Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation.

Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs), in CD4+ T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE.

Cbl Ubiquitin Ligases Control B Cell Exit from the Germinal-Center Reaction.

Selective expansion of high-affinity antigen-specific B cells in germinal centers (GCs) is a key event in antibody affinity maturation. GC B cells with improved affinity can either continue affinity-driven selection or exit the GC to differentiate into plasma cells (PCs) or memory B cells. Here we found that deleting E3 ubiquitin ligases Cbl and Cbl-b (Cbls) in GC B cells resulted in the early exit of high-affinity antigen-specific B cells from the GC reaction and thus impaired clonal expansion. Cbls were highly expressed in GC light zone (LZ) B cells, where they promoted the ubiquitination and degradation of Irf4, a transcription factor facilitating PC fate choice. Strong CD40 and BCR stimulation triggered the Cbl degradation, resulting in increased Irf4 expression and exit from GC affinity selection. Thus, a regulatory cascade that is centered on the Cbl ubiquitin ligases ensures affinity-driven clonal expansion by connecting BCR affinity signals with differentiation programs.

Carboxymethylated Desmodium styracifolium polysaccharide reduces the risk of calcium oxalate kidney stone formation by inhibiting crystal adhesion and promoting crystal endocytosis.

The inhibition of cell surface crystal adhesion and an appropriate increase in crystal endocytosis contribute to the inhibition of kidney stone formation. In this study, we investigated the effects of different degrees of carboxymethylation on these processes. An injury model was established by treating human renal proximal tubular epithelial (HK-2) cells with 98.3 ± 8.1 nm calcium oxalate dihydrate (nanoCOD) crystals. The HK-2 cells were protected with carboxy (-COOH) Desmodium styracifolium polysaccharides at 1.17% (DSP0), 7.45% (CDSP1), 12.2% (CDSP2), and 17.7% (CDSP3). Changes in biochemical indexes and effects on nanoCOD adhesion and endocytosis were detected. The protection of HK-2 cells from nanoCOD-induced oxidative damage by carboxymethylated Desmodium styracifolium polysaccharides (CDSPs) is closely related to the protection of subcellular organelles, such as mitochondria. CDSPs can reduce crystal adhesion on the cell surface and maintain appropriate crystal endocytosis, thereby reducing the risk of kidney stone formation. CDSP2 with moderate -COOH content showed the strongest protective activity among the CDSPs.

Risk Factors of Distant Metastatic Parathyroid Carcinoma and Insights into Therapeutic Perspectives.

BACKGROUND: Distant metastatic parathyroid carcinoma (DM-PC) is a rare but often lethal entity with limited data about prognostic indicators. We sought to investigate the risk factors, patterns, and outcomes of DM-PC. METHODS: In this observational cohort study, 126 patients who underwent surgery for PC at a tertiary referral center from 2010 to 2023 were enrolled, among whom 38 had DMs. Univariate and multivariate Cox regression analyses were used to assess the effects of prognostic factors on DM. RESULTS: The cumulative incidence of DM was 14.1%, 33.8%, and 66.9% at 5, 10, and 20 years in the duration of disease course, respectively. DM-PC patients suffered a worse 5-year overall survival of 37.1% compared with 89.8% in the non-DM patients (p < 0.001). DM-PC patients also suffered more previous operations (p < 0.001), higher preoperative serum calcium (p<0.001) and parathyroid hormone (PTH) levels (p < 0.001), lower frequencies of R0 resection (p < 0.001), higher rates of pathological vascular invasion (p = 0.020), thyroid infiltration (p = 0.027), extraglandular extension (p = 0.001), upper aerodigestive tract (UAT) invasion (p < 0.001), and lymph node metastasis (p < 0.001). Multivariate Cox regression revealed that non-R0 resection (HR 6.144, 95% CI 2.881-13.106, p < 0.001), UAT invasion (HR 3.718, 95% CI 1.782-7.756, p < 0.001), and higher preoperative PTH levels (HR 1.001, 95% CI 1.000-1.001, p = 0.012) were independent risk factors of DM. CONCLUSIONS: Upper aerodigestive tract invasion and higher preoperative PTH levels might be risk factors for possible metastatic involvement of PC. R0 resection and closer surveillance should be considered in such cases to minimize the risk of DM and to optimize patient care.

Microstructural white matter abnormalities in overactive bladder syndrome evaluation with diffusion kurtosis imaging tract-based spatial statistics analysis.

PURPOSE: This prospective study aimed to explore the microstructural alterations of the white matter in overactive bladder syndrome (OAB) using the Tract-based Spatial Statistics (TBSS) method of diffusion kurtosis imaging (DKI). METHODS: A total of 30 patients were enrolled and compared with 30 controls. White matter (WM) status was assessed using tract-based spatial statistics for DKI. The differences in DKI-derived parameters, including kurtosis fractional anisotropy (KFA), fractional anisotropy (FA), mean kurtosis (MK), mean diffusivity (MD), radial kurtosis (RK), axial kurtosis (AK), axial diffusivity (AD), and radial diffusivity (RD), were compared between the two groups using the TBSS method. The correlation between the altered DKI-derived parameters and the (OABSS) scores was analyzed. A receiver operating characteristic curve (ROC) was used to evaluate the diagnostic performance of different white matter parameters. RESULTS: As a result, compared with the HC group, the KFA, and FA values decreased significantly in the OAB group. Compared with the HC group, the MK and MD values increased significantly in the OAB group. The KFA values of the genu of corpus callosum (GCC) were significantly correlated with the OABSS scores (r = - 0.509; p = 0.004). The FA values of anterior corona radiata (ACR) were significantly correlated with OABSS scores (r = - 0.447; p = 0.013). The area under the ROC curve (AUC) for the genu of corpus callosum KFA values was higher than FA for the diagnosis of OAB patients. CONCLUSION: DKI is a promising approach to the investigation of the pathophysiology of OAB and a potential biomarker for clinical diagnosis of OAB.

Quality of life, sleep and anxiety status among patients with rosacea in the Yunnan plateau region: A 2-year retrospective study.

OBJECTIVE: To investigate the life, sleep quality and anxiety of rosacea patients in Yunnan and the improvement of these aspects after treatment. METHODS: A total of 141 patients with rosacea and 123 healthy controls were included in our study. The quality of life, sleep quality and anxiety of patients with rosacea and healthy controls were investigated by the Rosacea Severity Scores (RSSs), the Medical Outcomes Study 36-item short-form health survey (SF-36), the Pittsburgh Sleep Quality Index (PSQI) and Self-rating Anxiety Scale (SAS). The quality of life, sleep quality and anxiety of patients with rosacea were assessed again after treatment. RESULTS: Compared with healthy controls, patients with rosacea had significantly lower physical component scores (PCS) and mental component scores (MCS) but higher PSQI and SAS scores. After treatment, rosacea patients showed significantly higher MCS but lower PSQI and SAS scores. Correlation analysis showed a significant correlation between PCS, MCS, PSQI, SAS and RSSs. CONCLUSIONS: Patients with rosacea have a lower quality of life and sleep quality and tend to be more anxious than healthy controls. In addition, the mental quality of life, sleep quality and anxiety of rosacea patients can be significantly improved after treatment. Therefore, it is important to pay attention to the psychological status of rosacea patients. Psychological counseling and intervention are necessary to better prevent and treat rosacea.

MiRNA-224-5p regulates the defective permeability barrier in sensitive skin by targeting claudin-5.

BACKGROUND: Sensitive skin is hypersensitive to various external stimuli and a defective epidermal permeability barrier is an important clinical feature of sensitive skin. Claudin-5 (CLDN5) expression levels decrease in sensitive skin. This study aimed to explore the impact of CLDN5 deficiency on the permeability barrier in sensitive skin and the regulatory role of miRNAs in CLDN5 expression. MATERIALS AND METHODS: A total of 26 patients were retrospectively enrolled, and the CLDN5 expression and permeability barrier dysfunction in vitro were assessed. Then miRNA-224-5p expression was also assessed in sensitive skin. RESULTS: Immunofluorescence and electron microscopy revealed reduced CLDN5 expression, increased miR-224-5p expression, and disrupted intercellular junctions in sensitive skin. CLDN5 knockdown was associated with lower transepithelial electrical resistance (TEER) and Lucifer yellow penetration in keratinocytes and organotypic skin models. The RNA-seq and qRT-PCR results indicated elevated miR-224-5p expression in sensitive skin; MiR-224-5p directly interacted with the 3`UTR of CLDN5, resulting in CLDN5 deficiency in the luciferase reporter assay. Finally, miR-224-5p reduced TEER in keratinocyte cultures. CONCLUSION: These results suggest that the miR-224-5p-induced reduction in CLDN5 expression leads to impaired permeability barrier function, and that miR-224-5p could be a potential therapeutic target for sensitive skin.

The magnitude of germinal center reactions is restricted by a fixed number of preexisting niches.

Antibody affinity maturation occurs in the germinal center (GC), a highly dynamic structure that arises upon antigen stimulation and recedes after infection is resolved. While the magnitude of the GC reaction is highly fluctuating and depends on antigens or pathological conditions, it is unclear whether GCs are assembled ad hoc in different locations or in preexisting niches within B cell follicles. We show that follicular dendritic cells (FDCs), the essential cellular components of the GC architecture, form a predetermined number of clusters. The total number of FDC clusters is the same on several different genetic backgrounds and is not altered by immunization or inflammatory conditions. In unimmunized and germ-free mice, a few FDC clusters contain GC B cells; in contrast, immunization or autoimmune milieu significantly increases the frequency of FDC clusters occupied by GC B cells. Excessive occupancy of GC niches by GC B cells after repeated immunizations or in autoimmune conditions suppresses subsequent antibody responses to new antigens. These data indicate that the magnitude of the GC reaction is restricted by a fixed number of permissive GC niches containing preassembled FDC clusters. This finding may help in the future design of vaccination strategies and in the modulation of antibody-mediated autoimmunity.

MiR-221-5p regulates blood-brain barrier dysfunction through the angiopoietin-1/-2/Tie-2 signaling axis after subarachnoid hemorrhage.

AIM: To explore the potential role of microRNA miR-221-5p on the angiopoietin-1 (Ang-1)/Ang-2/Tie-2 signaling axis after subarachnoid hemorrhage (SAH) in a rat model. METHODS: Aspects of the rat's behavior were measured using the Kaoutzanis scoring system to test neurological responses. This included feeding behavior, body contraction, motor, and eye-opening responses. Brain sections were studied using transmission electron microscopy and Evans blue extravasation. Levels of Ang-1, Ang-2, and Tie-2 were determined by Western blot, while miR-221-5p was quantified using stem-loop real-time quantitative PCR (RT-qPCR). RESULTS: The SAH group responded worse to the neurological response test than the sham-operated group. The intercellular space was widened in the SAH group, but not in the sham-operated group. Evans blue dye leaked significantly more into brain tissue cells of the SAH group. Stem-loop qRT-PCR showed elevated miR-221-5p levels. Additionally, Ang-1 and Tie-2 were reduced but Ang-2 expression was increased after SAH. This led to a significant reduction of the Ang-1/Ang-2 ratio in the brain tissue, which was associated with the destruction of the blood-brain barrier. CONCLUSION: The data indicate that miR-221-5p might regulate blood-brain barrier dysfunction through the Ang-1/Ang-2/Tie-2 signaling axis, suggesting that it should be further investigated as a potential novel biomarker.

Recycling of Ti and Si from Ti-bearing blast furnace slag and diamond wire saw silicon waste by flux alloying technique.

Two industrial solid wastes, Ti-bearing blast furnace slag (TBFS) and diamond wire saw silicon waste (DWSSW), contain large amounts of Ti and Si, and their accumulation wastes resources and intensifies environmental pollution. In the present study, DWSSW was used as the silicon source to reduce titanium oxide in TBFS by electromagnetic induction smelting, and meanwhile Na3AlF6 was added as a flux to improve the recycling of the wastes. Ti and Si of the two wastes were simultaneously recovered in the form of alloy. The effects of different addition amount of Na3AlF6 flux in the mixture of DWSSW and TBFS on chemical composition, viscosity, basicity and structure of slag were investigated. The dissolution behavior of SiO2 in Na3AlF6 flux was theoretically deduced and experimentally verification. The optimized recovery rate of Ti and Si were obtained, and the research realizes the efficient recycling of DWSSW and TBFS simultaneously.

Inactivation of pathogenic microorganisms in water by electron beam excitation multi-wavelength ultraviolet irradiation: Efficiency, influence factors and mechanism.

Due to the limitations of traditional ultraviolet (UV) in microbial inactivation in water, it is necessary to explore a more suitable and efficient UV disinfection method. In this study, an electron beam excitation multi-wavelength ultraviolet (EBE-MW-UV) system was established and aims to analyze its differential microbial inactivation capabilities in comparison to single-wavelength UV-LEDs in waterborne applications. Furthermore, the inactivation mechanisms of this system on microorganisms were explored. The results showed that EBE-MW-UV had significantly higher inactivation effects on the Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Candida albicans in water compared to UV-LEDs (p＜0.05), and the inactivation effect of EBE-MW-UV on Escherichia coli and Pseudomonas aeruginosa at the same UV dose was 3.8 and 1.9 log higher than that of UV-LEDs, respectively, EBE-MW-UV exhibited better inactivation effects on Gram-negative bacteria. Further research found that, under the majority of irradiation doses, neither EBE-MW-UV nor UV-LEDs were significantly affected by the concentration of suspended solids (5 and 20 mg/L) or humic acids (2 and 5 mg/L) in the water. Mechanism analysis revealed that during the disinfection process of EBE-MW-UV, microbial DNA and proteins were initially damaged, which prevented the occurrence of dark repair and led to bacterial inactivation. In addition, UV irradiation led to the production of additional reactive oxygen species (ROS) inside the cells, increasing cell membrane permeability and exacerbating membrane damage. This was accompanied by a decrease in energy metabolism and depletion of ATP, ultimately resulting in microbial inactivation. Therefore, EBE-MW-UV demonstrated more effective disinfection than single-wavelength UV-LEDs, showing great potential. Our research gives new insights into the characteristics of multiple wavelength ultraviolet, and provides scientific basis for the selection of new light sources in the field of ultraviolet disinfection.

Near-Infrared Heptamethine Cyanine Photosensitizers with Efficient Singlet Oxygen Generation for Anticancer Photodynamic Therapy.

Near-infrared photosensitizers are valuable tools to improve treatment depth in photodynamic therapy (PDT). However, their low singlet oxygen (1O2) generation ability, indicated by low 1O2 quantum yield, presents a formidable challenge for PDT. To overcome this challenge, the heptamethine cyanine was decorated with biocompatible S (Scy7) and Se (Secy7) atom. We observe that Secy7 exhibits a redshift in the main absorption to ~840 nm and an ultra-efficient 1O2 generation capacity. The emergence of a strong intramolecular charge transfer effect between the Se atom and polymethine chain considerably narrows the energy gap (0.51 eV), and the heavy atom effect of Se strengthens spin-orbit coupling (1.44 cm-1), both of which greatly improved the high triplet state yield (61%), a state that determines the energy transfer to O2. Therefore, Secy7 demonstrated excellent 1O2 generation capacity, which is ~24.5-fold that of indocyanine green, ~8.2-fold that of IR780, and ~1.3-fold that of methylene blue under low-power-density 850 nm irradiation (5 mW cm-2). Secy7 exhibits considerable phototoxicity toward cancer cells buried under 12 mm of tissue. Nanoparticles formed by encapsulating Secy7 within amphiphilic polymers and lecithin, demonstrated promising antitumor and anti-pulmonary metastatic effects, exhibiting remarkable potential for advancing PDT in deep tissues.

Study on association factors of intestinal infectious diseases based-Bayesian spatio-temporal model.

BACKGROUND: Intestinal infectious diseases (IIDs) are a significant public health issue in China, and the incidence and distribution of IIDs vary greatly by region and are affected by various factors. This study aims to describe the spatio-temporal trends of IIDs in the Chinese mainland and investigate the association between socioeconomic and meteorological factors with IIDs. METHODS: In this study, IIDs in mainland China from 2006 to 2017 was analyzed using data obtained from the China Center for Disease Control and Prevention. Spatio-temporal mapping techniques was employed to visualize the spatial and temporal distribution of IIDs. Additionally, mean center and standard deviational ellipse analyses were utilized to examine the spatial trends of IIDs. To investigate the potential associations between IIDs and meteorological and socioeconomic variables, spatiotemporal zero-inflated Poisson and negative binomial models was employed within a Bayesian framework. RESULTS: During the study period, the occurrence of most IIDs has dramatically reduced, with uneven reductions in different diseases. Significant regional differences were found among IIDs and influential factors. Overall, the access rate to harmless sanitary toilets (ARHST) was positively associated with the risk of cholera (RR: 1.73, 95%CI: 1.08-2.83), bacillary dysentery (RR: 1.32, 95%CI: 1.06-1.63), and other intestinal infectious diseases (RR: 1.88, 95%CI: 1.52-2.36), and negatively associated with typhoid fever (RR: 0.66, 95%CI: 0.51-0.92), paratyphoid fever (RR: 0.71, 95%CI: 0.55-0.92). Urbanization is only associated with hepatitis E (RR: 2.48, 95%CI: 1.12-5.72). And GDP was negatively correlated with paratyphoid fever (RR: 0.82, 95%CI: 0.70-0.97), and bacillary dysentery (RR: 0.77, 95%CI: 0.68-0.88), and hepatitis A (RR: 0.84, 95%CI: 0.73-0.97). Humidity showed positive correlation with some IIDs except for amoebic dysentery (RR: 1.64, 95%CI: 1.23-2.17), while wind speed showed a negative correlation with most IIDs. High precipitation was associated with an increased risk of typhoid fever (RR: 1.52, 95%CI: 1.09-2.13), and high temperature was associated with an increased risk of typhoid fever (RR: 2.82, 95%CI: 2.06-3.89), paratyphoid fever (RR: 2.79, 95%CI: 2.02-3.90), and HMFD (RR: 1.34, 95%CI: 1.01-1.77). CONCLUSIONS: This research systematically and quantitatively studied the effect of socioeconomic and meteorological factors on IIDs, which provided causal clues for future studies and guided government planning.

Impact of blue light on skin pigmentation in patients with melasma.

BACKGROUND: The difference in skin pigmentation induced by blue light between melasma patients and healthy people has not been reported. This study aimed to explore the impact of different doses of blue light irradiation on the pigmentation of the skin of non-exposed areas in female melasma patients with III-IV-type skin and healthy women. MATERIALS AND METHODS: This observational study enrolled patients with melasma and healthy people at the First Affiliated Hospital of Kunming Medical University between January and April 2021. The outcomes were the degree of pigmentation, ΔL*, and ΔITA* values. RESULTS: Forty-two (21/group) participants were enrolled. After irradiation with different doses of blue light, different degrees of pigmentation could be observed in the irradiated area of the skin of female melasma patients and healthy women. The △L* and △ITA* values in the irradiated area of the skin of healthy women were higher than in female melasma patients after blue light irradiation at 20 J/cm2 (p < 0.05). There were no significant differences in the pigmentation scores, △L* values, and △ITA* values in the irradiated areas of skin at different time points after irradiation with the other doses of blue light (p > 0.05). CONCLUSION: Blue light at 20 J/cm2 induced a smaller change in pigmentation in melasma patients than in healthy women, but the effect of blue light at 40-80 J/cm2 was similar.

Spatio-temporal pattern and associate factors of intestinal infectious diseases in Zhejiang Province, China, 2008-2021: a Bayesian modeling study.

BACKGROUND: Despite significant progress in sanitation status and public health awareness, intestinal infectious diseases (IID) have caused a serious disease burden in China. Little was known about the spatio-temporal pattern of IID at the county level in Zhejiang. Therefore, a spatio-temporal modelling study to identify high-risk regions of IID incidence and potential risk factors was conducted. METHODS: Reported cases of notifiable IID from 2008 to 2021 were obtained from the China Information System for Disease Control and Prevention. Moran's I index and the local indicators of spatial association (LISA) were calculated using Geoda software to identify the spatial autocorrelation and high-risk areas of IID incidence. Bayesian hierarchical model was used to explore socioeconomic and climate factors affecting IID incidence inequities from spatial and temporal perspectives. RESULTS: From 2008 to 2021, a total of 101 cholera, 55,298 bacterial dysentery, 131 amoebic dysentery, 5297 typhoid, 2102 paratyphoid, 27,947 HEV, 1,695,925 hand, foot and mouth disease (HFMD), and 1,505,797 other infectious diarrhea (OID) cases were reported in Zhejiang Province. The hot spots for bacterial dysentery, OID, and HEV incidence were found mainly in Hangzhou, while high-high cluster regions for incidence of enteric fever and HFMD were mainly located in Ningbo. The Bayesian model showed that Areas with a high proportion of males had a lower risk of BD and enteric fever. People under the age of 18 may have a higher risk of IID. High urbanization rate was a protective factor against HFMD (RR = 0.91, 95% CI: 0.88, 0.94), but was a risk factor for HEV (RR = 1.06, 95% CI: 1.01-1.10). BD risk (RR = 1.14, 95% CI: 1.10-1.18) and enteric fever risk (RR = 1.18, 95% CI:1.10-1.27) seemed higher in areas with high GDP per capita. The greater the population density, the higher the risk of BD (RR = 1.29, 95% CI: 1.23-1.36), enteric fever (RR = 1.12, 95% CI: 1.00-1.25), and HEV (RR = 1.15, 95% CI: 1.09-1.21). Among climate variables, higher temperature was associated with a higher risk of BD (RR = 1.32, 95% CI: 1.23-1.41), enteric fever (RR = 1.41, 95% CI: 1.33-1.50), and HFMD (RR = 1.22, 95% CI: 1.08-1.38), and with lower risk of HEV (RR = 0.83, 95% CI: 0.78-0.89). Precipitation was positively correlated with enteric fever (RR = 1.04, 95% CI: 1.00-1.08), HFMD (RR = 1.03, 95% CI: 1.00-1.06), and HEV (RR = 1.05, 95% CI: 1.03-1.08). Higher HFMD risk was also associated with increasing relative humidity (RR = 1.20, 95% CI: 1.16-1.24) and lower wind velocity (RR = 0.88, 95% CI: 0.84-0.92). CONCLUSIONS: There was significant spatial clustering of IID incidence in Zhejiang Province from 2008 to 2021. Spatio-temporal patterns of IID risk could be largely explained by socioeconomic and meteorological factors. Preventive measures and enhanced monitoring should be taken in some high-risk counties in Hangzhou city and Ningbo city.

Isoindigo-Thiophene D-A-D-Type Conjugated Polymers: Electrosynthesis and Electrochromic Performances.

Four novel isoindigo-thiophene D-A-D-type precursors are synthesized by Stille coupling and electrosynthesized to yield corresponding hybrid polymers with favorable electrochemical and electrochromic performances. Intrinsic structure-property relationships of precursors and corresponding polymers, including surface morphology, band gaps, electrochemical properties, and electrochromic behaviors, are systematically investigated. The resultant isoindigo-thiophene D-A-D-type polymer combines the merits of isoindigo and polythiophene, including the excellent stability of isoindigo-based polymers and the extraordinary electrochromic stability of polythiophene. The low onset oxidation potential of precursors ranges from 1.10 to 1.15 V vs. Ag/AgCl, contributing to the electrodeposition of high-quality polymer films. Further kinetic studies illustrate that isoindigo-thiophene D-A-D-type polymers possess favorable electrochromic performances, including high optical contrast (53%, 1000 nm), fast switching time (0.8 s), and high coloration efficiency (124 cm2 C-1). These features of isoindigo-thiophene D-A-D-type conjugated polymers could provide a possibility for rational design and application as electrochromic materials.

Regulation of immune system development and function by Cbl-mediated ubiquitination.

Ubiquitination is a form of posttranslational protein modification that affects the activity of target proteins by regulating their intracellular degradation, trafficking, localization, and association with other regulators. Recent studies have placed protein ubiquitination as an important regulatory mode to control immune system development, function, and pathogenesis. In this review, we will mainly update the research progress from our laboratory on the roles of the Cbl family of E3 ubiquitin ligases in the development and function of lymphocytes and non-lymphoid cells. In addition, we will highlight our current understanding of the mechanisms used by this family of proteins, especially Cbl and Cbl-b, to co-ordinately regulate the function of various receptors and transcription factors in the context of immune regulation and diseases.

Dynamic neural reconfiguration for distinct strategies during competitive social interactions.

Information exchange between brain regions is key to understanding information processing for social decision-making, but most analyses ignore its dynamic nature. New insights on this dynamic might help us to uncover the neural correlates of social cognition in the healthy population and also to understand the malfunctioning neural computations underlying dysfunctional social behavior in patients with mental disorders. In this work, we used a multi-round bargaining game to detect switches between distinct bargaining strategies in a cohort of 76 healthy participants. These switches were uncovered by dynamic behavioral modeling using the hidden Markov model. Proposing a novel model of dynamic effective connectivity to estimate the information flow between key brain regions, we found a stronger interaction between the right temporoparietal junction (rTPJ) and the right dorsolateral prefrontal cortex (rDLPFC) for the strategic deception compared with the social heuristic strategies. The level of deception was associated with the information flow from the Brodmann area 10 to the rTPJ, and this association was modulated by the rTPJ-to-rDLPFC information flow. These findings suggest that dynamic bargaining strategy is supported by dynamic reconfiguration of the rDLPFC-and-rTPJ interaction during competitive social interactions.

A HER2 target antibody drug conjugate combined with anti-PD-(L)1 treatment eliminates hHER2+ tumors in hPD-1 transgenic mouse model and contributes immune memory formation.

PURPOSE: Disitamab vedotin (RC48) is an HER2-directed antibody-drug conjugate, emerging as an effective strategy for cancer therapy, which not only enhances antitumor immunity in previous animal models but also improves clinical outcomes for patients such as with gastric cancer, urothelium carcinoma, and HER2 low-expressing breast cancer. Here, we explore the combination therapeutic efficacy of this novel HER2-targeting ADC with immune checkpoint inhibitors in a human HER2-expressing syngeneic breast cancer model. METHODS: The human HER2+ cancer cell line is constructed by stable transfection and individual clones were isolated by single-cell sorting. Flow cytometry was performed to determine its binding activity. Cytotoxic effect was determined using an MTT assay with the supplement of RC48. Human PD-1 transgenic mice were used to analyze the in vivo antitumor effects of the ADC and its combination therapy with PD-1/PD-L1 antibody. RESULTS: The combination of RC48 and PD-1/PD-L1 immune checkpoint inhibition significantly enhanced tumor suppression and antitumor immunity. Tumor rejection in the synergistic groups was accompanied by massive T cell infiltration and immune marker activation. Furthermore, the combination therapy promoted immunological memory formation in the tumor eradication animals, protecting them from tumor rechallenge. CONCLUSION: A novel HER2-targeting ADC combined with immune checkpoint inhibitors can achieve remarkable effects in mice and elicit long-lasting immune protection in a hHER2+ murine breast cancer model. This study provides insights into the efficacy of RC48 therapeutic activity and a rationale for potential therapeutic combination strategies with immunotherapy.

Brainstem auditory evoked potential combined with high resolution cranial base CT can optimize the diagnosis of auditory nerve injury.

PURPOSE: Auditory nerve injury is one of the most common nerve injury complications of skull base fractures. However, there is currently a lack of auxiliary examination methods for its direct diagnosis. The purpose of this study was to find a more efficient and accurate means of diagnosis for auditory nerve injury. METHODS: Through retrospectively analyzing the results of brainstem auditory evoked potential (BAEP) and high-resolution CT (HRCT) in 37 patients with hearing impairment following trauma from January 1, 2018 to July 31, 2020, the role of the two inspection methods in the diagnosis of auditory nerve injury was studied. Inclusion criteria were patient had a clear history of trauma and unilateral hearing impairment after trauma; while exclusion criteria were: (1) severe patient with a Glasgow coma scale score ≤5 because these patients were classified as severe head injury and admitted to the intensive care unit, (2) patient in the subacute stage admitted 72 h after trauma, and (3) patient with prior hearing impairment before trauma. According to Goodman's classification of hearing impairment, the patients were divided into low/medium/severe injury groups. In addition, patients were divided into HRCT-positive and negative groups for further investigation with their BAEP results. The positive rates of BEAP for each group were observed, and the results were analyzed by Chi-square test (p < 0.05, regarded as statistical difference). RESULTS: A total of 37 patients were included, including 21 males and 16 females. All of them were hospitalized patients with GCS score of 6-15 at the time of admission. The BAEP positive rate in the medium and severe injury group was 100%, which was significantly higher than that in the low injury group (27.27%) (p < 0.01). The rate of BEAP positivity was significantly higher in the HRCT-positive group (20/30, 66.7%) than in the HRCT-negative group (1/7, 14.3%) (p < 0.05). Twenty patients (54.05%) were both positive for BEAP and HRCT test, and considered to have auditory nerve damage. Six patients (16.22%) were both negative for BEAP and HRCT test, and 10 patients (27.03%) were BAEP-negative but HRCT-positive: all the 16 patients were considered as non-neurological injury. The rest 1 case (2.70%) was BAEP-positive but HRCT-negative, which we speculate may have auditory nerve concussion. CONCLUSION: By way of BAEP combining with skull base HRCT, we may improve the accuracy of the diagnosis of auditory nerve injury. Such a diagnostic strategy may be beneficial to guiding treatment plans and evaluating prognosis.