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Tuberous sclerosis complex (TSC) is a rare genetic disease that is, besides cutaneous and visceral organ manifestations, typically associated with a severe, usually drug refractory epilepsy at a very early stage of the disease. Due to its direct effect on the mTOR signaling pathway dysregulated by TSC and its synergistic effects on other organ manifestations, the rapamycin derivative everolimus (EVE) is increasingly being used. The aim of this systematic review is to evaluate the efficacy, safety and tolerability of EVE in patients with TSC-associated, refractory epilepsy.
Vovchenko, Volodymyr ; Brandt, Bastian Benjamin ; Cuteri, Francesca ; Endrődi, Gergely ; Hajkarim, Fazlollah ; Schaffner-Bielich, Jürgen
We investigate the possible formation of a Bose-Einstein condensed phase of pions in the early Universe at nonvanishing values of lepton flavor asymmetries. A hadron resonance gas model with pion interactions, based on first-principle lattice QCD simulations at nonzero isospin density, is used to evaluate cosmic trajectories at various values of electron, muon, and tau lepton asymmetries that satisfy the available constraints on the total lepton asymmetry. The cosmic trajectory can pass through the pion condensed phase if the combined electron and muon asymmetry is sufficiently large: |le+lμ|≳0.1, with little sensitivity to the difference le−lμ between the individual flavor asymmetries. Future constraints on the values of the individual lepton flavor asymmetries will thus be able to either confirm or rule out the condensation of pions during the cosmic QCD epoch. We demonstrate that the pion condensed phase leaves an imprint both on the spectrum of primordial gravitational waves and on the mass distribution of primordial black holes at the QCD scale, e.g., the black hole binary of recent LIGO event GW190521 can be formed in that phase.
Ablikim, Medina ; Achasov, Mikhail N. ; Adlarson, Patrik ; Ahmed, Samer ; Albrecht, Malte ; Aliberti, Riccardo ; Amoroso, Antonio ; An, Q. ; Bai, X. H. ; Bai, Y. ; Bakina, Olga ; Baldini Ferroli, Rinaldo ; Balossino, Ilaria ; Ban, Yong ; Begzsuren, Khurelbaatar ; Berger, Niklaus ; Bertani, Monica ; Bettoni, Diego ; Bianchi, Fabrizio ; Biernat, Jacek ; Bloms, Johannes ; Bortone, Alberto ; Boyko, Igor R. ; Briere, Roy A. ; Cai, H. ; Cai, X. ; Calcaterra, Alessandro ; Cao, G. F. ; Cao, N. ; Çetin, Serkant Ali ; Chang, Jinfan ; Chang, W. L. ; Chelkov, Gueorgui A. ; Chen, D. Y. ; Chen, G. ; Chen, Hesheng ; Chen, M. L. ; Chen, S. J. ; Chen, X. R. ; Chen, Yuanbo ; Chen, Z. J. ; Cheng, W. S. ; Cibinetto, Gianluigi ; Cossio, Fabio ; Cui, X. F. ; Dai, Hongliang ; Dai, Xinchen ; Dbeyssi, Alaa ; Boer, Remco E. de ; Dedovich, Dmitri V. ; Deng, Ziyan ; Denig, Achim ; Denysenko, Igor ; Destefanis, Marco Giovanni Maria ; De Mori, Francesca ; Ding, Y. ; Dong, C. ; Dong, J. ; Dong, Liaoyuan ; Dong, Mingyi ; Dong, X. ; Du, Shuxian ; Fang, J. ; Fang, Shuangshi ; Fang, Y. ; Farinelli, Riccardo ; Fava, Luciano ; Feldbauer, Florian ; Felici, Giulietto ; Feng, C. Q. ; Fritsch, Miriam ; Fu, Chengdong ; Gao, Y. ; Gao, Y. ; Gao, Y. ; Gao, Y. G. ; Garzia, I. ; Gersabeck, Evelina ; Gilman, A. ; Goetzen, Klaus ; Gong, L. ; Gong, Wenxuan ; Gradl, Wolfgang ; Greco, M. ; Gu, L. M. ; Gu, Minhao ; Gu, S. ; Gu, Y. T. ; Guan, C. Y. ; Guo, Aiqiang ; Guo, L. B. ; Guo, R. P. ; Guo, Yuping ; Guskov, Alexey ; Han, T. T. ; Hao, Xiqing ; Harris, F. A. ; Hüsken, Nils ; He, K. L. ; Heinsius, Fritz-Herbert ; Heinz, C. H. ; Held, T. ; Heng, Yuekun ; Herold, Christoph ; Himmelreich, Mathilde ; Holtmann, Tobias ; Hou, Y. R. ; Hou, Zhilong ; Hu, Haiming ; Hu, J. F. ; Hu, T. ; Hu, Y. ; Huang, G. S. ; Huang, L. Q. ; Huang, X. T. ; Huang, Y. P. ; Huang, Z. ; Hussain, Tahir ; Ikegami Andersson, Walter ; Imoehl, William ; Irshad, M. ; Jaeger, S. ; Janchiv, S. ; Ji, Quan ; Ji, Qingping ; Ji, X. B. ; Ji, X. L. ; Jiang, H. B. ; Jiang, Xiaoshan ; Jiao, J. B. ; Jiao, Z. ; Jin, Shan ; Jin, Y. ; Johansson, Tord ; Kalantar-Nayestanaki, Nasser ; Kang, X. S. ; Kappert, Rosa ; Kavatsyuk, Myroslav O. ; Ke, B. C. ; Keshk, I. K. ; Khoukaz, Alfons ; Kiese, P. ; Kiuchi, R. ; Kliemt, Ralf ; Koch, L. ; Kolcu, Onur Bugra ; Kopf, Bertram ; Kuemmel, M. ; Küßner, Meike ; Kupsc, Andrzej ; Kurth, M. G. ; Kühn, Wolfgang ; Lane, John Jake ; Lange, Jens Sören ; Larin, Paul ; Lavania, Anita ; Lavezzi, Lia ; Lei, Z. H. ; Leithoff, H. ; Lellmann, Max ; Lenz, Thomas ; Li, C. ; Li, C. H. ; Li, Cheng ; Li, D. M. ; Li, F. ; Li, G. ; Li, H. ; Li, H. ; Li, Haibo ; Li, H. J. ; Li, J. L. ; Li, J. Q. ; Li, Ke ; Li, L. K. ; Li, Lei ; Li, P. L. ; Li, P. R. ; Li, S. Y. ; Li, Weidong ; Li, Weiguo ; Li, X. H. ; Li, X. L. ; Li, Z. Y. ; Liang, H. ; Liang, H. ; Liang, H. ; Liang, Y. F. ; Liang, Y. T. ; Liao, L. Z. ; Libby, J. ; Lin, C. X. ; Liu, B. J. ; Liu, C. X. ; Liu, D. ; Liu, Fu-Hu ; Liu, Fang ; Liu, Feng ; Liu, H. B. ; Liu, H. M. ; Liu, Huanhuan ; Liu, Huihui ; Liu, J. B. ; Liu, J. Y. ; Liu, K. ; Liu, K. Y. ; Liu, Ke ; Liu, L. ; Liu, M. H. ; Liu, Q. ; Liu, S. B. ; Liu, Shuai ; Liu, T. ; Liu, W. M. ; Liu, X. ; Liu, Y. B. ; Liu, Zhen-An ; Liu, Z. Q. ; Lou, Xinchou ; Lu, F. X. ; Lu, H. J. ; Lu, J. D. ; Lu, Junguang ; Lu, X. L. ; Lu, Y. ; Lu, Yunpeng ; Luo, Chenglin ; Luo, M. X. ; Luo, P. W. ; Luo, T. ; Luo, X. L. ; Lusso, S. ; Lyu, Xiao-Rui ; Ma, Fengcai ; Ma, H. L. ; Ma, Lianliang ; Ma, M. M. ; Ma, Qiumei ; Ma, R. Q. ; Ma, R. T. ; Ma, X. X. ; Ma, Xiaoyan ; Maas, Frank E. ; Maggiora, Marco ; Maldaner, Stephan ; Malde, Sneha ; Mangoni, Alessio ; Mao, Yajun ; Mao, Zepu ; Marcello, Simonetta ; Meng, Z. X. ; Messchendorp, Johannes Gerhardus ; Mezzadri, Giulio ; Min, T. J. ; Mitchell, Ryan Edward ; Mo, Xiaohu ; Mo, Y. J. ; Muchnoi, Nikolai Yu. ; Muramatsu, H. ; Nakhoul, Simon ; Nefedov, Yury ; Nerling, Frank ; Nikolaev, Ivan Borisovich ; Ning, Z. ; Nisar, Shabana ; Olsen, Stephen L. ; Ouyang, Qun ; Pacetti, Simone ; Pan, X. ; Pan, Y. ; Pathak, A. ; Patteri, P. ; Pelizäus, Marc ; Peng, H. P. ; Peters, Klaus ; Pettersson, J. ; Ping, J. L. ; Ping, R. G. ; Pitka, A. ; Poling, Ronald ; Prasad, Vindhyawasini ; Qi, H. ; Qi, H. R. ; Qi, K. H. ; Qi, Ming ; Qi, T. Y. ; Qi, T. Y. ; Qian, S. ; Qian, W. B. ; Qian, Z. ; Qiao, Congfeng ; Qin, L. Q. ; Qin, X. S. ; Qin, Zhonghua ; Qiu, Jinfa ; Qu, S. Q. ; Ravindran, Krishnakumar ; Redmer, Christoph Florian ; Rivetti, Angelo ; Rodin, Viktor ; Da Rocha Rolo, Manuel Dionisio ; Rong, Gang ; Rosner, Christoph ; Rump, Marcel Andre ; Sang, H. S. ; Sarantsev, Andrei V. ; Schelhaas, Yasemin ; Schnier, Claudius ; Schönning, Karin ; Scodeggio, Marco ; Shan, D. C. ; Shan, Wei ; Shan, Xinyu ; Shao, M. ; Shen, C. P. ; Shen, P. X. ; Shen, X. Y. ; Shi, H. C. ; Shi, R. S. ; Shi, X. ; Shi, X. D. ; Song, J. J. ; Song, W. M. ; Song, Y. X. ; Sosio, Stefano ; Spataro, Stefano ; Su, K. X. ; Sui, F. F. ; Sun, Gongxing ; Sun, H. K. ; Sun, J. F. ; Sun, L. ; Sun, S. S. ; Sun, T. ; Sun, W. Y. ; Sun, X. ; Sun, Y. J. ; Sun, Y. K. ; Sun, Y. Z. ; Sun, Z. T. ; Tan, Y. H. ; Tan, Y. X. ; Tang, C. J. ; Tang, G. Y. ; Tang, J. ; Teng, J. X. ; Thoren, Viktor ; Uman, Ismail ; Wang, B. ; Wang, C. W. ; Wang, D. Y. ; Wang, H. P. ; Wang, K. ; Wang, L. L. ; Wang, M. ; Wang, M. Z. ; Wang, Meng ; Wang, W. H. ; Wang, W. P. ; Wang, X. ; Wang, X. F. ; Wang, X. L. ; Wang, Y. ; Wang, Y. ; Wang, Y. D. ; Wang, Y. F. ; Wang, Y. Q. ; Wang, Z. ; Wang, Z. Y. ; Wang, Ziyi ; Wang, Zongyuan ; Wei, D. H. ; Weidenkaff, P. ; Weidner, Frederik ; Wen, Shuopin ; White, D. J. ; Wiedner, Ulrich ; Wilkinson, G. ; Wolke, Magnus ; Wollenberg, Leonard ; Wu, J. F. ; Wu, L. H. ; Wu, L. J. ; Wu, X. ; Wu, Z. ; Xia, L. ; Xiao, H. ; Xiao, S. Y. ; Xiao, Zhenjun ; Xie, X. H. ; Xie, Y. G. ; Xie, Y. H. ; Xing, T. Y. ; Xu, Guofa ; Xu, J. J. ; Xu, Q. J. ; Xu, W. ; Xu, Xinping ; Xu, Y. C. ; Yan, F. ; Yan, L. ; Yan, L. ; Yan, W. B. ; Yan, W. C. ; Yan, Xu ; Yang, H. J. ; Yang, Hongxun ; Yang, L. ; Yang, S. L. ; Yang, Y. H. ; Yang, Yongxu ; Yang, Yifan ; Yang, Zhi ; Ye, M. ; Ye, Minghan ; Yin, J. H. ; You, Z. Y. ; Yu, Boxiang ; Yu, C. X. ; Yu, G. ; Yu, J. S. ; Yu, T. ; Yuan, Chang-Zheng ; Yuan, L. ; Yuan, W. ; Yuan, X. Q. ; Yuan, Y. ; Yuan, Z. Y. ; Yue, C. X. ; Yuncu, A. ; Zafar, A. A. ; Zeng, Y. ; Zhang, B. X. ; Zhang, Guangyi ; Zhang, H. ; Zhang, H. H. ; Zhang, H. H. ; Zhang, Hongyu ; Zhang, J. J. ; Zhang, J. L. ; Zhang, J. Q. ; Zhang, J. W. ; Zhang, Jianyong ; Zhang, J. Z. ; Zhang, Jianyu ; Zhang, Jiawei ; Zhang, Lei ; Zhang, S. ; Zhang, S. F. ; Zhang, X. D. ; Zhang, X. Y. ; Zhang, Y. ; Zhang, Y. H. ; Zhang, Y. T. ; Zhang, Yan ; Zhang, Yao ; Zhang, Yi ; Zhang, Z. H. ; Zhang, Z. Y. ; Zhao, G. ; Zhao, J. ; Zhao, J. Y. ; Zhao, J. Z. ; Zhao, Lei ; Zhao, Ling ; Zhao, Ming-Gang ; Zhao, Q. ; Zhao, Shujun ; Zhao, Yubin ; Zhao, Y. X. ; Zhao, Zhengguo ; Zhemchugov, Alexey ; Zheng, B. ; Zheng, Jianping ; Zheng, Y. ; Zheng, Y. H. ; Zhong, B. ; Zhong, C. ; Zhou, L. P. ; Zhou, Q. ; Zhou, X. ; Zhou, X. K. ; Zhou, X. R. ; Zhu, A. N. ; Zhu, J. ; Zhu, K. ; Zhu, Kejun ; Zhu, S. H. ; Zhu, W. J. ; Zhu, Y. C. ; Zhu, Zian ; Zou, B. S. ; Zou, Jiaheng
The Born cross sections and effective form factors for process 𝑒+𝑒−→Ξ−¯Ξ+ are measured at eight center-of-mass energies between 2.644 and 3.080 GeV, using a total integrated luminosity of 363.9 pb−1 𝑒+𝑒− collision data collected with the BESIII detector at BEPCII. After performing a fit to the Born cross section of 𝑒+𝑒−→Ξ−¯Ξ+, no significant threshold effect is observed.
Schubert-Bast, Susanne ; Kay, Lara ; Simon, Andreas ; Wyatt, Geoffrey ; Holland, Rowena ; Rosenow, Felix ; Strzelczyk, Adam
Highlights
• Prevalence of probable DS identified from German healthcare data: 4.7 per 100,000.
• Healthcare costs: €11,048 per patient-year, mostly inpatient care 47%, medication 26%.
• Costs and hospitalizations greater in patients with rescue medication than without.
• Mean (SD) of 5.0 (2.5) different ASMs prescribed per patient over study period.
• Patients with probable DS had significantly higher mortality risk vs. controls (11.88% vs. 1.19%).
Abstract
Objective: Ten-year retrospective study to assess burden of illness in patients with probable Dravet syndrome (DS) identified from German healthcare data.
Methods: In the absence of an International Classification of Diseases code, patients with probable DS were identified using a selection algorithm considering diagnoses and drug prescriptions. Primary analyses were prevalence and demographics; secondary analyses included healthcare costs, annual hospitalization rate (AHR) and length of stay (LOS), medication use, and mortality.
Results: In the final study year, 64 patients with probable DS (mean [range] age: 33.2 [3–82] years; male: 48%) were identified. Prevalence: 4.7 per 100,000 people. During the study, 160 patients with probable DS were identified and followed up for 1,261 patient-years. Mean cost of healthcare was €11,048 per patient-year (PPY), mostly attributable to inpatient care (47%), medication (26%), and services and devices (19%). Annual healthcare costs were significantly greater for those with prescribed rescue medication (15% of patient-years) vs. without (€16,123 vs. €10,125 PPY, p < 0.001). Mean (standard deviation [SD]) AHR and LOS were 1.1 (1.7) and 17.5 (33.5) days PPY. AHR was significantly greater in patients with prescribed rescue medication vs. without (1.6 [2.0] vs. 1.0 [1.6] PPY, p < 0.001). Mean (SD) number of antiseizure medications prescribed was 2.6 (1.2) PPY and 5.0 (2.5) over the entire observable time for each patient. Mortality rate was significantly higher for probable DS vs. matched controls (11.88% [19 events] vs. 1.19% [172 events], p < 0.001).
Conclusion: Probable DS is associated with substantial healthcare costs in Germany.
Schommartz, Iryna ; Lembcke, Philip F. ; Schuetz, Henriette ; Wald de Chamorro, Nina ; Bauer, Martin ; Kaindl, Angela M. ; Buß, Claudia ; Shing, Yee Lee
From early to middle childhood, brain regions that underlie memory consolidation undergo profound maturational changes. However, there is little empirical investigation that directly relates age-related differences in brain structural measures to the memory consolidation processes. The present study examined system-level memory consolidations of intentionally studied object-location associations after one night of sleep (short delay) and after two weeks (long delay) in normally developing 5-to-7-year-old children (n = 50) and young adults (n = 39). Behavioural differences in memory consolidation were related to structural brain measures. Our results showed that children, in comparison to young adults, consolidate correctly learnt object-location associations less robustly over short and long delay. Moreover, using partial least squares correlation method, a unique multivariate profile comprised of specific neocortical (prefrontal, parietal, and occipital), cerebellar, and hippocampal subfield structures was found to be associated with variation in short-delay memory consolidation. A different multivariate profile comprised of a reduced set of brain structures, mainly consisting of neocortical (prefrontal, parietal, and occipital), and selective hippocampal subfield structures (CA1-2 and subiculum) was associated with variation in long-delay memory consolidation. Taken together, the results suggest that multivariate structural pattern of unique sets of brain regions are related to variations in short- and long-delay memory consolidation across children and young adults.
RESEARCH HIGHLIGHTS
Short- and long-delay memory consolidation is less robust in children than in young adults
* Short-delay brain profile comprised of hippocampal, cerebellar, and neocortical brain regions
* Long-delay brain profile comprised of neocortical and selected hippocampal brain regions.
* Brain profiles differ between children and young adults.
Strzelczyk, Adam ; Knake, Susanne ; Holtkamp, Martin ; Schulze-Bonhage, Andreas ; Lemke, Johannes ; Spiczak Brzezinski, Sarah von ; Berkenfeld, Ralf ; Rosenow, Felix ; Brandt, Christian ; Schmitt, Friedhelm C.
The Board of Directors of the German Society of Epileptology and the committee on epilepsy and syncope of the German Society of Neurology have reviewed the current data on vaccination to prevent coronavirus disease 2019 (COVID-19) and vaccination prioritization in people with epilepsy and provide a summary and recommendations.
Fusco, Claudia Mariateresa ; Desch, Kristina ; Dörrbaum, Aline Ricarda ; Wang, Mantian ; Staab, Anja ; Chan, Ivy C. W. ; Vail, Eleanor ; Villeri, Veronica ; Langer, Julian D. ; Schuman, Erin M.
Owing to their morphological complexity and dense network connections, neurons modify their proteomes locally, using mRNAs and ribosomes present in the neuropil (tissue enriched for dendrites and axons). Although ribosome biogenesis largely takes place in the nucleus and perinuclear region, neuronal ribosomal protein (RP) mRNAs have been frequently detected remotely, in dendrites and axons. Here, using imaging and ribosome profiling, we directly detected the RP mRNAs and their translation in the neuropil. Combining brief metabolic labeling with mass spectrometry, we found that a group of RPs rapidly associated with translating ribosomes in the cytoplasm and that this incorporation was independent of canonical ribosome biogenesis. Moreover, the incorporation probability of some RPs was regulated by location (neurites vs. cell bodies) and changes in the cellular environment (following oxidative stress). Our results suggest new mechanisms for the local activation, repair and/or specialization of the translational machinery within neuronal processes, potentially allowing neuronal synapses a rapid means to regulate local protein synthesis.
Fusco, Claudia Mariateresa ; Desch, Kristina ; Dörrbaum, Aline Ricarda ; Wang, Mantian ; Staab, Anja ; Chan, Ivy C.W. ; Vail, Eleanor ; Villeri, Veronica ; Langer, Julian D. ; Schuman, Erin M.
Owing to their morphological complexity and dense network connections, neurons modify their proteomes locally, using mRNAs and ribosomes present in the neuropil (tissue enriched for dendrites and axons). Although ribosome biogenesis largely takes place in the nucleus and perinuclear region, neuronal ribosomal protein (RP) mRNAs have been frequently detected remotely, in dendrites and axons. Here, using imaging and ribosome profiling, we directly detected the RP mRNAs and their translation in the neuropil. Combining brief metabolic labeling with mass spectrometry, we found that a group of RPs quickly associated with translating ribosomes in the cytoplasm and that this incorporation is independent of canonical ribosome biogenesis. Moreover, the incorporation probability of some RPs was regulated by location (neurites vs. cell bodies) and changes in the cellular environment (in response to oxidative stress). Our results suggest new mechanisms for the local activation, repair and/or specialization of the translational machinery within neuronal processes, potentially allowing remote neuronal synapses a rapid solution to the relatively slow and energy-demanding requirement of nuclear ribosome biogenesis.
Influence of macrophage polarization on the effectiveness of surgical therapy of peri-implantitis
(2021)
Galarraga‑Vinueza, Maria Elisa ; Obreja, Karinna Anne-Marie ; Khoury, Chantal Marie ; Begić, Amira ; Ramanauskaite, Ausra ; Sculean, Anton ; Schwarz, Frank
Purpose: To evaluate the influence of macrophage expression and polarization on the effectiveness of surgical therapy of peri-implantitis over a 6 month follow-up.
Methods: A total of fourteen patients (n = 14 implants) diagnosed with peri-implantitis underwent access flap surgery, granulation tissue removal, implantoplasty, and augmentation at intra-bony components using a natural derived bone mineral and application of a native collagen membrane during a standardized surgical procedure. Granulation tissue biopsies were prepared for immunohistochemical characterization and macrophage polarization assessment. M1 and M2 phenotype expression was identified and quantified through immunohistochemical markers and histomorphometrical analyses. Clinical evaluation and data collection were performed initially and after a healing period of 6 months. Statistical analyses were performed to associate infiltrated area, macrophage, and M1/M2 phenotype influence on peri-implant tissue healing parameters after a 6-month follow-up.
Results: Mean infiltrated compartment (ICT) values occupied a total percentage of 70.3% ± 13.0 in the analyzed granulation tissue biopsies. Macrophages occupied a mean area of 15.3% ± 7.0. M1 and M2 phenotypes were present in 7.1 ± 4.1% and 5.5 ± 3.7%, respectively. No statistically significant difference was observed between M1 and M2% expression (p = 0.16). The mean M1/ M2 ratio amounted to 1.5 ± 0.8. Surgical therapy was associated with statistically significant reductions in mean bleeding on probing (BOP), probing depth (PD) and suppuration (SUPP) scores at 6 months (p < 0.05). Linear regression analyses revealed a significant correlation between macrophage expression (CD68%) and changes in PD scores and M1 (%) expression and changes in mucosal recession (MR) scores at 6 months.
Conclusions: The present data suggest that macrophages might influence peri-implant tissue healing mechanisms following surgical therapy of peri-implantitis over a short-term period. Particularly, changes in PD and MR scores were statistically significantly associated with macrophage expression and phenotype.
Fendrr synergizes with Wnt signalling to regulate fibrosis related genes during lung development
(2021)
Ali, Tamer ; Rogala, Sandra ; Melissari, Maria-Theodora ; Währisch, Sandra ; Herrmann, Bernhard ; Grote, Phillip
Long non-coding RNAs are a very versatile class of molecules that can have important roles in regulating a cells function, including regulating other genes on the transcriptional level. One of these mechanisms is that RNA can directly interact with DNA thereby recruiting additional components such as proteins to these sites via a RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence (FendrrBox) from the lncRNA Fendrr in mice and find that this FendrrBox is partially required for Fendrr function in vivo. We find that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs, associated with lung fibrosis. A set of these genes contain a triplex site directly at their promoter and are expressed in fibroblasts. We find that Fendrr with the Wnt signaling pathway regulates these genes, implicating that Fendrr synergizes with Wnt signaling in lung fibrosis.