Nrf2 deletion causes “benign” simple steatosis to develop into nonalcoholic steatohepatitis in mice fed a high-fat diet

BACKGROUND: Nonalcoholic fatty liver disease begins with the aberrant accumulation of triglyceride in the liver. Its spectrum includes the earliest stage of hepatic simple steatosis (SS), nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Generally, hepatic SS is often self-limited; however 10%-30% of patients with hepatic SS progress to NASH. The cause(s) of the transition from SS to NASH are unclear. We aimed to test the contribution of nuclear erythroid 2-related factor 2 (Nrf2) on the progression of “benign” SS to NASH in mice fed a high fat diet. In doing so, we discovered the influence of fatty acid in that progression. METHOD: The involvement of Nrf2 in defending against the development of NASH was studied in an experimental model induced by a high-fat diet. Wild-type and Nrf2-null mice were fed the diet. Their specimens were analyzed for pathology as well as for fatty acid content and ratios. RESULT: In feeding the high-fat diet to the Wild-type and the Nrf2-null mice, the Wild-type mice increased hepatic fat deposition without inflammation or fibrosis (i.e., simple steatosis), while the Nrf2-null mice had significantly more hepatic steatosis and substantial inflammation, (i.e., nonalcoholic steatohepatitis). In addition, as a result of the high-fat diet, SFA (C20: 0, C22: 0) and MUFA (C18: 1, C20: 1) content in Nrf2-null mice were significantly higher than in Wild-type mice. In the Nrf2-null mice the PUFA/TFA ratio decreased; conversely, the MUFA/TFA ratio increased. CONCLUSION: The deletion of Nrf2 causes “benign” SS to develop into NASH in mice fed with a high-fat diet, through prompt fatty acid accumulation and disruption of hepatic fatty acid composition in the liver

S3: Social-network Simulation System with Large Language Model-Empowered Agents

Social network simulation plays a crucial role in addressing various challenges within social science. It offers extensive applications such as state prediction, phenomena explanation, and policy-making support, among others. In this work, we harness the formidable human-like capabilities exhibited by large language models (LLMs) in sensing, reasoning, and behaving, and utilize these qualities to construct the S$^3$ system (short for $\textbf{S}$ocial network $\textbf{S}$imulation $\textbf{S}$ystem). Adhering to the widely employed agent-based simulation paradigm, we employ prompt engineering and prompt tuning techniques to ensure that the agent's behavior closely emulates that of a genuine human within the social network. Specifically, we simulate three pivotal aspects: emotion, attitude, and interaction behaviors. By endowing the agent in the system with the ability to perceive the informational environment and emulate human actions, we observe the emergence of population-level phenomena, including the propagation of information, attitudes, and emotions. We conduct an evaluation encompassing two levels of simulation, employing real-world social network data. Encouragingly, the results demonstrate promising accuracy. This work represents an initial step in the realm of social network simulation empowered by LLM-based agents. We anticipate that our endeavors will serve as a source of inspiration for the development of simulation systems within, but not limited to, social science

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy1,2,3. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes1,3. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1)1,3,4. Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.This work was supported by an Alex's Lemonade Stand Young Investigator Award (S.C.M.), The CIHR Banting Fellowship (S.C.M.), The Cancer Prevention Research Institute of Texas (S.C.M., RR170023), Sibylle Assmus Award for Neurooncology (K.W.P.), the DKFZ-MOST (Ministry of Science, Technology & Space, Israel) program in cancer research (H.W.), James S. McDonnell Foundation (J.N.R.) and NIH grants: CA154130 (J.N.R.), R01 CA169117 (J.N.R.), R01 CA171652 (J.N.R.), R01 NS087913 (J.N.R.) and R01 NS089272 (J.N.R.). R.C.G. is supported by NIH grants T32GM00725 and F30CA217065. M.D.T. is supported by The Garron Family Chair in Childhood Cancer Research, and grants from the Pediatric Brain Tumour Foundation, Grand Challenge Award from CureSearch for Children’s Cancer, the National Institutes of Health (R01CA148699, R01CA159859), The Terry Fox Research Institute and Brainchild. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113)

The transcriptional landscape of Shh medulloblastoma

© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.info:eu-repo/semantics/publishedVersio

Failure of human rhombic lip differentiation underlies medulloblastoma formation

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB

A Rapid Beam Pointing Determination and Beam-Pointing Error Analysis Method for a Geostationary Orbiting Microwave Radiometer Antenna in Consideration of Antenna Thermal Distortions

When observing the Earth’s radiation signal with a geostationary orbiting (GEO) mechanically scanned microwave radiometer, it is necessary to correct the antenna beam pointing (ABP) in real time for the deviation caused by thermal distortions of antenna reflectors with the help of the on-board Image Navigation and Registration (INR) system during scanning of the Earth. The traditional ABP determination and beam-pointing error (BPE) analysis method is based on the electromechanical coupling principle, which usurps time and computing resources and thus cannot meet the requirement for frequent real-time on-board INR operations needed by the GEO microwave radiometer. For this reason, matrix optics (MO), which is widely used in characterizing the optical path of the visible/infrared sensor, is extended to this study so that it can be applied to model the equivalent optical path of the microwave antenna with a much more complicated configuration. Based on the extended MO method, the ideal ABP determination model and the model for determining the actual ABP affected by reflector thermal distortions are deduced for China’s future GEO radiometer, and an MO-based BPE computing method, which establishes a direct connection between the reflector thermal distortion errors (TDEs) and the thermally induced BPE, is defined. To verify the overall performance of the extended MO method for rapid ABP determination, the outputs from the ideal ABP determination model were compared to calculations from GRASP 10.3 software. The experimental results show that the MO-based ABP determination model can achieve the same results as GRASP software with a significant advantage in computational efficiency (e.g., at the lowest frequency band of 54 GHz, our MO-based model yielded a 4,730,000 times faster computation time than the GRASP software). After validating the correctness of the extended MO method, the impacts of the reflector TDEs on the BPE were quantified on a case-by-case basis with the help of the defined BPE computing method, and those TDEs that had a significant impact on the BPE were therefore identified. The methods and results presented in this study are expected to set the basis for the further development of on-board INR systems to be used in China’s future GEO microwave radiometer and benefit the ABP determination and BEP analysis of other antenna configurations to a certain extent

The application of freestanding titanate nanofiber paper for scattering layers in dye-sensitized solar cells

International Cooperation MOST-JST [2010DFA61410]; National Basic Research Program of China (973 Program) [2007CB607504]A titanate nanofiber paper with robust and good flexible property was successfully prepared by alkali hydrothermal synthesis with simple paper-making method. These nanofibers were about 80 nm in diameter and had a typical length in the range of tens of micrometers. Despite the transformation from titanate to TiO(2)-B phase was initially started, such nanofiber paper still kept its original shape and good flexibility after calcinations at 450 degrees C for 30 min. A solar cell with titanate nanofiber paper as scattering layer yielded an overall conversion efficiency of 4.90% under an incident solar energy of 100 mW/cm(2), about 27.5% higher than that without nanofiber paper. (C) 2011 Elsevier B.V. All rights reserved

The influence of nitric acid on electron transport and recombination for non-sintering Tio(2) photoanodes

National High Technology Research and Development Program of China (863 Program) [2011AA050522]; Qinghai Science & Technology Department [2010-N-S03]; Ministry of Science & Technology (MOST) of China [2010DFB23160]Nitric acid was added to binder-free TiO2 paste for the preparation of plastic TiO2 dye-sensitized photoanode at low temperature on conductive indium-tin oxide (ITO)-coated polyethylene naphthalate (PEN) substrate. The influence of nitric acid on the electron transport within the cells was scrutinized. It was found that the electron transport was accelerated by means of increasing nitric acid contents. Rheological behavior testing revealed that the increasing concentration of nitric acid leaded to a decrease of viscosity of the paste and then increased the coordination number within the photoanode, which represent the possible electron transfer pathways in the photoanode. This was confirmed by scanning electronic microscopy (SEM) results. Electrochemical impedance spectroscopy (EIS) results showed that the charge transport resistance in the TiO2 film (R-t) decreased gradually when the nitric acid content increased from 0 to 0.1 M, which was attributed to the increasing coordination number of TiO2 particles in the nanoporous film. Meanwhile, the increasing NO3- will prohibit the electron recombination between TiO2 and electrolyte proved by EIS measurements. However, excessive nitric acid also leaded to a corrosion of the ITO substrate and impaired the photovoltaic performance of the flexible devices. Hence, the devices prepared with nitric acid content of 0.025 M achieved the highest overall energy conversion efficiency of 5.30%. (C) 2012 Elsevier Ltd. All rights reserved