Development and validation of a novel criterion of histologic healing in ulcerative colitis defined by inflammatory cell enumeration in lamina propria mucosae: A multicenter retrospective cohort in China.

BACKGROUND: Histological healing is closely associated with improved long-term clinical outcomes and lowered relapses in patients with ulcerative colitis (UC). Here, we developed a novel diagnostic criterion for assessing histological healing in UC patients. METHODS: We conducted a retrospective cohort study in UC patients, whose treatment was iteratively optimized to achieve mucosal healing at Shanghai Tenth People's Hospital of Tongji University from January 2017 to May 2022. We identified an inflammatory cell enumeration index (ICEI) for assessing histological healing based on the proportions of eosinophils, CD177+ neutrophils, and CD40L+ T cells in the colonic lamina propria under high power field (HPF), and the outcomes (risks of symptomatic relapses) of achieving histological remission vs. persistent histological inflammation using Kaplan-Meier curves. Intrareader reliability and inter-reader reliability were evaluated by each reader. The relationships to the changes in the Nancy index and the Geboes score were also assessed for responsiveness. The ICEI was further validated in a new cohort of UC patients from other nine university hospitals. RESULTS: We developed an ICEI for clinical diagnosis of histological healing, i.e., Y = 1.701X1 + 0.758X2 + 1.347X3 - 7.745 (X1, X2, and X3 represent the proportions of CD177+ neutrophils, eosinophils, and CD40L+ T cells, respectively, in the colonic lamina propria under HPF). The receiver operating characteristics curve (ROC) analysis revealed that Y <-0.391 was the cutoff value for the diagnosis of histological healing and that an area under the curve (AUC) was 0.942 (95% confidence interval [CI]: 0.905-0.979) with a sensitivity of 92.5% and a specificity of 83.6% (P <0.001). The intraclass correlation coefficient (ICC) for the intrareader reliability was 0.855 (95% CI: 0.781-0.909), and ICEI had good inter-reader reliability of 0.832 (95% CI: 0.748-0.894). During an 18-month follow-up, patients with histological healing had a substantially better outcome compared with those with unachieved histological healing (P <0.001) using ICEI. During a 12-month follow-up from other nine hospitals, patients with histological healing also had a lower risk of relapse than patients with unachieved histological healing. CONCLUSIONS: ICEI can be used to predict histological healing and identify patients with a risk of relapse 12 months and 18 months after clinical therapy. Therefore, ICEI provides a promising, simplified approach to monitor histological healing and to predict the prognosis of UC. REGISTRATION: Chinese Clinical Trial Registry, No. ChiCTR2300077792.

Few-shot segmentation framework for lung nodules via an optimized active contour model.

BACKGROUND: Accurate segmentation of lung nodules is crucial for the early diagnosis and treatment of lung cancer in clinical practice. However, the similarity between lung nodules and surrounding tissues has made their segmentation a longstanding challenge. PURPOSE: Existing deep learning and active contour models each have their limitations. This paper aims to integrate the strengths of both approaches while mitigating their respective shortcomings. METHODS: In this paper, we propose a few-shot segmentation framework that combines a deep neural network with an active contour model. We introduce heat kernel convolutions and high-order total variation into the active contour model and solve the challenging nonsmooth optimization problem using the alternating direction method of multipliers. Additionally, we use the presegmentation results obtained from training a deep neural network on a small sample set as the initial contours for our optimized active contour model, addressing the difficulty of manually setting the initial contours. RESULTS: We compared our proposed method with state-of-the-art methods for segmentation effectiveness using clinical computed tomography (CT) images acquired from two different hospitals and the publicly available LIDC dataset. The results demonstrate that our proposed method achieved outstanding segmentation performance according to both visual and quantitative indicators. CONCLUSION: Our approach utilizes the output of few-shot network training as prior information, avoiding the need to select the initial contour in the active contour model. Additionally, it provides mathematical interpretability to the deep learning, reducing its dependency on the quantity of training samples.

SIA: A sustainable inference attack framework in split learning.

Split learning is a widely recognized distributed learning framework suitable for joint training scenarios with limited computing resources. However, recent research indicates that the malicious server can achieve high-quality reconstruction of the client's data through feature space hijacking attacks, leading to severe privacy leakage concerns. In this paper, we further enhance this attack to enable efficient data reconstruction while maintaining acceptable performance on the main task. Another significant advantage of our attack framework lies in its ability to fool the state-of-the-art attack detection mechanism, thus minimizing the risk of attacker exposure and making sustainable attacks possible. Moreover, we adaptively refine and adjust the attack strategy, extending the data reconstruction attack for the first time to the more challenging scenario of vertically partitioned data in split learning. In addition, we introduce three training modes for the attack framework, allowing the attacker to choose according to their requirements freely. Finally, we conduct extensive experiments on three datasets and evaluate the attack performance of attack frameworks in different scenarios, parameter settings, and defense mechanisms. The results demonstrate our attack framework's effectiveness, invisibility, and generality. Our research comprehensively highlights the potential privacy risks associated with split learning and sounds the alarm for secure applications of split learning.

Neoantigen-targeted TCR-engineered T cell immunotherapy: current advances and challenges.

Adoptive cell therapy using T cell receptor-engineered T cells (TCR-T) is a promising approach for cancer therapy with an expectation of no significant side effects. In the human body, mature T cells are armed with an incredible diversity of T cell receptors (TCRs) that theoretically react to the variety of random mutations generated by tumor cells. The outcomes, however, of current clinical trials using TCR-T cell therapies are not very successful especially involving solid tumors. The therapy still faces numerous challenges in the efficient screening of tumor-specific antigens and their cognate TCRs. In this review, we first introduce TCR structure-based antigen recognition and signaling, then describe recent advances in neoantigens and their specific TCR screening technologies, and finally summarize ongoing clinical trials of TCR-T therapies against neoantigens. More importantly, we also present the current challenges of TCR-T cell-based immunotherapies, e.g., the safety of viral vectors, the mismatch of T cell receptor, the impediment of suppressive tumor microenvironment. Finally, we highlight new insights and directions for personalized TCR-T therapy.

How to backdoor split learning.

Split learning, a distributed learning framework, has garnered significant attention from academic and industrial communities. In contrast to federated learning, split learning offers a more flexible architecture for participants with limited computing resources. However, the security of split learning has been questioned due to the separation of data and model control rights from usage rights. Currently, most research work focuses on inference attacks in split learning. In this paper, we first reveal the vulnerability of split learning to backdoor attacks and present two backdoor attack frameworks from both the server and client perspectives. Regarding the client-side attacker, we insert backdoor samples into the training data by utilizing the client's direct control over local data, and propose two methods for labeling backdoor samples that can be adapted to various application scenarios. Due to the server's lack of control over the client in split learning, it is infeasible for server-side attackers to inject backdoor samples into training data. Our strategy involves leveraging the server's control over the training process to shape the optimization direction of the client model, thereby enabling it to encode backdoor samples. Moreover, we introduce an auxiliary model into the attack framework to enhance the effectiveness of the backdoor attack. The auxiliary model can increase the distinction between backdoor samples and clean samples in the feature space to improve the sensitivity of the client model to backdoor samples. Extensive evaluations demonstrate the high attack accuracy of both proposed attack frameworks without causing any compromise to the performance of the main task. Our research uncovers the potential security risks and rings the alarm for the application of split learning.

Weakly supervised video-based cardiac detection for hypertensive cardiomyopathy.

INTRODUCTION: Parameters, such as left ventricular ejection fraction, peak strain dispersion, global longitudinal strain, etc. are influential and clinically interpretable for detection of cardiac disease, while manual detection requires laborious steps and expertise. In this study, we evaluated a video-based deep learning method that merely depends on echocardiographic videos from four apical chamber views of hypertensive cardiomyopathy detection. METHODS: One hundred eighty-five hypertensive cardiomyopathy (HTCM) patients and 112 healthy normal controls (N) were enrolled in this diagnostic study. We collected 297 de-identified subjects' echo videos for training and testing of an end-to-end video-based pipeline of snippet proposal, snippet feature extraction by a three-dimensional (3-D) convolutional neural network (CNN), a weakly-supervised temporally correlated feature ensemble, and a final classification module. The snippet proposal step requires a preliminarily trained end-systole and end-diastole timing detection model to produce snippets that begin at end-diastole, and involve contraction and dilatation for a complete cardiac cycle. A domain adversarial neural network was introduced to systematically address the appearance variability of echo videos in terms of noise, blur, transducer depth, contrast, etc. to improve the generalization of deep learning algorithms. In contrast to previous image-based cardiac disease detection architectures, video-based approaches integrate spatial and temporal information better with a more powerful 3D convolutional operator. RESULTS: Our proposed model achieved accuracy (ACC) of 92%, area under receiver operating characteristic (ROC) curve (AUC) of 0.90, sensitivity(SEN) of 97%, and specificity (SPE) of 84% with respect to subjects for hypertensive cardiomyopathy detection in the test data set, and outperformed the corresponding 3D CNN (vanilla I3D: ACC (0.90), AUC (0.89), SEN (0.94), and SPE (0.84)). On the whole, the video-based methods remarkably appeared superior to the image-based methods, while few evaluation metrics of image-based methods exhibited to be more compelling (sensitivity of 93% and negative predictive value of 100% for the image-based methods (ES/ED and random)). CONCLUSION: The results supported the possibility of using end-to-end video-based deep learning method for the automated diagnosis of hypertensive cardiomyopathy in the field of echocardiography to augment and assist clinicians. TRIAL REGISTRATION: Current Controlled Trials ChiCTR1900025325, Aug, 24, 2019. Retrospectively registered.

Hsa_circRNA_103124 upregulation in Crohn's disease promoted macrophage M1 polarization to maintain an inflammatory microenvironment via activation of the AKT2 and TLR4/NF-κB pathways.

An accumulating body of research indicates that circular RNAs participate in the pathogenesis of Crohn's disease (CD). Hsa_circRNA_103124, which was upregulated in the peripheral blood mononuclear cells of patients with CD, was reported to inhibit autophagy in our previous studies. However, how hsa_circRNA_103124 participates in CD progression remains unclear. In this study, TLR4 was found to be upregulated in THP1 cells overexpressing hsa_circRNA_103124. Bioinformatic analysis indicated that overexpressed hsa_circRNA_103124 was associated with the PI3K/AKT signaling pathway and TLR4-associated innate immunity in inflammatory bowel disease. Therefore, we inferred a possible role for hsa_circRNA_103124 in macrophage polarization. Hsa_circRNA_103124, AKT2 and TLR4 were significantly upregulated in the PBMCs of patients with CD. Further analysis revealed a positive correlation between hsa_circRNA_103124 and AKT2 (r = 0.8029, p < 0.0001), TLR4 (r = 0.2529, p = 0.0089) and the Crohn's disease activity index (r = 0.4535, p < 0.0001) in patients with CD. Notably, hsa_circRNA_103124 promoted macrophage M1 polarization with increased expression of CD80 and CD86, while it inhibited macrophage M2 polarization with decreased expression of CD206 and CD163. Hsa_circRNA_103124 promoted an inflammatory microenvironment by activating the AKT2 and TLR4/NF-κB signaling pathways in M1 polarized THP1 cells. Nevertheless, hsa-miR-650 reversed the role of hsa_circRNA_103124 in M1 polarization. Hsa_circRNA_103124 promoted the formation of neutrophil extracellular traps and reduced the expression of ZO-1. In summary, the results of this study indicated that hsa_circRNA_103124 promoted macrophage M1 polarization to maintain an inflammatory microenvironment via activation of the TLR4/NF-κB pathway in a hsa-miR-650/AKT2 dependent manner. Hsa_circRNA_103124 could serve as a potential biomarker and a novel therapeutic target in CD progression.

[Effect of Isodon ternifolius-medicated serum on hepatic stellate cells based on TLR4/NF-κB/NLRP3 signaling pathway].

The present study aimed to investigate the inhibitory effect and mechanism of Isodon terricolous-medicated serum on lipopolysaccharide(LPS)-induced hepatic stellate cell(HSC) activation. LPS-induced HSCs were divided into a blank control group, an LPS model group, a colchicine-medicated serum group, an LPS + blank serum group, an I. terricolous-medicated serum group, a Toll-like receptor 4(TLR4) blocker group, and a TLR4 blocker + I. terricolous-medicated serum group. HSC proliferation was detected by methyl thiazolyl tetrazolium(MTT) assay. Enzyme-linked immunosorbent assay(ELISA) was used to measure type Ⅰ collagen(COL Ⅰ), COL Ⅲ, transforming growth factor-ß1(TGF-ß1), intercellular adhesion molecule-1(ICAM-1), α-smooth muscle actin(α-SMA), vascular cell adhesion molecule-1(VCAM-1), cysteinyl aspartate-specific proteinase-1(caspase-1), and monocyte chemotactic protein-1(MCP-1). Real-time PCR(RT-PCR) was used to detect mRNA expression of TLR4, IκBα, and NOD-like receptor thermal protein domain associated protein 3(NLRP3), nuclear factor-κB(NF-κB) p65, gasdermin D(GSDMD), and apoptosis-associated speck-like protein containing a CARD(ASC) in HSCs. Western blot(WB) was used to detect the protein levels of TLR4, p-IκBα, NF-κB p65, NLRP3, ASC, and GSDMD in HSCs. The results showed that I. terricolous-medicated serum could inhibit the proliferation activity of HSCs and inhibit the secretion of COL Ⅰ, COL Ⅲ, α-SMA, TGF-ß1, caspase-1, MCP-1, VCAM-1, and ICAM-1 in HSCs. Compared with the LPS model group, the I. terricolous-medicated serum group, the colchicine-medicated serum group, and the TLR4 blocker group showed down-regulated expression of p-IκBα, NLRP3, NF-κB p65, GSDMD, and ASC, and up-regulated expression of IκBα. Compared with the TLR4 blocker group, the TLR4 blocker + I. terricolous-medicated serum group showed decreased expression of TLR4, p-IκBα, NLRP3, NF-κB p65, GSDMD, and ASC, and increased expression of IκBα. In conclusion, I. terricolous-medicated serum down-regulates HSC activation by inhibiting the TLR4/NF-κB/NLRP3 signaling pathway.

Ulcerative colitis alleviation of colon-specific delivered rhamnolipid/fullerene nanocomposites via dual modulation in oxidative stress and intestinal microbiome.

As a typical inflammatory bowel disease (IBD), ulcerative colitis (UC) has become prevalent worldwide in recent years. Though several materials have been proved to be effective in reducing intestinal oxidative stress to alleviate UC symptoms, dependence on high doses of exogenous drugs amplifies their safety risk for patients. To address this challenge, an oral therapy based on colon-targeting delivery of low-dose rhamnolipid (RL)/fullerene (C60) nanocomposites has been reported. With high biocompatibility being verified, RL/C60 largely mitigated the inflammation of mice with colitis shortly after its oral administration. Not only this, but also the intestinal microbiome of diseased mice was remarkably restored to the near-healthy level by our composites. Specifically, RL/C60 significantly promoted the colonization of intestinal probiotics and suppressed the biofilm formation of pathogenic bacteria, which is beneficial for reshaping the intestinal barrier. A close relationship of cytokines and oxidoreductases levels with gut flora further revealed that a change in RL/C60-induced intestinal microecology effectively improved the organismal immune system, which can be considered important for long-time recovery from UC.

Impact of extended nursing model after multi-disciplinary treatment on young patient with post-stroke.

BACKGROUND: Stroke has become one of the most serious life-threatening diseases due to its high morbidity, disability, recurrence and mortality rates. AIM: To explore the intervention effect of multi-disciplinary treatment (MDT) extended nursing model on negative emotions and quality of life of young patients with post-stroke. METHODS: A total of 60 young stroke patients who were hospitalized in the neurology department of our hospital from January 2020 to December 2021 were selected and randomly divided into a control group and an experimental group, with 30 patients in each group. The control group used the conventional care model and the experimental group used the MDT extended nursing model. After the in-hospital and 3-mo post-discharge interventions, the differences in negative emotions and quality of life scores between the two groups were evaluated and analyzed at the time of admission, at the time of discharge and after discharge, respectively. RESULTS: There are no statistically significant differences in the negative emotions scores between the two groups at admission, while there are statistically significant differences in the negative emotions scores within each group at admission and discharge, at discharge and post-discharge, and at discharge and post-discharge. In addition, the negative emotions scores were all statistically significant at discharge and after discharge when compared between the two groups. There was no statistically significant difference in quality of life scores at the time of admission between the two groups, and the difference between quality of life scores at the time of admission and discharge, at the time of discharge and post-discharge, and at the time of admission and post-discharge for each group of patients was statistically significant. CONCLUSION: The MDT extended nursing mode can improve the negative emotion of patients and improve their quality of life. Therefore, it can be applied in future clinical practice and is worthy of promotion.

Targeting autophagy receptors OPTN and SQSTM1 as a novel therapeutic strategy for osteoporosis complicated with Alzheimer's disease.

Alzheimer's disease (AD) is a common degenerative disease among the elderly population. In addition to cognitive impairment, AD is often accompanied by behavioral manifestations. However, little attention has been paid to changes in bone metabolism and related mechanisms in patients with AD. We found that AD mice (APPswe/PS1dE9) had reduced bone density, weakened bone strength, and amyloid beta (Aß) deposition in the bone tissue. It was further found that targeting autophagy receptors Optineurin (OPTN) and Sequestosome 1 (SQSTM1) increased bone density and bone strength in AD mice, promoted the clearance of Aß in the bone tissue, and maintained bone homeostasis. Our study suggests that abnormal Aß deposition may be the co-pathogenesis of AD and osteoporosis (OP). Targeting OPTN and SQSTM1 has a dual-functional effect of alleviating both AD and OP through selective autophagy that specifically targets Aß for clearance. Therapeutic strategies targeting autophagy may help guide the treatment of patients with AD complicated with OP.

Rational Molecular Design Strategy for High-Efficiency Ultrapure Blue TADF Emitters: Symmetrical and Rigid Sulfur-Bridged Boron-Based Acceptors.

Developing highly efficient blue thermally activated delayed fluorescence (TADF) emitters with a narrowband emission is still a challenge. Here, novel ultrapure blue TADF emitters of TSBA-Cz and TSBA-PhCz were designed and synthesized for organic light-emitting diodes (OLEDs). Photophysical and time-dependent density functional theory calculation results simultaneously show the similar intramolecular charge-transfer character of MR-type TADF emitters. Benefiting from the symmetrical and rigid molecular configuration, compounds TSBA-Cz and TSBA-PhCz emit a pure blue emission peak at 463 and 470 nm, a narrow full width at half-maximum (FWHM) of 30 and 36 nm, and a small singlet-triplet energy gap (ΔEST) of 0.21 and 0.18 eV, respectively, facilitating their excellent TADF behavior in doped films. Furthermore, highly efficient TADF-OLED devices using the TSBA-Cz and TSBA-PhCz with external quantum efficiencies of 23.4 and 21.3% emit ultrapure blue electroluminescence (EL) at 464 and 472 nm with a narrow FWHM of about 35 nm and CIE color coordinates of (0.14, 0.11) and (0.12, 0.18). This work provides novel TADF emitters for blue OLEDs with narrowband EL.

Neutralizing peripheral circulating IL1ß slows the progression of ALS in a lentivirus-infected OPTNE478G mouse model.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is irreversible and fatal within 3-5 years, with limited options for treatment. It is imperative to develop a symptom-based treatment that may increase the survival of ALS patients and improve their quality of life. Inflammation status, especially elevated interleukin 1ß (IL1ß), has been reported to play a critical role in ALS progression. Our study determined that neutralizing circulating IL1ß slows down the progression of ALS in an ALS mouse model. METHODS: The ALS mouse model was developed by microinjection of lentivirus-carrying OPTNE478G (optineurin, a mutation from ALS patients) into the intra-motor cortex of mice. Peripheral circulating IL1ß was neutralized by injecting anti-IL1ß antibody into the tail vein. Enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR) were carried out to determine the protein and gene expression levels of IL1ß. TUNEL assay was used to assess the neural cell death. Immunofluorescent staining of MAP2 and CASP3 was accomplished to evaluate neuronal cell apoptosis. Glial fibrillary acidic protein staining was performed to analyze the number of astrocytes. Rotarod test, grip strength test, balance beam test, and footprint test were conducted to assess the locomotive function after anti-IL1ß treatment. RESULTS: The model revealed that neuroinflammation contributes to ALS progression. ALS mice exhibited elevated neuroinflammation and IL1ß secretion. After anti-IL1ß treatment, ALS mice revealed decreased neural cell death and astrogliosis and gained improved muscle strength and motor ability. CONCLUSIONS: Blocking IL1ß is a promising strategy to slow down the progression of ALS.

Sepsis complicated with secondary hemophagocytic syndrome induced by giant gouty tophi rupture: A case report.

BACKGROUND: Gouty tophi are a chronic granulomatous caused by a deposition of monosodium urate crystal deposition in the body. Once broken, it may easily induce severe infection. Sepsis complicated with secondary hemophagocytic syndrome induced by gouty tophi rupture is extremely rare in the clinical setting, and no such serious complications have been reported in literature. CASE SUMMARY: This is a 52-year-old Chinese male patient with a 20-year history of gouty arthritis. At admission, the gout stone in the patient's right ankle was broken and it secreted a white mucoid substance. During the course of treatment, the patient suffered from systemic inflammatory response syndrome multiple times. His condition gradually deteriorated, further complicated by hemophagocytic syndrome. After thorough removal of gout lesions and active anti-infection treatment and control of blood uric acid level, combined with multidisciplinary cooperation, the patient was finally cured. CONCLUSION: Sepsis complicated with secondary hemophagocytic syndrome induced by gouty tophi rupture is extremely rare in the clinical setting. Timely and accurate diagnosis is very important to save patients' lives.

Transplantation of Nasal Olfactory Mucosa Mesenchymal Stem Cells Benefits Alzheimer's Disease.

Alzheimer's disease (AD) is a common neurodegenerative disease that contributes to 60-70% of dementia in elderly people and is currently incurable. Current treatments only relieve the symptoms of AD and slow its progression. Achieving effective neural regeneration to ameliorate cognitive impairment is a major challenge in the treatment of AD. For the first time, we alleviated symptoms of AD in APPswe/PS1dE9 mice (hereafter referred to as AD mice) by transplantation of olfactory mucosa mesenchymal stem cells (OM-MSCs). Our study demonstrated that OM-MSC transplantation promotes amyloid-ß (Aß) clearance, downregulates the inflammatory response, and increases the M2/M1 ratio; OM-MSCs promote the conversion of BV2 (microglia) from M1 to M2 and also Aß clearance in SH-SY5YAPPswe (AD cell model). OM-MSC-transplanted AD mice show improved cognitive learning and locomotive behavior. Our study suggests that OM-MSC transplantation could alleviate the symptoms of AD and promote Aß clearance through immunomodulation, thus demonstrating the great potential and social value of OM-MSC treatment for AD patients.

Ultrapure Blue Thermally Activated Delayed Fluorescence (TADF) Emitters Based on Rigid Sulfur/Oxygen-Bridged Triarylboron Acceptor: MR TADF and D-A TADF.

Organic light-emitting diodes (OLEDs) still face a significant challenge in finding blue thermally activated delayed fluorescence (TADF) emitters that can achieve narrowband emission and high efficiency. In this work, we successfully design and synthesize a novel kind of TADF emitters based on rigid sulfur/oxygen-bridged triarylboron acceptor for ultrapure blue with narrowband electroluminescence. Time-dependent density functional theory (TD-DFT) calculations and photophysical results indicate the different intramolecular charge-transfer (ICT) character of two emitters. Benefiting from the rigid aromatic framework, both emitters exhibited deep-blue emission at 444 and 447 nm with a small full-width at half-maximum (fwhm) of about 33 nm, and a small singlet (S1)-triplet (T1) energy gap (ΔEST) of 0.23 and 0.36 eV. Consequently, OLEDs based on PhCz-TOSBA and TPA-TOSBA exhibit deep blue electroluminescence at 456 nm with fwhm of about 55 nm, affording high external quantum efficiencies (EQEs) of 16.69% with CIE coordinates of (0.14, 0.15) and 16.65% with CIE coordinates of (0.14, 0.12), respectively. These findings show that PhCz-TOSBA and TPA-TOSBA are superior emitters in ultrapure blue TADF devices.

Baohuoside I Inhibits Osteoclastogenesis and Protects Against Ovariectomy-Induced Bone Loss.

Bone-resorbing osteoclasts are essential for skeletal remodelling, and the hyperactive formation and function of osteoclasts are common in bone metabolic diseases, especially postmenopausal osteoporosis. Therefore, regulating the osteoclast differentiation is a major therapeutic target in osteoporosis treatment. Icariin has shown potential osteoprotective effects. However, existing studies have reported limited bioavailability of icariin, and the material basis of icariin for anti-osteoporosis is attributed to its metabolites in the body. Here, we compared the effects of icariin and its metabolites (icariside I, baohuoside I, and icaritin) on osteoclastogenesis by high-content screening followed by TRAP staining and identified baohuoside I (BS) with an optimal effect. Then, we evaluated the effects of BS on osteoclast differentiation and bone resorptive activity in both in vivo and in vitro experiments. In an in vitro study, BS inhibited osteoclast formation and bone resorption function in a dose-dependent manner, and the elevated osteoclastic-related genes induced by RANKL, such as NFATc1, cathepsin K, RANK, and TRAP, were also attenuated following BS treatment. In an in vivo study, OVX-induced bone loss could be prevented by BS through interrupting the osteoclast formation and activity in mice. Furthermore, mechanistic investigation demonstrated that BS inhibited osteoclast differentiation by ameliorating the activation of the MAPK and NF-kB pathways and reducing the expression of uPAR. Our study demonstrated that baohuoside I could inhibit osteoclast differentiation and protect bone loss following ovariectomy.

Synergistic prognostic value of coronary distensibility index and fractional flow reserve based cCTA for major adverse cardiac events in patients with Coronary artery disease.

BACKGROUND: Coronary distensibility index (CDI), as an early predictor of cardiovascular diseases, has the potential to complement coronary computed tomography angiography (cCTA)-derived fractional flow reserve (CT-FFR) for predicting major adverse cardiac events (MACEs). Thus, the prognostic value of CT-FFR combined with CDI for MACEs is worth exploring. METHODS: Patients with a moderate or severe single left anterior descending coronary artery stenosis were included and underwent FFR and CDI analysis based on cCTA, followed up at least 1 year, and recorded MACEs. Multivariate logistic regression analysis was performed to determine independent predictors of MACEs. The area under of receiver operating characteristic (ROC) curve was used to evaluated evaluate the diagnostic performance of CT-FFR, CDI, and a combination of the two. RESULTS: All the vessel-specific data were from LAD. 150 patients were analysed. 55 (37%) patients experienced MACEs during follow-up. Patients with CT-FFR ≤ 0.8 had higher percentage of MACEs compared with CT-FFR > 0.8 (56.3% vs.7.3%, p < 0.05). Patients' CDI was significantly decreased in MACEs group compared with non-MACEs group (p < 0.05). Multivariate analysis revealed that diabetes (p = 0.025), triglyceride (p = 0.015), CT-FFR ≤ 0.80 (p = 0.038), and CDI (p < 0.001) are independent predictors of MACEs. According to ROC curve analysis, CT-FFR combined CDI showed incremental diagnostic performance over CT-FFR alone for prediction of MACEs (AUC = 0.831 vs. 0.656, p = 0.0002). CONCLUSION: Our study provides initial evidence that combining CDI with CT-FFR shows incremental discriminatory power for MACEs over CT-FFR alone, independent of clinical risk factors. Diabetes and triglyceride are also associated with MACEs.

Novel Homozygous PADI6 Variants in Infertile Females with Early Embryonic Arrest.

Early embryonic arrest denotes premature termination of development in preimplantation embryos, which is one of the major phenotypes of recurrent assisted reproduction failure. Padi6 is proven to be a member of the subcortical maternal complex (SCMC) in mice, which is essential in oocyte maturation and embryogenesis. We and other groups previously found that biallelic mutations in PADI6 caused female infertility manifesting as early embryonic arrest. In this study, we identified two novel homozygous variants (p.Cys163Arg, and p. Trp475*) of PADI6 in two infertile patients from a cohort of 75 females with the phenotype of early embryonic arrest. An in vitro expression study indicated severe decrease of PADI6, which might destruct the stability of SCMC. Our study expands the mutational spectrum of PADI6 and further supports the causality between PADI6 mutations and female infertility.

MUC1 triggers lineage plasticity of Her2 positive mammary tumors.

Aberrant overexpression of mucin 1 (MUC1) and human epidermal growth factor receptor 2 (HER2) are often observed in breast cancer. However, the role of concomitant MUC1/HER2 in the development of breast cancer has not been fully illustrated. Following analysis of public microarray datasets that revealed a correlation between double MUC1 and HER2 positivity and a worse clinical outcome, we generated a mouse model overexpressing both Her2 and MUC1 cytoplasmic domain (MUC1-CD) to investigate their interaction in mammary carcinogenesis. Coexpression of Her2 and MUC1-CD conferred a growth advantage and promoted the development of spontaneous mammary tumors. Genomic analysis revealed that enforced expression of MUC1-CD and Her2 induces mammary tumor lineage plasticity, which is supported by gene reprogramming and mammary stem cell enrichment. Through gain- and loss-of-function strategies, we show that coexpression of Her2 and MUC1-CD is associated with downregulation of tricarboxylic acid (TCA) cycle genes in tumors. Importantly, the reduction in TCA cycle genes induced by MUC1-CD was found to be significantly connected to poor prognosis in HER2+ breast cancer patients. In addition, MUC1 augments the Her2 signaling pathway by inducing Her2/Egfr dimerization. These findings collectively demonstrate the vital role of MUC1-CD/Her2 collaboration in shaping the mammary tumor landscape and highlight the prognostic and therapeutic implications of MUC1 in patients with HER2+ breast cancer.