Endometriosis (EMS) is a benign gynecological disease characterized by the growth of endometrial tissue outside the uterine cavity. Evidence shows that the survival of patients with ectopic endometrial implants is associated with a dysregulated immune microenvironment. CD4 + T cells can regulate EMS through diverse cytokines, the inflammatory response, and angiogenesis. CCR5 +CD4 + T cells exhibit increased cellular immunogenicity and play a role in infectious diseases, host defense, and cancer progression. However, the specific mechanisms of CCR5 +CD4 + T cells in EMS remain unknown. In the present study, flow cytometry and RNA-seq are utilized to assess the proportions and features of CCR5 +CD4 + T cells in EMS patients, RT-PCR and ELISA are used to assess the production of CCL5 by ectopic endometrial stromal cells (ecESCs). Two EMS models are established through C57B6 wild-type and CCL5 ‒/‒ mice and utilized to explore the in vivo effects of CCR5 +CD4 + T cells on ectopic lesions. Compared with CCR5 ‒CD4 + T cells, CCR5 +CD4 + T cells display a more activated and cytotoxic phenotype. Diminished CCR5 +CD4 + T cells and their impaired ability to produce IFN-γ are observed in the ectopic lesions of EMS patients and in murine EMS models. Impaired production of CCL5 has been detected in human ecESCs. Moreover, endometria stripped from CCL5 ‒/‒ mice are more likely to generate ectopic lesions in the peritoneum of recipient mice. These findings demonstrate that the attenuated recruitment of CCR5 +CD4 + T cells in ectopic lesions caused by decreased production of CCL5 in ecESCs may facilitate the progression of EMS.

Endometriosis is a common gynecological disease that causes severe pain and infertility. However, the available treatments for EMS are limited. SCM-198, a synthetic form of leonurine, possesses various abilities, including anti-inflammatory, immunomodulatory, antioxidant, anti-fibrotic, and anti-proliferative effects. Previous studies have shown that SCM-198 can inhibit the growth of ectopic lesions, but the specific mechanism remains unknown. The results of our studies indicate that SCM-198 significantly suppresses the endometriotic growth of EMS mice. Enrichment analysis of RNA-seq indicates that SCM-198 is involved in T cell differentiation, activation, cytokine production, stimulation of chemotaxis, and migration. Flow cytometry reveals that SCM-198 reverses the decreased proportions of IFN-γ + T cells and CCR5 + T cells in ectopic lesions. RNA-seq analysis shows that SCM-198 enhances the expression of CCL5 in the ectopic lesions, and western blot is conducted to verify this conclusion both in vivo and in vitro. These findings demonstrate that SCM-198 reverses the decreased proportions of IFN-γ + T cells and CCR5 + T cells, alleviating the growth of mouse ectopic lesions, and the changes in CCR5 + T cells are likely due to the reduced expression of CCL5.

The ETO-family transcriptional corepressors, including ETO, ETO2, and MTGR1, are all involved in leukemia-causing chromosomal translocations. In every case, an ETO-family corepressor acquires a DNA-binding domain (DBD) to form a typical transcription factor—the DBD binds to DNA, while the ETO moiety manifests transcriptional activity. A directly comparative study of these “homologous” fusion transcription factors may clarify their similarities and differences in regulating transcription and leukemogenesis. Here, we performed a side-by-side comparison between AML1-ETO and ETO2-GLIS2, the most common fusion proteins in M2-and M7-subtypes of acute myeloid leukemia, respectively, by inducible expression of them in U937 leukemia cells. We found that, although AML1-ETO and ETO2-GLIS2 can use their own DBDs to bind DNA, they share a large proportion of genome-wide binding regions dependent on other cooperative transcription factors, including the ETS-, bZIP- and bHLH-family proteins. AML1-ETO acts as either transcriptional repressor or activator, whereas ETO2-GLIS2 mainly acts as activator. The repressor-versus-activator functions of AML1-ETO might be determined by the abundance of cooperative transcription factors/cofactors on the target genes. Importantly, AML1-ETO and ETO2-GLIS2 differentially regulate key transcription factors in myeloid differentiation including PU.1 and C/EBPβ. Consequently, AML1-ETO inhibits, but ETO2-GLIS2 facilitates, myeloid differentiation of U937 cells. This function of ETO2-GLIS2 is reminiscent of a similar effect of MLL-AF9 as previously reported. Taken together, this directly comparative study between AML1-ETO and ETO2-GLIS2 in the same cellular context provides insights into context-dependent transcription regulatory mechanisms that may underlie how these seemingly “homologous” fusion transcription factors exert distinct functions to drive different subtypes of leukemia.

Insurmountable blood‒brain barrier (BBB) and complex pathological features are the key factors affecting the treatment of Alzheimer's disease (AD). Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing Aβ deposition or TAU protein need to be resolved urgently. Herein, a nanocleaner is designed with a rapamycin-loaded ROS-responsive PLGA core and surface modification with KLVFF peptide and acid-cleavable DAG peptide [R@(ox-PLGA)-KcD]. DAG can enhance the targeting and internalization effect of nanocleaner towards neurovascular unit endothelial cells in AD lesions, and subsequently detach from nanocleaner in response to acidic microenvironment of endosomes to promote the transcytosis of nanocleaner from endothelial cells into brain parenchyma. Then exposed KLVFF can capture and carry Aβ to microglia, attenuating Aβ-induced neurotoxicity. Strikingly, rapamycin, an autophagy promoter, is rapidly liberated from nanocleaner in the high ROS level of lesions to improve Aβ degradation and normalize inflammatory condition. This design altogether accelerates Aβ degradation and alleviates oxidative stress and excessive inflammatory response. Collectively, our finding offers a strategy to target the AD lesions precisely and multi-pronged therapies for clearing the toxic proteins and modulating lesion microenvironment, to achieve efficient AD therapy.

The optoelectrode arrays can modulate the neuron precisely with high time resolution and good reversibility compared to electrical stimulation. However, the integrated light-emitting diode (LED) or laser diode (LD) will introduce noise from the surroundings and affects the signal quality recording by the electrodes. Here, we present a polyimide (PI)-based flexible optoelectrode for low-noise neural recording. Compared with traditional electrode, this low-noise optoelectrode has a metal shield between the recording part and LED part which can isolate the electromagnetic noise from the active devices and Poly (3, 4-ethylenedioxythiophene) - poly (styrenesulfonate) (PEDOT: PSS) is electroplated to further increase the quality of the signal. It has been proved that the transient impulse aroused by turning ON/OFF the LED is eliminated in vitro bench test. In vivo, the electrode with metal shield has less high-frequency noise and 50 Hz power noise is suppressed compared with the electrode without shield.

A huge class of nonlinear dynamic systems can be approximated by the Nonlinear AutoRegressive with eXogenous inputs (NARX) models. This paper proposes a novel method, Sparse Augmented Lagrangian (SAL), for NARX model variable selection and parameter estimation. Firstly, Split Augmented Lagrangian Shrinkage Algorithm (SALSA) is applied to produce some intermediate models with subsampling technique, and then only the model terms with high selecting probability are chosen into the final model, followed by the model parameter estimation via SALSA. The model sparsity and algorithm convergence can be guaranteed through theoretical analysis. Two nonlinear examples and one real-world application from the process industry are used to demonstrate the effectiveness and advantages of the proposed method in comparison to several popular methods.

The leukemogenic AML1-ETO fusion protein is produced by the t(8;21) translocation, which is one of the most common chromosomal abnormalities in acute myeloid leukemia (AML). In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AETFC, that contains multiple transcription factors and cofactors. Among these AETFC components, E2A (also known as TCF3) and HEB (also known as TCF12), two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA (E-box) binding capacity to AETFC, and are functionally essential for leukemogenesis. However, we find that the third E protein, E2-2 (also known as TCF4), is specifically silenced in AML1-ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the basic helix-loop-helix (bHLH) DNA-binding domain of E2-2. Gene expression profiling and ChIP-seq analysis reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, consistent with the fact that E2-2 is a critical transcription factor in dendritic cell (DC) development, our studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with DC differentiation, and that restoration of E2-2 triggers a partial differentiation of the AML1-ETO-expressing leukemic cells into the DC lineage. Meanwhile, E2-2, but not E2A or HEB, represses MYC target genes, which may also contribute to leukemic cell differentiation and apoptosis. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene, THPO, is identified as a potential predictor of relapse. In a mouse model of human t(8;21) leukemia, E2-2 suppression accelerates the development of leukemia. Taken together, these results reveal that, in contrast to HEB and E2A, which facilitate AML1-ETO-mediated leukemogenesis, E2-2 compromises the function of AETFC and negatively regulates leukemogenesis. The three E proteins thus define a molecular heterogeneity of AETFC, which merits further study in different t(8;21) AML patients, as well as in its potential regulation of cellular heterogeneity of AML. These studies should improve our understanding of the precise mechanism of leukemogenesis and assist development of diagnostic and therapeutic strategies.

The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases. In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AML1-ETO-containing transcription factor complex (AETFC), that contains multiple transcription (co)factors. Among these AETFC components, HEB and E2A, two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA-binding capacity to AETFC, and are essential for leukemogenesis. However, the third E protein, E2-2, is specifically silenced in AML1-ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the bHLH DNA-binding domain. RNA-seq and ChIP-seq analyses reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with dendritic cell differentiation and represses MYC target genes. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene, THPO, is identified as a potential predictor of relapse. In a mouse model of human t(8;21) leukemia, E2-2 suppression accelerates leukemogenesis. Taken together, these results reveal that, in contrast to HEB and E2A, which facilitate AML1-ETO-mediated leukemogenesis, E2-2 compromises the function of AETFC and negatively regulates leukemogenesis. The three E proteins thus define a heterogeneity of AETFC, which improves our understanding of the precise mechanism of leukemogenesis and assists development of diagnostic/therapeutic strategies.

将电化学阻抗方法首次应用于血流储备分数(fractional flow reserve, FFR)和血流量的测量,使得在介入治疗心血管疾病时能够同时测量这2个参数.开发出了基于柔性MEMS技术的FFR传感器和流量传感器,首先将这2个传感器制作在一张Parylene-C薄膜上,其中包含了测量电极和传感器引线等,器件的总厚度为8 μm,具有良好的柔性,能够在极小的曲面(曲率半径0.2 mm)上工作;然后将该器件安装在医用导管的表面得到阻抗导丝.对2个传感器的有效性分别进行了体外验证,流量传感器在0~250 mL/min流量范围内的阻抗/流量响应具有较好的线性度,FFR传感器在FFR比值为0.6~1的范围内具有较高的辨识度.

This letter presents a high performance bimorph piezoelectric MEMS harvester with bulk PZT thick films on both sides of a flexible thin beryllium-bronze substrate via bonding and thinning technologies. The upper and lower PZT layers are thinned down to about 53 μm and 76 μm, respectively, and a commercial beryllium bronze with the thickness of about 50 μm is used as the substrate. The effective volume of this device is 30.6 mm3. The harvester with a tungsten proof mass generated the close-circuit peak-to-peak voltage of 53.1 V, the output power of 0.979 mW, and the power density of 31.99 mW/cm3 with the matching load resistance of 360 kΩ at the applied acceleration amplitude of 3.5 g and the applied frequency of 77.2 Hz. Meanwhile, in order to evaluate the stability, the device was measured continuously under applied acceleration amplitudes of 1.0 g and 3.5 g for one hour and demonstrated a good stability. Then, the harvester was utilized to light up LEDs and about twenty-one serial LEDs were lighted up at resonance under an applied acceleration amplitude of 3.0 g.

Background & AimsSerum Golgi protein 73 (GP73) is a potential biomarker for fibrosis assessment. We aimed to develop an algorithm based on GP73 and liver stiffness (LS) for further improvement of accuracy for significant fibrosis in patients with antiviral-naive chronic hepatitis B virus (HBV) infection. MethodsDiagnostic accuracy evaluation of GP73 and development of GP73-LS algorithm was performed in training cohort (n=267) with an independent cohort (n=133) for validation. ResultsA stepwise increasing pattern of serum GP73 was observed across fibrosis stages in patients with antiviral-naive chronic HBV infection. Serum GP73 significantly correlated (rho=0.48, P<.001) with fibrosis stage and was an independent predictor for the presence of significant fibrosis (OR, 95%CI: 1.02, 1.01-1.03, per increase in 1ng/mL, P<.001). Both LS (AUROC, 95%CI: 0.82, 0.77-0.87, accuracy: 74.7%) and GP73 (AUROC, 95%CI: 0.76, 0.71-0.82, accuracy: 71.5%) well-predicted significant fibrosis and outperformed APRI (AUROC, 95%CI: 0.69, 0.63-0.76, accuracy: 66%) and FIB-4 (AUROC, 95%CI: 0.66, 0.60-0.73, accuracy: 63.6%). Using GP73-LS algorithm, GP73<63 in agreement with LS<8.5 provided accuracy of 81.7% to excluded significant fibrosis. GP7363 in agreement with LS8.5 provided accuracy of 93.3% to confirm significant fibrosis. Almost 64% or 68% of patients in the training or validation cohort could be accurately classified. ConclusionsSerum GP73 is a robust biomarker for significant fibrosis diagnosis. GP73-LS algorithm provided better diagnostic accuracy than currently available approaches. More than 60% antiviral naive CHB patients could use this algorithm without resorting to liver biopsy. See Editorial on Page 1605

Sodium taurocholate cotransporting polypeptide (NTCP), encoded by gene SLC10A1, is a receptor for hepatitis B virus (HBV). The aim of the current study was to investigate the role of NTCP polymorphisms in HBV susceptibility, cirrhosis and hepatocarcinogenesis. A total 1221 cases [including 866 chronic hepatitis B (CHB), 238 liver cirrhosis (LC), 117 hepatocellular carcinoma (HCC) patients] and 1232 healthy controls (HCs) were recruited, and 6 single nucleotide polymorphisms (SNPs) were genotyped. Meta-analysis was executed among 14591 CHBs and 12396 HCs to determine the association between NTCP polymorphisms and HBV infection, cirrhosis or hepatocarcinogenesis. The frequency of rs2296651-GA was inversely correlated with CHB, LC or HCC patients [adjusted OR(95%CI)=0.16(0.11-0.23), p<0.001; 0.34(0.21-0.55), p=0.001; or 0.46(0.25-0.83), p=0.008], respectively, compared with HCs. Meta-analysis also showed that NTCP rs2296651-GA was inversely associated with HBV infection [OR(95%CI)=0.532(0.287-0.986), p=0.028, codominant] or HBV-related HCC [OR(95%CI)=0.701(0.564-0.872), p=0.001, recessive]. Furthermore, the frequency of rs943277-GA was positively correlated with HBV infection [adjusted OR(95%CI)=2.42(1.05-5.54), p=0.032, codominant]. Our data suggest that NTCP mutants contribute to the susceptibility of HBV infection or HBV-related HCC.

A facile method combined directly and selectively microplasma reduction of ion-exchanged Ag+ to Ag(0) nanoparticle precursors and electroless deposition is introduced to produce highly conductive silver patterns on polyimide (Ag/PI) film. Different silver patterns on both 2D and 3D substrates are successfully fabricated. These silver patterns are well defined and uniform over the whole treatment areas. The EDS, XRD and XPS results indicate that the produced silver is well crystallized in the metallic state with high quality. The resistivity of the straight silver pattern with the thickness of ca. 320 nm is down to 3.89 +/- 0.4 mu Omega cm, which is about 2.4 times of the bulk silver. Additionally, the result of folding test verifies the high adhesion strength and good mechanical flexibility of the fabricated silver film. Finally, the patterned Ag/PI film is demonstrated to be used as highly conductive path to light a LED bulb, and can be also empolyed as flexible electrode to sense and record biopotential signals. (C) 2017 The Electrochemical Society. All rights reserved.

Neural networks have drawn much attention in modern machine learning community as they have achieved many successful applications, such as image recognition, speech recognition and system identification. According to the principle of parsimony, simpler neural models are preferable to more complex ones if they have similar generalization performance. However, when building a neural networks model, the neuron number is often determined randomly or by trial-and-error. These methods can often lead to the over-complex networks with many redundant neurons and therefore may result in over-fitting problems. In this paper, a new approach is proposed for obtaining a simplified neural networks with fewer neurons but still keeping a good performance comparing to the initial fully networks. More specifically, the initial neural model with a fixed model size is built using Matlab toolbox. Then, the orthogonal matching pursuit method is employed to select important neurons and drop out redundant neurons, leading to a more compact model with reduced size. Two simulation examples are used to demonstrate the effectiveness of the proposed method.