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Clustered regularly interspaced short palindromic repeats (CRISPR-Cas12a), discovered a few years ago, is a method that detects even small levels of pathogens.Professor Kevin J Zwezdaryk and researchers at the Tulane University School of Medicine, USA, are working on a cost-effective, CRISPR-Cas12a-based pathogen detection tool aiming to upgrade patient care. Read more in Research Features Read the original research: doi.org/10.1016/j.bmt.2023.03.004

Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: Multiplex Gene Editing: Where Are We Now?, published by sarahconstantin on July 16, 2024 on LessWrong. We're starting to get working gene therapies for single-mutation genetic disorders, and genetically modified cell therapies for attacking cancer. Some of them use CRISPR-based gene editing, a new technology (that earned Jennifer Doudna and Emmanuelle Charpentier the 2020 Nobel Prize) to "cut" and "paste" a cell's DNA. But so far, the FDA-approved therapies can only edit one gene at a time. What if we want to edit more genes? Why is that hard, and how close are we to getting there? How CRISPR Works CRISPR is based on a DNA-cutting enzyme (the Cas9 nuclease), a synthetic guide RNA (gRNA), and another bit of RNA (tracrRNA) that's complementary to the gRNA. Researchers can design whatever guide RNA sequence they want; the gRNA will stick to the complementary part of the target DNA, the tracrRNA will complex with it, and the nuclease will make a cut there. So, that's the "cut" part - the "paste" comes from a template DNA sequence, again of the researchers' choice, which is included along with the CRISPR components. Usually all these sequences of nucleic acids are packaged in a circular plasmid, which is transfected into cells with nanoparticles or (non-disease-causing) viruses. So, why can't you make a CRISPR plasmid with arbitrary many genes to edit? There are a couple reasons: 1. Plasmids can't be too big or they won't fit inside the virus or the lipid nanoparticle. Lipid nanoparticles have about a 20,000 base-pair limit; adeno-associated viruses (AAV), the most common type of virus used in gene delivery, has a smaller payload, more like 4700 base pairs. 1. This places a very strict restriction on how many complete gene sequences that can be inserted - some genes are millions of base pairs long, and the average gene is thousands! 2. but if you're just making a very short edit to each gene, like a point mutation, or if you're deleting or inactivating the gene, payload limits aren't much of a factor. 2. DNA damage is bad for cells in high doses, particularly when it involves double-strand breaks. This also places limits on how many simultaneous edits you can do. 3. A guide RNA won't necessarily only bind to a single desired spot on the whole genome; it can also bind elsewhere, producing so-called "off-target" edits. If each guide RNA produces x off-target edits, then naively you'd expect 10 guide RNAs to produce 10x off-target edits…and at some point that'll reach an unacceptable risk of side effects from randomly screwing up the genome. 4. An edit won't necessarily work every time, on every strand of DNA in every cell. (The rate of successful edits is known as the efficiency). The more edits you try to make, the lower the efficiency will be for getting all edits simultaneously; if each edit is 50% efficient, then two edits will be 25% efficient or (more likely) even less. None of these issues make it fundamentally impossible to edit multiple genes with CRISPR and associated methods, but they do mean that the more (and bigger) edits you try to make, the greater the chance of failure or unacceptable side effects. How Base and Prime Editors Work Base editors are an alternative to CRISPR that don't involve any DNA cutting; instead, they use a CRISPR-style guide RNA to bind to a target sequence, and then convert a single base pair chemically - they turn a C/G base pair to an A/T, or vice versa. Without any double-strand breaks, base editors are less toxic to cells and less prone to off-target effects. The downside is that you can only use base editors to make single-point mutations; they're no good for large insertions or deletions. Prime editors, similarly, don't introduce double-strand breaks; instead, they include an enzyme ("nickase") that produces a single-strand "nick"...

Link to original articleWelcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: Multiplex Gene Editing: Where Are We Now?, published by sarahconstantin on July 16, 2024 on LessWrong. We're starting to get working gene therapies for single-mutation genetic disorders, and genetically modified cell therapies for attacking cancer. Some of them use CRISPR-based gene editing, a new technology (that earned Jennifer Doudna and Emmanuelle Charpentier the 2020 Nobel Prize) to "cut" and "paste" a cell's DNA. But so far, the FDA-approved therapies can only edit one gene at a time. What if we want to edit more genes? Why is that hard, and how close are we to getting there? How CRISPR Works CRISPR is based on a DNA-cutting enzyme (the Cas9 nuclease), a synthetic guide RNA (gRNA), and another bit of RNA (tracrRNA) that's complementary to the gRNA. Researchers can design whatever guide RNA sequence they want; the gRNA will stick to the complementary part of the target DNA, the tracrRNA will complex with it, and the nuclease will make a cut there. So, that's the "cut" part - the "paste" comes from a template DNA sequence, again of the researchers' choice, which is included along with the CRISPR components. Usually all these sequences of nucleic acids are packaged in a circular plasmid, which is transfected into cells with nanoparticles or (non-disease-causing) viruses. So, why can't you make a CRISPR plasmid with arbitrary many genes to edit? There are a couple reasons: 1. Plasmids can't be too big or they won't fit inside the virus or the lipid nanoparticle. Lipid nanoparticles have about a 20,000 base-pair limit; adeno-associated viruses (AAV), the most common type of virus used in gene delivery, has a smaller payload, more like 4700 base pairs. 1. This places a very strict restriction on how many complete gene sequences that can be inserted - some genes are millions of base pairs long, and the average gene is thousands! 2. but if you're just making a very short edit to each gene, like a point mutation, or if you're deleting or inactivating the gene, payload limits aren't much of a factor. 2. DNA damage is bad for cells in high doses, particularly when it involves double-strand breaks. This also places limits on how many simultaneous edits you can do. 3. A guide RNA won't necessarily only bind to a single desired spot on the whole genome; it can also bind elsewhere, producing so-called "off-target" edits. If each guide RNA produces x off-target edits, then naively you'd expect 10 guide RNAs to produce 10x off-target edits…and at some point that'll reach an unacceptable risk of side effects from randomly screwing up the genome. 4. An edit won't necessarily work every time, on every strand of DNA in every cell. (The rate of successful edits is known as the efficiency). The more edits you try to make, the lower the efficiency will be for getting all edits simultaneously; if each edit is 50% efficient, then two edits will be 25% efficient or (more likely) even less. None of these issues make it fundamentally impossible to edit multiple genes with CRISPR and associated methods, but they do mean that the more (and bigger) edits you try to make, the greater the chance of failure or unacceptable side effects. How Base and Prime Editors Work Base editors are an alternative to CRISPR that don't involve any DNA cutting; instead, they use a CRISPR-style guide RNA to bind to a target sequence, and then convert a single base pair chemically - they turn a C/G base pair to an A/T, or vice versa. Without any double-strand breaks, base editors are less toxic to cells and less prone to off-target effects. The downside is that you can only use base editors to make single-point mutations; they're no good for large insertions or deletions. Prime editors, similarly, don't introduce double-strand breaks; instead, they include an enzyme ("nickase") that produces a single-strand "nick"...

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.07.531588v1?rss=1 Authors: Sharp, B. M., Jiang, Q., Kim, P., Chen, H. Abstract: Large scale human genome wide association studies (GWAS) have identified a growing pool of genes associated with cigarette smoking. One of the most prominent, phosphodiesterase-4B (PDE4B), has been associated with multiple smoking phenotypes. Although PDE4B modulates the half-life of neuronal cAMP, its precise role in smoking behaviors is unknown. To address this knowledge gap, we inactivated PDE4B in bilateral medial nucleus accumbens shell (NAcs) neurons by injecting AAV containing a specific gRNA in female transgenic Cas9+ Long Evans rats These rats then were given 23-hour chronic access to nicotine intravenous self-administration (IVSA) under a schedule of increasing fixed ratios (FR). With the increased effort required at FR7, nicotine SA (i.e. active presses and drug infusions) declined significantly in controls, whereas it was maintained in the mutagenized group. A progressive ratio (PR) study also showed significantly greater cumulative nicotine infusions in the mutant group. Hence, we hypothesized that enhanced PDE4B protein activity would reduce nicotine IVSA. A positive allosteric modulator, 2-(3-(4-chloro-3-fluorophenyl)-5 ethyl-1H-1,2,4-triazol-1-yl)-N-(3,5 dichlorobenzyl)acetamide (MR-L2), was microinfused into NAcs bilaterally at FR3 or FR5; in both cohorts, MR-L2 acutely reduced nicotine IVSA. In summary, these studies show that the activity of PDE4B regulates the capacity of NAcs to maintain nicotine IVSA in face of the cost of increasing work. This finding and the results of the PR study indicate that PDE4B affects the motivation to obtain nicotine. These studies provide insight into the motivational effects of NAcs PDE4B that may impact the smoking behaviors mapped in human GWAS. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Alex Carlson recaps the action in the OTC, NASDAQ, and NYSE. He covers CYDY, TOMDF, SIRC, HKD, AMTD, APDN, MOHO, QNRX, KSPN, ENVB, HSCS, PSTX, GRNQ, XCUR, YELL, SYN, SYRS, GRNA, LEJU, and MOTS. All stocks have been discussed on https://insiderfinancial.com/ To sign up for our FREE alerts and eBook, go to: https://signup.insiderfinancial.com/ To sign up for FREE stocks and trade OTC on WeBull, go to: https://a.webull.com/i/insiderfinancial Disclosure: We have no business relationship with any company whose stock is mentioned in this video. Insider Financial is not an investment advisor; this video does not provide investment advice. Always do your own research, make your own investment decisions, or consult with your nearest financial advisor. This video is not a solicitation or recommendation to buy, sell, or hold securities. This video is our opinion, is meant for informational and educational purposes only, and does not provide investment advice. Past performance is not indicative of future performance. For more information, please read our full disclaimer: https://insiderfinancial.com/disclaimer/ cydy stock, tomdf stock, sirc stock, hkd stock, amtd stock, apdn stock, moho stock, qnrx stock, kspn stock, envb stock, hscs stock, pstx stock, grnq stock, xcur stock, yell stock, syn stock, syrs stock, grna stock, leju stock, mots stock, otc stocks, otc stocks list, penny stocks, penny stocks list, NASDAQ penny stocks, NYSE stocks, NYSE penny stocks #pennystocks #stocks #nasdaq

You can catch Part 1 with Christina on Episode 48!You asked for it, and we couldn't have agreed more that we NEEDED her back on the show! Culinary badass, Chef Christina Wilson, returns for an extra Jewcy catch-up where all subjects are truly up for discussion including the current state of the culinary world, gender/sexuality, lifestyle/culture, reality tv and personal/career development!Joining us from her hotel room at Caesars Palace, Las Vegas, we learn that Christina has been up to a lot since we last spoke, which includes relocating to Dallas, Texas and now owning the role as the VP of Culinary for GRNA. She speaks about some of the plans for restaurants expanding across North America! Want to learn what else is squeezed into every drop? You'll have to watch to find out!Christina's Links:Instagram (@chefchristinamwilson)Getting Jewcy Links:Watch This Episode on YouTube!Instagram (@getting_jewcy)Facebook (@gettingjewcy)Website

Dziś gośćmi Beaty Tadli w "Onet Rano." byli: Tomasz Siemoniak, Marta Górna, Krzysztof Marciniak, Łukasz Wiśniowski i Paweł Domagała. W części #WIEM Odeta Moro rozmawiała z Pawłem Ellerikiem o tym, jak nie dać się oszukać i bezpiecznie kupić wakacje w internecie.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.13.381160v1?rss=1 Authors: Liu, L., Li, K., Zou, L., Hou, H., Hu, Q., Liu, S., Wang, S., Wang, Y., Li, J., Song, C., Chen, J., Li, C., Du, H., Li, J.-L., Chen, F., Xu, Z., Sun, W., Sun, Q., Xiong, W. Abstract: Frameshift mutation caused by small insertions/deletions (indels) often generate truncated and non-functional proteins, which underlies 22% inherited Mendelian disorders in humans. However, there is no efficient in vivo gene therapy strategy available to date, especially in postmitotic systems. Here, we leveraged the non-homologous end joining (NHEJ) mediated non-random editing profiles to compensate the frameshift mutation in a USH1F mouse model - av3j. After treatment by the selected gRNA, about 50% editing products showed reading-frame restoration, and more than 70% targeted hair cells recovered mechanotransduction. In vivo treatment ameliorated the hearing and balance symptoms in homozygous mutant mice. Furthermore, a scale-up analysis of 114 gRNAs targeting 40 frameshift deafness mutations reveals that 65% loci have at least one gRNA with predicted therapeutic potential. Together, our study demonstrates that the NHEJ-mediated frame restoration is a simple and highly efficient therapeutic strategy for small-indel induced frameshift mutations. Copy rights belong to original authors. Visit the link for more info

In today's episode we discuss: —Epidemiology: Outcomes of COVID-19 in living donor liver transplant (LDLT) recipients are studied by hepatologists and leading liver transplant surgeons from the Institute of Liver Transplantation & Regenerative Medicine in Gurugram, India through a case series of 12 living donor liver transplant patients who tested positive for SARS-CoV-2 via RT-PCR. Most were symptomatic (n=11, 91.7%) with evidence of pneumonia on radiologic imaging (n=9, 75%) and with median duration of detectable virus of 12 days. While the majority (n=10, 83.3%) were on tacrolimus-based immunosuppression, all but one patient (n=11, 91.7%) survived with only supportive care. Because the patient who died had multiple other risk factors for severe COVID-19 (quadruple immunosuppression, hypertension, metabolic syndrome, diabetes), these authors suggest that liver transplant patients as a whole are not at particularly increased risk for mortality from COVID-19. · Hematological manifestations of SARS-CoV-2 in children are explored in a review of 15 articles meeting study criteria and found children with SARS-CoV-2 were less likely to be lymphopenic compared to adults, with the most common abnormalities being leukopenia in older children and lymphocytosis in infants/neonates. Thrombotic complications and platelets and erythrocytes abnormalities were relatively uncommon and more likely in children with multisystem inflammatory syndrome. Authors suggest these findings, which contrast hematologic changes observed in adults, may be a result of pediatric patients' immature ACE-2 expression and immune systems. —Understanding the Pathology: Mechanisms by Which SARS-CoV-2 May Impact Male Fertility are discussed in a letter to the editor based on Dutta and Sengupta's article "SARS-CoV-2 and male infertility: possible multifaceted pathology." They propose viral binding to angiotensin-converting enzyme 2 receptors on spermatogonia, Leydig cells, and Sertoli cells may cause overactivation and negatively impact spermatogenesis. Additionally, they urge further studies on SARS-CoV-2's ability to disrupt sperm formation and function because SARS-CoV-2 seems to disproportionately impact males in some studies. —R&D: Diagnosis & Treatments: REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in certain species based on virologists from Regeneron Pharmaceuticals results from an in vivo study of their proprietary therapeutic cocktail REGN-COV2's (human antibodies REGN10933, REGN10987) ability to reduce viral load via SARS-CoV-2 spike protein binding in resus macaques and golden hamsters. They found a 50 mg/kg dose significantly reduced SARS-CoV-2 gRNA (p

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CRISPR-Cas9を用いた全く新しいゲノム編集技術Prime editing (PE)についての原著論文を紹介しました。Show notes Search-and-replace genome editing without double-strand breaks or donor DNA. Anzalone et al., 2019, Nature…今回とりあげたPrime editing論文の原稿。 Functional Genetic Variants Revealed by Massively Parallel Precise Genome Editing. Shalon et al., 2018, Cell…In vivoでgRNAにコードさせたrepiar templateを逆転写反応後に相同組換えで導入する、というアイディアはこの論文が初出。この論文ではバクテリア由来のretronとよばれる配列を利用した。 26. Cool tech googlability…ep26では一塩基RNA編集を解説しました。 22. Evolutionary selected life…ep22ではdeaminaseを用いた一塩基ゲノム編集について最新論文を紹介しました。 Editorial notes 論文を読み進めるにつれ、細胞の中で起こるDNA修復、組み換え、複製機構を知り尽くした上でそのシステムをハックする、というエンジニアリングに大きな感銘を受けた。(soh) 書き込みたい情報をRNAに入れてそれをDNAに埋め込むPrime editingの衝撃たるや。細胞システムのハッキングの方法が美しくすばらしい。これからの稼働効率は日々改善されていくだろう。なぜか3人の音源を2人の音源として編集しました。(tadasu) 実はこの収録3人でやっていたのですが、僕の音源が飛んでしまったために編集で2人で話してるみたいになっているのです！申し訳ありません…。sohも書いてますがprime editingは様々な細胞内現象を熟知して作られている感がヤバイですね、勉強になりました。(coela)

Guaranaさんとおしゃべり④（全4回の最終回） Twitter: @_GRNA https://twitter.com/_GRNA?s=09 サッカー分析アカウント：カツオサイクロン @GATE12JPN https://twitter.com/GATE12JPN?s=09 ・Guaranaさんとサッカー　・試合に関する分析、考察　・独学用に始めたら人気に　・30過ぎてからの体力　・自分でボールを蹴ったことがあるからこそ響くスーパーゴール　・リコーダー、カスタネット　・休符はウン

Twitter: @_GRNA https://twitter.com/_GRNA?s=09 ・ゼベック・オンライン　・満島ひかり　・聴く音楽の変化　・ジャイルス・ピーターソン　・ピーター・バラカン　・駒沢公園　・Mixcloud, SoundCloud　・音楽の探し方の今昔　・ひとりでボタンを押すタイミング

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Guaranaさんとおしゃべりしました。 Twitter: @_GRNA https://twitter.com/_GRNA?s=09 ・町内・ツイキャス・空席・枠・アイテム

Arbetet på en gård kan vara både tungt och stressigt och när det är ont om tid kan olyckan vara framme.1500 skador per år rapporteras in från företag inom den gröna näringen. Tillsammans med byggnadssektorn och transportbranschen är den en av de mest olycksdrabbade. I Mitt Lantbruk pratar Peter Birch-Iensen den här gången med Patrik Hermansson, skadereglerare på Länsförsäkringar AB och arbetsmiljöingenjör Torsten Ivarsson. De kommer med tips och råd om hur gården kan bli en arbetsmiljö men också om vilket skydd som kan vara bra att ha om olyckan är framme.

After 15 Years in a Vegetative State, Nerve Stimulation Restores Consciousness Scientists Have Discovered a Drug That Fixes Cavities and Regrows Teeth This Rare Medical Condition Makes You Love Everyone Child and teen obesity rates soar globally, WHO reports Human Myostatin Knock-Out Targeting CRISPR-Cas9 Plasmid This plasmid expresses Cas9 and a gRNA targeting exon 1 of the human myostatin gene. DIY Human CRISPR Guide This is by no means meant to be a comprehensive guide and is instead meant to show people the ease at which CRISPR-Cas9 can be used to modify the adult human genome. This Guy Says He’s The First Person To Attempt Editing His DNA With CRISPR “I want to live in a world where people get drunk and instead of giving themselves tattoos, they’re like, ‘I’m drunk, I’m going to CRISPR myself,’” said Zayner, who has a few tattoos of his own, in an interview with BuzzFeed News. “It sounds crazy, but I think that would be a pretty interesting world to live in for sure.” GEEKOUT Blade Runner 2049 vs. Thor Ragnarok WT 360-670      

After a brief hiatus (being out of town), Notation brings you some October Drum & Bass goodness for your soul. TRACKLIST: 1. Brighton Love – Changing Faces, Ero Drummer, M.Bass ft. GRNA – Celcius Recordings 2. In The Sun – Fokuz, Satl – Fokuz Recordings 3. Roller Express – Slang Banger – Program 4. Who … Continue reading