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Triterpenoids are high-value plant metabolites with numerous applications in medicine, agriculture, food, and home and personal care products. However, plants produce triterpenoids in low abundance, and their complex structures make their chemical synthesis prohibitively expensive and often impossible. As such, the yeast Saccharomyces cerevisiae has been explored as an alternative means of production. An important triterpenoid is oleanolic acid because it is the precursor to many bioactive triterpenoids of commercial interest, such as QS-21 which is being evaluated as a vaccine adjuvant in clinical trials against HIV and malaria. Oleanolic acid is derived from 2,3-oxidosqualene (natively produced by yeast) via a cyclisation and a multi-step oxidation reaction, catalysed by a β-amyrin synthase and a cytochrome P450 of the CYP716A subfamily, respectively. Although many homologues have been characterised, previous studies have used arbitrarily chosen β-amyrin synthases and CYP716As to produce oleanolic acid and its derivatives in yeast. This study presents the first comprehensive comparison of β-amyrin synthase and CYP716A enzyme activities in yeast. Strains expressing different homologues are compared for production, revealing 6.3- and 4.5-fold differences in β-amyrin and oleanolic acid productivities and varying CYP716A product profiles, which are important to consider when engineering strains for the production of bioactive oleanolic acid derivatives.

Fed-batch cultures of Chinese Hamster Ovary cells have been used to produce high quantities of biotherapeutics, particularly monoclonal antibodies. However, a growing number of next-generation biotherapeutics, such as bi-specific antibodies and fusion proteins, are difficult to express using standard fed-batch processes. Decoupling cell growth and biotherapeutic production is becoming an increasingly desired strategy for the biomanufacturing industry, especially for difficult-to-express products. Cells are grown to a high cell density in the absence of recombinant protein production (the growth phase), then expression of the recombinant protein is induced and cell proliferation halted (the production phase), usually by combining an inducible gene expression system with a proliferation control strategy. Separating the growth and production phases allows cell resources to be more efficiently directed toward either growth or production, improving growth characteristics and enhancing the production of difficult to express proteins. However, current mammalian cell proliferation control methods rely on temperature shifts and chemical agents, which interact with many non-proliferation pathways, leading to variable impacts on product quality and culture viability. Synthetic biology offers an alternative approach by strategically targeting proliferation pathways to arrest cell growth but have largely remained unused in industrial bioproduction. Due to recent developments in microbial decoupling systems and advances in available mammalian cell engineering tools, we propose that the synthetic biology approach to decoupling growth and production needs revisiting.

A comparison of the genomes of two “outbreak” Vibrio cholerae isolates from Haiti with those of other isolates indicates that this outbreak strain is distinct from circulating Latin American isolates and bears striking similarity to recent isolates from South Asia. The outbreak of cholera that began in Haiti in late October 2010 illustrates the continued public health threat of this ancient scourge. 1 Cholera, an acutely dehydrating diarrheal disease that can rapidly kill its victims, is caused by Vibrio cholerae, a gram-negative bacterium. 2 This disease, which is usually transmitted through contaminated water, can and has spread in an explosive fashion. In the weeks since cases were first confirmed in the Artibonite province of Haiti on October 19, 2010, the disease has reached all 10 provinces in Haiti and has spread to the neighboring Dominican Republic on the island of Hispaniola. Of . . .

Neutralizing antibodies are important for immunity against SARS-CoV-2 and as therapeutics for the prevention and treatment of COVID-19. Here, we identified high-affinity nanobodies from alpacas immunized with coronavirus spike and receptor-binding domains (RBD) that disrupted RBD engagement with the human receptor angiotensin-converting enzyme 2 (ACE2) and potently neutralized SARS-CoV-2. Epitope mapping, X-ray crystallography, and cryo-electron microscopy revealed two distinct antigenic sites and showed two neutralizing nanobodies from different epitope classes bound simultaneously to the spike trimer. Nanobody-Fc fusions of the four most potent nanobodies blocked ACE2 engagement with RBD variants present in human populations and potently neutralized both wild-type SARS-CoV-2 and the N501Y D614G variant at concentrations as low as 0.1 nM. Prophylactic administration of either single nanobody-Fc or as mixtures reduced viral loads by up to 104-fold in mice infected with the N501Y D614G SARS-CoV-2 virus. These results suggest a role for nanobody-Fc fusions as prophylactic agents against SARS-CoV-2.

The endocannabinoid anandamide (AEA) is an antinociceptive lipid that is inactivated through cellular uptake and subsequent catabolism by fatty acid amide hydrolase (FAAH). Fatty acid binding proteins (FABPs) are intracellular carriers that deliver AEA and related N-acylethanolamines (NAEs) to FAAH for hydrolysis. The mammalian brain expresses three FABP subtypes: FABP3, FABP5, and FABP7. Recent work from our group has revealed that pharmacological inhibition of FABPs reduces inflammatory pain in mice. The goal of the current work was to explore the effects of FABP inhibition upon nociception in diverse models of pain. We developed inhibitors with differential affinities for FABPs to elucidate the subtype(s) that contributes to the antinociceptive effects of FABP inhibitors. Inhibition of FABPs reduced nociception associated with inflammatory, visceral, and neuropathic pain. The antinociceptive effects of FABP inhibitors mirrored their affinities for FABP5, while binding to FABP3 and FABP7 was not a predictor of in vivo efficacy. The antinociceptive effects of FABP inhibitors were mediated by cannabinoid receptor 1 (CB1) and peroxisome proliferator-activated receptor alpha (PPARα) and FABP inhibition elevated brain levels of AEA, providing the first direct evidence that FABPs regulate brain endocannabinoid tone. These results highlight FABPs as novel targets for the development of analgesic and anti-inflammatory therapeutics.

Molecular ‘assembly lines’, in which organic molecules undergo iterative processes such as chain elongation and functional group manipulation, are found in many natural systems, including polyketide biosynthesis. Here we report the creation of such an assembly line using the iterative, reagent-controlled homologation of a boronic ester. This process relies on the reactivity of α-lithioethyl tri-isopropylbenzoate, which inserts into carbon–boron bonds with exceptionally high fidelity and stereocontrol; each chain-extension step generates a new boronic ester, which is immediately ready for further homologation. We used this method to generate organic molecules that contain ten contiguous, stereochemically defined methyl groups. Several stereoisomers were synthesized and shown to adopt different shapes—helical or linear—depending on the stereochemistry of the methyl groups. This work should facilitate the rational design of molecules with predictable shapes, which could have an impact in areas of molecular sciences in which bespoke molecules are required. The iterative, reagent-controlled homologation of a boronic ester is used to create an ‘assembly line’ capable of synthesizing organic molecules that contain ten contiguous, stereochemically defined methyl groups and which have different shapes depending on the stereochemistry of those groups. Assembly-line synthesis of defined complex molecules Biological systems have evolved sophisticated machinery for organic synthesis resembling molecular assembly-line processes. Until now chemists have been able to mimic this type of approach only to synthesize peptides and oligonucleotides, creating simple amide (C–N) or phosphate (P–O) bonds. These authors emulate nature by creating a molecular assembly line through iterative reagent-controlled homologations of boronic esters. The process relies on the reactivity of α-lithioethyl tri-ispopropylbenzoate, which inserts into carbon–boron bonds with high fidelity and stereocontrol. Each chain-extension step generates a new boronic ester, which is immediately ready for further homologation. They use this method to generate several organic molecules that contain ten contiguous, stereochemically defined methyl groups. This work is a step towards the rational design and synthesis of complex molecules with predictable shape.

Increases in EVALI were identified in 2019. Using the National Syndromic Surveillance Program, which includes about 70% of U.S. EDs, researchers found a gradual increase in ED visits associated with shortness of breath and e-cigarette use from January 2017 through early June 2019. A sharp increase was identified in June, peaking in September. A subsequent decrease was observed.

Ian Krantz, Katsuhiko Shirahige and colleagues report the genetic characterization of a new clinical syndrome characterized by cognitive impairment, heart and pulmonary defects, and skeletal dysplasia, among other symptoms. They identify gain-of-function mutations in the super elongation complex gene AFF4 as causing the disorder. Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2). Using exome sequencing, we discovered missense mutations in AFF4, a core component of the SEC, in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia). Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 in CdLS and CHOPS syndrome. Direct molecular interaction of the SEC, cohesin and RNAP2 was demonstrated. These data support a common molecular pathogenesis for CHOPS syndrome and CdLS caused by disturbance of transcriptional elongation due to alterations in genome-wide binding of AFF4 and cohesin.

Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers (CRCs). Cancers arising in serrated lesions are usually in the proximal colon, and account for a disproportionate fraction of cancer identified after colonoscopy. We sought to provide guidance for the clinical management of serrated colorectal lesions based on current evidence and expert opinion regarding definitions, classification, and significance of serrated lesions. A consensus conference was held over 2 days reviewing the topic of serrated lesions from the perspectives of histology, molecular biology, epidemiology, clinical aspects, and serrated polyposis. Serrated lesions should be classified pathologically according to the World Health Organization criteria as hyperplastic polyp, sessile serrated adenoma/polyp (SSA/P) with or without cytological dysplasia, or traditional serrated adenoma (TSA). SSA/P and TSA are premalignant lesions, but SSA/P is the principal serrated precursor of CRCs. Serrated lesions have a distinct endoscopic appearance, and several lines of evidence suggest that on average they are more difficult to detect than conventional adenomatous polyps. Effective colonoscopy requires an endoscopist trained in the endoscopic appearance of serrated lesions. We recommend that all serrated lesions proximal to the sigmoid colon and all serrated lesions in the rectosigmoid > 5 mm in size, be completely removed. Recommendations are made for post-polypectomy surveillance of serrated lesions and for surveillance of serrated polyposis patients and their relatives.

We constructed a corpus of digitized texts containing about 4% of all books ever printed. Analysis of this corpus enables us to investigate cultural trends quantitatively. We survey the vast terrain of 'culturomics,' focusing on linguistic and cultural phenomena that were reflected in the English language between 1800 and 2000. We show how this approach can provide insights about fields as diverse as lexicography, the evolution of grammar, collective memory, the adoption of technology, the pursuit of fame, censorship, and historical epidemiology. Culturomics extends the boundaries of rigorous quantitative inquiry to a wide array of new phenomena spanning the social sciences and the humanities.