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Supplementary Data from MEX3C-Mediated Decay of SOCS3 mRNA Promotes JAK2/STAT3 Signaling to Facilitate Metastasis in Hepatocellular Carcinoma

This document contains Supplementary Materials and Methods and Supplementary Data.

MS identification of ILF2 interacting proteins.

Tumor metastasis is one of the major causes of high mortality in patients with hepatocellular carcinoma (HCC). Sustained activation of STAT3 signaling plays a critical role in HCC metastasis. RNA binding protein (RBP)–mediated posttranscriptional regulation is involved in the precise control of signal transduction, including STAT3 signaling. In this study, we investigated whether RBPs are important regulators of HCC metastasis. The RBP MEX3C was found to be significantly upregulated in highly metastatic HCC and correlated with poor prognosis in HCC. Mechanistically, MEX3C increased JAK2/STAT3 pathway activity by downregulating SOCS3, a major negative regulator of JAK2/STAT3 signaling. MEX3C interacted with the 3′UTR of SOCS3 and recruited CNOT7 to ubiquitinate and accelerate decay of SOCS3 mRNA. Treatment with MEX3C-specific antisense oligonucleotide significantly inhibited JAK2/STAT3 pathway activation, suppressing HCC migration in vitro and metastasis in vivo. These findings highlight a novel mRNA decay-mediated mechanism for the disruption of SOCS3-driven negative regulation of JAK2/STAT3 signaling, suggesting MEX3C may be a potential prognostic biomarker and promising therapeutic target in HCC.Significance:This study reveals that RNA-binding protein MEX3C induces SOCS3 mRNA decay to promote JAK2/STAT3 activation and tumor metastasis in hepatocellular carcinoma, identifying MEX3C targeting as a potential approach for treating metastatic disease.

Tumor metastasis is one of the major causes of high mortality in patients with hepatocellular carcinoma (HCC). Sustained activation of STAT3 signaling plays a critical role in HCC metastasis. RNA binding protein (RBP)–mediated posttranscriptional regulation is involved in the precise control of signal transduction, including STAT3 signaling. In this study, we investigated whether RBPs are important regulators of HCC metastasis. The RBP MEX3C was found to be significantly upregulated in highly metastatic HCC and correlated with poor prognosis in HCC. Mechanistically, MEX3C increased JAK2/STAT3 pathway activity by downregulating SOCS3, a major negative regulator of JAK2/STAT3 signaling. MEX3C interacted with the 3′UTR of SOCS3 and recruited CNOT7 to ubiquitinate and accelerate decay of SOCS3 mRNA. Treatment with MEX3C-specific antisense oligonucleotide significantly inhibited JAK2/STAT3 pathway activation, suppressing HCC migration in vitro and metastasis in vivo. These findings highlight a novel mRNA decay-mediated mechanism for the disruption of SOCS3-driven negative regulation of JAK2/STAT3 signaling, suggesting MEX3C may be a potential prognostic biomarker and promising therapeutic target in HCC. Significance: This study reveals that RNA-binding protein MEX3C induces SOCS3 mRNA decay to promote JAK2/STAT3 activation and tumor metastasis in hepatocellular carcinoma, identifying MEX3C targeting as a potential approach for treating metastatic disease.

Since December 2019, the novel coronavirus disease (COVID-19) caused by the syndrome coronavirus 2 (SARS-CoV-2) strain has spread widely around the world and has become a serious global public health problem. For this high-speed infectious disease, the application of X-ray to chest diagnosis plays a key role. In this study, we propose a chest X-ray image classification method based on feature fusion of a dense convolutional network (DenseNet) and a visual geometry group network (VGG16). This paper adds an attention mechanism (global attention machine block and category attention block) to the model to extract deep features. A residual network (ResNet) is used to segment effective image information to quickly achieve accurate classification. The average accuracy of our model in detecting binary classification can reach 98.0%. The average accuracy for three category classification can reach 97.3%. The experimental results show that the proposed model has good results in this work. Therefore, the use of deep learning and feature fusion technology in the classification of chest X-ray images can become an auxiliary tool for clinicians and radiologists.

Nicotine addiction and the occurrence of lymph node spread are two major significant factors associated with esophageal cancer’s poor prognosis; however, nicotine’s role in inducing lymphatic metastasis of esophageal cancer remains unclear. Here we show that OTU domain-containing protein 3 (OTUD3) is downregulated by nicotine and correlates with poor prognosis in heavy-smoking esophageal cancer patients. OTUD3 directly interacts with ZFP36 ring finger protein (ZFP36) and stabilizes it by inhibiting FBXW7-mediated K48-linked polyubiquitination. ZFP36 binds with the VEGF-C 3-‘UTR and recruits the RNA degrading complex to induce its rapid mRNA decay. Downregulation of OTUD3 and ZFP36 is essential for nicotine-induced VEGF-C production and lymphatic metastasis in esophageal cancer. This study establishes that the OTUD3/ZFP36/VEGF-C axis plays a vital role in nicotine addiction-induced lymphatic metastasis, suggesting that OTUD3 may serve as a prognostic marker, and induction of the VEGF-C mRNA decay might be a potential therapeutic strategy against human esophageal cancer., The mechanism of how VEGF-C is regulated to promote lymphatic metastasis of oesophageal cancer is unclear. Here the authors show that nicotine prevents the mRNA decay of VEGF-C mRNA and promotes lymphatic metastasis by downregulating deubiquitinase OTUD3 and RNA binding protein ZFP36.

The majority of clinical deaths among patients with triple-negative breast cancer (TNBC) are caused by uncontrolled cell proliferation and aggressive metastases, which is regulated by hyperactive glycogen synthase kinase 3 beta (GSK3β); however, the underlying mechanisms remain largely unknown. In the present study, we found that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) was specifically upregulated in TNBC, compared with that in normal tissues and non-TNBC. High PPP1R14C expression correlated significantly with shorter 5-year relapse-free survival and overall survival in patients with TNBC. Overexpressing PPP1R14C promoted, while suppression of PPP1R14C decreased the cell proliferation and the aggressive phenotype of TNBC cells, in vitro and in vivo. Importantly, we revealed that PPP1R14C interacted with and inactivated type 1 Ser/Thr protein phosphatase (PP1) to sustain GSK3β phosphorylation at S9, and induced the ubiquitylation and degradation of non-phosphorylated GSK3β (S9A) via recruiting E3 ligase, TRIM25. Furthermore, treating with C2 ceramide (C2), which recovered kinase activity of GSK3β, resulted in tumor growth inhibition in PPP1R14C-overexpressing TNBC cells. Our findings reveal a novel mechanism whereby PPP1R14C sustains inactive GSK3β, which might lead to targeted therapy for TNBC.

Osteochondral regeneration with the formation of hyaline cartilage and subchondral bone as well as the integration between the newly formed tissues with the host tissue still remains a great challenge. In this study, a construct containing an injectable continuous stratified scaffold and multiple cell systems was designed for enhancing osteochondral regeneration. Briefly, an injectable sodium alginate(SA)/bioglass (BG) composite hydrogel containing bone marrow stem cells (BMSCs) (SA/BG + BMSCs) was used for subchondral bone regeneration and an injectable thermosensitive SA/agarose (AG) composite hydrogel with co-culture of BMSCs and articular chondrocytes (ACs) (SA/AG + ACs/BMSCs) was applied for articular cartilage regeneration. The continuous SA phase and the stratified structure enable the scaffold to mimic the natural osteochondral structure. In addition, the SA/BG + BMSCs hydrogel could enhance the osteoblast differentiation of BMSCs by upregulating their alkaline phosphatase and collagen I gene expressions, and the SA/AG + ACs/BMSCs hydrogel could promote the chondrocyte differentiation of BMSCs by upregulating their Acan and collagen II gene expressions, which indicated that this stratified scaffold could mimic the natural osteochondral function. Furthermore, after the stratified construct was injected into a rat osteochondral defect model, obvious neonatal articular cartilage tissues and subchondral bone tissues with regular surface and highly integration with normal tissues could be observed. This structural and functional biomimetic construct, together with its proper swelling ratio, could not only stimulate the hyaline cartilage and subchondral bone regeneration in an entire osteochondral unit but also promote the integration between the newly formed tissues and the host tissue.

Electric mechanical transmission (EMT) is a low-cost production for the electric vehicle to expend its torque and speed. Gear shifting is the essential function of EMT, but it is a multi-stage process with nonlinearity and uncertainty. In practice, gear shifting control is a difficult problem because of the bad consistency and large shift shock. Hence, a single control method is hard to solve it with satisfying performance. In this paper, motivated by the analysis of experimental results, a novel multi-stage gear shifting control scheme is proposed to improve shifting position tracking performance and decrease shift shock. First, the entire process is divided into three stages and each stage is modeled based on historical data and theoretical analysis. Then, a multi-stage scheme is designed, which is composed of iterative learning control (ILC), linear quadratic regulator (LQR), and $\boldsymbol {H_{2}}$ control based on Takagi and Sugeno (T-S) model corresponding to each stage. Finally, the feasibility and effectiveness of the proposed scheme are verified by bench experiments, which might provide guides for the engineering application of the EMT.

Background: Frozen shoulders (FS) is a major clinical concern, where chronic synovial inflammation, abnormal angiogenesis, and fibrosis represent the critical pathologies in the glenohumeral capsule. However, no pharmacotherapy has been introduced to treat this pathology. Tetrandrine (TET) has been proposed as a treatment for many diseases due to its strong anti-inflammatory, anti-angiogenic, and anti-fibrotic effects. Purpose: To study the anti-inflammatory, anti-angiogenic, and anti-fibrotic effects of TET on FS, and identify whether TET can prevent the development of FS in rats. Study Design: A controlled laboratory study. Methods: Forty-eight male Sprague-Dawley (SD) rats were randomly divided into control, TET, and FS groups. The TET group was intraperitoneally injected with TET every 2 days. TET and saline treatment were started on the day of FS surgery. After 8 weeks, the animals were sacrificed, and samples were collected for X-ray examination, glenohumeral range of motion (ROM) evaluation, histology and immunohistochemistry analysis, transmission electron microscopy (TEM) observation, and profibrogenic factors as well as proinflammatory cytokines measurements. Results: No significant difference in shoulder ROM was observed between the TET and control groups, but a significant difference was noted between these groups and the FS group (P

Background Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high proliferative activity. TNBC tumors exhibit elevated MYC expression and altered expression of MYC regulatory genes, which are associated with tumor progression and poor prognosis; however, the underlying mechanisms by which MYC retains its high expression and mediates TNBC tumorigenesis require further exploration. Methods ACTL6A regulation of MYC and its target gene, CDK2, was defined using Co-IP, mass spectrometry and ChIP assays. To study the role of ACTL6A in TNBC, we performed soft-agar, colony formation, flow cytometry and tumor formation in nude mice. CDK2 inhibitor and paclitaxel were used in testing combination therapy in vitro and in vivo. Results ACTL6A bound MYC to suppress glycogen synthase kinase 3 beta (GSK3β)-induced phosphorylation on MYC T58, which inhibited ubiquitination of MYC and stabilized it. Moreover, ACTL6A promoted the recruitment of MYC and histone acetyltransferase KAT5 on CDK2 promoters, leading to hyperactivation of CDK2 transcription. ACTL6A overexpression promoted, while silencing ACTL6A suppressed cell proliferation and tumor growth in TNBC cells in vitro and in vivo, which was dependent on MYC signaling. Furthermore, co-therapy with paclitaxel and CDK2 inhibitor showed synergistic effects in tumor suppression. Notably, ACTL6A/MYC/CDK2 axis was specifically up-regulated in TNBC and high expression of ACTL6A was correlated to shorter survival in patients with TNBC. Conclusions These findings reveal a novel mechanism by which ACTL6A prolongs the retention of MYC in TNBC and suggest that pharmacological targeting ACTL6A/MYC/CDK2 axis might have therapeutic potential in patients with TNBC.

Additional file 1: Table S1. Primers. Table S2. Clinicopathological characteristics of 344 breast cancer patients and 220 triple-negative breast cancer patients. Table S3. Correlation between ACTL6A and clinicopathological characteristics of breast cancer patients. Table S4. Univariate and multivariate analysis of factors associated with 5-year overall survival and relapse-free survival in patients with TNBC.

Balancing mRNA nuclear export kinetics with its nuclear decay is critical for mRNA homeostasis control. How this equilibrium is aberrantly disrupted in esophageal cancer to acquire cancer stem cell properties remains unclear. Here we find that the RNA-binding protein interleukin enhancer binding factor 2 (ILF2) is robustly upregulated by nicotine, a major chemical component of tobacco smoke, via activation of JAK2/STAT3 signaling and significantly correlates with poor prognosis in heavy-smoking patients with esophageal cancer. ILF2 bound the THO complex protein THOC4 as a regulatory cofactor to induce selective interactions with pluripotency transcription factor mRNAs to promote their assembly into export-competent messenger ribonucleoprotein complexes. ILF2 facilitated nuclear mRNA export and inhibited hMTR4-mediated exosomal degradation to promote stabilization and expression of SOX2, NANOG, and SALL4, resulting in enhanced stemness and tumor-initiating capacity of esophageal cancer cells. Importantly, inducible depletion of ILF2 significantly increased the therapeutic efficiency of cisplatin and abrogated nicotine-induced chemoresistance in vitro and in vivo. These findings reveal a novel role of ILF2 in nuclear mRNA export and maintenance of cancer stem cells and open new avenues to overcome smoking-mediated chemoresistance in esophageal cancer. Significance: This study defines a previously uncharacterized role of nicotine-regulated ILF2 in facilitating nuclear mRNA export to promote cancer stemness, suggesting a potential therapeutic strategy against nicotine-induced chemoresistance in esophageal cancer.

This study examines whether speech rhythm affects speech recognition under "cocktail-party" conditions. Against a two-talker masker, but not a speech-spectrum noise masker, recognition of the last (third) keyword in a normal rhythmic sentence was significantly better than that of the first keyword. However, this word-position-related speech-recognition improvement disappeared for rhythmically hybrid target sentences that were constructed by grouping parts from different sentences with different artificially modulated rhythms (rates) (fast, normal, or slow). Thus, the normal rhythm with a constant rate plays a role in improving speech recognition against informational speech masking, probably through a build-up of temporal prediction for target words.

When aiming at hyperspectral classification, spectral characteristics are often considered, while spatial characteristics and information redundancy between spectra are neglected. We propose a method of feature extraction using a uniform local binary pattern and ensemble multiple models to classify features. This model uses a uniform local binary mode to extract the spatial features of hyperspectral images. The spatial features and the spectral features are fused to obtain high-dimensional fusion data, which are input into the sparse representation model for learning, and the residual of the test sample is obtained. At the same time, hyperspectral images have serious information redundancy, so we use the product moment correlation coefficient to reduce the interference between classes of sample information. Finally, through ensemble learning of different classification models, the hyperspectral classification can be accurately predicted. The experimental results on hyperspectral data show that this method can effectively improve the effect of hyperspectral image classification.

Although many strategies are contributed to improve hydrogel properties, enhancing highly self-healing behaviors and excellent mechanical properties of hydrogels are still intractable problems in today. Herein, we reported a strong hydrogel with highly efficient self-healing and robust mechanical properties base on the bulk polymerization method. In this work, the formation of the hydrogel is induced by the dense hydrogen bonds and the segment entanglement interactions, which facilitate the formation of network with excellent properties, including out of ordinary stability in a widely pH range and outstanding mechanical properties. The storage modulus and loss modulus of the obtained materials can be adjusted by the variation of the initiator ratio. Furthermore, the materials can be self-healing after 2 h at room temperature, without requiring any external stimuli. The swelling behaviors of the hydrogel can be modified by adjusting the initiator concentration, which further provides guidance for the manufacture of high-performance gels with precisely controllable mechanical behaviors.

// Xingjun Wang 1, * , Ying Sun 1, * , Shilong Han 1 , Chenxi Wu 2 , Yeqing Ma 1 , Yu Zhao 1 , Yingyao Shao 1 , Yujun Chen 1 , Lingzhi Kong 3 , Wenzhe Li 1 , Fan Zhang 3 and Lei Xue 1 1 Department of Interventional Radiology, Shanghai 10th People’s Hospital, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China 2 College of Chinese Medicine, North China University of Science and Technology, Tangshan 063210, China 3 Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China * These authors have contributed equally to this work Correspondence to: Xingjun Wang, email: 2011wxj_fly_ing@tongji.edu.cn Lei Xue, email: lei.xue@tongji.edu.cn Keywords: APLP1, cell migration, Drosophila , JNK Received: May 18, 2015 Accepted: April 20, 2017 Published: May 08, 2017 ABSTRACT The amyloid precursor like protein-1 (APLP1) is a member of the amyloid precursor protein (APP) family in mammals. While many studies have been focused on the pathologic role of APP in Alzheimer’s disease, the physiological functions of APLP1 have remained largely elusive. Here we report that ectopic expression of APLP1 in Drosophila induces cell migration, which is suppressed by the loss of JNK signaling and enhanced by the gain of JNK signaling. APLP1 activates JNK signaling through phosphorylation of JNK, which up-regulates the expression of matrix metalloproteinase MMP1 required for basement membranes degradation and promotes actin remodeling essential for cell migration. Our data thus provide the first in vivo evidence for a cell-autonomous role of APLP1 protein in migration.

Importance: Prior observational studies suggest that quality of care improvement (QCI) initiatives can improve the clinical outcomes of acute coronary syndrome (ACS). To our knowledge, this has never been demonstrated in a well-powered randomized clinical trial. Objective: To determine whether a clinical pathway-based, multifaceted QCI intervention could improve clinical outcomes among patients with ACS in resource-constrained hospitals in China. Design, Setting, Participants: This large, stepped-wedge cluster randomized clinical trial was conducted in nonpercutaneous coronary intervention hospitals across China and included all patients older than 18 years and with a final diagnosis of ACS who were recruited consecutively between October 2011 and December 2014. We excluded patients who died before or within 10 minutes of hospital arrival. We recruited 5768 and 0 eligible patients for the control and intervention groups, respectively, in step 1, 4326 and 1365 in step 2, 3278 and 3059 in step 3, 1419 and 4468 in step 4, and 0 and 5645 in step 5. Interventions: The intervention included establishing a QCI team, training clinical staff, implementing ACS clinical pathways, sequential site performance assessment and feedback, online technical support, and patient education. The usual care was the control that was compared. Main Outcomes and Measures: The primary outcome was the incidence of in-hospital major adverse cardiovascular events (MACE), comprising all-cause mortality, reinfarction/myocardial infarction, and nonfatal stroke. Secondary outcomes included 16 key performance indicators (KPIs) and the composite score developed from these KPIs. Results: Of 29 346 patients (17 639 men [61%]; mean [SD] age for control, 64.1 [11.6] years; mean [SD] age for intervention, 63.9 [11.7] years) who were recruited from 101 hospitals, 14 809 (50.5%) were in the control period and 14 537 (49.5%) were in the intervention period. There was no significant difference in the incidence of in-hospital MACE between the intervention and control periods after adjusting for cluster and time effects (3.9% vs 4.4%; odds ratio, 0.93; 95% CI, 0.75-1.15; P = .52). The intervention showed a significant improvement in the composite KPI score (mean [SD], 0.69 [0.22] vs 0.61 [0.23]; P

Many methods are used to improve the mechanical properties of hydrogels, but it is still challenging to generate comparable to natural hydrogels, let alone synchronously give it excellent self-healing properties. Herein, we synthesize a novel type of the aliphatic polycarbonate hydrogel with the above advantages. In this work, the ring-opening polymerization of 2-methyl-2-benzyloxy carbonyl propylene carbonate (MBC) and 1, 3-trimethylene carbonate (TMC) are initiated by the hydroxyl group of methoxy poly(ethylene glycol) (mPEG113, Mn = 5000). The effect of the TMC as flexible segments on the structure, mechanical properties, and self-healing behavior of the obtained materials is systematically studied. The swelling ratios of the obtained gels in water are enhanced as the content of the monomer TMC increases. The self-healing ability of the materials is drove by the hydrogen bonds and the hydrophobic associations to heal the fracture interfaces. The obtained gels exhibit outstanding mechanical properties and excellent ability of self-healing at room temperature. Both of these abilities can be adjusted by the variation of the TMC flexible segment. Thus, we provide a novel strategy for the fabrication of modified tough hydrogel, which will expand the modification field of hydrogels.

Epigenetic regulation plays an important role in tumor metastasis. KDM1A is a histone demethylase specific for H3K4me2/me1 demethylation, and has been found to be overexpressed in many cancers, including non-small cell lung cancer (NSCLC). However, the role of KDM1A in lung cancer remains unclear. Here, we show that KDM1A promotes cancer metastasis in NSCLC cells by repressing TIMP3 (tissue inhibitor of metalloproteinase 3) expression. Consistently with this, overexpression of TIMP3 inhibited MMP2 expression and JNK phosphorylation, both of which are known to be important for cell invasion and migration. Importantly, knockdown of TIMP3 in KDM1A-deficient cells rescued the metastatic capability of NSCLC cells. These findings were also confirmed by pharmacological inhibition assays. We further demonstrate that KDM1A removes H3K4me2 at the promoter of TIMP3, thus repressing the transcription of TIMP3. Finally, high expression of KDM1A and low expression of TIMP3 significantly correlate with a poor prognosis in NSCLC patients. This study establishes a mechanism by which KDM1A promotes cancer metastasis in NSCLC cells, and we suggest that KDM1A may be a potential therapeutic target for NSCLC treatment.

The neural mechanisms underlying forward suppression in the auditory cortex remain a puzzle. Little attention is paid to thalamic contribution despite the important fact that the thalamus gates upstreaming information to the auditory cortex. This study compared the time courses of forward suppression in the auditory thalamus, thalamocortical inputs and cortex using the two-tone stimulus paradigm. The preceding and succeeding tones were 20-ms long. Their frequency and amplitude were set at the characteristic frequency and 20 dB above the minimum threshold of given neurons, respectively. In the ventral division of the medial geniculate body of the thalamus, we found that the duration of complete forward suppression was about 75 ms and the duration of partial suppression was from 75 ms to about 300 ms after the onset of the preceding tone. We also found that during the partial suppression period, the responses to the succeeding tone were further suppressed in the primary auditory cortex. The forward suppression of thalamocortical field excitatory postsynaptic potentials was between those of thalamic and cortical neurons but much closer to that of thalamic ones. Our results indicate that early suppression in the cortex could result from complete suppression in the thalamus whereas later suppression may involve thalamocortical and intracortical circuitry. This suggests that the complete suppression that occurs in the thalamus provides the cortex with a "silence" window that could potentially benefit cortical processing and/or perception of the information carried by the preceding sound.

To determine the preliminary effectiveness of breast cancer screening among Chinese females, 1226714 women aged 35–69 years first received clinical breast examinations. Urban women with suspected cancer received mammography followed by breast ultrasound (BUS), while rural suspected women underwent BUS followed by mammography. After one-year follow-up, 223 and 431 breast cancers were detected among urban and rural women (respectively), with overall detection rates of 0.56/1000 and 0.52/1000. Higher detection rates were significantly associated with older age at screening for both urban and rural women; additionally, urban women were at significantly higher risk if they had no job, no insurance, or were obese; additional risk factors specific to rural women included Han nationality, higher income, being unmarried, and having a family history of cancer (all P values in situ. All abovementioned cancer characteristics were significantly better than clinic-detected cancers (all P values

This study investigated whether sound intensity affects listeners' sensitivity to a break in interaural correlation (BIC) embedded in wideband noise at different interaural delays. The results show that the detection duration threshold remained stable at the intensity between 60 and 70 dB SPL, but increased in accelerating fashion as the intensity decreased toward 40 dB SPL. Moreover, the threshold elevated linearly as the interaural delay increased from 0 to 4 ms, and the elevation slope became larger as the intensity decreased from 50 to 40 dB SPL. Thus, detecting the BIC is co-modulated by both intensity and interaural delay.

During the period 1997-2000 a technical assistance project to build capacity for community-based health promotion was implemented in seven cities and one province in China. The technical assistance project formed part of a much larger World Bank supported program to improve disease prevention capabilities in China, commonly known as Health VII. The technical assistance project was funded by the Australian Agency for International Development. It was designed to develop capacity within the Ministry of Health (MOH) and the cities and province in the management of community-based health promotion projects, as well as supporting institutional development and public health policy reform. There are some relatively unique features of this technical assistance which helped shape its implementation and impact. It sought to provide the Chinese MOH and the cities and province with an introduction to comprehensive health promotion strategies, in contrast to the more limited information, education and communication strategies. The project was provided on a continuing basis over 3 years through a single institution, rather than as a series of ad hoc consultancies by individuals. Teaching and learning processes were developmental, leading progressively to a greater degree of local Chinese input and management to ensure sustainability and maintenance of technical support for the project. Based on this experience, this paper presents a model for capacity building projects of this type. It describes the education, training and planning activities that were the key inputs to the project, as well as the limited available evidence on the impact of the project. It describes how the project evolved over time to meet the changing needs of the participants, specifically how the content of the project shifted from a risk-factor orientation to a settings-based focus, and the delivery of the project moved from an expert-led approach to a more participatory, problem based learning approach. In terms of impact, marked differences before and after the implementation of the training activities were identified in key areas for reform, in addition to the self reported positive change in knowledge, and a high level of participant satisfaction. Key lessons are summarized. Technical assistance projects of this kind benefit from continuity and a high level of coordination, the provision of culturally and linguistically appropriate teaching, and a clear understanding of the need to match workforce development with organizational/institutional development.

The primary auditory cortex (AI) modulates the sound information processing in the lemniscal subcortical nuclei, including the anteroventral cochlear nucleus, in a frequency-specific manner. The dorsal cochlear nucleus (DCN) is a non-lemniscal subcortical nucleus but it is tonotopically organized like the anteroventral cochlear nucleus. However, it remains unclear how the AI modulates the sound information processing in the DCN. This study examined the impact of focal electrical stimulation of AI on the auditory responses of the DCN neurons in mice. We found that the electrical stimulation induced significant changes in the best frequency (BF) of DCN neurons. The changes in the BFs were highly specific to the BF differences between the stimulated AI neurons and the recorded DCN neurons. The DCN BFs shifted higher when the AI BFs were higher than the DCN BFs and the DCN BFs shifted lower when the AI BFs were lower than the DCN BFs. The DCN BFs showed no change when the AI and DCN BFs were similar. Moreover, the BF shifts were linearly correlated to the BF differences. Thus, our data suggest that corticofugal modulation of the DCN is also highly specific to frequency information, similar to the corticofugal modulation of the anteroventral cochlear nucleus. The frequency-specificity of corticofugal modulation does not appear limited to the lemniscal ascending pathway.

Background— Substantial evidence-practice gaps exist in the management of acute coronary syndromes (ACS) in China. Clinical pathways are tools for improving ACS quality of care but have not been rigorously evaluated. Methods and Results— Between October 2007 and August 2010, a quality improvement program was conducted in 75 hospitals throughout China with mixed methods evaluation in a cluster randomized, controlled trial. Eligible hospitals were level 2 or level 3 centers routinely admitting >100 patients with ACS per year. Hospitals were assigned immediate implementation of the American Heart Association/American College of Cardiology guideline based clinical pathways or commencement of the intervention 12 months later. Outcomes were several key performance indicators reflecting the management of ACS. The key performance indicators were measured 12 months after commencement in intervention hospitals and compared with baseline data in control hospitals, using data collected from 50 consecutive patients in each hospital. Pathway implementation was associated with an increased proportion of patients discharged on appropriate medical therapy, with nonsignificant improvements or absence of effects on other key performance indicators. Conclusions— Among hospitals in China, the use of a clinical pathway for the treatment of ACS compared with usual care improved secondary prevention treatments, but effectiveness was otherwise limited. An accompanying process evaluation identified several health system barriers to more successful implementation. Clinical Trial Registration— URL: http://www.anzctr.org.au/default.aspx . Unique identifier: ACTRN12609000491268.