Learning from the nexus of autoimmunity and cancer.

The immune system plays critical roles in both autoimmunity and cancer, diseases at opposite ends of the immune spectrum. Autoimmunity arises from loss of T cell tolerance against self, while in cancer, poor immunity against transformed self fails to control tumor growth. Blockade of pathways that preserve self-tolerance is being leveraged to unleash immunity against many tumors; however, widespread success is hindered by the autoimmune-like toxicities that arise in treated patients. Knowledge gained from the treatment of autoimmunity can be leveraged to treat these toxicities in patients. Further, the understanding of how T cell dysfunction arises in cancer can be leveraged to induce a similar state in autoreactive T cells. Here, we review what is known about the T cell response in autoimmunity and cancer and highlight ways in which we can learn from the nexus of these two diseases to improve the application, efficacy, and management of immunotherapies.

CARD9S12N facilitates the production of IL-5 by alveolar macrophages for the induction of type 2 immune responses.

The adaptor CARD9 functions downstream of C-type lectin receptors (CLRs) for the sensing of microbial infection, which leads to responses by the TH1 and TH17 subsets of helper T cells. The single-nucleotide polymorphism rs4077515 at CARD9 in the human genome, which results in the substitution S12N (CARD9S12N), is associated with several autoimmune diseases. However, the function of CARD9S12N has remained unknown. Here we generated CARD9S12N knock-in mice and found that CARD9S12N facilitated the induction of type 2 immune responses after engagement of CLRs. Mechanistically, CARD9S12N mediated CLR-induced activation of the non-canonical transcription factor NF-κB subunit RelB, which initiated production of the cytokine IL-5 in alveolar macrophages for the recruitment of eosinophils to drive TH2 cell-mediated allergic responses. We identified the homozygous CARD9 mutation encoding S12N in patients with allergic bronchopulmonary aspergillosis and revealed activation of RelB and production of IL-5 in peripheral blood mononuclear cells from these patients. Our study provides genetic and functional evidence demonstrating that CARD9S12N can turn alveolar macrophages into IL-5-producing cells and facilitates TH2 cell-mediated pathologic responses.

The transcription factor Ofi1 is critical for white-opaque switching in natural MTLa/α isolates of Candida albicans.

Candida albicans, an opportunistic fungal pathogen, is able to switch between two distinct cell types: white and opaque. While white-to-opaque switching is typically repressed by the a1/α2 heterodimer in MTLa/α cells, it was recently reported that switching can also occur in some natural MTLa/α strains under certain environmental conditions. However, the regulatory program governing white-opaque switching in MTLa/α cells is not fully understood. Here, we collected 90 clinical isolates of C. albicans, 16 of which possess the ability to form opaque colonies. Among the known regulators implicated in white-opaque switching, only OFI1 exhibited significantly higher expression in these 16 strains compared to the reference strain SC5314. Importantly, ectopic expression of OFI1 in both clinical isolates and laboratory strains promoted switching frequency even in the absence of N-acetylglucosamine and high CO2 , the optimal condition for white-to-opaque switching in MTLa/α strains. Deleting OFI1 resulted in a reduction in opaque-formation frequency and the stability of the opaque cell in MTLa/α cells. Ofi1 binds to the promoters of WOR1 and WOR3 to induce their expression, which facilitates white-to-opaque switching. Ofi1 is conserved across the CTG species. Altogether, our study reported the identification of a transcription factor Ofi1 as the critical regulator that promotes white-to-opaque switching in natural MTLa/α isolates of C. albicans.

Zcf24, a zinc-finger transcription factor, is required for lactate catabolism and inhibits commensalism in Candida albicans.

Candida albicans is a normal resident of humans and also a prevalent fungal pathogen. Lactate, a nonfermentative carbon source available in numerous anatomical niches, can be used by C. albicans as a carbon source. However, the key regulator(s) involved in this process remain unknown. Here, through a genetic screen, we report the identification of a transcription factor Zcf24 that is specifically required for lactate utilization in C. albicans. Zcf24 is responsible for the induction of CYB2, a gene encoding lactate dehydrogenase that is essential for lactate catabolism, in response to lactate. Chromatin immunoprecipitation showed a significantly higher signal of Zcf24 on the CYB2 promoter in lactate-grown cells than that in glucose-grown cells. Genome-wide transcription profiling indicates that, in addition to CYB2, Zcf24 regulates genes involved in the ß-oxidation of fatty acids, iron transport, and drug transport. Surprisingly, deleting ZCF24 confers enhanced commensal fitness. This could be attributed to Crz1-activated ß-glucan masking in the zcf24 mutant. The orthologs of Zcf24 are distributed in species most closely to C. albicans and some filamentous fungal species. Altogether, Zcf24 is the first transcription factor identified to date that regulates lactate catabolism in C. albicans and it is also involved in the regulation of commensalism.

Narrow-linewidth and low RIN Tm/Ho co-doped fiber laser based on self-injection locking.

A narrow-linewidth and low relative intensity noise (RIN) Tm/Ho co-doped fiber laser based on a saturable absorber and self-injection locking was demonstrated for the first time. Utilizing self-injection locking technology, the frequency noise power spectral density is remarkably reduced by more than 17.1 dB from 1.21 × 106 Hz2/Hz to 7.30 × 103 Hz2/Hz when the frequency is approximately 1 kHz. Furthermore, a laser with a linewidth compressed to a quarter of the original linewidth from 44.386 kHz to 2.850 kHz, a RIN of less than -127.74 dB/Hz, and an optical signal-to-noise ratio of more than 71.6 dB can be obtained. Using a delay fiber, the relaxation oscillation peak frequencies move to lower frequencies, from 27.9 kHz to 15.8 kHz. The proposed laser is highly competitive in advanced coherent light detection fields, including coherent Doppler wind lidar, high-speed coherent optical communication, and precise absolute distance coherent measurement.

Equalization system of low differential mode delay few-mode fibers based on the neural network MIMO algorithm.

In recent years, with the development of information networks, higher requirements for transmission capacity have been recommended. Yet, at the same time, the capacity of single-mode fiber is rapidly approaching the theoretical limit. The multidimensional multiplexing technique is an effective way to solve this problem. Since the high differential mode delay (DMD) of transmission fiber increases the complexity of demultiplexing in equalization algorithms, we use an intelligent design method to optimize the trench-assisted gradient refractive index structure in this paper. The maximum DMD of the optimized optical fiber structure is 19.6 ps/km. A least mean squares-feedforward neural network constant modulus algorithm (LMS-FNNCMA) is also designed by using the theory of the least mean squares (LMS), constant modulus algorithm (CMA), and the multiple input multiple output (MIMO) neural networks. In order to verify the accuracy of the algorithm, a polarization division multiplexing-wavelength division multiplexing-mode division multiplexing (PDM-WDM-MDM) optical transmission system is constructed through simulation. The algorithm successfully realizes the de-crosstalk over a transmission distance of 1200 km at a rate of 1.2 Tbps under simulation conditions.

PIF4 negatively modulates cold tolerance in tomato anthers via temperature-dependent regulation of tapetal cell death.

Extreme temperature conditions seriously impair male reproductive development in plants; however, the molecular mechanisms underlying the response of anthers to extreme temperatures remain poorly described. The transcription factor phytochrome-interacting factor4 (PIF4) acts as a hub that integrates multiple signaling pathways to regulate thermosensory growth and architectural adaptation in plants. Here, we report that SlPIF4 in tomato (Solanum lycopersicum) plays a pivotal role in regulating cold tolerance in anthers. CRISPR (clustered regularly interspaced short palindromic repeats)-associated nuclease Cas9-generated SlPIF4 knockout mutants showed enhanced cold tolerance in pollen due to reduced temperature sensitivity of the tapetum, while overexpressing SlPIF4 conferred pollen abortion by delaying tapetal programmed cell death (PCD). SlPIF4 directly interacts with SlDYT1, a direct upstream regulator of SlTDF1, both of which (SlDYT1 and SlTDF1) play important roles in regulating tapetum development and tapetal PCD. Moderately low temperature (MLT) promotes the transcriptional activation of SlTDF1 by the SlPIF4-SlDYT1 complex, resulting in pollen abortion, while knocking out SlPIF4 blocked the MLT-induced activation of SlTDF1. Furthermore, SlPIF4 directly binds to the canonical E-box sequence in the SlDYT1 promoter. Collectively, these findings suggest that SlPIF4 negatively regulates cold tolerance in anthers by directly interacting with the tapetal regulatory module in a temperature-dependent manner. Our results shed light on the molecular mechanisms underlying the adaptation of anthers to low temperatures.

Mechanism of intestinal microbiota disturbance promoting the occurrence and development of esophageal squamous cell carcinoma--based on microbiomics and metabolomics.

Esophageal squamous cell carcinoma (ESCC) is a high-risk malignant tumor that has been reported in China. Some studies indicate that gut microbiota disorders can affect the occurrence and development of ESCC, but the underlying mechanism remains unclear. In this study, we aimed to explore the possible underlying mechanisms using microbiomics and metabolomics. Fifty ESCC patients and fifty healthy controls were selected as the study subjects according to sex and age, and fecal samples were collected. 16S rDNA sequencing and LC‒MS were used for microbiomics and nontargeted metabolomics analyses. We found significant differences in the composition of the gut microbiota and metabolites between the ESCC patients and control individuals (P < 0.05). ESCC patients exhibited increased abundances of Fusobacteriaceae and Lactobacillus, increased levels of GibberellinA34 and decreased levels of 12-hydroxydodecanoic acid; these metabolites could be diagnostic and predictive markers of ESCC. An increase in the abundance of Enterobacteriaceae and Lactobacillus significantly reduced the content of L-aspartate and pantothenic acid, which may be involved in the occurrence and development of ESCC by downregulating the expression of proteins in the pantothenate and coenzyme A biosynthesis pathways. An imbalance in the intestinal flora may decrease the number of eosinophils in peripheral blood, resulting in the activation of an inflammatory response and immune dysfunction, leading to ESCC deterioration. We hypothesize that this imbalance in the gut microbiota can cause an imbalance in intestinal metabolites, which can activate carcinogenic metabolic pathways, affect inflammation and immune function, and play a role in the occurrence and development of ESCC.

DEAR model in overweight endometrial cancer patients undergoing fertility-sparing treatment: A randomized controlled trial.

OBJECTIVE: To evaluate the effects of DEAR weight management in overweight patients undergoing fertility-sparing treatment for endometrial cancer or atypical hyperplasia. METHODS: Women with endometrial cancer or atypical hyperplasia who received fertility-sparing treatment and had a body mass index of >25 kg/m2 were randomly allocated to the DEAR (DEAR weight management) and control (self weight management) groups. Body morphology and composition, glycolipid metabolism, and tumor outcomes were assessed in both groups before and at 3 and 6 months after intervention. RESULTS: Overall, 72 subjects were included (36 in each group). Following intervention, the DEAR group showed significantly lower median body weight (69.45 vs. 78.05), body mass index (26.19 vs. 29.15), lipid accumulation index (29.21 vs. 57.86), body fat mass (24.00 vs. 29.30), visceral fat area (112.5 vs. 133.3), and glycolipid metabolic indices (except high density lipoprotein) than the control group (P < 0.05) and showed a decreasing trend. The test group achieved significantly higher complete remission (88.46% vs. 57.14%; P < 0.05); the time to complete remission did not differ significantly (P > 0.05). CONCLUSIONS: DEAR weight management can improve the studied parameters and complete remission rates in this population. REGISTRATION: NCT06169449.

Combined Effects of the Serum IgA/C3 Ratio and Glomerular C3 Staining on the Renal Outcome in Adult Immunoglobulin A Nephropathy.

INTRODUCTION: The aim of this study was to evaluate the predictive value of the serum IgA/C3 ratio and glomerular C3 deposits in kidney biopsy in adult IgA nephropathy. METHODS: The study included 718 adult IgAN patients diagnosed based on kidney biopsy. Patients without corticosteroids or immunosuppressive drugs >1 month were regularly followed up for at least 1 year or until the study endpoint. The optimum serum IgA/C3 ratio was calculated by the AUROC-based cutoff ratio. Proteinuria, creatinine, eGFR, serum IgA, and serum C3 were evaluated at baseline. Kidney biopsy was categorized using the Oxford classification, with a calculation of the MEST-C score. The degree of glomerular C3 staining was semiquantitatively determined (grade 0, no or trace; grade 1, mild; grade 2, moderate; grade 3, marked) by immunofluorescence microscopy. The patients were divided into four groups by the serum IgA/C3 ratio and glomerular C3 staining. RESULTS: The baseline data suggested that when the serum IgA/C3 ratio was at the same level, patients with a high glomerular C3 staining score (≥2) always had mesangial proliferation, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis (group 1 vs. group 2; group 3 vs. group 4). When glomerular C3 staining was at the same level, proteinuria was significantly higher in patients with serum IgA/C3<2.806 (group 1 vs. group 3; group 2 vs. group 4), which was contrary to previous studies that have suggested that the serum level of IgA/C3 was associated with disease severity. Hence, this study set out to investigate the combined effects of the serum IgA/C3 ratio and glomerular C3 staining on the renal outcome in adult IgA nephropathy. Renal survival analysis indicated that serum IgA/C3 ≥2.806 and glomerular C3 staining ≥2 (group 1) may be correlated with a poorer prognosis, especially in different clinicopathological characteristics of IgAN patients based on the subgroup analysis. Multivariate Cox analysis demonstrated that hypertension, serum creatinine, CKD stage, T1/2 and C3 staining were independent predictive factors of renal survival. CONCLUSIONS: The combination of serum IgA/C3 and C3 staining may contribute to improved optimization of the prognostic model in IgAN patients, especially patients with different sexes and degrees of disease. However, further study is required for validation in the future.

Self-regulation and comprehension in shared reading: The moderating effects of verbal interactions and E-book discussion prompts.

The study examined how children's self-regulation skills measured by the strengths and weaknesses of ADHD symptoms and normal behavior rating are associated with story comprehension and how verbal engagement and e-book discussion prompts moderate this relation. Children aged 3-7 (N = 111, 50% female, Chinese as first language) read an interactive Chinese-English bilingual story e-book with or without discussion prompts twice with their parents (2020-2021). Results demonstrated that the lower children's self-regulation skills, the more they struggled with story comprehension. Critically, our data suggest that embedding e-book discussion prompts and more verbalization in English can mitigate this negative association for children with inattention/hyperactivity. These findings have critical implications for future e-book design, interventions, and home reading practice for children with inattention/hyperactivity and those at risk for attention deficit/hyperactivity disorder.

Melatonin application during cryopreservation improves the development and clinical outcomes of human vitrified-warmed oocytes.

In this clinical study, we investigated the potential of melatonin (MT) supplementation in the freeze-thaw medium used for cryopreserved human oocytes. In total, 152 patients who underwent in vitro fertilization between January 2020 and December 2022 were included and categorized into different groups as follows: the donor group, comprising 108 patients who donated their oocytes, with 34 patients using a vitrification and warming medium supplemented with MT (D-MT subgroup) and 74 patients using conventional medium without MT (D-0 subgroup); and the autologous group, comprising 38 patients who used their own oocytes, with 19 patients using medium supplemented with MT (A-MT subgroup) and 19 patients using medium without MT (A-0 subgroup). After thawing, the surviving oocytes in the D-MT and A-MT subgroups and D-0 and A-0 subgroups were cultured in a fertilization media with and without 10-9 MMT for 2.5 h, respectively, followed by intracytoplasmic sperm injection insemination, embryo culture, and transfer. The survival, cleavage, high-quality embryo, clinical pregnancy, ongoing pregnancy, and implantation rates were significantly higher in the D-MT subgroup than in the D-0 subgroup (all P < 0.05). Similarly, the survival, fertilization, high-quality embryo, and high-quality blastocyst rates were significantly higher in the A-MT subgroup than in the A-0 subgroup (all P < 0.05). These findings indicate that MT addition during cryopreservation can enhance the development of vitrified-warmed human oocytes and improve clinical outcomes.

RACK1 promotes the occurrence and progression of cervical carcinoma.

BACKGROUND: RACK1 has been identified as a multifunctional cytosolic protein, and plays a pivotal role in multiple biological responses involved in several kinds of tumors, while its effect in cervical cancer has not been well elucidated yet. The study aimed to investigate the role of RACK1 in cervical cancer occurrence and progression. METHODS: The expression of RACK1 in cervical specimens was measured by immunohistochemical staining and Western blot assay. Transgenic mice were used to detect the role of RACK1 in modulating tumorigenesis in vivo. Cervical carcinoma cell lines were used to explore the underlying mechanisms of RACK1 on the behaviors of tumor cells in vitro. RESULTS: We found that RACK1 expression was upregulated in cancer tissues compared with adjacent tissues, and its expression was gradually increased from cervictis, and cervical intraepithelial neoplasis (CIN) to carcinoma. Genetic overexpression of RACK1 facilitated tumor formation and growth in nude mice. Mechanism studies disclosed that RACK1 over-expression prolonged the G0 /G1 phase by up-regulating the expression of cyclinD1, down-regulating p21 and p27 probably by modulating the phosphorylation of AKT. CONCLUSIONS: Taken together, we concluded that RACK1 stimulates tumorigenesis and progression of cervical cancer via modulating the proliferation of tumor cells, implying that targeting RACK1 may serve as a promising method for cervical cancer therapy.

Effects of fermentation on the structures of yellow compounds in citrus pomace.

To enhance the stability and light resistance of the yellow compounds in citrus pomace, our study successfully isolated and purified five compounds using ultrasonic-assisted extraction and column chromatography. The identified compounds include methyl linoleate, (2-ethyl)hexyl phthalate, 1,3-distearoyl-2-oleoylglycerol, 6,6-ditetradecyl-6,7-dihydroxazepin-2(3H)-one, and n-octadeca-17-enoic acid. The monomers extracted from fresh pomace, compounds 1 and 2, exhibit structural similarities to flavonoids and carotenoids. In contrast, the polymers isolated from fermented pomace, compounds 3, 4, and 5, share structural units with the fresh pomace compounds, indicating the transformation to stable polymeric forms. This suggests that the microbial fermentation process not only enhances the value of citrus pomace, but also provides a promising pathway for the synthesis of natural antioxidant yellow pigments with far-reaching theoretical and practical significance.

How does TCR-T cell therapy exhibit a superior anti-tumor efficacy.

TCR-engineered T cells have achieved great progress in solid tumor therapy, some of which have been applicated in clinical trials. Deep knowledge about the current progress of TCR-T in tumor therapy would be beneficial to understand the direction. Here, we classify tumor antigens into tumor-associated antigens, tumor-specific antigens, tumor antigens expressed by oncogenic viruses, and tumor antigens caused by abnormal protein modification; Then we detail the TCR-T cell therapy effects targeting those tumor antigens in clinical or preclinical trials, and propose that neoantigen specific TCR-T cell therapy is expected to be a promising approach for solid tumors; Furthermore, we summarize the optimization strategies, such as tumor microenvironment, TCR pairing and affinity, to improve the therapeutic effect of TCR-T. Overall, this review provides inspiration for the antigen selection and therapy strategies of TCR-T in the future.

Investigating the Association of Carotid Atherosclerotic Plaque MRI Features and Silent Stroke After Carotid Endarterectomy.

BACKGROUND: The predictive value of carotid plaque characteristics for silent stroke (SS) after carotid endarterectomy (CEA) is unclear. OBJECTIVE: To investigate the associations between carotid plaque characteristics and postoperative SS in patients undergoing CEA. STUDY TYPE: Prospective. POPULATION: One hundred fifty-three patients (mean age: 65.4 ± 7.9 years; 126 males) with unilateral moderate-to-severe carotid stenosis (evaluated by CT angiography) referred for CEA. FIELD STRENGTH/SEQUENCE: 3 T, brain-MRI:T2-PROPELLER, T1-/T2-FLAIR, diffusion weighted imaging (DWI) and T2*, carotid-MRI:black-blood T1-/T2W, 3D TOF, Simultaneous Non-contrast Angiography intraplaque hemorrhage. ASSESSMENT: Patients underwent carotid-MRI within 1-week before CEA, and brain-MRI within 48-hours pre-/post-CEA. The presence and size (volume, maximum-area-percentage) of carotid lipid-rich necrotic core (LRNC), intraplaque hemorrhage (Type-I/Type-II IPH) and calcification were evaluated on carotid-MR images. Postoperative SS was assessed from pre-/post-CEA brain DWI. Patients were divided into moderate-carotid-stenosis (50%-69%) and severe-carotid-stenosis (70%-99%) groups and the associations between carotid plaque characteristics and SS were analyzed. STATISTICAL TESTS: Independent t test, Mann-Whitney U-test, chi-square test and logistic regressions (OR: odds ratio, CI: confidence interval). P value <0.05 was considered statistically significant. RESULTS: SS was found in 8 (16.3%) of the 49 patients with moderate-carotid-stenosis and 21 (20.2%) of the 104 patients with severe-carotid-stenosis. In patients with severe-carotid-stenosis, those with SS had significantly higher IPH (66.7% vs. 39.8%) and Type-I IPH (66.7% vs. 38.6%) than those without. The presence of IPH (OR 3.030, 95% CI 1.106-8.305) and Type-I IPH (OR 3.187, 95% CI 1.162-8.745) was significantly associated with SS. After adjustment, the associations of SS with presence of IPH (OR 3.294, 95% CI 1.122-9.669) and Type-I IPH (OR 3.633, 95% CI 1.216-10.859) remained significant. Moreover, the volume of Type-II IPH (OR 1.014, 95% CI 1.001-1.028), and maximum-area-percentage of Type-II IPH (OR 1.070, 95% CI 1.002-1.142) and LRNC (OR 1.030, 95% CI 1.000-1.061) were significantly associated with SS after adjustment. No significant (P range: 0.203-0.980) associations were found between carotid plaque characteristics and SS in patients with moderate-carotid-stenosis. DATA CONCLUSIONS: In patients with unilateral severe-carotid-stenosis, carotid vulnerable plaque MR features, particularly presence and size of IPH, might be effective predictors for SS after CEA. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Drug-drug interaction of ciprofol injectable emulsion with mefenamic acid capsules in healthy subjects.

AIMS: To investigate the drug-drug interaction (DDI) of ciprofol injectable emulsion and mefenamic acid capsules in healthy subjects. METHODS: Twenty healthy subjects were enrolled in this single-centre, open-label, two-period DDI study. Ciprofol (0.4 mg kg-1 ) was administered as a single dose on days 1 and 5. A 500-mg oral loading dose of mefenamic acid was given on day 4 followed by a 250-mg maintenance dose every 6 h (a total of eight doses). Blood samples for pharmacokinetic analyses were collected. Depth of anaesthesia was monitored using the Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale and Bispectral Index scores (BISs). RESULTS: Compared with administration of ciprofol alone, administration with mefenamic acid showed no significant difference in exposure. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) for maximum plasma concentration (Cmax ), area under the plasma concentration-time curve calculated from 0 to the last measurement point (AUC0-last ) and AUC to infinity (AUC0-inf ) were 91.6% (86.5-96.9%), 103.3% (100.3-106.4%) and 107.0% (101.2-113.2%), respectively. The MOAA/S and BIS curves for the two treatment periods essentially coincided, indicating that the anaesthesia effect of ciprofol was not affected by mefenamic acid. Seven subjects (35%) reported eight adverse events (AEs) when ciprorol was administered alone and 12 subjects (60%) reported 18 AEs when ciprofol was administered in combination with mefenamic acid. All AEs were mild. CONCLUSIONS: Mefenamic acid, a UGT1A9 inhibitor, had no significant effect on the pharmacokinetics and pharmacodynamics of ciprofol in healthy subjects. Ciprofol was safe and well tolerated when administered with mefenamic acid.

Oriented Plate-like KNbO3 Polycrystals: Topochemical Mesocrystal Conversion and Piezoelectric and Photocatalytic Responses.

KNbO3 (KN) with a perovskite structure is an outstanding representative of lead-free piezoelectric materials, and its mesocrystals have broad application prospects in the fields of catalysis, energy storage, and conversion. However, the formation conditions of KN mesocrystals reported so far are difficult owing to their high aspect ratio and excellent preferred orientation. In this study, the solvothermal process was used successfully to prepare the flake-like potassium salt of Lindquist hexaniobate (K8Nb6O19·10H2O). Subsequently, the precursor niobate was calcined to prepare two-dimensional (2D) plate-like KN mesocrystals. The formation mechanism of the plate-like KN mesocrystals is further revealed from a paired topochemical mesocrystal conversion of K8Nb6O19·10H2O niobate. Finally, the microscopic piezoelectric and photocatalytic responses of the obtained plate-like KN mesocrystals were investigated. The high piezoelectric coefficient of plate-like KN mesocrystals implies that excellent charge separation promotes the photocatalytic performance of rhodamine B (RhB). This study provides a strategy for the efficient application of 2D oriented materials in the field of piezoelectricity and photocatalysis.

Intrinsic Abnormalities of Keratinocytes Initiate Skin Inflammation through the IL-23/T17 Axis in a MALT1-Dependent Manner.

Increasing evidence has supported the crucial role of CARD14 in the pathogenesis of psoriasis, whereas the precise cellular signaling involved in skin physiopathology remains poorly understood. In this article, we show that neither genetic ablation of Il17a nor elimination of T cells was sufficient to restrain the skin inflammation in a CARD14-E138A-mutation-induced psoriasis-like mouse model, whereas depletion of Il23, which extremely blocked the IL-23/T17 axis, was more effective. Targeting CBM complex by conditional deletion of MALT1 or BCL10 in keratinocytes abrogated both the cutaneous and systemic inflammation of heterozygous Card14 E138A/+ mice. Selective inactivation of keratinocyte-specific MALT1 proteolytic activity strongly ameliorated the Card14 E138A/+- and Card14 ΔQ136/+-induced skin disease, which was reproduced by using the imiquimod-induced mouse model. Together, our results suggest a sequence of events under CARD14-mutation-induced psoriasis condition that keratinocyte-intrinsic activation of CBM complex initiates the skin inflammation depending on the IL-23/T17 axis. Targeting keratinocytes by inactivation of MALT1 paracaspase activity might be a promising therapeutic target for early psoriasis treatment.

Association of image-defined risk factors with clinical features, tumor biology, and outcomes in neuroblastoma: a single-center retrospective study.

Image-defined risk factors (IDRF) in neuroblastoma have been developed to predict tumor resectability and surgical complications; however, the potential prognostic value of IDRF in neuroblastoma has been variably reported. Previous studies did not report the IDRF status separately from the International Neuroblastoma Risk Group (INRG) stage. Moreover, the association between IDRF and clinical and pathological factors has not been discussed further. In this retrospective study, we investigated the clinical and biological features of neuroblastoma at different INRG stages based on IDRF. Event-free survival (EFS) and overall survival (OS) related to the INRG stage were analyzed using log-rank tests, and the prognostic value of the IDRF number and type was also evaluated. Among 72 patients, 182 IDRF at diagnosis were found in 79.2%. The distribution of the INRG stages was 10 L1 (13.9.0%), 25 L2 (34.7%), and 37 M/MS (51.4%). Patients with stage M/Ms had a larger tumor volume, a higher percentage of age ≥ 18 months, elevated lactate dehydrogenase (LDH) level, elevated ferritin level, and a higher percentage of COG high-risk compared with stage L1 and L2 patients. EFS and OS were similar for stage L1 and L2 tumors but were significantly poorer for metastatic disease. However, EFS (P = 0.06) and OS (P = 0.07) were similar for IDRF-negative and positive neuroblastomas. Patients with stage M/Ms with IDRF-positive had poorer EFS (P = 0.001) and OS (P < 0.001) compared with patients in stage L2. An IDRF ≥ 4, vascular IDRF, and infiltrative IDRF of the tumor were significant indicators of poor prognosis.   Conclusion: Our study indicates that increasing the INRG stages based on IDRF is associated with various unfavorable clinical features of neuroblastoma. The principal determinant of survival in neuroblastoma is the presence of metastatic disease more than IDRF alone at diagnosis. Both the number and type of IDRF have important clinical significance in the protocol planning of neuroblastoma, rather than just considering the absence or presence of IDRF. What is Known: • The International Neuroblastoma Risk Group Staging System (INRGSS) now employs image-defined risk factors (IDRFs) to stratify and stage disease. • The presence of IDRF at diagnosis are associated with higher rates of operative complications and incomplete surgical resection. What is New: • The principal determinant of survival from neuroblastoma is the presence of metastatic disease at diagnosis, more than IDRF alone. • IDRF number and type should also be considered during the diagnosis and treatment planning of neuroblastoma, rather than just considering the absence or presence of IDRF.