WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy.

YAP and TAZ (YAP/TAZ), two major effectors of the Hippo signaling pathway, are frequently activated in human cancers. The activity of YAP/TAZ is strictly repressed upon phosphorylation by LATS1/2 tumor suppressors. However, it is unclear how LATS1/2 are precisely regulated by upstream factors such as Hippo kinases MST1/2. Here, we show that WWC proteins (WWC1/2/3) directly interact with LATS1/2 and SAV1, and SAV1, in turn, brings in MST1/2 to phosphorylate and activate LATS1/2. Hence, WWC1/2/3 play an organizer role in a signaling module that mediates LATS1/2 activation by MST1/2. Moreover, we have defined a minimum protein interaction interface on WWC1/2/3 that is sufficient to activate LATS1/2 in a robust and specific manner. The corresponding minigene, dubbed as SuperHippo, can effectively suppress tumorigenesis in multiple tumor models. Our study has uncovered a molecular mechanism underlying LATS1/2 regulation and provides a strategy for treating diverse malignancies related to Hippo pathway dysregulation.

Point-activated ESR1Y541S has a dramatic effect on the development of sexually dimorphic organs.

Mutations in the estrogen receptor α (ERα) occur in endocrine-resistant metastatic breast cancer. However, a major gap persists with the lack of genetically tractable immune competent mouse models to study disease. Hence, we developed a Cre-inducible murine model expressing a point-activated ESR1Y541S (ESR1Y537S in humans) driven by its endogenous promoter. Germline expression of mutant ESR1Y541S reveals dramatic developmental defects in the reproductive organs, mammary glands, and bones of the mice. These observations provide critical insights into the tissue-specific roles of ERα during development and highlights the potential use of our model in further developmental and cancer studies.

rAAV capsid mutants eliminate leaky expression from DNA donor template for homologous recombination.

Precise genomic editing through the combination of CRISPR/Cas systems and recombinant adeno-associated virus (rAAV)-delivered homology directed repair (HDR) donor templates represents a powerful approach. However, the challenge of effectively suppressing leaky transcription from the rAAV vector, a phenomenon associated to cytotoxicity, persists. In this study, we demonstrated substantial promoter activities of various homology arms and inverted terminal repeats (ITR). To address this issue, we identified a novel rAAV variant, Y704T, which not only yields high-vector quantities but also effectively suppresses in cis mRNA transcription driven by a robust promoter. The Y704T variant maintains normal functionality in receptor interaction, intracellular trafficking, nuclear entry, uncoating, and second-strand synthesis, while specifically exhibiting defects in transcription. Importantly, this inhibitory effect is found to be independent of ITR, promoter types, and RNA polymerases. Mechanistic studies unveiled the involvement of Valosin Containing Protein (VCP/p97) in capsid-mediated transcription repression. Remarkably, the Y704T variant delivers HDR donor templates without compromising DNA replication ability and homologous recombination efficiency. In summary, our findings enhance the understanding of capsid-regulated transcription and introduce novel avenues for the application of the rAAV-CRISPR/Cas9 system in human gene therapy.

An integrated framework for prognosis prediction and drug response modeling in colorectal liver metastasis drug discovery.

BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer globally, and liver metastasis (CRLM) is the primary cause of death. Hence, it is essential to discover novel prognostic biomarkers and therapeutic drugs for CRLM. METHODS: This study developed two liver metastasis-associated prognostic signatures based on differentially expressed genes (DEGs) in CRLM. Additionally, we employed an interpretable deep learning model utilizing drug sensitivity databases to identify potential therapeutic drugs for high-risk CRLM patients. Subsequently, in vitro and in vivo experiments were performed to verify the efficacy of these compounds. RESULTS: These two prognostic models exhibited superior performance compared to previously reported ones. Obatoclax, a BCL-2 inhibitor, showed significant differential responses between high and low risk groups classified by prognostic models, and demonstrated remarkable effectiveness in both Transwell assay and CT26 colorectal liver metastasis mouse model. CONCLUSIONS: This study highlights the significance of developing specialized prognostication approaches and investigating effective therapeutic drugs for patients with CRLM. The application of a deep learning drug response model provides a new drug discovery strategy for translational medicine in precision oncology.

Preloading Long-Chain Quaternary Ammonium Groups to Synthesize a High-Efficient Anion-Exchange Resin for Eliminating Bacterial Contaminants in Drinking Water.

Bacterial contamination in drinking water is a global health concern, necessitating the development of highly efficient treatment techniques. Anion-exchange resins (AERs) have long been employed for removing anionic contaminants from drinking water, but their performance for bacterial contamination is poor. Here, we develop a novel AER (AER6-1) with exceptional bactericidal effects and ultrafast adsorption rates of extracellular DNA (eDNA) (2.2- and 11.5-fold compared to other AERs) achieved through preloading quaternary ammonium groups (QAGs) with hexyl chain (-C6-N+-) on the resin exterior and successively grafting QAGs with a methyl chain (-C1-N+-) inside a resin pore. The AER6-1 outperforms other commercial AERs and ultraviolet disinfection, exhibiting superior elimination of total bacteria, potential pathogens (Escherichia coli and Pseudomonas aeruginosa), eDNA, and antibiotic resistance genes (mexF, mexB, and bacA) in actual drinking water, while maintaining a comparable anion exchange capacity with other commercial AERs. Theoretical calculations of density functional theory and xDLVO combined with XPS elucidate the crucial roles of hydrogen bonding and hydrophobic force provided by the resin skeleton and -C6-N+- in cleaving the bacterial cell membrane and increasing the adsorption kinetics on eDNA. This study broadens the scope of AERs and highlights an effective way of simultaneously removing bacterial and anionic contaminants from drinking water.

Decreased retinal vascular density is associated with cognitive impairment in CADASIL: an optical coherence tomography angiography study.

PURPOSE: This study aimed to assess alterations in retinal vascular density in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients using optical coherence tomography angiography (OCTA) and investigate their association with MRI and cognitive features. METHODS: Twenty-five patients with CADASIL and forty healthy controls were evaluated by Cirrus HD-OCT 5000 with AngioPlex OCTA to determine changes in macular retinal vasculature. Retinal vasculature parameters between two groups were compared. The MRI lesion burden and neuropsychological scales were also examined in patients. The association between OCTA parameters and MRI/cognitive features was evaluated using partial Spearman rank correlation. RESULTS: The vessel density and perfusion density of whole image in macular region (vessel density: t = - 2.834, p = 0.005; perfusion density: t = - 2.691, p = 0.007) were significantly decreased in patients with CADASIL. Moreover, vessel density of whole image in macular region was negatively associated with Fazekas scores (ρ = - 0.457; p = 0.025) and the number of lacunar infractions (ρ = - 0.425, p = 0.038) after adjustment for age. Decreased macular vessel density and perfusion density of whole image were also associated with MoCA scores (vessel density: ρ = 0.542, p = 0.006; perfusion density: ρ = 0.478, p = 0.018) and other domain-specific neuropsychological tests (p < 0.05) after adjustment for age. CONCLUSION: Decreased retinal vascular density was associated with increased MRI lesion burden and cognitive impairment in patients with CADASIL. Our findings suggest that the degree of retinal vascular involvement, as demonstrated by OCTA, may be consistent with the severity of MRI lesions and the degree of cognitive impairment in patients.

Topical vancomycin powder for the prevention of surgical site infections in spinal deformity surgery: a systematic review and meta-analysis.

PURPOSE: To assess the effectiveness and safety of topical vancomycin powder (VP) in preventing surgical site infections (SSIs) in spinal deformity surgeries. METHODS: A literature search was conducted on Web of Science, PubMed, and Cochrane Library databases for comparative studies of VP in spinal deformity surgeries published before February 2024. Two reviewers independently screened eligible articles based on the inclusion and exclusion criteria, assessed study quality, and extracted data. Data analysis was performed using Review Manager 5.4 software. RESULTS: Of all 143 papers screened, a meta-analysis was conducted on 10 articles, which included a total of 8,166 surgeries. The results of the meta-analysis indicated that the incidence of deep SSI in VP group was 0.28 times that in non-VP group (p < 0.001). In the subgroup analysis, VP treatment significantly reduced the risk of deep SSI in both adult spinal deformity (ASD) (RR 0.40, 95% CI 0.21-0.77, p = 0.006) and pediatric scoliosis (PS) (RR 0.25, 95% CI 0.16-0.38, p < 0.001) surgeries. However, this effect was not observed in neuromuscular scoliosis (NMS) patients (RR 0.66, 95% CI 0.26-1.66, p = 0.38). Bacterial culture results indicated that VP treatment significantly reduced polymicrobial infections (p = 0.007) and gram-positive infections (p = 0.001). CONCLUSION: From the literature available at present, VP was associated with reduced deep SSIs rates in spinal deformity patients. However, particular attention should be paid to the lack of the effectiveness of VP in NMS patients. The current literature did not report local cytotoxicity or renal toxicity related to VP in spinal deformity patients.

Preoperative supine pelvic incidence predicts standing pelvic incidence following S2AI fixation in patients with adult spinal deformity: a prospective study.

STUDY DESIGN: A prospective study. OBJECTIVE: The aim of this study was to investigate the PI change in different postures and before and after S2­alar­iliac (S2AI) screw fixation, and to investigate whether pre-op supine PI could predict post-op standing PI. Previous studies have reported PI may change with various positions. Some authors postulated that the unexpected PI change in ASD patients could be due to sacroiliac joint laxity, S2-alar-iliac (S2AI) screw placement, or aggressive sagittal cantilever technique. However, there was a lack of investigation on how to predict post-op standing PI when making surgical strategy. METHODS: A prospective case series of ASD patients undergoing surgical correction with S2AI screw placement was conducted. Full-spine X-ray films were obtained at pre-op standing, pre-op supine, pre-op prone, as well as post-op standing postures. Pelvic parameters were measured. Spearman correlation analysis was used to determine relationships between each parameter. RESULTS: A total of 83 patients (22 males, 61females) with a mean age of 58.4 ± 9.5 years were included in this study. Pre-op standing PI was significantly lower than post-op standing PI (p = 0.004). Pre-op prone PI was significantly lower than post-op standing PI (p = 0.001). By contrast, no significant difference was observed between pre-op supine and post-op standing PI (p = 0.359) with a mean absolute difference of 2.2° ± 1.9°. Correlation analysis showed supine PI was significantly correlated with post-op standing PI (r = 0.951, p < 0.001). CONCLUSION: This study revealed the PI changed after S2AI screw fixation. The pre-op supine PI can predict post-op standing PI precisely, which facilitates to provide correction surgery strategy with a good reference for ideal sagittal alignment postoperatively.

Potential impairment of spinal cord around the apical vertebral level in hyperkyphotic patients: findings from diffusion tensor imaging.

PURPOSE: To evaluate the neuronal metrics/microstructure of the spinal cord around apical region in patients with hyperkyphosis using diffusion tensor imaging (DTI). METHODS: Thirty-seven patients with hyperkyphosis aged 45.5 ± 19.6 years old who underwent 3.0 T magnetic resonance imaging (MRI) examination with DTI sequence were prospectively enrolled from July 2022 to July 2023. Patients were divided into three groups according to spinal cord/ cerebrospinal fluid (CSF) architecture on sagittal-T2 MRI of the thoracic apex (the axial spinal cord classification): Group A-circular cord with visible CSF, Group B-circular cord without visible CSF at apical dorsal, and Group C-spinal cord deformed without intervening CSF. The fractional anisotropy (FA) values acquired from DTI were compared among different groups. Correlations between DTI parameters and global kyphosis (GK)/sagittal deformity angular ratio (sagittal DAR) were evaluated using Pearson correlation coefficients. RESULTS: In all patients, FA values were significantly lower at apical level as compared with those at one level above or below the apex (0.548 ± 0.070 vs. 0.627 ± 0.056 versus 0.624 ± 0.039, P < 0.001). At the apical level, FA values were significantly lower in Group C than those in Group B (0.501 ± 0.052 vs. 0.598 ± 0.061, P < 0.001) and Group A (0.501 ± 0.052 vs. 0.597 ± 0.019, P < 0.001). Moreover, FA values were significantly lower in symptomatic group than those in non-symptomatic group (0.498 ± 0.049 v. 0.578 ± 0.065, P < 0.001). Pearson correlation analysis showed that GK (r2 = 0.3945, P < 0.001) and sagittal DAR (r2 = 0.3079, P < 0.001) were significantly correlation with FA values at apical level. CONCLUSION: In patients with hyperkyphosis, the FA of spinal cord at apical level was associated with the neuronal metrics/microstructure of the spinal cord. Furthermore, the DTI parameter of FA at apical level was associated with GK and sagittal DAR.

Prolonged efficacy of cefazolin in intraosseous regional prophylaxis for total knee arthroplasty: a rabbit model study.

BACKGROUND: A novel approach known as intraosseous regional administration (IORA) has emerged as a technique for delivering prophylactic antibiotics, and it results in higher tissue concentrations around the knee. It is hypothesized that IORA of cefazolin for antibiotic prophylaxis during total knee arthroplasty will result in sustained effective levels for a longer duration. The aim of the current study was to investigate temporal changes in peri-knee cefazolin blood concentrations after IORA of cefazolin. METHODS: Twelve rabbits were randomly divided into two groups, with six rabbits in each group. In control group a single intravenous bolus injection of cefazolin (10 mL, 100 mg) was administered into the marginal ear vein. In experimental groupexperimental group the same dose of cefazolin was injected into the left tibial marrow cavity after tourniquet inflation at the base of the left thigh. Blood samples were collected periodically at different timepoints, and cefazolin concentrations were determined. RESULTS: The intraosseous treatment resulted in significant differences in plasma cefazolin concentrations at all timepoints. Experimental group exhibited higher plasma cefazolin concentrations than control group. CONCLUSIONS: Cefazolin in intraosseous regional prophylaxis exhibits effectiveness in intraoperative antibiotic prophylaxis by maintaining concentrations above the minimum inhibitory concentration for extended durations, rather than relying solely on high concentrations.

Mitochondrial dysfunction mediated by thioredoxin-interacting protein: A crucial determinant in di(2-ethylhexyl) phthalate-induced liver failure.

Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that can interfere with the endocrine system and cause liver damage. However, the molecular mechanism of DEHP-induced liver injury is unclear. This study aimed to investigate the effects of DEHP on liver function and its relationship with thioredoxin-interacting protein (TXNIP) and mitochondrial oxidative stress pathway. We used C57BL/6 J mice and THLE-2 liver cells as in vivo and in vitro models, respectively, and treated them with different doses of DEHP, and measured the relevant biochemical indicators and molecular markers. We found that DEHP significantly increased the expression of TXNIP and NLRP3, while decreasing the expression of mitochondrial functional proteins, such as PGC-1α, TFAM, NRF1, NDUHA9, SDHA, MFN1. This resulted in mitochondrial dysfunction, manifested by reduced ATP generation, increased inflammatory factor release, elevated liver enzyme indicators, decreased mitochondrial membrane potential and increased oxidative stress. We further demonstrated that TXNIP upregulation activated NF-κB and MAPK signaling pathways, such as NF-κB, IκB, TAB2, TRAF6, ERK1, JNK, p38 MAPK, MEK1, which exacerbated oxidative stress and inflammation, leading to liver damage. Additionally, we found that treatment with the antioxidant MitoQ partially alleviated DEHP-induced liver toxicity, while silencing TXNIP more effectively restored mitochondrial function. Our study supports the hypothesis that DEHP induces mitochondrial oxidative stress through the TXNIP signaling pathway, resulting in liver dysfunction in mice, and suggests possible links between endocrine-disrupting chemicals and human diseases.

Detecting endolymphatic hydrops in patients with cranial nerve VIII schwannoma using hydrops MR examination.

PURPOSE: This study utilized Hydrops MRI in patients with cranial nerve (CN) VIII schwannoma to assess the concomitance with endolymphatic hydrops (EH), aiming to elucidate the mechanism of hydrops formation in these patients. METHODS: Twenty-six patients diagnosed as CN VIII schwannoma including vestibular schwannoma (VS) in 24 and intracochlear schwannoma (ICS) in 2 were enrolled. Fifteen patients received radiosurgery and 11 patients opted for a wait-and-scan approach. All patients underwent an inner ear test battery, followed by Hydrops MRI. Based on Hydrops MRI, 6 patients (23%) with positive EH were assigned to Group A, while the other 20 patients showing negative EH were assigned to Group B. RESULTS: The abnormality rates of inner ear test battery in Group A ran from the audiometry (100%), cervical vestibular-evoked myogenic potential (cVEMP) test (83%), ocular VEMP (oVEMP) test (67%) to the caloric test (33%), exhibiting a significantly declining sequence. This declining sequence is consistent with the decreasing order in the prevalence of EH from the cochlea (83%), saccule (50%) to utricle (50%). However, Group B did not show such decreasing trend, indicating that Groups A and B did not share the common mechanism. The mean tumor size prior to radiosurgery was 1.91 ± 0.89 cm, which significantly reduced to 1.53 ± 0.60 cm at a mean interval of 6 years following radiosurgery. In contrast, tumor size remained unchanged in those opted for a wait-and-scan approach. CONCLUSION: It is recommended to utilize Hydrops MRI for patients with CN VIII schwannoma during annual follow-up, particularly those experienced episodic vertigo and/or deteriorated hearing. The Hydrops MRI can not only monitor tumor size, but also detect the presence of EH, so as to guide treatment decision.

Relationship between vestibular schwannoma and endolymphatic hydrops.

BACKGROUND: Both vestibular schwannoma (VS) and Meniere's disease (MD) patients underwent hydrops MRI to clarify the relationship between VS and endolymphatic hydrops (EH). METHODS: Eighty patients with VS or MD underwent an inner ear test battery followed by hydrops MRI, and were then divided into 3 groups. Group A comprised 58 MD patients (62 ears) with positive EH but negative VS. Group B included 18 VS patients (18 ears) with negative EH, while Group C consisted of 4 patients (4 ears) who had VS concomitant with EH. Another 14 MD patients who tested negative for EH on hydrops MRI were initially excluded from this cohort, but were later included for comparison. RESULTS: The decreasing prevalence of EH at the cochlea, saccule and utricle in Group A was identified in 59 (95%), 42 (68%) and 40 (65%) ears, respectively, mimicking a declining sequence of abnormality rates running from audiometry (86%), cervical vestibular-evoked myogenic potential (cVEMP) test (55%) to the ocular (oVEMP) test (53%). However, such decreasing trend was not identified in Groups B and C. In Groups C and A combined, 4 (6%) of 62 EH patients had concomitant VS. Conversely, 4 (18%) of 22 VS patients in Groups C and B combined had concurrent EH. CONCLUSION: A very low (6%) rate of VS in EH patients indicates that VS in EH patients may be coincidental. In contrast, EH was identified in 18% prevalence of VS patients, mirroring the 22% prevalence of cochlear EH demonstrated in VS donors through histopathological studies.

Mn-Ce Symbiosis: Nanozymes with Multiple Active Sites Facilitate Scavenging of Reactive Oxygen Species (ROS) Based on Electron Transfer and Confinement Anchoring.

Regulating appropriate valence states of metal active centers, such as Ce3+/Ce4+ and Mn3+/Mn2+, as well as surface vacancy defects, is crucial for enhancing the catalytic activity of cerium-based and manganese-based nanozymes. Drawing inspiration from the efficient substance exchange in rhizobia-colonized root cells of legumes, we developed a symbiosis nanozyme system with rhizobia-like nano CeOx clusters robustly anchored onto root-like Mn3O4 nanosupports (CeOx/Mn3O4). The process of "substance exchange" between Ce and Mn atoms-reminiscent of electron transfer-not only fine-tunes the metal active sites to achieve optimal Ce3+/Ce4+ and Mn3+/Mn2+ ratios but also enhances the vacancy ratio through interface defect engineering. Additionally, the confinement anchoring of CeOx on Mn3O4 ensures efficient electron transfer in catalytic reactions. The final CeOx/Mn3O4 nanozyme demonstrates potent catalase-like (CAT- like) and superoxide dismutase-like (SOD-like) activities, excelling in both chemical settings and cellular environments with high reactive oxygen species (ROS) levels. This research not only unveils a novel material adept at effectively eliminating ROS but also presents an innovative approach for amplifying nanozyme efficacy.

Ultralarge Pixel Array Photothermal Film based on 3D Self-Suspended Microbridge Structure for Infrared Scene Projection.

Infrared emitter is highly desirable for applications in infrared imaging and infrared stealth technology. It is also a core device in infrared scene generation. Light-driven photothermal film has attracted considerable interest due to its outstanding photothermal properties and easy fabrication. However, the existing photothermal films suffer from low photothermal conversion efficiency (PCE) as well as small sizes. The improvement of the PCE is usually achieved at the expense of dynamic frame rate. Here, this work designs and fabricates a photothermal film based on 3D self-suspended microbridge structure. Silicon (Si) microbridges are introduced into each microstructure to manipulate the thermal conductivity of the films. By optimizing the parameters of the Si microbridges, the high PCE and fast frame rate are both achieved. Moreover, the 3D structure microbridge film is 4-inch in diameter, forming an ultralarge array with over 2200 × 2200 pixels. Finally, a high PCE infrared scene projector is realized based on this photothermal film. A visible image is projected on the film, the 3D-microstructured photothermal film absorbs the visible light and emits an infrared image same as the visible one with high resolution and fast frame rate due to the excellent photothermal properties.

Initiation of fatty acid biosynthesis in Pseudomonas putida KT2440.

Deciphering the mechanisms of bacterial fatty acid biosynthesis is crucial for both the engineering of bacterial hosts to produce fatty acid-derived molecules and the development of new antibiotics. However, gaps in our understanding of the initiation of fatty acid biosynthesis remain. Here, we demonstrate that the industrially relevant microbe Pseudomonas putida KT2440 contains three distinct pathways to initiate fatty acid biosynthesis. The first two routes employ conventional ß-ketoacyl-ACP synthase III enzymes, FabH1 and FabH2, that accept short- and medium-chain-length acyl-CoAs, respectively. The third route utilizes a malonyl-ACP decarboxylase enzyme, MadB. A combination of exhaustive in vivo alanine-scanning mutagenesis, in vitro biochemical characterization, X-ray crystallography, and computational modeling elucidate the presumptive mechanism of malonyl-ACP decarboxylation via MadB. Given that functional homologs of MadB are widespread throughout domain Bacteria, this ubiquitous alternative fatty acid initiation pathway provides new opportunities to target a range of biotechnology and biomedical applications.

Chloroform-infiltrated photonic crystal fiber with high-temperature sensitivity.

The temperature sensor is the core part of the temperature measurement instrument, and its performance directly determines the temperature measurement accuracy. Photonic crystal fiber (PCF) is a new type of temperature sensor with extremely high potential. In this paper, we propose a high-performance, structurally simple, liquid-filled PCF temperature sensor, which is based on a SMF-PCF-SMF (single mode fiber, SMF) sandwich structure. By adjusting the structural parameters of the the PCF, it is possible to obtain optical properties that are superior to those of ordinary optical fibers. This allows for more obvious responsive changes of the fiber transmission mode under small external temperature changes. By optimizing the basic structure parameters, a new PCF structure with a central air hole is designed, and its temperature sensitivity is -0.04696 nm/°C. When filling the air holes of PCFs with temperature-sensitive liquid materials, the response of the optical field against the temperature fluctuations can be effectively enhanced. The Chloroform solution is used to selectively infiltrate the resulting PCF owing to its large thermo-optical coefficient. After comparing various filling schemes, the calculation results show that the highest temperature sensitivity of -15.8 nm/°C is finally realized. The designed PCF sensor has a simple structure, high-temperature sensitivity, and good linearity showing great application potential.

Diffusion prepared pseudo-continuous arterial spin labeling reveals blood-brain barrier dysfunction in patients with CADASIL.

OBJECTIVES: Diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) is a newly proposed MRI method to noninvasively measure the function of the blood-brain barrier (BBB). We aim to investigate whether the water exchange rate across the BBB, estimated with DP-pCASL, is changed in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and to analyze the association between the BBB water exchange rate and MRI/clinical features of these patients. METHODS: Forty-one patients with CADASIL and thirty-six age- and sex-matched controls were scanned with DP-pCASL MRI to estimate the BBB water exchange rate (kw). The MRI lesion burden, the modified Rankin scale (mRS), and the neuropsychological scales were also examined. The association between kw and MRI/clinical features was analyzed. RESULTS: Compared with that in the controls, kw in patients with CADASIL was decreased at normal-appearing white matter (NAWM) (t = - 4.742, p < 0.001), cortical gray matter (t = - 5.137, p < 0.001), and deep gray matter (t = - 3.552, p = 0.001). After adjustment for age, gender, and arterial transit time, kw at NAWM was negatively associated with the volume of white matter hyperintensities (ß = - 0.754, p = 0.001), whereas decreased kw at NAWM was independently associated with an increased risk of abnormal mRS scale (OR = 1.058, 95% CI: 1.013-1.106, p = 0.011) in these patients. CONCLUSIONS: This study found that the BBB water exchange rate was decreased in patients with CADASIL. The decreased BBB water exchange rate was associated with an increased MRI lesion burden and functional dependence of the patients, suggesting the involvement of BBB dysfunction in the pathogenesis of CADASIL. CLINICAL RELEVANCE STATEMENT: DP-pCASL reveals BBB dysfunction in patients with CADASIL. The decreased BBB water exchange rate is associated with MRI lesion burden and functional dependence, indicating the potential of DP-pCASL as an evaluation method for disease severity. KEY POINTS: • DP-pCASL reveals blood-brain barrier dysfunction in patients with CADASIL. • Decreased BBB water exchange rate, an indicator of BBB dysfunction detected by DP-pCASL, was associated with MRI/clinical features of patients with CADASIL. • DP-pCASL can be used as an evaluation method to assess the severity of disease in patients with CADASIL.

Fabrication of magneticα-Fe2O3/Fe3O4heterostructure nanorods via the urea hydrolysis-calcination process and their biocompatibility with LO2and HepG2cells.

ß-FeOOH nanorods were prepared via the urea hydrolysis process with the average length of 289.1 nm and average diameter of 61.2 nm, while magneticα-Fe2O3/Fe3O4heterostructure nanorods were prepared via the urea calcination process withß-FeOOH nanorods as precursor, and the optimum conditions were the calcination temperature of 400 °C, the calcination time of 2 h, theß-FeOOH/urea mass ratio of 1:6. The average length, diameter, and the saturation magnetization of the heterostructure nanorods prepared under the optimum conditions were 328.8 nm, 63.4 nm and 42 emu·g-1, respectively. The Prussian blue test demonstrated that the heterostructure nanorods could be taken up by HepG2 cells, and cytotoxicity tests proved that the heterostructure nanorods had no significant effect on the viabilities of LO2 and HepG2 cells within 72 h in the range of 100-1600µg·ml-1. Therefore, magneticα-Fe2O3/Fe3O4heterostructure nanorods had better biocompatibility with LO2 and HepG2 cells.

Clinical relevance of glomerular C4d deposition in children with early IgA nephropathy or Henoch-Schönlein purpura nephropathy.

BACKGROUND: Both IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephropathy (HSPN) are characterized by glomerular mesangial IgA deposition. Several large studies on adults have suggested that glomerular C4d deposition has prognostic value in IgAN. However, there are few relevant studies on the clinical value of C4d deposition in children with IgAN or HSPN. METHODS: We performed a retrospective cohort study in pediatric patients with IgAN or HSPN. Clinicopathological data were collected at the time of kidney biopsy. Kidney C4d deposition was analyzed by immunohistochemistry. The end point was defined as a ≥ 20% decrease in estimated glomerular filtration from baseline. RESULTS: We enrolled 75 children, including 36 children with IgAN and 39 with HSPN. The prevalence of C4d deposition was 36% (27/75). C4d deposition was more abundant in children with proteinuria ≥ 50 mg/kg/day (51.9% versus 20.8%, P = 0.006) or nephrotic syndrome (37.0% versus 10.4%, P = 0.006). Mesangial hypercellularity (hazard ratio [HR], 5.745, 95% confidence interval [CI], 1.670-19.761, P = 0.006) and IgM deposition (HR, 4.522, 95% CI, 1.321-15.478, P = 0.016) were associated with C4d deposition. After a median follow-up of 22 months, seven (19.4%) IgAN patients and one (2.6%) HSPN patient had decreased kidney function. In children with IgAN, positive C4d was associated with decreased kidney function (P = 0.047). CONCLUSION: Glomerular C4d deposition was associated with mesangial hypercellularity and glomerular IgM deposition in IgAN and HSPN. Glomerular C4d deposition may be a risk factor for eGFR decline in children with IgAN. A higher resolution version of the Graphical abstract is available as Supplementary information.