gutMGene v2.0: an updated comprehensive database for target genes of gut microbes and microbial metabolites.

The gut microbiota is essential for various physiological functions in the host, primarily through the metabolites it produces. To support researchers in uncovering how gut microbiota contributes to host homeostasis, we launched the gutMGene database in 2022. In this updated version, we conducted an extensive review of previous papers and incorporated new papers to extract associations among gut microbes, their metabolites, and host genes, carefully classifying these as causal or correlational. Additionally, we performed metabolic reconstructions for representative gut microbial genomes from both human and mouse. gutMGene v2.0 features an upgraded web interface, providing users with improved accessibility and functionality. This upgraded version is freely available at http://bio-computing.hrbmu.edu.cn/gutmgene. We believe that this new version will greatly advance research in the gut microbiota field by offering a comprehensive resource.

Synthetically non-Hermitian nonlinear wave-like behavior in a topological mechanical metamaterial.

Topological mechanical metamaterials have enabled new ways to control stress and deformation propagation. Exemplified by Maxwell lattices, they have been studied extensively using a linearized formalism. Herein, we study a two-dimensional topological Maxwell lattice by exploring its large deformation quasi-static response using geometric numerical simulations and experiments. We observe spatial nonlinear wave-like phenomena such as harmonic generation, localized domain switching, amplification-enhanced frequency conversion, and solitary waves. We further map our linearized, homogenized system to a non-Hermitian, nonreciprocal, one-dimensional wave equation, revealing an equivalence between the deformation fields of two-dimensional topological Maxwell lattices and nonlinear dynamical phenomena in one-dimensional active systems. Our study opens a regime for topological mechanical metamaterials and expands their application potential in areas including adaptive and smart materials and mechanical logic, wherein concepts from nonlinear dynamics may be used to create intricate, tailored spatial deformation and stress fields greatly transcending conventional elasticity.

gutMDisorder v2.0: a comprehensive database for dysbiosis of gut microbiota in phenotypes and interventions.

Gut microbiota plays a significant role in maintaining host health, and conversely, disorders potentially lead to dysbiosis, an imbalance in the composition of the gut microbial community. Intervention approaches, such as medications, diets, and several others, also alter the gut microbiota in either a beneficial or harmful direction. In 2020, the gutMDisorder was developed to facilitate researchers in the investigation of dysbiosis of gut microbes as occurs in various disorders as well as with therapeutic interventions. The database has been updated this year, following revision of previous publications and newly published reports to manually integrate confirmed associations under multitudinous conditions. Additionally, the microbial contents of downloaded gut microbial raw sequencing data were annotated, the metadata of the corresponding hosts were manually curated, and the interactive charts were developed to enhance visualization. The improvements have assembled into gutMDisorder v2.0, a more advanced search engine and an upgraded web interface, which can be freely accessed via http://bio-annotation.cn/gutMDisorder/.

CircHAT1 regulates the proliferation and phenotype switch of vascular smooth muscle cells in lower extremity arteriosclerosis obliterans through targeting SFRS1.

This study aimed to decipher the mechanism of circular ribonucleic acids (circRNAs) in lower extremity arteriosclerosis obliterans (LEASO). First, bioinformatics analysis was performed for screening significantly down-regulated cardiac specific circRNA-circHAT1 in LEASO. The expression of circHAT1 in LEASO clinical samples was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of splicing factor arginine/serine-rich 1 (SFRS1), α-smooth muscle actin (α-SMA), Calponin (CNN1), cyclin D1 (CNND1) and smooth muscle myosin heavy chain 11 (SMHC) in vascular smooth muscle cells (VSMCs) was detected by Western blotting. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) and Transwell assays were used to evaluate cell proliferation and migration, respectively. RNA immunoprecipitation (RNA-IP) and RNA pulldown verified the interaction between SFRS1 and circHAT1. By reanalyzing the dataset GSE77278, circHAT1 related to VSMC phenotype conversion was screened, and circHAT1 was found to be significantly reduced in peripheral blood mononuclear cells (PBMCs) of LEASO patients compared with healthy controls. Knockdown of circHAT1 significantly promoted the proliferation and migration of VSMC cells and decreased the expression levels of contractile markers. However, overexpression of circHAT1 induced the opposite cell phenotype and promoted the transformation of VSMCs from synthetic to contractile. Besides, overexpression of circHAT1 inhibited platelet-derived growth factor-BB (PDGF-BB)-induced phenotype switch of VSMC cells. Mechanistically, SFRS1 is a direct target of circHAT1 to mediate phenotype switch, proliferation and migration of VSMCs. Overall, circHAT1 regulates SFRS1 to inhibit the cell proliferation, migration and phenotype switch of VSMCs, suggesting that it may be a potential therapeutic target for LEASO.

The benefit of omeprazole exposure on all-cause mortality and length of ICU/hospital stay might vary with age in critically ill pediatric patients: A cohort study.

PURPOSE: To investigate the association between proton pump inhibitors (PPIs) administration during hospitalization and mortality and length of stay in critically ill pediatric patients. MATERIALS AND METHODS: This is a retrospective observational cohort study on pediatric ICU patients (0 to 18 years). Propensity score matching (PSM), Kaplan-Meier curves, Cox proportional hazards model and Linear regression model was applied for assessing the effects of PPIs on mortality and other outcomes during hospitalization. RESULTS: A total of 2269 pediatric ICU patients were included, involving 1378 omeprazole (OME) users and 891 non-OME users. The results showed significant association between OME exposure and decreased ICU stay (ß -0.042; 95% CI -0.073--0.011; P = 0.008) but prolonged non-ICU hospital stay (ß 0.121; 95% CI 0.097-0.155; P = 0.040). No statistical significance was observed between OME exposure and reduced mortality, but the OME group had a slightly decreased tendency in 28-day mortality (HR 0.701; 95% CI 0.418-1.176) and in-hospital mortality (HR 0.726; 95% CI 0.419-1.257). Furthermore, subgroup analyses revealed that the decreased tendency of mortality were more obvious in patients less than 1 year old compared with older pediatric patients, although not statistically significant. In addition, we also observed that OME exposure was significantly associated with reduced mortality of general ICU subgroup. CONCLUSIONS: This study provided a sign that PPIs used only in the ICU, rather than throughout hospital stay, might provide more benefit for critically ill pediatric patients. Additionally, younger pediatric patients might gain relatively more benefit than older children when receiving PPIs.

Association of ambient temperature on acute ischemic stroke in Yancheng, China.

BACKGROUND: Acute ischemic stroke (AIS) is a major global public health issue. There is limited research on the relationship between ambient temperature and AIS hospital admissions, and the results are controversial. Our objective is to assess the short-term impact of ambient temperature on the risk of AIS hospital admissions in Yancheng, China. METHODS: We collected data on daily AIS hospital admissions, meteorological factors, and air quality in Yancheng from 2014 to 2019. We used Poisson regression to fit generalized linear models and distributed lag non-linear models to explore the association between ambient temperature and AIS hospital admissions. The effects of these associations were evaluated by stratified analysis by sex and age. RESULTS: From 2014 to 2019, we identified a total of 13,391 AIS hospital admissions. We observed that the influence of extreme cold and heat on admissions for AIS manifests immediately on the day of exposure and continues for a duration of 3-5 days. Compared to the optimal temperature (24.4 °C), the cumulative relative risk under extreme cold temperature (-1.3 °C) conditions with a lag of 0-5 days was 1.88 (95%CI: 1.28, 2.78), and under extreme heat temperature (30.5 °C) conditions with a lag of 0-5 days was 1.48 (95%CI: 1.26, 1.73). CONCLUSIONS: There is a non-linear association between ambient temperature and AIS hospital admission risk in Yancheng, China. Women and older patients are more vulnerable to non-optimal temperatures. Our findings may reveal the potential impact of climate change on the risk of AIS hospital admissions.

Development and Validation of a Prognostic Model to Predict Late Seizures After Traumatic Brain Injury: A Retrospective Analysis.

Posttraumatic epilepsy (PTE) is considered to be one of the most severe and enduring outcomes that can arise from traumatic brain injury (TBI). The authors' study aims to create and authenticate a prognostic model for forecasting the PTE occurrence after TBI. The clinical prognostic model was developed in 475 people who had a TBI history in Nanning using a multivariate logistic regression model. The score in the authors' prognostic model participants was subjected to external validation from other cities in Guangxi and assessed its performance with the area under the receiver operating characteristic curve (area under the curve), calibration plots, and decision curve analysis. Six variables were selected to establish the nomogram for PTE, including time, Glasgow Coma Scale, location, cranial imaging (midline shift), intracranial infection, and titanium mesh cranioplasty. The area under the curve was found to be 0.860 in the training cohort and 0.735 in the validation cohort, revealing that the nomogram exhibited a satisfactory level of discriminative ability. The calibration plots exhibited a substantial degree of concordance between the prognostic predictions generated by the nomogram and the observed outcomes in both the training and validation groups. In addition, the decision curve analysis demonstrated the clinical utility of the nomogram. The cutoff value for the training cohort was determined to be 0.381, whereas for the validation cohort, it was 0.380. This suggests that patients with a probability >0.381 should be given special consideration. A prognostic nomogram was formulated and verified to aid health care clinicians in assessing the prognosis of patients with PTE.

Intrinsically Honeycomb-Patterned Hydrogenated Graphene.

Since the advent of graphene ushered the era of 2D materials, many forms of hydrogenated graphene have been reported, exhibiting diverse properties ranging from a tunable bandgap to ferromagnetic ordering. Patterned hydrogenated graphene with micron-scale patterns has been fabricated by lithographic means. Here, successful millimeter-scale synthesis of an intrinsically honeycomb-patterned form of hydrogenated graphene on Ru(0001) by epitaxial growth followed by hydrogenation is reported. Combining scanning tunneling microscopy observations with density-functional-theory (DFT) calculations, it is revealed that an atomic-hydrogen layer intercalates between graphene and Ru(0001). The result is a hydrogen honeycomb structure that serves as a template for the final hydrogenation, which converts the graphene into graphane only over the template, yielding honeycomb-patterned hydrogenated graphene (HPHG). In effect, HPHG is a form of patterned graphane. DFT calculations find that the unhydrogenated graphene regions embedded in the patterned graphane exhibit spin-polarized edge states. This type of growth mechanism provides a new pathway for the fabrication of intrinsically patterned graphene-based materials.

Mode-locking fiber laser with dual wavelength continuous-waves-induced resonant spectral sidebands.

The optical spectrum of mode-locked lasers can exhibit multiple peaks resulting from different mechanisms such as modulation instability, dispersive waves (DWs), and coupling between continuous waves (CWs) and DWs. The latter was recently reported in a mode-locked fiber laser. Here we show that besides the coupling between single-wavelength CW and DWs, dual-wavelength CWs can also couple with DWs giving rise to quite different spectral peaks in a mode-locked fiber laser. In particular, we find that the sidebands of one CW can couple with the other CW, leading to an enhancement of the CWs.

Safety and efficacy of small-bowel capsule endoscopy examination in patients with Billroth II gastrojejunostomy.

BACKGROUND: Small-bowel capsule endoscopy (SBCE) has become an increasingly utilized imaging modality for patients suspected of having small intestinal diseases. However, data regarding the role of SBCE in patients with Billroth II gastrojejunostomy are limited. The objective is to evaluate the safety and efficacy of SBCE in Billroth II gastrojejunostomy patients. METHODS: We retrospectively studied patients with Billroth II gastrojejunostomy who underwent MiroCam capsule endoscopy between August 2013 and October 2019. Baseline patient characteristics; gastroscopic and SBCE findings; capsule transit time; and the occurrence of adverse events were collected and compared between groups with and without anastomotic lesions. RESULTS: In total, 30 patients were analyzed in the study. The median age was 59 years, and 26 patients (86.7%) were men. The majority of SBCE positive findings including ulcers (10.0%), angioectasias (6.7%) and polyps (6.7%). In patients with (n = 10) and without (n = 20) anastomotic lesions, the anastomotic lesion was significantly associated with a delayed gastric transit time (GTT) (P = 0.026), but the two groups showed no significant difference in completion (P > 0.05). All patients underwent successful SBCE examinations without adverse events, except device transit into the afferent loop, where it remained for nearly 2 h, occurred in one case with anastomotic ulcers. CONCLUSIONS: This retrospective study demonstrates that SBCE is a safe and effective diagnostic tool in patients with Billroth II gastrojejunostomy with a favorable gastroscopic evaluation within 7 days prior. The frequently real-time monitoring is suggested due to the risk of retention in the afferent loop, and a delayed food intake is required when a prolonged stay in the afferent loop occurred.

PRAPNet: A Parallel Residual Atrous Pyramid Network for Polyp Segmentation.

In a colonoscopy, accurate computer-aided polyp detection and segmentation can help endoscopists to remove abnormal tissue. This reduces the chance of polyps developing into cancer, which is of great importance. In this paper, we propose a neural network (parallel residual atrous pyramid network or PRAPNet) based on a parallel residual atrous pyramid module for the segmentation of intestinal polyp detection. We made full use of the global contextual information of the different regions by the proposed parallel residual atrous pyramid module. The experimental results showed that our proposed global prior module could effectively achieve better segmentation results in the intestinal polyp segmentation task compared with the previously published results. The mean intersection over union and dice coefficient of the model in the Kvasir-SEG dataset were 90.4% and 94.2%, respectively. The experimental results outperformed the scores achieved by the seven classical segmentation network models (U-Net, U-Net++, ResUNet++, praNet, CaraNet, SFFormer-L, TransFuse-L).

EIEN: Endoscopic Image Enhancement Network Based on Retinex Theory.

In recent years, deep convolutional neural network (CNN)-based image enhancement has shown outstanding performance. However, due to the problems of uneven illumination and low contrast existing in endoscopic images, the implementation of medical endoscopic image enhancement using CNN is still an exploratory and challenging task. An endoscopic image enhancement network (EIEN) based on the Retinex theory is proposed in this paper to solve these problems. The structure consists of three parts: decomposition network, illumination correction network, and reflection component enhancement algorithm. First, the decomposition network model of pre-trained Retinex-Net is retrained on the endoscopic image dataset, and then the images are decomposed into illumination and reflection components by this decomposition network. Second, the illumination components are corrected by the proposed self-attention guided multi-scale pyramid structure. The pyramid structure is used to capture the multi-scale information of the image. The self-attention mechanism is based on the imaging nature of the endoscopic image, and the inverse image of the illumination component is fused with the features of the green and blue channels of the image to be enhanced to generate a weight map that reassigns weights to the spatial dimension of the feature map, to avoid the loss of details in the process of multi-scale feature fusion and image reconstruction by the network. The reflection component enhancement is achieved by sub-channel stretching and weighted fusion, which is used to enhance the vascular information and image contrast. Finally, the enhanced illumination and reflection components are multiplied to obtain the reconstructed image. We compare the results of the proposed method with six other methods on a test set. The experimental results show that EIEN enhances the brightness and contrast of endoscopic images and highlights vascular and tissue information. At the same time, the method in this paper obtained the best results in terms of visual perception and objective evaluation.

A novel tumor suppressor ZBTB1 regulates tamoxifen resistance and aerobic glycolysis through suppressing HER2 expression in breast cancer.

Transcriptional repressor zinc finger and BTB domain containing 1 (ZBTB1) is required for DNA repair. Because DNA repair defects often underlie genome instability and tumorigenesis, we determined to study the role of ZBTB1 in cancer. In this study, we found that ZBTB1 is down-regulated in breast cancer and this down-regulation is associated with poor outcome of breast cancer patients. ZBTB1 suppresses breast cancer cell proliferation and tumor growth. The majority of breast cancers are estrogen receptor (ER) positive and selective estrogen receptor modulators such as tamoxifen have been widely used in the treatment of these patients. Unfortunately, many patients develop resistance to endocrine therapy. Tamoxifen-resistant cancer cells often exhibit higher HER2 expression and an increase of glycolysis. Our data revealed that ZBTB1 plays a critical role in tamoxifen resistance in vitro and in vivo To see if ZBTB1 regulates HER2 expression, we tested the recruitments of ZBTB1 on HER2 regulatory sequences. We observed that over-expressed ZBTB1 occupies the estrogen receptor α (ERα)-binding site of the HER2 intron in tamoxifen-resistant cells, suppressing tamoxifen-induced transcription. In an effort to identify potential microRNAs (miRNAs) regulating ZBTB1, we found that miR-23b-3p directly targets ZBTB1. MiR-23b-3p regulates HER2 expression and tamoxifen resistance via targeting ZBTB1. Finally, we found that miR-23b-3p/ZBTB1 regulates aerobic glycolysis in tamoxifen-resistant cells. Together, our data demonstrate that ZBTB1 is a tumor suppressor in breast cancer cells and that targeting the miR-23b-3p/ZBTB1 may serve as a potential therapeutic approach for the treatment of tamoxifen resistant breast cancer.

Choosing Optimal Microcarcinoma Patients for Active Surveillance Study (Compass): Effectiveness Evaluation of a Preoperative Clinical Framework.

OBJECTIVE: Active surveillance (AS) is a management alternative for patients with low-risk papillary thyroid microcarcinoma (PTMC). To decide the best candidates for AS, clinicians can use a framework to classify PTMC patients as ideal, appropriate, or inappropriate. This study aimed to explore the correlation between the framework categories and surgical pathology. METHODS: This multicenter retrospective study was conducted between 2014 and 2016. We included 1997 patients who underwent thyroid surgery for the first time due to suspected PTMC and were confirmed as PTMC by postoperative pathology. The consistency of modified preoperative risk stratification and the pathologic condition were evaluated using a consistency ratio and the Kappa coefficient. Stratified analysis was also performed to test consistency in different age groups. RESULTS: Based on the decision-making framework, 558 (27.9%) patients could receive AS while 810 (40.6%) patients did not require immediate surgery according to the actual postoperative pathology. The sensitivity, false-positive rate, specificity, false-negative rate, and consistency rate were 82.39%, 56.91%, 43.09%, 17.61%, and 66.45%, respectively. The Kappa value was 0.268. Stratified analysis showed that the sensitivity was 87.7% among patients aged 18 to 59 years. In the group aged ≥60 years, the specificity was up to 87.5%, but the sensitivity was low. CONCLUSION: The results of the modified risk-stratified clinical decision-making framework did not have a high consistency with the postoperative results. However, the framework showed a good effect in selecting patients for immediate surgery in the younger group and patients for AS in the older group.

Sizable Band Gap in Epitaxial Bilayer Graphene Induced by Silicene Intercalation.

Opening a band gap in bilayer graphene (BLG) is of significance for potential applications in graphene-based electronic and photonic devices. Here, we report the generation of a sizable band gap in BLG by intercalating silicene between BLG and Ru substrate. We first grow high-quality Bernal-stacked BLG on Ru(0001) and then intercalate silicene to the interface between the BLG and Ru, which is confirmed by low-energy electron diffraction and scanning tunneling microscopy. Raman spectroscopy shows that the G and 2D peaks of the intercalated BLG are restored to the freestanding-BLG features. Angle-resolved photoelectron spectroscopy measurements show that a band gap of about 0.2 eV opens in the BLG. Density functional theory calculations indicate that the large-gap opening results from a cooperative contribution of the doping and rippling/strain in the BLG. This work provides insightful understanding on the mechanism of band gap opening in BLG and enhances the potential of graphene-based device development.

Intelligent Intraoperative Haptic-AR Navigation for COVID-19 Lung Biopsy Using Deep Hybrid Model.

A novel intelligent navigation technique for accurate image-guided COVID-19 lung biopsy is addressed, which systematically combines augmented reality (AR), customized haptic-enabled surgical tools, and deep neural network to achieve customized surgical navigation. Clinic data from 341 COVID-19 positive patients, with 1598 negative control group, have collected for the model synergy and evaluation. Biomechanics force data from the experiment are applied a WPD-CNN-LSTM (WCL) to learn a new patient-specific COVID-19 surgical model, and the ResNet was employed for the intraoperative force classification. To boost the user immersion and promote the user experience, intro-operational guiding images have combined with the haptic-AR navigational view. Furthermore, a 3-D user interface (3DUI), including all requisite surgical details, was developed with a real-time response guaranteed. Twenty-four thoracic surgeons were invited to the objective and subjective experiments for performance evaluation. The root-mean-square error results of our proposed WCL model is 0.0128, and the classification accuracy is 97%, which demonstrated that the innovative AR with deep learning (DL) intelligent model outperforms the existing perception navigation techniques with significantly higher performance. This article shows a novel framework in the interventional surgical integration for COVID-19 and opens the new research about the integration of AR, haptic rendering, and deep learning for surgical navigation.

Observation of Flat Frequency Bands at Open Edges and Antiphase Boundary Seams in Topological Mechanical Metamaterials.

Motivated by the recent theoretical studies on a two-dimensional (2D) chiral Hamiltonian based on the Su-Schrieffer-Heeger chains [L. Zhu, E. Prodan, and K. H. Ahn, Phys. Rev. B 99, 041117(R) (2019)PRBMDO2469-995010.1103/PhysRevB.99.041117], we experimentally and computationally demonstrate that topological flat frequency bands can occur at open edges of 2D planar metamaterials and at antiphase boundary seams of ring-shaped or tubular metamaterials. Specifically, using mechanical systems made of magnetically coupled spinners, we reveal that the presence of the edge or seam bands that are flat in the entire projected reciprocal space follows the predictions based on topological winding numbers. The edge-to-edge distance sensitively controls the flatness of the edge bands and the localization of excitations, consistent with the theoretical analysis. The analog of the fractional charge state is observed. Possible realizations of flat bands in a large class of metamaterials, including photonic crystals and electronic metamaterials, are discussed.

High Ratio of Early Postoperative Calcitonin to Preoperative Calcitonin Could be a Novel Indicator of Poor Prognosis in Patients with Biochemical Incomplete Responses in Sporadic Medullary Thyroid Cancer.

OBJECTIVE: In a cohort of medullary thyroid cancer (MTC) patients with biochemical incomplete responses, 37 to 48% developed structural persistent disease; however, few indictors were available to distinguish those patients who were more likely to develop structural disease. We hypothesized that the relationship between preoperative calcitonin (Ctn) and postoperative Ctn (within 3 days after surgery) could be used to predict early prognosis of these patients. METHODS: A total of 92 sporadic MTC patients were enrolled in this study. Our team proposed a novel indicator of structural persistent MTC called the calcitonin ratio (CR; CR = postoperative Ctn/preoperative Ctn). Cox regression models and the Kaplan-Meier method were used to evaluate the prognostic capability of CR. The area under the time-dependent receiver-operating characteristic curves (AUC) and the Harrell concordance index (C-index) were used for analysis. RESULTS: The cutoff CR value used to determine MTC prognosis was 0.15. Multivariate Cox analysis revealed that CR (hazard ratio [HR]: 22.974, 95% confidence interval [CI]: 3.259 to 161.959, P = .002), tumor-node-metastasis (HR: 3.968, 95% CI: 1.360 to 21.857; P = .031), and multifocality (HR: 8.466, 95% CI: 1.286 to 55.716; P = .026) independently correlated with MTC prognosis. Kaplan-Meier survival curves demonstrated a lower proportion with structural persistent disease in patients with CR <0.15 (P<.001). The 3, 5, and 10-year AUC values were 0.798, 0.752, and 0.743, respectively. The C-index of CR was 0.788 (95% CI: 0.763 to 0.813). CONCLUSION: In this study, CR was identified as a sensitive and specific risk stratification marker for patients with biochemical incomplete responses in sporadic MTC. ABBREVIATIONS: ATA = American Thyroid Association; AUC = area under curve; CEA = carcinoembryonic antigen; CR = calcitonin ratio; Ctn = calcitonin; HR = hazard ratio; MTC = medullary thyroid cancer; ROC = receiver operating characteristic; TNM = tumor-node-metastasis.

Defects of CTLA-4 Are Associated with Regulatory T Cells in Myasthenia Gravis Implicated by Intravenous Immunoglobulin Therapy.

Myasthenia gravis (MG) is a CD4+ T cell-dependent autoimmune disease resulting from aberrant immune response mediated by circulating autoantibodies at the neuromuscular junction. Intravenous immunoglobulin (IVIg) is an expensive and commonly used immunotherapeutic approach to treat patients with MG. The mechanisms of actions involved in IVIg treatment, however, remain to be investigated. In an effort to examine the roles of various subsets of CD4+ T cells in the periphery blood of MG and uncover the mechanisms that contribute to the therapeutical effects of IVIg, we first demonstrated that a subset of CD4+ T cells, CTLA-4-expressing regulatory T (Treg) cells, were underrepresented and functionally defective in MG patients. The dynamic profiling during the IVIg therapy course further revealed an inverse relationship between the frequency of CTLA-4+ Treg and the quantitative MG (QMG) score that represents disease severity. Our mechanistic studies indicated that IVIg expands CTLA-4-Treg cells via modulating antigen-presenting dendritic cells (DCs). To determine the molecular defects of CTLA-4 in abnormities of Treg in MG patients, we demonstrated hypermethylation at -658 and -793 CpGs of CTLA-4 promoter in MG Tregs. Interestingly, IVIg therapy significantly reduced the methylation level at these two sites in MG patients. Overall, our study may suggest a role of CTLA-4 in functionally defected Treg cells in MG and its actions involved in IVIg therapy.

LHPP inhibits cell growth and migration and triggers autophagy in papillary thyroid cancer by regulating the AKT/AMPK/mTOR signaling pathway.

In recent decades, the incidence rate of papillary thyroid carcinoma (PTC) has been rapidly increasing. However, the molecular mechanism of the physiological and pathological processes of PTC is still largely unknown. Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a tumor suppressor and exerts anti-tumor effect in several human cancers, while the role and underlying mechanism of LHPP in PTC remain vague. In this study, we firstly evaluated the roles of LHPP in PTC and explored its underlying mechanism. Using clinical tissue samples, we detected the level of LHPP in PTC tissues and in matched adjacent normal tissues. Lower level of LHPP was found in PTC tissues than in matched adjacent normal tissues. Similar LHPP expression pattern was found in PTC cell lines when compared with that in normal human thyroid follicular epithelial cells. Then, we over-expressed LHPP in three PTC cell lines and results showed that ectopic LHPP expression consistently reduced cell viability, proliferation, and migration and triggered cell autophagy. Furthermore, over-expression of LHPP inhibited the activation of the AKT/mTOR pathway and promoted the AMPK signaling pathway. In addition, the activation of AKT/mTOR and inhibition of AMPK signaling pathways restored the role of ectopic LHPP expression in PTC cell lines, indicating that LHPP exerts its anti-tumor activity through regulating the AKT/AMPK/mTOR pathway. Ultimately, we illustrated that ectopic LHPP expression inhibited PTC tumor growth in vivo. In conclusion, we revealed that LHPP has an anti-tumor effect in PTC and indicated that LHPP might serve as an effective diagnostic and therapeutic target for PTC.