Design of the Firstâ inâ Class, Highly Potent Irreversible Inhibitor Targeting the Meninâ MLL Proteinâ Protein Interaction

The structureâ based design of Mâ 525 as the firstâ inâ class, highly potent, irreversible smallâ molecule inhibitor of the meninâ MLL interaction is presented. Mâ 525 targets cellular menin protein at subâ nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLLâ regulated gene expression in MLL leukemia cells. Mâ 525 demonstrates high cellular specificity over nonâ MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and coâ crystal structure of Mâ 525 in complex with menin firmly establish its mode of action. A single administration of Mâ 525 effectively suppresses MLLâ regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize Mâ 525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.Irreversible inhibitor Mâ 525 targets the meninâ MLL interaction. It is demonstrated that irreversible inhibition of menin is a promising therapeutic strategy for the treatment of MLL leukemia and may have advantages over reversible inhibitors.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141532/1/anie201711828.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141532/2/anie201711828-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141532/3/anie201711828_am.pd

Design of the Firstâ inâ Class, Highly Potent Irreversible Inhibitor Targeting the Meninâ MLL Proteinâ Protein Interaction

The structureâ based design of Mâ 525 as the firstâ inâ class, highly potent, irreversible smallâ molecule inhibitor of the meninâ MLL interaction is presented. Mâ 525 targets cellular menin protein at subâ nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLLâ regulated gene expression in MLL leukemia cells. Mâ 525 demonstrates high cellular specificity over nonâ MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and coâ crystal structure of Mâ 525 in complex with menin firmly establish its mode of action. A single administration of Mâ 525 effectively suppresses MLLâ regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize Mâ 525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.Der irreversible Inhibitor Mâ 525 greift an der Meninâ MLLâ Wechselwirkung an. Die irreversible Inhibition von Menin erweist sich als vielversprechende Strategie für die Behandlung von MLLâ Leukämie, mit möglichen Vorteilen gegenüber dem Einsatz reversibler Inhibitoren.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141701/1/ange201711828_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141701/2/ange201711828.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141701/3/ange201711828-sup-0001-misc_information.pd

Combined QTL and Genome Scan Analyses With the Help of 2b-RAD Identify Growth-Associated Genetic Markers in a New Fast-Growing Carp Strain

Common carp is one of the oldest and most popular cultured freshwater fish species both globally and in China. In a previous study, we used a carp strain with a long breeding tradition in China, named Huanghe, to create a new fast-growing strain by selection for fast growth for 6 years. The growth performance at 8 months of age has been improved by 20.84%. To achieve this, we combined the best linear unbiased prediction with marker-assisted selection techniques. Recent progress in genome-wide association studies and genomic selection in livestock breeding inspired common carp breeders to consider genome-based breeding approaches. In this study, we developed a 2b-RAD sequence assay as a means of investigating the quantitative trait loci in common carp. A total of 4,953,017,786 clean reads were generated for 250 specimens (average reads/specimen = 19,812,071) with BsaXI Restriction Enzyme. From these, 56,663 SNPs were identified, covering 50 chromosomes and 3,377 scaffolds. Principal component analysis indicated that selection and control groups are relatively clearly distinct. Top 1% of Fst values was selected as the threshold signature of artificial selection. Among the 244 identified loci, genes associated with sex-related factors and nutritional metabolism (especially fat metabolism) were annotated. Eighteen QTL were associated with growth parameters. Body length at 3 months of age and body weight (both at 3 and 8 months) were controlled by polygenic effects, but body size (length, depth, width) at 8 months of age was controlled mainly by several loci with major effects. Importantly, a single shared QTL (IGF2 gene) partially controlled the body length, depth, and width. By merging the above results, we concluded that mainly the genes related to neural pathways, sex and fatty acid metabolism contributed to the improved growth performance of the new Huanghe carp strain. These findings are one of the first investigations into the potential use of genomic selection in the breeding of common carp. Moreover, our results show that combining the Fst, QTL mapping and CRISPR–Cas9 methods can be an effective way to identify important novel candidate molecular markers in economic breeding programs

DeepSeek LLM: Scaling Open-Source Language Models with Longtermism

The rapid development of open-source large language models (LLMs) has been truly remarkable. However, the scaling law described in previous literature presents varying conclusions, which casts a dark cloud over scaling LLMs. We delve into the study of scaling laws and present our distinctive findings that facilitate scaling of large scale models in two commonly used open-source configurations, 7B and 67B. Guided by the scaling laws, we introduce DeepSeek LLM, a project dedicated to advancing open-source language models with a long-term perspective. To support the pre-training phase, we have developed a dataset that currently consists of 2 trillion tokens and is continuously expanding. We further conduct supervised fine-tuning (SFT) and Direct Preference Optimization (DPO) on DeepSeek LLM Base models, resulting in the creation of DeepSeek Chat models. Our evaluation results demonstrate that DeepSeek LLM 67B surpasses LLaMA-2 70B on various benchmarks, particularly in the domains of code, mathematics, and reasoning. Furthermore, open-ended evaluations reveal that DeepSeek LLM 67B Chat exhibits superior performance compared to GPT-3.5

Benchmarking the pH-Stability Relationship of Metal Oxide Anodes in Anion Exchange Membrane Water Electrolysis

Anion exchange membrane water electrolysis (AEMWE) is one of the most promising technologies for producing green hydrogen; however, they still suffer from durability issues. One task is to find suitable electrolyte conditions for anode catalysts that endow them with both high activity and stability. Herein, we benchmark the pH-stability relationship of four typical metal oxides as anode catalysts in the AEMWE. Their electrochemical performance and structural stability were in-depth analyzed through impedance, dissolved composition in the electrolyte, and correlated Pourbaix diagram. NiFe2O4 with the best activity and stability in the strong alkaline (pH = 14) shows terrible stability in pure water, which is then verified due to the severe Fe leaching, and it cannot be alleviated by alkaline pre-activation. Notably, Co3O4 shows comparable activity and stability to IrO2 in pure water and weak alkaline conditions. At pH = 12, it entails only ∼2.18 V to reach 1.0 A cm-2 and stabilizes for 40 h, being superior to others. This work screens out suitable transition metal oxides as a substitute for noble metals and their optimal application scenarios for AEMWE

AWFSD: Accelerated Wirtinger Flow with Score-based Diffusion Image Prior for Poisson-Gaussian Holographic Phase Retrieval

Phase retrieval (PR) is an essential problem in a number of coherent imaging systems. This work aims at resolving the holographic phase retrieval problem in real world scenarios where the measurements are corrupted by a mixture of Poisson and Gaussian (PG) noise that stems from optical imaging systems. To solve this problem, we develop a novel algorithm based on Accelerated Wirtinger Flow that uses Score-based Diffusion models as the generative prior (AWFSD). In particular, we frame the PR problem as an optimization task that involves both a data fidelity term and a regularization term. We derive the gradient of the PG log-likelihood function along with its corresponding Lipschitz constant, ensuring a more accurate data consistency term for practical measurements. We introduce a generative prior as part of our regularization approach by using a score-based diffusion model to capture (the gradient of) the image prior distribution. We provide theoretical analysis that establishes a critical-point convergence guarantee for the proposed AWFSD algorithm. Our simulation experiments demonstrate that: 1) The proposed algorithm based on the PG likelihood model enhances reconstruction compared to that solely based on either Gaussian or Poisson likelihood. 2) The proposed AWFSD algorithm produces reconstructions with higher image quality both qualitatively and quantitatively, and is more robust to variations in noise levels when compared with state-of-the-art methods for phase retrieval

Fe-doped and sulfur-enriched Ni3S2 nanowires with enhanced reaction kinetics for boosting water oxidation

Exploring cost-effective and highly-active oxygen evolution reaction (OER) electrocatalysts is a pressing task to propel water electrolysis for green hydrogen production. Herein, we constructed a class of Fe-doped and S-enriched Ni3S2 nanowires electrocatalysts for optimizing the target intermediates adsorption to decrease the OER overpotentials at various current densities. The optimal Ni3S2-1.4%Fe electrocatalyst possesses the most active sites and exhibits an ultralow overpotential of 190 mV at 10 mA cm−2 with an excellent stability of > 60 h, exceeding the majority of recently-reported Ni3S2-based electrocatalysts. The trivalence Fe-doping not only reduces the electron density of the Ni center, but also enables the sulfur enrichment on the Ni3S2 surface, which greatly improves the intrinsic activity and the number of target intermediates (∗OOH). A novel methanol-assisted electrochemical evaluation further reveals that the Ni3S2-1.4%Fe electrocatalyst demonstrates a weaker binding ability to ∗OH with the rapid generation of ∗OOH species, and thus gives a lower apparent activation energy compared with the surface sulfur reduced ones. This work provides a new perspective for regulating the adsorption of intermediates through doping strategy

Video_1_Case report: A girl with witnessed sleep apnea.MP4

IntroductionPfeiffer syndrome is a rare genetic disorder characterized by craniosynostosis, broad thumbs and big toes, and partial syndactyly of the hands and feet. This case report presents the case of a girl diagnosed with type 2 Pfeiffer syndrome who experienced severe obstructive sleep apnea (OSA).Case reportThe patient had been using an oropharyngeal airway since the age of 4 months due to snoring and witnessed apnea during sleep. At 11 months old, she was referred to our sleep clinic because of growth limitation and gross motor ability issues. Polysomnography (PSG) showed severe obstructive hypopnea before any treatment, and revealed severe central sleep apnea with the oropharyngeal airway in place. Positive airway pressure (PAP) therapy was initiated, which improved both her sleep and gross motor ability.ConclusionThis case report emphasizes the importance of thorough sleep studies for diagnosing sleep and breathing disorders in Pfeiffer syndrome patients and highlights the effectiveness of PAP therapy in managing these conditions.</p

Cardioprotective Effects of QiShenYiQi Dripping Pills on Transverse Aortic Constriction-Induced Heart Failure in Mice

QiShenYiQi dripping pills (QSYQ), a traditional Chinese medicine, are commonly used to treat coronary heart disease, and QSYQ was recently approved as a complementary treatment for ischemic heart failure in China. However, only few studies reported on whether QSYQ exerts a protective effect on heart failure induced by pressure overload. In this study, we explored the role of QSYQ in a mouse model of heart failure induced by transverse aortic constriction (TAC). Twenty-eight C57BL/6J mice were divided into four groups: Sham + NS group, Sham + QSYQ group, TAC + NS group, and TAC + QSYQ group. QSYQ dissolved in normal saline (NS) was administered intragastrically (3.5 mg/100 g/day) in the Sham + QSYQ and TAC + QSYQ groups. In the Sham + NS and TAC + NS groups, NS was provided every day intragastrically. Eight weeks after TAC, echocardiography, and cardiac catheterization were performed to evaluate the cardiac function, and immunofluorescent staining with anti-actinin2 antibody was performed to determine the structure of the myocardial fibers. Moreover, TUNEL staining and Masson trichrome staining were employed to assess the effects of QSYQ on cardiac apoptosis and cardiac fibrosis. Western blots and real-time polymerase chain reaction (PCR) were used to measure the expression levels of vascular endothelial growth factor (VEGF) in the heart, and immunohistochemical staining with anti-CD31 antibody was performed to explore the role of QSYQ in cardiac angiogenesis. Results showed that TAC-induced cardiac dysfunction and disrupted structure of myocardial fibers significantly improved after QSYQ treatment. Moreover, QSYQ treatment also significantly improved cardiac apoptosis and cardiac fibrosis in TAC-induced heart failure, which was accompanied by an increase in VEGF expression levels and maintenance of microvessel density in the heart. In conclusion, QSYQ exerts a protective effect on TAC-induced heart failure, which could be attributed to enhanced cardiac angiogenesis, which is closely related to QSYQ. Thus, QSYQ may be a promising traditional Chinese medicine for the treatment of heart failure induced by pressure overload such as hypertension