Study of RNA interference inhibiting rat ovarian androgen biosynthesis by depressing 17alpha-hydroxylase/17, 20-lyase activity in vivo

<p>Abstract</p> <p>Background</p> <p>17alpha-hydroxylase/17, 20-lyase encoded by CYP17 is the key enzyme in androgen biosynthesis pathway. Previous studies demonstrated the accentuation of the enzyme in patients with polycystic ovary syndrome (PCOS) was the most important mechanism of androgen excess. We chose CYP17 as the therapeutic target, trying to suppress the activity of 17alpha-hydroxylase/17, 20-lyase and inhibit androgen biosynthesis by silencing the expression of CYP17 in the rat ovary.</p> <p>Methods</p> <p>Three CYP17-targeting and one negative control oligonucleotides were designed and used in the present study. The silence efficiency of lentivirus shRNA was assessed by qRT-PCR, Western blotting and hormone assay. After subcapsular injection of lentivirus shRNA in rat ovary, the delivery efficiency was evaluated by GFP fluorescence and qPCR. Total RNA was extracted from rat ovary for CYP17 mRNA determination and rat serum was collected for hormone measurement.</p> <p>Results</p> <p>In total, three CYP17-targeting lentivirus shRNAs were synthesized. The results showed that all of them had a silencing effect on CYP17 mRNA and protein. Moreover, androstenedione secreted by rat theca interstitial cells (TIC) in the RNAi group declined significantly compared with that in the control group. Two weeks after rat ovarian subcapsular injection of chosen CYP17 shRNA, the GFP fluorescence of frozen ovarian sections could be seen clearly under fluorescence microscope. It also showed that the GFP DNA level increased significantly, and its relative expression level was 7.42 times higher than that in the control group. Simultaneously, shRNA treatment significantly decreased CYP17 mRNA and protein levels at 61% and 54%, respectively. Hormone assay showed that all the levels of androstenedione, 17-hydroxyprogesterone and testosterone declined to a certain degree, but progesterone levels declined significantly.</p> <p>Conclusion</p> <p>The present study proves for the first time that ovarian androgen biosynthesis can be inhibited by silencing CYP17 expression. It may provide a novel strategy for therapy of hyperandrogenism diseases, and also set an example for the use of RNAi technology in endocrine diseases.</p

THINKING OF THE SAFETY APPLICATION OF TCM BY YOU GU WU YUN, A CHINESE ANCIENT MEDICINE APPLICATION PRINCIPLE

Background: You Gu Wu Yun (有故无殒), a Chinese ancient medicine application principle, has played an important role in Traditional Chinese Medicine (TCM) clinical practice so far. Materials and Methods: It emphasized that disease, medicine and treatment method were interconnecting and the relationship among these three aspects should be handled reasonably. The major factors (including organism status, medicine source, medicine processing, compatibility of medicines, dose and course, dosage form) under the three aspects which have a more important and direct influence on the medicine clinical effect should be considered seriously in the TCM application. Results: However, it was analyzed that most of side effects of TCM may be due to the incorrect application, which violated this principle to a certain degree. In order to help people to understand the safety and toxicity of TCM objectively and provide a rational guidance for the safe and effective application of TCM, we will introduce the concept of You Gu Wu Yun and discuss these factors having influence on medicine in this review. An example will be shown in order to clarify how these factors work in medicine. Conclusions: As a unique medical system, TCM has its own theoretical basis and treatment principle. It stresses syndrom

Aligning Large Multimodal Models with Factually Augmented RLHF

Large Multimodal Models (LMM) are built across modalities and the misalignment between two modalities can result in "hallucination", generating textual outputs that are not grounded by the multimodal information in context. To address the multimodal misalignment issue, we adapt the Reinforcement Learning from Human Feedback (RLHF) from the text domain to the task of vision-language alignment, where human annotators are asked to compare two responses and pinpoint the more hallucinated one, and the vision-language model is trained to maximize the simulated human rewards. We propose a new alignment algorithm called Factually Augmented RLHF that augments the reward model with additional factual information such as image captions and ground-truth multi-choice options, which alleviates the reward hacking phenomenon in RLHF and further improves the performance. We also enhance the GPT-4-generated training data (for vision instruction tuning) with previously available human-written image-text pairs to improve the general capabilities of our model. To evaluate the proposed approach in real-world scenarios, we develop a new evaluation benchmark MMHAL-BENCH with a special focus on penalizing hallucinations. As the first LMM trained with RLHF, our approach achieves remarkable improvement on the LLaVA-Bench dataset with the 94% performance level of the text-only GPT-4 (while previous best methods can only achieve the 87% level), and an improvement by 60% on MMHAL-BENCH over other baselines. We opensource our code, model, data at https://llava-rlhf.github.io.Comment: Preprin

Size and thermal effects on sedimentation behaviors of two spheres

Gas-solid flows are commonly found in nature, as well as in industries. In such flows the size of the solid particles generally is not uniform. In addition, usually there is heat transfer between solid particles and gas flows. The hydrodynamics and heat transfer both make the behavior of gas-solid flows extremely complicated. In order to reveal these effects, in this paper three cases: (1) two isothermal, (2) two hot and (3) two cold spherical particles with various size ratios are investigated using lattice Boltzmann method-immersed boundary (LB-IB). It is observed that, for the first time, the tumbling duration of both two hot particles and two cold particles settling in vertical channel, is prolonged with size ratio increasing. The differences of threshold size ratio among the three cases are significant and the threshold size ratio of two hot particles is the largest one. Especially, it is found that heat transfer affects critically the interaction of two hot particles with low size ratios. In addition, against particle size ratio increasing, heat transfer effects on the interaction between two non-identical particles become weak

Two-Dimensional Lattice Boltzmann Model For Compressible Flows With High Mach Number

In this paper we present an improved lattice Boltzmann model for compressible Navier-Stokes system with high Mach number. The model is composed of three components: (i) the discrete-velocity-model by Watari and Tsutahara [Phys Rev E \textbf{67},036306(2003)], (ii) a modified Lax-Wendroff finite difference scheme where reasonable dissipation and dispersion are naturally included, (iii) artificial viscosity. The improved model is convenient to compromise the high accuracy and stability. The included dispersion term can effectively reduce the numerical oscillation at discontinuity. The added artificial viscosity helps the scheme to satisfy the von Neumann stability condition. Shock tubes and shock reflections are used to validate the new scheme. In our numerical tests the Mach numbers are successfully increased up to 20 or higher. The flexibility of the new model makes it suitable for tracking shock waves with high accuracy and for investigating nonlinear nonequilibrium complex systems

A longitudinal resource for population neuroscience of school-age children and adolescents in China

During the past decade, cognitive neuroscience has been calling for population diversity to address the challenge of validity and generalizability, ushering in a new era of population neuroscience. The developing Chinese Color Nest Project (devCCNP, 2013–2022), the first ten-year stage of the lifespan CCNP (2013–2032), is a two-stages project focusing on brain-mind development. The project aims to create and share a large-scale, longitudinal and multimodal dataset of typically developing children and adolescents (ages 6.0–17.9 at enrolment) in the Chinese population. The devCCNP houses not only phenotypes measured by demographic, biophysical, psychological and behavioural, cognitive, affective, and ocular-tracking assessments but also neurotypes measured with magnetic resonance imaging (MRI) of brain morphometry, resting-state function, naturalistic viewing function and diffusion structure. This Data Descriptor introduces the first data release of devCCNP including a total of 864 visits from 479 participants. Herein, we provided details of the experimental design, sampling strategies, and technical validation of the devCCNP resource. We demonstrate and discuss the potential of a multicohort longitudinal design to depict normative brain growth curves from the perspective of developmental population neuroscience. The devCCNP resource is shared as part of the “Chinese Data-sharing Warehouse for In-vivo Imaging Brain” in the Chinese Color Nest Project (CCNP) – Lifespan Brain-Mind Development Data Community (https://ccnp.scidb.cn) at the Science Data Bank