Novel Hydrogel Adjuvant of Chinese Medicine External Preparations for Accelerated Healing of Deep Soft Tissue Injuries.

Traditional Chinese medicine external prescriptions have displayed excellent clinical effects for treating deep soft tissue injuries. However, the effects cannot be fully utilized due to the limitations of their dosage forms and usage methods. It is still a challenge to develop a satisfactory adjuvant of traditional Chinese medicine external prescriptions. Herein, a hydrogel adjuvant was prepared based on gallic acid coupled ε-poly-l-lysine and partially oxidized hyaluronic acid. The resulting adjuvant shows great physicochemical properties, low hemolysis rate (still much less than 5% at 5 mg/mL), excellent antibacterial ability (about 95% at 2 mg/mL), strong antioxidant ability (1.687 ± 0.085 mmol FeSO4/(g hydrogel) at 1 mg/mL), as well as outstanding biocompatibility. A clinically used Chinese medicine external preparation was selected as an example to investigate the effectiveness of the adjuvant in treating deep soft tissue injuries. The results show that the prescription can be evenly dispersed in the adjuvant. Moreover, the introduction of the prescription has not significantly changed these advanced properties of the adjuvant. Importantly, the hydrogel adjuvant significantly improves the effectiveness of the prescription in treating deep soft tissue injuries. This work offers an alternative approach to the development of a new-type adjuvant of Chinese medicine external preparations and also provides a new strategy for the combination of traditional Chinese medicine and hydrogel to treat clinical diseases.

Causality-Based Visual Analysis of Questionnaire Responses.

As the final stage of questionnaire analysis, causal reasoning is the key to turning responses into valuable insights and actionable items for decision-makers. During the questionnaire analysis, classical statistical methods (e.g., Differences-in-Differences) have been widely exploited to evaluate causality between questions. However, due to the huge search space and complex causal structure in data, causal reasoning is still extremely challenging and time-consuming, and often conducted in a trial-and-error manner. On the other hand, existing visual methods of causal reasoning face the challenge of bringing scalability and expert knowledge together and can hardly be used in the questionnaire scenario. In this work, we present a systematic solution to help analysts effectively and efficiently explore questionnaire data and derive causality. Based on the association mining algorithm, we dig question combinations with potential inner causality and help analysts interactively explore the causal sub-graph of each question combination. Furthermore, leveraging the requirements collected from the experts, we built a visualization tool and conducted a comparative study with the state-of-the-art system to show the usability and efficiency of our system.

Barriers and facilitators of implementing electronic monitors to improve adherence and health outcomes in tuberculosis patients: protocol for a systematic review based on the Consolidated Framework for Implementation Research.

BACKGROUND: Tuberculosis (TB) has been regarded as 'a relentless scourge', increasing morbidity and mortality and burdening vulnerable populations. Poor adherence to TB treatment and ineffective traditional interventions hinders TB control. A novel TB approach called 'electronic monitors', equipping medication boxes with daily audio or visual reminders for electronically monitoring medication intake, seems promising in improving adherence and health outcomes and overcoming the weaknesses of traditional interventions. However, no review has systematically examined and synthesized the influencing factors of implementing electronic monitors. Implementation research offers the means to analyse the influencing factors of the implementation and its process, fitting well with the aim of this review. Therefore, the widely recognized Consolidated Framework for Implementation Research (CFIR), which offers a common taxonomy for evaluating intervention implementation, will be adopted to systematically identify barriers and facilitators of the electronic monitors for improving adherence and health outcomes in patients with TB. METHODS AND ANALYSIS: The systematic review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Literature research will be conducted in five electronic databases (Ovid MEDLINE, CINAHL, EMBASE, Cochrane Library and Web of Science) to identify the barriers and facilitators of implementing electronic monitors in patients with TB. The CFIR will be used as a guide for categorizing and synthesizing the barriers and facilitators. Study screening, data extraction, quality appraisal and data analysis will be conducted by two independent reviewers. The use of additional reviewers will solve any disagreements between the two reviewers. DISCUSSION: Given the increased prominence of TB epidemiology and the adherence problem of electronic monitors, there is a solid rationale for synthesizing the existing studies via the CFIR. The findings and conclusion of this review will lay bare the achievements and effectiveness of implementing electronic monitors, as well as the attendant gaps and limitations. Further strategies for facilitating the implementation of electronic monitors will also be explored. This review will be of essential significance for research and practice, supporting future academic research initiatives centred on patients with TB and aiding electronic monitor design in lowering the morbidity and mortality associated with TB disease. TRIAL REGISTRATION NUMBER: PROSPERO: CRD42023395747.

Interaction of glycine with Li+ in the (H2O)n (n = 0-8) clusters.

CONTEXT: We investigated the interaction between glycine and Li+ in water environment based on the Gly·Li+(H2O)n (n = 0-8) cluster. Our study shows that for Gly·Li+, Li+ binds to both carbonyl oxygen and amino nitrogen to form a bidentate structure, and the first three water molecules preferentially interact with Li+. For n = 0-5, the complexes of Gly·Li+(H2O)n exist in neutral form, and when the water number reached 6, the complex can coexist in neutral and zwitterionic form, then zwitterionic structures are dominant for n = 7, 8. The analyses by RDG, AIM, and ESP in conjunction with the calculated interaction energies show that the interaction between Li+ and Gly decreases gradually with the water molecules involved successively from n = 1 to 6 and then increases for n = 7-8. Additionally, the infrared spectra of Gly·Li+(H2O)n (n = 0-8) are also calculated. METHODS: The initial structures were optimized using Gaussian 09 program package in B3LYP-D3 (BJ)/6-311G(d, p) method, and the frequency was calculated with 6-311 + G(2d, p) basis set. GaussView5.0.9 was used to view simulation infrared spectra. The noncovalent interaction method (NCl), energy decomposition (EDA), atoms in molecules (AIM) analysis, and electrostatic potential (ESP) analyses were conducted using Multiwfn software to gain a deeper understanding of the interaction properties of Gly, Li+, and water.

Cell surface GRP78 regulates TGFß1-mediated profibrotic responses via TSP1 in diabetic kidney disease.

Introduction: Diabetic kidney disease (DKD) is the leading cause of kidney failure in North America, characterized by glomerular accumulation of extracellular matrix (ECM) proteins. High glucose (HG) induction of glomerular mesangial cell (MC) profibrotic responses plays a central role in its pathogenesis. We previously showed that the endoplasmic reticulum resident GRP78 translocates to the cell surface in response to HG, where it mediates Akt activation and downstream profibrotic responses in MC. Transforming growth factor ß1 (TGFß1) is recognized as a central mediator of HG-induced profibrotic responses, but whether its activation is regulated by cell surface GRP78 (csGRP78) is unknown. TGFß1 is stored in the ECM in a latent form, requiring release for biological activity. The matrix glycoprotein thrombospondin 1 (TSP1), known to be increased in DKD and by HG in MC, is an important factor in TGFß1 activation. Here we determined whether csGRP78 regulates TSP1 expression and thereby TGFß1 activation by HG. Methods: Primary mouse MC were used. TSP1 and TGFß1 were assessed using standard molecular biology techniques. Inhibitors of csGRP78 were: 1) vaspin, 2) the C-terminal targeting antibody C38, 3) siRNA downregulation of its transport co-chaperone MTJ-1 to prevent GRP78 translocation to the cell surface, and 4) prevention of csGRP78 activation by its ligand, active α2-macroglobulin (α2M*), with the neutralizing antibody Fα2M or an inhibitory peptide. Results: TSP1 transcript and promoter activity were increased by HG, as were cellular and ECM TSP1, and these required PI3K/Akt activity. Inhibition of csGRP78 prevented HG-induced TSP1 upregulation and deposition into the ECM. The HG-induced increase in active TGFß1 in the medium was also inhibited, which was associated with reduced intracellular Smad3 activation and signaling. Overexpression of csGRP78 increased TSP-1, and this was further augmented in HG. Discussion: These data support an important role for csGRP78 in regulating HG-induced TSP1 transcriptional induction via PI3K/Akt signaling. Functionally, this enables TGFß1 activation in response to HG, with consequent increase in ECM proteins. Means of inhibiting csGRP78 signaling represent a novel approach to preventing fibrosis in DKD.

A therapeutic target for CKD: activin A facilitates TGFß1 profibrotic signaling.

BACKGROUND: TGFß1 is a major profibrotic mediator in chronic kidney disease (CKD). Its direct inhibition, however, is limited by adverse effects. Inhibition of activins, also members of the TGFß superfamily, blocks TGFß1 profibrotic effects, but the mechanism underlying this and the specific activin(s) involved are unknown. METHODS: Cells were treated with TGFß1 or activins A/B. Activins were inhibited generally with follistatin, or specifically with neutralizing antibodies or type I receptor downregulation. Cytokine levels, signaling and profibrotic responses were assessed with ELISA, immunofluorescence, immunoblotting and promoter luciferase reporters. Wild-type or TGFß1-overexpressing mice with unilateral ureteral obstruction (UUO) were treated with an activin A neutralizing antibody. RESULTS: In primary mesangial cells, TGFß1 induces secretion primarily of activin A, which enables longer-term profibrotic effects by enhancing Smad3 phosphorylation and transcriptional activity. This results from lack of cell refractoriness to activin A, unlike that for TGFß1, and promotion of TGFß type II receptor expression. Activin A also supports transcription through regulating non-canonical MRTF-A activation. TGFß1 additionally induces secretion of activin A, but not B, from tubular cells, and activin A neutralization prevents the TGFß1 profibrotic response in renal fibroblasts. Fibrosis induced by UUO is inhibited by activin A neutralization in wild-type mice. Worsened fibrosis in TGFß1-overexpressing mice is associated with increased renal activin A expression and is inhibited to wild-type levels with activin A neutralization. CONCLUSIONS: Activin A facilitates TGFß1 profibrotic effects through regulation of both canonical (Smad3) and non-canonical (MRTF-A) signaling, suggesting it may be a novel therapeutic target for preventing fibrosis in CKD.

Integrin ß1/Cell Surface GRP78 Complex Regulates TGFß1 and Its Profibrotic Effects in Response to High Glucose.

Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Characterized by overproduction and accumulation of extracellular matrix (ECM) proteins, glomerular sclerosis is its earliest manifestation. High glucose (HG) plays a central role by increasing matrix production by glomerular mesangial cells (MC). We previously showed that HG induces translocation of GRP78 from the endoplasmic reticulum to the cell surface (csGRP78), where it acts as a signaling molecule to promote intracellular profibrotic FAK/Akt activation. Here, we identify integrin ß1 as a key transmembrane signaling partner for csGRP78. We show that it is required for csGRP78-regulated FAK/Akt activation in response to HG, as well as downstream production, secretion and activity of the well characterized profibrotic cytokine transforming growth factor ß1 (TGFß1). Intriguingly, integrin ß1 also itself promotes csGRP78 translocation. Furthermore, integrin ß1 effects on cytoskeletal organization are not required for its function in csGRP78 translocation and signaling. These data together support an important pathologic role for csGRP78/integrin ß1 in mediating key profibrotic responses to HG in kidney cells. Inhibition of their interaction will be further evaluated as a therapeutic target to limit fibrosis progression in DKD.

Interaction of Cysteine with Li+ and LiF in the Presence of (H2O) n (n = 0-6) Clusters.

The interaction between cysteine with Li+ and LiF in the microcosmic water environment was investigated to elucidate how ions interact with amino acids and the cation-anion correlation effect involved. The structures of Cys·Li+(H2O) n and Cys·LiF(H2O) n (n = 0-6) were characterized using ab initio calculations. Our studies show that the water preferentially interacts with Li+/LiF. In Cys·Li+(H2O)0-6, Li+ interacts with amino nitrogen, carbonyl oxygen, and hydrophobic sulfur of Cys to form a tridentate mode, whereas in Cys·LiF(H2O) n , Li+ and F- work in cooperation and interact with carbonyl oxygen and hydroxyl hydrogen of Cys to form a bidentate type. The neutral and zwitterionic forms are essentially isoenergetic when the water number reaches three in the presence of Li+, whereas this occurs at four water molecules in the presence of LiF. Further research revealed that the interaction between Li+/LiF and Cys was mainly electrostatic, followed by dispersion, and the weakest interaction occurs at the transition from the neutral form to zwitterionic form. Natural population analysis charge analyses show that for Cys·Li+(H2O) n , the positive charge is mostly concentrated on Li+ except for the system containing three water molecules. For Cys·LiF(H2O) n , the positive charge is centered on the LiF unit in the range n = 0-6, and at n = 5, electron transfer from Cys to water occurs. Our study shows that the contribution of anions in zwitterionic state stabilization should be addressed more generally along with cations.

The Impact of COVID-19 Epidemic on Tuberculosis Reports Among Students - Guizhou Province, China, 2020.

What is already known about this topic?: In 2020, the implementation of non-medical interventions during the coronavirus disease 2019 (COVID-19) epidemic has created a negative impact on tuberculosis (TB) control. It is unclear if the prevalence of TB among students in Guizhou Province was also affected. What is added by this report?: Among TB cases, the proportion of student TB patients was 19.91% in the back-to-school period in 2020, which was higher than the 13.37% registered in 2017-2019, but this decreased in the COVID-19 pandemic period. The time interval between symptom onset and care-seeking of the student TB patients was the shortest in the back-to-school and physical check-up periods. What are the implications for public health practice?: TB active screening was effective for timely detection and diagnosis of TB among students, which could prevent TB outbreaks in schools.

Ab initio study of hydrated cesium iodide dimer (CsI)2-/0(H2O)0-6 and the cation size effect on (MI)2-/0(H2O)0-6 (M = Li, Na, K, Cs).

The structures of microsolvated (CsI)2-/0(H2O)0-6 clusters were determined using ab initio calculations. Our studies show that one Cs atom at the apex was firstly separated from the pyramid-shaped (CsI)2- unit when the water number reaches 3, whereas CsI distances did not increase significantly from n = 0 to 6 for neutrals. Additionally, the atomic charge and reduced density gradient analyses were carried out; the results reveal that the extra electrons are almost entirely localized on terminal Cs atom and the Cs+-water interactions dominate in (CsI)2-(H2O)0-6. The water-water interactions show up at n = 5. The comparison of (CsI)2-/0(H2O)n with (MI)2-/0(H2O)n (M = Li, Na, K) shows that neutral (CsI)2 is the most difficult to be separated, which matches the law of matching water affinity. As for anions, the most difficult separation occurs in the case of small size (LiI)2- due to the effect of extra electrons, and (MI)2- with larger size cation is more likely to interact with water to form a pyramid structure.

Epidemiological Characteristics of Rifampicin-Resistant Tuberculosis in Students - China, 2015-2019.

What is already known about this topic? The number of students with tuberculosis (TB) has been increasing since 2015. However, the prevalence of rifampicin-resistant tuberculosis (RR-TB) among student population is unclear. What is added by the report? The number of students with RR-TB has significantly increased from 2015 to 2019, especially in the western region of China. The majority of patients were college students. Students with RR-TB were mainly new patients. What are the implications for public health practice? The following measures are recommended: strengthening TB surveillance in schools, promoting the application of convenient and rapid molecular drug susceptibility testing tools, and actively carrying out drug resistance screening and follow ups for cohabiting children of adult RR-TB patients.

Practical Experiences of Delivering Multidrug-Resistant Tuberculosis Comprehensive Supportive Care Services in China.

What is already known about this topic? The World Health Organization consolidated guidelines on recommend care for tuberculosis (TB) and support for multidrug-resistant TB (MDR-TB) patients. But guidelines have not provided detailed guidance or tools for health services providers to implement comprehensive patient care. What is added by this report? China CDC and the United States Agency for International Development-funded Control and Prevention of MDR-TB program introduced a differentiated and personalized comprehensive and supportive care services (CSC) to improve treatment adherence. What are the implications for public health practice? The CSC model helps MDR-TB patients complete treatment and improve treatment success rates, and scaling up the program and implementation in other parts of the country is worth consideration.

Activated Alpha 2-Macroglobulin Is a Novel Mediator of Mesangial Cell Profibrotic Signaling in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is caused by the overproduction of extracellular matrix proteins (ECM) by glomerular mesangial cells (MCs). We previously showed that high glucose (HG) induces cell surface translocation of GRP78 (csGRP78), mediating PI3K/Akt activation and downstream ECM production. Activated alpha 2-macroglobulin (α2M*) is a ligand known to initiate this signaling cascade. Importantly, increased α2M was observed in diabetic patients' serum, saliva, and glomeruli. Primary MCs were used to assess HG responses. The role of α2M* was assessed using siRNA, a neutralizing antibody and inhibitory peptide. Kidneys from type 1 diabetic Akita and CD1 mice and human DKD patients were stained for α2M/α2M*. α2M transcript and protein were significantly increased with HG in vitro and in vivo in diabetic kidneys. A similar increase in α2M* was seen in media and kidneys, where it localized to the mesangium. No appreciable α2M* was seen in normal kidneys. Knockdown or neutralization of α2M/α2M* inhibited HG-induced profibrotic signaling (Akt activation) and matrix/cytokine upregulation (collagen IV, fibronectin, CTGF, and TGFß1). In patients with established DKD, urinary α2M* and TGFß1 levels were correlated. These data reveal an important role for α2M* in the pathogenesis of DKD and support further investigation as a potential novel therapeutic target.

Impact of the gate-keeping policies of China's primary healthcare model on the future burden of tuberculosis in China: a protocol for a mathematical modelling study.

INTRODUCTION: In the past three decades, China has made great strides in the prevention and treatment of tuberculosis (TB). However, the TB burden remains high. In 2019, China accounted for 8.4% of global incident cases of TB, the third highest in the world, with a higher prevalence in rural areas. The Healthy China 2030 highlights the gate-keeping role of primary healthcare (PHC). However, the impact of PHC reforms on the future TB burden is unclear. We propose to use mathematical models to project and evaluate the impacts of different gate-keeping policies. METHODS AND ANALYSIS: We will develop a deterministic, population-level, compartmental model to capture the dynamics of TB transmission within adult rural population. The model will incorporate seven main TB statuses, and each compartment will be subdivided by service providers. The parameters involving preference for healthcare seeking will be collected using discrete choice experiment (DCE) method. We will solve the deterministic model numerically over a 20-year (2021-2040) timeframe and predict the TB prevalence, incidence and cumulative new infections under the status quo or various policy scenarios. We will also conduct an analysis following standard protocols to calculate the average cost-effectiveness for each policy scenario relative to the status quo. A numerical calibration analysis against the available published TB prevalence data will be performed using a Bayesian approach. ETHICS AND DISSEMINATION: Most of the data or parameters in the model will be obtained based on secondary data (eg, published literature and an open-access data set). The DCE survey has been reviewed and approved by the Ethics Committee of the School of Public Health, Sun Yat-sen University. The approval number is SYSU [2019]140. Results of the study will be disseminated through peer-reviewed journals, media and conference presentations.

Characteristics of rifampicin-resistant tuberculosis detection in China, 2015-2019.

BACKGROUND: The very high burden of rifampicin resistance tuberculosis (RR-TB) and the very low detection of RR-TB cases are a major challenge that China has been facing. This study analyzed the characteristics of RR-TB detection in China after the change of RR-TB detection strategy since 2015, aiming to provide reference and evidence for the development of more precise national drug resistance tuberculosis prevention and control policy. METHODS: We extracted data related to rifampicin resistance screening from the national Tuberculosis Information Management System (TBIMS) from 2015 to 2019, and used descriptive research methods to analyze the screening rate of presumptive RR-TB, the number and duration of RR-TB patients detected and drug resistance testing methods in each year. Chi-square test was used to compare the differences in component ratio or rate between years, and Kruskal Wallis test was used to compare the differences in median days for detection of RR-TB patients in each year. RESULTS: A total of 68,200 RR-TB cases were detected during 2015-2019, of which 48.1% were new cases. The number and detection rate of RR-TB cases increased year by year, from 10 019 and 14.3% in 2015 to 18 623 and 28.7% in 2019, respectively. Of the bacteriologically confirmed TB cases, 81.9% were tested for RR in 2019, a considerable increase from 29.5% in 2015. In 2019, only 41.0% of RR-TB cases had fluoroquinolones (FQs) susceptibility testing performed, and this proportion has been declining year by year since 2016. The proportion of application of rapid molecular tools increased from 24.0% in 2015 to 67.1% in 2019, and the median days to obtain RR results was significantly shortened. In 2019, 76.0% of RR-TB cases were diagnosed as presumptive RR-TB in county-level hospitals. CONCLUSIONS: After China modified the RR-TB detection strategy, the screening rate of RR and the number of RR-TB cases increased significantly. The RR testing methods now predominantly utilize rapid molecular tools. However, comprehensive measures should be implemented to close the gap in the detection of RR-TB cases. It is imperative to take FQs susceptibility testing seriously and effectively strengthen the laboratory capacity of county-level hospitals.

Activin A and Cell-Surface GRP78 Are Novel Targetable RhoA Activators for Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of kidney failure. RhoA/Rho-associated protein kinase (ROCK) signaling is a recognized mediator of its pathogenesis, largely through mediating the profibrotic response. While RhoA activation is not feasible due to the central role it plays in normal physiology, ROCK inhibition has been found to be effective in attenuating DKD in preclinical models. However, this has not been evaluated in clinical studies as of yet. Alternate means of inhibiting RhoA/ROCK signaling involve the identification of disease-specific activators. This report presents evidence showing the activation of RhoA/ROCK signaling both in vitro in glomerular mesangial cells and in vivo in diabetic kidneys by two recently described novel pathogenic mediators of fibrosis in DKD, activins and cell-surface GRP78. Neither are present in normal kidneys. Activin inhibition with follistatin and neutralization of cell-surface GRP78 using a specific antibody blocked RhoA activation in mesangial cells and in diabetic kidneys. These data identify two novel RhoA/ROCK activators in diabetic kidneys that can be evaluated for their efficacy in inhibiting the progression of DKD.

The epidemiologic impact and cost-effectiveness of new tuberculosis vaccines on multidrug-resistant tuberculosis in India and China.

BACKGROUND: Despite recent advances through the development pipeline, how novel tuberculosis (TB) vaccines might affect rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) is unknown. We investigated the epidemiologic impact, cost-effectiveness, and budget impact of hypothetical novel prophylactic prevention of disease TB vaccines on RR/MDR-TB in China and India. METHODS: We constructed a deterministic, compartmental, age-, drug-resistance- and treatment history-stratified dynamic transmission model of tuberculosis. We introduced novel vaccines from 2027, with post- (PSI) or both pre- and post-infection (P&PI) efficacy, conferring 10 years of protection, with 50% efficacy. We measured vaccine cost-effectiveness over 2027-2050 as USD/DALY averted-against 1-times GDP/capita, and two healthcare opportunity cost-based (HCOC), thresholds. We carried out scenario analyses. RESULTS: By 2050, the P&PI vaccine reduced RR/MDR-TB incidence rate by 71% (UI: 69-72) and 72% (UI: 70-74), and the PSI vaccine by 31% (UI: 30-32) and 44% (UI: 42-47) in China and India, respectively. In India, we found both USD 10 P&PI and PSI vaccines cost-effective at the 1-times GDP and upper HCOC thresholds and P&PI vaccines cost-effective at the lower HCOC threshold. In China, both vaccines were cost-effective at the 1-times GDP threshold. P&PI vaccine remained cost-effective at the lower HCOC threshold with 49% probability and PSI vaccines at the upper HCOC threshold with 21% probability. The P&PI vaccine was predicted to avert 0.9 million (UI: 0.8-1.1) and 1.1 million (UI: 0.9-1.4) second-line therapy regimens in China and India between 2027 and 2050, respectively. CONCLUSIONS: Novel TB vaccination is likely to substantially reduce the future burden of RR/MDR-TB, while averting the need for second-line therapy. Vaccination may be cost-effective depending on vaccine characteristics and setting.

miR299a-5p promotes renal fibrosis by suppressing the antifibrotic actions of follistatin.

Caveolin-1 (cav-1), an integral protein of the membrane microdomains caveolae, is required for synthesis of matrix proteins by glomerular mesangial cells (MC). Previously, we demonstrated that the antifibrotic protein follistatin (FST) is transcriptionally upregulated in cav-1 knockout MC and that its administration is protective against renal fibrosis. Here, we screened cav-1 wild-type and knockout MC for FST-targeting microRNAs in order to identity novel antifibrotic therapeutic targets. We identified that miR299a-5p was significantly suppressed in cav-1 knockout MC, and this was associated with stabilization of the FST 3'UTR. Overexpression and inhibition studies confirmed the role of miR299a-5p in regulating FST expression. Furthermore, the profibrotic cytokine TGFß1 was found to stimulate the expression of miR299a-5p and, in turn, downregulate FST. Through inhibition of FST, miR299a-5p overexpression augmented, while miR299a-5p inhibition diminished TGFß1 profibrotic responses, whereas miR299a-5p overexpression re-enabled cav-1 knockout MC to respond to TGFß1. In vivo, miR299a-5p was upregulated in the kidneys of mice with chronic kidney disease (CKD). miR299a-5p inhibition protected these mice against renal fibrosis and CKD severity. Our data demonstrate that miR299a-5p is an important post-transcriptional regulator of FST, with its upregulation an important pathogenic contributor to renal fibrosis. Thus, miR299a-5p inhibition offers a potential novel therapeutic approach for CKD.

PlotThread: Creating Expressive Storyline Visualizations using Reinforcement Learning.

Storyline visualizations are an effective means to present the evolution of plots and reveal the scenic interactions among characters. However, the design of storyline visualizations is a difficult task as users need to balance between aesthetic goals and narrative constraints. Despite that the optimization-based methods have been improved significantly in terms of producing aesthetic and legible layouts, the existing (semi-) automatic methods are still limited regarding 1) efficient exploration of the storyline design space and 2) flexible customization of storyline layouts. In this work, we propose a reinforcement learning framework to train an AI agent that assists users in exploring the design space efficiently and generating well-optimized storylines. Based on the framework, we introduce PlotThread, an authoring tool that integrates a set of flexible interactions to support easy customization of storyline visualizations. To seamlessly integrate the AI agent into the authoring process, we employ a mixed-initiative approach where both the agent and designers work on the same canvas to boost the collaborative design of storylines. We evaluate the reinforcement learning model through qualitative and quantitative experiments and demonstrate the usage of PlotThread using a collection of use cases.