared to the other two groups (P=0.001). Logistic regression analysis showed that CST overlap was a predictor of HGG (P=0.000). The rate of total tumor resection in the CST deformation group and overlap group was lower than in the CST symmetric group (P=0.008). There was a total of 41 postoperative hemiplegic patients, with 4 cases (23.5%) in the CST symmetric group, 11 cases (22.9%) in the CST deformation group, and 26 cases (59.1%) in the CST overlap group. CST overlap with the tumor predicted postoperative hemiplegia (P=0.016). Two-way ANOVA analysis of the affected/healthy side and CST morphology groups showed significant main effects of CST grouping and healthy-affected side (P=0.017 and P=0.010), with no significant interaction (P=0.31). The fractional anisotropy (FA) value in the CST overlap group and the affected side was lower. A decrease in the FA value on the affected side predicted postoperative hemiplegia (sensitivity 69.2%, specificity 71.9%). ConclusionWe have established a method to predict postoperative hemiplegia in high-risk motor functional area glioma patients based on preoperative CST morphological changes. CST overlap leads to a decrease in CST FA values. This method can be used for precise patient management and aid in accurate preoperative surgical planning.

Objective:To analyze the patterns of change of brain function among civil pilots in prospective memory tasks by using task-state functional magnetic resonance imaging (fMRI) and a cue-based repetitive search task.Methods:A total of 85 subjects were enrolled, including 47 civil pilots (pilot group) and 38 ordinary workers (control group). The task-state fMRI data during the execution of the prospective memory task was analyzed using a general linear model to find out about the activation patterns of brain functions in the 2 groups in the 3 phases of encoding, maintenance, and retrieval of the prospective memory task. The differences in activation patterns between the 2 groups and correlations between regions of interest and the rate of accuracy, reaction time and flying hours were analyzed.Results:The repeated measurement analysis of variance showed that there were no interactions of reaction time or of the rate of accuracy between the task and grouping ( P>0.05), and that the difference in the main effect of grouping was significant ( F=5.67, 15.46, P=0.020, <0.001). The difference in the main effect of grouping on the rate of accuracy was significant ( F=5.42, P=0.022), and the rate of accuracy in the pilot group was higher than in the control group ( P=0.048). In the phase of encoding, the activation in the bilateral cerebellum, bilateral superior frontal gyrus, bilateral fusiform gyrus, and temporal lobe regions decreased in the pilot group compared with the control group ( t=2.68-4.13, all P<0.05), while the activation in the fusiform gyrus and the right parietal superior gyrus increased, and the differences were statistically significant ( t=3.28, 3.35, 3.02, P=0.038, 0.024, 0.042). During the phase of maintenance, the pilot group showed significantly reduced activation in the bilateral cerebellum, bilateral medial superior frontal gyrus, bilateral middle occipital gyri, and the right middle temporal gyrus compared with the control group ( t=2.24-3.36, P<0.05 or 0.01). In the retrieval phase, activation in the right peri-calcarine cortex, bilateral caudate nuclei, and bilateral precentral and postcentral gyri was enhanced in the pilot group compared with the control group ( t=2.57-3.35, all P<0.05), especially in the right middle frontal gyrus ( t=3.12, P=0.007). In the encoding phase, activation was increased in the left fusiform gyrus and right parietal superior gyrus of the pilot group, which was positively correlated with flying hours in the last 3 months ( r=0.347, 0.418, P=0.020, 0.005). Conclusions:Due to long-term flights, the way in which such regions as the frontal lobe, cerebellum, and default mode network are activated in civil pilots is likely to undergo some changes during prospective memory activities, which is why they have higher processing efficiency when performing prospective memory tasks.

Objective:To investigate the clinical value of preoperative gadolinium ethoxy-benzyldiethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) in predicting microvascular invasion (MVI) and intratumoral tertiary lymphoid structures (TLSs) in hepatocellular carcinoma (HCC).Methods:The retrospective cohort study was conducted. The clinicopathological data of 304 HCC patients who were admitted to The First Affiliated Hospital of Army Medical University and 10 HCC patients who were admitted to The Second Affiliated Hospital of Chongqing Medical University from June 2021 to June 2023 were collected. There were 272 males and 42 females, aged (56±11)years. Using a random number table method, patients were divided into a training set including 220 cases and a validation set including 94 cases in a 7:3 ratio. Among the 314 patients, 106 cases had MVI and TLSs-positive HCC (MT-HCC), and 208 cases had non-MT-HCC. All patients underwent preoperative Gd-EOB-DTPA-enhanced MRI and radical resection. Observation indicators: (1) clinicopathological characteristics of MT-HCC and non-MT-HCC patients; (2) imaging characteristics of MT-HCC and non-MT-HCC patients; (3) imaging features associated with MT-HCC diagnosis; (4) nomogram predictive model construction and evaluation for MT-HCC. Comparison of measurement data with normal distribution between groups was analyzed using the t test. Comparison of measurement data with skewed distribution between groups was analyzed using the nonpara-meter rank sum test. Univariate analysis was conducted using the corresponding statistical methods based on data type. Multivariate analysis was conducted using the logistic regression model. A nomo-gram predictive model was constructed based on results of multivariate analysis, and receiver operating characteristic (ROC) curves were plotted to evaluate the model's performance with the area under curve (AUC). Calibration curve and decision curve analyses were used to assess the calibration and clinical validity of nomogram predictive model. Results:(1) Clinicopathological characteristics of MT-HCC and non-MT-HCC patients. In the training set, there were significant differences between MT-HCC and non-MT-HCC patients in terms of age, white blood cell count, and alpha fetoprotein level ( t=2.488, Z=-2.515, χ2=4.014, P<0.05). (2) Imaging characteristics of MT-HCC and non-MT-HCC patients. In the training set, there were significant differences in tumor morphology, intratumoral hemorrhage, peritumoral abnormal enhancement in arterial phase, capsule presence, intratumoral necrosis or ischemia >20%, intratumoral necrosis or ischemia >50%, peritumoral hypointensity in the hepatobiliary phase, intravascular tumor thrombus, arterial phase rim-like hyperenhancement, and mosaic architecture between MT-HCC and non-MT-HCC patients ( χ2=8.811, 5.586, 13.962, 31.616, 10.154, 4.835, 5.111, 14.425, 7.112, 5.526, P<0.05). (3) Imaging features associated with MT-HCC diagnosis. Results of multivariate analysis identified the absence of intratumoral hemorrhage, incom-plete capsule, and mosaic architecture as independent risk factors for diagnosing MT-HCC ( hazard ratio=3.846, 7.827, 2.345, P<0.05). (4) Nomogram predictive model construction and evaluation for MT-HCC. A nomogram predictive model for MT-HCC was constructed based on the independent risk factors (absence of intratumoral hemorrhage, incomplete capsule, and mosaic architecture) iden-tified in the multivariate analysis. The ROC curve analysis showed that AUC of nomogram predictive model was 0.778 (95% confidence interval as 0.714-0.843), with sensitivity and specificity of 0.857 and 0.573 in the training set. In the validation set, the area under the curve, sensitivity, and specifi-city were 0.825 (95% confidence interval as 0.745-0.926), 0.655, and 0.877, respectively. The calibra-tion curves for both the training set and the validation set closely aligned with the standard curve, indicating high calibration accuracy. The decision curve analysis demonstrated net clinical benefits at thresholds of 0.130-0.690 in the training set and 0.060-0.750 in the validation set. Conclusions:The absence of intratumoral hemorrhage, incomplete capsule, and mosaic architecture are independent risk factors for diagnosing MT-HCC. A nomogram model based on imaging features can predict MT-HCC in HCC patients.

The organization of the brain follows a topological hierarchy that changes dynamically during development. However, it remains unknown whether and how cognitive training administered over multiple years during development can modify this hierarchical topology. By measuring the brain and behavior of school children who had carried out abacus-based mental calculation (AMC) training for five years (starting from 7 years to 12 years old) in pre-training and post-training, we revealed the reshaping effect of long-term AMC intervention during development on the brain hierarchical topology. We observed the development-induced emergence of the default network, AMC training-promoted shifting, and regional changes in cortical gradients. Moreover, the training-induced gradient changes were located in visual and somatomotor areas in association with the visuospatial/motor-imagery strategy. We found that gradient-based features can predict the math ability within groups. Our findings provide novel insights into the dynamic nature of network recruitment impacted by long-term cognitive training during development.
Child ; Humans ; Cognitive Training ; Magnetic Resonance Imaging ; Brain ; Brain Mapping ; Motor Cortex

The patient,a 42-year-old male,with a history of hepatitis B and membranous nephropathy,had inter-mittent fever and chills 12 days before admission.In the first 2 days after admission,the patient's condition aggra-vated with redness,swelling and pain in the left scrotum and perineum.Immediate surgical debridement was per-formed.The patient had a persistent low fever,with blood and pus cultures showing Candida albicans positive,thus was diagnosed fungal necrotizing fasciitis and pyomyositis.The patient was treated with echinocandins mica-fungin(150 mg,qd)for antifungal infection,and was given encroaching dressing change,hyperbaric oxygen thera-py,nutritional support,etc.Two months after surgery,the patient's condition improved and he was discharged.The early clinical symptoms of necrotizing fasciitis and pyomyositis caused by Streptococcus spp.infection lack spe-cificity,thus are prone to be delayed.For patients with concomitant immune diseases,attention should be paid to the prevention and early treatment of complex infection.The appropriate selection of empirical antifungal agents at the early stage has clinical significance.

Objective To analyze the effects of probiotics combined with montmorillonite powder on intestinal mucosa and expressions of intestinal microorganism function-related genes in neonatal rats with rotavirus(RV)infection.Methods RV infection model was established by intragastric administration of SA11 strain rotavirus.Forty-eight suckling rats were randomly divided into normal group(0.9％NaCl),model group(0.9％NaCl),experimental group(0.06 g·mL-1 montmorillonite powder)and combined group(0.06 g·mL-1 montmorillonite powder+6.5 × 107 CFU·mL-1 Saccharomyces cerevisiae powder)with 12 rats in each group.The feces were collected for evaluation.The levels of serum tumor necrosis factor-a(TNF-a),interleukin-1 β(IL-1 β)and IL-17 were detected by enzyme-linked immunosorbent assay,the levels of aquaporin(AQP)in intestinal tissues was detected by real-time fluorescence quantitative polymerase chain reaction,and the counts of Bifidobacteria and Escherichia coli in feces were detected by bacterial 16srDNA fluorescence quantitative polymerase chain reaction.Results The feces scores in normal,model,experimental and combined groups were(1.01±0.10),(2.97±0.08),(2.84±0.03)and(2.77±0.03)points;TNF-α levels were(132.54±14.63),(185.66±19.64),(165.25±17.63)and(149.95±15.76)pg·mL-1;IL-1β levels were(172.32±18.68),(265.34±27.72),(202.34±21.34)and(186.24±19.46)pg·mL-1;IL-17 levels were(118.62±12.44),(173.24±18.25),(152.32±16.72)and(122.54±13.58)pg·mL-1;Bifidobacteria counts were(6.35±0.64),(4.31±0.44),(4.93±0.50)and(5.34±0.54)CFU·g-1;Escherichia coli counts were(6.14±0.62),(8.78±0.88),(8.46±0.85)and(8.12±0.83)CFU·g-1;mRNA levels of AQP2 were 1.02±0.05,0.72±0.07,0.89±0.08 and 1.21±0.12;mRNA expression levels of AQP4 were 1.04±0.07,0.42±0.05,0.78±0.08 and 1.19±0.12;mRNA expression levels ofAQP8 were 1.00±0.06,0.63±0.06,0.91±0.09 and 1.30±0.13,respectively.There were significant differences of above indexes between the model group with the normal,experimental and combined groups(all P＜0.05).Conclusion Montmorillonite powder combined with probiotics can improve fecal properties,reduce serum inflammatory factors and correct intestinal flora disorders in neonatal rats with RV infection,which may be related to improving the expressions of intestinal A QP2,AQP4 and AQP8.