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Quirui Nie,1 Hui Qian,2,3 Shenjian Chen,3 Wenwen Xiang,3 Yu Shen3,4 1Department of Gerontology, Nanchang First Hospital, Nanchang, People’s Republic of China; 2Department of Neurology, Fengxin County People’s Hospital, Fengxin, People’s Republic of China; 3Department of Neurology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China; 4Department of Neurology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of ChinaCorrespondence: Yu Shen, Department of Neurology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China, Email shenyu19950712@sina.comObjective: To compare the differences in risk factors and etiological classification between cerebral infarction in young patients and elderly patients, and explore the correlation between cerebral infarction in young patients and white matter lesions (WMLs).Methods: Sixty young patients with cerebral infarction and 142 elderly patients with cerebral infarction were included. The distributions of risk factors such as hypertension, diabetes, heart disease, smoking status, alcohol consumption status, migraine status, and WMLs in the two groups were carefully investigated and statistically analyzed.Results: According to the univariate analysis, the proportions of males, obese patients, patients with migraine, and patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) in the young group were significantly greater than those in the elderly group. Hypertension, heart disease, and hyperhomocysteinemia were significantly more common in the elderly group than in the young group. According to the TOAST classification, the incidence of stroke of undetermined etiology in the young group was greater than that in the elderly group, whereas the incidence of large-artery atherosclerosis (LAA) in the elderly group was greater than that in the young group. Binary logistic regression analysis revealed that male sex, migraine status, and obstructive sleep apnea-hypopnea syndrome were independently associated with cerebral infarction in young adults, whereas hypertension, heart disease, and hyperhomocysteinemia were independently related to cerebral infarction in elderly individuals. In addition, the incidence of WMLs in the migraine group of young cerebral infarction patients was significantly greater than that in the nonmigraine group.Conclusion: Compared with those in elderly patients with cerebral infarction, the risk factors for cerebral infarction in young patients are relatively controllable. Furthermore, more methods are needed to determine the etiology of unexplained cerebral infarction in young patients. WMLs are thought to have a relatively high incidence in young patients with cerebral infarction and are significantly associated with migraine.Keywords: cerebral infarction, white matter lesions, young people, risk factors, migraine

Guang Chen,1,* Caohua Lv,2,* Qing Nie,3 Xin Li,1 Yinyi Lv,1 Guoyan Liao,1 Shuangchun Liu,4 Weiwei Ge,2 Jinguang Chen,1 Yunting Du5 1Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, 318000, People’s Republic of China; 2Department of Dermatology, Taizhou Second People’s Hospital, Taizhou, 317200, People’s Republic of China; 3Weifang Centers for Disease Control and Prevention, Weifang, 261061, People’s Republic of China; 4Municipal Hospital Affiliated to Medical School of Taizhou University, Taizhou, 318000, People’s Republic of China; 5Department of Laboratory Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinguang Chen; Yunting Du, Tel/Fax +86 576 88661988, Email tongly0422@126.com; m15840557769@163.comBackground: The traditional Matricaria chamomilla L. has been used to treat dermatitis for thousands of years. Due to emerging trends in alternative medicine, patients prefer natural remedies to relieve their symptoms. Therefore, finding safe and effective plant medicines for topical applications on the skin is an important treatment strategy for dermatologists. German chamomile (Matricaria chamomilla L.) from the Compositae family is a famous medicinal plant, often known as the “star of medicinal species.”However, the function of Matricaria chamomilla essential oil on skin inflammation has not been thoroughly examined in earlier research.Methods: GC-MS analyzed the components of MCEO, and this study explored the anti-inflammation effects of MCEO on psoriasis with network pharmacological pathway prediction. Following this, we used clinical samples of psoriasis patients to confirm the secretory characteristic of relative inflammatory markers. The therapeutic effect of MCEO on skin inflammation was detected by examination of human keratinocytes HaCaT. At the same time, we prepared imiquimod-induced psoriatic-like skin inflammation in mice to investigate thoroughly the potential inhibition functions of MCEO on psoriatic skin injury and inflammation.Results: MCEO significantly reduced interleukin-22/tumor necrosis factor α/lipopolysaccharide-stimulated elevation of HaCaT cell inflammation, which was correlated with downregulating PI3K/Akt/mTOR and p38MAPK pathways activation mediated by MCEO in HaCaT cells treated with IL-22/TNF-α/LPS. Skin inflammation was evaluated based on the PASI score, HE staining, and relative inflammatory cytokine levels. The results showed that MCEO could significantly contribute to inflammatory skin disease treatment.Conclusion: MCEO inhibited inflammation in HaCaT keratinocytes induced by IL-22/TNF-α/LPS, the potential mechanisms associated with inhibiting excessive activation and crosstalk between PI3K/Akt/mTOR and p38MAPK pathways. MCEO ameliorated skin injury in IMQ-induced psoriatic-like skin inflammation of mice by downregulating the levels of inflammatory cytokines but not IL-17A. Thus, anti-inflammatory plant drugs with different targets with combined applications were a potential therapeutic strategy in psoriasis.Keywords: Matricaria chamomilla, essential oil, psoriasis, HaCaT, IMQ, mouse

Huanxin Liu,1 Yuling Xing,2 Qian Nie,1 Zhong Li,3 Cuiqiao Meng,1 Huijuan Ma2,4 1Health Examination Center, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China; 2Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China; 3Department of General Surgery, Shijiazhuang People’s Hospital, Shijiazhuang, 050011, People’s Republic of China; 4Key Laboratory of Metabolic Disease in Hebei Province, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of ChinaCorrespondence: Huijuan Ma, Department of Endocrinology, Hebei General Hospital, Shijiazhuang, 050051, People’s Republic of China, Tel +86 18032838686, Email huijuanma76@163.comObjective: Thyroid hormones (THs) exert instrumental effects in regulating lipids metabolism. Whereas, research investigating the relationship between sensitivity indices to THs and metabolic dysfunction-associated fatty liver disease (MAFLD) have contradicted this. This study was designed to approach the correlation between sensitivity indices to THs and MAFLD in euthyroid subjects.Methods: An overall sample of 6356 euthyroid participants were enrolled in a Chinese hospital. Free triiodothyronine to free thyroxine ratio (FT3/FT4), thyrotropin triiodothyronine resistance index (TT3RI), thyrotropin thyroxine resistance index (TT4RI), thyroid stimulating hormone index (TSHI) and thyroid feedback quantile-based indices (TFQIFT3 and TFQIFT4) were collected as sensitivity indicators to THs. Participants were split into two groups based on whether they suffered with MAFLD or not. And participants were categorized into quartiles based on sensitivity indicators to THs. The effects of sensitivity indices to THs on MAFLD were analyzed using regression analysis. Bootstrap was performed to assess the mediation effect of triglyceride glucose (TyG) index on the relationship between sensitivity parameters to THs and MAFLD.Results: The incidence of MAFLD in euthyroid subjects was 34.47%. As FT3/FT4, TT3RI and TFQIFT3 levels rose, so did the MAFLD prevalence. After adjustment for confounders, logistic regression analyses indicated that the high-level FT3/FT4 and TFQIFT3 still remained risk factors for MAFLD. The relevance of FT3/FT4 and MAFLD was stronger among those whose age ≤ 40 years and had non-visceral obesity. And the interrelation between TFQIFT3 and MAFLD was stronger in subjects whose age ≤ 40 years. Mediation analyses suggested that TyG index had a noteworthy indirect impact on the relationship between FT3/FT4, TFQIFT3 and MAFLD.Conclusion: Increased FT3/FT4 and TFQIFT3 were significantly related to MAFLD prevalence in populations with normal thyroid function. TyG index partly mediated the relevance between FT3/FT4, TFQIFT3 and MAFLD.Keywords: thyroid hormone sensitivity, metabolic dysfunction-associated fatty liver disease, triglyceride glucose index, mediation effect

Xia Liu,1,2,&ast; Xiaojing Jiao,1,&ast; Xiaowei Gong,3 Qingrong Nie,4 Yang Li,2 Guohua Zhen,5 Mengyu Cheng,6 Jianguo He,7 Yadong Yuan,3 Yuanhua Yang1 1Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Capital Medical University Daxing Teaching Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Beijing Fangshan District Liangxiang Hospital, Beijing, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 7Department of Cardiovascular Medicine, Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuanhua Yang, Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China, Email yyh1031@sina.com Yadong Yuan, The Second Hospital of Hebei Medical University, Hebei, 050004, People’s Republic of China, Email yyd1108@163.comBackground and Objective: The prevalence of venous thrombus embolism (VTE) in patients with chronic obstructive pulmonary disease (COPD) is higher than in patients without COPD. Owing to the similarity of clinical symptoms between PE and acute exacerbation COPD (AECOPD), PE is likely to be overlooked or underdiagnosed in patients with AECOPD. The aim of the study was to investigate the prevalence, risk factor, clinical characteristics, and prognostic impact of VTE in patients with AECOPD.Methods: This multicenter, prospective, cohort study was conducted in 11 research centers of China. Data on the baseline characteristics, VTE-related risk factors, clinical symptoms, laboratory examination results, computed tomography pulmonary angiography (CTPA) and lower limb venous ultrasound of AECOPD patients were collected. Patients were followed up for 1 year.Results: A total of 1580 AECOPD patients were included in the study. The mean (SD) age was 70.4 (9.9) years and 195 (26%) patients were women. The prevalence of VTE was 24.5% (387/1580) and PE was 16.8% (266/1580). VTE patients were older; had higher BMI; and longer course of COPD than non-VTE patients. The history of VTE, cor pulmonale, less purulent sputum, increased respiratory rate, higher D-dimer, and higher NT-proBNP/BNP were independently associated with VTE in hospitalized patients with AECOPD. The mortality at 1-year was higher in patients with VTE than patients without VTE (12.9% vs 4.5%, p< 0.01). There was no significant difference in the prognosis of patients with PE in segmental or subsegmental arteries and in main pulmonary arteries or lobar arteries (P> 0.05).Conclusion: VTE is common in COPD patients and is associated with poor prognosis. Patients with PE at different locations had poorer prognosis than patients without PE. It is necessary to perform active screening strategy for VTE in AECOPD patients with risk factors.Keywords: chronic obstructive pulmonary disease, venous thromboembolism, computed tomography pulmonary angiography, prognosis

Yilin Hou,1,2 Xiaoyu Hou,1,2 Qian Nie,3 Qiuyang Xia,1,2 Rui Hu,1,2 Xiaoyue Yang,1,2 Guangyao Song,2,4 Luping Ren2,4 1Graduate School, Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of China; 2Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China; 3Health Examination Center, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China; 4Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of ChinaCorrespondence: Guangyao Song; Luping Ren, Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China, Email sguangyao2@163.com; renluping1122@163.comPurpose: The aim of this study was to evaluate the association of bone turnover markers (BTMs) with type 2 diabetes mellitus (T2DM) and microvascular complications.Methods: A total of 166 T2DM patients and 166 non-diabetic controls matched by gender and age were enrolled. T2DM patients were sub-classified into groups based on whether they had diabetic peripheral neuropathy (DPN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). Clinical data including demographic characteristics and blood test results [serum levels of osteocalcin (OC), N-terminal propeptide of type 1 procollagen (P1NP), and β-crosslaps (β-CTX)] were collected. Logistic regression and restrictive cubic spline curves were performed to examine the association of BTMs with the risk of T2DM and microvascular complications.Results: After adjusting for family history of diabetes, sex and age, an inverse association was observed between elevated serum OC levels [O, p < 0.001] and increased serum P1NP levels , p < 0.001] with the risk of T2DM. Moreover, there was an inverse linear association of serum OC and P1NP levels with the risk of T2DM. However, β-CTX was not associated with T2DM. Further analysis showed a nonlinear association between OC and the risk of DR, while P1NP and β-CTX were not correlated with DR. Serum concentrations of BTMs were not associated with the risks of DPN and DKD.Conclusion: Serum OC and P1NP levels were negatively correlated with T2DM risk. Particularly, serum OC levels were associated with DR risk. Given that BTMs are widely used as markers of bone remodeling, the present finding provides a new perspective for estimating the risk of diabetic microvascular complications.Keywords: bone turnover markers, type 2 diabetes mellitus, microvascular complications

Jisong Yan,1 Hong Luo,1 Qi Nie,1 Shengling Hu,2 Qi Yu,2 Xianguang Wang1 1Department of Respiratory and Critical Care Medicine, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of China; 2Department of Infectious Diseases, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of ChinaCorrespondence: Qi Yu, Department of Infectious Diseases, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of China, Email fishns123@163.com Xianguang Wang, Department of Respiratory and Critical Care Medicine, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of China, Email 907395635@qq.comBackground: The growth of antibiotic resistance to Mycobacterium TB represents a major barrier to the goal of “Ending the global TB epidemics”. This study aimed to develop and validate a simple clinical scoring system to predict the unfavorable treatment outcomes (UTO) in multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) patients.Methods: A total of 333 MDR/RR-TB patients were recruited retrospectively. The clinical, radiological and laboratory features were gathered and selected by lasso regression. These variables with area under the receiver operating characteristic curve (AUC)> 0.6 were subsequently submitted to multivariate logistic analysis. The binomial logistic model was used for establishing a scoring system based on the nomogram at the training set (N = 241). Then, another independent set was used to validate the scoring system (N = 92).Results: The new scoring system consists of age (8 points), education level (10 points), bronchiectasis (4 points), red blood cell distribution width-coefficient of variation (RDW-CV) (7 points), international normalized ratio (INR) (7 points), albumin to globulin ratio (AGR) (5 points), and C-reactive protein to prealbumin ratio (CPR) (6 points). The scoring system identifying UTO has a discriminatory power of 0.887 (95% CI=0.835– 0.939) in the training set, and 0.805 (95% CI=0.714– 0.896) in the validation set. In addition, the scoring system is used exclusively to predict the death of MDR/RR-TB and has shown excellent performance in both training and validation sets, with AUC of 0.930 (95% CI=0.872– 0.989) and 0.872 (95% CI=0.778– 0.967), respectively.Conclusion: This novel scoring system based on seven accessible predictors has exhibited good predictive performance in predicting UTO, especially in predicting death risk.Keywords: multidrug- and rifampicin-resistant tuberculosis, treatment outcome, laboratory parameters, scoring system

Yu Shen,1,&ast; Qiurui Nie,2,&ast; Yibi Zhang,3 Qian Cao,1 Zhuo Hou,1 Lijun Xu1 1Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Cardiovascular Medicine, People’s Hospital Affiliated of Nanchang University, Jiangxi Provincial People’s Hospital, Nanchang, Jiangxi, People’s Republic of China; 3Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lijun XuDepartment of Neurology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Nanchang, Jiangxi, People’s Republic of ChinaEmail xulijun20050901@sina.comImportance: The treatment of cryptogenic stroke patients with patent foramen ovale to prevent recurrence of stroke, especially when patients consider drug prevention alone, has caused serious treatment dilemmas in clinical practice.Objective: To study the safety and efficacy of different treatment strategies using a network meta-analysis of randomized controlled trials in this population with cryptogenic stroke and patent foramen ovale.Study Selection: PUBMED, EMBASE, The Cochrane Library, WangFang, and China National Knowledge Infrastructure were searched to identify RCT comparing different treatment strategies. Eleven randomized studies were included (n = 5706).Main Outcomes: The primary efficacy outcome was recurrence of ischemic stroke, including fatal and non-fatal ischemic strokes. The primary safety outcome was major hemorrhage, but closure surgery includes systemic thrombotic events, persistent atrial fibrillation, surgical deaths and other major events.Results: In terms of efficacy and safety events, compared with antiplatelet, the OR of vitamin K antagonists for stroke recurrence was 0.81 (95% CI, 0.41– 1.6), the OR of surgical closure was 0.38 (95% CI, 0.16– 0.63), and the OR of NOAC was 0.79 (95% CI, 0.27– 2.3). Compared with antiplatelet, the safety event OR of vitamin K antagonists was 1.7 (95% CI, 0.65– 4.8), the OR of surgical closure was 1.7 (95% CI, 0.68– 3.8), and the OR of NOAC was 2.2 (95% CI, 0.67– 7.6).Conclusion: In terms of effectiveness, surgical occlusion has the best performance, while anticoagulation is the second best. Vitamin K antagonists and non-vitamin K antagonists are difficult to distinguish between the best in effectiveness. Antiplatelet drugs are considered the worst option. Regarding the safety results, it is generally believed that there are no obvious beneficial interventions, but antiplatelet drugs are considered to be relatively best, followed by surgical intervention and vitamin K antagonists, and non-vitamin K antagonists are considered to be the least safe.Keywords: cryptogenic stroke, patent foramen ovale, PFO, treatment strategies, network meta-analysis

Jing Zhu,1,2,* Zhiling Zhao,3,* Bin Wu,4 Zhihong Shi,5 Qingrong Nie,6 Zhen Fu,7 Zhaofu Zeng,1 Weihua Hu,1 Minglin Dong,1 Mengqing Xiong,1 Ke Hu1 1Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The People’s Hospital of China Three Gorges University, Yichang, Hubei, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Institute of Respiratory Diseases, Department of Respiratory, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China; 5Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Xian Jiaotong University, Xian, Shanxi, People’s Republic of China; 6Division of Respiratory Disease, Liangxiang Hospital of Yanjing Medical College, Capital Medical University, Beijing, People’s Republic of China; 7Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ke Hu Email huke-rmhospital@163.comObjective: The aim of this study was to explain “obesity paradox” in chronic obstructive pulmonary disease (COPD) by evaluating the effect of body mass index (BMI) on lung function in Chinese patients with COPD.Methods: A total of 1644 patients diagnosed with COPD were recruited from four Chinese tertiary hospitals and were divided into four groups including underweight, normal weight, overweight and obese according to BMI classification standard. The medical data of these patients were collected and used for the multiple linear regression analyses.Results: After adjustment for age, sex, educational level, economic status, smoking status, alcohol consumption, duration of COPD history, events of acute exacerbation in previous year, hypertension, diabetes mellitus, cardiovascular disease, cerebrovascular disease and osteoporosis, BMI had a curvilinear correlation with the forced expiratory volume in the first second (FEV1) in patients with Global Initiative for Obstructive Lung Disease (GOLD) 1– 2 grade (first-order coefficient β, 0.09; 95% CI, 0.03– 0.16; second-order coefficient β, − 0.002; 95% CI, − 0.003–-0.001; P< 0.01). However, BMI had a positive correlation with FEV1 in patients with GOLD 3– 4 grade (β, 0.01; 95% CI, 0.008– 0.017; P< 0.01) when BMI was used as a quantitative variable. When BMI was used as a qualitative variable, only FEV1 in overweight group with GOLD 1– 2 grade was significantly higher than that of normal weight group (P< 0.01). Interestingly, both overweight and obese groups had higher FEV1 in GOLD 3– 4 grade compared with normal weight group (β, 0.06; 95% CI, 0.02– 0.11; β, 0.11; 95% CI, 0.04– 0.18; P< 0.01). The effect of BMI on predicted percentage of FEV1 (FEV1%) was similar to that of FEV1 in different GOLD grades.Conclusion: Obesity only had a protective effect on lung function in COPD patients with GOLD 3– 4 grade rather than GOLD 1– 2 grade.Trial Registry: ClinicalTrials.gov, No.: NCT 03182309, URL: www.clinicaltrials.gov.Keywords: overweight, obesity

An efficient and reliable network alignment serves to find the mapping with maximum similarity between different networks, which is a way to improve our understanding of biology system and biological process. To build such network alignment is a foremost challenging task in computational biology because it involves the bipartite graph matching problem, which is an NP-hard problem. In this work, we propose a novel global biomolecular network alignment method named NFMA. Based on the minimum cost maximum flow problem (MCMFP) of network flow model, NFMA introduces opposite numbers to address the maximum cost problem so that the new model can get the alignment with maximum similarity. Furthermore, based on the existing method used to describe topological structure in undirected network, we present a new measure to identify topological information in directed network, which enables NFMA to extend to alignment in directed network. We conduct three experiments on classical yeast protein-protein interaction networks (PINs) and human PINs. We compare NFMA with other 7 eminent algorithms, and prove that NFMA can obtain an efficient and meaningful alignment which takes both biological similarity and topological similarity into consideration, and the time efficiency of NFMA is also outstanding in that it only takes approximately 250 seconds to get an accurate alignment when aligning two large networks.

Morphogens were originally defined as secreted signaling molecules that diffuse from local sources to form concentration gradients, which specify multiple cell fates. More recently morphogen gradients have been shown to incorporate a range of mechanisms including short-range signal activation, transcriptional/translational feedback, and temporal windows of target gene induction. Many critical cell-cell signals implicated in both embryonic development and disease, such as Wnt, fibroblast growth factor (Fgf), hedgehog (Hh), transforming growth factor beta (TGFb), and retinoic acid (RA), are thought to act as morphogens, but key information on signal propagation and ligand distribution has been lacking for most. The zebrafish provides unique advantages for genetics and imaging to address gradients during early embryonic stages when morphogens help establish major body axes. This has been particularly informative for RA, where RA response elements (RAREs) driving fluorescent reporters as well as Fluorescence Resonance Energy Transfer (FRET) reporters of receptor binding have provided evidence for gradients, as well as regulatory mechanisms that attenuate noise and enhance gradient robustness in vivo. Here we summarize available tools in zebrafish and discuss their utility for studying dynamic regulation of RA morphogen gradients, through combined experimental and computational approaches.

Background: Colon crypts, a single sheet of epithelia cells, consist of a periodic pattern of stem cells, transit-amplifying cells, and terminally differentiated cells that constantly renew and turnover. Experimental evidence suggests that Wnt signaling promotes and regulates stem cell division, differentiation, and possible cell migrations while intestinal BMP signaling inhibits stem cell self-renewal and repression in crypt formation. As more molecular details on Wnt and BMP in crypts are being discovered, little is still known about how complex interactions among Wnt, BMP, and different types of cells, and surrounding environments may lead to de novo formation of multiple crypts or how such interactions affect regeneration and stability of crypts.Results: We present a mathematical model that contains Wnt and BMP, a cell lineage, and their feedback regulations to study formation, regeneration, and stability of multiple crypts. The computational explorations and linear stability analysis of the model suggest a reaction-diffusion mechanism, which exhibits a short-range activation of Wnt plus a long-range inhibition with modulation of BMP signals in a growing tissue of cell lineage, can account for spontaneous formation of multiple crypts with the spatial and temporal pattern observed in experiments. Through this mechanism, the model can recapitulate some distinctive and important experimental findings such as crypt regeneration and crypt multiplication. BMP is important in maintaining stability of crypts and loss of BMP usually leads to crypt multiplication with a fingering pattern.Conclusions: The study provides a mechanism for de novo formation of multiple intestinal crypts and demonstrates a synergetic role of Wnt and BMP in regeneration and stability of intestinal crypts. The proposed model presents a robust framework for studying spatial and temporal dynamics of cell lineages in growing tissues driven by multiple signaling molecules. © 2012 Zhang et al.; licensee BioMed Central Ltd.

Exogenous environmental changes are known to affect the intrinsic characteristics of biological organizms. For instance, the synthesis rate of the morphogen decapentaplegic (Dpp) in a Drosophila wing imaginal disc has been found to double with an increase of 5.9°C in ambient temprerature. If not compensated, such a change would alter the signaling Dpp gradient significantly and thereby the development of thewing imaginal disc. To learn how flies continue to develop "normally" under such an exogenous change, we formulate in this paper a spatially two-dimensional reaction-diffusion system of partial differential equations (PDE) that accounts for the biological processes at work in the Drosophila wing disc essential for the formation of signaling Dpp gradient. By way of this PDE model, we investigate the effect of the apical-basal thickness and antero-posterior span of the wing on the shape of signaling gradients and the robustness of wing development in an altered environment (including an enhanced morphogen synthesis rate). Our principal result is a delineation of the role of wing disc size change in maintaining the magnitude and shape of the signaling Dpp gradient. The result provides a theoretical basis for the observed robustness of wing development, preserving relative but not absolute tissue pattern, when the morphogen synthesis rate is significantly altered. A similar robustness considerqation for simultaneous changes of multiple intrinsic system characteristics is also discussed briefly.

Receptor-mediated BMP degradation has been seen to play an important role in allowing for the formation of relatively stable P Mad patterns. To the extent that receptors act as a "sink" for BMPs, one would predict that the localized over-expression of signaling receptors would cause a net flux of freely diffused BMPs toward the ectopic, i.e., abnormally high concentration, receptor site. One possible consequence would be a depression of BMP signaling in adjacent areas since less BMPs are now available for binding with the same normal concentration of receptors at the adjacent areas. However, recent experiments designed to examine this possible effect were inconclusive. In this paper, we investigate the possibility of depression of Dpp signaling outside the area of elevated tkv in a Drosophila embryo by modeling mathematically the basic biological processes at work in terms of a system of nonlinear reaction diffusion equations with spatially varying (and possibly discontinuous) system properties. The steady state signaling morphogen gradient is investigated by the method of matched asymptotic expansions and by numerical simulations.

A previously investigated basic model (System B) for the study of signaling morphogen gradient formation that allows for reversible binding of morphogens (aka ligands) with signaling receptors, degradation of bound morphogens and diffusion of unbound morphogens is extended to include the effects of membrane-bound non-signaling molecules (or non-receptors for short) such as proteoglycans that bind reversibly with the same morphogens and degrade them. Our main goal is to delineate the effects of the presence of non-receptors on the existence and properties of the steady-state concentration gradient of signaling ligand-receptor complexes. Stability of the steady-state morphogen gradients is established and the time to reach steady-state behavior after the onset of morphogen production will be analyzed. The theoretical findings offer explanations for observations reported in several previous experiments on Drosophila wing imaginal discs.

Two simple reaction-diffusion systems of partial differential equations and auxiliary conditions governing the activities of diffusible ligands such as Dpp in anterior-posterior axis of Drosophila wing imaginal discs were previously formulated and investigated by numerical simulations in [Developmental Cell 2 (2002) 785-796]. System B focuses on diffusion, reversible binding with receptors and ligand-mediated degradation for a fixed receptor concentration uniform in time and space. System C extended this basic but meaningful model to allow for endocytosis, exocytosis and receptor synthesis and degradation. The present paper provides a mathematical underpinning for the computational studies of these two systems and some insight gained from our analysis. We will see for instance that the two boundary value problems governing the steady state for the two systems are identical in form. This result will enable us to avoid dealing with internalization explicitly when we investigate other complex morphogen activities such as the effects of (1) feedback and (2) diffusible and non-diffusible molecules competing for ligands and receptors to inhibit cell signaling and pattern formation. The principal contribution of the present work pertains to the extension of System C to allow for a ligand flux at the source end. The more general model has many significant consequences including the removal of a limitation of previous models on ligand synthesis rate for the existence of steady state behavior. Linear stability of the corresponding steady state behavior is established. While the actual decay rate of transients is less accessible in this new model, it is possible to obtain tight upper and lower bounds for the decay rate in terms of the (effective) degradation rate of the receptors and that of the ligand-receptor complexes. © 2005 Elsevier B.V. All rights reserved. All rights reserved.

In the development of a biological entity, ligands (such as Decapentaplegic (Dpp) along the anterior-posterior axis of the Drosophila wing imaginal disc) are synthesized at a localized source and transported away from the source for binding with cell surface receptors to form concentration gradients of ligand-receptor complexes for cell signaling. Generally speaking, activities such as diffusion and reversible binding with degradable receptors also take place in the region of ligand production. The effects of such morphogen activities in the region of localized distributed ligand source on the ligand-receptor concentration gradient in the entire biological entity have been modeled and analyzed as System F in [1]. In this paper, we deduce from System F, a related end source model (System A) in which the effects of the distributed ligand source is replaced by an idealized point stimulus at the border between the (posterior) chamber and the ligand production region that simulates the average effects of the ligand activities in the production zone. This aggregated end source model is shown to adequately reproduce the significant implications of System F and to contain the corresponding ad hoc point source model, System R of [2], as a special case. Because of its simpler mathematical structure and the absence of any limitation on the ligand synthesis rate for the existence of steady-state gradients, System A type models are expected to be used widely. An example of such application is the recent study of the inhibiting effects of the formation of nonsignaling ligand-nonreceptor complexes [3].