CCDC6-RET fusion protein regulates Ras/MAPK signaling through the fusion- GRB2-SHC1 signal niche.

Rearranged during transfection (RET) rearrangement oncoprotein-mediated Ras/MAPK signaling cascade is constitutively activated in cancers. Here, we demonstrate a unique signal niche. The niche is a ternary complex based on the chimeric RET liquid-liquid phase separation. The complex comprises the rearranged kinase (RET fusion); the adaptor (GRB2), and the effector (SHC1). Together, they orchestrate the Ras/MAPK signal cascade, which is dependent on tyrosine kinase. CCDC6-RET fusion undergoes LLPS requiring its kinase domain and its fusion partner. The CCDC6-RET fusion LLPS promotes the autophosphorylation of RET fusion, with enhanced kinase activity, which is necessary for the formation of the signaling niche. Within the signal niche, the interactions among the constituent components are reinforced, and the signal transduction efficiency is amplified. The specific RET fusion-related signal niche elucidates the mechanism of the constitutive activation of the Ras/MAPK signaling pathway. Beyond just focusing on RET fusion itself, exploration of the ternary complex potentially unveils a promising avenue for devising therapeutic strategies aimed at treating RET fusion-driven diseases.

Ectopic CXCR2 expression cells improve the anti-tumor efficiency of CAR-T cells and remodel the immune microenvironment of pancreatic ductal adenocarcinoma.

BACKGROUND: Recent progressions in CAR-T cell therapy against pancreatic ductal adenocarcinoma (PDAC) remain disappointing, which are partially attributed to the immunosuppressive microenvironment including macrophage-mediated T cell repletion. METHODS: We first characterized the expression patterns of macrophage-relevant chemokines and identified CXCR2 as the key factor regulating T cell trafficking and tumor-specific accumulation in PDAC microenvironment. After that, we synthesized and introduced a CXCR2 expression cascade into Claudin18.2 CAR-T cells and compared the behaviors of CAR-T cells in vitro and in vivo. The therapeutic potential of CXCR2 CAR-T was evaluated in two different allogeneic models: subcutaneous allografts and metastatic PDAC models. RESULTS: The results showed that CXCR2 CAR-T not only reduced the size of allografted PDAC tumors, but also completely eliminated the formation of metastases. Lastly, we investigated the tumor tissues and found that expression of ectopic CXCR2 significantly improved tumor-targeted infiltration and residence of T cells and reduced the presence of MDSCs and CXCR2 + macrophages in PDAC microenvironment. CONCLUSION: Our studies suggested that ectopic CXCR2 played a significant and promising role in improving the efficiency of CAR-T therapy against primary and metastatic PDAC and partially reversed the immune-suppressive microenvironment.

Identification and characterization of circular RNAs involved in the fertility stability of cotton CMS-D2 restorer line under heat stress.

BACKGROUND: As a vital type of noncoding RNAs, circular RNAs (circRNAs) play important roles in plant growth and development and stress response. However, little is known about the biological roles of circRNAs in regulating the stability of male fertility restoration for cytoplasmic male sterility (CMS) conditioned by Gossypium harknessii cytoplasm (CMS-D2) cotton under high-temperature (HT) stress. RESULTS: In this study, RNA-sequencing and bioinformatics analysis were performed on pollen grains of isonuclear alloplasmic near-isogenic restorer lines NH [N(Rf1rf1)] and SH [S(Rf1rf1)] with obvious differences in fertility stability under HT stress at two environments. A total of 967 circRNAs were identified, with 250 differentially expressed under HT stress. We confirmed the back-splicing sites of eight selected circRNAs using divergent primers and Sanger sequencing. Tissue-specific expression patterns of five differentially expressed circRNAs (DECs) were also verified by RT-PCR and qRT-PCR. Functional enrichment and metabolic pathway analysis revealed that the parental genes of DECs were significantly enriched in fertility-related biological processes such as pollen tube guidance and cell wall organization, as well as the Pentose and glucuronate interconversions, Steroid biosynthesis, and N-Glycan biosynthesis pathways. Moreover, we also constructed a putative circRNA-mediated competing endogenous RNA (ceRNA) network consisting of 21 DECs, eight predicted circRNA-binding miRNAs, and their corresponding 22 mRNA targets, especially the two ceRNA modules circRNA346-miR159a-MYB33 and circRNA484-miR319e-MYB33, which might play important biological roles in regulating pollen fertility stability of cotton CMS-D2 restorer line under HT stress. CONCLUSIONS: Through systematic analysis of the abundance, characteristics and expression patterns of circRNAs, as well as the potential functions of their parent genes, our findings suggested that circRNAs and their mediated ceRNA networks acted vital biological roles in cotton pollen development, and might be also essential regulators for fertility stability of CMS-D2 restorer line under heat stress. This study will open a new door for further unlocking complex regulatory mechanisms underpinning the fertility restoration stability for CMS-D2 in cotton.

eIF4E plays the role of a pathogenic gene in psoriasis, and the inhibition of eIF4E phosphorylation ameliorates psoriasis-like skin damage.

Psoriasis is a complex inflammatory skin disease with uncertain pathogenesis. eIF4E (eukaryotic translation initiation factor 4E) and its phosphorylation state p-eIF4E are highly expressed in psoriatic tissues. However, the role eIF4E played in psoriasis is still unclear. To investigate the function of eIF4E and p-eIF4E in psoriasis and to figure out whether eFT-508 (Tomivosertib, eIF4E phosphorylation inhibitor) can relieve the disease severity and become a promising candidate for the psoriasis treatment. We first verified the expression of eIF4E and p-eIF4E in psoriasis patients' lesional skin. Then, we demonstrated the effect of eIF4E and p-eIF4E on the abnormal proliferation and inflammatory state of keratinocytes by using eIF4E-specific small interfering RNA (si-eIF4E) and eFT-508. In this study, all cell experiments were performed under the psoriasis-model condition. Moreover, the external application of eFT-508 on imiquimod (IMQ)-induced psoriasis mice was performed to explore its potential clinical value. Results showed that eIF4E and p-eIF4E were significantly overexpressed in skin lesions of psoriasis patients. Knocking down eIF4E or adding eFT-508 can relieve the abnormal proliferation and the excessive inflammatory state of keratinocytes by reducing the expression of cyclin D1, IL-1ß, CXCL10, IL23, Wnt 5a, NBS1 and p-AKT from mRNA or protein levels. Furthermore, these results were consistent with those obtained from the in vitro experiments. Then, we conclude that eIF4E plays the role of the pathogenic gene in psoriasis, and eFT-508 may be a promising candidate for anti-prosoriasis drugs.

LncRNA lnc-SPRR2G-2 contributes to keratinocyte hyperproliferation and inflammation in psoriasis by activating the STAT3 pathway and downregulating KHSRP.

Psoriasis is a chronic inflammatory disease characterized by increased keratinocyte proliferation and local inflammation. Long noncoding RNAs (lncRNAs) play important regulatory roles in many immune-mediated diseases, including psoriasis. In this study, we aimed to investigate the role and mechanism of lnc-SPRR2G-2 (SPRR2G) in M5-treated psoriatic keratinocytes. Fluorescence in situ hybridization and quantitative real-time polymerase chain reaction (qRT-PCR) showed that lnc-SPRR2G-2 was significantly upregulated in psoriasis tissues and psoriatic keratinocytes. In psoriatic keratinocytes, functional and molecular experiment analyses demonstrated that SPRR2G regulated proliferation, cell cycle and apoptosis, and induced the expression of S100 calcium binding protein A7 (S100A7), interleukin (IL)-1ß, IL-8 and C-X-C motif chemokine ligand 10 (CXCL10). The function of SPRR2G in psoriasis is related to the STAT3 signaling pathway and can be inhibited by a STAT3 inhibitor. Moreover, KH-type splicing regulatory protein (KHSRP) was proved to be regulated by lnc-SPRR2G-2 and to control the mRNA decay of psoriasis-related cytokines (p < 0.05). In summary, we reported the functions of lnc-SPRR2G-2 and KHSRP in psoriasis. Our findings provide new insights for the further exploration of the pathogenesis and treatment of psoriasis.

Outcomes Using the Optimized Pitch and Language Strategy Versus the Advanced Combination Encoder Strategy in Mandarin-Speaking Cochlear Implant Recipients.

OBJECTIVES: The experimental Optimized Pitch and Language (OPAL) strategy enhances coding of fundamental frequency (F0) information in the temporal envelope of electrical signals delivered to channels of a cochlear implant (CI). Previous studies with OPAL have explored performance on speech and lexical tone perception in Mandarin- and English-speaking CI recipients. However, it was not clear which cues to lexical tone (primary and/or secondary) were used by the Mandarin CI listeners. The primary aim of the present study was to investigate whether OPAL provides improved recognition of Mandarin lexical tones in both quiet and noisy environments compared with the Advanced Combination Encoder (ACE) strategy. A secondary aim was to investigate whether, and to what extent, removal of secondary (duration and intensity envelope) cues to lexical tone affected Mandarin tone perception. DESIGN: Thirty-two CI recipients with an average age of 24 (range 7 to 57) years were enrolled in the study. All recipients had at least 1 year of experience using ACE. Each subject attended two testing sessions, the first to measure baseline performance, and the second to evaluate the effect of strategy after provision of some take-home experience using OPAL. A minimum take-home duration of approximately 4 weeks was prescribed in which subjects were requested to use OPAL as much as possible but were allowed to also use ACE when needed. The evaluation tests included recognition of Mandarin lexical tones in quiet and in noise (signal to noise ratio [SNR] +5 dB) using naturally produced tones and duration/intensity envelope normalized versions of the tones; Mandarin sentence in adaptive noise; Mandarin monosyllabic and disyllabic word in quiet; a subset of Speech, Spatial, and Qualities of hearing questionnaire (SSQ, speech hearing scale); and subjective preference for strategy in quiet and noise. RESULTS: For both the natural and normalized lexical tone tests, mean scores for OPAL were significantly higher than ACE in quiet by 2.7 and 2.9%-points, respectively, and in noise by 7.4 and 7.2%-points, respectively. Monosyllabic word recognition in quiet using OPAL was significantly higher than ACE by approximately 7.5% points. Average SSQ ratings for OPAL were significantly higher than ACE by approximately 0.5 points on a 10-point scale. In quiet conditions, 14 subjects preferred OPAL, 7 expressed a preference for ACE, and 9 reported no preference. Compared with quiet, in noisy situations, there was a stronger preference for OPAL (19 recipients), a similar preference for ACE (7 recipients), while fewer expressed no preference. Average daily take-home use of ACE and OPAL was 4.9 and 7.1 hr, respectively. CONCLUSIONS: For Mandarin-speaking CI recipients, OPAL provided significant improvements to lexical tone perception for natural and normalized tones in quiet and noise, monosyllabic word recognition in quiet, and subjective ratings of speech intelligibility. Subjects accessed both primary and secondary cues to lexical tone for perception in quiet and noise conditions. The benefits of lexical tone recognition were attributed to enhanced F0 rate cues encoded by OPAL, especially in a noisy environment. The OPAL strategy was well accepted by many of the Mandarin-speaking CI recipients.

SARS-CoV-2 spike protein potentiates platelet aggregation via upregulating integrin αIIbß3 outside-in signaling pathway.

Platelet hyperreactivity is one of the crucial causes of coagulative disorders in patients with COVID-19. Few studies have indicated that integrin αIIbß3 may be a potential target for spike protein binding to platelets. This study aims to investigate whether spike protein interacts with platelet integrin αIIbß3 and upregulates outside-in signaling to potentiate platelet aggregation. In this study, we found that spike protein significantly potentiated platelet aggregation induced by different agonists and platelet spreading in vitro. Mechanism studies revealed that spike protein upregulated the outside-in signaling, such as increased thrombin-induced phosphorylation of ß3, c-Src. Moreover, using tirofiban to inhibit spike protein binding to αIIbß3 or using PP2 to block outside-in signaling, we found that the potentiating effect of spike protein on platelet aggregation was abolished. These results demonstrate that SARS-CoV-2 spike protein directly enhances platelet aggregation via integrin αIIbß3 outside-in signaling, and suggest a potential target for platelet hyperreactivity in patients with COVID-19. HIGHLIGHTS: • Spike protein potentiates platelet aggregation and upregulates αIIbß3 outside-in signaling. • Spike protein interacts with integrin αIIbß3 to potentiate platelet aggregation. • Blocking outside-in signaling abolishes the effect of spike protein on platelets.

1,25-Dihydroxyvitamin D3 attenuates platelet aggregation potentiated by SARS-CoV-2 spike protein via inhibiting integrin αIIbß3 outside-in signaling.

Platelet hyperreactivity contributes to the pathogenesis of COVID-19, which is associated with a hypercoagulability state and thrombosis disorder. It has been demonstrated that Vitamin D deficiency is associated with the severity of COVID-19 infection. Vitamin D supplement is widely used as a dietary supplement due to its safety and health benefits. In this study, we investigated the direct effects and underlying mechanisms of 1,25(OH)2D3 on platelet hyperreactivity induced by SRAS-CoV-2 spike protein via Western blot and platelet functional studies in vitro. Firstly, we found that 1,25(OH)2D3 attenuated platelet aggregation and Src-mediated signaling. We further observed that 1,25(OH)2D3 attenuated spike protein-potentiated platelet aggregation in vitro. Mechanistically, 1,25(OH)2D3 attenuated spike protein upregulated-integrin αIIbß3 outside-in signaling such as platelet spreading and the phosphorylation of ß3, c-Src and Syk. Moreover, using PP2, the Src family kinase inhibitor to abolish spike protein-stimulated platelet aggregation and integrin αIIbß3 outside-in signaling, the combination of PP2 and 1,25(OH)2D3 did not show additive inhibitory effects on spike protein-potentiated platelet aggregation and the phosphorylation of ß3, c-Src and Syk. Thus, our data suggest that 1,25(OH)2D3 attenuates platelet aggregation potentiated by spike protein via downregulating integrin αIIbß3 outside-in signaling.

Research progress on incomplete partition type 3 inner ear malformation.

PURPOSE: This review aims to provides a comprehensive overview of the latest research progress on IP-III inner ear malformation, focusing on its geneticbasis, imaging features, cochlear implantation, and outcome. METHODS: Review the literature on clinical and genetic mechanisms associated with IP-III. RESULTS: Mutations in the POU3F4 gene emerge as the principal pathogenic contributors to IP-III anomalies, primarily manifesting through inner ear potential irregularities leading to deafness. While cochlear implantation stands as the primary intervention for restoring hearing, the unique nature of the inner ear anomaly escalates the complexity of surgical procedures and postoperative results. Hence, meticulous preoperative assessment to ascertain surgical feasibility and postoperative verification of electrode placement are imperative. Additionally, gene therapy holds promise as a prospective treatment modality. CONCLUSIONS: IP-III denotes X-linked recessive hereditary deafness, with cochlear implantation currently serving as the predominant therapeutic approach. Clinicians are tasked with preoperative assement and individualized postoperative rehabilitation.

Vestibular function and hearing preservation in children following a minimally invasive cochlear implantation.

PURPOSE: This retrospective cohort study aimed to investigate the effect of minimally invasive cochlear implantation (CI) on the vestibular function (VF) and residual hearing (RH) as well as their relationship in pediatric recipients before and after surgery. METHODS: Twenty-four pediatric patients with preoperative low frequency residual hearing (LFRH) (250 or 500 Hz ≤ 80 dB HL) who underwent minimally invasive CI were enrolled. Pure-tone thresholds, the cervical/ocular vestibular-evoked myogenic potential (cVEMP/oVEMP), and video head impulse test (vHIT) were all evaluated in the 24 pediatric patients with preoperative normal VF before and at 1 and 12 months after surgery. The relationship between changes in hearing and VF was analyzed preoperatively and at 1 and 12 months postoperatively. RESULTS: There were no significant differences on VF preservation and hearing preservation (HP) at both 1 and 12 months post-CI (p > 0.05). At 1 month post-CI, the correlations of the variations in vestibulo-ocular reflex (VOR) gains of horizontal semicircular canal (HSC) and posterior semicircular canal (PSC) and the shift in 250 Hz threshold were negatively correlated (r = - 0.41, p = 0.04 and r = - 0.43, p = 0.04, respectively). At 12 months post-CI, the shift in 250 Hz threshold negatively correlated to the variations in VOR gain of superior semicircular canal (SSC) (r = - 0.43, p = 0.04); the HP positively correlated to the variation in oVEMP-amplitude ratio (AR) (r = 0.41, p = 0.04). CONCLUSION: Our study confirmed that there were partial correlations between VF preservation and HP both in the short- and long-terms after atraumatic CI surgery, especially with the 250 Hz threshold. Regarding the variation of PSC function, the correlation with hearing status was variable with time after atraumatic CI surgery. Minimally invasive techniques for HP are successful and effective for the preservation of VF in pediatric patients both in the short- and long-terms.

Targeted degradation of KRAS protein in non-small cell lung cancer: Therapeutic strategies using liposomal PROTACs with enhanced cellular uptake and pharmacokinetic profiles.

The role of KRAS mutation in non-small cell lung cancer (NSCLC) initiation and progression is well-established. However, "undruggable" KRAS protein poses the research of small molecule inhibitors a significant challenge. Addressing this, proteolysis-targeting chimeras (PROTACs) have become a cutting-edge treatment method, emphasizing protein degradation. A modified ethanol injection method was employed in this study to formulate liposomes encapsulating PROTAC drug LC-2 (LC-2 LPs). Precise surface modifications using cell-penetrating peptide R8 yielded R8-LC-2 liposomes (R8-LC-2 LPs). Comprehensive cellular uptake and cytotoxicity studies unveiled that R8-LC-2 LPs depended on concentration and time, showcasing the superior performance of R8-LC-2 LPs compared to normal liposomes. In vivo pharmacokinetic profiles demonstrated the capacity of DSPE-PEG2000 to prolong the circulation time of LC-2, leading to higher plasma concentrations compared to free LC-2. In vivo antitumor efficacy research underscored the remarkable ability of R8-LC-2 LPs to effectively suppress tumor growth. This study contributed to the exploration of enhanced therapeutic strategies for NSCLC, specifically focusing on the development of liposomal PROTACs targeting the "undruggable" KRAS protein. The findings provide valuable insights into the potential of this innovative approach, offering prospects for improved drug delivery and heightened antitumor efficacy.

Nanotechnology Applications in Breast Cancer Immunotherapy.

Next-generation cancer treatments are expected not only to target cancer cells but also to simultaneously train immune cells to combat cancer while modulating the immune-suppressive environment of tumors and hosts to ensure a robust and lasting response. Achieving this requires carriers that can codeliver multiple therapeutics to the right cancer and/or immune cells while ensuring patient safety. Nanotechnology holds great potential for addressing these challenges. This article highlights the recent advances in nanoimmunotherapeutic development, with a focus on breast cancer. While immune checkpoint inhibitors (ICIs) have achieved remarkable success and lead to cures in some cancers, their response rate in breast cancer is low. The poor response rate in solid tumors is often associated with the low infiltration of anti-cancer T cells and an immunosuppressive tumor microenvironment (TME). To enhance anti-cancer T-cell responses, nanoparticles are employed to deliver ICIs, bispecific antibodies, cytokines, and agents that induce immunogenic cancer cell death (ICD). Additionally, nanoparticles are used to manipulate various components of the TME, such as immunosuppressive myeloid cells, macrophages, dendritic cells, and fibroblasts to improve T-cell activities. Finally, this article discusses the outlook, challenges, and future directions of nanoimmunotherapeutics.

The Impact of Harsh Parental Discipline and Emotional Warmth on Adolescent Problem Behaviors.

Purpose: This study, grounded in Social Information Processing Theory, integrates emotional warmth and harsh discipline into a unified model to investigate their differential effects on adolescents' internalized and externalized problem behaviors, as well as to explore the potential divergences in the mediating role of inhibitory control. Patients and Methods: Four hundred and twenty-eight adolescents completed validated scales of Egna Minnen av Barndoms Uppfostran (EMBU), Inhibitory Control and The Youth Self-Report (YSR), Data analysis was performed using SPSS 26.0 and Mplus7.4 to examine the relationship between harsh parental discipline, emotional warmth, adolescent inhibitory control, and internalized and externalized problem behaviors and the mediating effects. Results: The present study revealed that (1) Harsh parental discipline negatively predicted both internalized and externalized problems in adolescents, while emotional warmth from fathers positively predicted internalized problem behaviors; (2) Inhibitory control acted as a mediator in the impact of harsh parental discipline on problem behaviors, while the mediating effect between paternal emotional warmth and internalization issues was not significant. Conclusion: The impact of emotional warmth and harsh discipline on adolescent internalized and externalized problems varied. In families practicing a mixed parenting style, harsh discipline had a more significant effect on adolescents, primarily mediated through inhibitory control.

CytoGAN: Unpaired staining transfer by structure preservation for cytopathology image analysis.

With the development of digital pathology, deep learning is increasingly being applied to endometrial cell morphology analysis for cancer screening. And cytology images with different staining may degrade the performance of these analysis algorithms. To address the impact of staining patterns, many strategies have been proposed and hematoxylin and eosin (H&E) images have been transferred to other staining styles. However, none of the existing methods are able to generate realistic cytological images with preserved cellular layout, and many important clinical structural information is lost. To address the above issues, we propose a different staining transformation model, CytoGAN, which can quickly and realistically generate images with different staining styles. It includes a novel structure preservation module that preserves the cell structure well, even if the resolution or cell size between the source and target domains do not match. Meanwhile, a stain adaptive module is designed to help the model generate realistic and high-quality endometrial cytology images. We compared our model with ten state-of-the-art stain transformation models and evaluated by two pathologists. Furthermore, in the downstream endometrial cancer classification task, our algorithm improves the robustness of the classification model on multimodal datasets, with more than 20 % improvement in accuracy. We found that generating specified specific stains from existing H&E images improves the diagnosis of endometrial cancer. Our code will be available on github.

High Expression of miR-6785-5p in the Serum Exosomes of Psoriasis Patients Alleviates Psoriasis-Like Skin Damage by Interfering with the MNK2/p-eIF4E Axis in Keratinocytes.

Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and inflammation. MiRNAs and serum exosomes participate in the pathogenesis of many diseases. The objective of this study is to explore the function of miR-6785-5p in psoriatic keratinocytes and its upstream and downstream mechanisms. For our study, we employed qRT-PCR and fluorescence in situ hybridization to evaluate miR-6785-5p in psoriatic keratinocytes and conducted a microRNA microarray for identifying differentially expressed miRNAs in patient serum exosomes. We then cocultured keratinocytes with these exosomes, using immunofluorescence staining and qRT-PCR to assess uptake and miR-6785-5p overexpression. We explored miR-6785-5p's role through transfection with specific mimics and inhibitors and confirmed MNK2 as its target using a luciferase assay. MNK2's function was further examined using siRNA technology. Lastly, we applied an imiquimod-induced psoriasis mouse model, also employing siRNA, to investigate MNK2's role in psoriasis. MiR-6785-5p demonstrates a notable overexpression in the keratinocytes of psoriasis patients as well as in their serum exosomes. These keratinocytes actively uptake the miR-6785-5p-enriched serum exosomes. Functionally, miR-6785-5p appears to alleviate psoriasis-like skin damage, observable both in vitro and in vivo, by downregulating MNK2 expression. Psoriasis keratinocytes uptake serum exosomes highly expressing miR-6785-5p. MiR-6785-5p inhibits the abnormal proliferation and inflammatory state of keratinocytes by reducing MNK2 expression and interfering with the MNK2/p-eIF4E axis.

APIP regulated by YAP propels methionine cycle and metastasis in head and neck squamous cell carcinoma.

The Yes-associated protein (YAP) plays a vital role in tumor progression and metabolic regulation. However, the involvement of YAP in metabolic reprogramming of head and neck squamous cell carcinoma remains unclear. Using RNA sequencing and ultra-high-performance liquid chromatography-tandem mass spectrometry, we observed that YAP increased the levels of the main metabolites and enzymes involved in methionine metabolism. APIP, an enzyme involved in the methionine salvage pathway, was transcriptionally activated by YAP. Further experiments showed that APIP promotes HNSCC cells migration and invasion in vitro and tumor metastasis in adjacent lymph nodes and distant organs in vivo. APIP also increases the levels of metabolites in the methionine cycle. We further found that methionine reversed the inhibition of HNSCC migration and invasion by APIP knockdown. In vivo experiments demonstrated that methionine addition promoted tumor metastasis. Mechanistically, the methionine cycle phosphorylated and inactivated GSK3ß, then induced the epithelial mesenchymal transition pathway. Increased APIP expression was detected in patients with HNSCC, especially in tumors with lymph node metastasis. Metabolites of methionine cycle were also elevated in HNSCC patients. Our findings revealed that APIP, a novel target of YAP, promotes the methionine cycle and HNSCC metastasis through GSK3ß phosphorylation.

Characterization, in vitro elderly digestion, and organoids cell uptake of curcumin-loaded nanoparticles.

Curcumin, a bioactive compound, showed versatile in anti-inflammatory and anti-cancer ability, while their biological fate in elderly is unclear. In this study, curcumin-loaded nanoparticles based on octyl succinate hydrate (OSA) starch and sodium caseinate were prepared and the in vitro elderly digestion and absorption fate was investigated. The loading capacity of curcumin-loaded nanoparticles prepared from OSA starch (HI), sodium caseinate (SC) and OSA starch­sodium caseinate (HS) were all higher than 15%. Curcumin release behavior of the three nanoparticles during in vitro digestion conformed to first-order kinetics. Meanwhile, the transport efficiency of curcumin for HI, SC, and HS increased significantly than the free curcumin (near 1-fold), and the permeability were 1.9, 2.0, and 2.0 times, respectively. The gene expressions of TNF-α, SREBP2 and NPC1L1 in the organoids were enhanced than control group. This study provided scientific reference and guidance for encapsulation of curcumin and digestion and absorption properties in elderly.

Associations between parental autonomy support and depressive symptoms among Chinese college students: the chain-mediating effects of mindfulness and self-esteem.

Introduction: Despite extensive research on contextual factors will relieve college students' depressive symptoms, significant gaps remain in understanding the underlying mechanisms of this relationship, particularly through individual strength factors such as mindfulness and self-esteem. Based on self-determination theory, we explore the association between parental autonomy support and depressive symptoms among Chinese college students and whether mindfulness and self-esteem serve as mediators. Methods: A total of 1,182 Chinese college students aged 16 to 27 years (Mage = 20.33, SD = 1.63; female = 55.7%) participated in this research. Questionnaires pertaining to parental autonomy support, mindfulness, self-esteem, and depressive symptoms were administered. Results: The results revealed that depressive symptoms were negatively correlated with both paternal and maternal autonomy support, with mindfulness and self-esteem acting as chain-mediators. Specifically, mindfulness and self-esteem were positively impacted by parental autonomy support, whereas depressive symptoms were negatively impacted by mindfulness and self-esteem. Furthermore, paternal and maternal autonomy support significantly impacted depressive symptoms via both direct and indirect pathways. Indirect effects included three paths: mediation through mindfulness, mediation through self-esteem, and mediation through the mindfulness and self-esteem chain. Discussion: The study highlights the fundamental mechanisms that account for the association between Chinese college students' parental autonomy support and depressive symptoms, these insights can be used to prevent and manage mental health problems among Chinese college students. For example, parents' autonomy support can directly reduce depressive symptoms, but we can also indirectly promote college students' mental health by emphasizing the mediation role of students' mindfulness and self-esteem.

A deep learning framework for predicting endometrial cancer from cytopathologic images with different staining styles.

Endometrial cancer screening is crucial for clinical treatment. Currently, cytopathologists analyze cytopathology images is considered a popular screening method, but manual diagnosis is time-consuming and laborious. Deep learning can provide objective guidance efficiency. But endometrial cytopathology images often come from different medical centers with different staining styles. It decreases the generalization ability of deep learning models in cytopathology images analysis, leading to poor performance. This study presents a robust automated screening framework for endometrial cancer that can be applied to cytopathology images with different staining styles, and provide an objective diagnostic reference for cytopathologists, thus contributing to clinical treatment. We collected and built the XJTU-EC dataset, the first cytopathology dataset that includes segmentation and classification labels. And we propose an efficient two-stage framework for adapting different staining style images, and screening endometrial cancer at the cellular level. Specifically, in the first stage, a novel CM-UNet is utilized to segment cell clumps, with a channel attention (CA) module and a multi-level semantic supervision (MSS) module. It can ignore staining variance and focus on extracting semantic information for segmentation. In the second stage, we propose a robust and effective classification algorithm based on contrastive learning, ECRNet. By momentum-based updating and adding labeled memory banks, it can reduce most of the false negative results. On the XJTU-EC dataset, CM-UNet achieves an excellent segmentation performance, and ECRNet obtains an accuracy of 98.50%, a precision of 99.32% and a sensitivity of 97.67% on the test set, which outperforms other competitive classical models. Our method robustly predicts endometrial cancer on cytopathologic images with different staining styles, which will further advance research in endometrial cancer screening and provide early diagnosis for patients. The code will be available on GitHub.

Pentraxin 3 exacerbates psoriasiform dermatitis through regulation of macrophage polarization.

OBJECTIVE: To elucidate the mechanism of Pentraxin 3 (PTX3) in the pathogenesis of psoriasiform dermatitis using Ptx3-knockout (Ptx3-KO) background mice. METHODS: An Imiquimod (IMQ)-induced murine psoriatic model was created using Ptx3-KO (Ptx3-/-) and wild-type (Ptx3+/+) mice. Skin lesion severity and expression of inflammatory mediators (IL-6 and TNFα) were assessed using PASI score and ELISA, respectively. Cutaneous tissues from the two mice groups were subjected to histological analyses, including HE staining, Masson staining, and Immunohistochemistry (IHC). The PTX3, iNOS, COX2, and Arg1 expressions were quantified and compared between the two groups. We used RNA-seq to clarify the underlying mechanisms of the disease. Flow cytometry was used to analyze systemic Th17 cell differentiation and macrophage polarization. RESULT: The psoriatic region exhibited a higher PTX3 expression than the normal cutaneous area. Moreover, PTX3 was upregulated in HaCaT cells post-TNFα stimulation. Upon IMQ stimulation, Ptx3-/- mice displayed a lower degree of the psoriasiform dermatitis phenotype compared to Ptx3+/+ mice. Consistent with the RNA-seq results, further experiments confirmed that compared to the wild-type group, the PTX3-KO group exhibited a generally lower IL-6, TNFα, iNOS, and COX2 expression and a contrasting trend in macrophage polarization. However, no significant difference in Th17 cell activation was observed between the two groups. CONCLUSIONS: This study revealed that PTX3 was upregulated in psoriatic skin tissues and TNFα-stimulated HaCaT cells. We also discovered that PTX3 deficiency in mice ameliorated the psoriasiform dermatitis phenotype upon IMQ stimulation. Mechanistically, PTX3 exacerbates psoriasiform dermatitis by regulating macrophage polarization rather than Th17 cell differentiation.