The role of CD83 in the pathogenesis of immune thrombocytopenia.

BACKGROUND: CD83 are closely related to the pathogenesis of immune thrombocytopenia (ITP), but the exact mechanism remains unclear. AIM: To explore the relationship between CD83 and CD4+ T cell subsets and clarify the role of CD83 in the pathogenesis of ITP. METHODS: RT-qPCR and Flow cytometry were used to illustrate CD83 expression. The downregulation and overexpression of DC-CD83 were co-cultured with CD4+ T cells to detect cell proliferation, co-cultured supernatant cytokines and Tregs expression. RESULTS: The results indicate that the ITP patients showed higher expression of CD83 than the healthy controls. The proliferation of CD4+ T cells was inhibited by downregulation of DCs-CD83 but promoted by overexpression of DCs-CD83. siRNA-CD83 inhibited proinflammatory IFN-γ and IL-17 secretion while raising TGF-ß, IL-10 concentrations. Overexpression of DCs-CD83 promoted Tregs expression. CONCLUSION: The Th1/Th2 and Th17/Tregs polarization were reversed via interfering DCs with siRNA-CD83. CD83 plays an important role in ITP pathogenesis, suggesting novel treatment for ITP patients.

In Situ Polymerization of a Self-Healing Polyacrylamide-Based Eutectogel as an Electrolyte for Zinc-Ion Batteries.

Gel electrolytes have attracted extensive attention in flexible batteries. However, the traditional hydrogel electrolyte is not enough to solve the fundamental problems of zinc anodes, such as dendrite growth, side reactions, and freezing failure at temperatures below zero, which seriously restricts the development of zinc-ion batteries. As a flexible energy storage device, the zinc-ion battery inevitably undergoes multiple stretches, bends, folds, or twists in daily use. Here, a self-healing and stretchable eutectogel, designated as deep eutectic solvent-acrylamide eutectic gel (DA-ETG), was developed as a solid-state electrolyte for zinc-ion batteries. This gel was prepared by immobilizing a high-concentration ZnCl2 deep eutectic solvent (DES) into a polyacrylamide matrix through in situ polymerization under ultraviolet light. The eutectogel electrolyte showed exceptional mechanical properties with a maximum fracture strength of 0.6 MPa and a high ionic conductivity of 6.4 × 10-4 S cm-1. The in situ polymerization of the DA-ETG electrolyte in the assembly of a full solid-state zinc-ion battery increased the electrode-electrolyte interface area contact, reduced the ion transport distance between the electrode and electrolyte, minimized the internal resistance, and enhanced the battery's long-term cycling stability. Using the DA-ETG electrolyte, a remarkably high capacity of 580 mAh g-1 at 0.1 A g-1 was achieved by the zinc-ion battery, and a considerable capacity of 234 mAh g-1 was maintained even at 5 A g-1, showing exceptional rate performance. After 2000 cycles at 2 A g-1, the cell with the eutectogel retained a capacity of 85% with a cycling efficiency close to 98%, which demonstrated excellent cycling stability. The self-healing function enabled the prepared soft battery to be reused multiple times, with full contact between the electrode and electrolyte interface, and without device failures.

Scientific Discovery Framework Accelerating Advanced Polymeric Materials Design.

Organic polymer materials, as the most abundantly produced materials, possess a flammable nature, making them potential hazards to human casualties and property losses. Target polymer design is still hindered due to the lack of a scientific foundation. Herein, we present a robust, generalizable, yet intelligent polymer discovery framework, which synergizes diverse capabilities, including the in situ burning analyzer, virtual reaction generator, and material genomic model, to achieve results that surpass the sum of individual parts. Notably, the high-throughput analyzer created for the first time, grounded in multiple spectroscopic principles, enables in situ capturing of massive combustion intermediates; then, the created realistic apparatus transforming to the virtual reaction generator acquires exponentially more intermediate information; further, the proposed feature engineering tool, which embedded both polymer hierarchical structures and massive intermediate data, develops the generalizable genomic model with excellent universality (adapting over 20 kinds of polymers) and high accuracy (88.8%), succeeding discovering series of novel polymers. This emerging approach addresses the target polymer design for flame-retardant application and underscores a pivotal role in accelerating polymeric materials discovery.

The potential regulatory role of the non-coding RNAs in regulating the exogenous estrogen-induced feminization in Takifugu rubripes gonad.

Estrogen plays a pivotal role in the early stage of sex differentiation in teleost. However, the underlying mechanisms of estrogen-induced feminization process are still needed for further clarification. Here, the comparative analysis of whole-transcriptome RNA sequencing was conducted between 17beta-Estradiol induced feminized XY (E-XY) gonads and control gonads (C) in Takifugu rubripes. A total of 57 miRNAs, 65 lncRNAs, and 4 circRNAs were found to be expressed at lower levels in control-XY (C-XY) than that in control-XX (C-XX), and were up-regulated in XY during E2-induced feminization process. The expression levels of 24 miRNAs, and 55 lncRNAs were higher in C-XY than that in C-XX, and were down-regulated in E2-treated XY. Furthermore, a correlation analysis was performed between miRNA-seq and mRNA-seq data. In C-XX/C-XY, 114 differential expression (DE) miRNAs were predicted to target to 904 differential expression genes (DEGs), while in C-XY/E-XY, 226 DEmiRNAs were predicted to target to 2,048 DEGs. In C-XX/C-XY, and C-XY/E-XY, KEGG pathway enrichment analysis showed that those targeted genes were mainly enriched in MAPK signaling, calcium signaling, steroid hormone biosynthesis and ovarian steroidogenesis pathway. Additionally, the competitive endogenous RNA (ceRNA) regulatory network was constructed by 24 miRNAs, 21 lncRNAs, 4 circRNAs and 5 key sex-related genes. These findings suggested that the expression of critical genes in sex differentiation were altered in E2-treated XY T. rubripes may via the lncRNA-miRNA-mRNA regulation network to facilitate the differentiation and maintenance of ovaries. Our results provide a new insight into the comprehensive understanding of the effects of estrogen signaling pathways on sex differentiation in teleost gonads.

Spatial Access to Continuous Maternal and Perinatal Health Care Services in Low-Resource Settings: Cross-Sectional Study.

BACKGROUND: Maternal and perinatal health are fundamental to human development. However, in low-resource settings such as sub-Saharan Africa (SSA), significant challenges persist in reducing maternal, newborn, and child mortality. To achieve the targets of the sustainable development goal 3 (SDG3) and universal health coverage (UHC), improving access to continuous maternal and perinatal health care services (CMPHS) has been addressed as a critical strategy. OBJECTIVE: This study aims to provide a widely applicable procedure to illuminate the current challenges in ensuring access to CMPHS for women of reproductive age. The findings are intended to inform targeted recommendations for prioritizing resource allocation and policy making in low-resource settings. METHODS: In accordance with the World Health Organization guidelines and existing literature, and taking into account the local context of CMPHS delivery to women of reproductive age in Mozambique, we first proposed the identification of CMPHS as the continuum of 3 independent service packages, namely antenatal care (ANC), institutional delivery (ID), and postnatal care (PNC). Then, we used the nearest-neighbor method (NNM) to assess spatial access to each of the 3 service packages. Lastly, we carried out an overlap analysis to identify 8 types of resource-shortage zones. RESULTS: The median shortest travel times for women of reproductive age to access ANC, ID, and PNC were 2.38 (IQR 1.38-3.89) hours, 3.69 (IQR 1.87-5.82) hours, and 4.16 (IQR 2.48-6.67) hours, respectively. Spatial barriers for women of reproductive age accessing ANC, ID, and PNC demonstrated large variations both among and within regions. Maputo City showed the shortest travel time and the best equity within the regions (0.46, IQR 0.26-0.69 hours; 0.74, IQR 0.47-1.04 hours; and 1.34, IQR 0.83-1.85 hours, respectively), while the provinces of Niassa (4.07, IQR 2.41-6.63 hours; 18.20, IQR 11.67-24.65 hours; and 7.69, IQR 4.74-13.05 hours, respectively) and Inhambane (2.69, IQR 1.49-3.91 hours; 4.43, IQR 2.37-7.16 hours; and 10.76, IQR 7.73-13.66 hours, respectively) lagged behind significantly in both aspects. In general, more than 51% of the women of reproductive age, residing in 83.25% of Mozambique's land area, were unable to access any service package of CMPHS in time (within 2 hours), while only about 21%, living in 2.69% of Mozambique's land area, including Maputo, could access timely CMPHS. CONCLUSIONS: The spatial accessibility and equity of CMPHS in Mozambique present significant challenges in achieving SDG3 and UHC, especially in the Inhambane and Niassa regions. For Inhambane, policy makers should prioritize the implementation of a decentralization allocation strategy to increase coverage and equity through upgrading existing health care facilities. For Niassa, the cultivation of well-trained midwives who can provide door-to-door ANC and PNC at home should be prioritized, with an emphasis on strengthening communities' engagement. The proposed 2-step procedure should be implemented in other low-resource settings to promote the achievement of SDG3.

Nuclear receptors for epidermal lipid barrier: Advances in mechanisms and applications.

The skin plays an essential role in preventing the entry of external environmental threats and the loss of internal substances, depending on the epidermal permeability barrier. Nuclear receptors (NRs), present in various tissues and organs including full-thickness skin, have been demonstrated to exert significant effects on the epidermal lipid barrier. Formation of the lipid lamellar membrane and the normal proliferation and differentiation of keratinocytes (KCs) are crucial for the development of the epidermal permeability barrier and is regulated by specific NRs such as PPAR, LXR, VDR, RAR/RXR, AHR, PXR and FXR. These receptors play a key role in regulating KC differentiation and the entire process of epidermal lipid synthesis, processing and secretion. Lipids derived from sebaceous glands are influenced by NRs as well and participate in regulation of the epidermal lipid barrier. Furthermore, intricate interplay exists between these receptors. Disturbance of barrier function leads to a range of diseases, including psoriasis, atopic dermatitis and acne. Targeting these NRs with agonists or antagonists modulate pathways involved in lipid synthesis and cell differentiation, suggesting potential therapeutic approaches for dermatosis associated with barrier damage. This review focuses on the regulatory role of NRs in the maintenance and processing of the epidermal lipid barrier through their effects on skin lipid synthesis and KC differentiation, providing novel insights for drug targets to facilitate precision medicine strategies.

Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers.

Targeted radionuclide therapy is based on injections of cancer-specific molecules conjugated with radioactive nuclides. Despite the specificity of this treatment, it is not devoid of side-effects limiting its use and is especially harmful for rapidly proliferating organs well perfused by blood, like bone marrow. Optimization of radioconjugates administration accounting for toxicity constraints can increase treatment efficacy. Based on our experiments on disseminated multiple myeloma mouse model treated by 225Ac-DOTA-daratumumab, we developed a mathematical model which investigation highlighted the following principles for optimization of targeted radionuclide therapy. 1) Nuclide to antibody ratio importance. The density of radioconjugates on cancer cells determines the density of radiation energy deposited in them. Low labeling ratio as well as accumulation of unlabeled antibodies and antibodies attached to decay products in the bloodstream can mitigate cancer radiation damage due to excessive occupation of specific receptors by antibodies devoid of radioactive nuclides. 2) Cancer binding capacity-based dosing. The rate of binding of drug to cancer cells depends on the total number of their specific receptors, which therefore can be estimated from the pharmacokinetic curve of diagnostic radioconjugates. Injection of doses significantly exceeding cancer binding capacity should be avoided since radioconjugates remaining in the bloodstream have negligible efficacy to toxicity ratio. 3) Particle range-guided multi-dosing. The use of short-range particle emitters and high-affinity antibodies allows for robust treatment optimization via initial saturation of cancer binding capacity, enabling redistribution of further injected radioconjugates and deposited dose towards still viable cells that continue expressing specific receptors.

A novel H­tert immortalized human sebaceous gland cell line (XL-i-20) for the investigation of photodynamic therapy.

BACKGROUND: Acne vulgaris is a species-specific human disease. To date, there has been no established human sebocyte cell line of Asian origin. Our previous study has demonstrated the efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in the treatment of acne vulgaris, primarily attributed to its cytotoxic properties; however, its regulatory mechanism remains largely unknown. OBJECTIVES: To establish an immortalized human sebocyte cell line derived from Chinese population and investigate the underlying mechanism of ALA-PDT. METHODS: Human primary sebocytes were transfected with the human tert gene (h­tert). The biological characteristics, including cell proliferation, cell markers, and sebum secretion function, were compared between primary sebocytes and the immortalized sebocytes (XL-i-20). Stimulations such as ALA-PDT, were applied respectively to both primary sebocytes and XL-i-20 cells to assess changes in their cellular functions. The transcriptome differences between primary sebocytes and XL-i-20 sebocytes were investigated using RNA-seq analysis. The XL-i-20 cell line was used to establish a sebaceous gland (SG) organoid culture, serving as a representative model of SG for the investigation of ALA-PDT. RESULTS: The h­tert immortalized sebocyte cell line exhibited the ability to be consecutively cultured for more than fifty passages. Both primary and immortalized cells expressed sebocyte markers such as epithelial membrane antigens (EMA, or MUC-1), Cytokeratin 7 (CK7) and adipose differentiation-related protein associated antigens (ADRP), and maintained sebum secretion function. The proliferative capacity of XL-i-20 was found to be significantly higher than that of primary sebocytes. The responses of XL-i-20 to ALA-PDT were indistinguishable from those elicited by primary sebocytes. Cell viability and sebum secretion were decreased after ALA-PDT in both two cell lines, and lipid-related proteins (SREBP-1/PPARγ) were down-regulated. The transcriptome data consistently demonstrated upregulation of genes related to inflammatory responses and downregulation of genes involved in lipid metabolism in both cell types following PDT. The analysis of common differential genes of primary sebocytes and XL-i-20 sebocytes post ALA-PDT showed that TNF signaling pathways, MAPK signaling pathways and JAK-STAT signaling pathways were activated. The SG organoids were spherical, which expressed markers of FANS and PLET1. Ki-67 was down-regulated after ALA-PDT. CONCLUSIONS: We have developed an h­tert immortalized sebocyte cell line from an Asian population. The cell line, XL-i-20, maintains the essential characteristics of its parent primary sebocytes. Moreover, XL-i-20 sebocyte exhibited a significant respond to ALA-PDT, demonstrating comparable phenotypic and molecular changes to primary sebocytes. Therefore, XL-i-20 and its derived SG organoid serve as appropriate in vitro models for investigating the efficacy and mechanisms of ALA-PDT in SG-related diseases.

A Clinical Bacterial Dataset for Deep Learning in Microbiological Rapid On-Site Evaluation.

Microbiological Rapid On-Site Evaluation (M-ROSE) is based on smear staining and microscopic observation, providing critical references for the diagnosis and treatment of pulmonary infectious disease. Automatic identification of pathogens is the key to improving the quality and speed of M-ROSE. Recent advancements in deep learning have yielded numerous identification algorithms and datasets. However, most studies focus on artificially cultured bacteria and lack clinical data and algorithms. Therefore, we collected Gram-stained bacteria images from lower respiratory tract specimens of patients with lung infections in Chinese PLA General Hospital obtained by M-ROSE from 2018 to 2022 and desensitized images to produce 1705 images (4,912 × 3,684 pixels). A total of 4,833 cocci and 6,991 bacilli were manually labelled and differentiated into negative and positive. In addition, we applied the detection and segmentation networks for benchmark testing. Data and benchmark algorithms we provided that may benefit the study of automated bacterial identification in clinical specimens.

Echinatin suppresses cutaneous squamous cell carcinoma by targeting GSTM3-mediated ferroptosis.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers for which effective drugs are urgently needed. Echinatin, a natural compound extracted from Glycyrrhiza plants, has shown promising antitumour effects. However, the efficacy and the direct target of echinatin in cSCC remain unclear. PURPOSE: This study conducted a systematic investigation of the antitumour effects of echinatin on cSCC and the underlying mechanisms involved. STUDY DESIGN AND METHODS: Three cSCC cell lines, a xenograft model, and a UV-induced cSCC mouse model were used to investigate the potential protective effects of echinatin. The interactions between echinatin and glutathione S-transferase mu3 (GSTM3) and between echinatin and peroxiredoxin-2 (PRDX2) were evaluated by a proteome microarray assay, pull-down LC‒MS/MS analysis, surface plasmon resonance, and molecular docking. The potential mechanisms of GSTM3-mediated echinatin activity were analysed by using western blotting, lentivirus infection and small interfering RNA (siRNA) transfection. RESULTS: In this study, we found that echinatin inhibited the proliferation and migration of cSCC cells but had no cytotoxic effect on primary human keratinocytes. Furthermore, echinatin significantly inhibited tumour growth in vivo. Mechanistically, our data showed that echinatin could directly bind to GSTM3 and PRDX2. Notably, echinatin inhibited GSTM3 and PRDX2 levels by promoting their proteasomal degradation, which led to the disruption of ROS production. We then revealed that echinatin increased mitochondrial ROS production by inhibiting GSTM3. Moreover, echinatin triggered ferroptosis by inhibiting GSTM3-mediated ferroptosis negative regulation (FNR) proteins. In addition, echinatin regulated GSTM3-mediated ROS/MAPK signalling. CONCLUSION: Echinatin has good antitumour effects both in vitro and in vivo. Moreover, our findings indicate that GSTM3 and PRDX2 could function as viable targets of echinatin in cSCC. Consequently, echinatin represents a novel treatment for cSCC through the targeting of GSTM3-mediated ferroptosis.

Analysis of Polyfunctionality for Enhanced CAR T-Cell Therapy for Hematologic Malignancies.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising immunotherapeutic strategy for eradicating human cancers. Their therapeutic success and durability of clinical responses hinges, in large part, on their functional capacity, including the ability of these engineered cells to simultaneously expand and persist after infusion into patients. CD19 CAR T-cell polyfunctionality, assessing the simultaneous functions of cytokine production, proliferation, and cytotoxicity has been reported to correlate with clinical outcomes. Assay optimization is potentially limited by the heterogeneous nature of CAR T-cell infusion products and target specificity. We optimized a single-cell platform for polyfunctionality using CAR T cell products manufactured from healthy donors, engineered against a novel target, BAFF-R, and validated the protocol using CD19 CAR T cells. We observed distinct qualitative differences between BAFF-R and CD19 CAR T cells relative to the proportions of stimulatory vs. effector cytokines, based on target antigen density, and generally, CD19 CAR T cells exhibited lower indices of polyfunctionality. Finally, we applied our assay to the autologous BAFF-R CAR T-cell product generated from the first NHL patient treated on an ongoing clinical trial who had progressed after prior CD19 CAR T-cell therapy. We observed robust indicators of polyfunctionality, which correlated with successful CAR T cell expansion after infusion and achievement of durable complete remission ongoing after 18 months. The precise identification of factors determining the role of BAFF-R CAR T-cell fitness on toxicity and clinical outcome will require the application of this robust assay in the analysis of additional treated patients.

Silk fibroin catheter with stable bioinspired inner-surfaces for inhibition of bioadhesion.

Biofilm formation on indwelling medical devices such as catheters and ventilators due to the adhesion of bacteria poses significant challenges in healthcare. Surface modification with micro- and nano-structures offers a promising strategy to prevent bioadhesion and is safer than surface chemical modification approaches. Here, catheters were prepared using silk fibroin (SF) hydrogels and an infusion molding method, with the inner surface featuring a micropapillae structure inspired by lotus leaves (SF-CMP). After phenylethanol (PEA) fumigation treatment, the resulting catheters (SF-CMP PEA) displayed improved swelling resistance and mechanical properties compared to methanol-treated catheters (SF-CMP MeOH). PEA was more efficient than methanol in controlling the size, distribution, and content of silk crystalline ß-sheet blocks and thus the swelling and mechanical properties. Moreover, the micro-papillae structure on SF-CMP PEA remained stable over 35 days in solution, in contrast to SF-CMP MeOH, which lasted <7 days. SF-CMP PEA exhibited repellent effects against E. coli and S. aureusin vitro, and low cytotoxicity to the endothelial cells cultured on the unpatterned surface. Additionally, subcutaneous implantation studies showed reduced inflammation around the micropatterned samples compared to controls with a plain, unpatterned surface. The unique properties of SF-based materials, including tunable structures, biocompatibility, degradation, and drug-loading capability make them an attractive material for anti-bioadhesion in applications ranging from indwelling medical devices to tissue engineering scaffolds.

Simultaneous targeting of B-cell malignancies and human immunodeficiency virus with bispecific chimeric antigen receptor T cells.

Not available.

Designing combination therapies for cancer treatment: application of a mathematical framework combining CAR T-cell immunotherapy and targeted radionuclide therapy.

Introduction: Cancer combination treatments involving immunotherapies with targeted radiation therapy are at the forefront of treating cancers. However, dosing and scheduling of these therapies pose a challenge. Mathematical models provide a unique way of optimizing these therapies. Methods: Using a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies. Results: Therapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy. Discussion: Mathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity.

Neoadjuvant Photodynamic Therapy: An Updated Therapeutic Approach for Non-Melanoma Skin Cancers.

OPINION STATEMENT: Non-melanoma skin cancers (NMSCs) are the most common malignancy and surgical excision is considered treatment of choice for the majority of cases. However, surgery can be very extensive in cases of large, multiple, or cosmetic-sensitive tumors located on areas such as scalp and face or genital region, leading to significant functional and cosmetic deficit. Aminolaevulinic acid photodynamic therapy (ALA-PDT) has emerged as a widely used approach in a variety of skin diseases, demonstrating remarkable efficacy in treatment of actinic keratosis, Bowen disease and basal cell carcinoma. Besides, when employed as a preoperative intervention, ALA-PDT effectively reduces tumor size and minimizes subsequent local surgical morbidity. With its minimally invasive nature and proven effectiveness, ALA-PDT holds significant promise as a neoadjuvant treatment option for NMSCs. In cases where the tumor is large, invasive, multiple, or located in cosmetically and functionally sensitive areas, or when considering patient factors such as age, comorbidity, willingness to undergo surgery, and post-operative quality-of-life, surgical intervention or radiotherapy alone may be impracticable or unacceptable. In such scenarios, neoadjuvant ALA-PDT can offer remarkable outcomes. In order to further ensure the maximum benefit of patients from neoadjuvant PDT, collaboration with multidisciplinary teams and whole-process management may be in need.

Comparing Sonazoid contrast-enhanced ultrasound to contrast-enhanced CT and MRI for differentially diagnosing renal lesions: a prospective multicenter study.

PURPOSE: To evaluate the diagnostic performance of contrast-enhanced (CE) ultrasound using Sonazoid (SNZ-CEUS) by comparing with contrast-enhanced computed tomography (CE-CT) and contrast-enhanced magnetic resonance imaging (CE-MRI) for differentiating benign and malignant renal masses. MATERIALS AND METHODS: 306 consecutive patients (from 7 centers) with renal masses (40 benign tumors, 266 malignant tumors) diagnosed by both SNZ-CEUS, CE-CT or CE-MRI were enrolled between September 2020 and February 2021. The examinations were performed within 7 days, but the sequence was not fixed. Histologic results were available for 301 of 306 (98.37%) lesions and 5 lesions were considered benign after at least 2 year follow-up without change in size and image characteristics. The diagnostic performances were evaluated by sensitivity, specificity, positive predictive value, negative predictive value, and compared by McNemar's test. RESULTS: In the head-to-head comparison, SNZ-CEUS and CE-MRI had comparable sensitivity (95.60 vs. 94.51%, P = 0.997), specificity (65.22 vs. 73.91%, P = 0.752), positive predictive value (91.58 vs. 93.48%) and negative predictive value (78.95 vs. 77.27%); SNZ-CEUS and CE-CT showed similar sensitivity (97.31 vs. 96.24%, P = 0.724); however, SNZ-CEUS had relatively lower than specificity than CE-CT (59.09 vs. 68.18%, P = 0.683). For nodules > 4 cm, CE-MRI demonstrated higher specificity than SNZ-CEUS (90.91 vs. 72.73%, P = 0.617) without compromise the sensitivity. CONCLUSIONS: SNZ-CEUS, CE-CT, and CE-MRI demonstrate desirable and comparable sensitivity for the differentiation of renal mass. However, the specificity of all three imaging modalities is not satisfactory. SNZ-CEUS may be a suitable alternative modality for patients with renal dysfunction and those allergic to gadolinium or iodine-based agents.

PI3K/HSCB axis facilitates FOG1 nuclear translocation to promote erythropoiesis and megakaryopoiesis.

Erythropoiesis and megakaryopoiesis are stringently regulated by signaling pathways. However, the precise molecular mechanisms through which signaling pathways regulate key transcription factors controlling erythropoiesis and megakaryopoiesis remain partially understood. Herein, we identified heat shock cognate B (HSCB), which is well known for its iron-sulfur cluster delivery function, as an indispensable protein for friend of GATA 1 (FOG1) nuclear translocation during erythropoiesis of K562 human erythroleukemia cells and cord-blood-derived human CD34+CD90+hematopoietic stem cells (HSCs), as well as during megakaryopoiesis of the CD34+CD90+HSCs. Mechanistically, HSCB could be phosphorylated by phosphoinositol-3-kinase (PI3K) to bind with and mediate the proteasomal degradation of transforming acidic coiled-coil containing protein 3 (TACC3), which otherwise detained FOG1 in the cytoplasm, thereby facilitating FOG1 nuclear translocation. Given that PI3K is activated during both erythropoiesis and megakaryopoiesis, and that FOG1 is a key transcription factor for these processes, our findings elucidate an important, previously unrecognized iron-sulfur cluster delivery independent function of HSCB in erythropoiesis and megakaryopoiesis.