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Mashup Score: 9Widespread Gene Editing in the Brain via In Utero Delivery of mRNA Using Acid-Degradable Lipid Nanoparticles - 3 month(s) ago
In utero gene editing with mRNA-based therapeutics has the potential to revolutionize the treatment of neurodevelopmental disorders. However, a critical bottleneck in clinical application has been the lack of mRNA delivery vehicles that can efficiently transfect cells in the brain. In this report, we demonstrate that in utero intracerebroventricular (ICV) injection of densely PEGylated lipid nanoparticles (ADP-LNPs) containing an acid-degradable PEG–lipid can safely and effectively deliver mRNA for gene editing enzymes to the fetal mouse brain, resulting in successful transfection and editing of brain cells. ADP-LNPs containing Cre mRNA transfected 30% of the fetal brain cells in Ai9 mice and had no detectable adverse effects on fetal development and postnatal growth. In addition, ADP-LNPs efficiently transfected neural stem and progenitor cells in Ai9 mice with Cre mRNA, which subsequently proliferated and caused over 40% of the cortical neurons and 60% of the hippocampal neurons to b
Source: pubs.acs.orgCategories: General Medicine News, NeurologyTweet
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Mashup Score: 0Small Molecule Assembly Agonist Alters the Dynamics of Hepatitis B Virus Core Protein Dimer and Capsid - 3 month(s) ago
Chronic hepatitis B virus (HBV) poses a significant public health burden worldwide, encouraging the search for curative antivirals. One approach is capsid assembly modulators (CAMs), which are assembly agonists. CAMs lead to empty and defective capsids, inhibiting the formation of new viruses, and can also lead to defects in the release of the viral genome, inhibiting new infections. In this study, we employed hydrogen–deuterium exchange mass spectrometry (HDX-MS) to assess the impact of one such CAM, HAP18, on HBV dimers, capsids composed of 120 (or 90) capsid protein dimers, and cross-linked capsids (xl-capsids). HDX analysis revealed hydrogen bonding networks within and between the dimers. HAP18 disrupted the hydrogen bonding network of dimers, demonstrating a previously unappreciated impact on the dimer structure. Conversely, HAP18 stabilized both unmodified and cross-linked capsids. Intriguingly, cross-linking the capsid, which was accomplished by forming disulfides between an eng
Source: pubs.acs.orgCategories: General Medicine News, Infectious DiseaseTweet-
⚗️ The Bothner lab at @msuchembiochem employed hydrogen–deuterium exchange mass spectrometry to assess the impact of HAP18 on hepatitis B virus dimers, capsids composed of 120/90 capsid protein dimers, and cross-linked capsids. 👉 https://t.co/64EPuNYYYK https://t.co/1UlkzZCVJK
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Mashup Score: 8Preparation and Preclinical Characterization of a Simple Ester for Dual Exogenous Supply of Lactate and Beta-hydroxybutyrate - 3 month(s) ago
Elevation of the plasma levels of (S)-lactate (Lac) and/or (R)-beta-hydroxybutyrate (BHB) occurs naturally in response to strenuous exercise and prolonged fasting, respectively, resulting in millimolar concentrations of these two metabolites. It is increasingly appreciated that Lac and BHB have wide-ranging beneficial physiological effects, suggesting that novel nutritional solutions, compatible with high-level and/or sustained consumption, which allow direct control of plasma levels of Lac and BHB, are of strong interest. In this study, we present a molecular hybrid between (S)-lactate and the BHB-precursor (R)-1,3-butanediol in the form of a simple ester referred to as LaKe. We show that LaKe can be readily prepared on the kilogram scale and undergoes rapid hydrolytic conversion under a variety of physiological conditions to release its two constituents. Oral ingestion of LaKe, in rats, resulted in dose-dependent elevation of plasma levels of Lac and BHB triggering expected physiolog
Source: pubs.acs.orgCategories: General Medicine News, NeurologyTweet-
“Preparation and Preclinical Characterization of a Simple Ester for Dual Exogenous Supply of Lactate and Beta-hydroxybutyrate” by Thomas Poulsen et al. Journal of Agricultural and Food Chemistry https://t.co/Dx2UnLz9CW
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Mashup Score: 62Synthesis at the Interface of Chemistry and Biology - 4 month(s) ago
ConspectusChemical synthesis as a tool to control the structure and properties of matter is at the heart of chemistry─from the synthesis of fine chemicals and polymers to drugs and solid-state materials. But as the field evolves to tackle larger and larger molecules and molecular complexes, the traditional tools of synthetic chemistry become limiting. In contrast, Mother Nature has developed very different strategies to create the macromolecules and molecular systems that make up the living cell. Our focus has been to ask whether we can use the synthetic strategies and machinery of Mother Nature, together with modern chemical tools, to create new macromolecules, and even whole organisms with properties not existing in nature. One such example involves reprogramming the complex, multicomponent machinery of ribosomal protein synthesis to add new building blocks to the genetic code, overcoming a billion-year constraint on the chemical nature of proteins. This methodology exploits the conc
Source: pubs.acs.orgCategories: General Medicine News, General HCPsTweet-
In a new Accounts of Chemical Research article, Scripps Research President and CEO Peter Schultz, PhD, discusses his work that enabled his lab and collaborators to create new macromolecules and even whole organisms with properties not existing in nature. https://t.co/aaHePOeGbo https://t.co/mJNZIGXtwm
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Mashup Score: 111Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma - 5 month(s) ago
Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma.
Source: pubs.acs.orgCategories: General Medicine News, Hem/OncsTweet-
As we celebrate the approval of vorasidenib for treatment of grade II IDH-mutant, I would like to recognize those that developed the original compounds. See https://t.co/38HCJgegUc, https://t.co/Clj7dXFGZW and perhaps most importantly https://t.co/AfN36y1TZP. Fantastic job!
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Mashup Score: 15A High-Throughput Screening Platform Identifies FDA-Approved Drugs That Inhibit SREBP Pathway Activation - 5 month(s) ago
Sterol regulatory element-binding protein (SREBP) transcription factors are central regulators of lipid homeostasis and are essential for lipid metabolic reprogramming that supports tumor growth in multiple cancers. SREBP pathway inhibitors have been identified, but bioavailable compounds are lacking. To address this need, we designed a novel approach for screening a collection of 4,474 FDA-approved drugs. SREBPs are conditionally essential and required under low lipid conditions. Leveraging this property, we screened for drugs that inhibited pancreatic cancer cell growth in lipid-poor, but not lipid-rich, medium. The primary screen identified 83 drugs that inhibited cell growth in a lipid-dependent manner. Secondary assays examining SREBP target gene expression, SREBP proteolytic cleavage, and effects on human breast cancer cells identified 13 FDA-approved drugs that inhibit SREBP pathway activation. Taken together, we demonstrated that our screening approach can identify SREBP inhibi
Source: pubs.acs.orgCategories: General Medicine News, Hem/OncsTweet-
From @PeterEspenshade & colleagues @JohnsHopkins A High-Throughput Screening Platform Identifies FDA-Approved Drugs That Inhibit SREBP Pathway Activation https://t.co/rjs0256TNU The preclinical screens were done in a #PancreaticCancer cell line. Other recent studies from Peter… https://t.co/3583LwCdrz https://t.co/pc7Y0cIhtT
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Mashup Score: 3
Some antinuclear antibodies (ANAs) bind extracellular nucleic acids released into tumor environments and are pulled into the nuclei of live cancer cells through nucleoside salvage pathways, independent of tumor-specific surface antigens. Here we show that ANA nuclear penetration induces nuclear flux by the lysosomal protease cathepsin B and leverage this mechanism to design an antinuclear antibody–drug conjugate (ANADC) with cathepsin B-labile drug linker. The ANADC targets nucleic acid exhaust from necrotic tumors and crosses membrane barriers through nucleoside salvage as a DNA-seeking and tumor agnostic “antinuclear missile” cancer therapy.
Source: pubs.acs.orgCategories: General Medicine News, Hem/OncsTweet-
Cathepsin B Nuclear Flux in a DNA-Guided “Antinuclear Missile” Cancer Therapy https://t.co/X1LBukWDuY
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Mashup Score: 3
Some antinuclear antibodies (ANAs) bind extracellular nucleic acids released into tumor environments and are pulled into the nuclei of live cancer cells through nucleoside salvage pathways, independent of tumor-specific surface antigens. Here we show that ANA nuclear penetration induces nuclear flux by the lysosomal protease cathepsin B and leverage this mechanism to design an antinuclear antibody–drug conjugate (ANADC) with cathepsin B-labile drug linker. The ANADC targets nucleic acid exhaust from necrotic tumors and crosses membrane barriers through nucleoside salvage as a DNA-seeking and tumor agnostic “antinuclear missile” cancer therapy.
Source: pubs.acs.orgCategories: General Medicine News, Hem/OncsTweet-
Cathepsin B Nuclear Flux in a DNA-Guided “Antinuclear Missile” Cancer Therapy https://t.co/X1LBukWDuY
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Mashup Score: 2Semiquantitative Paper-Based Microfluidic Surrogate Virus Neutralization Test for SARS-CoV-2 Neutralizing Antibodies - 6 month(s) ago
Neutralizing antibodies (nAbs) produced from infection or vaccination play an important role in acquired immunity. Determining virus-specific nAb titers is a useful tool for measuring aquired immunity in an individual. The standard methods to do so rely on titrating serum samples against live virus and monitoring viral infection in cultured cells which requires high biosafety level containment. The surrogate virus neutralization test (sVNT) reduces the biohazards and it is suitable for designing rapid test device in a lateral flow assay (LFA) format. Here, we introduce the fabrication and development of a unique paper-based LFA device for determining the level of SARS-CoV-2 nAb in a sample with a semiquantitative direct colorimetric readout. A LFA-based gradient assay design was used to facilitate the sVNT, where the spike glycoprotein receptor binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2) stand in as proxies for viruses and cells, respectively. The gradient assay emp
Source: pubs.acs.orgCategories: General Medicine News, Infectious DiseaseTweet-
🔎 Scientists at @TorontoMet introduced the development of a paper-based lateral flow assay device for determining the level 📊 of #SARSCoV2 neutralizing #antibodies in a sample with a semiquantitative direct colorimetric readout. @an_chem | https://t.co/iqMElLisuY https://t.co/g4iAkmt59S
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Mashup Score: 1A Nanoparticle Vaccine Displaying Conserved Epitopes of the Preexisting Neutralizing Antibody Confers Broad Protection against SARS-CoV-2 Variants - 6 month(s) ago
The rapid development of the SARS-CoV-2 vaccine has been used to prevent the spread of coronavirus 2019 (COVID-19). However, the ongoing and future pandemics caused by SARS-CoV-2 variants and mutations underscore the need for effective vaccines that provide broad-spectrum protection. Here, we developed a nanoparticle vaccine with broad protection against divergent SARS-CoV-2 variants. The corresponding conserved epitopes of the preexisting neutralizing (CePn) antibody were presented on a self-assembling Helicobacter pylori ferritin to generate the CePnF nanoparticle. Intranasal immunization of mice with CePnF nanoparticles induced robust humoral, cellular, and mucosal immune responses and a long-lasting immunity. The CePnF-induced antibodies exhibited cross-reactivity and neutralizing activity against different coronaviruses (CoVs). CePnF vaccination significantly inhibited the replication and pathology of SARS-CoV-2 Delta, WIV04, and Omicron strains in hACE2 transgenic mice and, thus,
Source: pubs.acs.orgCategories: General Medicine News, Infectious DiseaseTweet-
Researchers developed a nanoparticle 💉 #vaccine with protection against #SARSCoV2 variants. 💡 Conserved epitopes of the neutralizing #antibody were presented on a self-assembling Helicobacter pylori ferritin to generate nanoparticles. @acsnano | https://t.co/vXnWdNcVJD https://t.co/FuG9axrqkl
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“Widespread Gene Editing in the Brain via In Utero Delivery of mRNA Using Acid-Degradable Lipid Nanoparticles” by Aijun Wang et al. ACS Nano https://t.co/ByMntoj244